Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-09-21
2001-06-26
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S330000
Reexamination Certificate
active
06252076
ABSTRACT:
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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-2-yl)pyrimidine represented by the following formula (I),
and its acid addition salts, wherein a pyrimidine derivative represented by the following formula (II-A),
in which Hal represents a halogen, is reacted with 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula (III);
second, to a process for preparation of the pyrimidine derivative represented by formula (II-A) and the compound of formula (E); 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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-2-yl)pyrimidine is prepared according to the following reaction scheme A:
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-tetrahydroisoquinolin-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 (III-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-tetrahydroisoquinolin-2-yl)pyrimidine represented by formula (I),
and its acid addition salts wherein a pyrimidine derivative represented by the following formula (II-A),
in which Hal represents a halogen, is reacted with 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by formula (III),
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 pound represented by the following formula (II), which includes the pyrimidine derivative represented by formula (II-A),
which R represents hydroxy or a halogen.
BEST MODE FOR CARRYING OUT THE INVENTION
According to the present invention, the compound of formula (I) an 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:
Since the starting compound of the reaction scheme 1 (i.e., the compound of formula (II-A)) contains a single reactive site (i.e., Hal), this reaction scheme does not produce any side product and, thus, optimizes the yield of the compound of formula (I), the desired product.
The present invention is described in more detail below.
Although the 4-halogeno-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine represented by formula (II-A) can be reacted according to the present invention with an equivalent amount of 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by formula (II-A), it is preferable to conduct the reaction using an excess, rather than an equivalent amount, of the latter. Since the latter is a liquid under reaction conditions, the unreacted 1-methyl-1,2,3,4-tetrahydroisoquinoline can be readily removed after the reaction has gone to completion.
The reaction of the present invention is preferably carried out in the presence of a solvent. Solvents which may be used for this purpose include N,N-dimethylformamide, n-butanol, n-pentanol, n-hexanol, dimethylsulfoxide, ethylene glycol, 1,2-propylene glycol, and mixtures thereof. Of these propylene glycol and ethylene glycol are most preferred, since use of either of these minimizes both reaction time and production of side products.
In the method of the present invention, the reaction scheme 1 is generally carried out in the presence of a base. Bases which can be used for this purpose include triethylanmine, N,N-dimethylaniline, pyridine and potassium acetate. The reaction temperature for the reaction between the compound of formula (II-A) and 1-methyl-1,2,3,4-tetrahydroisoquinoline of formula (III) is preferably in the range from 110° C. to 160° C. and the reaction time is preferably in the range from 16 hours to 72 hours.
5,6-Dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine of formula (I) as prepared according to the above method can be converted into its acid addition salt, preferably into the hydrochloride salt, by conventional methods. The resulting product can be purified by conventional working-up procedures, such as recrystallization, chromatography, and the like.
Since the compound of formula (I) prepared by the method of the present invention contains an asymmetric carbon atom (i.e., the carbon atom denoted by * in the formula immediately below), this compound be present in an (R)-(+)-isomer, an (S)-(−)-isomer, or a racemate wherein the R and S isomers are mixed in the ratio of 1:1. Unless indicated otherwise, the compound of formula (I) should be interpreted to include all of these isomers.
The (R)-(+)- and (S)-(−)-isomers of the compound of formula (I) can be readily be prepared from the R and S isomers, respectively, of the compound of formula (III).
The compound of formula (II-A), which is used as the starting material in the method of the present invention, is a novel compound which can be prepared according to the method depicted by the following reaction scheme 2:
In the reaction scheme 2, Hal represents a halogen.
As depicted by the reaction scheme 2, reacting 4-fluorophenylguanidine carbonate of formula (IV) with ethyl 2-methylacetoacetate of formula (V) yields 4-hydroxy-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine of formula (II-B), which may then be reacted with a halogenating agent to obtain the 4-halogeno-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine of formula (II-A).
4-Fluorophenylguanidine carbonate of formula (IV), which is used as the starting material for preparing the compound of formula (II-A) in the reaction scheme 2, can readily be prepared from 4-fluoroaniline using known methods (see, for example, European Patent No. 0,560,726). Specifically, the desired 4-fluorophenylguanidine carbonate can be prepared by reacting 4-fluoroaniline with a 50% cyanamide solution under acidic conditions using 30% to 37% hydrochloric acid while maintaining the temperature ranging from 75° C. to 95° C.
The first step of the reaction scheme 2 may be practiced in the presence of a solvent. Solvents which may be used for this purpose include acetonitrile, N,N-dimethylformamide and dimethylsulfoxide. This reaction is pre
Hong You Wha
Kim Hong Bae
Lee Young Nam
Ford John M.
Ladas & Parry
Yuhan Corporation
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