IE67294B1

IE67294B1 - Process for the preparation of 2-acylamino-9-acyl-6-halopurine

Info

Publication number: IE67294B1
Application number: IE451790A
Authority: IE
Inventors: Winfried Hertzsch
Original assignee: Hoechst Ag
Priority date: 1989-12-16
Filing date: 1990-12-14
Publication date: 1996-03-20
Also published as: DK0433845T3; DE3941658A1; DE59008852D1; IE904517A1; ES2071731T3; JPH0692965A; EP0433845A1; ATE120748T1; PT96179B; PT96179A; EP0433845B1

Abstract

2-Acylamino-9-acyl-6-halogeno-purine can be prepared by acylating 2-acylamino-6-halogeno-purine in the presence of a catalyst without the contaminating production of 2-diacylamino-9-acyl-6-chloro-purine.

Description

2-Acyl amino-9-acyl-6 -chloropurines are very widely utilizable intermediates in the pharmaceutical industry for nucleoside syntheses.

The preparation of 2-acetamido-9-acetyl-6-chloropurine by acetylation of 2-amino-6-chloropurine has already been described (Synthetic Procedures in Nucleic Acid Chemistry, Vol. 1, 1968, W.W. Zorbach and R.S. Tipson Ed., John Wiley & Sons, New York, 25 - 27) . In this case, the acetylation in position 9 of the purine ring is preferably carried out under reflux conditions. However, even after 5 to 10 minutes reaction time, 2-diacetamido9-acetyl-6-chloropurine is also formed as an impurity in addition to 2-acetamido-9-acetyl-6-chloropurine. The total yield of the two compounds is 75%.

Some experiments moreover show that under the abovemen tioned conditions at reflux temperatures of 135C to 140°C, not only are larger amounts of 2-diacetamido-9acetyl-6-chloropurine formed, but a replacement of chlorine by oxygen in position 6 of the purine ring additionally also takes place. These disadvantages particularly have an influence in the preparation of larger amounts of 2 -acetamido- 9 -acetyl- 6 - chloropur ine. On the production scale, longer heating and cooling times cannot be avoided, so that the high thermal loadings lead to strongly contaminated 2-acetamido-9-acetyl-6-chloropurine batches.

Surprisingly, it has now been found that by the use of a catalyst the purity of 2-acylamino-9-acyl-6-halopurine can be substantially improved in the preparation from 2acylamino- 6 -halopurine.

The invention thus relates to a process for the preparation of the compound of the formula I in which R1 and R2, which can be identical or different, are a straight-chain or branched alkanoyl group having 2 to 10 carbon atoms or an aralkanoyl group having 7 to 10 carbon atoms and X is fluorine, chlorine, bromine or iodine, by acylation of the compound of the formula II IX in which R1 and X have the abovementioned meaning, which comprises using pyridine or a pyridine derivative as the catalyst and carrying out the acylation at a temperature of between 10°C and 90°C.

The invention will now be described in detail in the following, in particular in its preferred embodiments.

The expression alkanoyl group having 2 to 10 carbon atoms is to be understood as meaning, for example, the radicals of the following acids: acetic acid, propionic acid, n-butyric acid, i-butyric acid, n-valeric acid, i-valeric acid, methylethylacetic acid, trimethylacetic acid, caproic acid, caprylic acid, capric acid, heptanoic acid and nonanoic acid. The expression aralkanoyl group having 7 to 10 carbon atoms means, for exasple, the radicals of the following compounds: benzoic acid, phenylacetic acid, phenylpropanoic acid, phenyl-n-butyric acid or phenyl-i-butyric acid.

The reaction, according to the invention, of 2-acylamino6-halopurine to give 2-acylamino-9-acyl-6-halopurine is carried out in the presence of an acylating agent, with V the aid of which the amino group in the 9-position of the compound of the formula IX can be substituted by a straight-chain or branched alkanoyl group having 2 to 10 carbon atoms or an aralkanoyl group having 7 to 10 carbon atoms. Acylating agents which can be used are carboxylic anhydrides, such as, for example, acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, caprylic anhydride, capric anhydride or caproic anhydride. However, mixed anhydrides can also be employed. In addition, acylating agents which can also be used are carboxylic acid halides, such as acetyl chloride, propionyl chloride, phenylacetyl chloride, phenylbutanoyl chloride, benzoyl chloride, acetyl bromide, or propionyl bromide. The acylating agents can be dissolved in an inert solvent beforehand. Inert solvents which can be used are compounds such as, for example, dimethylacetamide, toluene, benzene or N-methylpyrrolidone.

-Acylamino-6-halopurine is mixed with the acylating agent and heated with the addition of a catalyst. The following compounds can be used as catalyst: pyridine, pyridine derivatives such as, for example, 4dimethylaminopyridine, 4- (4-methyl-1-piperidinyl)pyridine, 4-pyrrolidinopyridine, 4-morpholinopyridine or N-methylimidazole. Preferably, 4-dimethylaminopyridine is used. 'i The molar ratio of 2-acyl amino-6-halopurine to the acylating agent can be varied within a range from 1:1 to 1:40. The reaction is preferably carried out in a range from 1:5 to 1:30. The molar ratio of catalyst to 2acylamino-6-halopurine can vary within a range from 1:5 to 1:100. Preferably, a molar ratio of 1:35 to 1:80 is maintained.

The reaction temperature is between 10°C and 90°C, in particular between 20°C and 70°C. The reaction time is between 0.5 and 7 hours, in particular between 1 and 3 hours. The course of the reaction is determined by sample removal and quantitative analysis of the final product with the aid of known titration methods. After this, the mixture is stirred at temperatures between 0°C and 10°C for a. further 0.5 to 2 hours. After filtration, the compound of the formula I is obtained in high purity.

The sequence of the individual process steps can also be varied. A person skilled in the art does not find it difficult to find the optimum sequence for the reaction process.

The preparation of 2-acylamino-6-halopurines is carried out in a manner known per se by halogenation and acylation of purines (EP 0,203,685; D.J. Brown, Heterocyclic Compounds, 135-197, 1971; Bowles W.A. et al., J. Med. Chem., 471-480, 6, 1963).

In comparison to the route known hitherto for the preparation of 2-acylamino-9-acyl-6-halopurines, the process according to the invention opens up the advantage of obtaining the final product in high purity and yield. The catalysts used catalyze the acylation in position 9 of the purine ring, but not the formation of 2-diacylamino-9-acyl-6-halopurines. All process steps which are needed for the separation of the 2-diacylamino-9-acyl-6halopurine derivatives thus become unnecessary.

The example shown below is used to illustrate the invention further.

Example: 1.1 kg (5.2 mol) o£ 2-acetamido-6-chloropurine are suspended in 11 1 of acetic anhydride and 87.0 g (0.71 mol) of 4-dime thyl aminopyridine are added. The mixture is stirred at 50°C for two hours, then cooled and stirred at 0°C to 5°C for half an hour. The product is filtered off, washed with diisopropyl ether and dried in vacuo at 50°C. 1.16 kg of 2-acetamido-9-acetyl-6-chloropurine are obtained.

Yield: 88% of theory Purity: 99.1% (titration) ^H-NMR (in DMSO) : δ (ppm): 2.25 N-C-CH3 2.93 9-COCH3 8.93 8-H 11.06 HN-CO-C

Claims

1. Patent claims:

1. A process for the preparation of the compound of the formula I X in which R 1 and R 2 , which can be identical or 5 different, are a straight-chain or branched alkanoyl group having 2 to 10 carbon atoms or an aralkanoyl group having 7 to 10 carbon atoms and X is fluorine, chlorine, bromine or iodine, by acylation of the compound of the formula IZ 10 in which R 1 and X have the abovementioned meaning, which conqprises using pyridine or a pyridine derivative as the catalyst and carrying out the acylation at a temperature of between 10°C and 90°C. ; t 2. The process as claimed in claim 1, wherein carboxylic anhydride or carboxylic acid halide are used as the acylating agent. The process as claimed in claim 1, wherein

2. 4-dimethylaminopyridine, 4- (4-methyl-1-piper idinyl) 3. pyridine, 4-pyrrolidinopyridine, 4-morpholinopyridine or N-methylimidazole are used as the pyridine derivative. 4. The process as claimed in one or more of claims 1 to

3. 5 3, wherein the molar ratio of the compound of the formula II to acylating agent is in the range from 1:1 to 1:40. 5. The process as claimed in claim 4, wherein the molar ratio is in the range from 1:5 to 1:30. 10

4. 6. The process as claimed in one or more of claims 1 to 5, wherein the molar ratio of catalyst to the compound of the formula II is in the range from 1:5 to 1:100.

5. 7. The process as claimed in claim 6, wherein the molar 15 ratio is between 1:35 to 1:80.

6. 8. The process as claimed in claim 1, wherein the reaction temperature is between 20°C and 70°C.

7. 9. A process according to claim 1 for the preparation of a compound of the formula I given and defined 2 θ therein, substantially as hereinbefore described and exemplified.

8. 10. A compound of the formula I given and defined in claim 1, whenever prepared by a process claimed in a preceding claim.