IL106758A - (1-cyanocyclohexyl)-malonic acid dialkyl esters and processes for their preparation - Google Patents

Description

/37/62-A-DIV (l-CYANOCYCLOHEXYL)-MALONIC ACID DIALKYL ESTERS AND PROCESSES FOR THEIR PREPARATION This application is a divisional application from Israel Patent Application N0. 91411 , hereafter referred to as the parent application.

This invention relates to (l-cyanocyclohexyl)- alonic acid dialkyl esters which are valuable starting materials for use in the preparation of the 2-aza-4-(alkoxycarbonyl)-spiro(4,5)decan-3-ones disclosed and claimed in the parent application.

According to a first aspect of the present invention there is provided a (1-cyanocyclohexyl )-malonic acid dialkyl ester of the formula :- coos in which R signifies a lower alkyl radical with 1 to 4 C-atoms. Preferred forms of the compound of formula (3) are (l-cyanocyclohexyl)-malonic acid dimethyl ester and (l-cyanocyclohexyl)-malonic acid diethyl ester. ccording to a second aspect of the present invention there is provided a process for the preparation of a (l-cyanocyclohexyl)-malonic acid dialkyl ester in accordance with the first aspect of the present invention wherein, a cyclohexylidene-malonic acid alkyl ester of the general formula: - · in which R signifies a lover alkyl radical of 1 to 4 C-atorr.s,- . is reacted either with hydrocyanic acid in the presence of a catalytic amount of an alkali metal cyanide, or with a stoichiometric amount of an alkali metal cyanide in an alcohol and subsequently with an acid, to form the corresponding (l-cyanocyclohexyl)-malonic acid dialkyl ester.

The starting material of formula (2) used in the process in accordance with the second aspect of the invention can be prepared in a simple and known way by a noevenagel condensation reaction of cyclohexanohe and an alk l malonate.

If HCN is employed it may be used in an amount of between 1 and 20 equivalents and preferably of between 3 and 5 equivalents, per equivalent of the the starting material (2). The amount of alkali metal cyanide employed as a catalyst may be between 0.1 and 50 mole % and preferably between 10 and 20 mole %, referred to the starting material (2). The alkali metal cyanide may be sodium or potassium cyanide and is preferably otassium cyanide.

The reaction may be carried out with or without a solvent. Preferred solvents include lower alcohols, such as methanol, ethanol, propanol, butanol, or alcohol/water mixtures; esters with lower alcohols in the ester group, such as ethyl acetate, methyl acetate, propyl acetate and; ketones, such as acetone and methyl ethyl ketone. However, the reaction is preferably carried out without a solvent. The reaction may be carried out at a temperature of between 20 and 150°C, and preferably between 90 and 120°C. The reaction is preferably carried out in a closed vessel (autoclave) and any build up of excess pressure in the vessel caused by the reaction temperature, is released.

If an alkali metal cyanide is employed without the addition of HCN (the second possibility), it may be used in an amount of between 1 and 5 equivalents, preferably 1 to 1.5 equivalents, per equivalent of the starting material (2) and the pH value of the reaction mixture may be maintained at a value of between 10.0 and 13.0 by the continuous addition of acid or alcohol. The alkali metal cyanide may be sodium or potassium cyanide and preferably potassium cyanide. As acids, mineral acids, such as for example hydrochloric acid or sulphuric acid, or organic acids, such as for example formic acid or acetic acid, may be used; the preferred acid being hydrochloric acid. As solvents, lower alcohols, such as methanol, ethanol, propanol, butanol, or alcohol/water mixtures may be used. However, the reaction is preferably carried out with the alcohol corresponding to the alkyl ester group. The reaction temperature may be between 0°C and the reflux temperature and is preferably carried out at the reflux temperature .

According to a third aspect of the present invention there is provided a process for the preparation of a (l-cyanocyclohexyl)-malonic acid dialkyl ester in accordance with the first aspect of the present invention wherein a cyclohexylidene cyanoalkylate of the formul in which R signifies a lover alkyl radical with 1 to 4 C-atoms, in a first step, is reacted either with a stoichiometric amount of alkali metal cyanide in an alcchol, or with hydrocyanic acid in the presence of a catalytic amount of an alkali metal cyanide, to form the corresponding (l-cyanocyclohexyl)-cyanoacetic acid alkyl ester of the formula :- with as set out above, which in a second step, is reacted in an alcohol with an acid to form the corresponding ( l-cyanocyclohexyl)-malonic acid dialkyl ester.

The starting material of formula (4) used in the process in accordance with the third aspect of the invention can also be prepared in a simple and known way by a Knoevenagel condensation reaction of cyclo-hexancr.e and a cyar.calkylate .

If HCN is employed in the first step, it may be used in an amount of between 1 and 20 equivalents and preferably of between 3 and 5 equivalents, per equivalent of the starting material (4). The amount of alkali metal cyanide employed as a catalyst may be between 0.1 and 50 mole % and preferably is between 10 and 20 mole %, referred to the starting material (4). The alkali metal cyanide may be sodium or potassium cyanide and is preferably potassium cyanide.

The reaction may be carried out with or without a solvent. Preferred solvents include lower alcohols, such as methanol, ethanol, propanol, butanol, or alcohol/water mixtures; esters with lower alcohols in the ester group, such as ethyl acetate, methyl acetate, propyl acetate and; ketones, such as acetone and methyl ethyl ketone. The reaction is preferably carried out without a solvent. The reaction in the first step may be carried out at a temperature of between 20 and 150°C. and preferably between 90 and 120°C.

The reaction is preferably carried out in a closed vessel (autoclave) and any build up of excess pressure in the vessel caused by the reaction temperature is released .

If an alkali metal cyanide is employed without the addition of HCN (the second possibility) it may be used in an amount of between 1 and 5 equivalents/ preferably 1 to 1.5 equivalents, per equivalent of the starting material (4).

As solvents, lower alcohols, such as methanol, ethanol, propanol or butanol, are preferred and the reaction is preferably carried out in the alcohol corresponding to the alkyl ester group.

In an embodiment of the third aspect of the invention the (l-cyanocyclchexyl)-cyanoacetic acid alkyl ester of formula (5) formed after the first step in the second step, is converted, preferably in a closed vessel, into the ( 1-cyanocyclohexyl) - alonic acid dialkyl ester of formula (3) with 1 to 100 equivalents of an acid and preferably with 10 to 20 equivalents of an acid, per equivalent of the material of formula (5). This reaction is carried out at a temperature of -20 to 50CC and a pressure of 1 to 10 bar, preferably at 0 to 2Q°C. and a pressure of 2 to 3 bar.

As acids, mineral acids, such as for example hydrochloric acid or sulphuric acid, as well as organic acids, such as for example formic acid or acetic acid, maybe used; the preferred acid being hydrochloric acid.

Solvents which may be used include alcohols corresponding to the alkyl ester group, alone or in combination with an ether, a hydrocarbon, for example toluene or hexane, or a halogenated hydrocarbon, for example methylene chloride.

The reaction to the ethyl ester is preferably carried out with ethanol. '■ Example 1 Cyclohexylidenemalonic acid dimethyl ester (not according to the invention) During the course of 65 minutes, a solution of titanium tetrachloride (95.1 g., 0.5 mole) in carbon tetrachloride (125 ml.) is added into tetrahydrofuran (1000 ml.) at about 0°C. under nitrogen.

Subsequently, a mixture of cyclohexanone (24.6 g., 0.25 mole) and alonic acid dimethyl ester (33.0 g. , 0.25 mole) is added thereto over 15 minutes at about 0°C. To the resulting yellow suspension pyridine (79.0 g., 1.0 mole) in THF (175 ml.) was added over 60 minutes and the mixture was further stirred for 18 hours at room temperature. Water (250 ml.) was added thereto and the resulting two phases were separated. The aqueous phase was extracted twice with, in each case, 90 ml. ethyl acetate and the combined organic phases were washed with sat. sodium chloride and sat. sodium carbonate solution (in each case 100 ml.), dried with magnesium sulphate, filtered and evaporated.

Distillation (81 to 83°C./1 π-bar) gave 22.5 g. of product, corres onding to 43% yield (ref. to malonate used) .

Example 2 ( 1-Cyanocyclohexyl) - alonic acid dimethyl ester A mixture of cyclohexylidenemalonic acid dimethyl ester (21.5 g./ 94 mMole), hydrocyanic acid (19 ml., 485 mMole) and potassium cyanide (0.92 g. 14 mMole) was heated in an autoclave for 6 hours to 120°C. After cooling to room temperature, the excess hydrocyanic acid was driven off with nitrogen. The crude product was dissolved in ethyl acetate and filtered. The evaporated filtrate (24.2 g.) was recrystallised from ethanol and gave 15.5. g. of product, corresponding to a yield of 69% (referred to the malonate used) .

M.p. 74 to 75°C.

½-NMR: (CDC1,, 300 KHz) 1.0 - 2.3 (m, 10H) 3.47 (s. 1H) 3.81 (s, 6H) Elementary analysis for C1 H17NO, (239.3): Calc. C 60.2% H 7.2% N 5.9% found C 60.6% H 7.3% N 6.5% calc . C 62.5% H 8.1% N 6.6% found C 62.9% H 8.3% N 7.2% Example 3 ( l-cyanocyclohexyl)-malonic acid diethyl ester was prepared using the methods of Examples 1-2 using the corresponding ethyl compounds and starting with a preparation of cyclohexylidene malonic acid diethyl ester. The yields correspond to those mentioned in Examples 1 and 2. ( l-Cyanocyclohexyl)-malcnic acid diethyl ester M.p. SO to 92CC.

^- : (CDC13, 300 .MHz) 1.30 (t, J ■ 7.2 Hz, 6H) 1.15-2.23 (n, 1CH) 3.40 (s, 1H) 4.20- .35 (n, 4H) Ele-er.tary analysis for Ο,,Η-.ΝΟ. (267.3): calc. C 62.= H 7.9 5.2 found C 62.9 H 7.9 5.5 Example ( 1-Cyanocyclohexy ) - alonic acid diethyl ester A mixture of potassiam cyanide (18.1 g., 0.27 mole) and cyclohexylidenemalonic acid diethyl ester (44.0 g., 0.18 mole) in ethanol (180 ml.) was heated to reflux and the pH of the mixture was kept at a value of 10.5 to 11.5 by the continuous additionof HCl/ethanol.

After a reaction time of 16 h., the mixture was cooled to 30°C. and adjusted to a pH value of about 5 by the addition of KCl/EtOH (24%, about 1 g., 0.1 mole).

The potassium chloride precipitated out, was filtered off and washed with ethanol (200 ml.).

The ethanol was evaporated off and the filtrate was recrystallised from ethanol to give a total of 42.1 g. of product, corresponding to a yield of 88%, referred to the cyclohexylidene-malonic acid ethyl ester used.

Example 5 Cyclohexylidene cyanoacetate (not according to the invention) .

A solution of cyclohexanone (58.9 g., 0.6 mole), cyancacetic acid ethyl ester (3.8 g., 0.5 mole), ammonium acetate (3.8 g.., 0.05 mole) and acetic acid (6.0 c., 0.1 mole) was heated to reflux in toluene (50 ml.). Subsequently, within 6 hours, 18 g. of the water phase was separated off on a water separator. The organic solution was washed three times with water (in each case 100 ml.) and distilled in a vacuum. The distillation (111 to 115°C./0.3 mbar) gave 71.4 g. of product, corresponding to 74% yield (referred to cyanoacetic acid ethyl ester used).

Example 6 ( 1-Cyanocyclohexyl) -cyanoacetic acid ethyl ester A suspension of potassium cyanide (33.0 gP / 0.5 mole) in ethanol (400 ml.) was heated to reflux and subsequently mixed with cyclohexylidene cyanoacetate (103.3 g., 0.5 mole). After a reaction time of 45 minutes, it was cooled to 60CC. and the pH was adjusted to a value of about 5 by passing in HCl gas (about 18 g., 0.5 mole). The precipitated potassium chloride was filtered off and washed with ethanol (200 ml.). The ethanol' as evaporated off and the filtrate was recrystallised from ethanol to give a total of 99.6 g. rf. d ct, corresponding to a yield of 94% (referred to cyclohexylidene cyanoacetate used) .

Example 7 ( 1-Cyanocyclohexyl ) -malcnic acid diethyl ester A mixture of ( 1-cyanocyclchexyl ) -cyanoacetic acid ethyl ester (2.50 g., 11.3 Kole) in ethanol (100 ml.) was saturated in an autoclave at 0°C. with HC1 gas (about 11 g., 0.3 mole). After a reaction time of 16 hours at 0°C./2 bar, the mixture was evaporated on a rotary evaporator, mixed with ethanol (3 ml.) a_nd water (10 ml.) and subsequently stirred at 0°C. for 4 hours, 2.27 g. of product were isolated by filtration, corresponding to a yield of 75% (referred to (l-cyanocyclohexyl)-cyanoacetic acid ethyl ester used) .

M.p. SO to 92CC.

Example 8 ( 1-Cyanocyclohexyl )cyancacetic acid ethyl ester Ethyl cyclohexylidene cyanoacetate (19.71 g, 100 mmol) was added to a suspension of potassium cyanide (1.33 g, 20 r-nol) in ethanol (100 ml) at 50°C. Hydrocyanic acid (23.1 ml, 84 mmol) was added to the mixture so that the pH remained in the range of 10.5 to 11.5.

After 6 hours at 5CCC the mixture was acidified with hydrogen chloride gas (55 rnmol). The precipitated potassium chloride was filtered off and washed with ethanol (50 ml). The filtrate was concentrated to 28 g and cooled to 0°C. The formed crystals were filtered off, washed with ethanol and dried. 18.10 g of product was ob air.c-d giving a yield of 82% (relative - -ml. acetone and stirred for 5 minutes. Thereafter, the resultant suspension was filtered, the residue washed with acetone and dried. A further 326 mg. of product was obtained with an m.p. of 117°C, Yield: 81%, referred to the lactam used (crude product) .

M.p. 114 to 117°C.

Elementary analysis for C9HlgN02Cl (207.7): calc. C 52.0% H 8.7% N 6.7% found C 50.1% H 8.9% N 7.0% Water content: 4.2% Example g ' ( l-Cyanocyclohexyl)cyanoacetic acid ethyl ester A solution of sodium cyanide (0.5 g, 10 mmol) in water (3 ml) was added at 20-30°C to a solution of ethyl cyclohexylidene cyanoacetate (2.0 g, 10 mmol) in ethanol (5 ml). After 1 hour a gas chromatogram of the reaction mixture (acidified with acetic acid) proved the formation of the product (86 area-% of (1-cyano-c v c 1 «.· P x v 1 i cvs n c .-. c e r. i c n o i d t h v 1 sr.t-r , 5 sr a o f v c \ c- x \· 1 ) c- n - o v :¾ n o a r. pt. o 106758/2 - i -

Claims (2)

CLAIMS 1· A (l-Cya-nocyclohexyl)-malonic acid dialkyl ester of the formula:- COO in vhich R signifies a lower alkyl radical with 1 to 4 C-atoms . "2. ( l-Cyanocyclohexyl)-malonic acid dimethyl ester. 3. ( l-Cyanocyclohexyl)-malonic acid diethyl ester. 4. A process for the preparation of a ( l-Cyanocyclohexyl)-malonic acid dialkyl ester as claimed in claim 1 wherein a cyclohexylidene-malonic acid alkyl ester of the general formula :- in which R signifies a lower alkyl radical of 1 to 4 C-itoms , is reacted either with hydrocyanic acid in the presence of a catalytic amount of an alkali metal cyanide, or with a stoichiometric amount of alkali metal cyanide in an alcohol and subseqently with an acid, to fern the corresponding ( 1-cyanocyclohexyl j-na Ionic acid dialkyl ester. - M - 5. A process for the preparation of ( 1-Cyanocyclo-hexyl)-malonic acid dialkyl ester as claimed in claim i wherein a cyclohexylidene cyanoalkylate of the formula :- in which R sicfnifies a lower alkyl radical of 1 to 4 C-atoms, in a first step, is reacted either with a stoichiometric amount of alkali metal cyanide in an alcohol, or with hydrocyanic acid, in the presence of a catalytic amount of an alkali metal cyanide, to form the corresponding ( l-cyanocyclohexyl)-cyanoacetic acid alkyl ester of the formula:- (5) 106758/2 - 20 -with R as set out above, which in a second step is reacted in an alcohol with an acid to form the corresponding ( 1-Cyanocyclohexyl) -malonic acid dialkyl ester. 6. A process as claimed in claim 4 , wherein the reaction is carried out at a temperature of between 20 and 150°C, with HCN present in an amount of 1 to 20 equivalents per equivalent of the compound of formula (2) and the alkali metal cyanide present in an amount of 0.1 to 50 mole %, referred to the compound of formula (2). 7. A process as claimed in claim 4 , wherein the compound of formula (2) is heated to reflux in an alcohol with 1 to 5 equivalents of an alkali metal cyanide per equivalent of the compound of formula (2). 8. A process as claimed in claim 5 , wherein, in the first step, an amount of 1 to 5 equivalents of the alkali metal cyanide per equivalent of the compound of formula (4), is reacted with the compound of formula (4) in an alcohol under reflux. - 24 - 9 . A process as claimed in claim 5 y wherein, in the first step, the compound of formula (4) is reacted at a temperature of between 20 and 150CC. with HCN in an amount of 1 to 20 equivalents per equivalent of the compound of formula (4), in the presence of an alkali metal cyanide in an amount of 0.1 to 50 mole %, referred to the compound of formula (4). 0 . A process as claimed in any of claims 5 , 8 and 9 wherein the second step is carried out at a temperature of between -20 and 50°C, under a pressure of 1 to 10 bar with 1 to 100 equivalents of an acid per equivalent of the compound of formula (5), and in an alcohol.

1. . A ( l-Cyanocyclohexyl)-malonic acid dimethyl ester substantially as hereinbefore described.

2. . A method of preparing a ( 1-Cyanocyclohexyl ) -malonic acid dimethyl ester substantially as hereinbefore described. ATTORNEYS FOR APPLICANTS