SU1346637A1 - Method of producing derivatives of hexahydro-2h-cyclopenta(b)furan-2-ols - Google Patents

Abstract

The invention relates to furan derivatives, in particular hexahydro-2H-cyclopentafuran-2-ols (GF), which are an intermediate product in the synthesis of prostaglandin F. Simplification of the process is achieved in a new way. Synthesis of GFs is carried out from the corresponding lactone and methoxybenzyl chloride or p-methoxy-1-methoxybenzene-1-chloride (molar ratio 1: 1-1.1) in toluene in the presence of diisopropyl-ethnlamine, followed by reduction of the protected lactone with diisobutyl aluminum hydride at (-75) - ( -80) C. The method provides a reduction in process time, solvent consumption and the number of stages. The general formula of HF is as follows: SNgT A H (L where Y is - OSbH4-m-C1 or (CH,) CH,; R and A are simultaneously C HjCHOCH or CHjOCeH CHOCHj.

Description

The invention relates to a process for the manufacture of substituted hexahydro-2H-cyclopenta (b) furan-2-ols of the general formula

where Y - OSbN4-m-C1, or

(CHj)

R, and A - at the same time - CgH CHOCHj or СН ОС Н СНОН ,.

The compounds of general formula (l) are important intermediates in the synthesis of prostaglandin p2 and its analogues. Prostaglandins are a group of naturally occurring, hydroxyl, unsaturated and saturated fatty acids with high biological activity, which represent an almost irreplaceable group with a broad spectrum of activity, rfanpHMep, and they regulate the endocrine, nervous, digestive, respiratory, and reproductive systems. Significant advances have been made in veterinary medicine in controlling estrus in cattle and in regulating the delivery of sows.

In the manufacture of intermediates in the synthesis of prostaglandin, the corresponding lactondiol (a) is reduced to lactol diol (B) with a modified complex hydride or in the form of free hydroxyl groups or protected in the form of ether, acyl derivatives or, most often, tetrahydropyranoside

where T is hydrogen, trialkylsilyl or. tetrahydropyranoside (USSR Patent No. 694069, class C 07 C 177/00, 1979),

These methods have a number of disadvantages. To protect the OH group, an excess of reagents are used, which contaminate the final product, and therefore, before the next reaction step, it must be isolated and sometimes purified from unwanted by-products. The reaction is carried out at high dilution under controlled conditions (temperature) and often requires a long reaction time.

The essence of the proposed method of making compounds of the general formula (l) is that by the lacton of the general formula

25

(Ii)

where Y has the indicated value, or its C-15 epimer (prostaglandin numbering) act with methoxy benzyl chloride or p-methoxy-1-methoxy benzyl chloride in toluene in the presence of diisopropylethylamine at 20-25 C in a 1: 1 molar ratio - 1.1 to obtain the protected lactone of the General formula

where A, R, and Y have the indicated meanings.

The process under these conditions takes place within a few minutes with a practically quantitative yield. The reaction mixture is washed with a saturated solution of sodium or potassium hydrogen carbonate, the organic phase is dried with an anhydrous inorganic salt and used in the next stage of the reaction, the reduction. With

By this reduction with a modified complex hydride, advantageously with diisobutyl aluminum hydride or sodium bis- (2-methoxyethoxy) ethoxy aluminium hydride, the lactone moiety in the substance of general formula (IV) translates from into lactic acid and the desired product of general formula (I) is obtained. This reaction can be carried out in temperature ranges (-80) - (+20) C in a molar ratio of 1: 1 to 2.5.

The proposed method of protecting hydroxyl groups has an advantage in purity of the product, in shortening the reaction time, saving of solvents and energy for stripping and stripping other reaction reagents, as well as in that the reaction is carried out in almost one step.

Example 1. 3aa; 4 (lE, 3S), 5oi., Danij- (±) -4- 4- (3-Chloro-phenoxy) -3- (1-methoxybenzyloxy) -1-butenyl-5- (1- methoxybenzyloxy) -hexahydro-2H-cyclopenta (b) furan-2-one of the general formula (IV), where Y is -OC H -m-SG, R, A СБН5СНОСН ,,; In N; p 1, is made as follows.

To a solution of 1.35 g of f4 mmol) of lacton-diol of the general formula (1 1), where Y is -OCgHj-M-Cl; n 1, and 1.3 g diisopropylethylamine in 100 np toluene at

While stirring, 1.4 g of the plant was added dropwise after controlling a thin layer of methoxybenzyl chloride in IO ml of toluene so that the temperature of the reaction mixture did not exceed 25 ° C. After 15 minutes of stirring, the reaction mixture decomposed 50% saturated sodium hydrogencarbonate solution. After that, the organic phase was separated, dried over magnesium sulfate and, after filtration, the drying agent was used for further reaction. The progress of the reaction was monitored by thin layer chromatography and compared with standards.

Example 2. 3aoi, 4p (lE, 3S) 5c (., (+) (3-Chlorophenoxy) -3- (1-methoxybenzyloxy) - -butenyl-5- (1-methoxybenzyloxy) -hexahydro-2H-cyclopenta (b a) furan-2-ol of the general formula (I), where Y is an OSbP, - m-C1; R, A CgHjCHOCH,; HH; n 1, the following is made.

To the solution of the lactone according to Example I was added at (-75) - (-80) ° C over 10 minutes IO ml of a 1.5 M solution of diisobutyl aluminum hydride in toluene. Then the reaction mixture was stirred at this temperature for another 30 minutes.

0

15 ml of methyl alcohol decomposed and, after adjusting the temperature to the laboratory, were poured into a solution of 200 ml of sodium chloride. The organic phase was separated, dried with magnesium sulphate and the solvents were stripped on a rotating vacuum evaporator. 2.1 g of an oily product are obtained, the structure of which is confirmed by mass spectrometry and NMR spectrometry.

Example 3., 4 / i, (1E, 3S), 5y, (±) -4- 7, 7-Difluoro-3- (1-marks 5 C-p-methoxybenzyloxy) -8-methyl-5 - oxa-1 , 8-nonadienyl-5- (1-methoxy-p-methoxymetypoxy) -hexahydro-2H-ckklopenta (b) furan-2-one of the general formula (III), where Y.jC (CH,) CH,; R, A CH, OSbN SNOCH; In N; p 1, is made as follows. To a solution of 347 ml of a lactone of the general formula (11), where Y OSI2CFjC (CH3) p 1, and 310 mg of diisopropyl5 ethylamine in 25 mP of toluene with vigorous stirring, 325 mg of p-methoxy-1-methoxybenzyl chloride in 4 ml of toluene are added at 20-25 C. After 10 minutes of mixing, when

five

0

the mathematics is finished, 17 ml of the saturated sodium bicarbonate solution is added, the organic phase is separated and dried with magnesium sulfate. After stripping the solvents in vacuum, 97% of a light yellow oily product was obtained, the structure of which was proved using spectral methods. Without further purification, the product was used for the last reaction.

Example 4. 3a "i, 4, (1E, 3SM, 5ot, tank - (±) -4-7, 7-Difluoro-3- (1-methoxy-p-methoxybenzshuxi) -8-methyl-5g oxa -1,8-nonadienip-5- (l-methoxy-p-methoxybenzyloxy) -hexahydro-2H-cyclopenta (b) furan-2-ol of general formula I, where Y is OCHiCF20 (CH,) CH, ;; R, A СН, OSbN, СНОН ,; п 1; В Н, is made as follows.

Under stirring at (-75) - (-80) s for 10 minutes, 2.5 ml of a 1.5 M solution of diisobutylaluminum minium chloride in toluene was added to a solution of lactone (600 ml of toluene). After stirring for 15 minutes at this temperature, the reaction mixture was worked up as indicated in Example 2. 602 mg of an oily product were obtained.

one whose structure is confirmed by mass and NMR spectrometry. Pr and m p 5. 3aci, 4 | i (lE, 3S), 5e (,, 6a () (+) - 4-h- (1-Propoxybenzyl-oxy) -1,1-octenyl-5 - (l-propoxybenzyloxy) -hexahydro-2H-cyclopenta- (b) furan-2-one of the general formula (III),

where y is CH

BUT; R, C, NTO CHCfcHj

manufactured in the following way.

To a solution of lactondiol (7.32 mg) of the general formula (P) (Y CH,; p 4) and 820 mg of diisopropylethylamine in 25 ml of toluene are added at C 950 mg of 1-propoxybenzyl chloride in 4 ml of the same solvent. When processing in Example 3, 985 mg of a light yellow product was obtained, which was used without further in the next reaction step (Example 6). The structure of the product is confirmed by mass spectra.

Example 6. C3a "i, 4p, (1E, 3S), 5et, 6a" i3- (±) -4- З- (l-Propoxybenyloxy) -1-octenyl-5- (l-propoxybenzyloxy) -hexahydro-2H-cyclopentane- (b) furan-2-ol of the general formula (l), where

CH

3

p 4; R,

 ,

manufactured as follows.

To a solution of lactone 980 mg from Example 5 in 35 ml of toluene was added with stirring at (-75) - (-80) C under argon atmosphere for 15 minutes, 2.3 ml of a 1.5 M solution of diisobutyl aluminum hydride in toluene. After stirring for 15 minutes at this temperature, 1) the reaction mixture was treated as in Example 2.

978 ml of an oily product, the structure of which was in accordance with the interpretation of the mass and H NMR spectra, was obtained.

Claims (1)

Invention Formula The method of obtaining derivatives of hexa-hydro-2H-cyclopenta (b) furan-2-ols of the general formula HE --one Y - С Нд-м-С or С (СН,) CH g R and A at the same time - -CgHyCHOCH, or -CH OS NdSNOSN ,, consisting in the fact that the lactone of the general formula about °.-L ., Y (, „ where Y has the indicated values, or its C-15 epimer is exposed to methoxybenzyl chloride or p-methoxy-1-methoxybenzyl chloride in toluene in the presence of diisopropylethylamine at a temperature of 20-25 C in a molar ratio of 1: 1-1.1 s obtaining a protected lactone of the General formula thirty I I 35 40 45 de A, R, and Y are as defined, followed by reduction with diisobutyl aluminum hydride at (-75) - (-80) s to obtain the desired product of the general formula (|). It is recognized as an invention according to the results of the examination carried out by the Office for the invention of the Czechoslovak Socialist Republic. Editor N.Rogulich Compiled by I. Fedoseeva Tehred M. Didyk Proofreader I. Muska Order 5093/24 Circulation 371 Subscription VNIIPI USSR State Committee for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5 Production and printing company, Uzhgorod, st. Project, 4