HU198921B - Process for producing 3-oxo-6-beta-/terc-butil-dimethyl-sililoximethyl/-7-alpha-hydroxy-2-oxabicyclo/3.3.o/octane - Google Patents

Abstract

Lactone derivs of general formula (1)-where R1 = 2-6C alkanoyl, benzoyl-phenyl-benzoyl, tetra-hydro-pyranyl, 1-6 alkyl, 2-8 alkoxy-alkyl or tri : halogen-acetyl gp. and R2 = hydrogen atom or tert-butyl-di: methyl-silyl gp. - are prepd. from 3-oxo-6-beta-hydroxy -methyl-7-alpha-hydroxy- 2-oxo-bicyclo-(3.3.0) - octane is treated by tert-butyl-di:methyl- chloro-silane, followed by treatment with an acid deriv. Cpds. of this type are useful as prostaglandin intermediates.

Description

The present invention relates to a new process for the preparation of 3-oxo- (6- (9-tert-butyldimethylsilyloxymethyl) -7a-hydrGX [1,2-oxabicyclof3.3.0] octane of formula (III).

The compound of formula (III) is known from the literature (Synt. Commun. 6 (1) p33-38 (1976), 174,555).

The compounds of formula (111) can be used to prepare key intermediates for the treatment of prostaglandin derivatives which are described in formula (I).

Compounds of formula I are known from the literature (Hungarian Patent Application No. 174,555, International Patent Application WO-81/022296, U.S. Patent No. 4,306,075, 94985/85). Useful intermediates for the synthesis of prostaglandin derivatives (pJS Bindra and R. Bindra, Prostaglandin Synthesis Academic Press, New York, 1977, Tetrahedron Lett. 24 (1) p47-50 / 1973), Chem. Lett. pl., 247 (1980), GDR 218,615, 1 Amer. Chem, Soc. 94, 7827 (1972).

In the synthesis of prostaglandin derivatives and their analogs, the distinction between primary and secondary hydroxyl groups of a diol of formula II is a major problem. The use of a protecting group selectively coupled to a primary hydroxyl group that is stable under a variety of reactions is required (e.g. mild chemical reduction, Jones oxidation, Wittig reaction, alkoxyalkyl, tetrahydropyranyl cleavage, hydrogenolysis of benzyl ether bond, base catalyzed reaction), but can also be selectively cleaved by a protected secondary hydroxyl group (s). So far, the above problem has been solved by trityl, trimethylsilyl, tert-butyldimethylsilyl on the primary hydroxyl group of lactone diol (II) or trichloroacetyl. (J. Am. Chem. Soc. 93, 1491 (1971)), after protection of the secondary hydroxyl group, the acid-sensitive protecting group from the primary hydroxyl group by acid hydrolysis, the trimethylsilyl group by methanolic citric acid, and the tertiary group. and the butyldimethylsilyl group was separated with an aqueous mixture of acetic acid tetrahydrofuran or tetra-n-butylammonium fluoride (Synthesis p. 817, 1985).

The disadvantages of the known solutions outlined above are the following:

1.) The regioselectivity of the tritylation is almost 100%, but its cleavage requires vigorous conditions and the reaction yield is relatively low. Trichloroacetylation or the regioselectivity of the trimethylsilylation is low, the yield is not favorable and the cleavage of these two protecting groups is also difficult. Further, when an acid-sensitive protecting group, such as tetrahydropyranyl, alkoxyalkyl, is attached to the secondary hydroxyl group of the resulting compound of formula I, the protecting group cannot be selectively removed from the primary hydroxyl group by acid hydrolysis. The stability of the protecting groups listed herein is also not satisfactory under the conditions of the reactions listed above.

2.) The tert-butyldimethylsilyl group can be coupled with a nearly 100% regioselectivity to the primary hydroxyl group of compound II (Example 12 of Hungarian Patent No. 174,555) by the method of Corey (J. Am. Chem. Soc., 94, 6190 (1972), which gives the compound of formula (III). The above protecting group can be removed almost quantitatively even in the presence of an acid-sensitive protecting group. Its stability is much better than the above protecting groups under the reaction conditions commonly used in the above-mentioned prostaglandin syntheses.

It is an object of the present invention to provide a process for preparing the compound of formula (KI) from the lactone diol of formula (II) with nearly 100% regioselectivity, within a short period of time and with a suitable scalability. Such a process is necessary for the compounds of formula (I) to be obtained in good yields and in pure amounts in kilograms, preferably by in situ equine conversion of the compound of formula (III).

174,555. s. In Example 12 of U.S. Pat. No. 5, the lactone diol of formula II is reacted with dimethyl tert-butylsilyl chloride in dimethylformamide in the presence of 2.2 molar equivalents of imidazole by stirring at room temperature for 6 hours. The reaction mixture was allowed to stand for a further 18 hours, worked up and the compound of formula (III) was recovered by crystallization.

Obviously, this method used at 10 tm, which requires a considerable amount of imidazole, which is difficult to remove from the reaction vessel, requires a long reaction time, and its selectivity and yield are greatly reduced as the method is scaled up, not applicable to commercially available compounds of Formula I with increased amounts of material.

It has been found that in the presence of at least 1 molar equivalent of pyridine in anhydrous solvent at -40 ° C to + 100 ° C, the lactone diol of formula (II) can be converted to the compound of formula (III) with tert-butyldimethylsilyl chloride regioselectivity in a short reaction time.

The resulting compound of formula (III) is further converted into compounds of formula (I) by methods known per se.

The above process can be excellently scaled without regioselectivity and yield loss.

The above assertion is supported by the following experimental results:

174,555. s. The procedure described in Example 12 of the Hungarian Patent Application was repeated, starting from 0.1 mol and 1 mol of lactondiol (III). The conversion, the ratio of the 6-silyl and 6,7-bis-silyl derivatives in the product changed as follows:

II Imid-Convert- 6-suction FBAR (%) 6,7-bis- lil originated. (%) silyl originated. (%) compound of formula (mole) azole (Mol) 0.01 0.02 96 92 4 0.1 0.2 65 35 30 0.1 0.1 48 30 18 1 2 55 20 35

In each case, 1.1 molar equivalents of tert-butyldimethylsilyl chloride were used.

It can be stated that, when the size is increased, the selectivity is greatly reduced and the bis-silyl product is predominantly formed. If the amount of imidazole is reduced, selectivity is not improved, but production is reduced.

Our announcement eliminates these disadvantages.

According to the invention is carried out by the formula (II) 3-oxo-6 _J ff-hydroxymethyl-7a-hydroxy-2-oxabicyclo [3.3.0] octane is at least one molar equivalent of anhydrous pyridine in an organic solvent at -40 ° C and + At a temperature of 100 ° C, it is preferably converted to the compound of formula (III) with 1 to 1.5 molar equivalents of tert-butyldimethylsilyl chloride. The resulting compound of formula (III) is optionally reacted, if desired, with an acid derivative of formula (IV), wherein R ¹ is benzoyl or phenylbenzoyl, and X is halogen or -OR ¹ , or is tetrahydropyranyl in a manner known per se, or alkoxyalkylating and optionally converting the resulting compound of formula (I) wherein R ¹ is as defined above, R ² is tert-butyldimethylsilyl, into a compound of formula (I) wherein R ² is hydrogen. The starting compound of formula (II) can be used in situ to produce the compound of formula (I) without the preparation of the compound of formula (III).

In the process described above, the organic solvents used are aromatic hydrocarbons or halogenated aromatic or aliphatic hydrocarbons, preferably benzene, toluene, halobenzenes, carbon tetrachloride or dichloromethane. A re. The reaction is carried out in the presence of pyridine, but can also be used, for example, with methyl or ethylpyridines. Pyridine and its alkylated derivatives may also be used as organic solvents if their melting point allows.

The reaction of the compound of formula (II) with tert-butyldimethylsilyl chloride is most preferably carried out at a temperature in the range of + 15 'C to + 60' C. The known methods of alkylation, acylation, tetrahydropyranylation, alkoxyalkylation used in the preparation of compounds of formula (I) are well known in the organic chemical literature. (For example, Greene, T.V .: Protective Groups in Organic Synthesis by John Wiley and Sons, N. Y. 1981.)

The known lactone diol of formula (II), which is used as starting material for the process of the present invention, can be prepared on an industrial scale (Tetrahedron Letters, p. 4639 (976)).

Further details of the invention are illustrated by the following embodiments, without limiting the scope of the invention to the solutions described therein.

Example 1

3-Oxo-6 /? - (tert-butyl-dimethyl-szililoximetil) -7ft-hydroxy-2-oxa-biciklof3.3.01oktán

Dissolve 500 g (2.90 mol) of 3-oxo-6β + hydroxymethyl-7α-hydroxy-2-oxabicyclo [3.3.0] octane (lactone diol) in 2 dm ^{3 of} anhydrous pyridine and add 461 g (05 moles) of tert-butyl dinoctyl chlorosilane. The reaction mixture was stirred for 4 hours at room temperature. After TLC monitoring of the reaction, the reaction mixture was poured into a 20 dm ³ of water and extracted with 4x3 dm ³ of ethyl acetate and the combined organic layer 3x2 dm ³ 1 N and finally with 2 dm ³ of water, hydrochloric acid solution of 1 dm ³ of saturated aqueous brine. The organic layer was dried over anhydrous sodium sulfate (200 g), filtered and the solvent was evaporated in vacuo.

The residue was crystallized from 2 dm ³ petroleum ether to give 727 g (92%) of 3-oxo-6β- (tert-butylmerylsilyloxymethyl) -7a-hydroxy-2-oxabicyclo | ) .3.0 | octane is obtained in the f irm of white plate crystals.

M.p. 58-59 ° C.

TLC: Rf = 0.46 petroleum ether / ethyl acetate 1: 1 MERCK Kieselgel 60 F254 ·

Example 2

? 3-oxo-6 / - (tert-butyl dimethyl szililoximetil) -7a-benzoyloxy-2-oxabicyclo | 3.3.01oktán

3-Oxo-6β-hydroxymethyl-7α-hydroxy-2-oxabicyclo [3.3.0] octane (500 g, 2.90 mol) was dissolved in pyridine (2 dm ³ ) and t-butyl (460 g, 3.05 mol) was added. dimethyl chloro silane. After stirring the reaction mixture for 4 hours at room temperature, 450 g (3.2 mol) of benzoyl chloride are added to the suspension after TLC monitoring of the reaction. The reaction mixture was stirred for an additional 4 hours at room temperature. After addition of 20 dm ³ water benzoyl silyl lactone was extracted with 4x3 dm ³ of ethyl acetate from the aqueous solution, and the combined organic layer was washed with 2 dm ³ of water, 3x2 dm ³ of 1N hydrochloric acid solution and 2 dm ³ of saturated aqueous brine. The organic solution was dried over sodium sulfate (200 g), filtered, and the solvent was evaporated in vacuo. The residue was crystallized from a solvent mixture of ethyl acetate-petroleum ether.

1020 g (90%) of 3-oxo-6- [5- (tert-butyl-j-methylsilyloxymethyl) -7a-benzoyloxy-2-oxabicyclo [3.3.0] octane are thus obtained in the form of white crystals.

Mp: 74-76'C.

Optical rotation: [α] ²⁰ D = -79 ° (c = 1.0 in CHCl ₃ ).

HU 198921 Β

TLC: Rf = 0.69 petroleum ether - ethyl acetate 2: 1 MERCK Kieselgel 60 F254

Example 3 (-) -3-Qxo-6β-hydroxymethyl) -7-benzoyloxy-2-oxabicyclo [3.3.01] octane

Dissolve 1000 g (2.56 mol) of (-) - 3-oxo-6- [3- (tert-butyldimethylsilyloxymethyl) -7a-benzoyloxy-2-oxabicyclo (3.3.0] octane in 4 dm ^{3 of} acetic acid and 2 dm ³ of water and the mixture was stirred for 3 hours at 40 ° C. after TLC checking, the reaction solution was diluted with 10 dm ³ of water and extracted 3x2 dm ³ of ethyl acetate and the combined organic layer was 1 dm ³ of water, 3x1 dm ³ saturated aqueous sodium bicarbonate and finally washed with 1 dm ³ of saturated aqueous brine. S-washed to neutral organic layer was dried over sodium sulfate, filtered, and the ethyl acetate is distilled off under vacuum to form the residue of about. 2 dm ^third product 2 dm ³ of petroleum ether After filtration, it was washed with petroleum ether / ethyl acetate (3: 1) and dried under infrared light to give the title compound (658 g, 93%) as a white crystalline solid.

119-120 ° C.

Optical rotation: [α] ² D -83 ° (c = 1.0 in CHCl 3).

TLC: Rf = 0.45 ethyl acetate.

Example 4 (-) - 3-Oxo-6β-hydroxymethyl-7L-benzoyloxy-2-oxabicyclo [3.3.01] octane (58.14 mol) 3-oxo-6β-hydroxymethyl-7α-hydroxy Dissolve 2-oxabicyclo [3.3.0] octane (lactone diol) in 40 dm ^{3 of} anhydrous pyridine and add 9.2 kg (61 mol) of tert-butyldimethylchlorosilane. The reaction mixture was stirred at 50 ° C for 2 hours and then benzoyl chloride (9.0 kg, 64 mol) was added. The slurry slurry S was stirred for an additional 2 hours at 50 ° C. The reaction mixture was diluted with 100 dm ^{3 of} water and the product was extracted with 3 x 20 kg of toluene. The combined toluene phase was transferred to a mixing apparatus and 20 kg of 6N hydrochloric acid solution was added and the mixture was heated under reflux for 3 hours. After cooling to room temperature, the lower aqueous phase was drained, and the organic phase distilled off the toluene. The residue was dissolved in ethyl acetate (25 kg), decolorized with charcoal, filtered and crystallized by addition of petroleum ether (30 kg). This gave 13.0 kg (81%) of the title compound as a white crystalline solid.

Example 5 (-) - 3-Oxo-6β-hydroxymethyl-7α- (p-phenylbenzoyloxy) -2-oxabicyclo [3.3.0] octane kg (29 mol) 3-oxo-6β-hydroxymethyl-7α hydroxy-2-oxabicyclo [3.3U] octane is dissolved in 20 kg of pyridine and then 4.6 kg (30.5 mol) of tert-butyldimethylchlorosilane are added. The reaction mixture was stirred at room temperature for 4 hours. After TLC monitoring, 6.7 kg (31 mol) of p-phenylbenzoyl chloride were added to the suspension and the reaction mixture was stirred at 60 ° C for 4 hours.

After addition of 100 kg of water, the product is extracted with 3 x 15 kg of toluene, 10 kg of 6N hydrochloric acid solution are added to the combined organic extracts and the mixture is heated under reflux for 3 hours. After cooling the first aqueous phase, the organic phase is evaporated to dryness in vacuo. The residue was crystallized from methanol-water (4: 1).

7880 g (77%) of the title compound are thus obtained in the form of white crystals.

130-131 ° C.

Optical Rotation: [0] ^ ^2% -87 ° (c = 1.0, CHCl3).

TLC: Rf = 0.28 ethyl acetate - petroleum ether 2: 1, MERCK, Kieselgel 60 ^ 254 ·

Example 6 (-) - 3-Oxo-6H-tert-butyldimethylsilyloxymethyl-7α-tetrahydropyranyloxy-2-oxabicyclo [3.3.3] octane

Dissolve 544 g (1.89 mole) of 3-oxo-6-tert-butyldimethylsilyl) ximethyl-7q-hydroxy-2-oxabicyclo [3.3.0] octane in 2.5 dm ^{3 of} anhydrous dichloromethane and add with stirring. g (2.1 mol) of freshly distilled dihydropyran and 0.1 g of ptoluenesulfonic acid (or 0.1 g of pyridinium tosylate). Within a few seconds, the reaction mixture begins to boil slightly and the exoler reaction is instantaneous. The reaction mixture was diluted with dichloromethane (3 dm ³⁾ , and the organic layer was washed with 2% sodium bicarbonate solution (1 dm ³ ) and dried over sodium sulfate. The solution was filtered and the solvent was evaporated in vacuo. 703 g (95%) of the title compound are obtained in the form of a slightly yellow viscous oil.

The crude product was dissolved in 1.5 dm ^{3 of} hexane and cooled slowly to -30 ° C with stirring with dry acetone-ice, and stirred for 1 hour. The pure product gradually precipitated out of solution as white crystalline material. It is filtered, washed with a little cold hexane and dried on a rotavapor in vacuo at 20 ° C with gentle agitation to constant weight.

Physicochemical characteristics: white crystalline solid, m.p .: 36-38 ° C, optical rotation: -38 ° (c = 1, OCHC1 ₃₎ = d M ^{2 O.}

TLC: Rf = 0.56 Hexane-ethyl acetate 3: 1.

Example 7 (-) - 3-Oxo-6H-tert-butyldimethylsilyloxymethyl-7q-tetrahydropyranyloxy-2-oxabicyclof3.3-octane

344 g (2 mol) of (-) - 3-oxo-6β-hydroxymethyl-7α-hydroxy-2-oxabicyclo [3.3.0] octane are dissolved in 1300 cm ^{3 of} anhydrous pyridine and 315 g (2.1 mol) are added. tert-butyl-dimethyl-chlorosilane. The reaction mixture was stirred at room temperature for 4 hours. After dilution with 10 dm ^{3 of} water, extract with ³ x 1 dm ^{3 of} dichloromethane and combine the combined organic extracts with 3 x 500 cm ^{3 of} hydrochloric acid,

Wash with 500 cm ^{3 of} saturated brine, dry over sodium sulfate, filter, and add 250 g (3 mol) of dihydropyran and 1 g of p-toluenesulfonic acid, respectively. The reaction mixture was stirred for 30 minutes at room temperature. After TLC monitoring, the reaction mixture was diluted with 2 dm ^{3 of} dichloromethane, washed with 1 dm ^{3 of} 5% sodium hydrogen carbonate solution, dried over sodium sulfate, filtered, and the solvent was evaporated in vacuo. The residual dense oil was purified by chromatography on a silica gel column (hexane: ethyl acetate = 4: 1).

622 g (84%) of the title compound are thus obtained in the form of a colorless crystalline solid which remains in a refrigerator. 15

Example 8

3-Oxo-6 / 3- (tert-butyl-dimethyl-szililoximetil) -7a-l-ethoxy-ethyloxy-2-oxabicyclo [3.3.0] octane

Dissolve 1000 g (3.5 mol) of 3-oxo-6 N-tert-butoxymethylsilyloxymethyl-7a-hydroxy-2-oxabicyclo [3.3.0] octane in 5 dm ^{3 of} anhydrous dichloromethane and then add g (4 mol) of ethyl vinyl ether 25 and 0.1 g of p-toluenesulfonic acid. The reaction mixture was stirred for 30 minutes at room temperature. After checking the reaction by thin layer chromatography, 1 ml of triethylamine was added to the solution, followed by washing with 1 dm ^{3 of} water. The organic phase is dried over sodium sulfate, filtered and the solvent is distilled off in vacuo.

1245 g (97%) of the title compound are thus obtained as a slightly yellow oil.

If analytically pure product ³⁵ pre-adjustment of the goal, then the product can be purified by column chromatography on silica gel with petroleum ether-ethyl acetate 4: 1 mixture using.

TLC: Rf = 0.33 petroleum ether 40: ethyl acetate 3: 1.

Example 9

3-Oxo-6β-hydroxy-7α-tetrahydropyranyloxy-2-oxabicyclo [3.3.01] octane 45

(-) -3-Oxo-6β-hydroxymethyl-7α-hydroxy-2-oxabicyclo [3.3.0] octane (688 g, 4 mol) was dissolved in 2.6 dm ^{3 of} anhydrous pyridine and 630 g (4.2 mol) was added. ) tert-butyldimethylchlorosilane. The reaction mixture was stirred at room temperature for 4 hours. After dilution with 20 dm ^{3 of} water, the mixture is extracted with dichloromethane (3x2 dm ³ ), the combined organic phases are washed with 1 N hydrochloric acid ( ³ x 500 cm ³⁾ followed by 1 dm ³ 5% sodium bicarbonate solution, dried over sodium sulfate, filtered, 500 g (6 moles) of dihydropyran and 2 g of p-toluenesulfonic acid were added to the filtrates, respectively. The reaction mixture was stirred for 30 minutes at room temperature. After TLC monitoring, 3 cm ^{3 of} triethylamine was added to the reaction mixture and the solvent was evaporated in vacuo.

The remaining solid mass (about 1300 g) was dissolved in 4 µl of tetrabydrofuran, and then 1134 g (3.6 mol) of tetrahutylammonium fluoride was added with stirring. The reaction mixture was stirred for 3 hours at room temperature.

The solvent was distilled off in vacuo, the residue was dissolved in ethyl acetate (5 dm ³ ), washed with water (2 x 1 dm ³ ), dried over sodium sulfate, filtered, and the solvent was distilled off in vacuo. The residual oil was purified on a silica gel column with a 1: 1 mixture of ethyl acetal and pelrol gel.

7 g (75 g) of the title compound are obtained in the form of a colorless oil.

TLC: Rf: 0.11 ethyl acetate (petroleum jelly 2: 1).

Claims (4)

PATENT CLAIMS A process for the preparation of 3-oxo-6 N-tert-butyldimethylsilyloxymethyl-7α-hydroxy-2-oxabicyclo [3.3.0] octane of formula (III). -hydroxymelyl-7α-hydroxy-2-oxabicyclo [3.3.0) octane and tert-butyldimethylsilyl chloride, characterized in that the compound of formula II is present in anhydrous organic solvent in the presence of at least 1 molar equivalent of pyridine. and + 100 ° C with tert-butyldimethylsilyl chloride. Process according to claim 1, characterized in that the organic solvent is pyridine. 3. A process according to claim 1, wherein 1 to 1.1 molar equivalents of tert-butyldimethylsilyl chloride are used. 4. A process according to claim 1 wherein the compound of formula II is reacted with tert-butyldimethylsilyl chloride at a temperature between + 15 ° C and 460 ° C.