GB1579859A

GB1579859A - Process for the production of 2,4-diamino-5-benzylpyrimidines

Info

Publication number: GB1579859A
Application number: GB16609/77A
Authority: GB
Original assignee: Nordmark Werke GmbH
Current assignee: Nordmark Werke GmbH
Priority date: 1976-04-24
Filing date: 1977-04-21
Publication date: 1980-11-26
Also published as: ZA772429B; DE2617967C3; DE2617967A1; DE2617967B2; IN145170B

Description

(54) A PROCESS FOR THE PRODUCTION OF 2,4-DIAMINO-5-BENZYLPYRIMIDINES (71) We, NORDMARK-WERKE Gesellschaft mit beschrankter Haftung Hamburg, Werk Uetersen/Holstein in D-2082 Uetersen, a body corporate under the laws of Federal Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in an by the following statement:- 2,4-Diamino-5-benzylpyrimidines are a group of compounds which have acquired considerable significance in the treatment of various infectious diseases.

Thus, 2,4-diamino-5-(3,4,5- trimethoxybenzyl)-pyrimidine (Trimethoprim) in particular has been universally used in combination with a sulphinamide for the control of bacterial infections. Recently, other compounds of this class have also acquired interest, not only for controlling bacterial diseases, but also for the treatment of protozoal infections, such as malaria (see for example DOS No.

2,218,220 and DOS No. 1,795,635).

2,4-Diamino-5-benzylpyrimidines can be produced by numerous processes with which Trimethoprim, for example, is obtainable with favourable results. In view of the wide use of this compound in the field of medicine, however, any saving of costs is desirable, especially in view of the generally heavy increase in the costs of public health services.

The present invention relates to a process for the production of 2,4-diamino-5benzylpyrimidines by which these compounds can be obtained in improved yields and more easily, even on a commercial scale, and hence much more inexpensively than by conventional processes.

The hitherto known processes can be divided into two main groups of which the first leads in several stages to 5-benzylpyrimidines hydroxylated on the pyrimidine ring, in which the hydroxyl groups either have to be converted into amino groups through the chlorine compounds or, when the hydroxyl groups are present in addition to the two amino groups, also have to be removed by reduction by way of the chlorine compounds. Processes such as these consist of a relatively large number of reaction stages and involve reactions with phosphorus halides and catalytic hydrogenations, both of which represent processes that are comparatively difficult to carry out on a commercial scale. In general, the high yields aften quoted for these processes are not readily reproducible, so that in overall terms these processes are no longer competitive.

In contrast to these multistage processes, the processes belonging to the second group involve fewer reaction stages, with the result that the overall yields are better and the end products can readily be obtained, in some cases even on a commercial scale.

In these processes, propionitriles substituted in the p-position by alkoxy, alkylthio or amino groups are condensed with substituted benzaldehydes to form A- alkoxy, p-alkylthio or amino-a-benzyl propionitriles or the isomeric alkoxy, p- alkylthio or amino-a-benzylacrylonitriles and these intermediate products are ringclosed with guanidine to form the 2,4-diamino-5-benzylpyrimidines.

The processes belonging to the second group have certain disadvantages which we have sought to eliminate in the process of the present invention.

Thus, the process according to DOS No. 1,445,176 gives 2,4-diamino-5benzylpyrimidines in yields of up to 300/c, based on the benzaldehydes used. In addition, the products of this process are heavily discoloured yellow by polymerisation products and are difficult to purify to pharmaceutical quality.

The process according to DOS No. 1,545,966 attempts to obviate these disadvantages by converting the p-alkoxy--benzalpropionitriles obtained as intermediate products in DOS No. 1,445,176 into A-dialkoxy-a-benzylpropionitriles in another intermediate stage and ring-closing these pdialkoxy-a- benzylpropionitriles with guanidine. Although the Trimethoprim for example thus obtained is purer, it is only obtained in a yield of 39.5 /O.

In the process according to British Patent Specification No. 1,261,455 anilinopropionitrile is condensed with 3,4,5-trimethoxybenzaldehyde in dimethyl sulphoxide in the presence of potassium tertbutylate and the intermediate product is reacted with guanidine to form Trimethoprim in a yield of 640%. To this end, the anilinopropionitrile has to be purified beforehand. Production of the potassium tert.-butylate from expensive potassium necessitates special precautionary measures. The intermediate product has to be isolated and also purified before the reaction with guanidine, because these yields can only be obtained if the condensation product of anilinopropionitrile and the aldehyde is present in the benzyl form and not in the isomeric benzal form. These disadvantages are obviated in a variant of the process according to DOS No. 2,010,166 in which morpholinopropionitrile is initially reacted with 3 ,4,5-trimethoxy- benzaldehyde and the condensation product subsequently converted, with aniline, in a further intermediate stage, to form the corresponding anilino compound. In this process, the disadvantage of using potassium tertbutylate is substituted for an additionai stage. However, the disadvantage of having to purify the intermediate product still remains. All other variants of British Patent Specification No. 1,261,455 give poorer yields.

Accordingly the present invention provides a process by which 2,4-diamino-5benzylpyrimidines corresponding to the general formula

can be obtained much more easily and in good yields. In the above formula R1, R2 and R3 which may be the same or different each represents a hydrogen atom, an alkoxy group containing 1 to 4 atoms, an alkyl group containing I to 4 carbon atoms a benzyloxy group or a halogen atom. The alkyl group and the alkyl part of the alkoxy group may contain a singly-bonded oxygen atom. The process according to the invention is distinguished by the fact that an aldehyde corresponding to the general formula.

wherein R1, R2 and R3 are defined above, is reacted with A-(imidazol-l-yl)- propionitrile corresponding to the formula

in an alkanol containing from 1 to 4 carbon atoms and, optionally, with a singlybonded oxygen atom in the carbon chain, optionally at elevated temperature in the presence of an alkaline catalyst, and the reaction mixture formed, which contains the compound

is reacted with guanidine at elevated temperature and thus ring-closed to form the 2,4-diamino-5-benzylpyrimidine of general formula I.

This result is particularly surprising because compounds corresponding to formula III, in which the imidazolyl radical is replaced by the triazolyl or pyrazolyl radical, give the required products in only insignificant yields and because the teaching of DOS No. 2,010,166 is confined solely to the use of saturated heterocyclically substituted propionitriles and hence leads directly away from the teaching of the present invention.

The substituents R1, R2 and R3 in general formulae I to III may be the same or different and represent alkyl or alkoxy groups containing from 1 to 4 carbon atoms and, optionally, an oxygen atom in the alkyl radical or the alkyl group of the alkoxy radical, a halogen atom (especially a chlorine atom) a benzyloxy group or a hydrogen atom. R1, R2 and R3 are preferably methoxy groups in the 3, 4 or 5position of the benzene ring (with the methylene group in the l-position).

The process follows a typical procedure in which imidazolyl propionitrile is initially produced in a known manner in a yield of almost 1000% by adding commercial-grade acrylonitrile to a melt of commercial-grade imidazole, after which an aldehyde of general formula II is added following the introduction of a lower alcohol and the condensation reaction giving the intermediate products of general formula IV is carried out by boiling under reflux for several hours in the presence of a basic catalyst. Without isolating the intermediate products, an alcoholic guanidine solution is then added, the solvent is distilled off and the residue is heated for e.g. 2 to 3 hours to a temperature of from 100 to 1200C. 2,4diamino-5-benzylpyrimidine is obtained in the form of a crystal sludge which is stirred with mater and, after filtration, gives the end product in substantially pure form. The end product is obtained in pharmaceutical quality simply by dissolution in dilute acetic acid, filtering the solution with carbon and precipitation with ammonia.

The alcohols used as solvents may be, for example, methanol, ethanol, propanol, butanol or ethylene glycol monomethyl ether, preferably methanol or ethanol.

The alkaline catalysts used are, for example, sodium or potassium alcoholates of the alcohols used as solvents, magnesium or calcium oxide or Triton-B (trimethyl benzyl ammonium hydroxide-the word "Triton" is a Registered Trade Mark), sodium hydroxide, but preferably sodium methylate or ethylate.

The reaction temperature applied in the production of the intermediate product III is generally the boiling temperature of the alcohol used, although the reaction may also be carried out with an increased reaction time at a temperature of 20"C, so that the reaction temperatures may be in the range from 200C to 1200C.

The following Examples illustrate the process of the present invention.

Example 1 13.7 g of trimethoxy benzaldehyde, 12 g of crude A-(imidazol-l-yl)-propionitrile and 5.4 g of sodium methylate were boiled under reflux for 15 hours in 150 ml of methanol. A solution of guanidine hydrochloride in 100 ml of methanol was then added, the methanol was distilled off and the residue stirred for 3 hours at 1 100C.

The crystal sludge formed was stirred with 200 ml of water and filtered after cooling, giving 15.8 g=78% of the theoretical (based on trimethoxy-benzaldehyde) of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine melting at 1980C.

For further purification, the product was dissolved with 10% active carbon in 10 times the quantity of dilute acetic acid and obtained in pure form from the resulting solution without any significant losses by precipitation with ammonia.

Example 2 27.2 g of 3,5-dimethoxy-4-benzyloxy benzaldehyde (produced by benzylating syringic aldehyde, m.p. 630C), 13 g of p-(imidazol-l-yl)-propionitrile and 40 g of a 40% solution of trimethyl benzammonium hydroxide (Triton B) were boiled under reflux for 10 hours in 200 ml of ethanol. A guanidine solution prepared from 28 g of guanidine hydrochloride and 16 g of sodium methylate in 100 ml of ethanol was then added, the ethanol was distilled off and the residue stirred for 2 hours at 100 C. The reaction mixture was stirred with 200 ml of water, filtered and recrystallised from ethanol, giving 23.5 g=64% of the theoretical (based on the aldehyde) of 2,4-diamino-5-(3,5-dimethoxy-4-benzyloxybenzyl)-pyrimidine melting at 167 C.

Example 3 14 g of 2,4-dichlorobenzaldehyde, 12 g of A-(imidazol-l-yl)-propionitrile and 5.4 g of sodium methylate were stirred for 10 hours at 600C in 100 ml of methyl glycol. A guanidine solution prepared from 28 g of guanidine hydrochloride and 16 g of sodium methylate was then added, the solvent mixture was distilled off and the residue stirred for 3 hours at 1200C. The reaction product was stirred with water and, after filtration, was dissolved in and reprecipitated from dilute acetic acid in the same way as in Example 1, giving 16.4 g=76 /n of the theoretical (based on the aldehyde) of 1,4-diamino-5-(2,4-dichlorobenzyl)-pyrimidine melting at 235"C.

Example 4 13.2 g of 3,4-dimethoxy-benzaldehyde, 12 g of /3-(imidazol-1-yl)-propionitrile and 4 g of sodium hydroxide were boiled under reflux for 15 hours in 200 ml of methanol, the methanol being allowed to distill off slowly and the methanol distilled off being periodically replaced by fresh methanol. A solution of guanidine in methanol prepared from 28 g of guanidine hydrochloride was then added, methanol was distilled off and the residue stirred for 3 hours at 1 100C. After working up as in Example 1, the residue gave 14.6 g=69 /n of the theoretical (based on the aldehyde) of 2,4-diamino-5-(3,4-dimethoxybenzyl)-pyrimidine melting at 238"C.

Example 5 Following the procedure of Example 1, the following compounds were obtained in equally good yields: 2,4-diamino-5-(4-chlorobenzyl)-pyrimidine melting at 2230 C from 4 chlorobenzaldehyde; 2,4-diamino-5-(2-chlorobenzyl)-pyrimidine melting at 2340C from 2 chlorobenzaldehyde 2,4-diamino-5-(4-methoxybenzyl)-pyrimidine melting at 2130C from 4 methoxybenzaldehyde; 2,4-diamino-5-(2,5-dimethoxybenzyl)-pyrimidine melting at 1710C from 2,5 dimethoxy benzaldehyde; 2,4-diamino-5-(2,5-dimethylbenzyl)-pyrimidine melting at 1860C from 2,5 dimethylbenzaldehyde.

Example 6 21.6 g of 3,5-dimethoxy-4-methoxyethoxy benzaldehyde and 12 g of A- (imidazol-l-yl)-propionitrile were boiled under reflux for 24 hours in a solution of 4 g of magnesium in 200 ml of methanol. A guanidine solution prepared from 28 g of guanidine hydrochloride in methanol was then added, the methanol was distilled off and the residue stirred for 2 hours at 1 100C. Working up as in the Example I gave 18 g=68 of the theoretical (based on the aldehyde) of 2,4- diamino-5-(3,5dimethoxy-4-methoxyethoxy benzyl)-pyrimidine melting at 1530C.

Example 7 13.7 g of trimethoxybenzaldehyde, 12 g of crude P-(imidazol-l-yltpropionitrile and 54 g of sodium methylate were stirred for 15 hours at 650C in 150 ml of methyl glycol. A guanidine solution prepared from 16 g of sodium methylate and 28 g of guanidine hydrochloride in 100 ml of methyl glycol was added and the mixture stirred for 4 hours at 120"C. The methyl glycol was then distilled off in vacuo at 60"C, the residue was stirred with 200 ml of water and filtered after cooling, giving 14.5 g=72 " of the theoretical of Trimethoprim melting at 1980C.

Example 8 The procedure of Example 1, including removal of the methanol by distillation, was repeated. The reaction mixture was then stirred for 3 hours at 80"C and worked up as in Example 1, giving 15 g=750/, of the theoretical of Trimethoprim melting at 1980C.

Example 9 The procedure of Example 1, including removal of the methanol by distillation, was repeated. The reaction mixture was then stirred for 1 hour at 1400C and worked up as in Example 1, giving 14 g=70 /O of the theoretical of Trimethoprim melting at 198 C.

WHAT WE CLAIM IS: 1. A process for the production of 2,4-diamino-5-benzylpyrimidines of the general formula

wherein R1, R2 and R3, which may be the same or different each represents a hydrogen atom, a lower alkoxy or lower alkyl groups containing from I to 4 carbon atoms and, optionally, a singly bonded oxygen atom in the alkyl radical or the alkyl group of the alkoxy radical, a benzyloxy group or a halogen atom, which comprises reacting an aldehyde corresponding to the general formula

in which R1, R2 and R3 are as defined above, with A-(imidazol-l-yl)-propionitrile optionally at an elevated temperature, in an alkanol containing from 1 to 4 carbon atoms and, optionally, a singly-bonded oxygen atom in the carbon chain, in the presence of an alkaline catalyst, and the reaction mixture formed, which contains the compound

in which R1, R2 and R3 are as defined above, is reacted with guanidine at elevated temperature.

2. A process as claimed in claim 1, wherein the reaction of the aldehyde with the p-(imidazol-l-yl)-propionitrile is carried out at a temperature of from 20 to 1200C.

3. A process as claimed in claim I or 2, wherein the reaction mixture containing compound IV is reacted with guanidine at a temperature of from 100 to 1200C.

4. A process as claimed in any of claims 1 to 3, wherein the alkaline catalyst is a sodium or potassium alcoholate, magnesium, calcium oxide, trimethyl benzyl ammonium hydroxide or sodium hydroxide.

5. A process as claimed in any of claims 1 to 4, wherein the alcohol is methanol, ethanol, propanol, butanol, or ethylene glycol monomethyl ether.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. Example 9 The procedure of Example 1, including removal of the methanol by distillation, was repeated. The reaction mixture was then stirred for 1 hour at 1400C and worked up as in Example 1, giving 14 g=70 /O of the theoretical of Trimethoprim melting at 198 C. WHAT WE CLAIM IS:

1. A process for the production of 2,4-diamino-5-benzylpyrimidines of the general formula

6. A process as claimed in claim 1 substantially as herein described with

reference to any of the Examples.

7. 2,4-diamino-5-benzyl pyrimidines whenever prepared by a process as claimed in any one of the preceding claims.