[go: up one dir, main page]

WO2010018895A1 - Procédé de préparation de dérivés n-phényl-2-pyrimidine-amine - Google Patents

Procédé de préparation de dérivés n-phényl-2-pyrimidine-amine Download PDF

Info

Publication number
WO2010018895A1
WO2010018895A1 PCT/KR2008/006850 KR2008006850W WO2010018895A1 WO 2010018895 A1 WO2010018895 A1 WO 2010018895A1 KR 2008006850 W KR2008006850 W KR 2008006850W WO 2010018895 A1 WO2010018895 A1 WO 2010018895A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
lower alkyl
phenyl
compound represented
methyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2008/006850
Other languages
English (en)
Inventor
Dong Yeon Kim
Dae Jin Cho
Gong Yeal Lee
Hong Youb Kim
Seok Hun Woo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Il Yang Pharmaceutical Co Ltd
Original Assignee
Il Yang Pharmaceutical Co Ltd
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
Application filed by Il Yang Pharmaceutical Co Ltd filed Critical Il Yang Pharmaceutical Co Ltd
Publication of WO2010018895A1 publication Critical patent/WO2010018895A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/18—Nitrogen atoms not forming part of a nitro radical with hetero atoms attached to said nitrogen atoms, except nitro radicals, e.g. hydrazine radicals
    • 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
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel method of preparing an N- phenyl-2-pyrimidine-amine derivative represented by Formula 1 : [2] [Formula 1]
  • R represents thiazole, imidazole, or pyrazine, each of which is substituted or unsubstituted (herein, a substituent group is an amino group or lower alkyl), R represents hydrogen, halogen, lower alkyl, or lower alkoxy, R represents lower alkyl
  • R represents: a C5 to ClO aliphatic group; a saturated or unsaturated monocyclic radical or a bi or tri-cyclic radical fused with any benzene ring, each of which contains 1 to 3 heteroatoms selected from the group including nitrogen, oxygen, and sulfur, and contains 5 to 7 ring members; or piperazinyl or homopiperazinyl, each of which is substituted with lower alkyl.
  • a preferred compound according to Formula 1 includes 4-methyl-N- [3-(4-methylimidazole- 1 -yl)-5-trifluoromethyl-phenyl] -3-(4-pyrazine-2-yl -pyrimidine-2-yl amino)benzamide. It has been known that the compound represented by Formula 1 can inhibit at least one kind of tyrosine kinase, for example, c-Abl, Bcr- AbI, and receptor tyrosine kinases (PDGF-R, Flt3, VEGF-R, EGF-R and c-Kit).
  • tyrosine kinase for example, c-Abl, Bcr- AbI, and receptor tyrosine kinases (PDGF-R, Flt3, VEGF-R, EGF-R and c-Kit).
  • the compound represented by Formula 1 may be used for treatment of various kinds of cancers in a warm blooded animal, such as lung cancer, stomach cancer, colon cancer, pancreatic cancer, liver cancer, prostate cancer, breast cancer, chronic or acute leukemia, hematological malignancy, brain tumor, bladder cancer, rectal cancer, uterine cervical cancer, lymphoma, etc.
  • a warm blooded animal such as lung cancer, stomach cancer, colon cancer, pancreatic cancer, liver cancer, prostate cancer, breast cancer, chronic or acute leukemia, hematological malignancy, brain tumor, bladder cancer, rectal cancer, uterine cervical cancer, lymphoma, etc.
  • the compound represented by Formula 1 is synthesized through hydrolysis of ethyl ester into carboxylic acid and then a reaction with aniline, and herein, diethyl cyano phosphonate is used as a coupling agent (see Reaction Scheme 1).
  • diethyl cyano phosphonate used for the condensation reaction is an expensive reagent, and an environmentally harmful and very toxic material, which has LD50 values of 25mg/Kg and 4mg/Kg in mice and rabbits (that is, rodents), respectively. Therefore, there is a requirement for an alternative method of conveniently, consistently, efficiently and rapidly preparing a high-purity compound (represented by Formula 1) with low production cost in high yield, which is not harmful for humans and the environment.
  • the present invention provides an alternative method of efficiently preparing a compound (represented by Formula 1) with high purity in consistent high yield.
  • the present invention provides a method of preparing the compound represented by Formula 1, which can reduce production cost by using inexpensive reagents.
  • the present invention provides a method of preparing the compound represented by Formula 1, which is harmless to humans and the environment by using safety reagents.
  • the present invention has been made to solve the above-mentioned problems occurring in the conventional synthesis method as shown in Reaction Scheme 1, thereby increasing the total yield by 70 to 90%.
  • the present invention provides a novel method including a reaction for preparing the compound represented by Formula 1, that is, an N-phenyl-2-pyrimidine-amine derivative, through direct condensation of the compound represented by Formula 2 and the compound represented by Formula 4, as starting materials, and a strong base, as a catalyst, as shown in Reaction Scheme 2. [19]
  • R represents thiazole, imidazole, or pyrazine, each of which is substituted or un- substituted (herein, a substituent group is an amino group or lower alkyl), [25] R represents hydrogen, halogen, lower alkyl, or lower alkoxy,
  • R represents lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl
  • R represents lower alkyl or lower alkyl substituted with 1 to 3 halogen atoms
  • R represents: a C5 to ClO aliphatic group; a saturated or unsaturated monocyclic radical or a bi or tri-cyclic radical fused with any benzene ring, each of which contains 1 to 3 heteroatoms selected from the group including nitrogen, oxygen, and sulfur, and contains 5 to 7 ring members; or piperazinyl or homopiperazinyl, each of which is substituted with lower alkyl.
  • the direct condensation of aniline (4) and ester (2) may generate the compound represented by Formula 1 through catalysis by a strong base such as potassium tert-butoxide.
  • a strong base such as potassium tert-butoxide.
  • other base materials such as metal hydride, metal halide, bulky alkyl lithium, metal alkoxide, metal bis(trimethylsilyl)amide or lithium dialkylamide, or a mixture thereof, may be used.
  • the metal may be lithium, sodium, magnesium or potassium.
  • organic solvent that may be used in the preparation method of the present invention
  • at least one organic solvent selected from the group including tetrahydrofuran, dimethylformamide, dimethylsulfoxide, toluene, N,N-dimethylacetamide, xylene, benzene and N-methylpyrrolidinone may be used.
  • the compound represented by Formula 1 may be prepared by the steps of: dissolving 1.0 equivalent of compound represented by Formula 4 in at least one organic solvent selected from the group including tetrahydrofuran, dimethylformamide, dimethylsulfoxide, toluene, N,N-dimethylacetamide, xylene, benzene and N-methylpyrrolidinone, at -50 to 5O 0 C, preferably at -20 to 3O 0 C, in the presence of 3.0 to 5.0 equivalents of base, preferably of 3.5 to 4.5 equivalents, dropwise adding the compound and stirring the mixture; and dissolving 1.0 to 1.2 equivalents of compound represented by Formula 2, preferably of 1.1 equivalents of the compound, in the selected organic solvent, dropwise adding the compound and stirring the mixture.
  • organic solvent selected from the group including tetrahydrofuran, dimethylformamide, dimethylsulfoxide, toluene, N,N-dimethylacetamide, xylene, benzene and N-
  • the above described method includes the following reaction.
  • R represents thiazole, imidazole, or pyrazine, each of which is substituted or un- substituted (herein, a substituent group is an amino group or lower alkyl), and [39] R represents lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl.
  • the compound represented by Formula 4a may be prepared by using the method disclosed in Korea Patent Registration No. 10-0674813.
  • the present invention is intended to include the disclosed method.
  • an N-phenyl-2-pyrimidine-amine derivative represented by Formula Ia may be prepared by a one-step condensation reaction through catalysis of a strong base with starting materials, that is, aniline (4a) and ester (2a).
  • the preparation method according to the present invention is efficient in that the method requires low production cost due to production process reduction, a simplified purification method, and high yield/purity by a selective reaction.
  • Lower alkyl includes 1 to 6 carbon atoms, and is linear or branched, and a preferable lower alkyl residue includes butyl (for example, n-butyl, sec-butyl, isobutyl, tert- butyl), propyl (for example, n-propyl or isopropyl), ethyl or methyl. Especially, a preferable lower alkyl residue includes methyl, ethyl, n-propyl or tert-butyl. Also, aliphatic indicates alkenyl, alkynyl, or alkyl.
  • lower alkoxy indicates a group containing a linear or branched, saturated aliphatic hydrocarbon residue having preferably 1 to 6 carbon atoms, and specifically includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, isopentoxy, hexoxy, etc.
  • Halogen indicates fluorine, chlorine, bromine, or iodine, and especially, fluorine, chlorine, or bromine.
  • the disclosed preparation method is ef- ficientin that the method requires low production cost due to production process reduction, a simplified purification method, and high yield/purity by a selective reaction, and also is environmentally friendly and consistent.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation d'un dérivé N-phényl-2-pyrimidine-amine. Par comparaison à un procédé classique, le procédé de préparation décrit est efficace en ce que le procédé nécessite un faible coût de production du fait d'un raccourcissement du procédé de production, d'un procédé de purification simplifié et d'un rendement/pureté élevés grâce à une réaction sélective, et est également respectueux de l'environnement et régulier.
PCT/KR2008/006850 2008-08-14 2008-11-20 Procédé de préparation de dérivés n-phényl-2-pyrimidine-amine Ceased WO2010018895A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020080080186A KR20100021321A (ko) 2008-08-14 2008-08-14 Ν-페닐-2-피리미딘-아민 유도체의 제조방법
KR10-2008-0080186 2008-08-14

Publications (1)

Publication Number Publication Date
WO2010018895A1 true WO2010018895A1 (fr) 2010-02-18

Family

ID=41669029

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2008/006850 Ceased WO2010018895A1 (fr) 2008-08-14 2008-11-20 Procédé de préparation de dérivés n-phényl-2-pyrimidine-amine

Country Status (5)

Country Link
KR (1) KR20100021321A (fr)
CN (1) CN101648946A (fr)
CL (1) CL2008003872A1 (fr)
TW (1) TW201006803A (fr)
WO (1) WO2010018895A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9132126B2 (en) 2011-04-19 2015-09-15 Il-Yang Pharm. Co., Ltd. Phenyl-isoxazole derivatives and preparation process thereof
KR20180032784A (ko) * 2016-09-23 2018-04-02 재단법인 대구경북첨단의료산업진흥재단 신규한 이미다졸일 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101956586B1 (ko) * 2012-03-27 2019-03-11 일양약품주식회사 약제학적 조성물 및 이의 제조방법
CN116102506B (zh) * 2022-06-23 2025-03-25 广州大学 一种基于氨基嘧啶骨架的多靶点激酶抑制剂及其制备方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066613A1 (fr) * 2002-02-07 2003-08-14 Novartis Ag Derives de n-phenyl-2-pyrimidine-amine
WO2004005281A1 (fr) * 2002-07-05 2004-01-15 Novartis Ag Inhibiteurs de tyrosine kinases
KR100674813B1 (ko) * 2005-08-05 2007-01-29 일양약품주식회사 Ｎ-페닐-2-피리미딘-아민 유도체 및 그의 제조방법

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066613A1 (fr) * 2002-02-07 2003-08-14 Novartis Ag Derives de n-phenyl-2-pyrimidine-amine
WO2004005281A1 (fr) * 2002-07-05 2004-01-15 Novartis Ag Inhibiteurs de tyrosine kinases
KR100674813B1 (ko) * 2005-08-05 2007-01-29 일양약품주식회사 Ｎ-페닐-2-피리미딘-아민 유도체 및 그의 제조방법

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9132126B2 (en) 2011-04-19 2015-09-15 Il-Yang Pharm. Co., Ltd. Phenyl-isoxazole derivatives and preparation process thereof
KR20180032784A (ko) * 2016-09-23 2018-04-02 재단법인 대구경북첨단의료산업진흥재단 신규한 이미다졸일 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물
KR102030886B1 (ko) * 2016-09-23 2019-10-10 재단법인 대구경북첨단의료산업진흥재단 신규한 이미다졸일 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물

Also Published As

Publication number Publication date
CL2008003872A1 (es) 2009-12-18
TW201006803A (en) 2010-02-16
CN101648946A (zh) 2010-02-17
KR20100021321A (ko) 2010-02-24

Similar Documents

Publication Publication Date Title
CN107176955B (zh) 一种巴瑞替尼的制备方法
CN106068268A (zh) 5‑氟‑4‑亚氨基‑3‑（烷基/取代烷基）‑1‑（芳基磺酰基）‑3,4‑二氢嘧啶‑2（1h）‑酮及其制备方法
KR20170075713A (ko) 이델라리십의 제조방법
CN101851193A (zh) 一种4-三氟甲基烟酸的制备方法
CN109265360B (zh) 一种α-芳基取代甘氨酸酯类衍生物的合成方法
TWI430999B (zh) 有機化合物之合成方法
CN111592533A (zh) 1,2,4-噁二唑联吡啶取代苯甲酰胺类化合物及其制备方法和应用
WO2010018895A1 (fr) Procédé de préparation de dérivés n-phényl-2-pyrimidine-amine
CN101481350B (zh) 诺氟沙星的合成工艺
JP2015512381A5 (fr)
JP2008201739A (ja) エダラボンの製造方法
CN105130908B (zh) 4,6‑二烷氧基‑2‑氰基甲基嘧啶的制备方法及其合成中间体
CN102491985B (zh) 6-氨基-2，2-二甲基-2H-吡啶[3，2-b][1，4]恶嗪-3(4H)-酮的合成方法
KR101653532B1 (ko) 호기성 산화법을 통한 보로닉산이 직접 포함된 벤즈이미다졸의 합성방법
CN108033892A (zh) 一种n-烷基亚氨基二乙酸的制备方法
CN116419922A (zh) 一种从泊马度胺选择性合成3,6′-二硫代泊马度胺的方法
HK1140486A (en) Process for the preparation of n-phenyl-2-pyrimidine-amine derivatives
JP5702956B2 (ja) 芳香族トリカルボン酸
JP5063585B2 (ja) ヒドロキシル化イソフラボンの製造方法
PL209729B1 (pl) Sposób wytwarzania chlorowodorku 2-[(2,3,4-trihydroksyfenylo)metylo]hydrazydu D,L-seryny
CN120112512A (zh) 制备(z)-3-(2-(5-溴-1h-吲哚-3-基)-2-氰基乙烯基)-4-甲氧基苯甲腈的方法
CN119775206A (zh) 一种达罗他胺关键中间体(s)-4-(1-(2-氨基丙基)-1h-吡唑-3-基)-2-氯苯甲腈的制备方法
CN103319392B (zh) 一种舒尼替尼中间体的制备方法
CN120004811A (zh) 一种新的合成2-肼基-取代嘧啶的方法
CN105622522B (zh) 一种瑞舒伐他汀钙关键中间体的合成方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08876741

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08876741

Country of ref document: EP

Kind code of ref document: A1