DD281598A5 - PROCESS FOR THE PREPARATION OF NEW 6-ALKYL-4-AMINO-2-HALOGEN METHYL-PYRIMIDINES - Google Patents

Abstract

The invention relates to a process for the preparation of novel 6-alkyl-4-amino-2-halomethyl-pyrimidines of the general formula I (X Cl, Br). The compounds mentioned are of interest as intermediates for pharmaceuticals. According to the invention, 6-alkyl-4-amino-2-iodomethyl-pyrimidines (X I and m NO) are reacted with chlorinating or brominating reagents in a solvent between 50 and 100C. Formula I {amino-methylpyrimidines; Chlormethylpyrimidine; Brommethylpyrimidine; transhalogenation; Iodmethylpyrimidine; side chain halogenation; bromination; chlorination}

Description

Field of application of the invention

The invention relates to a process for the preparation of novel 6-alkyl-4-amino-2-halomethyl-pyrimidines and their adducts with iodohalogens, which are of interest as intermediates for pharmaceuticals.

Characteristic of the known state of the art

For the preparation of Halogenmethyleterocyclen a number of methods are known which are based on the direct halogenation of methyl groups.

Dio chlorination or bromination of methylpyrmidines with elemental CMor or bromine is generally less selective. In addition to the monohalomethyl products, di- and trihalomethylpyrimidines are also frequently obtained (J. Chem. Soc., 1959, 525).

Another disadvantage is the most preferred occurring nuclear halogenation. Pyrimidines are usually first halogenated in the 5-position before a Seitenkettenhalogenierung expires. Thus, the bromination of 2-amino-4,6-dimethylpyrimidine gives first the 5-bromo derivative and only then the 2-amino-5-bromo-4-bromomethyl-6-methyl-pyrimidine and 2-amino-5-bromo 4,6-bisbromomethyl-pyrimidine (J. Org. Chem. 10, 327 [1945)]. The core halogenation can only be prevented if the 5-position is already occupied. An example of the regiospecific monobromination is 5-acetyl-4-bromomethyl-2-phenylpyrimidine (J.Amer.Chem. Soc., 70, 1088 [1948]). However, substituents in the 5-position can be split off only with extreme difficulty, so that only side-chain halogenated pyrimidines are not accessible by protective group technology. In some cases, the use of N-bromo- or N-chlorosuccinimide preferably leads to side-chain substitution. Thus, 4,6-dichloro-2,5-dimethyl-pyrimidine gives on reaction with N-bromosuccinimide preferably 5-bromomethyl-4,6-dichloro-2-methyl-pyrimidine (Pharm. Bull. 1,287 [1953]), while 4 -Amino-2,6-dimethyl-pyrimidine in the presence of N-bromine or N-chlorosucdnimide to the corresponding 4-amino-5-halo-2,6-dimethyl-pyrimidine reacts (Tetrahedron 22,2401 [1966]).

If the methyl groups of pyrimidines are deactivated by strongly electron-donating substituents, the halogenation fails completely. Thus, 4,5-diamino-2-methyl-pyrimidine can not be brominated even under drasvic conditions (Aust. J. Chem. 20, 1041 [1967]). In addition, phenyl substituents or activated methylene groups in the side chain of pyrimidines can compete with the bromination of methyl groups and completely prevent them. You put

For example, 2-anilino-4,6-dimethyl-pyrimidine with one equivalent of bromine to give a mixture of the 5-bromo, 4-Bromanilino- and the corresponding Dibrompyrimidin (J. Amer. Chem. Soc. 74.3922 1952)).

Another fundamental possibility is the conversion of functionalized methylpyrimides into halomethyl-pyrimidene. The esterification of 4-amino-2-chloro-5-hydroxymethyl-pyrimidin with thionyl chloride leads to the 4-amino-2-chloro-5-chloromethyl-pyrimidine and with hydrogen bromide to the amino-S-bromomethyl-chloro-pyrimidine ( Liebigs Ann. 588.45 [1954]). The method is only of minor importance for the synthesis of Hfilogenmethylpyrimidines, since the hydroxymethylpyrirnidine used as starting material are difficult to access.

The regiospecific introduction of chloromethyl or bromomethyl groups is also possible by direct synthesis of Pyrimidinrlnges. The position of the halomethyl group is already determined by the choice of reactants. The reaction of chloroacetamidine with 1,3-tetramethoxypropane provides the 2-clormethyl-pyrimidine (DE-OS 2932643). The disadvantage of this variant is that the starting compounds are difficult to access and thus the synthesis is not economically justifiable.

Object of the invention

The aim of the invention is to develop, while avoiding the disadvantages mentioned, a method according to which 6-alkyl-4-amino-2-halomethyl-pyrimidines can be prepared economically advantageous.

Explanation of the essence of the invention

The object of the invention is to prepare using readily available pyrimidines 4-amino-6-alkyl-2-halomethylpyrimidines.

The object of the invention is achieved by a process for the preparation of novel 4-amino-6-alkyl-2-halomethylpyrimidines of the general formula I

X is chlorine or bromine, R ^{1 is an} alkyl radical, R ^{2 is} hydrogen or a halogen radical, R ^{3 is} an amino or alkylamino radical and

m and η = O or 1 or m = 1 and η = 3, characterized in that pyrimidines of the general formula I, in which X is iodine, m and η - O and R ¹ , R ² and R ^{3 are} the abovementioned Meanings, in a solvent, preferably an acid and optionally water as a diluent, with chlorinating or Bromierungsreagenzien in

Temperature range of -50 to 100 ° C has been implemented. The process is broadly understood in that the iodomethylpyrimidine is dissolved in a chlorinated solvent.

or Bromierungsreagenzien is reacted. As the solvent, inorganic or organic acids are preferably used, and the iodomethylpyrimidine may be dissolved or suspended therein.

The reaction is in the temperature range of ⁰ to 100 -BO C, preferably at -20 to 30 ° C, durchgefül · rt. As a result of the Reaction is first obtained the corresponding pyrimidine-iodohalogen adducts (m «1, n = 1 or 3), which in acids little

are soluble and precipitate. The free pyrimidines (m and η = 0) can be released from the iodohalide adducts by alkaline hydrolysis. They precipitate in aqueous solution as precipitates or can by salting out to

Crystallization be brought. The new <η 2-halomethyl-pyrimidines of the general formula I were obtainable only in this way. The halogenation of

unsubstituted methyl pyrimidines (X, R ² = H) gave, in spite of the excess of halogen, only the corresponding 5-halopyrimidines.

In addition to the rehalogenation of the 2-methyl group, if R ² = H, it is possible according to the invention to simultaneously iodine in the

5-position of pyrimidines introduce.

In this case, react with a maximum of 1 equivalent halogenating agent and at temperatures of O ⁰ C to the

to suppress competing nuclear attack. Preferably, chlorine is used as the halogenating agent for this purpose.

It reacts selectively with the iodomethyl group and the leaving iodine monochloride is sufficiently reactive to the core amino acid of the Pyrimidine. The 2-iodomethylpyrimidines used as starting materials for the reaction are prepared by iodination of 2-methylpyrimidines

readily available (DD-WP 238974). In addition, it is possible according to the invention to couple the synthesis of the 2-iodomethylpyrimidines with the perhalogenation. In this case, the 2-methyl-pyrimidine in a known manner in an acid with iodine and a

Oxidizing reacted and without intermediate isolation of the acidic solution with chlorination or Bromizing reagents added. The 2-methyl-pyrimidines of the general formula I are simple by ring closure reaction

produced. For example, 4-amino-2,6-dimethylpyrimidine is obtained by trimerization of acetonitrile in the presence more

Bases (J. prakt. Chem. 27, 152 [1883]). The novel compounds which can be prepared by the process according to the invention are

thus much easier and available in higher yields than comparable halomethylpyrimidines.

The novel compounds obtainable by the process according to the invention are valuable starting materials or Intermediates for drug syntheses, especially for the synthesis of antibacterial 'N-pyiimidinyl-sulfanilamide. Ausführungsbelsplele example 1

4-Amino-5-bromo-2-chloromethyl-6-methyl-pyrimidine

8.2 g f 0.025 mol) of 4-amino-5-bromo-2-iodo-methyl-6-methyl-pyrimidine are dissolved in 60 ml of about 5% strength hydrochloric acid and, while stirring, a stream of chlorine is passed over the solution. After 1 hour, the resulting yellow precipitate is filtered off, suspended in 75 ml of water and neutralized with the addition of some sodium thiosulfate with 10% sodium hydroxide solution. When the suspension reacts resistant alkaline, is again suction filtered and the solid dried at 60 to 7O ⁰ C.

Yield: 2.0 g (34% of theory);

Melting point (i-PrOH): 150 to 153 ⁰ C;

Analysis for C ₈ H ₇ CiBrN ₃

Calc .: C30.47 H2.98 Br33.79 Cl 14.99 N 17.77

Found: C 30.56 H 2.97 Br 33.99 Cl 14.92 N 18.00

Example 2

4-Amino-5-bromo-2-bromomethyl-6-methyl-pyrimidine-IBr adduct 12.45 g (0.06 mol) of 4-amino-2-iodomethyl-6-methyl-pyrimidine are dissolved in 100 ml of acetic acid. Within 10 to 15 minutes 16.0 g (0.2 mol) of bromine are added dropwise with stirring and stirred for a further 1 hour. It is cooled to 10 to 15 ⁰ C, the precipitated orange precipitate was filtered off with suction, washed with acetic acid and dried at 60 to 70 ⁰ C.

Yield: 18.7 g (77% of theory);

Melting point: 150 to 155 ° C (dec.);

Analysis for C ₆ H ₇ Br ₃ IN ₃

calc .: C 14,77 H 1.45 Br49,15 126.02 N 8,61 Found .: C 14.52 H 1.40 Br48,82 125.74 N 8.39

Example 3

4-Amino-5-bromo-2-bromnibthyl-6-methyl-pyrimidine

Analogously to Example 2, but with the difference that the IBr adduct obtained is suspended in 250 ml of water and treated with vigorous stirring with 10% sodium hydroxide solution until the suspension is constantly alkaline. The resulting precipitate is filtered off, washed with water and dried at 60 to 7O ⁰ C.

Yield: 9.0 g (64% of theory);

Melting point (EtOH): 168 to 170 ° C (dec.);

Analysis for C ₆ H ₇ Br ₂ N ₃

Calcd .: C, 25.65, H, 2.51, Br, 56.88, N, 14.96

Found: C25.52 H2.50 Br57,13 N 15,08

Example 4

4-Amino-2-bromomethyl-5-chloro-6-methyl-pyrimidine

14.2 g (0.05 mol) of 4-amino-5-chloro-2-iodomethyl-6-methyl-pyrimidine are suspended in 100 ml of acetic acid. With vigorous stirring, 8.0 g (0.1 mol) of bromine are added dropwise within 1 minute at room temperature. The mixture is stirred for a further 30 minutes, the orange precipitate is filtered off with suction, washed with a little acetic acid and dried at 60 to 70 ° C. The precipitate (suspended in 100 ml of water) and the mother liquor are neutralized separately with 10 or 20% sodium hydroxide solution. The precipitated precipitates are filtered off, washed with a little water and dried at 60 to 70 ° C.

Total yield: 10.5 g (89% of theory);

Melting point (i-PrOH): 158 to 16O ⁰ C (dec.);

Analysis for C ₆ H ₇ BrCIN ₃

Calc .: C30.47 H 2.98 Br33.79 Cl 14.99 N 17.77

Found: C30.12 H 2.89 Br33.52 Cl 14.71 N 17,47

Example 5

4-amino-2-chlormathyl-5-iodo-6-methyl-pyrimidine

12.45 g (0.05 mol) of 4-amino-2-iodomethyl-6-methyl-pyrimidine are dissolved in 6 g ml of about 5% hydrochloric acid. The solution is cooled to ⁰ ° C. and, while stirring at this temperature, 3.5 g (0.1 mol) of chlorine are introduced within 30 minutes. The mixture is then stirred for 2 hours at 5 ⁰ C and allowed to stand for 24 hours at room temperature. There are 2 phases, which are separated

be neutralized with 10% sodium hydroxide solution. In the process, dark oils separate, which solidify after stirring with diethyl ether. The resulting solids are filtered off, washed with water and dried at 60 to 7O ⁰ C.

Yield: 6.0 g (42% of theory);

Melting point (nitromethane): 125 to 128 ^° C .;

Analysis for C ₆ H ₇ CIIN ₃

Calc .: C 25.42 H 2.49 Cl 12.51 144.76 N 14.82

Found: C25.29 H 2.49 Cl 12.64 144.76 N 14.98

Example 6

4-amino-2-chloromethyl-6-methyl-pyrimidine

Analogously to Example 5, but with the difference that after completion of the reaction, the aqueous phase is neutralized with 10% sodium hydroxide solution, filtered from precipitated solid and the filtrate mixed with 50ml of 50% sodium hydroxide solution. It is allowed to coagulate, sucks off the precipitated colorless precipitate, washed with a little water and dried at 60 to 70 ⁰ C.

Yield: 1: g (17% of theory);

Melting point (benzene): 138 to 140 ° C; Analysis for C ₈ HaCIN ₃

bee: C 45,73 H 5,12 Cl 22,49 N 26,66

Found: C 45.78 H 5.09 Cl 22.61 N 27.02

Example 7

4-Amino-5-chloro-2-chloromethyl-6-methyl-pyrimidine-ICI ₃ adduct 12.45 g (0.05 mol) of 4-amino-2-iodomethyl-6-methyl-pyrimidine is about 5% in 60 ml Dissolved hydrochloric acid and slowly while stirring chlorine into the solution. The rising

Temperature to about 4O ⁰ C and it settles an oil that begins to solidify after 1 hour. After another hour

the reaction is complete and the resulting yellow precipitate is filtered off with suction, washed with water and dried in air.

Yield: 12.75 g (60% of theory); Melting point: 115 to 12O ⁰ C (dec.); Analysis for C ₈ H ₇ Cl ₆ IN ₃

boron: C 16.94 H 1.66 Cl 41.68 129.84 N 9.88

Found: C 17.10 H 1.75 CI41.25 129.88 N 10.21

Example 8

4-Amino-6-bromo-2-chloromethyl-6-methyl-pyrimidine (one-pot method)

40.4 g (0 / z mol) 4-ΑΓηίηο-5- ^ οην2,6-αΐΓηβΙηνΙ · ρνΓΐπιΙαίη be concentrated in 100 ml of water with the addition of 20 ml

Sulfuric acid dissolved. To the solution are added 50 ml of carbon tetrachloride and 22.8 g (0.18 mol) of iodine. After that will be

13.6 g (0.12 mol) of 30% hydrogen peroxide are added dropwise at boiling temperature with vigorous stirring in about 3 hours. It is allowed to cool and the aqueous phase is separated from the carbon tetrachloride layer and unused iodine. With stirring, chlorine is then passed into the solution until a yellow precipitate is formed. This warms up the solution and the

Temperature is to be maintained by temporary cooling by means of ice / water below 4O ⁰ C. To complete the reaction one passes

another 30 minutes chlorine in the reaction mixture. Subsequently, the precipitate (suspended in 300 ml

Water) and the mother liquor separately mixed with 10% sodium hydroxide solution to pH 9-10. The raw products will be

filtered off with suction, washed with water and dried at 60 to 70 ° C.

Total yield: 20.35 g (43% of theory); Melting point (i-PrOH): 150 to 152 ⁰ C.

Claims (5)

claims: 1. A process for the preparation of new 6-alkyl-4-amino-2-halomethyl-pvrimidines of general formula I, th in the X is chlorine or bromine, R ^{1 is an} alkyl radical, R ^{2 is} hydrogen or a halogen radical, R ^{3 is} an amino or alkylamino radical and m and η = 0 or 1 or m = 1 and η = 3, characterized in that pyrimidines of the general formula I in which X is iodine, m and η = 0 and R ¹ , R ² and R ^{3 are} the abovementioned Meanings have, in a solvent, preferably an acid and optionally water as a diluent, with chlorinating or Bromierungsreagenzien in the temperature range from -50 to 100 ⁰ C implemented. 2. The method according to claim 1, characterized in that in the case of R ² = H in the reaction at the same time the corresponding 5-iodo-pyrimidines (X = Cl or Br, R ² = I) are obtained. 3. Process according to Claims 1 and 2, characterized in that chlorine and bromine are preferably used as halogenating reagents. 4. The method according to claim 1 to 3, characterized in that the reaction is preferably carried out at -20 to 30 ⁰ C. 5. The method according to claim 1 and 4, characterized in that the 2-halomethyl-pyrimidines (R ¹ = Cl, Br) are obtained directly from the corresponding 2-methyl-pyrimides (X = H) by the 2-methyl pyrimidine iodinated according to known methods in an acid with the addition of an oxidizing agent and reacted without intermediate isolation with chlorinating or Bromierungsreagenzien.