HU227158B1 - Production of beraprost ester by selective reduction - Google Patents

Abstract

Beraprost ester and salts of general formula (1) are prepared by general reduction of novel intermediate compounds.

Description

The present invention relates to a novel process for the preparation of beraprost and its salts of formula (I) and to novel intermediates of formula (VII) for the synthesis, wherein R is a straight or branched C 1 -C 4 alkyl group and TBDMS is a tert-butyldimethylsilyl group They are.

The salts of beraprost of formula (I), in particular the sodium salt thereof, are oral prostacyclin derivatives which are effective in the treatment of chronic arterial thrombosis, peripheral vascular disease and hypertension in the lungs.

The compound of formula (I) and its salts, which are commercially available pharmaceutical compositions, consist of a mixture of four stereoisomers.

The preparation of the compound of formula (I) and salts thereof is described in European Patent Application Publication No. 084856A and Japanese Patent Application Publication No. 59-134787A, and in Tetrahedron 55 p 2449-2474 (1999). .

In Figure 1, TBDMS is tert-butyldimethylsilyl, Ac is acetyl, and the W-H-E reaction is the Wittig-Horner-Emmon's reaction.

As can be seen in the prior art, the yield of the above reaction pathway is moderate and the purity of the intermediates thus obtained is poor.

Therefore, it is our goal to provide a synthesis route that provides better yields, intermediates and end products that are cleaner and easier to clean.

Surprisingly, it has been found that when the secondary hydroxyl group of the diol of formula IX is protected with an acid-cleavable 2-tetrahydropyranyl protecting group, this protecting group is protected by the Wittig-Horner-Emmon's reaction [Chem. Port. 89, pp. 863-927 (1989)], and under certain conditions in a manner which provides very good stereoselectivity, a significant increase in yield is achieved, both in the overall synthesis route and in the reduction of the enon.

According to the present invention, the diol of formula (IX), wherein R is as defined in claim 1, is converted to the tert-butyldimethylsilyl compound of formula (VIII) wherein R is as defined in claim 1, converting the 11-hydroxy group of the resultant compound (VIII) into a tetrahydropyranyloxy group to give a compound of formula VII wherein R is

TBDMS as defined in claim 1, TBDMS is as defined above, THP is tetrahydropyranyl, and then the alcohol (VI) is prepared from the compound (VII) by cleavage of the tert-butyldimethylsilyl protecting group. R is as defined above - alcohol is oxidized to the aldehyde of formula (V): (V) general formula - where R is as defined above - is isolated aldehyde or without isolation of the phosphonate of formula (X) - wherein R ¹ is 1- C 4 straight or branched alkyl, the resulting compound of formula IV, wherein R is as defined above, is deprotected and the resulting compound of formula III, wherein R is as defined above, is reduced , subjecting the resulting compound of formula II, wherein R is as defined above, to hydrolysis, and the resulting acid of formula (I) is isolated and then reacted with a base to form its salt and the salt is isolated, or the resulting acid of formula (I) is reacted with a base without isolation and the resulting salt is isolated.

The formation and cleavage of the TBDMS and THP protecting groups are carried out by methods known per se.

The starting compounds of formula IX and the phosphonates of formula X used in the process of the present invention may be prepared, for example, as described in Tetrahedron 55 p 2449-2474 (1999).

The formation and cleavage of the TBDMS and THP protecting groups are carried out by methods known per se.

(Handbook of Reagents for Organic Synthesis, Activating and Protecting Groups, Eds. A.J. Pearson and W.J. Roush, John Wiley & Sons, Chichester, 1999. ISBN 0471-97927-9).

The diols of formula (VI) may be oxidized to the corresponding protected aldehyde by Moffatt oxidation (DMSO / H3PO4, DCC), or by Swern oxidation (oxalyl chloride, DMSO, triethylamine) or by Corey's N-chlorosuccinimide. dimethylsulfide reagent; Cr (VI) reagents such as Collins reagent (pyridinium dichromate) or pyridinium chlorochromate, and Dess-Martin periodinane [1,1,1-triacetoxy-1,1-dihydro-1,2-benzodoxol-3 (1H on) or using the so-called TEMPO (2,2,6,6-tetramethylpiperidine-1-oxy) reagent. (Handbook of Reagents for Organic Synthesis, Oxidizing and Reducing Agents, Eds. S. D. Bürke and R. L. Danheiser, John Wiley & Sons, Chichester, 1999. ISBN 0-471-97926-0).

The stereoselective reduction of the compounds of formula (III) is preferably carried out with diisobutylaluminum-2,6-ditertiary butyl-4-methylphenoxide.

Preferably, the compounds of formula (II) are hydrolyzed alkaline to the beraprost of formula (I).

Further details of our process are illustrated in the following examples, without limiting our claims.

Examples

Example 1 Compound of Formula VIII wherein R is methyl

Dissolve diol (IX) (3.06 g, 0.01 mol) where R is methyl and dissolve in pyridine (10.5 ml) and add tert-butyldimethylchlorosilane (3.31 g, 0.011 mol). After stirring for 3 hours, the reaction mixture was poured into water (150 mL) and the aqueous layer was extracted with toluene-hexane = 1: 1. The combined organic layer was washed with 2M sodium hydrogen sulfate solution, then with 1M sodium hydrogen carbonate solution, water and brine.

It is dried over sulfate and evaporated. The residue (pale yellow oil) / _Rf (hexane-acetone 3: 1) = 0.45, _Rf (diisopropyl ether-acetone-water, 40: 25: 1) = 0.76 / (4.2 g (100%) which is the title compound in the next step without purification.

Example 2 Compound of Formula VII - where R is methyl, TBDMS is tert-butyldimethylsilyl

Dissolve 4.2 g (0.01 mol) of the compound (Vili) obtained in the previous example in distilled toluene (14 ml), add dihydropyran (1.4 ml, 0.015 mol) and a solution of p-toluenesulfonic acid in tetrahydrofuran (30 ml). mg / 3 ml). The reaction mixture was stirred for 1 hour and then quenched with 32 μΙ triethylamine. This compound, which is a pale yellow oil / _Rf (hexane-acetone 3: 1) without 0.88 / toluene solution of treated = 0.60, _Rf (1 diisopropyl ether-acetone-water, 40: 25) to the next reaction step.

Example 3 Compound of Formula VI - wherein R is methyl

To a solution of the above compound (VII) in toluene is added tetrabutylammonium fluoride trihydrate (3.94 g, 0.0126 mol) and stirred for 1.5 hours at 45-50 ° C. The reaction mixture was cooled, washed with 2M sodium hydrogen sulfate solution (7 mL), water (2 x 14 mL) and brine (14 mL), dried over sodium sulfate and evaporated. The residue was purified by column chromatography to give the pure product as a pale yellow oil.

Yield: 2.73 g (70%)

R _f (hexane-acetone 3: 1) = 0.11

R f (diisopropyl ether-acetone-water 40: 25: 1) = 0.41

Example 4 Compound of Formula IV - wherein R is methyl, THP is tetrahydropyranyl Compound (VI) (3.9 g, 1 mmol) is dissolved in distilled toluene (25 mL) and 1M phosphoric acid dimethyl (1.37 mL) is added. sulfoxide solution followed by dicyclohexylcarbodiimide (3.5 g, 1.7 mmol). The reaction mixture was stirred for 3 hours and after 1 hour additional 0.65 ml of 1M dimethyl sulfoxide in phosphoric acid was added.

The resulting reaction mixture containing the aldehyde of formula (V), wherein R is methyl, THP is tetrahydropyranyl, is cooled to -10 ° C. A 60% sodium hydride oil dispersion (460 mg, 1.15 mmol) was suspended in distilled toluene (5 mL) under nitrogen and then 2.55 g (1.1 mmol) of the phosphonate (X) was added at 15 ° C. ¹ represents a methyl group solution in 6 ml of distilled toluene. The reaction mixture is stirred for 20 minutes at 15 ° C and the solution containing the phosphonate sodium salt is added dropwise at -10 ° C to the reaction mixture containing the above aldehyde (V). After stirring for 2 hours, the reaction mixture was poured into 15 ml of 1M sodium hydrogen sulfate solution and stirred at room temperature until the total amount of unreacted dicyclohexylcarbodiimide was converted to dicyclohexylurea (DCU). The DCU was filtered, washed with toluene (3x5 mL). The filtrate was separated, the aqueous layer was washed with toluene (2 x 5 mL), the combined organic layers washed with 10% sodium bicarbonate solution (15 mL), water (15 mL) and brine (15 mL) and dried over sodium sulfate. , evaporate. The dry residue was purified by silica gel column chromatography (hexane: ethyl acetate) to give the pure product.

Yield: 386 mg (78%) of a pale yellow oil R _f (hexane-ethyl acetate 1: 1) = 0.61 R _f (diisopropylether-ethyl acetate-acetic acid 50: 50: 1.5) = 0, 58

Example 5 Compound of Formula III - wherein R is methyl

495 mg (1 mmol) of the compound of formula IV obtained in the above example, where R is methyl, are dissolved in methanol (7.6 ml), 70 μΙ concentrated hydrochloric acid is added. The reaction mixture was stirred for 15 minutes, then neutralized with solid sodium bicarbonate and evaporated. The residue is dissolved in toluene, the inorganic salts are filtered, the filtrate was concentrated to give a pale yellow oil, _Rf (diisopropylether-ethylacetate-acetic acid 50: 50: 1.5) = 0.50, is obtained. Yield: 411 mg (100%)

Example 6 Compound of Formula II - wherein R is methyl

51.4 g (0.22 mol) of 2,6-di-t-butyl-4-methylphenol are dissolved in distilled toluene (500 ml) under a nitrogen atmosphere. 15.5 g (0.11 mol) of diisobutylaluminum hydride distillate are added dropwise at 0 ° C. toluene (80 mL). The reaction mixture was stirred for 1 hour at 0 ° C and then cooled to -78 ° C. 4.51 g (0.011 mol) of the compound of formula III obtained in the previous example, wherein R is methyl, are distilled at -78 ° C to an adisobutylaluminum 2,6-di-t-butyl-4-methylphenoxide reagent. toluene (40 mL). The reaction mixture was stirred overnight at -50 ° C and quenched with 2M hydrochloric acid (270 mL). After stirring for 30 min, the phases were separated, the aqueous phase was washed with toluene (2 x 150 mL), the combined organic layers were saturated brine (200 mL), 10% sodium bicarbonate (150 mL), then saturated brine (2 x 200 mL). ), dried over sodium sulfate and concentrated. From the residue the pure product is obtained by purification, a colorless oil / _Rf (diisopropylether-ethylacetate-acetic acid 50: 50: 1.5) = 0.24, _Rf (toluene-dioxan-acetic acid 20:10 : 1) = 0.50 /.

Yield: 2.50 g (55%)

Example 7 Beraprost of formula (I)

2.6 g (0.0063 mol) of the compound of formula (II) wherein R is methyl are dissolved in methanol (10 ml), carefully added dropwise to the solution

HU 227 158 Β1

9.5 ml of 1M sodium hydroxide solution. After stirring for 1 hour, methanol was distilled off from the reaction mixture, the aqueous residue was extracted with methyl tert-butyl ether, and the combined organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was crystallized from ethyl acetate-hexane to give the pure product as colorless crystals, having _Rf value (toluene-dioxan-acetic acid 20: 10: 1) = 0.41.

98-112 ° C

Yield: 2.18 g (87%)

Example 8

Beraprost sodium salt

Beraprost (I) (3.98 g, 0.01 mol) was dissolved in distilled methanol (40 ml) and 10 ml (0.01 mol) of 1M sodium hydroxide solution was added. The solution was concentrated in vacuo to give the title pure product consisting of colorless crystals.

Yield: 4.2 g (100%)

M.p.> 205 ° C

MERCK Kieselgel 60 F ₂₅₄ 0.2 mm thick sheets 5 cm long were used for the above TLC tests.

Claims (9)

PATENT CLAIMS A process for the preparation of a compound of formula I wherein R is a straight or branched C 1 -C 4 alkyl group and its salts, in particular its sodium salt, characterized in that the diol of formula IX wherein R is as defined in claim 1 The compound of formula (VIII) wherein R is as defined above, TBDMS is tert-butyldimethylsilyl, is converted to the tetrahydropyranyloxy group of compound (VII) to give the 11-hydroxy group of the compound of formula (VII). where R is as defined above, TBDMS is as defined above, THP is tetrahydropyranyl, and the compound of Formula VII is prepared by cleavage of the tert-butyldimethylsilyl protecting group to form the alcohol of Formula VI followed by The alcohol of formula VI, wherein R is as defined above, is oxidized to the aldehyde of formula V k, the (V) - wherein R is as defined above - is isolated or without isolation of the aldehyde phosphonate of formula (X) - wherein R ¹ is C 1 -C 4 straight or branched alkyl, the resulting compound of formula IV, wherein R is as defined above, is deprotected, and the resulting compound of formula III, wherein R is as defined above reducing the resulting compound of formula II, wherein R is as defined above, and isolating the resulting acid of formula I, then reacting it with a base to form its salt and isolating the salt of formula (I) without isolating the acid with a base and isolating the resulting salt. Process according to claim 1, characterized in that the acid of formula (I) is converted into its sodium salt and isolated. 3. A process according to claim 1, wherein the compound of formula (II) is hydrolyzed alkaline to the acid of formula (I). A process according to claim 1 wherein the compound of formula (III) wherein R is as defined above is reduced with diisobutylaluminum-2,6-di-tert-butyl-4-methylphenoxide to form (II). wherein R is as defined in claim 1. The process of claim 1, wherein the compound of formula (IV) wherein R is as defined in claim 1 is converted to the compound of formula (III) by acid hydrolysis. 6. A process according to claim 1, wherein the compound of formula V, wherein R is as defined in claim 1, is isolated in situ or in a reaction mixture under the conditions of the Wittig-Horner-Emmon's reaction. ) wherein R is as defined in claim 1. 7. A process according to claim 1, wherein the alcohol of formula VI is oxidized with a mixture of phosphoric acid dimethyl sulfoxide and dicyclohexyldiimide to an aldehyde of formula V, optionally further isolated without isolation according to claim 1. . Compounds of formula VII wherein R is as defined in claim 1, THP is tetrahydropyranyl, TBDMS is tert-butyldimethylsilyl. 9. A compound of Formula VII wherein R is methyl, THP is tetrahydropyranyl, TBDMS is tert-butyldimethylsilyl.