DK142143B - Analogous Process for Preparation of 2,3-Methylene Prostaglandin F2alfa or E2 Derivatives. - Google Patents

Description

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\ Ra / (11) PUBLICATION WRITING 1 421 43 DENMARK (51) int. ci.3 p 07 c Section 177/00 (21) Application No. 5529/74 (22) Filed on 1 * Jul. 1974 (24) Race day 1. Christmas. 197 ^ · (44) The application presented and the writ of publication published on the 8th S ep. 1 980

DIRECTORATE OF

THE PATENT AND TRADEMARK BASIS <3 °) Prior, Fri.

Q. Jul. 1975, 9959/75, CH 4 May 1974, 6049/74, CH

<71> SANDOZ A.G., CH-4002 Basel, CH.

(72) Inventor: Pletro Bollinger, 58 Gustnekerstrasse, CK-41C3 Bott = mingen, CH.

(74) Plenipotentiary in the proceedings:

Plougmann & Vlngtpft Patent Bureau. (54) Analogous Process for Preparation of 2,5-Methylene Prostaglandin F2alfa or E2 Derivatives.

The present invention relates to an analogous process for the preparation of novel racemic or optically active cyclopropane derivatives of the general formula I

D ~ 2 3 COOIT

OH

where D represents a carbocycle of the formula Ile or Fire 2 U2U3 hon \

V

110 ✓

HAY

ISLAND

(Fire ✓

HAY

is hydrogen or an alkyl group of 1-8 carbon atoms, an optionally alkyl-substituted cycloalkyl group having a total of 3-10 2

carbon atoms or an aralkyl group having 7-12 carbon atoms, and R

3 and R represents hydrogen or an alkyl group of 1-4 carbon atoms, or pharmacologically tolerable salts with bases of compounds of the general formula I wherein R 1 is hydrogen.

In the formulas set forth herein, dashed connecting lines indicate that the substituents are bound to the cyclopentane ring in α-configuration, i.e., are below the cyclopentane plane. Strongly drawn connecting lines indicate that the substituents are bound to the cyclopentane ring in (3-kdn configuration, i.e., above the cyclopentane plane. The wavy connecting line at the carbon atom at the 15-position of formula I indicates that the hydroxy group is in α or β configuration.

With respect to Formula X, examples of optionally alkyl-substituted cycloalkyl groups having a total of 3-10 carbon atoms may be mentioned cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2- methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl, 3-tert.butylcyclopentyl, cyclohexyl, 4-tert.butylcyclohexyl, 3-isopropylcycloentyl 2-dimethylcyclohexyl, cycloheptyl cyclooctyl, cyclononyl and cyclodecyl. As examples of aralkyl groups having 7-12 carbon atoms may be mentioned benzyl, phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2- (1-naphthylethyl) and 1- (2-naphthylmethyl) - U2U3 3

The novel cyclopropane derivatives of the general formula I

is produced by the method according to the invention, which is property 4

preferably by splitting the protecting group or groups R by hydrolysis into compounds of the general formula III

COOR ^ - III

OR4 12 3 4 wherein R, R and R are each as defined above, R represents a trialkylsilyl or tetrahydropyranyl group, and A represents a carbocycle of formula Ile or Ilf

HAY

\ Ile

Va / 4 /

R ^ O

0th

Χχχ 4 ^

R ^ O

then, if desired, for the preparation of compounds of general formula I wherein hydrogen is prepared compounds of general formula I wherein R 1 is an alkyl group of 1-8 carbon atoms, an optionally alkyl-substituted cycloalkyl group having a total of 3-10 carbon atoms or an aralkyl group of 7-12 carbon atoms is converted by hydrolysis to the free acids and then, if desired, to prepare compounds of general formula I wherein R R is an alkyl group of 1-8 carbon atoms, an optionally alkyl-substituted cycloalkyl group having a total of 3-10 carbon atoms or an aralkyl group of 7-12 carbon atoms, compounds of the general formula I wherein R is hydrogen is esterified with an ester corresponding to R 2 U 2 U 3 4 esterifying agent and, if desired, for the preparation of pharmaceutically acceptable salts with bases of compounds of general formula I, compounds of general formula I wherein R 1 is hydrogen are treated with corresponding inorganic or organic bases.

The trialkylsilyl group preferably contains 1-6 carbon atoms.

The hydrolysis of the tetrahydropyranyl and / or trialkylsilyl groups is carried out in known manner, preferably with acetic acid / tetrahydrofuran / water or with methanol / hydrochloric acid or sulfuric acid at temperatures between -10 and +150 ° G.

The starting compounds used are compounds of the general formula IIla

Bad OR4

wherein R 1, R 2, and R 4 each have the meaning given above and A 'represents the carbocycle of formula IXf, are novel and can be prepared by a compound of general formula IV

3, 2 3 4 where R, R, R and r each have the meaning given above and G represents the carbocycle of formula Ile is oxidized. One oxidation suitable reagent is the Collins reagent (pyridine chromium trioxide), the Jones reagent (Cr03 / H '/ acetone) and the sulfide reagent U2U3 "C; z ci eier r >>

Cl - in the latter case, when a carboxylic acid is used as starting material, it preferably protects, e.g. with a tert.butyldimethylsilyl group.

Compounds of general formula IV can be prepared by the known compound of general formula V

E

OR4 2 3 4 wherein R, R and R each have the meaning given above and E represents a carbocycle of the formula Vc A '

, A

RO

4

wherein the group represented by the symbol R in the formula Vc has the meaning given above, is reacted with a compound of the general formula VI

* Θ Λ i

5 ff) / \ ^ COOR

(r3) 3p ^ -ch2-ch ^ - VI

Wherein R is as defined above, R represents a naphthyl or phenyl group which is unsubstituted or substituted by a lower alkyl group, or represents a lower alkyl group, and X represents chlorine, iodine or bromine.

The reaction is carried out in a manner known per se, e.g. by a Wittig reaction, preferably in dimethyl sulfoxide at temperatures between 20 and 8 ° C.

The compounds used as starting compounds with the general precursor

flour VI, wherein R, R and X each have the meaning given above, are novel and can e.g. is prepared by the known 4-halogen-1-butene of the general formula VII

x-ch2-ch2-ch = ch2 VII

wherein X represents chloro, iodo or bromo, reacted with the known diazoacetic acid alkyl ester of the general formula VIII

n2ch-coor,; l VIII

represents an alkyl group of 1-8 carbon atoms, the isomer mixture obtained consisting of cyclopropane carboxylic acid alkyl esters of the general formula IX

CH_ 2 \ i

X-CH2-CH2-CH-CH-COOR'x IX

wherein R 'and X each have the meaning given above are cleaved in the cis and trans isomers, then the ester group is optionally hydrolyzed, then a racemate cleavage is optionally performed, and the free acid is optionally esterified to form of an ester having an alcohol of the formula R 1 - OH, wherein R 1 is the same as R 1, except hydrogen, and then reacting

with a phosphine compound of the general formula X

5 i

(R) 3P X

5 where R has the meaning given above.

The novel cyclopropane derivatives of general formula I wherein I

R 1 is hydrogen, can be converted to pharmaceutically tolerable salts by, e.g. neutralized with a corresponding amount of inorganic or organic bases.

7 U2U3

Pharmacologically tolerable salts of end products of general formula I are those with pharmacologically tolerable metal cations, ammonium and amine cations or quaternary ammonium cations.

Optically active compounds can be prepared from optically active intermediates using the synthesis described above. If racemic intermediates are used, racemic end products are obtained and these or precursor compounds thereof can then be resolved in a manner known per se in the optically active isomers thereof.

In the process of the invention, acids when hydrogen and esters are prepared when R 1 is an alkyl group of 1-8 carbon atoms, an optionally alkyl-substituted cycloalkyl group having a total of 3-10 carbon atoms, or an aralkyl group of 7-12 carbon atoms. If an acid is prepared, it can be converted to an ester of formula I wherein R R represents an alkyl group of 1-8 carbon atoms, an optionally substituted cycloalkyl group of 3-10 carbon atoms or an aralkyl group of 7-12 carbon atoms. with an ester corresponding to this meaning of R1. If the final products are in the form of esters, these can be converted to the free acids by hydrolysis.

The novel cyclopropane derivatives of the general formula I are highly effective in producing various biological reactions and must therefore be used for pharmacological purposes. Examples of such reactions may be cited: a uterine stimulating effect, an inhibition of gastric secretion, a bronchodilatory effect, a decrease in arterial blood pressure, a nasal decongestation, an inhibition of platelet aggregation, and a skin graft-promoting effect.

The various PGFjq analogous compounds of the general formula i are effective on uterus in situ at doses of 1 - 100 micrograms. The compounds are suitable for initiating births, for eliminating a delayed abortion and for menstrual induction. For this purpose, 0.1 - 20 mg / kg is used depending on the application per day. day.

Furthermore, the various PGF2α analogous compounds of general formula I are useful for reducing and suppressing excessive gastric secretion. The gastric secretion inhibitory effect was detectable on pentagastrin- and histamine-induced 142U3 δ gastric secretions in rats at doses of 1 - 100 µg / kg. The novel compounds of the general formula I are effective on rat stomach strips at doses of 1 - 100 µg. The amount to be administered is in doses of approx. 0.1-20 µg per kg body weight per day.

The various compounds of general formula I are suitable as swelling inhibitors. remedies for the nose of mammals such as humans. For this purpose, the compounds are used in amounts of from ca. 10 µg to approx. 20 mg per ml of a pharmacologically suitable liquid agent.

Furthermore, the various PGE 2 9 PGF2a compounds of general formula X are suitable for the treatment of asthma. Preferably, amounts of from about 10 to about 100 may be used. 0.1 to 20 µg per kg body weight 1 -4 times per day.

The various PGE2 and PGF2a compounds of general formula I are also useful for inhibiting platelet aggregation. The amount to be administered is in doses of approx. 0.1 and approx. 20 µg pr. kg body weight per day.

The various PGE1 compounds of general formula I are suitable for lowering blood pressure. For this purpose, the compounds are administered in single doses or in multiple sub doses at a total of 0.1 -20 µg per ml. kg body weight per day.

While the known prostaglandins in many fields of application exhibit only a short-term biological effect, the novel compounds prepared by the process of the invention exhibit a significantly longer lasting effect in addition to a more specific effect in eliciting prostaglandin-like reactions. Due to the longer lasting effect, it is sufficient to use fewer and smaller doses of the novel compounds to achieve a particular effect. For the purposes stated, the novel compounds are administered in various dosage forms, e.g. orally in the form of tablets, capsules or fluids, rectally in the form of suppositories or subcutaneously, intramuscularly or intravenously.

9 U2U3

In order to demonstrate the particular beneficial effect of the compounds prepared by the process according to the invention compared to known prostaglandins, comparative experiments have been made and the results are shown in the table below. The effect on rat uterus in situ is determined by the method of G.W. Bisset, J. Haidar, Z.E. Lewin "Memoirs of the Society for Endocrinology",

No. 14, Endogenous substances affecting the myometrium, edited by V.R. Pickles and R.J. Fitzpatrick, Cambridge University Press 1966, 185 - 198.

Table

Effect on rat uterus in situ after intravenous administration (mean, n = 3) Threshold "Effect duration dose (2 x threshold dose,

No. Compound (µg / kg minutes) 1 16,16-Dimethyl-2,3-trans (+) - methylenorostaglandin F (Example 3) 6.7 135 2 Prostaglandin F2a (known) 6.7 6 3 16, 16-dimethyl-2,3-trans (-) - methylene prostaglandin E2 (Example 9) 0.11 83 4 prostaglandin E2 (known) 5 10 5 16,16-dimethyl-2,3-trans (-) - methylene prostaglandin E2-methyl ester (Example 10) (5Ζ, 11α, 13Ε, 15α, 16a) -11,15-dihydroxy-9-keto-16-methyl-2,3-trans (-) methylene prostate 5,13-diacetic acid (example 14) o, 42 127 7 16,16-dimethylprostaglandin F2a (known) 0.83 14 8 Prostaglandin F2q (known) 8.3 9

It can be seen from the table that the introduction of hindering groups in position 16, e.g. at 16,16-dimethyl-prostaglandin F2a (German Publication No. 2,217,044), already leads to an extension of the duration of action, the half-life being of the order of 10 minutes (compound # 7). First, however, the simultaneous presence of a cyclopropane residue at position 2.3 leads to a substantial extension of the action time (half-life of several hours, compounds Nos. 1, 3, 5 and 6 in the table). For comparison purposes, the table also lists the duration of action of known prostaglandins (compounds no.

2, 4, 7 and 8).

The novel compounds can be administered as drugs in suitable drug forms together with pharmacologically inert excipients.

The process according to the invention is further illustrated by the following examples:

Example 1.

2,3-Trans-methylene-prostaglandin F2a · 40 mg of 2,3-methylene-trans-11, 15-bis-tetrahydropyranylprostaglandin F2a is dissolved in 2 ml of a mixture of acetic acid, tetrahydrofuran and water (3: 1: 1), and the solution is heated for 2 hours at 60 ° C.

After evaporation under reduced pressure, the residue is cleaved on 3 g of silica gel with chloroform containing 17% methanol to give the pure title compound, mp 108 - 112 ° C.

NMR spectrum (CDCl3) 90 MHz, i.a. signals at: 4 H (m) 5.45 vinyl protons 3 H 3.8 - 4.2 ppm CH-OH 3 H (^) 0.9 ppm methyl.

The 2,3-trans-methylene-1,1,15-bis-tetrahydropyranylprostaglandin F2a used as the starting compound is prepared as follows: a) 2- (2-Bromethyl) -cyclopropane carboxylic acid ethyl ester.

To a suspension of 2.48 g of copper powder heated in 22 g of 4-bromo-1-butene, slowly add 40 ml of diazoacetic acid ethyl ester dropwise with vigorous stirring. After 2 hours at 100 ° C, the mixture is filtered and the cis-trans isomeric cyclopropylcarboxylic acid esters are decomposed by chromatography on 900 g of silica gel with benzene as the eluent.

u U2K3

Trans-cyclopropane-2- (2-bromethy1) -carboxylic acid ethyl ester.

IR spectrum (methylene chloride), i.a. bands what: 1710, 1420, 1200 and 1180 cm "1.

NMR spectrum (CDCl3) 60 MHz, i.a. signals at: 2 H 4.17 ppm (0-CH 2 -CH 3) 2 H 3.45 ppm (-CH 2 -CH 2 ~ Br) 3 H 1.25 ppm (CH 3 -CH 2 -} M + = 220.

b) Trans-cyclopropane-2- (2-bromethyl) carboxylic acid.

To a cooled mixture of 6.4 ml of 33% hydrochloric acid and 1.7 ml of concentrated sulfuric acid is added with vigorous stirring 1 g of trans-cyclopropane-2- (2-bromoethyl) carboxylic acid ethyl ester. After 1 hour at room temperature, the solution is heated for 15 minutes at 100 ° C. The cooled solution is poured onto 60 ml of cold saturated aramonium sulfate solution and extracted three times with methylene chloride and the combined extracts are washed with water, dried and evaporated under reduced pressure. The residue is cleaved on 40 g of sillcagel with chloroform in 1% methanol (50 ml fractions) to give the title compound.

IR spectrum (methylene chloride), i.a. drilling time at: 3450 - 2700, 1700, 1460, 1215 cm "1.

NMR spectrum (CDCl3) 60 MHz, i.a. signals at: 1H 10.5 ppm (-COOH) 2H 3.42 ppm (-CH2-OH2-Br) 2H 1.83 ppm (CH-CH2-CH2-) M + = 193.

Trans-cyclopropane-2- (2-bromoethyl) -carboxylic acid methyl ester.

Dissolve 200 mg of the trans acid in 10 ml of methanol and treat at room temperature (20 ° C) with an ethereal diazomethane solution. After removal of the solvent under reduced pressure, the residue (220 mg) is chromatographed on silica gel with benzene to give the corresponding methyl ester.

12R spectrum (methylene chloride), i.a. bands at: 1720, 1210, 1120 cm "1.

NMR spectrum (CDCl3) 100 MHz, i.a. signals at: 3H 3.68 ppm COOCH-, 2H 3.45 (t) CH2-Br 2H 1.9 (m) CH2-CH2-Br.

The same compound can be prepared by treating the trans acid with 3-methyl-1-p-tolyltriazine.

c) 2- (2-Carboxy-1-trans-cyclopropyl) -ethyl-triphenylphosphonium bromide.

To 5 g of (-) - trans-cyclopropane-2- (2-bromethyl) carboxylic acid in 100 ml of absolute benzene is added 10 g of triphenylphosphine and refluxed for 42 hours. After removal of solvent under reduced pressure, the residue is cleaved on 600 g of silica gel with a chloroform-methanol-acetic acid mixture (300 ml fractions) to give the title compound.

IR spectrum (methylene chloride), i.a. bands at: 3400 - 3000, 1725, 1440, 1115 cm "1.

NMR spectrum (CDCl3) 60 MHz, i.a. signals at: 15 H 7.75 ppm (aromatic H) 2 H 3.8 ppm (CH 2 - P -) · d) 2,3-Trans-methylene-11, 15-bis-tetrahydropyranylprostaglandin F2a.

70 mg of sodium hydride are dissolved in 0.7 ml of dimethyl sulfoxide and kept for 40 minutes at 75 ° C under the nitrate. After cooling, the triphenylphosphonium salt of (-) - ethyl trans-cyclopropane carboxylic acid is added in 1 ml of abso-. add dimethyl sulfoxide to the brown solution.

142143 13

Then stir for 1.5 hours at room temperature, then 145 mg of 2β (3α-tetrahydro-pyranyloxy-1'-transoctenyl) -5β-hydroxy-3α-tetahydropyranyloxy-cyclopentane are added to 1.2 ml of this solution. acetaldehydlactol. The reaction mixture is allowed to stand for 15 minutes at room temperature, heated for 3 hours at 75 ° C, then poured onto 20 g of ice, carefully adjusted to a pH of 3 and extracted with methylene chloride. Chromatography on 20 g of silica gel with chloroform and 2% methanol gives the title compound in pure form.

iR spectrum (methylene chloride), i.a. ribbon at 3500, 1710 cm -1.

NMR spectrum (CDCl3) 90 MHz, i.a. signals at: 4 H (m) 5.4 ppm 2 H 4.7 ppm 3 H (¾-) 0.9 ppm.

Example 2.

By analogy to Example 1 and using similar starting compounds, the following compounds are prepared with forums; lane I: a) 2,3-Cis-methylene prostaglandin NMR spectrum (CDCl3) 90 MHz i.a. signals at: 4H 0.68 - 0.91 ppm _CH3, / <2

7H 1.9 - 2.4 ppm aliphaphic H

3H 3.51-4.16 ppm ^ CHOH

4H 5.15-5.75 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. ribbon by; 3580, 3400, 1710 - 1695 cm "1.

B) 2/3-Cis-methylene prostaglandin P2a ^ methyl ester.

NMR spectrum (CDG1) 90 MHz i.a. signals at: 4H 0.68 - 0.89 ppm -ΟΗ3, - <£ Γ-

7H 1.9 - 2.4 ppm aliphatic H

3H 3.58 ppm -0-CH3

3H 3.58 - 4.15 ppm> CHOH

4H 5.2-5.2 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1710 cm "1.

c) 2,3-Trans-methylene prostaglandin P2a methyl ester.

NMR spectrum (CDCl3) 90 MHz b1-a. signals at: 4H 0.7 - 0.89 ppm

7H 1.88-2.38 ppm aliphatic H

3H 3.6 ppm -0-CH3

3H 3.58-4.15 ppm> CHOH

4H 5.1 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3580, 34Q0, 1725 - 1705 cm-1.

d) 2,3-Trans-methylene prostaglandin F 2a ethyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.7 - 1.2 ppm -CH3 r <Ca

7H 1.88-2.38 ppm aliphatic H

3H 3.6 - 4.1 ppm> CHOH

2H 4.1 - 4.4 ppm -COOCl 4 4H 5.1 - 5.7 ppm vinylptotons.

IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm ”1.

E) 2,3-Cis-methylene prostaglandin F2a ethyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.7--1.18 ppm

7H 1.88 - 2.38 ppm aliphatic H

5H 3.6 - 4.4 ppm CHOH, -COOCHg-4H 5.1 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm "1.

Example 3

16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin F2a · 200 mg of 16,16-dimethyl-2,3-trans (+) -methylene-11,15-bis-tetrahydropyranyl-prostaglandin F2a is dissolved in 7 ml of a mixture of acetic acid / tetrahydrofuran / water (3: 1: 1) and kept for 5 hours at 40 ° C. After evaporation under reduced pressure, the residue is chromatographed on 23 g of silica gel with chloroform 7% methanol to give the pure compound as heading 20. [α] D = +88 ° (c ** 1.01 CHClg).

IR spectrum (methylene chloride), i.a. bands at: 3600 - 3400, 1695 cm "1.

NMR spectrum (CDCl3) 100 MHz, i.a. signals at:

4 H 5.5 ppm vinyl-H 6 H 'v' 4 ppm 3 x CH-OH

6 H 1.28 ppm 2 x CH 2 -C-.

The 16,16-dimethyl-2,3-trans (+) - methylene-11, 15-bis-tetrahydropyranylprostaglandin F2a used as the starting compound is prepared as follows: a) (+) - Trans-cyclopropane-2- (2- bromoethyl) carboxylic acid.

To 66 g of trans-cyclopropane-2- (2-bromethyl) carboxylic acid in 200 ml of methylene chloride is added 29 g of (-) - ephedrine in 200 ml of methylene chloride and the mixture is allowed to stand for 2.5 hours at 20 ° C. - Hexane crystals are formed, filtered and recrystallized from • 16 142143 methylene chloride / hexane and methylene chloride / ethyl acetate Melting point 125 - 126 ° C? lain 55 + 22 ° (c - 1.26 CHCl3). 20 methylene chloride / dilute hydrochloric acid releases the (+) acid: [a] D ~ + 75.3 ° (c - 1.94 CHCl 3).

b) 2- (2-Carboxy-1- (+) - trans-cyclopropyl) ethyl-triphenylphosphonium bromide.

To 6.3 g of (+) - trans-cyclopropane-2- (2-bromethyl) carboxylic acid in 150 ml of absolute benzene is added 10.3 g of triphenylphosphine and the mixture is refluxed for 65 hours. After cooling, the undone precipitated crystals are filtered off. Melting point 121 - 125 ° C; [α] p = + 17.5 ° (c = 1.18 CHCl 3). The IR and NMR spectrum correspond to the IR and NMR spectrum of the racemic compound.

c) 16,16-Dimethyl-2,3-trans (+) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin * 600 mg of sodium hydride is dissolved in 6 ml of absolute dimethyl sulfoxide and kept under nitrogen for 55 minutes at 75 ° C. After cooling, 2.1 ml of this solution is slowly dropped into a pre-prepared solution of 1.95 g of triphenylphosphonium salt of (+) - trans-cyclopropane-2- (2-bromoethyl) carboxylic acid in 5 ml of absolute dimethyl sulfoxide and the mixture is stirred under nitrogen for 45 minutes.

To a pre-prepared solution of 1 g of 28- (11116 ^^ 1-3) -α-tetrahydropyranyloxy-1'-transctenyl) -5α-hydroxy-3α-tetrahydropyranyloxycyclopentane acetaldehyde lactol in 1 ml of absolute dimethyl sulfoxide is added at 20 ° C. 4.5 ml of the above-prepared ylid solution and keep the mixture for 50 minutes at 60 ° C. After adding an additional 4.5 ml of the ylide solution, stir for an additional 1 hour at 60 ° C. The cooled reaction mixture is poured onto ice and the aqueous phase is adjusted to a pH of 3-5 and extracted three times with methylene chloride. The crude product obtained is chromatographed on 140 g of silica gel with chloroform and 1-5% methanol to give the title pure compound. [α] D = + 35.5 ° (c = 1.07 CHCl13).

IR spectrum (methylene chloride), i.a. bands at: 3500, 1695 cm "· 1.

NMR spectrum (CDCl3) 90 MHz, i.a. signals at:

4 5.5 ppm viny 1-H

2 H 4.6 ppm THP-H.

Example 4

By analogy to Example 3 and using similar starting compounds, the following compounds of formula I are prepared: a) 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin F 2a methyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 10H 0.7 - 0.89 ppm C23, - <ilr

7H 1.88-2.38. ppm aliphatic H

3H 3.55-3.6 ppm "0CS3

3H 3.58-4.15 ppm ^ CHOH

4H 5.2 - 5.8 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm-1.

b) 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin F 2a ethyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 13H 0.7 - 1.2 ppm -¾

7H 1.88 - 2.38 ppm aliphatic H

3H 3.6 - 4.1 ppm ^ CHOH

2H 4.1 - 4.4 ppm - COOCH 2 - 4H 5.1 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm-1.

c) 2,3-Trans (+) - methylene prostaglandin F2a 'NMR spectrum (CDCl3) 90 MHz i.a. signals at: 3H 0.9 ppm -CH3

3H 3.8 - 4.2 ppm 2> CHOH

4H 5.3 - 5.6 ppm vinyl protons.

IR spectrum (methylene chloride), inter alia, bands at: 3600, 3400, 1730 - 1710 cm -1.

d) 2,3-Trans (+) - methylene prostaglandin F 2a "methyl ester.

NMR spectrum (CPC13) 90 MHz i.a. signals at:

4H 0.7 - 0.89 ppm -CH 3, -CCS

7H 1.88-2.38 ppm aliphatic H

3H 3.6 ppm ~ 0-CH3

3H 3.58-4.15 ppm ^ CHOH

4H 5.1 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm "1.

e) 2,3-Trans (+) - methylene prostaglandin F 2a ethyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.7 - 1.2 ppm

7H 1.88-2.38 ppm aliphatic H

3H 3.6 - 4.1 ppm> CHOH

2H 4.1 - 4.4 ppm -COOCH2 ~ 4h 5.1 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm ”1.

Example 5, 16,16-Dimethyl-2,3-trans (+) -methylene prostaglandin E2 · 100 mg of 16,16-dimethyl-2,3-trans (+) -methylene-11,15-bis-tetrahydropylamine Dissolve ranyl prostaglandin F2a in 1 ml of absolute toluene and add 26.7 mg of tert.butyldimethylchlorosilane under nitrogen. The reaction solution is cooled to 0 ° C, 18 mg of triethylamine is added, stirred for 2.5 hours at 20 ° C, cooled to -30 ° C and slowly dropped over 35 minutes to a solution of 108 mg of N chlorosuccinimide in 4 ml of absolute toluene and 60 mg of dimethylsulfoxide. After a further 2.75 hours at -20 ° 0, 220 mg of triethylamine is added dropwise into 1 ml of pentane and worked up for an additional 10 minutes with ether / water. The residue (100 mg) is chromatographed on 8 g of silica gel with chloroform containing 2% methanol. In this way, 16,16-dimethyl-2,3'-trans (+) - methylene-11, 15 - bis-tetrahydropyranylprostaglandin E2-tert.butyldimethylsilylester is obtained.

IR spectrum (methylene chloride), i.a. bands at: 1735, 1695 cm-1.

50 mg of the above ester are dissolved in 0.7 ml of acetone, and at 0.2 ° C are added 0.2 ml of water and 0.25 ml of a solution of 246 mg of sodium acetate in 3 ml of acetone, 1 ml of water and 180 mg of acetic acid. After 45 minutes at 0 ° C and 1.5 hours at 25 ° C, the mixture is stirred and then worked up with ether.

The residue consisting of the acid is dissolved in 2 ml of acetic acid / water / tetrahydrofuran (3: 1: 1) and allowed to stand for 2.5 hours at 38 ° C. After evaporation under reduced pressure, the residue is chromatographed on 2.5 g of silica gel with chloroform containing 3% methanol. The pure connection specified in the heading is obtained.

IR spectrum (methylene chloride, including bands at: 1735, 1695 cm -1

NMR spectrum (CDCl3) 90 MHz, i.a. signals at: 4 H 5.3 - 5.8 ppm (vinyl protons) 5 H 3.7 - 4.2 ppm 2 x -CH-OH + -COOH.

Example 6

By analogy to Example 5 and using similar starting compounds, the following compounds of Formula I are obtained: 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin E2 methyl ester.

NMR Spectrum (CDC10) 90 MHz i.a. signals at: 10H 0.8 - 1.0 ppm -CH-2, 2H 2.56-3.2 ppm) COCH2 + 3H 3.6 ppm -COOCH ^ 4H 5.1-5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1745 - 1705 cm "1.

b) 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin E2 ethyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at:

13H 0.8 - 1.1 ppm -CH3, -O

1H 2H 2.6 - 3.3 ppm - C - CH 2 - 2H 4.1 - 4.3 ppm - COCH 2 - 4H 5.15 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1745 - 1705 cm "1.

c) 2,3-Trans (+) - methylene prostaglandin E2 methyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 4H 0.7 - 0.9 ppm - CH 3, 0 2H 2.55 - 2.95 ppm - C - CH 2 - 3H 3.65 ppm - COOCH 3 4H 5.1 - 5.65 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1740 - 1705 cm "1.

d) 2,3-Trans (+) - methylene prostaglandin E2-ethyl ester.

1421 A3 21 NMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.8 - 1.1 ppm “CS3 ~

ISLAND

2H 2.6 - 2.9 ppm - C - CH2 ~ 2H 4.1 - 4.25 ppm - COOCH2 - 4H 5.2 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride). Among other things, bands at: 3400, 1740 - 1705 cm "1.

Example 7

16,16-Dimethyl-2,3-trans (-) - methylene prostaglandin F2a.

109 mg of 16,16-dimethyl-2,3-trans (-) - methylene-11, 15-bis-tetrahydro-pyranylprostaglandin F₂O are dissolved in 3.5 ml of a mixture of acetic acid, tetrahydrofuran and water (3: 1: 1 ) and allowed to stand for 6 hours at 40 ° C. After evaporation under reduced pressure, the residue is chromatographed on 5 g of silica gel with chloroform containing 7% methanol to give ΟΛ the pure title compound. [o] * +13, 8 * (c = 1.02 ct; ci3).

IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1695 cm-1.

NMR spectrum (CDCl3) 90 MHz, i.a. signals at:

4 H 5.3 - 5.7 ppm vinyl-H 7 H 3.9 - 4.3 ppm 3 x 3 CH-OH + COOH

CH3 \ 1.28 ppm ^ ch3 ^

The 16,16-dimethyl-2,3-trans (-) - methyl-11,15-bis-tetrahydropyranylprostaglandin F2a used as the starting compound can be prepared as follows: a) (-) - Trans-cyclopropane-2- ( 2-bromoethyl) carboxylic acid.

By analogy as described in Example 3 a), with (+) - 20-ephedrine, the title compound is prepared. [α] D = -75.0 ° (c = 1.56 CHCl 3).

142143 22

The spectroscopic data of the title compound are identical to the (+) acid data.

b) 2- (2-Carboxy-1- (-) - trans-cyclopropyl) ethyl-triphenylphosphonium bromide.

To 61 g of (-) - trans-cyclopropane-2- (2-bromethyl) carboxylic acid in 200 ml of absolute benzene is added 10 g of triphenylphosphine and the mixture is refluxed for 63 hours. After cooling, the precipitated crystals are filtered off. Melting point 120 - 122 ° C [α] D = 17.3 (c - 1.19 CHCl 3).

The IR and NMR spectra correspond to the spectra of the enantiomeric compound.

c) 16,16-Dimethyl-2,3-trans (-) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin 2α * 300 mg sodium hydride is suspended in 3 ml of absolute dimethyl sulfoxide and left under nitrogen for 45 minutes at 75 After cooling, 0.9 ml of this solution is slowly dripped to a pre-prepared solution of 1 g of triphenylphosphonium salt of (-) - trans-cyclopropane-2- (2-bromethyl) carboxylic acid in 2.5 ml of absolute dimethyl sulfoxide, and stir for 45 minutes under nitrogen.

To a solution of 500 mg of 23- (41,4'-dimethyl-3, a-tetrahydropyranyl-oxy-11-trans-octenyl) -5a-hydroxy-3a-tetrahydropyranyloxycyclopentane-acetaldehyde lactol in 0.6 ml of absolute tetrahydrofuran is slowly dripped 1 , 9 ml of the above-prepared ylid solution. After 40 minutes at 60 ° C, an additional 1.9 ml of ylide solution is added dropwise and the mixture is kept for an additional 1 hour at 60 ° C. The cooled reaction mixture is poured onto 100 g of ice and the aqueous phase is adjusted to a pH of 3 - 4 and extracted three times with methylene chloride. The crude product obtained is purified by chromatography on 40 g of silica gel to give the pure title compound with chloroform and 2% methanol.

IR spectrum (methylene chloride), i.a. bands at: 3500, 1695 cm-1.

23 142143

Example δ.

By analogy to Example 7 and using similar starting compounds, the following compounds of formula I are prepared: a) 16,16-Dimethyl-2,3-trans (-) -methylene prostaglandin F 2 (j-methyl ester).

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 10H 0.7 - 0.89 ppm -CH

7H 1.88 - 2.38 ppm aliphatic H

3H 3.6 ppm -COOCELj

3H 3.58-4.15 ppm> CHOH

4h 5.1 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm "1.

b) 16,16-Dimethyl-2,3-trans (-) - methylene prostaglandin F 2a ethyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 13H 0.7 - 1.2 ppm

7H 1.88 - 2.38 ppm aliphatic H

3H 3.6 - 4.1 ppm> CHOH

2H 4.1 - 4.4 ppm - COOCH 2 4H 5.1 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm "1.

c) 2,3-Trans (-) - Methylene Prostaglandin Melting Point 103 - 105 ° C.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 4H 0.9 ppm

3H 3.7 - 4.3 ppm) CHOH

4H 5.3 - 5.6 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3600, 3500, 1695 - 1710 cm "1.

D) 2,3-Trans (-) - methylene prostaglandin F 1 -methyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 4H 0.7 - 0.89 ppm

7H 1.88 - 2.38 ppm aliphatic H

3H 3.6 ppm -COOCH3

3H 3.58 - 4.15 ppm> CHOH

4H 5.1 -5.7 ppm vinyl protanes.

IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 -1705 cm ”1.

e) 2,3-Trans (-) - methylene prostaglandin F 2a ethyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.7 - 1.2 ppm -CH 2, - <r: p

7H 1.88 - 2.38 ppm aliphatic H

3H 3.6 - 4.1 ppm> CHQH

2H .4.1 - 4.4 ppm. -COOCHg 4H 5.1 - 5.7 ppm vinyl protons.

IR spectrum, (methylene chloride), inter alia, bands at: 3580, 3400, 1725 - 1705 cm -1.

Example 9

16,16-Dimethyl-2,3-trans (-) -methylene prostaglandin E2.

177 mg of 16,16-dimethyl-2,3-trans (-) - methano-11,15-bis-tetrahydro-pyranylprostaglandin F2a are dissolved in 1.5 ml of absolute toluene. A solution of 47.2 mg of tert.butyldimethylchlorosilane in toluene is dropped under nitrogen. The reaction solution is cooled to 0 ° C, 32 mg of triethylamine is added, stirred for 2.5 hours at 2 ° C, cooled to -30 ° C and slowly drizzled to a solution of 191 mg of N-chlorosuccinimide in 6 ml of absolute toluene and 106.3 mg of dimethyl sulfide. After 2 hours at -30 ° C / -20 ° C, 300 mg of triethylamine is added in 1 ml of pentane which is stirred for 10 minutes and worked up with ether / water. The residue (192 mg) is chromatographed on 12 g of silica gel with chloroform containing 1¾ methanol.

142143 25

The obtained silylester (IR spectrum (methylene chloride), including bands at 1735 and 1675 cm -1) is dissolved in 2.7 ml of acetone. To the solution cooled to 0 ° C is added 0.9 ml of water and 1.2 ml of a solution of 246 mg of sodium acetate in 3 ml of acetone, 1 ml of water and 180 mg of acetic acid. The reaction mixture is stirred for 30 minutes at 0 ° C and for 1.5 hours at 25-30 ° C and then worked up with ether. The residue (IR spec. Drum (methylene chloride), including bands at 3500, 1735 and 1695 cm -1) is dissolved in 3 ml of acetic acid, water and tetrahydrofuran (3: 1: 1) and stirred for 6 hours at 40 ° C. After evaporation under reduced pressure, the residue is chromatographed on 4.5 g of silica gel with chloroform containing 2% methanol to give the title compound.

IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1735 and 1695 cm "1.

NMR spectrum (CDCl3) 90 MHz, i.a. signals at approx .:

ISLAND

2.6 - 2.85 ppm (1H) H

OH

5.2 - 5.6 ppm (4H)

H

Example 10.

By analogy to Example 9 and using similar starting compounds, the following compounds of formula I are prepared; a) 2,3-Trans (-) - methylene prostaglandin Ej.

Melting point 105 - 107 ° C.

NMR Spectrum (CDCl3) 90 MHz i.a. signals at:

2H 3.8 -4.2 ppm CH-GH

3H 0.85 - 0.90 ppm -CH 3 4H 5.2 -5.6 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 142143 26 3600, 3500, 173Q - 1735, 1695 cm ”1.

b) 16,16-Dimethyl-2,3-trans (-) - methylene prostaglandin E2 methyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 10H 0.8 - 1.0 ppm ~ CH3, - <1 ^ - 2H 2.56 - 3.2 ppm -COCH2 ~ 3H 3.6 ppm -C00CH3 4h 5.1 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1740 - 1705 cm ”1.

c) 16.16 "Dimethyl-2,3-trans (-) - methylene prostaglandin E2 ethyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 13H 0.8 - 1.1 ppm - CH3, 2H 2.6 - 3.3 ppm - COCH2 - 2H 4.1 - 4.3 ppm - COQCH2 - 4H 5.15 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1745 - 1705 cm ”1.

d) 2,3-Trans (-) - methylene prostaglandin E 2 -methyl ester.

NMR spectrum (CDCl3) 90 MHz i.a. signals at: 4H 0.7 - 0.9 ppm - CH3, * <1I - 2H 2.5 - 2.95 ppm - COCH2 - 3H 3.65 ppm - COOCH3 4H 5.1 - 5.65 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1740 - 1705 cm-1.

e) 2,3-Trans (-) - methylene prostaglandin E2 ethyl ester.

272U3 NMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.8 - 1.1 ppm 2H 2.6 - 2.9 ppm - COCH2 - 2H 4.1 - 4.25 ppm - COOCH ^ 4H 5.2 - 5.7 ppm vinyl protons.

IR spectrum (methylene chloride), i.a. bands at: 3400, 1740 - 1705 cm-1.

Example 11.

16,16-Dimethyl-9α, 11α, 158-trihydroxy-2,3- (+) -methylene-prosta '-' S-cis, -13-trans-diacetic acid.

230 mg of 16,16-dimethyl-9a-hydroxy-11a, 158'-bis-tetrahydropyranyl-oxy-2,3 - (+) - methylerr-prosta-5-cis, 13-trans-diacetic acid is dissolved in 15 ml of a mixture of acetic acid, tetrahydrofuran and water (3: 1: 1) and allowed to stand for 42 hours at room temperature. After evaporation under reduced pressure, the residue is chromatographed on 14 g of silica gel with chloroform and 4% methanol to give the pure title compound.

Thin layer chromatography: benzene / dioxane / additive (20: 10: 1) R R value = 0.52.

IR spectrum (methylene chloride): bands at 3600, 3500, 1710 -1695 cm "1.

NMR spectrum (CDCl3): i.a. signals at:

4 H approx. 5.5 ppm vinyl H

3 H approx. 4 ppm 3 x CHOH

The 16,16-dimethyl-9α-hydroxy-11α, 15β-bis-tetrahydropyranyloxy-2,3- (+) -methylbenzene-prosta-5-cis, 13-trans-diacetic acid used as starting material can be prepared as follows a) 5a-Hydroxy-28- (3, -oxo-4,4,4-dimethyl-trans-1, "octenyl) 3a-p - phenylbenzoyloxy-1a-cyclopentaneacetic acid Y-lactone.

142143 28

A solution of 124.8 g of dimethyl 2-oxo-3,3-dimethylheptyl phosphonate in 170.3 ml of absolute dimethoxyethane is added with stirring to a cold (5 ° C) suspension of 11.35 g of sodium hydride in 994.5 ml of absolute dime. -thoxyethan. The mixture is stirred for 1 hour at 20 ° C, the clear yellow solution is cooled to -18 ° C and then a solution of the optically active aldehyde (2 (3-carboxaldehyde-5α-hydroxy-3α) cooled to 2 ° C is added). p-phenylbenzoyloxycyclopentaneacetic acid-Y-lactone) in 2109 ml of absolute dimethoxyethane. After 2 hours at about 0 ° C, the mixture is cooled to about -15 ° C and adjusted to a pH of 6 by dropwise addition of glacial acetic acid. In vacuo, and 2 liters of petroleum ether are added to the residue (201.6 g of tan oil) to give off white crystals during the night, mp 100 - 101.5 ° C.

b) 5α-Hydroxy-2β- (3'-hydroxy-4 ', 4'-dimethyl-trans-11-octylene) -3α-β-phenylbenzoyl-1α-cyclopentaneacetic acid Y-lactone.

A solution of 53.6 g of ketone (Example 11a) in 281 ml of absolute dimethoxyethane is added dropwise over 5 minutes to 734.6 ml of a cooled zinc borohydride-dimethoxyethane mixture (1 ml contains 28.7 mg of zinc borohydride). . The mixture is stirred for 3.5 hours at 2 - 5 ° C and for an additional 45 minutes at 5 -1 ° C. The mixture is then cooled to -15 ° C and adjusted to a pH of 6 with a 10% aqueous sodium hydrogen tartrate solution (about 150 ml). To the reaction mixture is added 3x1 liters of ether and decanted off. The organic phase is washed twice with 1 liter of saturated saline solution each time, dried and evaporated in vacuo to give 59 g of a mixture of the α- and β-isomers which is decomposed by chromatography on 9 kg of silica gel. With methylene chloride / ethyl acetate (92: 8), 30 g of the apolar α-isomer is isolated and with methylene chloride / ethyl acetate (91: 9) elute 9 g of the isomer.

c) 3a, 5a-Dihydroxy-2β- (3'B-hydroxy-4 ', 4'-dimethyl-trans- [1-octenyl) - 1a-cyclopentaneacetic acid Y-lactone.

Dissolve 7.3 g of B-alcohol (Example 11b) in 306 ml of absolute methanol and, under nitrogen, add 306 mg of sodium in 15.3 ml of absolute methanol and allow the mixture to stand at room temperature for 5 hours. Then, the reaction mixture is cooled using an ice bath and over 20 minutes, 26 ml of a 101 methanolic tartaric acid solution is added. After distilling off the solvent in vacuo, the crystalline residue is partitioned between methylene chloride and saturated brine, the organic phase is dried and evaporated, and the crystalline residue is chromatographed on 500 g of silica gel with benzene and 5% acetone. This gives 5.0 g of diol in the form of a viscous oil.

Thin layer chromatogram: toluene / acetone (2: 1) Rf value = 0.2.

d) 3α, 5α-Dihydroxy-2β- (3′β-hydroxy-4β, 4′-dimethyl-trans-1′-octenyl) - 1-cyclopentaneacetic acid-Y-lactone-3,3′-bis-tetrahydropyranyl ether.

A solution of 5 g of diol (example uc) in 285 ml of absolute toluene is added at -10 ° C to a solution of 4.28 g of dihydropyran and 100 mg of p-toluenesulfonic acid in 40.7 ml of absolute toluene and stirred for 1.5 hours. at room temperature. Then the mixture is washed with 150 ml of 10% potassium hydrogen carbonate solution and then with 400 ml of saturated brine. The aqueous phases are extracted with benzene and the organic phases are evaporated in vacuo. 8.4 g of oily crude product are obtained which are chromatographed on 450 g of silica gel. Using toluene and 5% acetone, elute 7.0 g of the pure title compound.

e) 2β- (4 ', 4'-Dimethyl-31β-tetrahydropyranyloxy-1'-trans-ocphenyl) -5α-hydroxy-3α-tetrahydropyranyloxycyclopentane acetaldehyde-Y-lactyl.

A solution of 7.0 g of bis-tetrahydropyran ether (example d) in 300 ml of absolute toluene is cooled to -70 ° C and 25 ml of dlisobutyl aluminum hydride solution (20% in toluene) is added over 25 minutes. After 1 hour, 185 ml of tetrahydrofuran / water (2: 1) is added to the solution which is filtered and the filtrate is washed with saturated sodium chloride solution, dried and evaporated. This gives 5.9 g of the title compound (isomer mixture).

f) 16,16-Dimethyl-9a-hydroxy-11a, 15β-bis-tetrahydropyranyloxy-213- (+) -methylene-prosta-5-cis, 13-trans-diacetic acid, 800 mg of sodium hydride is suspended in 8, 3 ml of absolute diraethylsulfoxide and kept for 45 minutes at 75 ° C under nitrogen. 2.8 ml of this solution is slowly dropped at room temperature to a pre-prepared solution of 2.55 g of triphenylphosphonium salt of (+) - trans-cyclopropane-1- (2-bromethyl) carboxylic acid in 6 ml of absolute dimethyl sulfoxide and stirred under nitrogen. for another 80 minutes.

1421 A3 30

To a solution of 644 mg of 20- (41,4'-dimethyl-3'3-tetrahyclropyra-nyloxy-1'-trans-octenyl) -5α-hydroxy-3α-tetrahydropyranyloxycyclopentanacetaldehyde-γ-lactol in 2 ml of absolute dimethyl sulfoxide and 1 ml of absolute tetrahydrofuran slowly drop 2.8 ml of the ylide solution prepared above. After 40 minutes standing at 55 ° C, an additional 2.7 ml of ylide solution is added dropwise and stirred for another 2 hours at 55 ° C. The cooled reaction mixture is poured onto 120 g of ice and the aqueous phase is adjusted to a pH of 3- 4 and extracted four times with 120 ml of methylene chloride each time. The organic phase is washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The resulting crude product is chromatographed on 75 g of silica gel to give the purified title compound with chloroform and 2 - 3% methanol.

Thin layer chromatography: ethyl acetate and 10% methanol R 2 value = 0.49.

IR spectrum (methylene chloride): bands at 3500, 1710 - 1695, 1200 and 1030 cm "*.

NMR Spectrum (CDCl)): 100 MHz, i.a. signals at: 4 H 5.8-5.2 ppm vinyl protons

2 H 4.7-4.4 ppm THP-H

9 H 0.9-0.8 ppm methyl-H.

Example 12.

16,16-Dimethyl-11a, 150-dihydroxy-9-keto-2,3 - (+) - methylene-prosta-5-cis, 13-trans-diacetic acid.

295 mg of 16,16-dimethyl-9a-hydroxy-11a, 150-bis-tetrahydropyranyl-oxy-2,3 - (+) - methylbene-prosta-5-cis, 13-trans-diacetic acid are dissolved in 3 ml of absolute toluene, and under nitrogen 89 mg of tert.butyldimethylchlorosilane is added. The reaction solution is cooled to 0 ° C and slowly a solution of 60 ml of triethylamine in 0.6 ml of absolute toluene is added dropwise. After 48 hours at room temperature, the mixture is cooled to -25 ° C and a pre-cooled solution of 324 mg of N-chlorosuccinimide in 13 ml of absolute toluene and 180 mg of dimethyl sulfide is slowly added dropwise over 30 minutes. After a further 2.5 hours standing, 502 mg of triethylamine is dropped into 2 ml of pentane and the mixture is stirred for an additional 20 minutes at room temperature and worked up with ether / water. The residue is dissolved in 15 ml of acetic acid / tetrahydrofuran / water (3: 1: 1) and allowed to stand for 43 hours at room temperature. After evaporation under reduced pressure, the residue is chromatographed on 15 g of silica gel. The pure title compound is eluted with chloroform and 3% methanol.

Thin layer chromatography: chloroform and 10% methanol R 2 value = 0.27.

IR spectrum (methylene chloride): bands at 3600, 1740 and 1695 cm NMR spectrum (CDCl3): i.a. signals at:

4 H 5.8-5.3 ppm vinyl H

4 H 3.7 - 4.2 ppm 2 x CH-OH

Example 13

(5Z, 9a, 11a, 13E, 15a) -9,11,15-trihydroxy-16-n-butyl-2,3-trans (-) - methylene-prosta-5,13-dienoic acid. * 600 mg of sodium hydride is suspended in 6 ml of absolute dimethylsulfoxide and kept under nitrogen for 45 minutes at 75 ° C. After cooling, 4.5 ml of this solution is slowly dripped to a pre-prepared solution of 4.08 g of 2- (2-carboxy-1 - (-) - trans-cyclopropyl) ethyl-triphenylphosphonium bromide in 10 ml of absolute dimethyl sulfoxide and stirred. then for 35 minutes under nitrogen.

To a solution of 2.1 g of 2β- (4'-n-butyl-3'a-tetrahydropyranyloxy-1'-trans-octenyl) -5a-hydroxy-3a-tetrahydropyranyloxycyclopentane-acetaldehyde lactol in 6 ml of absolute tetrahydrofuran and 6 ml dimethylsulfoxide is slowly dipped 8 ml of the above-prepared ylid solution. After 60 minutes at 50 ° C, 8 ml of ylide solution is again dripped and the mixture is kept for an additional 1 hour at 50 ° C. The cooled reaction mixture is poured onto 150 g of ice and the aqueous phase is adjusted to a pH of 3 - 4 and extracted three times with methylene chloride. The crude product obtained is purified by chromatography on 190 g silica gel to give chloroform and 2% methanol (5Z, 9a, 11a, 13E, 15a) -9,11,15-trihydroxy-16-n-butyl-2,3- trans - (-) - methylene-prosta-5,13-dienoic acid-ll, 15-bis-tetrahydropyranyl ether.

200 mg (53, 9α, 11a, 13E, 15a) -9,11,15-trihydroxy-16-n-butyl-2,3-trans- (-) -methylene-prosta-5,13- diacid-11, 15-bis-tetrahydro-pyranyl ether is dissolved in 7 ml of a mixture of acetic acid, tetra-hydrodrofuran and water (3: 1: 1) and kept for 2 hours at 35 ° C. After evaporation under reduced pressure at 25 ° C, the residue is chromatographed on silica gel with chloroform and 2 - 5% methanol to give the pure title compound.

IR spectrum (methylene chloride), i.a. bands at 3600 - 3300 and 1720 - 1630 cirf1, NMR spectrum (CDCl3) 90 MHz, bl.ft. signals at about: 0.7 - 1.0. ppm (7H) -CH

3.8 - 4.2 ppm (7H) + QH, -COQH, X

H OH

5.35 - 5.6 ppm (4H) vinyl protons.

Analogously, (5Z, 9a, 11a, 13E, 15a, 16a) -9,11,15-trihydroxy-16-methyl-2,3-trans - (-) -methylene-prosta-5,13- .

IR Spectrum (KBr), i.a. bands at 3400 "3600 and 1695 cm NMR Spectrum (QDCl 3) 90 MHz, including signals at: 0.88 ppm (3H) -CH3 (C2q) 0.92 ppm (3H) -CH3 (Clg)

H

0.8-1 ppm (1H).

3.8 - 4.2 ppm (3H)> CHOB (C9, C10, C15) 4.4 - 4.8 ppm (2H) (-COOH, OH) 5.3 - 5.7 ppm (4H) vinyl protons.

33 142143

Example 14.

(5Z, 11α, 13E, 15α) -11,15-dihydroxy-16-n-butyl-9-keto-2,3-trans (-) - methylene-prosta-5,13-diacetic acid.

600 mg of the (5Ζ, 9α, 11α, 13Ε, 15α) described in Example 13 ~ 9,11,15 - trihydroxy-16-n-butyl-2,3-trans (-) - methylene-prosta-5, 13-diacetic acid - 11,15-bis-tetrahydropyranyl ether is dissolved in 100 ml of absolute acetone and oxidized at -20 ° C according to Jones. After 1 hour 0.5 ml of methanol is added, after a further 10 minutes the suspension is poured into 200 ml of ice water and extracted three times with methylene chloride, the organic phase is washed with water, dried with sodium sulfate and evaporated and the residue is kept for 40 minutes. at 409C. .

in 60 ml of acetone / water (2: 1) and 0.5 ml of 2N hydrochloric acid. Neutralize with 2N sodium hydroxide solution, evaporate the acetone and extract the aqueous solution four times with methylene chloride, dry over sodium sulfate, evaporate and chromatograph over 45 g of silica gel with a chloroform-methanol mixture.

IR spectrum (methylene chloride), i.a. bands at 3600 - 3300 and 1740 - 1690 cm-1.

NMR spectrum (CDCl3) 90 MHz, i.a. signals at about: 0.75 - 1.0 ppm (7H), -CH, J-

2.6 - 2.9 ppm (2H) HY

3.9 - 4.2 ppm (2H)

g OH

5.3 - 5.7 ppm (4H) vinyl protons.

Analogously, (5Z, 11α, 13E, 15a, 16cx) is obtained - 11,15-dihydroxy-9-keto-16-methyl-2,3-trans (-) - methylene-prosta-5,13-diacetic acid.

Claims (1)

IR Spectrum (KBr), i.a. bands at 3450 - 3620, 1740 and 1695 cm -1. NMR Spectrum (CDC1-) 90 MHz, inter alia, signals at: H 0.7 - 1 ppm (7H) -CH3 (C16) / -CH3 (C2Q ), 2.55 - 2.92 ppm (2H) -CH2 - (C1) 3.8 - 4.1 ppm (2H) ✓CHQH (CU, C15) 5.3 - 5.7 ppm (4H) vinyl protons 5.7-5.87 ppm (3H) (~ COOH, OH) Patent Claims Analogous process for the preparation of racemic or optically active 2,3-methylbenzene-prstagstagin or E E deriv derivatives of the general formula X OH wherein D represents a is a hydrogen or an alkyl group of 1-8 carbon atoms, an optionally alkyl-substituted cycloalkyl group having a total of 3-10 carbon atoms, or a carbocycle of the formula Ile or Ild HO \ \ O * "S S HO ° \ Ud HO7, κ 142 1 A3 aralkyl group having 7-12 carbon atoms and R and R represent hydrogen or an alkyl group having 1-4 carbon atoms / or, if R 1 is hydrogen, pharmaceutically tolerable salts thereof with bases, characterized in that the protecting group (s) R in a connection to the general fo Rmel III C00R1 HI OR4 12 3 4 wherein R, R and R are each as defined above, R represents a trialkylsilyl or tetrahydropyranyl group, and A represents a carbocycle of formula Ile or Ilf HO