19-Methyl-9-Keto-15-Hydroxy-Prost-18-Enoic Acid Derivatives and Process of Their Preparation

The invention will be illustrated by the following experimental examples, which, however, in no way limit its range.

To a solution of dimethyl methylphosphonate (36 g.) in anhydrous tetrahydrofurane (260 ml.), cooled to -74.degree. C. and under nitrogen, 132 ml. of n-butyllithium (2.2 N in hexane) are added. After 15 minutes, 20 g of methyl 5-methyl-4-hexenoate are added. The reaction mixture is stirred at -74.degree. C. for 60 minutes, then the temperature is allowed to rise spontaneously to 0.degree. C. The mixture is diluted with water (390 ml.), the tetrahydrofurane is evaporated in vacuo and the aqueous phase is extracted with CH.sub.2 Cl.sub.2 (4.times.150 ml.). The organic layer is washed with water to neutrality, dehydrated over sodium sulphate and the solvent evaporated in vacuo. The residue is distilled under reduced pressure, to yield 20 g. of dimethyl (6-methyl-hept-5-en-2-one)-phosphonate.

B.p.=128-130 at 0.5 mm Of Hg.

For C.sub.10 H.sub.19 O.sub.4 P--calculated: C=51.24;H=8.18;P=13.25; found: C=51.19;H=8.12;P=13.29.

As described in Example 1(a), from 12.5 g. of dimethyl methylphosphonate, 43 ml. of n-butyllithium (2,2 N in hexane), 90 ml. of anhydrous tetrahydrofurane, 8 g. of methyl 2,2,5-trimethyl-4-hexenoate, 6 g. of dimethyl (3,3,6-trimethyl-hept-5-en-2-one)-phosphonate are obtained.

B.p.=127.degree.-130.degree. C. at 0.3 mm of Hg.

For C.sub.12 H.sub.23 O.sub.4 P--calculated: C=54.92; H=8.84; P=11.83; found: C=54.86; H=8.76; P=11.91.

The solution of 2-(6-carboxyhexyl)-cyclopent-2-en-1-one methyl ester (5.4 g.), nitromethane (5.4 ml.), N,N,N', N'-tetramethylguanidine (0.32 ml.) is left for 18 hours at room temperature. The mixture is washed with HCl 3 N and the organic layer is separated. The aqueous phase is then extracted with diethyl ether (4.times.20 ml.) and the ethereal extracts are added to the above-mentioned organic layer. The so obtained solution is washed with water to neutrality, dried over sodium sulphate and the solvent is removed in vacuo. From the oily residue, by chromatography on silica (120 g.) and elution with benzine/ethyl acetate (4:1), 4.8 g. of pure 2-(6-carboxyhexyl)-3-nitromethyl-cyclopentan-1-one methyl ester are obtained.

oil, .nu..sub.max.sup.film : 1745, 1555 cm.sup.-1

N.M.R. (.delta.; CDCl.sub.3): 3.63 3H, s, OCH.sub.3); 4.22-4.80 (2H,m, CH.sub.2 NO.sub.2).

By the same method, from 2-(methyl cis-hept-2-en-7-oate)-cyclopent-2-en-1-one, the 2-(methyl cis-hept-2-en-7-oate)-3-nitromethyl-cyclopentan-1-one is obtained.

oil, .nu..sub.max.sup.film : 1740, 1555 cm.sup.-1 ;

N.M.R. (.delta.; CDCl.sub.3): 3.64 (3H, s, OCH.sub.3); 4.14-4.87 (2H, m, --CH.sub.2 NO.sub.2); 5.05-5.75 (2H, m, cis CH.dbd.CH).

The solution of 2-(6-carboxyhexyl)-3-nitromethyl-cyclopentan-1-one, methyl ester (14 g.) in benzene (200 ml.), ethylene glycol (16.1 ml.), p-toluenesulphonic acid (0.315 g.), is heated to boiling for 16 hours. The reaction water is separated in a Marcusson apparatus. The mixture is washed with an aqueous saturated NaHCO.sub.3 -solution (50 ml.), then with water to neutrality, dried over sodium sulphate and the solvent is evaporated in vacuo. From the oily residue, by chromatography on silica (300 g.) and elution with benzene/ethyl acetate (6:1), 13 g. of 1-ethylenedioxy-2-(6-carboxyhexyl)-3-nitromethyl-cyclopentane, methyl ester, are obtained.

oil, .nu..sub.max.sup.film : 1740, 1555 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 3.64 (3H, s, OCH.sub.3); 3.88 (4H, s, --O--CH.sub.2 --CH.sub.2 --O--); 4.06-4.68 (2H, m, CH.sub.2 NO.sub.2).

By the same method, from 2-(methyl cis-hept-2-en-7-oate)-3-nitromethyl-cyclopentan-1-one, the 1-ethylenedioxy-2-(methyl cis-hept-2-en-7-oate)-3-nitromethyl-cyclopentane is prepared.

oil, .nu..sub.max.sup.film : 1740, 1550 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 3.62 (3H, s, --CH.sub.3); 3.85 (4H, s, --O--CH.sub.2 --CH.sub.2 --O--); 3.98-4.70 (2H,m, --CH.sub.2 NO.sub.2); 5.23-5.50 (2H,m,cis CH.dbd.CH).

To the solution of 0.82 g. of sodium in 72 ml. of anhydrous methanol, at 10.degree. C. and under nitrogen, a solution of 1-ethylenedioxy-2-(6-carboxyhexyl)-3-nitromethyl-cyclopentane, methyl ester (10.7 g.) in anhydrous methanol (72 ml.) is added, drop by drop. After stirring for 15 minutes at room temperature, the solution of ammonium acetate (65.5 g.), TiCl.sub.3 15% (118 ml.), H.sub.2 O (214 ml.) is rapidly added, and the mixture is stirred for 50 minutes under nitrogen, then extracted with diethyl ether (3.times.200 ml.). The organic layer is washed with a saturated solution of NaHCO.sub.3 in water, then with water to neutrality.

After drying over Na.sub.2 SO.sub.4, the solvent is evaporated in vacuo, yielding 8.2 g. of an oily residue, which is used as such for the Wittig reaction.

oil .nu..sub.max.sup.film : 2710, 1735 cm.sup.-1.

By the same method, starting from 1-ethylenedioxy-2-(methyl cis-hept-2-en-7-oate)-3-nitromethyl-cyclopentane, the 1-ethylenedioxy-2-(methyl cis-hept-2-en-7-oate)-3-formyl-cyclopentane is obtained.

oil .nu..sub.max.sup.film : 2710, 1730 cm.sup.-1.

N.M.R. (.delta.: CDCl.sub.3): 3.65 (s, 3H, --OCH.sub.3); 3.88 (4H, s, --O--CH.sub.2 --CH.sub.2 --O--); 5.25-5.60 (2H, m, cis CH.dbd.CH); 9.50-9.65 (1H, d, CHO).

At -35.degree. C., 0.82 g. of a suspension of NaH 50% in mineral oil is added to a solution of dimethyl (3,3,6-trimethyl-hept-5-en-2-one) phosphonate (4.5 g.), 1-ethylenedioxy-2-(6-carboxyhexyl)-3-formyl-cyclopentane methyl ester (4.85 g.) in anhydrous 1,2-dimethoxyethane (150 ml.): the freezing bath is removed and the mixture is stirred for 3 hours under nitrogen. (The mixture reaches the room temperature in about 1 hour). After cautious addition of 1 ml of methanol, the mixture is poured on icy water (200 ml.), then extracted with diethyl ether (2.times.70 ml). The ethereal extract is washed with water to neutrality, dried on Na.sub.2 SO.sub.4 and the solvent evaporated in vacuo. The oily residue (8 g.) is purified by chromatography on SiO.sub.2 (200 g.). By elution with hexane/ethyl acetate (2:1), 4.5 g. of 9-ethylenedioxy-15-keto-16,16,19-trimethyl-prosta-13,18-dienoic acid, methyl ester, are obtained.

oil.sub.max.sup.film : 1745, 1690, 1625 cm.sup.-1.

N.M.R. (.delta.: CDCl.sub.3): 1.09 (6H, s, 2(CH.sub.3)-C.sub.16); 1.58 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.67 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.62 (3H, s, --OCH.sub.3); 3.88 (4H, s, --O--CH.sub.2 --CH.sub.2 --O); 4.80-5.18 (1H, m, C.sub.18 -H); 6.45 (1H, d=15 cps, C.sub.14 -H); 6.82 (1H,dd, J=15 cps, J=7.5 cps, C.sub.13 -H).

By the same method the following compounds are prepared:

1. 9-Ethylenedioxy-15-keto-19-methyl-prosta-13,18-dienoic acid, methyl ester, starting from the sodium derivative of dimethyl (6-methyl-hept-5-en-2-one)-phosphonate.

oil .nu..sub.max.sup.film : 1745, 1675, 1630 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 1.63 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.68 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.63 (3H, s, --OCH.sub.3); 3.87 (4H, s, --C--CH.sub.2 --CH.sub.2 --O--); 4.90-5.30 (1H, m, C.sub.18 -H); 6.04 (d, J=15.5 cps, C.sub.14 -H); 6.71 (dd, J=15.5 cps, J=8 cps, C.sub.13 -H).

2. 9-Ethylenedioxy-15-keto-16,16,19-trimethyl-prosta-5cis,13-trans,18-trienoi c acid, methyl ester, starting from 1-ethylenedioxy-2-(methyl cis-hept-2-en-7-oate)-3-formyl-cyclopentane and from the sodium derivative of dimethyl (3,3,6-trimethyl-hept-5-en-2-one)-phosphonate.

oil, .nu..sub.max.sup.film : 1745, 1690, 1625 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3); 1.05 (3H, s, CH.sub.3 -C.sub.16); 1.08 (3H, s, CH.sub.3 -C.sub.16); 1.58 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.62 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.63 (3H,s,OCH.sub.3); 3.87 (4H, s, --OCH.sub.2 --CH.sub.2 O); 4.77-5.18 (1H, m, C.sub.18 -H); 5.18-5.50 (2H, m, cis --CH.dbd.CH--); 6.44 (1H, d, J.dbd.15 cps, C.sub.14 -H); 6.80 (1H, dd, J=15 cps, J=7.5 cps, C.sub.13 -H).

3. 9-Ethylenedioxy-15-keto-19-methyl-prosta-5cis,13-trans,18-trienoic acid, methyl ester, starting from 1-ethylenedioxy-2-(methyl cis-hept-2-en-7-oate)-3-formyl-cyclopentane and from the sodium derivative of dimethyl(6-methyl-hept-5-en-2-one)phosphonate.

oil, .nu..sub.max.sup.film : 1740, 1675, 1630 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3); 1.63 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.67 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.63 (3H, s, --OCH.sub.3); 3.86 (4H, s, --O--CH.sub.2 --CH.sub.2 --O--); 4.90-5.50 (3H, m, C.sub.18 -H, cis --CH.dbd.CH--); 6.05 (1H, d, J=16 cps, C.sub.14 -H); 6.66 (1H, dd, J=16 cps, J=8 cps, C.sub.13 -H).

To a solution of 9-ethylenedioxy-15-keto-16,16,19-trimethyl-prosta-13,18-dienoic acid, methyl ester, (5.2 g.) in methanol (40 ml.), 0.89 g of sodium borohydride are gradually added, while the temperature is kept under 35.degree. C. The mixture is stirred for 30 minutes, then diluted with 300 ml. of water and extracted with ethyl acetate (3.times.100 ml). The organic layer is washed with water to neutrality, dried over Na.sub.2 SO.sub.4 and the solvent is evaporated in vacuo, to obtain a residue (4.9 g) which is suspended in acetic acid 65% (60 ml.) and stirred at room temperature for 60 minutes. The so obtained solution is diluted with water (200 ml.) and extracted with diethyl ether (3.times.100 ml). The organic phase is washed with an aqueous, saturated solution of NaHCO.sub.3, then with water to neutrality, dried over Na.sub.2 SO.sub.4, and the solvent is evaporated in vacuo. The oily residue (4.2 g. is purified by chromatography on SiO.sub.2 (400 g.); the eluent is benzene/ethyl acetate (4:1). One gram of 9-keto-15.beta.-hydroxy-16,16,19-trimethyl-prosta-13,18-dienoic acid, methyl ester, 0.5 g. of 9-keto-15.alpha.-hydroxy-16,16,19-trimethyl-prosta-13,18-dienoic acid, methyl ester, and 2.1 g. of a mixture of 15.alpha.- and 15.beta.-isomers are obtained.

(15.beta.)oil:.nu..sub.max.sup.film : 3510, 1745 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 0.82 (3H, s, CH.sub.3 -C.sub.16); 0.84 (3H, s, CH.sub.3 -C.sub.16); 1.62 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.72 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.64 (3H, s, --OCH.sub.3); 3.73-3.95 (1H, m, C.sub.15 -H); 5.05-5.45 (1H, m, C.sub.18 -H); 5.58-5.77 (2H, m, trans CH.dbd.CH)

(15.alpha.)oil:.nu..sub.max.sup.film : 3505, 1745 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 0.83 (3H, s, CH.sub.3 -C.sub.16); 0.87 (3H, s, --CH.sub.3 -C.sub.16); 1.62 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.72 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.64 (3H, s, --OCH.sub.3); 3.75-3.92 (1H, m, C.sub.15 -H); 4.95-5.40 (1H, m, C.sub.18 -H); 5.56-5.74 (2H, m, trans CH.dbd.CH).

By the same method the following compounds are prepared:

1. From 9-ethylenedioxy-15-keto-19-methyl-prosta-13,18-dienoic acid, methyl ester, the 9-keto-15-hydroxy-19-methyl-prosta-13,18-dienoic acid, methyl ester is obtained.

oil, .nu..sub.max.sup.film : 3460, 1740 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 1.62 (3H, broad singlet, C.sub.19 -CH.sub.3); 1.69 (3H, broad singlet, C.sub.19 -CH.sub.3), 3.64 (3H, s, --OCH.sub.3); 3.98-4.24 (1H, m, C.sub.15 -H); 5.02-5.30 ((1H, m, C.sub.18 -H); 5.52-5.62 (1H, m, trans CH.dbd.CH).

2. From 9-ethylenedioxy-15-keto-16,16,19-trimethyl-prosta-5-cis,13-trans,18-trieno ic acid, methyl ester, the 9-keto-15.alpha.-hydroxy-16,16,19-trimethyl-prosta-5-cis,13-trans,18-trien oic acid, methyl ester is obtained.

oil, .nu..sub.max.sup.film : 3510, 1740 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 0.86 (3H, s, CH.sub.3 -C.sub.16); 0.88 (3H, s, CH.sub.3 -C.sub.16); 1.64 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.74 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.65 (3H, s, --OCH.sub.3); 3.76-3.95 (1H, m, C.sub.15 -H); 5.00-5.50 (3H, m, C.sub.18 -H, cis--CH.dbd.CH--); 5.58-5.75 (2H, m, trans--CH.dbd.CH--).

3. From 9-ethylenedioxy-15-keto-16,16,19-trimethyl-prosta-5-cis,13-trans,18-trieno ic acid, methyl ester, the 9-keto-15.beta.-hydroxy-16,16,19-trimethyl-prosta-5-cis,13-trans,18-trieno ic acid, methyl ester is obtained.

oil, .nu..sub.max.sup.film : 3510, 1740 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3); 0.85 (3H,s,CH.sub.3 -C.sub.16); 0.89 (3H,s,CH.sub.3 -C.sub.16); 1.64 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.74 (3H,broad singlet, CH.sub.3 -C.sub.19); 3.65 (3H,s, --OCH.sub.3); 3.72-3.94 (1H,m, C.sub.15 -H); 5.02-5.54 (3H, m, C.sub.18 -H,cis--CH.dbd.CH--); 5.58-5.78 (2H,m,trans--CH.dbd.CH--).

Method A

To the solution of 4.4 g of 9-ethylenedioxy-15-keto-19-methyl-prost-13,18-dienoic acid, methyl ester, in ethanol (60 ml.) are added 0.8 g of Raney-nickel washed with ethanol and the mixture is hydrogenated at room temperature under pressure. After absorption of the theoretical quantity of hydrogen the catalyzer is separated by filtration and the solvent evaporated in vacuo, to yield 3.9 g of 9-ethylenedioxy-15-keto-19-methyl-prost-18-enoic acid, methyl ester.

Method B

To the solution of 3.6 g of 9-ethylenedioxy-15-keto-19-methyl-prost-13,18-dienoic acid, methyl ester, in ethyl acetate (100 ml.) 0.18 g of Pd/C (5%) are added and the mixture is hydrogenated at room temperature under pressure. After absorption of the theoretical quantity of hydrogen the catalyzer is separated by filtration and the solvent evaporated in vacuo to yield 3.4 g of 9-ethylenedioxy-15-keto-19-methyl-prost-18-enoic acid, methyl ester.

oil: .nu..sub.max.sup.film 1740, 1720 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 1.61 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.67 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.64 (3H, s, --OCH.sub.3); 3.88 (4H, s, --O--CH.sub.2 --CH.sub.2 --O--); 4.88-5.23 (1H, m, C.sub.18 -H).

By the same method, starting from 9-ethylenedioxy-15-keto-16,16,19-trimethyl-prosta-13,18-dienoic acid, methyl ester, the 9-ethylenedioxy-15-keto-16,16,19-trimethyl-prost-18-enoic acid, methyl ester is obtained.

oil .nu..sub.max.sup.film : 1745, 1710 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 1.05 (3H, s, CH.sub.3 -C.sub.16); 1.07 (3H, s, CH.sub.3 -C.sub.16); 1.59 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.70 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.64 (3H, s, --OCH.sub.3); 3.67 (4H, s, --O--CH.sub.2 --CH.sub.2 --O--); 4.82-5.18 (1H, m, C.sub.18 -H).

The mixture of Fe(CO).sub.5 (0.784 g), NaOH (80 mg) in 2 ml of methanol/water (95:5) is stirred for 10 minutes at room temperature under nitrogen. To the obtained solution are added 0.392 g of 9-ethylenedioxy-15-keto-19-methyl-prosta-5-cis,13-trans-18 trienoic acid, methyl ester, and the mixture is stirred for 48 hours at room temperature under nitrogen. The solvent is evaporated at reduced pressure; by chromatography on silica(15 g) and elution with benzine/ethyl acetate (9:3) 0.3 g of 9-ethylenedioxy-15-keto-19-methyl-prosta-5-cis,18-dienoic acid, methyl ester, are obtained.

oil, .nu..sub.max.sup.film : 1740, 1710, 1630 cm.sup.-1.

N.M.R. (.delta.; CDCL.sub.3): 1.62 (3H, broad singlet; CH.sub.3 -C.dbd.), 1.67 (3H, broad singlet, ##STR12## 3.65 (4H, s, --OCH.sub.2 CH.sub.2 O--), 3.85 (3H, s, --OCH.sub.3), 4.85-5.25 (1H, m, --CH.dbd.C), 5.25-5.58 (2H, m, --CH.dbd.CH--).

To the solution of 2.4 g of 9-ethylenedioxy-15-keto-16,16,19-trimethyl-prost-18-enoic acid, methyl ester in methanol (20 ml.) 0.4 g of sodium borohydride are gradually added while the temperature is kept under 35.degree. C. The mixture is stirred for 30 minutes, then diluted with water (150 ml.) and extracted with ethyl acetate (3.times.70 ml.). The organic layer is washed with water to neutrality, dried over sodium sulphate and the solvent is removed in vacuo. The oily residue (2.2 g) is suspended in 65% acetic acid (30 ml.) and stirred at room temperature for 60 minutes. The obtained solution is diluted with water (100 ml.) and extracted with diethyl ether (3.times.70 ml). The organic layer is washed with aqueous saturated NaHCO.sub.3 solution to neutrality, dried over sodium sulphate and the solvent is evaporated. From the oily residue (1.8 g), by chromatography on silica (200 g) and elution with benzene/ethyl acetate (4:1), 0.48 g of 9 -keto-15.beta.-hydroxy-16,16,19-trimethyl-prost-18-enoic acid, methyl ester, 0.40 g of 9-keto-15.alpha.-hydroxy-16,16,19-trimethyl-prost-18-enoic acid, methyl ester and 0.48 g of a mixture of 15.alpha. and 15.beta. are obtained.

15.alpha. oil .nu..sub.max.sup.film : 3490, 1740 cm.sup.-1.

N.M.R. (.delta., CDCl.sub.3): 0.85 (3H, s, CH.sub.3 -C.sub.16), 0.87 (3H, s, CH.sub.3 -C.sub.16); 1.62 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.73 (3H, broad singlet, CH.sub.3 -C.sub.19); 8.18-3.45 (1H, m, C.sub.15 -H); 3.64 (3H, s, --OCH.sub.3); 5.08-5.43 (1H, m, C.sub.18 -H).

15.beta. oil .nu..sub.max.sup.film : 3500, 1740 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 0.85 (3H, s, CH.sub.3 -C.sub.16); 0.87 (3H, s, CH.sub.3 -C.sub.16); 1.62 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.73 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.12-3.44 (1H, m, C.sub.15 -H); 3.64 (3H, s, --OCH.sub.3); 5.05-5.45 (1H, m, C.sub.18 -H).

To the solution of 3.3 g of 9-ethylenedioxy-15-keto-19-methyl-prost-18-enoic acid, methyl ester (obtained as described in Example IIa) in diethyl ether (30 ml.) is added drop by drop in 30 minutes a solution of CH.sub.3 MgI (0.24 g of Mg, 0.6 ml of CH.sub.3 I, 30 ml of diethyl ether). After stirring for 30 minutes an aqueous saturated NH.sub.4 Cl-solution (15 ml.) is added and the stirring is continued until two clear phases are obtained. The organic layer is separated, washed with water to neutrality, dried over sodium sulphate and the solvent is evaporated in vacuo. The oily residue is suspended in acetic acid 65% (45 ml.) and stirred for 60 minutes at room temperature. The solution is then diluted with water (130 ml.) and extracted with diethyl ether (3.times.70 ml.); the organic layer is washed with an aqueous saturated NaHCO.sub.3 -solution, then with water to neutrality, dried over sodium sulphate and the solvent is evaporated in vacuo, obtaining 2.2 g of an oily residue. By chromatography on silica (90 g) and elution with hexane/ethyl acetate (2:1) 1.6 g of 9-keto-15-hydroxy-15,19-dimethyl-prost-18-enoic acid, methyl ester are obtained.

oil .nu..sub.max.sup.film : 3500, 1740 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 1.20 (3H, s, CH.sub.3 -C.sub.15); 1.63 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.70 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.86 (3H, s, --OCH.sub.3); 5.03-5.27 (1H, m, C.sub.18 -H)

By the same method are prepared:

(1) 9-Keto-15-hydroxy-15,19-dimethyl-prosta-13,18-dienoic acid, methyl ester starting from 9-ethylenedioxy-15-keto-19-methyl-prosta-13,18-dienoic acid, methyl ester.

oil .nu..sub.max.sup.film : 3460, 1740 cm.sup.-1.

N.M.R. (.delta.; CDCl.sub.3): 1.30 (3H, s, CH.sub.3 -C.sub.15); 1.62 (3H, s, CH.sub.3 -C.sub.19); 1.70 (3H, s, CH.sub.3 -C.sub.19); 3.66 (s, 3H, --OCH.sub.3); 5.02-5.27 (1H, m, C.sub.18 -H); 5.65 (2H, d, J=3 cps, trans CH.dbd.CH).

(2) 9-Keto-15-hydroxy-15,19-dimethyl-prosta-5-cis,18-dienoic acid, methyl ester starting from 9-ethylenedioxy-15-keto-19-methyl-prosta-5-cis,18-dienoic acid, methyl ester.

oil .nu..sub.max.sup.film : 3500, 1740 cm.sup.-1. N.M.R. (.delta.; CDCl.sub.3): 1.21 (3H, s, CH.sub.3 -C.sub.15); 1.63 (3H, broad singlet, CH.sub.3 -C.sub.19); 1.69 (3H, broad singlet, CH.sub.3 -C.sub.19); 3.64 (3H, s, --OCH.sub.3); 4.92-5.22 (1H, m, C.sub.18 -H); 5.23-5.48 (2H, m, cis--CH.dbd.CH--).

The solution of 0.5 g of 9-keto-15-hydroxy-19-methyl-prosta-13,18-dienoic acid, methyl ester, 0.170 g of NaOH in water (1.5 ml), methanol (4.5 ml) is left for two hours at room temperature under nitrogen, then diluted with water (22 ml) and extracted with diethyl ether (10 ml). The aqueous layer is acidified (congo red) with HCl (5%), then extracted with diethyl ether (3.times.15 ml). The ethereal solution is washed with water to neutrality, dried over sodium sulphate and the solvent evaporated in vacuo to yield 0.44 g of 9-keto-15-hydroxy-19-methyl-prosta-13,18-dienoic acid (oil).

By the same method are prepared:

1. 9-Keto-15.alpha.-hydroxy-16,16,19-trimethyl-prosta-13,18-dienoic acid (oil which solidifies slowly)

2. 9-Keto-15.beta.-hydroxy-16,16,19-trimethyl-prosta-13,18-dienoic acid (oil)

3. 9-Keto-15.alpha.-hydroxy-16,16,19-trimethyl-prost-18-enoic acid (oil)

4. 9-Keto-15.beta.-hydroxy-16,16,19-trimethyl-prost-18-enoic acid (oil)

5. 9-Keto-15-hydroxy-15,19-dimethyl-prost-18-enoic acid (oil)

6. 9-Keto-15-hydroxy-15,19-dimethyl-prosta-13,18-dienoic acid (oil)

7. 9-Keto-15.alpha.-hydroxy-16,16,19-trimethyl-prosta-5-cis,13-trans,18-trien oic acid (oil)

8. 9-Keto-15.beta.-hydroxy-16,16,19-trimethyl-prosta-5-cis,13-trans,18-trieno ic acid (oil)

9. 9-Keto-15-hydroxy-15,19-dimethyl-prosta-5-cis,18-dienoic acid (oil).