FI58117B - FREQUENCY REQUIREMENT FOR THERAPEUTIC TREATMENT OF 2,3-METHYLENE PROSTAGINES - Google Patents

Description

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Patent- och refiitentynltan AimMcm utlaftf och utUkrift * n pubiieund 29 · 08.80 (32) (33) (31) Requested «toikuut — Bugtrd priority 09-07.73 OU.05.7 ^ Switzerland-Switzerland (CH) 9959 / T3

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(71) Sandoz AG, Basel, Switzerland-Switzerland (CH) (72) Pietro Bollinger, Bottmingen, Switzerland-Switzerland (CH) (7 * 0 Oy Kolster Ab (5 * 0 Method for the preparation of therapeutically useful 2,3-methylene prostaglandins - Förfärande for the treatment of therapeutic agents 2,3-methylprostaglandin

The present invention relates to a method of developing a novel formula

S

D r2 ^ 3 V ^ XC00R1 *

OH

for the preparation of optically active or racemic compounds according to the formula wherein D is a carbon ring of the formula -0 58117 2

OH

! O

cc - cc HO '"HO' '

Ilc Ild 1. ... ..2.3.

R is hydrogen or an alkyl group having 1 to 2 carbon atoms, and R and R represent hydrogen or an alkyl group having 1 to 1 carbon atoms.

In the formulas Ilc-IId shown here, the dashed hyphens indicate that the substituents in the οί configuration are attached to the cyclopentane ring, i.e., are below the level of the cyclopentane ring. are above the level of the cyclopentane ring. The tortuous hyphen in formula C-15 indicates that the hydroxyl group may be -Ur or -configurate i os s a.

The novel 2,3-methylene prostaglandins of the formula I are prepared by hydrolytic cleavage of the protecting group or protecting groups R of the formula COOR111.

0RU

12 3, wherein R, R and R are as defined above, 1+. „. ...

R is a tetrahydropyranyl group, and A is a carbon ring of the formula

pH

ί 0 kv Is it ^ hV '' k.

Ile Ilf

The hydrolysis of the tetrahydropyranyl groups is carried out in a manner known per se, preferably with a mixture of acetic acid, tetrahydrofuran and water, a mixture of methanol and hydrochloric acid or sulfuric acid at temperatures of -10 to 150 ° C.

3 5811 7 Used as starting materials of formula COOR 1 IIIa

A 'k RJ

OR

the capped compounds wherein R 1, R 2, R 2 and R 2 are as defined above and A is a carbon ring of formula IIf are novel and can be prepared by oxidation of the formula

CR IV

wherein R 1, R 2, R 2 and R 2 are as defined above and G is a carbon ring of formula IIe. Suitable reagents for oxidation are Collis reagent (pyridine bromide trioxide), Jones reagent (CrO 2 / H + / acetone) and sulfide reagent / CH 3 ° (z-s, Z = Cl or Jk).

O-,

“V

o in which case, when a carboxylic acid is used as starting material, it is preferably protected, e.g. with a tert-butyldimethylsilyl group. Compounds of formula IV may be prepared by reacting QR 4 2 of formula 4 581 1 7. a known compound according to b, wherein in the formula R, R and R are as defined above, and E is a k 'of formula s-x

RO

k ...

wherein R is as defined above to react with a compound of formula

Cl 1 X ^ CO® (R5) 3 ^ -ΟΗ2-ΟΗ2 - ^ "^^

VI

wherein R 1 is as defined above, R 1 is a naphthyl or phenyl group which is unsubstituted or substituted by a lower alkyl group, or R 1 is a lower alkyl group, and X is chlorine, iodine or bromo.

The reaction is carried out in a manner known per se, for example by the Wittig reaction, preferably at temperatures of 20 to 0 ° C. The compounds of the formula VI used as starting materials, in which R1, R1 and X have the same meaning as above, are novel and can be prepared, for example, by reacting the known i * -halogen-1-butene of the formula

x-ch2-ch2-ch = ch2 VII

wherein X is chlorine, iodine or bromine, to react with a known diazoacetic acid alkyl ester of formula

N2CH-COCR'1 VIII

wherein R'1 is an alkyl group having 1 to 2 carbon atoms, a mixture of isomers of a cyclopropanecarboxylic alkyl ester of the formula 5 58117

X-CH2-CH2-CH-— CH-COOR 'IX

wherein R'1 and X are as defined above for the decomposition into cis and trans isomers, after which the ester group R'1 is optionally hydrolysed, after which the racemate is optionally decomposed, after which the free acid is optionally esterified in a manner known per se and then reacted with phosphine. with a compound of formula

(r5) 3p X

where Re has the above meaning.

Optically active compounds are obtained from optically active intermediates according to the process steps described above. When racemic intermediates are used, racemic end products are obtained, these or their precursors can be divided into their optically active isomers in a known manner.

The process according to the invention gives acids when R 1 represents hydrogen and esters when R 1 represents an alkyl radical having 1 to 2 carbon atoms.

The new 2,3-methylene prostaglandins of the formula I are very effective as inducers of various biological reactions and are therefore suitable for pharmacological purposes. For example, the following are some of these reactions: uterine stimulating effect, prevention of gastric fluid secretion, bronchodilator effect, lowering of arterial blood pressure, reduction of nasal congestion, prevention of blood particle aggregation, and skin graft promoting effect.

Various PGFs of formula I. .-type compounds are active in the uterus in situ at doses of 1-100 .mu.g. They are suitable for initiating childbirth, preventing abortion, and initiating menstruation. For this purpose, 0.1-20 mg / kg per day is always used, depending on the method of use. The various PGF2β-type compounds of the formula I are still suitable for reducing and preventing the secretion of excessive gastric fluid. The inhibitory effect on gastric secretion could be demonstrated by the inhibition of pentagastrin- and histamine-induced gastric secretion in rats at doses of 1-100 μg / kg. In the gastric stiffening of rats, the new compounds of the formula I were effective in doses of 1-100. The amounts to be administered are about 0.1-20 pg / kg body weight per day.

6 581 1 7

Various compounds of formula I may be used as anti-edematous agents in mammals and humans. For this purpose, the compounds are used in amounts of from about 10 to about 20 mg per ml of pharmacologically acceptable liquid medium.

The various PGE and PGF compounds of formula I are still suitable for the treatment of asthma. Preferably, amounts of about 0.1-20 μg per kg of body weight are used 1-1 + times a day.

The various PGE and PGF compounds of formula I are also suitable for blood particle doi.

prevention of association. Doses ranged from about 0.1 to about 20 ug per kg of body weight per day.

The various PGE compounds of formula I are suitable for lowering blood pressure. For this purpose, the compounds are taken as a medicament in a single dose or in several sub-doses totaling from 0.1 to 20 μg per kg of body weight per day.

While the hitherto known prostaglandins in several applications have shown only a short-term biological effect, the novel compounds according to the invention are characterized by a considerably longer duration of action in addition to the specific effects of their prostaglandin-like reactions. Due to the longer duration of action, fewer and lower doses of the new compounds are sufficient to produce a certain effect. For these purposes, the novel compounds are administered as medicaments in various dosage forms, e.g. orally in the form of tablets, capsules or liquids, rectally as suppositories or subcutaneously, intramuscularly or intravenously.

To demonstrate the beneficial effect of the compounds of the invention over known prostaglandins, comparative experiments have been performed, the results of which are shown in the table below. The effect on the rat uterus in situ is defined in G.W. Bisset. H. Haidar, Z.E. Levin, "Memoirs of the Society for Endocrinology," no. 1L, Endogenous substances affecting the Myometrium, advanced by V.R. Pickles and R.J. Fitzpatrick, Cambridge University Press 1966, pp. 185-198.

7 581 1 7

Table

Effect on Swedish uterus after in situ intravenous excitation (mean, n = 3) No. Compound Threshold dose Exposure time jig / kg (2 x threshold dose) min.

11,16-dimethyl-2,3-trans (+) - methylene prostaglandin F? 6.7 135 (Example 3) 2 Prostaglandin (known) 6.7 6 3 16,16-dimethyl-2,3-trans (-) - 4-methylene-prostiglandin 0.11 83 (Example 9) k Prostaglandin E2 (known) ) 5 10 5 16,16-dimethyl-2,3-trans (-) - methylene-prostaglandin E-methyl ester 0.053 105 (Example 10) 6 (5Z, 11% 13Ε, 15 <χ, ΐ6ο () - 11.15 dihydroxy-9-keto-16-methyl-2,3-trans- (-) - methylene-prosta-5,13-dienoic acid 0,1 + 2,127 _____ i§example_11 + _) _______________________________________________________ 7,16,16-dimethyl-prostaglandin

Fg (known) 0.83 μl * 8 Prostaglandin F_ (known) 8.3 9 'The table shows that already by removing blocking groups at position 16, such as 16,16-dimethylprostaglandin in FgQ 2 (DE-A-2 217 OUU), the duration may be extended. The half-life is about 10 min. however, it is only the presence of a cyclopropane group at position 2.3 that substantially prolongs the action time (half-life several hours, compounds Nos. 1,3,5 and 6 in the table).

For comparison, the table also shows the action times of known prostaglandins.

The new compounds can be used as medicaments in suitable dosage forms with pharmacologically inert excipients.

The following examples further illustrate the invention.

8 581 1 7

Example 1: 2.3-trans-methylene-prostaglandin 1 * 0 mg of 2,3-trans-methylene-11,15-bis-tetrahydropyranyl-prostaglandin (20) is dissolved in 2 ml of a mixture of acetic acid, tetrahydrofuran and water (3 : 1: 1) and the solution is heated at 60 ° for 2 hours.

The solvent is evaporated off under reduced pressure, the residue is separated on 3 g of silica gel with 17% methanol in chloroform. Melting point 108-112 °.

HMR (CDCl 3) 90 MHz mm:

4 H (m) 5.45 vinyl protons 3H 3.8-4.2 ppm CH-OH

3H (X) 0.9 ppm methyl.

The starting 2,3-trans-methylene-11,15-his-tetrahydropyranyl-prostaglandin F2 is prepared as follows: a) 2-((Bromoethyl) -cyclopropanecarboxylic acid ethyl ester in a suspension of copper powder (2.48 g) heated to 100 ° 4- in bromo-1-butene (22 g), 40 ml of diazoacetic acid ethyl ester are added slowly and with vigorous stirring. After 2 hours at 100 ° C, the mixture is filtered and the isomeric cyclopropylcarboxylic acid esters are separated by chromatography on 900 g of silica gel using benzene as eluent.

Trans-2- (2-bromoethyl) -cyclopropanecarboxylic acid ethyl ester IR (methylene chloride) mm: 1710, 1420, 1200, 1180 cm -1 NMR (CDCl 3) 60 MHz mm: 2 H 4.17 ppm (O-CH 2 -CH 3) 2 H 3 , 45 ppm (-CH 2 -CH 2 -Br) 3H 1.25 ppm (CH 3 -CH 2 -) M + = 220 b _) - Trans-2- (2-bromoethyl) -cyclopropanecarboxylic acid to a mixture cooled to 0 ° with 6.4 nm of 33% hydrobromic acid and 1.7 ml of concentrated sulfuric acid, 1 g of trans-2- (2-bromoethyl) -cyclopropanecarboxylic acid ethyl ester are added with vigorous stirring After standing for one hour at room temperature, the solution is heated at 100 ° for 15 minutes.

The cooled solution is poured into 60 ml of cold saturated ammonium sulphate solution, extracted 3 times with methylene chloride, the combined extracts are washed with water, dried and evaporated to dryness under reduced pressure. The residue was partitioned between 40 g of silica gel with 1% methanol in chloroform (50 ml fractions) to give the title compound.

IR (methylene chloride) mm: 3450-2700, 1700, 1460, 1215 cm -1 1981 NMR (CDCl 3) 60 MHz nun: 1H 10.5 ppm (-C00H) 2 H 3.1 + 2 ppm (-CH CH 2 -Br) 2 H 1.83 ppm (CH-CH 2 -CH 2) M + = 193

Trans-2- (2-bromoethyl) -5-cyclopropanecarboxylic acid methyl ester 200 mg of trans acid are dissolved in 10 ml of methanol and treated at room temperature at 20 ° with an ethereal solution of diazomethane. 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.

IR (methylene chloride) mm; 1720, 1210, 1120 cm -1 NMR (CDCl 3) 100 MHz mm: 3 H 3.68 ppm (C 20 CH 3 2 H 3.1 + 5 (t) (CH 2 -Br 2 H 1.9 (m) CH 2 -CH 2 - br

The same compound is obtained by treating the trans acid with 3-methyl-1-p-tolyl-triazine.

c) 2- (2-Carboxy-1-trans-cyclopropyl) -ethyl-triphenylphosphonium bromide To 5 g of (-) - trans-2- (2-bromoethyl) -cyclopropanecarboxylic acid in 100 ml of absolute benzene is added 10 g of triphenylphosphine and the mixture boil under reflux for 1 + 2 hours. After removal of the solvent under reduced pressure, the residue was partitioned between 600 g of silica gel with chloroform-methanol-acetic acid mixtures (300 ml fractions) to give the title compound.

IR (methylene chloride) mm: λ max-3000, 1725, 10 IU, 1115 cm -1 NMR (CDCl 3) 60 MHz nm: δ H 7.75 ppm (aromatic H) 2 H 3.8 ppm (CH 2 Cl 2). ).

d) 2,3-Trans-methylene "11,15-bis-tetrahydropyranyl-proetaglandin 70 mg of sodium hydride are dissolved in 0.7 ml of dimethyl sulfoxide and the solution is kept under a nitrogen atmosphere at 75 ° for 1 + 0 minutes. After cooling, (-) - a solution of the triphenylphosphonium salt of trans-ethyl-cyclopropanecarboxylic acid in 1 ml of absolute dimethyl sulfoxide.

It is then stirred for 1 1/2 hours at room temperature, and to this solution (1.2 ml) is then added 11 + 5 mg of 2 (1R- (3N- (3-tetrahydropyranyloxy-1'-trans-octenyl)). hydroxy-3-tetrahydropyranyloxycyclopentane-acetaldehyde-lactol The mixture is allowed to stand for 15 minutes at room temperature, then heated for 3 hours at 75 °, then the mixture is poured onto 20 g of ice, the pH is carefully adjusted to 3 and the mixture is extracted with methylene chloride. : 11a 'W 58117 silica gel with 2% methanol in chloroform gives the title compound in pure form.

IR (methylene chloride) mm: 3500, 1710 cm -1 MR (CDCl 3) 90 MHz mW: U H (m) 5.1+ ppm 2 H U, 7 ppm 3 H (t) 0.9 ppm Example 2

As in Example 1, the following compounds of formula I are prepared analogously from the corresponding starting materials: a) 2, β-cis-methylene prostaglandin NMR spectrum (CDCl 3) 90 MHz, mm: 1+ H 0.68-0.91 ppm _Cl 3 / Γϋ.

7 H 1.9-2.1 + ppm aliphatic H

3 H 3.51 -, 16 ppm> CHOH 1+ H 5.15 - 5.75 ppm vinyl protons IR spectrum (methylene chloride), mfrl; 3580, 3 00, 177-I695 cm-1.

b) 2,3-cis-Methylene prostaglancin F2 N-methyl ester NMR Spectrum (CDCl3) 90 MHz, mm: 1+ H 0.68-0.89 ppm -CH3.7H 1.9-2.1 + ppm -0-Cjl-

1 S m> CHOH

h H 5.2-5.2 ppm vinyl protons IR spectrum (methylene chloride) mm: 3580, 3.00, 1725-1710 cm -1.

c) 2,3-Trans-methylene prostaglandin F-methyl ester NMR spectrum (CDCl 3 90 MHz, mm: 1+ H 0.7-0.89 ppm

7 H 1.88-2.38 ppm aliphatic H

3 H 3.6 ppm -O-CH 2

3 H 3.58-1 +, 15 ppm> CHOH

1 H 5.1-5.7 ppm vinyl protons IR spectrum (methylene chloride), mm: 3580, 3I + OO, 1725-1705 cm-1.

11 58117 d) 2,3-Trans-methylene prostaglandin F 6 -ethyl ester NMR spectrum (CDCl 3) 90 MHz, mm:

7 H 0.7-1.2 ppm -CH 3, H 7 H 1.88-2.38 ppm aliphatic H

3 H 3.6-1 +, 1 ppm> CHOH

2 H 1 +, 1-1 +, 1 + ppm -COOCl 2 - 1+ H 5.1 ~ 5 * 7 ppm vinyl protons IR spectrum (methylene chloride), mm: 3580, 31 + 00, 1725-1705 cm e) NMR Spectrum (2,3Cl) of 2,3-cis-methylene prostaglandin N-ethyl ester 90 MHz, mm: 7 H 0.7-1.18 ppm -CH3, H

7 H 1.88-2.38 ppm aliphatic H

5 H 3.6-1 +, 1 + ppra) CHOH, COOCHg- 1+ H 5.1-5.7 ppm vinyl protons IR spectrum (methylene chloride), mm: 3580, 31 + 00, 1725-1705 cm-1.

Example 3: 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin 200 mg of 16,16-dimethyl-2,3H: trans- (+) - methylene-11,15-tetrahydropyranylprostaglandin Fα is dissolved in 7 ml of a mixture of acetic acid, tetrahydrofuran and water (3: 1: 1) and the solution is kept for 5 hours at 1 + 0 °. After evaporation under reduced pressure, the residue is chromatographed on 23 g of silica gel with 7% methanol in chloroform to give the pure title compound. Λ max Q + + 88 ° (c = 1.01 CH 3 Cl).

IR (methylene chloride) mm: 36OO-3I + 0.100 cm -1 NMR (CDCl 3) 100 MHz mm:

1+ Η ^ 5.5 ppm vinyl-H

6 Ha / 1 + ppm 3 x CH-OH

6 H 1.28 ppm 2 x CH2-C

The starting 1,6,16-dimethyl-2,3-trans (+) - methylene-11,15-bis-tetrahydropyranyl prostaglandin F 1 is prepared as follows: a) (+) - Trans-2- (2-bromoethyl) -cyclopropanecarboxylic acid 66 g To 200 g of trans-2- (2-bromoethyl) -cyclopropanecarboxylic 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 1/2 hours at 20 °. Addition of crystals of N-hexane. Filter and crystallize from methylene chloride / hexane and methylene chloride / ethyl acetate. Melting point 125-126 °; - + 22 ° (c = 1.26 CHCl 3). Shaking at about 20 ° C with methylene chloride / dilute hydrochloric acid liberates (+) - acid: = + 75.3 (c = 1.9U CHCl3).

b) 2- (2-Carboxy-1- (+) - trans-cyclopropyl) ethyl triphenylphosphonium bromide To 6.3 g of (+) - trans-2- (2-bromoethyl) -cyclopropanecarboxylic acid in 150 ml of abs. benzene is added 10 g of .3 g of triphenylphosphine, and the mixture is refluxed for 65 hours. After cooling, the separated crystals are filtered off. Melting point 121-125 °; = + 17.5 ° (c = 1.18 CHCl 3). IR and NMR are the same as for the racemic compound.

12 5 81 1 7 c) 16,16-Dimethyl-2,3-trans (+) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin F 600 mg of sodium hydride are dissolved in 6 ml of abs. dimethyl sulfoxide and the solution is heated at 75 ° under a nitrogen atmosphere for 55 minutes. After cooling, 2.1 ml of the solution are slowly added dropwise to a pre-prepared solution of (+) - trans-cyclopropane-2- (2-bromoethyl) carboxylic acid triphenylphosphonium salt (1.95 g) in 5 ml of abs. dimethyl sulfoxide, then stirred under a nitrogen atmosphere for 45 minutes.

To a pre-prepared solution of 2 / 3- (4,4,4-dimethyl-3'-tetrahydropyranyloxy-1'-trans-octenyl) -50 (hydroxy-3b-tetrahydropyranyloxycyclopentane-acetaldehyde-lactol (Ig) in 1 ml of abs. dimethyl sulfoxide is added at 20 ° to 4.5 ml of the ylide solution described above and the mixture is kept at 60 ° for 50 minutes.

Add a further 4.5 ml of the supernatant solution and stir again at 60 ° for one hour. The cooled reaction mixture is poured onto ice, the pH of the aqueous phase is adjusted to 3-5, and extracted 3x with methylene chloride. The crude product obtained is chromatographed on 140 g of silica gel with chloroform containing 1-5% methanol to give the pure title product.

* + 35.5 ° (c = 1.07 CHCl 3).

IR (methylene chloride) mm: 3500, 1695 cm -1 NMR (CDCl 3) 90 MHz mm: 4 H -> - 5.5 ppm vinyl-H 2 H 4.6 ppm THP-H Example 4

As in Example 3, the following compounds of formula I are prepared analogously from the corresponding starting materials: a) 16,16-dimethyl-2,3-trans (+) - methylene prostaglandin F-methyl ester NMR spectrum (CDCl 3) 90 MHz, δ: 10 H 0, 7-0.89 ppm -CH 2

7 H 1.88-2.38 ppm aliphatic H

3 H 3.55-3.6 ppm -OCH 3

3 H 3.58-4.15 ppm CHOH

4 H 5.2-5.8 ppm vinyl protons IR spectrum (methylene chloride), mm: 3580, 3400, 1725-1705 cm -1.

15 5 81 1 7 b) 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin N-ethyl ester NMR spectrum (CDCl 3) 90 MHz, mm: 13 H 0.7-1.2 ppm - CHG,

7 H 1.88-2.38 ppm aliphatic H

3 H 3.6-4.1 ppm 'CHOH

2 H 4.1-4.4 ppm -C00CH2 4 H 5.1-5.7 ppm vinyl protons IR spectrum (methylene chloride), mm: 3580, 3400, 1725-1705 cm-1.

- c) 2,3-trans (+) - methylene prostaglandin F.

_2oC

Nuclear Magnetic Resonance Spectrum (CDCl 3) 90 MHz, mm: 3 H 0.9 ppm

"3 H 3.8-4.2 ppm CHOH

4 H 5.3-5.6 ppm vinyl protons IR spectrum (methylene chloride), mm: 36ΟΟ, 3400, 1730-1710 cm -1.

d) 2,3-trans (+) - methylene prostaglandin F2-methyl ester NMR spectrum (CDCl3) 90 MHz, mm: 4 H 0.7-0.89 ppm -CH2,

7 H 1.88-2.38 ppm aliphatic H

3 H 3.6-ppm -O-CH 2

3 H 3.58-4.15 ppm> CHOH

4 H 5.1-5.7 ppm vinyl protons IR spectrum (methylene chloride), mm: 3580, 3400, 1725-1705 cm-1.

e) 2,3-trans (+) - methylene prostaglandin F2-ethyl ester NMR spectrum (CDCl3) 90 MHz, mm :,

7 H 0.7-1.2 ppm “CH

7 H 1.88-2.38 ppm aliphatic H

3 H 3.6-4.1 ppm ^ CHOH

2 H 4.1-4.4 ppm -COOCHg- 4 H 5.1-5.7 ppm vinyl protons IR spectrum (methylene chloride), mm: 3580, 3400, 1725-1705 can-1.

, U 58117

Example 5: 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin Eg 31+ mg of 16,16-dimethyl-2,3-trans (+) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin are dissolved To 2 ml of acetic acid-water-tetrahydrofuran mixture (3: 1: 1), and the solution is allowed to stand for 2 1/2 hours at 38 °. Evaporate under reduced pressure, chromatograph the residue on 2.5 g of silica gel with chloroform containing 3% methanol. The pure title compound is obtained.

IR (methylene chloride) mm .: 1735, 1695 cm 1 NMR (CDCl 3) 90 MHz mm .: 1+ H 5.3-5.8 ppm (vinyl protons)

5 H 3.7 - ^, 2 ppm 2 x -CH-OH + -C00H

The starting 16,16-dimethyl-2,3-trans (+) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin E 1 was prepared as follows: 100 mg of 16,16-dimethyl-2,3-trans (+) -methylene-11,15-bis-tetrahydropyranyl-prostaglandin is dissolved in 1 ml of abs. toluene, and 26.7 mg of tert-butyldimethylchlorosilane is added to the solution under a nitrogen atmosphere. The reaction solution is cooled to 0 ° and 18 mg of triethylamine are added, stirred for a further 2 1/2 hours at 20 °, cooled to -30 ° and the solution is slowly added dropwise over 35 minutes to a solution of 108 mg of N-chlorosuccinimide 1+ ml of abs. toluene and 60 mg of dimethyl sulphide. 2 After 3A hours at -20 °, 220 mg of triethylamine and 1 ml of pentane are added dropwise to the solution and, after standing for a further 10 minutes, treated with ether / water. The residue (100 mg) is chromatographed on 8 g of silica gel with chloroform with 2% methanol. There is thus obtained 16,16-dimethyl-2,3 trans (+) - methylene-11,15-bis-tetrahydropyranyl prostaglandin-Eg-tert-butyldimethylsilyl ester.

IR (methylene chloride) strips, e.g., 1735, 1695 cm -1 Dissolve 50 mg of the ester described above in 0.7 ml of acetone, add 0.2 ml of water and 0.25 ml of a solution of 2 x 6 ml at 0 °. mg of sodium acetate in 3 ml of acetone, 1 ml of water and 180 ml of acetic acid. Stir for 1 + 5 minutes at 0 ° and 1 1/2 hours at 25 ° and then treat with ether. 16,16-Dimethyl-2,3-trans (+) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin Eg.

Example 6

As in Example 5, the following compounds of formula I are prepared analogously from the corresponding starting materials: 16,16-dimethyl-2,3-trans (+) - methylene prostaglandin N-methyl ester.

NMH spectrum (CO2C 90 MHz, mm:

10 H 0, H-1.0 ppm -CH 2, H

2 H 2.56-3.2 ppm.) COCHg- 3 H 3.6 ppm -C00CH3 1+ H 5.1-5.7 ppm vinyl protons IR spectrum (methylene chloride), mm: 3600, 31 + 00, 17 ^ 5-1705 cm 1.

15 5 81 1 7 b) 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin E2-ethyl ester NMR Spectrum (CDCl 3) 90 MHz, ν max: 13 H 0.8-1.1 ppm -CH , 2 H 2.6-3.3 ppm -C-CH 2> 2 H 2 H 2.6-3.3 ppm -C 1 H 2 -2H, 1-U, 3 ppm -COOCH 2 -H 5.15 -5.7 ppm vinyl protons IR spectrum (methylene chloride), mm .: 36ΟΟ, 3.00, I7U5-I705 cm-1.

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

NMR spectrum (CDCl 3) 90 MHz, mn:

U H 0.7-0.9 ppm -CH3, ^ <JjH

0 2 H 2.55-2.95 ppm -C-CHg- 3 H 3.65 ppm -C00CH3 1 * H 5.1-5.65 ppm vinyl protons IR spectrum (methylene chloride), mm .: 3600, 31+ 00, 17 ^ 0-1705 cm-1.

d) 2,3-trans (+) - methylene prostaglandin Eg-ethyl ester, NMR spectrum (CDCl 3) 90 MHz, mm .: 7 H 0.8-1.1 ppm -CH-

0 J

2 H 2.6-2.9 ppm -ii-CHg- 2 H 1.1-1 +, 25 ppm -COOCHg- 'b H 5.2-5.7 ppm vinyl protons IR spectrum (methylene chloride), mm, : 31 * 00, 17140-1705 cm -1.

Example 7: 16,16-Dimethyl-2,3-trans (-) - methylene prostaglandin F-109 mg of 16,16-dimethyl-2,3-trans (-) - methylene-11,15 bis-tetrahydropyranyl- prostaglandin F2o (is dissolved in 3.5 ml of a mixture of acetic acid, tetrahydro-uranium, water (3: 1: 1) and the solution is allowed to stand for 6 hours at 1 * 0 °. Evaporate under reduced pressure, the residue is chromatographed on 5 g: 11a silica gel with chloroform with 7% methanol to give the pure title product fa / p0 = + 13.8 ° (c = 1.02 CHCl3) IR (methylene chloride) mm .: 36ΟΟ, 31 * 00, 1695 can ”1 NMR (CDCl 3) 90 MHz mm .:

1+ H 5.3-5.7 ppm vinyl-H 7 H 3.9-1 *, 3 ppm 3 x CH-OH + C00H

CH3 \ 1.28 ppm ch3 ie 58117 The 16,16-dimethyl-2,3-trans (-) - methano-11,15-bis-tetrahydropyranyl prostaglandin Fg <^ used as starting material is prepared as follows: a) (-) - trans'- 12- (2-bromoethyl) -cyclopropanecarboxylic acid

The title compound is obtained in analogy to Example 3a) with (+) - ephedrine. 07 DEG -75.0 DEG (c = 1.56 CHCl3).

The spectroscopic parameters of the title compound are identical to those of the (+) - acid.

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

To 6 g of (-) - trans-2- (2-bromoethyl) -cyclopropanoic acid in 200 ml of abs. Benzene is added 10 g of triphenylphosphine, and the mixture is refluxed for 63 hours. After cooling, the separated crystals are filtered off.

Melting point 120-122 °; M ™ - -17.3 (c = 1.19 CHCl 3) IR and NMR are consistent with the corresponding enantiomeric compounds.

e) 16,16-Dimethyl-2,3-trans- (-) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin F-300 mg of sodium hydride suspended in 3 ml of abs. dimethyl sulfoxide are kept under a nitrogen atmosphere at 75 ° for 1 + 5 minutes. After cooling, 0.9 ml of this solution is slowly added dropwise to a pre-prepared solution of (-) - trans-2- (2-bromoethyl) -cyclopropanecarboxylic acid triphenylphosphonium salt (1 g) in 2.5 ml of dimethyl sulfoxide, and the mixture is stirred under a nitrogen atmosphere for 45 minutes.

To a solution of 500 mg of 2 / 3- (U ', U, -dimethyl-3, ε-tetrahydropyranyl-oxy-1'-trans-octyl) -50 (-hydroxy-3-tetramethyl) ahydropyranyl oxy cyclopentane i-acetaldehyde lactol in 0.6 ml of abs. tetrahydrofuran, slowly add 1.9 ml of the overdose described above, after 1 + 0 minutes at 60 ° add another 1.9 ml of overdose and allow the mixture to stand for a further time. for 1 hour at 60 [deg.] C. The cooled reaction mixture is poured onto 100 g of ice, the pH of the aqueous phase is adjusted to 3 * * + and the aqueous phase is extracted 3 times with methylene chloride, and the crude product obtained is purified by chromatography on 50 g of silica gel with chloroform. is 2% methanol to give the pure title product.

IR (methylene chloride) nm: 3500, 1695 cm -1

Example 8

As in Example 7, the following compounds of formula I are prepared analogously from the corresponding starting materials: a) 16,16-dimethyl-2,3 'trans (-) - methylene prostaglandin F 2 O-methyl ester.

NMR spectrum (CDCl 3) 90 MHz, mm: 10 H 0.7-0.89 ppm

7 H 1.88-2.38 ppm aliphatic H

3 H 3.6 ppm -COOCH 2

3 H 3.58-1 +, 15 ppm> CHOH

UH 5.1-5.7 ppm vinyl protons 11 58117 IR spectrum (methylene chloride), mm .: 3580, 3 00, 1725-1705 cm -1 b) 16,16-dimethyl-2,3-trans (-) - methylene prostaglandin F ^ -ethyl ester.

Nuclear Magnetic Resonance Spectrum (CDCl 3) 90 MHz, mm .: 13 H 0.7-1.2 ppm

7 H 1.88-2.38 ppm aliphatic H

3 H 3,6-U, 1 ppm ”> 0Η0Η 2 H ktl-kth ppm -COOCHg it H 5.1-5.7 ppm vinyl protons IR spectrum (methylene chloride), mm .: 3580, 3 00, 1725- 1705 cm "1.

c) 2,3-trans (-) - methylene prostaglandin F2 melting point 103-105 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl 3) 90 MHz, δ: U H 0.9 ppm -CH 3

3 H 3.7-i *, 3 ppm) CHOH

i + H 5.3-5.6 ppm vinyl protons IR spectrum (methylene chloride), mm .: 3600, 3500, 1695-1710 cm-1.

d) 2,3-trans (-) - methylene prostaglandin F2-methyl ester

Nuclear Magnetic Resonance Spectrum (CDCl 3) 90 MHz, mm: H 0.7-0.89 ppm -CH.3, SH

7 H 1.88-2.38 ppm aliphatic H

3 H 3.6 ppm -C00CH3 3 H 3.58-i, 15 ppm) CHOH it H 5.1-5.7 ppm vinyl protons IR spectrum (methylene chloride), mm .: 3580, 3 ^ + 00, 1725 -1705 cm -1.

e) 2,3-trans (-) - methylene prostaglandin Fg 2 style ester.

NMR spectrum (CDCl 3) 90 MHz, mm .:

7 H 0.7-1.2 ppm -CH 2, · <β 7 H 1.88-2.38 ppm aliphatic H 3 H 3.6-lt, 1 ppm ^ CHOH

2 H i +, 1-it, U ppm -COOCHg ^ H 5.1-5.7 ppm vinyl protons.

IR spectrum (methylene chloride), mm .: 3580, 300, 1725-1705 cm -1.

, p. 58117

Example 9 · 16,16-Dimethyl-2,3-trans (-) - methylene prostaglandin 78 78 mg of 16,16-dimethyl-2,3-trans (-) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin are dissolved 3 ml of acetic acid, water, tetrahydrofuran (3: 1: 1) and the solution are stirred for 6 hours at 1 + 0 °. After evaporation, the residue is chromatographed under reduced pressure on 1.5 g of silica gel with chloroform containing 2% methanol. The pure title compound is obtained.

IR (methylene chloride) mm .: 3600, 3.00, 1735, 1695 cm -1 NMR (CDCl 3) 90 MHz mm. : 50 about 2.6-2.85 ppm (1H) δ ~ * ^

OH

about 5.2-5.6 ppm (1 + H) H

The starting 1,16,16-dimethyl-2,3-trans (-) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin Eg was prepared as follows: 177 mg of 16,16-dimethyl-2,3-trans (-) - Methylene-11,15-bis-tetrahydropyranyl-prostaglandin is dissolved in 1.5 ml of toluene. 1 + 7.2 mg of tert-butyldimethylchlorosilane dissolved in toluene are added dropwise to the solution under a nitrogen atmosphere. The reaction mixture is cooled to 0 °, 32 mg of triethylamine are added and stirred for 2 1/2 hours at 20 °, the mixture is cooled to -30 ° and slowly added to a solution of 191 mg of N-chlorosuccinimide in 6 ml of abs. toluene in 106.3 mg of dimethyl sulfide. After 2 hours at -30 to -20 °, 300 mg of triethylamine in 1 ml of pentane are added, the mixture is stirred for a further 10 minutes and the work-up is carried out with an ether / water mixture. The residue (192 mg) is chromatographed on 12 g of silica gel with chloroform containing 1% methanol.

The silyl ester obtained (strips in IR-methylene chloride, e.g. 1735, 1675 cm ') is dissolved in 2.7 ml of acetone. To a solution cooled to 0 ° are added 0.9 ml of water and 1.2 ml of a solution of 21 + 6 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 °, for 1 1/2 hours at 25-30 °, then further treated with ether. 16,16-Dimethyl-2,3-trans (-) - methylene-11,15-bis-tetrahydropyranyl-Prostaglandin Eg (IR in methylene chloride, e.g. 3500, 1735 and 1695 cm-1) is obtained as a precipitate.

Example 10

As in Example 9, the following compounds of formula I are prepared analogously from the corresponding starting materials: a) 2,3-trans (-) - methylene prostaglandin Eg.

Melting point: 105-107 ° C

NMR spectrum (CDCl 3) 90 MHz, mm .:

2 H 3.8-1 +, 2 ppm> CH-OH

3 H 0.85-0.90 ppm -CH 3 1+ H 5.2-5.6 ppm vinyl protons IR spectrum (methylene chloride), mm .: 3600, 3500, 1730-1735, 1695 cm-1.

19 5 81 1 7 b) 16,16-Dimethyl-2,3 'trans (-) - methylene prostaglandin E2 methyl ester.

Nlfl spectrum (CDCl 3) 90 MHz, mm ·: 10 H 0.8-1.0 ppm -CH 2 H 2 H 2.56-3.2 ppm -COCH 2 ~ 3 H 3.6 ppm -C00CH3 4 H 5.1 "5.7 ppm vinylpropane IR spectrum (methylene chloride), m.p .: 3600, 3400, 1740-1705 cm-1.

c) 16-16-Dimethyl-2,3-trans (-) - methylene-niprostaglandin N-ethyl ester NMR Spectrum (CDCl 3) 90 MHz, mm ·: 13 H 0.8-1.1 ppm-λmax ^ .γΗ 2 H 2.6-3.3 ppm -COCHg- 2 H 4.1-4.3 ppm -COOCHg- 4 H 5.15 ~ 5.7 ppm vinyl protons IR spectrum (methylene chloride), mm .: 3600, 3400, 1745-1705 cm-1.

d) 2 «3-trans (-N-methyleneprotaglandin N-methyl ester NMR spectrum (CDCl 3) 90 MHz, nm: 4 H 0.7-0.9 ppm 2 H 2.5-2.95 ppm - COCH 2 3 3 H 3.65 ppm -COOCH 2 H 5.1-5.65 ppm vinyl protons IR spectrum (methylene chloride), mm .: 3600, 3400, 1740-1705 cm-1.

e) 2,3-trans (-) - methylene prostaglandin E2-ethyl ester NMR spectrum (CDCl 3) 90 MHz, nm: δ H 0.8-1.1 ppm -CH 2, 2 H 2.6-2.9 ppm -COCH 2 -2H 4.1-4.25 ppm -COOCH 2 -4H 5.2-5.7 ppm vinyl protons IR spectrum (methylene chloride), mm .: 3400, 1740, -1705 cm -1.

; \ f 58117 20

Example 11; 16,16-Dimethyl-9X-<? 15β-trihydroxy-2,3- (+) -methylene-prost-5α, 13-trans-dienoic acid 230 mg 16,16-dimethyl-9X -hydroxy-1, 15β-bis-tetrahydro-pyranyloxy-2,3 - (+) - methylene-Prosta-5cis, 13-trans-dienoic acid is dissolved in 15 ml of a mixture of acetic acid, tetrahydrofuran and water (3: 1: 1) , and the solution is kept for b2 hours at room temperature. After evaporation under reduced pressure, the residue is chromatographed on 10 g of silica gel with U% methanol in chloroform to give the pure title compound.

Thin layer chromatography: benzene, dioxane, acetic acid (20: 10: 1)

Rf λ 0.52 IR (methylene chloride) mm .: 3600, 3500, 1710 - 1695 cm -1 NMR (CDCl 3) δ ·:

U H approx. 5.5 ppm vinyl H 3 H approx. H ppm 3 x CHOH

The 16,16-dimethyl-9e-hydroxy-11α, 15β-bis-tetrahydro-pyrrole-2,3-(+) - methylene-Prosta-5cis, 13-trans-diene acid used as starting material is prepared as follows: a ) 5 * -Hydroxy-2β (3'-oxo-N, N-dimethyl-trans-1-octenyl) -3'-p-phenylbenzoyloxy-1α, -cyclopentanoic acid lactone

A solution of 12.8 g of dimethyl 2-oxo-3,3-dimethyl-heptyl phosphonate in 170.3 ml of abs. dimethoxyethane, is added with stirring to a cold (5 °) suspension of 11.35 g of sodium hydride in 99.5 ml of abs. dimethoxyethane. The mixture is stirred for 1 hour at 20 °, the bright yellow solution is cooled to -18 °, then the optically active aldehyde (2H-carboxy-aldehyde-5H-hydroxy-3 * - cooled to 0 °) is added. p-phenyl-benzyloxy-cyclopentane-acetic acid-?-lactone) in 2109 ml of abs. dimethoxyethane. After 2 hours at about 0 °, cool again to about -15 ° and adjust to pH 6 dropwise with acetic acid. The solvent is distilled off in vacuo, 2 l of petroleum ether are added to the residue (201.6 g of a tan oil), whereupon white crystals separate overnight. Melting point 100-101.5 °.

b) 5K-Hydroxy-2β- (3'-hydroxy-N, N * -dimethyl-trans-1-octenyl) -3'-p-phenylbenzoyl-lot-cyclopentane-acetic acid-β-lactone

A solution of 53.6 g of ketone (Example "a) in 28 ml of absolute dimethoxyethane is added dropwise over 5 minutes to 73.6 ml of a zinc borohydride-dimethoxyethane mixture cooled to 18 ° (1 ml). 28.7 mg of zinc borohydride) is stirred for 3 1/2 hours at 2-5 ° and further for L5 minutes at 5 ~ 10 ° C. It is then cooled to -15 ° and the pH is adjusted to 6 with icy sodium hydrogen tartrate. Aqueous ether (ca. 150 ml) is added to the reaction mixture 3 times with 1 l of ether and the mixture is then decanted, the organic phase is washed twice with 1 l of saturated brine, dried and evaporated in vacuo to give 59 g of a mixture of F and isomers. which is separated by chromatography on 9 kg of silica gel Methylene chloride-ethyl acetate (92: 8) is used to isolate 30 g of the apolar o (-isomer), eluting with 9 g of ethylene-ethyl acetate (91: 9). isomer.

c) 3 ° * .5-N-dihydroxy-2? (S, N-hydroxy-1 * ', N-dimethyl-trans-1-octenyl) -1H-cyclopentaneacetic acid N, N-lactone 7 * 3 g of β- alcohol a (Example 11b) is dissolved in 306 ml of abs. methanol and 306 mg of sodium in 15 * 3 ml of abs. methanol and allowed to stand for 5 hours at room temperature. The reaction mixture is then cooled in an ice bath and 26 ml of a methanolic solution of 10 Arista tartaric acid are added over a period of 20 minutes. 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, the crystalline residue is chromatographed on 500 g of silica gel with benzene containing 5% acetone. This gives 5 * 0 g of glycol as a viscous oil.

Thin layer chromatography Toluene: acetone 2. Rf = 0.2 'd) Sgs-efc-dihydroxy-phenyl-hydroxy-1 (1'-dimethyl-trans-1-octenyl) -l-cyclopentaneacetic acid-fr- lactone S, N'-bis-tetrahydropyranyl ether A solution of 5 g of diol (Example Ile) in 2 to 5 ml of abs. toluene, is added at -10 ° to a solution of 1 +, 28 g of dihydropyrene, 100 mg of p-toluenesulfonic acid in 1 + 0.7 ml of abs. toluene, and stirred for 1 1/2 hours at room temperature. Wash with 150 ml of 10 Aris potassium bicarbonate solution and then with 1 + 00 ml of saturated brine. The aqueous phases are extracted with benzene, the organic phases are evaporated in vacuo. 8.1+ g of oily crude product are obtained, which is chromatographed on 1 * 50 g of silica gel. 7 * 0 g of pure title compound are eluted with toluene containing 5% acetone.

e) 2f (1 * 1,1 * '- dim, ethyl-3 * / (-) - tetrahydropyranyloxy-1'-trans-octenyl) -5 (* - - hydroxy-3 (*) - tetrahydropyrenyloxy-cyclopentane-acetaldehyde) γ-lactol A solution of 7.0 g of bistetrahydropyran ether (Example IId) in 300 ml of abs. toluene, cooled to -70 ° and 25 m3 of diisobutylaluminum hydride solution (20% in toluene) are added over 25 minutes. After 1 hour, 185 ml of tetrahydrofuran: water (2: 1) are added to the solution, it is filtered, the filtrate is washed with saturated sodium chloride solution, dried and evaporated. This gives 5.9 g of the title compound (mixture of isomers).

f) 16,16-Dimethyl-9β-hydroxy-11β, 15β-bis-tetrahydropyranyloxy-2,3- (+) - methylene-Prosta-5c is, 13-trans-dienoic acid 800 mg of sodium hydride are suspended 8.3 ml to abs. dimethyl sulfoxide and kept under nitrogen for 1 * 5 minutes at 75 ° 5. 2.8 ml of this solution are slowly added dropwise at room temperature to a pre-prepared solution of 2.55 g of the triphenylphosphonium salt of (+) - trans-cyclopropane-2- (2-bromoethyl) -carboxylic acid in 6 ml of abs. dimethyl sulfoxide, and stirred under nitrogen for 80 minutes.

To a solution of 61 + 1 + mg of 2? - (1 + ', 1 +, - dimethyl-3, E'-tetrahydro-pyrenyloxy-1'-trans-octenyl) -5 ° (-hydroxy-3', N-tetrahydro- pyranyloxy-cyclopentanone-acetaldehyde 22,581 1 7 hydro-γ-lactol in 2 ml of abs. dimethyl sulfoxide and 1 ml of abs. tetrahydrofuran, 2.8 ml of the ylide solution described above are slowly added dropwise. 2.7 ml of the ylide solution are again added dropwise to the solution and the mixture is stirred for a further 2 hours at 55 [deg.] C. The cooled reaction mixture is poured into 120 g of ice, the pH of the aqueous phase is adjusted to 3-1 + and extracted 1+ times with 120 ml. The organic phase is washed twice with water, dried over sodium sulfate and evaporated under reduced pressure, and the crude product obtained is chromatographed on 75 g of silica gel to give the pure title compound in chloroform with 2-3% methanol.

Thin layer chromatography: ethyl acetate 10% methanol Rf = 0.1 + 9 IR (methylene chloride) mm .: 3500, ITI 0-1695 s 1200, 1030 cm -1 NMR (CDCl 3) 100 MHz mm .:

1+ H 5.8-5.2 ppm vinyl protons 2 H If, 7-1 +, ¾ ppm THP-H 9 H 0.9-0.8 ppm methyl-H

Example 12: 16,16-Dimethyl-1H-1,15,3-dihydroxy-9-keto-2,3- (+) -methylene-Prosta-5-cis, 13-trans-dienoic acid 295 mg of 16,16-dimethyl -9-Keto-10α, 15β-bis-tetrahydropyranyloxy-2,3 - (+) - methylene-Prosta-5-cis, 13-trans-dienoic acid is dissolved in 15 ml of acetic acid, tetrahydrofuran, water (3: 1: 1) and allowed to stand for 1 + 3 hours at room temperature. After evaporation under reduced pressure, the residue is chromatographed on 15 g of silica gel. Elution with chloroform with 3% methanol gives the title compound in pure form.

Thin layer chromatography: chloroform 10% methanol Rf = 0.27 1-1 IR (methylene chloride), mm .: 3600, 171 + 0, 1695 cm NMR (CDCl 3) mm .:

1+ H 5.8-5.3 ppm vinyl H

1+ H 3.7-1 +, 2 ppm 2 x CH-OH

Dissolve 295 mg of 16,16-dimethyl-9o (-hydroxy-11o +, 15,3-bis-tetrahydro-pyranyloxy-2,3 - (+) - methylene-Prosta-5-cis, 13-trans-dienoic acid in 3 ml of: After the reaction solution is cooled to 0 DEG C. and a solution of 60 ml of triethylamine in 0.6 ml of abs. toluene is slowly added dropwise after 1 + 8 hours to 1 ml of absolute toluene and treated with 89 mg of tert-butyldimethylchlorosilane under nitrogen. at room temperature, the solution is cooled to -25 ° and a precooled solution of 32 l + mg of N-chlorosuccinimide in 13 ml of abs. toluene and 180 mg of dimethyl sulphide is slowly added dropwise over 30 minutes. 502 mg of triethylamine in 2 ml of pentane, stirred for a further 20 minutes at room temperature and treated with an ether / water mixture to give 16,516-dimethyl-9-keto-11α-, 15,3-bis-tetrahydropyranyloxy as a precipitate. -2,3- (+) - Methylene-Prosta-5-cis, 13-trans-dienoic acid tert-butyldimethyl ester 360 mg the ester is dissolved in 7.2 ml of acetone and added at 0 [deg.] C. dropwise 2 .mu.l of water and 3.6 ml of a solution of 738 mg of sodium acetate in 9 ml of acetone, 6 ml of water and 5 .mu.M acetic acid. Stir for 30 minutes at 0 ° C and 2.5 hours at 25 ° C and finally treat with methylene chloride. 16,16-Dimethyl-9-keto-11,15,3-bis-tetrahydropyranyloxy-2,3- (+) -methylene-Prosta-5-cis, 13-trans-dienoic acid is obtained as a precipitate.

Example 13: (5Z, 90 ° C, 13E, 15O-9,11,15-trihydroxy-16-n-butyl-2,3-trans - (-) - methylene-Prosta-5,13-dienoic acid 200 mg (5Z (9,11,11,13E, 15o *) - 9,11,15-trihydroxy-16-n-butyl-2,3-trans - (-) - methylene-Prosta-5,13-diene-11, 15-Bis-tetrahydropyranyl ether is dissolved in 7 ml of a mixture of acetic acid, tetrahydrofuran and water (3: 1: 1) and the solution is allowed to stand for 2 hours at 35 [deg.] C. It is then evaporated under reduced pressure at 25 [deg.] C. and the residue is chromatographed on silica gel with 2-5% methanol in chloroform to give the pure title compound IR (methylene chloride) mm .: 3600-3300, 1720-1680 cm-1.

NMR (CDCl 3) 90 MHz mm .:

0.7-1.0 ppm (7H) -CH 2

3.8-1 +, 2 ppm (7H) -OH, -C00H,

6.35-5.6 ppm (UH) vinyl protons H OH

In an analogous manner, (5Z, 90 °, 1W, 13E, 15ot, 160 () - 9.11, 15-trihydroxy-16-methyl-2,3-trans - (-) - methylene-Prosta ~ 5.13 -dienic acid, IR (in KBr), mm .: 3 00-3600 and 1695 cm -1 NMR (CDCl 3) 90 MHz, mm .: 3 H 0.88 ppm -CH 3 (Cl 2) 3 H 0.92 ppm -CH_3 (Cl2)

B

1 H 0.8-1 ppm 3 H 3.8-1 *, 2 ppm CH-OH (C, Cl (), C) 2 H 1 +, 1 + -1 +, 8 ppm (-C00H, OH) 1+ H 5.3-5.7 ppm vinyl protons Used as starting material (5Z, 9oi, 11oi, 13E, 15o-9.11,15-trihydroxy-16-n-butyl-2,3-trans - (-) - methylene -prosta-5,13-dienoic acid 11,15-bis-tetrahydropyranyl ether is prepared as follows: 600 mg of sodium hydride are suspended in 6 ml of anhydrous dimethyl sulfoxide and the suspension is heated for 1 + 5 minutes under nitrogen at 75 [deg.] C. The mixture is cooled. 5,8117 g of H, 5 ml of it are slowly added dropwise under nitrogen to a pre-prepared solution of U.08 g of 2- (2-carboxy-1 - (-) - trans-cyclopropyl) ethyltriphenylphosphonium bromide in 10 ml of anhydrous dimethyl sulfoxide and the mixture stirred under nitrogen for 35 minutes.

8 ml of the ylide solution obtained above are slowly added dropwise to a solution of 2.1 g of 2- [(U'-n-butyl-3 '/ 7C-tetrahydropyranyloxy-1'-trans-octenyl) -5-tetrahydroxy-3 <* tetrah tetrahydropyranyloxycyclopentane acetaldehyde lactol in 6 ml of anhydrous tetrahydrofuran and 6 ml of dimethyl sulfoxide. After heating for 60 minutes at 50 [deg.] C., 8 ml of ylide solution are added dropwise again and the mixture is left to stand again at 50 [deg.] C. for one hour. The cooled reaction mixture is poured onto 150 g of ice, the pH of the aqueous phase is adjusted to 3-U and extracted 3 times with methylene chloride. The crude product obtained is purified by chromatography on 190 g of silica gel to give (5Z, 9, J <, 11 13E, 15 <^ ·) _9,11,15-trihydroxy-16-n-butyl with chloroform containing 2% methanol. -2,3-trans - (-) - methylene-prosta-3,13-dienoic acid 11,15-bis-tetrahydro-pyranyl.

Example 1U: (5Z, 11c *, 13E, 15β) -11,15-Dihydroxy-16-n-butyl-9-keto-2,3-trans - (-) - methylene-Prosta-5,13-dienoic acid 1.1 g (5Z, 11c <, 13E, 15ot) -11,15-dihydroxy-16-n-butyl-9-keto-2,3-trans - (-) - methylene-Prosta-5,13-dienoic acid -11.15-Bis-tetrahydropyranyl ether is kept for 60 minutes at 60 ° C in 60 ml of a 2: 1 mixture of acetone and water containing 0.5 ml of 2N hydrochloric acid, neutralized with 2N sodium hydroxide solution, the acetone is evaporated off and the aqueous solution is evaporated. extracted with methylene chloride 1 time. Dry over sodium sulfate, evaporate to dryness and chromatograph on 5 g of silica gel with chloroform-methanol mixtures.

IR (methylene chloride) mm .: 3600-3300, 17U0-1690 cm-1 NMR (CDCl3) 90 MHz mm .:

0.75-1.0 ppm (7Η) ^ <Γ H, CH

0 2.6-2.9 ppm (2H) δ _ ^ - “

3.9 ", 2.2 ppm (2H)

5.3-5.7 ppm (UH) vinyl protons

In an analogous manner, (5Z, 11of, 13E, 15 <*, 16ot) -11,15-dihydroxy-9-keto-16-methyl-2,3-trans - (-) - methylene-Prosta-5,13-dienoic acid is obtained. , 25 5811 δ IR (in KBr) mm .: 31 + 50-3620, 17 I + O and 1695 cm -1 NMR (CDCl 3) 90 MHz, mm .: 7 H 0.7-1 ppm -CH 3 (C ), -CH 3 (C 2), 12 H 2.55-2.92 ppm -CH 3 - (C 10) 2 H 3,8-U, 1 ppm> CHOH (C 11 C) 2 H 5> 3-5 .7 ppm vinyl protons 3 H 5.7-5.87 ppm (-C00H, OH) (5Z, 11 «1, 1 3E, 15ot) -1,15-dihydroxy-16-n-butyl-9-keto -2,3-Trans - (-) - Methylene-Prosta-5,13-dienoic acid 11,15-bis-tetrahydropyranyl ether is prepared as follows: „600 mg of the compound described in Example 13 (5Z, 9« t, 1 Loi ·, 13E, 15 <1) 9 9,11,15-trihydroxy-16-n-butyl-2,3-trans - (-) - methylene-Prosta-5,13-dienoic acid-11,15-bis- the tetrahydropyranyl ether is dissolved in 100 ml of absolute acetone and oxidized at -20 ° C by the Jones method. After 1 hour, 0.5 ml of methanol is added, and after a further 10 minutes the suspension is poured into 200 ml of ice water, extracted 3 times with methylene chloride, the organic phase is washed with water, dried over sodium sulfate and evaporated to dryness to give (5Z, 11 <, 13E , 15 <1) -11,15-dihydroxy-16-n-butyl-9-keto-2,3-trans - (-) - methylene-Prosta-5,13-dienoic acid-11,15 “bis- tetrahydropyranyl.

Claims (1)

26 581 1 7 Claim: A process for the preparation of therapeutically useful racemic or optically active 2,3-methylene prostaglandins of the formula "3 COOK1! OH wherein D is a carbon ring of formula OH 0 / v T or J_1 ho 'ho' Ile 1 .23 R is hydrogen or an alkyl group having 1 to 2 carbon atoms and R and R represent hydrogen or an alkyl group having 1 to 1 carbon atoms , characterized by that. . . 1+ .... the protecting group or protecting groups R are hydrolytically cleaved from a compound of formula a "'^ / ^ Xxcoor1 III. · · .... L1 · 12. k wherein R, R and R are as defined above, R is tetrahydropyranyl group, and A is a carbon ring of the formula OH: I or ^ R ^ O '' He Hf