DD202702A5 - PROCESS FOR THE PREPARATION OF 2,4-DIAMINO-5- (3 ', 4', 5 ', - TRIMETHOXYBENZYL) -PYRIMIDINE - Google Patents

Abstract

The invention relates to a novel process for the preparation of 2,4-diamino-5- / 3 ', 4', 5'-trimethoxybenzyl / pyrimidine by the reaction of a substituted alpha- / 3,4,5-trimethoxybenzyl / -beta acrylonitrile with guanidine. The 2,4-diamino-5- / 3 ', 4', 5'-trimethoxybenzyl / pyrimidine / trimethoprim / is used in medicine for the treatment of bacterial infections use. The process according to the invention is characterized in that alpha / 3,4,5-trimethoxybenzal / -beta-methoxypropionitrile is reacted with a diethylene glycol monoalkyl ether at a temperature of 60 to 90 ° C. in the presence of an alkali metal alkoxide, and the "benzyl" obtained. Isomer of formula II, wherein R represents an alkyl group of 1 to 4 carbon atoms, cycled, if desired without separation, with guanidine in the presence of an alkanol of 4 to 8 carbon atoms. The inventive method allows the economical production of trimethoprim also on an industrial scale. The total yield based on 3,4,5-trimethoxybenzaldehyde is approximately 80% of theory.

Description

9 A 1 Π R 3 3 "" ^ Berlin, 11.10.1932

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A process for the preparation of 2,4-DxaminG-5- (3 ^{f f} i4 »5 ¹ -trimethoxybenzyl) -pyrimidin

Field of application of the invention

The invention relates to a novel process for the preparation of 2,4-ßiamino-5- (3 '»4 *, 5'-trimetho: xybenzyl) pyrimidine of the formula I.

(I)

by the reaction of a substituted oL- (3 »4» 5-trimethoxybenzyl) -β-aoronitrile with guanidine

The 2,4-diamino-5- (3 '»4'» 5'-triinetiioxybenzyl) -pyriinidine of the formula I (trimethoprim) is a valuable drug of chemotherapeutic effect, which is used in the first row for the treatment of bacterial infections use.

Well-known technical solutions

Numerous processes have already been described for the preparation of the compound of the formula I. Part of these known processes are accomplished through the use of a substituted c £ - (3 »4,5-trimethoxybenzyl) -β-acrylonitrile.

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5o 3> 4,5-Triinethoxybenzaldehyd is condensed with ß-alkoxypropionitrile (GB-PS 957 797). The condensation product which forms sigH in a yield greater than 80 % of theory consists of about 80 % o6 - (3,4,5-IrimetiiCKybenzal) -β-alkoxypropionitrile and 20 % c * - (3> 4,5-). Trimethoxybenzyl) -β-alkoxyacrylonitrile In the next stage of the reaction, the condensation product is cyanated with guanidine. Only the "benzyl" compound participates in this reaction, and the "benzal" compound, meanwhile, hardly isomerizes into the "benzyl" compound , Thus, a maximum yield of 28 % of the theory can be achieved in the cyclization, as a result, the total yield based on 3 »4,5-trimethoxybenzaldehyde is at most 20 to 24 % of theory,

According to British Pat. No. 1,261,455, the economy of the above known process is attempted to be improved in such a way that the condensation product of 3,3,5-trimethoxybenzaldehyde and β-alkoxypropionitrile has been reacted with a minine. The * c - (3 , 4,5-trimethoxybenzal) -β-aminopropionitrile can be isomerized to the corresponding "benzyl" isomer in a yield of 40-50 % of theory. The latter compound can be celated with guanidine in 80 % yield of theory. Also in this Pail, the total yield based on 3 »4» 5-trimethoxybenzaldehyde is below 40% of theory.

According to British Patent 1,554,493, & - (3,4,5-triyaethoxybenzal) -β- (2-alkoxyethyl) -propionitrile is obtained by the condensation of 3,4,5-trimethoxybenzaldehyde with β- (2-alkoxyethyl) 2-yl ) propionitrile in a yield of above SO % of theory, then after separation and thorough purification at

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isomerized to the corresponding "benzyl" isomer at a temperature of 90 to 95 ^° C. and in the presence of a base. "Benzyl" isomer obtained Daa is converted with guanidine in trimethoprim in a yield of about 80 % of theory. Thus, the trimethoprim is obtained on a laboratory scale in a yield of 64 to 72 % of theory *

Although the latter known process is already of higher economic efficiency, there are various difficulties in industrial application. Thus, water evolves in the condensation of 3 ', 4'-5-trimethoxybenzaldehyde with β- (2-alkoxyethoxy) -propionitrile, and this ater is distilled at a high temperature of about 120 ⁰ G · at this temperature, the tfj- (3 "4" 5-irimethoxybenzal.) - .beta.-hydrolyzed (2-alkoxyäthoxy) propionitrile in the presence of water, our studies is iiach actually hydrolyzes the nitrile group, and the corresponding carboxylic acid is formed in an amount of a few percent. This lifting fraction, which gives rise to tarry lifting products, especially in the production on a large scale in the Tordergrund · Thus, the total yield, the laboratory on a 64 to 72 % of the theory is that even at a scale of about 10 moles fall to 50 to 55 % of theory, hence the host The suitability of the latter known method is insufficient on an industrial scale.

Object of the invention

It is an object of the invention to substantially increase the yield in the preparation of trimethoprim and to maintain this even when produced on an industrial scale.

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Essence of the invention

The invention has for its object to provide a novel process for the preparation of 2,4-diamino-5- (3 ^f »4 ', S'-trimethoxybenzyl) .- pyriraidine,

Ss has been found that the 2,4-Dianiino-5- (3 ^t "4 ^1, 5'-trißiethoxybenzyD-pyrijaidin can be produced economically in an industrial scale, if one οϋ- (3" 4,5-TrimethoxybenzaJL) β-2iethoxypropionitrile of the formula III

(III)

with a Diäthylenglykolmonoalkyläther of formula 17

Ho-CH ₂ GH ₂ -O-OH ₂ CH ₂ -OR (17),

wherein R is an alkyl group having 1 to 4 carbon atoms, at a temperature of 60 to 90 ⁰ G in the presence of a Alkalimetallalkosides umsetzf and the resulting "benzyl" isomer of the formula II

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GH GH ₃ O

Gh-O-GH ₂ GH ₂ -O-GH ₂ GH ₂ -OR (II),

wherein R has the above meaning - desirably without separation - with the guanidine in the presence of an alkanol having 4 to 8 carbon atoms cyclized.

The in the implementation of oil - ^(3,4,5-r i- ^ iniethos: ybenzal) - -beta-aethoxypropionitrii of formula III practically formed with the Diäthylenglykolmonoalkyläther the Pormel IT theoretical yield "benzal" -isomer of IPorniel Ha

GI

GH ₃ O

GH ₂ -O-OH ₂ GH ₂ -O-CH ₂ GH ₂ -Or

GH ₃ O

wherein R has the above meaning, is converted at a temperature of 60 to 90 ⁰ G in almost theoretical yield in the corresponding "benzyl" isomer of the oriel II, which is of high purity and also without separation and purification with guanidine can be cyclized.

The diethylene glycol monoalkyl ether of. Formula IV is beneficial diethylene glycol monomethyl ether. The connection of

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Formula IV is generally used in excess. In this Pail, this reaction component also plays the role of the solvent.

The alkali metal alkoxide is suitably an inorganic base, 25 · B, sodium methoxide, itfatriumäthoxid, potassium methoxide, etc. ·

The "benzyl" isomer of formula II and the "benzal" isomer of formula Ha are novel compounds. It is not necessary to separate the "benzal" isomer, this compound is usually added for 1 to 2 hours under the reaction conditions of the present invention theoretical yield into the "benzyl" isomer überfuhrt. The resulting "benzyl" isomer may also be separated, but if desired it is reacted with guanidine without separation.

The "benzyl" isomer of Formula II is conveniently cyclized with guanidine in the presence of an alkanol of 4 to 8 carbon atoms. As an alkahole of 4 to 8 carbon atoms, tertiary butanol or isobutanol is advantageously used. Of course, other solvents, ζζB, other alkanols, such as methanol, in addition to the alkanol with 4 to ". 8 carbon atoms in the reaction of the" benzyl "isomer with guanidine present ·

According to a preferred embodiment of the process according to the invention, the compound of the formula II is reacted without separation with guanidine. In this case, the diethylene glycol monoalkyl ether of the formula IV is also present if it has been used in excess in the preparation of the benzyl compound.

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The guanidine is useful as the acid addition salt, e.g. B. hydrochlorides of the "benzyl" compound, and released in the Reaktionsgeniisch with a base, preferably a Älkalimetallalkoxid from the 3 _a lz.

The implementation of the "benzyl" compound with guanidine is advantageously at a temperature of 70 to 100 ⁰ G, master at the boiling point dee "reaction mixture performed ·

The no- (3,4,5-trimethoxybenzal) -β-methoxypropionitrile used as the starting compound is prepared in a manner known per se by the reaction of 3,4,5-trimethoxybenzaldehyde with β-methoxypropionitrile. The β-methoxypropionitrile is obtained from acrylonitrile with methanol in an alkaline medium.

The inventive method allows the economical production of trimethoprim from the compound of formula III in one step also on an industrial scale, The total related to 3,4,5-irimethoxybenaaldehyd total yield is about 80 % of theory. The purity of the product is sufficient for therapeutic use.

embodiment

The process of the invention will be explained in more detail with reference to the following examples.

Preparation of the starting compound

1.75 g of potassium hydroxy are dissolved in 115 ml of methanol, and 55 g of acrylonitrile are dissolved in 20 ml of the resulting solution.

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utes added, the 'temperature is maintained by cooling below 40 ⁰ C · The reaction mixture is then stirred at 40 ⁰ G for one hour · 100 3.4 g _5-r are Trimetho3 To the mixture: ybenzaldehyd added and the reaction is conducted at 60 ⁰ C performed for 8 hours. The cooled to 30 ⁰ G mixture is added 55 ml of methanol and in several portions 30 g of potassium hydroxide was added · The crystal suspension formed is stirred for 5 hours, then cooled to 20 ⁰ G, and 500 ml of water to the crystal mass are added within 15 minutes · The Product is crystallized at a temperature of 5 to 10 ⁰ G, the precipitated crystals are filtered off, washed three times with 15 ml of methanol and three times with 100 ml of water, finally dried.

116 g of Ä, '- (3 »4,5-trimethoxybenzal) -β-metho3: ypropionitrile are obtained, which melts at 81 to 83 ⁰ G. The yield is 86 % of theory,

example 1

A mixture of 120 ml of anhydrous DjLäthylenglykolmonome thylather - 100 g 0 ^ - (3,4,5-Trimethöxybenzal) -ß-methoxypropionitrile and 5 g of powdered Uatriummethoxid be heated to 74 to 76 ⁰ G maintained for 3 hours at this temperature To the cooled to 30 ⁰ C mixture 160 ml of isobutanol, 40 ml of methanol, 85 g of guanidine hydrochloride and 50 g of powdered Hatriummethoxid be added, and the mixture at 35 to 40 ⁰ G for one hour and then at 90 to 92 ⁰ G 7 Stirred for hours. The resulting crystal suspension is cooled to 20 ⁰ G, filtered off, on the suction filter three times with 20 ml of methanol, then with 500 ml of water

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washed at 30 to 35 ⁰ G and dried ·

In such a way, 102 g of 2,4-diamino-5- (3 ^l > 4 ', 5'-trimethoxybenzyl) -pyrimidine, which melts at 198 to 201 ⁰ C. The graduation is 93 % of theory »

Example 2

A · du- C3> 4, 5-trimethoxybenzyl) -β- / "" 2- (2'-methoxyethoxy) -ethoxy-T-acrylonitrile

A mixture of 120 ml of anhydrous diethylene glycol monomethyl ether, 100 g oL - (3 "4, 5- ^ imetHoxybenzal) -ß-methoxypropionitrile and 5 g is latriummethoxid heated to 74 to 76 G ⁰ and stirred at this temperature for 3 hours, then at 20 cooled ⁰ g and poured into the mixture of 300 ml benzene and 500 ml of water »the organic phase is" separated, washed twice with 200 ml of water and the solvent was evaporated "the remaining 110 g of crude product is purified by distillation · the pure £ 6- (3,4,5-trimethoxybenzyl) -beta-2f "2- (2 ¹ -methoxyäthoxy) -äthox2; 7-acrylonitrile boiling at 208-214 ⁰ G under a pressure of 0.02 mm Hg"

B · 2,4-DIaBUnO-SO ¹ »4 ¹ , 5 * -trimethoxybenzyD-pyrimidine

To a mixture of 200 ml of isobutanol, 80 ml of methanol, 170 g of guanidine hydrochloride and 100 g of sodium methylate are added 200 g of 00- (3,4-bis-trimethoxybenzyl) -β- / "2- (2- ^f -methoxyethoxy) -ethoxy-acrylonitrile added in 120 ml of isobutanol. The reaction mixture is heated and boiled for 7 hours, then cooled to 20 ⁰ G. The crystal mass obtained is

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filtered off, washed three times with 20 ml of methanol on the hatch, then suspended in 500 ml of lukewarm water, filtered off again, washed through with water and finally dried.

There are thus obtained 174.5 g of 2,4-diamino-5- (3 ', 4 *, 5'-trimethoxybenzyl) -pyrimidine; The product melts at 198 to 201 ⁰ G. The yield is 95 % of theory.

Example 3

A mixture of 350 kg of anhydrous diethylene glycol monomethyl ether 300 kg CO - (3,4,5-2-Vime-ehoxybenzal) -ß-metho2: ypropionitril and 20 kg of powdered sodium methoxide is stirred for 4 hours at 78 to 80 ⁰ G and then 30 ⁰ G cooled · to the reaction mixture are added to 540 liters of isobutanol, 120 liters of "methanol 275 kg of guanidine hydrochloride and 16O kg of powdered itfatriummethylat, and the mixture is at 35 to 40 ⁰ G. for one hour and then at 90 to 92 ⁰ G 7 hours stirring. The resulting suspension is cooled to 20 ⁰ G, centrifuged and washed methanol with 200 liters · The wet product obtained is suspended in 1500 liters of water at 30 to 35 ⁰ G, then centrifuged, washed with 500 liters \ 7asser and dried ·

Thus, 300 kg of 2,4-diamino-5- (3 ', 4 ^l , 5 * -trimethoxybenzyl) -pyrimidine are obtained. The product "melts at 198-201 ⁰ G. The yield is 91% of '· Iheorie

Claims (1)

Brf ind unga ans pr ach # 1 A process for preparing 2,4-Biamino-5- (3 ^f "4 ^1, 5'-trijaiethoxybenzylj-pyrimidine of the formula I GH ₃ O by the reaction of a substituted .ρϋ- (3> 4,5-ΪΓΧ-methoxybenzyl) -J3-acrylonitrile with guanidine, characterized in that a qC - (3 »4» 5-irimethoxybenzal) -ßmethoxypropionitrile of the formula III (III) with a Diäthylenglykolmonoalkyläther the Pormel IY (IY), wherein R is an alkyl group having 1 to 4 carbon atoms, at a temperature of 60 to 90 ⁰ G in the presence of an alkali metal alkoxide, and the resulting 10 53 3 - ¹² - 11.10.1982 AP C 07 D / 241 053 60 969/12 "Benzyl" isomer of formula II GH-O-GH ₂ CH ₂ -O-GH ₂ CH ₂ -Or (II), wherein R has the above meaning, optionally without separation, cyclized with the guanidine in the presence of an alkanol having 4 to 8 carbon atoms. 2o method according to item 1, characterized in that one uses as the compound of formula IV Diäthylenglykolmonoinethyläther, 3 · Process according to item 1, characterized in that the sodium metal methoxide used is the alkali metal alkoxide. 4. The method according to item 1, characterized in that one carries out the reaction of the compound of formula III with the Diäthylenglykolmonoalkyläther of formula IV at 70 to 80 ⁰ C.