HU188901B - Process for preparing 5z-forms of 2,3,4-trinor-1,5-inter-m-phenylene-prostacyclin derivatives - Google Patents

Abstract

A process for preparing 5Z forms of 2,3,4-trinor-1,5- inter-m-phenyleneprostacyclin derivatives of the formula I: <IMAGE> where R1 is H, a cation or lower alkyl, R2 is H or methyl, A is -CH2-CH2-, (trans)-CH=CH- or -C=C-, and B is alkyl or a cyclohexyl group which is optionally substituted by a lower alkyl group, by isomerizing a compound of the formula IIE: <IMAGE> where R1' is lower alkyl or an aralkyl group, and, where appropriate, subsequently converting R1' into R1. The isomerization is brought about by the compound IIE being treated, in the presence of an anhydrous solvent, with at least one salt of an organic base and an organic sulphonic acid or a fluorinated or chlorinated acetic acid. The 5Z compounds are biologically more active than the corresponding 5E isomers.

Description

(57) EXTRAS

The present invention relates to a process for the preparation of a compound of formula (I)

R 1 is hydrogen, a cation or a straight or branched C 1-6 alkyl group and

A is a straight-chain pentyl or cyclohexyl-5Z form which can be prepared by reacting a compound of formula (1IE) (wherein A is as defined in formula (I) and R 'is a straight or branched C 1 -C 6 alkyl group) or an aralkyl group containing one or two alkyl atoms) by isomerization of the organic base to at least one salt of an organic base with an organic sulfonic acid or a fluorinated or chlorinated acetic acid in the presence of anhydrous and non-alcoholic solvent. above) and then, where appropriate, or

(HE)

HO r λ

I HO H H (HZ)

C - When R 'represents an aralkyl group having one or two alkyl atoms, it is obligatory to saponify the -COORi group to a hydrogen atom or a -COORi group containing a cation.

-1188,901

No. 45,842. European Patent Application Laid-Open Patent Application Publication No. 4,194,198 and other conforming patents disclose 2,3,4-trinor-1,5-inter-m-phenylene prostacyclin derivatives of formula (V). In the formula, R ¹ is hydrogen, a cation or a residue of an alcohol;

R ² is hydrogen or methyl;

A 'is -CH ₂ -CH ₂ -, (trans) -CH = CH- or -C = C - and

B is an alkyl group or a cyclohexyl group optionally substituted with a lower alkyl group;

wherein the phenyl group has the E, EZ or preferably Z configuration relative to the double bond.

In the process of the cited European Patent Application, the compounds of formula (V) are first obtained in the 5EZ configuration and must be separated if necessary. Compounds having the 5Z configuration have a stronger biological activity and are therefore the preferred configuration. In the preparation of the desired 5Z compounds according to the state of the art, at least 50% of the preformed EZ form was lost, since it was not possible to convert the less interesting compounds into Z derivatives.

It has now been found that the compounds of formula (I) (i.e., the 5Z forms of the compounds given in

R j is hydrogen, a cation or a straight or branched C 1-6 alkyl group and

A is straight-chain pentyl or cyclohexyl) can be readily prepared by reacting a compound of formula (HE) wherein A is as defined above and R 1 is a straight or branched C 1 -C 6 alkyl or C 1 -C 2 alkyl moiety ) by isomerization to form a compound of formula (HZ) (wherein R1 and A are as defined above) and optionally, or when R1 is aralkyl having one or two alkyl atoms, R1 is hydrogen or saponification.

In the process of the present invention, the isomerisation is carried out by treating the compound of formula IIE in the presence of an anhydrous and non-alcoholic solvent with at least one salt of an organic base and an organic sulfonic acid or a chlorinated or chlorinated acetic acid.

Preferably, R1 as a cation represents sodium or potassium. In addition, in the meaning of R, cation, e.g. it may also represent calcium, magnesium, ammonium or amine ions. Amine ions are e.g. derived from mono-, di- or trimethylamine, -ethylamine, -ethanolamine, tris-hydroxymethyl-amine, basic amino acids (e.g., arginine or lysine), or other safos commonly used in prostagkmdin or prostacyclin chemistry .

If R! preferably represents methyl.

It is present in the compounds of formula (1). inter alia, the carbon atom bearing the A group (at position 15) is of RS or preferably of S configuration.

Preferably, R 1 is straight or branched

C 1-4 alkyl (especially methyl) or aralkyl (preferably benzyl).

The present invention is based on the discovery that the compounds of formula (IIE) and (HZ) form two extreme positions of the equilibrium system and that the operations of the present invention (treatment with certain defined salts in the presence of anhydrous and non-alcoholic solvents) ΠΖ is shifted towards the formation of compounds of formula (II), and thus the 5Z compounds of formula (TIZ) can be prepared in high yield starting from the compounds of formula (IIE). Of course, not only pure 5E compounds, but also mixtures of 5E and 5Z compounds can be used as starting materials to give the 5Z-enriched isomeric mixture. It is preferable to use isomeric mixtures of the compounds of formula IIE and HZ as starting materials (e. G., 5EZ compounds prepared according to the European Patent Application cited at the beginning of the specification - wherein R ¹ is a residue of an alcohol corresponding to R ¹ ). The isomer of formula IIE in the above 5 EZ mixtures is converted to the corresponding isomer of formula HZ in very good yield.

As polar solvents as possible are preferred in the process of the present invention. Particularly preferred are e.g. dimethylsulfoxide, hexamethylphosphoric triamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2H) -pyrimidinone, formamide, tetrahydrothiophene-1,1-dioxide, or other solvents thereof, or mixtures of less polar solvents, such as water and alcohol, such as tetrahydrofuran or dichloromethane.

Taste isomerization or equilibrium shift occurs via an intermediate step in which the acid component of the salt used in the process of the present invention is the compound of formula (HE)

Adds to the double bond of a 5,6-pin. This supposed intermediate, when using an organic sulfonic acid salt, e.g. corresponding to formula (ΠΙ) wherein R 'and A are as defined above and X is an organic portion of the sulfonic acid used as the salt).

From the intermediate of formula (111), the sulfonic acid must be cleaved again under the reaction conditions used to form the compound (10). The above or similar reaction mechanism is also supported by the fact that e.g. When using the pyridine salt of deuterated or tritiated trifluoroacetic acid, the compound of formula (IIE) forms a compound of formula (ΠΖ) containing deuterium or thorium instead of hydrogen at the 5-position.

The isomerization reaction of the present invention is generally carried out for about 1 hour. 0 ° C and approx. It can be carried out at a temperature of 50 ° C. Preferably, at room temperature - i.e., about 20 ° C. 20-25 ° C - can be worked.

Salts of organic bases, especially heteroaromatic bases or Ν, Ν-dialkylaniline derivatives, may be used to precede the isomerization reaction of the present invention. Particularly preferred are pyridine or Ν, Ν-dimethylaniline. and the corresponding salts of N-ethylaniline, N-propylaniline, p-phenethidine or p-toluidine.

The above organic bases are organic sulfonic acids

188,901 or its salts with fluorinated or chlorinated acetic acid. The salts of the organic bases with monovalent organic sulfonic acids or trifluoroacetic acid or trichloroacetic acid are particularly preferred in the process of the present invention. As the monobasic organic sulfonic acid, e.g. methanesulfonic acid or ethanesulfonic acid, or very preferably mono- or bicyclic aromatic sulfonic acids (e.g., benzenesulfonic acid, toluenesulfonic acid, chlorobenzenesulfonic acid, methoxybenzenesulfonic acid or naphthalenesulfonic acid).

In general, it is preferable to use a single salt of an organic base with an acid as defined above. However, in the process, salts with different bases of the same base or with different bases of the same acid or with different acids of different bases can be used together. In a particularly preferred embodiment of the process according to the invention, the pyridine salt of p-toluenesulfonic acid is used as the sole salt.

The amount of salt is not critical to the successful completion of the isomerization reaction. The salt may be used in a catalytic amount (i.e., 0.01 mol or 0.001 mol relative to 1 mol of compound (Ι1 pl)) or in equimolar amounts or in excess of compound (IIE). In view of the hypothesis outlined above (i.e., the formation of the intermediate of formula (III)) and the required reaction time and processability of the reaction mixture, it is generally advisable to use equimolar salts of the starting material (HE).

Optional hydrolysis after the isomerization reaction (saponification of the -COOR group in HZ) is conveniently carried out in an aqueous alcoholic solution (e.g., aqueous methanol or ethanol). The saponification may be carried out, where appropriate, or, where R 1 is aralkyl, a mandatory operation. One to five moles of sodium hydroxide or potassium hydroxide are added per vc of the compound of formula (HZ) and generally about 1 to about 5 mol. We can work 10-50 "'Con. The reaction time is about 20 minutes. 6 to 48 hours and the conversion can be followed by TLC. The compound of formula (I) obtained in the form of its sodium or potassium salt may, if desired, be reacted with other salts or C 1-6 -alkyl halides by conventional means (e.g., ion exchange chromatography) to give R 1 -C 6 -alkyl. can be converted to general compounds.

The 5Z isomers (i.e., the compounds of Formula I) can be obtained by reverse-phase high performance liquid chromatography (HPLC), in particular in the absence of the corresponding 5E isomer.

The compounds of formula (I) have, as already mentioned, a higher biological activity than the corresponding 5E isomers. To demonstrate this enhanced activity, the effects of the following two compounds are compared:

[(5E, 13E, 9a, 11a, 11S, 10S, 3S-inter-m-phenylene-O-epoxy-1,15-dihydroxy-15-cyclohexyl-16,17,18, 19,20-pentanor] -prosta-5,13-dienoic acid sodium salt (hereinafter "Compound A");

[(5Z, 13Ε, 9α, 11a, 15S) -2,3,4-Trinor-1,5-inter-m-phenylene-6,9-epoxy-1,115-dihydroxy-15-cyclohexyl-16,17, 18,19,20-pentanor] -prost-5,13-dienoic acid, sodium salt (hereinafter "Compound B").

1C _N5 as that dose level which, in the arachidonic acid-induced human platelet aggregation in vitro inhibits the experimental conditions employed, 50% of cases. Of Compound 1C _N5 of 0.5 pmol /, while the B-compounds by only 0.01 μΐ / l.

The relative antihypertensive activity was determined in awake spontaneous hypertonic rats. The measurement is performed using a permanent catheter: the test compounds are administered intravenously; the ED 50 of 5,6-dihydro-prostacyclin for this test is 0.005 mg / kg and is arbitrarily set to 1. Compound A has a relative activity of <0.1 in relation to 5,6-dihydro-pros: acyclin, and Compound B has a relative activity of <0.25.

The following examples further illustrate the process without limiting the invention to the examples. Values for correcting the temperatures in the examples. Rf values were determined by TLC on silica gel.

Example 1

a) 0.5 [(5E, 13Ε, 9α, 1Ια, 15S) -2,3,4-trinor-1,5-inter-m-phenylene-9,11,15-trilydroxy-15-cyclohcxyl-16 17,18,19,20-pentanor] -prosta-5,13-dienoic acid methyl ester [90% isomer purity 101-102 ° C, [α] -36.8 °, c = 1.0, methanol] is dissolved in 6.3 ml of diethyl ether in 3 ml of methanol, the oil is cooled to 0 ° C and 6.3 ml of saturated sodium bicarbonate solution is added first to exclude light. followed by the dropwise addition of a solution of 2.15 g of iodine in 10 ml of diethyl ether at the same temperature (0 ° C). The reaction mixture was stirred at 0 ° C for 4 hours and then saturated sodium thiosulfate solution was added until colorless.

The organic layer was separated, the aqueous layer was extracted with diethyl ether (2 x 25 mL) and the combined organic phases were dried over magnesium sulfate under cooling. The solution was replaced in vacuo with the exclusion of light and stored at a constant weight of 0.1 to 0.1 Torr.

0.65 g of a yellow oily product is obtained, which is dissolved in 6.5 ml of anhydrous toluene at 20-25 [deg.] C. and 0.5 ml of 1,5-thiazabicyclo [4.3.0] non-5-ene is added and Stir for 20 hours. The mixture was diluted with 60 mL of toluene and three times with 15 mL of saturated sodium bicarbonate solution. followed by washing with 15 ml of water. The organic phase was dried over magnesium sulfate and concentrated in vacuo at 40 ° C. The residue was chromatographed on silica gel eluting with 98: 2 ethyl acetate-methanol.

5 g of an oil are obtained which is ca. 70% of [(13E, 9a, 1α-15S) -2,3,4-trinor-1,5-internophenylene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16, 17,18,19,20-Pentanor] -prosta-5,13-dienoic acid methyl ester consists of 5E and 5Z chlorides in a 9: 1 ratio.

Form 5E, as determined by thin layer chromatography (HPTLC RP-8 F 254 S type plates, manufactured by E. Merck; eluent: 80:20 methanol / water) showed 0.24 Rf. Under the same conditions, Form 5Z has an Rf of 0.17.

b) 250 mg. a mixture of isomers, predominantly 5E-fortune, prepared according to (a)

188 901 for carrying out the isomerization process

It is dissolved in 2.5 ml of anhydrous dimethyl sulphoxide and mixed at 2025 ° C with a solution of 160 mg of pyridinium p-toluenesulphonate in 2.5 ml of anhydrous dimethyl sulphoxide. The reaction mixture was stirred at 20-25 ° C.

After 3 hours, a 1 ml sample was taken, added to 5 ml of saturated sodium bicarbonate solution, extracted three times with 2.5 ml of ethyl acetate, and the combined organic phases were washed three times with 1 ml of water and dried over potassium carbonate. and evaporated in vacuo. The residual isomer total batch is determined as described below.

After 72 hours, the bulk of the reaction mixture was worked up as described above. 200 mg of product are obtained, the content of which is determined by 5E and 5Z isoinerometers, respectively, by high performance liquid chromatography on "Lichrosorb RP 18" (particle size 10 μιη, Merck AG, mobile phase 75:25 methanol / water).

Response Time (Hours) 5Z / 5E Ratio 0 0.1 3 8.5 72 9.5

c) 200 mg of the product obtained are dissolved in 7 ml of methanol, mixed with 1.8 ml of 1N sodium hydroxide solution at 25 ° C and stirred for 48 hours at 25 ° C. By high performance liquid chromatography (0.01: sodium bicarbonate, 45:55 methanol in water; Kieselgel RP 18 on Merck AG) followed by freeze drying to [(13E, 9a, 1l, 15S) -2.3, 4-Trinor-1,5-inter-in-phenyl-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor] -prost-5,13-dienoic acid Pure sodium salts of 5Z and 5E forms are obtained. Yields: 145.6 mg and 15.3 mg, respectively. The obtained products are disclosed in U.S. Patent No. 45,842. were found to be identical to the products described in Example 3 of the European Patent Application, Publication Nos.

d) The procedure of (b) is carried out with the modification that the reaction mixture is worked up after 24 hours and isomerized with the salts listed in the table below.

Example 2

A mixture of 1.5 g of the predominantly Form E mixture obtained in Example 1a) was dissolved in 15 ml of hexamethylphosphoric triamide and 955 mg of pyridinium p-toluenesulfonate and 15 ml of hexamethylphosphoric triamide were added. The reaction mixture was stirred at 25 ° C for 16 hours, treated with saturated sodium bicarbonate solution (150 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous potassium carbonate and concentrated in vacuo at 35-40 ° C. The residue (1.5 g) was dissolved in methanol (50 mL), treated with 1N sodium hydroxide solution (13 mL) at 25 ° C, stirred at 25 ° C for 48 hours, and worked up as described in Example le (high pressure). liquid chromatography followed by freeze-drying). A [(13Ε, 9α, 11a, 15S) -2,3,4-trinor-1,5-inter-m-phenylene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16,17 18,19,20-jentanorj-prostate-SJS-dienoic acid, sodium salt 5Z (703 mg) and 5E (115 mg). The resulting compounds are identical to those obtained in Example le).

Example 3

The procedure described in Example 1 b) is carried out with the exception that the solvents given in the table below are used, with 2 ml of pyridinium trifluoroacetate being used per ml of product of Example 1a) and the reaction is worked up after 16 hours.

5Z / 5E

Solvent isomer ratio at beginning to end

Dimethylsulfoxide and • Chloroethane

1: 1 mixture Dimethyl sulphoxide and 0.1 6.7 tetrahydrofuran 1: 1 mixture 0.1 7.5

Used salt Salt / substituent ^x molar ratio 5Z / 5E Isomer ratio at the beginning in the end A salt of N, N-dimethylaniline with p-sulfol sulfolic acid 1.67 0.1 8.9 Pyridine salt with ti'ifluoroacetic acid 1.67 0.1 8.1

^x Substrate = product of example la).

Example 4

The procedure described in Example 1b) is carried out by varying the substrate with different 1 (13E, 9a, 11a, 15S) -2,3,4-trinor-1,5-inter-rn-above-6,9-epoxy. 11,15-Dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor] -prost-5,13-dienoic acid esters (R 1 = pure 5E isomers, i.e. 5Z) are used. / 5E ratio. O), the solvent is anhydrous dimethyl sulfoxide and the salts of pitidine with the acids listed in the table are used and the reaction is worked up after the time indicated in the table. The isomer ratio of 5Z / 5E is shown in the last column of the table.

-4188 901

rj Pyridine salts with the following acids Salt / szubszt- maté molar gold Reaction- time (Hours) 5Z / 5E gold isopropyl p-toluene- sulfonic acid 1 24 2.7 n-hexyl trifluoro- acetic acid 0.1 16 5.0 benzyl trifluoro- acetic acid 0.1 20 6.5

Example J.

The procedure described in Example 1b) is carried out with the change that [(13E, 9a, 11a, 15S) -2,3,4-trinor-1,5-inter-m-phenylene-6,9-epoxy-11 , 15-20-Dihydroxy-prostta-5,13-dienoic acid methyl ester in the form of a 1.1: 1 mixture of 5Z and 5E isomers, using equimolar amounts of pyridinium p-toluenesulfonate salt and the reaction in the following table. in the solvents listed above and at the indicated temperature for 25 and more years. The table shows a significant increase in the ratio of the 5Z isomer in the product obtained.

__ "___, _____ 30

Solvent Month- moderation (° C) Reaction- time (Hours) 5Z / 5E gold Dimethyl sulfoxide 20-25 2 4.1 35 Dimethyl sulfoxide and tetrahydrofuran 1: 1 mixture 0 16 7.6 40 1,3-dimethyl-3,4,5,6- tetrahydro-2 (lH) - -pyrimidinone 50 1 6.7

1b), ld) and 2-5. The salt solutions used in the examples are conveniently prepared by co-dissolving an equimolar amount of the appropriate base and acid in the specified (dried) solvent. The resulting mixture can be used for the isomerization reaction of the present invention with θθ. However, it is also possible to isolate the salt first and then dissolve it in a suitable solvent or solvent mixture.

Claims

Claims (2)

A process for the preparation of 2,3,4-ttinor-1,5-inter-m-phenylene-prostacyclin derivatives of the general formula (1) in which θθ R 1 is hydrogen, a cation or a straight or branched C 1 -C 6 alkyl group and A is a straight-chain pentyl or cyclohexyl group - _ 5Z-foils, characterized in that a compound of formula IIE (wherein A is as defined in formula 1 and R 1 is a straight or branched C 1 -C 6 alkyl group or one or two C 2 alkyl moieties) aralkyl) isomerized by treatment of at least one salt of an organic base with at least one salt of an organic sulfonic acid or a trifluoroacetic or chlorinated acetic acid in the presence of anhydrous and non-alcoholic solvents to a compound of general formula (IIZ) - or, when Rj is mandatory for an aralkyl group containing one or two carbon atoms, the --COORj group is R! is hydrogenated to form a COOR containing a hydrogen atom or a cation. A process according to claim 1, characterized in that it is. the isomerization reaction is carried out at a temperature of 0 ° C to 50 ° C. Process according to claims 1 and 2, characterized in that the isomerization reaction is carried out in the presence of a polar solvent, water and alkanol. 4. Process according to any one of claims 1 to 3, characterized in that the isomerization reaction is carried out in the presence of dimethylsuloxy, hexamethylphosphoric triamide, 1,3-dimethyl-3,4,5,6-h trachydro-2 (1H) -pyrimidinone, formamide or tetrahydrofuran. let's do it. 5. Process according to any one of claims 1 to 4, characterized in that the isomerization reaction uses salts derived from monobasic organic sulfonic acids or trifluoroacetic acid or trichloroacetic acid. 6. Process according to any one of claims 1 to 3, characterized in that salts derived from heteroaromatic bases are used in the isomerization reaction. 7. Process according to any one of claims 1 to 3, characterized in that pyridine p-lolenesulfonate is used for the isomerization reaction. 8. Process according to any one of claims 1 to 3, characterized in that pyridinium p-toluenesulfonate is used in an approximately equimolar amount with the starting material (IIE). 9. Process according to any one of claims 1 to 3, characterized in that the starting material is a compound of formula (IIE) wherein R 1 is methyl. 10. A process according to any one of claims 1 to 8, using [(5Z, 13 11.9α, 1 Ια, Ι5S) -2,3,4-trinor-1,5-inter-m-phenylene 6,9-epoxy-1 1,15-dihydroxy-15 - cyclohexyl-16,17,18.19,20-pentanor for the preparation of the sodium or potassium salt of J-prostate-5,13-dienoic acid, characterized in that: (5E, 13E, 9.5, 11E, 15S) -2,3,4 -trinor-1,5-inter-m-phenylene-6,0-eopoxy-1,1,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanorj-prosla-5,13-dicanoic acid- The mcl ester is contacted with pyridinium p-toluenesulfonate at 0 ° C to 50 ° C, preferably at room temperature, preferably in the presence of a polar solvent, most preferably dimethylsulfoxide, and the methyl ester of compound 5Z formed after the equilibrium is known per se. isolated and saponified with sodium hydroxide or potassium hydroxide to form the desired sodium salt or potassium salt. 2 pieces of figure _ 5 -5188 901 NGO ₄ : C 07 D 307/935