Process for preparation of pyrimidine derivatives

Details Process for preparation of pyrimidine derivatives Process for preparation of pyrimidine derivatives

1998-10-21

1999-11-23

Ford, John M.

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

Organic compounds

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

544323, C07D23948

Patent

active

059903112

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquin olin-2-yl)pyrimidine represented by the following formula (I) and its acid addition salts; second, to a process for preparation of an intermediate for preparing the compound (I); and, third, to a novel intermediate compound. More specifically, the present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquin olin-2-yl)pyrimidine represented by the following formula (I), ##STR4## and its acid addition salts, wherein a pyrirnidine derivative represented by the following formula (II-A), ##STR5## in which Hal represents a halogen, is reacted with 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula (III); ##STR6## second, to a process for preparation of the pyrimidine derivative represented by formula (II-A) and the compound of formula (III); and, third, to a novel intermediate compound including the pyrimidine derivative represented by formula (II-A).


BACKGROUND ART

5,6-Dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquino lin-2-yl)pyrimidine of the above formula (I) inhibits gastric acid secretion by means of a reversible proton-pump inhibiting effect and, therefore, can be used as an anti-ulcer agent. This compound was developed by the inventors of the present invention, who then applied for patents for the compound and/or its method of preparation in Korea and other countries (see International Publication No. WO 96/05177).
According to the method disclosed in the above patent application, 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquin olin-2-yl)pyrimidine is prepared according to the following reaction scheme A: ##STR7## Since the starting material of the above reaction scheme has two reactive sites (i.e., the two Cl atoms), the first reaction inevitably produces a side product, which reduces the yield of the desired compound.
The present inventors have long labored to develop a novel method for preparing 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquin olin-2-yl)pyrimidine of formula (I) without producing side products. As a result, we have discovered that the desired compound of formula (I) can be efficiently prepared without side products by reacting the pyrimidine derivative represented by formula (II-A) with 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by formula (III) and, thus, have completed the present invention.


DISCLOSURE OF THE INVENTION

The present invention relates to a novel process for preparation of 5,6-dimethyl -2-(4-fluorophenylamino)-4-(1-methyl -1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by formula (I) and its acid addition salts.
More specifically, the present invention relates to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquin olin-2-yl)pyrimidine represented by formula (I), ##STR8## and its acid addition salts wherein a pyrimidine derivative represented by the following formula (II-A), ##STR9## in which Hal represents a halogen, is reacted with 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by formula (III), ##STR10##
In addition, the present invention relates to a process for preparation of the pyrimidine derivative of formula (II-A) and the compound of formula (III).
Further, the present invention relates to a novel intermediate compound represented by the following formula (II), which includes the pyrirnidine derivative represented by formula (II-A), ##STR11## in which R represents hydroxy or a halogen.


BEST MODE FOR CARRYING OUT THE INVENTION

According to the present invention, the compound of formula (I) can be prepared by reacting the compound of formula (II-A) with 1-methyl-1,2,3,4-tetrahydroisoquinoline of formula (III), as depicted in the following reaction scheme 1: ##STR12##
Since the starting compound of the reaction scheme 1 (i.e., the compound of

REFERENCES:
patent: 5750531 (1998-05-01), Lee et al.
Chemical Abstracts, vol. 96, Apr. 12, 1982, p. 697, col. 1, abstract No. 122741v, "Herbicides . . . ".
Chemical Abstracts, vol. 118, Jun. 21, 1993, p. 347, col. 2, abstract No. 249869w, "Biosynthesis . . . ".
Chemical Abstracts, vol. 106, Feb. 2, 1987, p. 526, col. 1, abstract No. 32801k, "Carbon dioxide . . . ".
Chemical Abstracts, vol. 96, Jun. 21, 1982, p. 726, col. 1, abstract No. 217665n, "Synthesis . . .".

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