Title of Invention	"PROCESS FOR PREPARATION OF PYRIMIDINE DERIVATIVES"
Abstract	A process for preparing 5,6-dimethyl-2-(4-fluoro- phanyl-amino)-4-(1- methyl-1,2 ,3,4-tetrdhydroisoqui- nolin-.?-yl) pyri rnidine represented by the follow- in,} formula (I), and its acid addition salts, wherein a pyrimidine derivative repr-. ssnted by the following formula (II-A), in which Hal representes a halogen, is reacted with 1-rnethyl-1 ,2, 3 ,4-tetrahydroisoquinolins represented by the following formula (III), optionally in the presence of a solvent and optionally in the presen- ce of the base as herein described.

Title of Invention

"PROCESS FOR PREPARATION OF PYRIMIDINE DERIVATIVES"

Abstract

A process for preparing 5,6-dimethyl-2-(4-fluoro- phanyl-amino)-4-(1- methyl-1,2 ,3,4-tetrdhydroisoqui- nolin-.?-yl) pyri rnidine represented by the follow- in,} formula (I), and its acid addition salts, wherein a pyrimidine derivative repr-. ssnted by the following formula (II-A), in which Hal representes a halogen, is reacted with 1-rnethyl-1 ,2, 3 ,4-tetrahydroisoquinolins represented by the following formula (III), optionally in the presence of a solvent and optionally in the presen- ce of the base as herein described.

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-n,uinolin-2-yl)pyrimidine represented by the following formula (I) and its acid addition salts; second, to a process for preparation of an intermediate for preparing the compound (I); and, third, to a novel intermediace compound- More specifically, the present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-nuorophenylamino)-4-(l-mechyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by the following formula (I), (Formula Removed) and its acid addition salts, wherein a pyrimidine derivative represented by the following formula (D-A), (Formula Removed) in which Hal represents a halogen, is reacted with l-methyl-1,2,3,-1-tetrahydroisoquinoline represented by the following formula (El); (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). BACKGROUND ART 5,6-Dimethyl-2-(4-fluorophenylarrano)-4-(l-methyl-l,2,3,4-tetra-hydroisoo.uinolin-2-yl)pyrimidine of the above formula (I) inhibits gastric acid secretion by means of a reversible proton-pump inhibiting effect and. therefore, can be used as an anti-ulcer agent. This compound was developed by the inventors of the present invention, who then applied for patents for the compound and/or its method of preparation in Korea and other countries (see International Publication No. WO 96/05177). According to the method disclosed in the above patent application, 5,G-dimethyl-2-(4-fluorophenyIajnino)-4-(l-methyl-1,2,3,4- tetrahydroisoq uinolin-2-yl)pyrimid.ine is prepared according to the following reaction scheme A- Reaction scheme A (Scheme Removed) Since the starting material of the above reaction scheme has two reactive sites (i.e., the two Cl atoms), the first reaction inevitably produces a side product, which reduces the yield of the desired compound. The present inventors have long labored to develop a novel method for preparing 5,6-dimethyl'2-(4-fIuorophenylainino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinoUn-2-yl)pynmidine of formula (I) without producing side products. As a result, we have discovered that the desired compound of formula (I) can be efficiently prepared without side products by reacting the pyrimidine derivative represented by formula (11^ A) with l-methyl-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-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-1,2,3.4- tetrahydroiso-ciuinolin-2-yl)pyrimidine represented by formula (I) and its acid addition 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-tetrahydroisoquinolin-2-yl)pyrimidlne represented by formula (I), (Formula Removed) and its acid addition salts wherein a pyrimidine derivative represented by the following formula (n-A), (Formula Removed) in which Hal represents a halogen, is reacted with l-methyl-1,2,3,4-tetrahydroisoquinoline represented by formula (III), (Formula Removed) In addition, the present invention relates to a process for preparation of the pyrimidine derivative of formula (II-A) and the compound of formula (HI). Further, the present invention relates to a novel intermediate compound represented by the following formula (II), which includes the pyrimidine derivative represented by formula (II-A), (Formula Removed) in R represents hydroxy and a halogen. In accordance with the present invention there is also disclosed a process for preparing 5,6- dimethyl-2-(4-fluorophenyl-amJno)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine represented by the following formula (I), (Formula Removed) and its acid addition salts, wherein a pyrimidine derivative represented by the following formula (II-A), (Formula Removed) in which Hal representes a halogen, is reacted with 1 -methyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula (III), optionally in the presence of a solvent and optionally in the presence of the base as herein described. (Formula Removed) Although the 4-halogeno-2-(4-fluorophenylamino)-5,6-dimethyl-pyrimidine represented by formula (DhA) can be reacted according to the present invention with an equivalent amount of l-methyl-1,2,3,4-tetra-hydroisoquinoline represented by formula (III), it is preferable to conduct lhe 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-1,2,3,4-tetrahydroisoquinoline can be readily removed after the reaction has gone to completion. The reaction of the present invention is preferably carried out in the presence of a solvent. Solvents which may be used for this purpose include N,N-dimethylformamide, n-butanol, n-pcntanol, n-hexanol, dimethylsulfoxide, ethylene glycol, 1,2-propylene glycol, and mixtures thereof. Of these propylene glycol and ethylene glycol are most preferred, since use of either of these minimizes both reaction time and production of side products. In the method of the present invention, the reaction scheme 1 is generally carried out in the presence of a base. Bases which can be used for this purpose include triethylamine, N,N-dimethylaniline, pyridine and potassium acetate. The reaction temperature for die reaction between the compound of formula (II-A) and 1-methyl-1,2,3,4-tetrahydroJsoquinoline of formula (in) is preferably in the range from 110 C to 160"C and the reaction time is preferably in the range from 16 hours to 72 hours. 5,6-Dimethyl-2-(4-fluorophenylanuno)-4-(l-methyl-l.,2,3,4-tetra-hydroisoquinolin-2-yl)pyrimidine of formula (I) as prepared according to die above method can be converted into its acid addition salt, preferably into the hydrochloride salt, by conventional medinds- 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 •iTonr denoted by in the formula immediately below), this compound be present in an (ll)-(-)-isomer, an (S)-(-)-isomer, or a racemate wherein the R and S isomers are mixed in the ratio of 1:1. . Unless indicated otherwise, the compound of formula (I) should be interpreted to include all of these isomers. (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: Reaction scheme (Scheme 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-fluorophenylarnino)-5,6-dimethyl-pyrimidine of formula UI-B), which may then be reacted with a haJogenating agent to obtain the 4-ha]ogeno-2-(4-fluorophenyljimin>-5,6-dimethylpyrimidine of fonnula (U-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 he prepared by reacting 4-fluoroaniline with a 50% cyanamide solution under acidic conditions using 30% to 37% hydrochloric acid while maintaining the temperature ranging from 751 to 95 "C. The first step of the reaction scheme 2 may be .practiced in the presence of a solvent. Solvents which may he used for this purpose include acetonitrile, N.N-dimethylformamide and dimethylsulfoxide. This /eaction is preferably carried out at a temperature-ranging—f-reffi 110^ to 160 °C. In the second step of the reaction scheme 2, 4-hydroxy-2-(4~ fluorophenylarnino)-5,6-dimethylpyrimidine 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 l^N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane and l,2-dichloroben2ene. It is preferable to maintain the reaction temperature in the range from 75°C to 951. Although the second step of the reaction scheme 2 can be practiced by isolating the intermediate after the first reaction step hns been completed, it is preferable to conduct the first and second steps in a single vessel. Specifically, 4-hydroxy-2-(4-fluorophenylamino)-5,6- dimelhylguanidine 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-phenylaniino)-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 be 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-Methy{-l,2,3,4-tetyahydroisoquinoline 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-methyI-l,2,3,4-tetrahydroisoquinoline is prepared by reacting (R)- or (S)-methylben2ylamine 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, respecti¬vely, 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 -(methylthin)-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 -methylbenzylamine 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-tetrahydroisoquinoline is explained in more detail below. According to the present invention, l-methyl-l,2,3,4-tetrahydro-isoquinoline of formula (DI) 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. (Scheme 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-bromoethann\| tn produce N-(2-hydroxyethyl)- a -mcthylbenxylamine, which in turn is reacted with the brominating agent to produce N-(2-bromoethyD- a-methylbenzylamine hydrobromide. In the third step, N-(2-bromoethyD- a -methylbenzylamine hydrobromide is reacted with a Lewis acid to produce the desired l-methyl-1,2,3,4-tetrahyd.rotso-quinoline of formula (III). Reaction solvents which can be used in the first step include acetonitrile, N,N-dimethylformamide. dichloromethane and 1,2-dichlorn-ethane and the reaction temperature is preferably maintained in the range from 4()"C to 60"C. Reaction solvents which can be used in the second step include 1,2-dichloroethane, acetic acid, water and 1,2-dichloro-benzene, and the reaction temperature is preferably maintained in the range from 110"C to 145"C. Brominating agents which can be used in this reaction include bromine, bromic aicd, aqueous bromic acid solution, and phosphorus trihromide. Although the first and second steps of the reaction scheme 3 can be practiced by isolating N-(2-hydroxyetIiy1)- a -methylbenzylamine produced as the intermediate after the first reaction step has been completed, it is preferable to conduct the first and second reaction steps without isolating the intermediate. Thus, the brominating agent is added to the vessel that contains the products of the first reaction step. Then, N-(2-bromoethyl)- a -methylbenzylamine produced in the second reaction step is cyclized by reaction with a Lewis acid to prepare the desired l-methyl-l,2,3,4-tetrahydroisoquinnline of formula (Til). Reaction solvents which can be used in this reaction include decalin, 1,2-dichloroethane and 1,2-dichlorobenzene and Lewis acids for this cyclization reaction include aluminum (III) chloride, zinc chloride and ferrous chloride. Since l-methyl-l,2,3,4-tetrahydroisoquinoline can be economically prepared according to the above method, the desired 5,6-dimethyl -2-(4-fluorophenylamino)-4-(l-methyl-l>2,3,4-tecrahydroisoquinolin-2-y]) -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 (U)-()- or (S)-(-)-isomer as the starting material for preparation of che compound of formula (I) according to the present invention, each isomeric form of the compound of formula (III) 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. Preparation • 4~fluoroohenyltni}inidjng 882g(747mt!) of 32% hydrochloric acid was added to 1000g(8.9 mole) of 4-fluoroaniline. the mixture was wanned to 87°C, and 780™! (9. 9 mole) of 50% cyanamide solution was addeddropwise thereto over"? hours. The reaction solution was adjusted to pH 2.4 by adding thereto I20m£ of 32% hydrochloric acid, stirred for 3 hours, and cooled to 60 'C. Aqueous sodium carbonate solution (NazCCh 578g/water 1640tnt!) 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 600m? of water and then with 2000m£ of ethyl acetate, and finally dried to obtain 1395g of the title compound, which had a light gray color. Yield : 81.4% m.p. NMR(DMSO-ds, ppm) : 5.50-6.88(bs, 5H), 6.87(m, 2H), 7.17 2H) j?x ample 1 : 4-hvdroxv-2-(4-fluoropfrenylamino)-5.6-diinethylDVri-midine 54.5g(253.2 mmole) of 4-fluorophenylguanidine carbonate produced id the Preparation above was suspended in SOiiiH of N,N-dimethylform-;unide and 37.8g(262.2 mmole) of ethyl 2-methylacetoacetate and the resulting suspension was refluxed at 140C for 3 hours. The reaction solution was diluted again with lOOnvE of N,N-dJmethylformamide and cooled to 80 'C, 160mi of isopropylalcohol was added thereto and the resulting mixture was stirred for 30 minutes. The resuking solid product was filtered, washed with 15Qm£ of acetone, and finally dried to obtain 41g of the title compound. Yield : 61.4% m.p. : 256C NMR(DMSO-d6, ppm) : 1.83(s, 3H), 2.19(s, 3H), 7.18(t, 2H), 7.68 (m, 2H), 9.36(bs, 1H), 10.63(bs, 1H) Kxamole 2 : 4-^lnro-2-(4-fluQrQDh^nv1nTninn)-5,fi-dimethylDVrimi-dine 40.5g( 174.1 mmole) of 2-(4-fluorophenyIamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in BQmi of N,N-dimethylformamide and the resulting suspension was heated to 80 'C. .'U.9g( 19.4ml, 210.1 mmole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 851!. 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 150m£ of 50% aqueous methanol solution and then dried to obtain 42. 3g of the title compound. Yield : 96.7% m.p. : 114'C NMR(CDCh, ppm) : 2.21(s, 3H), 2.41(s, 3H), 7.0l(t, 2H), 7.l8(bs, 1H), 7.56U, 2H) 3 : 4-cbloro-2-(4-fIuorophenylaminoJ-5.6-dImethyluvrimi-sline 1390g(7.6 mole) of 4-fluorophenylguanidine carbonate produced by the Preparation above was suspended in ISOOm'. of N,N-dimethylform-amide and I200g(8.4 mole) of ethyl 2-methylacetoacetate. The resulting suspension was heated under refluxing for one hour, distilled at normal pressure to llOOmii and then distilled until the temperature of the reaction solution reached 160 'C. 1600ml of N,N-dimethylformamide was added Lo the residue and then cooled to SQ°C. 1388g(840mt!, 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 and then diluted with 2000ml 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 1500mC. of 50% aqueous methanol solution and then dried. The dried, yellowish-brown powder thereby obtained was dissolved in 4000ml> of methanol under refluxing ana men cooieu iu j.uC. The resulting solid product was filtered and dried to obtain 1186g of the title compound. Yield : 62.4% m.p. : 1141C NMRfCDCb, ppm) : 2.21(s, 3H), 2.41(s, 3H), 7.0 Kt, 2H), 7.18(bs, 1H), 7.56(t, 2H) Kx ample 4 i 4-broino-2-(4~fluQrophenylamino)-5.6--diinethv!DVT-i-mjdine 5g(21.44 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6- dimethylpyrimidine produced in Example 1 was suspended in 4Qml of N,N-dimethylformamide and the resulting suspension was warmed to 65 T. 8.1g(30 mmole) of phosphorus tribromide was added dropwise thereto over 20 minutes and the resulting mixture was allowed to react at 75'C for 30 minutes. The reaction solution was cooled to room temperature, poured onto 50Qg of ice-water, adjusted to pH 11 with sodium hydroxide solution, stirred for 30 minutes and then adjusted again ro pH 5.5 with dilute hydrochloric acid. The resulting yellow solid product was washed with 100m£ of water and the dried to obtain 4.1g of the title compound. Yield : 64.58% m.p. : 123r NMRCCDCb ppm) : 2.21(s, 3H), 2.42(s, 3H), 6.98(t, 2H), 7.24U, 1H), 7.54(g, 2H) Fvamnle 5 : 1-methyl-1,2,3,4-tetrahydroisoquinolin^ (1) Preparation of N-(2-hydroxyethyl)- a-methylbenzylamine: 103.08g(0.86 mole) of a -methylbenzylamine was dissolved in 110 mi! of dichloromethane and I27.56g(1.02 mole) of 2-bromoethanol 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 I09g of the title compound, which had a pale yellow color. Yield : 76.7% m.p. : 60'C/0.5torr NMRCCDCla. 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 N-(2-bromoethyl)- a -methylbenzylamine hydrobromide: 100g(605.32 mmole) of N-(2-hydroxyethyU- 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 126°C for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 4(55mK of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 550m(! of acetone, and SOflmf! 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 400m£ 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 450m£ of acetone, diluted with 680m£ of ether and then allowed to stand at O'C for 12 hours. The resulting solid product was filtered, collected, and washed with 450m£ of ethyl acetate to obtain 32.5g of the second crop of the title compound. Yield : 69.23% m.p. : !86-187r NMRCCDCb, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q. 1H), 7.40-7.72(m, 5H), 9.51(bs, 1H), 9.91(bs, 1H) (3) Preparation of 1-methyl-1.2,3,4-tetrahydroisoquinoline 50.0gU61.8 mmole) of N-(2-bromoethyl)- a -methylbenzylamine hydrobromide produced in Example 5(2) above was suspended in 450raC of decalin and then heaced to 140 1). 64.70g(485.4 mmole) of anhydrous aJuminum chloride (A1CU) 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-water with stirring. 150m£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with lOOOmi 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 2lOOm£ of ethyl acetate. The extracts were combined, washed with 420m£ 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. Ig of the title compound. Yield : 75.99% b.p. : 79-80C/0.5torr NMR(CDCb. ppm) : 1.59(d, 3H), 2.14 3.10-3.22(m, 1H), 3.34-3.45(m. 1H), 4.22(q, 1H), 7.18-7.31(m, 4H) I'xamnlc 6 ? l~methyl*1.2.3.4-~tetr'ahvdroisoqiiinoling (1) Preparation of N-(2-bromoethyl)- a -methylbenzylamine hydrobromide- 76.61g(630 mmole) of a -methylbenzylamine was dissolved in of die hlorome thane and 94.8g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51 "C for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350m£ of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to lOt: and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 m(! of ethyl acetate and then dried to obtain 128.9g of the title ompound. Yield : 66.2% m.p. = 186-1871C NMR(CDCb, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q,1H), 7.40-7.72(m, 5H), 9.51(bs, IH). 9.91(bs, 1H) (2) Preparation of l-methyl-l,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 60m£ of l,2-dichloroben2ene and then heated to 145t. 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. 30m£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130m£ 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 250mt> of ethyl acetate. The extracts were combined, washed with 40mH of saturated saline, dehydrated with anhydrous magnesium sulfate 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. : 79-80t/0.5torr NMR(CDClj. 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 IH), 7.l8-7.31(m, 4H) 7 : 1-methyl-1.2.3.4-tetrahvdroisQqutnoUne 200g(647.17 mmole) of N-(2-bromoethyl)- a -methylbenzylamiTie hydrobromide produced in Example 5(2) or Example 6(1) above was suspended in IQOmi of decalin and then heated to 150 C. 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. 210m£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 2500mi 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 3000m?. of ethyl acetate. The extracts were combined, washed with 550m Yield : 82.8% b.p. : 79-80r/0.5torr NMR(CDCLi. ppm) : 1.59(d, 3H), 2.l4(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) 8 • (R)-(+)-l-methyl-lr2.3,4-fftrrahvdroisoquinoline (1) Preparation of (R)-(+)-N-(2-hydroxyethyl)-a -methylbenzylamine: 51.45g(0.43 mmole) of (R)-(+0- a -methylbenzylamine was dissolved in 52mf. of dichloromethane and 63.78g(0.51 mmole) of 2-bromo-ethanol was added thereto. This mixture was stirred at 51 'C for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 54g of the title compound having pale yellow color. m.p. : 60t:/0.5torr [ff]DM = 55* (c=l, in CHC13) NMR(CDCb. 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-bromoethyD- a-methylbenzylamine hyd-robromide: 11.0g(66.58 mmole) of (R)-(+)-N-(2-hydroxyethyl)- c-methylben-/ylamine produced in Example 8(1) above was suspended in 52x1 of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126"C for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature and 47m£ of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 55n)P. of acetone, and SOiif. of ethyl acetate and 7Qmi 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 30ml! of ethyl acetate and then dried to obtain lOg of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 6Qm(! of ethanol and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in 50:n? of acetone, diluted with 7Qxi of ether and then allowed to stand at O'C for 12 hours. The resulting solid product was filtered, collected and washed with 3QmH of ethyl acetate to obtain 3.1g of the second crop of the title compound. Yield : 64% m.p. : 186-187 "C U]o20 : "-32.11 (c=l, in CHCh) NMR(CDClj, ppm) : 1.94(d, 3H), 3.2Km, 2H), 3.82(m, 2H), 4.42( 1H), 7.40-7.72(m, 5H), 9.51(bs, 1H), 9.9l(bs, 1H) CU Preparation of (R)-(-O-l-methyl-l,2,3,4-tetrahydroisoquinoline 5.0g(16,18 mmole) of (R)-(t-)-N-(2-bromoethyl)- ff-methylbenzyl-amine hydrobromide produced in the above (2) was suspended in 50m(i of clecalin and the resulting suspension was heated to 140°C. 6.470g (48.54 mmole) of anhydrous aluminum chloride (AlCb) 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. 20mZ 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 resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250m£ of ethyl acetate. The extracts were combined, washed with 40m£ 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. : 79-80 t/0.5tor [a]D2u : +85.5- (c=l. in CHC13) NMR(CDC1:1, 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( 1H), 7.18-7.31(m, 4H) (1) Preparation of (R)-( + )-N-(2-bromoethyl)- a -methylbenzylanline hyd¬robromide: 76.61g(630 mmole) of (R)-(+)-a -methylbenzylamine was dissolved in 71mt of dichloromethane and 94.8g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51 'C for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 2afi.4mt!(2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and then allowed to react at 126 "C for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250ii£ of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350m£ of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10 T and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 5Q:n£ of ethyl acetate, and then dried to obtain 127.5g of the title compound. Yield : 65.5% m.p. : 186-187 "C [ff]D?0 : +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, 5H), 9.51(bs, 1H), 9.91(bs, 1H) (2) Preparation of (R)-(+)-l-methyl-l,2,3,4-tetrahydroisoquinoline 10.0g(30.1 iTunole) of (R)-(>)-N-(2-bromoethyl)- a -methylbenzyl-luiiine hydrobromide produced in Example 9(1) above was suspended in (jOmi! of 1,2-dichlurobenzene and then heated to 1451. 13.47g(96.54 rvunole) of anhydrous aluminum chloride (AlCb) 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 stirring. 30nvE of con. hydrochloric acid was added (•.hereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130m£ of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250m£ of ethyl acetate. The extracts were combined, washed with 40mli of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.06g of the title compound. Yield = 69% b.p. : 79-80°C/0.5torr UlD20 •• +85.5' (c=l, in CHCb) NMR(CDCb, 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 10 '• (Rl-(+)-\|-methyl-lr2.3.4-tetrahydroiso 73.45g(240 mmole) of (R)-(+)-N-(2-bromoethyl)- or-methylbenzyt-amine hydrobromide produced in Example 9(1) above was suspended in 260nu! of decalin and the resulting suspension was heated to 150'C. 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. 70m£ of con. hydrochloric acid was added thereto and the resulting mixture was stirred far 10 minutes. This solution was washed three times, each time with 700m?. of ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and extracted three times, each time with 900ni! of c:thyl acetate. The extracts were combined, washed with 200ni! 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 [a]D20 : +85.5' (c=l, in CHCh) NMR(CDCLi, 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) jfoample 11 : (S)--T-methyl~1.2.3.4-tetrahvdrolsQqiiinQline (1) Preparation of (S)-(-)-N-(2-hydroxyethyD- o-methylhenzylamine: 108.23g(0.903 mmole) of (S)-(-)- a -methylbenzylamine was dissolved in 140ms! of dichloromethane and 144.0g(1.071 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51 "C for 52 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 117.4g of the title compound, which had a pale yellow color. Yield : 78.7% m.p. : 60'C/0.5torr [alo° • -55' (c-1. in CHCh) NMR(CDCl:i. ppm) : 1.38(d, 3H), 2.40(bs, 1H), 2.61(m, 2H), 3.58(m. 2H), 3.78(q, 1H), 7.l8-7.38(m, 5H) (2) Preparation of (S)-(-)-N-(2-bromoethyD- a -methylbenzylamine hyd-robromide: 22,lg(l33.l6 mmole) of (S)-(-)-N-(2-hydroxyechyl)- a -mcthyl- bezylamine produced in Example 11(1) above was suspended in 105:nS of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126'C for 30 minutes under refluxing. Then, the reaction solution was distilled for 2 hours under normal pressure at constant temperature and 95aii of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 112:n£ of acetone, and I00m£ of ethyl acetate and 150mi! 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 70nv£ 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 130iiuJ of ethanol and then concentrated under reduced pressure. The residue was dissolved in 104 !'.i C for 12 hours. The resulting solid product was filtered, collected and washed with 75mii of ethyl acetate to obtain 6.7g of the second crop of the tide compound. Yield : 64.8% m.p. : 186-187t [ale20 : -32.1 (c-1, in CHCb) NMR(CDCl3, 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 (SM-)-l-methyl-l,2,3,4-tetrahydroisoquinoHne 5.0g(16.18 nunole) of (S)-(-)-N-(2-bromoethyl)- a -methylbenzyl- amine hydrobromide produced in Example (2) above was suspended in 50 m anhydrous aluminum chloride (AlCb) 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. 20 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with IQQini of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 :n£ of ethyl acetate. The extracts were combined, washed with 40raC. of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure tt; remove ethyl acetate. The residue was distilled to obtain 1.75g of the title compound. Yield : 73-5% b.p. : 79-80 C/0.5torr [fflo20 : -85.5' (c=l, in CHCb) NMRtCDCh, 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 1H), 7.18-7.31(m, 4H) 12 '• fSl-(->-l-methv1-1.2.3.4-tetTahvdroisoquinoline (1) Preparation of (S)-(-)-N-(2-bromoethyD- a -methylbenzylamine hyd robromide: 176.20g(1449 minole) of (S)-(-)- a -methylbenzylamine was dissolved in 185mf. of dtchloromethane and 218.04g( 1748 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51 C for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 658^2(5750 mmole) of 48% aqueous hydrobromic acid solution was added thereto and the solution thereby obtained was allowed to react at 126 °C for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature to remove 580ir.£ of water as the by-product and uqueous hydrobromic acid solution. The residue was dissolved in 760mC. of Jsopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10'C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 150;i\e of ethyl acetate and then dried to obtain 306.5g of the title ompound. Yield : 68.4% m.p. : 1851: ta]D20 : -32.11 (cl, in CHCh) NMRtCDCln, ppm) : 1.94(d, 3H), 3.2l(m, 2H), 3.82(m, 2H), 4.42( 1H), 7.40-7.72 1H) (2) Preparation of (S)~(-)-l-methyl-l,2,3,4-tetrahydroisoquinoline 10.0g(30.1 mmole) of (S)-(-)-N-(2-bromoethyD- or-methylbenzyl-amine hydrobromide produced in Example 12(1) above was suspended in fiOme of 1,2-dichlorobenzene and then heated to 145"C. 13.47g(96.54 mmole) of anhydrous aluminum chloride (AlCb) 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. 30m£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130mi of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and then extracted three times, each time with 250ni£ of ethyl acetate. The extracts were combined, washed with 40nrf of saturated saline, dehydrated with anhydrous' magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.lOg of the title compound. Yield : 69.96% b.p. : 79-80r/O.Storr [a]D2° : -85.5' (c-1, in CHCla) NMR(CDCb, 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) p.xample 13 : (S)-(-l-l-methyl-l,2t3t4-tetrahvdroisQquinonno 73.45g(240 mmole) of (S)-(-)-N-(2-bromoethyl)- a -mechylbenzyl-amine hydrobromide produced in Example 12(1) above was suspended in 260im! of decalin and the resulting suspension was heated to 150'C. 05.10g(7lO mmule) 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 I600g of ice-water with stirring. 70in£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 700ivP. 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 900^^ of ethyl acetate. The extracts were combined, washed with 200m£ 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. : 79-80r/0.5torr [a In80 = -85.5 (c«l, in CHCla) NMR(CDCl.i. 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(o. 1H), 7.18-7.31(m, 4H) Preparation of 5.6-dimethyl-2-(4-fluQronhenylamino)-4-(l-methyl-l.2.3.4-tetrahvdrQisoquinolin-2-yl)pvrimidine and its hvdrochloride In Examples 14 to 20, inclusive, l-methyl-1.2,3,4-tetrahydrois-quinoline prepared according to the method disclosed in International Publication No. WO 94/14795 was used as the reactant. 2-65g(27 mmole) of potassium acetate and 4.0g(26.9 mmole) of 1 -methyl- 1,2,3,4- tetrahydroisoquinoline were added to 85m£ of n-hexanol and then warmed to 80C. 6.17g(24.5 mmole) of 4-ch1oro-2-{4-fluoro-phenylarruno)-5,6-dimethylpyrimidine was added thereto and then reacted al 140'C for 28 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluo-rophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoQuinolia-2-yl)pyrimidinc. The rcacLion solution was cooled to room temperature, diluted with 20 in Yield : 62.4% m.p. : 2551C NMR(CDCh. ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38U, 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)8.l2g(11.2m4, 80.3 mmole) of triethylamine, 30,-nP. of n-butanol and b'.58g(44.1 trunole) of l-methyl-l,2,3,4-tetrahydroisoquinoline were added to 40mi of ethylene glycol. 10.1g(40.1 mmole) of 4-chloro-2-(4-fluoro-phenylamino)-5,6-dirnethylpyTimidine was added thereto and then reacted at 130"C for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-naethyl-l,2,3,4-tetrahydroisoquinolin-2-yl)-pyri-midine. This product was treated according to the procedure detailed in Example 14 to obtain 14.7g of purified 5,6-dimethyl-2-(4-fluorophenyl-utnino)-4-(l-methyI-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydro-chloride. Yield : 91% m.p. : 256 r NMR(CDCl:i. ppm) 1.58(d, 3H), 2.2l(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) 45«i! of triethylamine, SOmJ of n-butanol and 32g(217 mmole) of l-methy]-l,2,3,4-tetrahydroisoquinoline were added to 150nu! of ethylene glycnl. 51.3g(203.8 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylprrunidine was added thereto and then reacted at 135"C for 28 hours undfer refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-metliyl-l,2,3,'l~tetrahydroisoquinoUn-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain o'b'g of purified 5,6-dimethyl-2-(4-fluorophenylanuno)-4-(l-methyl-l,2, 3,4-tetrahydrois()-(\|uinolin-2-yl)pyrimidine hydrochloride. Yield : 81.1% m.p. : 256'C NMR(CDC]j, 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), 7.25(m, 6H), 7.6l(m, 2H), 1.0.33 is, 1H), I3,43(bs, 1H) 75m8 of triethylamine and 65g(442 mmole) of 1-methyl- 1,2. 3,4-tetrahydroisoquinoline were added to 100m£ of 1,2-propylene glycol. \|00.9jf(0.40 inmole) of 4-chloro-2-(4-fluorophcnyliimino)-5,6-dime-Lhylpyrimitline was added thereto and then reacted at 120'C for 64 hoars under refluxing Lo prepare 5,6-dimethyl-2-(4-fluorophenylaTriino)-4-(l-inethyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinc. This product was ireaied accordinn to the procedure detailed in Example 14 to obtain 9lg of purified 5.G-dimethyl-2-(4-fluoropheny1amino)-4-( 1-methyl- 1,2,3, 1-teLrahydroisoquinorm-2-yl)pyrimidine hydrochloride. Yield : 57.1% m.p- : 258r NMR(CDCI:», 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, GH), 7.61(m, 2H). 10.33 (s, 1H), 13.43(bs, 1H) Example 720inl! of triethylamine and 695g(4.72 mmole) of 1-methyl-1,2,3,4-lecraliydroisoyiunolinc were added to 2100m!> of 1,2-propylene glycol. 1179^(4.68 mmole) of 4-chloro-2-(4-fluorophonylamino)-5.6-dimethyl-pyrimidine was added thereto and the mixture thereby obtained was reacted at 130"C for 58 hours to prepare 5,6-dimethyl-2-(4-f1uoropheny1-amino)-4-(l-methyl-l,2,3I4-tetrahydroisoquinolin-2-yl)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-teirahydroisoquinolin-2-yl)pyrimidine hydrochloride. Yield : 66.9% m.p. : 2581 NMR(CDCb. 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 19 I10nyl> of n-butanol, 240m£ of triethylamine and 236g(1.60 mmole) of l-methyl-l,2,3,4-cetrahydroisoquinoline were added to GOCbP of ethylene glycol. 400g(1.59 mmole) of 4-chloro-2-(4-fluorophenyl- arnino)-5,6-dimethylpyrimidine was added thereto and then reacted at 140 V. for 48 huurs to prepare 5,6-dimethyl-2-(4-fUiorophenylamino)-4-(\|-methyl-l,2,3,4-(etrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 485g of purified 5,6-dJraethyl-2-(4-fluorophenylamjno)-4-(l-inethyl-l,2,3,4-tetrahydroisoqiunolin-2-yl)pyrinudine hydrochloride. Yield : 76.5% m.p. : 257"C NMR(CDCl:i. ppm) 1.58(d, 3H), 2-21U, 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), 7.61(m, 2H), 10.33 ($, IH), I3.43(bs, IH) Example 20 240n\i! of triethylamine and 9.7g(65.8 mmole) of 1-methyl-1,2.3,4- tetrahydroisoquinoline were added to 25ml of 1,2-propylene glycol. Then, 15g(51 mmole) of 4-bromo-2-(4-fluprophenylaminu)-5,6- dimethyl-pyrimicline was added thereto and the mixture thereby obtained was reacted at HOC for 28 hours. The resulting produce 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-yUpyrimidine hydrochloride. Yield : 78% m.p. : 257 "C NMR(CDCla, 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 8.12g(ll.2mt'., 80.3 nunole) of triethylamine, 30:n2 of n-butanol and 6-.cJ8g(44.1 mmole) of l-methyl-l,2.3,4-tetrahydroisociuinolme as prepared in Example 5 were added to 40mfi of ethylene glycol. 10. l(j(40.1 rnmole) of 4-chloro-2-(4-fluorophenylamino)-5)6-dimethylpyrirnidirie was added thereto and then reacted at 130 C for 30 hours under refluxing to prepare 5,fi-dimethyl-2-( The reaction solution was cooled to room temperature, diluted with 30[iitJ of acetone and then added dropwise to 2QOi;td of water with stirring. After it had been stirred for 2 hours, the resulting solid product \vas filtered, washed with 60m£ of water, dissolved in 250m altered, washed with 30m£ of ethanol ~and~then— dried to obtain 9.82g purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetra-hydroisoquinolin-2-yl)pyrimidine hydrochloride. Yield : 66.53% m.p. = 255t: NMR(CDCb, 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) of triethylamine and 65g(442 mmole) nf l-methyl- 1,2.3,4- tetrahydroisoquinoline as prepared in Example 7 were added to lOOmi! of 1,2-propylene glycol. 100.9g(0.40 mmole) of 4-chloro-2-(4-fluoro- phenylamino)-5,6-dimethylpyTimidine was added thereto and then reacted nL 120 "C for 64 hours to prepare 5,6-dimethyl-2-(4-fluorophenyIamino)-4-( l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Exzumple 21 to obtain 'J5.lg of purified 5,6-dimethyl-2-(4-fluorophenylsmino)-4-(l-meLh> 1-] .2,3,4-tetrahydroisociuinolin-2-yl)pyrinudine hydrochlonde. YkM ; 59.67% m> : 2581: N1MR(CDC1:,, 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), 13.43(bs, IH) of triethylamine and 9.7g(65.8 mmole) of l-methyl- 1,2.3.4-tetraliydrdsoquinoline as prepared in Example 7 were added to 25:nV. of 1,2-propyfcne glycol. 15g(51 mmole) of 4-bn>mo-2-(4-fluorophen>\|- amino)-5,6-dimet.hylpyrimidine was added thereto and then reacted at 120 C for 28 hours to prepare 5,6-dimethyl-2-(4-fluorophenylarnino)-4-(l-methyl-l,2,3,4-tetraliydroisoquiTiolin-2-yl)pyTimidine. 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- 1,2,3,4-tetrahydroisoquinoiin-2-yl)pyrimidine hydrochloride. Yield : 73.28% m.p. : 257 1 NMIKCDCh, 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). I3.43(bs, 1H) 8.12g(11.2m?., 80.3 mmole) of triethylamine, 30me of n-butanol and r».58g(44.1 mmole) of (R)-()-l-methyl-l,2,3,4-tetrahydroi-sonuinnrme as prepared in Example 9 were added to 40m£ of ethylene glycol. 10. Ig (40.1 mmole) of 4-chloro-2-(4-fluoropheny)amino)-5,6-dimethylpyrin\itline was added thereto and then reacted at 130°C for 30 hours under reflu.xing r.n prepare 5,f>-dimethyl-2-(4-fluorophenylamtno)-4-( 1-melhyl- 1,2,3, -1-tetrahydroisoquinolin-2-yl)pyrinudine. The reaction solution was cooled to room temperature, diluted with 30m£ of acetone and then added dropwise to 200m£ of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60tn£ of water, dissolved in 250!)rf of dichloromethane and then washed successively with 35m£ of 4N-HC1, 35iirf of water and then 40m?. of 4N- sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate. concentrated under reduced pressure, and then diluted with 200m£ 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 30m£ of ethanol and then dried to obtain 9.21g of purified (R)-(-O-5,6-dimethyl-2-(4-fluorophenylarninn)-4-(l-methyl-l,2,3,4-tetraJiydroisoquinolin-2-yl)pyrimidJne hydrochloride. Yield : 62.4% m.p. : 255 1 [fllo20 : «-250* (c-1, in CHCh) NMR(CDCl.-i, 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 23mE of criethylamine and 16g(108.5 mmole) of (RM+J-l-meLhyl- 1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to 75mf. of ethylene glycol. 25.7g(101.8 mmole) of 4-chloro-2-(4-fluoro- phenyIamJno)-5,6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 135"C for 28 hours under refluxing to prepare (R)-( + )-5,6-dirtiethyl-2-(4-fluoropheny In mino)-4-(l -methyl -1,2,3, 4-ieLruhydroisof\|uinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 24 to obtain 33y of purified 5,6-dimeihyl-2-(4-fluorophenylamino)-4- (1-methy 1-1, 2,3,4- tctrn-hydroisoquinolin-2-yl)-pyrimidine hydrochloride. Yield : 81.1% m.p. : 257 "C [a]D° : -^250' (c-1, in CHCh) NMR(CDCl:i. ppm) : 1.58(d. 3H), 2.21(s, 3H). 2.38(s, 3H), 2.84 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 of triethylaniine and 9.7g(65.8 mmole) of (R)-()-l-meLhyl- ,2,3,4-tetrahydrnisoquinoline as prepared in Example 10 were added to 25mf of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(4-fiuoro-phenylamino)-5.6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 120t for 28 hours. The reaction product was thentreated according to the procedure detailed in Example 24 to obtain 16.2g of purified 5)6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride. Yield : 79.97% m.p. : 257'C [a]n20 • -250' (c=l, in CHC13) NMRfCDCl.,, ppm) : 1.58 2H), 4.23(m, 1H). 5.38(q, 1H), 7.25(m, 6H), 7.61(m, 2H), 10.33(s, 1H), I3.43(bs, IH) r.xample 27 8.l2g(H.2me, 80.3 mmole) of triethylamine, 30me of n-butanol and 6.582(44.1 mmole) of (S)-(-)-l-methyl-1.2,3,4-tetrahydroisoquinolinc as prepared in Example 13 were added to 40me of echylene glycol. lO.lg (40.1 mmole) of 4-chloro-2-(4-fIuorophenylamino)-r>,ti-dimethylpyrimJdine was added thereto and then reacted at 130TJ for 30 hours under refluxing to prepare (S)-(-)-5,6-dimethy\|-2-(4-fluorophenylamino)-4-(l-ethyl-l,2,3,4-tetrahydroisoquinolin-2-yi)pyriinidine. The reaction solution was cooled to room temperature, diluted with 30rae of acetone and then added dropwise to 200^ Of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60nii! of water, dissolved in 250m(! of dichloromethane and washed successively with 35m£ of 4N-HC1, 35nu> nf water and 40m of 4N-sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate. concentrated under reduced pressure, and then diluted with 200mi of ethanol. To this reaction solution was added 45g of cone, hydrochloric acid, and the ixture was stirred for 5 hours. The resulting solid product was filtered, washed witli 30mi of ethanol and then dried to obtain 8.95of purified (S)-(-)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-i, 2,3,4- tetrahydro)soquinolin-2-yl)pyrimidine hydrochloride. Yield : 60.6% m.p. - 255 "C [a]D'° : -250' (c=l, in CHC13) NMR(CDCI.,, ppm) : 1.58(d, 3H). 2.21(s, 3H), 2.38 1H), 3.12(m, 1H), 3.fil(m, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, 1H), I3.43(bs, 1H) Example 28 of triethylamine and 9.7g(65.8 mmolc) of (S)-(-)-l-methyl-1.2,3,4-tetrahydroistMiuinoline as prepared in Example 13 were added to 25T(! of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(-l-fluoro-phenylajiuno)-5,6-dirnechylpyrimidine was added thereto and then reacted at HOT. for 38 hours. The reaction product was treated according to the procedure detailed in Example 27 to obtain 15.86y of purified 5.6-climethyl-2-(4-fluorophenylaniino)-4-(l-methyl-l,2,3,4-tetrahydroiso-q u i nol i n - 2 - y 1 )pyri rtu'dine hydrochloride. Yield : 78% m.p. : 257 C [a]Di0 : -250' (c=l, in CHCh) NMR(CDC1:I, ppm) : 1.58(d, 3H), 2.2l(s, 3H), 2.38(s, 3H), 2.84(m. 1H), 3.l2(m, 1H), 3.6L(m. 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25{m, 6H), 7.6l(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H) We claim 1. A process for preparing 5,6-dimethyl-2-(4-fluorophenyl-arnino)-4-(1- methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by the following formula (I),(Formula Removed)0 and its acid addition salts, wherein a pyrimidine derivative represented by the following formula (II-A), (Formula Removed) in which Hal representes a halogen, is reacted with 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula (III), optionally in the presence of a solvent and optionally in the presence of the base as herein described. (Formula Removed) 2. The process as claimed in claim 1, wherein the acid addition salt is hydrochloride. 3. The process as claimed in claim 1, wherein the reaction is carried out in the presence of a solvent. 4. The process as claimed in claim 3, wherein the solvent is N,N- dimethylformamide, n-butanol, n-pentanol, n-hexanol, dimethylsulfoxide, ethylene glyeol, 1,2-propylene glycol, or a mixture thereof. 5. The process as claimed in claim 1, wherein the reaction is carried out in the presence of a base. 6. The process as claimed in claim 5, wherein the said base is triethylamine, N-N-dimethylaniline, pyridine, or potassium acetate. 7. The process as claimed in claim 1, wherein the compound of formula (I) in the form of a (R )-(+)-isomer is prepared using (R )- (+)-1 -methyl-1,2,3,4-tetrahydroisoquinoline. 8. A process as claimed in claim 1, wherein the compound of formula (I) in the form of a (S)"(-)-isomer is prepared using (S)-(-)-1 -methyl- 1,2,3,4-tetrahydroisoquinoline. 9. A process for preparing 5,6-dlmethyl-2-(4-fluorophenyl-amino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine substantially as herein described in claim 1 with reference to any one of the examples 14 to 28.

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-n,uinolin-2-yl)pyrimidine represented by the following formula (I) and its acid addition salts; second, to a process for preparation of an intermediate for preparing the compound (I); and, third, to a novel intermediace compound- More specifically, the present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-nuorophenylamino)-4-(l-mechyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by the following formula (I),

(Formula Removed)
and its acid addition salts, wherein a pyrimidine derivative represented by the following formula (D-A),
(Formula Removed)
in which Hal represents a halogen, is reacted with l-methyl-1,2,3,-1-tetrahydroisoquinoline represented by the following formula (El);

(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).
BACKGROUND ART
5,6-Dimethyl-2-(4-fluorophenylarrano)-4-(l-methyl-l,2,3,4-tetra-hydroisoo.uinolin-2-yl)pyrimidine of the above formula (I) inhibits gastric acid secretion by means of a reversible proton-pump inhibiting effect and. therefore, can be used as an anti-ulcer agent. This compound was developed by the inventors of the present invention, who then applied for patents for the compound and/or its method of preparation in Korea and other countries (see International Publication No. WO 96/05177).
According to the method disclosed in the above patent application, 5,G-dimethyl-2-(4-fluorophenyIajnino)-4-(l-methyl-1,2,3,4- tetrahydroisoq uinolin-2-yl)pyrimid.ine is prepared according to the following reaction scheme A-
Reaction scheme A
(Scheme Removed)
Since the starting material of the above reaction scheme has two reactive sites (i.e., the two Cl atoms), the first reaction inevitably produces a side product, which reduces the yield of the desired compound.
The present inventors have long labored to develop a novel method for preparing 5,6-dimethyl'2-(4-fIuorophenylainino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinoUn-2-yl)pynmidine of formula (I) without producing side products. As a result, we have discovered that the desired compound of formula (I) can be efficiently prepared without side products by reacting the pyrimidine derivative represented by formula (11^ A) with l-methyl-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-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-1,2,3.4- tetrahydroiso-ciuinolin-2-yl)pyrimidine represented by formula (I) and its acid addition
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-tetrahydroisoquinolin-2-yl)pyrimidlne represented by formula (I),

(Formula Removed)
and its acid addition salts wherein a pyrimidine derivative represented by the following formula (n-A),
(Formula Removed)
in which Hal represents a halogen, is reacted with l-methyl-1,2,3,4-tetrahydroisoquinoline represented by formula (III),

(Formula Removed)
In addition, the present invention relates to a process for preparation of the pyrimidine derivative of formula (II-A) and the compound of formula (HI).
Further, the present invention relates to a novel intermediate compound represented by the following formula (II), which includes the pyrimidine derivative represented by formula (II-A),
(Formula Removed)
in R represents hydroxy and a halogen.
In accordance with the present invention there is also disclosed a process for preparing 5,6-
dimethyl-2-(4-fluorophenyl-amJno)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)
pyrimidine represented by the following formula (I),

(Formula Removed)
and its acid addition salts, wherein a pyrimidine derivative represented by the following formula (II-A),
(Formula Removed)
in which Hal representes a halogen, is reacted with 1 -methyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula (III), optionally in the presence of a solvent and optionally in the presence of the base as herein described.

(Formula Removed)
Although the 4-halogeno-2-(4-fluorophenylamino)-5,6-dimethyl-pyrimidine represented by formula (DhA) can be reacted according to the present invention with an equivalent amount of l-methyl-1,2,3,4-tetra-hydroisoquinoline represented by formula (III), it is preferable to conduct lhe 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-1,2,3,4-tetrahydroisoquinoline can be readily removed after the reaction has gone to completion.
The reaction of the present invention is preferably carried out in the presence of a solvent. Solvents which may be used for this purpose include N,N-dimethylformamide, n-butanol, n-pcntanol, n-hexanol, dimethylsulfoxide, ethylene glycol, 1,2-propylene glycol, and mixtures thereof. Of these propylene glycol and ethylene glycol are most preferred, since use of either of these minimizes both reaction time and production of side products.
In the method of the present invention, the reaction scheme 1 is generally carried out in the presence of a base. Bases which can be used for this purpose include triethylamine, N,N-dimethylaniline, pyridine and potassium acetate. The reaction temperature for die reaction between the compound of formula (II-A) and 1-methyl-1,2,3,4-tetrahydroJsoquinoline of formula (in) is preferably in the range from 110 C to 160"C and the reaction time is preferably in the range from 16 hours to 72 hours.
5,6-Dimethyl-2-(4-fluorophenylanuno)-4-(l-methyl-l.,2,3,4-tetra-hydroisoquinolin-2-yl)pyrimidine of formula (I) as prepared according to die above method can be converted into its acid addition salt, preferably into the hydrochloride salt, by conventional medinds- 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
•iTonr denoted by in the formula immediately below), this compound be present in an (ll)-(-)-isomer, an (S)-(-)-isomer, or a racemate wherein the R and S isomers are mixed in the ratio of 1:1. . Unless indicated otherwise, the compound of formula (I) should be interpreted to include all of these isomers.
(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:
Reaction scheme
(Scheme 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-fluorophenylarnino)-5,6-dimethyl-pyrimidine of formula UI-B), which may then be reacted with a haJogenating agent to obtain the 4-ha]ogeno-2-(4-fluorophenyljimin>-5,6-dimethylpyrimidine of fonnula (U-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 he prepared by reacting 4-fluoroaniline with a 50% cyanamide solution under acidic conditions using 30% to 37% hydrochloric acid while maintaining the temperature ranging from 751 to 95 "C.
The first step of the reaction scheme 2 may be .practiced in the presence of a solvent. Solvents which may he used for this purpose include acetonitrile, N.N-dimethylformamide and dimethylsulfoxide. This
/eaction is preferably carried out at a temperature-ranging—f-reffi 110^ to 160 °C.
In the second step of the reaction scheme 2, 4-hydroxy-2-(4~ fluorophenylarnino)-5,6-dimethylpyrimidine 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 l^N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane and l,2-dichloroben2ene. It is preferable to maintain the reaction temperature in the range from 75°C to 951.
Although the second step of the reaction scheme 2 can be
practiced by isolating the intermediate after the first reaction step hns
been completed, it is preferable to conduct the first and second steps in a
single vessel. Specifically, 4-hydroxy-2-(4-fluorophenylamino)-5,6-
dimelhylguanidine 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-phenylaniino)-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 be 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-Methy{-l,2,3,4-tetyahydroisoquinoline 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-methyI-l,2,3,4-tetrahydroisoquinoline is prepared by reacting (R)- or (S)-methylben2ylamine 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, respecti¬vely, 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 -(methylthin)-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 -methylbenzylamine 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-tetrahydroisoquinoline is explained in more detail below.
According to the present invention, l-methyl-l,2,3,4-tetrahydro-isoquinoline of formula (DI) 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.
(Scheme 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-bromoethann| tn produce N-(2-hydroxyethyl)- a -mcthylbenxylamine, which in turn is reacted with the brominating agent to produce N-(2-bromoethyD- a-methylbenzylamine hydrobromide. In the third step, N-(2-bromoethyD- a -methylbenzylamine hydrobromide is reacted with a Lewis acid to produce the desired l-methyl-1,2,3,4-tetrahyd.rotso-quinoline of formula (III).
Reaction solvents which can be used in the first step include acetonitrile, N,N-dimethylformamide. dichloromethane and 1,2-dichlorn-ethane and the reaction temperature is preferably maintained in the range from 4()"C to 60"C. Reaction solvents which can be used in the second step include 1,2-dichloroethane, acetic acid, water and 1,2-dichloro-benzene, and the reaction temperature is preferably maintained in the range from 110"C to 145"C. Brominating agents which can be used in this reaction include bromine, bromic aicd, aqueous bromic acid solution, and phosphorus trihromide.
Although the first and second steps of the reaction scheme 3 can
be practiced by isolating N-(2-hydroxyetIiy1)- a -methylbenzylamine produced as the intermediate after the first reaction step has been completed, it is preferable to conduct the first and second reaction steps without isolating the intermediate. Thus, the brominating agent is added to the vessel that contains the products of the first reaction step.
Then, N-(2-bromoethyl)- a -methylbenzylamine produced in the second reaction step is cyclized by reaction with a Lewis acid to prepare the desired l-methyl-l,2,3,4-tetrahydroisoquinnline of formula (Til). Reaction solvents which can be used in this reaction include decalin, 1,2-dichloroethane and 1,2-dichlorobenzene and Lewis acids for this cyclization reaction include aluminum (III) chloride, zinc chloride and ferrous chloride.
Since l-methyl-l,2,3,4-tetrahydroisoquinoline can be economically prepared according to the above method, the desired 5,6-dimethyl -2-(4-fluorophenylamino)-4-(l-methyl-l>2,3,4-tecrahydroisoquinolin-2-y]) -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 (U)-(*)- or (S)-(-)-isomer as the starting material for preparation of che compound of formula (I) according to the present invention, each isomeric form of the compound of formula (III) 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.
Preparation • 4~fluoroohenyltni}inidjng
882g(747mt!) of 32% hydrochloric acid was added to 1000g(8.9 mole) of 4-fluoroaniline. the mixture was wanned to 87°C, and 780™! (9. 9
mole) of 50% cyanamide solution was addeddropwise thereto over"? hours. The reaction solution was adjusted to pH 2.4 by adding thereto I20m£ of 32% hydrochloric acid, stirred for 3 hours, and cooled to 60 'C. Aqueous sodium carbonate solution (NazCCh 578g/water 1640tnt!) 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 600m? of water and then with 2000m£ of ethyl acetate, and finally dried to obtain 1395g of the title compound, which had a light gray color.
Yield : 81.4%
m.p.
NMR(DMSO-ds, ppm) : 5.50-6.88(bs, 5H), 6.87(m, 2H), 7.17 2H)
j?x ample 1 : 4-hvdroxv-2-(4-fluoropfrenylamino)-5.6-diinethylDVri-midine
54.5g(253.2 mmole) of 4-fluorophenylguanidine carbonate produced id the Preparation above was suspended in SOiiiH of N,N-dimethylform-;unide and 37.8g(262.2 mmole) of ethyl 2-methylacetoacetate and the resulting suspension was refluxed at 140*C for 3 hours. The reaction solution was diluted again with lOOnvE of N,N-dJmethylformamide and cooled to 80 'C, 160mi of isopropylalcohol was added thereto and the resulting mixture was stirred for 30 minutes. The resuking solid product was filtered, washed with 15Qm£ of acetone, and finally dried to obtain 41g of the title compound.
Yield : 61.4% m.p. : 256C
NMR(DMSO-d6, ppm) : 1.83(s, 3H), 2.19(s, 3H), 7.18(t, 2H), 7.68
(m, 2H), 9.36(bs, 1H), 10.63(bs, 1H)
Kxamole 2 : 4-^lnro-2-(4-fluQrQDh^nv1nTninn)-5,fi-dimethylDVrimi-dine
40.5g( 174.1 mmole) of 2-(4-fluorophenyIamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in BQmi of N,N-dimethylformamide and the resulting suspension was heated to 80 'C. .'U.9g( 19.4ml, 210.1 mmole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 851!. 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 150m£ of 50% aqueous methanol solution and then dried to obtain 42. 3g of the title compound.
Yield : 96.7% m.p. : 114'C
NMR(CDCh, ppm) : 2.21(s, 3H), 2.41(s, 3H), 7.0l(t, 2H), 7.l8(bs,
1H), 7.56U, 2H)
3 : 4-cbloro-2-(4-fIuorophenylaminoJ-5.6-dImethyluvrimi-sline
1390g(7.6 mole) of 4-fluorophenylguanidine carbonate produced by the Preparation above was suspended in ISOOm*'. of N,N-dimethylform-amide and I200g(8.4 mole) of ethyl 2-methylacetoacetate. The resulting suspension was heated under refluxing for one hour, distilled at normal pressure to llOOmii and then distilled until the temperature of the reaction solution reached 160 'C. 1600ml of N,N-dimethylformamide was added Lo the residue and then cooled to SQ°C. 1388g(840mt!, 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 and then diluted with 2000ml 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 1500mC. of 50% aqueous methanol solution and then dried. The dried, yellowish-brown powder thereby obtained was dissolved in 4000ml> of methanol under refluxing
ana men cooieu iu j.uC. The resulting solid product was filtered and dried to obtain 1186g of the title compound.
Yield : 62.4% m.p. : 1141C
NMRfCDCb, ppm) : 2.21(s, 3H), 2.41(s, 3H), 7.0 Kt, 2H), 7.18(bs,
1H), 7.56(t, 2H)
Kx ample 4 i 4-broino-2-(4~fluQrophenylamino)-5.6--diinethv!DVT-i-mjdine
5g(21.44 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-
dimethylpyrimidine produced in Example 1 was suspended in 4Qml of
N,N-dimethylformamide and the resulting suspension was warmed to 65
T. 8.1g(30 mmole) of phosphorus tribromide was added dropwise
thereto over 20 minutes and the resulting mixture was allowed to react at
75'C for 30 minutes. The reaction solution was cooled to room
temperature, poured onto 50Qg of ice-water, adjusted to pH 11 with sodium hydroxide solution, stirred for 30 minutes and then adjusted again ro pH 5.5 with dilute hydrochloric acid. The resulting yellow solid product was washed with 100m£ of water and the dried to obtain 4.1g of the title compound.
Yield : 64.58% m.p. : 123r
NMRCCDCb ppm) : 2.21(s, 3H), 2.42(s, 3H), 6.98(t, 2H), 7.24U,
1H), 7.54(g, 2H)
Fvamnle 5 : 1-methyl-1,2,3,4-tetrahydroisoquinolin^
(1) Preparation of N-(2-hydroxyethyl)- a-methylbenzylamine:
103.08g(0.86 mole) of a -methylbenzylamine was dissolved in 110 mi! of dichloromethane and I27.56g(1.02 mole) of 2-bromoethanol 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 I09g of the title compound, which had a pale yellow color.
Yield : 76.7% m.p. : 60'C/0.5torr
NMRCCDCla. 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 N-(2-bromoethyl)- a -methylbenzylamine hydrobromide:
100g(605.32 mmole) of N-(2-hydroxyethyU- 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 126°C for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 4(55mK of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 550m(! of acetone, and SOflmf! 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 400m£ 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 450m£ of acetone, diluted with 680m£ of ether and then allowed to stand at O'C for 12 hours. The resulting solid product was filtered, collected, and washed with 450m£ of ethyl acetate to obtain 32.5g of the second crop of the title compound.
Yield : 69.23%
m.p. : !86-187r
NMRCCDCb, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q.
1H), 7.40-7.72(m, 5H), 9.51(bs, 1H), 9.91(bs,
1H)
(3) Preparation of 1-methyl-1.2,3,4-tetrahydroisoquinoline
50.0gU61.8 mmole) of N-(2-bromoethyl)- a -methylbenzylamine hydrobromide produced in Example 5(2) above was suspended in 450raC of decalin and then heaced to 140 1). 64.70g(485.4 mmole) of anhydrous aJuminum chloride (A1CU) 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-water with stirring. 150m£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with lOOOmi 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 2lOOm£ of ethyl acetate. The extracts were combined, washed with 420m£ 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. Ig of the title compound.
Yield : 75.99%
b.p. : 79-80*C/0.5torr
NMR(CDCb. ppm) : 1.59(d, 3H), 2.14 3.10-3.22(m, 1H), 3.34-3.45(m. 1H), 4.22(q,
1H), 7.18-7.31(m, 4H)
I'xamnlc 6 ? l~methyl**1.2.3.4-~tetr'ahvdroisoqiiinoling
(1) Preparation of N-(2-bromoethyl)- a -methylbenzylamine hydrobromide-
76.61g(630 mmole) of a -methylbenzylamine was dissolved in of die hlorome thane and 94.8g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51 "C for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350m£ of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to lOt: and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 m(! of ethyl acetate and then dried to obtain 128.9g of the title ompound.
Yield : 66.2%
m.p. = 186-1871C
NMR(CDCb, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q,1H), 7.40-7.72(m, 5H), 9.51(bs, IH). 9.91(bs,
1H)
(2) Preparation of l-methyl-l,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 60m£ of l,2-dichloroben2ene and then heated to 145t. 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. 30m£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130m£ 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 250mt> of ethyl acetate. The extracts were combined, washed with 40mH of saturated saline, dehydrated with anhydrous magnesium sulfate 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. : 79-80t/0.5torr
NMR(CDClj. 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 IH), 7.l8-7.31(m, 4H)
7 : 1-methyl-1.2.3.4-tetrahvdroisQqutnoUne
200g(647.17 mmole) of N-(2-bromoethyl)- a -methylbenzylamiTie
hydrobromide produced in Example 5(2) or Example 6(1) above was
suspended in IQOmi of decalin and then heated to 150 C. 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. 210m£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 2500mi 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 3000m?. of ethyl acetate. The extracts were combined, washed with 550m Yield : 82.8%
b.p. : 79-80r/0.5torr
NMR(CDCLi. ppm) : 1.59(d, 3H), 2.l4(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)
8 • (R)-(+)-l-methyl-lr2.3,4-fftrrahvdroisoquinoline (1) Preparation of (R)-(+)-N-(2-hydroxyethyl)-a -methylbenzylamine:
51.45g(0.43 mmole) of (R)-(+0- a -methylbenzylamine was dissolved in 52mf. of dichloromethane and 63.78g(0.51 mmole) of 2-bromo-ethanol was added thereto. This mixture was stirred at 51 'C for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 54g of the title compound having pale yellow color.
m.p. : 60t:/0.5torr [ff]DM = *55* (c=l, in CHC13)
NMR(CDCb. 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-bromoethyD- a-methylbenzylamine hyd-robromide:
11.0g(66.58 mmole) of (R)-(+)-N-(2-hydroxyethyl)- c-methylben-/ylamine produced in Example 8(1) above was suspended in 52x1 of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126"C for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature and 47m£ of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 55n)P. of acetone, and SOiif. of ethyl acetate and 7Qmi 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 30ml! of ethyl acetate and then dried to obtain lOg of the first crop of the title compound. The filtrate was then concentrated. The residue was dissolved in 6Qm(! of ethanol and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in 50:n? of acetone, diluted with 7Qxi of ether and then allowed to stand at O'C for 12 hours. The resulting solid product was filtered, collected and washed with 3QmH of ethyl acetate to obtain 3.1g of the second crop of the title compound.
Yield : 64%
m.p. : 186-187 "C
U]o20 : "-32.11 (c=l, in CHCh)
NMR(CDClj, ppm) : 1.94(d, 3H), 3.2Km, 2H), 3.82(m, 2H), 4.42( 1H), 7.40-7.72(m, 5H), 9.51(bs, 1H), 9.9l(bs,
1H)
CU Preparation of (R)-(-O-l-methyl-l,2,3,4-tetrahydroisoquinoline
5.0g(16,18 mmole) of (R)-(t-)-N-(2-bromoethyl)- ff-methylbenzyl-amine hydrobromide produced in the above (2) was suspended in 50m(i of clecalin and the resulting suspension was heated to 140°C. 6.470g (48.54 mmole) of anhydrous aluminum chloride (AlCb) 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. 20mZ 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 resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250m£ of ethyl acetate. The extracts were combined, washed with 40m£ 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. : 79-80 t/0.5tor
[a]D2u : +85.5- (c=l. in CHC13)
NMR(CDC1:1, 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( 1H), 7.18-7.31(m, 4H)
(1) Preparation of (R)-( + )-N-(2-bromoethyl)- a -methylbenzylanline hyd¬robromide:
76.61g(630 mmole) of (R)-(+)-a -methylbenzylamine was dissolved in 71mt of dichloromethane and 94.8g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51 'C for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 2afi.4mt!(2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and then allowed to react at 126 "C for 30
minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250ii£ of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350m£ of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10 T and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 5Q:n£ of ethyl acetate, and then dried to obtain 127.5g of the title compound.
Yield : 65.5%
m.p. : 186-187 "C
[ff]D?0 : +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, 5H), 9.51(bs, 1H), 9.91(bs,
1H)
(2) Preparation of (R)-(+)-l-methyl-l,2,3,4-tetrahydroisoquinoline
10.0g(30.1 iTunole) of (R)-(>)-N-(2-bromoethyl)- a -methylbenzyl-luiiine hydrobromide produced in Example 9(1) above was suspended in (jOmi! of 1,2-dichlurobenzene and then heated to 1451. 13.47g(96.54 rvunole) of anhydrous aluminum chloride (AlCb) 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 stirring. 30nvE of con. hydrochloric acid was added (•.hereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130m£ of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250m£ of ethyl acetate. The extracts were combined, washed with 40mli of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.06g of the title compound.
Yield = 69%
b.p. : 79-80°C/0.5torr
UlD20 •• +85.5' (c=l, in CHCb)
NMR(CDCb, 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 10 '• (Rl-(+)-|-methyl-lr2.3.4-tetrahydroiso 73.45g(240 mmole) of (R)-(+)-N-(2-bromoethyl)- or-methylbenzyt-amine hydrobromide produced in Example 9(1) above was suspended in 260nu! of decalin and the resulting suspension was heated to 150'C. 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. 70m£ of con. hydrochloric acid was added thereto and the resulting mixture was stirred far 10 minutes. This solution was washed three times, each time with 700m?. of ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and extracted three times, each time with 900ni! of c:thyl acetate. The extracts were combined, washed with 200ni! 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
[a]D20 : +85.5' (c=l, in CHCh)
NMR(CDCLi, 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)
jfoample 11 : (S)--T-methyl~1.2.3.4-tetrahvdrolsQqiiinQline (1) Preparation of (S)-(-)-N-(2-hydroxyethyD- o-methylhenzylamine:
108.23g(0.903 mmole) of (S)-(-)- a -methylbenzylamine was dissolved in 140ms! of dichloromethane and 144.0g(1.071 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51 "C for 52 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 117.4g of the title compound, which had a pale yellow color.
Yield : 78.7% m.p. : 60'C/0.5torr [alo° • -55' (c-1. in CHCh)
NMR(CDCl:i. ppm) : 1.38(d, 3H), 2.40(bs, 1H), 2.61(m, 2H), 3.58(m. 2H), 3.78(q, 1H), 7.l8-7.38(m, 5H)
(2) Preparation of (S)-(-)-N-(2-bromoethyD- a -methylbenzylamine hyd-robromide:
22,lg(l33.l6 mmole) of (S)-(-)-N-(2-hydroxyechyl)- a -mcthyl-
bezylamine produced in Example 11(1) above was suspended in 105:nS of
48% aqueous hydrobromic acid solution and the resulting suspension was
reacted at 126'C for 30 minutes under refluxing. Then, the reaction
solution was distilled for 2 hours under normal pressure at constant
temperature and 95aii of aqueous hydrobromic acid and water, the reaction
by-product, was removed. The residue was dissolved in 112:n£ of
acetone, and I00m£ of ethyl acetate and 150mi! 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 70nv£ 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 130iiuJ of ethanol and then
concentrated under reduced pressure. The residue was dissolved in 104
!'.i C for 12 hours. The resulting solid product was filtered, collected and
washed with 75mii of ethyl acetate to obtain 6.7g of the second crop of
the tide compound.
Yield : 64.8%
m.p. : 186-187t
[ale20 : -32.1 (c-1, in CHCb)
NMR(CDCl3, 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 (SM-)-l-methyl-l,2,3,4-tetrahydroisoquinoHne
5.0g(16.18 nunole) of (S)-(-)-N-(2-bromoethyl)- a -methylbenzyl-
amine hydrobromide produced in Example (2) above was suspended in 50
m anhydrous aluminum chloride (AlCb) 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. 20 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with IQQini of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 :n£ of ethyl acetate. The extracts were combined, washed with 40raC. of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure tt; remove ethyl acetate. The residue was distilled to obtain 1.75g of the title compound.
Yield : 73-5%
b.p. : 79-80 C/0.5torr
[fflo20 : -85.5' (c=l, in CHCb)
NMRtCDCh, 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 1H), 7.18-7.31(m, 4H)
12 '• fSl-(->-l-methv1-1.2.3.4-tetTahvdroisoquinoline
(1) Preparation of (S)-(-)-N-(2-bromoethyD- a -methylbenzylamine hyd
robromide:
176.20g(1449 minole) of (S)-(-)- a -methylbenzylamine was
dissolved in 185mf. of dtchloromethane and 218.04g( 1748 mmole) of
2-bromoethanol was added thereto. This mixture was stirred at 51 C for
50 hours to complete the reaction. The reaction solution was
concentrated under reduced pressure and 658^2(5750 mmole) of 48% aqueous hydrobromic acid solution was added thereto and the solution thereby obtained was allowed to react at 126 °C for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature to remove 580ir.£ of water as the by-product and uqueous hydrobromic acid solution. The residue was dissolved in 760mC. of Jsopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10'C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 150;i\e of ethyl acetate and then dried to obtain 306.5g of the title ompound.
Yield : 68.4%
m.p. : 1851:
ta]D20 : -32.11 (c*l, in CHCh)
NMRtCDCln, ppm) : 1.94(d, 3H), 3.2l(m, 2H), 3.82(m, 2H), 4.42( 1H), 7.40-7.72 1H)
(2) Preparation of (S)~(-)-l-methyl-l,2,3,4-tetrahydroisoquinoline
10.0g(30.1 mmole) of (S)-(-)-N-(2-bromoethyD- or-methylbenzyl-amine hydrobromide produced in Example 12(1) above was suspended in fiOme of 1,2-dichlorobenzene and then heated to 145"C. 13.47g(96.54 mmole) of anhydrous aluminum chloride (AlCb) 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. 30m£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130mi of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium
hydroxide, and then extracted three times, each time with 250ni£ of ethyl acetate. The extracts were combined, washed with 40nrf of saturated saline, dehydrated with anhydrous' magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.lOg of the title compound.
Yield : 69.96%
b.p. : 79-80r/O.Storr
[a]D2° : -85.5' (c-1, in CHCla)
NMR(CDCb, 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)
p.xample 13 : (S)-(-l-l-methyl-l,2t3t4-tetrahvdroisQquinonno
73.45g(240 mmole) of (S)-(-)-N-(2-bromoethyl)- a -mechylbenzyl-amine hydrobromide produced in Example 12(1) above was suspended in 260im! of decalin and the resulting suspension was heated to 150'C. 05.10g(7lO mmule) 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 I600g of ice-water with stirring. 70in£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 700ivP. 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 900^^ of ethyl acetate. The extracts were combined, washed with 200m£ 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. : 79-80r/0.5torr
[a In80 = -85.5* (c«l, in CHCla)
NMR(CDCl.i. 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(o. 1H), 7.18-7.31(m, 4H)
Preparation of 5.6-dimethyl-2-(4-fluQronhenylamino)-4-(l-methyl-l.2.3.4-tetrahvdrQisoquinolin-2-yl)pvrimidine and its hvdrochloride
In Examples 14 to 20, inclusive, l-methyl-1.2,3,4-tetrahydrois-quinoline prepared according to the method disclosed in International Publication No. WO 94/14795 was used as the reactant.
2-65g(27 mmole) of potassium acetate and 4.0g(26.9 mmole) of 1 -methyl- 1,2,3,4- tetrahydroisoquinoline were added to 85m£ of n-hexanol and then warmed to 80*C. 6.17g(24.5 mmole) of 4-ch1oro-2-{4-fluoro-phenylarruno)-5,6-dimethylpyrimidine was added thereto and then reacted al 140'C for 28 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluo-rophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoQuinolia-2-yl)pyrimidinc.
The rcacLion solution was cooled to room temperature, diluted with 20 in Yield : 62.4%
m.p. : 2551C
NMR(CDCh. ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38U, 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)8.l2g(11.2m4, 80.3 mmole) of triethylamine, 30,-nP. of n-butanol and b'.58g(44.1 trunole) of l-methyl-l,2,3,4-tetrahydroisoquinoline were added to 40mi of ethylene glycol. 10.1g(40.1 mmole) of 4-chloro-2-(4-fluoro-phenylamino)-5,6-dirnethylpyTimidine was added thereto and then reacted at 130"C for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-naethyl-l,2,3,4-tetrahydroisoquinolin-2-yl)-pyri-midine. This product was treated according to the procedure detailed in Example 14 to obtain 14.7g of purified 5,6-dimethyl-2-(4-fluorophenyl-utnino)-4-(l-methyI-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydro-chloride.
Yield : 91% m.p. : 256 r NMR(CDCl:i. ppm)
1.58(d, 3H), 2.2l(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)
45«i! of triethylamine, SOmJ of n-butanol and 32g(217 mmole) of l-methy]-l,2,3,4-tetrahydroisoquinoline were added to 150nu! of ethylene glycnl. 51.3g(203.8 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylprrunidine was added thereto and then reacted at 135"C for 28 hours undfer refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-metliyl-l,2,3,'l~tetrahydroisoquinoUn-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain
o'b'g of purified 5,6-dimethyl-2-(4-fluorophenylanuno)-4-(l-methyl-l,2, 3,4-tetrahydrois()-(|uinolin-2-yl)pyrimidine hydrochloride.
Yield : 81.1% m.p. : 256'C NMR(CDC]j, 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), 7.25(m, 6H), 7.6l(m, 2H), 1.0.33 is, 1H), I3,43(bs, 1H)
75m8 of triethylamine and 65g(442 mmole) of 1-methyl- 1,2. 3,4-tetrahydroisoquinoline were added to 100m£ of 1,2-propylene glycol. |00.9jf(0.40 inmole) of 4-chloro-2-(4-fluorophcnyliimino)-5,6-dime-Lhylpyrimitline was added thereto and then reacted at 120'C for 64 hoars under refluxing Lo prepare 5,6-dimethyl-2-(4-fluorophenylaTriino)-4-(l-inethyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidinc. This product was ireaied accordinn to the procedure detailed in Example 14 to obtain 9lg of purified 5.G-dimethyl-2-(4-fluoropheny1amino)-4-( 1-methyl- 1,2,3, 1-teLrahydroisoquinorm-2-yl)pyrimidine hydrochloride.
Yield : 57.1% m.p- : 258r NMR(CDCI:», 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, GH), 7.61(m, 2H). 10.33 (s, 1H), 13.43(bs, 1H)
Example
720inl! of triethylamine and 695g(4.72 mmole) of 1-methyl-1,2,3,4-lecraliydroisoyiunolinc were added to 2100m!> of 1,2-propylene glycol. 1179^(4.68 mmole) of 4-chloro-2-(4-fluorophonylamino)-5.6-dimethyl-pyrimidine was added thereto and the mixture thereby obtained was

reacted at 130"C for 58 hours to prepare 5,6-dimethyl-2-(4-f1uoropheny1-amino)-4-(l-methyl-l,2,3I4-tetrahydroisoquinolin-2-yl)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-teirahydroisoquinolin-2-yl)pyrimidine hydrochloride.

Yield : 66.9% m.p. : 2581 NMR(CDCb. 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 19
I10nyl> of n-butanol, 240m£ of triethylamine and 236g(1.60 mmole)
of l-methyl-l,2,3,4-cetrahydroisoquinoline were added to GOCbP of
ethylene glycol. 400g(1.59 mmole) of 4-chloro-2-(4-fluorophenyl-
arnino)-5,6-dimethylpyrimidine was added thereto and then reacted at 140 V. for 48 huurs to prepare 5,6-dimethyl-2-(4-fUiorophenylamino)-4-(|-methyl-l,2,3,4-(etrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 485g of purified 5,6-dJraethyl-2-(4-fluorophenylamjno)-4-(l-inethyl-l,2,3,4-tetrahydroisoqiunolin-2-yl)pyrinudine hydrochloride.

Yield : 76.5% m.p. : 257"C NMR(CDCl:i. ppm)
1.58(d, 3H), 2-21U, 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), 7.61(m, 2H), 10.33 ($, IH), I3.43(bs, IH)
Example 20
240n\i! of triethylamine and 9.7g(65.8 mmole) of 1-methyl-1,2.3,4-
tetrahydroisoquinoline were added to 25ml of 1,2-propylene glycol. Then, 15g(51 mmole) of 4-bromo-2-(4-fluprophenylaminu)-5,6- dimethyl-pyrimicline was added thereto and the mixture thereby obtained was reacted at HOC for 28 hours. The resulting produce 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-yUpyrimidine hydrochloride.
Yield : 78%
m.p. : 257 "C
NMR(CDCla, 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 8.12g(ll.2mt'., 80.3 nunole) of triethylamine, 30:n2 of n-butanol and 6-.cJ8g(44.1 mmole) of l-methyl-l,2.3,4-tetrahydroisociuinolme as prepared in Example 5 were added to 40mfi of ethylene glycol. 10. l(j(40.1 rnmole) of 4-chloro-2-(4-fluorophenylamino)-5)6-dimethylpyrirnidirie was added thereto and then reacted at 130 *C for 30 hours under refluxing to prepare 5,fi-dimethyl-2-( The reaction solution was cooled to room temperature, diluted with 30[iitJ of acetone and then added dropwise to 2QOi;td of water with stirring. After it had been stirred for 2 hours, the resulting solid product \vas filtered, washed with 60m£ of water, dissolved in 250m altered, washed with 30m£ of ethanol ~and~then— dried to obtain 9.82g purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetra-hydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 66.53%
m.p. = 255t:
NMR(CDCb, 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)
of triethylamine and 65g(442 mmole) nf l-methyl- 1,2.3,4-
tetrahydroisoquinoline as prepared in Example 7 were added to lOOmi! of
1,2-propylene glycol. 100.9g(0.40 mmole) of 4-chloro-2-(4-fluoro-
phenylamino)-5,6-dimethylpyTimidine was added thereto and then reacted nL 120 "C for 64 hours to prepare 5,6-dimethyl-2-(4-fluorophenyIamino)-4-( l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Exzumple 21 to obtain 'J5.lg of purified 5,6-dimethyl-2-(4-fluorophenylsmino)-4-(l-meLh> 1-] .2,3,4-tetrahydroisociuinolin-2-yl)pyrinudine hydrochlonde.
YkM ; 59.67%
m> : 2581:
N1MR(CDC1:,, 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), 13.43(bs, IH)
of triethylamine and 9.7g(65.8 mmole) of l-methyl- 1,2.3.4-tetraliydrdsoquinoline as prepared in Example 7 were added to 25:nV. of 1,2-propyfcne glycol. 15g(51 mmole) of 4-bn>mo-2-(4-fluorophen>|-
amino)-5,6-dimet.hylpyrimidine was added thereto and then reacted at 120 *C for 28 hours to prepare 5,6-dimethyl-2-(4-fluorophenylarnino)-4-(l-methyl-l,2,3,4-tetraliydroisoquiTiolin-2-yl)pyTimidine. 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- 1,2,3,4-tetrahydroisoquinoiin-2-yl)pyrimidine hydrochloride.
Yield : 73.28%
m.p. : 257 1
NMIKCDCh, 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). I3.43(bs, 1H)
8.12g(11.2m?., 80.3 mmole) of triethylamine, 30me of n-butanol and r».58g(44.1 mmole) of (R)-(*)-l-methyl-l,2,3,4-tetrahydroi-sonuinnrme as prepared in Example 9 were added to 40m£ of ethylene glycol. 10. Ig (40.1 mmole) of 4-chloro-2-(4-fluoropheny)amino)-5,6-dimethylpyrin\itline was added thereto and then reacted at 130°C for 30 hours under reflu.xing r.n prepare 5,f>-dimethyl-2-(4-fluorophenylamtno)-4-( 1-melhyl- 1,2,3, -1-tetrahydroisoquinolin-2-yl)pyrinudine.
The reaction solution was cooled to room temperature, diluted with 30m£ of acetone and then added dropwise to 200m£ of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60tn£ of water, dissolved in 250!)rf of dichloromethane and then washed successively with 35m£ of 4N-HC1, 35iirf of water and then 40m?. of 4N- sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate. concentrated under reduced pressure, and then diluted with 200m£ 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 30m£ of ethanol and then dried to obtain
9.21g of purified (R)-(-O-5,6-dimethyl-2-(4-fluorophenylarninn)-4-(l-methyl-l,2,3,4-tetraJiydroisoquinolin-2-yl)pyrimidJne hydrochloride.
Yield : 62.4%
m.p. : 255 1
[fllo20 : «-250* (c-1, in CHCh)
NMR(CDCl.-i, 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 23mE of criethylamine and 16g(108.5 mmole) of (RM+J-l-meLhyl-
1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to
75mf. of ethylene glycol. 25.7g(101.8 mmole) of 4-chloro-2-(4-fluoro-
phenyIamJno)-5,6-dimethylpyrimidine was added thereto and the mixture
thereby obtained was reacted at 135"C for 28 hours under refluxing to
prepare (R)-( + )-5,6-dirtiethyl-2-(4-fluoropheny In mino)-4-(l -methyl -1,2,3,
4-ieLruhydroisof|uinolin-2-yl)pyrimidine. This product was treated
according to the procedure detailed in Example 24 to obtain 33y of purified 5,6-dimeihyl-2-(4-fluorophenylamino)-4- (1-methy 1-1, 2,3,4- tctrn-hydroisoquinolin-2-yl)-pyrimidine hydrochloride.
Yield : 81.1%
m.p. : 257 "C
[a]D*° : -^250' (c-1, in CHCh)
NMR(CDCl:i. ppm) : 1.58(d. 3H), 2.21(s, 3H). 2.38(s, 3H), 2.84 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 of triethylaniine and 9.7g(65.8 mmole) of (R)-(*)-l-meLhyl-
,2,3,4-tetrahydrnisoquinoline as prepared in Example 10 were added to 25mf of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(4-fiuoro-phenylamino)-5.6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 120t for 28 hours. The reaction product was thentreated according to the procedure detailed in Example 24 to obtain 16.2g of purified 5)6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 79.97%
m.p. : 257'C
[a]n20 • -250' (c=l, in CHC13)
NMRfCDCl.,, ppm) : 1.58 2H), 4.23(m, 1H). 5.38(q, 1H), 7.25(m, 6H), 7.61(m, 2H), 10.33(s, 1H), I3.43(bs, IH)
r.xample 27
8.l2g(H.2me, 80.3 mmole) of triethylamine, 30me of n-butanol and 6.582(44.1 mmole) of (S)-(-)-l-methyl-1.2,3,4-tetrahydroisoquinolinc as prepared in Example 13 were added to 40me of echylene glycol. lO.lg (40.1 mmole) of 4-chloro-2-(4-fIuorophenylamino)-r>,ti-dimethylpyrimJdine was added thereto and then reacted at 130TJ for 30 hours under refluxing to prepare (S)-(-)-5,6-dimethy|-2-(4-fluorophenylamino)-4-(l-ethyl-l,2,3,4-tetrahydroisoquinolin-2-yi)pyriinidine.
The reaction solution was cooled to room temperature, diluted with
30rae of acetone and then added dropwise to 200^ Of water with stirring.
After it had been stirred for 2 hours, the resulting solid product was
filtered, washed with 60nii! of water, dissolved in 250m(! of dichloromethane
and washed successively with 35m£ of 4N-HC1, 35nu> nf water and 40m of
4N-sodium hydroxide solution. The dichloromethane layer was
dehydrated with anhydrous magnesium sulfate. concentrated under reduced pressure, and then diluted with 200mi of ethanol. To this reaction solution was added 45g of cone, hydrochloric acid, and the
ixture was stirred for 5 hours. The resulting solid product was filtered, washed witli 30mi of ethanol and then dried to obtain 8.95of purified (S)-(-)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-i, 2,3,4- tetrahydro)soquinolin-2-yl)pyrimidine hydrochloride.
Yield : 60.6%
m.p. - 255 "C
[a]D'° : -250' (c=l, in CHC13)
NMR(CDCI.,, ppm) : 1.58(d, 3H). 2.21(s, 3H), 2.38 1H), 3.12(m, 1H), 3.fil(m, 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, 1H), I3.43(bs, 1H)
Example 28
of triethylamine and 9.7g(65.8 mmolc) of (S)-(-)-l-methyl-1.2,3,4-tetrahydroistMiuinoline as prepared in Example 13 were added to 25T(! of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(-l-fluoro-phenylajiuno)-5,6-dirnechylpyrimidine was added thereto and then reacted at HOT. for 38 hours. The reaction product was treated according to the procedure detailed in Example 27 to obtain 15.86y of purified
5.6-climethyl-2-(4-fluorophenylaniino)-4-(l-methyl-l,2,3,4-tetrahydroiso-q u i nol i n - 2 - y 1 )pyri rtu'dine hydrochloride.
Yield : 78%
m.p. : 257 C
[a]Di0 : -250' (c=l, in CHCh)
NMR(CDC1:I, ppm) : 1.58(d, 3H), 2.2l(s, 3H), 2.38(s, 3H), 2.84(m.
1H), 3.l2(m, 1H), 3.6L(m. 2H), 4.23(m, 1H), 5.38(q, 1H), 7.25{m, 6H), 7.6l(m, 2H), 10.33 (s, 1H), 13.43(bs, 1H)

We claim
1. A process for preparing 5,6-dimethyl-2-(4-fluorophenyl-arnino)-4-(1-
methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by the
following formula (I),(Formula Removed)0
and its acid addition salts, wherein a pyrimidine derivative represented by the following formula (II-A),
(Formula Removed)
in which Hal representes a halogen, is reacted with 1-methyl-1,2,3,4-tetrahydroisoquinoline represented by the following formula (III), optionally in the presence of a solvent and optionally in the presence of the base as herein described.
(Formula Removed)
2. The process as claimed in claim 1, wherein the acid addition salt
is hydrochloride.
3. The process as claimed in claim 1, wherein the reaction is carried
out in the presence of a solvent.
4. The process as claimed in claim 3, wherein the solvent is N,N-
dimethylformamide, n-butanol, n-pentanol, n-hexanol,
dimethylsulfoxide, ethylene glyeol, 1,2-propylene glycol, or a
mixture thereof.
5. The process as claimed in claim 1, wherein the reaction is carried
out in the presence of a base.
6. The process as claimed in claim 5, wherein the said base is
triethylamine, N-N-dimethylaniline, pyridine, or potassium acetate.
7. The process as claimed in claim 1, wherein the compound of
formula (I) in the form of a (R )-(+)-isomer is prepared using (R )-
(+)-1 -methyl-1,2,3,4-tetrahydroisoquinoline.
8. A process as claimed in claim 1, wherein the compound of formula
(I) in the form of a (S)"(-)-isomer is prepared using (S)-(-)-1 -methyl-
1,2,3,4-tetrahydroisoquinoline.
9. A process for preparing 5,6-dlmethyl-2-(4-fluorophenyl-amino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine substantially as herein described in claim 1 with reference to any one of the examples 14 to 28.

Documents:

1094-del-1997-abstract.pdf

1094-del-1997-claims.pdf

1094-del-1997-complete specification (granted).pdf

1094-DEL-1997-Correspondence Others-(01-06-2011).pdf

1094-DEL-1997-Correspondence Others-(12-05-2011).pdf

1094-DEL-1997-Correspondence Others-(13-09-2011).pdf

1094-del-1997-correspondence-others.pdf

1094-del-1997-correspondence-po.pdf

1094-del-1997-description (complete).pdf

1094-del-1997-form-1.pdf

1094-DEL-1997-Form-16-(12-05-2011).pdf

1094-del-1997-form-2.pdf

1094-del-1997-form-29.pdf

1094-del-1997-form-3.pdf

1094-del-1997-form-4.pdf

1094-del-1997-form-6.pdf

1094-del-1997-pa.pdf

1094-del-1997-petition-123.pdf

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Patent Number

186440

Indian Patent Application Number

1094/DEL/1997

PG Journal Number

35/2001

Publication Date

01-Sep-2001

Grant Date

05-Apr-2002

Date of Filing

29-Apr-1997

Name of Patentee

YUHAN CORPORATION

Applicant Address

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

Inventors:

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

PCT International Classification Number

C07D 239/86

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