SU345672A1 - - Google Patents

Description

METHOD OF OBTAINING 2- (LOW ALKYL) -3- (LI31

LLKIL) -4-Phenyl-3- or 4-cyclohexenvinyl

ACIDS AND ITS DERIVATIVES

The invention relates to methods for producing compounds of the general formula

 but)

in which R is hydrogen, lower alkanoyloxy, halo, cyclopentoxyl, hydroxyl, lower alkyl, or lower alkoxyl;

R and R are Ci-C3 alkyl;

R - CD-C2O alkyl, Ci-C2o alkenyl, monooxy-lower alkyl, dioxy-lower alkyl, adamantyl, lower alkyladamantyl, phenyl, lower alkylphenyl, lower alkylphenphenyl, cycloalkyl, lower alkylcycloalkyl, lower alkyl, alkyl, phenyl, cycloalkyl, lower alkylcycloalkyl, lower alkyl, carbonyl, phenyl, cycloalkyl, lower alkylcycloalkyl, lower alkyl, phenyl, alkyl, phenyl, cycloalkyl furyl, lower alkylfuryl, lower carbalkoxyphenyl, iieridyl, lower alkylpyriidyl, or phenylcyclohexenylmethyl, in which the phenyl group may be substituted with R, as defined above;

dashed lines indicate double bonds in position 3 or 4.

These compounds can be used as physiologically active substances, more effective than the known derivatives of 2- (lower alkyl) -3- (lower alkyl) -4-phenyl-3-or 4-cyclohexenecarboxylic acid.

The compounds of formula I are prepared by reacting an acid or its derivative with the general formula

where R, R and R are as defined above, RI is halo, the group is OMe, in which Me is a metal or hydroxyl, with an appropriate esterifying agent and isolating or transesterifying the ester obtained by a known method.

If in the starting compound of formula I and RI is halogen or hydroxyl, then in the compound of formula II Ri is OMe, then it is desirable to take the compound of formula RHal, where Hal is halide, or alkylsulfonate as the esterifying agent.

Anhydrous magnesium sulphate or anhydrous sodium sulphate is used for drying organic solutions. The digestion is carried out in vacuum, the melting temperatures are corrected.

Example 1 | 3,1; -dioxinronnl-2-methyl-3ethyl-4-cyclohexylcarboxylate.

A solution of 2.0 g of 2-methyl-3-ethyl-4-feinl-4-cyclohexenecarbonoic acid, 0.5 g of sodium hydroxide in 25 ml of methyl syrrht and 60 ml of dougylformamund is extracted to a volume of 40 and the residue obtained is added 4 ml glycerylmonochlordendrnna. The resulting mixture is heated for 2.5 hours. And i is then evaporated to give udaloine dimethylformamide. The residue is shaken with an icing ether m and water 101, the ether layer is washed with a twice-cooled 5% soda n four times with water. After snapping the dried solution into a solution, a viscous, oily product is obtained which slowly crystallizes. After non-recrystallization from a mixture of HpocToii efnr-hexane, 1.30 g of small white glony, t. Nl. 72-UZ S.

Bichisleio,%: C 71.67; H 8.23.

CigHaeOj.

Found,%: C 71.78; H 8.17.

Example 2. 1-y damantil-2-methyl-3-ethnl-4fennl-4-cyclohexeicarboxylate.

A mixture of 3.0 g of 2-methpl-3-ethyl-4-fennl-4-cyclohexenecarboxylic acid and 15 ml of thionyl chloride was heated for 15 minutes with a reflux condenser, the resulting yellow solution was evaporated and the volatile oil and product was dried. Obtain 3.0 g of fluid oil 1H1 of total chlorohydride, t. Kip. 100-102 ° C / 0.02 mm; njf 1.5527.

The distilled acid chloride is added to a cooled (5-10 ° C), thoroughly mixed solution of 1.5 mol. equivalent of 1-hydroxy-mandantap in 20 ml of dried and hydride, lured to 15 minutes at 25 ° C and heated for 15 minutes at 90-95 ° C. The mixture is then cooled, 5 ml of water are added to it and thoroughly stirred for 2 hours. After diluting with 150 ml of the npocToio ether, the phase is washed and subsequently with twice cold 5% hydrochloric acid to remove pyridine II twice cold with 5% saturated sodium hydroxide. The ethereal solution is dried, evaporated, and the oil residue is chromatographed on a column with polysulfuric acid, prepared in a mixture of benzene and hexane. As a result of elution with benzene and ether, an ester and carboxylic acid free ester is obtained. The desired product is recrystallized; from the hetyl alcohol II, it is reheated under high vacuum.

Calculated,%: C 82.49; P 9.05.

S2bPz4O2.

Found,%: C 82.32; H 9.17. Example 3. Benzpdrnl-2-methyl-3-ethyl-4fepnl-4-cyclohexenecarboxyl-iol is used as in Example 2, using 1-okenendamantane beishydrol.

The snapshot compound is a viscous oil (yellow product, e.t. bale 190-200 ° C / 0.001 mm. Calculated,%: C 84.84; H 7.37.

С29ПзоО2.

Found,%: C 85.05; H 7.45. EXAMPLE 4. Cyclopeptl-2-methnl-3-ethyl-4-phenyl-4-cyclohexylcarboxylate was prepared in analogy to Example 2, but was used instead of 1-oxadamantane cyclonentanol.

After not (without a pre-chromatographic H1), an oily product is obtained with so on. 125-130 C / 0.001 li, which is cured and non-recrystallized in place of methanol alcohol. Get white flakes, t. Il. 58-59 ° C. 75% yield.

Calculated,%: C 80.73; P 9.03. Paideno,%: C, 80.81; P 9.01.

Example 5. Decyl-2-meth | 1L-3-ethyl-4-fenpl4-cyclohexenecarboxonlate is prepared as in Example 2, but n-decyl alcohol is used instead of 1-hydroxy-admantaium.

After chromatographs and reheatings, a pale yellow, flowing, oily product is obtained. 175-180С / 0,001 mm. Calculated,%: C 81.20; P 10.48. Paydeno,%: C, 80.78, 80.75; P 10.29, 10.49. Prn meper 6. (2-Methyl-3-ethyl-4-feiyl-4-piclohexene-1) - methyl - 2 - methyl - 3-ethyl-4-phenyl-4-cyclohexeicarboxylate.

To a stirred solution of 2.9 g of (2-methyl-Zethyl-4-phenyl-4-cyclohexyl-1) -methanol in 12 ml of pyridine was added 3 g of distilled 2-methyl-3-ethyl-4-phenyl-4-cyclohexenecarbonyl chloride. (obtained as in example 2). The mixture is heated for 20 minutes at 90-95 ° C, ice is added to it, ether is added, agitated and separated. The ether layer is washed twice with cold dilute with hydrochloric acid, and then with water and diluted with an additional patrom. The residue, after drying and evaporation of the ethereal solution, is ground to powder together with pentane and maintained at 0 ° C. 2.4 g of crystalline solid product are obtained, which is crystallized from ethyl ether and acetone. 1.65 g of the desired product was isolated in the form of white granules with a melting point of 20 ml. 153-- 156 ° C.

Calculated,%: C 84.16; P 8,83.

Sz2P4o02.

Paideio,%: C 84.05; H 8.88. EXAMPLE 7. 2-Adamantl-2-methyl-3-ethyl-4phenyl-4-cyclohexenecarboxylate.

From 3.0 g of 2-methyl-3-ethpl-4-phenyl-4-cyclohexenecarboic acid, as in Example 2, the chlorohydride is obtained, which is added to a solution of 2-oxyadamantane in 10 ml of dried pyridine after the distillation. The mixture was kept for 10 minutes at 25 ° C, heated at 90-95 ° C for 10 minutes, six drops of water were added to it and heated for another 5 minutes. After cooling, it is diluted with ether, washed successively with dilute hydrochloric acid, water and dilute potassium carbonate. After evaporation and evaporation of the ether solution, a yellow solid product is obtained in a scc11, which is chromatographed on a column of silica gel; neutral alumina oxide. With benzene-ether ether mixture, a colorless oily substance is obtained which slowly cures. This substance is recrystallized twice from hexaia, and 1.8 g of the expected product are obtained in the form of fine white prisms with a melting point of mp. 83-84 ° C.

Calculated,%: C 82.49; H 9.05.

S2bN.3402.

Found,%: C 82.57; P 8.95.

Example 8. 1-Adamantnemethyl-2-methyl-3ethyl-4-phenyl-4-cyclohexenecarboxylate.

The distilled acid chloride, which is prepared analogously to example 2 from 3.0 g of 2-methyl-Zethyl-4-phenyl-4-cyclohexepicarboxylic acid, is treated with 2.0 g of 1-adamantylmetapol in pyridine, as indicated in Example 7. After processing and chromatography, as in Example 7, 2.8 g of a very viscous oily desired product is obtained, which is distilled off at 180-190 ° C / 0.001 mm with partial decomposition.

Calculated,%: C 82.60; H 9.24.

SzNSbOo.

Found,%: C 82.87; H 9.23.

Example 9. Benzyl-2-methyl-3-ethyl-4-phenyl-4-cyclohexenecarboxylate was prepared, in analogy to example 2, from cyclohexenecarbonylchlorod and benzyl alcohol. After chromatography and distillation, a clear oily product is obtained, i.e. 170-173 ° C / 0.001 ml :.

Calculated,%: C 82.59; H 7.84.

Found,%: C 82.79; H 7.88.

At capacity 10, 2-nonadecyl-2-methyl-3-ethnl4-phenyl-4-diclohexepcarboxylate is prepared, as in measure 2, from cyclohexenecarbonyl chloride and 2-noiadecanol. After chromatography on alumina, a crude product is obtained, but containing snnr of the fatty series. As a result of the preparation, a yellow product is obtained, that is, 230–235 ° C / 0.001 mm.

Calculated,%: C 82.29; H 11.45.

Sz.N5,02.

Found,%: C 82.19; H 11.7).

Example 11. 2-Methyl-2-b} tenyl-2-lgutyl-3ethyl-4-fe1 yl-3-ts 1kl () hexoncarboxylate noulu aig logy- 1 2 nz cyclohexenecarbonyl chloride n 2,3-limnillillilovnogo. After purification by alumina and distillation, a colorless oily product, i.e., PPC, is obtained. 125-130С / 0,001 mm.

Calculated,%: C, 80.73; H 9.03.

Found,%: C 80.57; H 8.89.

Prnmer 12. 2-Methyl-2-butenyl-2-methyl-3ethyl-4-phenyl-4-cyclohexenecarboxylate was prepared as in Example 11.

A colorless oily product is isolated with a so on. 135-140 ° C / 0.001 mm.

Calcd.,%: C, 80.73; H 9.03.

CotHzsO, (312,4).

Found,%: C 81.06; H 9.02.

Example 13. 1-Furylmethyl-2-methyl-3-ethyl 4-phenyl-4-cyclohexenecarboxylate gives 113 cyclohexenyl chloride and furyl alcohol as in Example 2. After chromatography and recrystallization from ether, the expected product is obtained in white spots with white color. square 83-84 ° C.

Calculated,%: C 77.75; H 7.46.

C2 | H240z.

Found%: C 78.02; H 7.67.

Prnmer 14. / g-Carbomethoxyfenpl-2-methyl-3-ethyl-4-fennl-4 - cyclohexenecarboxylate get pz cyclohexenecarbonyl chloride c methyl- / g-hydroxybenzoate according to the method of example 13. The target product is a white granules with m.p. . 105-106 ° C. Vychnseno,%: C 76.16; H 6.93. S24Noe04. I

Found,%: C 76.08; H 6.91. Example 15. 2- (L-Piperidnno) -ethyl-2-methyl-3-ethyl-4-phenyl-4 - cytlohexenecarboxplat is prepared from cyclohexenecarbonylchloridine and - (p-hydroxyethyl) -n1 sherndin, following the procedure of example 2, but with acid do not rinse, but pyridine is removed by evaporation. After chromatographic distillation, an oily yellow product with m.p. 165-170 ° C / 0.001 mm.

Calculated,%: C 77.70; H 9.36. SZZNZOZ. Found,%: C 77.71; H 9.10.

Example 16. Decyl-2-methyl-3-ethyl-4- (lcyclopentoxyphenyl) -3-cyclohexenecarboxylate is prepared, as in Example 2, from 0.5 g of 2-methyl-3-ethyl-4- (p-cyclopentoenfennl) - 3-cyclohexencarboic acid and n-alcohol. 0.5 g of the desired product is isolated in the form of a yellow viscous oily substance with m.p. 205-210 ° С / 0.001 mm.

Calculated,%: C 79.43; H 10.32. Sz, N. | 50, (469.7).

Found%: C 79.08; H 10.41. Example 17. Decl-2-methyl-3-ethyl-4- (poxnfen gl) -3- and 4-cyclohexenecarboxyl.

From 2.0 g of 2 - methyl-3-ethnl-4 - ("- acetoxyphenyl) -3- and 4-cyclohexenecarboxylic acids (a mixture of isomers), chlorinendrid is prepared, analogously to example 2, and is immediately treated with n-declum sprint The product is chromatographed and distilled as in nrnmera 2. Obtain 0.6 g decyl-2-methyl-zethyl-4- (g-acetoxyphenyl) -3- and 4-nnclohexenecarboxylate, which is a viscous pale yellow substance. colors with t. Kip. 170-180 ° C / 0.001 m.h. Calculated,%: C 75.97; H 9.56. C28H49O2. Found,%: C 75.84; H 9.69. The resulting mixture of isomers (1: 1 ratio) is heated for 8 minutes under reflux in the presence of 30 M. L of methyl alcohol containing 4 ml of water and 0.8 g of potassium bicarbonate. The resulting clear solution is evaporated to remove the methyl alcohol and the oily product is extracted with ether. The extract is dried, evaporated, the residue is distilled and 0.5 g of a very viscous oily substance of a pale yellow color is obtained, i.e. kin. 185-195 ° C / 0.001 mm. This substance is a mixture of (about 1: 1) decyl-2-methyl-3-ethyl-4- (α-oxyphenyl) -3-cyclohexenecarboxylate and decyl-2-methyl-3-ethyl-4 (d-oxyphenyl) - 4-cyclohexenecarboxylate. Calculated,%: C 77.95; H 10.07. C2BH4oOz (400.6). Found,%: C 76.96; H 10.01. Hp and mep 18. Decyl-2-methyl-3-ethyl-4- (mtolyl) -3-cyclohexenecarboxylate. A mixture of 0.5 g of 2-methyl-3-ethyl-4- (lg-tolne) -3-cyclohexenecarboxylic acid and 5 ml of thionyl chloride is heated for 15 minutes. under reflux, diluted with 10 ml of toluene and BI.J. evaporated in vacuo to give the acid chloride (oily substance). To the acid chloride is added a solution of 1 ml of decyl alcohol in 5 ml of pyridine, heated at 95 ° C for 20 minutes, diluted with hexano.m and washed with dilute hydrochloric acid. The hexane solution is dried and diluted, the residue is chromatographed on alumina. The product obtained after elution with benzene and hexane is distilled and 0.4 g of decyl-2-methyl-3-ethyl-4- (g-tolyl) -3- | cyclohexenecarboxylate, which is a viscous oily substance, is isolated. - yellow color with t. Kip. 155-160 ° C / 0.001 mm. Calculated,%: C 81.36; H 10.62. C27H4202 (398.6). Found,%: C 81.24; H 10.75. Example 19. 2-Methyl-2-butenyl-2-methyl-3ethyl-4- (p-anisyl) -3-cyclohexenecarboxylate was prepared as in Example 18, using as the starting compound 0.7 g of 2-methyl-3-ethyl-4- (p-anisyl) -3-cyclohexeicarboic acid and 2-methyl-2-butene-1-ol. 0.55 g of a pale yellow oily substance with m.p. 145-150 C / 0.001 lgm. Calculated,%: C 77.15; H 8.83. SzgNZoOz (342.5). Found,%: C 77.33; H 9.01. Example 20. 2-Furylmethyl-2-methyl-3-ethyl 4- (o-anisyl) -4-cyclohexenecarboxylate is prepared, as in example 18, starting from 0.7 g of 2-methyl-3-ethyl-4- (o-anisyl) -4-cyclohexenecarboxylic acid and furfuryl alcohol. After appropriate purification, a solid is isolated, after crystallization of which white prisms with so-called silt are formed from hexane. 81-82 ° C. The presence of water of crystallization in the H-arc is confirmed by the presence of 64t 5 10 15 20 25 30 35 40 45 50 55 60 65 weak hydroxylic bonds in the IR spectrum and the results of chemical analysis. Calculated,%: C 73.62; H 7.44. C22H2BO4-1 / 4H2O (358.9). Found,%: C 73.35; H 7.33. Example 21. Benzyl-2-methyl-3-ethyl-4 - ("cyclopentoxyphenyl) - 3-niclohexenecarboxonate is obtained in the same way as irimer 18, and using 0.7 C 2-methyl-3-ethyl-4 - (d- cyclopeitoxyfepyl) -3cyclohexencarboic acid and benzyl alcohol. 0.4 g of a viscous oily product are obtained with a bale. 190-200 ° C / 0.001 mm. Calculated,%: C, 80.34; H 8.19. C28H3O3 (418.6). Found,%: C 80.45; H 8.34. Example 22. Dodecyl-2-methyl-3-ethyl-4- (L1-chlorophenyl) -4-cyclohexenecarboxylate is prepared from ng-chloro-substituted cyclohexenecarbonyl chloride and "-decodol" following the procedure of Example 2. After chromatography on alumina and distillation of the crude ester, not containing fatty alcohol, a colorless oily product is obtained with m.p. 195-200 ° C / 0.001 mm. Calc.,%: C 75.21; H 9.69. С98Н4.зС1Ог. Found,%: C 75.28; H 9.63. Example 23. Decyl-2-methyl-3-ethyl-4 - (haacetoxyphenyl) -3-cyclohexenecarboxylate. The crude acid chloride obtained analogously to example 2 of 0.6 g of 2-methyl-3-ethyl-4 - (/ g-acetoxyphosphol) -3-cyclohexeneicarboxylic acid and 5 ml of thionyl chloride is treated with decyloE; m alcohol in pyridine, following the procedure of example 2 After chromatography on alumina and distillation, an oily product is obtained with a pale yellow color and a boiling point. 180-190 ° C / 0.001 mm. Calculated,%: C 75.97; H 9.56. C28H4204 (442.6). Found,%: C 75.84; H 9.69. Example 24. p-Methoxyethyl-2-methyl-3-ethyl4-phenyl-4-cyclohexenecarboxylate is obtained from D-cyclohexenecarbonyl chloride and ethyliglycol monomethyl ether, following the procedure of nimer 2. The desired product is a pale yellow oily substance with m. cues. 130-135 ° C / 0.001 mm. Calculated,%: C 75.46; H 8.67. C19H2bOz (302.4). Found,%: C 75.40; H 8.50. Example 25. Carbethoxymethyl-2-methyl-Zethyl-4-phenyl-4-cyclohexylcarboxylate is obtained from A-cyclohexenecarbonyl chloride and glycol ethyl, following the procedure of nimer 2. A colorless oily product is isolated with a t. Bale. 150-155С / 0,001 mm. Calculated,%: C, 72.70; H 7.93. C2OH, B04 (330.4). Found,%: C 72.77; H 8.09. The subject matter of the invention is 1. A method for producing 2- (lower alkyl) -3 (i; H3UHn t alkyl) -4-feipl-3- or 4-cyclohexenecarboxylic acid and its derivatives of the general formula

ten

the dashed lines in the colp designate a double bond, either in position 3 or in position PI1 4, oGa11chayuy, iys by the fact that the acid or its derivative of the general formula

II

C-R,

(P)

where R is hydrogen, lower alkanoyloxy, halogen, cyclopentoxyl, hydroxyl, lower alkyl or lower alkoxy;

R and R each represents one of the lower alkyls containing up to 3 carbon atoms;

-R - Co-C2v alkyl, alkenyl, vklyuchayushy to 20 carbon atoms, monooksi-lower alkyl, dihydroxy-lower alkyl, adamantyl, lower alkiladamaitil, phenyl, lower alkylphenyl, lower alkildifenil, cycloalkyl, lower alkylcycloalkyl, lower alkyl, lower carbalkoxy, lower alkyl, lower alkoxy, furyl, lower alkylfuryl, lower carbalkoxyphenyl, nineridyl, lower alkylpineridyl, or phenylcyclohexenylmethyl, in which phenyl group can be substituted by R, having the values given above; the cyclohexenyl group contains substituents that are hydrogen or lower alkyl containing up to 3 carbon atoms;

ten

where R, R and R are as defined above, RI is a halide, a group is ODE, in which Me is a metal, or hydroxyl, is treated with an appropriate etherifying agent, and the resulting ester is isolated or subjected to nonresterificifacin by a known method.

2. The method according to claim 1, which is cleaned by the fact that if a compound of formula II, where Ri is halogen or hydroxyl, is taken as the starting product, then alcohol of the general formula ROH, where R has the above values, is taken as the etherification agent, prisugsgvpp ospananp.

3. The method according to claim 1, wherein if B takes the compound of formula P as the starting compound, where Ri is the group-OMe, then its agent is the compound of the formula RHal, where Hal is halo, or alkyl sulfonate.