DK157930B - Process for preparing the 5Z form of 2,3,4-trinor-1,5- inter-m-phenyleneprostacyclin derivatives - Google Patents

Description

. DK 157930B

The invention relates to a particular method of manufacture. forming the 5Z form of 2,3,4-trinor-1,5-inter-m-phenylene prostacyclin derivatives of the general formula I

5; CHRISTMAS /

| R, OOC -C

A

θ-Λ-C-B

Y Λ HO HO R 2 where: R 1 is a hydrogen atom, a cation or a straight chain or branched alkyl group having 1-6 C atoms, R 2 is hydrogen or methyl, A is a group -CH 2 -CH 2 -f ( trans) -CH = CH- or -C = C-, and B is an alkyl group of 5-9 C atoms of structure: R3

I J

20 - C - (CH 2) 3-CH 3 R 4 wherein R 3 and R 4 are the same or different and are hydrogen, methyl or ethyl, or is an optionally substituted cyclohexyl group with a methyl or ethyl group, which process is characterized by the characteristic part of claim 1.

Danish Patent Specification No. 154,214 discloses 2,3,4-trinor-1,5-inter-m-phenylene prostacyclin derivatives of the formula: HO --- 35 A1-C - B 'COOR1

'l 2 HO R

DK 157930B

2 wherein R 1 is a hydrogen atom, a cation or an alcohol-2 residue, R is hydrogen or methyl, Afer a group -CE 2 -C 3 - ((trans) -CH = CH- or -C = C-, and B 'is an alkyl group or an optionally substituted cyclohexyl group optionally substituted with a lower alkyl group, wherein the phenyl group exhibits an E, EZ or preferably Z 1 configuration with respect to the double bond. In the process described in the aforementioned patent application, the products of said formula are first obtained as 5EZ derivatives, which then may be divided. Since the 5Z forms are distinguished by higher biological activity, the compounds of this configuration are preferred. For their recovery, the method of the prior art has had to discard at least 50% of the first-obtained EZ form, since the less interesting E-compound could not be transferred in the Z-derivative.

It has now surprisingly been found that the 5Z compounds of the above Formula I can be readily recovered by the process of the invention, which is characterized by the fact that a 5E form of the formula IIE: C

CfN (IIE)

(S— A - C ^ B

Wherein R 2f A and B are as defined above for Formula I and R 1 'is a straight or branched alkyl group having 1-6 C atoms or an aralkyl group having 1-2 C atoms in the alkyl group, isomerization by the action of at least one salt of a heteroaromatic base or of an N, N-dialkyl-aniline derivative and an organic sulfonic acid or a fluorine.

DK 157930 B

3

straight or chlorinated acetic acid and in the presence of a reaction medium containing anhydrous and alcohol-free polar solvent to form a 5Z compound of the corresponding formula IIZ

0 ^ 1 (IIZ) \ /; Λ HO HO R2 15 wherein Rj ', R £, A and B are as defined above, whereupon, if desired, the group COOR ^' is saponified or transesterified to the group COOR ^ wherein R R is a hydrogen atom, a cation or a straight chain or branched alkyl group having 1-6 C atoms.

When R 1 is a cation, it is preferably a sodium or potassium ion. Other suitable cations are, for example, calcium, magnesium, ammonium or amine ions, such amines being, for example, derived from mono-, di-trimethylamine, ethylamine, ethanolamine, trishydroxymethylamine, basic amino acids such as arginine or lysine, or others in the usual bases of prostaglandin or prostacy c linkemia.

If R 2, on the other hand, is an alkyl group,. this is especially a methyl or ethyl group.

R 2 is hydrogen or a methyl group, the carbon atom (15) to which, inter alia, the group R 2 is attached, in the compounds of formula I may be in the RS or preferably S configuration.

Preferably R 1 is a straight or branched alkyl group having 1-4 C atoms, in particular a methyl or ethyl group, or - when an aralkyl group - a benzyl group.

DK 157930 B

4

If B is an alkyl group of 5-9 C atoms, it corresponds to the structure: * 3 - C - (CH ~) - CH

5 | J J

R 4 where and R 1 are the same or different and are hydrogen, methyl or ethyl.

On the other hand, if B is a cyclohexyl group, it may be substituted by a methyl or ethyl group at 10 4 'position.

Preferred meanings for B are. a cyclpibasyl group or an alkyl group of the above structure wherein R 1 and R 2 are each hydrogen or each is methyl, or: where R 9 is hydrogen and R 2 is ethyl.

A preferably represents the trans-CH = CH structure. In this case, the compounds of formula I are of particular interest when the 15S configuration is present at the same time.

According to the invention, it is recognized that the compounds of formulas IIE and IIZ constitute the final bed of an equilibrium system which is displaced by the measures according to the invention (treatment with certain salts in the presence of polar, water and alcohol-free solvent) in favor of the formation of the compounds. of formula IIZ, so that from the 5E compounds of formula IIE, the 5Z compounds of formula IIZ can be obtained in high yield. Of course, it is not necessary to start from the pure 5E compounds, but 50 mixtures thereof can also be used with 5Z compounds, whereby the process according to the invention leads to an increase in the proportion of the 5Z form in the isomer mixture. In particular, such mixtures may be used in which the compounds of formulas IIE and IIZ are present in about the same amounts of 55 [i.e., e.g. 5EZ compounds of the formula set forth at the outset (if R 1 is therein an alcohol group corresponding to the group R

DK 157930 B

The requirements of the patent application, cited at the outset, and the proportion of the compound contained in i in formula ΪΪΕ are then transferred extensively in the isomer of: formula IIZ.

5: For the process of the invention, the solvents to be used are the better suited, the more polar they are. In particular, dimethylsulfoxide, hexame-1-methylphosphoric acid triamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, formamide or tetrahydrothiophene-1,1-10 dioxide may also be mixed together or with less polar, aqueous and non-alcoholic solvents such as tetrahydrofuran or dichloromethane proved to be suitable.

The isomerization or equilibrium setting presumably proceeds over an intermediate step at which the acid contained in the salt to be added according to the invention is added to the double bond at the 5,6-position of the compound of formula IIE. Such a hypothetical intermediate may thus (using the salt of an organic sulfonic acid) have, for example, the formula: hn jCx C

25 H

X-SO2-0 ^ J (III) () ">» /

0 ~ A wB

30 i / s HO HO R2 wherein R 1, R 2, A and B are as defined above and X is the organic residue of the sulfonic acid used in salt form.

From this intermediate of formula III, after the reaction conditions, the sulfonic acid is again decomposed to form the compound of formula IIZ.

For such or similar course of reaction, it follows that

DK 157930 B

6, for example, using the pyridine salt of deuterated or tritiated trifluoroacetic acid, from compounds of formula IIE, compounds of formula IXZ are obtained, wherein the hydrogen atom at 5 ° position is replaced by 5 deuterium or tritium.

The inventive isomerization reaction is generally carried out at temperatures between ca. 0 and about 50 ° C, preferably operating at room temperature, i. at about. 20-25 ° C, 10 As mentioned above, the salts used to induce the isomerization reaction of the invention are derived from heteroaromatic bases or N, N-dialkylaniline derivatives. Suitable bases are preferably pyridine or Ν, Ν-dimethylaniline, but also, for example, N-ethylaniline, N-propylaniline, p-phenetidine or p-toluidine are suitable.

As regards the acids contained in the salts used, these are organic sulfonic acids or fluorinated or chlorinated acetic acids, in particular one basic organic sulfonic acids and trifluoroacetic or trichloroacetic acid. As one basic organic sulfonic acids, aliphatic sulfonic acids such as methane or ethanesulfonic acid, but especially aromatic one- or two-core sulfonic acids, such as benzenesulfonic acid, toluene sulfonic acid, chlorobenzenesulfonic acid, methoxybenzenesulfonic acid, are considered. or naphthalene sulfonic acid.

It is generally preferred to use only one salt of one of said bases with one of the acids, but it is also possible to use several of the same base and different acids or of the same acid and different bases derived or salts of different bases and different acids. However, it is particularly preferred in the process of the invention to use only the pyridine salt of p -toluenesulfonic acid.

The amount of salt used is not critical to the course of the isomerization reaction. Thus, catalytic amounts [i.e. far less (e.g. 0.01

DK 157930 B

7 or 0.001} than. one mole of salt per mole of compound of formula ΙΙΈ], about the same molar amounts or also an excess of salt, which, given the above-mentioned hypothesis (formation of the intermediate of formula III), as well as the required reaction time and questions regarding the work-up of the reaction mixture is recommended to use about the same molar amounts of the compound of formula IIE and of the salt.

The optionally saponification of the -COOR₂ group optionally in association with the isomerization reaction is conveniently carried out in aqueous alcoholic solution such as in aqueous methanol or aqueous ethanol with the addition of (calculated on the compound of formula IIZ) the 1 to 5 times molar amount of sodium or potassium hydroxide at approx. 10-50 ° C. The reaction lasts approx. 6-48 hours and can be followed by thin layer chromatography. The compounds of formula I thus obtained in the form of sodium or potassium salts can, if desired, be transferred in other salts in the usual manner (for example, by ion exchange chromatography) or (for example, by treatment with C alkyl halides) in esters of formula I wherein is an alkyl group of 1-6 C atoms.

The 5Z-ies, i.e., the compounds of formula I, can be obtained in pure form by high pressure liquid chromatography (HPLC) under 25 "reversed-phase" conditions, in particular also free of the corresponding 5E isomers.

As mentioned above, the 5Z compounds of formula I, as compared to the corresponding 5E isomers, are characterized by increased biological activity. As an example of the differences in the biological properties of such isomeric compounds, the following experimentally found results with [(5E, 13E, 9a, 11a, 15S) - 2,3,4-trinor-1,5-inter -m-phenylene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor] -prosta-5,13-35 diacetic acid sodium salt (hereinafter: designated "Compound A" J and [(5Z, 13E, 9a, 11a, 15S) -2,3,4-trinor-1,5-inter-m-phenylene-6,9-epoxy-11,15-dihydroxy 15-cyclohexyl-16,17, 18,19,20-pentanor] -prosta-5,13-diacetic acid sodium salt (i

DK 157930 B

8 hereinafter referred to as "Compound B").

IC5Q / ie the concentration that prevented, in the experimental conditions, in 50% of the cases, an induction of the aggregation of human platelets with arachidonic acid 5 in vitro, for Compound A is 0.5 µmol per liter, but for Compound B is only 0.01 µmol per liter.

The relative blood pressure lowering effect on awake, spontaneously hypertonic rats (measurement over permanent catheters, intravenous use of the test compounds, for these 5,6-difiydroprostacycline is 0.005 / kg under these conditions and this effect is set to 1) is for Compound A <0.1, but for Compound B 0.25.

The process of the invention is further described by the following examples in which all temperatures 15 are uncorrected. The R ^ values were found in thin layer chromato-. graphically on silica gel. 1

DK 157930B

9

Example 1 al 0.5 g of [(5E, 13E, 9a, 11a, 15S1-2,3,4-Trinor-1,5-inter-m-phenylene-9,11,15-trihydroxy-15-cyclohexyl-16 , 17,18,19, 20-pentanor] -prosta-5,13-diacetic acid methyl ester (isomeric purity 90%, mp 101-102 ° C, [a] +1 - -36.8 at c = 1.0 (methanol) was dissolved in 6.3 ml of diethyl ether and 3 ml of methanol and cooled to 0 ° C, and with the exclusion of light, 6.3 ml of saturated sodium bicarbonate solution was added first and then at the same temperature (0 ° C dropwise). to a solution of 2.15 g of iodine in 10 ml of diethyl ether was added, the reaction mixture was stirred at 0 ° C for 4 hours and then saturated sodium thiosulfate solution was added until decolorized.

The organic layer was separated, the aqueous phase 15 was extracted two more times with 25 ml of diethyl ether each time, and then the combined organic phases were dried under cooling with magnesium sulfate. The solution was then evaporated under vacuum to light and stored at 0.1 Torr until weight constancy.

0.65 g of a yellow oily product was dissolved, dissolved in 6.5 ml of dry toluene at 20-25 ° C and after the addition of 0.5 ml of 1,5-diazabicyclo (4.3.0) -5-one stirred for 15-20 hours.

It was then diluted with 60 ml of toluene and 25 washed three times with 15 ml of saturated sodium bicarbonate solution each time and then with 15 ml of water. The organic phase was dried over magnesium sulfate, evaporated in vacuo at 40 ° C, and then the residue was chromatographed on silica gel with a mixture of ethyl acetate and methanol (98:21,

Hereby 0.5 g of an oil which, for about 70%, consisted of the isomer mixture (the 5E and 5Z forms in an isomer ratio of 9:11 of [(13E, 9a, 11a, r5S) -2). 3,4-trinor-1,5-inter-m-phenylene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor] -prosta-5, dien-13-acid methyl ester.

. . DK 157930 Β 10.

The 5E Form showed by thin layer chromatography (final plates HPTLC RP-8 F 254 S from E.Merck AG, methanol / water = 80:20) an R 2 value of 0.24. Under the same conditions, the 5Z form of this product showed an R 2 value of 0.17.

(B) Of the mixture obtained under (a), predominantly of the 5E form, to carry out the isomerization method of the invention, 250 mg was dissolved in 2.5 ml of dry dimethyl sulfoxide and at 20 solution of 160 mg of pyridinium p-toluenesulfonate in 2.5 ml of dry dimethyl sulfoxide. The reaction mixture was stirred at 20-25 ° C.

After three hours, a sample of 1 ml was added, added to 5 ml of saturated sodium bicarbonate solution, shaken three times with 2.5 ml of ethyl acetate each time, and the total organic phases were washed three times with 1 ml of water each time. After drying over potassium carbonate, the solution was evaporated in vacuo. The evaporation residue, as further described below, was examined for the isomer ratio.

After 72 hours, the bulk of the reaction mixture was worked up in an analogous manner, yielding 200 mg of a product whose contents of the 5E and 5Z forms, respectively, were found by high-pressure liquid chromatography on "Lichro-sorb RP 18" grain size 10 µm (Merck AG) under using methanol / water = 75:25 as mobile phase.

52

Reaction time «Relationship-f ™. (t.imer.1 .................... ^ 0 0.1 30 3 8.5 .7.2 ............ ..... 9.5 c) Of the product thus obtained, 200 mg was dissolved in 7 ml of methanol and 1.8 ml of 1 N sodium hydroxide solution was added at 25 ° C and stirred for 48 hours at 25 ° C. By high-pressure liquid chromatography with methanol: water = 45:55 (containing 0.01% sodium bicarbonate) on silica gel RP 18 (Merck AG) and subsequent freeze drying

DK 157930 B

11 pure sodium salts of the 5Z and 5E forms (145.6 mg and 15.3 mg, respectively) of [(13Ε, 9α, 11α, 15S) -2,3,4-trinor-1,5-inter-m -phenylene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor] -prosta-5,13-diacetic acid, which was identical to those for example in Example 3 of the above described Danish Patent Publication No. 154> 214.

(d) The same procedure as in (b) above was used, but was already worked up after 24 hours, 10 and the isomerization was induced with the salts listed in the following tables:

Salt of: sold / ^ 10 Ratio §§ substrate'5 * begin- .... .

N, N-Dimethylaniline and p-toluenesulfone 1.67 0.1 8.9 Acidic acid Trl 1.67 0.1 8.1 Fluoroacetic Acid Substrate = Product of Example 1a

Example 2

1.5 g of the E-form mixture obtained in Example 1a was used, and this amount was dissolved in 15 ml of hexamethylphosphoric acid triamide, to which was added a solution of 955 mg of pyridinium p-touenesulfonate in 15 ml. hexamethylphosphoric triamide and the mixture was stirred for 16 hours at 25 ° C. Then, 30 ml of saturated sodium iurobicarBonatop 1 solution was introduced, extracted three times with 50 ml of ethyl acetate each time, and the combined organic phases were washed three times with 20 ml of water each time. After drying over anhydrous potassium carbonate, the solvent was distilled off in vacuo 35 at 35-40 ° C to yield 1.5 g of evaporation residue. This was dissolved in 50 ml of methanol, which was added at 25 ° C to 13 ml of 1N sodium hydroxide solution. 48 hours stirring at 25 ° C was worked up as in Example 1c

DK 157930B

12 (using high pressure liquid chromatography and subsequent freeze drying) to give 703 mg of the 5Z form and 115 mg of the 5E form of the sodium salt of [(13E, 9a, 11a, 15S) - 2,3,4-trinor-1, 5-inter-m-phenylene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor] -prosta-5,13-diacetic acid which was identical to the products obtained in Example 1c.

Example 3 The same procedure was used as in Example 1b, but the solvents listed in the following table and 2 mmol of pyridinium trifluoroacetate were used. mmol of the product obtained in Example 1a and worked up after 16 hours. The isomerization thus obtained is shown in the following table:

Relationships ||

Solvent: 1:11 end 20 Dimethylsulfoxide / n η, 7 dichloromethane 1: 1

Dimethylsulfoxide / n.

tetrahydrofuran 1: 1 '' 1 2 3 4 5 6 7 8 9 10 11

Example 4 2

The procedure described in Example 1b was used as substrate esters of the procedure described in Example 1b. [(13ΕΓι-9η ,, ΙΙα, 1551 .-- 2 ^ 3, 4-4 trinor-1,5-inter-m-phenylene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16 17,18,19,20-pentanor] -prosta-5,13-diacetic acid, 6 wherein R R has the meaning given in the following table, in the form of the pure 5E isomers (ie, the ratio 5Z: 5E = zero ), 8 dry dimethyl sulfoxide as the solvent and the salts listed in Table 9, and after the indicated times 10 reached the isomer ratio indicated in the last column of the table, 11 ie mixtures in which each time the 5Z form constituted the major part: 13

DK 1579-30 B

Pyridine salt Mole ratio Reacti- 5Z

RI of 5E

1 substrate (hours) 2 Isopropyl p-Toluenesulfone 1 24 2.7 acid.

n-Hexyl Trifluoro-0.1 16 5.0 Acetic Acid.

Benzyl Trifluoro 0.1 20 6.5 Acetic Acid 10 ----

Example 5

In the procedure described in Example 1b, [(13E, 9a, 11ct, 15S) -2,3,4-trinor-1,5-inter-m-phenylene-6,9-epoxy-11, 15 dihydroxy] -prosta-5,13-diacetic acid methyl ester in the form of a mixture of the 5Z and 5E isomers (ratio 5Z: 5E = 1.1) as well as equimolar amounts of pyridinium p-toluenesulfonate and the isomerization reaction was carried out at the temperatures and times in the solvents listed in the table below, a clear increase in the proportion of the 5Z isomer was also obtained:

Temp Reactivity - Solvent Raturation Time - ^ = ................ (° C). . . (. H).

Dime.thylsulfox.id. . ....... 2.0-2.5 ..... 2. 4.1

Dimethylsulfoxide + q 16 7 6 te.trahy.drof.ur.an. (. 1: .1). . ....... 30,1,3-Dimethyl-3,4,5,6-tetrahydro-r 2 (1H) - 50 1 6,7 pyrimidinone

The saline solutions used in Examples 1b, Id and 2-5 are conveniently prepared by dissolving equimolar amounts of the respective base and acid in the respective (dried) solvent. The resulting mixture could immediately be used as such

Claims (9)

A process for preparing the 5Z form, of 2,3,4-trinor-1,5-inter-m-phenylene-prostacyclin derivatives 10 of the general formula I A - C - BY Λ HO HO R2 where: R 1 is a hydrogen atom, a cation or a straight or branched alkyl group having 1-6 C atoms, R 2 is hydrogen or methyl, A is a group - CH 2 -CH 2 - (trans) -CH = CH- or -C = C-, and B is an alkyl group of 5-9 C atoms of structure: R 3 r - C - (CH 2) 3-CH 3 R 4 where R 3 and R 2 are the same or different and are hydrogen, methyl or ethyl, or are an optionally substituted cyclohexyl group optionally with a methyl or ethyl group, characterized in that a 5E form compound of formula IIE DK 157930 B JX C ---- COOR. ' O ^ l (IIE) 5 T Λ HO HO R2 10 where R2, A and B are as defined for formula I and R | is a straight-chain or branched alkyl group having 1-6 C atoms or an aralkyl group having 1-2 C or a fluorinated or chlorinated acetic acid and in the presence of a reaction medium containing anhydrous and non-alcoholic polar solvent to form a 5Z compound of the corresponding formula IIZ XX / h , where λ, R 2, A and B are as defined above, 2 then, if desired, the group -COOR 2 is a hydrogen atom, 4 a cation, or a straight or branched alkyl group 5 p with 1-6 C atoms. 6. Process according to Claim 1, characterized in that the isomerization reaction is carried out at temperatures between approx. 0 ° C and approx. 50 ° C. DK 157930B Process according to claim 1 or 2, characterized in that the isomerization reaction is carried out using dimethylsulfoxide, hexa-methylphosphoric triamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) - pyrimidinone, formamide or tetrahydrothiophene-1,1-dioxide as solvent. Process according to any one of claims 1 to 3, characterized in that the salts used for the isomer isation are derived from organic, monobasic sulfonic acids or from trifluoroacetic or trichloroacetic acid. Process according to any one of claims 1-4, characterized in that the salts used for the isomerization are derived from heteroaromatic bases. Process according to any one of claims 1-5, characterized in that pyridinium p-toluenesulfonate is used as salt. Process according to any one of claims 1 to 6, characterized in that approximately the same molar amounts of a compound of formula IIE and of pyridinium p-toluenesulfonate are used. A process according to any one of claims 1-7, characterized in that the group '25. the compound of formula IIE is a methyl or ethyl group, R 2 is a hydrogen atom and A is a trans-CH = CH group. 9. Process for Preparation of Sodium * or Potassium Salt of [(5Z, 13E, 9a, 11a, 15Sl-2,3,4-trinor-1,5-inter-m-phenylene-6,9-epoxy) -11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor] -prosta-5,13-diacetic acid, according to any one of claims 1-8, characterized by , that [(5E, 13E, 9a, 11a, 15Sl-2,3,4-trinor-1,5-inter-m-phenylene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl) -16,17,18,19,20-pentanor] -prosta-5,13-diacetic methyl or ethyl ester isomerized by the action of pyridinium p-toluenesulfonate at a temperature of from about 0 ° C to approx. 50 ° C, preferably at room temperature and preferably in the presence of dimethylsulfoxide as polar solvent, after which the methyl or ethyl ester of the resulting 5Z compound, after adjusting the equilibrium, is isolated in a manner known per se and saturated. 5 is treated with sodium or potassium hydroxide solution to form the desired sodium or potassium salt.