JP2008094834A - 2−(ピリジンー2−イルアミノ)−ピリド[2,3−d]ピリミジン−7−オン類の合成 - Google Patents
2−(ピリジンー2−イルアミノ)−ピリド[2,3−d]ピリミジン−7−オン類の合成 Download PDFInfo
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- JP2008094834A JP2008094834A JP2007232730A JP2007232730A JP2008094834A JP 2008094834 A JP2008094834 A JP 2008094834A JP 2007232730 A JP2007232730 A JP 2007232730A JP 2007232730 A JP2007232730 A JP 2007232730A JP 2008094834 A JP2008094834 A JP 2008094834A
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- Prior art keywords
- compound
- formula
- palladium
- bis
- alkyl
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- DDZFNEVGSZKHPR-UHFFFAOYSA-N 2-(pyridin-2-ylamino)-6h-pyrido[2,3-d]pyrimidin-7-one Chemical class N=1C2=NC(=O)CC=C2C=NC=1NC1=CC=CC=N1 DDZFNEVGSZKHPR-UHFFFAOYSA-N 0.000 title description 3
- 230000015572 biosynthetic process Effects 0.000 title description 2
- 238000003786 synthesis reaction Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 136
- 238000000034 method Methods 0.000 claims abstract description 53
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 18
- 150000003624 transition metals Chemical class 0.000 claims abstract description 18
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 13
- 230000008569 process Effects 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 8
- 229940045996 isethionic acid Drugs 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 21
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 16
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 229910052744 lithium Inorganic materials 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 13
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 230000026030 halogenation Effects 0.000 claims description 10
- 238000005658 halogenation reaction Methods 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 claims description 9
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalene Chemical compound C1=CC=C2C(C=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- 125000006413 ring segment Chemical group 0.000 claims description 8
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 7
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 7
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims description 6
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 6
- 101150003085 Pdcl gene Proteins 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 6
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 claims description 6
- KFGVRWGDTLZAAO-UHFFFAOYSA-N cyclopenta-1,3-diene dicyclohexyl(cyclopenta-1,3-dien-1-yl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.C1CCC(CC1)P(C1CCCCC1)c1ccc[cH-]1 KFGVRWGDTLZAAO-UHFFFAOYSA-N 0.000 claims description 6
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical group [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 6
- 235000011056 potassium acetate Nutrition 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 6
- 125000006242 amine protecting group Chemical group 0.000 claims description 5
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 5
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
- QVQGTNFYPJQJNM-UHFFFAOYSA-N dicyclohexylmethanamine Chemical compound C1CCCCC1C(N)C1CCCCC1 QVQGTNFYPJQJNM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002941 palladium compounds Chemical class 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000007822 coupling agent Substances 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 3
- 150000003457 sulfones Chemical class 0.000 claims description 3
- 150000003462 sulfoxides Chemical class 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 claims 2
- 125000006267 biphenyl group Chemical group 0.000 claims 2
- YLQBEKUKMJWXMC-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-ylphosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.P[c-]1cccc1 YLQBEKUKMJWXMC-UHFFFAOYSA-N 0.000 claims 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 44
- 230000002062 proliferating effect Effects 0.000 abstract description 8
- -1 5-piperazin-1-yl-pyridin-2-ylamino Chemical group 0.000 description 75
- 239000002585 base Substances 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 31
- 238000002360 preparation method Methods 0.000 description 24
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- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 description 18
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 8
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- SUWKOEMQNOBJEQ-UHFFFAOYSA-N tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C([N+]([O-])=O)N=C1 SUWKOEMQNOBJEQ-UHFFFAOYSA-N 0.000 description 8
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- 125000000466 oxiranyl group Chemical group 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- SCWKOLRZBMGTNT-UHFFFAOYSA-N tert-butyl 4-[6-[[6-(1-butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino]pyridin-3-yl]piperazine-1-carboxylate Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=C)OCCCC)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCN(C(=O)OC(C)(C)C)CC1 SCWKOLRZBMGTNT-UHFFFAOYSA-N 0.000 description 1
- ZSUHBFDUYDVOFZ-UHFFFAOYSA-N tert-butyl 4-[6-[[8-cyclopentyl-6-(1-ethoxyethenyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino]pyridin-3-yl]piperazine-1-carboxylate Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=C)OCC)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCN(C(=O)OC(C)(C)C)CC1 ZSUHBFDUYDVOFZ-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
本発明は、置換2−(ピリジン−2−イルアミノ)−ピリド[2,3−d]ピリミジン−7−オン類及びそれらの中間体を製造するための新規な合成ルートに関する。
本発明は、次の式(以下、“式1”と称する)を有する置換2−(ピリジン−2−イルアミノ)−ピリド[2,3−d]ピリミジン−7−オン類:
R3は、水素、OH、−NH2、アリール、C1−C8アルキル、C3−C7シクロアルキル又はC3−C7−へテロサイクリルであり;
R5は、−(CR7R8)mNR7−又は−(CR7R8)m−(N環原子を含む3〜10員のヘテロサイクル)であり、mは、0、1、2又は3であり;そして
R7及びR8は、各々独立してH又はC1−C6アルキルである)
又はその薬学的に許容可能な塩を製造するための新規な方法に関する。
R3は、水素、OH、−NH2、アリール、C1−C8アルキル、C3−C7シクロアルキル又はC3−C7−ヘテロサイクリルであり;
R5は、−(CR7R8)mNR7−又は−(CR7R8)m−(N環原子を含む、3〜10員のヘテロサイクル)であり、mは、0、1、2又は3であり;そして
R7及びR8は、各々独立してH又はC1−C6アルキルである}を製造するための方法であって、
(a)式:
R1は、水素、C1−C6アルキル、C1−C6ハロアルキル、C1−C6ヒドロキシアルキル又はC3−C7シクロアルキルであり;
R2は、Br又はIであり;
R3は、水素、OH、−NH2、アリール、C1−C8アルキル、C3−C7シクロアルキル又はC3−C7−ヘテロサイクリルであり;
R4は、−(CR7R8)m−N(PG)R7及び−(CR7R8)m−(PG保護N環原子を含む3〜10員のヘテロサイクル)からなる群から選択される−R5−PGであり、PGは、酸不安定性アミン保護基であり;
R5、即ち当該PGを有さないR4は、−(CR7R8)mNR7−又は−(CR7R8)m−(N環原子を含む3〜10員のヘテロサイクル)であり、mは、0、1、2又は3であり;
R6は、C1−C6アルキルであり;そして
R7及びR8は、各々独立してH又はC1−C6アルキルである}
とを、遷移金属触媒、塩基及び場合によりホスフィン物質の存在下で、適切な溶媒中で反応させて、式Ie又はIf;
(b1)式Ie又はIfの化合物のR5を、PGを除去することにより脱保護する工程
を含む方法を提供する。
(a)式:
R1は、水素、C1−C6アルキル、C1−C6ハロアルキル、C1−C6ヒドロキシアルキル又はC3−C7シクロアルキルであり;
R2は、Br又はIであり;
R3は、水素、OH、−NH2、アリール、C1−C8アルキル、C3−C7シクロアルキル又はC3−C7−ヘテロサイクリルであり;
R4は、−(CR7R8)m−N(PG)R7及び−(CR7R8)m−(PG保護N環原子を含む、3〜10員のヘテロサイクル)からなる群から選択される−R5−PGであり、PGは、酸不安定性アミン保護基であり;
R5、即ち当該PGを有さないR4は、−(CR7R8)mNR7−又は−(CR7R8)m−(N環原子を含む、3〜10員のヘテロサイクル)であり、mは、0、1、2又は3であり;
R6はC1−C6アルキルであり;そして
R7及びR8は、各々独立してH又はC1−C6アルキルである}
とを、遷移金属触媒、塩基及び場合によりホスフィン物質の存在下で、適切な溶媒中で反応させて、式Ie又はIf;
(b)続いて、式Ie若しくはIfの化合物、又はその混合物と、イセチオン酸とを、適切な溶媒中で反応させて式Iの化合物を生成させる工程
を含む方法を提供する。
この態様の別の特定の側面において、及び矛盾しないあらゆる他の特定の側面との組み合わせにおいて、式Iの化合物は、化合物1:
当該態様の別の特定の側面において、及び矛盾しないあらゆる他の特定の側面との組み合わせにおいて、工程(a)における遷移金属触媒は、テトラキス(トリフェニルホスフィン)パラジウム [(Ph3P)4Pd]、トリス(ジベンジリデンアセトン)ジパラジウム [Pd2(dba)3]、ビス(ジベンジリデンアセトン)パラジウム(0) [(dba)2Pd]、酢酸パラジウム [Pd(OAc)2]、塩化パラジウム (PdCl2)、ビス(ベンゾニトリル)ジクロロパラジウム [(C6H5CN)2PdCl2] 及び(ビス−(ジフェニルホスフィノフェロセン)パラジウムジクロリド ジクロロメタンコンプレックス (Pd(dppf)2Cl2)からなる群から選択されるパラジウム化合物であり、工程(a)におけるホスフィン化合物は、2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフタレン (BINAP)、1,3 ビス(ジフェニルホスフィノ)プロパン、トリフェニルホスフィン (Ph3P)、トリオルトトリルホスフィン [(o-CH3Ph)3P] 及びトリ−t−ブチルホスフィンから選択される。好ましくは、当該遷移金属触媒は、(ビス−(ジフェニルホスフィノフェロセン)パラジウムジクロリド ジクロロメタンコンプレックス (Pd(dppf)2Cl2)である。
(c)式Ic:
(d)当該式Ic1の化合物と、式Ic3:
を含む方法を提供する。
別の側面において、及び矛盾しないあらゆる他の態様との組み合わせにおいて、本発明は、式Id:
(e)式Ic:
(f)式Ic2の化合物を、ハロゲン化条件下でハロゲン化して、式Idの化合物を生成させる工程;
を含む方法を提供する。
別の態様において、及び矛盾しないあらゆる他の態様との組み合わせにおいて、本発明は、式 Ic:
(g)式Ib:
、塩基、遷移金属触媒及び場合によりホスフィン物質の存在下で、適切な溶媒中で反応させる工程;及び
(h)工程(g)で生じた生成物を分子内環化反応させて式Icの化合物を生成させる工程を含む方法を提供する。
別の態様において、そして矛盾しないあらゆる他の態様との組み合わせにおいて、本発明は、式Ib:
(i)式Ia:
本発明は、2−(2’−ピリジル)ピリド[2,3−d]ピリミジノン類を、非制御(uncontrolled)細胞増殖性疾患を治療するために有用である化合物として特定しており、当該疾患には、ガン、再狭窄及びリウマチ様関節炎のような増殖性疾患が含まれるが、これらに限定されない。さらに、これら化合物は、炎症及び炎症性疾患を治療するために有用である。さらに、これら化合物は、抗感染症剤としての有用性も有する。その上、これら化合物は、正常な非形質転換細胞の細胞周期の進行を阻害するそれらの能力による化学的保護剤(chemoprotective atent)としての有用性も有する。本発明の化合物の多くは、セリン/トレオニンキナーゼであるサイクリン依存性キナーゼ4及びサイクリン依存性キナーゼ6についての選択性において予測できない向上を示す。それら化合物は既に合成されており、種々の方法によって患者に投与することができる。
本発明における「ハロゲン」との用語は、フッ素、臭素、塩素及びヨウ素を意味する。
本発明の化合物の多くは、サイクリン依存性キナーゼであるcdk4の選択的な阻害剤である。即ち、それらは、cdk2の様な他のサイクリン依存性キナーゼを包含するチロシンキナーゼ及び他のセリン−トレオニンキナーゼを阻害するよりも強力にcdk4を阻害する。cdk4阻害についてのそれらの選択性にも関わらず、本発明の化合物は、cdk4を阻害する濃度よりも高い濃度においてではあるが他のキナーゼも阻害しうる。しかしながら、本発明の化合物は、cdk4の阻害に必要な濃度と類似する濃度においてCdk6も阻害し得る。なぜなら、cdk6は、cdk4と構造的に類似しており、それと類似した機能を発揮するからである。
本発明の好ましい態様は、cdk2を阻害するのに必要な投与量よりも低い投与量においてcdk4を阻害する方法であって、式Iの好ましい化合物をcdk2に勝ってcdk4を選択的に阻害する量で投与することを含む方法を提供する。
本発明の化合物の製造の例示がスキーム1〜2中に示される。
本発明の化合物は、一般的なスキームIに従って製造され得る。他の方法で指定しない限り、R1、R2、R3、R4、R5、R6、X1、Ra及びRbは上で定義した通りのものである。
化合物Idへの進行は2つの工程を含む。
当業者は、次の実施例によって実証されている様に、出発物質を変動させ、追加の工程を用いて本発明により包含される化合物を製造できることを理解するであろう。次の実施例は、例証的目的だけのためのものであり、本発明を限定するものと意図するものでもなければいかなる方法によってもそのように解釈されるべきものでもない。当業者は、本発明の精神及び範囲に違反することなく変動及び修飾を行うことができることを理解するであろう。
6−ブロモ−8−シクロペンチル−2−メタンスルフィニル−5−メチル−8H−ピリド[2,3−d]ピリミジン−7−オン(10.00g、0.027mol、参照により本明細書中に組み込まれるWO01/707041の実施例6における様に製造されたもの)及び10.37g(0.0373mol)の4−(6−アミノ−ピリジン−3−イル)−ピペラジン−1−カルボン酸tert−ブチルエステルのトルエン(100mL)中懸濁液が、窒素下で油浴中で7時間加熱された。薄層クロマトグラフィー(SiO2、10%MeOH/DCM)が、両方の出発物質の存在を示した。その懸濁液を還流下で更に18時間加熱した。生じた懸濁液を室温に冷却し、濾過して4−[6−(6−ブロモ-8−シクロペンチル−5−メチル−7−オキソ−7,8−ジヒドロ−ピリド[2,3−d]ピリミジン−2−イルアミノ)−ピリジン−3−イル]−ピペラジン−1−カルボン酸tert−ブチルエステル(5.93g、38%)を得た。融点>250℃。MS(APCI) M+ +1: 計算値584.2、実測値584.2
比較例1B:4−{6−[8−シクロペンチル−6−(1−エトキシ−ビニル)−5−メチル−7−オキソ−7,8−ジヒドロ-ピリド[2,3−d]ピリミジン−2−イルアミノ]−ピリジン−3−イル}−ピペラジン−1−カルボン酸tert−ブチルエステルの製造
4−[6−(6−ブロモ−8−シクロペンチル−5−メチル−7−オキソ−7,8−ジヒドロ−ピリド[2,3−d]ピリミジン−2−イルアミノ)−ピリジン−3−イル]−ピペラジン−1−カルボン酸tert−ブチルエステル(5.93g、0.010mol、比較例1Aにおける様に製造されたもの)、テトラキス(トリフェニルホスフィン)パラジウム(0)(1.40g、0.00121mol)、及びトリブチル(1−エトキシビニル)スズ(5.32mL、0.0157mol)のトルエン(30mL)中懸濁液が、還流下で3.5時間加熱された。この混合物を冷却し,濾過して固体を得た。この固体を15分にわたる5%-66%の酢酸エチル/ヘキサンのグラジェントを用いてシリカゲルクロマトグラフィーにより精製して、4−{6−[8−シクロペンチル−6−(1−エトキシ−ビニル)−5−メチル−7−オキソ−7,8−ジヒドロ−ピリド[2,3−d]ピリミジン−2−イルアミノ]−ピリジン−3−イル}−ピペラジン−1−カルボン酸tert−ブチルエステルを黄色フォームとして得た(4.50g、78 %)。MS (APCI) M++1: 計算値576.2、実測値576.3
比較例1C:6−アセチル−8−シクロペンチル−5−メチル−2−(5−ピペラジン−1−イル−ピリジン−2−イルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オン塩酸塩の製造
塩化水素ガスを氷浴冷却した4−{6−[8−シクロペンチル−6−(1−エトキシ−ビニル)−5−メチル−7−オキソ−7,8−ジヒドロ-ピリド[2,3−d]ピリミジン−2−イルアミノ]−ピリジン−3−イル}−ピペラジン−1−カルボン酸tert−ブチルエステル(4.50g、0.00783mol、2005−0059670A1における様にして製造された)のDCM(100mL)溶液中へバブリングした。生じた懸濁液に栓をして室温で一晩撹拌し、次いでジエチルエーテル(200mL)で希釈した。この固体をろ取により集め、ジエチルエーテルで洗浄し、そして乾燥させて、6−アセチル−8−シクロペンチル−5−メチル−2−(5−ピペラジン−1−イル−ピリジン−2−イルアミノ)−8H−ピリド[2,3−d]ピリミジン−7−オンの塩酸塩を黄色固体として得た(4.01g、92%)。融点200℃。HPLC, C18逆相、22分間で0.1%TFA/H2O中10%-95%グラジェントの0.1%TFA/CH3CN:11.04分において99.0%。MS (APCI) M+ +1:計算値448.2、実測値448.3。元素分析C24H29N7O2・2.4 H2O・1.85 HClの計算値: C、51.64; H、6.44; N、17.56、Cl(トータル)、11.75。実測値:C、51.31; H、6.41; N、17.20; Cl(トータル)、12.11。
1.0kg(5mol)5−ブロモ−2−ニトロピリジンに、1.2kg(6.4mol)のBocピペラジン(tert−ブチル ピペラジン−1−カルボキシレート)を、2.6LのDMSO及び0.5kgのトリエチルアミン中で窒素下で加えた。混合物を65−70℃に加熱し、30時間維持した後、固体がいくらか析出した。水を加え、反応液を25℃に2時間に渡って冷却した。生じたスラリーをろ過し、洗浄し、45℃で乾燥して1.2kg(79%粗収率)のカナリアイエローの固体中間体(2A)を得た。これは、更に生成することなく続く工程において用いられた。
Parr反応容器中に60.0gの20%Pd(OH)2/C、1213.1g(3.9mol)の中間体2a、及びイソプロパノールが充填されて撹拌され、次いで、ガスの下でパージされ、続いて触媒を加圧下で除去した。ろ液を〜20℃で真空下で濃縮して917gの乾燥褐色粉末が残った(粗収率〜84%)。
エタノール中の1g(0.004mol)の5−ブロモ−2、4−ジクロロピリミジンへ、1.5kg(0.018mol)のシクロペンチルアミンを窒素下で加えた。混合物を25℃で2時間撹拌した。水を加えて生成物を析出させ、固体をヘキサン4:1を用いて再結晶して白色結晶生成物(3A)を得た。
41.5g(0.15mol)の5−ブロモ−2−クロロ−4−シクロペンチルアミノピリミジン3a及び32.3g(0.375mol)のクロトン酸を100LのTHF及び105ml(1.6mol)のジイソプロピルエチルアミン中で窒素下で混合した。スラリーを撹拌し、窒素を3回排出して再充填した後、860mg(0.0022mol)のパラジウムジクロリドジベンゾニトリルコンプレックス及び685mg(0.0022mol)のトリ−オルト−トリルホスフィンが添加され、生じたスラリーを更に3回脱気した。次いで、16時間70℃で混合物を加熱し撹拌した後、35mlの無水酢酸を添加し、混合物をさらに1.5時間撹拌した。混合物を冷却し、100mlのMTBEで希釈し、次いで1N HClで抽出し、その後炭酸水素ナトリウム水及び食塩水。有機層を硫酸マグネシウム上で乾燥し、ろ過し、真空下で濃縮し、IPAから再結晶して、31.2g(68%)の粗精製生成物(3)を得た。
10g(0.04mol)の中間体3及び13g(0.16mol)の酢酸ナトリウムを、50mlの氷酢酸及び12g(0.08mol)の臭素と、窒素下で混合した。この溶液を50℃に加熱し、35時間撹拌し、次いで室温に冷却した。亜硫酸水素ナトリウムを、臭素色が消失するまで加え、次いでクエンチングし、ろ過し、そして洗浄して固体を得て、続いて500mlの熱IPA中に溶解し、熱時ろ過し、冷却した。生じた結晶を更にろ取し、真空化で65℃で乾燥して8g(61%)の粗精製生成物(4A)を得た。
3.78g(2.10当量;13.6mmol)の中間体1、25mlのトルエン及びリチウムビス(トリメチルシリル)アミドの1M THF液(13.6mmol;13.6mL;12.1g)を10分間窒素下で混合して暗色溶液を生成させた。別のビーカー中で中間体4a(1.00当量、6.47mmol;2.50g)をトルエン中でスラリー化させ、次いで1を含有する混合物中へ添加して30分撹拌した後、合わされた混合物を25mlの1M炭酸水素ナトリウムでクエンチングし、濾過した。或いは、その合わされた混合物は、塩化アンモニウムでクエンチングされてもよい。ろ過ケーキをトルエン、次いでアセトン、次いで水で洗浄し、60℃で乾燥させて3.5g(92%)の灰黄色固体4を得た。
Claims (23)
- 式I:
(a)式:
R1は、水素、C1−C6アルキル、C1−C6ハロアルキル、C1−C6ヒドロキシアルキル又はC3−C7シクロアルキルであり;
R2は、Br又はIであり;
R3は、水素、OH、−NH2、アリール、C1−C8アルキル、C3−C7シクロアルキル又はC3−C7−へテロサイクリルであり;
R4は、−(CR7R8)m−N(PG)R7、及び−(CR7R8)m−(PG保護N環原子を含む3〜10員ヘテロサイクル)からなる群から選択される−R5−PGであり、そしてPGは、酸不安定性アミン保護基であり;
R5、即ちPGを有さないR4は、−(CR7R8)mNR7−又は−(CR7R8)m−(N環原子を含む3〜10員ヘテロサイクル)であり、mは、0、1、2又は3であり;
R6は、C1−C6アルキルであり;そして
R7及びR8は、各々独立してH又はC1−C6アルキルである}
、遷移金属触媒、塩基、及び場合によりホスフィン物質の存在下で、適切な溶媒中で、反応させ、式Ie又はIf;
(b)続いて式Ie又はIfの化合物又はそれらの混合物とイセチオン酸とを、適切な溶媒中で反応させる工程
を含む方法。 - 前記遷移金属触媒が、テトラキス(トリフェニルホスフィン)パラジウム [(Ph3P)4Pd]、トリス(ジベンジリデンアセトン)ジパラジウム [Pd2(dba)3]、ビス(ジベンジリデンアセトン)パラジウム(0) [(dba)2Pd]、酢酸パラジウム [Pd(OAc)2]、塩化パラジウム (PdCl2)、ビス(ベンゾニトリル)ジクロロパラジウム [(C6H5CN)2PdCl2] 及び(ビス−(ジフェニルホスフィノフェロセン)パラジウムジクロリド ジクロロメタンコンプレックス (Pd(dppf)2Cl2)からなる群から選択されるパラジウム化合物であり、前記ホスフィン化合物が、2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフタレン (BINAP)、1,3 ビス(ジフェニルホスフィノ)プロパン、トリフェニルホスフィン (Ph3P)、トリオルトトリルホスフィン [(o-CH3Ph)3P] 及びトリ−t−ブチルホスフィンから選択されるものである、請求項1又は2に記載の方法。
- 前記遷移金属触媒が(ビス−(ジフェニルホスフィノフェロセン)パラジウムジクロリド ジクロロメタンコンプレックス (Pd(dppf)2Cl2)である、請求項1又は2に記載の方法。
- 工程(a)における塩基が、ジイソプロピルエチルアミン、炭酸リチウム、ジシクロへキシルメチルアミン及びトリエチルアミンからなる群から選択されるものである、請求項1、2、3又は4に記載の方法。
- 前記塩基がジイソプロピルエチルアミンである、請求項5に記載の方法。
- 前記ハロゲン化条件が、酢酸、酢酸カリウム又は酢酸ナトリウムの存在下における(R2)2である、請求項7に記載の方法。
- 前記リチウム塩基がリチウムビス(トリメチルシリル)アミドである、請求項7又は8に記載の方法。
- X1がClである、請求項7、8又は9に記載の方法。
- 前記ハロゲン化条件が、酢酸、酢酸カリウム又は酢酸ナトリウムの存在下での(R2)2である、請求項11に記載の方法。
- 前記リチウム塩基が、リチウムビス(トリメチルシリル)アミドである、請求項11又は12に記載の方法。
- X1がClである、請求項11、12又は13に記載の方法。
- 前記遷移金属触媒が、テトラキス(トリフェニルホスフィン)パラジウム [(Ph3P)4Pd]、トリス(ジベンジリデンアセトン)ジパラジウム [Pd2(dba)3]、ビス(ジベンジリデンアセトン) パラジウム(0) [(dba)2Pd]、酢酸パラジウム [Pd(OAc)2]、塩化パラジウム (PdCl2)、ビス(ベンゾニトリル)ジクロロパラジウム [(C6H5CN)2PdCl2] 及び(ビス-(ジフェニルホスフィノフェロセン)パラジウムジクロリド ジクロロメタンコンプレックス (Pd(dppf)2Cl2) からなる群から選択されるパラジウム化合物であり、前記ホスフィン化合物が、2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフタレン (BINAP)、1,3 ビス(ジフェニルホスフィノ)プロパン、トリフェニルホスフィン (Ph3P)、トリオルトトリルホスフィン [(o-CH3Ph)3P] 及びトリ−t−ブチルホスフィンから選択される、請求項15に記載の方法。
- 工程(g)における塩基がジイソプロピルエチルアミンであり、工程(g)における遷移金属触媒がパラジウムジクロリドジベンゾニトリルであり、工程(g)がトリオルトトリルホスフィンの存在下で行われる、請求項15に記載の方法。
- RaがHであり、分子内環化がカップリング剤の存在下で行われる、請求項15又は16に記載の方法。
- RaがHであり、分子内環化が無水酢酸又は酢酸クロリドの存在下で行われる、請求項15又は16に記載の方法。
- 式Ic:
R2はBr又はIであり;そしてR3は水素、OH、−NH2、アリール、C1−C8アルキル、C3−C7シクロアルキル又はC3−C7−へテロサイクリルである)の化合物を製造するための方法であって;
(a)式Ib:
(b)工程(a)で生じた生成物を無水酢酸で適切な溶媒中で処理して式Icの化合物を生成させる工程を含む方法。 - 工程(a)の溶媒がトルエン及びTHFから選択される、請求項20に記載の方法。
- 前記遷移金属触媒が、テトラキス(トリフェニルホスフィン)パラジウム [(Ph3P)4Pd]、トリス(ジベンジリデンアセトン)ジパラジウム [Pd2(dba)3]、ビス(ジベンジリデンアセトン)パラジウム(0) [(dba)2Pd]、酢酸パラジウム [Pd(OAc)2]、塩化パラジウム (PdCl2)、ビス(ベンゾニトリル)ジクロロパラジウム [(C6H5CN)2PdCl2] 及び(ビス−(ジフェニルホスフィノフェロセン)パラジウムジクロリド ジクロロメタンコンプレックス (Pd(dppf)2Cl2)からなる群から選択されるパラジウム化合物であり、そして前記ホスフィン化合物が、2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフタレン (BINAP)、1,3 ビス(ジフェニルホスフィノ)プロパン、トリフェニルホスフィン (Ph3P)、トリオルトトリルホスフィン [(o-CH3Ph)3P] 及びトリ−t−ブチルホスフィンから選択される、請求項21に記載の方法。
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Cited By (4)
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JP2014162794A (ja) * | 2013-02-21 | 2014-09-08 | Pfizer Inc | 選択的cdk4/6阻害剤の固体形態 |
JP2017186376A (ja) * | 2013-02-21 | 2017-10-12 | ファイザー・インク | 選択的cdk4/6阻害剤の固体形態 |
JP2016512831A (ja) * | 2013-03-15 | 2016-05-09 | コンサート ファーマシューティカルズ インコーポレイテッド | 重水素化されたパルボシクリブ |
JP2018503634A (ja) * | 2015-02-03 | 2018-02-08 | ジエンス ヘンルイ メデイシンカンパニー リミテッドJiangsu Hengrui Medicine Co.,Ltd. | サイクリン依存性タンパク質キナーゼインヒビターのヒドロキシエチルスルホン酸塩、その結晶形およびその製造方法 |
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CN101511829A (zh) | 2009-08-19 |
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WO2008032157A3 (en) | 2008-10-23 |
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US7781583B2 (en) | 2010-08-24 |
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WO2008032157A2 (en) | 2008-03-20 |
ZA200901270B (en) | 2010-05-26 |
CA2662768A1 (en) | 2008-03-20 |
TW200821309A (en) | 2008-05-16 |
US20080125588A1 (en) | 2008-05-29 |
BRPI0716880A2 (pt) | 2013-10-15 |
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