Title of Invention	"A PROCESS FOR PREPARING A 4-HALOGENO-2-(4-FLUOROPHENYL-ARNINO)-5,6-DIMETHYLPYRIMIDINE"
Abstract	The present invention relates, first to a process for preparation of 5,6-dimethyl-2-(4vf]uorophenylamino)-4-(l-metliyl-l,2,3,3*-tetrahydroiso-quinolin-2-yl)pyrimidine represented by the following formula (I) and its add 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 inveminn relates, first, to a process for preparation of 5,6-dimethyl-2'(4-fluoropheny!.-unino)-4-(l-meihyl-l,2,3,4-tetrahydroisoquinoltn-2-yl)pyrimidine represented by the following formula (1), (Formula Removed) urtd its acid addition salts by reacting a pyrimidine derivative represented by the following formula (II-A), (Formula Removed in which Hal represents a halogen, with l-methyl-l,2,3.4~tetrahydro-isoquinoline represented by the following formula (III) (Formula Removed) 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 UI-A).

Title of Invention

"A PROCESS FOR PREPARING A 4-HALOGENO-2-(4-FLUOROPHENYL-ARNINO)-5,6-DIMETHYLPYRIMIDINE"

Abstract

The present invention relates, first to a process for preparation of 5,6-dimethyl-2-(4vf]uorophenylamino)-4-(l-metliyl-l,2,3,3*-tetrahydroiso-quinolin-2-yl)pyrimidine represented by the following formula (I) and its add 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 inveminn relates, first, to a process for preparation of 5,6-dimethyl-2'(4-fluoropheny!.-unino)-4-(l-meihyl-l,2,3,4-tetrahydroisoquinoltn-2-yl)pyrimidine represented by the following formula (1), (Formula Removed) urtd its acid addition salts by reacting a pyrimidine derivative represented by the following formula (II-A), (Formula Removed in which Hal represents a halogen, with l-methyl-l,2,3.4~tetrahydro-isoquinoline represented by the following formula (III) (Formula Removed) 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 UI-A).

Full Text	PROCESS FOR PREPARATION OF PYRIMIDINE DERIVATIVES TECHNICAL FIELD The present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3)4-tetrahydroiso-c\|uinolin-2-yl)pyrimidine represented by the following formula (I.) and ics acid addition salts; second, to a process for preparation of an intermediate for preparing the compound (I); and, third, to a novel intermediace compound. More specifically, the present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinoHn-2-yl)pyrimidine represented by the following formula (I), (Formula Removed) and its acid addition salts, wherein a pyriraidine derivative represented by the following formula (II-A), (Formula Removed) in which Hal represents a halogen, is reacted with 1-methyl-1,2,3,-J-tetrahydroisoqumoline represented by the following formula (III); (Formula Removed) .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). (Formula Removed) BACKGROUND ART 5,6-Dimethyl-2-(4-fluorophenylanuno)-4-(l-methyl-l,2,3,4-tetra-hydroisoquinolin-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 fur 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-dimethyt-2-(4-fluorophenyIamino)-4-(l-methyl-lI213,4-tetrahydroii,() \Reaction Scheme-A (Formula Removed) Since the starting material of the above reaction scheme has two reactive sites (i.e., the two Ci atoms), the first reaction inevitably produces a side product, which reduces the yield of the desired compound. The present inventors have Jong labored to develop a novel method for preparing S,6-dimethyl-2j(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinoiin-2-yl)pyriinidine of formula (!) 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 l-mettiy\|-l,2,3,4-tetrahydroisoquinoline represented by-formula (HI) and, thus, have completed the present invention. DISCLOSURE OF THE INVENTION The present invention relates to a novel process for preparation of 5.6-dimechyl-2-(4-fluorophenylainino)-4-(l-methyl-1,2,3,4-tetrahydroiso-tiuinolin-2-yl)pyrimidine represented by formula (I) and its acid additionsalts. More specifically, the present invention relates to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-1.2,3,4-tetrahydroUoqiiinolin-2-yl)pyrimidine represented by fonnula (I), and Its acid addition salts wherein a pyrimidine derivative represented by the following formula (II-A), (Formula Removed) in which Hal represents a halogen, is reacted with i-methyl-1,2.3,4-tctrahydroisoquinoline represented by fonnula (III), (Formula Removed) In addition, the present invention relates to a process for preparation of the pyrimidine derivative of formula (D-A) and the compound of fonnula (III). Further, the present invention relates to a novel intermediate compound represented by the following formula (II), which includes the pyrimidine derivative represented by formula (n-A), (Formula Removed) 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 l-methyl-1.2,3,4-tetrahydroisoquinoline of formula (II), as depicted in the following reaction scheme 1' Reaction scheme 1 (Formula Removed) 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-fluonJphenylamino)-5,6-dimethyl-pyrimidine represented by formula (Ef-A) can be reacted according to the present invention with an equivalent amount of 1-methyl-1,2,3,4-tetra-hyclroisoquinoline represented by formula (III), 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 l-methyl-l,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-pcntanol, n-hexanol, dimethylsuUoxide, 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 he used for this purpose include triethylamine, N,N-dimethylaniline, pyridine arid potassium acetate. The reaction temperature fur the reaction between the compound of formula (H-A) and 1-methyl-1,2,3,4-tetrahydroisoquinoline of formula (ffl) is preferably in the range from llOt to 160T and the reaction time is preferably in the range from 16 hours to 72 hours. 5,6-Dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-1.,2,3,4-tetra-hydroisoquinolin-2-yI)pyrimidine of formula (I) as prepared according to die above method can be converted into its acid addition salt, preferably into die 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)-(-O-isomer, an (S)-(-)-isomer, or a racemate wherein the R and S isomers are mixed in the ratio of l;l. Unless indicated otherwise, the compound of formula (I) should be interpreted to include all of these isomers. (Formula Removed) 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: (Formula Removed) In the reaction scheme 2, Hal represents a halogen. As depicted by the reaction scheme 2, reacting 4-fluorophenyl-guanidine carbonate of formula (IV) with ethyl 2-methylacetoacetate of formula (V) yields 4-hydroxy-2-(4-fluorophenylamino)-5,6-dimethyl-pyrimidine of formula (II-B), which may then be reacted with a halogenating agent to obtain the 4-halogeno-2-(4-fluorophenylarninn-) 5,6-dimethylpyrimitiine of formula (H-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-fluoroaruline with a 50% cyanamide solution under acidic conditions using 30% to 37% hydrochloric acid while maintaining the temperature ranging from 75 to 951. 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 acetonkrile, N,N-dimethylformamide and dimethylsulfoxide This reaction is preferably carried out at a temperature ranging from 11.0 "C to 160ºC. In the second step of the, reaction scheme 2, 4-hydroxy-2-(4-fluorophenylanuno)-5,6-dimethylpyriniidine of formula (II-B) obtained from the first step Of the reaction scheme 2 is converted into the compound of formula (II-A) by reacting the former with a halogenating agent. Halogenating agents which can be used for this purpose include phosphorus oxychloride, oxalyl chloride, thionyl chloride and phosphorus tribromide. This halogenation reaction is carried out in the presence of a solvent. Reaction solvents which can be used for this purpose include preferably N,N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane and l,2-dichloroben2ene. It is preferable to maintain the reaction temperature in the range from 75ºC to 95ºC. Although the second step of the reaction scheme 2 can be practiced 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 vessel. Specifically, 4-hydroxy-2-(4-fluorophenylamino)-5,6-climeihylguanidine of formula (II-B) is prepared from 4-fluorophenyl-guanidine cabonate and then, without isolation, can be successively reacted with the halogenating agent to yield 4-halogeno-2-(4-fluoro-phenylammo)-5,6-dimethylpyrimidine (II-A). The compound of formula (II-A), which is used as the starting material for preparation of the compound of formula (I) according to the present invention, is novel, as is the compound of formula (II-B) produced as the intermediate in the reaction scheme 2. Both novel compounds can he represented by the following formula (II), which is within the scope of the present invention, (Formula Removed) in which R represents hydroxy or a halogen. l-Methyl-l,2,3,4-tetrahydroisoquinoline of formula (III), which is also used as the starting material in the reaction scheme 1, is a known compound and can be preapred by known methods (see, for example, International Publication No. WO 94/14795). According to this known method, (R)- or (S)-l-methyl-l,2,3,4-tetrahydroisoquinoline is prepared by reacting (R)- or (S)-methylbenzylamine with a -chloro- a -(methyl-thio)-acetylchloride and stannous chloride (SnCh) to produce (R)- or (S)-l-methyl-4-methylthio-l,2,3,4-tetrahydroisoquinolin-3-one, respectively, then reacting the resulting compound with Raney nickel to remove a methylthio group, and finally adding a reducing agent. However, this method is disadvantageous, since a -chloro- a -(methylthio)-acetylchloride, which is used as the starting material, is both unstable and explosive, so that this method cannot be practiced on an industrial scale. Further, since the reaction step is long, the total yield is low, which makes this method uneconomical. The present inventors have long labored to find a more efficient method for producing l-methyl-l,2,3,4-tetrahydroisoQuinoline. We have discovered that l-methyl-l,2,3,4-tetrahydroisoquinoline can be employed economically and safely by successively reacting a -methylbenzylainine with 2-bromoethanol, a brominating agent, and a Lewis acid. Such a process for preparing l-methyl-l,2,3.4-tetrahydroisoquinoline is novel and is encompassed within the scope of the present invention. This novel process for preparing l~methyl-l,2,3,4-tetrahydroisoquim>line is explained in more detail below. According to the present invention, 1-methyl-1,2,3,4-tetrahydro-isoquinoline of formula (IT!) can be prepared by reacting a-methyl-benzylamine successively with 2-bromoethanol, a brominating agent and Lewis acid. The method of the present invention employs the following reaction scheme 3. Reaction scheme 3 (Formula Removed All of the starting materials and reactants used in the reaction scheme 3 are known compounds and can be obtained as commercial products. In the first step a -methylbenzylamine is reacted with 2-bromoethanol to produce N-(2-hydroxyethyl)-rt-mcthylbenzylamine, which in turn is reacted with the brominating agent to produce N-(2-bromoethyf)- a - methylbenzylamine hydrobromide. In the third step, N-(2-bromrtethyl)- -methylbenzylamine hydrobromide is reacted with a Lewis acid to produce the desired 1-methyl -l,2,3,4-tetrahydroiso-ciuinoline of formula (III). Reaction solvents which can be used in the first step include acetonitrile, N.N-dimechylforroamide, dichloromethane and 1,2-dichlorn-ethane and the reaction temperature is preferably maintained in the range from 401C to 601. Reaction solvents which can be used in the second step include 1,2-dichloroethane, acetic add, water and 1,2-dichloro-benzene, and the reaction temperature is preferably maintained in the range from 110ºC to 145ºC. Brominating agents which can be used in this reaction include bromine, bromic aicd, aqueous bromic acid solution, and phosphorus trihrnmide. Although the first and second steps of the reaction scheme 3 can the desired 1 -methyl- 1,2,3,4-tetrahydroisoquinoline of formula (Til). Reaction solvents which can be used in this reaction include decalin, 1,2-dichIoroethane and 1,2-dichlorobenzene and Lewis acids for this cyclization reaction include aluminum (HI) chloride, zinc chloride and ferrous chloride. Since I -methyl- 1,2,3,4 -tetrahydroisoquinoline can be economically prepared according to the above method, the desired 5,6-dimethyl -2-(4-nuorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-y1) -pyrimidine of formula (I) according to the present invention can also be economically prepared using this compound as the reactant. In order to use the compound of formula (III) in the form of (R)-(-O- or (S)-(-)isomer as the starting material for preparation of the compound of formula (I) according to the present invention, each isomeric form of the compound of formula (HI) can be efficiently prepared using the corresponding (R)-(+)- or (S)-(-)-methylbenzylamine as the starting material used in the method depicted 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 manner limited by these examples. Prearatio : 4-fluoronvlguan 882g(747mf) of 32% hydrochloric acid was added to 1000g(8.9 mole) of 4-fluoroaniline, the mixture was warmed lit 87°C, and 780mf.(9.9 mole) of 50% cyanamide solution was added dropwisc thereto over 2 hours. The reaction solution was adjusted to pH 2.4 by adding thereto 120mlof 32% hydrochloric acid, stirred for 3 hours, and coaled to 60'C. Aqueous sodium carbonate solution (Na2CO3 578g/water I640ml) was added dropwise to the reaction solution over 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 600mlof water and then with 2000ml of ethyl acetate, and finally dried to obtain 1395g of the title compound, which had a light gray color. Yield : 81.4% m.p. : 1751: NMR(DMSO-d6, ppm) : 5.50-6.88(bs, 5H), 6.87(m, 2H), 7.17 2H) midine 54.5g(253.2 mmole) of 4-fluorophenytguanidine carbonate produced in the Preparation above was suspended in 50m? of N,N-dimethylform-jimide and 37.8g(262.2 mmole) of ethyl 2-methylacetoacetate and the resulting suspension was refluxed at 140X1 for 3 hours. The reaction solution was diluted again with 100ml of N,N-dimethylformamide and cooled to 80ºC, I60ml of isopropylalcohol was added thereto and the resulting mixture was stirred for 30 minutes. The resulting solid product was filtered, washed with 150ml of acetone, and finally dried to obtain 41g of the title compound. Yield : 61.496 m.p. : 256C NMR(DMSO-de, ppm) : 1.83(s, 3H), 2.19(st 3H), 7.18(t, 2H), 7.68 (m, 2H), 9.36(hs, 1H), 10.63 Example 2 : 4-chloro-2-(4Qroonbenylamino)-5,6-dimethyloyimi- 0.5g(174.1 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in 80ml of N,N-dimethylfonnamide and the resulting suspension was heated to 80 'C. :31..9g(l9.4ml, 210.1 mmole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 85 T. The reaction solution was stirred for 30 minutes and then 400g of ice-water was added thereto with stirring. The mixture was adjusted to pH 11 by adding sodium hydroxide and then the resulting solid product was filtered. The separated solid product was washed with 150ml of 50% aqueous methanol solution and then dried to obtain 42. 3g of the title compound. Yield : 96.7% m.p. •• 114ºC NMR(CDCln, ppm) : 2.21(s, 3H), 2.41(s, 3H), 7.0l(t, 2H), 7.l8(bs, 1H), 7.56U, 2H) : 4-ghlorn-2-(4~fluomnhenvlamino)-5.6-dimethvlDvrimi- 1390g(7.6 mole) of 4-fluorophenylguanidine carbonate produced hy ihe Preparation above was suspended in 1300ml of N.N-dimethylfomi- amide and I200g(8.4 mole) of ethyl 2-methyiacetoacetate. The resulting ispension was heated under refluxing for one hour, distilled at normal •essure to llOOmi! and then distilled until the temperature of the reaction ilution reached 160 ºC. 1600ml of N,N-dimethylformamide was added Lo ie residue and then cooled to 80º C. 1388g(840ml, 9.1 mole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 80 1 to 85'C. The reaction solution was stirred for 30 minutes «nd then diluted with 2000m* of N.N-dimethyl- formamide. To the diluted reaction solution was added 7000ml of water over 40 minutes with stirring. The reaction solution was stirred for 4 hours and the resulting solid product was filtered, washed with 1500ml. of 50% aqueous methanol solution and then dried. The dried, yellowish-brown powder Lhereby obtained was dissolved in 4000ml of methanol under refluxingand then cooled to 10 1. The resulting solid product was filtered and dried to obtain 1186g of the tide compound. Yield : 62.4% m.p. : 114ºC: NMRfCDCb, ppm) : 2.2l(s, 3H), 2.41(s, 3H), 7.01(t, 2H), 7-18(bs, 1H), 7,56(t, 2H) 4 : 4-bromo-2-(-fluoroohenvlamino)-5.6-dimethylpvri- 5g(21.44 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in 40m£ of N,N-dimethylformamide and the resulting suspension was warmed to 65 "C. 8.1g(30 mmole) of phosphorus tribromide was added dropwise thereto over 20 minutes and the resulting mixture was allowed to react ai 75X3 for 30 minutes. The reaction solution was cooled to room temperature, poured onto 500g of ice-water, adjusted to pH 11 with sodium hydroxide solution, stirred for 30 minutes and then adjusted again r.n pH 5.5 with dilute hydrochloric acid. The resulting yellow solid product was washed with 100ml of water and the dried to obtain 4.1g of the title compound. Yield : 64.58% m.p. : 123 r NMR(CDC13 PPm) : 2.21(s, 3H), 2.42(s. 3H), 6.98(t, 2H), 7,24(s, 1H), 7.54(g, 2H) : t-methyl- 1,2,3,4- tetrahydroisoouinoline (1) Preparation of N-(2-hydroxyethyl)-a-methylben2ylamine: 103.08g(0.86 mole) of a -methylbenzylamine was dissolved in 110 mi of dichlororaethane and 127.560(1.02 mole) of 2-bromoethanul was added thereto. This mixture was stirred at 52 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 109g of the title compound, which had a pale yellow color. Yield : 76.7% m.p. = 60'C/0.5toiT NMR(CDCb, ppm) : 1.38(d, 3H), 2.40 (2) Preparation of N-(2-bromoethyl)-a-niethylben2ylamine hydrobromide: 1000(605.32 mmole) of N-(2-hydroxyethyl)- a-methylbenzylamine produced in Example 5(1) above was suspended in 515m£ of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126ºC for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 465ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 550ml of acetone, and 500mH of ethyl acetate and 670ml! of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to O'C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 400ml of ethyl acetate and then dried to obtain 97g of the first crop of the title ompound. The filtrate was then concentrated. The residue was dissolved in 450ml of acetone, diluted with 680ml of ether and then allowed to stand at O'C for 12 hours. The resulting solid product was filtered, collected, and washed with 450ml of ethyl acetate to obtain 32.Sg of the second crop of the title compound. Yield : 69.23% m.p. : 186-187ºC NMR(CDCl;i, ppm) : 1.94(d, 3H), 3.2l(m, 2H), 3.82(m, 2H), 4.42(a. 1H), 7.40-7.72(m, 5H), 9.51(bs, IH), 1H) (3) Preparation of 1-methyl-1,2,3,4-tetrahydroisoquinoline 50.0g( 161.8 mmoie) of N-(2-bromoethyl)- a -methylbenzylamine hydrobromide produced in Example 5(2) above was suspended in 450ml of decalin and then heated to 140ºC. 64.70g(485.4 mmole) of anhydrous aluminum chloride (A1C13) was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature, and then cooled to room temperature. The supernatant was removed and the lower layer was added to 800g of ice-warcr with stirring. 150ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with l000ml 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 2100ml of ethyl acetate. The extracts were combined, washed with 420ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 18.1g of the title compound. Yield : 75.99% b.p. : 79-80ºC/0.5torr NMRfCDCb. ppm) : 1.59(d, 3H), 2.14 3.10-3.22(m, 1H), 3.34-3.45(m, 1H), 4.22(q, IH), 7.18-7.31(m, 4H) (1) Preparation of N-(2-bromoethyl)- a -methylbenzy famine hydrobromide 76.6lg(630 mmole) of a-methylbenzylamine was dissolved in 77ml of dichloromethane and 94.8g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51ºC for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4ml(2500 mmole) of 4896 aqueous hydrobromic acid solution was added thereto and allowed to react at 126X) for 30 minutes under rofluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250ml! of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350ml of isopnopyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10£ and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50mlof ethyl acetate and then dried to obtain 128.9g of the title ompound. Yield : 66.29% m-p. : 186-187ºC NMK(CDClj, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42 1H), 7.40-7.72(m, 5H), 9.51(bs, 1H). 9.9l(bs, 1H) (2) Preparation of 1-methyl- 1,2,3,4-tetrahydroisoquinoline 10.0g(30.1 mmole) of N-(2-bromoethyl)-a-methylbenzylamine hydrobromide produced in Example 6(1) above was suspended in 60ml of 1,2-dichiorobenzene and then heated to 145ºC. 13.47g(96.54 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature, cooled to room temperature and poured onto 250g of icewater with stirring. 30ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 1.2 with sodium hydroxide and then extracted three times, each time with 250ml of ethyl acetate. The extracts were combined, washed with 40ml of saturated saline, dehydrated with anhydrous magnesium suifate and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 2.90g of the title compound. Yield : 65.39% b.p. : 79-80ºC/0.5torr NMR(CDCI3. ppm) : 1.59(d, 3H), 2,14(s, 1H), 2.76-3.02(m, 2H), 3.10-3.22(m, IH), 3.34-3.45(m, IH), 4.22(q, IH), 7.l8-7.31(m, 4H) 200g(647.17 mmole) of N-(2-bromoethyl)-a -methylbenzylamine hydrobroroide produced in Example 5(2) or Example 6(1) above was suspended in 700ml of decalin and then heated to ISOTC. 261.5g(1961 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for s further 30 minutes at constant temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 3500g of ice -water with stirring. 210ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 2500ml 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 3000ml of ethyl acetate. The extracts were combined, washed with 550ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 78.9g of the title compound. Yield : 82.8% b.p. • 79-80r/0.5torr NMRCCDCI. ppm) : 1.59(d, 3H), 2.l4(s, W). 2.76-3.02(m, 2H), 3.10-3.22(m, 1H), 3.34-3.45 1H), 7.l8-7.31(m, 4H) 8 : (1) Preparation of (R)-{+)-N-(2-hydroxyethyl)-a-metfiylbenzylamine: 51.45g(0.43 mmole) of (R)-(+)- a -methylbenzylamine was dissolved in 52ml, of dichloromethane and 63.78g(0.51 mmole) of 2-bromo-ethanol was added thereto. This mixture was stirred at 51ºC1 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 54g of the title compound having pale yellow color. Yield : 76% m.p. : 60ºC/0.5torr [a]p20: +55' (c=l, in CHCl3) NMR(CDC13, ppm) : 1.38(d, 3H), 2.40(bs, 1H), 2.61(m, 2H), 3.58(m, 2H), 3.78(q, 1H), 7.18-7.38(m, 5H) (2) Preparation of (R)-(+)-N-(2-bromoethyl)- a-methylbenzylaminc hyd-robromide: 11..0g(66.58 mmole) of (R)-(+)-N-(2-h1ydroxyethyl)-a-methylben-zylumine produced in Example 8(1) above was suspended in 52ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at I26ºC for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature and 47ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 55ml of acetone, and 50ml of ethyl acetate and 70ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0ºC and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 30ml of ethyl acetate and then dried to obtain l0g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 60ml! of ethanol and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in 50ml of acetone, diluted with 70ml of ether and then allowed to stand at 0ºC fur 12 hours. The resulting solid product was filtered, collected and washed with 30ml. of ethyl acetate to obtain 3.1g of the second crop of the title compound. Yield : 64% m.p. : 186-187ºC [a]o20 : +32.1' (c=l, in CHCI3) NMR(CDCb, ppm) : 1.94(d, 3H), 3.2l(m, 2H), 3.82 1H), 7.40-7.72(m, 5H), 9.51(bs, 1H), 9.91(bs, 1H) (3) Preparation of (R)-(+)-l-methyl-l,2,3,4-tetrahydroisoquinoline 5.0g(16,18 mmole) of (R)-(+)-N-(2-bromoethyl)-a-methylbcnzyl-amine bydrobromide produced in the above (2) was suspended in 50ml of decalin and the resulting suspension was heated to 140ºC. 6.4702 (48.54 mmolc) of anhydrous aluminum chloride (AlCl3 was added thereto over 40 minur.es. The reaction solution was stirred for further 30 minutes at constant temperature, and cooled to room temperature. The supernatant was removed and the lower layer was added to 70g of ice-water with stirring. 20ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 100ml 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 250ml of ethyl acetate. The extracts were combined, washed with 40ml A of saturated saline, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 1.70g of the title compound. Yield : 71.4% b.p. : 79-80ºC/0.5tor [a]D20 : +85.5' (c=l. in CHCI3) NMR(CDCl3, ppm) : 1.59(d, 3H), 2.14(s, 1H). 2.76-3.02(m. 2H), 3.10-3.22(n, 1H), 3.34-3.45(m. 1H), 4.22( 1H), 7.18~7.31(m, 4H) Example:(R)-(+)-1-methvl-l.2.3,4-terabydroisoouiooline (1) Preparation of (R)-(+)-N-(2-broraoethyl)-a -methylbenzylamine hyd-robromide: 76.61g(630 mmole) of (R)-(+) a -methylbenzylamine was dissolved in 77ml of dichloromethane and 94,8g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51 ºC for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4ml(2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and then allowed to react at 126ºC for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350ml of isopropyi alcohol with refluxing for 30 minutes, and this solution was cooled to 10ºC and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50ml of ethyl acetate, and then dried to obtain 127-5g of the title compound. Yield : 65.596 m.p. : 186-187ºC []o20 : +32. 1' (c=l, in CHCI3) NMR(CDC13, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q, IH), 7.40-7.72(m, 5H), 9.51(bs, 1H), 9.9l(bs, 1H) (2) Preparation of (R)-(+)-l-methyl-lt2,3,4-tetrahydrotsoquinoline 10.0g(30.1 mmole) of (R)-(+)-N-(2-bromoethyl)-a-methylbenzyl-amine hydrobromide produced in Example 9(1) above was suspended in 60ml of 1,2-dichJorobenzene and then heated to 145ºC. 13.47g(96.54 mmole) of anhydrous aluminum chloride (AlCI3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at same temperature, cooled to room temperature and poured onto 250g of ice-water with seining. 30mL of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130ml of dichioromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250ml of ethyl acetate. The extracts were combined, washed with 40ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetace. The residue was distilled to obtain 3.06g of the title compound. Yield : 69% b.p. : 79-80ºC/0.5torr [a] : +85.5' (c=l. in CHCI3) NMR(CDCI3, ppm) : 1.59(d, 3H), 2.14(s, 1H), 2.76-3.02(m, 2H), 3.10-3.22 1H), 7.18-7.31(m, 4H) Example 10 : 73.45g(240 mmole) of (R)-(+)-N-(2-bromoethyl)-a-methylbenzyl-arnine hydrobromide produced in Example 9(1) above was suspended in 260mlof decalin and the resulting suspension was heated to 150ºC. 95.1.0g(7lO mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at same temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 1600g of ice-water with stirring. 70ml of con. hydrochloric acid was added thereto and the resulting mixture was stirred for 10 minutes. This solution was washed three times, each time with 700mlof ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and extracted three times, each time with 900ml of ethyl acetate. The extracts were combined, washed with 200ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 28.2g of the title compound. Yield : 79.7% b.p. : 79-80'C/0.5torr Ub20 : 85.5* (c=l, in CHCb) NMR(CDCln, ppm) : 1.59(d, 3H), 2.14(s, 1H), 2.76-3.02(m, 2H), 3.10-3.22(m, 1H), 3.34-3.45(m, 1H), 4.22(q, 1H), 7.l8-7.31(m, 4H) Example 11 : (S)-( -)l-methvl-1,2,3,4-tetrahvdroisoquinonline (1) Preparation of (S)-(-)-N-(2-hydroxyethyl)-a-methylhenzylamine: 108.23g(0.903 mmole) of (S)-(-α -methylbenzylamine was dissolved in 140ml of dichloromethane and 144.0g( 1.071 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51ºC 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 117.4g of the title compound, which had a pale yellow color. Yield : 78.7% m.p. : 60ºC/0.5torr [a]D20 : -55' (c =1, inCHCl3) NMRtCDCl:,, ppm) : 1.38(d, 3H), 2.40(bs, 1H), 2.61(m, 2H), 3.58(m. 2H), 3.78(q, 1H), 7.18-7.38(m, 5H) (2) Preparation of (S)-(-)-N-(2-bromoethyl)-α-methylbenzylamine hyd-robromide: 22.1g( 133.16 mmole) of (S-)-N-(2-hydroxyechyl)- α -methyl-bezylamtne produced in Example 11(1) above was suspended in 105ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 1.26ºC for 30 minutes under refluxing. Then, the reaction solution was distilled for 2 hours under normal pressure at constant. temperature and 95ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 112ml of acetone, and I00ml of ethyl acetate and 150ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 70ml of ethyl acetate and then dried to obtain 20g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 130ml of ethanol and then concentrated under reduced pressure. The residue was dissolved in 104 me of acetone, diluted with 143ml of ether, and then allowed to stand at 0 "C for 12 hours. The resulting solid product was filtered, collected and washed with 75ml of ethyl acetate to obtain 6.7g of the second crop of the title compound. Yield :- 64.8% m.p. : 186-187ºC [a D20: -32.1 (c-1, in CHCb) NMR(CDC13, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q, 1H), 7.40-7.72(m, SH), 9.51(bs, 1H), 9.9l(bs, 1H) (3) Preparation of (S)-(-)-l-methyl-l,2,3,4-tetrahydroisoquinonline 5.0g(16.l8 mmole) of (S)-(-)-N-(2-bromoethyl)-a -methylbenzyl-amine hydrobromide produced in Example (2) above was suspended in 50 ml of decalin and then heated to 140ºC. 6.47g(48.54 mmole) of anhydrous aluminum chloride (AlCI3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, and cooled to room temperature. The supernatant was removed and the lower layer was added to 70g of ice-water with stirring. 20ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 100m! of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250ml of ethyl acetate. The extracts were combined, washed with 40ml. of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 1.75g of the title compound. Yield : 73.5% b.p. : 79-80ºC/0.5torr [αlD20 : -85.5' (c=l, inCHCl3) NMR(CDCI3, ppm) : 1.59(d, 3H), 2.14(s, IH), 2.76-3.02(m, 2H). 3.10-3.22(m, IH), 3.34-3.45(m, IH), 4.22(q, IH), 7.18-7.31 Example 12 : (S)(--l-methyl-1,2,3,4-tetrahydroisoquioonline (1) Preparation of (S)-(-)-N-(2-bromoethyl)- a -methylbenzylamine hyd- robromide: 176.20g(1449 mmole) of (S)-(-)- α-methylbenzylamine was dissolved in185ml of dichloromethane and 218.04g1748 mmole) of 2-bromocthanol was added thereto. This mixture was stirred at 51ºC for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 658ml(5750 mmole) of 48% aqueous hydrobrotmic acid solution was added thereto and the solution thereby obtained was allowed to react at 126ºC for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature to remove 580ml of water as the by-product and aqueous hydrobromic acid solution. The residue was dissolved in 760ml. of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10ºC and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 150ml of ethyl acetate and then dried to obtain 306.5g of the title ompound. Yield : 68.4% m.p. : 185ºC [α20] : -32. 1' (c-1, inCHCI3) NMR(CCDCI3, ppm) : 1.94(d, 3H), 3.2l(m, 2H), 3.82(m, 2H), 4.42(q, 1H), 7.40-7.72(m, 5H), 9.51(bs, 1H), 9.91(bs, 1H) (2) Preparation of (S)-(-)-l-methyl-l,2,3,4-tetrahydroisoquinoline 10,0g(30.1 mmole) of (S)-(-)-N-(2-bromoethyl)-a-rnethylbenzyl-amine hydrobromide produced in Example 12(1) above was suspended in 60ml of 1,2-dihlorobenzene and then heated to 145ºC. 13-47g(96.54 mmole) of anhydrous aluminum chloride (AlCI3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, cooled to room temperature and poured onto 250g of ice-water with stirring. 30ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and then extracted three times, each time with 250ml of ethyl acetate. The extracts were combined, washed with 40mlof saturated saline, dehydrated with anhydrous magnesium sulfate. and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.10g of the title compound. Yield : 69.96% b.p. : 79-80ºC:/0.5torr[ab20 : -85.5" (c, in CHCI3) NMR(CDCI3, ppm) : 1.59(d, 3H), 2.14(s, 1H), 2.76-3.02(m, 2H), 3.10-3.22(m, 1H), 3.34-3.45(m, 1H), 4.22(q, 1H), 7.18-7.31(m, 4H) Example 13: (S)-(-)-l-l-methvl-1.2.3.4-tetrahvdrisqquinonline 73.45g(240 mmole) of (S)-(-)-N-(2-bromoethyl)- a-methylbenzyl -amine hydrobromide produced in Example 12(1) above was suspended in 260ml! of decalin and the resulting suspension was heated to 150ºC. 05.10g(7lO mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 1600g of ice-water with stirring. 70ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 700ml! 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 900ml! of ethyl acetate. The extracts were combined, washed with 200ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 27.6g of the title compound. Yield : 78.1% b.p. : 79-80ºC/0,5torr [α]D20 : -85.5' (c-1. in CHCI3) NMR(CDCI3. ppm) : l.59(d, 3H), 2.14(s, 1H), 2.76-3.02(m. 2H), 3.lO-3.22(m, 1H), 3.34-3.45(m, 1H), 4.22(q, 1H), 7.18-7.31(rn, 4H) Preparation of 5.6-dimethyl -2-(4-Ouoronhenylamino)-4-(1-methyl-l,2,3,4-tetrahydroisouolinn--2-yl)pvrimidine and its hydrochloridg In Examples 14 to 20, inclusive, l-methyl-l,2,3,4-tetrahydroiso-quinoline prepared according to the method disclosed in International Publication No. WO 94/14795 was used as the reactant. Exarnple 14: 2.65g(27 mmole) of potassium acetate and 4.0g(26.9 mmole) of l-methyl-l,2,3,4-tetrahydroisoquinoline were added to 85mi of n-hexanol and then warmed to 80ºC. 6.17g(24.5 mmole) of 4-chloro-2-(4-fluoro-phenylanuno)-5,6-dimethylpyrinudine was added thereto and then reacted a1 140'C for 28 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluo-rophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrim dinc. The reaction solution was cooled to room temperature, diluted with 20ml of acetone and then added dropwise to 120ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 30ml of water, dissolved in 150ml of dichloromethanc and then washed successively with 20ml of 4N-HC1, 20ml of water and then 20ml of 4N-sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with100ml of ethanol. To this reaction solution was added 30g of cone, hydrochloric acid, and die mixture thereby obtained was stirred for 5 hours. The resulting solid product was filtered, washed with 20ml of ethanol and then dried to obtain 6.1g of purified 5,6-dimethyl-2-(4-nuorophenylamino)-4-(l-methyl-1,2,3,4-tetrahydroisoquinou'n-2-yl)pyrimidine hydrochloride. Yield : 62.4% m.p. : 255r NMR(CDCI3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.l2(m, 1H). 3.61(m, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H), 7.6(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H) Example 15: 8.12g( 11.2ml, 80.3 mmole) of triethylamine, 30ml. of n-butanol and 6.58g(44.1 mmole) of l-methyl-l,2,3,4-tetrahydroisoquinoline were added to 40ml of ethylene glycol. 10.1g(40.1 mmole) of 4-ehloro-2-(4-fluoro-phenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130ºC For 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-Methyl-l,2,3)4-tetrahydroisoquinolin-2-yl)-pyri-midine. This product was treated according to the procedure detailed in Example 14 u> obtain 14.7g of purified 5,6-dimethyl-2-(4-fluorophenyl-arnino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydro-chloride. Yield : 91% m.p. : 256ºC NMR(CDCl3 ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.61(m, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H). 7.61(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H) Example 16: 45ml of triethylamine, 50ml of n-butanol and 32g(217 mmole) of l-methyl-l,2.3,4-tetrahydroisoqujnoline were added to 150ml of ethylene glycol. 51.3g(203.8 mmole) of 4-chloro-2-(4-fluorophenylanuno)-5,6-dimethylpyrimidine was added thereto and then reacted at 135'C for 28 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-( 1-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyriniidine. This product was created according to the procedure detailed in Example 14 to obtain 66a of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyhl,2, 3,4-tetrahydroiso-c\|uinolin-2-yl)pyrimidine hydrochloride. Yield : 81.196 m.p. : 256"C NMR(CDCI3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.6Km, 2H), 4.23(m. 1H), 5.38(q, 1H), 7.25(m, 6H), 7.6l(m, 2H), 10.33 (s, 1H). I3.43(bs, 1H) Example 17: 75ml of triethylamine and 65g(442 mrnole) of 1 -methyl-1,2,3,4-tetrahydroisoquinoline were added to 100ml of 1,2-propylene glycol. 100.9g(0.40 mmole) of 4-chloro-2-(4-fluornphcnylamino)-5,6-dime-ihylpyrimidine was added thereto and then reacted at 120t) for 64 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinc. This product was treated according to the procedure detailed in Example 14 to obtain 9lg of purified 5.6-dimethyl-2-(4-fluorophenylamino)-4-( 1 -methyl-1,2,3,1-teLrahydroisoquinolin-2-yl)pyrimidine hydrochloride. Yield : 57.1% m.p. : 258ºC NMR(CDCI3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.6l(m. 2H), 4.23(m, 1H), 5.38(q, 1H), 7.2S(m, 6H), 7.61(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H) Example 18: 720ml of triethylamine and 695g(4.72 mmole) of 1-methyl-1,2,3,4-letraliydroisoniunoline were added to 2100ml of l,2-propy!ene glycol. 1179«(4.68 mmole) of 4-chloro-2-(4-fluorophcnylamino)-5,6-dimethyl-pyrimidine was added thereto and the mixture thereby obtained was reacted at 130ºC for 58 hours to prepare 5,6-dimethyl-2-(4-f1uoropheny1-ainino)-4-(l-methyl-lr213,4-tetrahydroisoquinolin-2-y!)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 1250g of purified 5,6-dimethyl-2-(4-fIuornphenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride. Yield = 66.9% m.p. : 258 1 NMR(CDCI3. ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.61(m, 2H), 4.23(m. 1H), 5.38(q, IH), 7.25(m, 6H), 7.6l(m, 2H), 10.33 (s, IH), 13.43(bs, IH) 110ml of n-butanol, 240ml of triethylamine and 236g(1.60 mmole) of 1-methyl- 1,2,3,4- wtrahydroisoquinoline were added to 600mlof ethylene glycol. 400g(1.59 mmole) of 4-ch1oro-2-(4-fluorophenyl-arnino)-5,6-dimethylpyrimidine was added thereto and then reacted at 140 ºC. for 48 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-( I -methyl- l,2,3,4-(.etrahydroisoquinoUn-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 485g of purified 5,6-dirnethyl-2-(4-fluorophenylamino)-4-(l-rnethyl-1, 2,3,4- tetrahydroisoqtiinolin-2-yl)pyrimidine hydrochloride. Yield : 76.5% m.p. : 257ºC NMR(CDCI3. ppm) : 1.58(d, 3H), 2.21(s, 3H>, 2.38(s, 3H), 2.84(m, IH), 3.12(m, IH), 3.61 (m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m. 6H), 7.61(m, 2H), 10.33 (s, IH), I3.43(bs, IH) Example 20 240ml! of triethylamine and 9.7g(65-8 mmole) of l-methyl- 1,2.3,4- tetrahydroisoquinnline were added to 25ml of 1,2-propylene glycol. Then, 15g(51 mmole) of 4-bromo-2-(4-fluorophenylamino)-5,6- dimethyl-pyrimidine was added thereto and the mixture thereby obtained was reacted at 110ºC for 28 hours. The resulting product was treated according to the procedure detailed in Example 14 to obtain 15.86g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetra-hydroisoquinolin-yl)pyrimidine hydrochloride. Yield : 78% m.p. : 257ºC NMRfCDCI3, ppm) : 1.58(d, 3H), 2.21(s, 311), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.61(m, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H), 7.61(m, 2H), 10.33 Example 21 8.12g(11.2ml, 80.3 mmole) of triethylamine, 30ml of n-butanol and 6.58g(44.1 mmole) of l-methyl-1.2,3,4-tetrahydroisoquinoline as prepared in Example 5 were added to 40ml of ethylene glycol. 10.1g(40.1 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130ºC for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetra-hydroisoquinolin-2-yl)pyrimidine. The reaction solution was cooled to room temperature, diluted with 30ml of acetone and then added dropwise to 200ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60ml of water, dissolved in 250ml of dichloromethane and washed successively first with 35ml of 4N-HCI, 35ml of water and then with 40ml of 4N-sodium hydroxide soludon. The dichloromechane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 200ml of ethanol. To this reaction solution was added 45g of concentrated hydrochloric acid, and the mixture was stirred for 5 hours. The resulting solid product was filtered, washed with 30mlof ethanol and then dried to obtain 9.82g of purified S,6-dimethyl-2-(4-fluorophenylamino)-4-(l-mechy]-l,2,3,4-tetra-hydroisoquinolin-2-yl)pyrimidine hydrochloride. Yield : 66.53% m.p. = 2551 NMR(CDCl3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.6l(m, 2H), 10.33 (s, IH), 13.43(bs, IH) Example 22 75ml of triethylanine and 65g(442 mmole) of l-methyl-1,2,3,4-tetrahydroisoquinnline as prepared in Example 7 were added to 100ml of 1,2-propylene glycol. 100.9g(0.40 mmole) of 4-chloro-2-(4-fluto-phenylamio)-5,6-dimethylpyrinmdine was added thereto and then reacted nt 120ºC for 64 hours to prepare 5,6-dimethy!-2-(4-fIuorophenylamino)-4-( l-methyl-1.2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated accurding to the procedure detailed in Example 21 to obtain 95. Ig of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-meihyl-].2,3,4-tetiahydroisociuinolin-2-yl)pyriinidine hydrochloride. Yield : 59.67% m.p : 258 ºC NMR(CDCl3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, IH), 3.l2(m, IH), 3.6l(m. 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m. 6H), 7.61(m, 2H), 10.33 (s, IH), I3.43(bs. IH) Example 23 I4ml of triethylamine and 9.7g(65.8 mmole) of l-methyl-1,2,3,4-tetraliydrasoquinoline as prepared in Example 7 were added to 25ml of 1,2-propytne glycol. 15g(51 mmole) of 4-hromo-2-(4-fluorophenyl- amino)-5,6-dimethylpyrimidine was added thereto arid then reacted at 120 C for 28 hours to prepare 5,6-diethyl-2-(4-fluorophenylanuno)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 21 to obtain 14.9g of purified 5,6-dimethyl 2-{4-fluorophenylamino)-4-(l-methyl-l,2,3,4-ietrahydroisoquinolin-2-yl)pyrunidine hydrochloride- Yield : 73.28% m.p. : 257 ºC NMR(CDCl3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.l2(m, 1H), 3.61(m, 2H), 4.23(m, 1H), 5.38(q, 1H>, 7.25(m, 6H). 7.61(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H) 8.l2g(11.2ml 80.3 mmole) of triethylamine, 30ml of n-butanol and f».58g(44.1 mmole) of (R)-(+)l-methyl-l,2,3,4-tetrahydroisoquinoline as prepared in Example 9 were added to 40ml of ethylene glycol. 10.1g (40.1 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130 ºC for 30 hours under rettuxing to prepare 5/>-dimethyl-2-(4-fluorophenylam(no)-4-( 1-methyl- 1,2,3, -t-tetrahydroisoquinolin-2-yl)pyriroidine. The reaction solution was cooled to room temperature, diluted with 30m? of acetone and then added dropwise to 200 raC of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60ml of water, dissolved in 250nrf of dichloromethane and then washed successively with 3S»( of 4N-HC1, 35mJ of water and then 40mf. of 4N- sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfatc, concentrated under reduced pressure, and then diluted with 200ml of ethanol. To this reaction solution was added 45g of cone, hydrochloric acid, and the resulting mixture was stirred for 5 hours. The. resulting solid product was filtered, washed with 30ml of ethanol and then dried to obtain 9.21g of purified (R)-(+)-5,6-dimethyl-2-(4-f!uorophenylarnino)-4-O-methyl- l,2,3,4-tetraliydroisoquinolin-2-yI)pyrimidine hydrochloride. Yield : 62.4% m.p. : 255 ºC [a]D20 : +250º (c=1, in CHCI3) NMR(CDCI3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.61(m, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H, 7.61(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H) Example 25 23ml of triethylamine and 16g( 108.5 mmole) of (R)-(+-)-l-melhyl-1,2,3,4- tetrahydroisoquinoline as prepared in Example 10 were added to 75ml of ethylene glycol. 25.7g(101.8 mmole) of 4-chloro-2-(4-fluoni-pheny]amJno)-5,6-dimethylpyrimidlne was added thereto and the mixture thereby obtained was reacted at 135ºC for 28 hours under reflu.ving to prepare (R)-( + )-5,6-dimethyl-2-(4-fJuorophenylamino)-4-(l -methyl- 1,2,3, 4-ielrahydroisonu«nolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 24 to obtain 33g of purified 5,6-dimet.hyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tctra-hydroisoquinolin-2-yl)-pyrimidine hydrochloride. Yield : 81.196 m.p. : 257 "C [a]D20 : ^250' (c=l, in CHCW NMR(CDC!:«, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m. 1H), 3.12(m, 1H), 3-6Um, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H), 7.61(m, 2H). 10-33 (s, 1H), 13.43(bs, 1H) 14m« of triethylamine and 9.7g(65.8 mmole) of (R)- 1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to 25ml of 1,2-propylene glycol. 15g(51 ramole) of 4-bromo-2-(4-fIuoro-phenylarnino)-5,6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 120TC for 28 hours. The reaction product was thencreated according to the procedure detailed in Example 24 to obtain I6.2g of purified 5,6-dimethyl-2-(4-fluoropheny!amino)-4-( l-methyl-l,2,3,4-tetrahydroisoquinoh'n-2-yl)pyrimidine hydrochloride. Yield : 79.97% m.p. : 257 'C [oh20: +250' T (c=l, inCHCI3) NMR(CDCI3i, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m. 1H), 3.X2(m, 1H), 3.61(m, 2H). 4.23(m, 1H), 5.38(q, , 1H), 7.25(m, 6H), 7.61(m. 2H), 10.33(s, IH), I3.43(bs, IH) Example 27 8.l2g(11.2ml, 80.3 mmole) of triethylamine, 30ml of n-butanol and 6.58g(44.1 mmole) of (S)-(-)-l-methyl-l,2,3,4-tetrahydroisoquinolme as prepared in Example 13 were added to 40me of ethylene glycol. 10. lg (40.1 mmole) of 4-chloro-2-(4-fluorophenylanunoH5,6-dimethylpyrimidinfe was added thereto and then reacted at 130 T: for 30 hours under refluxing to prepare (S)-(-)-5I6-dimethy\|-2-(4-fluoropheny!amino)-4-(l-ethyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. The reaction solution was cooled to room temperature, diluted with 30mlof acetone and then added dropwise to 200ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60ml of water, dissolved in 250m( of dichloromethane and washed successively with 35ml of 4N-HCI, 35ml1 of water and 40mc of 4N-sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 200ml of ethanol. To this reaction solution was added 45g of cone, hydrochloric acid, and the mixture was stirred for 5 hours. The resulting solid product was filtered, washed* with 30ml of ethanol and then dried to obtain 8.95g of purified (S)-(-)-5,6-dunfithyl-2-(4-fluorophenylamino)-4-(l-methyl-i,2,3,4-tetrahydro)soquinolin-2-yl)pyrimidine hydrochJoride. Yield : 60.6% m.p. : 255 C [a Jo* : -250' (c=l, in CHC13) NMR(CDCl.-i, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), S.GKm, 2H), 4.23(m. 1H), 5.38(q, 1H), 7.2S(m, 6H). 7.61(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H) Example 28 of trie thy lamine and 9.7g(65.8 mmolc) of (SH-)-l-methyl-1.2,3,4-tetrahydroistMiuinoline as prepared in Example 13 were added to 25ml! of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(l-fluoro-phenyIarnino)-5,6-dirnethylpyrimidine was added thereto and then reacted at ll0ºC: for 38 hours. The reaction product was treated according to the procedure detailed in Example 27 to obtain 15.86gof purified 5.6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroiso-c\|uinolin-2-yl)pyrirrudine hydrochloride. Yield : 78% m.p. : 257 C [a ]Do20 : -250' (c-1, in CHCI3) NMR(CDCl:t, ppm) : 1.58(d, 3H), 2.2l(s, 3H), 2.38(s, 3H), 2.84(m. IH), 3.l2(m, 1H), 3.6 Km, 2H), 4.23(m, 1H), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 1033 (s, IH), 13.43(bs, IH) We claims:- 1. A process for preparing a 4-halogeno-2-(4-fluorophenyl-amino)-5, 6-dimethylpyrimidine represented by the following formula, (I) (Formula Removed) in which Hall represents a halogen, characterized in that 4-fluorophenyl-guanidine carbonate represented by the following formula (II) (Formula Removed) is reacted with ethyl 2-methylacetoacetate represented by the following formula (III)(Formula Removed) to prepare 4-hydroxy-2-(4-fluorophenylamino)5,6-dJmethylpyrimidine represented by the following formula (IV)(Formula Removed) which is then reacted with a halogenating agent. 2. A pyrimidine derivative represented by the following formula (V) (Formula Removed) in which R represents hydroxy or a halogen. A process for preparing a 4-halogeno-2-(4-fluorophenyl-amino)-5,6-dimethylpyrimidine substantially as herein described with the foregoing description and the accompanying examples. A pyrimidine derivative substantially as herein described with the foregoing description and the accompanying examples.

Full Text

PROCESS FOR PREPARATION OF PYRIMIDINE DERIVATIVES
TECHNICAL FIELD
The present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3)4-tetrahydroiso-c|uinolin-2-yl)pyrimidine represented by the following formula (I.) and ics acid addition salts; second, to a process for preparation of an intermediate for preparing the compound (I); and, third, to a novel intermediace compound. More specifically, the present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinoHn-2-yl)pyrimidine represented by the following formula (I),
(Formula Removed)
and its acid addition salts, wherein a pyriraidine derivative represented by the following formula (II-A),
(Formula Removed)
in which Hal represents a halogen, is reacted with 1-methyl-1,2,3,-J-tetrahydroisoqumoline represented by the following formula (III);
(Formula Removed)
.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).
(Formula Removed)
BACKGROUND ART
5,6-Dimethyl-2-(4-fluorophenylanuno)-4-(l-methyl-l,2,3,4-tetra-hydroisoquinolin-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 fur 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-dimethyt-2-(4-fluorophenyIamino)-4-(l-methyl-lI213,4-tetrahydroii,() \Reaction Scheme-A
(Formula Removed)

Since the starting material of the above reaction scheme has two reactive sites (i.e., the two Ci atoms), the first reaction inevitably produces a side product, which reduces the yield of the desired compound.
The present inventors have Jong labored to develop a novel method for preparing S,6-dimethyl-2j(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinoiin-2-yl)pyriinidine of formula (!) 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 l-mettiy|-l,2,3,4-tetrahydroisoquinoline represented by-formula (HI) and, thus, have completed the present invention.
DISCLOSURE OF THE INVENTION
The present invention relates to a novel process for preparation of 5.6-dimechyl-2-(4-fluorophenylainino)-4-(l-methyl-1,2,3,4-tetrahydroiso-tiuinolin-2-yl)pyrimidine represented by formula (I) and its acid additionsalts.
More specifically, the present invention relates to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-1.2,3,4-tetrahydroUoqiiinolin-2-yl)pyrimidine represented by fonnula (I),

and Its acid addition salts wherein a pyrimidine derivative represented by the following formula (II-A),

(Formula Removed)

in which Hal represents a halogen, is reacted with i-methyl-1,2.3,4-tctrahydroisoquinoline represented by fonnula (III),
(Formula Removed)
In addition, the present invention relates to a process for preparation of the pyrimidine derivative of formula (D-A) and the compound of fonnula (III).
Further, the present invention relates to a novel intermediate compound represented by the following formula (II), which includes the pyrimidine derivative represented by formula (n-A),

(Formula Removed)

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 l-methyl-1.2,3,4-tetrahydroisoquinoline of formula (II), as depicted in the following reaction scheme 1'
Reaction scheme 1

(Formula Removed)

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-fluonJphenylamino)-5,6-dimethyl-pyrimidine represented by formula (Ef-A) can be reacted according to the present invention with an equivalent amount of 1-methyl-1,2,3,4-tetra-hyclroisoquinoline represented by formula (III), 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 l-methyl-l,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-pcntanol, n-hexanol, dimethylsuUoxide, 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 he used for this purpose include triethylamine, N,N-dimethylaniline, pyridine arid potassium acetate. The reaction temperature fur the reaction between the compound of formula (H-A) and 1-methyl-1,2,3,4-tetrahydroisoquinoline of formula (ffl) is preferably in the range from llOt to 160T and the reaction time is preferably in the range from 16 hours to 72 hours.
5,6-Dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-1.,2,3,4-tetra-hydroisoquinolin-2-yI)pyrimidine of formula (I) as prepared according to die above method can be converted into its acid addition salt, preferably into die 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)-(-O-isomer, an (S)-(-)-isomer, or a racemate wherein the R and S isomers are mixed in the ratio of l;l. Unless indicated otherwise, the compound of formula (I) should be interpreted to include all of these isomers.
(Formula Removed)
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:
(Formula Removed)
In the reaction scheme 2, Hal represents a halogen.
As depicted by the reaction scheme 2, reacting 4-fluorophenyl-guanidine carbonate of formula (IV) with ethyl 2-methylacetoacetate of formula (V) yields 4-hydroxy-2-(4-fluorophenylamino)-5,6-dimethyl-pyrimidine of formula (II-B), which may then be reacted with a halogenating agent to obtain the 4-halogeno-2-(4-fluorophenylarninn-) 5,6-dimethylpyrimitiine of formula (H-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-fluoroaruline with a 50% cyanamide solution under acidic conditions using 30% to 37% hydrochloric acid while maintaining the temperature ranging from 75 to 951.
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 acetonkrile, N,N-dimethylformamide and dimethylsulfoxide This
reaction is preferably carried out at a temperature ranging from 11.0 "C to 160ºC.
In the second step of the, reaction scheme 2, 4-hydroxy-2-(4-fluorophenylanuno)-5,6-dimethylpyriniidine of formula (II-B) obtained from the first step Of the reaction scheme 2 is converted into the compound of formula (II-A) by reacting the former with a halogenating agent. Halogenating agents which can be used for this purpose include phosphorus oxychloride, oxalyl chloride, thionyl chloride and phosphorus tribromide. This halogenation reaction is carried out in the presence of a solvent. Reaction solvents which can be used for this purpose include preferably N,N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane and l,2-dichloroben2ene. It is preferable to maintain the reaction temperature in the range from 75ºC to 95ºC.
Although the second step of the reaction scheme 2 can be practiced 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 vessel. Specifically, 4-hydroxy-2-(4-fluorophenylamino)-5,6-climeihylguanidine of formula (II-B) is prepared from 4-fluorophenyl-guanidine cabonate and then, without isolation, can be successively reacted with the halogenating agent to yield 4-halogeno-2-(4-fluoro-phenylammo)-5,6-dimethylpyrimidine (II-A).
The compound of formula (II-A), which is used as the starting material for preparation of the compound of formula (I) according to the present invention, is novel, as is the compound of formula (II-B) produced as the intermediate in the reaction scheme 2. Both novel compounds can he represented by the following formula (II), which is within the scope of the present invention,
(Formula Removed)
in

which R represents hydroxy or a halogen.

l-Methyl-l,2,3,4-tetrahydroisoquinoline of formula (III), which is also used as the starting material in the reaction scheme 1, is a known compound and can be preapred by known methods (see, for example, International Publication No. WO 94/14795). According to this known method, (R)- or (S)-l-methyl-l,2,3,4-tetrahydroisoquinoline is prepared by reacting (R)- or (S)-methylbenzylamine with a -chloro- a -(methyl-thio)-acetylchloride and stannous chloride (SnCh) to produce (R)- or (S)-l-methyl-4-methylthio-l,2,3,4-tetrahydroisoquinolin-3-one, respectively, then reacting the resulting compound with Raney nickel to remove a methylthio group, and finally adding a reducing agent. However, this method is disadvantageous, since a -chloro- a -(methylthio)-acetylchloride, which is used as the starting material, is both unstable and explosive, so that this method cannot be practiced on an industrial scale. Further, since the reaction step is long, the total yield is low, which makes this method uneconomical.
The present inventors have long labored to find a more efficient method for producing l-methyl-l,2,3,4-tetrahydroisoQuinoline. We have discovered that l-methyl-l,2,3,4-tetrahydroisoquinoline can be employed economically and safely by successively reacting a -methylbenzylainine with 2-bromoethanol, a brominating agent, and a Lewis acid. Such a process for preparing l-methyl-l,2,3.4-tetrahydroisoquinoline is novel and is encompassed within the scope of the present invention. This novel process for preparing l~methyl-l,2,3,4-tetrahydroisoquim>line is explained in more detail below.
According to the present invention, 1-methyl-1,2,3,4-tetrahydro-isoquinoline of formula (IT!) can be prepared by reacting a-methyl-benzylamine successively with 2-bromoethanol, a brominating agent and Lewis acid. The method of the present invention employs the following reaction scheme 3.

Reaction scheme 3

(Formula Removed
All of the starting materials and reactants used in the reaction scheme 3 are known compounds and can be obtained as commercial products. In the first step a -methylbenzylamine is reacted with 2-bromoethanol to produce N-(2-hydroxyethyl)-rt-mcthylbenzylamine, which in turn is reacted with the brominating agent to produce N-(2-bromoethyf)- a - methylbenzylamine hydrobromide. In the third step, N-(2-bromrtethyl)- -methylbenzylamine hydrobromide is reacted with a Lewis acid to produce the desired 1-methyl -l,2,3,4-tetrahydroiso-ciuinoline of formula (III).
Reaction solvents which can be used in the first step include acetonitrile, N.N-dimechylforroamide, dichloromethane and 1,2-dichlorn-ethane and the reaction temperature is preferably maintained in the range from 401C to 601. Reaction solvents which can be used in the second step include 1,2-dichloroethane, acetic add, water and 1,2-dichloro-benzene, and the reaction temperature is preferably maintained in the range from 110ºC to 145ºC. Brominating agents which can be used in this reaction include bromine, bromic aicd, aqueous bromic acid solution, and phosphorus trihrnmide.
Although the first and second steps of the reaction scheme 3 can
the desired 1 -methyl- 1,2,3,4-tetrahydroisoquinoline of formula (Til). Reaction solvents which can be used in this reaction include decalin, 1,2-dichIoroethane and 1,2-dichlorobenzene and Lewis acids for this cyclization reaction include aluminum (HI) chloride, zinc chloride and ferrous chloride.
Since I -methyl- 1,2,3,4 -tetrahydroisoquinoline can be economically prepared according to the above method, the desired 5,6-dimethyl -2-(4-nuorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-y1) -pyrimidine of formula (I) according to the present invention can also be economically prepared using this compound as the reactant.
In order to use the compound of formula (III) in the form of (R)-(-O- or (S)-(-)isomer as the starting material for preparation of the compound of formula (I) according to the present invention, each isomeric form of the compound of formula (HI) can be efficiently prepared using the corresponding (R)-(+)- or (S)-(-)-methylbenzylamine as the starting material used in the method depicted 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 manner limited by these examples.
Prearatio : 4-fluoronvlguan
882g(747mf) of 32% hydrochloric acid was added to 1000g(8.9 mole) of 4-fluoroaniline, the mixture was warmed lit 87°C, and 780mf.(9.9
mole) of 50% cyanamide solution was added dropwisc thereto over 2 hours. The reaction solution was adjusted to pH 2.4 by adding thereto 120mlof 32% hydrochloric acid, stirred for 3 hours, and coaled to 60'C. Aqueous sodium carbonate solution (Na2CO3 578g/water I640ml) was added dropwise to the reaction solution over 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 600mlof water and then with 2000ml of ethyl acetate, and finally dried to obtain 1395g of the title compound, which had a light gray color.
Yield : 81.4% m.p. : 1751:
NMR(DMSO-d6, ppm) : 5.50-6.88(bs, 5H), 6.87(m, 2H), 7.17 2H)
midine
54.5g(253.2 mmole) of 4-fluorophenytguanidine carbonate produced in the Preparation above was suspended in 50m? of N,N-dimethylform-jimide and 37.8g(262.2 mmole) of ethyl 2-methylacetoacetate and the resulting suspension was refluxed at 140X1 for 3 hours. The reaction solution was diluted again with 100ml of N,N-dimethylformamide and cooled to 80ºC, I60ml of isopropylalcohol was added thereto and the resulting mixture was stirred for 30 minutes. The resulting solid product was filtered, washed with 150ml of acetone, and finally dried to obtain 41g of the title compound.
Yield : 61.496 m.p. : 256C
NMR(DMSO-de, ppm) : 1.83(s, 3H), 2.19(st 3H), 7.18(t, 2H), 7.68
(m, 2H), 9.36(hs, 1H), 10.63 Example 2 : 4-chloro-2-(4Qroonbenylamino)-5,6-dimethyloyimi-
0.5g(174.1 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in 80ml of N,N-dimethylfonnamide and the resulting suspension was heated to 80 'C. :31..9g(l9.4ml, 210.1 mmole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 85 T. The reaction solution was stirred for 30 minutes and then 400g of ice-water was added thereto with stirring. The mixture was adjusted to pH 11 by adding sodium hydroxide and then the resulting solid product was filtered. The separated solid product was washed with 150ml of 50% aqueous methanol solution and then dried to obtain 42. 3g of the title compound.
Yield : 96.7% m.p. •• 114ºC
NMR(CDCln, ppm) : 2.21(s, 3H), 2.41(s, 3H), 7.0l(t, 2H), 7.l8(bs, 1H), 7.56U, 2H)
: 4-ghlorn-2-(4~fluomnhenvlamino)-5.6-dimethvlDvrimi-
1390g(7.6 mole) of 4-fluorophenylguanidine carbonate produced hy
ihe Preparation above was suspended in 1300ml of N.N-dimethylfomi-
amide and I200g(8.4 mole) of ethyl 2-methyiacetoacetate. The resulting
ispension was heated under refluxing for one hour, distilled at normal
•essure to llOOmi! and then distilled until the temperature of the reaction
ilution reached 160 ºC. 1600ml of N,N-dimethylformamide was added Lo
ie residue and then cooled to 80º C. 1388g(840ml, 9.1 mole) of
phosphorus oxychloride was added thereto over one hour at constant
temperature of 80 1 to 85'C. The reaction solution was stirred for 30
minutes «nd then diluted with 2000m* of N.N-dimethyl- formamide. To
the diluted reaction solution was added 7000ml of water over 40 minutes
with stirring. The reaction solution was stirred for 4 hours and the
resulting solid product was filtered, washed with 1500ml. of 50% aqueous
methanol solution and then dried. The dried, yellowish-brown powder
Lhereby obtained was dissolved in 4000ml of methanol under refluxingand then cooled to 10 1. The resulting solid product was filtered and dried to obtain 1186g of the tide compound.
Yield : 62.4% m.p. : 114ºC:
NMRfCDCb, ppm) : 2.2l(s, 3H), 2.41(s, 3H), 7.01(t, 2H), 7-18(bs,
1H), 7,56(t, 2H)
4 : 4-bromo-2-(-fluoroohenvlamino)-5.6-dimethylpvri-
5g(21.44 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in 40m£ of N,N-dimethylformamide and the resulting suspension was warmed to 65 "C. 8.1g(30 mmole) of phosphorus tribromide was added dropwise thereto over 20 minutes and the resulting mixture was allowed to react ai 75X3 for 30 minutes. The reaction solution was cooled to room temperature, poured onto 500g of ice-water, adjusted to pH 11 with sodium hydroxide solution, stirred for 30 minutes and then adjusted again r.n pH 5.5 with dilute hydrochloric acid. The resulting yellow solid product was washed with 100ml of water and the dried to obtain 4.1g of the title compound.
Yield : 64.58% m.p. : 123 r
NMR(CDC13 PPm) : 2.21(s, 3H), 2.42(s. 3H), 6.98(t, 2H), 7,24(s, 1H), 7.54(g, 2H)
: t-methyl- 1,2,3,4- tetrahydroisoouinoline
(1) Preparation of N-(2-hydroxyethyl)-a-methylben2ylamine:
103.08g(0.86 mole) of a -methylbenzylamine was dissolved in 110 mi of dichlororaethane and 127.560(1.02 mole) of 2-bromoethanul was added thereto. This mixture was stirred at 52 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 109g of the title compound, which had a pale yellow color.
Yield : 76.7% m.p. = 60'C/0.5toiT
NMR(CDCb, ppm) : 1.38(d, 3H), 2.40 (2) Preparation of N-(2-bromoethyl)-a-niethylben2ylamine hydrobromide:
1000(605.32 mmole) of N-(2-hydroxyethyl)- a-methylbenzylamine produced in Example 5(1) above was suspended in 515m£ of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126ºC for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 465ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 550ml of acetone, and 500mH of ethyl acetate and 670ml! of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to O'C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 400ml of ethyl acetate and then dried to obtain 97g of the first crop of the title ompound. The filtrate was then concentrated. The residue was dissolved in 450ml of acetone, diluted with 680ml of ether and then allowed to stand at O'C for 12 hours. The resulting solid product was filtered, collected, and washed with 450ml of ethyl acetate to obtain 32.Sg of the second crop of the title compound.
Yield : 69.23%
m.p. : 186-187ºC
NMR(CDCl;i, ppm) : 1.94(d, 3H), 3.2l(m, 2H), 3.82(m, 2H), 4.42(a.
1H), 7.40-7.72(m, 5H), 9.51(bs, IH),
1H)
(3) Preparation of 1-methyl-1,2,3,4-tetrahydroisoquinoline

50.0g( 161.8 mmoie) of N-(2-bromoethyl)- a -methylbenzylamine hydrobromide produced in Example 5(2) above was suspended in 450ml of decalin and then heated to 140ºC. 64.70g(485.4 mmole) of anhydrous aluminum chloride (A1C13) was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature, and then cooled to room temperature. The supernatant was removed and the lower layer was added to 800g of ice-warcr with stirring. 150ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with l000ml 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 2100ml of ethyl acetate. The extracts were combined, washed with 420ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 18.1g of the title compound.
Yield : 75.99%
b.p. : 79-80ºC/0.5torr
NMRfCDCb. ppm) : 1.59(d, 3H), 2.14 3.10-3.22(m, 1H), 3.34-3.45(m, 1H), 4.22(q,
IH), 7.18-7.31(m, 4H)
(1) Preparation of N-(2-bromoethyl)- a -methylbenzy famine hydrobromide
76.6lg(630 mmole) of a-methylbenzylamine was dissolved in 77ml of dichloromethane and 94.8g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51ºC for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4ml(2500 mmole) of 4896 aqueous hydrobromic acid solution was added thereto and allowed to react at 126X) for 30 minutes under rofluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250ml! of aqueous

hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350ml of isopnopyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10£ and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50mlof ethyl acetate and then dried to obtain 128.9g of the title ompound.
Yield : 66.29%
m-p. : 186-187ºC
NMK(CDClj, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42 1H), 7.40-7.72(m, 5H), 9.51(bs, 1H). 9.9l(bs,
1H)
(2) Preparation of 1-methyl- 1,2,3,4-tetrahydroisoquinoline
10.0g(30.1 mmole) of N-(2-bromoethyl)-a-methylbenzylamine hydrobromide produced in Example 6(1) above was suspended in 60ml of 1,2-dichiorobenzene and then heated to 145ºC. 13.47g(96.54 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature, cooled to room temperature and poured onto 250g of ice*water with stirring. 30ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 1.2 with sodium hydroxide and then extracted three times, each time with 250ml of ethyl acetate. The extracts were combined, washed with 40ml of saturated saline, dehydrated with anhydrous magnesium suifate and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 2.90g of the title compound.
Yield : 65.39%
b.p. : 79-80ºC/0.5torr
NMR(CDCI3. ppm) : 1.59(d, 3H), 2,14(s, 1H), 2.76-3.02(m, 2H),
3.10-3.22(m, IH), 3.34-3.45(m, IH), 4.22(q,
IH), 7.l8-7.31(m, 4H)

200g(647.17 mmole) of N-(2-bromoethyl)-a -methylbenzylamine hydrobroroide produced in Example 5(2) or Example 6(1) above was suspended in 700ml of decalin and then heated to ISOTC. 261.5g(1961 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for s further 30 minutes at constant temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 3500g of ice -water with stirring. 210ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 2500ml 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 3000ml of ethyl acetate. The extracts were combined, washed with 550ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 78.9g of the title compound.
Yield : 82.8%
b.p. • 79-80r/0.5torr
NMRCCDCI. ppm) : 1.59(d, 3H), 2.l4(s, W). 2.76-3.02(m, 2H),
3.10-3.22(m, 1H), 3.34-3.45 1H), 7.l8-7.31(m, 4H)
8 :
(1) Preparation of (R)-{+)-N-(2-hydroxyethyl)-a-metfiylbenzylamine:
51.45g(0.43 mmole) of (R)-(+)- a -methylbenzylamine was dissolved in 52ml, of dichloromethane and 63.78g(0.51 mmole) of 2-bromo-ethanol was added thereto. This mixture was stirred at 51ºC1 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 54g of the title compound having pale yellow color.

Yield : 76% m.p. : 60ºC/0.5torr [a]p20: +55' (c=l, in CHCl3)
NMR(CDC13, ppm) : 1.38(d, 3H), 2.40(bs, 1H), 2.61(m, 2H), 3.58(m, 2H), 3.78(q, 1H), 7.18-7.38(m, 5H)
(2) Preparation of (R)-(+)-N-(2-bromoethyl)- a-methylbenzylaminc hyd-robromide:
11..0g(66.58 mmole) of (R)-(+)-N-(2-h1ydroxyethyl)-a-methylben-zylumine produced in Example 8(1) above was suspended in 52ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at I26ºC for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature and 47ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 55ml of acetone, and 50ml of ethyl acetate and 70ml of ether were added thereto. The reaction solution was stirred for 30 minutes, cooled to 0ºC and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 30ml of ethyl acetate and then dried to obtain l0g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 60ml! of ethanol and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in 50ml of acetone, diluted with 70ml of ether and then allowed to stand at 0ºC fur 12 hours. The resulting solid product was filtered, collected and washed with 30ml. of ethyl acetate to obtain 3.1g of the second crop of the title compound.
Yield : 64%
m.p. : 186-187ºC
[a]o20 : +32.1' (c=l, in CHCI3)
NMR(CDCb, ppm) : 1.94(d, 3H), 3.2l(m, 2H), 3.82 1H), 7.40-7.72(m, 5H), 9.51(bs, 1H), 9.91(bs,
1H)
(3) Preparation of (R)-(+)-l-methyl-l,2,3,4-tetrahydroisoquinoline

5.0g(16,18 mmole) of (R)-(+)-N-(2-bromoethyl)-a-methylbcnzyl-amine bydrobromide produced in the above (2) was suspended in 50ml of decalin and the resulting suspension was heated to 140ºC. 6.4702 (48.54 mmolc) of anhydrous aluminum chloride (AlCl3 was added thereto over 40 minur.es. The reaction solution was stirred for further 30 minutes at constant temperature, and cooled to room temperature. The supernatant was removed and the lower layer was added to 70g of ice-water with stirring. 20ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 100ml 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 250ml of ethyl acetate. The extracts were combined, washed with 40ml A of saturated saline, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 1.70g of the title compound.
Yield : 71.4%
b.p. : 79-80ºC/0.5tor
[a]D20 : +85.5' (c=l. in CHCI3)
NMR(CDCl3, ppm) : 1.59(d, 3H), 2.14(s, 1H). 2.76-3.02(m. 2H),
3.10-3.22(n, 1H), 3.34-3.45(m. 1H), 4.22(
1H), 7.18~7.31(m, 4H)
Example:(R)-(+)-1-methvl-l.2.3,4-terabydroisoouiooline
(1) Preparation of (R)-(+)-N-(2-broraoethyl)-a -methylbenzylamine hyd-robromide:
76.61g(630 mmole) of (R)-(+) a -methylbenzylamine was dissolved in 77ml of dichloromethane and 94,8g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51 ºC for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4ml(2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and then allowed to react at 126ºC for 30

minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350ml of isopropyi alcohol with refluxing for 30 minutes, and this solution was cooled to 10ºC and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50ml of ethyl acetate, and then dried to obtain 127-5g of the title compound.
Yield : 65.596
m.p. : 186-187ºC
[]o20 : +32. 1' (c=l, in CHCI3)
NMR(CDC13, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q,
IH), 7.40-7.72(m, 5H), 9.51(bs, 1H), 9.9l(bs,
1H)
(2) Preparation of (R)-(+)-l-methyl-lt2,3,4-tetrahydrotsoquinoline
10.0g(30.1 mmole) of (R)-(+)-N-(2-bromoethyl)-a-methylbenzyl-amine hydrobromide produced in Example 9(1) above was suspended in 60ml of 1,2-dichJorobenzene and then heated to 145ºC. 13.47g(96.54 mmole) of anhydrous aluminum chloride (AlCI3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at same temperature, cooled to room temperature and poured onto 250g of ice-water with seining. 30mL of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130ml of dichioromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250ml of ethyl acetate. The extracts were combined, washed with 40ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetace. The residue was distilled to obtain 3.06g of the title compound.
Yield : 69%

b.p. : 79-80ºC/0.5torr
[a] : +85.5' (c=l. in CHCI3)
NMR(CDCI3, ppm) : 1.59(d, 3H), 2.14(s, 1H), 2.76-3.02(m, 2H),
3.10-3.22 1H), 7.18-7.31(m, 4H)
Example 10 : 73.45g(240 mmole) of (R)-(+)-N-(2-bromoethyl)-a-methylbenzyl-arnine hydrobromide produced in Example 9(1) above was suspended in 260mlof decalin and the resulting suspension was heated to 150ºC. 95.1.0g(7lO mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at same temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 1600g of ice-water with stirring. 70ml of con. hydrochloric acid was added thereto and the resulting mixture was stirred for 10 minutes. This solution was washed three times, each time with 700mlof ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and extracted three times, each time with 900ml of ethyl acetate. The extracts were combined, washed with 200ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 28.2g of the title compound.
Yield : 79.7%
b.p. : 79-80'C/0.5torr
Ub20 : *85.5* (c=l, in CHCb)
NMR(CDCln, ppm) : 1.59(d, 3H), 2.14(s, 1H), 2.76-3.02(m, 2H),
3.10-3.22(m, 1H), 3.34-3.45(m, 1H), 4.22(q,
1H), 7.l8-7.31(m, 4H)
Example 11 : (S)-( -)l-methvl-1,2,3,4-tetrahvdroisoquinonline
(1) Preparation of (S)-(-)-N-(2-hydroxyethyl)-a-methylhenzylamine:

108.23g(0.903 mmole) of (S)-(-α -methylbenzylamine was dissolved in 140ml of dichloromethane and 144.0g( 1.071 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51ºC 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 117.4g of the title compound, which had a pale yellow color.
Yield : 78.7% m.p. : 60ºC/0.5torr [a]D20 : -55' (c =1, inCHCl3)
NMRtCDCl:,, ppm) : 1.38(d, 3H), 2.40(bs, 1H), 2.61(m, 2H), 3.58(m. 2H), 3.78(q, 1H), 7.18-7.38(m, 5H)
(2) Preparation of (S)-(-)-N-(2-bromoethyl)-α-methylbenzylamine hyd-robromide:
22.1g( 133.16 mmole) of (S-)-N-(2-hydroxyechyl)- α -methyl-bezylamtne produced in Example 11(1) above was suspended in 105ml of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 1.26ºC for 30 minutes under refluxing. Then, the reaction solution was distilled for 2 hours under normal pressure at constant. temperature and 95ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 112ml of acetone, and I00ml of ethyl acetate and 150ml 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 70ml of ethyl acetate and then dried to obtain 20g of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 130ml of ethanol and then concentrated under reduced pressure. The residue was dissolved in 104 me of acetone, diluted with 143ml of ether, and then allowed to stand at 0 "C for 12 hours. The resulting solid product was filtered, collected and washed with 75ml of ethyl acetate to obtain 6.7g of the second crop of the title compound.

Yield :- 64.8%
m.p. : 186-187ºC
[a D20: -32.1 (c-1, in CHCb)
NMR(CDC13, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q,
1H), 7.40-7.72(m, SH), 9.51(bs, 1H), 9.9l(bs,
1H)
(3) Preparation of (S)-(-)-l-methyl-l,2,3,4-tetrahydroisoquinonline
5.0g(16.l8 mmole) of (S)-(-)-N-(2-bromoethyl)-a -methylbenzyl-amine hydrobromide produced in Example (2) above was suspended in 50 ml of decalin and then heated to 140ºC. 6.47g(48.54 mmole) of anhydrous aluminum chloride (AlCI3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, and cooled to room temperature. The supernatant was removed and the lower layer was added to 70g of ice-water with stirring. 20ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 100m! of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250ml of ethyl acetate. The extracts were combined, washed with 40ml. of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 1.75g of the title compound.
Yield : 73.5%
b.p. : 79-80ºC/0.5torr
[αlD20 : -85.5' (c=l, inCHCl3)
NMR(CDCI3, ppm) : 1.59(d, 3H), 2.14(s, IH), 2.76-3.02(m, 2H).
3.10-3.22(m, IH), 3.34-3.45(m, IH), 4.22(q,
IH), 7.18-7.31 Example 12 : (S)(--l-methyl-1,2,3,4-tetrahydroisoquioonline
(1) Preparation of (S)-(-)-N-(2-bromoethyl)- a -methylbenzylamine hyd-

robromide:
176.20g(1449 mmole) of (S)-(-)- α-methylbenzylamine was dissolved in185ml of dichloromethane and 218.04g1748 mmole) of 2-bromocthanol was added thereto. This mixture was stirred at 51ºC for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 658ml(5750 mmole) of 48% aqueous hydrobrotmic acid solution was added thereto and the solution thereby obtained was allowed to react at 126ºC for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature to remove 580ml of water as the by-product and aqueous hydrobromic acid solution. The residue was dissolved in 760ml. of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10ºC and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 150ml of ethyl acetate and then dried to obtain 306.5g of the title ompound.
Yield : 68.4%
m.p. : 185ºC
[α20] : -32. 1' (c-1, inCHCI3)
NMR(CCDCI3, ppm) : 1.94(d, 3H), 3.2l(m, 2H), 3.82(m, 2H), 4.42(q,
1H), 7.40-7.72(m, 5H), 9.51(bs, 1H), 9.91(bs,
1H)
(2) Preparation of (S)-(-)-l-methyl-l,2,3,4-tetrahydroisoquinoline
10,0g(30.1 mmole) of (S)-(-)-N-(2-bromoethyl)-a-rnethylbenzyl-amine hydrobromide produced in Example 12(1) above was suspended in 60ml of 1,2-dihlorobenzene and then heated to 145ºC. 13-47g(96.54 mmole) of anhydrous aluminum chloride (AlCI3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, cooled to room temperature and poured onto 250g of ice-water with stirring. 30ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium

hydroxide, and then extracted three times, each time with 250ml of ethyl acetate. The extracts were combined, washed with 40mlof saturated saline, dehydrated with anhydrous magnesium sulfate. and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.10g of the title compound.
Yield : 69.96%
b.p. : 79-80ºC:/0.5torr[ab20 : -85.5" (c, in CHCI3)
NMR(CDCI3, ppm) : 1.59(d, 3H), 2.14(s, 1H), 2.76-3.02(m, 2H),
3.10-3.22(m, 1H), 3.34-3.45(m, 1H), 4.22(q,
1H), 7.18-7.31(m, 4H)
Example 13: (S)-(-)-l-l-methvl-1.2.3.4-tetrahvdrisqquinonline
73.45g(240 mmole) of (S)-(-)-N-(2-bromoethyl)- a-methylbenzyl -amine hydrobromide produced in Example 12(1) above was suspended in 260ml! of decalin and the resulting suspension was heated to 150ºC. 05.10g(7lO mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 1600g of ice-water with stirring. 70ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 700ml! 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 900ml! of ethyl acetate. The extracts were combined, washed with 200ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 27.6g of the title compound.
Yield : 78.1%
b.p. : 79-80ºC/0,5torr
[α]D20 : -85.5' (c-1. in CHCI3)

NMR(CDCI3. ppm) : l.59(d, 3H), 2.14(s, 1H), 2.76-3.02(m. 2H),
3.lO-3.22(m, 1H), 3.34-3.45(m, 1H), 4.22(q, 1H), 7.18-7.31(rn, 4H)
Preparation of 5.6-dimethyl -2-(4-Ouoronhenylamino)-4-(1-methyl-l,2,3,4-tetrahydroisouolinn--2-yl)pvrimidine and its hydrochloridg
In Examples 14 to 20, inclusive, l-methyl-l,2,3,4-tetrahydroiso-quinoline prepared according to the method disclosed in International Publication No. WO 94/14795 was used as the reactant.
Exarnple 14:
2.65g(27 mmole) of potassium acetate and 4.0g(26.9 mmole) of l-methyl-l,2,3,4-tetrahydroisoquinoline were added to 85mi of n-hexanol and then warmed to 80ºC. 6.17g(24.5 mmole) of 4-chloro-2-(4-fluoro-phenylanuno)-5,6-dimethylpyrinudine was added thereto and then reacted a1 140'C for 28 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluo-rophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrim dinc.
The reaction solution was cooled to room temperature, diluted with 20ml of acetone and then added dropwise to 120ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 30ml of water, dissolved in 150ml of dichloromethanc and then washed successively with 20ml of 4N-HC1, 20ml of water and then 20ml of 4N-sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with100ml of ethanol. To this reaction solution was added 30g of cone, hydrochloric acid, and die mixture thereby obtained was stirred for 5 hours. The resulting solid product was filtered, washed with 20ml of ethanol and then dried to obtain 6.1g of purified 5,6-dimethyl-2-(4-nuorophenylamino)-4-(l-methyl-1,2,3,4-tetrahydroisoquinou'n-2-yl)pyrimidine hydrochloride.
Yield : 62.4%

m.p. : 255r
NMR(CDCI3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.l2(m, 1H). 3.61(m, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H), 7.6(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H)
Example 15:
8.12g( 11.2ml, 80.3 mmole) of triethylamine, 30ml. of n-butanol and 6.58g(44.1 mmole) of l-methyl-l,2,3,4-tetrahydroisoquinoline were added to 40ml of ethylene glycol. 10.1g(40.1 mmole) of 4-ehloro-2-(4-fluoro-phenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130ºC For 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-Methyl-l,2,3)4-tetrahydroisoquinolin-2-yl)-pyri-midine. This product was treated according to the procedure detailed in Example 14 u> obtain 14.7g of purified 5,6-dimethyl-2-(4-fluorophenyl-arnino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydro-chloride.
Yield : 91%
m.p. : 256ºC
NMR(CDCl3 ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.61(m, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H). 7.61(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H)
Example 16:
45ml of triethylamine, 50ml of n-butanol and 32g(217 mmole) of l-methyl-l,2.3,4-tetrahydroisoqujnoline were added to 150ml of ethylene glycol. 51.3g(203.8 mmole) of 4-chloro-2-(4-fluorophenylanuno)-5,6-dimethylpyrimidine was added thereto and then reacted at 135'C for 28 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-( 1-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyriniidine. This product was created according to the procedure detailed in Example 14 to obtain
66a of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyhl,2, 3,4-tetrahydroiso-c|uinolin-2-yl)pyrimidine hydrochloride.
Yield : 81.196
m.p. : 256"C
NMR(CDCI3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.6Km, 2H), 4.23(m. 1H), 5.38(q, 1H), 7.25(m, 6H), 7.6l(m, 2H), 10.33 (s, 1H). I3.43(bs, 1H)
Example 17:
75ml of triethylamine and 65g(442 mrnole) of 1 -methyl-1,2,3,4-tetrahydroisoquinoline were added to 100ml of 1,2-propylene glycol. 100.9g(0.40 mmole) of 4-chloro-2-(4-fluornphcnylamino)-5,6-dime-ihylpyrimidine was added thereto and then reacted at 120t) for 64 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinc. This product was treated according to the procedure detailed in Example 14 to obtain 9lg of purified 5.6-dimethyl-2-(4-fluorophenylamino)-4-( 1 -methyl-1,2,3,1-teLrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 57.1%
m.p. : 258ºC
NMR(CDCI3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.6l(m. 2H), 4.23(m, 1H), 5.38(q, 1H), 7.2S(m, 6H), 7.61(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H)
Example 18:
720ml of triethylamine and 695g(4.72 mmole) of 1-methyl-1,2,3,4-letraliydroisoniunoline were added to 2100ml of l,2-propy!ene glycol. 1179«(4.68 mmole) of 4-chloro-2-(4-fluorophcnylamino)-5,6-dimethyl-pyrimidine was added thereto and the mixture thereby obtained was
reacted at 130ºC for 58 hours to prepare 5,6-dimethyl-2-(4-f1uoropheny1-ainino)-4-(l-methyl-lr213,4-tetrahydroisoquinolin-2-y!)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 1250g of purified 5,6-dimethyl-2-(4-fIuornphenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield = 66.9%
m.p. : 258 1
NMR(CDCI3. ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
1H), 3.12(m, 1H), 3.61(m, 2H), 4.23(m. 1H), 5.38(q, IH), 7.25(m, 6H), 7.6l(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
110ml of n-butanol, 240ml of triethylamine and 236g(1.60 mmole) of 1-methyl- 1,2,3,4- wtrahydroisoquinoline were added to 600mlof ethylene glycol. 400g(1.59 mmole) of 4-ch1oro-2-(4-fluorophenyl-arnino)-5,6-dimethylpyrimidine was added thereto and then reacted at 140 ºC. for 48 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-( I -methyl- l,2,3,4-(.etrahydroisoquinoUn-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 485g of purified 5,6-dirnethyl-2-(4-fluorophenylamino)-4-(l-rnethyl-1, 2,3,4- tetrahydroisoqtiinolin-2-yl)pyrimidine hydrochloride.
Yield : 76.5%
m.p. : 257ºC
NMR(CDCI3. ppm) : 1.58(d, 3H), 2.21(s, 3H>, 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61 (m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m. 6H), 7.61(m, 2H), 10.33 (s, IH), I3.43(bs, IH)
Example 20
240ml! of triethylamine and 9.7g(65-8 mmole) of l-methyl- 1,2.3,4-

tetrahydroisoquinnline were added to 25ml of 1,2-propylene glycol. Then, 15g(51 mmole) of 4-bromo-2-(4-fluorophenylamino)-5,6- dimethyl-pyrimidine was added thereto and the mixture thereby obtained was reacted at 110ºC for 28 hours. The resulting product was treated according to the procedure detailed in Example 14 to obtain 15.86g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetra-hydroisoquinolin-yl)pyrimidine hydrochloride.
Yield : 78%
m.p. : 257ºC
NMRfCDCI3, ppm) : 1.58(d, 3H), 2.21(s, 311), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.61(m, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H), 7.61(m, 2H), 10.33 Example 21
8.12g(11.2ml, 80.3 mmole) of triethylamine, 30ml of n-butanol and 6.58g(44.1 mmole) of l-methyl-1.2,3,4-tetrahydroisoquinoline as prepared in Example 5 were added to 40ml of ethylene glycol. 10.1g(40.1 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130ºC for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetra-hydroisoquinolin-2-yl)pyrimidine.
The reaction solution was cooled to room temperature, diluted with 30ml of acetone and then added dropwise to 200ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60ml of water, dissolved in 250ml of dichloromethane and washed successively first with 35ml of 4N-HCI, 35ml of water and then with 40ml of 4N-sodium hydroxide soludon. The dichloromechane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 200ml of ethanol. To this reaction solution was added 45g of concentrated hydrochloric acid, and the mixture was stirred for 5 hours. The resulting solid product was

filtered, washed with 30mlof ethanol and then dried to obtain 9.82g of purified S,6-dimethyl-2-(4-fluorophenylamino)-4-(l-mechy]-l,2,3,4-tetra-hydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 66.53%
m.p. = 2551
NMR(CDCl3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.6l(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Example 22
75ml of triethylanine and 65g(442 mmole) of l-methyl-1,2,3,4-tetrahydroisoquinnline as prepared in Example 7 were added to 100ml of 1,2-propylene glycol. 100.9g(0.40 mmole) of 4-chloro-2-(4-fluto-phenylamio)-5,6-dimethylpyrinmdine was added thereto and then reacted nt 120ºC for 64 hours to prepare 5,6-dimethy!-2-(4-fIuorophenylamino)-4-( l-methyl-1.2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated accurding to the procedure detailed in Example 21 to obtain 95. Ig of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-meihyl-].2,3,4-tetiahydroisociuinolin-2-yl)pyriinidine hydrochloride.
Yield : 59.67%
m.p : 258 ºC
NMR(CDCl3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, IH), 3.l2(m, IH), 3.6l(m. 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m. 6H), 7.61(m, 2H), 10.33 (s, IH), I3.43(bs. IH)
Example 23
I4ml of triethylamine and 9.7g(65.8 mmole) of l-methyl-1,2,3,4-tetraliydrasoquinoline as prepared in Example 7 were added to 25ml of 1,2-propytne glycol. 15g(51 mmole) of 4-hromo-2-(4-fluorophenyl-
amino)-5,6-dimethylpyrimidine was added thereto arid then reacted at 120 *C for 28 hours to prepare 5,6-diethyl-2-(4-fluorophenylanuno)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 21 to obtain 14.9g of purified 5,6-dimethyl 2-{4-fluorophenylamino)-4-(l-methyl-l,2,3,4-ietrahydroisoquinolin-2-yl)pyrunidine hydrochloride-
Yield : 73.28%
m.p. : 257 ºC
NMR(CDCl3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.l2(m, 1H), 3.61(m, 2H), 4.23(m, 1H), 5.38(q, 1H>, 7.25(m, 6H). 7.61(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H)

8.l2g(11.2ml 80.3 mmole) of triethylamine, 30ml of n-butanol and f».58g(44.1 mmole) of (R)-(+)l-methyl-l,2,3,4-tetrahydroisoquinoline as prepared in Example 9 were added to 40ml of ethylene glycol. 10.1g (40.1 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130 ºC for 30 hours under rettuxing to prepare 5/>-dimethyl-2-(4-fluorophenylam(no)-4-( 1-methyl- 1,2,3, -t-tetrahydroisoquinolin-2-yl)pyriroidine.
The reaction solution was cooled to room temperature, diluted with 30m? of acetone and then added dropwise to 200 raC of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60ml of water, dissolved in 250nrf of dichloromethane and then washed successively with 3S»( of 4N-HC1, 35mJ of water and then 40mf. of 4N- sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfatc, concentrated under reduced pressure, and then diluted with 200ml of ethanol. To this reaction solution was added 45g of cone, hydrochloric acid, and the resulting mixture was stirred for 5 hours. The. resulting solid product was filtered, washed with 30ml of ethanol and then dried to obtain

9.21g of purified (R)-(+)-5,6-dimethyl-2-(4-f!uorophenylarnino)-4-O-methyl- l,2,3,4-tetraliydroisoquinolin-2-yI)pyrimidine hydrochloride.
Yield : 62.4%
m.p. : 255 ºC
[a]D20 : +250º (c=1, in CHCI3)
NMR(CDCI3, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), 3.61(m, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H, 7.61(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H)
Example 25
23ml of triethylamine and 16g( 108.5 mmole) of (R)-(+-)-l-melhyl-1,2,3,4- tetrahydroisoquinoline as prepared in Example 10 were added to 75ml of ethylene glycol. 25.7g(101.8 mmole) of 4-chloro-2-(4-fluoni-pheny]amJno)-5,6-dimethylpyrimidlne was added thereto and the mixture thereby obtained was reacted at 135ºC for 28 hours under reflu.ving to prepare (R)-( + )-5,6-dimethyl-2-(4-fJuorophenylamino)-4-(l -methyl- 1,2,3, 4-ielrahydroisonu«nolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 24 to obtain 33g of purified 5,6-dimet.hyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tctra-hydroisoquinolin-2-yl)-pyrimidine hydrochloride.
Yield : 81.196
m.p. : 257 "C
[a]D20 : ^250' (c=l, in CHCW
NMR(CDC!:«, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m. 1H), 3.12(m, 1H), 3-6Um, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H), 7.61(m, 2H). 10-33 (s, 1H), 13.43(bs, 1H)

14m« of triethylamine and 9.7g(65.8 mmole) of (R)-
1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to 25ml of 1,2-propylene glycol. 15g(51 ramole) of 4-bromo-2-(4-fIuoro-phenylarnino)-5,6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 120TC for 28 hours. The reaction product was thencreated according to the procedure detailed in Example 24 to obtain I6.2g of purified 5,6-dimethyl-2-(4-fluoropheny!amino)-4-( l-methyl-l,2,3,4-tetrahydroisoquinoh'n-2-yl)pyrimidine hydrochloride.
Yield : 79.97% m.p. : 257 'C
[oh20: +250' T (c=l, inCHCI3)
NMR(CDCI3i, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m. 1H), 3.X2(m, 1H), 3.61(m, 2H). 4.23(m, 1H), 5.38(q, , 1H), 7.25(m, 6H), 7.61(m. 2H), 10.33(s, IH), I3.43(bs, IH)
Example 27
8.l2g(11.2ml, 80.3 mmole) of triethylamine, 30ml of n-butanol and 6.58g(44.1 mmole) of (S)-(-)-l-methyl-l,2,3,4-tetrahydroisoquinolme as prepared in Example 13 were added to 40me of ethylene glycol. 10. lg (40.1 mmole) of 4-chloro-2-(4-fluorophenylanunoH5,6-dimethylpyrimidinfe was added thereto and then reacted at 130 T: for 30 hours under refluxing to prepare (S)-(-)-5I6-dimethy|-2-(4-fluoropheny!amino)-4-(l-ethyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine.
The reaction solution was cooled to room temperature, diluted with
30mlof acetone and then added dropwise to 200ml of water with stirring.
After it had been stirred for 2 hours, the resulting solid product was
filtered, washed with 60ml of water, dissolved in 250m( of dichloromethane
and washed successively with 35ml of 4N-HCI, 35ml1 of water and 40mc of
4N-sodium hydroxide solution. The dichloromethane layer was
dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 200ml of ethanol. To this reaction solution was added 45g of cone, hydrochloric acid, and the

mixture was stirred for 5 hours. The resulting solid product was filtered, washed* with 30ml of ethanol and then dried to obtain 8.95g of purified (S)-(-)-5,6-dunfithyl-2-(4-fluorophenylamino)-4-(l-methyl-i,2,3,4-tetrahydro)soquinolin-2-yl)pyrimidine hydrochJoride.
Yield : 60.6%
m.p. : 255 C
[a Jo* : -250' (c=l, in CHC13)
NMR(CDCl.-i, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, 1H), 3.12(m, 1H), S.GKm, 2H), 4.23(m. 1H), 5.38(q, 1H), 7.2S(m, 6H). 7.61(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H)
Example 28
of trie thy lamine and 9.7g(65.8 mmolc) of (SH-)-l-methyl-1.2,3,4-tetrahydroistMiuinoline as prepared in Example 13 were added to 25ml! of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(l-fluoro-phenyIarnino)-5,6-dirnethylpyrimidine was added thereto and then reacted at ll0ºC: for 38 hours. The reaction product was treated according to the procedure detailed in Example 27 to obtain 15.86gof purified
5.6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroiso-c|uinolin-2-yl)pyrirrudine hydrochloride.
Yield : 78%
m.p. : 257 C
[a ]Do20 : -250' (c-1, in CHCI3)
NMR(CDCl:t, ppm) : 1.58(d, 3H), 2.2l(s, 3H), 2.38(s, 3H), 2.84(m. IH), 3.l2(m, 1H), 3.6 Km, 2H), 4.23(m, 1H), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 1033 (s, IH), 13.43(bs, IH)

We claims:-
1. A process for preparing a 4-halogeno-2-(4-fluorophenyl-amino)-5, 6-dimethylpyrimidine represented by the following formula, (I)
(Formula Removed)
in which Hall represents a halogen, characterized in that 4-fluorophenyl-guanidine carbonate represented by the following formula (II) (Formula Removed)
is reacted with ethyl 2-methylacetoacetate represented by the following formula (III)(Formula Removed)
to prepare 4-hydroxy-2-(4-fluorophenylamino)5,6-dJmethylpyrimidine represented by the following formula (IV)(Formula Removed)
which is then reacted with a halogenating agent.

2. A pyrimidine derivative represented by the following formula (V)
(Formula Removed)

in which R represents hydroxy or a halogen.
A process for preparing a 4-halogeno-2-(4-fluorophenyl-amino)-5,6-dimethylpyrimidine substantially as herein described with the foregoing description and the accompanying examples. A pyrimidine derivative substantially as herein described with the foregoing description and the accompanying examples.

Documents:

996-del-2000-(granted specification).pdf

996-del-2000-abstract.pdf

996-del-2000-assignment.pdf

996-del-2000-claims.pdf

996-DEL-2000-Correspondence Others-(01-06-2011).pdf

996-DEL-2000-Correspondence Others-(12-05-2011).pdf

996-del-2000-Correspondence Others-(13-09-2011).pdf

996-del-2000-correspondence others.pdf

996-del-2000-correspondence-po.pdf

996-del-2000-description(complete).pdf

996-del-2000-form-1.pdf

996-DEL-2000-Form-16-(12-05-2011).pdf

996-del-2000-form-19.pdf

996-del-2000-form-2.pdf

996-del-2000-form-3.pdf

996-del-2000-form-5.pdf

996-del-2000-gpa.pdf

996-del-2000-petition-137.pdf

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Patent Number

212563

Indian Patent Application Number

996/DEL/2000

PG Journal Number

50/2007

Publication Date

14-Dec-2007

Grant Date

04-Dec-2007

Date of Filing

07-Nov-2000

Name of Patentee

YUHAN CORPORATION

Applicant Address

#49-6, TAEBANG-DONG, TONGJAK-KU, SEOUL, KOREA.

Inventors:

#	Inventor's Name	Inventor's Address
1	HONG YOU WHA	CHUKONG APT. #301-105, 78, SEUKSU-DONG, ANYANG-SI, KYONGGI-DO, KOREA.
2	LEE YOUNG NAM	JEONGOUN VILLA #6-102, 781-23, CHOWON-DONG, CHANGAN-KU, SUWON-SI, KYONGGI-DO, KOREA.
3	KIM HONG BAE	#964-5, HOGAE-1-DONG, ANYANG-SI, KYONGGI-DO, KOREA.

PCT International Classification Number

C07D 401/04

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	96-14538	1996-05-04	Republic of Korea
2	96-14539	1996-05-04	Republic of Korea