US 3,959,475 AGrant
Substituted 1,3-Dihydrospiro(isobenzofuran)s
Issue Date:1976-05-25
•48 Claims
•1 Drawing Sheets
Abstract
Novel substituted 1,3-dihydrospiro[isobenzofuran]s and methods of preparing the same are described. These compounds are useful as antidepressants, tranquilizers, analgetic agents and intermediates therefor.
Metadata
Assignee
- American Hoechst Corporation
Inventors
- Victor J. Bauer
- Raymond W. Kosley, Jr.
Application Information
Application Number:US 5026504
Filing Date:1974-09-03
Priority Date:1973-12-12
Art Unit:121
Classifications
IPC:
C07D49110
Field of Search:
260424293.58;326.24;326.5 D;346.2 R267;274;285
Patent Drawings (1 sheets)
Description
The invention is further illustrated by the following examples. Temperatures are given in degrees C.
EXAMPLE 1
1,3-Dihydro-3-hydroxy-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine
a. A mixture of 400 g. of o-bromobenzoic acid, 230 g. of thionyl chloride, and 1 ml. of dimethylformamide is heated slowly to reflux, and then for one hour under reflux. The excess thionyl chloride is distilled under reduced pressure, and the residue is dissolved in 1 l. of dichloromethane. The resulting solution is added dropwise with stirring to a solution of 520 g. of 2-amino-2-methylpropanol in 1 l. of dichloromethane cooled to 0.degree., and the mixture is stirred for 2 hours at 0.degree. and filtered. The solid is air dried, stirred for 1 hour in 2 l. of warm water, filtered, washed liberally with water, and air dried to an off-white solid, 2-bromo-N-(1-hydroxy-2-methyl-2-propyl)benzamide, m.p. 142.degree.-145.degree..
b. 254 g. of 2-bromo-N-(1-hydroxy-2-methyl-2-propyl)benzamide are added to 200 ml. of cold (0.degree.) stirred thionyl chloride in the course of 15 minutes. The solution is stirred at 0.degree. for 1/2 hour and at room temperature for 12 hours, and is then poured into 1.5 l. of ether. The solid which separates is collected, washed with ether, dried, and then added at 0.degree. to 1 l. of 20% aqueous sodium hydroxide. The mixture is extracted with ether, and the ether solution is dried over potassium carbonate and concentrated to an oil. Crystallization from hexane provides colorless crystals, m.p. 39.degree.-40.degree., of 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline.
c. A Grignard reagent is prepared by the dropwise addition of a solution of 53.3 g. of 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline and 500 ml. of anhydrous tetrahydrofuran to a refluxing stirred mixture of 6.2 g. of magnesium shavings and 100 ml. of tetrahydrofuran. Initiation with iodine crystals is sometimes required. After addition, the mixture is heated under reflux for 2 hours. Then, a solution of 25 ml. of 1-methyl-4-piperidone in 25 ml. of tetrahydrofuran is added dropwise, and the solution is heated under reflux for 2 hours and allowed to cool to room temperature. Approximately 25 ml. of saturated aqueous ammonium chloride is added, the mixture is filtered, and the solid is washed with benzene. The combined organic solution is washed with water and saturated aqueous sodium chloride, dried over potassium carbonate, and concentrated to an oil. Crystallization from ethanol gives colorless crystals, m.p. 162.degree.-163.degree., of 4-[2-(4,4-dimethyl-2-oxazolin-2-yl)-phenyl]-4-hydroxy-1-methylpiperidine.
d. A solution of 6.0 g. of 4-[2-(4,4-dimethyl-2-oxazolin-2-yl)phenyl]-4-hydroxy-1-methylpiperidine and 70 ml. of 3N hydrochloric acid is heated under reflux for 3 hours, cooled to 0.degree., and made basic with sodium hydroxide. The mixture is extracted with chloroform, and the chloroform solution is dried over potassium carbonate and concentrated to a solid. Recrystallization from benzene provides colorless crystals, m.p. 147.degree.-148.degree., of 1,3-dihydro-1'-methylspiro[isobenzofuran-1,4'-piperidine]-3-one.
e. A solution of 2.20 g. of 1,3-dihydro-1'-methylspiro[isobenzofuran-1,4'-piperidine]-3-one in 60 ml. of dry tetrahydrofuran is added dropwise in the course of 15 minutes to 12 ml. of cold stirred 2M phenyllithium in benzene-ether. The solution is stirred at 0.degree. for 1 hour and at room temperature for 1 hour, diluted with water, and extracted with benzene. The benzene solution is dried over anhydrous potassium carbonate and concentrated to an oil. Trituration with ether followed by recrystallization from ethanol gives colorless crystals, m.p. 182.degree.-183.degree..
Analysis: Calc. for C.sub.19 H.sub.21 NO.sub.2 : C 77.62%; H 7.17%; N 4.74%; Found : C 77.45%; H 7.34%; N 4.84%.
EXAMPLE 2
1,3-Dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine]
A solution of 8.5 g. of 1,3-dihydro-3-hydroxy-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidin e], Example 1, in 150 ml. of tetrahydrofuran is added dropwise in 30 minutes to a stirred suspension of 2.0 g. of lithium aluminum hydride in 150 ml. of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes and at 50.degree. for 1 hour, cooled, diluted cautiously with water, and extracted with chloroform. The chloroform solution is dried over potassium carbonate and concentrated to a solid. Recrystallization from benzene gives colorless crystals, m.p. 190.degree.-191.degree. of 4-hydroxy-4-(.alpha.-hydroxy-.alpha.-phenyl-2-tolyl)-1-methylpiperidine.
A solution of 4.4 g. of 4-hydroxy-(.alpha.-hydroxy-.alpha. -phenyl-2-tolyl)-1-methylpiperidine, 30 ml. of glacial acetic acid, and 7.5 ml. of conc. hydrochloric acid is heated under reflux for 10 minutes, cooled to 0.degree., diluted with water, made basic with sodium hydroxide, and extracted with chloroform. The chloroform solution is dried over potassium carbonate and concentrated to a solid. Recrystallization from hexane gives colorless crystals, m.p. 123.degree.-124.degree., of 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], (hydrochloride salt, m.p. 255.degree.).
Analysis: Calc. for C.sub.19 H.sub.21 NO: C 81.68%; H 7.58%; N 5.01%; Found : C 81.73%; H 7.65%; N 5.02%.
EXAMPLES 3-22
In the following odd and even numbered examples, the procedures are the same as in Examples 1 and 2, respectively. The compositions and structures of the starting materials I and IV, of the intermediates II, III, V, VI and VIII, and of the final products VII (odd numbered examples) and IX (even numbered examples) are indicated in Table I and shown in Formulae I-IX of the attached drawing.
EXAMPLE 23
1,3-Dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine]
To a cold (20.degree.) stirred solution of 30 g. of 0-bromobenzyhydrol, 85 ml. of anhydrous tetrahydrofuran, and 21 ml. of hexane is added during 1.25 hours 131 ml. of 2.0 M n-butyllithium in hexane. After 3 hours, a solution of 14.8 g. of 1-methyl-4-piperidone in 50 ml. of tetrahydrofuran is added in the course of 10 minutes at -15.degree.. The mixture is stirred at -15.degree. for 2 hours and at room temperature for 15 hours and then treated with saturated aqueous ammonium chloride. The layers are separated, and the solid which precipitates in the organic phase is collected. Recrystallization from toluene provides colorless crystals, m.p. 190.degree.-191.degree., of 4-hydroxy-4-(.alpha.-hydroxy-.alpha.-phenyl-2-tolyl)-1-methylpiperidine.
A solution of 89 g. of 4-hydroxy-4-(.alpha.-hydroxy-.alpha.-phenyl-2-tolyl)-1-methylpiperidine and 400 ml. of 88% formic acid is heated under reflux for 2 hours, cooled, diluted with water, made basic with sodium hydroxide, and extracted with chloroform. The chloroform solution is dried over magnesium sulfate, and concentrated to a solid. Recrystallization from hexane gives colorless crystals, m.p. 123.degree.-124.degree., of 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine].
EXAMPLES 24-43
The compositions and structures of the compounds XII of Example 23 and of the compounds XII of Examples 24 to 43 prepared in the same manner, as well as the compositions and structures of the starting materials X and of the intermediates XI are indicated in Table II and shown in the attached drawing:
TABLE II - STARTING MATERIALS
Friedel-Crafts acylation of m-bromoanisole with benzoyl chloride and p-fluorobenzoyl chloride provides 2-bromo-4-methoxybenzophenone, m.p. 83.degree.-84.degree., and 2-bromo-4'-fluoro-4-methoxybenzophenone, m.p. 79.degree.-81.degree., respectively, which are reduced with sodium borohydride to 2-bromo-4-methoxybenzhydrol, b.p. 160.degree. (0.05 mm.), and 2-bromo-4'-fluoro-4-methoxybenzhydrol, a liquid. Acylation of benzene with 2-bromo-5-chlorobenzoyl chloride, 2-bromo-4,5-methylene dioxybenzoyl chloride, and 2-bromo-4,5-dimethoxybenzoyl chloride provides 2-bromo-5-chlorobenzophenone, 2-bromo-4,5-methylene-dioxybenzophenone, and 2-bromo-4,5-dimethoxybenzophenone, m.p. 76.degree.-77.degree., which are reduced with sodium borohydride to 2-bromo-5-chlorobenzhydrol, 2-bromo-4,5-methylenedioxybenzhydrol, and 2-bromo-4,5dimethoxybenzhydrol, m.p. 83.degree.-85.degree.. Acylation of anisole with 2-bromobenzoyl chloride provides 2-bromo-4'-methoxybenzophenone, m.p. 93.degree.-95.degree., which is reduced to 2-bromo-4'-methoxybenzhydrol, m.p. 64.degree.-65.degree.. Reaction of 2-bromo-4-methylbenzaldehyde and phenylmagnesium bromide provides 2-bromo-4-methylbenzhydrol.
Addition of o-tolymagnesium bromide, p-chlorophenyl-magnesium bromide, p-trifluoromethylphenylmagnesium bromide, 3,4-methylenedioxyphenyllithium, 3,4-dimethoxyphenyllithium, p-tolylmagnesium bromide, m-fluorophenylmagnesium bromide, and p-fluorophenylmagnesium bromide to 2-bromobenzaldehyde provide, respectively, 2-bromo-2'-methylbenzhydrol; 2-bromo-4'-chlorobenzhydrol; 2-bromo-4'-trifluoromethylbenzhydrol, b.p. 125.degree. (0.2 mm.), 2-bromo-3',4'-methylenedioxybenzhydrol; 2-bromo-3',4'-dimethyoxybenzhydrol; 2-bromo-4'-methylbenzhydrol, b.p. 145.degree. (0.25 mm.); 2-bromo-3'-fluorobenzhydrol; 2-bromo-4'-fluorobenzhydrol, m.p. 77.degree.-79.degree.. Also the addition of p-fluorophenylmagnesium bromide to 2-bromo-4-fluorobenzaldehyde provides 2-bromo-4,4'-difluorobenzhydrol, m.p. 78.degree.-80.degree.. The 2-bromo-4-fluorobenzaldehyde is prepared by chromium trioxide oxidation of 2-bromo-4-fluorotoluene followed by hydrolysis of the intermediate acetal diacetate.
Friedel-Crafts acylation of 3-bromofluorobenzene with benzoyl chloride or p-fluorobenzoyl chloride provide, respectively, 2-bromo-4-fluorobenzophenone, b.p. 111.degree.-114.degree. (0.05 mm.), and 2-bromo-4,4'-difluorobenzophenone. These are reduced to 2-bromo-4-fluorobenzhydrol and 2-bromo-4,4'-difluorobenzhydrol, m.p. 78.degree.-80.degree..
Addition of methyllithium to 2-bromobenzophenone provides 2-bromophenyl methyl phenyl carbinol. Addition of methyl magnesium iodide to methyl o-bromobenzoate provides 2-bromophenyl dimethyl carbinol.
EXAMPLE 44 1,3-Dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine]
A solution of 152 g. of 2-bromobenzhydrol, 1 liter of methanol, and 45 ml. of conc. hydrochloric acid is heated under reflux for 24 hours, cooled, stirred with 100 g. of potassium carbonate, filtered, and distilled to provide 2-bromobenzhydryl methyl ether, b.p. 126.degree.-128.degree. (0.7 mm.).
To a cold (-60.degree.) stirred solution of 2-bromobenzhydryl methyl ether in 38 ml. of tetrahydrofuran and 14 ml. of hexane is slowly added 53 ml. of 2.1 M n-butyllithium in hexane. After 2 hours, a solution of 10.7 g. of 1-methyl-4-piperidone in 15 ml. of tetrahydrofuran is added dropwise, and the suspension is stirred at -60.degree. for 3 hours and at room temperature for 15 hours. Ice and water are added and the mixture is extracted with chloroform. The chloroform solution is dried over sodium sulfate and concentrated to a mixture of 4-hydroxy-4-(.alpha.-methoxy-.alpha.-phenyl-2-tolyl)-1-methylpiperidine and benzhydrol methyl ether. This oil is heated under reflux for 30 minutes if 240 ml. of acetic acid containing 60 ml. of hydrochloric acid. Dilution with water and addition of excess sodium hydroxide effects precipitation of a solid. Recrystallization from hexane provides 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], m.p. 123.degree.-124.degree..
EXAMPLE 45 1'-Benzyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,3'-pyrrolidine]
By following the manipulative procedure described above in Example 44, substituting N-benzyl-3-pyrrolidone for 1-methyl-4-piperidone gives a pale yellow oil which crystallizes on standing to give rhombic crystals, m.p. 85.degree.-87.degree., from low boiling petroleum ether.
Analysis: Calc. for C.sub.24 H.sub.23 NO: C 84.41%; H 6.78%; N 4.10%; Found : C 84.15%; H 6.91%; N 4.13%.
EXAMPLE 46
1'-Benzyl-1,3-dihydro-3-p-tolyspiro[isobenzofuran-1,4'-piperidine]
A. 2-Bromo-4'-methylbenzhydrol is treated according to the manipulative procedure described above in Example 44 to give 2-bromo-4'-methylbenzhydryl methyl ether, b.p. 125.degree. (0.25 mm.). B. By following the manipulative procedure described above in Example 45, 2-bromo-4'-methylbenzhydryl methyl ether and 1-benzyl-4-piperidone are reacted to produce a white powder, m.p. 98.degree.-99.degree., from isopropanol.
Analysis: Calc. for C.sub.26 H.sub.27 NO: C 84.51% H 7.37%; N 3.79%; Found : C 84.72%; H 7.50%; N 3.79%.
EXAMPLE 47
1'-Benzyl-1,3-dihydro-3-p-fluorophenyl-6-methoxyspiro[isobenzofuran-1,4'-pi peridine]
A. 2-Bromo-4'-fluoro-4 -methoxybenzhydrol is treated according to the manipulative procedure described above in Example 44 to give 2-bromo-4'-fluoro-4-methoxybenahydryl methyl ether as an oil.
B. By following the manipulative procedure described above in Example 45, 2-bromo-4'-fluoro-4-methoxybenzhydryl methyl ether and 1-benzyl-4-piperidone are reacted to produce a white solid, m.p. 86.degree.-88.degree., form heptane.
Analysis: Calc. for C.sub.26 H.sub.26 FNO.sub.2 : C 77.39%; H 6.50%; N 3.47%; Found : C 76.84%; H 6.54%; N 3.46%.
EXAMPLE 48
1'-Benzyl-1,3-dihydro-6-fluoro-3-p-fluorophenylspiro[isobenzofuran-1,4'-pip eridine]
A. 2-Bromo-4,4'-difluorobenzyhydrol is treated according to the manipulative procedure described above in Example 44, to give 2-bromo-4,4'-difluorobenzhydryl methyl ether, b.p. 105.degree. (0.05 mm.).
B. By following the manipulative procedure described above in Example 45, 2-bromo-4,4'-difluorobenzhydryl methyl ether and 1-benzyl-4-piperidone are reacted to produce an oil.
EXAMPLE 49
1,3-Dihydro-1'-ethoxycarbonyl-3-phenylspiro[isobenzofuran1,4'-piperidine]
A solution of 7.7 g. of 1'-benzyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 4), 40 ml. of benzene and 2.5 ml. of ethyl chloroformate is heated under reflux for 18 hours and concentrated to a solid. Recrystallization from cyclohexane provides colorless crystals, m.p. 115.degree.-119.degree..
Analysis: Calc. for C.sub.21 H.sub.23 NO.sub.3 : C 74.75%; H 6.87%; N 4.15%; Found : C 74.55%; H 7.00%; N 4.06%.
The compositions and structures of the compounds IX of Examples 50 through 64, tabulated below, are prepared in an analogous manner.
EXAMPLE 65
1,3-Dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine]
A. A solution of 6.3 g. of 1,3-dihydro-1'-ethoxycarbonyl-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 49), 300 ml. of ethanol, and 240 ml. of 20% aqueous potassium hydroxide is heated under reflux for 9 hours, cooled, concentrated to 250 ml., diluted with water, and extracted with chloroform. The chloroform solution is dried over potassium carbonate and concentrated. The residue is recrystallized from cyclohexane to provide colorless crystals, m.p. 119.degree.-123.degree..
Analysis: Calc. for C.sub.18 H.sub.19 NO: C 81.48%; H 7.22%; N 5.28%; Found : C 81.55%; H 7.56%; N 5.12%.
Hydrochloride salt, m.p. 262.degree..
B. A mixture of 2.9 G. of 1'-benzyl-1,3-dihydro-3-phenylspiro[phenylspiro[isobenzofuran-1,4'-piperid ine], (Example 4), 0.4 g. of 10% palladium on carbon, 20 ml. of 95% ethanol, and 2 ml. of conc. hydrochloric acid is hydrogenated at 50 p.s.i. and 50.degree.. After hydrogen uptake ceases, the mixture is filtered and the filtrate concentrated. Recrystallization of the residue from cyclohexane provides colorless crystals, m.p. 119.degree.-123.degree..
The compositions and structures of the compounds XIII of Examples 66 through 79, tabulated below, are prepared in analogous manner.
EXAMPLE 80
1'-Acetyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperdine]
To a cold stirred solution of 6.0 g. of 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 65), 2.4 g. of triethylamine, and 50 ml. of chloroform is added dropwise a solution of 2.0 g. of acetyl chloride and 50 ml. of chloroform. The mixture is stirred for 2 hours at room temperature, washed with water, dried over sodium sulfate, and concentrated. The residue is recrystallized from chloroform to provide colorless crystals, m.p. 128.degree.-130.degree..
Analysis: Calc. for C.sub.20 H.sub.21 NO.sub.2 : C 77.89%; H6.90%; 4.55%; Found : C 78.06%; H 6.99%; N 4.43%.
The compositions and structures of the compounds IX of Examples 81 through 88, tabulated below, are prepared in analogous manner.
EXAMPLE 89
1,3-Dihydro-1'-ethyl-3-phenylspiro[isobenzofuran-1,4'piperidine]
To a stirred suspension of 0.53 g. of lithium aluminum hydride in 50 ml. of tetrahydrofuran is added dropwise a solution of 2.20 g. of 1'-acetyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 80), in 50 ml. of tetrahydrofuran. The mixture is heated under reflux for 2 hours, cooled, quenched cautiously with water, and extracted with ether. The ether solution is dried over sodium sulfate and concentrated to a solid. Recrystallization from chloroform provides colorless crystals, m.p. 113.degree.-115.degree..
Analysis: Calc. for C.sub.20 H.sub.23 HO: C 81.87%; H 7.91%; N 4.77%; Found : C 81.76%; H 8.10%; N 4.62%.
The compositions and structures of the compounds IX of Examples 90 through 98, tabulated below, are prepared in analogous manner.
EXAMPLE 99
1,3-Dihydro-1'-[3-(p-fluorobenzoyl)propyl]-3-phenylspiro[isobenzofuran-1,4' -piperidine]
A stirred mixture of 4.9 g. of 1.3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 65), 4.9 g. of .omega.-chloro-p-fluorobutyrophenone ethylene ketal, 10 g. of potassium carbonate, and 50 ml. of butanol is heated under reflux for 46 hours and filtered. The filtrate is concentrated to an oil, which is stirred with 50 ml. of 3N hydrochloric acid and 50 ml. of ethanol. The mixture is made basic with sodium hydroxide and extracted with benzene. The benzene solution is dried over sodium sulfate and concentrated. The residue is recrystallized from ether to provide colorless crystals, m.p. 137.degree.-138.degree..
Analysis: Calc. for C.sub.28 H.sub.28 FNO.sub.2 : C 78.30%; H 6.57%; N 3.26%; Found : C 78.28%; H 6.59%; N 3.12%.
The compositions and structures of compounds IX of Examples 100 through 111, tabulated below, are prepared in analogous manner. The acid hydrolysis step of Example 99 is omitted when the alkylating agent does not contain a ketal group.
EXAMPLE 112
1'-Benzyl-1,3-dihydro-3,5-dimethoxy-3-phenylspiro[isobenzofuran-1,4'-piperi dine]
A solution of 1'-benzyl-1,3-dihydro-3-hydroxy-5-methoxy-3-phenylspiro[isobenzofuran-1,4' -piperidine] (prepared by method of Example 1), methanol, and a catalytic amount of methanolic hydrogen chloride is heated under reflux, cooled, made basic with sodium hydroxide, and diluted with water. The mixture is extracted with ethyl acetate, and the ethyl acetate solution is dried over sodium sulfate and concentrated to a solid. Recrystallization from acetone-water provides colorless crystals, m.p. 129.degree.-133.degree..
Analysis: Calc. for C.sub.27 H.sub.29 NO.sub.3 : C 78.03%; H 7.05%; N 3.37%; Found: C 78.15%; H 7.12%; N 3.23%.
EXAMPLE 113
1,3-Dihydro-3-(4-hydroxyphenyl)-1'-methylspiro[isobenzofuran-1,4'-piperidin e]
A solution of 3.5 g. of 1,3-dihydro-3-(4-methoxyphenyl)-1'-methylspiro[isobenzofuran-1,4'-piperidi ne], (Example 12), and 20 ml. of 48% hydrobromic acid is heated under reflux, cooled, diluted with water, neutralized with sodium bicarbonate, and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated to an oil. Trituration with ether provides crystals, m.p. 132.degree.dec. Recrystallization raises the melting point to 273.degree.dec.
EXAMPLE 114
1,3-Dihydro-6-hydroxy-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine
By following the manipulative procedure described above in example 113, 1,3-dihydro-6-methoxy-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidin e], (Example 25), gives a faintly pink solid, m.p. 207.degree.-212.degree..
Analysis: Calc. for C.sub.19 H.sub.21 NO.sub.2 : C 77.25%, H 7.18%; N 4.74%; Found: C 77.05%; H 7.23%; N 4.74%.
EXAMPLE 115
1,3-Dihydro-5-hydroxy-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine ]
By following the manipulative procedure described above in Example 113, 1,3-dihydro-5-methoxy-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidin e], (Example 24), gives a cream colored solid, m.p. 193.degree.-200.degree..
Analysis: Calc. for C.sub.19 H.sub.21 NO.sub.2 : C 77.25%; H 7.18%; N 4.74%; Found: C 77.00%; H 7.40%; N 4.66%.
EXAMPLE 116
1,3-Dihydro-6-hydroxy-3-phenylspiro[isobenzofuran-1,4'-piperidine]
A suspension of 2.0 g. of 1,3-dihydro-6-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine], (Example 73), and 32 ml. of a 48% hydrobromic acid solution is heated at reflux, effecting the separation of a hydrobromide salt as a crystalline precipitate. The mixture is poured into ice-water with stirring, the precipitate collected by filtration, the filter cake washed with water, and dried. Recrystallization from ethanol gives colorless crystals, m.p. 274.degree.-276.degree., dec.
Analysis: Calc. for C.sub.18 H.sub.19 NO.sub.2.HBr: C 59.67%; H 5.58%; N 3.87% Br 22.06%; Found: C 59.83%; H 5.64%; N 3.95% Br 21.86%.
EXAMPLE 117
1,3-Dihydro-1'-(3-hydroxy-3-phenylpropyl)-3-phenylspiro[isobenzofuran-1,4'- piperidine]
A solution of 2.5 g. of 1'-(2-benzoylethyl)-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidin e], (Example 107), 30 ml. of methanol, and 0.35 g. of sodium borohydride is stirred at room temperature for 4 hours, diluted with water, and extracted with chloroform. The chloroform solution is dried over sodium sulfate and concentrated to provide 1,3-dihydro-1'-(3-hydroxy-3-phenylpropyl)-3-phenylspiro[isobenzofuran-1,4' -piperidine].
EXAMPLE 118
1,3-Dihydro-1'-[4-p-fluorophenyl)-3-hydroxybutyl]-3-phenylspiro[isobenzofur an-1,4'-piperidine]
By following the manipulative procedure described above in Example 117, 1,3-dihydro-1'-[3-(p-fluorobenzoly)propyl]-3-phenylspiro[isobenzofuran-1,4 '-piperidine], (Example 99), produces a yellow oil. The oil is triturated with an ether-petroleum ether mixture to give white crystals which are recrystallized from ethanol to give a white crystalline solid, m.p. 151.degree.-154.degree..
Analysis: Calc. for C.sub.28 H.sub.30 FNO.sub.2 : C 77.93%; H 7.01%; N 3.25%; Found: C 77.78%; H 7.07%; N 3.19%.
EXAMPLE 119
1,3-Dihydro-3-p-hydroxyphenyl-1'-methylspiro[isobenzofuran-1,4'-piperidine]
A mixture of 1.0 g. of 1,3-dihydro-3-p-methoxyphenyl-1'-methylspiro[isobenzofuran-1,4'-piperidine ] (Example 12), 1.0 g. of a 57% sodium hydride dispersion, and dimethylformamide is stirred under nitrogen. To the stirring mixture is rapidly added 2.0 ml. of ethanethiol. The mixture is refluxed under nitrogen for 4 hours, cooled, poured into ice-water, and acidified with 1N hydrochloric acid. The product is collected, dried, and dissolved in boiling dimethyl sulfoxide, and the solution is filtered. Upon cooling small colorless crystals, m.p. 273.degree. dec., separate.
Analysis: Calc. for C.sub.19 H.sub.21 NO.sub.2 : C 77.26%; H 7.17%; N 4.74%; Found: C 76.28%; H 7.33%; N 4.71%.
EXAMPLE 120
1'-Benzyl-1,3-dihydro-3,3-diphenylspiro[isobenzofuran-1,3'-piperidine]
Reaction of 1'-benzyl-1,3-dihydrospiro[isobenzofuran-1,3'-piperidine]-3-one with a large excess of phenyllithium by the method described in Example 1 provides off-white crystals, m.p. 144.degree.-146.degree..
Analysis: Calc. for C.sub.31 H.sub.29 NO: C 86.27%; H 6.77%; N 3.25%; Found: C 86.22%; H 7.09%; N 3.21%.
EXAMPLE 121
(-)-1,3-Dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine]
To a stirred solution of 0.80 g. of 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine], (Example 65), and 3 ml. of methanol is added a solution of 1.16 g. of di-(p-toluoyl)-d-tartaric acid in 6 ml. of methanol. The solution is concentrated to dryness, and the residue is recrystallized three times from methanol-water to provide colorless crystals. The crystals are dissolved in methanol and treated with an excess of aqueous sodium hydroxide. The mixture is extracted with ether, and the ether solution is dried over sodium sulfate and concentrated to an oily solid. Recrystallization from cyclohexane provides off-white crystals, m.p. 99.degree.-107.degree., [.alpha.].sub.D.sup.25.degree. = 126.0.degree. (c=1.35, MeOH).
EXAMPLE 122
(+)-1,3-Dihydro-3-phenylspiro]isobenzofuran-1,4'-piperidine]
The compound, colorless crystals, m.p. 104.degree.-112.degree., [.alpha.].sub.D.sup.25.degree. = +134.4.degree. (c=1.35, MeOH), is prepared from 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine], (Example 65), and di-(p-toluoyl)-1-tartaric acid by the method described in Example 121, or is alternatively recovered from the aqueous-methanolic mother liquors of Example 121.
EXAMPLE 123
1,3-Dihydro-1',3-dimethyl-3-phenylspiro[isobenzofuran-1,4'-piperidine]
A solution of 1.4 g. of 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], (Example 2), in 20 ml. of tetrahydrofuran is cooled to -50.degree. and treated dropwise with 4 ml. of butyllithium in hexane. Stirring is continued for 30 minutes under nitrogen. To the solution is slowly added 900 mg. of dimethylsulfate in 10 ml. of tetrahydrofuran. The mixture is stirred at -10.degree. for 1 hour and overnight at ambient temperature. Ice is added, the mixture is extracted with ether, and the organic solution is concentrated to an oil. The oil is converted to the hydrobromide salt and recrystallized from ethyl acetate to give crystals, m.p. 122.degree.-125.degree..
Analysis: Calc. for C.sub.20 H.sub.23 NO.HBr: C 64.17%; H, 6.46%; N 3.74%; Br 21.35%; Found: C 64.27%; H 6.68%; N 3.42%; Br 20.98%.
The compositions and structures of compounds XII of Examples 124 through 126, tabulated below, are prepared from 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], (Example 2), in analogous manner.
EXAMPLE 127
1'-Cyclopropylmethyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,3'-pyrrolidi ne]
Reaction of 1,3-dihydro-3-phenylspiro[isobenzofuran-1,3'-pyrrolidine] with cyclopropylcarbonyl chloride by the method of Example 80, followed by lithium aluminum hydride reduction by the method of Example 89 provides an amine. The amine is converted to its hydrobromide salt, m.p. 187.degree.-190.degree., from an acetone-ethyl acetate mixture.
Analysis: Calc. for C.sub.21 H.sub.23 NO.HBr: C 65.28%; H 6.26 %; N 3.62%; Found: C 65.08%; H 6.36%; N 3.45%.
Claims
We claim:
1. A compound of the formula ##SPC4## in which R is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, halogen, hydroxy, or methylenedioxy; R.sub.1 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, phenylalkyl of the formula (CH.sub.2).sub.x --PhR, diphenylalkyl of the formula (CH.sub.2).sub.m --CH(PhR).sub.2, diphenylmethoxyalkyl of the formula --(CH.sub.2).sub.m --OCHPh.sub.2, alkanoyl of 2 to 6 carbon atoms, phenylalkanoyl of the formula --CO(CH.sub.2).sub.x --PhR, benzoyl of the formula --COPhR, benzoylalkyl of the formula --(CH.sub.2).sub.m --COPhR, phenylhydroxyalkyl of the formula --(CH.sub.2).sub.m CHOHPhR, alkoxycarbonyl of 2 to 6 carbon atoms, phenyloxycarbonyl, or cycloalkylcarbonyl of 4 to 8 carbon atoms; R.sub.2 is alkyl of 1 to 6 carbon atoms or phenyl of the formula PhR.sub.m ; Y is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy or phenyl of the formula PhR; Ph is phenyl; m, n and n' are integers from 1 to 3, the sum of n and n' being from 3 to 5; and x is an integer from 1 to 4, and the optical antipodes and the pharmaceutically acceptable acid addition salts thereof.
2. A compound as defined in claim 1 in which R is hydrogen, akyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, fluorine, chlorine, hydroxy or methylenedioxy; R.sub.1 is hydrogen, alkyl of 1 to 6 atoms, cycloalkylalkyl of 4 or 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, phenylalkyl of the formula --(CH.sub.2).sub.m --PhR, diphenylalkyl of the formula --(CH.sub.2).sub.m --CH(PhR).sub.2, alkanoyl of 2 to 4 carbon atoms, phenylalkanoyl of the formula --CO(CH.sub.2).sub.m --PhR, benzoylalkyl of the formula --(CH.sub.2).sub.m --COPhR, benzoyl of the formula --COPhR, alkoxycarbonyl of 2 or 3 carbon atoms, or cycloalkylcarbonyl of 4 to 7 carbon atoms; R.sub.2 is alkyl of 1 to 3 carbon atoms, or phenyl of the formula --PhR", R" being hydrogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, methylenedioxy or trifluoromethyl; Y is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 4 carbon atoms or phenyl of the formula --PhR", and Ph, m, n and n' are as defined in claim 1.
3. The compound defined in claim 1 which is 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
4. The compound defined in claim 1 which is 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
5. The compound defined in claim 1 which is 1,3-dihydro-1'-cyclopropylmethyl-3-phenylspiro[isobenzofuran-1,4'-piperidi ne] and the pharmaceutically acceptable acid addition salts thereof.
6. The compound defined in claim 1 which is 1,3-dihydro-1'-[3-(p-fluorobenzoyl)propyl]-3-phenylspiro[isobenzofuran-1,4 '-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
7. The compound defined in claim 1 which is 1,3-dihydro-3-(p-fluorophenyl)spiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
8. The compound defined in claim 1 which is 1,3-dihydro-6-fluoro-1'-methyl-3-(p-fluorophenyl)spiro[isobenzofuran-1,4'- piperidine] and the pharmaceutically acceptable acid addition salts thereof.
9. The compound defined in claim 1 which is 1,3-dihydro-3-phenylspiro[isobenzofuran-1,3'-pyrrolidine] and the pharmaceutically acceptable acid addition salts thereof.
10. The compound defined in claim 1 which is 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,3'-pyrrolidine] and the pharmaceutically acceptable acid addition salts thereof.
11. The compound defined in claim 1 which is 1'-cyclopropylmethyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,3'-pyrrolid ine] and the pharmaceutically acceptable acid addition salts thereof.
12. The compound defined in claim 1 which is 1,3-dihydro-3-p-tolylspiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
13. The compound defined in claim 1 which is 1,3-dihydro-6-fluoro-3-p-fluorophenylspiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
14. The compound defined in claim 1 which is 1,3-dihydro-6-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
15. The compound defined in claim 1 which is 1,3-dihydro-3-p-fluorophenyl-1'-methylspiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
16. The compound defined in claim 1 which is 1,3-dihydro-3-p-methoxyphenylspiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
17. Process for the preparation of a compound as defined in claim 1 which comprises reacting an o-bromobenzyl alcohol or an o-bromobenzyl alkyl ether with an alkyllithium to form the corresponding lithium o-lithiobenzyloxide or o-lithiobenzyl alkyl ether, reacting said lithium o-lithiobenzyloxide or o-lithiobenzyl alkyl ether with a cycloazalkanone to prepare the corresponding (.alpha. -hydroxy-o-tolyl)cycloazalkanol or (.alpha. -hydroxy-o-tolyl)cycloazalkyl alkyl ether, and treating said (.alpha. -hydroxy-o-tolyl)cycloazalkanol or (.alpha. -hydroxy-o-tolyl)cycloazalkyl alkyl ether with acid to effect cyclization to the corresponding 1,3-dihydrospiro[isobenzofuran-cycloazalkane].
18. A pharmaceutical composition which comprises between about 0.5 and about 70 percent by weight of a compound defined in claim 1 as an essential active ingredient, the balance being a pharmaceutically acceptable carrier therefor.
19. The compound defined in claim 1 which is 1,3-dihydro-6-hydroxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
20. The compound defined in claim 1 which is 1,3-dihydro-5-hydroxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
21. The compound as defined in claim 1 which is 1,3-dihydro-3-(4-hydroxyphenyl)spiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
22. The compound defined in claim 1 which is 1,3-dihydro-1'-ethoxycarbonyl-3-methylspiro[isobenzofuran-1,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
23. The compound defined in claim 1 which is 1,3-dihydro-1'-[3-(p-fluorobenzoyl)propyl]-3-methylspiro[isobenzofuran-1,4 '-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
24. The compound defined in claim 1 which is 1,3-dihydro-1'-[4,4-di(p-fluorophenyl)butyl]-3-methylspiro[isobenzofuran-1 ,4'-piperidine] and the pharmaceutically acceptable acid addition salts thereof.
25. The compound defined in claim 1 which is 1,3-dihydro-1'-cyclopropylmethyl-3-methylspiro[isobenzofuran-1,4'-piperidi ne] and the pharmaceutically acceptable acid addition salts thereof.
26. A method of treating depression, depressing the central nervous system or alleviating pain which comprises administering to a patient a pharmaceutically effective amount of a compound defined in claim 1.
27. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
28. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
29. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-1'-cyclopropylmethyl-3-phenylspiro[isobenzofuran-1,4'-piperidi ne] or a pharmaceutically acceptable acid addition salt thereof.
30. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-3-(p-fluorophenyl)spiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
31. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-6-fluoro-1'-methyl-3-(p-fluorophenyl)spiro[isobenzofuran-1,4'- piperidine] or a pharmaceutically acceptable acid addition salt thereof.
32. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-3-phenylspiro[isobenzofuran-1,3'-pyrrolidine] or a pharmaceutically acceptable acid addition salt thereof.
33. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,3'-pyrrolidine] or a pharmaceutically acceptable acid addition salt thereof.
34. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1'-cyclopropylmethyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,3'-pyrrolid ine] or a pharmaceutically acceptable acid addition salt thereof.
35. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-3-p-tolylspiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
36. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-6-fluoro-3-p-fluorophenylspiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
37. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-6-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
38. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-3-p-fluorophenyl-1'-methylspiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
39. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-3-p-methoxyphenylspiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
40. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-6-hydroxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
41. The method of treating depression as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-3-(4-hydroxyphenyl)spiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
42. The method of depressing the central nervous system as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-1'-cyclopropylmethyl-3-phenylspiro[isobenzofuran-1,4'-piperidi ne] or a pharmaceutically acceptable acid addition salt thereof.
43. The method of depressing the central nervous system as defined in claim 26 in which the pharmaceutically effective compound is 1,3-dihydro-1'-[3-(p-fluorobenzoyl)propyl]-3-phenylspiro[isobenzofuran-1,4 '-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
44. The method of depressing the central nervous system as defined in claim 26 in which the pharmaceutically effective compound is 1'-cyclopropylmethyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,3'-pyrrolid ine] or a pharmaceutically acceptable acid addition salt thereof.
45. The pharmaceutical composition defined in claim 18 in which the essential active compound is 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
46. The pharmaceutical composition defined in claim 18 in which the essential active compound is 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
47. The pharmaceutical composition defined in claim 18 in which the essential active compound is 1,3-dihydro-1'-[3-(p-fluorobenzoyl)propyl]-3-phenylspiro[isobenzofuran-1,4 '-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
48. The pharmaceutical composition defined in claim 18 in which the essential active compound is 1,3-dihydro-3-(p-fluorophenyl)spiro[isobenzofuran-1,4'-piperidine] or a pharmaceutically acceptable acid addition salt thereof.
Patent Citations (1)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US3686186 | 1972-08-01 | Houlihan et al. |
Non-Patent Literature (1)
- Braenden et al., Bull. World Health Org. 13, 937, 956-961, (1955).