FI76790C - Process for Preparation of 2,4-Diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine - Google Patents

Description

76790

PROCEDURE FOR THE PREPARATION OF 2,4-DIAMINO-5- (3 ', 4', 5'-TRIMETHOXYBENTYL) PYRIMIDINE

The present invention relates to an improved process for the preparation of 2,4-diamino-5- (3 ', 4 *, 5'-trimethoxybenzyl) pyrimidine, wherein the compound of general formula * II ch3 ° CH3OY> CH2-i (II)) == / ch-o-CH2-CH2-or

CHjO

(wherein R is an alkyl group having 1 to 4 carbon atoms) is reacted with guanidine.

2,4-Diaraino-5- (3 ', 4, 5'-trimethoxy-benzyl) pyrimidine of formula I ch3o. CH3O - CH2 - NH2 (i)

CHjO

is a well-known chemotherapeutic agent (hereinafter referred to as trimethoprim).

Several methods for preparing a compound of formula I are known, some of which are via α- (3,4,5-trimethoxybenzyl) -8- (substituted) acrylonitriles.

Hungarian patent no. 149,799, 3,4,5-trimethoxy-benzaldehyde is condensed with 8-alkoxypropionitrile. The yield of the condensation reaction is more than 80 pounds and thus ____ .. im__ __ 2,76790 The condensation product obtained contains about 80 $ 6 α- (3,4,5-trimethoxybenzal) -β-alkoxypropionitrile and 20 56 α- (3,4,5-trimethoxybenzyl) - β-alkoxyacrylic nitrile. The condensation product is then reacted with guanidine. However, only the benzyl derivative participates in the reaction with guanidine, while the benzal compound isomerized to the benzyl compound to a very small extent. Thus, the yield of trimethoprim is at most 28% and the total yield at 3,4,5-trimethoxybenzaldehyde is at most 20-24 *.

Hungarian patent no. 162,316, the process described above can be made more economical by condensing 3,4,5-trimethoxybenzaldehyde with β-alkoxypropionitrile, reacting the condensation product thus obtained with an amine, the α- (3,4,3-trimethoxybenzaldehyde) thus obtained ) - β-aminopropionitrile is isomerized to the corresponding benzyl derivative and this is reacted with guanidine. However, the overall yield of trimethoprim relative to the starting 3,4,5-trimethoxybenzaldehyde is only average.

The Hungarian patent no. 174,318, 3,4,5-trimethoxybenzaldehyde is reacted with β- (2-alkoxyethoxy) propionitrile. There is thus obtained α- (3,4,5-trimethoxybenzal) -6- (2-alkoxyethoxy) propionitrile of general formula Ha

CH 3 O

y ~ \? ch3 ° ~ \ / CHi (IIa) \ = / ch2-o-ch2-ch2-or ch30 3 76790 (where R is as defined above) in more than 80% yield, And then this is isolated, thoroughly purified and isomerized 90-95 In the presence of a base to give the corresponding benzyl isomer of formula II, which is then reacted with guanaldehyde to form trimethimide in about 80% yield. Thus, the total yield of laboratory-scale trimethoprim production is about 64-72 *.

Although the method described above is much more economically advantageous than before, there are serious problems with its use on an industrial scale. In the reaction between 3,4,5-trimethoxy-benzaldehyde and (1- (2-alkoxylethoxy) propionitrile, water is formed, which distills off at about 120 ° C. At this high temperature * <- (3,4,5-trimethoxy-benzal ) - (*> - (2-alkoxyethoxy) propionitrile is hydrolyzed by the presence of water.

It has been shown that under these conditions the nitrile group is hydrolyzed and the corresponding carboxylic acid is formed by a few percent. This side reaction results in the formation of tarry by-products, which play a significant role in increasing the batch size.

Thus, the total yield of 64-72 * achieved on a laboratory scale drops to about 50-55 * Even when the batch size is about 10 moles. It can be stated that the known method described above is economically unsatisfactory.

U.S. Pat. 4,115,650 According to Examples 1 and 2, 3,4,5-trimethoxy-N-methoxymethylcinnamic acid nitrile prepared from 3,4,5-trimethoxybenzaldehyde and N-methoxypropionitrile, i.e. X- (3,4,5-trimethoxy-benzalaldehyde- methoxypropionitrile to react in the presence of an alkanol, an alkali metal alcoholate and ethylene glycol monomethyl ether to form a mixture of the corresponding enol ether, i.e. x- (3,4,5-trimethoxybenzyl) - [i-methoxyacrylonitrile] and its diacetal, ___ ίγ = ___ 4 76790 is cyclized with guanidinyl to 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimldine. Since only the enol ether is cyclizable with guanidine in good yield, it is not surprising that the final impurity The yield of the product, calculated on the basis of a cinnamic acid nitrile derivative, is only 74%.

The present invention is directed to an economically viable process for the preparation of 2,4-diamino-5- (3 ', 4', S'-trimethoxybenzyl) pyrimidine.

It has now been found that the β- (3,4,5-trimethoxybenzal) -methoxypropionitrile of formula III, CH 2 O, CH 2 = CH 2 = C <Ilr), = == / ch 2 -och 3 ch 3 can be trans-etherified according to the general formula The benzal isomer of formula Ha in almost quantitative yields is reacted with an ethylene glycol monoalkyl ether of general formula IV ho-ch2-ch2-or (IV) 5 76790 (where R is as defined above) and the compound of general formula Ha can be easily converted to the corresponding benzyl of general formula II. to the isomer in almost theoretical yields. The benzyl isomer of general formula II is so pure that it can be reacted with guanidine without isolation and purification to give trimethoprim.

This invention provides a process for the preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine of general formula I by reacting a compound of general formula II wherein R is an alkyl group having 1 to 4 carbon atoms) with guanidine by preparing said compound of general formula II by reacting an α- (3,4,5-trimethoxybenzal) -β-methoxypropionitrile of formula III with an ethylene glycol monoalkyl ether of general formula IV (wherein R is as defined above) to give an alkali metal alkoxide in the presence of 60-90 ° C and the compound of general formula II thus obtained is reacted - if desired without separation - with guanidine in the presence of an alkanol having 4 to 8 carbon atoms.

It is preferred to use ethylene glycol monomethyl ether as the compound of general formula IV. It is preferred to use the compound of general formula IV in excess, in which case it also acts as a solvent.

As the alkali metal alkoxide, it is preferable to use sodium methoxide.

It is not necessary to separate the benzal isomer of general formula IIa obtained by the reaction of α - (3,4,5-trimethoxybenzal) - β-methoxypropionitrile of formula III with ethylene glycol monoalkyl ether of general formula IV. When a temperature of 60 to 90 ° C - preferably 80 to 90 ° C is used under the reaction conditions, the benzyl isomer is formed quantitatively in a few hours. The benzyl isomer of general formula II can be isolated or, if desired, reacted with guanidine without isolation.

ΊΓΖ ___ _ e 76790

The benzyl isomer of general formula II is reacted with guanidine with an alcohol having 4 to 8 carbon atoms. For this purpose, it is preferable to use tert-butanol or isobutanol. The reaction between the benzyl isomer and guanidine can be carried out in the presence of another organic solvent (e.g., another alcohol such as methanol) in addition to the alcohol having 4 to 8 carbon atoms.

If, according to a preferred embodiment of this invention, a compound of general formula II is reacted with guanidine without isolation, the ethylene glycol monomethyl ether of general formula IV is always present in the ring-forming step of the reaction, provided that it is used in excess in the preparation of the benzyl derivative.

It is preferred to add guanidine in the form of an acid addition salt - e.g. hydrochloride - to the reaction mixture containing the benzyl derivative and to release guanidine from its acid addition salt in the reaction mixture by means of a base, preferably alkali metal alkoxy.

The reaction between the benzyl isomer and guanidine is preferably carried out at 70 to 100 ° C, preferably at the boiling point of the reaction mixture.

The ot- (3,4,5-trimethoxybenzal) -β-methoxypropionitrile of formula III is prepared in a known manner by reacting 3,4,5-trimethoxybenzaldehyde with β-methoxypropionitrile. β-Methoxypropionitrile is prepared by reacting acrylonitrile with methanol in a basic medium.

The process according to the invention makes it possible to prepare trimethoprim economically. The disadvantages associated with the method according to Hungarian Patent No. 174,318 have been eliminated.

7 76790

The total yield, based on 3 to 4,5-trimethoxybenzaldehyde, is about $ 80. According to the present invention, trimethoprim can be prepared from a compound of formula III in one step. The purity of the obtained product meets the therapeutic requirements.

The following examples are intended to illustrate the invention.

Example 1 Preparation of starting material 1.75 g of potassium hydroxide are dissolved in 115 ml of methanol.

To the resulting solution is added 55 g of acrylonitrile within 20 minutes at less than 40 ° C. The mixture is stirred for 1 hour at 40 DEG C. and then 100 g of 3,4,5-trimethoxy-benzaldehyde are added. The reaction mixture is stirred for 8 hours at 60 [deg.] C. and then cooled to 30 [deg.] C. and 55 ml of methanol and 30 g of potassium hydroxide are added in small portions. The resulting suspension is stirred for 5 hours, cooled to 20 ° C and 500 ml of water are added over 15 minutes.

The product is crystallized at 5-10 ° C, filtered, washed three times with 15 ml of methanol and three times with 100 ml of water and dried. 116 g of i * - (3,4,5-trimethoxybenzyl) -β-methoxypropionitrile are thus obtained. Sp. 8l-83 ° C. Yield: 86%.

Example 2 Preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine

A mixture of 100 g of * - (3,4,5-trimethoxybenzal) -N-methoxypropionitrile in 100 ml of anhydrous ethylene glycol and

monomethyl ether And 5 g of sodium methoxy are stirred in 3 l

hours at 82-84 ° C. The reaction mixture is cooled to 30 ° C and β 76790 is then added with 160 ml of isobutanol, 40 ml of methanol, 85 g of guanidine hydrochloride and 50 g of powdered sodium methoxy. The reaction mixture is stirred for one hour at 35-40 ° C and for 7 hours at 90-92 ° C. The crystal suspension is cooled to 20 ° C, filtered and washed on the filter three times with 20 ml of methanol. The resulting wet substance is washed with 500 ml of lukewarm water (30-35 ° C) and dried. 102.5 g of the title compound are obtained. Yield: 93.6%. Sp. 198-201 ° C.

Example 3

A mixture of 250 kg of (3,4,5-trimethoxybenzal) -b-methoxypropionitrile, 250 liters of anhydrous ethylene glycol monomethyl ether and 12.5 kg of sodium methylate is stirred for 3 hours at 85-88 ° C. Cool to 30 ° C, add 400 liters of isobutanol, 100 liters of methanol, 212.5 kg of guanldine hydrochloride and 125 kg of finely divided sodium methylate. The reaction mixture is stirred for 1 hour at 35-40 ° C and then for 7 hours at 90 ° C. The crystal suspension is cooled, centrifuged and washed with methanol. The product is washed with water at 30 ° C, centrifuged and dried. 254 kg (92%) of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) -pyrimidine are thus obtained.

The total yield based on 3,4,5-trimethoxybenzaldehyde is 79% ·

Claims (5)

9,76790 A process for the preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine of the general formula I CH2O NH2 CH5O - / y-NH2 (I) CH * O to give a compound of the general formula II CH30v \ = / ch-o-ch2-ch2-or ch3o josssrR is an alkyl group having 1 to 4 carbon atoms, reacted with guanidine, characterized in that a compound of general formula II is prepared by reacting an α- (3 → 4.5) compound of general formula III -trimethoxy-benzal) -8-methoxypropionitrile ch3o_y ~ \ in CH30 -f V CH = C y = / E h2-och3 (iii) ch3o to react with an ethylene glycol monoalkyl ether of general formula IV 76790 H0-CH2-CH2-O <iv) wherein R is as defined above, in the presence of an alkali metal alkoxide in the temperature range 60-90 ° C and reacting the resulting compound of general formula II - if desired without isolation - with guanidine in the presence of an alkanol having 4 to 8 carbon atoms. Process according to Claim 1, characterized in that the reaction between the compound of the formula III and the ethylene glycol monoalkyl ether of the formula IV is carried out in the temperature range BO to 90 ° C. Process according to Claim 1, characterized in that sodium methoxide is used as the alkali metal alkoxide. ιι 76790 A process for the preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) -pyrimidine of the formula I CH30 nh2 ch3o- ^ ^ -ch2— ^ ^ -nh2 (I) ch3o genome addition of a compound of formula II CH30 \ _ CN ch3o _ // _ch2 - C (II) \ = / 1) - 'ch-o-ch2-ch2-or ch3o color R is an alkyl group with 1-4 cholaters and guanidine, selected from the group consisting of compounds of formula (II) of the genome of α- (3,4,5-trimethoxybenzal) -β-methoxypropionitrile of formula III CH30 \, CN i (III) ch3o - </ y— ch = c) ch2-och3 ch3o with ethylene glycol monoalkylate with the formula IV HO-CH2-CH2-OR (IV)