DK155668B - METHOD FOR PREPARING 2,4-DIAMINO-5- (3 ', 4', 5'-TRIMETHOXYBENZYL) -PYRIMIDINE - Google Patents

Description

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The present invention relates to a particular process for the preparation of 2,4-diamino-5- (3,4,4,5,5-tri-methoxybenzyl) -pyrimidines of the formula CELO NHO 5 CH 2 O- / CH-V. -NH- (X)

3 V / 2 W

οά / 10 by reacting an α- (3,4,5-trimethoxybenzyl) -β- (substituted) acrylonitrile with guanidine.

2,4-Diamino-5- (31,41,51-trimethoxybenzyl) -pyrimidine, known as trimethoprim, is a valuable pharmaceutical composition with very potent antibacterial activity.

Several methods have been described for the preparation of trimethoprim, part of which is carried out using α- (3,4,5-trimethoxybenzyl) -β- (substituted) acrylonitrile.

Thus, according to GB patent specification no.

20 957.797 3,4,5-trimethoxybenzaldehyde with β-alkoxypropionitrile to produce a condensation product in a yield of over 80%. The reaction product consists of approx. 80% α- (3,4,5-trimethoxybenzal) -β-alkoxy-acrylonitrile and approx.

20% α- (3,4,5-trimethoxybenzyl) -β-alkoxyacrylonitrile. In the subsequent step, the condensation product is cyclized with guanidine. However, only the "benzyl" compound participates in the cyclization reaction, while practically no isomerization of the "benzal" compound to the "benzyl" compound. As a result, a yield of trimethoprim exceeding 28% cannot be obtained, i.e. the total yield calculated for 3,4,5-trimethoxybenzaldehyde is no more than 20-24%.

According to GB Patent No. 1,261,455, the condensation product of 3,4,5-trimethoxybenzaldehyde and β-35-alkoxypropionitrile is reacted with an amine to give α- (3,4,5-

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-trimethoxybenzal) -β-aminopropionitrile, which can be isomerized to the corresponding "benzyl" isomer in a 40-50% yield. The latter isomer can be cyclized with guanidine to give trimethoprim in 80% yield. However, the overall yield of trimethoprim, calculated for 3.4.5-trimethoxybenzaldehyde, even by this method is lower than 40%.

According to GB Patent No. 1,554,493, 3.4.5-trimethoxybenzaldehyde is reacted with a β- (2-alkoxy-ethoxy) -10-propionitrile to give α- (31,4 ', 5'-trimethoxybenzal) -β- ( 2-alkoxyethoxy) -pripionitrile in a yield of more than 80%. After separation and careful purification, this compound is isomerized to the corresponding "benzyl" isomer in the presence of a base at a temperature in the range 90-95 ° C. The "benzyl" isomer is reacted with guanidine to give trimethoprim in a yield of ca. 80%.

Thus, the overall yield is 64-72% by laboratory scale.

Although the last described process is actually more economical than the former, some difficulties arise when applied at the factory level. The water formed by the condensation reaction of 3,4,5-trimethoxybenzaldehyde and β - (2-alkoxyethoxy) propionitrile is distilled off at high temperature, e.g. ca. 120 ° C. At such a high temperature, the α- (3,4,5-trimethoxybenzal) -β- (2-alkoxyethoxy) propionitrile is hydrolyzed by the water present. It has now been found, according to the invention, that the hydrolysis of the nitrile group takes place as a parallel reaction and the corresponding carboxylic acid is prepared. In this reaction, tar-like byproducts are formed. The amount thereof is increased by the use of larger batch quantities. Thus, the total yield obtained from the laboratory scale of 64-72% becomes as low as 50-55% with a batch size of approx. 10 mol.

As a result, in GB patent no.

35 1,554,493 discloses not sufficiently economical for industrial use.

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The object of the present invention is to provide an economically industrially useful process for the preparation of 2,4-diamino-5- (3 ', 41,5' - trimethoxybenzyl) pyrimidine.

According to the invention, it has been found that if α- (3,4,5-trimethoxybenzal) -β-methoxypropionitrile of the formula CH-O 3

X___ CN

CH 2 - / - -CH = C (XII) V- / 1H 2 -OCH 3 CH 2 / reacted with a diethylene glycol monoalkyl ether of the formula ho-ch2ch2-o-ch2ch2 or (IV) wherein R is an alkyl group having 1-4 carbon atoms, the "benzal" isomer of the formula CH 3

20 \ _. CN

CH30- / \ -CH = C (IIa)

_ // CH2-0-CH2CH2-0-CH2CH2-0R

αΗ3οκ 25 where R has the meaning given above, and is prepared in theoretical yield, for the corresponding "benzyl" isomer of the formula CH

\ _ CN

/ - \ in 30 CH30-./ \ -CH2-C (II) V-carbonyl-ch2ch2-o-ch2ch2-or where R has the meaning given above, already at a temperature as low as 60-90 ° C and in almost theoretical yield.

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The "benzyl" isomer thus prepared is of such purity that it - optionally without separation and purification - can be cyclized with guanidine to form trimethoprim.

According to the present invention, 5,4-diamino-5- (3 ', 41,5'-trimethoxybenzyl) pyrimidine of formula (I) is prepared by reacting an α- (3,4,5-trimethoxybenzyl) -β- (substituted) acrylonitrile with guanidine, wherein an α- (3,4,5-trimethoxybenzal) -β-methoxypropionitrile of formula (III) is reacted with a diethylene glycol monoalkyl ether of formula (IV) at 60-90 ° C. in the presence of an alkali metal alkoxide, and the benzyl isomer of formula (II) prepared is reacted - optionally without separation - with guanidine in the presence of an alkanol of 4-8 carbon atoms.

As the compound of formula (IV) is used for stepwise diethylene glycol monomethyl ether. This compound is commonly used in excess, and in this case no separate solvent is required.

As the alkali metal alkoxide, sodium methoxide, sodium ethoxide, potassium methoxide, etc. are preferably used.

The "benzyl" isomer of formula (II) as well as the "benzal" isomer of formula (IIa) are novel compounds. The "benzal" isomer need not be isolated, and in the process of the invention it is quantitatively converted to the "benzyl" isomer in usually 1-2 hours. The "benzyl" isomer formed can be isolated, but if desired, it is cyclized with guanidine without isolation.

The "benzyl" isomer of formula (II) is cyclized with guanidine, preferably ± the presence of an alkanol having from 4 to 8 carbon atoms, such as a tertiary butanol or isobutanol. Of course, other organic solvents may also be present in the cyclization reaction, e.g. a further alkanol such as methanol.

If the compound of formula (II) is not isolated before the cyclization with guanidine, there is also any

DK 155668B

An excess of the diethylene glycol monoalkyl ether of formula (IV) used in the preceding reaction is present in the cyclization.

Guanidine is preferably used as an acid addition salt such as hydrochloride. In this case, guanidine is released from the acid addition salt in the reaction mixture with a base which may conveniently be alkali metal alkoxide.

The cyclization of the "benzyl" isomer is generally carried out at 70-100 ° C, especially at the boiling point of the reaction mixture.

The α- (3,4,5-trimethoxy-benzal) -β-methoxy-propionitrile of formula (III) used as the starting material is prepared from 3,4,5-trimethoxy-benzaldehyde with 15-β-methoxy-propionitrile. The latter compound is prepared by reaction of acrylonitrile with methanol in alkaline medium.

The process of the present invention allows the economical preparation of trimethoprim. The total yield, calculated for 3,4,5-trimethoxybenzaldehyde, which is approx. 80%, is not adversely affected by the use of larger batches. Very high purity trimethoprim suitable for pharmaceutical purposes are prepared from the compound of formula (III) in a single step.

The invention is further illustrated in the following examples.

Preparation of the starting compound.

Dissolve 1.75 g of potassium hydroxide in 115 ml of methanol in a 4 liter flask. 55 g of acrylonitrile is added to the solution over 20 minutes and under cooling to avoid temperatures above 40 ° C. The reaction mixture is stirred at 40 ° C for 1 hour, then 100 g of 3,4,5-trimethoxybenzaldehyde is added. The mixture is heated to 60 ° C and stirred for 8 hours at this temperature, after which

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cool to 30 ° C. 55 ml of methanol and 30 g of potassium hydroxide / the latter are added in several portions.

The resulting suspension is stirred for 5 hours, then cooled to 20 ° C and 500 ml of water is added over 15 minutes. The product is crystallized at 5-10 ° C, filtered, washed with 3 portions on each 15 ml of methanol and 3 portions on each 100 ml of water, and then dried.

116 g (86%) of α- (3,4,5-trimethoxybenzal) - β-methoxy-propionitrile, m.p. 81-83 ° C.

Example 1 120 ml of anhydrous diethylene glycol monomethyl ether, 100 g (0.38 mol) of α- (3,4,5-trimethoxybenzal) -β-methoxy-propionitrile and 5 g of powdered sodium methoxide are added to a 1 liter flask. The reaction mixture is heated to 74-76 ° C, stirred for 3 hours at this temperature and then cooled to 30 ° C. 160 ml of isobutanol, 40 ml of methanol, 85 g of guanidine hydrochloride and 50 g of powdered sodium methoxide are added. The mixture is stirred at 35-40 ° C for 1 hour, then heated to 90-92 ° C and stirred for 7 hours at the boiling point of the mixture. The resulting suspension is cooled to below 20 ° C, then filtered, washed with 3 portions of each 20 ml of methanol, then with 500 ml of water at 30-35 ° C and dried.

102 g (93%) of 2,4-diamino-5- (3 ', 41,5'-trimethoxybenzyl) pyrimidine, m.p. 198-201 ° C.

Example 2 A. α- (3,4,5-Trimethoxybenzyl) -β- [2- (2'-methoxyethoxy) -ethoxy] -acrylonitrile.

A mixture of 120 ml of anhydrous diethylene glycol-30-monomethyl ether, 100 g of α- (3,4,5-trimethoxybenzal) - methoxypropionitrile and 5 g of sodium methoxide is heated to 74-76 ° C for 3 hours, then cooled to 20 °. C. The mixture is poured into a mixture of 300 ml of benzene and 500 ml of water.

The organic phase is separated, washed with 2 portions of 35 each 200 ml of water and evaporated. It as the residue emerged

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110 g of crude product is purified by distillation. The pure compound "has a boiling point of 208-214 ° C at 0.02 mm Hg.

B. 2,4-Diamino-5- (31,4 ', 51-trimethoxybenzyl) -pyrimidine.

To a mixture of 200 ml of isobutanol, 80 ml of meth anol, 190 g of guanidine hydrochloride and 100 g of sodium methoxide are added 200 g of α- (3,4,5-trimethoxybenzyl) -β- [2- (methoxyoxy) -ethoxy] -acrylonitrile dissolved in 120 ml of isobutanol. The reaction mixture is heated and refluxed for 7 hours, then cooled to 20 ° C. The crystalline product is filtered, washed with 3 portions of each 20 ml of methanol, then suspended in 500 ml of water, filtered, washed with water and dried.

174.5 g (95%) of 2,4-diamino-5- (3 ', 41,5'-15-trimethoxybenzyl) pyrimidine, m.p. 198-201 ° C.

Example 3

A mixture of 350 kg of anhydrous diethylene glycol - monomethyl ether, 300 kg of α- (3,4,5-trimethoxybenzal) -β-methoxypropionitrile and 20 kg of powdered sodium methoxide is heated to 78-80 ° C for 4 hours. The mixture is cooled to 30 ° C and 540 l of isobutanol, 120 l of methanol, 275 kg of guanidine hydrochloride and 160 kg of powdered sodium methoxide are added. The reaction mixture is stirred at 35-40 ° C for 1 hour and then at 90-92 ° C for 7 hours under reflux. The resulting suspension is cooled to 20 ° C, centrifuged and washed with 200 liters of methanol. The resulting wet product is suspended in 1500 L of water at 30-35 ° C, centrifuged, washed with 500 L of water and dried.

300 kg (91%) of 2,4-diamino-5- (31,41,51-trimethoxybenzyl) pyrimidine, m.p. 198-201 ° C.

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Claims (4)

A process for the preparation of 2,4-diamino-5- (3 ', 41,51-trimethoxybenzyl) -pyrimidine of the formula CH-0 NEL · 3 \ \ 2 5 / ~ N \ CH-O- / V. -NEL · (I) 3 \ .// 2 W / * CH30 '10 by reaction of an α- (3,4,5-trimethoxybenzyl) -β- (substituted) acrylonitrile with guanidine, characterized in that an - (3,4,5-trimethoxybenzal) -β-methoxypropionitrile of the formula CH3 ° 15 \ ___ CN / \ 1 CH-O- /. -CH = C (III) VV CH 2 -OCH 3 CH 3 O 20 is reacted with a diethylene glycol monoalkyl ether of the formula ho-CH 2 CH 2 -O-CH 2 CH 2 -or (IV) wherein R is an alkyl group of 1-4 carbon atoms, at 60-90 ° C in the presence of an alkali metal alkoxide and the resulting benzyl isomer of the formula CH_O 3 \ \ __ .. CN / \ I CH-O- /> -CH 2 -C (II) 3 \\ // 2 II CH-0 -CH2CH2-0-CH2CH2-0R Where R has the meaning given above, it is reacted - optionally without isolation - with guanidine in the presence of an alkanol of 4-8 carbon atoms. 35 9 DK 155668 B o Process according to claim 1, characterized in that the diethylene glycol monoalkyl ether is diethylene glycol monomethyl ether. A process according to claim 1 or 2, characterized in that the alkali metal alkoxide is sodium methoxide. Process according to any one of claims 1-3, characterized in that the reaction of the α- (3,4,5-trimethoxybenzal) -β-methoxypropionitrile of formula (III) with the diethylene glycol monomethyl ether is carried out at 70 80 ° C. 15 20 25 30 35