US 4,044,043 AGrant
Derivatives of 9-Oxo-13-Trans-Prostenoic Acid Esters
Issue Date:1977-08-23
•34 Claims
Abstract
This disclosure describes homologues, analogues, congeners, and derivatives of 9-oxo-13-trans-prostenoic acid and of 9-hydroxy-13-trans-prostenoic acid, having antimicrobial activity and prostaglandin-like hypotensive activity.
Metadata
Assignee
- American Cyanamid Company
Inventors
- Karel Francis Bernady
- Middleton Brawner Floyd, Jr.
- John Frank Poletto
- Robert Eugene Schaub
- Martin Joseph Weiss
Application Information
Application Number:US 5747945
Filing Date:1975-05-05
Priority Date:1971-07-14
Art Unit:127
Classifications
IPC:
C07C17700
Field of Search:
260468 D;514 D
Patent Drawings
This patent does not have any drawings.
Description
The invention will be described in greater detail in conjunction with the following specific examples.
EXAMPLE 1
Preparation of 2-carbalkoxy(methyl/ethyl)-2-(4-carbethoxybutyl)-cyclopentan-1-one
To a stirred solution of the sodium cyclopentanone car boxylate enolate in dimethoxyethane, prepared from 187 g. (1.248 moles) of 2-cyclopentanone carboxylate (mixed methyl and ethyl esters), 52.4 g. (1.248 moles) sodium hydride (57.2% in mineral oil) and 1.6 l. of dimethoxyethane, is added dropwise 309 g. (1.212 moles) of ethyl 5-iodovalerate. The reaction mixture is stirred and heated at reflux for 18 hours. The mixture is cooled and filtered. The solvent is removed from the filtrate by evaporation and the residue is poured into dilute hydrochloric acid and extracted with ether. The combined extracts are washed with water and saline, dried over magnesium sulfate and evaporated to give an oil. The oil is distilled under reduced pressure to give 274 g. of a light yellow oil, b.p. 140.degree.-143.degree. C. (0.17 mm).
EXAMPLE 2
Preparation of 2-(4-carboxybutyl)cyclopentan-1-one
A stirred mixture of 274 g. of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 1), 600 ml. of 20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs in approximately one-half hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are washed with saline and dried over magnesium sulfate and evaporated. The residue is evaporated twice with toluene to give 144 g. of an oil.
EXAMPLE 3
Preparation of 2-(4-carbethoxybutyl)cyclopentane-1-one
A stirred solution of 124 g. (0.673 mole) of 2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and 1 g. of p-toluensulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The ether solution is washed with saline, dilute sodium bicarbonate solution and again with saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of colorless oil, b.p. 106.degree.-109.degree. C. (0.23 mm).
EXAMPLE 4
Preparation of 2-carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)-cyclopentane-1-one
In the manner described in Example 1, treatment of 2-cyclopentane carboxylate (mixed methyl and ethyl esters) with sodium hydride in dimethoxyethane followed by ethyl 4-iodobutyrate gives a yellow oil, b.p. 136.degree.-137.degree. C. (0.16 mm).
EXAMPLE 5
Preparation of 2-(3-carboxypropyl)cyclopentan-1-one
In the manner described in Example 2, treatment of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(3-carbethoxypropyl)cyclopentan-1-one (Example 4) with a 20% hydrochloric acid and acetic acid mixture give a yellow oil.
EXAMPLE 6
Preparation of 2-(4-carbethoxypropyl)cyclopentan-1-one
In the manner described in Example 3, treatment of 2-(3-carboxypropyl)cyclopentan-1-one (Example 5)with p-toluenesulfonic acid monohydrate in ethanol gives a colorless oil, b.p. 93.degree. C. (0.10 mm).
EXAMPLE 7
Preparation of ethyl and methyl 2-(6-carbethoxyhexyl)-1-cyclopentanon-2-carboxylate
In the manner described in Example 1, ethyl and methyl 2-cyclopentanone carboxylate is reacted with ethyl 7-bromoheptanoate to furnish the subject product, b.p. 147.degree. C. (0.09 mm).
EXAMPLE 8
Preparation of 2-(6-carboxyhexyl)cyclopentan-1-one
In the manner described in Example 2, ethyl and methyl 2-(6-carbethoxyheyl)-1-cyclopentanone-2-carboxylate (Example 7) is hydrolyzed to furnish the subject product, b.p. 143.degree. C. (0.05 mm).
EXAMPLE 9
Preparation of 2-(6-carbethoxyhexyl)cyclopentan-1-one
In the manner described in Example 3, 2-(6-carboxyhexyl)cyclopentan-1-one (Example 8) is esterified to furnish the subject product, b.p. 110.degree. C. (0.03 mm).
EXAMPLE 10
Preparation of ethyl (methyl) 7-(2-carbethoxycyclohexan-1-on-2-yl)heptanoate
To a stirred suspension of 51 g. of sodium hydride (57% in mineral oil) in 675 ml. of dimethylformamide is added 200 g. of 2-cyclohexanone carboxylate (60% ethyl - 40% methyl esters) over a 1-5 hr. period with external cooling to maintain the temperature at 20.degree.-25.degree. C. The reaction mixture is stirred at ambient temperature for 15 minutes and heated to 50.degree. C. over 15 minutes. To the stirred mixture is added 300 g. of ethyl 7-bromoheptanoate during a 10 minute period. The reaction mixture is stirred at 50.degree.-60.degree. C. for 4 hours, cooled, and poured into water. The product is obtained by ether extraction. The extract is washed successively with water and saturated sodium chloride, dried and evaporated to give a liquid which is purified by distillation, IR 1735 cm.sup.-1 (ester carbonyls) and 1710 cm.sup.-1 (ketone carbonyl).
EXAMPLE 11
Preparation of 7-(cyclohexan-1-on-2-yl)heptanoic acid
A stirred mixture of 380 g. of mixed methyl and ethyl esters of 7-(2-carbethoxycyclohexan-1-on-2-yl)heptanoate (Example 10), 202 ml. of concentrated sulfuric acid, 970 ml. of glacial acetic acid, and 970 ml. of water is refluxed for 22.5 hours. The cooled reaction mixture is treated with 380 g. of sodium carbonate and 2 liters of water and is extracted with ether. Acidic material is partitioned from the ether extract with 1.0M sodium carbonate. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated to give an oil.
EXAMPLE 12
Preparation of ethyl 7-(cyclohexan-1-on-2-yl)heptanoate p A solution of 232 g. of 7-cyclohexan-1-on-2-yl)heptanoic acid in 2500 ml. of ethanol is refluxed for 4.5 hours with 3.8 g. of p-toluenesulfonic acid monohydrate. The solution is diluted with 200 ml. of benzene, and boiling is continued for 2 hours as 200 ml. of distillate is removed. The volume of the solution is concentrated to 500 ml. After dilution with 500 ml. of ether the solution is extracted with a solution prepared from 50 ml. of saturated sodium bicarbonate, 50 ml. of saturated sodium chloride, and 100 ml. of water. The extract washed with saturated sodium chloride, dried, and evaporated. The product is purified by distillation to give a liquid, IR 1740 cm.sup.-1 (ester carbonyl) and 1715 cm.sup.-1 (ketone carbonyl).
EXAMPLE 13
Preparation of 2-carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)cyclohexan-1-one
The subject compound is prepared in the manner described in Example 10 by treatment of 2-cyclohexanone carboxylate (mixed methyl and ethyl esters) with sodium hydride and ethyl 4-iodobutyrate.
EXAMPLE 14
Preparation of 2-(3-carbethoxypropyl)cyclohexan-1-one
This compound is prepared from 2-carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)cyclohexan-1-one (Example 13) by decarbalkoxylation according to the procedure described in Example 11 followed by esterification by the procedure of Example 12.
EXAMPLE 15
Preparation of 2-(5-carbethoxypentyl)cyclohexn-1-one
This compound is prepared by alkylation of 2-cyclohexanone carboxylate (mixed methyl and ethyl esters) with ethyl 6-bromohexanoate according to the procedure of Example 10, followed by decarbalkoxylation according to the procedure of Example 11 and finally esterification by the procedure of Example 12.
EXAMPLE 16
Preparation of 2-(7-carbethoxyheptyl)cyclohexan-1-one
Alkylation of 2-cyclohexanone carboxylate (mixed methyl and ethyl esters) with ethyl 8-bromoctanoate in accordance with the procedure of Example 10, followed by decarbalkoxylation by the procedure of Example 11 and then esterification by the procedure of Example 12 is productive of the subject compound.
EXAMPLE 17
Preparation of 2-carbalkoxy(methyl/ethyl)-2-(carbethoxymethyl)cyclopentan-1-one
In the manner described in Example 1, treatment of cyclopentanone-2-carboxylate (mixed methyl and ethyl esters) with sodium hydride in dimethoxyethane followed by ethyl bromoacetate provides a yellow oil, b.p. 130.degree.-131.degree. C. (7 mm).
EXAMPLE 18
Preparation of 2-(carboxymethyl)cyclopentan-1-one
In the manner described in Example 2, the 2-carbalkoxy-2-carbethoxymethylcyclopentanone of Example 17 is decarbalkoxylated to provide 2-carboxymethylcyclopentan-1-one.
EXAMPLE 19
Preparation of 2-carbethoxymethylcyclopentan-1-one
In the manner of Example 3, 2-(carboxymethyl)cyclopentan-1-one (Example 18) is esterified to provide the subject ester.
EXAMPLE 20
Preparation of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene
A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml. of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118.degree. C. or less (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is heated in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g (87%) of pale yellow oil, b.p. 118.degree. C. (0.07 mm).
EXAMPLE 21
Preparation of 1-acetoxy-2-(carbethoxymethyl)cyclopent-1-one
In the manner described in Example 20, treatment of 2-(carbethoxymethyl)cyclopentan-1-one (Example 19) with acetic anhydride and p-toluenesulfonic acid monohydrate gives an oil, b.p. 130.degree.-131.degree. C. (7 mm).
EXAMPLE 22
Preparation of 1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-one
In the manner described in Example 20, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 98.degree.-103.degree. C. (0.35 mm).
EXAMPLE 23
Preparation of 1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-ene
In the manner described in Example 20, treatment of 2-l(4-carbethoxybutyl)cyclopentan-1-one (Example 3) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 109.degree.-110.degree. C. (0.37 mm).
EXAMPLE 24
Preparation of ethyl 7-(1-acetoxycyclohex-1en-2-yl)heptanoate
A stirred solution of 28.0 g. of ethykl l7-(cyclohexan-1-on-2-yl)heptanoate (Example 12), 170 mg. of pltoluenesulfonic acid monohydrate, and 25.6 g. of acetic anhydride is heated for 5 hours while allowing 8.0 g. of distillate to distill. The cooled solution is poured into a stirred, ice-cold mixture of 500 ml. of saturated sodium bicarbonate and 250 ml. of hexane. After one hour the hexane phase is separated, dried, and evaporated. The crude product is distilled to give a liquid, IR 1760 cm.sup.-1 (vinyl ester carbonyl) and 1740 cm.sup.-1 (ethyl ester carbonyl).
EXAMPLE 25
Preparation of 1-acetoxy-2-(3-carbethoxypropyl)cyclohex-1-one
Treatment of 2-(3-carbethoxypropyl)cyclohexan-1-one (Example 14) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.
EXAMPLE 26
Preparation of 1-acetoxy-2-(5-carbethoxypentyl)cyclohex-1-ene
Treatment of 2-(5-carbethoxypentyl)cyclohexan-1-one (Example 15) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.
EXAMPLE 27
Preparation of 1-acetoxy-2-(7-carbethoxyheptyl)cyclohex-1-ene
Treatment of 2-(7-carbethoxyheptyl)cyclohexan-1-one (Example 16) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.
EXAMPLE 28
Preparation of 2-(6-carbethoxyhexyl)cyclopent-2en-1-one
To a rapidly stirred mixture of 50 g. of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene (Example 20) in 150 ml. of chloroform, 200 ml. of water and 18.8 g. of calcium carbonate, cooled in an ice bath, is added dropwise over a period of about 30 minutes, a solution of 30 g. of bromine in 50 ml. of carbon tetrachloride. After stirring for an additional 45 minutes the chloroform layer is separated and washed successively with dilute sodium triosulfate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure.
The residual oil is dissolved in 50 ml. of N, N-dimethylformamide and added to a mixture of 33 g. of lithium bromide and 32 g. of lithium carbonate in 375 ml. of N,N-dimethylformamide, previously dried by refluxing with 375 ml. of benzene under a Dean-Stark apparatus followed by distillation of the benzene. The mixtre is stirred at the reflux temperature for 30 minutes, then cooled and poured into 850 ml. of ice-cold water. The resulting mixture is acidifed (cautiously) with 4N hydrochloric acid and extracted with ether three times. The combined ether extracts are washed with saturated sodium chloride solution dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure to afford 41.5 g. of an amber oil. In order to convert any isomeric material to the desired product, 41.5 g. of the above material is treated with 0.500 g. of p-toluenesulfonic acid monohydrate in 450 ml. of absolute alcohol at the reflux temperature for 18 hours. The solution is taken to dryness under reduced pressure. The resulting gum is dissolved in ether and washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure. The residual oil is distilled to give 30.2 g. of product; b.p. 118.degree. C (0.05 mm); .lambda.MeOH/max 229 .mu. (.epsilon.9950); .lambda..sub.max 5.75, 5.85, 6.15, 8.45 .mu.; vapor phase chromatography shows 99% product, containing 1% 2-(6-carbethoxyhexyl)cyclopentan-1-one.
this product can be purified by the following procedure. A mixture of 120 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone, containing approximately 5% of the saturated analogue, and 7.67 g. (10 mole percent) of p-carboxyphenylhydrazine in 400 ml. of absolute ethanol is stirred at ambient temperatures for 18 hours and is then refluxed for 1 hour. The mixture is cooled, the solvent is evaporated, and the residue is taken up into 150 ml. of chloroform and passed through a column of 450 g. of aluminum oxide (Merck). The filtrate is evaporated to yield a colorless oil containing <0.5% of the saturated impurity.
EXAMPLE 29
Preparation of 2-(carbethoxymethyl)cyclopent-2en-1-one
In the manner described in Example 28, treatment of 1-acetoxy-2-(carbethoxymethyl)cyclopent-1-ene (Example 21) with bromine and subsequent dehydrobromination with lithium bromide-lithium carbonate in N,N-dimethylformamide gives an amber oil. This material is subjected to chromatography on diatomaceous earth using an n-heptane:methyl cellosolve system. Removal of the solvent from hold back volume 4.5-4.7 gives an oil which is then further treated with hydroxylamine hydrochloride, sodium acetate in ethanol at room temperature for 18 hours to give the desired product; b.p. 71.degree. C. (0.12 mm); .lambda..sub.max.sup.MeOH 222 m.mu. (10,300); .lambda..sub.max 5.75, 5.85, 6.15, 8.65 .mu..
EXAMPLE 30
Preparation of 2-(3-carbethoxypropyl)cyclopent-2-en-1-one
In the manner described in Example 28, bromination of 1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-ene (Example 22) followed by dehydrobromination with lithium bromide and lithium carbonate is productive of the subject compound.
EXAMPLE 31
Preparation of 2-(4-carbethoxybutyl)cyclopent-2-en-1-one
In the manner described in Example 28, treatment of 1-acetoxyl-2-(4-carbethoxybutyl)cyclopent-1-ene (Example 23) with bromine and subsequent treatment of the brominated product with a mixture of lithium bromide and lithium carbonate in N,N-dimethylformamide is productive of the subject compound. Treatment of this product with p-carboxyphenylhydrazine by the procedure of Example 28 furnishes a product which contains less than 0.5% of the corresponding saturated ketone.
EXAMPLE 32
Preparation of 1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene
To a mixture of 35.97 g. (0.151 mole) of 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 28) and 15.0 g. (0.180 mole) of methoxyamine hydrochloride in 300 lml. of absolute ethanol is added 25 ml. of pyridine and the resulting solution is stirred for 20 hours at ambient temperatures. The solvent is evaporated and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and the solvent is evaporated to yield an oil. Distillation yields 38.7 g. of a colorless oil, b.p. 115.degree.-118.degree. C. (0.075 mm). IR (film): 1740, 1627, 1053, 890 cm.sup.-1. .lambda..sub.max (MeOH) 243 (13,000). NMR.delta.(CDCl.sub.3): 3.89.
EXAMPLE 33
Preparation of 1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene
To an ice cooled solution of 34.10 g. (0.128 mole) of 1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene (Example 32) in 200 ml. of benzene under nitrogen is added dropwise 225 ml. of a 25% solution of diisobutyl aluminum hydride in hexane. The resulting solution is stirred for 2 hours at 0.degree.-5.degree. C., poured onto ice and dilute hydrochloric acid, and the aqueous phase is saturated with sodium chloride. The organic phase is spearated, washed with saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to yield an oil. The latter is dissolved in 100 ml. of hot hexane and cooled to yield 24.3 g. of crystals, m.p. 62.degree.-64.degree. C. IR (KBr) 3260, 1630, 1059, 893 cm.sup.-1. .lambda..sub.max 243 (14,200). NMR (CDCl.sub.3).delta.: 2.37.
EXAMPLE 34
Preparation of 1-methoximino-2-(7-p-toluenesulfonyloxypheptyl)-2-cyclopentene
To a solution of 5.00 g. (0.0222 mole) of 1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene (Example 33) in 50 ml. of dry pyridine at 0.degree. C. is added 8.45 g. (0.0444 mole) of p-toluenesulfonyl chloride and the resulting solution is chilled at 5.degree. C. overnight. The mixture is partitioned between 300 ml. of ice water and diethyl ether. The organic phase is washed with 1:1 ice cold hydrochloric acid, cold water, and cold saturated brine, dried (NaSO.sub.4 /K.sub.2 CO.sub.3), and evaporated under reduced pressure at room temperature to yield an oil. The latter is dissolved in 600 ml. of hexane, treated with 0.5 g. of Darco, filtered and evaporated to yield 7.7 g. of a colorless oil. IR (film) 1600, 1192, 1182, 1053, 890 cm.sup.-1. .lambda..sub.max (MeOH) 228 and 243.
EXAMPLE 35
Preparation of 1-methoximino-2-(8,8-dicarbethoxyoctyl)-2-cyclopentene
To an alcoholic solution of sodiodiethyl malonate, prepared from 0.847 g. (0.0368 g. atoms) of sodium, 100 ml. of absolute ethanol, and 7.05 g. (0.0440 mole) of diethyl malonate is add 7.7 g. of the tosylate of Example 34 and the mixture is refluxed for 2 hours under a nitrogen atmosphere. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to yield an oil. The excess diethyl malonate is distilled off under reduced pressure to yield 6.45 g. of a yellowish oil. IR (film) 1755, 1728, 1625, 1054, 890 cm.sup.-1.
EXAMPLE 36
Preparation of 1-methoximino-2-(8,8-dicarboxyoctyl)-2-cyclopenten
A mixture of 6.45 g. of the diester of Example 35 and 6.72 g. of potassium hydroxide in 150 ml. of 1:1 aqueous methanol is refluxed for 1 hour, cooled, and is partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, and the organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4) and evaporated to yield a solid. The solid is crystallized from benzene to yield 4.15 g. of tan crystals, m.p. 135.degree.-137.degree. C. (-CO.sub.2).
EXAMPLE 37
Preparation of 1-methoximino-2-(8-carboxyoctyl)-2-cyclopentene
A solution of 3.926 g. (0.0126 mole) of the diacid of Example 36 in 20 ml. of xylene is refluxed for 1.5 hours, cooled, and evaporated to yield a tan solid. IR (KBr) 1720, 1618, 1179, 1050, 986 cm.sup.-1.
EXAMPLE 38
Preparation of 2-(8-carboxyoctyl)cycopent-2-en-1-one
The acid methoxime from Example 37 is refluxed for 5 hours with 55 ml. of acetone and 20 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to yield a tan solid. IR (KBr) 1745, 1665 cm.sup.-1. .lambda..sub.max (MeOH) 228 (12.600).
EXAMPLE 39
Preparation of 2-(8-carbethoxyoctyl)cyclopent-2-en-1-one
The acid ketone from Example 38 is Fisher esterified with 100 ml. of absolute ethanol, 100 ml. of benzene, and 20 mg. of p-toluenesulfonic acid for 6 hours, cooled, and the solvent is evaporated. The resulting oil is dissolved in 3:1 benzene-ether and the solution is passed through a column of 100 g. of Florisil.sup..RTM.. The filtrate is evaporated and the residue is distilled to yield 2.97 g. of a colorless oil, b.p. 137.degree.-139.degree. C. (0.05 Torr).
EXAMPLE 40
Preparation of ethyl 7-(cyclohex-2-en-1-one-2-yl)heptanoate
To a stirred solution of ethyl 7-(1-acetoxycyclchex-1-en-2-yl)heptanoate (Example lb 24) in 750 ml. of acetic acid and 125 ml. of pyridine at 10.degree. C. is added a solution of 13.8 g. of bromine in 200 ml. of acetic acid over 20 minutes. The resulting solution is allowed to stand at ambient temperature for 45 minutes and is then decolorized with sodium sulfite. The solution is poured into 800 ml. of half-saturated sodium chloride and extracted with 1:1 hexane-ether. The extract is washed successively with water and saturated sodium chloride, dried over sodium carbonate, and evaporated to give 32 g. of the crude bromoketone. To a stirred suspension of 14.2 g. of lithium bromide and 16.6 g. of lithium carbonate in 250 ml. of anhydrous dimethylformamide at 80.degree. C. is added the above bromoketone. The stirred mixture is heated to boiling over 20 minutes and refluxed for 15 minutes. The cooled mixture is poured into 1000 ml. of water, acidified with dilute hydrochloric acid, and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated. The product is purified by distillation to give a liquid, IR 1740 cm.sup.-1 (ester carbonyl), 1685 cm.sup.-1 (ketone carbonyl), and 1650 cm .sup.-1 (olefin); NMR (CCl.sub.4) 6.63 (multiplet, vinyl proton).
EXAMPLE 41
Preparation of 1-(3-carbethoxypropyl)cyclohex-2-en-1-one
In accordance with the procedure of Example 40, bromination of 1-acetoxy-2-(3-carbethoxypropyl)cyclohex-1-ene (Example 25) followed by treatment with lithium bromide and lithium carbonate is productive of the subject compound.
EXAMPLE 42 Preparation of 2-(5-carbethoxypentyl)cyclohex-2-en-1-one
By the procedure of Example 40, bromination of 1-acetoxy-2-(5-carbethoxypentyl)cyclohexl-1ene (Example 26) followed by treatment with lithium bromide and lithium carbonate is productive of the subject compound.
EXAMPLE 43
Preparation of 2-(7-carbethoxyheptyl)cyclohex-1-en-2-one
By the procedure of Example 40, bromination of 1-acetoxy-2-(7-carbethoxyheptyl)cyclohex-1-ene (Example 27) followed by treatment with lithium bromide and lithium carbonate is productive of the subject compound.
EXAMPLE 44
Preparation of ethyl 9-oxo-13-trans-prostenoate
A solution of 1.102 g. of 1-octyne in 2 ml. of benzene is treated with 11.5 ml. of 15% diisobutylaluminum hydride in toluene and the solution is heated to 50.degree. C. for 2 hours. The solution is cooled, its solvent is removed in vacuo, and the resulting oil is treated with 5.45 ml. of 5.10% methyl lithium in diethyl ether with ice cooling. To the resulting solution is added 1.830 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 28) and the solution is stirred at ambient temperatures for 18 hours. The solution is poured onto ice and dilute hydrochloric acid, and the mixture is extracted with diethyl ether. The organic phase is washed with dilute sodium bicarbonate, water, and saturated brine, dried, and evaporated. The residue is purified by chromatography on Florisil.sup..RTM. and distillation to yield 1.878 g. of an oil, IR 1736 cm.sup.-1 (ester and ketone carbonyls) 969 cm.sup.-1 (trans vinyl group); NMR (CDCl.sub.3).delta.5.14-5.87 (multiplet, 2H, vinyl protons, J trans=15 Hz); Mass Spectrum, parent peak at 350 mu.
EXAMPLE 45
Preparation of ethyl 20-butyl-9-oxol-l13-trans-prostenoate
In the manner described in Example 44, 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from 1-dodecyne, diisolbutylaluminum hydride, and methyl lithium. the crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls) 967 cm.sup.-l (trans vinyl group).
EXAMPLE 46
Preparation of ethyl 9-oxo-18,19,20-trinor-13-trans-prostenoate
In the manner described in Example 44, 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from 1-pentyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by distillation to give a liquid, IR 1740 cm.sup.-1 (ester and ketone carbonyls) 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 47
Preparation of ethyl 15-methyl-9-oxo-17,18,19,20-tetranor-13-trans-prostenoate
In the manner described in Example 44, 2-(6-carbethexyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from 3-methyl-1-butyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by distillation to give a liquid, IR 1740 cm.sup.-1 (ester and ketone carbonyls) 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 48
Preparation of ethyl 20-chloro-9-oxo-13-trans-prostenoate
In the manner described in Example 44, 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from 8-chloro-1-octyne [W. J. Gensler and G. R. Thomas, J. Amer. Chem. Soc., 73, 4601 (1951)], diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 49
Preparation of ethyl 9-oxo-20-nor-13-trans-prostenoate
A solution of 5.30 g. of 1-heptyne in 10 ml. of benzene is treated with 40 ml. of 1.2N diisobutylaluminum hydride in hexane and heated at 50.degree. C. for 2 hours. The solution is cooled in an ice bath and diluted with 25 ml. of ether. To the solution is added 30 ml. of 1.6M n-butyl lithium in hexane. After stirring for 20 minutes at 15.degree.-25.degree. C. the resulting solution is treated with a solution of 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 28). The mixture is stirred at 5.degree.-25.degree. C. for 18-20 hours and the product then is hydrolyzed with a mixture of ice and hydrochloric acid. The crude product, obtained from the organic phase, is purified by chromatography on silica gel to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls) and 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 50
Preparation of ethyl 20-methyl- 9-oxo-13-trans-prostenoate
In the manner described in Example 49, 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from 1-nonyne, diisobutylaluminum hydride and n-butyl lithium. The crude product obtained by acid hydrolysis and evaporation of organic solvent is purifed by chromatography on silica gel to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls) and 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 51
Preparation of ethyl 17-methyl-9-oxo-19,10-dinor-13-trans-rpostenoate
In the manner described in Example 49, 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from 5-methyl-1-hexyne, diisobutylaluminum hydride and n-butyl lithium. The crude product obtained by acid hydrolysis and evaporation of the organic solvent is purified by chromatography on silica gel to give an oil, IR 1740 cm.sup.- (ester and ketone carbonyls) and 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 52
Preparation of ethyl 20-chloro-9-oxo-17,18,19-trino-13-trans-prostenoate
In the manner described in Example 49, 2-(6-carbethoxyhexyl)-2(Example 28) is added to the reagent prepared from 5-chloro-1-pentyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by distillation to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls) and 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 53
Preparation of ethyl 9-oxo-13-propyl-18,19,20-trinor-13-trans-prostenoate
In the manner described in Example 49, 2-(6-carbethoxyhexyl)l-2-cyclopentenone (Example 28) is added to the reagent prepared from 4-octyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product mixture, obtained by acid hydrolysis and evaporation of the organic solvent, is separated by chromatography on silica gel and distillation to give ethyl 9-oxo-13-propyl-18,19,20-trinor-13-trans-prostenoate as an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls); NMR (CCl.sub.4) .delta.5.2 ppm (multiplet, vinyl proton) and a second oil (ethyl 9-oxo-17,18,19,20-tetranorprostanoate), IR 1740 cm.sup.-1 (ester and ketone carbonyls) NMR (CCl.sub.4) .delta.1.0 ppm (multiplet, terminal methyl group).
EXAMPLE 54
Preparation of cis-5-octen-1-yne
A 57% sodium hydride dispersion (9.66 g., 0.23 mole) is washed free of mineral oil in a nitrogen atmosphere with hexane. The hydride is heated at 75.degree. C. with 220 ml. of dimethylsulfoxide for 45 minutes. The resulting green solution is cooled to 18.degree. C. and treated with a solution of 4-pentynyl-triphenylphosphonium iodide (100 g., 0.22 mole) in 220 ml. of dimethylsulfoxide over a 25 minute period. The resulting red solution is stirred at ambient temperature for 45 minutes. To the solution is added a solution of freshly distilled propionaldehyde (14.0 g., 0.24 mole) in 10 ml. of dimethylsulfoxide over a ten minute period at 25.degree. C. After standing at room temperature, the reaction is quenched with half-saturated brine and brought to pH 4 with 4N HCl. The product is extracted with an ether-hexane mixture, and the extract is washed successively with water and brine, dried over MgSO.sub.4, and concentrated. The crude product is fractionanted with a spinning band column to give a colorless distillate, b.p. 121.degree.-122.degree. C., IR 3270, 2110 and 1645 cm.sup.-1.
EXAMPLE 55
Preparation of ethyl 9-oxo-13-trans-17-cis-prostadienoate
In the manner described in Example 49, 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from cis-5-octen-1-yne (Example 54), diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by distillation to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls) and 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 56
Preparation of ethyl 9-oxo-6,7-dinor-13-trans-prostenoate
In the manner described in Example 44, 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from 1-octyne, diisobutylaluminum hydride, and methyl lithium. The product is obtained by acid hydrolysis, ether extraction and distillation to yield a colorless oil, b.p. 149.degree. -150.degree. C. (0.075 mm.). IR 1740 cm.sup.-1 (ester and ketone carbonyls) 963 cm.sup.-1 (trans-vinyl group).
EXAMPLE 57
Preparation of ethyl 20-chlorol-9-oxo-6,7-dinor-13-trans prostenoate
In the manner described in Example 49, 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from 8-chloro-1-octyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls) 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 58
Preparation of ethyl 9-oxo-6,7,20-trinor-13-trans-prostenoate
In the manner described in Example 44, 2-(6-carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from 1-heptyne, diisobutylaluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica get chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls) 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 59
Preparation of ethyl 9-oxo-6,7-dinor-13-trans-17-cis-prostadienoate
In the manner described in Example 55, 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from cis-5-octen-1-yne (Example 54), diisobutylaluminum hydride, and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls) 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 60
Preparation of ethyl 20-chloro-9-oxo-6,7,17,18,19-pentanor-13-trans-prostenoate
In the manner described in Example 49, 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from 5-chloro-1-pentyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 61
Preparation of ethyl 17-methyl-9-oxo-6,7,19,20-tetranor-13-transprostenoate
In the manner described in Example 49, 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from 5-methyl-l-hexyne, diisobutylaluminum hydride and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 62
Preparation of ethyl 9-oxo-13-propyl-6,7,18,19,20-pentanor-13-trans-prostenoate
In the manner described in Example 44, 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from 4-octyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls).
EXAMPLE 63
Preparation of ethyl 9-oxo-3,4,5,6,7-pentanor-13-trans-prostenoate
In the manner described in Example 44, 2-(carbethoxymethyl)-2-cyclopentenone (Example 29) is added to the reagent prepared from 1-octyne, diisobutylaluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 64
Preparation of ethyl 9-oxo-3,4,5,6,7-pentanor-13-trans-17-cis-prostadienoate
In the manner described in Example 55, 2-(carbethoxymethyl)-2-cyclopentenone (Example 29) is added to the reagent prepared from cis-5-octen-1-yne (Example 54), diisobutylaluminum hydride, and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 65
Preparation of ethyl 20-chloro-9-oxo-3,4,5,6,7,17,18,19-octanor-13-trans-prostenoate
In the manner described in Example 49, 2-(carbethoxymethyl)-2-cyclopentenone (Example 29) is added to the reagent prepared from 5-chloro-1-pentyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls) 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 66
Preparation of ethyl 9-oxo-5,6,7-trinor-13-trans-prostenoate
In the manner described in Example 44, 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 30) is added to the reagent prepared from 1-octyne, diisobutylaluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 67
Preparation of ethyl 9-oxo-20-propyl-5,6,7-trinor-13-transprostenoate
In the manner described in Example 44, 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 30) is added to the reagent prepared from 1-undecyne, diisobutylaluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 68
Preparation of ethyl 9-oxo-5,6,7,18,19,20-hexanor-13-trans-prostenoate
In the manner described in Example 44, 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 30) is added to the reagent prepared from 1-pentyne, diisobutylaluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 69
Preparation of ethyl 20-chloro-9-oxo-5,6,7-trinor-13-transprostenoate
In the manner described in Example 44, 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 30) is added to the reagent prepared from 8-chloro-1-octyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.31 1 (trans-vinyl group).
EXAMPLE 70
Preparation of ethyl 9-oxo-7a,7b-bis-homo-13-trans-prostenoate
In the manner described in Example 44, 2-(8-carbethoxyoctyl)-2-cyclopentenone (Example 39) is added to the reagent prepared from 1-octyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 71
Preparation of ethyl 20-chloro-9-oxo-7a,7b-bis-homo-17,18,19-trinor-13-trans-prostenoate
In the manner described in Example 49, 2-(8-carbethoxyoctyl)-2-cyclopentenone (Example 39) is added to the reagent prepared from 5-chloro-1-pentyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 72
Preparation of ethyl 20-butyl-9-oxo-7a,7b-bis-homo-13-transprostenoate
In the manner described in Example 44, 2-(8-carbethoxyoctyl)-2-cyclopentenone (Example 39) is added to the reagent prepared from 1-dodecyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 73
Preparation of ethyl 15-methyl-9-oxo-7a,7b-bis-homo-17,18,19,20-tetranor-13-trans-prostenoate
In the manner described in Example 44, 2-(8-carbethoxyoctyl)-2-cyclopentenone (Example 39) is added to the reagent prepared from 3-methyl-1-butyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 74
Preparation of ethyl 9-oxo-10a-homo-13-trans-prostenoate
In the manner described in Example 49, 2-(6-carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from 1-octyne, diisobutylaluminum hydride and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm.sup.-1 (ester carbonyl), 1750 cm.sup.-1 (ketone carbonyl), and 967 cm.sup.-1 (transvinyl group).
EXAMPLE 75
Preparation of ethyl 20-butyl-9-oxo-10a-homo-13-trans-prostenoate
In the manner described in Example 49, 2-(6-carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from 1-dodecyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm.sup.-1 (ester carbonyl), 1750 cm.sup.-1 (ketone carbonyl), and 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 76
Preparation of ethyl 20-chloro-9-oxo-10a-homo-13-trans-prostenoate
In the manner described in Example 49, 2-(6-carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from 8-chloro-1-octyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm.sup.-1 (ester carbonyl), 1750 cm.sup.-1 (ketone carbonyl), and 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 77
Preparation of ethyl 20-chloro-9-oxo-17,18,19-trinor-10a-homo-13-trans-prostenoate
In the manner described in Example 49, 2-(6-carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from 5-chloro-1-pentyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm.sup.-1 (ester carbonyl), 1750 cm.sup.-1 (ketone carbonyl), and 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 78
Preparation of ethyl 9-oxo-18,19,20-trinor-10a-homo-13-transprostenoate
In the manner described in Example 49, 2-(6-carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from 1-pentyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm.sup.-1 (ester carbonyl), 1750 cm.sup.-1 (ketone cabonyl), and 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 79
Preparation of ethyl 9-oxo-10a-homo-13-trans-17-cis-prostadienoat
In the manner described in Example 49, 2-(6-carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from cis-5-octen-1-yne (Example 54), diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm.sup.-1 (ester carbonyl), 1750 cm.sup.-1 (ketone carbonyl), and 967 cm.sup.-1 (trans-vinyl group).
EXAMPLES 80-92
The 10a-homo-prostenoate derivatives of Table IV below are obtained in the manner described in Example 49 by addition of the indicated 2-(.omega.-carbethoxyalkyl)-2-cyclohexenone to the reagent prepared from the appropriate 1-alkyne (listed in the Table), diisobutylaluminum hydride, and n-butyl lithium. The crude products, obtained as oils by acid hydrolysis and evaporation of the organic solvent, are purified by chromatography on silica gel and distillation; IR 1740 cm.sup.-1 (ester carbonyl), 1750 cm.sup.-1 (ketone carbonyl), and 967 cm.sup.-1 (trans-vinyl group).
EXAMPLE 93
Preparation of ethyl 9-oxo-5,6,7-trinor-10a-homo-13-trans-17-cis-prostadienoate
In the manner described in Example 49, 2-(3-carbethoxypropyl)-2-cyclohexenone (Example 41) is added to the reagent prepared from cis-5-octen-1-yne (Example 54), diisobutylaluminium hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm.sup.-1 (ester carbonyl), 1750 cm.sup.-1 (ketone carbonyl), and 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 94
Preparation of ethyl 9-oxo-7a,10a-bis-homo-13-trans-17-cis-prostadienoate
In the manner described in Example 49, 2-(7-carbethoxyheptyl)-2-cyclohexenone (Example 43) is added to the reagent prepared from cis-5-octen-1-yne (Example 54), diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm.sup.-1 (ester carbonyl), 1750 cm.sup.-1 (ketone carbonyl) and 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 95
Preparation of ethyl 20-iodo-9-oxo-17,18,19-trinor-13-trans-prostenoate
A stirred mixture of 51.5 g. of ethyl 20-chloro-9-oxo-17,18,19-trinor-13-trans-prostenoate (Example 52), 30 g. of sodium iodide, and 250 ml. of acetone is refluxed for 10 hours. An additional 10 g. of sodium iodide is added, and the reaction is continued for 2 hours. The reaction mixture is filtered, concentrated to a volume of 150 ml., diluted with water, and extracts with ether. The extract is washed with saturated sodium chloride, dried, and evaporated to give an oil.
EXAMPLE 96
Preparation of ethyl 20-iodo-9-oxo-13-trans-prostenoate
A stirred mixture of 30 g. of ethyl 20-chloro-9-oxo-13-trans-prostenoate (Example 48), 25 g. of sodium iodide and 225 ml. of acetone is refluxed for 12 hours. The reaction mixture is concentrated, diluted with water, and extracted with ether. The extract is washed with saturated sodium chloride, dried, and evaporated to give an oil.
EXAMPLES 97-107
Treatment of the corresponding 20-chloroprostenoate or 20-chloro-17,18,19-trinor-prostenoate with sodium iodide in acetone by the procedure of Example 95 provides the 20-iodo derivatives of Table V below.
EXAMPLE 108
Preparation of ethyl 9-oxo-18-thia-13-trans-prostenoate
To 6.0 ml. of a stirred, ice-cold solution of 0.5M 5-ethylisothiouronium iodide in 10:1 ethanol:water is added 264 mg. of sodium hydroxide dissolved in 2.0 ml. of ethanol and 4.0 ml. of water. The mixture is stirred under nitrogen at ambient temperature for 15 min. and then cooled in the ice bath while a solution of ethyl 20-iodo-9-oxo-17,18,19-trinor-13-trans-prostenoate (434 mg.) (Example 95) in 3 ml. of ethanol is added. The reaction mixture is stirred successively at 0.degree. for 15 min., at ambient temperature for 15 min., and at 40.degree. for 5 min. The mixture is diluted with water and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated. The crude product is purified by chromatography on silica gel to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls) and 967 cm.sup.-1 (trans vinyl group); NMR (CCl.sub.4) .delta.2.47 ppm (multiplet, methylenethio groups).
EXAMPLES 109-114
Treatment according to the procedure of Example 108; of the various 20-iodo-17,18,19-trinor-trans-prostenoates of Table VI (below) with sodium ethyl mercaptide (prepared in situ as in Example 108) is productive of the various 18-thiaprostenoates of the Table.
EXAMPLE 115
Preparation of ethyl 9-oxo-18-oxythia-13-trans-prostenoate
To a stirred, ice-cold solution of the 18-thiaprostenoate of Example 108 (11.5 g., 31 mmole) in 150 ml. of ethanol is added a solution of sodium metaperiodate (6.65 g., 31.2 mmole) in 55 ml. of water during a twenty min. period. The mixture is allowed to stand at 10.degree. C. for 17 hours. Excess periodate is destroyed by the addition of one ml. of ethylene glycol, and the mixture is filtered. The filtrate is concentrated to one-third of the original volume, diluted with water, and extracted with ether. The extract is washed with brine, dried over MgSO.sub.4, and concentrated. Column chromatography of the residue on silica gel with chloroform-ether mixture gives an oil, IR 1740 (ester and ketone carbonyls), 1040 (sulfoxide), and 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 116
Preparation of ethyl 9-oxo-18-oxythia-5,6,7-trinor-10a-homo-13-trans-prostenoate
This sulfoxide is prepared by treatment of the corresponding sulfide (Example 113) with sodium metaperiodate by the procedure of Example 115.
EXAMPLE 117
Preparation of ethyl 9-oxo-18-oxythia-7a,7b-bis-homo-13-trans-prostenoate
Treatment of the sulfide of Example 111 with sodium metaperiodate by the procedure of Example 115 is productive of the subject sulfoxide.
EXAMPLE 118
Preparation of ethyl 20,20-dicarbethoxy-9-oxo-18,19-dinor-13-trans-prostenoate
To a solution of sodium ethoxide, prepared from 426 mg. of sodium, in 20 ml. of ethanol is added a solution of 3.96 g. of diethyl malonate in 10 ml. of ethanol over a 10 min. period. After stirring for 45 min., a solution containing 5.21 g. of ethyl 20-iodo-9-oxo-17,18,19-trinor-13-trans-prostenoate (Example 95) in 10 ml. of ethanol is added, and the resulting solution is refluxed for 16 hours. The solution is concentrated to one-third of the original volume, diluted with 50 ml. of ether, and treated with 40 ml. of 0.2N HCl. The ether phase is washed with brine, dried over MgSO.sub.4, and concentrated. Column chromatography of the residue on silica gel with chloroform-ether mixtures gives an oil, IR 1740 (ester and ketone carbonyls) and 967 cm.sup.-1 (trans vinyl group); nmr 3.2.delta. (triplet, alkyl-malonate methine hydrogen)
EXAMPLES 119-121
Treatment of the appropriate ethyl 20-iodo-17,18,19-trinorprostenoates with diethyl sodio malonate by the procedure of Example 118 is productive of the triester products of Table VII below.
EXAMPLE 122
Preparation of ethyl 9,9-ethylenedioxy-20-iodo-17,18,19-trinor-13-prostenoate
A solution of 25.2 g. of ethyl 20-iodo-9-oxo-17,18,19-trinor-13-trans-prostenoate (Example 95), 5.6 ml. of ethylene glycol and 110 mg. of p-toluenesulfonic acid monohydrate in 170 ml. of benzene is refluxed for 4 hours with azeotropic removal of water. The solution is concentrated to a volume of 50 ml. Column chromatography of the solution on Florisil .RTM. with benzene gives a liquid, IR 1740 (ester carbonyl), 967 (trans vinyl group), and 952 cm.sup.-1 (ethylene ketal).
EXAMPLES 123-127
Ketalization with ethylene glycol in the presence of p-toluenesulfonic acid of the appropriate 20-iodo-9-oxo-prostenoates by the procedure of Example 122 provides the ketals of Table VIII, which follows.
EXAMPLE 128
Preparation of ethyl 9,9-ethylenedioxy-18-oxa-13-trans-prostenoate
To a stirred, ice-cold suspension of 1.68 g. of 57% sodium hydride in oil and 20 ml. of dimethylformamide (DMF) is added a solution of 2.5 ml. of ethanol in 5 ml. of DMF over a 15 min. period. The mixture evolves gas and is stirred at room temperature for 45 min. To the resulting suspension is added a solution of 9.57 g. of ethyl 9,9-ethylenedioxy-20-iodo-17,18,19-trinor-13-trans-prostenoate (Example 122) in 15 ml. of DMF over a 10 min. period at 10.degree.-15.degree. C. The resulting dark mixture is stirred at ambient temperature for 45 min. and then poured into 200 ml. of ice water. The mixture is brought to pH 7 with 4N HCl and extracted with ether. The extract is washed with brine, dried over MgSO.sub.4, and concentrated. Column chromatography of the residue on silica gel with benzene-ether mixtures gives a liquid, IR 1740 (ester carbonyl), 967 (trans vinyl group), and 952 cm.sup.-1 (ethylene ketal); nmr 3.4.delta. (triplet superimposed on quartet, O-methylene ether groups).
EXAMPLES 129-131
Treatment of the appropriate 20-iodoprostenoate ketals with sodium ethoxide by the procedure of Example 128 is productive of the 18-oxaprostenoate ketals of Table IX, which follows.
EXAMPLE 132
Preparation of ethyl 9,9-ethylenedioxy-20-phthalimido-13-trans-prostenoate
A stirred mixture of 8.80 g. of ethyl 9,9-ethylenedioxy-20-iodo-13-trans-prostenoate (Example 127), 3.28 g. of potassium phthalimide, and 25 ml. of DMF is heated at 70.degree. C. for 2 hours. The cooled mixture is diluted with water and extracted with ether. The extract is washed with brine, dried over potassium bicarbonate, and concentrated to give an oil, IR 1770 (phthalimide group), 1735 (ester carbonyl group), 1710 (phthalimide group), 967 (trans vinyl group), and 950 cm.sup.-1 (ethylene ketal).
EXAMPLE 133
Preparation of 20-amino-9-oxo-13-trans-prostenoic acid hydrochloride
A stirred mixture of 9.3 g. of ethyl 9,9-ethylenedioxy-20-phthalimido-13-trans-prostenoate (Example 132), 2.25 g. of potassium hydroxide, 85 ml. of methanol, and 1.0 ml. of water is refluxed for 2 hours. After addition of 2.25 g. of potassium hydroxide and 2.0 ml. of water, the mixture is refluxed for an additional one hour. The solution is concentrated to remove methanol, and the residue is refluxed with 75 ml. of 4N HCl for 18 hours. The upper phase of the resulting two-phase system is dissolved in water and concentrated to give an oil, IR 1730 (ketone carbonyl group), 1710 (acid carbonyl group), and 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 134
Preparation of ethyl 9,9-ethylenedioxy-20-pyrrolidino-17,18,19-trinor-13-trans-prostenoate
A mixture of 4.17 g. of potassium carbonate, 9.95 g. of pyrrolidine, and 55 ml. of dimethylformamide (DMF) is stirred at 50.degree. C. To the mixture is added a solution of 13.5 g. of ethyl 9,9,l-ethylenedioxy-20-iodo-17,18,19-trinor-13-trans-prostenoate (Example 122) in 15 ml. of DMF over a 40 min. period. After an additional 30 min. at 50.degree. C. the mixture is cooled and treated with 200 ml. of water. The mixture is extracted with 5:1 (v/v) ether:hexane. The extract is washed with brine, dried with potassium carbonate, and concentrated. Column chromatography of the residue on Florisil .RTM. with benzene-ether mixtures gives an oil, IR 1740 (ester carbonyl group), 967 (trans vinyl group), and 950 cm.sup.-1 (ethylene ketal).
EXAMPLES 135-138
Treatment of the iodoprostenoate ketals of Table X (below) by the procedure of Example 134 with the indicated amine is productive of the aminoprostenoate ketals of the table.
EXAMPLE 139
Preparation of 20-mercapto-9-oxo-13-trans-prostenoic acid
A solution of 9.53 g. of ethyl 20-iodo-9-oxo-13-trans-prostenoate (Example 96) and 1.60 g. of thiourea in 20 ml. of ethanol is refluxed for 45 min. The resulting solution of the corresponding 20-S-isothiouronium salt is diluted with 140 ml. of methanol and a solution of 5.30 g. of potassium hydroxide in 20 ml. of water. The resulting solution is allowed to stand at room temperature for 19 hours. The solution is concentrated to a volume of 100 ml. and diluted with 200 ml. of water. The solution is acidified with 4N HCl and extracted with ether. The extract is washed with brine, dried over MgSO.sub.4, and concentrated. Column chromatography of the residue on silica gel with chloroform-ether mixtures gives an oil, IR 1740 (ketone carbonyl), 1710 (acid carbonyl), and 967 cm.sup.-1 (trans vinyl group); nmr 2.4 .delta. (methylene thiol group).
EXAMPLES 140-142
Treatment of the 20-iodoprostenoates of Table XI, below according to the procedure of Example 139 with thiourea produces the corresponding 20-S-isothiouronium salt, which on treatment with sodium hydroxide solution is productive of the 20-mercaptoprostenoic acids of the table.
EXAMPLE 143
Preparation of 9-oxo-20-pyrrolidino-17,18,19-trinor-13trans-prostenoic acid
A stirred mixture of 9.20 g. of ethyl 9,9-ethylenedioxy-20-pyrrolidino-17,18,19-trinor-13-trans-prostenoate (Example 134), 0.02 ml. of concentrated sulfuric acid, 35 ml. of glacial acetic acid, and 17.5 ml. of water is refluxed for 17 hours. The cooled reaction mixture is treated with 58 mg. of sodium bicarbonate and concentrated to near-dryness. The residue is treated with water and extracted with ether. The ether phase is back-extracted with 0.1N HCl, and all aqueous phases are concentrated to give the subject amino acid.
EXAMPLES 144-147
Hydrolysis of the aminoprostenoate ketals of Table XII below by the procedure of Example 143 is productive of the aminoprostenoic acids of the table.
EXAMPLE 148
Preparation of 2-(4-carbethoxybutyl)-2-cyclopentenonemethoxime
Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 31) with methoxyamine hydrochloride in the manner described in Example 32 gives an oil, b.p. 107.degree.-109.degree. C. (0.05 mm). IR (film): 1740, 1628, 1050, 885 cm.sup.-1. .lambda..sub.max (MeOH) 243 (13,600).
EXAMPLE 149
Preparation of 2-(5-hydroxypentyl)-2-cyclopentenomethoxime
Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenomethoxime (Example 148) with diisobutyl aluminum hydride in the manner described in Example 33 gives crystals, m.p. 33.degree.-35.degree. C. IR (KBr) 3420, 1630, 1050, 886 cm.sup.-1. .lambda..sub.max.sup.MeOH 243 (12,020).
EXAMPLE 150
Preparation of 2-(5-tosyloxypentyl)-2-cyclopentenomethoxime
Treatment of 2-(5-hydroxypentyl)-2-cyclopentenomethoxime (Example 149) with p-toluenesulfonyl chloride in pyridine in the manner described in Example 34 gives a colorless oil. IR (film) 1600, 1190, 1180, 1050, 885 cm.sup.-1.
EXAMPLE 151
Preparation of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentenomethoxime
To a solution of sodio diethyl ethylmalonate, prepared from 1.63 g. (0.0387 mole) of sodium hydride in mineral oil (57.2%), 100 ml. of ethylene glycol dimethyl ether and 8.5 g. (0.0452 mole) of ethyl diethyl malonate, is added 7.5 g. of tosylate from Example 150 in 20 ml. of ethylene glycol dimethyl ether and the mixture is refluxed for 3 hours and then allowed to stand at room temperature for 18 hours under nitrogen atmosphere. The reaction mixture is filtered and most of the solvent is removed. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (MgSO.sub.4), and evaporated to yield an oil. The excess ethyl diethyl malonate is distilled off under reduced pressure to yield 6.7 g. or a yellow oil. IR (film) 1755, 1728, 1627, 1050, 885 cm.sup.-1.
EXAMPLE 152
Preparation of 2-(6,6-dicarboxyoctyl)-2-cyclopentenomethoxine
Treatment of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentenomethoxime (Example 151) with potassium hydroxide, and 1:1 aqueous methanol in the manner described in Example 36 gives a light yellow oil.
EXAMPLE 153
Preparation of 2-(6-carboxyoctyl)-2-cyclopentenomethoxime
In the manner described in Example 37, treatment of 2-(6,6-dicarboxyoctyl)-2-cyclopentenomethoxime (Example 152) with xylene at reflux for 18 hours gives a yellow oil.
EXAMPLE 154
Preparation of 2-(6-carboxyoctyl)-2-cyclopentenone
Treatment of 2-(6-carboxyoctyl)-2-cyclopentenomethoxime (Example 153) with acetone and 2N hydrochloric acid in the manner described in Example 38 gives a light yellow oil.
EXAMPLE 155
Preparation of 2-(6-carbethoxyoctyl)-2-cyclopentenone
Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone (Example 154) with thionyl chloride and then treatment of the acid chloride with ethanol in the manner described in Example 264 give an amber oil. The oil is placed on a magnesia-silica gel column and eluted with 3:1 benzene:ether. The solvent is removed and the residue is distilled, b.p. 122.degree. C. (0.06 mm).
EXAMPLES 156-161
Treatment of 2-(6-carbethoxyoctyl)-2-cyclopentenone (Example 155) in the manner of Example 44 with the reagents prepared from the alkyne indicated in Table XIII below, diisobutylaluminum hydride and methyl lithium is productive of the prostenoate esters of the first three Examples of this table. Saponification of the ester by the procedure of Example 177 provides the corresponding prostenoic acids.
EXAMPLE 162
Preparation of ethyl 9.alpha.- and 9.beta.-hydroxy-13-trans-prostenoate
A solution of 1 g. of ethyl 9-oxo-13-trans-prostenoate (Example 44) in 40 ml. of absolute alcohol containing 41 mg. of sodium borohydride is stirred at room temperature (protected from moisture) for 19 hours. The mixture is poured into 100 ml. of water and the resulting solution is extracted several times with ether. The combined ether extracts are washed several times with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 806 mg. of an oil. Distillation furnished 700 mg. (70%) of product as a pale yellow oil; b.p. 179.degree. C. (0.13 mm); .lambda..sub.max 2.98, 5.78, 5.81 (shoulder), 8.50, 10.30 .mu.; nmr 2H multiplet .delta. 5.36 (olefinic protons), 2H triplet 4.13 (OCH.sub.2 of ester), 3H distorted triplet 1.23 (methyl of ester) and 3H distorted triplet 0.90 (terminal methyl).
EXAMPLES 163-176
The following alcohols (as mixtures of 9.alpha.- and 9.beta.-epimers) of Table XIV are prepared by sodium borohydride reduction of the corresponding 9-ketones according to the procedure of Example 162.
EXAMPLE 177
Preparation of 20-butyl-9-oxo-13-trans-prostenoic acid
A solution of 2.33 g. of ethyl 20-butyl-9-oxo-13-trans-prostenoate (Example 45) and 1.30 g. of potassium hydroxide in 35 ml. of methanol and 3.5 ml. of water is allowed to stand at room temperature for 24 hours. The reaction mixture is concentrated in vacuo, diluted with water, and washed with ether. The aqueous phase is acidified to pH 2 and extracted with ether. The extract is washed with saturated sodium chloride, dried, and evaporated to give an oil, IR 1745 cm.sup.-1 (ketone carbonyl), 1710 cm.sup.-1 (acid carbonyl), and 967 cm.sup.-1 (trans vinyl group).
EXAMPLE 178
Preparation of 9-oxo-13-trans-prostenoic acid
A mixture of 0.140 g. of ethyl 9-oxo-13-trans-prostenoate (Example 44) and 0.072 g. of potassium hydroxide in 6 ml. of 1:1 aqueous methanol is stirred at ambient temperature for 17 hours. The resulting solution is acidified with hydrochloric acid, extracted with diethyl ether, and the organic phase is washed with water and saturated brine, dried, and the solvent removed to yield 0.128 g. of an oil, IR 1739 cm.sup.-1 (ketone carbonyl) 1706 cm.sup.-1 (acid carbonyl), 969 cm.sup.-1 (trans vinyl group); NMR (CDCl.sub.3) 5.34-5.67 (multiplet, 2H, vinyl protons, J trans=15 Hz), 10.47 (broad singlet, 1H, carboxyl proton, exchangeable); Mass spectrum, parent peak at 322 m.mu..
EXAMPLE 179
Preparation of 9-oxo-6,7-dinor-13-trans-prostenoic acid
In the manner described in Example 178, ethyl 9-oxo-6,7-dinor-13-trans-prostenoate (Example 56) is saponified with potassium hydroxide, acidified, and worked-up by ether extraction and evaporative distillation at 160.degree. C (0.005 Torr) to yield a colorless oil.
EXAMPLE 180
Preparation of 9.alpha.- and 9.beta.-hydroxy-13-trans-prostenoic acid
A suspension of 1.8 g. of ethyl 9.alpha.- and 9.beta.-hydroxy-13-trans-prostenoate (Example 162) in 40 ml. of aqueous methanol (1:1) containing 890 mg. of potassium hydroxide is stirred at ambient temperature for 18 hours. The resulting solution is cooled, acidified with 1N hydrochloric acid and extracted several times with ether. The combined ether extracts are washed with sodium chloride solution, dried with anhydrous magnesium sulfate, and taken to dryness to give 1.61 g. (98%) of product as an oil; .lambda..sub.max 2.95, 3.40, 3.75, 5.85, 10.31 .mu.; nmr 2H singlet .delta. 6.10 (hydroxyl and carboxyl protons), 2H multiplet 5.40 (olefinic protons), and 3H distorted triplet 0.90 (terminal methyl).
EXAMPLES 181-251
In the manner described in Example 177, the carboxylic acids of Table XV (below) are prepared by saponification of the corresponding ethyl esters at room temperature in methanol-water followed by acidification and extraction with ether. Infrared characterization of the cyclopentanone derivatives gives bands at about 1745 cm.sup.-1 (ketone carbonyl), 1710 cm.sup.-1 (acid carbonyl) and 967 cm.sup.-1 (trans vinyl group). The cyclohexanone derivatives also show the 967 cm.sup.-1 band, but the carboxylic acid and ketone carbonyl functions give bands occurring at about 1715 cm.sup.-1.
EXAMPLE 252
Preparation of 20-carboxy-9-oxo-18,19-dinor-13-trans-prostenoic acid
A solution of ethyl 20,20-dicarbethoxy-9-oxo-18,19-dinor-13-trans-prostenoate (Example 118), prepared from 10.42 g. of iodo compound (Example 95), is dissolved in 240 ml. of methanol and treated with a solution of 9.50 g. of potassium hydroxide in 24 ml. of water. The solution is allowed to stand at room temperature for 42 hours. Most of the methanol is removed in vacuo, and the residue is dissolved in 200 ml. of water. After acidification with 4N HCl the acidic product is extracted with ether. The extract is washed with brine, dried over MgSO.sub.4, and evaporated. The residue is heated at 120.degree. C. for 1.5 hours and subjected to column chromatography on silica gel with chloroform ether mixtures to give an oil, IR 1745 cm.sup.-1 (ketone carbonyl), 1715 cm.sup.-1 (acid carbonyl), and 967 cm.sup.-1 (trans vinyl group).
EXAMPLES 253-255
Hydrolysis and decarboxylation, according to the procedure of Example 252, of the appropriate 20,20-dicarbethoxy-18,19-dinorprostenoates provides the 20-carboxy-18,19-dinorprostenoic acids of Table XVI.
EXAMPLE 256
Preparation of ethyl 18-oxa-9-oxo-13-trans-prostenoate
A solution of 1.07 g. of ethyl 9,9-ethylenedioxy-18-oxa-13-trans-prostenoate (Example 128) and 27 mg. of p-toluenesulfonic acid monohydrate in 10 ml. of acetone is allowed to stand at room temperature for 17 hours. The bulk of the acetone is evaporated, and the residue is treated with 25 ml. of water and extracted with ether. The extract is washed successively with dilute NaHCO.sub.3 and brine and dried over MgSO.sub.4. Evaporation of the solvent gives an oil, IR 1740 (ester and ketone carbonyls) and 967 cm.sup.-1 (trans vinyl group).
EXAMPLES 257-259
Treatment of the appropriate 18-oxaprostenoate ketals with acetone and p-toluenesulfonic acid by the procedure of Example 256 is productive of the ethyl 18-oxa-9-oxo-13-trans-prostenoates of Table XVII, which follows.
EXAMPLES 260-263
Saponification of the appropriate ethyl 18-oxa-9-oxo-13-trans-prostenoates by the procedure of Example 177 is productive of the 18-oxa-9-oxo-13-trans-prostenoic acids of Table XVIII which follows.
EXAMPLE 264
Preparation of 3'-pyridyl 9-oxo-13-trans-prostenoate
9-Oxo-13-trans-prostenoic acid (Example 178) is converted to 9-oxo-13-trans-prostenoyl chloride by treatment with thionyl chloride. A benzene solution of 9-oxo-13-trans-prostenoyl chloride (24.8 moles) is slowly added to a slight excess of 3-hydroxypyridine (26 moles) in 100 ml. of benzene containing 5 ml. of triethylamine. The mixture is magnetically stirred and refluxed for 30 min. The reaction mixture is filtered and taken to dryness and the residue is dissolved in ether and washed successively with saline, dilute sodium bicarbonate solution, dried and taken to dryness. The oil is purified by adsorption chromatography on a magnesia-silica gel column and eluted with benzene to give a dark yellow oil.
EXAMPLES 265-278
In the manner described in Example 264, the various prostenoic acids of the following table are converted with thionyl chloride to the corresponding prostenoyl chlorides and thence with the indicated alcohols to the various prostenoic acid esters of Table XIX, which follows.
EXAMPLE 279
Preparation of 4-chloro-1-tetrahydropyranyloxybutane
To 9.25 g. (0.11 mole) of dihyropyran containing 3 drops of phosphorus oxychloride is added 10 g. (0.092 mole) of 4-chlorobutanol-1dropwise over a period of 2 hours with stirring. The reaction mixture is then allowed to stir overnight at room temperature. The reaction mixture is concentrated, the residue is placed on a Florisil .RTM. column and the product is eluted with benzene to give 14.4 g. (81%) of the subject compound as an oil.
EXAMPLE 280
Preparation of diethyl 1,1-dimethyl-5-tetrahydropyranylpentylmalonate
To 486 mg. (0.02 g.-atoms) of magnesium in 5 ml. of toluene containing one molar equivalent of tetrahyrofuran per equivalent of magnesium and one percent iodine (calculated in weight of magnesium) is added dropwise 3.86 g. (0.02 mole) of 4-chloro-1-tetrahydropyranyloxybutane over a period of one hour with stirring, under nitrogen at 70.degree. C. The reaction mixture is stirred at 70.degree. C. for four hours. This reagent is then added dropwise to 3 g. (0.015 mole) of ethyl isopropylidenemalonate in 40 ml. of tetrahydrofuran containing 392 mg. of tetrakis [iodo(tri-n-butylphosphine)copper (I)] and stirred at room temperature for 2 hours. The reaction mixture is poured into cold dilute hydrochloric acid and extracted with ether. The ether extract is dried over magnesium sulfate and concentrated to give 5.92 g. of subject product as an oil.
EXAMPLE 281
Preparation of diethyl 1,1-dimethyl-5-hydroxypentylmalonate
A solution of 3.5 g. (0.01 mole) of diethyl 1,1-dimethyl-5-tetrahydrofuranyloxypentylmalonate in 70 ml. of ethanol containing 3 ml. of hydrochloric acid is allowed to stir at room temperature for 18 hours. The solution is concentrated, diluted with water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated to give 3.262 g. of a light yellow oil. The oil is purified by distillation, b.p. 116.degree.-117.degree. C. (0.05 mm).
EXAMPLES 282
Preparation of 3,3-dimethyl-7-hydroxyheptanoic acid
A mixture of 32 g. (0.117 mole) of diethyl 1,1-dimethyl-5-hydroxypentylmalonate, 25 g. of potassium hydroxide and 600 ml of methanol-water (1:1) is heated at reflux for 8 hours and then allowed to stand at room temperature for 18 hours. The methanol is removed, diluted with water and the reaction mixture is acidified with concentrated hydrochloric acid. The mixture is extracted with ether. The extract is washed with water and saline, dried over anhydrous magnesium sulfate and concentrated to give 27 g. of 1,1-dimethyl-5-hydroxypentylmalonic acid. This crude oil is dissolved in 200 ml. of bis-(2-methoxyethyl)ether and is heated at reflux for 4 hours and then allowed to stand at room temperature overnight. The solvent is removed and the reaction mixture is diluted with water and extracted with ether. The organic solution is washed with saline, dried over magnesium sulfate and concentrated to give 18 g. of product as an oil.
EXAMPLE 283
Preparation of ethyl 3,3-dimethyl-7-chloroheptanoate
To a solution of 3.484 g. (0.02 mole) of 3,3-dimethyl-7-hydroxyheptanoic acid in 25 ml. of chloroform containing 3 drops of dimethylformamide is added 5.8 ml. (0.08 mole) of thionyl chloride and the solution is then heated at reflux for 3-4hours. The solution is concentrated to give the intermediate 3,3-dimethyl-7-chloro-1-heptanoyl chloride. The acid chloride is dissolved in a minimum amount of benzene and added slowly to 20 ml. benzene, 10 ml. of ethanol and 2.65 ml. of collidine. The solution is heated at reflux for one hour and then concentrated. The residue is dissolved in ether, washed with water, dilute sodium bicarbonate solution and saline. The organic solution is dried over magnesium sulfate and concentrated to give 3.57 g. of product as a yellow oil.
EXAMPLE 284
Preparation of ethyl 3,3-dimethyl-7-iodoheptanoate
To a solution of 3.57 g. (0.0162 mole) of ethyl 3,3-dimethyl-7-chloroheptanoate in 100 ml. of methyl ethyl ketone is added 4 g. of sodium iodide and the mixture heated at reflux for 18 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between ether and water. The aqueous phase is extracted several times with ether. The extract is washed with sodium bisulfite solution, water and saline. The organic solution is dried over magnesium sulfate and concentrated to give 4.182 g. of a yellow oil. The material is purified by distillation, b.p. 86.degree.-87.degree. C. (0.18 Torr).
EXAMPLE 285
Preparation of 2-carbalkoxy(methyl/ethyl)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1 -one
This compound is prepared by treatment of sodio cyclopentanone carboxylate enolate with ethyl 3,3-dimethyl-7-iodohep tanoate by the procedure described in Example 1.
EXAMPLE 286
Preparation of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one
This compound is prepared by decarbalkoxylation of 2-carbalkoxy (mixed methyl and ethyl ester)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one by the procedure described in Example 2.
EXAMPLE 287
Preparation of 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one
Esterification of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one with ethanol by the procedure of Example 264 is productive of the subject compound.
EXAMPLE 288
Preparation of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene
This compound is prepared from 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one and acetic anhydride by the process described in Example 20.
EXAMPLE 289
Preparation of 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-2-en-1-one
This compound is prepared from 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-l-ene via bromination and dehydrobromination according to the procedure described in Example 28.
EXAMPLE 290
Preparation of 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene
In the manner described for the preparation of the compound of Example 32, 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 30) and methoxyamine hydrochloride.
EXAMPLE 291
Preparation of 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene
In the manner described for the preparation of the compound of Example 33, 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene and diisobutylaluminum hydride.
EXAMPLE 292
Preparation of 2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene
To an ice cold solution of 4.833 g. (0.0266 mole) of 2-(4-hydroxypentane)-1-methoximino-2-cyclopentene in 50 ml. of dry tetrahydrofuran under nitrogen is added 16.7 ml. of 1.6 molar n-butyl lithium in hexane, dropwise. The reaction mixture is stirred for 0.5 hour and then 4.85 g. (0.029 mole) of ethyl bromoacetate is added dropwise. The reaction mixture is stirred overnight at room temperature and then refluxed for 1.5 hours. The reaction is cooled and poured into water and extracted several times with ether. The ether extracts are washed with saline, dried over magnesium sulfate, and concentrated. The residue is placed on an alumina column, chloroform being used as a wash solvent. The combined washings are concentrated to dryness to give 4.903 g. of product an a yellow oil.
EXAMPLE 293
Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone
In the manner described in Example 38, treatment of 2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene with acetone and 2N hydrochloric acid at reflux gives the subject compound as a yellow oil.
EXAMPLE 294
Preparation of 2-(6-carbethoxy-5-oxahexyl)-2-cyclopentenone
In the manner described in Example 39, treatment of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol produces the subject product as a light yellow oil.
EXAMPLE 295
Preparation of 2-(4-p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene
In the manner described in Example 34, treatment of 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene with p-toluene sulfonyl chloride in pyridine gives the subject product as a light yellow oil; IR (film): 1600, 1190, 1050, 885 cm.sup.-1.
EXAMPLE 296
Preparation of 2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentene
To a stirred mixture of 1.465 g. (0.0348 mole) of sodium hydride (57.2% in mineral oil) in 50 ml. of dimethoxyethane, under nitrogen, is added slowly 4.8 g. (0.0347 mole) of ethyl-2-mercaptoacetate. The reaction mixture is stirred at room temperature for one hour and then a solution of 7.8 g. (0.0231 mole) of 2-(4-p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene in 30 ml. of dimethoxyethane is added dropwise and stirred at room temperature for 18 hours. The solution is heated at reflux for one hour, cooled and poured into cold dilute hydrochloric acid and then extracted with ether. The combined ether extracts are washed with saline, dried over magnesium sulfate and evaporated to give 7.6 g. of subject product as a yellow oil.
EXAMPLE 297
Preparation of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone
In the manner described in Example 38, treatment of 2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentene with acetone and 2N hydrochloric acid at reflux gives the subject product as a yellow oil.
EXAMPLE 298
Preparation of 2-(6-carbethoxy-5-thiahexyl)-2-cyclopentenone
In the manner described in Example 39, treatment of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol gives the subject ester as a yellow oil.
EXAMPLE 299
Preparation of ethyl 9-oxo-3,3-dimethyl-13-trans-prostenoate
In the manner described in Example 44, treatment of 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-2-en-1-one with the reagent prepared from 1-octyne, diisobutylaluminum hydride and methyl lithium provides the subject product as a yellow oil.
EXAMPLE 300
Preparation of ethyl 9-oxo-3-thia-13-trans-prostenoate
In the manner described in Example 44, treatment of 2-(6-carbethoxy-5-thiahexyl)-2-cyclopentenone with the reagent prepared from 1-octyne, diisobutylaluminum hydride and methyl lithium gives the subject 3-thiaprostenoate as a yellow oil.
EXAMPLE 301
Preparation of ethyl 3-oxa-9-oxo-13-trans-prostenoate
In the same manner as for the preparation of the compound of Example 44, ethyl 3-oxa-9-oxo-13-trans-prostenoate is prepared by the addition of 2-(6-carbethoxy-5-oxahexyl)-2-cyclopentenone to the reagent prepared from 1-octyne, diisobutylaluminum hydride and methyl lithium.
EXAMPLES 302-313
In the manner of Example 44, treatment of the gem-dimethyl, oxa, or thia cyclopentenone esters of Examples 289, 294 and 298, respectively, with the alanate complex obtained from the alkynes indicated in Table XX below, diisobutylaluminum hydried and methyl lithium, is productive of the 3,3-dimethyl, 3-oxa, or 3-thia prostenoates of the Table.
EXAMPLE 314
Preparation of 2-(carbethoxymethyl)-3-(1-trans-octenyl)-1,1-dioxolano-cyclopentane
A mixture of 10.142 g. (0.0362 mole) of 2-(carbethoxy-methyl)-3-(1-octenyl)cyclopentanone (ethyl 9-oxo-3,4,5,6,7-pentanor-13-trans-prostenoate, Example 63), 3.49 g. (0.0562 mole) of ethylene glycol, 0.344 g. of p-toluenesulfonic acid monohydrate, and 30 ml. of benzene is refluxed for 4.5 hours with azeotropic removal of water. The mixture is cooled, placed onto a column of 130 g. of Florisil.sup..RTM. in benzene and the ketal is eluted off with benzene. The filtrate is evaporated to yield 9.53 g. of a colorless oil.
EXAMPLE 315
Preparation of 2-(formylmethyl)-3-(1-trans octenyl)-1,1-diomolano-cyclopentane
To a solution of 1.00 g. (0.00308 mole) of 2-carbethoxymethyl)-3-(1-trans-octenyl)-1,1-dioxolano cyclopentane in 5 ml. of heptane at -78.degree. C. and under nitrogen is added dropwise 2.60 ml. of a solution of 25% diisobutylaluminum hydride in hexane. The resulting solution is stirred at -78.degree. C. for 2.5 hours and then poured into cold dilute hydrochloric acid. The organic phase is washed with saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to yield 0.863 g. of a colorless oil. IR 2695, 1723, 1045, 970 cm.sup.-1.
EXAMPLE 316
Preparation of 2-(6-carboxy-2-cis-hexenyl)-3-(1-trans-octenyl)-1,1-dioxolano cyclopentane
A mixture of 0.194 g. (0.007952 mole) of sodium hydride (free of mineral oil) and 5.5 ml. of dimethylsulfoxide is heated to 70.degree. C. until gas evolution ceases under a nitrogen atmosphere. The resulting solution is cooled below room temperature and treated with a solution of 1.400 g. (0.00316 mole) of 4-carboxybutyltriphenyl phosphonium bromide [E. J. Corey et al., J. Am. Chem. Soc., 91, 5675 (1969)] in 6 ml. of dimethylsulfoxide. To the resulting red solution is added 0.738 g. (0.00263 mole) of 2-(formylmethyl)-3-(1-trans-octenyl)-1,1-dioxolano cyclopentane in 2 ml. of dimethylsulfoxide and the mixture is stirred at room temperature for 2.25 hours. The mixture is poured into ice water, sodium hydroxide solution is added to pH 12, and the neutral materials are extracted with diethyl ether. The basic phase is acidified with dilute hydrochloric acid and is extracted with diethyl ether. The organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to a semicrystalline mass. The latter is triturated with hot hexane, the solids are filtered off, and the filtrate is evaporated to yield an oil. IR: 1705, 1040, 970, 722 cm.sup.-1.
EXAMPLE 317
Preparation of 9-oxo-5-cis-13-trans-prostadienoic acid
A solution of 0.726 g. of 2-(6-carboxy-2-cis-hexenyl)-3-(1-trans-octenyl)-1,1-dioxolano cyclopentane and 19 mg. of p-toluenesulfonic acid monohydrate in 30 ml. of acetone is stirred at ambient temperatures for 66 hours. The volatile material is removed in vacuo and the residue is passed through a column of silica gel in chloroform collecting those fractions which contain product. The solvent is evaporated to yield the subject product as an oil. IR: 1740, 1705, 970, 722 cm.sup.-1.
EXAMPLE 318
Preparation of ethyl 9-oxo-5-cis-13-trans-prostadienoate
By the procedure described in Example 264, 9-oxo-5-cis-13-trans-prostadienoic acid is esterified with ethyl alcohol to the subject ethyl ester.
EXAMPLES 319-330
Treatment of the 9-oxo-13-trans-prostenoate esters of the following Table with sodium borohydride in ethanol by the method described in Example 162 is productive of the 9-hydroxy-(mixture of .alpha. and .beta. epimers)-prostenoates of the following Table
EXAMPLES 331-357
Saponification of the esters of the following table by the procedure of Example 177 is productive of the carboxylic acid of this table.
EXAMPLE 358
Preparation of 1-9-oxo-5-cis,13-trans-prostadienoic acid
To a solution of 8.9 gm. of 1-15-0 -acetyl PGA.sub.2 methyl ester [W. P. Schneider, R. D. Hamilton, L. E. Rhuland; J. Amer. Chem. Soc., 94 2122 (1972)] and 10.97 gm. of tripropylsilane is added 170 mg. tristriphenylrhodium chloride. The resulting solution is heated in a 90.degree. C. oil bath for 6 hours, stirred in room temperature for 48 hours, and heated 2 more hours at 85.degree. C. At this point an additional 50 mg. of tristriphenylrhodium chloride is added and the solution is heated 5 more hours.
The reaction mixture is cooled, diluted with 300 ml. of toluene and concentrated in vacuo to give 18 gm. of an oil. The oil is dissolved in 30 ml. of methanol, and after stirring 5 minutes the solution is concentrated in vacuo. The residue is partitioned between 30 ml. of nitromethane and 30 ml. of cyclohexane. The cyclohexane phase is extracted with 20 ml. additional nitromethane. The combined nitromethane extracts are concentrated in vacuo, and 50 ml. of benzene is added and removed in vacuo to give 3.9 gm. of an oil. The cyclohexane fraction is concentrated in vacuo to give 12.3 gm. of an oil.
11.3 gm. of the oil from the cyclohexane extraction is dissolved in 700 ml. of methanol, 6 ml. of 5% aqueous sodium bicarbonate is added and the solution is stirred four days. The solution is concentrated in vacuo and 100 ml. of ether is added. The ether solution is washed twice with 50 ml. of brine, dried and concentrated in vacuo to give 8.8 gm. of an oil. This oil is dissolved in 50 ml. of hexane and extracted 3 times with 20 ml. of nitromethane. The nitromethane is concentrated in vacuo to give 4 gm. of an oil, which is combined with the 3.9 gm. of oil from the initial nitromethane extract and the 7.9 gm. is chromatographed on a 48 inch by 3 inch flat diameter nylon tube packed with 1 kg. acid-washed silica-gel. The column is developed with 7% ethyl acetate-in-benzene. The fraction corresponding to R.sub.f 0.25 - 0.55 is removed and washed 4 times with 1 liter of ether. Concentration of the ether solution gives 6 gm. of 11-deoxy-15-O-acetyl PGE.sub.2 methyl ester.
The fraction corresponding to R.sub.f 0.55 - 0.75 is removed and the material is eluted with 4,500 ml. ether washes. Concentration of the ether yields 1-methyl 9-oxo-5-cis,13-trans-prostadienoate; i.r.: 1730 cm.sup.-1, 975 cm .sup.-1 ; pmr: CDCL.sub.3 .delta. (3.68, s, 3H, COOCH.sub.3), (5.4, m, 4H, vinyl). GLC analysis of the product obtained after oxidative ozonolysis indicates the presence of hexanoic acid, thereby establishing the location of the trans = at C.sub.13 -C.sub.14. Saponification of this ester by the procedure described in Example 178 provides 1-9-oxo-5-cis,13-trans-prostadienoic acid.
EXAMPLE 359
Preparation of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene
To a cold solution of 9.85 g. (0.05 mole) of 1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene (Example 149) and 7.6 g. (0.075 mole) of triethylamine in 100 ml. of methylene chloride at -10.degree. C. is added 6.3 g. (0.055 mole) of methanesulfonyl chloride at a rate to maintain a temperature of -10.degree. to 0.degree. C. The mixture is then stirred for 15 minutes and then poured into ice water. The organic phase is washed with cold 10% hydrochloric acid, cold saturated sodium bicarbonate solution, and cold saturated brine, dried (MgSO.sub.4), and evaporated to yield a solid, m.p. 78.degree.-80.degree. C.
EXAMPLE 360
Preparation of 1-methoximino-2-(6-fluoro-6,6-dicarbethoxyhexyl)-2-cyclopentene
To a solution of sodio diethyl fluoromalonate, prepared from 2.062 g. (0.0491 mole) of sodium hydride in mineral oil (57.2%), 40 ml. of dry N,N-dimethylformamide and 8.174 g. (0.0458 mole) of diethyl fluoromalonate, is added dropwise 11.32 g. (0.0413 mole) of 1-methoximino-2-(5-methylsulfonyloxypentyl)-2-cyclopentene (Example 359) in 60 ml. of N,N-dimethylformamide. The mixture is refluxed for 2 hours under a nitrogen atmosphere. The mixture is concentrated and partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to yield 13.631 g. (92%) of a yellow oil.
EXAMPLE 361
Preparation of 1-methoximino-2-(6-fluoro,6,6-dicarboxyhexyl)-2-cyclopentene
A mixture of 13.631 g. of the diester of Example 360 and 16 g. of potassium hydroxide in 364 ml. of 1:1 aqueous methanol is refluxed for 5 hours, cooled, concentrated, and is partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, and the organic phase is washed with saturated brine, dried (MgSO.sub.4) and evaporated to yield a solid. The solid is crystallized from diethyl ether petroleum ether (30.degree.-60.degree. C.) to give 10 g. (90%) of white crystals, m.p. 143.degree.-145.degree. C. (--CO.sub.2).
EXAMPLE 362
Preparation of 1-methoximino-2-(6-fluoro-6-carboxyhexyl)-2-cyclopentene
A solution of 10 g. of the diacid of Example 361 in 60 ml. of 2-methoxyethyl ether is refluxed for 7 hours, cooled, and evaporated to yield 8.5 g. (95%) of a tan solid. A sample is crystallized from diethyl ether-petroleum ether (30.degree.-60.degree. C.) to give white crystals, m.p. 98.degree.-100.degree. C.
EXAMPLE 363
Preparation of 2-(6-fluoro-6-carboxyhexyl)cyclopent-2-en-1-one
The acid methoxime (8.5 g.) from Example 362 is refluxed for 5 hours with 180 ml. of acetone and 64 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO.sub.4) and evaporated to yield 7.4 g. (98%) of a light yellow oil.
EXAMPLE 364
Preparation of 2-(6-fluoro-6-carbethoxyhexyl)cyclopent-2-en-1-one
The acid ketone (7.4 g.) from Example 363 is Fisher esterified with 300 ml. of absolute ethanol and 400 mg. of p-toluenesulfonic acid for 18 hours, cooled, and the solvent is evaporated. The resulting oil is dissolved in ether, washed with dilute sodium bicarbonate solution, and saline, dried (MgSO.sub.4) and evaporated to give 7.306 g. (86%) of a light yellow oil.
Example 365
Preparation of 2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene
Treatment of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 359) with sodio diethyl phenylmalonate bu the procedure of Example 35 is productive of the subject compound.
Example 366
Preparation of 2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene
Alkaline hydrolysis of 2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 365) by the procedure of Example 36 is productive of the subject diacid.
Example 367
Preparation of 2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene
Decarboxylation of 2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 366) by the procedure of Example 37 is productive of the subject compound.
EXAMPLE 368
Preparation of 2-(6-carboxy-6-phenylhexyl)-2-cyclopentene-1-one
Methoxime cleavage of 2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 367) in the manner of Example 38 is productive of the subject ketone.
EXAMPLE 369
Preparation of 2-(6-carbethoxy-6-phenylhexyl)-2-cyclopenten-1-on
Fisher esterification of the carboxylic acid of Example 368 in the manner of Example 39 is productive of the subject keto-ester.
EXAMPLE 369A
Preparation of 2-(6-carbethoxyheptyl)-2-cyclopenten-1-one
The subject compound is prepared from 2-(5-tosyloxypentyl)-2-cyclopentenone-1-methoxime (Example 150) by treatment with sodio diethyl methylmalonate (procedure of Example 151), followed by saponification (procedure of Example 152), decarboxylation (procedure of Example 153), methoxime cleavage (procedure of Example 154) and esterification (procedure of Example 155).
EXAMPLES 370 - 403C
Treatment of the listed cyclopentenone with the alanate reagent prepared from diisobutylaluminum hydride, methyl lithium, and the 1-alkyne listed in Table XXIII below, all in the manner of Example 44, furnishes the product prostenoate esters of the Table.
EXAMPLES 404 - 426
Treatment of the ethyl 9-oxo-13-trans-prostenoates listed in Table XXIV below with sodium borohydride in the manner of Example 162 furnishes the product 9.alpha.- and 9.beta.-hydroxy derivatives of the table. The 9.alpha./9.beta. mixture (approximately 1:1) can be separated into 9.alpha.-hydroxy and 9.beta.-hydroxy components by the usual chromatographic procedures.
EXAMPLES 427 - 438C
In the manner described in Example 177 the listed prostenoate esters of Table XXV below are saponified to the corresponding product prostenoic acids of the table. The individual 9.alpha.-hydroxy and 9.beta.-hydroxy prostenoic acids of Examples 461-483C, inclusive, can be separated from each other by chromatographic procedures.
EXAMPLE 484
Preparation of 9.alpha.-hydroxy-13-trans-prostenoic acid
To a solution of 1 g. of 9-oxo-13-trans-prostenoic acid (Example 178) in 5 ml. of tetrahydrofuran, cooled in an ice bath is added, in an atmosphere of nitrogen, 9 ml. of a 0.76 molar solution of lithium perhydro-9b-boraphenalylhydride [Brown et al., J.A.C.S., 92, 709 (1970)] in tetrahydrofuran. After 40 minutes at 0.degree. C., the reaction mixture is treated with 3.6 ml. of 3N sodium hydroxide followed by 3.6 ml. of 30% hydrogen peroxide. After the addition of 50 ml. of ether, the solution is acidified with 2N hydrochloric acid. The ether phase is washed with saturated NaCl solution, dried with anhydrous MgSO.sub.4 and taken to dryness. The material is chromatographed on 50 g. of silica gel. The column is washed with 250 ml. portions of 5% ether-in-benzene, 10% ether-in-benzene, and 15% ether-in-benzene these washings are discarded. Elution with 800 ml. of 20% ether-in-benzene, followed by evaporation of the eluate, gives 665 mg of product as a viscous oil. This material shows one spot on tlc; nmr (COCl.sub.3) .delta. 6.14 (S, 2, -OH and -COOH), 5.40 (m, 2, trans --CH.dbd.CH--), 4.26, 3.90 (m, 1, epimeric > CHOH, 95% trans, 5% cis), 2.35 (t, 2, --CH.sub.2 COOH), 0.90 (distorted t, 3, terminal --CH.sub.3).
EXAMPLE 485
Preparation of dl-9.alpha.-hydroxy-13-trans-prostenoic acid and dl-9.beta.-hydroxy-8-epi-13-trans-prostenoic acid
To a stirred, -78.degree. C., solution of 1M lithium tri(sec-butyl)borohydride, 92.5 ml. (2.2 molar equivalents), in pentane: -tetrahydrofuran (1:1) under nitrogen is added dropwise a solution of 12.58 g. (0.0391 mol) of dl-9-oxo-13-trans-prostenoic acid (Example 178), in 20 ml. of tetrahydrofuran. The reaction mixture is allowed to stir at -78.degree. C. for 40 minutes and then 52 ml. of 2.5N sodium hydroxide is added followed by dropwise addition of 52 ml. of 30% hydrogen peroxide. The dry-ice bath is removed and reaction is allowed to come to room temperature. Diethyl ether (150 ml.) is added and the reaction mixture is acidified with 10% aqueous hydrochloric acid. The organic phase is separated and the aqueous phase re-extracted with ether. The combined ether extract is washed with saline, dried over magnesium sulfate and evaporated to give 13.68 g. of a light yellow oil. The crude material is submitted to dry column chromatography*using 900 g. of Woelm silica gel and is developed with cyclohexane-ethyl acetate-acetic acid (60:40:2) to yield 9.3 (74%) of an oil, which can be crystallized from hexane to give dl-9.alpha.-hydroxy-13-trans-prostenoic acid as white crystals, m.p. 48.degree.-49.degree. C.
The dl-9.beta.-hydroxy-8-epi-13-trans-prostenoic acid is isolated from the above dry column chromatography as an oil and crystallized from hexane to give 318 mg. (2.5%) of white crystals, m.p. 27.degree.-28.degree. C.
Dry column chromatography is performed in the following manner. The crude reaction mixture is dissolved in a minimum amount of dichloromethane and is placed atop 900 g. of Woelm silica gel (activity III) packed in a 87 .times. 2 inch (flat diameter) nylon tube. The column is developed with one column length volume of cyclohexane-ethyl acetate-acetic acid (60:40:2) and is then divided into 1 inch segments. The segments are washed with 25 ml. of ether and tlc [silica gel, solvent system:cyclohexane:ethyl acetate:acetic acid (60:40:2) 3% cupric acetate in 9% phosphoric acid] of the segments is used to locate the products. The segments containing the products are combined and the products are extracted from the silica gel with diethyl ether are then isolated on evaporation of solvent.
dl-9.alpha.-Hydroxy-13-trans-prostenoic acid is found along the column at R.sub.f 0.35 - 0.56 and the dl-9.beta.-hydroxy-8-epi-13-trans-prostenoic acid at R.sub.f 0.65 - 0.67.
EXAMPLES 486 - 519
Reduction of the 9-oxo-prostenoic acids listed in Table XXVI below with lithium (tri-sec-butyl) borohydride in the manner described in Example 485 provides the product 9.alpha.-hydroxy-prostenoic acids of the table. In addition, there is also obtained a lesser amount of the corresponding 9.beta.-hydroxy-8-epi-13-trans-prostenoic acid, separated from the major product by chromatography.
EXAMPLE 520
Ethyl 10-hydroxymethylene-9-oxo-13-trans-prostenoate
A mixture of 25 g. of ethyl 9-oxo-13-trans-prostenoat (Example 44), 25 g. of sodium hydride oil dispersion (57%), 29 ml. of ethyl formate, and 500 ml. of anhydrous benzene is stirred under nitrogen for 18 hours. Excess sodium hydride is destroyed by the addition of methanol. The mixture is extracted three times with water. The combined extracts are acidifed with 4N hydrochloric acid. The oil which separates is extracted with ether, and the ether extract is washed several times with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 26.3 g. (97%) of product. The material gives a positive enol test with alcoholic ferric chloride solution.
EXAMPLE 521
Ethyl 10-anilinomethylene-9-oxo-13-trans-prostenoate
A solution of 1 g. of ethyl 10-hydroxymethylene-9-oxo-13-trans-prostenoate (Example 520) in 75 ml. of absolute ethanol containing 0.270 g. of aniline is kept at ambient temperature, under nitrogen atmosphere for 6 days, then at the reflux temperature for 48 hours. The solution is taken to dryness. A solution of the residue in ether is washed with 1% potassium hydroxide solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness affording 0.881 g. of product as an oil.
EXAMPLE 522
Ethyl 10-cyclohexylaminomethylene-9-oxo-13-trans-prostenoate
A solution of 1 g. of ethyl 10-hydroxymethylene-9-oxo-13-trans-prostenoate (Example 520) in 25 ml. of absolute ethanol, containing 0.290 g. of cyclohexylamine is treated in the manner described in Example 521 to give 0.915 g. of product as an oil.
EXAMPLE 523
Ethyl 9-oxo-10-piperidinomethylene-13-trans-prostenoate
A solution of 1 g. of ethyl 10-hydroxymethylene-9-oxo-13-trans-prostenoate (Example 520) in 25 ml. of absolute ethanol containing 0.250 g. of piperidine was treated in the manner described in Example 521 to give 0.812 g. of product as an oil.
EXAMPLE 524
Ethyl 10-cyano-9-oxo-13-trans-prostenoate
A solution of 3 g. of ethyl 10-hydroxymethylene-9-oxo-13-trans-prostenoate (Example 520) in 100 ml. of anhydrous benzene containing 1.79 g. of O,N-bis(trifluoroacetyl)hydroxylamine and 0.63 ml. of reagent pyridine is refluxed for 2 hours, and then kept at ambient temperature for 18 hours. The solution is taken to dryness. The residue is dissolved in ether and the resulting solution is washed with ice cold 1% potassium hydroxide, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.3 g. of product as an oil.
EXAMPLE 525
Ethyl 9-oxo-10-phenyl-13-trans-prostenoate
To a solution prepared by the interaction of 181 mg. of potassium with 50 ml. of anhydro-t-butanol is added 2 g. of ethyl 10-hydroxymethylene-9-oxo-13-trans-prostenoate (Example 520), followed by the addition of 1.41 g. of diphenyliodonium chloride. The resulting suspension is stirred at the reflux temperature for 24 hours. The solvent is partially removed and the reaction mixture is diluted with water and acidified with concentrated hydrochloric acid. The solution is extracted several times with ether. The sombined extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. The residue is dissolved in 50 ml. of methanol and the solution is treated with 3 ml. of 1N methanolic sodium methoxide at the reflux temperature in an atmosphere of nitrogen for 1 hour. The cooled solution is acidified with glacial acetic acid, flooded with water and the resulting mixture is extracted several times with ether. The combined extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 2.1 g. of product as an oil.
EXAMPLE 526
Ethyl 10-ethoxyalyl-9-oxo-13-trans-prostenoate
To a solution of 1.72 g. of sodium in 260 ml. of absolute ethanol, under nitrogen atmosphere, is added, with ice bath cooling, 11 g. of freshly distilled diethyloxalate in one portion. To the resulting solution is added dropwise at a fast rate, 25 g. of ethyl 9-oxo-13-trans-prostenoate (Example 44). The solution is stirred at 0.degree. C. for an additional 15 minutes, then at ambient temperature for 18 hours. The solution is poured into 800 ml. of water and the resulting solution is extracted with ether. The aqueous phase is acidified with 4N hydrochloric acid and extracted several times with ether. The combined extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 28.8 g. (90%) of product as an oil.
EXAMPLE 527
Ethyl 10-diethylaminomethylene-9-oxo-13-trans-prostenoate
A solution of 3.79 g. of ethyl 10-hydroxy-methylene-9-oxo-13-trans-prostenoate (Example 520) in 75 ml. of absolute ethanol containing 1.14 ml. of diethylamine is heated at the reflux temperature for 18 hours, then taken to dryness. The residue is dissolved in ether and the solution is washed several times with ice cold 1% potassium hydroxide solution; then with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 2.0 g. of product as an oil.
EXAMPLE 528
Ethyl 10-methyl-9-oxo-13-trans-prostenoate
A mixture of 3 g. of ethyl 10-ethoxalyl-9-oxo-13-trans-prostenoate (Example 526) and 2 g. of anhydrous potassium carbonate in 60 ml. of acetone containing 5 ml. of methyl iodide is stirred at ambient temperature in a stoppered flask for 11 days. The solids are filtered. The mother liquor is taken to dryness and the residual oil is dissolved in ether. The solution is washed several times with ice cold 1N potassium hydroxide solution, dried with anhydrous magnesium sulfate and taken to dryness to afford 2.53 g. of product as an oil.
EXAMPLE 529
Ethyl 10-methylthio-9-oxo-13-trans-prostenoate
A solution of 2 g. of ethyl 10-ethoxalyl-9-oxo-13-trans-prostenoate (Example 526) in 25 ml. of glyme is added to a suspension of 196 mg. of sodium hydride (60% dispersion in oil). After about 30 minutes there is added 900 mg. of methyl p-toluenethiosulfonate. The solution is stirred at the reflux temperature under nitrogen atmosphere for 18 hours. The filtered solution is taken to dryness. The residue is dissolved in ether and the solution is washed with 1% potassium hydroxide solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.5 g. of product as an oil.
EXAMPLE 530
Ethyl 10-benzoyloxy-9-oxo-13-trans-prostenoate
To a stirred suspension of 196 mg. of sodium hydride (60% dispersion in oil) in 35 ml. of anhydrous benzene is added a solution of 2 g. of ethyl 10-ethoxalyl-9-oxo-13-trans-prostenoate (Example 526) in 35 ml. of benzene. After about 30 minutes there is added at 0.degree. C., a solution of 1.075 g. of dibenzoylperoxide in 10 ml. of benzene. The solution is allowed to stir at ambient temperature for 7 days. The solution is washed with ice cold 1% potassium hydroxide solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.33 g. of oil. The oil is chromatographed on 30 g. of silica gel. The column is washed with 200 ml. of benzene, 100 ml. of 10% ether-in-benzene, 100 ml. of 50% ether-in-benzene. These washings are discarded. Elution with 200 ml. of ether affords 802 mg. of product as an oil.
EXAMPLE 531
Ethyl 9-pyrrolidyl-9,13-trans-prostadienoate
A solution of 6 g. of ethyl 9-oxo-13-trans-prostenoate (Example 44) in 125 ml. of anhydrous benzene containing 20 mg. of p-toluenesulfonic acid and 2.2 ml. of pyrrolidine is stirred at the reflux temperature for 18 hours. Water is collected by a Dean-Stark apparatus. The solution is taken to dryness, dissolved in ether and filtered for clarification. Evaporation of the solvent affords 5.6 g. of product as an oil.
EXAMPLE 532
Ethyl 10-fluoro-9-oxo-13-trans-prostenoate
Perchloryl fluoride is bubbled into a solution of 3 g. ethyl 9-pyrrolidyl-10,13-trans-prostadienoate (Example 531) in 400 ml. of anhydrous benzene at a fast rate for a period of 4 minutes. The solution is flushed with nitrogen, washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to afford 2.6 g. of product as an oil.
EXAMPLE 533
Ethyl 9-methylene-13-trans-prostenoate
Sodium hydride (830 mg. as 57% oil dispersion) in a 300 ml. 2-necked flask is washed several times with hexane to remove mineral oil. The flask is equipped with a rubber stopple and reflux condenser. Dimethyl sulfoxide (20 ml.) is introduced by means of a syringe and the mixture is stirred in an nitrogen atmosphere at 75.degree.-80.degree. C. for 45 minutes. The resulting solution is cooled in an ice water bath and 7.09 g. of methyltriphenylphosphonium bromide in 10 ml. of hot dimethylsulfoxide is introduced. The resulting brown colored solution is stirred at room temperature for 10 minutes and then there is added 6 g. of ethyl 9-oxo-13-trans-prostenoate (Example 44). The red colored reaction solution is stirred at ambient temperature for 20 hours. The solution is poured into 150 ml. of water. An equal volume of hexane is added and the mixture is filtered from precipitated salts. The hexane layer is separated and the aqueous phase is extracted several times with hexane. The combined hexane extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 3 g. of oily material. Vapor phase chromatography shows the material to contain unreacted ethyl 9-oxo-13-trans-prostenoate which is removed in the following manner. The oily material is allowed to react with 1 g. of semicarbazide hydrochloride and 2 g. of anhydrous sodium acetate in 30 ml. of ethanol containing 7 ml. of water at 100.degree. C. for 10 minutes, then at ambient temperature for 2 hours. The resulting solution is flooded with water and extracted several times with ether. The combined ether extracts are washed with water, dried with anhydrous magnesium sulfate and taken to dryness to afford 3 g. of oily material, which is chromatographe on 90 g. of silica gel. The column is washed with 600 ml. of benzene and this eluate is taken to dryness to give 1.22 g. of product as an oil.
EXAMPLE 534
9-Methylene-13-trans-prostenoic acid
A suspension of 1.2 g. of ethyl 9-methylene-13-trans-prostenoate (Example 533) in 16 ml. of 50% aqueous methanol containing 445 mg. of potassium hydroxide is stirred at 50.degree. C for 4 hours, then at ambient temperature for 18 hours. The resulting solution is acidified with 3N hydrochloric acid and extracted several times with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 950 mg. (84%) of product as an oil.
EXAMPLE 535
9-Oxo-13-trans-prostenoic acid p-nitrophenylhydrazone
A solution of 9-oxo-13-trans-prostenoic acid (Example 178) in 10 ml. of ethanol containing one drop of glacial acetic acid and 500 mg. of p-nitrophenylhydrazine in 10 ml. of absolute ethanol is heated on the steam bath for 5-10 minutes, then allowed to stand at ambient temperature for 18 hours. The solid is collected to give 537 mg. of product, m.p. 108.degree.-109.degree. C (dec).
EXAMPLE 536 - 541
The treatment of 9-oxo-13-trans-prostenoic acid (Example 178) by the procedure of Example 535 with hydroxylamine semicarbazide, thiosemicarbazide and the various listed phenylhydrazines affords the corresponding carbonyl derivatives of the following table.
EXAMPLES 542 - 549
Treatment of the listed 9-oxo-13-trans-prostenoic acids of the table below with hydroxylamine hydrochloride and two equivalents of sodium acetate by the procedure described in Example 535 provides the product oximes of the table.
EXAMPLE 550
Ethyl 9-hydroxy-9-methyl-13-trans-prostenoate
To a Grignard solution prepared from 250 mg. of magnesium and 0.7 ml. of methyl iodide in 15 ml. of ether under nitrogen atmosphere is added dropwise a solution of 3 g. of ethyl 9-oxo-13-trans-prostenoate (Example 44) in 15 ml. of ether, and the resulting pasty solution is stirred for 18 hours. The ethereal layer is washed successively with saturated ammonic chloride solution and water, dried with anhydrous magnesium sulfate and taken to dryness to give 2.9 g. of oily material. Vapor phase chromatography indicated the presence of unreacted starting material. This material was pooled with similar material from other experiments for removal of unreacted starting material in the following manner. Pooled material (12 g.) is dissolved in 100 ml. of absolute ethanol and 25 ml. of water and treated with 4 g. of semicarbazide hydrochloride and 8 g. of sodium acetate at 85.degree.-90.degree. C. for 10 minutes. The resulting solution after standing at ambient temperature for 18 hours is partitioned between water and ether. The combined extracts are washed with water, dried with anhydrous magnesium sulfate and taken to dryness to give 9.6 g. of oily material. The oil is chromatographed on 300 g. of silica gel. Elution with 1200 ml. of 20% ether-in-benzene gives 4.82 g. of product; nmr (COCl.sub.3) .delta. 5.40 (m, 2, trans --CH=CH--), 4.13 (q, 2, -OCH.sub.2 CH.sub.3), 1.28 (t, 3, o CH.sub.2 CH.sub.3) 1.29, 1.16 (s, C.sub.9 epimeric-OH), 0.92 (distorted t, 3, terminal CH.sub.3); nmr (CDCl.sub.3 with tris(dipivalomethanato)europium added) two new singlets at .delta. 4.78 and 4.73 (total of 3 protons, about equally divided), 9-CH.sub.3 epimers.
EXAMPLE 551
9-Hydroxy-9-methyl-13-trans-prostenoic acid
A. To a Grignard solution prepared from 670 mg. (3 mol equivalent) of magnesium and 1.73 ml. of methyl iodide in 10 ml. of ether under nitrogen atmosphere is added dropwise a solution of 3 g. of 9-oxo-13-trans-prostenoic acid (Example 178) in 15 ml. of ether and the resulting pasty solution is stirred at ambient temperature for 30 minutes. Saturated ammonium chloride (50 ml.) is added followed by 15 ml. of water and 50 ml. of ether. The ethereal layer is washed with ammonium chloride solution, water, dried with anhydrous magnesium sulfate and evaporated to give 2.6 g. (83% of 9-hydroxy-9-methyl-13-trans-prostenoic acid; nmr (CDCl.sub.3) .delta. 5.70 (s, 2, OH and COOH), 5.40 (m, 2, trans --CH=CH), 1.29, 1.16 (s, C.sub.9 epimeric-OH), 0.91 (t, 3, terminal-CH.sub.3).
B. Purified ethyl 9-hydroxy-9-methyl-13-trans-prostenoate Example 550 is saponified according to the procedure described in Example 178. There is obtained 1.74 g. (95%) of syrupy product.
EXAMPLE 552
Preparation of ethyl 9-hydroxy-9-phenyl-13-trans-prostenoate
In the manner described above for the preparation of ethyl 9-hydroxy-9-methyl-13-trans-prostenoate (Example 550 ), treatment of 3 g. of ethyl 9-oxo-13-trans-prostenoate (Example 44) with phenylmagnesium bromide, prepared from 1.5 g. of bromobenzene and 230 mg. of magnesium in 25 ml. of ether furnished 3 g. of crude product. Removal of starting ketone by means of its semicarbazone as described above furnishes 1.1 g. (30%) of product; glo of product gave two closely related peaks in the proportion of about 9:1.
EXAMPLE 553
Preparation of 9-hydroxy-9-phenyl-13-trans-prostenoic acid
In the manner described above in Example 178 saponification of 1.1 g. of ester furnishes 815 mg. (79%) of product.
EXAMPLE 554
Preparation of ethyl 9.beta.-hydroxy-8-epi-13-trans-prostenoate
Treatment of 9.beta.-hydroxy-8-epi-13-trans-prostenoic acid (Example 544) with ethanol and p-toluenesulfonic acid, and purification all as described in Example 560 yields the title compound as an oil.
EXAMPLE 555
Preparation of ethyl 9.beta.-mesyloxy-8-epi-13-trans-prostenoate
To a solution of 1.0 g. ethyl 9.beta.-hydroxy-8-epi-13-trans-prostenoate (Example 554) in 5 ml. of dry pyridine cooled to 0.degree. C. is added dropwise 0.344 g. of methanesulfonyl chloride and the mixture is stirred at 0.degree. C. for 2 hours. The mixture is poured onto crushed ice and extracted into ether. The organic phase is washed with cold water and saturated brine, dried (M.sub.g SO.sub.4) and evaporated in vacuo to yield the title compound.
EXAMPLE 556
Preparation of ethyl 9.beta.-acetoxy-8-epi-13-trans-prostenoate
A mixture of 1.1 g. of ethyl 9.beta.-mesyloxy-8-epi-13-trans-prostenoate (Example 555) and 0.970 g. of anhydrous tetraethylammonium acetate in 5 ml. of anhydrous 1:1 hexamethylphosphoramide-acetone is stirred at 65.degree. C. for 2 days and then cooled. The mixture is poured into ice water and is extracted into ether. The organic phase is washed with water and saturated brine, dried (MgSO.sub.4) and evaporated in vacuo. The residue is purified by dry column chromatography upon silica gel using 4:1 benzene-ethyl acetate as eluting solvent to yield the title compound.
EXAMPLE 557
Preparation of 9.alpha.-hydroxy-8-epi-13-trans-prostenoic acid
A mixture of 0.50 g. of ethyl 9.alpha.-acetoxy-8-epi-13-trans-prostenoate (Example 556) and 0.30 g. of potassium hydroxide in 5 ml. of 1:1 aqueous methanol is heated to 75.degree. C. for 24 hours cooled, and partially evaporated in vacuo. The residue is acidified with excess dilute hydrochloric acid and is extracted into ether. The organic phase is washed with water and saturated brine, dried (MgSO.sub.4), and evaporated to yield an oil. The latter is purified by dry column chromatography upon silica gel using 60:40:2 cyclohexane-ethyl acetate-acetic acid to yield the title compound.
EXAMPLE 558
Preparation of dl-9.alpha.-(hydrogenphthaloyloxy)-13-trans-prostenoic acid
A mixture of 1 g. (3.08 mmol) of dl-9.alpha.-hydroxy-13-trans-prostenoic acid (Example 543) 479 mg. (3.04 mmol) of phthalic anhydride in 5 ml. of dry pyridine is stirred under nitrogen, in an oil bath at 110.degree. C. for 3 hours. The still warm solution is then poured onto 10 g. of ice containing 5 ml. conc. hydrochloric acid. The reaction mixture is extracted with diethyl ether and the combined extracts washed with saline, dried over magnesium sulfate and concentrated. The residue is triturated with benzene, the insoluble phthalic acid is filtered and the solvent is evaporated to give 1.395 g. of an oil. The crude product is purified by dry column silica gel chromatography as described in Example 543 to give 1.082 g. of product, Rf 0.27-0.54, as an oil.
EXAMPLE 559
Preparation of (-) bis 1-(-)-.alpha.-phenylethylamine salt of dl-9.alpha.-(hydrogenphthaloyloxy)-13-trans-prostenoic acid and
(+) bis d-(+)-.alpha.-phenylethylamine salt of dl- 9.alpha.-(hydrogenphthalcyloxy)-13-trans-prostenoic acid
To a solution of 895 mg. (1.91 mmols) of dl-9.alpha.-(hydrogenphthaloyloxy)-13-trans-prostenoic acid in 8 ml. of diethyl ether is added a solution of 464 mg. (3.82 mmol) of (-)-.alpha.-phenylethylamine [.alpha.].sub.D.sup.20 -39.degree. (neat), and is stirred for 1 hour. The reaction mixture is concentrated and the residue is dissolved in a minimum amount of ethyl acetate-chloroform (1:1) and allowed to cool in the ice box for 18 hours. The 1 g. of bis salt which separates is recrystallized three times from acetone to constant melting point and rotation to give 238 mg. of salt, m.p. 108.degree.-109.degree. C. [.alpha.].sub.D.sup.25 -58.degree. (CHCl.sub.3, C=1.02). The mother liquors are concentrated and the partially active (+) bis salt is decomposed by treating with water, concentrated hydrochloric acid (2:1) to give 323 mg. of the hydrogenphthalate. In the manner described above the hydrogenphthalate is treated with (+)-.alpha.-phenylethylamine, [.alpha.].sub.D.sup.25 + 39.degree. (neat), to give 279 mg. of bis salt. The salt is recrystallized three times from acetone to give 157 mg. of white crystals, m.p. 108.degree.-109.degree. C., [.alpha.].sub.D.sup.25 = +58.degree. (CHCl.sub.3, C=0.881).
EXAMPLE 560
Preparation of dl-ethyl 9.alpha.-hydroxy-13-trans-prostenoate
A solution of 200 mg. (0.0616 mmol) of dl-9.alpha.-hydroxy-13-trans-prostenoic acid, 5 mg. of p-toluenesulfonic acid monohydrate in 50 ml. of ethanol is heated at reflux for 18 hours. The ethanol is evaporated and the residue is dissolved in ether and the solution is washed with sodium bicarbonate solution, saline, dried over magnesium sulfate and concentrated to give 204 mg. (95%) of an oil IR 3600 cm.sup.-1 (hydroxyl) 1740 cm.sup.-1 (ester carbonyl) 962 cm .sup.-1 (trans-vinyl group).
EXAMPLE 561
Preparation of (-)-9.alpha.-hydroxy-13-trans-prostenoic acid
A mixture of 0.156 g. of potassium hydroxide and 0.215 g. of the bis 1-(-)-.alpha.-methylbenzylamine salt of 9.alpha.-hydrogenphthaloyloxy-13-trans-prostenoic acid (Example 559) in 2.5 ml. of water is heated to 100.degree. C. for 20 hours, cooled, acidified with excess dilute hydrochloric acid, and extracted with ether. The organic phase is washed with water and saturated brine, dried (MgSO.sub.4), and evaporated to an oil. The latter is purified by thick layer chromatography on silica gel using 60:40:2 - cyclohexane-ethyl acetate-acetic acid as eluting solvent to yield the title compound, m.p. 31.degree.-33.degree. (hexane), [.alpha.].sub.D.sup.25 = -48.degree. (+1) (C = 1.24, CHCl.sub.3).
EXAMPLE 562
Preparation of (+)-9.alpha.-hydroxy-13-trans-prostenoic acid
Treatment of the bis d-(+)-.alpha.-methylbenzylamine salt of 9.alpha.-hydrogenphthaloyloxy-13-trans-prostenoic acid (Example 560) with potassium hydroxide in water and purification all as described in the preceding Example 561 yields the title compound, m.p. 33-34.degree. (hexane), [.alpha.].sub.D.sup.25 +=46.degree. (.+-.1) (C = 1.395, CHCl.sub.3).
EXAMPLE 563
Preparation of (+)-9-oxo-13-trans-prostenoic acid
To a solution of 0.100 g. of (-)-9.alpha.-hydroxy-13-trans-prostenoic acid in 2 ml. of distilled acetone at 0.degree.C. is added dropwise standard Jones reagent [K. Bowden, I. M. Heilbron, E. R. H. Jones, and B. C. L. Weedon, J. Chem. Soc., 39 (1946) ] until a slight excess is obtained. The mixture is hand swirled for 2 minutes and is then treated dropwise with isopropanol to destroy the excees oxidant. The reaction mixture is diluted with water and extracted into methylene chloride. The organic phase is washed with water and saturated brine, dried (MgSO.sub.4) and evaporated to an oil. The latter is purified by thick layer chromatography upon silica gel using 60:40:2 - cyclohexane-ethyl acetate-acetic acid to yield the title compound as an oil, [.alpha.].sub.D.sup.25 =+55.degree. (.+-.1) (C = 0.991, CHCl.sub.3).
EXAMPLE 564
Preparation of (-)-9-oxo-13-trans-prostenoic acid
Treatment of (+)-9.alpha.-hydroxyprostenoic acid in acetone with Jones reagent and purification all as described in the preceding Example 563 yields the title compound as an oil, [.alpha.].sub.D.sup.25 = -51.degree. (.+-.1) (C = 1.11, CHCl.sub.3).
EXAMPLE 565
Preparation of (+)-ethyl 9.alpha.-((-).alpha.-methoxy-.alpha.-trifluoromethylphenylacetoxy)-13-tran s-prostenoate and (-)-ethyl 9.alpha.-((-).alpha.-methoxy-.alpha.-trifluoromethylphenylacetoxy)-13-tran s-prostenoate (-)-9.alpha.-hydroxy-13-trans-prostenoic acid and (+)-9.alpha.-hydroxy-13-trans-prostenoic acid
To a stirred solution of 234 mg. (0.683 mmol) of dl-ethyl 9.alpha.-hydroxy-13-trans-prostenoate (Example 560) in 1.5 ml. of dry pyridine, under nitrogen, is slowly added 217 mg. (0.860 mmol) of (-) (.alpha.-methoxy-.alpha.-trifluoromethylphenylacetyl chloride [J. A. Dale, D. L. Drill and H. S. Mosher, J. Org. Chem., 34 2543 (1969)] and is allowed to stir at room temperature for 2 hours. The pyridine is removed in vacuo and the residue is partitioned between water and diethyl ether. The organic phase is washed with dilute hydrochloric acid, sodium bicarbonate solution, saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 188 mg. of dl-ethyl 9.alpha.-((-).alpha.-methoxy-.alpha.-trifluoromethylphenylacetoxy)-13-tran s-prostenoate as a colorless oil, b.p. 180.degree.-190.degree. C. (bath temperature) at 0.8 torr. The latter is separated by thick layer chromatography on silica gel using 1-chlorobutane as eluting solvent and 3 developments to yield (-)-ethyl 9.alpha.-((-).alpha. -methoxy-.alpha.-trifluoromethylphenylacetoxy)-13-trans-prostenoate as the more mobile diastereoisomer, [.alpha.].sub.D.sup.25 = 19.degree. (C = 1.0, CHCl.sub.3) and (+)-ethyl 9.alpha.-((-).alpha.-methoxy-.alpha.-trifluoromethylphenylacetoxy)-13-tran s-prostenoate as the less mobile diastereoisomer [.alpha.].sub.D.sup.25 = +3.degree. (C = 1.51, CHCl.sub.3).
Each diastereoisomeric ethyl 9.alpha.-((-).alpha.-methoxy-.alpha.-trifluoromethylphenylacetoxy)-13-tran s-prostenoate is saponified to its corresponding enantiomeric 9.alpha.-hydroxy-13-trans-prostenoic acid by refluxing 100 mg. of the diastereoisomer with 300 mg. of potassium hydroxide in 1:1 aqueous methanol for 24 hours, cooling, partially evaporating the solvent in vacuo, acidifying with dilute hydrochloric acid, extracting into ether, washing the organic phase with water and saturated brine, drying with MgSO.sub.4, and evaporating. The residue is purified by thick layer chromatography upon silica gel using 60:40:2 cyclohexane-ethyl acetate-acetic acid as eluting solvent to yield the desired enantiomeric 9.alpha.-hydroxy-13-trans-prostenoic acid.
EXAMPLE 566
Preparation of (+)-ethyl 9.alpha.-((+)-1-phenylethylcarbamoyl)-13-trans-prostenoate and (-)-ethyl 9.alpha.-((+)-1-phenylethylcarbamoyl)-13-trans-prostenoate (-)-9.alpha.-hydroxy-13-trans-prostenoic acid and (+)-9.alpha.-hydroxy-13-trans-prostenoic acid
Each diastereoisomeric ethyl 9.alpha.-((+)-1-phenylethylcarbamoyl)-13-trans-prostenoate is saponified to its corresponding enantiomeric 9.alpha.-hydroxy-13-trans-prostenoic acid by refluxing 100 mg. of the diastereoisomer with 300 mg. of potassium hydroxide in 1:1 aqueous methanol for 24 hours, cooling, partially evaporating the solvent in vacuo, acidifying with dilute hydrochloric acid, extracting into ether, washing the organic phase with water and saturated brine, drying with MgSO.sub.4, and evaporating. The residue is purified by thick layer chromatography upon silica gel using 60:40:2 cyclohexaneethyl acetate-acetic acid as eluting solvent to yield the desired enantiomeric 9.alpha.-hydroxy-13-trans-prostenoic acid.
EXAMPLE 567
Preparation of (+)-ethyl 9-(L-1-carboxy-1-isobutylmethoxyimino)-13-trans-prostenoate and (-)-ethyl 9-(L-1-carboxy-1-isobutylmethoxyimino)-13-trans-prostenoate (-)-ethyl-9-oxo-13-transprostenoate, and (+)-ethyl-9-oxo-13-trans-prostenoate
A mixture of 0.460 g. of (+)-ethyl 9-oxo-13-trans-prostenoate, 0.300 g. of L-1-carboxy-1-isobutylmethoxime hydrochloride [E. Testa, B. J. R. Nicolaus, L. Mariani, and G. Pagani, Helv. Chim. Acta, 47 766 (1963)], and 0.7 ml. of pyridine in 10 ml. of methanol is stirred at room temperature for 4 hours and then evaporated in vacuo. The residue is partitioned between water and ether. The organic phase is washed with water and saturated brine, dried (MgSO.sub.4), and evaporated. The residue is subjected to dry column chromatography upon silica gel to afford the title oximes.
Each diastereoisomeric ethyl 9-(L-1-carboxy-1-isobutylmethoximino)-13-trans-protenoate is hydrolyzed to its corresponding enantiomeric ethyl 9-oxo-13-trans-prostenoate by treating 0.100 g. of the diastereoisomeric alkoxime with 0.200 g. of ammonium acetate in 5 ml. of 1:2 aqueous tetrahydrofuran and 0.069 g. of titanium trichloride at 60.degree. C. for 4 hours under an inert atmosphere. The resulting mixture is partitioned between water and ether, and the organic phase is washed with water and saturated brine, dried (MgSO.sub.4), and evaporated. The residue is purified by thick layer chromatography on silica gel using 4:1 benzene-ethyl acetate to yield the enantiomeric ethyl 9-oxo-13-trans-prostenoate as an oil.
Claims
We claim:
1. An optically active compound of the formula: ##STR27## wherein n is the integer 1 or 2; Y is a divalent radical selected from the group consisting of those of the formulae: ##STR28## R.sub.1 is selected from the group consisting of a straight chain alkyl group having from 3 to 10 carbon atoms, a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched methyl group, a straight chain alkenyl group having from 3 to 6 carbon atoms, a straight chain .omega.-haloalkyl group having from 3 to 6 carbon atoms, a straight chain .omega.-mercaptoalkyl group having from 3 to 6 carbon atoms, a straight chain .omega.-carboxyalkyl group having from 3 to 6 carbon atoms, and moieties of the formulae: ##STR29## wherein p is an integer from 2 to 4, inclusive, q is an integer from 3 to 6, inclusive, R.sub.3 is an alkyl group having from 1 to 3 carbon atoms, R.sub.4 is selected from the group consisting of hydrogen and lower alkyl, R.sub.5 is selected from the group consisting of hydrogen and lower alkyl, and R.sub.4 and R.sub.5 taken together with the N(itrogen) is selected from the group consisting of pyrrolidino, piperidino and morpholino; R.sub.2 is selected from the group consisting of hydroxy, alkoxy having from 1 to 4 carbon atoms, pyridoxy, 2,2,2-trichloroethoxy, and a moiety of the formula: ##STR30## wherein P, R.sub.4 and R.sub.5 are as hereinabove defined; and Z is a divalent radical selected from the group consisting of those of the formulae: ##STR31## wherein m is an integer from 1 to 8, inclusive, and p, q and R.sub.3 are as hereinabove defined; and the pharmaceutically acceptable cationic salts thereof when R.sub.1 is an .omega.-carboxyalkyl group or when R.sub.2 is hydroxy.
2. The compound according to claim 1 wherein n is 1, Y is ##STR32## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 1-9-oxo-13-trans-prostenoic acid.
3. The compound according to claim 1 wherein n is 1, Y is ##STR33## R.sub.1 is n-hexyl, R.sub.2 is .gamma.-dimethylaminopropyloxy, and Z is --(CH.sub.2).sub.6 --; l-3-dimethylaminopropyl 9-oxo-13-trans-prostenoate.
4. The compound according to claim 1 wherein n is 1, Y is ##STR34## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.3 --; l-9-oxo-5-cis-13-trans-prostadienoic acid.
5. The compound according to claim 1 wherein n is 1, Y is ##STR35## R.sub.1 is 6-chlorohexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-20-chloro-13-trans-prostenoic acid.
6. The compound according to claim 1 wherein n is 1, Y is ##STR36## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; l-9-oxa-13-trans-prostenoic acid.
7. The compound according to claim 1 wherein n is 1, Y is ##STR37## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.4 --S--CH.sub.2 --; l--9-oxo-3-thia-13-trans-prostenoic acid.
8. The compound according to claim 1 wherein n is 1, Y is ##STR38## R.sub.1 is --(CH.sub.2).sub.3 --S--CH.sub.2 CH.sub.3, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 ; l-9-oxo-18-thia-13-trans-prostenoic acid.
9. The compound according to claim 1 wherein n is 1, Y is ##STR39## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.4 --C(CH.sub.3).sub.2 --CH.sub.2 ; l-9-oxo-3,3-dimethyl-13-trans-prostenoic acid.
10. The compound according to claim 1 wherein n is 1, Y is ##STR40## R.sub.1 is 3-cis-hexenyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-17-cis-13-trans-prostadienoic acid.
11. The compound according to claim 1 wherein n is 1, Y is ##STR41## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2 ).sub.6 --; l-9.alpha.-hydroxy-13-trans-prostenoic acid.
12. The compound according to claim 1 wherein n is 1, Y is ##STR42## R.sub.1 is n-hexyl, R.sub.2 is .gamma.-diethylaminopropyloxy, and Z is --(CH.sub.2).sub.6 --; l-3-diethylaminopropyl 9.alpha.-hydroxy-13-trans-prostenoate.
13. The compound according to claim 1 wherein n is 1, Y is ##STR43## R.sub.1 is 3-chloropropyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9.alpha.-hydroxy-20-chloro-17,18,19-trinor-13-transprostenoic acid.
14. The compound according to claim 1 where n is 2, Y is ##STR44## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --;1-9-oxo-10a-homo-13-trans-prostenoic acid.
15. The compound according to claim 1 wherein n is 2, Y is ##STR45## R.sub.1 is n-hexyl, R.sub.2 is ethoxy, and Z is --(CH.sub.2).sub.6 --; l-ethyl 9-oxo-10a-homo-13-trans-prostenoate.
16. The compound according to claim 1 wherein n is 2, Y is ##STR46## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is -(CH.sub.2).sub.6 -; l-9.alpha.-hydroxy-10a-homo-13-trans-prostenoic acid.
17. A racemic compound consisting of an optically active compound of the formula: ##STR47## and the mirror image thereof wherein n is the integer 1 or 2; Y is a divalent radical selected from the group consisting of those of the formulae: ##STR48## R.sub.1 is selected from the group consisting of a straight chain alkyl group having from 3 to 10 carbon atoms, a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched methyl group, a straight chain alkenyl group having from 3 to 6 carbon atoms, a straight chain .omega.-haloalkyl group having from 3 to 6 carbon atoms, a straight chain .omega.-mercaptoalkyl group having from 3 to 6 carbon atoms, a straight chain .omega.-carboxyalkyl group having from 3 to 6 carbon atoms, and moieties of the formulae: ##STR49## wherein p is an integer from 2 to 4, inclusive, q is an integer from 3 to 6, inclusive, R.sub.3 is an alkyl group having from 1 to 3 carbon atoms, R.sub.4 is selected from the group consisting of hydrogen and lower alkyl, R.sub.5 is selected from the group consisting of hydrogen and lower alkyl, and R.sub.4 and R.sub.5 taken together with the N(itrogen) is selected from the group consisting of pyrrolidino, piperidino and morpholino; R.sub.2 is selected from the group consisting of hydroxy, alkoxy having from 1 to 4 carbon atoms, pyridoxy, 2,2,2-trichloroethoxy, and a moiety of the formula: ##STR50## wherein p, R.sub.4 and R.sub.5 are as hereinabove defined; and Z is a divalent radical selected from the group consisting of those of the formulae: ##STR51## wherein m is an integer from 1 to 8, inclusive, and p, q and R.sub.3 are as hereinabove defined; and the pharmaceutically acceptable cationic salts thereof when R.sub.1 is an .omega.-carboxyalkyl group or when R.sub.2 is hydroxy.
18. The compound according to claim 17 wherein n is 1, Y is ##STR52## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-13-trans-prostenoic acid.
19. The compound according to claim 17 wherein n is 1, Y is ##STR53## R.sub.1 is n-hexyl, R.sub.2 is .gamma.-dimethylaminopropyloxy, and Z is --(CH.sub.2).sub.6 --; dl-3-dimethylaminopropyl 9-oxo-13-trans-prostenoate.
20. The compound according to claim 17 wherein n is 1, Y is ##STR54## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.3 -; dl-9-oxo-5-cis-13-trans-prostadienoic acid.
21. The compound according to claim 17 wherein n is 1, Y is ##STR55## R.sub.1 is 6-chlorohexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-20-chloro-13-trans-prostenoic acid.
22. The compound according to claim 17 wherein n is 1, Y is ##STR56## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; dl-9-oxo-3-oxa-13-trans-prostenoic acid.
23. The compound according to claim 17 wherein n is 1, Y is ##STR57## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.4 --S--CH.sub.2 --; dl-9-oxo-3-thia-13-trans-prostenoic acid.
24. The compound according to claim 17 wherein n is 1, Y is ##STR58## R.sub.1 is --(CH.sub.2).sub.3 --S--CH.sub.2 CH.sub.3, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 ; dl-9-oxo-13-thia-18-trans prostenoic acid.
25. The compound according to claim 17 wherein n is 1, Y is ##STR59## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.4 --C(CH.sub.2 --CH.sub.3 --;dl-9-oxo-3,3-dimethyl-13-trans-prostenoic acid.
26. The compound according to claim 17 wherein n is 1, Y is ##STR60## R.sub.1 is 3-cis-hexenyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-17-cis-13-trans-prostadienoic acid.
27. The compound according to claim 17 wherein n is 1, Y is ##STR61## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9.alpha.-hydroxy-13-trans-prostenoic acid.
28. The compound according to claim 17 wherein n is 1, Y is ##STR62## R.sub.1 is n-hexyl, R.sub.2 is .gamma.-diethylaminopropyloxy, and Z is --(CH.sub.2) .sub.6 --; dl-3-diethylaminopropyl 9.alpha.-hydroxy-13-trans-prostenoate.
29. The compound according to claim 17 wherein n is 1, Y is ##STR63## R.sub.1 is 3-chloroproyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9.alpha.-hydroxy-20-chloro-17,18,19-trinor-13-trans-prostenoic acid.
30. The compound according to claim 17 wherein n is 2, Y is ##STR64## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-10.alpha.-homo-13-trans-prostenoic acid.
31. The compound according to claim 17 wherein n is 2, Y is ##STR65## R.sub.1 is n-hexyl, R.sub.2 is ethoxy, and Z is --(CH.sub.2).sub.6 --; dl-ethyl 9-oxo-10a-homo-13-trans-prostenoate.
32. The compound according to claim 17 wherein n is 2, Y is ##STR66## R.sub.1 is n-hexyl, R.sub.2 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9.alpha.-hydroxy-10a-homo-13-trans-prostenoic acid.
33. The compound l-9-oxo-2-ethyl-13-trans-prostenoic acid.
34. The compound dl-9-oxo-2-ethyl-13-trans-prostenoic acid.
Patent Citations (1)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| DT2,234,706 | 1973-02-01 |
Non-Patent Literature (2)
- Sih et al. Tet. Letters, 2435 (1978).
- Bernady et al. Tet. Letters, 4083 (1972).