IE913764A1 - Epoxycarbacyclin precursors, their production and use - Google Patents

Abstract

The invention concerns epoxycarbacyclin intermediates, a method for preparing them from the Z-isomers of corresponding carbacyclin precursors, and their use in the preparation of pharmacologically active carbacyclins.

Description

EPOXYCARBACYCLIN PRECURSORS, THEIR PRODUCTION AND USE The invention relates to epoxycarbacyclin intermediate products, process for their stereospecific production from Z isomers of the corresponding carbacyclin precursors and their use for the production of pharmaceutically effective carbacyclins.

A process is described in EP 335827, which protects the Z allyl alcohols of formula IV on the hydroxy group by formation of the acetate and by hydroxylation and periodate cleavage of the double bonding is returned to the starting material (ketone), from which the allyl alcohols can be produced again.

But in the synthesis of the allyl alcohols an about 50/50 mixture of stereoisomers III and IV is then formed, which has to be separated chromatographically.

Epoxycarbacyclin carboxylic acid derivatives of the general formula and their use for conversion of Z to E isomers, in which the oxygen atom is lacking in the upper chain, are known from DE 33 38 832.

E. Vedeja and P.L. Fuchs describe the inversion of simple epoxides with this method (J.Am.Chem.Soc. (1973), 822 and J.Am.Chem.Soc. (1971) 4072).

In the synthesis of (5E)-3-oxa-6a-carba-prostaglandin-l2 derivatives of the formula OH in which A, W, D, E and R“ have the meaning indicated in formula I, a step is passed through, which consists of up to approximately 50% of the desired allyl alcohol with an Econfigured double bond III mu . , · 2 in which A, W, D, E and R have the meaning indicated in general formula I, and up to approximately 50% of the allyl alcohol IV, unusable for the further synthesis, with a Z-configured double bond • · 2 in which A, W, D, E and R have the meaning indicated in formula I.

The mixture of E and Z alcohols of formulas III and IV have to be separated chromatographically.

Such E-configured alcohols of formula III are converted to pharmacologically effective (5E)-3-oxa-6a-carba-prostaglandin-l2 derivatives in DE 30 48 906, 33 06 123 and 33 06 125 (see also W Skuballa et al., J.Med.Chem. (1986),29, 313).

By the epoxycarbacyclin intermediate products of formula I it is possible advantageously to feed to the carbacyclin synthesis process as E isomers Z-configured allyl alcohols of formula IV which are valuable for further synthesis.

The invention consists of epoxycarbacyclin precursors of formula I, in which A means a C=C group, W means a hydroxymethylene group, in which the OH group is protected by a trialkylsilyl, diphenylalkylsilyl or triphenylsilyl group, D means a —CH-CH2 group, E means a-C^c group, R1 means a hydroxy group, which can be substituted like the hydroxy group in W, R means a straight-chain or branched alkyl, alkenyl or alkinyl group with 1-7 C atoms and R3 represents a tetrahydropyranyl or tetrahydrofuranyl group.

The alkyl radicals of the trialkylsilyl group in W and R1 can be the same or different and contain 1-8 C atoms, such as, e.g., dimethyl-tert-butylsilyl, triethylsilyl, triisopropylsilyl, thexyldimethylsilyl (thexyl = 2,3,3-trimethylpropyl).

The alkyl radical of the diphenylalkylsilyl group in W and R1 can mean, e.g., methyl, ethyl, propyl, tert-butyl and hexyl, i.e., they exhibit 1-6 C atoms. The straight-chain or branched alkyl group with 1-7 C atoms in R can be, e.g.: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, nhexyl, n-heptyl. Alkyl groups with 1-4 C atoms are preferred.

Alkenyl with 1-7 C atoms for R means propenyl, butenyl, 2butenyl, 3-butenyl, isobutenyl, etc. Alkenyls with 1-4 C atoms . 2 are preferred. In the alkmyl groups with 1-7 C atoms for R alkinyls with 1-4 Catoms are also preferred, such as, e.g., CH2 CaCH, CBC-CH3, CH2, -CsC-CHj , CH2-CH2-C5CH, etc.

Moreover, the invention relates to a process for the production of compounds of formula I, characterized in that a bicyclof3.3.0]oct-3-ylidene ethanol of formula II OH . . in which A, W, D, E, R and R have the above-indicated meanings, is epoxidized with dihydrofuran or dihydropyran after previous reaction performed under acid catalysis.

The reaction with dihydrofuran or dihydropyran takes place under acid catalysis in an inert solvent, such as fc tetrahydrofuran, diethyl ether, dioxane, ethylene glycol dimethyl ether, methylene chloride, hexane, heptane, toluene to an acetal.

The acid catalysis can take place by mineral acids such as hydrochloric acid or sulfuric acid or an acid ion exchanger or organic acids, such as trifluoroacetic acid. The reaction temperature is not critical, suitably it takes place at room temperature.

The epoxidizing of the protected derivatives can be performed with reagents known to one skilled in the art, but the magnesium salt of perphthalic acid or m-chloroperbenzoic acid are preferred.

The reaction can take place with addition of sodium bicarbonate or potassium bicarbonate to prevent acid-catalyzed decomposition reaction.

The epoxidizing is generally performed between 0°C and 60°C in an inert solvent such as hexane, heptane, dichloromethane, 1,2-dichloroethane, diethyl ether or tetrahydrofuran.

Moreover, the invention consists in the use of the epoxycarbacyclin precursors of formula I for the production of allyl alcohols of formula III, • · 1 2 in which A, W, D, E, R and R have the above-indicated meaning, by reaction with a phosphorus compound of formula VI, Ll-PIR4)? ,vrjt . 4 in which R means a Cg-Cjg aryl group or a Cy-Cjj aralkyl group, subsequent reaction with a compound of formula VII r5.q ivill. in which R^ means a Cj-C4 alkyl group and Q means a halogen atom, a Cj-C4 alkyl sulfonyloxy group or a C5-C7 aryl sulfonyloxy group, and cleavage of the allyl hydroxyl protecting group.

The protected epoxides of formula I can be opened with a phosphorus compound of formula VI.

The reaction takes place between 0°C and 3 0°C in an inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane, 1,2-dichloroethane, hexane, toluene, etc.

The reaction of the ring-opened epoxy compounds with R^Q takes place between 0°C and 50°C in an inert solvent, such as tetrahydrofuran, diethyl ether, dichloromethane, hexane, toluene, ,E 913764 etc., preferably in the solvent, in which the epoxide opening is performed (one-pot reaction).

The phosphonium salt IX spontaneously suffers an elimination to derivatives of formula X, in which A, W, D, E, R1, R2 and R3 have the meaning indicated in formula I.

The compounds of general formula X are converted by cleavage of the allyl hydroxyl protecting group R3 into the E allyl alcohols of formula III.

The selective cleavage of the protecting group takes place under acid catalysis.

Mineral acids such as hydrochloric acid or sulfuric acid or organic acids, such as trifluoroacetic acid, citric acid, etc., in water, methanol or ethanol lead to the decomposition of the very sensitive allyl alcohol (III) or the silyl protecting groups are cleaved off.

It has been surprisingly found that protecting group cleavage into isopropanol with acid ion exchanger (Amberlyst 15) at raised temperature is achieved very cleanly and completely.

Thus with the above-described five-step process the complete and stereospecific conversion of the compounds with formula IV to compounds of formula III is achieved.

After completion of the reaction, the desired product can be recovered from the reaction mixture by the usual methods. For example, a suitable recovery method comprises pouring the reaction mixture into water, extraction with an organic solvent not miscible with water, drying the organic extract and finally distillation of the solvent from the extract to recover the desired product.

The product can optionally be further purified with the usual techniques, such as recrystallization, preparative thinlayer chromatography or column chromatography.

The corresponding reactions with compounds of formula IV with unprotected hydroxyl group (R_>=H) are not achieved.

The selection of the tetrahydrofuranyl group or tetrahydropyranyl group as OH protecting group is critical, since neither reacts with the phosphorus compound and can be cleaved in the presence of silyl ether or of sensitive allyl alcohol III.

Starting compounds III and IV are described in US patent 4,423,067 and US patent application Ser No. 581,851.

The invention is explained by the following examples: Example 1 (IS,2S,3R,5R)-3-tert-Butyl-dimethylsilyloxy-2((3S,4S)-3-tertbutyl-dimethylsilyloxy-4-methyl-l,6-nonadiinyl]-7-[(Z)-2perhydro-2-furyloxy)-ethylidene]-bicyclo[3.3.0]octane g of 2-(Z)-(IS,5S,6S,7R)-7-tert-butyl-dimethyldilyloxy-6 [(3S,4S)-3-tert-butyl-dimethylsilyloxy-4-methyl-l,6-nonadiinyl]bicyclo[3.3.0]-oct-3-ylidene ethanol is dissolved under nitrogen in 1000 ml of hexane. At room temperature 2 g of Amberlyst 15 and 64 g of dihydrofuran are added. The yellowish solution is stirred for 12 more hours at room temperature. TLC control (hexane/methyl tert-butyl ketone 8:2) shows complete reaction (Rf AM = 0.13, RF prod. = 0.55). 150 ml of sodium bicarbonate solution is quickly instilled and it is stirred for 30 more minutes. The hexane phase is separated, dried on sodium sulfate and concentrated by evaporation in a rotary evaporator. The isolation of the product takes place by column chromatography (2000 g of silica gel, mobile solvent: hexane/ethyl acetate 95:5).

Yield: 47.8 g = 84.7% of theory.

(IS,2S,3R,5S)-3-tert-Butyl-dimethylsilyloxy-2-[(3S,4S)-3tert-butyl-dimethylsilyloxy-4-methyl-l,6-nonadiinyl]-7-[(Z)-2perhydro-2-furyloxy)-ethylidene]-bicyclo[3.3.0]octane Analysis: Cld.

Fnd.

C 70.29 69.92 H .16 .07 O .3 Si 9.13 Step 2 (IS,5S,6S,7R)-7-tert-Butyl-dimethylsilyloxy-6-[(3S,4S)-3tert-butyl-dimethylsilyloxy-4-methyl-l,6-nonadiinyl]-3-(perhydro2-furyloxymethyl)spiro-[bicyclo[3.3.0]octane-3,2'-oxirane] 66.26 g of monoperoxyphthalic acid-Mg salt x 6H2O and 127.4 g of NaHCOj are suspended in 500 ml of THF and 46.5 g of (IS,2S,3R,5S)-3-tert-butyl-dimethylsilyloxy-2-[(3S,4S)-3-tertbutyl -dimethylsilyloxy-4 -methyl- 1 , 6-nonadiinyl]-7-((Z)-2perhydro-2-furyloxy)-ethylidene]-bicyclo[3.3.0]octane is instilled. The suspension is stirred for 3 hours at room temperature and then heated for 4 hours to 50°C. The mixture is cooled to room temperature, 300 ml of MTB is added and 175 ml of saturated sodium sulfite solution is instilled, at the same time, the temperature of the solution is held at 20°. The reaction mixture is diluted with 200 ml of water and 100 ml of MTB and the phases are separated. The aqueous phase is extracted twice with 200 ml of MTB each, and the combined, organic phases are washed twice with 200 ml of water each, dried on sodium and concentrated by evaporation in a rotary evaporator. (MTB = methyl tert-butyl ketone) Yield: 46.06 g = 96.5% of theory.

(IS,5S,6S,7R)-7-tert-Butyl-dimethylsilyloxy-6-((3S,4S)-3tert-butyl-dimethylsilyloxy-4-methyl-l,6-nonadiinyl)-3-(perhydro2-furyloxymethyl)spiro-[bicyclo[3.3.0]octane-3,2-oxirane] Analysis: C H 0 Si Cld. 68.51 9.90 12.67 8.90 Fnd. 68.37 9.71 Step 3 Lithium diphenyl phosphide g of chlorodiphenylphosphine is instilled in 3.67 g of lithium wire in a dry 100 ml three-necked flask in 50 ml of THF at a 20-22°C internal temperature. It is stirred overnight at room temperature (20-23°C) , in this way, the reaction is completed. The excess Li wire remains on the surface of the solution. An aliquot of the deep red solution is gathered with a syringe, hydrolyzed with water in a measuring flask and an aliquot from it is titrated against 0.01 n HCl.

Yield: quantitative Analysis: titration against 0.01 n HCl overall alkali content 1.55 m Step 4 (1S,2S,3R,5S)-3-tert-Butyl-dimethylsilyloxy-2-[(3S,4S)-3tert-butyl-1,6-nonadiinyl]-7-[2-perhydro-2-furyloxyl-1diphenylphosphanyl-ethyl]-bicyclo[3.3.0]octan-7-ol and (IS,2S,3R,5S)-3-tert-butyl-dimethylsilyloxy-2-[(3S,4S)-3tert-butyl-dimethylsilyloxy-4-methyl-l,6-nonadiinyl]-7-(2perhydro-2-furyloxy)-1-diphenylmethyl-phosphonium-ethyl]bicyclo[3.3.0]octan-7-ol-iodide and lE 913764 (IS,2S,3R,5S)-3-tert-butyl-dimethylsilyloxy-2-[(3S,4S)-3tert-butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl]-7-[(E)-2perhydro-2-furyloxy)-ethylydene]-bicyclo[3.3.0]octane 45.5 g of (1S,5S,6S,7R)-7-tert-butyl-dimethylsilyloxy-6[(3S,4S)-3-tert-butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl ] 3-(perhydro-2-furyloxymethyl)-spiro-[bicyclo[3.3.0]octane-3,2 ' oxirane] is dissolved in 280 ml of abs. THF. A solution of 110 ml of lithium diphenyl phosphide (1.55 m) is instilled at about a 10°C internal temperature. Toward the end of the addition, the solution turns dark red. It is stirred for one more hour at 1020°C. At 10-20°C, 19.64 ml of methyl iodide is instilled. The solution becomes colorless and a white precipitate (methyl diphenylphosphine oxide) precipitates. It is stirred for 15 more minutes. 200 ml of water and 200 ml of MTB are added to the reaction mixture, the phases are separated and the aqueous phase is extracted with 100 ml of MTB. The combined organic phases are washed with 200 ml of water and 100 ml of saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The crude product is filtered on 600 g of silica gel (mobile solvent: hexane/ethyl acetate 95:5), MTB = methyl tert-butyl ketone.

Yield: 35.5 g = 80.0% of theory.

(IS,2S,3R,5S)-3—tert-Butyl—dimethylsilyloxy—2—[(3S,4S)-3tert-butyl-diraethylsilyloxy-4-methyl-l,6-nonadiinyl]-7-[(E)-2perhydro-2-furyloxy)-ethylidene]-bicyclo[3.3.0]octane Analysis: C H 0 Si Cld. 70.29 10.16 10.4 9.13 Fnd. 70.21 9.85 — Step 5: 2-<(E)- (IS, 5S, 6S,7R)-7-tert-Butyl-dimethylsilyloxy-6[(3S,4S)-3-tert-butyl-dimethylsilyloxy-4-methyl-l,6-nonadiinyl] bicyclo[3.3.0]oct-3-ylidene>-ethanol g of (IS,2S,3R,5S)-3-tert-butyl-dimethylsilyloxy-2[(3S,4S)-3-tert-butyl-dimethylsilyloxy-4-methyl-l,6-nonadiinyl] 7-[(E)-2-(perhydro-2-furyloxy)-ethylidene]-bicyclo[3.3.0]octane is dissolved in 375 ml of isopropanol. 6 g of amberlyst 15 is added at 20-23°C and the mixture is heated for 4.5 hours to a 50°C internal temperature. The solution is cooled to 20-23°C, the ion exchanger is filtered off, rewashed with 100 ml of isopropanol and the filtrate is mixed with 100 ml of saturated sodium bicarbonate solution (pH 8-9). The mixture is concentrated by evaporation to about 150 ml and taken up in 200 ml of ethyl acetate and 200 ml of water, the organic phase is separated and the aqueous phase is extracted three times with 200 ml of ethyl acetate each. The combined organic phases are washed with 200 ml of saturated common salt solution, dried on sodium sulfate, filtered and concentrated by evaporation in a rotary evaporator. The crude product is chromatographically purified on silica gel.

Yield: 19.48 g = 73.3% of theory.

Analysis Cld. 70.52 10.36 8.81 Si .31 Fnd. 70.23 9.91

Claims (6)

1. Epoxycarbacyclin precursors of formula I, in which A means a -CsC group, W means a hydroxymethylene group, in which the OH group is protected by a trialkylsilyl, diphenylalkylsilyl or triphenylsilyl group, ch 3 I D means a -CH-CH2 group, E means a -CsC group, R 1 means a hydroxy group, which can be substituted like the hydroxy group in W, R 2 means a straight-chain or branched alkyl, alkenyl or alkinyl group with 1-7 C atoms and R^ represents a tetrahydropyranyl or tetrahydrofuranyl group.

2. Process for the production of compounds of formula I, characterized in that a bicyclo[3,3.0]oct-3-ylidene-ethanol of formula II IS • · 1 2 in which A, W, D, E, R and R have the above-indicated meanings, is epoxidated after-previous reaction with dihydrofuran or dihydropyran performed under acid catalysis.

3. Use of epoxycarbacyclin precursors of formula I for the production of allyl alcohols of formula III • . 12 . . in which A, W, D, E, R and R have the above-indicated meaning, by reaction with a phosphorus compound of formula VI, Li-P(R 4 ) 2 (VI), in which R 4 means a Cg-CjQ aryl group or a C7-C13 aralkyl group, subsequent reaction with a compound of formula VII, (VII) in which R^ means a C,-C

4. Alkyl group and Q means a halogen atom a CJ-C4 alkylsulfonyloxy group or a C5-C7 arylsulfonyloxy group, and cleavage of the allylic hydroxyl protecting group. -204. A compound substantially as hereinbefore described with reference to the Examples.

5. A process substantially as hereinbefore described with reference to the Examples.

6. A use substantially as hereinbefore described with reference to the Examples.