CH621548A5 - Process for the stereoselective preparation of a bicyclic 3alpha-hydroxylactone - Google Patents

Description

The aim of the present invention is to provide a new process for the preparation of bicyclic 3a-hydroxy-lactone intermediates which are suitable in large batches for the preparation of prostaglandic compounds. In this process, the bicyclic 3-oxo-lactone (for example of the formula III or IV) is to be reduced in a highly stereoselective manner to the corresponding 3a-hydroxy-lactone.

The invention therefore relates to a new process for the highly stereoselective preparation of a bicyclic 3a-hydroxy-lactone of the formula

40

45

(V)

•H

c = c.

50

R13O u / C-R.7

H / \ II

HELL!

The new process is characterized in that the side chain oxo group of a lactone of the formula

55

60

r 1 3 0

(XII)

c = c

OC-R7

II il

0 Li

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with a Kalimtrialkylborhydrid of formula k. b h - c h

\ cHs) m +, - CHs J 3

where m is 0, 1, 2 or 3, stereoselectively reduced.

Residues 13 that are particularly suitable are residues of the formula

JT

(1) -c-nh- "

wherein Rj and R2, which may be the same or different, denote hydrogen, chlorine, fluorine, bromine, alkyl radicals having 1 to 3 carbon atoms or alkoxy radicals having 1 to 3 carbon atoms, or

(2)

0

ii

• c-n ff

R2 Ri where R! and R2, which may be the same or different for each phenyl ring, have the meaning given above.

Particularly preferred groups R13 are the phenylcarbamoyl radical

»^,

-C-NH-

and the p-tolylcarbamoyl group

K® B® H

(CH2) m ~ CH3

(CH2) m + 1-CH3

20th

where m has the meaning given above. Borohydride with m = 0 is preferred, that is, the potassium trisec-butylborohydride.

The present process and in particular the preferred embodiments provide surprising and unexpected advantages over known processes for the preparation of the hydroxy products.

First of all, the process according to the invention is surprising and unexpectedly more stereoselective than previously known processes, so that the ratio between a- and / j-hydroxy-lactone product is increased unexpectedly.

Secondly, the method according to the invention is surprisingly cheaper for large batches or for technical production of the end products,

1. the determining groups used here avoid the use of residues (e.g. p-phenylphenylcarb-amoyl) which are known to form carcinogenic or suspect by-products as carcinogens,

2. the reducing agent can be produced simply, directly and cheaply,

3. the 25 reaction conditions required to achieve optimal stereoselectivity are less stringent than in previous methods and

4. The process involves the crystallization of essentially pure 2,3,4,5,6-pentanor-PGFto compounds

30 Exclusion of 15/3 hydroxy epimer allowed, so that the chromatographic separation of the C-15 epimer mixtures of the PG products can be avoided.

The reaction scheme A below describes the preparation of starting compounds of the formula XII used in the process according to the invention, the process according to the invention itself and also the further processing of compounds obtained according to the invention.

In Scheme A, Li, R7 and Ru have the meaning given above, M denotes potassium, sodium or lithium.

The compound of formula XI is known or can be easily prepared by known methods. From compound XI, compound XII is obtained, for. B. by replacing the hydrogen atom of the 3-hydroxyl group on the cyclopentane ring with a group R13. If R13 is a phenyl or substituted phenylcarbamoyl radical, the corresponding phenyl or substituted phenyl isocyanate of the formula can be used

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45

CH3

Further preferred groups Rî3 are those in which one of the radicals Rt and R2 is hydrogen and the other is methyl or methoxy or chlorine.

The reducing agents used in the process according to the invention belong to the class of potassium trialkylborohydrides of the formula

50

Use Ri,

wherein Ri and R2 have the meaning given above. The reaction is preferably carried out at 0 to 25 ° C. It is convenient to work in pyridine as a diluent or in a diluent such as tetra-hydrofuran which contains a catalytic amount of pyridine. Other pyridine-like bases can also be used, such as the picolines or lutidines. Stronger tertiary amine bases, for example triethylamine, can also be used. However, pyridine alone is preferably used as the diluent.

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6

Scheme A

(XI)

c = c

H "C

ii

0

c-r7 lx

(XII)

r iso h /

c = c;

h c

11

0

yj-r, Li v 0

9a

(V)

H

r> 30 »—c — rt

/ \ H

H OH Li ni /

HO

R13O

^ CH2C00'M + / h

• .C-C 'h ^ c-

V

/ \

H OH Li

(XIV)

c r7

15

20th

40

4th

HO

, CH2-COO ~ M +

(XV)

/> c = cC

HO H \ C- / '

v

- C R7

'v, 11

H bH Li

HO

ÇC

CH2-COOH H

(XVI)

, c = c

HO H "'C R7

/ \ il

H OH Lx v 0

0 "

(XVII)

H

X = C 'HO ^ .C

/ \ il

H OH Lx

After the reaction has ended, by-products such as, for example, N, N'-diphenylurea or a correspondingly substituted phenylurea are generally separated from product XII by crystallization. In a preferred embodiment, however, this purification by crystallization is omitted and the crude reaction product is introduced into the following process steps from Scheme A.

If Rj3 is a diphenylcarbamoyl radical, compound XII is preferably prepared as described for compound XI using diphenylcarbamoyl chloride 55 or a substituted diphenylcarbamoyl chloride

Formula D ki

60

N-C

"ci

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wherein Rt and R2 have the meaning given above. The reaction takes place e.g. B. with the addition of 1 equivalent of sodium hydride to the above mixture. After the reaction has ended, excess sodium hydride can be destroyed by adding an organic acid, for example acetic acid. The pure product can optionally be isolated from the reaction mixture in a conventional manner.

The compound V is obtained from the compound XI by the strongly stereoselective reduction according to the invention. This reduction is preferably carried out at low temperatures of -78 to 120 ° C. in order to ensure high selectivity. Temperatures of approximately -110 ° C. are particularly preferred. The diluent for this reduction preferably consists of a mixture of diethyl ether and tetrahydrofuran in a ratio of 3: 1. Other proportions are also possible in this diluent mixture, but the freezing point of the tetrahydrofuran at -65 ° C prevents its exclusive use. The presence of sufficient tetrahydrofuran to ensure the solution of the reactants is desirable.

Another preferred condition for this reduction and the subsequent steps before the extraction of the borane (from the compound of formula XIV) is that all reactants are made oxygen free by passing nitrogen through them. This is particularly necessary in order to prevent the trialkylborane formed during the reduction of compound XII from being destroyed.

The reduction is then carried out according to the invention by adding a potassium trialkylborohydride of the formula

(ch

(CH.

where m has the meaning given above. It is preferred to use 1.2 to 1.4 molar equivalents of potassium trialkyl borohydride per molar equivalent of compound XII.

The potassium trialkylborohydrides of the above formula can be obtained from the corresponding trialkylboranes of the formula

(ch in which m has the meaning given above, are obtained by reaction with potassium hydride. The procedure is usually carried out according to known processes for reacting potassium hydride with trialkylboranes, see for example CA Brown, Loc. cit. The boranes can be prepared by various known methods. According to a preferred process, they are obtained by reacting diborane with an olefin of the formula

CH3- (CH2) m-CH = CH- (CH2) m-CH3

where m has the meaning given above.

The compound of formula XIV can then be produced by opening the lactone ring. For this purpose, sodium, potassium or lithium hydroxide in aqueous solution is usually suitably used in a manner known per se.

The above solution containing the compound XIV further contains the trialkylborane formed in the reduction of the compound XII. The trialkylborane is preferably separated from the compound XIV, for example by extraction with diethyl ether, and the trialkylborane obtained in this way can then be reacted with potassium hydride in the above manner, the potassium trialkylborohydride which can be used to reduce the compound XII to V being regenerated.

The compound of formula XV can be prepared from compound XIV by hydrolysis of the residues RJ3. This hydrolysis is usually carried out in a manner known per se, for example by adding lithium, potassium or preferably sodium hydroxide with heating. The reaction is usually complete after about 24 hours at a reaction temperature of about 85 ° C., although higher temperatures can also be used to shorten the reaction time.

Compound XVI can then be prepared from Compound XV by separating out undesirable organic by-products, then acidifying and crystallizing. The extraction of the unwanted organic by-products takes place e.g. B. by first adjusting the pH of the solution containing compound XV with a mineral acid such as phosphoric acid to about 9.0. The mixture obtained in this way is generally extracted with an organic diluent, preferably methylene chloride. The methylene chloride extract contains the unwanted organic by-products and is therefore discarded. The acidification can then be carried out by carefully cooling the aqueous phase (0 to 5 ° C.) and acidifying to pH 4 with further mineral acid. The XVI product can then be isolated by extraction, for example with ethyl acetate, and crystallization by conventional methods.

In the above manner, compound XVI is usually obtained in crystalline form, which practically excludes the corresponding 15/3 hydroxy ximer from XVI. The above process therefore eliminates the chromatographic separation of the 15a and 15β-hydroxy epimers which result from the reduction of compound XII to compound XIII.

The compound of formula XVI is known to be a very useful intermediate for the preparation of various PGF, PGE, PGA and PGB compounds. For example, the compound XVI can be converted into the lactone XVII in a known manner, and this is the very useful intermediate for the preparation of the said prostaglandin-like compounds.

In the following examples, the infrared absorption spectra were recorded with a Perkin-Elmer Model 421 spectrophotometer. Unless otherwise specified, undiluted samples were used. The ultraviolet spectra were recorded on a Cary Model 15 spectrophotometer.

The NMR spectra were recorded on a Varian A-60, A-600 or T-60 spectrophotometer on deuterochloroform solutions with tetramethylsilane as the internal standard.

The mass spectra were recorded with a double-focusing high-resolution mass spectrometer CEG model 1108 or with a gas chromatograph / mass spectrometer LKB model 9000. Unless otherwise stated, trimethylsilyl derivatives were used.

The solvent system A-IX used in thin layer chromatography consists of ethyl acetate / acetic acid / 2,2,4-trimethylpentane / water in a ratio of 90: 20: 50: 100, see M. Hamberg and B. Samuelsson, J. Biol. Chem 241, 257 (1966).

“Skellysolve B” means a mixture of isomeric hexanes.

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In the following examples and preparations, the Ri3 group is usually referred to as the "determining group".

The term silica gel chromatography is used to mean elution, collecting the fractions and combining those fractions which, according to the thin-layer chromatogram, contain the desired product free of starting material and impurities.

The melting points were determined using a Fisher-Johns melting point apparatus.

The specific rotations [a] were determined on solutions in the specified solvent at room temperature using an automatic polarimeter Perkin-Elmer model 141.

example 1

2,3,4,5,6-Pentanor-PGFla from 3β, 5a-dihydroxy-2 / j- (3-oxo-trans-1-octenyl) -l «-cyclopentanacetic acid-y-lactone with the phenylcarbamoyl radical as R13- Group (Formula XVI:

C-R7

II = n-pentyl)

Li

A. 3.97 g of 3 ", 5" -dihydroxy-2 / 3- (3-oxo-trans-l-octenyl) -lc-cyclopentanacetic acid-y-lactone are dissolved in 6 ml of dry pyridine. A solution of 2.14 g of phenyl isocyanate and 6 ml of dry pyridine, which has cooled to 0 ° C., is added to the resulting solution under a nitrogen atmosphere. The addition is carried out by dropping in the course of 30 minutes. The reaction mixture is then a further 30 min

Stirred at 0 ° C. and then allowed to warm to room temperature while stirring until the end of the reaction was determined according to thin-layer chromatogram (ethyl acetate in Skellysolve B 1: 1). The reaction is complete after about 18 hours, giving the phenyl urethane derivative of the starting lactone.

The pure product can optionally be isolated by adding 10 to 15 volumes of water to the reaction mixture and then extracted with 45 ml of ethyl acetate. The combined ethyl acetate phases are washed once with water and twice with 1 molar aqueous phosphoric acid solution. Finally, the organic phase is washed with water, dried over sodium sulfate and concentrated to an oil at reduced pressure and 35 ° C. This is dissolved in benzene and the solution is cooled to about 5 ° C while maintaining this temperature for 1 hour. A precipitate of diphenylurea is formed, which is filtered off and washed with cold benzene. The organic phase is then concentrated in vacuo to give 6.05 g of the phenylurethane derivative of the starting lactone. After recrystallization from methanol, this product gives a melting point of 92 to 94 ° C, NMR absorption in deuterochloroform at 5.1, 6.15, 6.7 and 7.3 ò. Characteristic infrared absorptions are also observed at 1695, 1730 and 1770 cm-1.

B. Excluding moisture, 6.0 g of the reaction product according to Part A are dissolved in 25 ml of dry tetrahydrofuran and the resulting mixture is then diluted with 120 ml of dry diethyl ether. Oxygen is excluded from the solution by passing nitrogen through the solution for several minutes. This solution is then cooled to -110 ° C in a nitrogen atmosphere, first cooling to -78 ° C in a 95% ethanol bath with dry ice and then to -110 by periodic addition of liquid nitrogen so that the reaction temperature is maintained ° C cooled further. 54.8 ml of 0.5M potassium tri-sec-butylborohydride in tetrahydrofuran, made up to 100 ml with dry diethyl ether, are then added to this cooled solution. The addition is carried out by dropping in the course of 2 to 3 hours. The progress of the reaction is followed by thin layer chromatography (ethyl acetate and Skellysolve B 7: 3). The addition of potassium tri-sec-butylborohydride solution is stopped as soon as the starting material is used up. The reaction is then stopped by adding 10 ml of oxygen-free methanol and 25 ml of oxygen-free water. The reaction mixture is allowed to warm to 10 to 20 ° C. The resulting lactone XIII is used without purification or characterization in the following process steps.

C. 9 ml of oxygen-free 10% aqueous sodium hydroxide solution are added to the reaction product according to section B with stirring. The reaction mixture is allowed to warm to room temperature, and the progress of the reaction is followed by thin layer chromatography.

D. Then tri-sec-butylborane is extracted from the reaction mixture according to Part C by adding 25 ml of oxygen-free water, shaking and then separating out the lower aqueous phase. The organic phase is washed once with a partially saturated sodium chloride solution, which is then added to the aqueous extract. The combined aqueous phases are extracted with diethyl ether. This creates three phases: an aqueous phase, a tetrahydrofuran-containing phase and the ether phase. The ether phase is combined with the organic phase obtained above, and this combined organic phase is dried over magnesium sulfate and concentrated to an oil under oxygen-free conditions. This consists essentially of tri-sec-butyl-borane, which is slightly contaminated by diphenylurea.

E. The organic and tetrahydrofuran phases obtained in the extraction according to Part D are added to 4.2 g of sodium hydroxide. The mixture is heated to 85 ° C. for 16 to 18 hours, during which the 11-phenyl urethane group hydrolyzes. The progress of this reaction is conveniently followed by thin-layer silica gel chromatography. The resulting mixture is then cooled to room temperature and the pH is adjusted to 9.0 by adding 2 molar phosphoric acid. Then the mixture is extracted twice with methylene chloride and the methylene chloride extracts are discarded. The aqueous phase is cooled to 0 to 5 ° C and carefully acidified to pH 4. The resulting acidic solution is then saturated with solid sodium chloride. This saturated aqueous solution is then extracted with 400 ml of ethyl acetate and the organic extracts are washed twice with saturated sodium chloride solution to remove unwanted by-products. The resulting organic phase is cooled and benzene is added until the mixture becomes cloudy. This organic mixture is then dried over sodium sulfate and freed from the solvent at 30 ° C. in vacuo. During this process, the product XIV crystallizes out. Ethyl acetate is added to a volume of 20 to 30 ml and the ethyl acetate mixture is then cooled to 0 ° C. for 2 hours in order to complete the crystallization. Then the ethyl acetate is filtered off and the residue is washed with cold ethyl acetate. The resulting crystals are dried to constant weight, giving 3.13 g of pure product of the formula XVI.

Preparation 1 conversion of the tri-sec-butylborane to the potassium tri-sec-butylborohydride

Tri-sek-butylborane (see Example 1, Section D) is dissolved in 100 ml of oxygen-free Skellysolve B. The diphenylurea present in this mixture, which is insoluble in Skellysolve B, is separated. The solvent is concentrated in vacuo in a nitrogen atmosphere, giving the tri-sec-butylborane.

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621 548

1.5 g of 57% potassium hydride suspension in mineral oil are dissolved in 25 ml of dry oxygen-free tetrahydrofuran. The resulting slurry is cooled to 0 ° C in a nitrogen atmosphere. Then 1.575 g of tri-sek-butylborane in 5 ml of tetrahydrofuran are added dropwise over the course of 10 minutes.

The resulting mixture is allowed to warm to room temperature and stirred for 1 hour. The stirring is then switched off, the finely divided solid settling out overnight. The resulting mixture is then filtered through a fine sintered glass filter in a nitrogen atmosphere to give a clear, light yellow solution of the title compound.

Example 2

2,3,4,5,6-Pentanor-PGF2a from 3a, 5a -D ihy droxy-2/3 - (3-oxo-trans-l-octenyl) -la-cyclopentanacetic acid-y-lactone with the diphenylcarbamoyl radical as the determining one Group.

A. At room temperature, 5.0 g of the lactone XI in 70 ml of tetrahydrofuran and 3.4 g of diphenylcarbamoyl chloride are mixed with stirring in a nitrogen atmosphere. Then sodium hydride (300 mg) is slowly added as a 57% suspension in mineral oil. The progress of the reaction is monitored by thin-layer chromatography and turns out to be complete after about 3 hours. The reaction is stopped by slowly adding acetic acid.

Then the diphenylcarbamoyl derivative is purified by evaporation of the solvent, addition of ice water extraction with methylene chloride and washing, drying and concentration of the methylene chloride extract. The melting point is 80 to 82 ° C, UV spectrum Amax. (Ethanol) 230 rqw e 22 528). Characteristic NMR absorptions are observed at 4.0, 6.0, 6.6 and 7.25 <5 and characteristic IR absorptions at 1666, 1686, 1700 and 1775 cm-1.

B. The title compound is obtained by subjecting the reaction product from Section A to the procedures of Sections B through E of Example 1 in turn.

Example 3

2,3,4,5,6-Pentanor-PGFia from 3a, 5a-dihydroxy-2 / i- (3-oxo-trans-l-octenyl) -la-cyclopentanacetic acid-y-lactone with the p-tolylcarbamoyl radical as the determining one Group.

A. The lactone XI, p-tolyl isocyanate and triethylamine are stirred at room temperature in freshly distilled tetrahydrofuran. As soon as the reaction turns out to be complete according to the thin-layer chromatogram, the tetrahydrofuran is evaporated off and the resulting mixture is mixed with cold water and then extracted with methylene chloride. The pure p-tolyl urethane derivative XII is isolated by using silica gel chromatography and then crystallizing from ethyl acetate and Skellysolve B. The melting point is 80.5 to 82.5 ° C, UV spectrum (ethanol) Amax. 234 ny * (e = 26 933); The NMR spectrum shows characteristic absorptions at 5.05, 6.17, 6.8 and 7.0 to 7.4 ò.

B. From the reaction product according to section A, the title compound is obtained by the process of sections B to E of Example 1.

Example 4

2,3,4,5,6-Pentanor-PGFla from 3a, 5a-dihydroxy-2 / 3- (3-oxo-trans-l-octenyl) -la-cyclopentanacetic acid -; '- lactone with the 3- (2nd , 5-dichlorophenyl) carbamoyl radical as the determining group.

À. The lactone of the formula XI and 2,5-dichlorophenyl isocyanate are stirred together in dry pyridine at room temperature. As soon as the reaction has ended (according to the thin-layer chromatogram), the product is isolated by adding cold water and extracting with ethyl acetate. The ethyl acetate extract is a silica gel chromato-

subjected to graphie and the product is crystallized from ethyl acetate and Skellysolve B, whereby pure product is obtained. This shows a value Rf of 0.11 in the thin layer chromatogram (ethyl acetate and Skellysolve B 1: 1).

B. If the reaction mixture according to section A is used in the process of sections B-E of Example 1, the title compound is obtained.

Example 5

2,3,4,5,6-Pentanor-PGFi "from 3a, 5a-dihydroxy-2 /? - (3-oxo-trans-l-octenyl) -la-cyclopentanacetic acid-y-lactone with the 3- (p -Bromphenyl) carbamoylrest as the determining group.

A. If the procedure of Example 4, Part A is repeated, but replacing the 2,5-dichlorophenyl isocyanate with p-bromophenyl isocyanate, the corresponding 3- (p-bromophenyl) urethane compound is obtained.

B. If the reaction product according to Section A is used in the process of Sections B-E of Example 1, the title compound is obtained.

Example 6

2,3,4,5,6-Pentanor-PGFla from 3a, 5a-dihydroxy-2 / 3- (3-oxo-trans-l-octenyl) -la-cyclopentanacetic acid -; '- lactone with the 3- (p -Athoxyphenyl) carbamoyl residue as the determining group.

A. If the procedure of Example 4, Part A is repeated, but using p-ethoxyphenyl isocyanate instead of 2,5-dichlorophenyl isocyanate, the corresponding 3- (p-ethoxyphenyl) urethane derivative of the lactone starting material is obtained. It melts at 91 to 93 ° C.

B. From the reaction product according to section A, the title compound is obtained by the process of sections B-E of Example 1.

If the procedures of Examples 1 to 6 are repeated, but with the replacement of the potassium tri-sec-butylborohydride by one of the following potassium borohydrides tri- (3-hexyl) -,

Tri- (4-octyl) - or tri- (5-decyl) borohydride,

so you get the product XVI.

Furthermore, by the methods of the preceding examples and the preceding paragraph, replacing the lac-ton starting material with a 3a, 5a-dihydroxy-la-cyclopentanacetic acid - / - lactone which has one of the following substituents in the 2/5-position carries: the 3-oxo-4-methyl-trans-1-octenyl-,

3-oxo-4,4-dimethyl-trans-1-octenyl-, 3-oxo-4-fluoro-trans-l-octenyl-,

3-oxo-4,4-difluoro-trans-1-octenyl-, 3-oxo-4-phenoxy-trans-1-butenyl-, 3-oxo-4- (m-chlorophenoxy) -trans-1-butenyl- , 3-oxo-4- (m-trifluoromethylphenoxy) -trans-l-butenyl-, 3-oxo-4- (p-fluorophenoxy) -trans-l-butenyl-, 3-oxo-4-phenoxy-trans-l -pentenyl-, 3-oxo-4- (m-chlorophenoxy) -trans-l-pentenyl-, 3-oxo-4- (m-trifluoromethylphenoxy) -trans-l-pentenyl-, 3-oxo-4- (p -fluorophenoxy) -trans-l-pentenyl-, 3-oxo-4-methyl-4-phenoxy-trans-l-pentenyI-, 3-oxo-4-methyl-4- (m-chlorophenoxy) -trans-l- pentenyl-, 3-oxo-4-methyl-4- (m-trifluoromethylphenoxy) -trans-

1-pentenyl.

3-oxo-4-methyl-4- (p-fluorophenoxy) -trans-l-pentenyl-,

3-oxo-5-phenyl-trans-l-pentenyl-,

3-oxo-5- (m-chlorophenyl) -trans-l-pentenyl-,

3-oxo-5- (m-trifluoromethylphenyl) -trans-l-pentenyl-,

3-oxo-5- (p-fluorophenyl) -trans-l-pentenyl-,

3-oxo-4-methyl-5-phenyl-trans-l-pentenyl-,

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3-oxo-4-methyl-5- (m-chlorophenyl) -trans-l-pentenyl-, 3-oxo-4-methyl-5- (m-trifluoromethylphenyl) -trans-1-pentenyl-,

3-oxo-4-methyl-5- (p-fluorophenyl) -trans-l-pentenyl-, 3-0x0-4,4-dimethyl-5-phenyl-trans-l-pentenyl-, 3-oxo-4, 4-dimethyl-5- (m-chlorophenyl) -trans-l-pentenyl, 3-oxo-4,4-dimethyl-5- (m-trifluoromethylphenyl) -trans-

1-pentenyl,

3-oxo-4,4-dimethyl-5- (p-fluorophenyl) trans

1-pentenyl,

3-oxo-4-fluoro-5-phenyl-trans-l-pentenyl-, 3-oxo-4-fluoro-5- (m-chlorophenyl) -trans-l-pentenyl-, 3-oxo-4-methyl- 5- (m-trifluoromethylphenyl) trans-l-pentenyl,

3-oxo-4-methyl-5- (p-fluorophenyl) -trans-l-pentenyl-, 3-oxo-4,4-difluoro-5-phenyl-trans-l-pentenyl-, 3-oxo-4, 4-difluoro-5- (m-chlorophenyl) -trans-l-pentenyl-, 3-oxo-4,4-difIuor-5- (m-trifluoromethylphenyl-trans-1-pentenyl-,

3-oxo-4,4-difluoro-5- (p-fluorophenyl-trans-l-pentenyl-,

3-oxo-trans-l-cis-5-octadienyl-,

3-oxo-4-methyl-trans-l-cis-5-octadienyl-,

3-oxo-4,4-dimethyl-trans-l-cis-5-octadienyl-,

3-oxo-4-fluoro-trans-l-cis-5-octadienyl- or

3-oxo-4,4-difluoro-trans-l-cis-5-octadienyl radical,

the corresponding 2,3,4,5,6-pentanor-PGFla compound, that is

16-methyl,

16,16-dimethyl,

16-FIuor-,

16,16-difluoro,

16-phenoxy-17,18,19,20-tetranor-, 16- (ra-chlorophenoxy) -17,18,19,20-tetranor-, 16- (m-trifluoromethylphenoxy) -l 7,18,19,20 -tetranor-, 16- (p-fluorophenoxy) -l 7,18,19,20-tetranor-,

16-phenoxy-l 8,19,20-trinor-,

16- (m-chlorophenoxy) -18,19,20-trinor-, 16- (m-trifluoromethylphenoxy) -l 8,19,20-trinor-, 16- (p-FIuorphenoxy) -l 8,19,2 O -trinor-, 16-methyl-16-phenoxy-l 8,19,20-trinor-,

5 16-methyl-l 6- (m-chlorophenoxy) -l 8,19,20-trinor-, 16-methyl-l 6- (m-trifluoromethylphenoxy) -l 8,19,20-trinor,

16-methyl-l 6- (p-fluorophenoxy) -l 8,19,20-trinor-,

17-phenoxy-18,19,20-trinor-,

io 17- (m-chlorophenyl) -l 8,19,20-trinor-,

17- (m-trifluoromethylphenyl) -l 8,19,20-trinor-, 17- (p-fluorophenyl) -l 8,19,20-trinor-, 16-methyl-17-phenyl-18,19,20- trinor-, 16-methyl-17- (m-chlorophenyl) -18,19,20-trinor-, 15 16-methyl-17- (m-trifluoromethylphenyl) -18,19,20-trinor-,

16-methyl-l 7- (p-fluorophenyl) -l 8,19,20-trinor-, 16,16-dimethyl-l 7-phenyl-l 8,19,20-trinor-, 16,16-dimethyl- 17- (m-chlorophenyl) -l 8,19,20-trinor-, 20 16,16-dimethyl-l 7- (m-trifhiormethyl) -l 8,19,20-trinor-, 16,16-dimethyl- 17- (p-fluorophenyl) -18,19,20-trinor-, 16-fluorine-l 7-phenyl-18,19,20-trinor-, 16-fluoro-17- (m-chlorophenyl) -18,19 , 20-trinor-, 16-fluorine-l 7- (m-trifluoromethylphenyl) -l 8,19,20-25 trinor-,

16-fluoro-17- (p-fluorophenyl) -l 8,19,20-trinor-, 16,16-difluoro-l 7 -phenyl-18,19,20-trinor-, 16,16-difluoro-l 7 - (m-chlorophenyl) -18,19,20-trinor-, 16,16-difluoro-17- (m-trifluoromethylphenyl) -18,19,20-3o trinor-,

16,16-difluoro-17- (p-fluorophenyl) -18,19,20-trinor-, cis-17,18-didehydro-,

16-methyl-cis-17,18-didehydro-,

16,16-dimethyl-cis-l 7,18-didehydro-, 35 16-fluoro-cis-17,18-didehydro- or

16,16-difluoro-cis-l 7,18-didehydro-2,3,4,5,6-pentanor-PGF10.

Claims (7)

621 548 PATENT CLAIMS 1. Process for the stereoselective production of a bicyclic 3-hydroxy-lactone of the formula (V) R13O H •H / c-r- /\ 1 h oh left (T): 10th means when R3 and R4, which may be the same or different, are hydrogen or methyl, and R13 is a group of the formula ■ Ri -L // wherein A or a mixture of and R3 \ A R_ R R- R, R_ R wherein R 1 and R 2, which may be the same or different, denote hydrogen, chlorine, fluorine, bromine, alkyl radicals having 1 to 3 carbon atoms or alkoxy radicals having 1 to 3 carbon atoms, or (2) 30th A where R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, with the proviso that one of the radicals R3 and R4 is fluorine only if the other is hydrogen or fluorine, R7 (1) - (CH2) k-CH3, where k is a number from 2 to 6, wherein R 1 and R 2, which can be the same or different for each phenyl ring, have the meaning given above, characterized in that the side chain oxo group of a lactone of the formula (2) (T), 45 50 (XII) wherein T represents chlorine, fluorine, trifluoromethyl, an alkyl radical with 1 to 3 carbon atoms or alkoxy radical with 1 to 3 carbon atoms and s represents the number 0, 1, 2 or 3, with the proviso that no more than two radicals T of alkyl 55 are different and the individual radicals T can be the same or different, '"C-C // r13o h "C-C-r7 i! ï 0 Li (3) (t), 60 wherein T and s have the meaning given above, 65 or (4) cis-CH = CH-CH2-CH3, provided that R7 only with a potassium trialkylborohydride of the formula k © b © h \\ cH2) m + 1-CHs where m is 0, 1, 2 or 3, stereoselectively reduced. 2. The method according to claim 1, characterized in that the group R13 is a radical of the formula 3rd 621 548 (1) is where Rj and R2 have the meaning given above. 3. The method according to claim 2, characterized in that the group Rt3 is the phenylcarbamoyl or p-tolylcarbamoyl radical. 4. The method according to claim 3, characterized in that R3 and R4 both represent hydrogen. 5. The method according to claim 4, characterized in that R7 is a radical of the formula - (CH2) k-CH3, wherein k has the meaning given in claim 1. 6. The method according to claim 5, characterized in that R7 is the n-butyl radical. 7. The method according to claim 6, characterized in that R13 the rest O 10th 15 Understood prostaglandins or prostaglandin analogues, whose position corresponds to the position of the carbon atom of the same number in prostanic acid. The C-15 alcohol function of the PGF2q above has an S configuration. For this and other stereochemical properties of prostaglandins, reference is made to Nature, 212, 38 (1966). Analogues of these prostaglandins are known which can be used for the same pharmacological purposes as the prostaglandins. Many of these analogs, which have the same cyclopentane ring structure as different prostaglandins, show changes in the C-7-a side chain or C-13/3 side chain or both. 3a, 5a-dihydroxy-2 / 3- (3-oxo-trans-l-octenyl) -la-cyclo-pentanoacetic acid-y-lactone-3-acetate or -3-phenylbenzoate [E. J. Corey et al., J. Am. Chem. Soc. 92, 397 (1970) and E. J. Corey et al., 93, 1491 (1971)] is known to be a useful intermediate for the production of optically active PGF2a and PGE2. This bicyclic lactone corresponds to the formula means. 11 -C-NH - </ y 20th 25th 30th R11O (in the) H The prostaglandins are a group of pharmacologically useful cyclopentane derivatives with 20 carbon atoms. They include, for example, the compounds PGF3a, PGF2a, PGF] a and corresponding PGE, PGA, PGB and PGFp compounds. Each of these prostaglandins can be regarded as a derivative of prostanoic acid, which has the following formula and numbering C — c: ^ C- (CH2) 4-CH3 0 wherein Rn represents the acetyl or p-phenylbenzoyl radical. Corresponding bicyclic lactones of the following formula are known for the production of prostaglandin analogs with a modified 35 C-12-β side chain COOH CO 40 ü Compare Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and literature there. 45 Bold lines in the above formula and the following formulas indicate substituents above the cyclopentane ring (i.e./3 configuration). Dashed lines indicate substituents below the level of the cyclopentan ring (i.e. a configuration). If serpentine lines are used in 50 of the formulas, the binding of the substituents is in the "- or / 3-configuration, or it is a where Lt mixture of a and β isomers. The connection PGF2tt, for example, that of the formula (IV) c = c H R12Ó H' HO 55 C00H 60 or a mixture of 65 and corresponds to, has a hydroxyl substituent in positions C-9, C-II and C-15, which has the a configuration. At C-9, C-11 and C-15 the carbon atoms of the C-C-R7 ii h 0 Li / \ r3 r4 R3 R4 / \ r3 r4 / \ R3 R4 621 548 4th R3 and R4, which may be the same or different, are hydrogen, methyl or fluorine, provided that only one of the radicals R3 and R4 is fluorine, when the other is hydrogen or fluorine, R7 (1) - (CH2) k- CH3, where k is a number from 2 to 6. (2) wherein T is chlorine, fluorine, trifluoromethyl, an alkyl radical with 1 to 3 carbon atoms or alkoxy radical with 1 to 3 carbon atoms and s is the number 0, 1, 2 or 3, provided that no more than two radicals T are different from alkyl and the different radicals T may be the same or different, wherein T and s have the meaning given above, or (4) cis-CH = CH-CH2-CH3, provided that R7 only then (T) s -o-0t ^ means when R3 and R4, which may be the same or different, are hydrogen or methyl and R12 is hydrogen or a carboxyacyl radical. Any formula used in this specification that represents a prostaglandin, prostaglandin analogue or an intermediate therefor shows the optically active form of the compound. The optical isomer thus represented has the same relative stereochemical configuration as the corresponding prostaglandin from mammalian tissue, or in the case of an intermediate product, the stereochemical configuration that provides a prostaglandin-like product with the same relative stereochemical configuration as the corresponding prostaglandin from mammalian tissue. Each prostaglandin or prostaglandin analogue (i.e. the prostaglandin-like compounds) is named according to a nomenclature system that specifies each position of the carbon structure and the respective substitution or structural change from the corresponding parent prostaglandin in this position. This nomenclature system is described in N.A. Nelson, J. of Med. Chem., 17 911 (1974). To convert the 2-oxolactones of the formula IV into corresponding prostaglandin-like compounds, the 3-oxo group of the β-side chain of the compound III or IV has to be reduced to form a 3-hydroxy-lactone, the 3-hydroxy group being the potential 15-hydroxy group a later PG connection. In numerous cases it is desirable to prepare the 3 "-hydro-xy-epimer preferably over the 3β-hydroxy-epimer, since this stereochemical arrangement is retained in the later conversions to prostaglandin-like compounds by known methods. Compounds with the same configuration at C-15 as PGF2a of formula II are thus obtained, and in many cases these compounds show the more desirable pharmacological properties. Great efforts have therefore been directed towards stereochemically controlling the above reduction. In the known methods for achieving stereochemical control of the reduction, various organic radicals can be used instead of the radicals Rn or R12 in the processes. 25th 30th 35 compounds of the formulas III or IV can be used together with certain reagents. Regarding the use of p-phenylbenzoyl and carbamoyl such as. B. p-phenyl-phenylcarbamoyl and phenylcarbamoyl radicals instead of the radicals Rn or RJ2 in combination with reducing agents such as lithium limonene hexyl borohydride, i.e. h c (ch3) 2-ch (ch3) 2 V ch3- CHa Lithium hexyl-di-sec-butyl borohydride and lithium tri-sec-butyl borohydride can be found in E. J. Corey et al., J. Am. Chem. Soc., 94, 8616 (1972). Furthermore, the production and use of lithium tri-sec-butylborohydride by H.C. Brown et al., J. Am. Chem. Soc., 94: 7159 (1972). C. A. Brown, J. Am. Describes the preparation and use of potassium tri-sec-butylborohydride. Chem. Soc., 95, 4101 (1973).