FI76789B - PROCEDURE FOR FRAMSTATION OF 2,4-DIAMINO-5- (3 ', 4', 5'-TRIMETOXYBENYL) PYRIMIDINE. - Google Patents

Description

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PROCEDURE FOR THE PREPARATION OF 2f4-DIAMIN0-5- (3 ', 4', 5'-TRIMETHOXYBENYL) -PYRIMIDINE

This invention relates to a novel process for the preparation of 2,4-diamino-5- (3,4,4,5'-trimethoxybenzyl) pyrimidine of formula I CH 3 O 2 ch 3 O- [N-NH 2 (i)

CHjO

by reacting alpha- (3,4-trimethoxybenzyl) -beta- (substituted) acrylonitrile with guanidine.

2,4-Diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine, known as trimethoprim, is a valuable pharmaceutical agent with a very potent bactericidal effect.

Several methods for preparing trimetoprim are known, some of which proceed through alpha- (3,4-trimethoxybenzyl) -beta- (substituted) -acrylonitrile.

Thus, in British Patent Publication no. 95,5797 3,4,5-Trimethoxybenzaldehyde is condensed with beta-alkoxypropionitrile to give the condensation product in more than 80% yield. The reaction product contains about 80 56 alpha- (3,4,5-trimethoxybenzal) -beta-alkoxyacrylonitrile and about 20 # alpha- (3,4,5-trimethoxybenzyl) -beta-alkoxyacrylonitrile. In the next step, the condensation product is cyclized with guanidine. However, only the "benzyl compound" participates in the cyclization and in the meantime virtually no isomerization of the "benzal compound" to the "benzyl compound" occurs. Thus, the yield of trimethoprim cannot exceed 28 i.e. The total yield calculated according to 3 »4» 5-trimethoxybenzaldehyde is at its best 20 -24 2 76789

British Patent Publication no. 1,261,455, the condensation product of 3,4,5-trimethoxybenzaldehyde and beta-alkoxypropionitrile is reacted with an amine to give alpha- (3,4,5-trimethoxybenzal) -beta-aminopropionitrile, which can be isomerized to the corresponding "benzyl -isomer "in 40-50% yield. The latter isomer can be cyclized with guanidine to give trimethoprim in 80% yield. However, the total yield of trimethoprim based on 3,4,5-trimethoxybenzaldehyde is also less than 40% in this process.

British Patent Publication no. 1,554,493, 3 ', 4,5-trimethoxybenzaldehyde is reacted with beta- (2-alkoxy-3-ethoxy) -propionitrile to give alpha- (3', 4 ', 5, -trimethoxybenzal) -beta- (2-alkoxyethoxy) propionitrile in more than 80% yield. After separation and thorough purification, the latter compound is isomerized to the corresponding "benzyl isomer" in the presence of a base at 90-95 ° C. When the resulting "benzyl isomer" is reacted with guanidine, trimethoprim is obtained in about 80 $ 6 yield. Thus, the overall yield is 64-72% on a laboratory scale.

Although the latter process is more economical than before, there are some difficulties in using it on an industrial scale. The water formed in the condensation reaction between 3> 4,5-trimethoxybenzaldehyde and beta- (2-alkoxyethoxy) propionitrile is distilled off at a high temperature, e.g. at about 120 ° C. At such a high temperature, alpha- (3,4,5-trimethoxybenzal) -beta- (2-alkoxyethoxy) propionitrile is hydrolyzed by the presence of water. Experience has shown that the hydrolysis of the nitrile group takes place in a simultaneous reaction to form the corresponding carboxylic acid. As a result of this reaction, tar-like by-products are formed, the amount of which increases with the use of larger batches.

Thus, the total yield obtained on a laboratory scale decreases to 64-72% to 50-55 # when the batch size is about 3,76789 10 moles.

Accordingly, British Patent Publication no. The process according to 1,554,493 is not sufficiently economical on an industrial scale.

Further, U.S. Pat. 4,115,650 according to Examples 1 and 2, 3,4,5-trimethoxy-o (-methoxymethylcinnamic acid nitrile) prepared from 3,4,5-trimethoxybenzaldehyde and β-methoxypropionitrile, i.e. X- (3,4,5-trimethoxybenzal) - - - 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) - / 3-methoxyacrylonitrile and diacetal) This mixture is then cyclized with guanidine to 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine The critical reaction step is the re-isomerization of the cinnamic acid nitrile derivative to β- (3,4,5-trimethoxybenzyl) -β-methoxyacrylonitrile. Namely, only the latter isomer is able to eyclize with guanidine in good yield, and under the reaction conditions of the prior art method, the re-isomerization is far from quantitative, for which reason the yield of the impure final product Kane calculated on the basis of the li-acid nitrile derivative is 74% in total.

In contrast, in the process of the invention, the cinnamic acid nitrile is obtained from the derivative and proceeded via an intermediate of formula (II) to give the desired final product in 95% yield.

The present invention is directed to an economical process for the industrial production of 2,4-diamino-5- (3 ', 4', 5'-trimethoxy-benzyl) pyrimidine.

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It has now been found that when alpha- (3R, 5-trimethoxybenzal) -beta-methoxypropionitrile of formula III is introduced, ch3p> = \? CH3P -4 CH = C (III) ^ - 'J ch2-pch3 ch3p to react with a diethylene glycol monoalkyl ether of formula IV ho-ch2ch2-o-ch2ch2-or <iv> wherein R is an alkyl group having 1 to 4 carbon atoms, formed in theoretical yield the "benzal isomer" of formula IIa ch3o / = \ | N (Ha) ^ \> -CH1 ^ _ (J ch2-p-ch2ch2-p-ch2ch2-pr ch3o '5 76789 wherein R is as defined above is isomerized to the corresponding The "benzyl isomer" according to II is ch3o> = \ ίΝ CH30- \ y ~ CH2 '(f (u)

^ -V CH-O-CH2CH2-O-CH2CH2-OR

CH 3 O

where R is as defined above, already at 60-90 ° C in almost theoretical yield. The "benzyl isomer" thus obtained is of such a purity that it can be cyclized with guanidine, if desired without separation and purification, to give trimethoprim.

The 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine of formula I is prepared according to the invention by reacting alpha- (3,4,5-trimethoxybenzyl) -beta- (substituted) acrylic -nitrile is reacted with guanidine by reacting an alpha- (3,4,5-trimethoxybenzal) -beta-methoxypropionitrile of formula III with a diethylene glycol monoalkyl ether of formula IV at 60-90 ° C

: in the presence of an alkali metal alkoxide and thus obtained of formula II

The benzyl isomer according to claim 1 is reacted - if desired without ‘separation’ - with guanidine in the presence of an alkanol having 4 to 8 carbon atoms.

As the compound of formula IV, it is preferred to use diethylene glycol monomethyl ether. Generally, this compound is 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.

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The "benzyl isomer" of formula II and the "benzal isomer" of formula IIa are novel compounds. The "benza-li isomer" does not need to be separated in the process of this invention and is quantitatively converted to the "benzyl atom" generally in 1 to 2 hours. The "benzyl isomer" can be separated, but if desired it can still be cyclized without separation.

The "benzyl isomer" of formula II is cyclized with guanidine in the presence of an alkanol having 4 to 8 carbon atoms, such as tertiary butanol or isobutanol. Of course, other organic solvents may also be present in the cyclization reaction, such as another alcohol, e.g., raethanol.

If the compound of formula II is not isolated prior to cyclization with guanidine, any excess of diethylene glycol monoalkyl ether of formula IV used in the previous reaction will also be present in the cyclization.

Guanidine is preferably used as an acid addition salt such as the hydrochloride. In this case, the guanidine is liberated from the acid addition salt in the reaction mixture by means of a base, preferably a time-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 starting alpha- (3,5-trimethoxybenzal) -beta-methoxypropionitrile of formula III is prepared from 3,4,5-trimethoxybenzaldehyde with beta-methoxypropionitrile. The latter compound is obtained by the reaction between acrylonitrile and methanol in a basic medium.

The process according to the invention makes it possible to prepare trimethoprim economically. The total yield of about 80 # calculated from 3> 4,5-trimethoxybenzaldehyde is not adversely affected by the batch size of 76789. High purity, pharmaceutically acceptable trimethoprim is obtained from the product of formula III in a single step.

The invention is illustrated by the following examples.

Preparation of the starting material Dissolve 1.75 g of potassium hydroxide in 115 ml of methanol in a 4-liter flask. Within 20 minutes, 55 g of acrylonitrile are added to the solution while cooling so that the temperature does not rise above 40 ° C. The reaction mixture is stirred for 1 hour at 40 [deg.] C. and then 100 g of 5,4,5-trimethoxybenzaldehyde are added. The mixture is heated to 60 ° C where it is stirred for 8 hours and then cooled to 30 ° C. Add 55 ml of methanol and in small portions a total of 30 g of potassium hydroxide. The resulting suspension is stirred for 5 hours, then cooled to 20 [deg.] C. and 500 ml of water are added over 15 minutes. The product is crystallized at 5-10 ° C, filtered, washed with methanol (3 x 15 ml) and water (3 x 100 ml) and dried.

116 g (86%) of alpha- (3,4,5-trimethoxybenzal) -beta-methoxypropionitrile are thus obtained, m.p. 81-83 ° C.

Example 1 120 ml of anhydrous diethylene glycol monomethyl ether, 100 g (0.38 mol) of alpha- (3,4,5-trimethoxybenzal) -beta-methoxypropionitrile and 5 g of powdered sodium methoxide are placed in 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 for 1 hour at 35-40 ° C, then heated to 90-92 ° C, which is the boiling point where it is stirred for 7 hours. The resulting suspension is cooled to below 20 ° C, filtered, washed with methanol (3 x 20 ml) and water (500 ml) at 30-35 ° C and dried.

102 g (93%) of 2,4-diamino-5- (3 *, 4 ', 5'-triraethoxybenzyl) pyrimidine are thus obtained, m.p. 198-201 ° C.

Example 2 A * A. alpha- (3,4,5-trimethoxybenzyl) -beta- [2- (2'-methoxy-ethoxy) -ethoxy] -acrylonitrile

A mixture of 120 ml of anhydrous diethylene glycol monomethyl ether, 100 g of alpha- (3,4,5-trimethoxybenzal) -beta-methoxypropionitrile and 5 g of sodium methoxide is heated at 74-76 ° C for 3 hours and then cooled to 20 ° C. ° C. The mixture thus obtained is poured into a mixture of 300 ml of benzene and 500 ml of water. The organic phase is separated, washed with water (2x200ml) and evaporated. The crude product obtained as a residue is purified by distillation. The pure compound has a boiling point of 208-214 ° C (0.02 mm Hg).

B. 2,4-Diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyriridine

To a mixture of 200 ml of isobutanol, 80 ml of methanol, 190 g of guanidine hydrochloride and 100 g of sodium methoxy are added 200 g of alpha- (3,4,5-trimethoxybenzyl) -beta-2- (methoxyethoxy) ethoxy acrylonitrile dissolved in 120 ml: is isobutanol. The reaction mixture is heated to reflux for 7 hours and then cooled to 20 ° C. The crystalline product is filtered, washed with methanol (3x20ml), suspended in 500 ml of water, filtered, washed with water and dried.

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

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Example 3

A mixture of 350 kg of anhydrous diethylene glycol monomethyl ether, 300 kg of alpha- (3,4,5-trimethoxybenzal) -beta-methoxypropionitrile and 20 kg of powdered sodium methoxy is heated for 4 hours at 78-80 ° C. The mixture is cooled to 30 [deg.] C. and 540 liters of isobutanol, 120 liters of methanol, 275 kg of guanidine hydrochloride and 160 kg of powdered sodium methoxy are added. The reaction mixture is stirred for 1 hour at 35-40 ° C, then for 7 hours at 90-92 ° C under reflux. The resulting suspension is cooled to 20 ° C, centrifuged, washed with 200 liters of methanol. The wet product obtained is suspended in water at 30-35 ° C, centrifuged, washed with 500 liters of water and dried. 300 kg (91 E) of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine are thus obtained, m.p. 198-201 ° C.

Claims (4)

A process for the preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine of the formula I -Nh210) = / CH3O by reacting an α- (3,4,5-trimethoxybenzyl) -0- (substituted) acrylonitrile with guanidine, characterized in that an α- (3,4,5- trimethoxybenzal) -β-methoxypropionitrile of formula III CH 3 O 30 CN 20 // λ | (III) CH 2 CH 2 O R (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 that the benzyl isomer of formula II is obtained 35. X I di) CH $ O - (/ \) - CH 2 -C 11> - ch-o-ch 2ch 2 -o-ch 2ch 2 -or ch 3 o where R is as defined above, converted - optionally