CS225011B1 - The production of substituted hexahydro-2h-cyclopenta-/b/-furane-2-yl - Google Patents

Description

The present invention relates to a process for the manufacture of substituted hexahydro-2H-cyclopenta (b) furan-2-ol, and addresses the issue of product purity and economics. SUMMARY OF THE INVENTION The lactone or its β-15 epimer is treated with a 1-alkoxybenzyl halide in an aromatic hydrocarbon solution in the presence of a tertiary amine at a temperature of -20 to +40 ° C in a molar ratio of 1/2: 1.0 to 1, 1. A protected lactone is obtained which, after reduction with a complex hybrid at -80 to + ⁴ ° C, provides the desired product.

The compounds produced above are important intermediates in the synthesis of prostaglandin P ₂ alpha and its analogs. Prostaglandins are biologically active substances used in human and veterinary medicine.

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

(I) wherein ϊ denotes alkyl or alkenyl of 1 to 6 carbon atoms, wherein the alkyl or alkenyl optionally contains 1 to 4 fluorine atoms or phenoxy optionally substituted with 1 to 3 halogen atoms such as chlorine, fluorine, or trifluoromethyl or alkoxy containing 1 up to 3 carbon atoms in the alkyl group,

A is OR or hydrogen

V is hydrogen or OR, wherein when A is OR, V is hydrogen and when A-hydrogen is V, OR is where R is the radical R ² -C -CH ^CHOROR where

R ¹ represents alkyl having 1 to 4 carbon atoms, for

R is hydrogen or alkyl or alkoxy of 1 to 2 carbon atoms and n is 1 to 6.

The compounds of formula I are important intermediates in the synthesis of prostaglandin ^and analogs. Prostaglandins are a group of naturally occurring hydroxylated unsaturated 1 saturated fatty acids with high biological activity. In contemporary human and veterinary medicine they represent a practically irreplaceable group with a wide spectrum of efficacy, for example they regulate the endocrine, nervous, digestive, respiratory and reproductive systems. Significant success has been achieved in veterinary medicine in the management of heat in cattle and in the regulation of farrowing in sows.

In the processes known to date for the production of intermediates in the synthesis of prostaglandin, the corresponding lactondiol (6) is converted to the lactoldiol (b) by a modified complex hydride either in the form of free hydroxyl groups or protected as ether, acyl derivatives or most commonly tetrahydropyranoside.

b) ^{С 5Нц}

T is hydrogen, trialkylsilyl or tetrahydropyranoside).

These methods have a number of disadvantages. To protect the OH group, an excess of reagents that contaminate the end product is used and must therefore be isolated and sometimes purified from undesirable by-products prior to the next reaction step. Further, the reaction is carried out in large dilution under controlled conditions (temperature) and often requires a long reaction time.

These known processes are followed in a positive manner by the process according to the invention, which overcomes the disadvantages of the processes known so far.

According to the invention, the process for the preparation of the compounds of the formula I is characterized in that the compound of the formula II is reacted

(II) wherein n and Ϊ are as defined above,

2250 * 1 or its C-15 epimer (prostaglandin numbering), treated with 1-alkoxybansyl halide of formula III,

(III) where

2

R and R are as defined above and

X represents halogen, preferably chlorine or bromine, in an aromatic hydrocarbon solution in the presence of a tertiary amine at a temperature of -20 to +40 ° C in a molar ratio of 1/2: 1.0 až to 1.1. the desired product of formula IV

(IV) wherein R, A, B, and Ϊ and n are as defined above, will arise from the above conditions within minutes in virtually quantitative yield.

Next, the reaction mixture is washed with a saturated solution of sodium or potassium bicarbonate, the organic phase is dried with anhydrous inorganic salt and used in the next reaction step - reduction. In this reduction with a complex hydride, preferably diisobutylaluminum-amide or sodium bis- (2-methoxysynthoxy) n-methoxyaluminium hydride, the lactone moiety in the compound of formula IV is converted to the lactol compound to give the product of formula I,

This reaction can be carried out in the temperature range of -80 to +20 ° C in a molar ratio of components up to 2.5.

The process for protecting hydroxyl groups according to the invention has the advantage of purity of the product, shortening of the reaction time, saving of solvents and energy for their evaporation and other reagents. Since the reaction is carried out practically in one step, it is also advantageous from an economic point of view.

The process according to the invention is illustrated by several embodiments.

Said d 1 (3a alpha, 4beta) (1E, 3S *), 5alpha, 6a alpha) - (i) -44 (4- (C-chloro-snox - / - 3- / 1-methoxybenzylsxy) -1-butenyl -5- (1-methoxybenzoyloxy) hexahydro-22-cyclopenta [f] furu-2-one of formula IV, wherein Y = OC 3 H 4 -mCC, R = A = C 4 H 4 CHOCH 4, Β = Η, n = 1, was produced as follows:

To a solution of 1.35 g (4 millimoles) of the lactondiol of formula II, where Y = OCCH H-mCl, n = 13, and 1.3 g of diisopropylethylamine in 100 ml of toluene, is added dropwise a solution of 1.4 g of meehoxobenzyl chloride in 10 ml of toluene so. so that the temperature of the reaction mixture did not exceed 25 ° C. After stirring for 15 minutes, the reaction mixture was quenched with 50 mL of saturated sodium bicarbonate solution. The organic phase was then separated, dried over magnesium sulphate and used for further reaction after filtering off the desiccant. The course of the reaction was monitored by thin layer chromatography and compared with standards.

Example 2 / 3a alpha, 4beta11E, 3s +), 5alpha, 6a alpha / - [beta] - [4/4] (C-chlorobenzyl) -3- (1-ethoxybenzyl) -1-butenyl-5- (1-methoxybenzyl) hexahydro [alpha] 22- The compound of formula I wherein Y = OC ₆ H ₄ -mCl, R = A = C ₈ H ₄ HOOHH p Β = Η, n = 1, was produced as follows:

10 ml of a 1.5 M solution of diisobutylaluminum hydride in toluene were added to the lactone solution of Example 1 at -75 to -80 ° C over 10 minutes. The reaction mixture was stirred at this temperature for a further 30 minutes, quenched with 15 ml of methanol and, after warming to room temperature, poured into a solution of 200 ml of sodium chloride. The organic phase was separated, dried over magnesium sulfate and the solvents evaporated on a rotary evaporator. 2.1 g of an oily product were obtained, the structure of which was confirmed by mass spectrometry and NMR spectrometry.

EXAMPLE 3 / За alpha 4beta (1E, 3S), 5alpha, 6a alpha / - (1) -4 / 7,7-difluoro-3- (1-methoxy-p-methoxybenzyl _oxy) -8-methyl- 5-oxa-1,8-nonadienyl] -5- (1-methoxy-p-methoxymethyloxy) hexahydro-2H-cyclopenta- (b) furan-2-one of formula IV wherein Y = OCH ₂ CF ₂ C / CH ₃ / = CH ₂ , R = A = CH ₃ OG ₆ H ₄ CHOCH ₃ , t = H, n = 1, was produced as follows:

К solution of 347 mg of the lactone of Formula II where Y = OCH ₂ CF ₂ C / _CH3 / _CH2, n = 1 and 310 mg of diisopropylethylamine in 25 mL of toluene was added with vigorous stirring 325 mg of p-methoxy-L-methoxybenzyl chloride in 4 ml of toluene at 20-25 ° C. After stirring for 10 minutes, when observation was complete by thin layer chromatography, 17 ml of saturated sodium bicarbonate solution were added, the organic phase was separated and dried over magnesium sulfate. After evaporation of the solvents in vacuo, 97% of a light yellow oily product was obtained, the structure of which was proved by spectral methods. Without further purification, it was used for the next reaction.

EXAMPLE 4 [alpha] alpha, 4beta (1E, 3S ⁺ ), 5alpha, 6a alpha / - (-) - 4- (7,7-difluoro-3- (1-methoxy-p-methoxybenzyloxy) -8-methyl-5) -oxa-1,8-nonadienyl / -5- (1-methoxy-p-methoxybenzyloxy) hexahydro-2H-cyclopenta / b] furan-2-ol of formula I wherein Y = OCH ₂ CF ₂ C (CH ₃ ) = GH ₂ , R = A = CH ₃ OCgH ₄ CHOCH ₃ , n = 1, В = H, was produced as follows:

To the lactone solution (600 mg in 22 ml of toluene) was added 2.5 ml of a 1.5 M solution of diisobutylaluminum hydride in toluene over 10 minutes with stirring at -75 to 80 ° C. After stirring at this temperature for 15 minutes, the reaction mixture was worked up as in Example 2. 602 mg of an oily product were obtained, the structure of which was confirmed by mass and NMR spectrometry.

EXAMPLE 5 [alpha] alpha, 4beta (1E, 3S), 5alpha, 6a alpha / - (1) -4- (3- (1-propoxybenzyloxy) -1-1-octenyl) 5 (1-propoxybenzyloxy) hexahydro-2H- cyclopenta / bZfuran-2-one of the general formula IV, wherein Y = CH ₃ , n = 4, R = (^ ΗγΗ ^ Η ^) was produced as follows:

К solution of lactone diol (732 mg) of formula II (Y = CH _3> n = 4) and 820 mg of diisopropylethylamine in 25 ml of toluene at 25 ± 5 ° C was added 950 mg of 1-propoxybenzylchloridu in 4 ml of the same solvent. After working up analogously to Example 3, 985 mg of a pale yellow oily product was obtained, which was used in the next step without further purification (see Example 6). The structure of the product was confirmed by mass spectra.

EXAMPLE 6 [alpha] 4, [alpha] 4beta (1E, 3S), 5alpha, 6a alpha] - (1) -4-3-1 (propoxybenzyloxy) -1-octenyl) -5- (1-propoxybenzyloxy) hexahydro-2H-cyclopenta] b) furan-2-one of formula I, wherein Y = CH ₃ , n = 4, R = C 2 OCH 2 -, was prepared by the following procedure:

To a solution of the lactone 980 mg of Example 5 in 35 ml of toluene was added, over a period of 15 minutes, 2.3 ml of a 1.5 M solution of diisobutylaluminium trihydride in toluene with stirring at -75 to -80 ° C. After 15 minutes at this temperature Michiana reaction mixture was treated as in Example 2, and was isolated 978 mg of an oily product, whose structure ^{and with} tulle uhlase with int er ^p RETAC ^s mass and ^1H NMR spectra.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of substituted (2-hexyl-2-cyano) (b) furan-2-oles of the general formula I (I) wherein Y is C 1 -C 6 -alkyl or alkenyl, wherein alkyl or alkenyl optionally contains 1 to 4 fluorine atoms or phenoxy optionally substituted with 1 to 3 halogen atoms such as chloro, fluoro, or triftsremyl, or alkoxy containing 1 to 3 carbon atoms in the chain, A ee is OR or hydrogen, V is hydrogen or OR, where A is OR, and V is hydrogen, and if> 1 is hydrogen, V is sapina ^O R where ^{R is} : R zbytekC ^ HCCHOR ¹ , k ^d e r1 denotes alkyl having 1 to 4 carbon atoms, O R 'is hydrogen or alkyl or alkoxy having from 1 to 2 carbon atoms in the chain and n is 1 to 6, characterized in that the lactone (II) wherein η, Y is as defined above, or its The C-15 epimer acts on a 1-alkoxybenzyloxygenide of formula III (III) wherein 1 2 R and R are as defined above and X represents halogen, preferably chlorine or bromine, in a solution of an aromatic hydrocarbon in the presence of a tertiary amine at a temperature of -20 to +40 ° C in a molar ratio of 1/2: 1.0 to 1.1 to give the protected lactone of formula IV ( IV) wherein A, B, R, η, Y are as defined above, which upon reduction with a complex hydride at -80 to +20 ° C gives the product of formula (I) above. 2. A process according to claim 1 wherein the aromatic hydrocarbon is toluene or xylene. 3. A process according to claim 1, wherein the tertiary emine is diisopropylethylamine, triethylainine or pyridine. 4. The process of claim 1 wherein the complex hydride is diisobutylaluminum hydride or sodium bis-2-methoxyethoxyethoxyaluminum hydride.