Process for preparing 2-amino-4,6-dichloropyrimidine

Details Process for preparing 2-amino-4,6-dichloropyrimidine Process for preparing 2-amino-4,6-dichloropyrimidine

1996-03-05

1997-12-16

Ford, John M.

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C07D23930, C07D23942

Patent

active

056986955

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND

The present invention is an improved process for producing 2-amino-4,6-dichloropyrimidine. Said pyrimidine is useful as an intermediate in the production of pesticides and pharmaceuticals.
U.S. Pat. No. 3,991,190 and Banks et at., J. Am. Chem. Soc., (1951), 73, 3011-3012 disclose processes for making the subject pyrimidine wherein 2-amino-4,6-dihydroxypyrimidine and excess phosphorus oxychloride (used as both a reactant and solvent) are reacted under reflux (105.degree.-110.degree. C.) in the presence of dimethylaniline (hereinafter referred to as "neat" processes). U.S. Pat. No. 4,929,729 and Kokai Patent No. Sho 64(1989)-83071 disclose processes for making the subject pyrimidine wherein 2-amino-4,6-dihydroxypyrimidine and phosphorus oxychloride are reacted in inert solvent at reflux in the presence of acid-removing agent (hereinafter referred to as "solvent" processes).
The present invention is advantageous over the prior methods for one or more of the following reasons: i) improved product yield, ii) shorter reaction time, iii) reduced amounts of phosphorus oxychloride which is a highly corrosive and toxic reagent and iv) no need for recycle or disposal of inert solvent.


SUMMARY OF THE INVENTION

This invention is an improved process for the preparation of 2-amino-4,6-dichloropyrimidine (I) comprising reacting 2-amino-4,6-dihydroxypyrimidine (I) and phosphorus oxychloride (III) according to Equation 1: ##STR1## the reaction being conducted by charging an acid-removing agent such as an amine base, most preferably N,N-dimethylaniline, to a mixture of II and III at a temperature of from 40.degree. to 90.degree. C., preferably 40.degree. to 80.degree. C., most preferably 55.degree.-68.degree. C.; the mole ratio of (III) to (II) being from about 2.8:1 to 5:1, preferably about from 3.4:1 to 4.2:1, and the mole ratio of acid-removing agent to II being from about 1.7-2.5:1. The process is carried out without the need for reflux temperatures, large excesses of phosphorus oxychloride or inert solvent.


DETAILS OF THE INVENTION

In accordance with present invention, the process is typically carried out by first slurrying 2-amino-4,6-dihydroxypyrimidine (II) in phosphorus oxychloride (III) in the ratio of one mole of II in 2.8 to 5 mole, preferably 3.4 to 4.2 mole, of III. Starting materials 1I and 1II are known and commercially available (Aldrich Chemical Co., Milwaukee, Wis.). The ratio of III to II is determined by the minimum amount of III needed to provide a slurry with low enough viscosity to be pumped and processed readily. More than 5: I moles of III to II is not desirable and is just lost in the quench step, described hereinafter.
The slurry of II and III is heated to reaction temperature which can be from 40.degree. to 90.degree. C. For reasons of economy and purity of final product, the reaction temperature is preferably 40.degree.-80.degree. C., and most preferably 55.degree.-68.degree. C. At temperatures above 90.degree. C., the yield decreases due relatively increased side reaction. At temperatures below 40.degree. C., the reaction time becomes unacceptably slow.
At reaction temperature, acid-removing agent is charged, either continuously or in small increments, to the slurry of II and III. The total amount charged is preferably 1.7 to 2.5 mole of acid-removing agent per mole of II in the slurry. Reaction during this step is rapid and exothermic, and the rate of addition of acid-removing agent is limited by the ability to maintain the proper reaction temperature range. Amine bases which can be employed as acid-removing agents include N,N-dimethylaniline, N,N-diethylaniline, triethylamine, pyridine and picoline. Most preferred is N,N-dimethylaniline.
A hold period at reaction temperature at the end of addition of the acid-removing agent can be employed to make certain II is completely reacted, although this step is not required.
The product pyrimidine (I) can be isolated by quenching the reaction mixture with water to consume the small excess of phosphorous oxychloride; then filtering, w

REFERENCES:
patent: 3991190 (1976-11-01), Garzia et al.
patent: 4929729 (1990-05-01), Haga et al.
Banks et al., J. Am. Chem. Soc. 73:3011-3012 (1951).
M. Israel et al., J. Med. Chem., 7:792-799 (Nov. 1964).

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