DE2433176A1 - 2-Halopyrimidine derivs - prepd. from cyanoimino acetates via N-cyano cyanoimino acetates - Google Patents

Abstract

2-Halopyrimidine derivs. (I; R = lower alkyl1 X = halo) are prepd. by reacting cyanoimino acetates, N is approx. = CCH2C(OR) = NH.HM (M = mineral acid residue), with N is approx. = CNH2 followed by reaction of resulting N-cyano cyanoimino acetates, N is approx. = CCH2C(OR) = NC is approx. = N, with HX. In an example, a suspension of 2.6 g. N is approx. = C-CH2C-(OMe)=NH.HCl 2.6, N is approx. = CNH2 1.68, and molecular sieve 4 angstroms 5 g in C6H6 was stirred 5 hr. at 25 degrees C to give 2.26 g N is approx. = CCH2C(OMe)=NC is approx. = N (II). BF3-Et2O (0.14 g) was added to 1.23 g II in C6H6-Et2O, 1.07 g 20.5% HCl-Et2O added at 25 degrees C, and the mixt. reacted 6 hr. at 25 degrees C to give 1.48 g I (R = Me, X = Cl).

Description

"2-Halopyrimidine Derivatives and Processes for Their Preparation." The invention relates to 2-halopyrimidine derivatives represented by the general formula I: wherein R represents a hydrogen atom, a halogen atom, a lower alkyl group, an aryl group and an amine group and R4 represents a lower alkyl group and X represents a halogen atom, and it also relates to new intermediates useful for their preparation. The compounds represented by Formula I are important in a wide variety of fields such as medicine itself or as starting materials for the manufacture of sulfa-pharmaceuticals, purine bases, and the like.

So far is only a method of making the by the general Formula. .1 shown 2 -halo-4-alkoxy- 6-arnino-pyrimidine derivatives known and in this process are 6-amino-2, 4-dichloro-pyrimidine derivatives with sodium alcoholate (cf.

Chemical & Pharmaceutical Bulletin Volume 13, page 557 (1965) and Japanese Patent No. 19804/1966) brought to reaction. As in the reports is described, however, the main product is 2-alkoxy-4-chloro-6-aminopyrimidine and the 4-alkoxy-2-chloro derivative is obtained as a by-product in low yield, because the reactivity of the halogen atom in the 2-position of the pyrimidine ring is far greater than the reactivity of the halogen atom in the 4-position of the pyrimidine ring. As regards the known method described above, it is chemically impossible to use 2-halo-4-alkoxy-6-aminopyrimicline derivatives as the main product to obtain. In addition to the chlorination, such processes have a number of undesirable effects Reaction steps that can cause environmental pollution, for example by phosphoric acid salts obtained from the phosphorus oxychloride. So the procedure is almost worthless as an industrial process.

The inventors have made numerous studies for them Avoid disadvantages and they found a new method of making by the formula I represented pyrimidine bases.

The inventors succeeded in eliminating the disadvantages of the prior art known method completely and a very useful method for the preparation of the compound I from an industrially available at a low price Develop connection.

The method according to the invention is represented by the following reaction equation: (w @@ i @ RR, R4 and X have the meanings given above and M stands for a mineral acid radical such as halogen).

Explained in more detail, the invention thus relates to a method for production of pyrimidine bases represented by the formula I by condensation of by the formula II represented cyanoacetimidate derivatives with cyanamide III in the presence or Al) being a solvent, where N represented by the formula IV - Cyanocyanoacetimidatderivate arise, and subsequent cyclization of the obtained Product IV in the presence of a hydrogen halide.

The starting materials used in the present invention II can be obtained from malononitrile or its derivatives in good yield according to the method by S.M. McElvain (J. Am. Chem.

Soc. 71, 40 (1949)) and is cyanamide III a commercially available connection at a low price. I3is1lng is there regarding of the analogous method with respect to the first stage of the present invention is two Reports, namely (A) W. Lwowski, SYNTHESIS 263 (1971 and (B) K.R. Huffman et al, J. Org. Chem. 28, 1816 (1963). The main points of these two reports are compiled below.

N-cyanoimidate derivatives of the formula: (where R is an alkyl or aryl group and R 2 is an alkyl group) are prepared by using alkyl or aryl imidate derivatives of the formula: (where R 1 and R2 have the same meanings as above) with cyanamide (A) in an aqueous solvent adjusted to pH 6.5-7.0 with Na2HPO4 or (B) in an alcoholic solvent. However, these reactions only take place in the case in which the group R1 does not have any functional groups such as cyano, hydroxy or halogen. However, if the radical R 1 has functional groups, a completely different type of reaction takes place, which leads to a different substance, as is expressly written in the right-hand column on page 18i6 in reference (B).

As previously described, it has heretofore been believed that N-cyanocyanoalkylimidates of the formula IV which have a substituent cannot be obtained by that the starting material II is reacted with cyanamide. When trying the starting material II with cyanamide under the conditions described in the aforementioned reports (A) and (B) to implement, the inventors were accordingly able to achieve the desired according to the invention Compound IV not received. With a subsequent closer examination of this Response was called llesult. received in unexpected effect.

This effect resides in that in the case where the alkyl group the alkylimidate derivative has a substituent as shown in formula II, it is sufficient to use derivatives of alkylimidate hydrohalides with cyanamide in an inert React solvent to obtain the desired compound IV. Accordingly all compounds represented by Formula IV are new compounds. as Solvents in this reaction cannot be used with alcohols. However are polyhalogenated hydrocarbons such as chloroform, I) chloroethylene, trichloroethane or carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene or Xyiol desirable it but can also be ethers, ketones, esters or Petroleum carbons can be used and, in general, non-polar Use solvent. To make the reaction run more smoothly, one can use silicate compounds, such as silica gel, natural or synthetic zeolite, molecular sieves, metal oxides such as aluminum oxide, zinc oxide, magnesium oxide or titanium oxide and inorganic salts, such as calcium carbonate, barium carbonate, calcium sulfate, barium sulfate, calcium chloride or use barium chloride.

The reaction is carried out at a temperature from 0 to GOOC and preferably generally carried out at 15 to 30 ° C. To the product IV from the reaction mixture To isolate will be the by-product, namely the ammonium salt like ammonium chloride and the silicate or inorganic additives filtered off. Then it will Removal of the reaction solvent by distillation, the compound IV in high purity.

In addition, according to the invention, a new method of production was found the pyrimidine base was found by cyclizing a new compound such as IV. To the To prepare pyrimidine base I, is the compound IV in a suitable Solvent dissolved and it is introduced or hydrogen halide in the solution the solution is mixed with a solvent containing hydrogen halide. By cyclizing the compound IV, two kinds of pyrimidine base can be obtained will. However, the desired compound, 2-halopyrimidine, can be selectively obtained by adding the compound IV in the presence of a Lewis acid, such as boron trifluoride ethyl ether r complex cyclized.

In the above reaction, the solvents can be used which do not react with hydrogen halide and compound IV.

Even more suitable is a solvent that has a suitable amount of Can dissolve hydrogen halide. In general, ethers such as ethyl, propyl ethers, aromatic hydrocarbons such as benzene, toluene or xylene, ketones such as acetone, Methyl ethyl ketone or methyl isobutyl ketone, polyhalogenized carbons, such as chloroform, dichloroethylene, trichloroethane or carbon tetrachloride or used a mixture of these.

The reaction temperature is not limited. Generally runs the reaction easily at 15 to 30 ° C, but it can also at 0 up to 60 C. One mole equivalent or more of hydrogen halide is used per mole of compound IV and an oil) excess amount (3 to 6-fold molar excess l) ezogell on compound IV) is particularly preferred. The concentration of hydrogen halide in the solution is not limited. For example, the reaction takes place in one 20% ethereal solution of hydrogen halide or a 1% ethylene dichloride solution of hydrogen halide.

Obgl e I the product I as its hydrogen halide salt from the reaction solution If it precipitates, it is easily converted by subsequent treatment in an aqueous solution to the free base.

It can then be used in the usual way, such as by filtering, easily won.

As previously described, the reaction (11) - (IV) - (I) represents an epoch-making one Processes for synthetic chemistry and industry as they are not only the Production of pyrimidine bases allowed, which was previously difficult to synthesize but because these reactions were also carried out under very mild conditions and isolation of the product is extremely simple; Furthermore it is not necessary to use a halogenating agent, that could lead to environmental pollution.

It is expected that the compounds I in a wide area be applied. When a compound (I: R 1 = CH3, R2 = H; X = Cl) to react is brought with sodium ethylate or reductively dehalogenated in the usual way it can easily be converted into 2,4-dimethoxy-ß-aminopyrimidine or 4-methoxy-thiaminopyrimidine These compounds are important as the basis for sulfa-pharmaceuticals are.

The present invention is illustrated by the following examples: EXAMPLE 1 2.97 g of methyl ct-methyleyanoacetimidate hydrochloride are suspended and 1.26 g of cyanamide in 30 ml of benzene and left to react for 5 hours at 25 ° C. Afterward the precipitated ammonium chloride is filtered off and the filtrate is in vacuo concentrated to dryness, giving 2.38 g of methyl N-cyano-α-methylcyanoacetimidate (Yield 86.8%). Melting point 68.50C.

Analyac C6H7N3O C H N calc .: 52.54 5.15 30.64% found: 52.57 5.14 30.62 % Example 2 4.21 g of methyl α-phenylcyanoacetimidate hydrochloride are mixed and 1.26 g of cyanamide at room temperature and the mixture is allowed to react for 5 hours. Then 50 parts of benzene are added to the reaction mixture in order to obtain the product obtained to extract. The extracted solution is concentrated to dryness in vacuo, 3.06 g of methyl N-cyano-α-phenylcyanoacetimidate (yield 76.8%) receives.

The structure of this compound is determined by nuclear magnetic resonance (NMR) and infrared spectroscopy (IR) confirmed.

Example 3 2.97 g ethyl cyanoacetimidate hydrochloride, 1.26 g cyanamide and 5.0 g of aluminum oxide are suspended in 30 ml of benzene. Then treated one in the manner described in Example 1 and thus obtained 2.29 g of ethyl N-cyanoacetimidate (Yield 83.6%). Melting point 64.5 ° C.

Analysis C6H7N3O C H N calc .: 52.55 5.15 30.64% found: 52.47 5.12 30.38 % Example 4 3.25 g of n-propyl yanoacetimidate hydrochloride and 1.26 g of cyanamide treated in the manner described in Example 1 and 2.18 g of oily are obtained n-Propyl N -cyanocyanoacetimidate (yield 72.1%). The structure of this connection is confirmed by IR and NMR.

Analysis C7H9N3O C H N calc .: 55.62 6.00 27.80% found: 54.80 6.27 27.13 % Example 5 3.25 g of isopropyl cyanoacetimidate hydrochloride and 1.26 g of cyanamide are used treated in the manner described in Example 1 and obtained 2.07 g of iso-propyl-N-cyanocyanoacetimidate (Yield 68.5%) of melting point 66.5 ° C.

Analysis C7H9N3O C H N calc .: 55.62 6.00 27.80% found: 55.41 5.91 27.66 % Example 6 2.69 g methyl cyanoacctimidate hydrochloride, 1.68 g Cyanamide and 5.0 g molecular sieve (type 4A, 0.25 mm (60 mesh) through) suspended in 30 ml of benzene and the suspension is stirred for 5 hours at 25 ° C brought to reaction.

After the reaction, insoluble materials are filtered off and then the filtrate is concentrated to dryness in vacuo, giving 2.26 g of methyl N-cyanocyanoacetimidate (Yield 91.2%) with a melting point of 45.50C.

Analysis C5H5N3O C H N calc .: 48.78 4.09 34.13% found: 48.61 4.12 33.98 % After 1.23 g of methyl N-cyanocyanoacetimidate obtained above in 10 ml of a mixed solvent benzene-ether (1: 2) has dissolved, is added 0.14 g of boron trifluoride-ethyl ether complex to the solution and sets 10.7 g of a 20.5 % ethereal solution of hydrogen chloride is added dropwise to the solution at 25 ° C. Afterward the solution is left for 6 hours react at the same temperature. After the reaction has ended, the solvent is distilled off, leaving a residue is obtained. The residue is dissolved in 10 ml of water and the solution is with Sodium bicarbonate solution neutralized to cause precipitation. The rainfall are then collected by filtration, washed with water and dried, 1.48 g of 2-chloro-4-methoxy-6-aminopyrimidine (yield 92.5%) having a melting point Receives 1860C.

Example 7 After 1.37 g of methyl N-cyano-α-methyl-cyanoacetimidate, obtained in the manner described in Example 1 in 15 ml of a mixed one Solvent benzene-ether (1: 2) has dissolved, add 0.14 g of boron trifluoride-ethyl ether complex to the solution and add 1.1 g of hydrogen chloride to the solution at 2s 0C in the course of 2 hours little by little to. The solution is then left at the same temperature for 3 hours react. After the reaction has ended, the solvent is distilled off, with a residue is obtained. The residue is dissolved in 10 ml of water and the solution is neutralized with sodium bicarbonate solution to cause precipitation.

The precipitates are then collected by filtration, washed with water and dried, giving 1.42 g of 2-chloro-4-methoxy-5-methyl-6-aminopyrimidine (Yield 81 6%) with a melting point of 189 ° C.

Analysis C6H8N3OCl C H N C1 calc .: 41.51 4.65 24.24 20.24% found: 41.54 4.95 23.77 20.66% Example 8 After 1.99 g of methyl N-cyanocyanoacetimidate, obtained in the same manner as described in Example 2 in 15 ml of ether dissolved, 6.6 g of a 16.7% ethereal solution of hydrogen chloride are added 25 0C to the solution. The solution is then left at the same temperature for 5 hours react.

The solution obtained is treated in the same way as in FIG second half of Example 7, and 1.66 g are obtained 2-chloro-4-methoxy-5-phenyl-6-aminopyrimidine (Yield 70.3%) with a melting point of 213 ° C.

Analysis C11H10N3OCl (235,6.75) C H N Cl calc .: 56.06 4.28 17.83 15.04 % found: 56.04 4.31 17.71 15.67% Example 9 1.37 g of ethyl N-cyanocyanoacetimidate, obtained in the same manner as described in Example 3 becomes the same Treated manner as described in Example 7 and 1.49 g of 2-chloro-4-ethoxy-6-aminopyrimidine are obtained (Yield 85.6%) of melting point 1330C.

Analysis C6H8N3OCl C H N Cl calc .: 41.51 4.64 24.20 20.42% found: 41.69 4.67 24.34 20.63% Example 10 2.69 g of methyl cyanoacetimidate hydrochloride, 1.68 68 g of cyanamide and 5.0 g of molecular sieves (type 4A, 0.25 mm (60 mesh)) are in 30 ml of benzene are suspended and the suspension reacts at 25 ° C. for 5 hours brought. After the reaction has ended, insoluble materials are filtered off and 30 ml of ether solution containing 0.28 g of boron trifluoride-ethyl ether complex are added to the filtrate and then 2.9 g of gaseous hydrogen chloride are added slowly introduced into the mixture at 20 to 250C. After the mixture 6 hours was stirred at the same temperature, the solvent is distilled off, wherein a residue is obtained.

The residue is dissolved in 20 ml of water and the solution is with Sodium bicarbonate solution neutralized to cause precipitation. Afterward the precipitates are collected by filtration, washed with water and dried, 2.59 g of 2-chloro-4-methoxy-6-aminopyrimidine (yield 81.1%) from melting point 18 60C received.

Example 11 After 1.23 g of methyl N-cyanocyanoacetimidate were added to 10 ml of acetic acid has dissolved, 10.7 g of a 20% ethereal solution are added dropwise of hydrogen chloride at 15 to 25 ° C to dissolve.

The solution is then left to react for 6 hours at room temperature. After the reaction has ended, the solvent is distilled off, whereby one Obtains residue. The residue is dissolved in 10 ml of water and the solution becomes neutralized with sodium bicarbonate solution to cause precipitation.

The precipitates are then collected by filtration, washed with water and dried to give 1.47 g of crude crystals. the Crystals are recrystallized from dilute hydrochloric acid, whereby 1.33 g of 2-chloro-4-methoxy-6-aminopyrimidine (yield 83.1 olo), melting point 186 up to 187 ° C.

Claims (12)

Patent claims 1.) Compounds of the formula wherein R2 represents a halogen atom, a lower alkyl group, an aryl group and an amino group and R4 represents a lower alkyl group and X represents a halogen atom. 2.) 2-Chloro-4-methoxy-5-methyl-6-aminopyrimidine. 3. ) 2 - Chlo r - 4 - methoxy - 5 - phenyl - 6 - aminopyrimidine. 4.) Compound of the formula: wherein R represents a hydrogen atom, a halogen atom, a lower alkyl group, an aryl group and an amino group, and R4 represents a lower alkyl group. 5.) Methyl- N- cyanocyano ac etim id at. 6.) Ethyl-N-cyanoacetimidate. 7th ) n -P ropyl-N -cyanocyanoacetimidate. 8.) Iso-propyl-N-cyano-cyanoacetimidate. 9.) Methyl N-cyano-α-methylcyanoacetimidate. 10.) Methyl N-cyano-α-phenylcyanoacetimidate. 11.) Process for the preparation of a 2-halopyrimidine derivative according to the general formula: where R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, an aryl group and an amino group and R4 represents a lower alkyl group and X represents a halogen atom, characterized in that a cyanoacetimidate derivative of the general formula: wherein R² and R4 have the above meanings, reacts with cyanamide, the N-cyanocyanoacetimidate derivative of the general formula: arises, in which R2 and R4 have the above meanings, and then the N-Cyanocyanoacetimidatderivat reacts with hydrogen halide. 12.) Process for the preparation of a 2-halopyrimidine derivative of the general formula: wherein R, R4 and X have the meanings given in claim 11, characterized in that an N-cyanoacetimidate derivative of the general formula: wherein R2 and R4 have the meanings given in claim 11, reacts with hydrogen halide.