DE2640487A1 - PROSTAGLANDIN E, F AND A DERIVATIVES, MEDICINAL PRODUCTS AND INTERMEDIATES CONTAINING THESE COMPOUNDS - Google Patents

Description

^l! Prostaglandin E, F and Α derivatives, medicinal products containing these compounds and intermediates "

Priority: 9/10/1975, V.St.A., No. 611 855

The invention relates to prostaglandin E, F and Α derivatives of the general formulas A and B

^ CH ₂ -OC- (CH ₂ ) _n -COOQ

and

η η

f? CH ₂ -C = C- (CHa) _n -COOQ

/ ^s

H OM

(A)

(B)

in which η is an integer with a value of 2 to 5, M is a hydrogen atom, a lower α-alkoxyalkyl, lower Alkyl or acj ^ l radical, R an alkyl, alkenyl or aralkyl radical, Q is a hydrogen atom or a lower alkyl radical, X is a hydroxyl group, an acyloxy or alkoxy group, A is

709815/1194 ^J.

- G.

Hydrogen atom and. Y is a hydroxyl group, an acyloxy or is an alkoxy radical or A and Y together represent a carbonyl oxygen atom. M is preferably hydrogen a tom or a methyl group, Q a hydrogen atom or is a methyl group and R is an alkyl radical having 3 to 6 carbon atoms. The alkoxy radicals are preferably methoxy groups.

The bonds represented by a wavy line mean that the substituent is either above or below the plane of the paper stands.

The compounds of the invention are valuable drugs with prostaglandin-like effects. So can the connections used to contract smooth muscles such as the pregnant uterus. Thus, the connections of the invention can be used to induce childbirth or induction of abortion. Some of the compounds of the invention cause a regression of the corpus luteum and can therefore be used for oastrus synchronization of animals in agriculture be used. This has advantages with artificial insemination. Some of the compounds of the invention work relaxing on the bronchial muscles. They can therefore be used to treat bronchial asthma. To this Purpose they are applied as an aerosol. These compounds are also inhibitors of gastric acid and pepsin secretion. They can therefore be used for the prophylaxis or therapy of duodenal ulcers can be used.

7 0 H 8 1 5/1 1 Π U

- * - 264048?

Some of the compounds of the invention are antihypertensive Effect, and therefore they can be used to treat hypertension.

In addition, some of the compounds of the invention have an inhibitory effect on the aggregation of platelets. This is interesting because there is an increased tendency towards aggregation found in patients whose vascular system is diseased or at risk. These include atherosclerotics and those at risk of heart attacks with angina pectoris, patients with thrombangiitis obliterans and patients after serious operations. Platelet aggregation In addition to the coagulation processes, it is an important and already effective factor in the development of thromboembolism in the initial stage Diseases.

Some of the compounds of the invention are opposed to the action of the essential prostaglandin inactivating enzyme Prostaglandin 15-ctehydrogenase resistant. You can even serve as inhibitors of this important enzyme. This makes the effects of these substances compared to the natural ones Prostaglandins lengthened or strengthened.

The compounds of the invention can be in the form of customary dosage forms administered orally, parenterally or locally.

The compounds of the general formulas A and B are according to the invention in a multistage process starting from an epoxydiol of the formula I or II given below

709815/119 4

represents. The following reaction scheme explains the preparation of special compounds of the general formula VII, VIII and IX, which fall under the general formulas A and B.

709815/1 194

r-

S.

OH

OH

OH

(H)

^ A ICsC-C-W-R

(III)

F .H \ /

a. Ri = CH ₃ ; W = C; R = alkyl radical

^F / ^H

b. R ₁ = CH ₃ ; W = C-, R = alkyl radical

OH

OH

C-C-C-C-R

IV a

OH

\ ^N C = CC- C- R

H OM

IV c

OH

OH

OH

ΞC _C _ _C _ _R

H OM
IV b

OH

IV d

70981 5/119 4

2640A87

OH

-C = CCCR
OH H OM

) H H 'OM

(V)

(VI)

(VII)

(VIII)

709815/1194

(IX)

The epoxydiols of the formula I and II are prepared as follows: The 2- (2-carboxymethylene) -cyclopent-S-enolactone is reduced with LiAlH ₄ to the corresponding racemic 2- (2-hydroxyethyl) -cyclopent-3-enol, which is reduced with ( +) (R) -OC-phenethyl isocyanate or (-) (S) -OC-phenethyl isocyanate is refluxed for 36 hours in anhydrous toluene under nitrogen as a protective gas. The diastereomer mixtures of (+) (R) - and (-) (S) -Bis-N-OO-phenethylcarbamate are obtained. The diastereomer mixtures are first recrystallized from benzene. The diastereomer which has crystallized out is filtered off, the mother liquor is evaporated and the residue is recrystallized from acetone. The other diastereomer crystallizes out. The diastereomers are with LiAlH. reduced to the corresponding optically active 2- (2-hydroxyethyl) cyclopent-3-enols. These compounds are converted into the corresponding epoxydiols by reaction with m-chloroperbenzoic acid. The method is described in patent application P filed at the same time.

The epoxydiols of the formula I and II are made with an aluminum acetylide of the general formula III converted to the corresponding new triols of the general formula IV.

The triols of the general formula IV are then converted into the end products. Each of the four stereoisomers of the triols of the general formula IV, namely the compounds IVa to d, by selective oxidation with oxygen in the presence oxidized by platinum to the corresponding new lactones of general formula V. The lactones of the general formula V are then treated with a reducing agent such as diisobutylaluminum hydride, reduced to the new hemiacetals of the general formula VI. The hemiacetals of the general formula VI are then a Wittig reaction, for example by conversion with a ylid that differs from 5-triphenylphosphoniovalerian- ■ acid derived, subjected. After dealkylation, for example the cleavage of a butyl radical, with trifluoroacetic -J

709815/1194

Ά.

acid, the prostaglandin F derivatives according to the invention are of the general formula VII obtained. These dihydroxy compounds can be added to the ketones of the general formula VIII and IX, i.e. the prostaglandin E and Α derivatives, are oxidized. For example, the compounds of the general formula VII with N-trimethylsilyl diethylamine at reduced temperature reacted and then with an oxidizing agent, for example a chromium trioxide-pyridine complex, oxidized will. The silyl group is then split off. The corresponding ketones of the general formula VIII are obtained. These ketones can by treatment with an acidic catalyst, for example a mineral acid such as hydrochloric acid or Sulfuric acid, to the corresponding ot, ß-unsaturated ketones of the general formula IX are dehydrated.

According to the invention, the epoxydiols of the formula I and II are with an aluminum acetylide of the general formula IHa

_Y ^F ~, H

^ AiC = C-q-c-R / /

YO H OM

implemented. Y denotes an alkyl radical, R denotes an alkyl, alkenyl or aralkyl radical and M denotes a hydrogen atom, an alkyl or lower α-alkoxyalkyl radical. Is preferably used as Alumi niumacetylid a fluorinated alkylalkoxyaluminum acetylide, in particular a fluorinated lower-alkyl-lower-alkoxyaluminum acetylide, such as a fluorinated methyl methoxyaluminum acetylide ,. used.

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In the general formula IHa, Y preferably denotes one lower alkyl radical, such as the methyl group., M a hydrogen atom or a lower alkyl radical, R a lower alkyl or alkenyl radical. The fluorine atom is either in the α or ß position. The substituents in the compounds of

general formula HIa can be changed and / or modified

will. These substituents also appear in those of the invention End products. The radical R can, for example, be an alkyl radical, such as the propyl, butyl or pentyl group, or an aralkyl radical, such as a p-fluorobenzyl, phenethyl or Phenoxymethylene group. The substituent M can be a hydroxyl group, a lower alkoxy or lower α-alkoxyalkyl radical represent. The substituents R and M also appear in the end products according to the invention.

The invention also relates to the process for producing the aluminum acetylides in a multistage process, starting from an a-fluoroalkanecarboxylic acid alkyl ester, such as Ethyl 2-fluorohexanoate. This procedure is carried out by the following Reaction scheme explained:

^L 709815/1194 ^J

^ 640487

10. HO ^

^ C-CHF-R. / CHCHF-R

^ ^ HO ■

(X) (XI)

R = alkyl radical, R = alkyl radical

HC = C - C - CR ■ + - HC = C _{- C n} ^{- S} C - R

H 'OM H \ m

(XII) (XIII)

a. M = H; R = alkyl radical a. M = H; R = alkyl or

lower alkoxyalkyl radical

b. M = alkyl or lower b. M = alkyl radical;

α-alkoxyalkyl radical R = alkyl radical

c. M = ^oc \ ^ - R = alkyl- ^c * ^{M = 00} V ^ ^{; R =} alkyl- or

or

d. M = OC d. M = ^o

U >> -C-NH ₃ OOC

■ ι

CH ₃ ^ ^H 3

R = alkyl or R »alkyl or

Aralkyl aralkyl group

-C- R

YO H OM

Y = alkyl radical

M = H, alkyl or lower α-alkoxyalkyl radical

R = alkyl, alkenyl or aralkyl radical

709815/1194

In the first stage, the ot-fluoroalkanecarboxylic acid alkyl ester of the general formula X,

like ethyl 2-fluorohexanoate, with a reducing agent, such as diisobutylaluminum hydride, reduced to the corresponding fluoroalkanal hydrate of the general formula XI. The compounds of the general formula XI can, for example, by reaction with an acetylene magnesium halide compound, such as acetylene magnesium bromide, to be converted into a mixture of the compounds of the general formulas XII and XIII. After conversion into the crystalline phthalic acid esters (compounds (XIIc) and (XIIIc) and fractionated Crystallization can be separated into its components. The phthalic acid esters obtained can with an optically active base as an auxiliary, such as a-phenethylamine, in the corresponding Salt transferred and split into the optical antipodes. The compounds of the general formula XIId and XIIId received. The amine salts obtained are then treated with a base such as an alkali metal hydroxide, for example sodium or potassium hydroxide, saponified to give the free alcohols of the general formulas XIIa and XIIIa. the Free alcohols can then be converted into the corresponding alkyl ethers, for example the tert-butyl ethers, by reaction with a Olefin and a mineral acid such as isobutylene and hydrochloric acid. It will be the connections of the general Formula XIIb and XIIIb are obtained. These alkyl ethers can then be converted into the corresponding aluminum derivatives by reaction with a lithium alkyl such as butyllithium, followed by reaction with an alkylalkoxyaluminum halide, such as methyl meth-

709815/1194 ^J.

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oxyaluminium chloride, into the corresponding fluorinated aluminum acetylides the general formula III are converted.

The examples illustrate the invention.

example 1

Production of ervthro-4-fluoro-i-octyn-3-ol (XIIa. R = n-butyl) and threo-4-fluoro-1-octyn-3-ol (XIIIa, R = n-butyl) a) 2 -Fluorohexanal hvdrat

A solution of 9.50 g (58.6 mmol) of ethyl 2-fluorocaproate (X, R = n-butyl) in 45 ml of anhydrous hexane in a 300 ml flask equipped with a 50 ml dropping funnel with pressure compensation is cooled under nitrogen as protective gas to -75 ⁰ C. A solution of diisobutylaluminum hydride in 30 ml of hexane is injected into the dropping funnel through a rubber septum. This solution is prepared from 15 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene by evaporating the toluene under reduced pressure and dissolving the residue in hexane. The addition of the diisobutyl aluminum hydride solution takes 35 minutes. The mixture is then stirred magnetically ^{at -70 + 3 ° C. for 5 hours.} Then 75 ml of 10 percent hydrochloric acid are added dropwise at the same temperature. The cooling bath (dry ice-acetone bath) is then removed and the mixture is stirred further until a homogeneous solution is obtained. The aqueous solution is then saturated with sodium chloride and extracted three times with 100 ml of methylene chloride each time. The methylene chloride extracts are combined, saturated three times with 25 ml each

709815/1194 '-J

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Godfather

ATENTANi-MLr

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H S'EßERTSTRASSE A £ O 4 UHO /

TELEPHONE 4740 Γ5

ter sodium chloride solution and dried over magnesium sulfate. The solvent is then distilled off under reduced pressure. A liquid residue remains which is distilled under reduced pressure. Yield 6.04 g of 2-fluorohexanal hydrate (XI, R - η-butyl) with a boiling point of 70 to 80 ° C./167 torr.

The ethyl 2-fluorocaproate is after that of Elkik and Assadi-Far, Compt. Rend. Series C, 262, 763 (1966). According to this method you can other compounds of the general formula III in which R is an alkyl or alkenyl radical can also be prepared. For example For the preparation of compounds of the general formula III, the radical R can be replaced by an alkyl or alkenyl radical with 3 to 6 carbon atoms or by an aralkyl radical with 7 to 9 carbon atoms.

b) (-) -erythro- and (-) -threo ^ -Fluoro-i-octin ^ -ol A solution of ethylmagnesiurabromide in diethyl ether (prepared from 4.0 g (164 mmol) of magnesium turnings and 20.4 g (187 mmol ) ethyl bromide is added dropwise under nitrogen to a 3 to ⁰ C, cooled to 2 saturated solution of acetylene in the tetrahydrofuran which is first placed into a 500 ml three-necked flask equipped with a stirrer and dropping funnel.

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The dropping funnel is then charged with a solution of 4.70 g (34.6 mmol) of 2-fluorohexanal hydrate in 10 ml of anhydrous tetrahydrofuran. The solution is added dropwise within 10 minutes at 2 to 3 ⁰ C in the Grignard reagent solution under stirring. The resulting gray-colored heterogeneous mixture is stirred ^{at 0 ° C. under nitrogen for 1 hour.} The ice bath is then removed and the mixture stirred for an additional 20 minutes. The reaction mixture is then sucked off with a 50 ml injection syringe and quickly injected into a vigorously stirred saturated aqueous solution of ammonium chloride at 0.degree. The tetrahydrofuran layer is separated off and the aqueous solution is extracted three times with 50 ml of diethyl ether each time. The tetrahydrofuran solution and the ether extracts are combined and washed four times with 25 ml of sodium chloride solution each time and dried over sodium sulfate. Thereafter, the solution is concentrated carefully in a rotary evaporator at a bath temperature of 20 ⁰ C. The residue (8.71 g) is distilled under reduced pressure through a Vigreux column with a vacuum jacket. Yield 3.87 g (78 % of theory of the title compound as a colorless oil with a boiling point of 82.5 to 85 ° C / 10 Torr. C ₈ H ₁₂ OF; CHF

ber.i 66.63 9.09 13.18
found: 66.69 8.89 13.61.

The product consists of a mixture of the erythro and threo forms in a ratio of 2 _r 2: 1.

709 815/1194

^Γ 264Θ487

c) ervthro- and threo-4-fluoro-1-octin-5-ol-hvdrogem3hthalat In a 50 ml flask equipped with a reflux condenser, 0.576 g (4.0 mmol) of the 2.2: 1 - Mixture of the erythro and threo form of 4-fluoro-1-octyn-3-ol, 0.592 g (4.0 mmol) of phthalic anhydride and 0.8 ml of anhydrous pyridine. The mixture is heated for 2 hours at an oil bath temperature 115-120 ⁰ C to reflux, then cooled to room temperature and acidified with hydrochloric acid under ice-cooling lOprozentiger to a pH-value of the second The acidified mixture is extracted four times with 5 ml of benzene each time. The benzene extracts are combined, washed four times with 2 ml of sodium chloride solution each time and dried over sodium sulfate. The solvent is then distilled off under reduced pressure. 1.12 g (96 % of theory ) of a yellow-brown viscous oil remain, which is digested in 1 ml of hexane and crystallized. After washing with a further 2 ml of hexane, 0.630 g of almost colorless crystals with a melting point of 74.5 to 78.5 ° C. are obtained. The hexane wash solutions provide 386 mg of an oil. The crystals are recrystallized twice from a mixture of carbon tetrachloride and hexane. Yield 0.38 g (34% d. Th.) Erythro-hydrogen phthalate in colorless crystals melting at 82 to 82.6 ⁰ C. After three recrystallizations from "a mixture of diethyl ether and hexane is an analytically pure product, mp 83 to 84 ⁰ C. ·
C ₁₆ H ₁₇ O ₄ F; CHF

calc .: 65.74 5.86 6.50
found: 65.58 5.77 6.22

70.9815 / 1 194

The oil from the hexane washing solutions and the mother liquors from the recrystallization of the erythro isomer are combined and recrystallized several times from a mixture of carbon tetrachloride and hexane (1: 3). In doing so, a further amount of the erythro isomer is obtained. Thereafter, the pure threo isomer is obtained, which, after recrystallization twice from a mixture of ethyl acetate and hexane, _{melts at 79 to 79 f} 5 ° C. The elemental analysis gave the following values: C 65.67 % i H 5.91 %; F 6.32 %.

d) Cleavage of erythro- and threo-4-fluoro-1-octin-3-ol Production of (; 5S, 4s) -4-fluoro-1-octin-3-ol hydrogen phthalate (S) -a-phenethvlamine salt

A solution of 292 mg (0.1 mmol) of erythro-4-fluoro-1-octyn-3-ol hydrogen phthalate in 2 ml of methylene chloride is cooled in an ice water bath and with 121 mg (0.1 mmol) of (-) - (S) -oc-phenethylamine offset. The mixture is then warmed to 25 ° C for 20 minutes. The solvent is then reduced under reduced pressure Distilled off pressure and the residue left to crystallize for 15 hours in the cold. After two recrystallizations the pure phenethylamine salt is obtained from the ethyl acetate salt.

e) Preparation of (3S _< 4s) -4-fluoro-1-octyn-3-ol

The Phenäthylaminsalz is dissolved in 5 ml of 5 per cent sodium hydroxide solution and the solution allowed to stand for 30 minutes at 5 to 10 ⁰ C. The reaction mixture is then cooled and extracted 6 times with 1.0 ml of diethyl ether each time. The ether extracts are

709815/1194

the combined, washed three times with 10 ml of 0.5 η hydrochloric acid each time until the pH value is 1, then washed with 10 ml of sodium chloride solution, 2 ml of 5 percent sodium bicarbonate solution and again with 10 ml of sodium chloride solution. The solution is then dried over magnesium sulfate and the diethyl ether is separated off by fractional distillation. The residue represents the pure (3S, 4s) -4-fluoro-1-octyn-3-ol.

f) Preparation of (3S _f 4S) -3-tert-butoxy-4-fluoro-1-octyne Under nitrogen as protective gas, 7 ml of isobutylene are condensed from a bomb at a temperature below -20 ° C. and 25 ml of precooled methylene chloride are condensed diluted. The resulting solution is cooled to -60 ° C. and treated with 2.9 g (21 mmol) of (3S, 4S) -4-fluoro-1-octyn-3-ol in 15 ml of methylene chloride and 0.70 ml of boron trifluoride diethyl etherate and 0.34 ml of anhydrous phosphoric acid are added in the order given. The mixture is then ^{warmed to -15 to 0} ° C. and stirred at this temperature for 40 minutes. The pale yellow solution is again cooled to -50 ⁰ C and poured with vigorous stirring into 70 ml of ice-cold saturated sodium bicarbonate solution, which is cooled in an ice bath. The heterogeneous mixture is stirred vigorously until the organic phase has an alkaline reaction. The methylene chloride layer is then separated, washed with 40 ml of water and 30 ml of brine and dried over sodium sulfate. After evaporation of the solution in a rotary evaporator, 9.87 g of a colorless oil are obtained, which is chromatographed on 70 g of silica gel. Less polar Impurities are gen eluted with hexane. Then the product is with

70981S / 1 194 -

100 ml of a mixture of pentane and diethyl ether (9: 1) eluted. The eluate is evaporated and the crude tert-butoxyfluorooctine is distilled at 57 ° C. under reduced pressure within 3 to 4 minutes. Yield 3.69 g (91 % of theory) of pure compound.
C ₁₂ H ₂₁ OF; CHF

calc .: 71.96 10.57 9.49
found: 71.71 10.48 9.79-

When using threo-4-fluoro-1-octyn-3-ol hydrogen phthalate (3S, 4R) -3-tert-butoxy-4-fluoro-1-octyne is obtained in the same manner as described above.

Example 2
Preparation of the triol (compound IVd, M = tert-butyl,

R = n-butyl)

In a 50 ml three-necked flask dried in a drying cabinet, which is provided with a septum, a dropping funnel and a condenser with a nitrogen inlet tube 1.3 g (6.5 mmol) of (3S, 4S) -3-tert-butoxy-4-fluoro-1-octyne under nitrogen as protective gas presented in 1.5 ml of anhydrous toluene. The mixture is cooled in an ice bath and 3.82 ml (6.5 mmol) of a 1.7 molar solution of n-butyllithium in hexane were added dropwise over 45 minutes. The mixture is then stirred in the cold for a further 15 minutes. The solution is then poured into a 4.3 ml syringe (4.3 mmol) of a 1.0 molar solution of methyl methoxyaluminum chloride offset. The mixture is then stirred in the cold for 50 minutes. The pale yellow colored solution is on

709815/1194

Warmed to room temperature, and a solution of 72 mg (0.5 mmol) of the epoxydiol (compound II) in 1.6 ml of toluene is injected by means of a syringe. The mixture is set to 35+ for 3 1/4 hours. 2 ° C warmed. It is then cooled in an ice bath and saturated sodium sulfate solution is added until the evolution of gas has subsided. About 2 ml are required for this. Then the mixture is stirred for 5 minutes at 2O ⁰ C and then transferred to a 250 ml Erlenmeyer flask containing 100 ml of diethyl ether. Anhydrous sodium sulfate is added and the mixture is stirred for 10 minutes. The sodium sulfate is then filtered off and washed thoroughly with diethyl ether. The filtrate and the washing solution are evaporated. 1.4 g of a yellow oil remain, which is chromatographed on 30 g of silica gel. A mixture of pentane and diethyl ether (9: 1) is used as the mobile phase. 1.09 g of (3S, 4S) -3-tert-butoxy-4-fluoro-1-octyne, which is purified by distillation, are obtained. By further eluting the silica gel with a mixture of pentane and ethyl acetate (1: 4) containing 0.1 % pyridine, 76.6 mg of product (compound IVd; M = tert-butyl, R = η-butyl) are obtained . To separate off a by-product from which hydrogen fluoride was split off, the crude product mixture is hydrolyzed with 2.5 ml of a 0.03 normal solution of hydrogen chloride in a mixture of acetonitrile and water (2: 1) at room temperature for 16 hours. The mixture is then neutralized to a pH value of 7 with solid sodium bicarbonate, then saturated with solid sodium chloride and extracted four times with 3 ml of diethyl ether each time

709815/1104

Treated sodium sulfate and evaporated to dryness. There are 69.5 mg of the triol (M = tert-butyl, R = n-eutyl) and obtain a small amount of a by-product which is a ketone. These two products are made by preparative Thin-layer chromatography on two silica gel plates with the dimensions 20 × 20 cm and a thickness of 2.5 mm separated. The plates are eluted three times with ethyl acetate. The top band is extracted with ethyl acetate. Yield 36.7 ^ g of the 16-fluorotriol (M = tert-butyl. R = η-butyl). The immediate the band below is extracted with ethyl acetate. 6 mg of the by-product with ketone character are obtained.

Following the procedure described above, but using of the other enantiomeric diol epoxide (compound I) the corresponding fluorinated triol (compound IVb) is obtained.

Use the connections as described above I and II and the aluminum compound obtained from (3S, 4R) -3-tert-butoxy-4-fluoro-1-octyne is prepared, the corresponding fluorinated triols (compounds IVa and IVc) are obtained.

Example 3

Preparation of the 15-tert-butoxylactone (compound Vd) 121 mg of platinum dioxide (Engelhart No. 46) in 11 ml of distilled water are reduced with hydrogen for 1 3/4 hours at room temperature and atmospheric pressure. Then the reaction

709815/1 194

-2T-

vessel evacuated several times and flushed and filled four times with nitrogen. Oxygen is then passed into the catalyst slurry for 5 minutes. A solution of 16 mg of the fluorotriol (compound IVd) from Example 2 in 5.4 ml of a mixture of acetone and water (1: 4) is then added over 2 minutes through a dropping funnel. The dropping funnel is then washed with 0.8 ml of acetone. The reaction vessel is placed in an ^{oil bath at 57 °} C. and oxygen is passed directly into the heterogeneous mixture. When the reaction has ended (5 2/3 hours) the catalyst is filtered off through diatomaceous earth and the diatomaceous earth is washed thoroughly with ethyl acetate. The aqueous layer is extracted three times with ethyl acetate. The ethyl acetate extracts are combined and washed successively with 5 percent hydrochloric acid and saturated sodium chloride solution and then filtered under reduced pressure on a suction filter. Yield 54.6 mg (92 % of theory ) of crude lactone, which is purified by preparative thin-layer chromatography using a mixture of ethyl acetate and hexane (5: 1) as the mobile phase. Yield 35 mg (59.1 % of theory ) of pure lactone (compound Vd).

In the manner described above, but using the other diastereomeric 16-fluorotriols from Example 2, are the corresponding diastereomeric lactones (compounds V) are obtained.

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Example 4

Preparation of 16-Fluorhemjacetals (Compound VId) A solution of 3 ₉ 9 mg (0.0115 mmol) of the 3 prepared according to Example 16-Fluorlactons (compound Vd) in ^, 1 ml of toluene at -60 to -65 ° C with 26 ml (0.031 mmol) of a 1.2 molar solution of diisobutylaluminum hydride in toluene were added under nitrogen as a protective gas. The reduction is over after 90 minutes. The reaction mixture is then acidified with 5 percent hydrochloric acid and warmed to room temperature. Solid, anhydrous sodium sulfate in ethyl acetate is added and the mixture is stirred vigorously and the salts are filtered off on a suction filter. The filtrate is evaporated under reduced pressure. 4.6 mg of the crude 16-fluorohemiacetal remain. The product is purified by thin layer chromatography. Ethyl acetate is used as the mobile phase. Yield 2.7 mg (70 % of theory ) of pure 16-fluorohemiacetal.

When using the other diastereomeric 16-fluorolactones prepared according to Example 3, the corresponding obtained diastereomeric hemiacetals.

example
' Manufacture of

«(Compound VIId)

A 50 ml, dry, two-necked flask is filled with nitrogen rinsed and treated with 74.6 mg of a 45 percent suspension of sodium hydride in mineral oil, the three times with anhydrous .Hexane was washed under nitrogen. Then will

7098 15/1194. . __,

1 ml of anhydrous dimethyl sulfoxide (freshly distilled over calcium hydride and stored over a molecular sieve) was added. The suspension obtained is heated to 70 to 75 ° C. on a water bath for 1 hour. Thereafter, the resultant grayish green colored solution is cooled to 25 ⁰ C and slowly (dried for 24 hours at 70 ⁰ C under reduced pressure) achieved by means of a syringe through a rubber septum with 372 mg of 5-Triphenylphosphoniovaleriansäurebromid slowly added in 1 ml dimethyl sulfoxide. After 10 minutes, 0.11 ml of the resulting red-colored solution (0.0456 mmol) are removed using a syringe and dissolved in 2.6 mg (0.0076 mmol) of the 16-fluorohemiacetal obtained according to Example 4 (compound VId) in 20 ml of dimethyl sulfoxide added under nitrogen. The mixture is heated for 2 1/2 hours at 55 ⁰ C, then in an ice bath cooled and acidified with hydrochloric acid 0,5prozentiger carefully to a pH-value of the second After adding aqueous saline solution, the solution is four times with 2 ml of ethyl. acetate extracted. The ethyl acetate extracts are combined, washed once with 2 ml and once more with 1 ml of sodium chloride solution and dried over sodium sulfate. The solvent is then evaporated under reduced pressure and the crude product obtained is digested with 2 ml of diethyl ether and 5 drops of ethyl acetate, inoculated with triphenylphosphoniovaleric acid chloride ν and left to stand in the refrigerator for 15 hours. The crystals of the unreacted acid are spun off and washed once with 2 ml and once more with 1 ml of diethyl ether. The ethyl acetate-diethyl ether solution is evaporated under reduced pressure, the residue in 1 ml of diethyl

^L 7 0 9 815/1194.

ether dissolved, 2 drops of hexane and allowed to stand for 4 hours at -10 ⁰ C. Here another amount of the falls

unreacted acid. Thereafter, the mixture of diethyl ether and hexane is distilled off and the residue is taken up in aqueous sodium carbonate solution (pH 9) and four times extracted with diethyl ether. The ether extracts are mixed with 3 drops of saturated sodium carbonate solution in 0.5 ml of saline solution and finally washed back with saline. The ethereal solution containing the triphenylphosphine oxide and other impurities is discarded. The aqueous phase is acidified to pH 1 with 5 percent hydrochloric acid and extracted four times with ethyl acetate. The ethyl acetate extract is washed back with 1 ml of saline solution over sodium sulfate dried and evaporated to dryness under reduced pressure. 2.9 mg of crude reaction product remain.

This product is dissolved in 100 microliters of trifluoroacetic acid and 10 microliters of anisole at 0 ^° C. and left to stand for 90 minutes. Then the trifluoroacetic acid and the anisole are finally distilled off under reduced pressure at 1 torr. The residue obtained is hydrolyzed with 0.1 ml of a 1/3 saturated solution of sodium carbonate at 25 ^° C. for 30 minutes. In this way, esters of trifluoroacetic acid are separated off. The hydrolysis solution is then extracted three times with 1 ml of diethyl ether each time. The ether extracts are combined and washed back with aqueous sodium carbonate solution and saline solution (0.5 ml saline solution + 3 drops of saturated sodium carbonate solution) and finally with 0.5 ml saline solution.

709815/1194 ^J.

Γ Π

- 25 -

see. The aqueous solutions are combined, acidified to pH 1 with 5 percent strength hydrochloric acid which is saturated with common salt and extracted four times with 2 ml of ethyl acetate each time. The ethyl acetate extracts are combined, washed with 0.5 ml of sodium chloride solution and dried over sodium sulfate. The majority of the solvent is then distilled off under reduced pressure. A further amount of solvent is added to the residue and the mixture is evaporated in order to separate off traces of trifluoroacetic acid. The residue is purified by high pressure liquid chromatography on silica gel. The pure (15S, 16S) -i6-fluoro-13-dehydro-PGF _2CC (compound VIId) is obtained.

In the manner described above, but using the other diastereomeric fluoro half-acetals from Example 4, the corresponding diastereomeric 16-fluoro-13-dehydroprostaglandin F _2a compounds (compounds VIl) are obtained.

Examples Preparation of (15S.i6S) -16-fluoro-15-dehvdro-PGE .-, - methvlester (compounds VIIId, Q =
(15S, 16S) -16-fluoro-13-dehydro-PGF ₂ -methyl ester is reacted from the compound prepared according to Example 5 with a solution of diazomethane in diethyl ether containing 10 % methanol at 0 ^° C. for 10 minutes. The solvent is then evaporated. 20 mg of the methyl ester obtained in 0.4 ml of anhydrous acetone are mixed with 0.8 ml of N-trimethylsilyl diethylamine at -40 ° C. under nitrogen as a protective gas. According to Istündi-

7098 15/1194 -J

^Γ - Ä *.

ger reaction is added to the reaction mixture with 0.6 ml of anhydrous methanol and heated to 25 ⁰ C. The reaction mixture is then evaporated to dryness under reduced pressure. The main product obtained is the 11,15-bis-trimethylsilyl derivative, which is oxidized in situ with Collins reagent (prepared from 36 mg of chromium trioxide and 55 microliters of pyridine in 0.8 ml of methylene chloride) for 5 minutes at 25 ° C. Thereafter, by treatment for one hour with a mixture of 1 ml of methanol, 0.1 ml of v / water and 0.05 eu. Acetic acid split off the silyl group. High pressure liquid chromatography on silica gel, after eluting with different volume ratios of hexane and ethyl acetate, yields 10 mg (15S, 16S) -16-fluoro-13-dehydro-PGrE ₂ -raethyl ester ((compound VIIId) Q =)

The corresponding fluoro-13-dehydroprostaglandin E2 methyl esters (compounds VIII) are obtained in the manner described above, but using the other diastereoisomeric fluoro-13-dehydroprostaglandin mp _{0 T compounds from Example 5.}

Example 7 Preparation of (15S, 16S) -16-fluoro-13-dehvdro-PGA2-raethvlester (compound IXd, Q = CH ₃ )

A solution of 20 mg of the (15S, 16S) -16-fluoro-i3-dehydro-PGE ₂ methyl ester prepared according to Example 6 in 2 ml of a 0.5 normal solution of hydrogen chloride in a mixture of tetrahydrofuran and water (1: 1 ) is 72 hours at 25 ° C

70981 δ / 1194- _j

~ * ΙΪλ> 2640Α87

vigorously stirred. The solution is then adjusted to pH 4 and extracted with ethyl acetate. The ethyl acetate extract is backwashed once with saline solution. The solvent is then evaporated under reduced pressure. 13.3 mg (15S, 16s) -i6-fluoro-13-dehydro-PGAp-methyl ester remain as residue.

In the manner described above, but using the other diastereomeric methyl esters prepared according to Example 6, the corresponding 16-fluoro-PGA ₂ derivatives (compounds IX) are obtained.

The compounds with free hydroxyl groups prepared according to the invention can be converted into the corresponding acyl and alkyl derivatives in a manner known per se. For example can remove the free hydroxyl groups with an acylating agent that is different from a carboxylic acid with at most

the
12 carbon atoms can be converted to / corresponding acyloxy derivatives. Furthermore, the free hydroxyl groups can be converted into the corresponding alkoxy derivatives with alkylating agents. Alkylating agents which provide lower alkyl radicals are particularly preferred.

709815/1194

Claims (10)

Claims 2640487 1. J Prostaglandin E, F and A derivatives of the general formula A and B H, ; CH ₂ -C = C- (CHs) _n -COOQ E, H and ¹ C = C H * 0M π υπ in which η is an integer with a value of 2 to 5, M is a hydrogen atom, a lower α-alkoxyalkyl, lower Alkyl or acyl radical, R an alkyl, alkenyl or aralkyl radical, Q a hydrogen atom or a lower alkyl radical, X a Hydroxyl group, an acyloxy or alkoxy group, A is a hydrogen atom and Y is a hydroxyl group, an acyloxy or alkoxy group or A and Y together represent a carbonyl oxygen atom. 2. Prostaglandin E and F derivatives of the general formula COOQ and in which A, Y, Q and R have the meaning given in claim 1. . 709815/1194 L. Γ Π 3 · Prostaglandin A derivatives of the general formula COOQ κ ^ τ COOQ hC-C-C-R H "OH in which Q and R have the meaning given in claim 1. 4. Medicinal product, characterized by a content of a compound according to claim 1 to 3 and usual carrier substance mouth / or diluents and / or auxiliaries. 5. Cyclopentane derivatives of the general formula in which X, Y, R and M have the meaning given in claim 1. 6. Lactones of the general formula ■ Q »CcY ) f H '' 0M J 70981B / 1194 in which Y, A, X, M and R have the meaning given in claim 1. 7 · Lactones according to Claim 6 of the general formula YA ^Y A X ' ■ _d ^y , ι and F H VV " ^N s (= CCCR - - / χ ^R OH hf ^N 0H ^0H H "OH in which Y, A and R have the meaning given in claim 1. 8. Aluminum acetylides of the general formula F H AIC = C-C-C-R / X H OM in which R _{1 represents} a lower alkyl radical and M and R have the meaning given in claim 1. 9-aluminum acetylides according to claim 8 of the general formula ' ψ η Ir = Ep r r R Hn + CH ₃ O in which R has the meaning given in claim 1. 709815/1194 10. Process for the preparation of the cyclopentane derivatives according to Claim 5 of the general formula given, in which Y is a hydroxyl group, characterized in that one Epoxycyclopentane of the general formula in which X represents a hydroxyl group, an acyloxy or alkoxy radical, with an aluminum acetylide of the general formula FH (lower alkyl) ~ \ J * AIC = C C C-R (lower alkyl) ~ ° ^{H 0M} in which R is an alkyl, alkenyl or aralkyl radical and M is a hydrogen atom, a lower α-alkoxyalkyl, lower alkyl or acyl radical means to implement. 709815/1