DE2232348A1 - 2-omega-carboxyalkyl) cyclopentanols and (m)ethyl - esters prepn - from cyclopentanone and alkenoic acids or esters - Google Patents

Abstract

Cpds. of formula (I): (where n = 2-17; R is H, Me or Et) are prepd. by reacting CH2=CHCmH2mCOOR (where m = 0-15) with excess cyclopentanone in the presence of an initiator, pref. a cpd. releasing free radicals, pref. at 60-200 degrees C, to give a cpd. (II) of formula: (I); is = O and reducing this to (I), pref. with a complex metal hydride, e.g. NaBH4, at -40 to +40 degrees C. Cpds. (I) and (II) are expected to have pharmacological activity; Cpd (II) n = 6, R=Me is a prostaglandin intermediate.

Description

Title: Process for the preparation of 2 - / # - hydroxy- and / or -alkoxycarbonylalkyl / -1-cyclopentanols The invention relates to a process for the preparation of 2 - / # - hydroxy- and / or -alkoxycarbonyl / -1-cyclopentanols in general Formula I. wherein n is an integer from 2 to 17 and R is a hydrogen atom or a methyl or ethyl radical.

This process starts from unsaturated acids or esters of the general formula II CH2 = OHCnH2nOOOR (11), in which n is an integer from 0 to 15 and R is the same as in formula I; by addition of cyclopentanone, these compounds initially form 2- / -hydroxy- and / or -alkoxy carbonalalkyl / -1-cyclopentanones of the general formula III wherein n and R are the same as in formula I.

Hydroxy acids are formed by reducing these keto acids or their esters or hydroxy esters of the general formula I. The preparation of the compounds of the general Formula I in the manner cited in this invention has been used in the literature not described. The hydroxyl group on the cyclopentane ring is in transposition to the alkyl chain, as can be seen from the manufacturing process and the comparison with can assume similar cases.

Of the prepared intermediates of the general formula III became the lower homologues for the first time described. As the first the compound with n = 3, R = H and 02H5 became known, manufactured as an intermediate in the synthesis of methyl azulene (F.§orm: Collection Czechoslov. Chem. Oommun. 12, 251, 1947) by alkylating Oyklopentanonäthylcarboxylat with 4-bromobutyronitrile and by subsequent hydrolysis and esterification. Furthermore, the connection with n = 4, R = H and O2H5 known, again produced by alkylation of cyclopentanone ethyl carboxylate with ethyl 5-iodo-valerate and by subsequent hydrolysis and esterification. The resulting ethyl ester of the corresponding ketonic acid was then also treated with aluminum isopropoxide in isopropyl alcohol to the corresponding hydroxy acid of the general formula I / n = 4, R == C2H5 / reduced (G.O.

Aspinal, W. Baker: J. Rohem. Soc. 1950, 743). From the higher homologues of the compounds of general formula III is a keto acid with n = 10 and 12 and R = H and CH3 l 2- / 10-Hydroxyearbonyldecyl / -1-cyclopentanone] known by radical addition of undecylenic acid to cyclopentanone (G. 1. Nikisin, G. V0 Somov, A.D.

Petrov: Doklady Akad. Nauk SSSR 136, 1099, 1961), and a ketonic acid and its methyl ester (Formula III, n = 10 and 12, R = H and CH3) made from Hydnocarpic and Chaulmoogric acid, by oxidation of the corresponding hydroxy acids (n = 10 and 12, R = H) with chromium trioxide (S. M. Bala, V.K. Balakrishnan, H.H. Mathur, S.L.

Bhattacharya: Indian J. Rohem. 4, 229, 1966). A keto acid (formula III, n = 6, R = H), produced again from cyclopentanone ethyl carboxylate by alkylation with ethyl 7-brorheptanoate and by subsequent hydrolysis, was published in a preliminary communication on the synthesis of a prostaglandin derivative described (J.F.

Bagli, T. Bogri, R. Deghenghi, K. Wiesner: Tetrah.

Letters 1966, 465).

The process for the preparation of 2-A-hydroxy- and / or -alkoxycarbonylalkyl / -1-cyclopentanones the general formula I according to the invention is characterized in that one initially to unsaturated acids or their esters of the general formula II with Cyclopentanone acts in the excess in the presence of an initiator, whereupon the resulting products, d. H. 2- / u /. Hydroxy and / or alkoxy carbonylalkyl / -1-cyclopentanone of the general formula III to the corresponding hydroxy acids, or

their esters of general formula I reduced.

In the reaction of unsaturated acids or their esters the general Formula II with cyclopentanone is expediently used as a suitable one Initiator such a substance that is capable of releasing free radicals, for example organic peroxides / dibenzoyl peroxide, di-tert. Butyl peroxide and the like) or Azo-bis-isobutyronitrile. This reaction is carried out at a temperature which favors the formation of free radicals, especially at temperatures from 60 to 2000C, through.

The subsequent reduction of 2- / «r-hydroxy and / or alkoxycarbonylalkyl / -1-cyclopentanones of the general formula III can be most advantageously with a complex metal hydride, for example sodium borohydride, at temperatures from -40 to + 40 ° C.

The reaction of the unsaturated acids or esters of the general formula II with cyclopentanone proceeds easily, the isolation of the reaction products is simple, the yields are good. The starting compounds are more easily accessible and cheaper than those in the methods described so far. The reduction also delivers the ketonic acids and esters of the general formula III with sodium borohydride are high Yields, so that the compounds of general formula I are easily accessible in this way are. The homologue of the ketoester of the formula III with n = 6 and R = CH3 represents in more recently the starting material for certain syntheses of prostaglandin derivatives, as already mentioned. From those published in recent literature Work on substances with a similar structure to the compounds of formulas I and III shows that the hydroxy or. Keto acids of the general formulas I and III suggest interesting physiological effects.

Examples 1. A mixture of 4.26 g (0.03 mol) of ethyl heptenate, 5.2 g cyclopentanone and 0.9 g (0.006 mol) dibenzoyl peroxide was during 6 hours to 20 g (total 0.3 mol) of cyclopentanone with stirring at one temperature from 900ru added dropwise. The reaction mixture was then boiled for a further 2 hours of the cyclopentanone heated. After 'distilling off the excess substances were by fractional distillation 2.4 g / 23% of theory / 2- / 6-ethoxycarbonylhexyl / -1-cyclopentanone with b.p. 125 to 12906 / 0.4 torr isolated. For C14H2403 / mole weight 240.3 / calc .: 69.96 C, 10.070 H; found: 70.24% O, 10.20% H.

2. A mixture of 4.26 g (0.03 mol) of ethyl heptenate, 5.2 g of cyclopentanone and 0.9 g / 0.006 mol) di-tert. Butyl peroxide was boiling for 6 hours of cyclopentanone was added dropwise to 20 g (total of 0.3 mol) of cyclopentanone. After that the reaction mixture was heated to boiling for a further 2 hours. After distilling off the excess and unreacted starting materials were fractionated by Distillation 4.0 g (35% of theory) 2- / 6-ethoxycarbonalhexyl / -1-cyclopentanone insulated with bp 125 to 12600 / 0.3 torr. Calculated for O14H2403 (molar weight 240.3): 69.96S C, 10.07% H; found 70.05% C, 10.25XH.

3. A mixture of 54.7 g (0.385 mole) methyl heptenate, 50.5 g (0.6 Mol) cyclopentanone and 8.8 g (0.06 mol) di-tert. Butyl peroxide was during 6.5 Hours at Boiling point of cyclopentanone to 285 g (3.4 mol) Cyclopentanone was added dropwise, after which the reaction mixture was continued for 2.5 hours heated to boiling.

After distilling off the unreacted starting materials were through fractional distillation 37.0 g (42.5 ffi of theory) 2- / 6-methoxycarbonylhexyl / -1-cy-0 klopentanon with sap. Recovered 110 to 111 0 / 0.8 torr.

Calculated for C13H2203 (mol. Wt. 226.3): 69.00% C, 9.80% H; found: 69.12f C, 9.64% H. Characteristic maxima of the infrared spectrum: 825w, 1170s, 1210W, 1255w, 1445m, 1750s cm 4. To 630 g (7.5 moles) of boiling cyclopentanone was added a mixture of 120 g (0.94 mol) of methyl hexenate, 28 g (0.19 mol) for 5 hours di-tert. Butyl peroxide and 160g (1.9 mol) cyclopentanone added. After that was the reaction mixture is heated to boiling for a further 2 hours. After distilling off the Unreacted starting materials were 115.4 g by fractional distillation (70% of theory) 2- / 5-methodycarbonylpentyl / -1-cyclopentanone with boiling point 124 bis 125 ° C / 0.5 torr isolated. Calculated for C12H2003 (mol. Wt. 212.3): 67.90 C, 9.50% H; found: 68.05% C, 9.50 foH.

Characteristic maxima of the infrared spectrum: 1170m, 1205w, 1235m, 1445w, 1735s cm-1.

5. A mixture of 5.7 g (0.06 mole) hexenoic acid, 12 g cyclopentanone and 1.45 g (0.01 mol) di-tert. Butyl peroxide was during 4 hours added dropwise to 30 g (total of 0.5 mol) of boiling cyclopentanone. After another 2 hours Boiling and after distilling off the unreacted starting materials were through fractional distillation 2.4 g (25% of theory) at 155 to 165 ° C / 0.3 Torr boiling fraction isolated.

The crude 2- / 5-hydroxycarbonylpentyl / -1-cyclopentanone was through Action of diazomethane in methyl ester with bp. 130 to 132 ° C / 1 Torr converted. The product showed in thin layer chromatography (Al203, benzene-chloroform) the same Rf value as the product made in Example 4. The infrared spectrum both substances were identical.

6. Cyclopentanone boiling at 200 g was added for 6.5 hours Mixture of 59.5 g (0.5 mol) of methyl undecylenate, 8.8 g (0.06 mol) of di-tert. Butyl peroxide and 52.3 g (total of 3 mol) of cyclopentanone were added dropwise.

The mixture was then heated to boiling for a further 2 hours after distilling off the excess and unreacted starting materials by fractional distillation 45 g (53% of theory) of 2- / 10-methoxycarbonyldecyl / -1-cyclopentanone with Sdp.

154 to 1600C / 0.45 torr isolated. For C17H3003 (molar weight 282.4) calculated: 72.30% C, 10.71% H; found: 72.29wo C, 10.84% H. Infrared spectrum: 1175m, 1205w, 1235m, 1270m, 1450m, 1735 cm ~ 1.

A sample of the methyl ester was boiled for 3 hours with a 10% of its own sodium hydroxide solution hydrolyzed. After the usual work-up, 2- / 10-hydroxycarbonaldecyl / 1-cyclopentanone became obtained with m.p. 45 to 460C. The literature gives a melting point of 51.6 to 520C to (G.I. Nikisin, G.V. Somov, A.D. Petrov: Dokl. Akad. Nauk SSSR 136, 1099, 1961). For C16H2803 / mol. Wt. 268.4) calculated: 71.61% C, 10.52% H; found: 72.11% C, 10.65% H.

Reduction 7. To a solution of 10.6 g (0.05 mol) of 2- / 5-methoxycarbonylpentyl / -1-cyclopentanone in 250 ml of isopropyl alcohol was for 1 hour at a temperature of 0 ° to -10 ° C with stirring to 5 ° C cooled solution of 7.6 g (0.2 mol) of sodium borohydride added dropwise in 65 ml of water. Stirring was continued for an additional 3 hours with constant cooling continued. After this, 100 ml of acetone and a solution of 40 ml of acetic acid were added added dropwise in 80 ml of water. The reaction mixture then became the solvents distilled off under reduced pressure and the residue was extracted with ether. The ethereal solution was twice with a 10% sodium hydrogen carbonate solution and shaken twice with water and dried with magnesium sulfate. To Distilling off ether, the residue was distilled under reduced pressure. There were 8.6 g (85% of theory) 2- / 5-methoxycarbonylpentyl / -1-cyclopentanol with Sdp.

106-10900 / 0.2 Torr isolated. Calculated for C12H2203 (mol. Wt. 214.3): 67.26% C, 10.35% H; Found: 67.11% C, 1040ie H. On thin layer chromatography the product showed up as a uniform substance, with a distinctly lower one Rf value than for the starting ketoester. A similar study with analogous results was also carried out in Examples 9 and 10. Infrared spectrum: 795s, 1050, 1235, 1370w, 1445, 1735s, 3450cm -1 8. To a solution of 2.8 g (0.01 mol) of 2- / 5-hydroxycarbonylpentyl / -1-cyclopentanone in 30 ml abs. Methanol became a solution of 0.76 g (0.02 mol) over 20 minutes Sodium borohydride in 40 ml of abs. Methanol was added dropwise at a temperature of 200C. The next day the reaction mixture was diluted with 10 ml of water and 10 ml Hydrochloric acid (1: 3) added. The product was shaken out with ether, the ether extract washed with water and dried with magnesium sulfate. To Distilling off ether were 1.6 g (80% of theory) of the crude 2- / 5-hydroxycarbonalpentyl / -1-cyclopentanol isolated, which was identified as the methyl ester. The esterification was using of diazomethane carried out in a conventional method. The methyl ester obtained was with the methyl ester prepared according to Example 7 by means of thin-layer chromatography (Al203, Benzene-chloroform). The infrared spectra of both methyl esters were identical.

9. To a solution of 3.2 g (0.015 mol) of 2- / 6-methoxycarbonylhexyl / -1-cyclopentanone in 80ml isopropyl alcohol was under the same conditions as in Example 7 a A solution of 2.3 g (0.06 mol) of sodium borohydride in 20 ml of water was added. On similar ones As in Example 7, 2.9 g (85% of theory) of 2- / 6-methoxycarbonylhexyl / -1 -cyclopentanol with bp 110 to 112 ° C / 0.2 Torr isolated. For C13H2403 (mol. Wt. 228.3) Calculated: 68.39% C, 10.60% H; found: 68.74% C, 10.90% H. Infrared spectrum: 1175, 1205, 1255w, 1365w, 1445, 1750s, 3400cm 1.

10. To a solution of 8.5 g (0.03 mol) of 2- / 10-methoxycarbonyldecyl / -1-cyclopentanone in 150 ml of isopropyl alcohol were under similar conditions as in Example 7 2.3 g (0.06 mol) of sodium borohydride in 20 ml of water were added. On the one in the example 7 described manner were 7.2 g (84% of theory) 2- / 10-methoxycarbonyldecyl / -1 -cyclopentanol with bp 164 to 167 ° C / 0.2 Torr isolated. For C17H3203 (mol. Wt. 284.4) calculated: 71.79% C, 11.34% H; found 72.05% C, 11.50% H; Infrared spectrum: 1180, 1215w, 1230, 1370w, 1448, 1738s, 3460 cm.

Claims (4)

PATENT CLAIMS: Process for the preparation of 2 - / # - hydroxy and / or alkoxycarbonylalkyl / -1-cyclopentanols of the general formula I. where n is an integer from 2 to 17 and R is a hydrogen atom or a methyl or ethyl radical, characterized in that unsaturated acids or their esters of the general formula II CH2 = OHCnH2nCOOR (11) where n is an integer starting from 0 to 15 and R is the same as in formula I, acts with excess cyclopentanone in the presence of an initiator, whereupon the resulting products, ie 2- / ar'-hydroxy- and / or alkoxycarbonylalkyl / -1-cyclopentanones of the general formula III where n and R are the same as in formula I, reduced to the corresponding hydroxy acids or their esters of general formula I. 2. The method according to claim 1, characterized in that g e k e n n -z e i c h n e t that the initiator is a substance that is capable of releasing free radicals, for example organic peroxides or azo-bis-isobutyronitrile, used. 3. The method according to claim 1, characterized in that g e k e n n -z e i c h n e t that the reaction of Cyclopentann with the unsaturated compound of the general Formula II at a temperature that favors the formation of free radicals, in particular at temperatures from 60 to 2000C. 4. The method according to claim 1, characterized in that g e k e nn -z e i c.h n 6 t that that. one the reduction of droxy- on / or alkoxyearbonylalkyl / -1-cyclopentanones of the general formula II with a complex metal hydride, for example sodium borohydride, at temperatures from -40 to +400 C.