SU806672A1 - Method of preparin2-(6-carbaloxyhexyl)cyclopenten-2-ones-1 - Google Patents

Description

I

This invention relates to a process for the preparation of 2- (6-carbalkoxyhexyl) cyclopenten-2-oHOB-1 of the general formula 1

ABOUT

(

where R is methyl, ethyl and H-butyl.

2- (b-carbalkoxyhexyl) cyclopentect-2-ones-1 are important intermediates (a- for the production of synthetic prostaglandins, which later acquired practical importance as a new class of physiologically active compounds.

A known method for the preparation of a 2- (6 -carbalkoxyhexyl) cycle of an openH 2-one-1 by brominating 2- (b-carbmethoxIhexyl) cyclopentanone-1 with bromine in ethylene glycol. In the reaction, a series of isomeric bromoketals is formed, which are dehydrobrominated with sodium hydroxide in methanol, followed by the conversion of the catalys to the unsaturated chum overall formula

(lOf). The yield of the target product is not more than 40% of the theory {l.

The disadvantage of this method is the low yield of the target product.

A known method for the preparation of 2- (b-carbalkoxyhexyl) cyclopenten-2-one-1 by converting 2- (6-carbethoxyhexyl) cyclopentanone-1 to .1-acetoxy-2- - (6-carbethoxyhexyl) cyclopenten-1 Which is purified by elemental bromine and dehydrobrominated in dimethylformamide (DMF). The isomeric products formed during dehydrobromination are converted to 2- (6-carbethoxy-sigexyl) cyclopenten-2-one-1 by boiling for 18 h in ethanol in the presence of h-toluene-sulfonic acid. The resulting product contains 2- (b-carbethoxyhexyl) cyclopentanone-1, which is removed by treating with l-carboxyphenylhydrazine in ethanol for 19h 2j.

The disadvantage of this method is the multistage and duration of the process. 380 Methods are known for the preparation of 2- (b carbalkoxyhexyl) cyclopengen-2-ones-1 by brominating the ketone form, 2 (b -carbalkoxyhexyl) cyclopenganones. As a brominating agent, acetylbromia is used with lead heratacetate in dichloromethane at 0-10 ° C. Dehyarobromonation is carried out with dimethylaniline, tricethylamine or thermally. The yield of the compounds of general formula (1 a, b) is 40-50% of theory 4. The disadvantage of this method is the low yield of the target product. A known method for the preparation of 2- (b-carBalkoxyhexyl) cyclopeiten-2-one-1 by brominating 2- (in -carbalkoxyhexyl) cyclopenganone-1 using pyridinium bromide-perbromine in an inert organic solvent. The yield of the target product of the general formula 1 is 54-71%. A disadvantage of the known method is the low yield of the target product. The closest solution to the technical problem is to obtain 2-6 - (carbethoxyhexyl) cyclopenten-2-one-1 by brominating 2- (6-carbethoxyhexyl) cyclopentanone-phenyl trimethyl ammonium perbromide in a tetrahydrofuran solution at room temperature. After appropriate treatment, the reaction mixture is dehydrobromized with collidine at 150 ° C for 5 minutes. The final product is isolated by chromatography on silica gel. Yield .2- (b -carbethoxyhexyl.) Cyclopentech-2-one-1 of the general formula (16) 52%. Fe iltrimethylammonium perbromide is synthesized in two stages: by methylation of di-methylaniline with dimethyl sulfate, phenyltrimethylammonium metaodolphosphate is obtained, which forms perbromide upon treatment with bromine. Perbromica is purified by 1-3-fold crystallization. (- (By-in) -0- ((I where R bNu (a)} "However, the practical application of well-known methods for obtaining 2- (b-carbaloxyhexyl) cyclopenten-2-one-1 limits the laboriousness and efficiency of the process as well as relatively low and extremely reproducible yields of the final product, hard-to-use romatizing agents are used, the synthesis of which requires additional time and chemicals. The aim of the invention is to simplify the process and increase the yield of the target product. (6 -carbalkoxyhexyl) cyclopenten-2-ones-1 of the general formula 1. About jV-rcr // -COOR where R is methyl, ethyl or c-butyl, is prepared by brominating 2- (6 -carbalkoxyhexyl) cyclopentanones-1 and .second dehydrobromination of the resulting 2-bromo-substituted 2- (6 -carbalkoxy-hexyl) qI: clopentanone-1, and a distinctive feature is the bromination with N-bromosuccinimide in carbon tetrachloride at boiling, and the dehydrobromination of 2-bromo-substituted 2- (b-carbalkoxyhexyl) cyclopentanone-1 and isomerization of the formation of secondary bromide 2 -carbalkokksheksilitsen) cyclopentanone-1 is carried out. boiling the reaction mixture with dimethylformamide and the corresponding absolute alcohol. The bromiro-eani process is carried out in the presence of catalytic amounts of azodiisobutyronitrile. The isomerization of 2- (b-carbalkoxyhexylidene) cyclopentanone-1 is carried out in the presence of catalytic amounts of vn-toluenesulfonic acid. The process uses the known sequence of bromination-dehydrobromination reactions using the available brominating and dehydrobrominating agents O CHS. (CHLCOOK HCON -jKOH (CH) COOR J (Sc, g 9 (

According to ripeanai-fieMOMy, 2- {6 -carbalkoxyhexyl) cyclo 1ten-2-ones-1 is prepared in one process station by brominating 2- (b-carbalcoxyhexyl) cyclopentanone-1 bromosuccinimide (NBS) while boiling in CC. The presence in the reaction mixture of catalytic amounts of the initiator of the free radical reactions of azotiobutyronitrile significantly reduces the reaction time (up to 10 minutes). Brominated compounds (W-V) are not isolated in pure form. After separating the succinimide formed in the bromination reaction, the 2-bromo derivatives are dehydrobrominated by adding the dehydrobromoating agent DMF and the corresponding absolute alcohol directly to the reaction solution and boiling for 2 hours (Example 1). At the same time, simultaneously with dehydrobromination, 2- (6-carbalkoxyhexyl) cyclopenten-2-ones-1 isomeric 2- {6 -carbalkoxyhexylidene) cyclopentanones-1 are transformed, which are formed along with (1 a-b) during dehydrobromination of the bromo product (W a-c) The hydrogen bromide formed during dehydrobromination in this case serves as an isomerization catalyst (IV 1).

Another option for preparing (1 a-) from (W-a-b) is the cehidrobromination of 2-bromo product in a CC 8 solution in the presence of only one DMF that is added directly to the reaction bromination solution (Example 2). According to GLC and TLC, the product is dehydro-. Bromination contains, along with the 2- (6-carbalkoxyhexyl) cycle, open-2-one-1 3-10% of the isomeric 2- (6-hsarbalkoxyhexylidene) cyclopentanone-1 (IVA-b). In order to obtain an individual target product, isomerization is carried out by separately boiling the crude mixture 1 + 1 V in an appropriate absolute alcohol, in the presence of catalytic amounts. h-toluene sulfonic acid.

In its pure form, 2- (6-carboxy alkoxyhexyl) cyclopengen-2-ones-1 is recovered by distillation in vacuo. Outputs are.

50-87% on the original saturated analog. The advantages of the proposed method

its simplicity, the use of cheap and affordable raw materials (brominating agent and solvents), as well as rather high yields of the target product. In addition, the N-bromosuccinium formed in the bromination of the saturated kegon N-bromosuccinium. Succiiiimide, after bromination, isaol re-brominated. in reaction.

Example 1. Preparation of 2- (b-carbethoxyhexyl) cyclopenten-2-one. -1;

To a solution of 24.0 g (0.1 mol) of 2- (b-carbatoxyhexyl) cyclopentanone-1 (P 5) in IOO ml of Csb was added 22.2 g (0.125 mol) of M & 5 and boiled with stirring in for 2 h. The progress of the reaction is monitored by thin layer chromatography on plates of the iciufobB system

benzene: ether (9: 1), sprayed with a solution of vanillin (3 g of vanillin is dissolved in 100 ml of ethanol and 1 ml of O is added) and kept for 3-5 minutes at 120-130 C. The boiling is continued until

complete disappearance of the brown spot of the starting compound (0.4). ft. 2-bromo-derivative (Sh b) 0.61, brown spot. The precipitation is filtered, washed with 15 ml of CCC. 12 g of succinimide are obtained.

25 ml of DMF and 150 ml of absolute ethanol are added to the filtrate. The solution is boiled in water for 1.5-2-2 hours. The course of dehydrobromination and isomerization is monitored by TLC. Under the aforementioned chromatographic conditions, R for (1U b) 0.29, bright red spot, for the target product (1 b) 10 O, 27, orange spot. At the end of the isomerization, 5 g of active carbon is added to the solution, incubated for 10 minutes and filtered. After cooling, 200 ml of water was added to the filtrate. The organic layer is separated, washed with water (IxlOO ml), dried over anhydrous. or MqjSO .. The solvent is evaporated in a vacuum water jet pump at a bath temperature not higher than 40-45 C. The residue is distilled in vacuum. T. Kip. 135-14O C / 1 mm Hg. Art. The yield of 2- (6-carbethoxyhexyl) cyclopenten-2-one-1

20.6 g (87% oteorii) with 9 7-100% content of the basic substance (according to GLC).

Example 2. Preparation of 2- (b -carbhegoxyhexyl) cyclopenten-2-one-1. V K solution of 24.0 g (O, 1 mol) of 2- (b-carbethoxyhexyl) cyclopentanone-1 (P b) in 1OO ml of CCC. 22.5 g (0.125 mol) of N & 5, 0.2 g of azodiisobutyronitrile are added and boiled for 1 O min. Completeness of bromination is checked by the TLC method (R

, Cj-jHg and) practically coincide). The reaction mixture is cooled, the succinimide is separated, washing it with 15 ml

all

To the filtrate was added 2 O ml of DMF, heated to 45-50 ° C and held for 10 minutes. The progress of dehydrobromide is monitored by TLC. After cooling, to the solution, 1 L O ml of water was added, separating the organic layer from the south, washed with water (2 X 100 ml) and dried over a good N. or . The solvent is evaporated in vacuum at a bath temperature not higher. 110 M; I of the corresponding absolute alcohol, 2 g of n-toluenesulfonic acid were added to the ostag and boiled for about 5 hours. The progress of isomerization was followed by the TGX method. After the isomerization is complete, 150 ml of water is added to the solution and the alcohol is distilled off. A saturated solution of N ANSO (30 ml) is added to the residue and extracted with ether (3 x 10 O ml). The ether solution is dried with anhydrous MqjpD and the ether is evaporated in a water jet pump. The residue is dissolved in benzene: ether (5: 1) and filtered through a column with 120 g of P degree of activity. 40O ml of benzene: ethnr (5: 1) solution are eluted. The solvent is evaporated, the residue is distilled in vacuum, Yield 19 g (80%). T, boiling point 135140 s / 1 mm. IR : 1638, 1715, 1740 cm, 0 - 1.2740. Literary information: T. kip., O5 JK: 1635 1720, 1745. Examples 3-4. Similar to example 2, they receive: 1) 2- (6 - carbmegok; sigexyl) cyclope nten-2-he 1 (1 a): T. Kip. 127-; 135/1 mm. Yield 51%, IR: 1635, 1715, 174O. .EZ -1,4784. Literary data: T. Kip. 117120 ° С / О, 8 mm, IR: 1640, 1720, 1750 cm, p - 1.4695. . f. 2) 2- (6-carbocytohexyl) cyclo ten-2-one-1 (1 in). T. Kip. 150-165H: / l. mm Yield 50%. C 7O, 1; H 9.5. Found,%: 6 i: C 72.1; H 9.8. Calculated, 1715,. IR: 1638, Invention Formula. 1. A process for the preparation of 2- (6- "arbal coxyhexyl) cyclopenten-2-ones-1 of general formula 1. r- (2 R is methyl, ethyl or and -butyl, by brominating 2- (6 -carbalkoxyhexyl) cycloclopentanon-1 and the subsequent dehydrobrominated 2-bromo-substituted 2- (6 -carbalkoxyhexyl) cyclopentanone-1 obtained, characterized in that, in order to simplify the process and increase the yield of the target product, the bromination is performed with N-bromosuccinnmide in medium four; - the formation of 2-bromo substituted 2- (6-carbalkoxyhexyl) cyclopentanone-1 and isomerysis The formation of the resulting 2- (b-carbalkoxyhexylcene) cyclopentanoni-1 is carried out by boiling the reaction mixture with dimethylformamide and the corresponding absolute alcohol. 2. The method according to claim 1, characterized by the fact that the bromination process is carried out in the presence of catalytic amounts, azodiisobutyronitrile. 3, A method according to claim 1, characterized in that the isomerization process of 2- (6-carbalkoxyhexylidene) cyclopentanone-1 is carried out in the presence of catalytic amounts. And toluenesulfonic acid. Sources of information taken by the WHO attention during the expiration 1. NoVaitjL.SzantcKv.C, SVM-thesig, 1973, p. 353. 2; Patent of USA N 3835179, cl. 260-468, published. 197.6. 3. The patent of Germany N 2232349,. 12 25/00, published. 1974. 4.Patent of France No. 2309503,. C O7 C 49/46, published. 1976. 5. US patent M 4O39563, cl. 26О-41О.9, published., 1977. 6. o.Attoinaisi, G., sas e-IOt-i, (a, ROSini, G, ZZ 1973, SW, .p. 31. (prototype). 7.3) .V6re.6ir (aer, t., Scr. 1 .. 1919, 52, p. 283.

Claims (2)

Claim . "1. The method of obtaining 2- (6 ^g -carbal-hydroxyhexyl) cyclopenten-2-ones-1 of the general formula 1. Where R is methyl, ethyl or m-butyl, by bromination of 2- (b '- carbalkoxyhexyl) cyclopentanones-1 and subsequent dehydrobromination of the obtained 2-bromza 5 substituted 2- (6 ¹ -carbalkoxyhexyl) cyclopentanones-1, characterized in that , in order to simplify the process and increase the yield of the target product. bromination is carried out with N-bromo 10 succinimide in a medium of carbon tetrachloride at boiling, and the dehydrogenation of 2-bromo substituted 2- (6 ¹ -carbalkoxyhexyl) cyclopentanone-1 and isomerization of the resulting side 2- (6 ^f 15 -carbalkoxyhexylhexylone) cyclopentanone mixtures with cimethylformamide and the corresponding absolute alcohol. 2. The method of pop. 1, distinguish-. 20 sh and th I heme that the process of bromination is carried out in the presence of Katali. tical amounts, azodioeobutyronitrile. ' ^s 3. Method pop. 1, characterized in that the process of isomerization of 2- (6 '-carbalkoxyhexylidene) cyclopentanone-1 is carried out in the presence of catalytic amounts. And -toluene sul30 foxic acid.