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WO1998018784A1 - Procede de preparation de derives de pyrimidine - Google Patents

Procede de preparation de derives de pyrimidine 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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WO
WIPO (PCT)
Prior art keywords
methyl
formula
represented
mmole
added
Prior art date
Application number
PCT/KR1997/000204
Other languages
English (en)
Inventor
You Wha Hong
Young Nam Lee
Hong Bae Kim
Original Assignee
Yuhan Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1019960049380A external-priority patent/KR0185292B1/ko
Priority claimed from KR1019960049382A external-priority patent/KR100209587B1/ko
Priority claimed from KR1019960049381A external-priority patent/KR100193080B1/ko
Application filed by Yuhan Corporation filed Critical Yuhan Corporation
Priority to HU9903520A priority Critical patent/HU226752B1/hu
Priority to BR9712392-7A priority patent/BR9712392A/pt
Publication of WO1998018784A1 publication Critical patent/WO1998018784A1/fr

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Classifications

    • 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

La présente invention se rapporte, premièrement, à un procédé de préparation de la 5,6-diméthyl-2-(4-fluorophénylamino)-4-(1-méthyl-1,2,3,4-tétrahydroisoquinoline-2-yl)pyrimidine, représentée par la formule (I), et de ses sels d'addition acide, deuxièmement, à un procédé de préparation d'un intermédiaire servant à préparer le composé (I), et troisièmement, à un nouveau composé intermédiaire. Plus précisément, la présente invention se rapporte, premièrement à un procédé de préparation de la 5,6-diméthyl-2-(4-fluorophénylamino)-4-(1-méthyl-1,2,3,4-tétrahydroisoquinoline-2-yl)pyrimidine représentée par la formule (I), et de ses sels d'addition acide, qui consiste à faire réagir un dérivé de la pyrimidine représenté par la formule (II-A), dans laquelle Hal est un halogène, la 1-méthyl-1,2,3,4-tétrahydroisoquinoline étant représentée par la formule (III), deuxièmement à un procédé de préparation d'un dérivé de pyrimidine représenté par la formule (II-A) et du composé de formule (III), et troisièmement, à un nouveau composé intermédiaire contenant le dérivé de pyrimidine représenté par la formule (II-A).
PCT/KR1997/000204 1996-10-29 1997-10-27 Procede de preparation de derives de pyrimidine WO1998018784A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
HU9903520A HU226752B1 (en) 1996-10-29 1997-10-27 Process for preparation of pyrimidine derivatives
BR9712392-7A BR9712392A (pt) 1996-10-29 1997-10-27 Processos para preparar 5,6-dimetil-2-(4-fluorofenil-amino) -4- (1-metil-1,2,3,4 - tetraidroisoquinolin - 2 -il) pirimidina, 4 - halogeno - 2 - (4 - fluorofenilamino) -5,6 -dimetil-pirimidina e 1-metil-1,2,3,4-tetraidroisoquinolina, e, derivado de pirimidina

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR1996/49382 1996-10-29
KR1996/49380 1996-10-29
KR1996/49381 1996-10-29
KR1019960049380A KR0185292B1 (ko) 1996-10-29 1996-10-29 (s)-피리미딘 유도체의 제조방법
KR1019960049382A KR100209587B1 (ko) 1996-10-29 1996-10-29 피리미딘 유도체의 제조방법
KR1019960049381A KR100193080B1 (ko) 1996-10-29 1996-10-29 (r)-피리미딘 유도체의 제조방법

Publications (1)

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WO1998018784A1 true WO1998018784A1 (fr) 1998-05-07

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Application Number Title Priority Date Filing Date
PCT/KR1997/000204 WO1998018784A1 (fr) 1996-10-29 1997-10-27 Procede de preparation de derives de pyrimidine

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AR (1) AR009133A1 (fr)
BR (1) BR9712392A (fr)
HU (1) HU226752B1 (fr)
TR (1) TR199900943T2 (fr)
WO (1) WO1998018784A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000029403A1 (fr) * 1998-11-17 2000-05-25 Yuhan Corporation Nouveaux derives de pyrimidine et leurs procedes de preparation
WO2002088088A1 (fr) * 2001-04-27 2002-11-07 Sb Pharmco Puerto Rico Inc. Procede de preparation d'un 1-methyl-1,2,3,4-tetrahydroisoquinoline ou son sel
US6852739B1 (en) 1999-02-26 2005-02-08 Nitromed Inc. Methods using proton pump inhibitors and nitric oxide donors
US7211590B2 (en) 2002-08-01 2007-05-01 Nitromed, Inc. Nitrosated proton pump inhibitors, compositions and methods of use
WO2007064128A1 (fr) 2005-12-01 2007-06-07 Yuhan Corporation Composition pour la prevention ou le traitement de lesions mucosales dans le tractus gastro-intestinal
WO2007115305A2 (fr) 2006-04-04 2007-10-11 Cogentus Pharmaceuticals, Inc. Formes de dosage orales incluant un inhibiteur de l'agrégation plaquettaire et un inhibiteur acide
CN102993173A (zh) * 2012-12-28 2013-03-27 山东大学 洛氟普啶的制备方法
WO2016078542A1 (fr) * 2014-11-19 2016-05-26 江苏天士力帝益药业有限公司 Procédé de préparation de chlorhydrate de révaprazan
JP2017534635A (ja) * 2014-11-19 2017-11-24 江蘇天士力帝益薬業有限会社Ｊｉａｎｇｓｕ Ｔａｓｌｙ Ｄｉｙｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． レバプラザン塩酸塩の結晶多形及びその調製方法
CN107759562A (zh) * 2016-08-21 2018-03-06 常州四药制药有限公司 一种盐酸洛氟普啶的制备方法

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EP0388838A2 (fr) * 1989-03-22 1990-09-26 Ciba-Geigy Ag Parasiticide
WO1994014795A1 (fr) * 1992-12-29 1994-07-07 Yuhan Corporation Derives de la quinazoline
WO1996005177A1 (fr) * 1994-08-13 1996-02-22 Yuhan Corporation Nouveaux derives de pyrimidine et procedes de preparation

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GB1182584A (en) * 1966-03-31 1970-02-25 Ici Ltd Pyrimidine derivates and the use thereof as fungicides
EP0388838A2 (fr) * 1989-03-22 1990-09-26 Ciba-Geigy Ag Parasiticide
WO1994014795A1 (fr) * 1992-12-29 1994-07-07 Yuhan Corporation Derives de la quinazoline
WO1996005177A1 (fr) * 1994-08-13 1996-02-22 Yuhan Corporation Nouveaux derives de pyrimidine et procedes de preparation

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CHEMICAL ABSTRACTS, Vol. 121, No. 21, 21 November 1994, (Columbus, Ohio, USA), page 1218, Abstract No. 256215v, PLAZIAK A.S. et al., "An Evaluation of the Ortho Effect in Iso-Cytosine Derivatives: 2-Aralkylamino- and 2-Arylamino-3,4-Dihydropyrimidin-4(3H)-Ones"; & POL. J. CHEM., 1993, 67(5), 849-56, (Eng). *
CHEMICAL ABSTRACTS, Vol. 96, No. 25, 21 June 1982, (Columbus, Ohio, USA), page 726, Abstract No. 217665n, SCULLY F.E. Jr. et al., "Synthesis of Dihydroisoquinolines and 1-Substituted Tetrahydroisoquinolines"; & HETEROCYCLES, 1982, 19(4), 653-6, (Eng). *
CHEMICAL ABSTRACTS, Vol. 99, No. 19, 07 November 1983, (Columbus, Ohio, USA), page 597, Abstract No. 158207b, SEEBACH D. et al., "Alkylation of Isoquinoline Skeleton in the I-Position. Lithiated 2-Pivaloyl- and 2-Bis(Dimethylamino)Phosphinoyl-1,2,3,4-Tetrahydroisoquinolines"; & TETRAHEDRON, 1983, 39(12), 1963-74, (Eng). *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6545008B1 (en) 1998-11-17 2003-04-08 Yuhan Corporation Pyrimidine derivatives and processes for the preparation thereof
RU2236407C2 (ru) * 1998-11-17 2004-09-20 Юхан Корпорейшн Производные пиримидина
WO2000029403A1 (fr) * 1998-11-17 2000-05-25 Yuhan Corporation Nouveaux derives de pyrimidine et leurs procedes de preparation
US7332505B2 (en) 1999-02-26 2008-02-19 Nitromed, Inc. Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use
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AR009133A1 (es) 2000-03-08
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HUP9903520A3 (en) 2002-01-28
HUP9903520A1 (hu) 2000-05-28
HU226752B1 (en) 2009-09-28

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