DD300230A5 - PROCESS FOR THE PREPARATION OF 2,4,6- (TRI-ALKYLTHIO) -PYRIMIDINE-5-CARBONITRILES - Google Patents

Abstract

The invention relates to a process for the preparation of * I. It is the object of the invention to prepare these hitherto unknown compounds from readily available starting materials. The task is to find a technically feasible synthetic route. The object is achieved by reacting 3-alkylthio-3-amino-2-cyano-acrylonitriles with carbon disulfide in the presence of a base to give compounds III and subsequent reaction with alkylating agents. The compounds obtained are of pharmaceutical interest. Formulas I and III {* * Intermediates for the pharmaceutical industry; Gastro therapeutics; biologically active compounds}

Description

reactants, these are then reacted with alkylating agents of formula IV, wherein X is a chlorine, bromine or iodine atom and R 'is a hydrogen atom, alkyl radicals having 1-4 carbon atoms, aryl radicals, the

X-CH ₂ -R ¹

IV

optionally substituted by halogen atoms, the cyano group, sec. Aminocarbonylreste or the benzoyl ddrstellt, to the compounds of formula I as defined above of R and

S-CH ₂ -R

R 'be implemented.

2. The method according to claim 1, characterized in that the reaction is carried out to compound III using mixtures of pyridine and sodium methylate solution and the alkylation of III takes place with catalysis of sodium or triethylamine.

3. The method according to claim 1, characterized in that the reaction to I takes place in two stages, wherein the compounds III can be used as crude products for alkylation.

Field of application of the invention

The invention relates to a process for the preparation of 2,4,6-tri (alkylthio) -pyrimidine-5-carbonitriles. Such compounds may gain importance as pharmaceuticals, in particular as Gastroprotektiva and as starting materials for the preparation of other pharmacologically active compounds.

Characteristic of the known state of the art

2,4,6-tri (alkylthio) -pyrimidine-5-carbonitriles are unknown. The methods known from the literature for the preparation of pyrimidine derivatives which have a cyano group or a substituent convertible into the cyano group in the 5-position and have one or two alkylthioglyups in the 2-, 4- or 6-position can be used for the synthesis of the 2,4-based compounds according to the invention, Do not use 6-tri (alkylthio) -pyrimidine-5-carbonitrile because the required starting materials can not be obtained or only under complicated conditions. Pyrimidine-5-carbonitriles having an alkylthio substituent are obtainable by a method of Soto and coworkers (JLSoto, A. Lorente, JLG & rcia NavioAn.Quim.77, C, 255 (1981), JLSoto, A. Lorente, JL Garcia Navio , JJ Vaquero J. Heterocyclic Chem.22,49 [1985]). This preparation process yielded 2-methyl-4-methylthio-6-aryl-pyrimidine-5-carbonitriles and 2-phenyl-4-methylthio-6-aryl-pyrimidine-5-carbonitriles by reacting 2-cyano-3-alkoxy-acrylonitriles with thioamides and subsequent alkylation with methyl iodide.

In addition, the reaction of ketene dithioacetals with carboxylic acid amides leads to 2-aryl-3,4-dihydro-4-oxo-6-methylthiopyrimidine-5-carbonitriles (S. Kohra, Y. Tominaga, Y. Matsuda, G. Kobayashi Heterocycles 20, 9, 1745-1750 [1983]). 2,6-diaryl-4-mercapto-pyrimidine-5-carbonitriles, which can be easily converted into the 4-alkylthio derivatives by alkylation, are available from Liebscher starting from 2,5-diphenyl-1,2,4-dithiazolium salts and malononitrile ( J. Liebscher DD Pat., 129907) and Goerdeler and Wieland (J.Goerdeler, D.Wieland Chem. Ber., 100, 47 [1967]) by cyclization of N (3-aminothioacryloyamides).

Pyrimidines having two alkylthio substituents without cyano group have been described by Eilingsfeld and co-workers (H.Eilingsfeld, M. Patsch, H.Scheuermann DE 1670203). Starting from malonic acid bis-thioimic acid ester, 4,6-dialkylthio-pyrimidines were synthesized by reaction with carboxylic acid halides and anhydrides. The reaction of thioethers of the mercaptoacetic ester with formic acid ester, thiourea, and alkylating agents gave 1-H-2,5-di (alkylthio) -4, according to Brown and co-workers (Th Brown, JC Emmett, GJ Durant, CR Ganellin DD Pat 126563) -oxo-4-H-pyrimidine. Additions to dimercapto or dialkylthiopyrimidines starting from corresponding dithioxothiazines by reaction with primary amines were described by Schroth and co-workers (W. Schroth, A. Hildebrandt, U. Becker, 3rd Friday, A. Akram, R. Spitzner Z. Chem. 1985, 25, 20-21).

Object of the invention

The aim of the invention is to produce 2,4,6-tri (alkylthio) -pyrimidine-5-carbonitriles in a simple manner.

Explanation of the essence of the invention

The object of the invention is a technically feasible synthesis route for the preparation of 2,4,6-tri (alkylthio) -pyrimidine-5-carbonitriles of the formula I, wherein R is the methyl or Bcnzylrest and R 'is hydrogen, alkyl radicals

S-CH ₂ -R

1-4 carbon atoms, aryl radicals which are optionally substituted by halogens, the cyano group, sec. Aminocarbonyl radicals and the benzoyl radical means to find. The object is achieved in that S-alkylthio-S-amino ^ cyano-acrylonitriles of the formula II,

RH ₂ CS _x , CN CC

⁷ " ^X CN

wherein R represents a methyl or benzyl group, reacted with carbon disulfide and a base to give pyrimidines of the formula III and then compounds III

S-CH ₂ -R

with alkylating agents of the formula IV, wherein X is chlorine, bromine

X-CH ₂ -R'IV

or iodine and R 'has the meaning given above, are reacted. The compounds III are conveniently isolated.

embodiments

example 1

Compound III with R = CH ₃

To 10g (70mmol) of compound II is added 20ml of 5molaro sodium methylate solution. Subsequently, 20ml of carbon disulfide are added with cooling and the mass diluted with 20ml of dry pyridine. The batch 10d is allowed to stand at room temperature and then acidified with ice-cold 1N hydrochloric acid. The orange-yellow precipitate is sucked off.

washed neutral with water and pressed to clay. The compound is used for further reactions as a crude product. Purification is carried out by recrystallization from 80% aqueous DMF. The yield is 9.49 g (63%), the compound melts at 227 ⁰ C (dec.).

Example 2

Compound I with R = R '= CH ₃

option A

9.52 g (40 mmol) of compound III (R = CH ₃ ) are suspended in 100 ml of methanol and admixed with 16 ml (80 mmol) of a 5 molar sodium methylate solution. After cooling to 0 ° C., 11.4 g (80 mmol) of methyl iodide are added to the batch. The mixture is allowed to stand for one hour at room temperature, the precipitated solid is filtered off with suction, the mother liquor is concentrated to one third of the original volume and again separated crystallized product. This gives 6.5 g (67%) of the crystalline product which has a melting range of 152-153 ° C (from acetonitrile).

Variant B

Analog variant A, but instead of sodium methylate 8g (80mmr> l) triethylamine are used. The yield is

Example 3

Compound I with R = CH ₃ and R '= C ₄ H ₉

0.215 g (1 mmol) of compound III are in 5 ml abs. Suspended methanol and then treated with 0.2 g (2 mmol) of triethylamine. After adding 0.37 g (2 mmol) of n-butyl iodide, the mixture is allowed to stand overnight at room temperature and then the solution is concentrated to one fifth of the original volume. The crystallized product is filtered off with suction. The yield is 0.189 g (58%), compound melts at 53 ⁰ C (from 80% aqueous ethanol).

Example 4

Compound I with R = CH ₃ and R '= CN

0.215 g (1 mmol) of compound III and 0.2 g (2 mmol) are analogously to Example 3 with 0.15 g (2 mmol) of chloroacetonitrile in 5 ml abs.

Methanol reacted. There are obtained 0.175 mg (60%) of the product, which melts at 239 ⁰ C with decomposition (from propanol / methyl glycol).

Example 5

Compound I with R = CH ₃ and R '= CH ₂ C ₆ H ₆

0.215 g (1 mmol) of compound III and 0.2 (2 mmol) of triethylamine are analogously to Example 3 with 0.25 g (2 mmol) of benzyl chloride in 5 ml abs. Methanol reacted. To obtain 0,142g (36%) of the final product which has a melting range of 99-100 ⁰ C.

Examples

Compound I with R = CH ₃ and R '= COC ₈ H ₆

0.215 g (1 mmol) of compound III are suspended in 5 ml of chloroform (dried) and then admixed with 0.2 g (2 mmol) of triethylamine. Add 0.3 g (2 mmol) of phenacyl chloride and allow the mixture to stand overnight. Thereafter, the mixture is poured into ice-water, the chloroform layer washed with water, dried over calcium chloride and concentrated.

This gives 0.257 g (57%) of the yellow product having a melting range of 180-182 ⁰ C (from acetonitrile).

Step Example! 7

Compound I with R = CH ₃ and R '= CON O

option A

10.75 g (50 mmol) of compound III are suspended in 100 ml of methanol and then admixed with 13 g (130 mmol) of triethylamine. After addition of 21.26 g of chloroacetic acid morpholide with stirring, the mixture is stirred for a further 30 minutes and the precipitate is filtered off with suction. There are obtained 10.8 g (46%) of the yellow compound, which melts at 171-172 ⁰ C (from methyl glycol).

Variant B

Analog variant Ades example 7, but instead of triethylamine, sodium methylate (100 mmol, 5molare solution) is used as the base. This gives 11.5 g (49%) of the compound.

Examples

Compound I with R = CH ₂ C ₆ H ₆ and R '= CH ₃

0.7 g (2.4 mmol) of compound III with R = CH ₂ C ₆ H ₆ are suspended in 20 ml of methanol, admixed with 1.44 ml of a 5 molar sodium methylate solution (5 mmol) and 0.71 g (5 mmol) of methyl iodide and after one hour the precipitated product is sucked off. The mother liquor is on a fourth! Concentrated the original volume, recrystallized product separated and recrystallized from methylene glycol / ethanol. This gives 0.49 g (64%) of the product, which has a melting range of 154-155 ⁰ C.

Claims (1)

1. A process for the preparation of 2,4,6-tri (alkylthio) -pyrimidine-5-carbonitriles _; characterized in that S-alkylthio-S-amino-cyano-acrylonitriles of the formula II, RH ₂ CS _n , CN IC CH ₂ N ' wherein R represents a hydrogen atom or the benzyl radical, with carbon disulfide to compounds of formula III S-CH ₂ -R