MXPA99004041A - Process for preparation of pyrimidine derivatives - Google Patents

Abstract

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 formula (I) and its acid addition salts, second to a process for preparation of an intermediate for preparing thecompound (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 formula (I), and its acid addition salts by reacting a pyrimidine derivative represented by formula (II-A), in which Hal represents a halogen, with 1-methyl-1,2,3, 4-tetrahydroisoquinoline represented by formula (III), second, to a process for preparation of the pyrimidine derivative of formula (II-A) and the compound of formula (III);and third, to a novel intermediate compound including the pyrimidine derivative of formula (II-A).

Description

PROCESS FOR THE PREPARATION OF PYRIMIDINE DERIVATIVES Technical Field The present invention is concerned first with a process for the preparation of 5,6-dimethyl-2-. { 4-fluorophenylamino) -4- (1-methyl-1,2,4,4-tetrahydroisoquinolin-2-yl) pyrimidine represented by the following formula (I) and its acid addition salts; secondly, with a process for the preparation of an intermediary for the preparation of compoteto (I); and third with a new intermediate compound. More specifically, the present invention is concerned, first, with a process for the preparation of 5,6-dimethyl-2- (4-fluoro-phenylamino) -4- (1-methyl-1,2,3,4-tetrahydroisoquinoline-2-) il) pyrimidine represented by the following formula (I), and its acid addition salts, wherein a pyrimidine derivative represented by the following formula (II-A), wherein Hal represents a halogen, is reacted with 1-methyl-1,2,4,4-tetrahydroisoquinoline represented by the following formula (III); second, with a process for the preparation of the pyrimidine derivative represented by the formula (II-A) and the compound of the formula III); and thirdly with a new intermediate compound - which includes the pyrimidine derivative represented by the formula (II-A).

BACKGROUND OF THE INVENTION The 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine of the formula (I) above inhibits the gastric acid secretion ^ by means of a reversible proton pump inhibitory effect and can therefore be used as an anti-ulcer agent. This compound was developed by the inventors of the present invention, who applied for patents for the compound and / or its preparation method in Korea "other countries (see International Publication No. WO 96/05177) In accordance with the method described in the above patent application, 5,6-dimethyl-2- (4- fluorophenylamino) - '4- (1-methyl-1, 2, 3, -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 (ie, the two Cl atoms), the first reaction inevitably produces a side or secondary product, which reduces the yield of the desired compound. Work has been done for a long time to develop a new method for preparing 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1,2,3,4-tetrahydroisoqui-nolin- 2-yl) pyrimidine of the formula (I) without producing secondary or side products. As a result, it has been discovered that the desired compound of formula (I) can be efficiently prepared without side products by reacting the pyrimidine derivative represented by the formula (II-A) with 1-methyl-1, 2, 3, 4-tetrahydroisoquinoline represented by the formula (III), and thus the present invention has been completed.

BRIEF DESCRIPTION OF THE INVENTION The present invention is concerned with a new process for the preparation of 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2,3,4-tetrahydroxysoquinolin) -2-yl) pyramidine represented by the formula (I) and its acid addition salts. More specifically, the present invention is concerned with a process for the preparation of 5,6-dimethyl-2- (4-fluorophenyla ino) -4- (1-methyl-1,2,3,4-tetrahydroisoquinoline) -2-yl) pyrimidine represented by the formula (I), (D 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-1,2,4,4-tetrahydroisoquinoline represented by the formula (III), In addition, the present invention is concerned with a process for the preparation of the pyrimidine derivative of formula (II-A) and the compound of formula (III). In addition, the present invention is concerned with. a novel intermediate compound represented by the following formula (II), which includes the pyrimidine derivative represented by the formula (II-A), wherein R represents hydroxy or a halogen.

BEST MODE FOR CARRYING OUT THE INVENTION In accordance with 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 (II), as illustrated in the following reaction scheme 1: Reaction scheme 1 Since the starting compound of reaction scheme 1 is the compound of formula (II-A)) contains a single reactive site (ie, Hal), this reaction scheme does not produce any secondary product and thus optimizes the yield of the compound of formula (I), of the desired product. The present invention is described in more detail later herein. Although the 4-halogen-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine represented by the 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 the formula (III), it is preferable to conduct the reaction by using an excess, rather than an equivalent amount of the latter. Since the latter is liquid under the reaction conditions, unreacted 1-methyl-1,2,3,4-tetrahydroisoquinoline can be easily separated after the reaction has progressed to confirmation. The reaction of the present invention is preferably carried out in the presence of a solvent. Solvents that can be used for this purpose include N, N-dimethylformamide, n-butanol, n-pentanol, n-hexanol, dimethylsulfoxide, ethylene glycol, 1-propylene glycol and mixtures thereof. Of these, propylene glycol and ethylene glycol are more preferred, since the use of either one of these minimizes the reaction time and the production of side products. In the method of the present invention, the reaction scheme 1 is carried out in general in the presence of a base. The bases that can be used for this purpose include triethylamine, 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 of 110 ° C to 160 ° C and the reaction time is preferably in the range of 16 hours to 12 hours.

The 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine of formula (I) as prepared in accordance with the above method, it can be converted to its acid addition salt, preferably to the hydrochloride salt, by conventional methods. The resulting product can be purified by conventional 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 (that is, the carbon atom denoted by * in the formula immediately below), this compound is present in an (R ) - (+) isomer and 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) must be construed to include all these isomers.

The (R) - (+) and (S) - (-) isomers of the compound of formula (I) can be prepared easily 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 new compound which can be prepared in accordance with the method illustrated by the following reaction scheme 2: Reaction scheme 2 ro. - NH O 0 H2N? NH-¿rx -F ° J (TV) (V) (p-B) (p-A) In reaction scheme 2, Hal represents a halogen. As illustrated by reaction scheme 2, by reacting the carbonate of 4-fluorofeaylguanidine of formula (IV) with ethyl 2-methylacetoacetate of formula. (V) produces 4-hydroxy-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine of formula (II-B), which can then be reacted with a halogenating agent to obtain the 4-halogeno-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine of formula (II-A). The 4-fluorophenylguanidine carbonate of formula (IV), which is used as the starting material for the preparation of the compound of formula (II-A) in reaction scheme 2, can be easily 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 a fluctuating temperature of 75%. ° C to 95 ° C. The first step of reaction scheme 2 can be carried out in the presence of a solvent. Solvents which can be used for this purpose include acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide. This reaction is preferably carried out at a temperature ranging from 110 ° C to 160 ° C. In the second stage of reaction scheme 2, the 4-hydroxy-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine of formula (II-B) obtained from the first step of reaction scheme 2 is converted to the compound of formula (II-A) by reacting the first with a halogenating agent. The halogenating agents that can be used for this purpose they include phosphorous oxychloride, oxalyl chloride, thionyl chloride and phosphorous tribromide. This halogenation reaction is carried out in the presence of a solvent. The reaction solvents that can be used-for this purpose include preferably N, N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane and 1,2-dichlorobenzene. It is preferable to maintain the reaction temperature in the range of 75 ° C to 95 ° C_. Although the second step of reaction scheme 2 can be carried out by isolating the intermediate after the first reaction step has been completed, it is preferable to conduct the first and second steps in a single container. Specifically, the 4-hydroxy-2- (4-fluorophenyla ino) -5,6-dimethylguanidine of formula (II-B) is prepared from 4-fluorophenylguanidine carbonate and then, without isolation, can be reacted successively with the halogenating agent to produce 4-halogeno-2- (4-fluorophenyla ino) -5,6-dimethylpyrimidine (II- -A). The compound of formula (II-A) which is used as the starting material for the preparation of the compound of formula (I) according to the present invention is new, as is the compound of formula (II-B) produced as the intermediary in the reaction scheme 2. Both new compounds can be represented by the following formula (II), which is within the scope of the present invention, wherein, R represents hydroxyl or a halogen. The 1-methyl-1,2,3,4-tetrahydroisoquinoline of formula (III), which is also used as the starting material in reaction scheme 1, is a known compound and can be prepared by known methods (cf. for example, International Patent Publication No. WO 94/14795). According to this known method, (R) - or (S) -1-methyl-1,2,4,4-tetrahydroisoquinoline is prepared by reacting (R) - or (SJ-methylbenzylamine with a-chloro- a- (methylthio) acetylchloride and stannous chloride (SnCl.) to produce (R) - (S) -l-methyl-4-methylthio-1,2,4,4-tetrahydroisoquinolin-3-one, respectively, then react the resulting compound with Raney nickel to remove a methylthio group, and finally addition of a reducing agent, however, this method is disadvantageous, since the a-chloro-a- (methylthio) -acetylchloride which is used as the starting material is unstable and explosive, so that this method can not be implemented on an industrial scale. reaction is long, the total yield is low, which makes this method non-economic. It has been working for a long time to find a more efficient method to produce 1-methyl-1, 2, 3, 4-tetrahydroisoquinoline. It has been discovered that 1-methyl-1,2,3,4-tetrahydroisoquinoline can be used inexpensively and safely by successively reacting α-methylbenzylamine with 2-bromoethanol, a brominating agent and a Le is acid. Such a process for the preparation of 1-methyl-1,2,3-tetrahydroisoquinoline is new and is contemplated by the scope of the present invention. This new process for the preparation of 1-methyl-1, 2, 3, 4-tetrahydroisoquinoline is explained in more detail later herein. According to the present invention, 1-methyl-1,2,3,4-tetrahydroisoquinoline of formula (III) can be prepared by reacting a-methylbenzylamine successively with 2-bromoethanol, a brominating agent and Lewis acid. . The method of the present invention employs the following reaction scheme 3.

Scheme d? reaction 3 All starting materials and reagents used in reaction scheme 3 are known compounds and can be obtained as commercial products. In the first stage, a-methylbenzyl amine. it is reacted with 2-bromoethanol to produce N- (2-hydroxyethyl) -a-methylbenzylamine, which in turn is reacted with the brominating agent to produce N- (2-bromoethyl) -a-methylbenzylamine hydrobromide. In the third step, the N- (2-bromoethyl) -a-methylbenzylamine hydrobromide is reacted with a Lewis acid to produce the desired 1-methyl-1,2,3,4-tetrahydroisoquinoline of formula (III) . Reaction solvents that can be used in the first stage include acetonitrile, N, N- dimethylformamide, dichloromethane and 1,2-dichloroethane and the reaction temperature is preferably maintained in the range of 40 ° C to 60 ° C. Reaction solvents that can be used in the second step include 1,2-dichloroethane, acetic acid, water and 1,2-dichloro-benzene, and the reaction temperature is preferably maintained in the range of 110 ° C to 145 ° C. ° C. Broming agents that can be used in this reaction include bromine, bromic acid, aqueous solution of bromic acid and phosphorous tribromide. Although the first and second steps of reaction scheme 3 can be carried out by isolating the N- (2-hydroxyethyl) -a-methylbenzylamine produced as the intermediate after the first stage of the reaction has been completed, it is preferable to conduct the first and second reaction stages without isolation of the intermediate. Thus, the brominating agent is added to the container containing the products of the first reaction stage. Then, the N- (2-bromoethyl) -a-methylbenzylamine produced in the second reaction step is cyclized by reaction with a Lewis acid to prepare the desired 1-methyl-1,2,3-tetrahydroisoquinoline of formula (III ). The reaction solvents that can be used in this reaction include decalin, 1,2-dichloroethane and 1,2-dichlorobenzene and Lewis acids for this reaction of Cyclization include aluminum chloride (III), zinc chloride and ferrous chloride. Since 1-methyl-1,2,3-tetrahydroisoquinoline can be prepared economically according to the above method, 5,6-dimethyl-2- (4-fluorophenylamino) -4- 1-methyl- 1, 2, 3, 4-tetrahydroisoqui-nolin-2-yl) pyrimidine of formula (I) according to the present invention can also be economically prepared by using this compound as the reagent. In order to use the compound of formula (III) in the form of the isomer (R) - (+) or. (S) - (-), as the starting material for the preparation of the compound of formula (I) according to the present invention, each isomeric form of the compound of formula (III) can be prepared efficiently by using the corresponding one (R ) - (+) - or (S) - (-) -methylbenzylamine as the starting material used in the method illustrated in the reaction scheme 3. The present invention will be illustrated in detail by the following examples. However, it should be understood that the present invention is not in any way limited by these examples.

Preparation: 4-fluorophenylguanidine carbonate 882 g (747 ml) of 32% hydrochloric acid are added to 1000 g t8.9 moles) of 4-fluoroaniline, the mixture was heated to 87 ° C, and 780 ml (9.9 moles) of cyanamide solution were added to the mixture. 50% drop by drop to it for 2 hours. The reaction solution was adjusted to a pH of 2.4 by addition thereto of 120 ml of 32% hydrochloric acid, stirred for 3 hours, and cooled to 60 ° C. An aqueous solution of sodium carbonate (Na2C03 578 g / water 1640 ml), was added dropwise to the reaction solution for 30 minutes. The reaction mixture was stirred for 40 minutes and then cooled to 15 ° C. The resulting gray solid product was filtered, washed first with 600 ml of water and then 2000 ml of ethyl acetate and finally dried to obtain 1395 g of the title compound, which had a light gray color. Yield: 81.4% Melting point. 175 ° C NMR (DMSO-d 6, ppm): 5.50-6.88 (br s, 5H), 6.87 Tm, 2H9, 7.17 (m, 2H).

Example 1: 4-hydroxy-2- (4-fluorophenylamino) -5,6-dimethyl-pyrimidine 54.5 g (253.2 mmoles) of 4-fluorophenylguanidine carbonate produced in the above preparation were suspended in 50 ml of N, N-dimethylformamide and 37.8 g (262.2 mmoles) of ethyl 2-methylacetoacetate and the resulting suspension was refluxed at a temperature of 140 ° C for 3 hours. The reaction solution was again diluted with 100 ml of N, N-dimethylformamide and cooled to 80 ° C. 160 ml of isopropyl alcohol were added thereto and the resulting mixture was stirred for 30 minutes. The resulting solid product was filtered, washed with 150 ml of acetone, and finally dried to obtain 41 g of the title compound. Yield: 61.4% Melting point: 256 ° C NMR (DMSO-d_, ppm): 1.83 (s, 3H), 2.19 (s, 3H), 7.18 (t, 2H), 7.68 (m, 2H), 9.36 (sa, 1H), 10.63 (sa, 1H) Example 2: 4-Chloro-2- (4-fluorophenylamino) -5,6-dimethylpyridine 40.5 g (174.1 mmoles) of 2- (4-fluorophenylamino) -4-hydroxy-5,6-dimethylpyrimidine produced in the Example 1 were suspended in 80 ml of N, N-dimethylformamide and the resulting suspension was heated to 80 ° C. 31.9 g (19.4 ml, 210.1 mmol) of phosphorous oxychloride were added thereto for one hour at a constant temperature of 85 ° C. The reaction solution was stirred for 30 minutes and then 400 g of ice-water was added to the solution. same with agitation. The mixture was adjusted to pH 11 by the addition of sodium hydroxide and then the resulting solid product was filtered. The separated solid product was washed with 150 ml of 50% aqueous methanol solution and then dried to obtain 42.3 g of the title compound. _ Yield: 96.7% Melting point. : 114 ° C FMN (CDC1., Ppm): 2.21 (s, 3H), 2.41 (s, 3H), 7.01 (t, 2H), 718 (s at 1H), 7.56 (t, 2H) Example 3: 4-chloro-2- (4-fluorophenylamino) -5,6-dimethylpyri-midi at 1390 g (7.6 moles) of the 4-fluorophenylguanidine carbonate produced by the above preparation were suspended in 1300 ml of N, N dimethylformamide and 1206 g (8.4 moles) of ethyl 2-methylacetoacetate. The resulting suspension was heated under reflux for one hour, distilled at normal pressure to 1100 ml and then distilled until the temperature of the reaction reached 160 ° C. 1600 ml of N, N-dimethylformamide were added to the residue and then cooled to 80 ° C. 1388 g (840 ml, 9.1 moles) of phosphorous oxychloride were added to it for one hour at a constant temperature of 80 ° C to 85 ° C. The reaction solution was stirred for. 30 minutes and then diluted with 2000 ml of N, N-dimethylformamide.

To the diluted reaction solution 7000 ml of water were added for 40 minutes with stirring. The reaction solution was stirred for 4 hours and the resulting solid product was filtered, washed with 1500 ml of 50% aqueous methanol solution and then dried. The dry yellow-brown powder obtained by dissolving in 400 ml of methanol under reflux and then cooled to 10 ° C. The resulting solid product was filtered and dried to obtain 1186 g of the title compound. Yield: 62.4% Melting point. : 114 ° C NMR (CDC13, ppm): 2.21 (s, 3H, 2/41 (s, 3H), 7.01 (t, 2H), 7.18 (sa, ÍH), 7.56 (t, 2H) " Example 4: 4-bromo-2- (4-fluorophenylamino) -5,6-dimethyl-pyrimidine 5 g (21.44 mmol) of the 2- (4-fluorophenylamino) -4-hydroxy-5,6-dimethylpyrimidine produced in the Example 1, were suspended in 40 ml of N, N-dimethylformamide and the resulting suspension was heated to 65 ° C. 8.1 g (30 mmol) of tribrole were added dropwise thereto. phosphorous for 20 minutes and the resulting mixture is allowed to react at a temperature of 75 ° C for 30 minutes. The reaction solution was cooled to room temperature, poured on 500 g of ice-water, adjusted to pH 11 with sodium hydroxide solution, stirred for 30 minutes and then adjusted again to pH 5.5 with dilute hydrochloric acid. The resulting yellow solid product was washed with 100 ml of water and then dried to obtain 4.1 g of the title compound. Yield: 64.58% Melting point: 123 ° C NMR (CDC13 ppm): 2.21 (s, 3H), 2.42 (s, 3H), 6.98 (t, 2H), 7.24 (s, ÍH, 7.54 (g, 2H ) Example 5: 1-methyl-1,2,3,4-tetrahydroisoquinoline (1) Preparation of N- (2-hydroxyethyl) -a-methylbenzylamine: 103.08 g (0.86 moles) of a-methylbenzylamine were dissolved in 110 ml of dichloromethane and 127.56 g (1.02 moles) of 2-bromoethanol were added thereto. This mixture was stirred at 32 ° C for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 109 g of the title compound having a pale yellow color. Yield: 76.7% Melting point: 60 ° C / 0.5 torricellis NMR (CDC13, ppm): 1.38 (d, 3H), 2.40 (sa, ÍH), 2.61 (m, 2H), 3.58 (, 2H), 3.78 (q, ÍH), 7.18-7.38 (m, 5) (2) Preparation of N- (2-bromoethyl) -a-methylbenzylamine hydrobromide 100 g (605.32 mmoles) of N- (2-hydroxyethyl) -a-ethylbenzylamine produced in example 5 (1) above were suspended in 515 ml. of an aqueous solution of 48% hydrobromic acid and the resulting suspension was reacted at a temperature of 126 ° C for 30 minutes under reflux. Then, the reaction solution was distilled for 2 hours under constant temperature noon pressure and 465 ml of aqueous hydrobromic acid water, the secondary reaction product was separated, the residue was dissolved in 550 ml of acetone, and 500 ml of ethyl acetate and 670 ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0 ° C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 400 ml of ethyl acetate and then dried to obtain 97 g of the first crop of the title compound. Then, the filtrate was concentrated. The residue was dissolved in 450 ml of acetone, diluted with 680 ml of ether and then allowed to stand at a temperature of 0 ° C for 12 hours. The resulting solid product was filtered, collected and washed with 450 ml of ethyl acetate to obtain 32.5 g of the second crop of the title compound. Rend: 69.23% Melting point: 186-187 ° C NMR (CDCl 3, ppm): 1.94 (d, 3H), 3.21 (m, 2H), 3.82 (m, 2H), 4.42 (q, ÍH), 7.40-7.72 (m , 5H), 9.51 (sa, 1H), 9.91 (sa, 1H). (3) Preparation of l-methyl-l, 2,3,4-tetrahydroisoquinoline 50. 0 g (161.8 mmol) of N- (2-bromoethyl) -a-methylbenzylamine bromide produced in example 5 (2) above were suspended in 450 ml of decalin and then heated to 140 ° C. 64.70 g (485.4 mmol) of aluminum chloride anhydride (A1C13) were added thereto for 40 minutes. The reaction solution was stirred for an additional 30 minutes at constant temperature and then cooled to room temperature. The supernatant was removed and the lower layer was added to. 800 g of ice-water with agitation. 150 ml of concentrated hydrochloric acid were added to it and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 1000 ml of ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 2100 ml of ethyl acetate. The extracts were combined, washed with 420 ml of saturated saline solution, dehydrated with sulphate, magnesium anhydride and then evaporated under reduced pressure. to separate the ethyl acetate. The residue was distilled to obtain 18.1 g of the title compound. Yield: 75.99% boiling point: 79-80 ° C / 0.5 Torricellis NMR (CDC13, ppm): 1.59 (d, 3H), 2.14 (s, HI) ), 2. 76-3.02 (m, 2H), 3.10-3.22 (m, ÍH), 3.34-3.45 (, 1H), 4.22 (q, ÍH), 7.18-7.31 (m, 4H).

Example 6: 1-methyl-1,2,3,4-tetrahydroisoquinoline (1) Preparation of N- (2-bromoethyl) -a-methylbenzylamine hydrobromide: 76.61 g (630 mmol) of a-methylbenzylamine were dissolved in 77 ml. of dichloromethane and 94.8 g (760 mmoles) of 2-bromoethanol were added thereto. This mixture was stirred at a temperature of 51 ° C for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 ml (2500 mmol of an aqueous solution of 48% hydrobromic acid were added thereto and allowed to react at a temperature of 16 ° C for 30 minutes under, of reflux. Then, the reaction solution was distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water, the by-product of the reaction, were removed or separated. The residue was dissolved in 350 ml of isopropyl alcohol with reflux for 30 minutes and this solution was cooled to 10 ° C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate and then dried to obtain 128.9 g of the title compound. Yield: 66.2% Melting point: 186-187 ° C NMR (CDC13, ppm): 1.94 (d, 3H), 3.21 (m, 2H), 3.82 (m, 2H), 4.42 (q, 1H), 7.40 -7.72 (m, 5H), 9.51 (sa, ÍH), 9.91 (sa, 1H). (2) Preparation of l-methyl-l, 2,3,4-tetrahydroisoquinoline . 0 g (30.1 mmol) of N- (2-bromoethyl-α-methylbenzylamine hydrobromide produced in example 6 (1) above were suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145 ° C. 13.47 g ( 96.54 mmoles) of aluminum chloride anhydride were added thereto for 40 minutes.The reaction solution was stirred for an additional 30 minutes at constant temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. My hydrochloric acid was concentrated therein and the mixture was stirred for 10 minutes.This solution was washed three times, each time with 130 ml of dichloromethane and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with magnesium sulfate anhydride and then evaporated under reduced pressure to separate the ethyl acetate. The residue was distilled to obtain 2.90 g of the title compound. Yield: 65.39% Boiling point .: 79-80 ° C / 0.5 Torricellis NMR (CDC13, ppm): 1.59 (d, 3H), 2.14 (s, 1H), 2.76-3.02 (m, 2H), 3.10-3.22 (m, ÍH), 3.34-3.45 (m, 1H9, 4.22 (q, ÍH), 7.18-7.31 (m, 4H).

Example 7: 1-methyl-1,2,4-tetrahydroisoquinoline 200 g (647.17 mmol) of the N-J 2 -bromoethyl) -a-methylbenzylamine hydrobromide produced in example 5 (2) or example 6 (1) above, were suspended in 700 ml of decalin and then heated to 150 ° C. 261.5 g (1961 mmol) of the anhydride aluminum chloride were added thereto for 40 minutes. The reaction solution was stirred for an additional 30 minutes at constant temperature, and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 3500 g of ice-water with stirring. 210 ml of concentrated hydrochloric acid were added thereto, and the mixture was stirred for 10 minutes. This solution was washed three times, each time with _2500 ml of ethyl acetate and then the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 3000 ml of ethyl acetate. The extracts were combined, washed with 550 ml of saturated saline, dehydrated with magnesium sulfate, anhydride and then evaporated under reduced pressure to separate the ethyl acetate. YES residue was distilled to obtain 78.9 g of the title compound. Yield: 82.8% Boiling point .: 79-80 ° C / 0.5 Torricellis NMR (CDC13, ppm): 1.59 (d, 3H), 2.14 (s, ÍH), 2.76-3.02- (, 2H), 3.10-3.22 (m, IH), 3.34-3.45 (m, ÍH), 4.22 (q, 1H9, 7.18-7.31 (m, 4H).

Example 8: (R) - (+) -1-methyl-1,2,4,4-tetrahydroisoquinoline (1) Preparation of the (R) - (+) - N- (2-hydroxyethyl) -a-methylbenzylamine: 51.45 g (0.43 mmol) of (R) - (+) - α-methylbenzylamine were dissolved in 52 ml of dichloromethane and 63.78 g (0.51 mol) of 2-bromoethanol were added thereto. This mixture was stirred at 51 aC for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 54 g of the title compound having a pale yellow color. _ Yield: 76% Melting point. : 60 ° C / 0. 5 Torricellis [a] D20: + 55 ° (c = l, in CHC13) NMR (CDC1., Ppm): 1.38 (d, 3H9, Z. 40 (sa, 1H9, 2. 61 (m, 2H) , 3.58 (m, 2H), 3 .78 (q, 1H), 7. 18-7.38 (m, 5H)(2) Preparation of the (R) - (+) - N- (2-bromoethyl) -a-methylbenzylamine bxomhydrate 11.0 g (66.58 mmol) of the (R) - (+) - N- (2-hydroxyethyl) - α-methylbenzylamine produced in Example 8 (1) above were suspended in 52 ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126 ° C for 30 minutes under reflux conditions. The reaction solution was distilled for 2 hours under normal pressure at constant temperature and 47 ml of aqueous hydrobromic acid and water, the secondary product of the reaction, were separated. The residue was dissolved in 55 ml of acetone, and 50 ml of ethyl acetate and 70 ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0 ° C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 30 ml of ethyl acetate and then dried to obtain 10 g of the first crop of the title compound. Then, the filtrate _was concentrated. The residue was dissolved in 60 ml of ethanol and the The resulting mixture was concentrated under reduced pressure. The residue was dissolved in 50 ml of acetone, diluted with 70 ml of ether and then allowed to stand at 0 ° C for 12 hours. The resulting solid product was filtered, collected and washed with 30 ml of ethyl acetate to obtain 3.1 g of the second crop of the title compound. Yield: 64% Melting point. : 186-187sC [a] D20: + 32. 1 ° (c = 1, in CHC13) NMR (CDC13, ppm): 1.94 (d, 3H), 3.21 (m, 2H), 3. 82 (m, 2H), 4. 42 (q, ÍH), 7. 40-7 .72 (, 5H9, 9. 51 (sa, 1H), 9 .91 (sa, ÍH). (3) Preparation of (R) -. { +) -1-methyl-l, 2, 3, 4-tetrahydro-isoquinoline 5.0 g (16.18 mmol) of (R) - (+) - N- (2-bromoethyl-α-methylbenzylamine hydrobromide produced in the example ( 2) above were suspended in 50 ml of decalin and the resulting suspension was heated to 140 ° C. 6.470 g (48.54 mmoles) of anhydrous aluminum chloride (A1C13) were added thereto for 40 minutes.The reaction solution was stirred for 30 additional minutes at constant temperature and cooled to room temperature The supernatant was removed and the lower layer added to 70 g of ice-water with agitation. 2Q ml of concentrated hydrochloric acid were added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 100 ml of ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to remove ethyl acetate.The residue was distilled to obtain 1.70 g of the title compound. : 71.4% Boiling point: 79-80 ° C / 0.5 Torricellis [a] Dzo: + 85. 5 ° (c = l, in CHC13) NMR (CDC13, ppm): 1.59 fd. 3H), 2 14 (s, ÍH), 2 .76-3 .02 (m, 2H), 3 .10-3 .22 (m, 1H), 3 .34-3 .45 (m, 1H), 4. (q, ÍH), 7, 18-7 .31 (m, 4H).

Example 9: (R) - (+) -1-methyl-1,2,4,4-tetrahydroisoquinoline (1) Preparation of (R) - (. +) - N- (2-bromoethyl) -a-methylbenzylamine hydrobromide: 76.61 g (630 mmol) of (R) - (+) -a-methylbenzylamine were dissolved in 77 of dichloromethane and 94.8 g (760 mmoles) of 2-bromoethanol were added thereto. This mixture was stirred at a temperature of 51 ° C for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and added to 286.4 ml (2500 mmol) of an aqueous solution of hydrobromic acid at 48%, and allowed to react at a temperature of 126 ° C for 30 minutes under reflux conditions. . Then, the reaction solution was distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water were separated from the secondary product. of the reaction. The residue was dissolved in 350 ml of isopropyl alcohol with reflux for 30 minutes and this solution was cooled to 10 ° C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate and then dried to obtain 127.5 g of the title compound. Yield: 65.5% Melting point: 186-187 ° C [a] .20: + 32.1 ° (C = 1, in CHC13) NMR (CDCl 3, ppm): 1.94 (d, 3H), 3.21 (m, 2H ), 3.82 20 (m, 2H), 4.42 (q, 1H), 7.40-7.72 (m, 5H), 9.51 (sa, ÍH), 9.91 (sa, ÍH). (2) Preparation of (R) - (+) -1-methyl-1,2,3-tetrahydroisoquinoline . 0 g (30.1 mmoles) of (R) - (+) - N- (2-bromoethyl) -a-methylbenzylamine hydrobromide produced in example 9 (1) above were suspended in 60 ml of 1,2-dichlorobenzene and then heated at 145 ° C. -13.47 g (96.54 mmoles) of anhydrous aluminum chloride (A1C1) were added thereto for 40 minutes. The reaction solution was stirred for an additional 30 minutes at the same temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. 30 ml of concentrated hydrochloric acid was added thereto, and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130 ml of dichloromethane and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to separate the ethyl acetate. The residue was distilled to obtain 3.06 g of the title compound. Yield: 69% Boiling point .: 79-80 ° C / 0.5 Torricellis [a] D20: + 85.5 ° (c = l, in CHC13) NMR (CDC13, ppm): 1.59 (d, 3H), 2.14 (s) , 1H9, 2.76-3.02 (m, 2HJ, 3.10-3.22 (m, 1H9, 3.34-3.45 (m, ÍH), 4.22 (c, ÍH), 7.18-7.31 (m, 4H).

Example 10: (R) - (-.) -1-methyl-l, 2,3,4-tetrahydroisoquinoline 73. 45 g (240 mmol) of the hydrobromide of (R) - (+) - N - (2-bromoethyl) -a-methylbenzylamine produced in example 9 (1) above were suspended in 260 ml of decalin and the resulting suspension was heated at 150 ° C. 95.10 g (710 mmoles) of anhydrous aluminum chloride were added thereto for 40 minutes. The reaction solution was stirred for an additional 30 minutes at the same temperature and then cooled to room temperature. The supernatant was separated and the lower layer was poured over 1600 g of ice-water with stirring. 70 ml of concentrated hydrochloric acid were added thereto and the resulting mixture was stirred for 10 minutes. This solution was washed three times, each time with 700 ml of ethyl acetate and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and extracted three times, each time with 900 ml of ethyl acetate. The extracts were combined, washed with 200 ml of saturated saline, dehydrated with anhydrous magnesium sulfate and evaporator under reduced pressure to separate the ethyl acetate. The residue was distilled to obtain 28.2 g of the title compound. Yield: 79.7% Boiling point .: 79-80 ° C / 0.5 Torricellis __ [a] Dzo: + 85. 5 ° (c = 1, in CHC13) NMR (CDCl 3, ppm): 1.59 (d, 3H), 2. 14 (s, 1H), 2 .76-3. 02 (m, 2H), 3. 10-3.22 (m, ÍH), 3.34-3. 45 (m, ÍH), 4 .22 (q, ÍH), 7. 18-7. 31 (m, 4H).

Example 11: (S) - (-) -1-methyl-1,2,4,4-tetrahydroisoquinoline (1) Preparation of (S) - (-) - N- (2-hydroxyethyl) -a-methylbenzylamine: 108.23 g (0.903 mmole) of (S) - (-) - cmethylbenzylamine were dissolved in 140 ml of dichloromethane and 144.0 g (1071 mmoles) of 2-bromoethanol were added thereto. This mixture was stirred at 51 ° C for 52 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 117.4 g of the title compound, which had a pale yellow color. Yield: 78.7% Melting point: 60 ° C / 0.5_Torricellis [a] D20: -55 ° (c = 1, in CHCl.) NMR (CDCl 3, ppm): 1.38 (d, 3H), 2.40 (sa, 1H9, 2. 61 (m, 2H), 3.58 (m, 2H), 3.78 (c, ÍH), 7.18-7.38 (m, 4H) (2) Preparation of (S) - (-) - N- (2-bromoethyl) -a-methylbenzylamine hydrobromide: 22. 1 g (133.16 mmoles) of the (S) - (-) - N- (2-hydroxyethyl) -a-methylbenzylamine produced in example 11 (1) above were suspended in 105 ml of an aqueous solution of hydrobromic acid at room temperature. 48% and the resulting suspension was reacted at 126 ° C for 30 minutes under reflux conditions. Then, the reaction solution was distilled for 2 hours under normal pressure at constant temperature and 95 ml of aqueous hydrobromic acid and water, the secondary reaction product, were separated. The residue was dissolved in 112 ml of acetone and 100 ml of ethyl acetate and 150 ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0 ° C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 70 ml of ethyl acetate and then dried to obtain 20 g of the first crop of the title compound. Then, the filtrate was concentrated. The residue was dissolved in 130 ml of ethanol and then concentrated under reduced pressure. The residue was dissolved in 104 ml of acetone, diluted with 143 ml of ether, and then allowed to stand at 0 ° C for 12 hours. The resulting solid product was filtered, collected and washed with 75 ml of ethyl acetate to obtain 6.7 g of the second crop of the title compound. Performance: 64.8% Melting point. : 186-187 ° C _a] D20: -32. 1 ° (c = 1, in CHC13) NMR (CDCl 3, ppm): 1.94 (d, 3H), 3.21 fm, 2H), 3. 82 (m, 2H), 4. 42 (q, ÍH); 7 40-7 .72 (m, 5H), 9. 51 (sa, ÍH), 9. 91 (sa, ÍH). (3) Preparation of the (S) - < -) -1-methyl-l, 2,3,4-tetrahydro-isoquinoline 5.0 g (16.18 mmol) of (S) - (-) - N- (2-bromoethyl-α-methylbenzylamine hydrobromide produced in the example ( 2) were suspended in 50 ml of decalin and then heated to 140 ° C. 6.47 g (48.54 mmoles) of anhydrous aluminum chloride (A1C13) were added thereto for 40 minutes.The reaction solution was stirred for 30 minutes. additional minutes at constant temperature, and cooled to room temperature The supernatant was removed and the lower layer was added to 70 g of ice-water with stirring, 20 ml of concentrated hydrochloric acid were added thereto and the mixture was stirred for 10 minutes This solution was washed three times, each time with 100 ml of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of acetate. of ethyl .. The extracts were combined, washed with 40 ml of saturated saline solution, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to separate the ethyl acetate. The residue was distilled to obtain 1.75 g of the title compound. __ Yield: 73.5% Boiling point .: 79-80 ° C / 0.5 Torricellis [a] .20: - 85.5 ° (c = l, in CHC13) NMR (CDCI3, ppm): 1.59 (d, 3H), 2.14 (s, ÍH), 2.76-3.02 (m, 2H), 3.10-3.22 (m, ÍH), 3.34-3.45 (, 1H), 4.22 (q, ÍH), 7.18-7.31 (m, 4H).

Example 12: (S) - (-) ~ l-met? L-l, 2,3,4-tetrahydroquinoline (1) Preparation of (S) - (-) - N- (2-bromoethyl-α-methylbenzylamine hydrobromide: 176.20 g (1449 mmol) of (S) - (-) - α-methylbenethylamine were dissolved in 185 ml of dichloromethane and 218.04 g (1748 mmoles) of 2-bromoethanol were added thereto.This mixture was stirred at 51 ° C for 50 hours to complete the reaction.The reaction solution was concentrated under reduced pressure and added to 658 ml ( 5750 mmoles) of an aqueous solution of 48% hydrobromic acid and the solution obtained by this is allowed to react at a temperature of 126 ° C for 30 minutes under reflux conditions.The reaction solution was distilled for 2 hours under pressure normal at constant temperature to separate 580 ml of water as a product secondary aqueous solution of hydrobromic acid. The residue was dissolved in 760 ml of isopropyl alcohol with reflux for 30 minutes and this solution was cooled to 10 ° C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 150 ml of ethyl acetate and then dried to obtain 306.5 g of the title compound. Yield: 68.4% Melting point: 185 ° C [a] D20: -32.1 ° (C = 1, in CHC13) NMR (CDC13, ppm): 1.94 (d, 3H), 3.21 (m, 2H), 3.82 (, 2H), 4.42 (q, 1H), 7.40-7.72 (m, 5H), 9.51 (sa, ÍH), 9.91 (sa, ÍH). (2) Preparation of (S) - (-) -1-methyl-l, 2,3,4-tetrahydro-isoquinoline 10.0 g (30.1 mmol) of (S) - (-) - N- (2) hydrobromide -bromoethyl) -a-methylbenzylamine produced in the example. 12 (1) above were suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145 ° C. 13.47 g (96.54 mmoles) of anhydrous aluminum chloride (A1C13) were added to. same for 40 minutes. The reaction solution was stirred for an additional 30 minutes at the same constant temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. they added 30 ml of concentrated hydrochloric acid to it, and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130 ml of dichloromethane and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to separate the ethyl acetate. The residue was distilled to obtain 3.10 g of the title compound. Yield: 69.96% Boiling point .: 79-80 ° C / 0.5 Torricellis _a] D20: -85.5 ° (c = l, in CHC13) KMN (CDC13, ppm): 1.59 (d, 3H), 2.14 (s, 1H9, 2. 76-3.02 (m, 2H), 3.10-3.22 (m, 1H9, 3.34-3.45 (m, ÍH), 4.22 (c, Tñ), 7.18-7.31 (m, 4H).

Example 13: (S) - (-) -1-methyl-1,2,4,4-tetrahydroisoquinoline 73.45 g (240 mmol) of the hydrobromide of (S) - (-) - N- (2-bromoethyl J-) The methylbenzylamine produced in Example 12 (1) above was suspended in 260 ml of decalin and the resulting suspension was heated to 150 ° C. 95.10 g (710 mmol) of anhydrous aluminum chloride were added thereto for 40 minutes. reaction solution was shaken for 30 additional minutes at constant temperature and then cooled to room temperature. The supernatant was separated and the lower layer was poured on 1600 g of ice-water with stirring. 70 ml of concentrated hydrochloric acid were added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 700 ml of ethyl acetate, and then the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 10 900 ml of ethyl acetate. . The extracts were combined, washed with 200 ml of saturated saline, dehydrated with anhydrous magnesium sulfate and evaporated under reduced pressure to separate the ethyl acetate. The residue was distilled to obtain 27.6 g of the title compound. Yield: 78.1% Boiling point. : 79-80 ° C / 0 .5 Torricellis [a] _20: -85.5 ° (c = 1, in CHC13) NMR (CDC13, ppm): 1. 59 (d, 3H), 2. 14 (s, ÍH), 20 2 .76-3. 02 (m, 2H), 3. 10-3.22 (m, ÍH), 3 .34-3. 45 (m, ÍH), 4 .22 (q, IH), 7. 18-7. 31 (m, 4H).

Preparation of 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1- __ methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine and its hydrochloride In Examples 14 to 20, inclusive, 1-methyl-1,2,3,4-tetrahydroisoquinoline prepared according to the method described in International Patent Publication No. WO 94/14795 was used as the reagent. Example 14 2.65 g (27 mmol) of potassium acetate and 4.0 g (26.9 mols) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 85 ml of n-hexanol, and then heated to 80 ° C. 6.17 g (24.5 mmoles) of 4-chloro-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and then reacted at 140 ° C for 28 hours under reflux conditions to prepare the 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl, 2, 3, 4-tetrahydroisoquinol-2-yl) pyrimidine. The reaction solution was cooled to room temperature, diluted with 20 ml of acetone and then added dropwise to 120 ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was The residue was filtered, washed with 30 ml of water, dissolved in 150 ml of dichloromethane and then washed successively with 20 ml of HC1-4N, 20 ml of water and then 20 ml of hydroxide solution. 4N sodium The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under pressure reduced and then diluted with 100 ml of ethanol. This μg of concentrated hydrochloric acid was added to the reaction solution and the mixture obtained by this was stirred for 5 hours, the resulting solid product was filtered, washed with 20 ml of ethanol and then dried to obtain 6.1 g of the hydrochloride of 5,6. -dimethyl-2- (4-fluorophenylamino) -4-1-methyl-1,2,4,4-tetrahydroisoquinolin-2-yl) pyrimidine. Yield: 62.4% Melting point. : 255 ° C NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (, ÍH), 3.12 (m, ÍH), 3.61 (m, 2H), 4.23 (m, ÍH), 5.38 (q, ÍH), 7.25 (, 6H), 7.61 (m, 2H), 10.33 (s, ÍH), 13.43 (sa, ÍH).

Example 15 8.12 g (11.2 ml, 80 V3 mmoles) of triethylamine, 30 ml of n-butanol and 6.58 g (44.1 mmoles) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 40 ml of ethylene glycol. 10.1 g (40.1 mmoles) of 4-chloro-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and then reacted at 130 ° C for 30 hours under reflux conditions to prepare the 5,6-Dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2,3,4-tetrahi-droisoquinolin-2-yl) -pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 14.7 g of the purified 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquionlin-2-yl) pyrimidine hydrochloride. Yield: 91% Melting point: 256 ° C NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, ÍH), 3.12 (m, ÍH), 3.61 (m, 2H), 4.23 (m, ÍH), 5.38 (q, ÍH), 7.25 (m, 6H), 7.61 (, 2H), 10.33 (s, 1H), 13.43 (sa, ÍH) .

Example 16 45 ml of triethylamine, 50 ml of n-butanol and 32 g (317 mmoles) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 150 ml of ethylene glycol. 51.3 g (203.8 mmoles) __ of 4-chlora-2- (4-fluorophenylamino) -5,6-dimethyl-pyrimidine were added thereto and then reacted at 135 ° C for 28 hours under reflux conditions to prepare the 5,6-Dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2,3, -tetrahydroisoquinolin-2-yl) -pyrimidine. This product was treated according to the procedure detailed in example 14 to obtain 66 g of 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4 hydrochloride. purified tetrahydroisoquinolin-2-yl) pyrimidine. Yield: 81.1% Melting point: 256 ° C NMR (CDCl 3, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, HH), 3.12 (m, 1H), 3.61 (m, 2H), 4.23. (m, ÍH), 5.38 (q, ÍH), 7.25 (m, 6H), 7.61 (m, 2H), 10.33 Ts, 1H), 13.43 (sa, 1H).

Example 17 75 ml of triethylamine and 65 g (442 mmoles) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 100 ml of 1,2-propylene glycol. 100.0 g (0.40 mmoles) of 4-chloro-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and then reacted at 120 ° C for 64 hours under reflux conditions to prepare the 5, 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1,2,4,4-tetrahydroisoquinolin-2-yl) -pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 91 g of 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4 hydrochloride. purified tetrahydro-isoquinolin-2-yl) pyrimidine. Yield: 57.1% melting point: 258"C NMR (CDCl 3, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, ÍH), 3.12 (m, 1H), 3.61 (m, 2H), 4.23 (m, ÍH), 5.38 (q, 1H), 7.25 (m, 6H), 7.61 (m, 2H), 10.33 - (s, ÍH), 13.43 (sa, ÍH).

Example 18 720 ml of triethylamine and 695 g (4.72 mmoles) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 2100 ml of 1,2-propylene glycol. 1179 g (4.68 mmoles) of 4-chloro __: 2- (4-fluorophenylamino) -5, 6-dimethylpyrimidine were added thereto and mixture obtained by this. is reacted at 130 ° C for 58 hours to prepare 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1,2,3,4-tetrahydroquinolin-2-yl) -pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 1250 g of 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4-hydrochloride. purified tetrahydroisoquinolin-2-yl) pyrimidine. Yield: 66.9% Melting point: 258 ° C NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, ÍH), 3.12 (m, ÍH), 3.61 (m, 2H), 4.23 (m, ÍH), 5.38 (q, 1H), 7.25 (m, 6H), 7.61 (, 2H), 10.33 (s, ÍH), 13.43 (sa, ÍH) .

Example 19 110 ml of n-butanol, 240 ml of triethylamine and 236 g (1.60 mmoles) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 6000 ml of ethylene glycol. 40_0 g (1.59 mmoles) of 4-chloro-2- (4-fluorophenylamino) -5,6- dimethylpyrimidine were added thereto and then reacted at 140 ° C for 48 hours to prepare the 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4- tetrahydroisoquinolin-2-yl) -pyrimidine. This product was treated according to the procedure detailed in "Example 14 to obtain 485 g of 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3, 4 hydrochloride. -tetrahydroisoquinolin-2-yl) purified pyrimidine Yield: 76.5% Melting point: 257 ° C NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, ÍH), 3.12 (m, ÍH), 3.61 (m, 2H), 4.23 (m, 1H), 5.38 (q, 1H), 7.25 (m, 6H), 7.61 (m, 2H), 10.33 (m, 1H), s, 1H), 13.43 (sa, ÍH).

Example 20 240 ml of triethylamine and 9.7 g (65.8 mmol) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 25 ml of 1,2-propylene glycol. Then, 15 g (51 mmoles) of 4-chloro-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and the mixture obtained by this was reacted at 110 ° C for 28 hours. The resulting product was treated in accordance with. the procedure detailed in Example 14 to obtain 15.86 g of the hydrochloride of 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1- purified methyl-1, 2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine. Yield: 78% Melting point: 257 ° C NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, 1H), 3.12 (m, 1H), 3.61 (, 2H), 4.23 (m, 1H), 5.38 (q, 1H), 7.25 (m, 6H), 7.61 (, 2H), 10.33 (s, ÍH), 13.43 (sa, 1H).

Example 21 8.12 g (11.2 ml, 80.3 mmol) triethylamine, 30 ml n-butanol and 6.58 g (44.1 mmoles) of 1-methyl-1,2,3,4-tetrahydroisoquinoline as prepared in Example 5 were "added to 40 ml of ethylene glycol, 10.1 g (40.1 mmoles) of ~ 4-chloro-2- (4-fluorophenylamino) -5,6-dimethyl-pyrimidine were added thereto and then reacted at 130 ° C. 30 hours under reflux conditions to prepare the 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1,2,3-tetrahydroisoquinolin-2-yl) pyrimidine. cooled to room temperature, diluted with 30 ml of acetone and then added dropwise to 200 ml of water with stirring, after which it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60 ml of water, dissolved in 250 ml of dichloromethane and then washed successively with 35 ml_ of HC1-4N, 35 ml of water and then 40 ml of 4N sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure and then diluted with 200 ml of ethanol. To this reaction solution was added 45 g of concentrated hydrochloric acid and the mixture was stirred for. 5 hours. The resulting solid product was. filter, wash with 30 ml of ethanol and then dry to obtain 9 ^ 82 g of 5,6-dimethyl-2- (4-fluorophenylamino) -4-1-methyl-1,2,3,4-tetrahydroisoquinolin-2 hydrochloride. -yl) pyrimidine. Yield: 66.53% melting point: 255 ° C NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, ÍH), 3.12 (m , ÍH), 3.61 (m, 2H), 4.23 (m, ÍH), 5.38 (q, 1H), 7.25 (m, 6H), 7.61 (m, 2H), 10.33 (s, ÍH), 13.43 (sa, ÍH).

Example 22 75 ml of triethylamine, and 65 g (442 mmoles) of 1-methyl-1,2,3,4-tetrahydroisoquinoline, as prepared in example 7, were added to 100 ml of 1,2-propylene glycol. 1Q0.9 g (0.40 mmoles) of 4-chloro-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and then reacted at 12 ° C for 64 hours to prepare the 5-6 dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1,2,4,4-tetrahydroisoquinolin-2-yl) -pyrimidine. This product was treated according to the procedure detailed in Example 21 to obtain 95.1 g of the hydrochloride of 5,6-dimethyl-2- (4-fluorofylamino) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquionlin-2-yl) pyrimidine purified. Yield: 59.67% Melting point: 258 ° C NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, ÍH), 3.12 (m, ÍH), 3.61 (m, 2H), 4.23 (m, ÍH), 5.38 (q, 1H), 7.25 (m, 6H), 7.61 (m, 2H), 10.33 (s, ÍH), 13.43 (sa, ÍH) ).

Example 23 14 ml of triethylamine, and 9.7 g (65.8 mmol) of 1-methyl-1,2,3,4-tetrahydroisoquinoline as prepared in example 7, were added to 25 ml of 1,2-propylene glycol. 15 g (51 mmol) of 4-bromo-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and then reacted at 120 ° C for 28 hours to prepare the 5,6-dimethyl- 2- (4-fluorophenylamino) -4- (1-methyl-1, 2,3,4-tetrahydroisoquinolin-2-yl) -pyrimidine. This product was treated according to the procedure detailed in example 21 to obtain 14.9 g of 5,6-dimethyl-2- (4-) hydrochloride fluorophenylamine) -4- (1-methyl-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) pyrimidine purified. Yield: 73.28% Melting point: 257 ° C NMR (CDC13, pprt): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, 1H), 3.12 (m, 1H), 3.61 (, 2H), 4.23 (m, 1H), 5.38 (q, ÍH), 7.25 (m, 6H), 7.61 (, 2H), 10.33 (s, 1H), 13.43 (sa, ÍH).

Example 24 8.12 g (11.2 ml, 80.3 mmol) of triethylamine, 30 ml of n-butanol and 6.58 g (44.1 mmol) of the (R) - (+) - 1-methyl-1,2,3,4-tetrahydroisoquinoline as prepared in Example 9, they were added to 40 ml of __ -ethylene glycol. 10.1 g (40.1 mmoles) of 4-chloro-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and then "reacted at 130 ° C for 30 hours under reflux conditions to prepare the reaction. , 6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine The reaction solution was cooled to room temperature, diluted with 30 ml. of acetone and then added dropwise to 200 ml of water with stirring, after it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60 ml of water, dissolved in 250 ml. of dichloromethane and then washed successively with 35 ml of HC1-4N, 35 ml of water and then 40 ml of 4N sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure and then diluted with 200 ml of ethanol. To this reaction solution was added 45 g of concentrated hydrochloric acid and the resulting mixture was stirred for 5 hours. The resulting solid product was filtered, washed with 30 ml of ethanol and then dried to obtain 9.21 g of the hydrochloride of (R) -. { +) -5,5-dimethyl-2- (4-fluorophenylamino) -4-1-methyl-1,2,4,4-tetrahydroisoquinolin-2-yl) pyrimidine purified. Yield: 62.4% Melting point: 255 ° C [a] _20: + 250 ° (c = l, in CHC13) KMN (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, ÍH), 3.12 (m, ÍH), 3.61 (m, 2H), 4.23 (m, ÍH), 5.38 (q, 1H), 7.25 (m, 6H), 7.61 ( m, 2H), 10.33 (s, ÍH), 13.43 (sa, ÍH).

Example 25 23 ml of triethylamine, and 16 g (108.5 mmol) of the (R) - (+) -1-methyl-1,2,4,4-tetrahydroisoquinoline, as prepared in Example 10, was added to 75 ml of ethylene glycol. 25.7 g (101.8 mmol) of 4-chloro-2- (4- fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and the mixture obtained by this was reacted at a temperature of 1351C for 28 hours under reflux conditions to prepare the (R) - (+) - 5,6-dimethyl -2- (4-fluorophenylamino) -4- (1-methyl-1,2,4,4-tetrahydroisoqui-nolin-2-yl) -pyrimidine. This product was treated according to the procedure detailed in Example 24 to obtain 33 g of 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2,3, 4- hydrochloride. purified rahydroisoquinolin-2-yl) pyrimidine. Yield: 81.1% Melting point: 257 ° C NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, 1H), 3.12 (m, ÍH), 3.61 (, 2H), 4.23 (m, ÍH), 5.38 (q, ÍH), 7.25 (m, 6H), 7.61 (, 2H), 10.33 (s, ÍH), 13.43 (sa, 1H).

Example 26 14 ml of triethylamine and 9.7 g (65.8 mmol) of (R) - (+) - 1-methyl-1,2,4,4-tetrahydroisoquinoline, as prepared in example 10, were added to 25 ml. of 1,2-propylene glycol. 15 g (51 mmoles) of 4-bromo-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and the mixture obtained by this was reacted at 120 ° C for 28 hours. Lugo, the product, of The reaction was treated according to the procedure detailed in Example 24 to obtain 16.2 g of 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2,3,4-tetrahydroisoquinolin hydrochloride. -2-yl) purified pyrimidine. Yield: 79.97% Melting point: 257 ° C [a] D20: + 250 ° (c = 1, in CHC13) NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 ( s, 3H), 2.84 (m, ÍH), 3.12 (m, ÍH), 3.61 (m, 2H), 4.23 (m, ÍH), 5.38 (q, ÍH), 7.25 (m, 6H), 7.61 (m , 2H), 10.33 __ (s, ÍH), 13.43 (sa, ÍH).

Example 27 8.12 g (11.2 ml, 80.3 mmol) of triethylamine, ml of n-butanol and 6.58 g (44.1 mmol) of the (S) - (-) - 1-methyl-1,2,3,4-tetrahydroisoquinoline as prepared in example 13 were added to 40 ml. of ethylene glycol. 10.1 g (40.1 mmoles) of 4-chloro-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and then, they were reacted at a temperature of 130 ° C for 30 hours under reflux conditions to prepare (S) - (-) - 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-ethyl-1,2,4,4-tetrahydro-isoquinolin-2-yl) pyrimidine.

The reaction solution was cooled to room temperature, diluted with 30 ml of acetone and then added dropwise to 200 ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60 ml of water, dissolved in 250 ml of dichloromethane and then washed successively with 35 ml of HC1-4N, 35 ml of water and 40 ml of 4N sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure and then diluted with 200 ml of ethanol. To this reaction solution was added 45 g of concentrated hydrochloric acid and the mixture was stirred for 5 hours. The resulting solid product was filtered, washed with 30 ml of ethanol and then dried to obtain 8.95 g of the (S) - (-) - 5,6-dimethyl-2- (4-fluorophenylamino) -4-1-methyl ester hydrochloride. -1, 2,3, 4-tetrahydroisoquinolin-2-yl) pyrimidine purified. Yield: 60.6% melting point. : 255 ° C [a] .20: -250 ° (c = l, in CHC13) NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 2.84 (m, 1H), 3.12 (m, ÍH), 3.61 (m, 2H), 4.23 (m, 1H), 5.38 (q, 1H), 7.25 (m, 6H), 7.61 (m, 2H), 10.33 (m, 1H), s, ÍH), 13.43 (sa, ÍH).

Example 28 15 ml of triethylamine and 9.7 g (65.8 mmol) of the (S) - (-) - 1-methyl-1,2,4,4-tetrahydroisoquinoline, as prepared in example 13, were added at 25 ° C. my 1,2-propylene glycol. 15 g (51 mmol) of 4-bromo-2- (4-fluorophenylamino) -5,6-dimethylpyrimidine were added thereto and then reacted at a temperature of 110 ° C for 38 hours. The reaction product was treated according to the procedure detailed in Example 27 to obtain 15.86 g of the hydrochloride, 5,6-dimethyl-2- (4-fluorophenylamino) -4- (1-methyl-1, 2, 3,4-tetrahydroquinolin-2-yl) pyrimidine purified. Yield: 78% Melting point: 257 ° C [a] D20: -250 ° (c = 1, in CHC13) NMR (CDC13, ppm): 1.58 (d, 3H), 2.21 (s, 3H), 2.38 ( s, 3H), 2.84 (m, ÍH), 3.12 (m, 1H), 3.61 (m, 2H), 4.23 (, ÍH), 5.38 (q, ÍH), 7.25 (m, 6H), 7.61 (m, 2H), 10.33 (s, 1H), 13.43 (sa, ÍH).

Claims (14)

1. Claims 1. A process for the 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, characterized in that a pyrimidine derivative represented by the following formula (II-A), in which Hal represents a halogen, is reacted with the 1-methyl-1, 2, 3, 4-tetrahydroquinoline represented by the following formula (III, (iro
2. 2. The process according to claim 1, characterized in that the acid addition salt is hydrochloride.
3. 3. The process in accordance with the. claim 1, characterized in that the reaction is carried out in the presence of a solvent.
4. 4. The process according to claim 3, characterized in that the solvent is N, N-dimethylformamide, n-butanol, n-pentanol, n-hexanol, dimethyl sulfoxide, ethylene glycol, 1,2-propylene glycol or a mixture thereof.
5. 5. The process according to claim 1, characterized in that the reaction is carried out in the presence of a base.
6. 6. The process in accordance with the claim 5, characterized in that the base is triethylamine, N, N-dimethylaniline, pyridine or potassium acetate.
7. The process according to claim 1, characterized in that the compound of formula .. (I) in the form of an isomer (R) - (+) - is prepared by using the (R) - (+) - 1- methyl-1, 2,3,4-tetrahydroisoquinoline.
8. 8. The process according to claim 1, characterized in that the compound of formula (I) in the form of an (S) - (-) - isomer is prepared by using (S) - (-) - 1-methyl -l, 2, 3, 4-tetrahydroisoquinoline. -
9. 9. A pyrimidine derivative represented by the following formula (II), in which R represents a halogen.
10. 10. A process for the preparation of 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula (III), characterized in that in the first step, the α-methyldinylamine is reacted with 2-bromoethanol to prepare the N- (2-hydroxyethyl) -a-methylbenzylamine; in the second step, the N- (2-hydroxyethyl) -a-methylbenzylamine is reacted with a brominating agent to prepare the N- (2-bromoethyl) -a-methylbenzylamine hydrobromide; and then in the third step, the N- (2-bromoethyl) -a-methylbenzylamine hydrobromide is reacted with a Lewis acid ".
11. 11. The process according to claim 11, characterized in that the brominating agent used in the second stage is selected from the group consisting of bromine, aqueous solution of bromic acid and phosphorous tribromide. _
12. 12. The process according to claim 11, characterized in that the Lewis acid used in the third stage is selected from the group consisting of aluminum chloride (III), zinc chloride, and ferrous chloride.
13. 13. The process according to claim 11, characterized in that the compounds of formula (III) in the form of the (R) - (+) - isomer is prepared = by using the (R) - (+) -a-methylbenzylamine . The process according to claim 11, characterized in that the compound of formula (III) in the form of the (S) - (-) -isomer is prepared by using (S) - (-) -a-methylbenzylamine.