GB1574113A

GB1574113A - Production of derivatives of malonic acid

Info

Publication number: GB1574113A
Application number: GB473978A
Authority: GB
Original assignee: Anic SpA
Current assignee: Anic SpA
Priority date: 1977-02-24
Filing date: 1978-02-06
Publication date: 1980-09-03
Also published as: FR2381738A1; FR2381738B1; DD134083A5; DE2807625C2; CS207500B1; IT1075123B; DE2807625A1; CH636336A5

Abstract

By means of a novel process, malonic acid derivatives of the formula (I) <IMAGE> are synthesised, where Z, R', R'', R''', B and C are as defined in claim 1. The process comprises reacting a compound of the formula (II) <IMAGE> with an aliphatic alcohol of the formula R'''OH and carbon monoxide in the presence of a base B and a compound C. X and Y are also defined in claim 1. The products obtained are useful intermediates for the preparation of barbiturates and some group B vitamins.

Description

(54) PRODUCTION OF DERIVATIVES OF MALONIC ACID (71) We, ANIC S.p.A., an Italian company, of Via Mariano Stabile, 216, Palermo, Italy, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the following statement: This invention relates to processes for producing certain derivatives of malonic acid.

It is known that esters of malonic acid can be produced starting from the corresponding alpha-halo ethers by replacement of the halogen atom by a nitrile group and subsequent alcoholysis of the latter. This procedure involves the use of a highly polluting reagent such as potassium cyanide, with inherent serious problems of purification of the effluents.

It is also known that certain derivatives of malonic acid find use in the field of the organic syntheses in general and more particularly in the production of barbiturates, of hypnotics and of the vitamins B1 and B6.

According to one aspect of the present invention, there is provided a process for producing a derivative of malonic acid having the following general formula:

which comprises reacting a compound of the following general formula: -

with an alcohol having the formula R30H and carbon monoxide in the presence of a base B and of a compound C, wherein Z is a cyano, esterified carboxy or optionally substituted carbamoyl group, Xis a halogen atom, R' is a hydrogen atom or a hydrocarbon radical, R2is a hydrogen atom or a hydrocarbon radical, R3 is a hydrocarbon radical, B is an inorganic or an organic base, and C is a palladium complex or elemental palladium.

According to another aspect of the present invention, there is provided a process for producing a derivative of malonic acid having the following general formula:

which comprises reacting a compound of the following general formula:

with an alcohol having the formula R30H and carbon monoxide in the presence of a base B and of a compound C, wherein X is a halogen atom, Y is a halogen equal to or different from X, Z is a cyano, esterified carboxyl or optionally substituted carbamoyl group, Rl is a hydrogen atom or a hydrocarbon radical, R is a hydrogen atom or a hydrocarbon radical, R3 is a hydrocarbon radical, B is an inorganic or organic base, and C is a palladium complex or elemental palladium.

Preferably each of the radicals R l and R2, which are the same or different, is a hydrogen atom or an aryl, alkyl, alkaryl or aralkyl radical.

The radical R may be, for instance, alkyl or alkaryl, or may be alkyl or aralkyl. Preferably R3 is an aliphatic radical.

The palladium when present in elemental form is preferably in finely divided state.

The processes of the different aspects of the present invention can be expressed, in simplified terms, as follows:

wherein X, Y, Z, R1, R2, R3,B and C are as defined above.

The base B can be selected from inorganic bases, for example the bicarbonates and carbonates of alkali metals and alkaline earth metals, and alkaline earth metal oxides, as well as from organic bases, for example aliphatic tertiary amines and pyridines.

By way of example, among the palladium compounds which can act as catalysts in the process of the present invention, there can be mentioned the complexes of divalent palladium as represented by the general formula L lL2PdX lX2 wherein L l and L2, which are the same or different, are monodentate neutral ligands, such as phosphines, arsines and stibines, which are of an alkyl or aryl nature, and X l and X2 are monovalent anionic groups, which may be the same or different, such as halogen atoms or carboxylates, cyanides, thioalcoholates or alkoxy carbonyls.

Another suitable complex is that having the formula L3PdXlX2, where X' and X2 are as defined above and L3 is a bidentate ligand such as a diphosphine, diarsine, phenanthroline, dipyridyl and their substituted derivatives.

There can also be used the complexes of zerovalent palladium as represented by the formulae PdL4n, wherein n = 2,3,4 and L4 is an alkyl- or aryl-phosphine or isonitrile; and the carbonyls of zerovalent palladium having the formula Pdx(CO)yLz wherein x = 1 or 3 y is 1 or 3, z is 3 or 4, and L is an aryl phosphine. The reaction can also be carried out in the presence of an activating agent or promoter, which can be selected from the halides and the carboxylates of alkali metals or of alkaline earth metals.

The reaction may, if desired, be effected in the presence of an organic diluent, preferably, but not exclusively, a polar or an aprotic solvent, such as tetrahydrofuran, dioxan, tetrahydropyran, mono- or dialkyl ethers of ethylene glycol, of homologous glycols and of dioxyethyleneoxypropylene glycol, hexamethylphosphoramide, N-methylpyrrolidone, N,Ndimethylformamide, and tetramethylenesulphone.

The reaction is preferably carried out at a temperature in the range from 50"C to 200"C, more preferably from 80"C to 1500C, under a pressure range from 1 to 200 atmospheres preferably from 1 to 70 atmospheres.

The following Examples illustrate the present invention without limiting the same.

EXAMPLE 1 Into a stainless steel autoclave were introduced 24.6 grams of methyl chloroacetate. 15.8 grams of methanol, 19.1 grams of sodium bicarbonate, 2.2 grams of PdI2(PPh3)2 and 80 ml of hexamethylphosphoramide. The autoclave, after it had been closed and purged with nitrogen, was charged with carbon monoxide to a pressure of 50 kilograms/sq cm. and heated to 100"C for 4 hours. The reaction mixture was analyzed by gas liquid chromatography (GLC), and indicated a conversion of methyl chloroacetate of 100 %with a yield of dimethylmalonate of 79%.

EXAMPLE 2 There were introduced into an autoclave 39.6 grams of methylene chloride, 7.9 grams of methanol, 25.2 grams of triethylamine, 1.7 grams of Pd(C12(PPh3)2 and 1.6 grams of potassium iodide. Carbon monoxide was introduced into the autoclave to a pressure of 50 kg/sq.cm, and the autoclave was maintained at 100"C for 8 hours. Analysis of the reaction mixture showed a conversion of methanol of 25 % with a selectivity with respect to dimethyl malonate of 87%.

EXAMPLE 3 Into an autoclave were introduced 8.0 grams of benzylidene dichloride, 3.9 grams of methanol, 10.5 grams of 2,6-lutidine, 1.1 gram of Pd(OCOCH3)(COOCH3)(PPh3)2 and 40 ml of hexamethylphosphoramide. The autoclave was pressurized to 50 kg/sq.cm with carbon monoxide and maintained at 1000for 4 hours. Analysis of the reaction mixture showed the formation of the dimethyl ester of the phenylmalonic acid with a yield of 55%.

EXAMPLE 4 There were introduced into an autoclave 37.5 grams of chloroacetonitrile, 23 grams of ethanol, 10 grams of magnesiumoxide, 1.8 grams of Pd(CO)(PPh3)3 and 80 ml of "glyme" (i.e. the dimethyl ether of ethylene glycol). The autoclave was pressurised to 50 kg/sq cm.

with CO and maintained at 800C for 4 hours. Analysis of the reaction mixture showed a conversion of chloroacetonitrile of 100 % with a selectivity with respect to ethyl cyanacetate of 68%.

EXAMPLE 5 There were introduced into an autoclave 65 grams of N,N-diethylchloroacetamide, 25 grams of ethanol, 25 grams of triethylamine, 1.5 grams of Pd(COOCH3)2(PPh3)2 and 150 ml of N,N-dimethylformamide. The autoclave was pressurised to 50 kg/sq cm. of CO and kept at 100"C for 4 hours. Analysis of the reaction product showed a conversion of 92% for the N,N-diethylchloroacetamide with a selectivity of 81% in terms of N,N-diethylmalonamide monoethyl ester.

WHAT WE CLAIM IS: 1. A process for producing a derivative of malonic acid having the following general formula:

which comprises reacting a compound of the following general formula:

with an alcohol having the formula R30H and carbon monoxide in the presence of a base B and of a compound C, wherein Z is a cyano, esterified carboxy or optionally substituted carbamoyl group, Xis a halogen atom, R1 is a hydrogen atom or a hydrocarbon radical, R2 is a hydrogen atom or a hydrocarbon radical, R3 is a hydrocarbon radical, B is an inorganic or an organic base, and C is a palladium complex or elemental palladium.

2. A process according to claim 1, wherein each of the radicals R1 and R2, which are the same or different, is a hydrogen atom or an aryl, alkyl, alkaryl or aralkyl radical.

3. A process according to claim 1 or 2, wherein the radical R3 is an alkyl or alkaryl radical.

4. A process according to claim 1 or 2, wherein the radical R3 is an alkyl or aralkyl radical.

5. A process for producing a derivative of malonic acid having the following general formula

which comprises reacting a compound of the following general formula:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. 100"C for 4 hours. The reaction mixture was analyzed by gas liquid chromatography (GLC), and indicated a conversion of methyl chloroacetate of 100 %with a yield of dimethylmalonate of 79%. EXAMPLE 2 There were introduced into an autoclave 39.6 grams of methylene chloride, 7.9 grams of methanol, 25.2 grams of triethylamine, 1.7 grams of Pd(C12(PPh3)2 and 1.6 grams of potassium iodide. Carbon monoxide was introduced into the autoclave to a pressure of 50 kg/sq.cm, and the autoclave was maintained at 100"C for 8 hours. Analysis of the reaction mixture showed a conversion of methanol of 25 % with a selectivity with respect to dimethyl malonate of 87%. EXAMPLE 3 Into an autoclave were introduced 8.0 grams of benzylidene dichloride, 3.9 grams of methanol, 10.5 grams of 2,6-lutidine, 1.1 gram of Pd(OCOCH3)(COOCH3)(PPh3)2 and 40 ml of hexamethylphosphoramide. The autoclave was pressurized to 50 kg/sq.cm with carbon monoxide and maintained at 1000for 4 hours. Analysis of the reaction mixture showed the formation of the dimethyl ester of the phenylmalonic acid with a yield of 55%. EXAMPLE 4 There were introduced into an autoclave 37.5 grams of chloroacetonitrile, 23 grams of ethanol, 10 grams of magnesiumoxide, 1.8 grams of Pd(CO)(PPh3)3 and 80 ml of "glyme" (i.e. the dimethyl ether of ethylene glycol). The autoclave was pressurised to 50 kg/sq cm. with CO and maintained at 800C for 4 hours. Analysis of the reaction mixture showed a conversion of chloroacetonitrile of 100 % with a selectivity with respect to ethyl cyanacetate of 68%. EXAMPLE 5 There were introduced into an autoclave 65 grams of N,N-diethylchloroacetamide, 25 grams of ethanol, 25 grams of triethylamine, 1.5 grams of Pd(COOCH3)2(PPh3)2 and 150 ml of N,N-dimethylformamide. The autoclave was pressurised to 50 kg/sq cm. of CO and kept at 100"C for 4 hours. Analysis of the reaction product showed a conversion of 92% for the N,N-diethylchloroacetamide with a selectivity of 81% in terms of N,N-diethylmalonamide monoethyl ester. WHAT WE CLAIM IS:

1. A process for producing a derivative of malonic acid having the following general formula:

which comprises reacting a compound of the following general formula:

with an alcohol having the formula R30H and carbon monoxide in the presence of a base B and a compound C, wherein Xis a halogen atom, Y is a halogen equal to or different from X, Z is a cyano, esterified carboxyl or optionally substituted carbamoyl group, R1 is a hydrogen atom or a hydrocarbon radical, R2 is a hydrogen atom or a hydrocarbon radical, R3 is a hydrocarbon radical, B is an inorganic or organic base, and C is a palladium complex or elemental palladium.

6. A process according to claim 5, wherein each of the radicals R' and R2, which are the same or different, is a hydrogen atom or an aryl, alkyl, alkaryl or aralkyl radical.

7. A process according to claim 5 or 6, wherein the radical R3 is an alkyl or alkaryl radical.

8. A process according to claim 5 or 6, wherein the radical R3 is an alkyl or aralkyl radical.

9. A process according to any preceding claim, wherein the base B is selected from bicarbonates and carbonates of alkali metals and alkaline earth metals, and oxides of alkaline earth metals.

10. A process according to any one of claims 1 to 8, wherein the base B is selected from aliphatic tertiary amines and pyridines.

11. A process according to any preceding claim, wherein the compound C is a complex of palladium having the formula L L2PdXlX, wherein L1 and L2 are monodentate neutral ligands, and X1 and X2 are monovalents anionic atoms or groups, L1and L2 being the same or different, and Xl and X2 being the same or different.

12. A process according to claim 11, wherein Ll and L2 are selected from phosphines, arsines and stibines, which are of an alkyl or aryl nature.

13. A process according to any one of claims 1 to 10, wherein the compound C is a palladium complex having the formula L3PdX1X2 wherein L3 is a bidentate ligand, and X1 and X2, which are the same or different, are monovalent anionic atoms or groups.

14. A process according to claim 13, wherein L3 is selected from diphosphine, phenanthroline, diarsine, dipyridyl and their substituted derivatives.

15. A process according to any one of claims 11 to 14, wherein Xl and X2 are selected from halogen atoms and carboxylates, cyanides, thioalcoholates and alkoxycarbonyls.

16. A process according to any one of claims 1 to 10, wherein the compound C is a complex of zerovalent palladium which has the general formula PdL4n wherein L4 is selected from aryl or alkyl phosphines or isonitriles, and n has a value of from 2 to 4.

17. A process according to any one of claims 1 to 10, wherein the compound C is a complex of zerovalent palladium which has the general formula Pdx(CO)yLz in which x is 1 or 3, y is 1 or 3, z is 3 or 4, and L is an aryl phosphine.

18. A process according to any preceding claim, wherein the reaction is carried out in the presence of an activating agent or promoter.

19. A process according to claim 18, wherein the activating agent or promotor is selected from among halides and carboxylates of the alkali metals and of the alkaline earth metals.

20. A process according to any preceding claim, wherein the reaction is carried out in the presence of an organic solvent.

21. A process according to claim 20, wherein the organic solvent is a polar aprotic solvent.

22. A process according to claim 21, wherein the polar aprotic solvent is selected from tetrahydrofuran, dioxan, tetrahydropyran, mono- and dialkyl ethers of ethylene glycol, of homologous glycols and of dioxyethyleneoxypropylene glycol, N-methylpyrrolidone, N,Ndimethylformamide, hexamethylphosphoramide and tetramethylenesulphone.

23. A process according to any preceding claim, wherein the reaction is carried out at a temperature in the range from 50"C to 200"C.

24. A process according to claim 23, wherein the reaction temperature is in the range from 80"C to 1500C.

25. A process according to any preceding claim, wherein the reaction is effected at a pressure of from 1 to 200 atmospheres.

26. A process according to claim 25, wherein the reaction pressure is in the range from 1 to 70 atmospheres.

27. A process for producing a compound having the formula I defined in Claim 1 or having the formula II defined in claim 5, substantially as described in any one of the foregoing Examples.

28. A derivative of malonic acid, whenever produced by a process according to any preceding claim.