Title of Invention

PROCESS FOR PREPARING MALONIC ESTERS

Abstract The present invention relates to a process for preparing malonic esters of the general formula where R is C1-10-alkyl, C3-10-alkenyl or aryl C1-4-alkyl, wherein an alkali metal salt of malonic acid is reacted with a halide of the general formula R-X (II), where R is as defined above and X is chlorine, bromine or iodine, in the presence of water and a phase-transfer catalyst.
Full Text

L.P- 1830, Foreign Countries
LONZA AG, Munchensteinerstrasse 38, CH-4052 Basle Process for preparing malonic esters

Description
The invention relates to a process for preparing malonic esters of the general formula

where R is C1-10-alkyl, C3-10-alkenyl or aryl-C1-4-alkyl.
The two customary methods of preparing malonic esters start from derivatives of chloroacetic acid. In one method, an ester of chloroacetic acid is reacted with carbon monoxide and alcohol in the presence of a catalyst based on cobalt carbonyl (DE-A 23 59 963, DE-A 25 24 389) while in the other method a salt of chloroacetic acid is reacted with cyanide to form cyanoacetate in a first step and this intermediate is then reacted with alcohol in a second step to convert it into the malonic ester. The latter method in particular is associated with safety and ecological problems owing, to the toxicity of hydrocyanic acid and cyanides and the large amounts of waste. The obvious method of preparing esters by direct esterification of the acid with the appropriate alcohol plays no role in this case; conversely, malonic acid is prepared by hydrolysis of malonic esters (or cyanoacetic acid).
It is an object of the present invention to provide an alternative route to malonic esters. This object is achieved according to the invention by thevprocess of Claim 1.
It has been found that alkali metal salts of malonic acid can be reacted with halides of the general formula R-X (11), where R is C1-10-alkyl, C3-10-alkenyl or aryl-C1-4-alkyl and X is chlorine, bromine or iodine, in the presence of water to give the corresponding malonic esters of the general formula


where R is as defined above, if a phase-transfer catalyst is present.
Here and in the following, C1-10-alkyl can be any linear or branched, primary, secondary or tertiary alkyl group having 1-10 carbon atoras, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl' etc.
C3-10-alkenyl is a linear or branched alkenyl group having 3-10 carbon atoms, in particular one whose double bond is separated from the free valence by at least one saturated carbon atom, for example allyl, methallyl, 2-butenyl (crotyl)' 3-butenyl, 2-pentenyl, etc,
Aryl-C1-4-alkyl is, in particular, a phenyl-substituted C1-4-alkyl group such as benzyl, phenethyl or 3-phenylpropyl, where the phenyl group may also bear one or more identical or different substituents such as C1-4-alkyl, C1-4-alkoxy or halogen.
Here and in the following, phase-transfer catalysts are 'the compounds customarily used for this purpose, in particular quaternary ammonium or phosphonium salts.
As alkali . metal salt of malonic acid, preference i5 given to using disodium malonate.
As halide R-X (II), preference is given to using a chloride or bromide.
The alkali metal salt of malonic acid is preferably used in the form of an aqueous solution. Particular preference is given to the solutions obtained by catalytic oxidation of 1, S-'propandiol in the presence of aqueous alkali metal hydroxide• The preparation of such solutions is described, for example, in DE-A 41 07 986.
hs phase-transfer catalyst, preference is given to using a quaternary ammonium salt• Particular preference is given to tetra-n-C4-ic)-alkylammonium, benzyl tri-n-Ci-8-alkylammonium and methyltri-n-C'4-io-alkylaxnmonium halides, where halide is preferably

chloride or bromide• Examples which may be mentioned here are tetrabutylamrtionium and tetrahexylammonium bromides and benzyltributylammonium chloride.
The process of the invention is advantageously carried out at temperatures of 80-150'C, when using low-boiling halides (II) conveniently under superatmospheric pressure.
Apart from water, it is advantageous to use an inert solvent which is not miscible with water. Examples of suitable solvents of this type are relatively unreactive aliphatic or aromatic chlorinated hydrocarbons such as chlorobenzene or ethers such as tert-butyl methyl ether.
The following examples illustrate the manner in which the process of the invention may be carried out, without implying a restriction.
Example 1 Dimethyl malonate
In an autoclave, 10 g (about 0.2 mol) of methyl chloride were passed into a solution of 2.96 g (20 mmol} of disodium malonate and 0.64 g (2 mmol) of tetrabutylammonium bromide in 5 ml of water while cooling in ice• The mixture was heated to 100°C over a pei;iod of 4 5 minutes' with the pressure in the autoclave rising from 4 bar to 14 bar. After a reaction time of 3 hours at 100°C, the mixture was cooled to room temperature and depressurized. The aqueous phase was brought from pH 4.6 to pH 5.7 using 1 M sodium hydroxide solution and extracted with tert-butyl m.ethyl ether (2x10 ml). The combined organic phases were dried over sodium, sulphate and analysed by gas chromatography (internal standard: dimethyl succinate). Yield: 48%,
A yield of 46% was obtained in tert-butyl methyl ether/water (v:v=8;5) as reaction medium under otherwise/identical/conditions.

Example 2 Diethyl malonate
In an autoclave, 10.9 g (0,1 mol) of ethyl bromide were added to a solution of 2.96 g (20 ramol) of disodium malonate and 0*64 g (2 mitiol) of tetrabutylammonium bromide in 5 ml of water and 10 ml of tert-butyl methyl ether. The mixture was heated to 100°C over a period of 30 minutes, with the pressure in the autoclave rising to 3.5 bar. After a reaction time of 3' hours at the mixture was cooled to room temperature and depressurized. The aqueous phase was brought from pH 4.2 to pH 5.5 using 1 M sodium hydroxide solution and extracted with tert-butyl methyl ether (2x5 ml). The combined organic phases were dried over sodium sulphate and analysed by gas chromatography (internal standard: dimethyl succinate)-Yield: 45%.
Sxample 3 Dibenzyl malonate
In an autoclave, 17.1 g (0-1 mol) of benzyl bromide were added to a solution of 2.96 g (20 mmol) of disodium malonate and 0,64 g (2 mmol) of tetrabutylammonium bromide in 5 ml of water and 10 ml of tert-butyl methyl ether. The mixture was heated to 100'C over a period of 30 minutes' with the pressure in the autoclave rising to 2,5 bar. After a reaction time of 3' hours at 100'0, the mixture was cooled to room temperature and depressurized. The aqueous phase was brought from pH 1.8 to pH 5.8 using 1 M sodium hydroxide solution and extracted with tert-butyl methyl ether (2x5 ml). The combined organic phases were dried over sodium sulphate, the solvent was distilled off on a rotary evaporator and the residue was freed of solvent residues under reduced pressure (1 mbar). Yield: 2.43 g (43%) .

'H NMR (CDCI3, 400 MHz):6' 7 .25-7 , 40 (m, lOH) ; 5,16{s,4H); 3.47 (s,2H).
When using benzyl chloride instead of benzyl bromide, a yield of 34% was obtained under identical reaction conditions,
Example 4 Diallyl malonato
In an autoclave, 7.65 g (0.1 mol) of allyl chloride were added to a solution of 2.96 g (20 mmol) of disodium malonate and 0.64 g {2 mmol) of tetrabutylammonium bromide in 5 ml of water and 10 ml of chlorobenzene. The mixture was heated to 100°C over a period of 30 minutes, with the pressure in the autoclave rising to 2.5 bar. After a reaction time of 3' hours at 100 "C, the mixture was cooled to room temperature and depressurized- The aqueous phase was extracted with tsrt-butyl methyl ether (2x5 ml). The combined organic phases were dried over sodium sulphate and analysed by gas chromatography (internal standard: dimethyl succinate)-Yield: 16%.
Examples 5-12 Dimethyl malonate
General procedure:
In an autoclave, 10 g (0.2 mol) of methyl chloride were passed into a solution of 2.96 g (20 mmol) of disodium malonate and 0.1 equivalents (2 mmol) ' of the phase-transfer catalyst in 5 ml of water and 10 ml of chlorobenzene while cooling in ice. The mixture was heated to the desired temperature over a period of 30 minutes. After a reaction time of 3 hours at the appropriate temperature, the mixture was cooled to room temperature and depressurized. The aqueous phase was brought to pH 5 • 5-6.5 using 1 M sodium

hydroxide solution and extracted with tert-butyl methyl ether (2x10 ml)• The combined organic phases were dried over sodium sulphate and analysed by gas chromotography (internal standard: dimethyl succinate)- The reaction conditions and the yields achieved are summarized in Table 1 below.
'TBAB = tetrabutylammionium bromide,
THAB=tetrahexylammonium bromide, BTBACl =
benzyltributylammonium chloride
'GC, internal standard: dimethyl succinate
'with addition of 10 moll of KBr



1. Process for preparing malonic esters of the
general formula

where R is C1-10-alkyl, C3-10-alkenyl or aryl-C1-4-alkyl, characterized in that an alkali metal salt of malonic acid is reacted with a halide of the general formula R-X (II)f where R is as defined above and X is chlorine, bromine or iodine, in the presence of water and a phase-transfer catalyst.
2. Process according to Claim 1, characterized in that the alkali metal salt of malonic acid which is used is disodium malonate,
3. Process according to Claim 1 or 2, characterized in that X is chlorine or bromine.

4. Process according to any of Claims 1 to 3, characterised in that the alkali metal salt of malonic acid is used in aqueous solution.
5. Process according to Claim 4, characterized in that the aqueous solution of the alkali metal salt is a solution obtained by catalytic oxidation of 1,3-prppandiol in the presence of aqueous alkali metal hydroxide.
6- Process according to any of Claims 1 to 5, characterized in that the phase-transfer catalyst used is a quaternary ammonium salt.
7, Process according to Claim 6, characterized in that the quaternary ammonium salt used is a tetra-n-C4-10-alkylammonium, benzyltri-n-C1-6-alkylammonium or methyltri-n-C4-10 alkylammonium halide, preferably chloride or bromide.

8, Process for preparing malonic esters of the general formula, substantial1y as herein described and exemplied-


Documents:

0009-mas-2000 abstract-duplicate.pdf

0009-mas-2000 petition.pdf

009-mas-2000-abstract.pdf

009-mas-2000-claims filed.pdf

009-mas-2000-claims grand.pdf

009-mas-2000-correspondnece-others.pdf

009-mas-2000-correspondnece-po.pdf

009-mas-2000-description(complete) filed.pdf

009-mas-2000-description(complete) grand.pdf

009-mas-2000-form 1.pdf

009-mas-2000-form 19.pdf

009-mas-2000-form 26.pdf

009-mas-2000-form 3.pdf

009-mas-2000-form 5.pdf

009-mas-2000-other documents.pdf

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Patent Number 210644
Indian Patent Application Number 9/MAS/2000
PG Journal Number 50/2007
Publication Date 14-Dec-2007
Grant Date 08-Oct-2007
Date of Filing 06-Jan-2000
Name of Patentee M/S. LONZA LTD
Applicant Address MUNCHENSTEINETRASSE 38,CH 4002 BASEL.
Inventors:
# Inventor's Name Inventor's Address
1 DR STEFAN HILDBRAND BARETSTRASSE 8a,CH 3930 VISP
2 DR PAUL HANSELMANN HOLZAACHRA 25,CH 3902,BRIG-GLIS.
PCT International Classification Number C07C 67/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 99100411.0 1999-01-11 EUROPEAN UNION