DD151624A1 - METHOD OF PREPARING 3-DIMETHYLAMINO-2-CYANACRYLIC ACID ESTERS - Google Patents

Abstract

3-Dimenthylamino-2-cyanoacrylic acid esters can advantageously be prepared in good yields by reacting a cyanoacetic acid ester with dimethylformamide in the presence of thionyl chloride as a hardening agent in a molar ratio of 1: 1: 1 to 1: 2: 2 at temperatures between room temperature and 90 ° C condensed in the absence of acid acceptors such as tertiary organic bases in an indifferent solvent.

Description

the invention

Process for the preparation of 3-dimethylamino-2-cyanoacrylates

Field of application of the invention

The invention relates to a process for the preparation of 3-dimethylamino-2-cyanoacrylic acid esters of the general formula

IT - CH = C · COOR

where R is an optionally branched lower alkyl radical having 1 to 4 C atoms »

These compounds serve as intermediates, for example, for the preparation of medicaments such as the 4-hydroxy-1H-pyrazolo / ~ 3,4-d7pyrimidine (allopurinol), a therapeutic agent for the treatment of gout.

222 001

'- 2 ·.'. Characteristic of the known technical solutions

Ea is known that 3-dimethylamino "2-eyanacrylsäureester can be prepared by condensation of cyanoacetic acid esters with dimethylformamide dialkylaeetalen or bis-dimethylamino-alkoxymethanen, this synthesis route is complicated, since suitable for the implementation of dimethylformamide dialkyl acetals and bis-dimethylaminoalkoxymethane cumbersome way of producing manufactured »

Thus, dimethylformamide dialkyl acetals are prepared by alkylation of dimethylformamide with dialkyl sulfates (Chem. Ber. 96, 1350 (1963)) and subsequent treatment with alkali metal alcoholates (Chem. Ber. 221a ¹ (1968)). Their isolation from the alcoholic reaction mixture is described in DD-PS Ur. 94 359 described as cumbersome and time-consuming · The Äbdestill- tion method improved by this patent, however, is difficult to realize on an industrial scale ·

The bis-aimethylamino-alkozymethane arise when treating the resultant of the Dirnethylforiaamid-dialkyl sulphate adducts and dimethylamine H, U, IP, H ^f -Tetramethylformamiainium sulfates (with alcohol-free alkali metal in ether, cyclohexane or hexane Chem · Ber. 101, 41 ( 1968)) ·

The hitherto most simple method of production of 3-dimethylamino ~ 2-cyanoacrylic acid esters consists in refluxing Cyaneasigeatern and dimethylformamide with a 10-fold Acetanhydridüberschuß (Arch Pharm 2 ^ j _x 516 (1962).). · The low yield 35-40% of theory and the disproportionately large amount of acetic anhydride are substantial disadvantages of this method. In addition, according to our investigations, in particular with variation of the reaction conditions to achieve a better space-time yield, this process is post-combusted both by the accumulation of large quantities of carbon monoxide gaseous by means of additional equipment and, because of the mixture of starting and reaction products, which are difficult to separate by distillation, without special equipment, are not suitable for a technical application and are also not very environmentally friendly »

When this process is modified to use phosphorus oxychloride in place of acetic anhydride, the yield is about 47% of theory for ethyl 3-dimethylamino-2-cyanoacrylate, when excess dimethylformamide is used as the solvent (Z. obs., Chim 4050 (1962)), but the work-up is very complicated. Thus, the reactants are combined with cooling at 0 ⁰ C and then heated. It must be poured on ice, neutralized, extracted, dried and finally distilled under vacuum, the disadvantage is that in the technical implementation of this method in addition to the Peinvakuumdestillationsanlage also a brine cooling is required.

When working with phosphorus oxychloride in benzene, the yield drops to 7 % of theory (Chem. Ber. _X 2278 (1961)). .

Cyanoacetic acid ethyl ester and dimethylformamide could also be condensed in the presence of ethyl chloroformate and triethylamine to give compound I (R - C ₂ Hc ^- J ¹ ".) The yield was only 31 % of theory, since in a lifting reaction 2 moles of ethyl cyanoacetate with one mole of dimethylformamide to methenyl 3-Ethoxy-2-cyanoacrylic acid ethylacetate was obtained without the addition of the auxiliary base (Tetrahedron Letters, 1JySg, 3279) The expensive ethyl chloroformate and the low yield do not justify the use of this acid chloride for the preparation of 3-dimethylamino -2- · eyanacrylsäureäthylester.

When using phosgene as a condensing agent in the reaction of ethyl cyanoacetate with dimethylformamide with the addition of triethylamine has been achieved with 75 % of theory, the best known from the literature yield (Chem * Ber * % ^ 2278 (1961)). However, this synthesis variant has a number of disadvantages, such as the additional use of an auxiliary base combined with the technologically complicated separation of the triethylammonium chloride, complicated handling of the phosgene and necessary distillation of the reaction product *,

Object of the invention

The invention makes it possible to prepare the 3-dimethylamino-2-cyanoacrylic acid esters of the general formula I from cyanoacetic acid esters and dimethylformamide in an economically favorable manner and in high purity. ;

All waste products of the process according to the invention are gaseous and can be easily removed.

The space-time yield for the process according to the invention is about three times the phosgene or phosphorus oxychloride variant and about nine times that of the acetic anhydride process. The yield is between 68 and theory based on cyanoacetic ester used.

The process of the invention is also characterized by simple technological operations and low requirements for the equipment. "Compared to the previously described in the literature and using acid chlorides such as POClO, COCl ₂ or 8-chloroformate Ethyläthylester running process accounts for the liquid-Plüssig- or Pest-Plus separations to remove the alkali or triethylammonium salts.

The time-consuming and demanding apparatus vacuum distillation to obtain the 3-dimethylamino-2-cyan. acrylic acid ester is also no longer required.

Moreover, it is by the present method, the avoided with previous procedures notwendi ge cooling to 0 ⁰ C "" On an industrial scale for the apparatus and energy-intensive brine cooling would be required.

The uncontrollable lifting reactions which are to be feared in the known methods for keeping the required low temperatures during the addition of the reactants in the known methods are avoided in the method according to the invention. This simultaneously increases the protection quality compared with the previously known methods.

Explanation of the essence of the invention

The object of the invention is a technically easy to carry out process for the preparation of 3-dimethylamino-2-eyanacrylsäureestern the general formula

U - CH = C - COOR I

/ I CH ₃ CN

wherein R has the meaning given above, by condensation of cyanoacetic esters of the general formula

- COOR II

wherein R has the abovementioned meaning to find with dimethylformamide, which allows the preparation of the compounds of general formula I in an economically favorable manner and in high purity * '

Surprisingly, this reaction can be achieved by reacting cyanoacetic esters of the general formula II, dimethylformamide and thionyl chloride in a molar ratio of 1: 1: 1 to 1: 2: 2, preferably 1: 1: 1 to 1: 1.25: 1.25 at temperatures between room temperature and 90 ⁰ C ₁ is preferably 40 to 90 ⁰ C, in the absence of acid acceptors v / ie tertiary organic bases in an inert Lösungemittel, for example a hydrocarbon such as toluene or a halogenated hydrocarbon such as carbon tetrachloride or methylene chloride, is reacted.

The reaction time is generally 2 to 6 hours, but it can be extended depending on the reaction procedure.

A particular embodiment of the invention is to provide the cyanoacetic acid ester and the dimethylformamide and to gradually add the thionyl chloride.

Hach completion of reaction is conveniently distilled off the solvent, whereby 90 ⁰ G should not be übereehritten if possible, the distillation residue in alcohols such. B. isopropanol or other organic solvent and crystallized the 3-dimethylamino-2-cyanoacrylic acid ester of the general formula I in good quality and yield »

The high yield without the use of a hydrochloric acid acceptor is all the more astonishing, as it is known that eich Cyanessigsäureäthylesteri: dimethylformamide and · phosphorus oxychloride in the presence of hydrogen chloride in Molverhältnia 1: 2: 2 convert to a substituted Azapentamethiniumsalz in 89 $ iger yield (Coil.

  - δ -

czechoslov · chem, Commun. & 1565 (1976)). However, according to the process of the invention, the ethyl 3-dimethylamino-2-cyanoacrylate was obtained in 79% yield when the same Mo ratio was chosen.

Embodiment Example 1

113.1 g of ethyl cyanoacetate, 73.1 g of dimethylformamide and 200 ml of carbon tetrachloride are heated to boiling in a 500 ml three-necked flask. Into this solution is added dropwise with stirring within 3 hours 119 g of thionyl chloride. Bach complete addition is stirred for 2 hours at reflux and the carbon tetrachloride in a water jet vacuum at bath temperatures up to 90 ⁰ C distilled off.

Hach TJV spectrometry salary determination (measurement at the UV maximum at 285 microns) contains the distillation residue 129 g of ethyl 3 ~ bimethylamino-2-cyanoacrylsäure, corresponding to 79 % of theory based on ethyl cyanoacetate ·

Example 2

In a 500 ml three-necked flask, 113.1 g of 97% pure ethyl cyanoacetate, 91.5 g of dimethylformamide and 200 ml of carbon tetrachloride are heated to reflux. Within 3 hours, while stirring 149 g of thionyl chloride and stirred for further 2 hours under reflux Wasseratrahlpumpenvakuum · In is up to a maximum bath temperature of 90 ⁰ C · to concentrated hot residue is added 240 ml of isopropanol is stirred under water-cooling,

sucks and washed with isopropanol * Uach drying gives 111 g of 3 ~ dimethylamino-2-cyanoacrylatäthylester corresponding to 68 % of theory based on ethyl cyanoacetate * F, 78.5 to 80 ⁰ C,

Example 3

56.6 g Cyanesaigaäureäthyleater 97% pure, 36.6 g of dimethylformamide and 100 ml of methylene chloride are heated to reflux. 59.5 g of thionyl chloride are added dropwise with stirring within 3 hours, stirred for 3 hours at reflux temperature and distilled daa solvent to a maximum bath temperature of 90 ⁰ C ·

The yield of 3-dimethylamino-2-cyanoacrylsäureäthyleater is 69.8 % of theory (UV spectrometric determination) ·

Example 4

113.1 g of 97% pure Cyaneasigsäureäthyleater, 73.1 g of dimethylformamide and 200 ml of carbon tetrachloride are heated in a 500 ~ ml three-necked flask to reflux and dripped over 3 hours 149 g of thionyl chloride at reflux temperature * The carbon tetrachloride is distilled off in a light Vfesserstrahl.pumpenvakuum. It is concentrated to a bath temperature of max * 90 ⁰ C.

The result is a yield of 3-dimethylamino-2-cyanoacrylsäureäthylester of 83.4% of theory based on cyaneacetic acid ethyl ester used (UV spectrometric determination),

222 001

Beiapiel 5

113.1 g of Cyane8sigsäureäthyleater 97 $ ig, 146.2 g of dimethylformamide and 200 ml of carbon tetrachloride before in a 1-1 three-necked flask. Ea is heated with stirring under reflux and within 3 hours 238 g of thionyl chloride are added dropwise at reflux temperature. The! Carbon tetrachloride is distilled off at Waaaeratrahlpumpenvakuum up to a maximum bath temperature of 90 ⁰ C "

The content of deacidyl acetate on 3-dimethylamino-2-cyanoacrylic acid ethyl ester corresponds to a yield of 79 % of theory, based on the cyaneate acid ethylacetate used,

Beiapiel 6

99 g of methyl cyanoacetate, 91.5 g of dimethylformamide and 200 parts of carbon tetrachloride carbon are reacted analogously to example 2 ". 109.5 g of 3-dimethylamino-2-cyanoacrylic methacrylate are obtained as described. Baa is 71 % of theory ,

Claims (3)

claims The process for the preparation of 3-dimethylamino-2 ~ cyan acrylic acid esters of the general formula - CH = G - COOR
I
CN in which R is an optionally branched lower alkyl radical having 1 to 4 C-atoms, by condensation of cyanoacetic acid esters with dimethylformamide and in the presence of a condensing agent such as acetic anhydride, phosphorus oxychloride, ethyl chloroformate or phosgene and optionally in the presence of a tertiary organic base as acid acceptor, characterized in that a cyanoacetic acid ester of the general formula ITC - CH ₂ - COOR 'II wherein R has the abovementioned meaning, with dimethylformamide in the presence of. Thionylchlorid as condensing agent in a molar ratio of 1: 1: 1 to 1: 2: 2, preferably 1: 1: 1 to 1: 1.25: 1.25, at temperatures condensed between room temperature and 90 C, preferably between 40 and 90 ⁰ C in the absence of acid acceptors such as tertiary organic bases in an inert solvent. 'I'll UUi ~ 12 - 2, process according to item 1, characterized in that as indifferent organic solvent, a hydrocarbon such as toluene or a halogenated hydrocarbon such as carbon tetrachloride or methylene chloride is used * 3 Process according to items 1 and 2, characterized in that the cyanoacetic acid ester of the formula II and the dimethylformamide are initially introduced and the thionyl chloride is gradually added.