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WO1998018784A1 - Process for preparation of pyrimidine derivatives - Google Patents

Process for preparation of pyrimidine derivatives Download PDF

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Publication number
WO1998018784A1
WO1998018784A1 PCT/KR1997/000204 KR9700204W WO9818784A1 WO 1998018784 A1 WO1998018784 A1 WO 1998018784A1 KR 9700204 W KR9700204 W KR 9700204W WO 9818784 A1 WO9818784 A1 WO 9818784A1
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WIPO (PCT)
Prior art keywords
methyl
formula
represented
mmole
added
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PCT/KR1997/000204
Other languages
French (fr)
Inventor
You Wha Hong
Young Nam Lee
Hong Bae Kim
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Yuhan Corporation
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Publication date
Priority claimed from KR1019960049382A external-priority patent/KR100209587B1/en
Priority claimed from KR1019960049381A external-priority patent/KR100193080B1/en
Priority claimed from KR1019960049380A external-priority patent/KR0185292B1/en
Application filed by Yuhan Corporation filed Critical Yuhan Corporation
Priority to HU9903520A priority Critical patent/HU226752B1/en
Priority to BR9712392-7A priority patent/BR9712392A/en
Publication of WO1998018784A1 publication Critical patent/WO1998018784A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino) -4- (1 -methyl- 1,2,3,4-tetr ahydroiso- quinolin-2-yl)pyrimidine represented by the following formula (I) and its acid addition salts; second, to a process for preparation of an intermediate for preparing the compound (I); and, third, to a novel intermediate compound.
  • the present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by the following formula (I),
  • the first reaction inevitably produces a side product, which reduces the yield of the desired compound.
  • the present inventors have long labored to develop a novel method for preparing 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine of formula (I) without producing side products.
  • the desired compound of formula (I) can be efficiently prepared without side products by reacting the pyrimidine derivative represented by formula (II-A) with l-methyl-l,2,3,4-tetrahydroisoquinoline represented by formula (HI) and, thus, have completed the present invention.
  • the present invention relates to a novel process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroiso- quinolin-2-yl)pyrimidine represented by formula (I) and its acid addition salts.
  • 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)py ⁇ imidine represented by formula (I),
  • the present invention relates to a process for preparation of the pyrimidine derivative of formula (LI-A) and the compound of formula (LU). Further, the present invention relates to a novel intermediate compound represented by the following formula (LI), which includes the pyrimidine derivative represented by formula (II-A),
  • R represents hydroxy or a halogen
  • the compound of formula (I) can be prepared by reacting the compound of formula ( ⁇ -A) with l-methyl-l,2,3,4-tetrahydroisoquinoline of formula (ID, as depicted in the following reaction scheme 1:
  • the starting compound of the reaction scheme 1 i.e., the compound of formula (LI- A)
  • contains a single reactive site i.e., Hal
  • this reaction scheme does not produce any side product and, thus, optimizes the yield of the compound of formula (I), the desired product.
  • the reaction of the present invention is preferably carried out in the presence of a solvent.
  • Solvents which may be used for this purpose include N,N-dimethylformamide, n-butanol, n-pentanol, n-hexanol, dimethylsulfoxide, ethylene glycol, 1,2-propylene glycol, and mixtures thereof. Of these propylene glycol and ethylene glycol are most preferred, since use of either of these minimizes both reaction time and production of side products.
  • 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 the reaction between the compound of formula (H-A) and 1-methyl- 1,2,3,4-tetrahydroisoquinoline of formula (HI) is preferably in the range from 110 ° C to 160 ° C and the reaction time is preferably in the range from 16 hours to 72 hours.
  • 5,6-Dimethyl-2-(4-fluorophenylamino)-4-(l -methyl- 1,2,3,4-tetra- hydroisoquinolin-2-yl)pyrimidine of formula (I) as prepared according to the above method can be converted into its acid addition salt, preferably into the hydrochloride salt, by conventional methods.
  • the resulting product can be purified by conventional working-up procedures, such as recrystallization, chromatography, and the like.
  • the compound of formula (I) prepared by the method of the present invention contains an asymmetric carbon atom (i.e., the carbon atom denoted by * in the formula immediately below), this compound be present in an (R)-(+)-isomer, an (S)-(-)-isomer, or a racemate wherein the R and S isomers are mixed in the ratio of 1:1. Unless indicated otherwise, the compound of formula (I) should be interpreted to include all of these isomers.
  • Hal represents a halogen
  • 4-Fluorophenylguanidine carbonate of formula (IV), which is used as the starting material for preparing the compound of formula (H-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).
  • the desired 4-fluorophenylguanidine carbonate can be prepared by reacting 4-fluoroaniline with a 50% cvanamide solution under acidic conditions using 30% to 37% hydrochloric acid while maintaining the temperature ranging from 75 ° C to 95 °C .
  • the first step of the reaction scheme 2 may be practiced in the presence of a solvent.
  • Solvents which may be used for this purpose include acetonitrile, N,N- dimethylformamide and dimethylsulfoxide. This reaction is preferably carried out at a temperature ranging from 110°C to
  • Reaction solvents which can be used for this purpose include preferably N,N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane and 1,2-dichlorobenzene. It is preferable to maintain the reaction temperature in the range from 75 ° C to 95 °C .
  • the second step of the reaction scheme 2 can be practiced by isolating the intermediate after the first reaction step has been completed, it is preferable to conduct the first and second steps in a single vessel.
  • 4-hydroxy-2-(4-fluorophenylamino)-5,6- dimethylguanidine 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- phenylamino) -5,6-dimethylpyrimidine (H-A).
  • R represents hydroxy or a halogen
  • (R)- or (S)-l-methyl-l,2,3,4-tetrahydroisoquinoline is prepared by reacting (R)- or (S)-methylbenzylamine with a -chloro- a -(methyl- thio)-acetylchloride and stannous chloride (SnCl 2 ) to produce (R)- or (S)-l-methyl-4-methylthio-l,2,3,4-tetrahydroisoquinolin-3-one, respectively, then reacting the resulting compound with Raney nickel to remove a methylthio group, and finally adding a reducing agent.
  • the present inventors have long labored to find a more efficient method for producing 1 -methyl -1,2,3,4-tetrahydroisoquinoline.
  • 1 -methyl- 1,2,3,4-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 1-methyl- 1,2,3,4-tetrahydroisoquinoline is novel and is encompassed within the scope of the present invention. This novel process for preparing 1-methyl- 1, 2,3, 4-tetrahydroisoquinoline is explained in more detail below.
  • 1-methyl- 1,2,3, 4-tetrahydro- isoquinoline of formula (HI) can be prepared by reacting a -methylbenzylamine successively with 2-bromoethanol, a brominating agent and Lewis acid.
  • the method of the present invention employs the following reaction scheme 3. Reaction scheme 3
  • N-(2-hydroxyethyl)- a -methylbenzylamine is reacted with the brominating agent to produce N-(2-bromoethyl) - a -methylbenzylamine hydrobromide.
  • N-(2-bromoethyl) - a -methylbenzylamine hydrobromide is reacted with a Lewis acid to produce the desired 1-methyl- 1,2,3,4-tetrahydroisoquinoline of formula (LLD.
  • Reaction solvents which can be used in the first step include acetonitrile, N,N-dimethylformamide, dichloromethane and 1,2-dichloro- ethane and the reaction temperature is preferably maintained in the range from 40 ° 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 HOC to 145 ° C .
  • Brominating agents which can be used in this reaction include bromine, bromic aicd, aqueous bromic acid solution, and phosphorus tribromide.
  • the first and second steps of the reaction scheme 3 can be practiced by isolating N- (2 -hydroxyethyl) - 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.
  • the brominating agent is added to the vessel that contains the products of the first reaction step.
  • 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-tetrahydroisoquinoline of formula (HI).
  • 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 (IH) chloride, zinc chloride and ferrous chloride.
  • each isomeric form of the compound of formula (HI) can be efficiently prepared using the corresponding (R)-( + )- or (S)-(-)-methylbenzylamine as the starting material used in the method depicted in the reaction scheme 3.
  • Example 1 4-hvdroxy-2-(4-f.uorophenylamino)-5.6-dimethv1nvri- midine
  • Example 2 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimi- dine 40.5g ( 174.1 mmole ) of 2- ( 4-fluorophenylamino)-4-hydroxy-5,6- dimethylpyrimidine produced in Example 1 was suspended in 80m of N,N-dimethylformamide and the resulting suspension was heated to 80 °C. 31.9g(19.4m£, 210.1 mmole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 85 ° C . 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.
  • the reaction solution was stirred for 30 minutes and then diluted with 2000m(! of N,N-dimethyl- formamide.
  • To the diluted reaction solution was added 7000m£ of water over 40 minutes with stirring.
  • the reaction solution was stirred for 4 hours and the resulting solid product was filtered, washed with 1500m£ of 50% aqueous methanol solution and then dried.
  • the dried, yellowish-brown powder thereby obtained was dissolved in 4000m£ of methanol under refluxing and then cooled to 10 ° C .
  • the resulting solid product was filtered and dried to obtain 1186g of the title compound.
  • the resulting solid product was filtered, washed with 400ml! of ethyl acetate and then dried to obtain 97g of the first crop of the title ompound.
  • the filtrate was then concentrated.
  • the residue was dissolved in 450m of acetone, diluted with 680m£ of ether and then allowed to stand at 0°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.
  • 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 30m ⁇ 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 60m6 of ethanol and the resulting mixture was concentrated under reduced pressure.
  • the residue was dissolved in 50m ⁇ ! of acetone, diluted with 70m ⁇ ! of ether and then allowed to stand at 0°C for 12 hours.
  • the resulting solid product was filtered, collected and washed with 30m2 of ethyl acetate to obtain 3.1g of the second crop of the title compound.
  • 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 70m£ of ethyl acetate and then dried to obtain 20g of the first crop of the title compound.
  • the filtrate was then Q concentrated.
  • the residue was dissolved in 130ml! of ethanol and then concentrated under reduced pressure.
  • the residue was dissolved in 104 ml! of acetone, diluted with 143m£ of ether, and then allowed to stand at 0 ° C for 12 hours.
  • the resulting solid product was filtered, collected and washed with 75m of ethyl acetate to obtain 6.7g of the second crop of 5 the title compound. Yield : 64.8% m.p. : 186- 187 ° C
  • the reaction solution was cooled to room temperature, diluted with 20ml! of acetone and then added dropwise to 120m of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 30ml of water, dissolved in 150m£ of dichloromethane and then washed successively with 20ml of 4N-HC1, 20m£ of water and then 20m£ of 4N ⁇ sodium hydroxide solution.
  • the dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with lOO ⁇ of ethanol. To this reaction solution was added 30g of cone, hydrochloric acid, and the mixture thereby obtained was stirred for 5 hours.
  • 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 60m2 of water, dissolved in 250m£ of dichloromethane and washed successively first with 35m£ of 4N-HC1, 35m£ of water and then with 40m£ of 4N- sodium hydroxide solution.
  • the dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 200ml! of ethanol. To this reaction solution was added 45g of concentrated hydrochloric acid, and the mixture was stirred for 5 hours.
  • reaction solution was cooled to room temperature, diluted with
  • 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.
  • the reaction solution was cooled to room temperature, diluted with 30ml of acetone and then added dropwise to 200ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60m£ of water, dissolved in 250m£ of dichloromethane and washed successively with 35m£ of 4N-HC1, 35m£ of water and 40ml! of 4N- sodium hydroxide solution.
  • the dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 200m2 of ethanol. To this reaction solution was added 45g of cone, hydrochloric acid, and the mixture was stirred for 5 hours.
  • reaction product was treated according to the procedure detailed in Example 27 to obtain 15.86g of purified 5, 6-dimethyl-2-(4-fluorophenylamino ) -4-( 1-methyl- 1,2, 3,4- tetrahydroiso- quinolin-2-yl)pyrimidine hydrochloride.

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Abstract

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

Description

PROCESS FOR PREPARATION OF PYRIMIDINE DERIVATIVES
TECHNICAL FIELD
The present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino) -4- (1 -methyl- 1,2,3,4-tetr ahydroiso- quinolin-2-yl)pyrimidine represented by the following formula (I) and its acid addition salts; second, to a process for preparation of an intermediate for preparing the compound (I); and, third, to a novel intermediate compound. More specifically, the present invention relates, first, to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by the following formula (I),
Figure imgf000003_0001
and its acid addition salts, wherein a pyrimidine derivative represented by the following formula (LI- A),
Figure imgf000003_0002
in which Hal represents a halogen, is reacted with 1 -methyl- 1,2,3,4- tetrahydroisoquinoline represented by the following formula (LTD;
Figure imgf000004_0001
second, to a process for preparation of the pyrimidine derivative represented by formula (LI- A) and the compound of formula (HI); and, third, to a novel intermediate compound including the pyrimidine derivative represented by formula (LI- A).
BACKGROUND ART
5,6-Dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetra- hydroisoquinolin-2-yl)pyrimidine of the above formula (I) inhibits gastric acid secretion by means of a reversible proton-pump inhibiting effect and, therefore, can be used as an anti- ulcer agent. This compound was developed by the inventors of the present invention, who then applied for patents for the compound and/or its method of preparation in Korea and other countries (see International Publication No. WO 96/05177).
According to the method disclosed in the above patent application, 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4-tetrahydroisoq uinolin-2-yl)pyrϊmidine is prepared according to the following reaction scheme A:
Reaction scheme A
Figure imgf000005_0001
Figure imgf000005_0002
Since the starting material of the above reaction scheme has two reactive sites (i.e., the two Cl atoms), the first reaction inevitably produces a side product, which reduces the yield of the desired compound.
The present inventors have long labored to develop a novel method for preparing 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine of formula (I) without producing side products. As a result, we have discovered that the desired compound of formula (I) can be efficiently prepared without side products by reacting the pyrimidine derivative represented by formula (II-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-l,2,3,4-tetrahydroiso- quinolin-2-yl)pyrimidine represented by formula (I) and its acid addition salts.
More specifically, the present invention relates to a process for preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l -methyl- 1,2,3,4- tetrahydroisoquinolin-2-yl)pyτimidine represented by formula (I),
Figure imgf000006_0001
and its acid addition salts wherein a pyrimidine derivative represented by the following formula (II-A),
Figure imgf000006_0002
in which Hal represents a halogen, is reacted with 1 -methyl- 1,2,3,4- tetrahydroisoquinoline represented by formula (III),
Figure imgf000006_0003
In addition, the present invention relates to a process for preparation of the pyrimidine derivative of formula (LI-A) and the compound of formula (LU). Further, the present invention relates to a novel intermediate compound represented by the following formula (LI), which includes the pyrimidine derivative represented by formula (II-A),
Figure imgf000007_0001
in which R represents hydroxy or a halogen.
BEST MODE FOR CARRYING OUT THE INVENTION
According to the present invention, the compound of formula (I) can be prepared by reacting the compound of formula (ϋ-A) with l-methyl-l,2,3,4-tetrahydroisoquinoline of formula (ID, as depicted in the following reaction scheme 1:
Reaction scheme 1
Figure imgf000007_0002
Since the starting compound of the reaction scheme 1 (i.e., the compound of formula (LI- A)) contains a single reactive site (i.e., Hal), this reaction scheme does not produce any side product and, thus, optimizes the yield of the compound of formula (I), the desired product.
The present invention is described in more detail below. Although the 4-halogeno-2-(4-fluorophenylamino)-5,6-dimethyl- pyrimidine represented by formula (LI-A) can be reacted according to the present invention with an equivalent amount of 1 -methyl- 1,2,3, 4-tetra- hydroisoquinoline represented by formula (EH), it is preferable to conduct the reaction using an excess, rather than an equivalent amount, of the latter. Since the latter is a liquid under reaction conditions, the unreacted l-methyl-l,2,3,4-tetrahydroisoquinoline can be readily removed after the reaction has gone to completion.
The reaction of the present invention is preferably carried out in the presence of a solvent. Solvents which may be used for this purpose include N,N-dimethylformamide, n-butanol, n-pentanol, n-hexanol, dimethylsulfoxide, ethylene glycol, 1,2-propylene glycol, and mixtures thereof. Of these propylene glycol and ethylene glycol are most preferred, since use of either of these minimizes both reaction time and production of side products.
In the method of the present invention, the reaction scheme 1 is generally carried out in the presence of a base. Bases which can be used for this purpose include triethylamine, N,N-dimethylaniline, pyridine and potassium acetate. The reaction temperature for the reaction between the compound of formula (H-A) and 1-methyl- 1,2,3,4-tetrahydroisoquinoline of formula (HI) is preferably in the range from 110°C to 160°C and the reaction time is preferably in the range from 16 hours to 72 hours.
5,6-Dimethyl-2-(4-fluorophenylamino)-4-(l -methyl- 1,2,3,4-tetra- hydroisoquinolin-2-yl)pyrimidine of formula (I) as prepared according to the above method can be converted into its acid addition salt, preferably into the hydrochloride salt, by conventional methods. The resulting product can be purified by conventional working-up procedures, such as recrystallization, chromatography, and the like.
Since the compound of formula (I) prepared by the method of the present invention contains an asymmetric carbon atom (i.e., the carbon atom denoted by * in the formula immediately below), this compound be present in an (R)-(+)-isomer, an (S)-(-)-isomer, or a racemate wherein the R and S isomers are mixed in the ratio of 1:1. Unless indicated otherwise, the compound of formula (I) should be interpreted to include all of these isomers.
Figure imgf000009_0001
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 (IH).
The compound of formula (H-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 2
Figure imgf000010_0001
(H-B)
(Π-A)
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 (II-B), which may then be reacted with a halogenating agent to obtain the 4-halogeno-2-(4-fluorophenylamino)- 5,6-dimethylpyrimidine of formula (II-A).
4-Fluorophenylguanidine carbonate of formula (IV), which is used as the starting material for preparing the compound of formula (H-A) in the reaction scheme 2, can readily be prepared from 4-fluoroaniline using known methods (see, for example, European Patent No. 0,560,726). Specifically, the desired 4-fluorophenylguanidine carbonate can be prepared by reacting 4-fluoroaniline with a 50% cvanamide solution under acidic conditions using 30% to 37% hydrochloric acid while maintaining the temperature ranging from 75 °C to 95 °C .
The first step of the reaction scheme 2 may be practiced in the presence of a solvent. Solvents which may be used for this purpose include acetonitrile, N,N- dimethylformamide and dimethylsulfoxide. This reaction is preferably carried out at a temperature ranging from 110°C to
1601
In the second step of the reaction scheme 2, 4-hydroxy-2-(4- fluorophenylamino)-5,6-dimethylpyrimidine of formula (H-B) obtained from the first step of the reaction scheme 2 is converted into the compoimd of formula (H-A) by reacting the former with a halogenating agent. Halogenating agents which can be used for this purpose include phosphorus oxychloride, oxalyl chloride, thionyl chloride and phosphorus tribromide. This halogenation reaction is carried out in the presence of a solvent. Reaction solvents which can be used for this purpose include preferably N,N-dimethylformamide, dimethylsulfoxide, 1,2-dichloroethane and 1,2-dichlorobenzene. It is preferable to maintain the reaction temperature in the range from 75 °C to 95 °C .
Although the second step of the reaction scheme 2 can be practiced by isolating the intermediate after the first reaction step has been completed, it is preferable to conduct the first and second steps in a single vessel. Specifically, 4-hydroxy-2-(4-fluorophenylamino)-5,6- dimethylguanidine 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- phenylamino) -5,6-dimethylpyrimidine (H-A).
The compound of formula (H-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 (H-B) produced as the intermediate in the reaction scheme 2. Both novel compounds can be represented by the following formula (H), which is within the scope of the present invention,
Figure imgf000011_0001
in which R represents hydroxy or a halogen.
1 -Methyl- 1,2,3,4-tetrahydroisoquinoline of formula (HI), which is also used as the starting material in the reaction scheme 1, is a lcnown compound and can be preapred by known methods (see, for example, International Publication No. WO 94/14795). According to this lcnown method, (R)- or (S)-l-methyl-l,2,3,4-tetrahydroisoquinoline is prepared by reacting (R)- or (S)-methylbenzylamine with a -chloro- a -(methyl- thio)-acetylchloride and stannous chloride (SnCl2) to produce (R)- or (S)-l-methyl-4-methylthio-l,2,3,4-tetrahydroisoquinolin-3-one, respectively, then reacting the resulting compound with Raney nickel to remove a methylthio group, and finally adding a reducing agent. However, this method is disadvantageous, since a -chloro- a -(methylthio)-acetylchloride, which is used as the starting material, is both unstable and explosive, so that this method cannot be practiced on an industrial scale. Further, since the reaction step is long, the total yield is low, which makes this method uneconomical.
The present inventors have long labored to find a more efficient method for producing 1 -methyl -1,2,3,4-tetrahydroisoquinoline. We have discovered that 1 -methyl- 1,2,3,4-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 1-methyl- 1,2,3,4-tetrahydroisoquinoline is novel and is encompassed within the scope of the present invention. This novel process for preparing 1-methyl- 1, 2,3, 4-tetrahydroisoquinoline is explained in more detail below.
According to the present invention, 1-methyl- 1,2,3, 4-tetrahydro- isoquinoline of formula (HI) can be prepared by reacting a -methylbenzylamine successively with 2-bromoethanol, a brominating agent and Lewis acid. The method of the present invention employs the following reaction scheme 3. Reaction scheme 3
2-bromoethanol
(first step)
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
(III)
All of the starting materials and reactants used in the reaction scheme 3 are lcnown compounds and can be obtained as commercial products. In the first step a -methylbenzylamine is reacted with
2-bromoethanol to produce N-(2-hydroxyethyl)- a -methylbenzylamine, which in turn is reacted with the brominating agent to produce N-(2-bromoethyl) - a -methylbenzylamine hydrobromide. In the third step, N-(2-bromoethyl) - a -methylbenzylamine hydrobromide is reacted with a Lewis acid to produce the desired 1-methyl- 1,2,3,4-tetrahydroisoquinoline of formula (LLD.
Reaction solvents which can be used in the first step include acetonitrile, N,N-dimethylformamide, dichloromethane and 1,2-dichloro- ethane and the reaction temperature is preferably maintained in the range from 40°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 HOC to 145°C . Brominating agents which can be used in this reaction include bromine, bromic aicd, aqueous bromic acid solution, and phosphorus tribromide.
Although the first and second steps of the reaction scheme 3 can be practiced by isolating N- (2 -hydroxyethyl) - 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-tetrahydroisoquinoline of formula (HI). 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 (IH) chloride, zinc chloride and ferrous chloride.
Since 1-methyl- 1,2,3,4-tetrahydroisoquinoline can be economically prepared according to the above method, the desired 5,6-dimethyl -2- (4-fluorophenylamino)-4-( 1-methyl- 1,2, 3, 4-tetrahydroisoquinolin-2-yl) -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 (IH) in the form of (R)-( + )- or (S)-( -)-isomer as the starting material for preparation of the compound of formula (I) according to the present invention, each isomeric form of the compound of formula (HI) can be efficiently prepared using the corresponding (R)-( + )- or (S)-(-)-methylbenzylamine as the starting material used in the method depicted in the reaction scheme 3.
The present invention will be illustrated in detail by the following examples. However, it should be understood that the present invention is not in any manner limited by these examples.
Preparation : 4-fluoroDheπyltruanidine carbonate
882g(747m«) of 32% hydrochloric acid was added to 1000g(8.9 mole) of 4-fluoroaniline, the mixture was warmed to 87°C , and 780m£(9.9 mole) of 50% cyanamide solution was added dropwise thereto over 2 hours. The reaction solution was adjusted to pH 2.4 by adding thereto 120mϋ of 32% hydrochloric acid, stirred for 3 hours, and cooled to 60°C. Aqueous sodium carbonate solution (Na2CO3 578g/water 1640m£) 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. : 175 °C
NMR(DMSO-d6, ppm) : 5.50-6.88(bs, 5H), 6.87(m, 211), 7.17(m,
2H)
Example 1 : 4-hvdroxy-2-(4-f.uorophenylamino)-5.6-dimethv1nvri- midine
54.5g(253.2 mmole) of 4-fluorophenylguanidine carbonate produced in the Preparation above was suspended in 50mϋ of N,N-dimethylform- amide 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 100m£ of N,N-dimethylformamide and cooled to 80°C. 160m£ of isopropylalcohol was added thereto and the resulting mixture was stirred for 30 minutes. The resulting solid product was filtered, washed with 150m£ of acetone, and finally dried to obtain 41g of the title compound.
Yield : 61.4% m.p. : 256 °C
NMR(DMSO-d6, ppm) : 1.83(s, 3H), 2.19(s, 3H), 7.18(t, 2H), 7.68
(m, 2H), 9.36(bs, IH), 10.63(bs, IH)
Example 2 : 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimi- dine 40.5g(174.1 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6- dimethylpyrimidine produced in Example 1 was suspended in 80m of N,N-dimethylformamide and the resulting suspension was heated to 80 °C. 31.9g(19.4m£, 210.1 mmole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 85 °C . 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. : 114t NMR(CDCl3, ppm) : 2.21(s, 3H), 2.41(s, 311), 7.01(t, 211), 7.18(bs,
IH), 7.56(t, 2H)
Example 3 : 4-chloro-2- (4-fluoronhcnylamino)-5,6-dimethylpyrimi- diπe
1390g(7.6 mole) of 4-fluorophenylguanidine carbonate produced by the Preparation above was suspended in 1300m£ of N,N-dimethylform- amide and 1206g(8.4 mole) of ethyl 2-methylacetoacetate. The resulting suspension was heated under refluxing for one hour, distilled at normal pressure to 1100ml! and then distilled until the temperature of the reaction solution reached 160 °C . 1600m£ of N,N- dimethylformamide was added to the residue and then cooled to 80°C . 1388g(840m2, 9.1 mole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 80 °C to 85°C . The reaction solution was stirred for 30 minutes and then diluted with 2000m(! of N,N-dimethyl- formamide. To the diluted reaction solution was added 7000m£ of water over 40 minutes with stirring. The reaction solution was stirred for 4 hours and the resulting solid product was filtered, washed with 1500m£ of 50% aqueous methanol solution and then dried. The dried, yellowish-brown powder thereby obtained was dissolved in 4000m£ of methanol under refluxing and then cooled to 10 °C . The resulting solid product was filtered and dried to obtain 1186g of the title compound.
Yield : 62.4% m.p. : 114°C
NMR(CDC13, ppm) : 2.21(s, 3H), 2.41(s, 3H), 7.01(t, 2H), 7.18(bs,
IH), 7.56(t, 2H)
F.ynmple 4 : 4-bromo-2- (4~fluorophenylaπιino)-5.6-dimethylpyri- midine
5g(21.44 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6- dimethylpyrimidine produced in Example 1 was suspended in 40m£ of N,N-dimethylformamide and the resulting suspension was warmed to 65 °C . 8.1g(30 mmole) of phosphorus tribromide was added dropwise thereto over 20 minutes and the resulting mixture was allowed to react at 75 "C for 30 minutes. The reaction solution was cooled to room temperature, poured onto 500g of ice- water, adjusted to pH 11 with sodium hydroxide solution, stirred for 30 minutes and then adjusted again to 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. : 123 °C
NMR(CDC13 ppm) : 2.21(s, 3LI), 2.42(s, 3H), 6.98(t, 2H), 7.24(s,
IH), 7.54(g, 2H)
Exnmnle 5 : l-methyl- 1.2.3.4-tetrahvdroisoαmnoHne
(1) Preparation of N-(2-hydroxyethyl)- a -methylbenzylamine:
103.08g(0.86 mole) of a -methylbenzylamine was dissolved in 110 m6 of dichloromethane and 127.56g( 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 109g of the title compound, which had a pale yellow color.
Yield : 76.7% m.p. 60°C/0.5torr
NMR(CDC13, ppm) : 1.38(d, 3H), 2.40(bs, IH), 2.61(m, 2H), 3.58(m,
2H), 3.78(q, IH), 7.18-7.38(m, 5H)
(2) Preparation of N-(2-bromoethyl)~ a -methylbenzylamine hydrobromide:
100g(605.32 mmole) of N-(2-hydroxyethyl)- a -methylbenzylamine produced in Example 5(1) above was suspended in 515m£ of 48% aqueous hydrobromic acid solution and the resulting suspension was reacted at 126 "C for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 465m2 of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 550m of acetone, and 500m£ of ethyl acetate and 670m£ 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 400ml! of ethyl acetate and then dried to obtain 97g of the first crop of the title ompound. The filtrate was then concentrated. The residue was dissolved in 450m of acetone, diluted with 680m£ of ether and then allowed to stand at 0°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. : 186-187°C
NMR(CDC13, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q,
IH), 7.40-7.72(m, 5H), 9.51(bs, IH), 9.91(bs,
IH)
(3) Preparation of l-methyl-l,2,3,4-tetrahydroisoquinoline 50.0g(161.8 mmole) of N-(2-bromoethyl)- a -methylbenzylamine hydrobromide produced in Example 5(2) above was suspended in 450mϋ of decalin and then heated to 140°C . 64.70g(485.4 mmole) of anhydrous aluminum chloride (AlC ) 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 1000m£ 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 2100m£ of ethyl acetate. The extracts were combined, washed with 420m2 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. lg of the title compound.
Yield : 75.99% b.p. : 79-80°C/0.5torr NMR(CDC13, ppm) : 1.59(d, 311), 2.14(s, HI), 2.76-3.02(m, 211),
3.1()-3.22(m, IH), 3.34-3.45(m, HI), 4.22(q,
IH), 7.18-7.31(m, 4H)
Example 6 : l-methyl- 1.2.3.4-tetrahvdfoisoαuinoIine
(1) Preparation of N-(2-bromoethyl)- a -methylbenzylamine hydrobromide:
76.61g(630 mmole) of a -methylbenzylamine was dissolved in 77m£ 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 286.4m(!(2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and 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 250m£ 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 °C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50m£ of ethyl acetate and then dried to obtain 128.9g of the title ompound.
Yield : 66.2% m.p. : 186- 187 °C
NMR(CDC13, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q, 0 IH), 7.40-7.72(m, 5H), 9.51(bs, IH), 9.91(bs,
IH)
(2) Preparation of l-methyl-l,2,3,4-tetrahydroisoquinoline
5 10.0g(30.1 mmole) of N- (2-bromoethyl)- a -methylbenzylamine hydrobromide produced in Example 6(1) above was suspended in 60m2 of 1,2-dichlorobenzene and then heated to 145 "C . 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 o 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 12 with sodium 5 hydroxide and then extracted three times, each time with 250m2 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 2.90g of the title compound. 0
Yield : 65.39% b.p. : 79-80°C/0.5torr
NMR(CDC13, ppm) : 1.59(d, 3H), 2.14(s, IH), 2.76-3.02(m, 2H),
3.10-3.22(m, IH), 3.34-3.45(m, IH), 4.22(q, 5 IH), 7.18-7.31(m, 4H) Eynmnle 7 : l-methyl- 1.2.3.4-tetrahvdroisoαuinoline
200g(647.17 mmole) of N-(2-bromoethyl)- a -methylbenzylamine hydrobromide produced in Example 5(2) or Example 6(1) above was suspended in 700ml! 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 0 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 2500mϋ of ethyl acetate, and then the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and then extracted three times, each time with 3000ml! of ethyl acetate. 5 The extracts were combined, washed with 550m of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 78.9g of the title compound.
0 Yield : 82.8% b.p. : 79-80°C/0.5torr
NMR(CDC13, ppm) : 1.59(d, 311), 2.14(s, IH), 2.76-3.02(m, 211),
3.10-3.22(m, HI), 3.34-3.45(m, HI), 4.22(q, IH), 7.18-7.31(m, 4H) 5
Example 8 : (R)-( + )- l-methyl- 1,2,3,4-tetrahydroisoquinoline
(1) Preparation of (R)-(+)-N-(2-hydroxyethyl)- a -methylbenzylamine:
Q 51.45g(0.43 mmole) of (R)-( + )- a -methylbenzylamine was dissolved in 52m£ of dichloromethane and 63.78g(0.51 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 the residue was subjected to fractional 5 distillation to obtain 54g of the title compound having pale yellow color. Yield : 76% m.p. : 60°C/0.5torr [ a h20 : +55° (c=l, in CHC13)
NMR(CDC13, ppm) : 1.38(d, 3H), 2.40(bs, IH), 2.61(m, 2H), 3.58(m,
2H), 3.78(q, IH), 7.18-7.38(m, 5H)
(2) Preparation of (R)-(+)-N-(2-bromoethyl)- a -methylbenzylamine hydrobromide:
11.0g(66.58 mmole) of (R)-( + )-N-(2-hydroxyethyl)- a -methylbenzylamine produced in Example 8(1) above was suspended in 52m<! 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 55mϋ of acetone, and 50m(! of ethyl acetate and 70ml! 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 30mϋ 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 60m6 of ethanol and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in 50m<! of acetone, diluted with 70m<! of ether and then allowed to stand at 0°C for 12 hours. The resulting solid product was filtered, collected and washed with 30m2 of ethyl acetate to obtain 3.1g of the second crop of the title compound.
Yield : 64% m.p. : 186- 187 °C
I a h20 : +32.1° (c=l, in CHC13)
NMR(CDC13, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q,
IH), 7.40-7.72(m, 5H), 9.51(bs, IH), 9.91(bs,
IH)
(3) Preparation of (R)-( + )-l-methyl-l,2,3,4-tetralιydroisoquinoline 5.0g(16.18 mmole) of (R)-( + )-N-(2-bromoethyl)- a -methylbenzylamine hydrobromide produced in the above (2) was suspended in 50m£ of decalin and the resulting suspension was heated to 140 "C . 6.470g (48.54 mmole) of anhydrous aluminum chloride (AICI3) 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. 20m£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with lOOmβ 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°C/0.5tor [ a 20 ■ +85.5° (c=l, in CHCI3)
NMR(CDC13, pm) : 1.59(d, 311), 2.14(s, IH), 2.76-3.02(m, 2H),
3.10-3.22(m, IH), 3.34-3.45(m, IH), 4.22(q,
IH), 7.18-7.31(m, 4H)
Example 9 : (R)- ( + )- l-methyl- 1.2,3.4-tetrahvdroisoouinoline
(1) Preparation of (R) -( + )-N-(2-bromoethyl)- a -methylbenzylamine hyd¬ robromide:
76.61g(630 mmole) of (R)-( +)- a -methylbenzylamine was dissolved in 77m£ 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 286.4m£(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 250ml! 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 °C and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50mϋ of ethyl acetate, and then dried to obtain 127.5g of the title compound.
0 Yield : 65.5% m.p. : 186-187°C
U ]D 20 : +32.1* (c = l, in CIICls)
NMR(CDC13, ppm) : 1.94(d, 311), 3.21(m, 211), 3.82(m, 2H), 4.42(q,
IH), 7.40-7.72(m, 511), 9.51(bs, IH), 9.91(bs, 5 IH)
(2) Preparation of (R)-( + )-l-methyl-l,2,3,4-tetrahydroisoquinoline
10.0g(30.1 mmole) of (R)-( + )-N-(2-bromoethyl)- a -methylbenzyl¬ 0 amine hydrobromide produced in Example 9(1) above was suspended in 60m<! of 1,2-dichlorobenzene and then heated to 145°C. I3.47g(96.54 mmole) of anhydrous aluminum chloride (A1C13) 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 5 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 12 with sodium hydroxide and then extracted three times, each time with 250mϋ of ethyl Q acetate. The extracts were combined, washed with 40m6 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.
5 Yield : 69% b.p. : 79-80°C/0.5torr [ a h20 : +85.5° (c=l, in CHC13)
NMR(CDC13, ppm) : 1.59(d, 3H), 2.14(s, IH), 2.76-3.02(m, 2H),
3.10-3.22(m, IH), 3.34-3.45(m, IH), 4.22(q, IH), 7.18-7.31(m, 4H)
Evnmnle 10 : (R)-( + )- l-methyl- l,2,3,4-tetrahvdroisoouinoline
73.45g(240 mmole) of (R)-( + )-N-(2-bromoethyl)- a -methylbenzyl- amine hydrobromide produced in Example 9(1) above was suspended in
260mg of decalin and the resulting suspension was heated to 150 °C.
95.10g(710 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 for 10 minutes. This solution was washed three times, each time with 700ml! of ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and extracted three times, each time with 900m(! of ethyl acetate. The extracts were combined, washed with 200m2 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 [ α ]D 20 : +85.5° (c=l, in CHCI3)
NMR(CDC13, ppm) : 1.59(d, 3H), 2.14(s, IH), 2.76-3.02(m, 2H), 3.10-3.22(m, IH), 3.34-3.45(m, IH), 4.22(q,
IH), 7.18-7.31(m, 4H)
Example 11 : (S)-(-)- l-methyl- 1.2.3.4~tetrahydroisoquinoline
(1) Preparation of (S)-(-)-N-(2-hydroxyethyl)- a -methylbenzylamine: 108.23g(0.903 mmole) of (S)-(-)- a -methylbenzylamine was dissolved in 140ml! 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% 0 m.p. : 60°C/0.5torr
U ]D 20 : -55° (c=l, in CHC13)
NMR(CDC13, ppm) : 1.38(d, 311), 2.40(bs, IH), 2.61(m, 2H), 3.58(m,
2H), 3.78(q, IH), 7.18-7.38(m, 511)
5 (2) Preparation of (S)-(-)-N-(2-bromoethyl)- a -methylbenzylamine hydrobromide:
22.1g(133.16 mmole) of (S)-(-)-N-(2-hydroxyethyl)- a -methyl- bezylamine produced in Example 11(1) above was suspended in 105m2 of 0 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 95m(! of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 112ml! of 5 acetone, and 100ml! of ethyl acetate and 150m£ 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 70m£ of ethyl acetate and then dried to obtain 20g of the first crop of the title compound. The filtrate was then Q concentrated. The residue was dissolved in 130ml! of ethanol and then concentrated under reduced pressure. The residue was dissolved in 104 ml! of acetone, diluted with 143m£ of ether, and then allowed to stand at 0 °C for 12 hours. The resulting solid product was filtered, collected and washed with 75m of ethyl acetate to obtain 6.7g of the second crop of 5 the title compound. Yield : 64.8% m.p. : 186- 187 °C
[ a h20 : -32.1° (c=l, in CHC13)
NMR(CDC13, ppm) : 1.94(d, 3H), 3.21(m, 2H), 3.82(m, 2H), 4.42(q,
IH), 7.40-7.72(m, 5H), 9.51(bs, IH), 9.91(bs,
IH)
(3) Preparation of (S)-(-)-l-methyl-l,2,3,4-tetrahydroisoquinoline
5.0g(16.18 mmole) of (S)-(-)-N-(2-bromoethyl)- a -methylbenzylamine hydrobromide produced in Example (2) above was suspended in 50 ml of decalin and then heated to 140 °C . 6.47g(48.54 mmole) of anhydrous aluminum chloride (A1C13) 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. 20mϋ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with lOOmβ of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250m2 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 1.75g of the title compound.
Yield : 73.5% b.p. : 79-80 °C/0.5torr l a 20 ■ -85.5° (c=l, in CHC ) NMR(CDC13) ppm) : 1.59(d, 3H), 2.14(s, IH), 2.76-3.02(m, 2H),
3.10-3.22(m, IH), 3.34-3.45(m, IH), 4.22(q,
IH), 7.18-7.31(m, 4H)
Example 12 : (S)-(-)- l-methyl- 1.2.3.4-tetrahvdroisoquinoline
(1) Preparation of (S)-(-)-N-(2-bromoethyl)- a -methylbenzylamine hyd- robromide:
176.20g(1449 mmole) of (S)-(-)- a -methylbenzylamine was dissolved in 185m£ of dichloromethane and 218.04g( 1748 mmole) of
5 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 658m£(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
10 refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature to remove 580m£ of water as the by-product and aqueous hydrobromic acid solution. The residue was dissolved in 760m of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10°C and then allowed to stand for 3 hours.
15 The resulting solid product was filtered, washed with 150ml! of ethyl acetate and then dried to obtain 306.5g of the title ompound.
Yield : 68.4% m.p. : 185 °C 20 C tf -D20 = -32.1° (c=l, in CHC )
NMR(CDC13, ppm) : 1.94(d, 311), 3.21(m, 211), 3.82(m, 211), 4.42(q,
III), 7.40-7.72(m, 511), 9.51(bs, IH), 9.91(bs, IH)
25 (2) Preparation of (S)-(-)-l-methyl-l,2,3,4-tetraiιydroisoquinoline
10.0g(30.1 mmole) of (S)-(-)-N-(2-bromoethyl)- -methylbenzyl¬ amine hydrobromide produced in Example 12(1) above was suspended in 60m£ of 1,2-dichlorobenzene and then heated to 145°C . 13.47g(96.54
„ mmole) of anhydrous aluminum chloride (AICI3) 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
3 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 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 3.10g of the title compound.
Yield : 69.96% b.p. : 79-80°C/0.5torr [ α ]D 20 : -85.5° (c=l, in CHC13) NMR(CDC13, ppm) : 1.59(d, 3H), 2.14(s, IH), 2.76-3.02(m, 2H),
3.10-3.22(m, 111), 3.34-3.45(m, IH), 4.22(q,
IH), 7.18-7.31(m, 4H)
Example 13 (S )- ( - )- 1-methyl- 1,2,3,4-tetrahydroisoquinoline
73.45g(240 mmole) of (S)-( -)-N-(2-bromoethyl) - a -methylbenzylamine hydrobromide produced in Example 12( 1) above was suspended in 260mf! of decalin and the resulting suspension was heated to 150 °C . 95.10g(710 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 1600g of ice-water with stirring. 70m£ of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 700m£ 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 900nιl! of ethyl acetate. The extracts were combined, washed with 2Q0ml 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. : 79-80°C/0.5torr [ a h20 : -85.5° (c=l, in CHC13) NMR(CDC13, ppm) : 1.59(d, 3H), 2.14(s, IH), 2.76-3.02(m, 2H),
3.10-3.22(m, IH), 3.34-3.45(m, IH), 4.22(q, IH), 7.18-7.31(m, 4H)
Preparation of 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-
1J2.3.4-tetrahvdroisoαuinolin-2-yl)pyrimidine and its hvdrochloride
In Examples 14 to 20, inclusive, 1-methyl- 1,2,3,4-tetrahydroisoquinoline prepared according to the method disclosed in International Publication No. WO 94/14795 was used as the reactant.
Eynmnle 14
2.65g(27 mmole) of potassium acetate and 4.0g(26.9 mmole) of l-methyl-l,2,3,4-tetrahydroisoquinoline were added to 85m£ of n-hexanol and then warmed to 80 °C . 6.17g(24.5 mmole) of 4-chloro-2-(4-fluoro- phenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 140°C for 28 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluo- rophenylamino)-4-( 1-methyl- 1,2,3, 4- tetrahydroisoquinolin-2-yl)pyrimidine.
The reaction solution was cooled to room temperature, diluted with 20ml! of acetone and then added dropwise to 120m of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 30ml of water, dissolved in 150m£ of dichloromethane and then washed successively with 20ml of 4N-HC1, 20m£ of water and then 20m£ of 4N~sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with lOO δ of ethanol. To this reaction solution was added 30g of cone, hydrochloric acid, and the mixture thereby obtained was stirred for 5 hours. The resulting solid product was filtered, washed with 20ml? of ethanol and then dried to obtain 6.1g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 62.4% m.p. : 255 °C
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Example 15
8.12g(11.2ml!, 80.3 mmole) of triethylamine, 30m£ of n-butanol and 6.58g(44.1 mmole) of l-methyI-l,2,3,4-tetrahydroisoquinoline were added to 40m£ of ethylene glycol. 10.1g(40.1 mmole) of 4-chloro-2-(4-fluoro- phenylarrιino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130°C for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4- fluorophenylamino)-4-( 1- methyl- 1,2,3, 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- aιnino)-4-( 1-methyl- 1, 2,3,4- tetralιydroisoquinoIin-2-yl)pyrimidine hydro- chloride.
Yield : 91% m.p. : 256 °C
N R(CDC13, ppm) : 1.58(d, 311), 2.21(s, 311), 2.38(s, 311), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 211), 10.33 (s, IH), 13.43(bs, HI)
Example 16
45m£ of triethylamine, 50m of n-butanol and 32g(217 mmole) of l-methyl-l,2,3,4-tetralαydroisoquinoline were added to 150ml of ethylene glycol. 51.3g(203.8 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6- dimethylpyrimidine was added thereto and then reacted at 135 °C for 28 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)- 4-(l -methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 66g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2, 3,4-tetrahydroiso-quinolin-2-yl)pyrimidine hydrochloride.
Yield : 81.1% m.p. : 256 °C
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 311), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Exnmple 17
75m£ of triethylamine and 65g(442 mmole) of 1-methyl-l, 2,3,4- tetrahydroisoquinoline were added to 100ml! of 1,2-propylene glycol. 100.9g(0.40 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dime- thylpyrimidine was added thereto and then reacted at 120 °C for 64 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 91g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4- tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 57.1% m.p. : 258 °C NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Example 18
720m£ of triethylamine and 695g(4.72 mmole) of 1-methyl -1,2,3,4- tetrahydroisoquinoline were added to 2100ml! of 1,2-propylene glycol. 1179g(4.68 mmole) of 4-chloro-2-(4-fluorophenylamino)-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-fluorophenyl- am o)-4-(l-methyl-l,2,3,4-tetxahydroisoquinolin-2-yl)ρyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 1250g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 66.9% m.p. •" 258 °C
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH),
5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33
(s, IH), 13.43(bs, IH)
Exnmnlp; 19
llOmϋ of n-butanol, 240m£ of triethylamine and 236g(1.60 mmole) of l-methyl-l,2,3,4-tetrahydroisoquinoline were added to 600m£ of ethylene glycol. 400g(1.59 mmole) of 4-chloro-2-(4-fluorophenyl- amino)-5,6-dimethylpyrimidine was added thereto and then reacted at 140 °C for 48 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4- (l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 485g of purified 5,6-dimethyl-2-(4-fluorophenylamino) -4-(l-methyl- l,2,3,4-tetral ydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 76.5% m.p. : 257 "C
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33
(s, IH), 13.43(bs, IH)
Ryam lR 20
240m£ 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-fluorophenylamino)-5,6- dimethyl- pyrimidine was added thereto and the mixture thereby obtained was reacted at 110°C for 28 hours. The resulting product was treated according to the procedure detailed in Example 14 to obtain 15.86g of purified 5,6-dimethyl-2-(4-fluorophenylamino) -4-( 1-methyl- 1,2,3,4-tetra- hydroi soquinolin - yl )pyrimidine hydrochloride.
Yield : 78% m.p. : 257°C
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 311), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 611), 7.61(m, 2H), 10.33 (s, HI), 13.43(bs, III)
Example 21
8.12g(11.2m£, 80.3 mmole) of triethylamine, 30ml! of n-butanol and 6.58g(44.1 mmole) of 1-methyl- 1,2,3,4-tetrahydroisoquinoline as prepared in Example 5 were added to 40m£ of ethylene glycol. 10.1g(40.1 mmole) of 4-chloro-2-(4-fluorophenylarnino)-5,6-dimethylpyrirnidine was added thereto and then reacted at 130 °C for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-( 1-methyl- 1,2, 3,4-tetra- hydroisoquinolin-2-yl)pyrimidine.
The reaction solution was cooled to room temperature, diluted with 30m£ of acetone and then added dropwise to 200mϋ of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60m2 of water, dissolved in 250m£ of dichloromethane and washed successively first with 35m£ of 4N-HC1, 35m£ of water and then with 40m£ of 4N- sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 200ml! of ethanol. To this reaction solution was added 45g of concentrated hydrochloric acid, and the mixture was stirred for 5 hours. The resulting solid product was filtered, washed with 30ml of ethanol and then dried to obtain 9.82g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-( 1-methyl- 1,2,3,4-tetra- hydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 66.53% m.p. : 255 °C
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, III), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Example 22
75m£ of triethylamine and 65g(442 mmole) of 1-methyl- 1,2,3,4- tetraliydroisoquinoline as prepared in Example 7 were added to 100ml! of 1,2-propylene glycol. 100.9g(0.40 mmole) of 4-chloro-2-(4-fluoro- phenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 120°C for 64 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)- 4- (1 -methyl- 1, 2,3, 4-tetralιydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 21 to obtain 95. lg of purified 5,6-dimethyl-2-(4-fhιorophenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 59.67% m.p. : 258 °C
NMR(CDC13, ppm) : 1.58(d, 311), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, 111), 3.61(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)
Example 23
14m of triethylamine and 9.7g(65.8 mmole) of 1-methyl- 1,2,3,4- tetrahydroisoquinoline as prepared in Example 7 were added to 25ml of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(4-fluorophenyl- amino)-5,6-dimethylpyrimidine was added thereto and then reacted at 120 °C for 28 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl-l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 21 to obtain 14.9g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4- tetrahydroisoquinolin- 2 - yDpyrimidine hydrochloride.
Yield : 73.28% m.p. : 257 °C NMR(CDC1 , ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 311), 2.84(m,
III), 3.12(m, IH), 3.61(m, 211), 4.23(m, IH), 5.38(q, HI), 7.25(m, 6H), 7.61(m, 211), 10.33 (s, IH), 13.43(bs, IH)
Example 24
8.12g(11.2m6, 80.3 mmole) of triethylamine, 30m£ of n-butanol and 6.58g(44.1 mmole) of (R)-( + )- 1-methyl- 1,2,3,4-tetrahydroisoquinoline as prepared in Example 9 were added to 40m£ of ethylene glycol. 10. lg (40.1 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130 °C for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl-l,2,3,4- tetrahydroisoquinolin-2-yl)pyrimidine.
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 60m£ of water, dissolved in 250m of dichloromethane and then washed successively with 35ml of 4N-HC1, 35m£ 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 30mϋ of ethanol and then dried to obtain 9.21g of purified (R)-(+)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 62.4% m.p. 255 "C
[ ff ]D 20 : +250° (c = l, in CHCI3)
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H),' 10.33 (s, IH), 13.43(bs, IH)
Exnmpl 25
23ml of triethylamine and 16g(108.5 mmole) of (R)-(+)- l~methyl- 1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to 75m£ of ethylene glycol. 25.7g(101.8 mmole) of 4-chloro-2-(4-fluoro- phenylamino)-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-dimethyl-2-(4-fluorophenylamino)-4-( 1-methyl- 1,2,3, 4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 24 to obtain 33g of purified 5, 6-dimethyl-2-(4-fluorophenylamino) -4- (1-methyl- 1,2,3, 4-tetra- hydroisoquinolin-2-yl) -pyrimidine hydrochloride.
Yield : 81.1% m.p. : 257 °C
[ α ]D 20 = +250° (c=l, in CHC13)
NMR(CDC13, ppm) : 1.58(d, 311), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33
(s, IH), 13.43(bs, IH)
Eynmple 26
14πv£ of triethylamine and 9.7g(65.8 mmole) of (R)-( + )-l-methyl- 1,2,3,4-tetrahydroisoquinoline as prepared in Example 10 were added to 25ml of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(4-fluoro- phenylamino)-5,6-dimethylpyrimidine was added thereto and the mixture thereby obtained was reacted at 120 °C 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 ID20 : +250° (c=l, in CHCla)
NMR(CDC13, ppm) : 1.58(d, 311), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, HI), 3.12(m, HI), 3.61(m, 211), 4.23(m, IH), 5.38(q, IH), 7.25(m, 611), 7.61(m, 2H), 10.33(s, IH), 13.43(bs, IH)
Example 27
8.12g(11.2m£, 80.3 mmole) of triethylamine, 30m6 of n-butanol and 6.58g(44.1 mmole) of (S)-(-)-l-methyl-T,2.3,4-tetrahydroisoquinoline as prepared in Example 13 were added to 40m£ of ethylene glycol. 10. lg
(40.1 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130 °C for 30 hours under refluxing to prepare (S)-(-)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(l- ethyl- 1,2,3, 4-tetrahydroisoquinolin-2-yl)pyrimidine.
The reaction solution was cooled to room temperature, diluted with 30ml of acetone and then added dropwise to 200ml of water with stirring. After it had been stirred for 2 hours, the resulting solid product was filtered, washed with 60m£ of water, dissolved in 250m£ of dichloromethane and washed successively with 35m£ of 4N-HC1, 35m£ of water and 40ml! of 4N- sodium hydroxide solution. The dichloromethane layer was dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and then diluted with 200m2 of ethanol. To this reaction solution was added 45g of cone, hydrochloric acid, and the mixture was stirred for 5 hours. The resulting solid product was filtered, washed with 30ml of ethanol and then dried to obtain 8.95g of purified (S)-(-)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(l-methyl- l,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Yield : 60.6% m.p. : 255 C
I a h20 : -250° (c=l, in CHC13)
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m, IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH),
5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33 (s, IH), 13.43(bs, IH)
Exnmple 28
15ml of triethylamine and 9.7g(65.8 mmole) of (S)-(-)-l-methyl- 1,2,3,4-tetrahydroisoquinoline as prepared in Example 13 were added to 25m£ of 1,2-propylene glycol. 15g(51 mmole) of 4-bromo-2-(4-fluoro- phenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 110°C for 38 hours. The reaction product was treated according to the procedure detailed in Example 27 to obtain 15.86g of purified 5, 6-dimethyl-2-(4-fluorophenylamino)-4-( 1-methyl- 1,2, 3,4- tetrahydroiso- quinolin-2-yl)pyrimidine hydrochloride.
Yield : 78% m.p. : 257 °C l a ]O 20 : -250° (c=l, in CHC13)
NMR(CDC13, ppm) : 1.58(d, 3H), 2.21(s, 3H), 2.38(s, 3H), 2.84(m,
IH), 3.12(m, IH), 3.61(m, 2H), 4.23(m, IH), 5.38(q, IH), 7.25(m, 6H), 7.61(m, 2H), 10.33
(s, IH), 13.43(bs, IH)

Claims

WHAT IS CLAIMED IS :
1. A process for preparing 5,6-dimethyl-2-(4-fluorophenyl- amino) -4- (1-methyl- 1, 2, 3,4-tetrahydroisoquinolin-2-yl)pyrimidine represented by the following formula (I),
Figure imgf000040_0001
and its acid addition salts, characterized in that a pyrimidine derivative represented by the following formula (π-A),
Figure imgf000040_0002
in wlαich Hal represents a halogen, is reacted with 1-methyl- 1,2,3,4- tetraliydroisoquinoline represented by the following formula (HI),
Figure imgf000040_0003
2. The process as defined in claim 1, characterized in that the acid addition salt is hvdrochloride.
3. The process as defined in claim 1, characterized in that the reaction is carried out in the presence of a solvent.
4. The process as defined in claim 3, characterized in that the solvent is N,N-dimethylformamide, n-butanol, n-pentanol, n-hexanol, dimethylsulfoxide, ethylene glycol, 1,2-propylene glycol, or a mixture thereof.
5. The process as defined in claim 1, characterized in that the reaction is carried out in the presence of a base.
6. The process as defined in claim 5, characterized in that the base is triethylamine, N,N~dimethylaniline, pyridine, or potassium acetate.
7. The process as defined in claim 1, characterized in that the compound of formula (I) in the form of a (R)-( + )-isomer is prepared using (R)-( + )- 1-methyl- 1,2,3,4-tetrahydroisoquinoline.
8. The process as defined in claim 1, characterized in that the compound of formula (I) in the form of a (S)-(-)-isomer is prepared using (S)-( -)-l-methyl- 1,2,3,4-tetrahydroisoquinoline.
9. A process for preparing a 4-halogeno-2-(4-fluorophenyl- amino)-5,6-dimethylpyrimidine represented by the following formula (H-A),
Figure imgf000041_0001
in which Hal represents a halogen, characterized in that 4- fluorophenyl - guanidine carbonate represented by the following formula (IV),
Figure imgf000042_0001
is reacted with ethyl 2-methylacetoacetate represented by the following formula (V),
Figure imgf000042_0002
to prepare 4-hydroxy-2-(4-fluorophenylarrιino)-5,6-dimethylpyrimidine represented by the following formula (II-B),
Figure imgf000042_0003
which is then reacted with a halogenating agent.
10. A pyrimidine derivative represented by the following formula (H),
Figure imgf000042_0004
in which R represents hydroxy or a halogen.
11. A process for preparing l-methyl-l,2,3,4-tetrahydroiso- quinoline represented by the following formula (HI),
Figure imgf000043_0001
characterized in that in the first step a -methylbenzylamine is reacted with 2-bromoethanol to prepare N- (2 -hydroxyethyl) - a -methylbenzyl- amine; in the second step N-( 2 -hydroxyethyl)- a -methylbenzylamine is reacted with a brominating agent to prepare N-(2-bromoethyl)- - methylbenzylamine hydrobromide; and then in the third step N-(2- bromoethyl)- a -methylbenzylamine hydrobromide is reacted with a Lewis acid.
12. The process as defined in claim 11, characterized in that the brominating agent used in the second step is selected from the group consisting of bromine, aqueous bromic acid solution, and phosphorus tribromide.
13. The process as defined in claim 11, characterized in that Lewis acid used in the third step is selected from the group consisting of aluminum (IH) chloride, zinc chloride, and ferrous chloride.
14. The process as defined in claim 11, characterized in that the compound of formula (HI) in the form of (R)-( + )-isomer is prepared using (R)-(+)- a -methylbenzylamine.
15. The process as defined in claim 11, characterized in that the compound of formula (IH) in the form of (S)-(-)-isomer is prepared using (S)-(-)- a -methylbenzylamine.
PCT/KR1997/000204 1996-10-29 1997-10-27 Process for preparation of pyrimidine derivatives WO1998018784A1 (en)

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BR9712392-7A BR9712392A (en) 1996-10-29 1997-10-27 Processes for preparing 5,6-dimethyl-2- (4-fluorophenyl-amino) -4- (1-methyl-1,2,3,4 - tetrahydroisoquinolin - 2-yl) pyrimidine, 4 - halogeno - 2 - (4 - fluorophenylamino) -5,6-dimethyl-pyrimidine and 1-methyl-1,2,3,4-tetrahydroisoquinoline, and, derived from pyrimidine

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KR1996/49381 1996-10-29
KR1019960049381A KR100193080B1 (en) 1996-10-29 1996-10-29 Method for preparing (R) -pyrimidine derivative
KR1019960049380A KR0185292B1 (en) 1996-10-29 1996-10-29 Method for preparing (S) -pyrimidine derivative
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