WO2024048714A1 - PROCÉDÉ DE PRODUCTION DE 6-(4,4-DIMÉTHYLCYCLOHEXYL)-4-[(1,1-DIOXO-1λ6-THIOMORPHOLIN-4-YL)MÉTHYL]-2-MÉTHYLTHIÉNO[2,3-D]PYRIMIDINE OU D'UN DE SES SELS - Google Patents
PROCÉDÉ DE PRODUCTION DE 6-(4,4-DIMÉTHYLCYCLOHEXYL)-4-[(1,1-DIOXO-1λ6-THIOMORPHOLIN-4-YL)MÉTHYL]-2-MÉTHYLTHIÉNO[2,3-D]PYRIMIDINE OU D'UN DE SES SELS Download PDFInfo
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- WO2024048714A1 WO2024048714A1 PCT/JP2023/031795 JP2023031795W WO2024048714A1 WO 2024048714 A1 WO2024048714 A1 WO 2024048714A1 JP 2023031795 W JP2023031795 W JP 2023031795W WO 2024048714 A1 WO2024048714 A1 WO 2024048714A1
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- compound
- compound represented
- reaction
- stirred
- methylthieno
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- 150000003839 salts Chemical class 0.000 title claims abstract description 22
- USFNNXLOYXNESM-UHFFFAOYSA-N 4-[[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl]-1,4-thiazinane 1,1-dioxide Chemical compound C=12C=C(C3CCC(C)(C)CC3)SC2=NC(C)=NC=1CN1CCS(=O)(=O)CC1 USFNNXLOYXNESM-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 232
- 238000000034 method Methods 0.000 claims abstract description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- PXQMSTLNSHMSJB-UHFFFAOYSA-N 4,4-dimethylcyclohexan-1-one Chemical compound CC1(C)CCC(=O)CC1 PXQMSTLNSHMSJB-UHFFFAOYSA-N 0.000 abstract description 7
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 135
- -1 1,1-dioxo-1λ 6 -thiomorpholin-4-yl Chemical group 0.000 description 127
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 97
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 83
- 239000000243 solution Substances 0.000 description 82
- 239000000203 mixture Substances 0.000 description 65
- 239000013078 crystal Substances 0.000 description 63
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- 239000000725 suspension Substances 0.000 description 45
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 44
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- 229910052757 nitrogen Inorganic materials 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000003054 catalyst Substances 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 23
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 19
- 229910052739 hydrogen Inorganic materials 0.000 description 19
- 239000001257 hydrogen Substances 0.000 description 19
- 229910052763 palladium Inorganic materials 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 238000001816 cooling Methods 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- VYUDXHRVZLZWMP-UHFFFAOYSA-N 4-chloro-2-methylthieno[2,3-d]pyrimidine Chemical compound CC1=NC(Cl)=C2C=CSC2=N1 VYUDXHRVZLZWMP-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 150000001793 charged compounds Chemical class 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 12
- 150000002170 ethers Chemical class 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- QNXCZSIJXKHBGL-UHFFFAOYSA-N 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid Chemical compound Cc1nc(C(O)=O)c2cc(sc2n1)C1CCC(C)(C)CC1 QNXCZSIJXKHBGL-UHFFFAOYSA-N 0.000 description 7
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 7
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 7
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N DBU Substances C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 150000001924 cycloalkanes Chemical class 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 150000008282 halocarbons Chemical class 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 229910010082 LiAlH Inorganic materials 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229910052703 rhodium Inorganic materials 0.000 description 4
- 239000010948 rhodium Substances 0.000 description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000011995 wilkinson's catalyst Substances 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 3
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 150000001925 cycloalkenes Chemical class 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- YEACCBWVDDIELV-UHFFFAOYSA-N 2-(4,4-dimethylcyclohexyl)acetaldehyde Chemical compound CC1(C)CCC(CC=O)CC1 YEACCBWVDDIELV-UHFFFAOYSA-N 0.000 description 2
- CDGGZDOQRUNQJW-UHFFFAOYSA-N 2-acetamido-5-(4,4-dimethylcyclohexyl)thiophene-3-carboxamide Chemical compound CC(=O)NC1=C(C=C(S1)C1CCC(C)(C)CC1)C(N)=O CDGGZDOQRUNQJW-UHFFFAOYSA-N 0.000 description 2
- AZDKYLVUXUNUSF-UHFFFAOYSA-N 2-amino-5-(4,4-dimethylcyclohexyl)thiophene-3-carboxamide Chemical compound CC1(C)CCC(CC1)c1cc(C(N)=O)c(N)s1 AZDKYLVUXUNUSF-UHFFFAOYSA-N 0.000 description 2
- JXMFNTQQCVNKRZ-UHFFFAOYSA-N 2-methylthieno[2,3-d]pyrimidine Chemical compound CC1=NC=C2C=CSC2=N1 JXMFNTQQCVNKRZ-UHFFFAOYSA-N 0.000 description 2
- HAUNPYVLVAIUOO-UHFFFAOYSA-N 4,4-dimethylcyclohex-2-en-1-one Chemical compound CC1(C)CCC(=O)C=C1 HAUNPYVLVAIUOO-UHFFFAOYSA-N 0.000 description 2
- MEMQVSDWHKFLIV-UHFFFAOYSA-N 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine Chemical compound Cc1nc(Cl)c2cc(sc2n1)C1CCC(C)(C)CC1 MEMQVSDWHKFLIV-UHFFFAOYSA-N 0.000 description 2
- DFJFXYSQTSMDJE-UHFFFAOYSA-N 6-(4,4-dimethylcyclohexyl)-2-methyl-3H-thieno[2,3-d]pyrimidin-4-one Chemical compound Cc1nc2sc(cc2c(=O)[nH]1)C1CCC(C)(C)CC1 DFJFXYSQTSMDJE-UHFFFAOYSA-N 0.000 description 2
- VJTVVUFGRJGSQX-UHFFFAOYSA-N 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile Chemical compound Cc1nc(C#N)c2cc(sc2n1)C1CCC(C)(C)CC1 VJTVVUFGRJGSQX-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 125000005233 alkylalcohol group Chemical group 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001934 cyclohexanes Chemical class 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 150000002642 lithium compounds Chemical class 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical group C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- MYIPEPGIRJMNHF-UHFFFAOYSA-N 2,3,4-trimethyl-3-(2,3,4-trimethylpentan-3-yloxy)pentane Chemical group CC(C)C(C)(C(C)C)OC(C)(C(C)C)C(C)C MYIPEPGIRJMNHF-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- VVKVBQDZJLGAFG-UHFFFAOYSA-N 3-(1-methylindol-3-yl)propanoic acid Chemical compound C1=CC=C2N(C)C=C(CCC(O)=O)C2=C1 VVKVBQDZJLGAFG-UHFFFAOYSA-N 0.000 description 1
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical group C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 1
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N N,N′-Dicyclohexylcarbodiimide Substances C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 1
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- JMQGGPRJQOQKRT-UHFFFAOYSA-N diphenyl hydrogen phosphate;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 JMQGGPRJQOQKRT-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- ZDLGAHAMTHJYOA-UHFFFAOYSA-N ethyl 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate Chemical compound CCOC(=O)c1nc(C)nc2sc(cc12)C1CCC(C)(C)CC1 ZDLGAHAMTHJYOA-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ULKSWZAXQDJMJT-UHFFFAOYSA-M magnesium;2,2,6,6-tetramethylpiperidin-1-ide;chloride Chemical compound [Cl-].CC1(C)CCCC(C)(C)N1[Mg+] ULKSWZAXQDJMJT-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 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
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ZIEWSZYVEDTXGH-UHFFFAOYSA-N pyrimidine-4-carbonitrile Chemical compound N#CC1=CC=NC=N1 ZIEWSZYVEDTXGH-UHFFFAOYSA-N 0.000 description 1
- YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 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
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- KFZUDNZQQCWGKF-UHFFFAOYSA-M sodium;4-methylbenzenesulfinate Chemical compound [Na+].CC1=CC=C(S([O-])=O)C=C1 KFZUDNZQQCWGKF-UHFFFAOYSA-M 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 239000013077 target material Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine or
- the present invention relates to a method for producing the salt.
- Patent Document 1 International Publication 2015/056771A1 discloses 6-(4,4-dimethylcyclohexyl)-4-[(1,1 - dioxo -1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine is described. Furthermore, as a method for synthesizing the compound represented by Formula I, a synthetic method including a method of forming a thienopyrimidine skeleton from a cyclohexane derivative through thiophene cyclization is described. This synthetic method requires a large number of steps and also involves the use and production of toxic compounds.
- the problem of the present invention is to solve the problem of 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]
- the purpose of the present invention is to develop a synthetic method for pyrimidine or its salt that is efficient and more preferable from the viewpoint of green chemistry.
- 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d] Pyrimidine or a salt thereof can be synthesized efficiently and more preferably from the viewpoint of green chemistry.
- 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine has the following formula: This is a compound represented by I.
- the compound represented by Formula I may be in a free form that does not form an ester or salt, or may form a salt with an acid or the like.
- Such salts are preferably pharmaceutically acceptable salts, but are not limited thereto, and include, for example, acid addition salts with inorganic acids, organic acids, etc.
- inorganic acids include examples of organic acids include formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, and lactic acid. , malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, carbonic acid, etc. Yes, but not limited to this.
- a compound may be described using a structural formula, such as "a compound represented by formula X,” but it may also be simply described as compound X. Therefore, the compound represented by Formula I may be simply referred to as "Compound I".
- the present invention provides, in one embodiment, 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3 -d] A method for producing pyrimidine or its salt. When producing various hydrates, solvates, crystal polymorphs, etc. of the compound represented by Formula I, the hydrates may be obtained by appropriately known methods.
- the labeling may be carried out appropriately by a known method.
- the functional group can be replaced with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from raw materials to intermediates.
- protecting groups include the protecting groups described in "Greene's Protective Groups in Organic Synthesis” (4th edition, 2006), which can be selected and used as appropriate depending on the reaction conditions. Good, but not limited to this.
- a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
- lower alkyl typically refers to a straight chain or branched chain having 1 to 6 carbon atoms (hereinafter also referred to as C 1-6 , hereinafter the number of carbon atoms is expressed in the same manner).
- alkyl such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.
- Examples of the "lower alkyl group” include a methyl group, an ethyl group, a propyl group, and the like, with an ethyl group being preferred.
- Cycloalkane is typically a C 3-8 saturated hydrocarbon ring, including, but not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclo Examples include octane.
- the "cycloalkane” is preferably a C 5-6 cycloalkane, such as cyclohexane or cyclopropane, preferably cyclopropane.
- Halogen means F, Cl, Br, or I.
- a 1M NaOH aqueous solution means a 1 mol/L NaOH aqueous solution.
- 4-chloro-2-methylthieno[2,3-d]pyrimidine or a derivative thereof is used as a starting material. That is, in the present invention, the following formula: For 4-chloro-2-methylthieno[2,3-d]pyrimidine or its derivatives represented by the following formula: By selectively adding the compound represented by the 6-position, the following formula: A compound represented by is obtained.
- International Publication No. 2015/056771A1 describes a method for synthesizing the compound represented by Formula I, but it involves cyclizing thiophene from a cyclohexane derivative and finally forming a thienopyrimidine skeleton, which requires a large number of steps. The yield of the target compound is also low.
- the basic skeleton of the target compound is formed at an early stage by adding 4,4-dimethylcyclohexanone to the 6-position of 4-chloro-2-methylthieno[2,3-d]pyrimidine.
- the number of steps can be reduced and the yield can be significantly improved.
- 1-(4-chloro-2-methylthieno[2,3 -d]pyrimidin-6-yl)-4,4-dimethylcyclohexan-1-ol (A-200) the solvent is not particularly limited as long as it does not interfere with the reaction, but for example, THF is typically used.
- the base include, but are not limited to, typically organic lithium compounds such as n-BuLi, sec-BuLi, lithium diisopropylamide, and lithium hexamethyldisilazide. , preferably n-BuLi can be used.
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically ethers such as THF, diethyl ether, and cyclopentyl methyl ether, or aromatic hydrocarbons such as toluene and xylene can be used.
- ethers such as THF, diethyl ether, and cyclopentyl methyl ether, or aromatic hydrocarbons such as toluene and xylene can be used.
- THF can be used.
- the base is not particularly limited as long as the reaction proceeds, but typically organic lithium compounds such as n-BuLi, sec-BuLi, lithium diisopropylamide, and lithium hexamethyldisilazide can be used. , preferably n-BuLi can be used.
- Organic amines such as, but not limited to, DIPEA, triethylamine, DBU, pyridine may additionally be used to convert cycloalkanes to cycloalkenes in one pot.
- DIPEA triethylamine
- DBU triethylamine
- pyridine may additionally be used to convert cycloalkanes to cycloalkenes in one pot.
- the halogen in A-101 is not particularly limited as long as the reaction proceeds, but Br is preferably used.
- the manufacturing method according to the present invention is performed using the following formula:
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically an aprotic polar solvent such as MeCN, DMF, or DMSO can be used, and MeCN can be preferably used.
- the present invention provides the following formula: From the compound represented by the following formula:
- R is an alkyl group
- the method may further include a step of obtaining a compound represented by:
- This reaction is not particularly limited as long as the reaction progresses, but for example, 6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (A- 300), for example, is typically carried out in the presence of an alkyl alcohol and an acid or acid halide (optionally in a suitable solvent).
- an acid or acid halide HCl, acyl chloride, etc. can be used, and as a solvent, EtOH or any mixed solvent containing EtOH can be used.
- This reaction is not particularly limited as long as the reaction progresses, but for example, typically, after adding the alkyl alcohol and acid under cooling, the reaction is carried out at around room temperature, and the mixture is stirred at 40°C to 60°C for several hours to overnight. It can be done by
- the present invention provides the following formula:
- the method may include a step of obtaining a compound represented by: Ethyl 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (A-400) was reduced to [6-( The process of obtaining 4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-500) is particularly Although not limited, the reaction may be carried out using a solvent inert to the reaction and in the presence of a reducing agent.
- the reaction conditions are not particularly limited, but can be, for example, typically cooling to heating, preferably at -20°C to 80°C, for 0.1 hour to 3 days.
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically ethers, aromatic hydrocarbons, alcohols, halogenated hydrocarbons, or mixed solvents thereof can be used.
- the reducing agent is not limited to these, typically sodium borohydride (NaBH 4 ), lithium aluminum hydride (LiAlH 4 ), borane (BH 3 ), reducing agents described in the following literature, etc. are used. NaBH4 may be used with CaCl2 .
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as EtOH and MeOH, ethers such as THF, etc. can be used.
- Metal catalysts include, but are not limited to, typically palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , rhodium catalysts such as Wilkinson catalysts, etc., and are suitable. Pd(OH) 2 can be used for.
- As the hydrogen source formic acid, ammonium formate, etc. can also be used in an equivalent to excess amount of compound A-500, instead of hydrogen gas. [Literature] M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)", ACS, 1996; “Experimental Chemistry Course (5th edition)” edited by the Chemical Society of Japan, Volume 19 (2005) (Maruzen)
- the present invention provides the following formula:
- the method may further include a step of obtaining a target compound represented by:
- This amination step may be carried out by any suitable method known in the art, for example by direct amination, typically with a catalyst, or by converting the hydroxyl group into a leaving group. be able to.
- the hydroxyl group of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (A-600) is substituted with a halogen, an alkylsulfonate, a fluoroalkylsulfonate, etc.
- thiomorpholine-1,1-dioxide A-20
- A-20 thiomorpholine-1,1-dioxide
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically includes aromatic hydrocarbons such as toluene and xylene, ethers such as Et 2 O, THF, DME, and dioxane, DCM, DCE, Halogenated hydrocarbons such as chloroform, DMF, DMSO, EtOAc, MeCN, and mixed solvents thereof can be used.
- an organic base such as TEA, DIPEA or NMO
- an inorganic base such as K 2 CO 3 , Na 2 CO 3 or KOH
- the present invention provides the following formula: From the compound represented by the following formula: After obtaining the compound represented by, the compound is reduced to form the following formula:
- the method may include a step of obtaining a compound represented by: Hydrolysis of ethyl ester of 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (A-400)
- A-400 The process for obtaining 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-100) is well known in the art.
- reaction may be carried out by any known appropriate method, and is not particularly limited as long as the reaction proceeds, but for example, it may be carried out typically in the presence of an aqueous alkaline solution using a solvent inert to the reaction.
- the reaction conditions are not particularly limited, but can be, for example, typically cooling to heating, preferably at 0° C. to 50° C., for 0.1 hour to 3 days.
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF, or mixed solvents thereof can be used.
- the alkaline aqueous solution is not particularly limited as long as the reaction proceeds, but typically, for example, a NaOH aqueous solution, a KOH aqueous solution, a LiOH aqueous solution, etc. can be used.
- 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-100) is reduced to The step of obtaining 4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-200) may be performed by hydrogenation reaction of compound (B-100).
- This reaction is not particularly limited as long as the reaction proceeds, but for example, compound B-100 is preferably mixed with a metal catalyst in a hydrogen atmosphere, in a solvent inert to the reaction, and typically by cooling to heating. The mixture may be stirred at room temperature, usually for 1 hour to 5 days.
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF, etc. can be used.
- the metal catalyst include, but are not limited to, palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , and rhodium catalysts such as Wilkinson's catalyst.
- As the hydrogen source formic acid, ammonium formate, etc.
- the present invention provides the following formula:
- the compound is reduced to form the following formula:
- the method may include a step of obtaining a target compound represented by 4-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonyl]-1 ⁇ 6 -thiomorpholine-1,1-dione (B-300) is 6 -(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (B-200) and thiomorpholine-1-dioxide (A-20).
- Compound B-200 and Compound A-20 are used in equal amounts or in excess of one of them, in the presence of a condensing agent, in a solvent inert to the reaction, typically by cooling to heating, and preferably Stir at -20°C to 60°C, usually for 0.1 hour to 5 days.
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically includes aromatic hydrocarbons, halogenated hydrocarbons such as DCM, ethers, DMF, DMSO, EtOAc, CH 3 CN, or water, Mixed solvents of these can be used.
- the condensing agent is not limited thereto, for example, typically WSC, CDI, HATU, DCC, DMTMM, etc. can be used.
- Additives such as HOBt may facilitate the reaction.
- Organic bases such as pyridine, TEA, DIPEA or NMO, inorganic bases such as K 2 CO 3 , Na 2 CO 3 or KOH may facilitate the reaction.
- Compound B-300 can also be produced from a reactive derivative of carboxylic acid and compound A-20.
- Reactive derivatives include, but are not limited to, acid halides obtained by reacting the carboxylic acid of compound B-200 with a halogenating agent, typically phosphorus oxychloride, thionyl chloride; chloroformic acid; Examples include mixed acid anhydrides obtained by reacting with isobutyl, ethyl chlorocarbonate, etc.; active esters obtained by condensation with HOBt, etc.; preferred is ethyl chlorocarbonate.
- the reaction of the reactive derivative with compound A-20 is carried out with an organic base such as pyridine, TEA, DIPEA or NMO in a solvent inert to the reaction, typically by cooling to heating, preferably from -20°C to 60°C.
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically includes halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, CH 3 CN, water, or a mixed solvent thereof. Can be used. Moreover, the above organic base can also serve as a solvent.
- the solvent is not particularly limited as long as the reaction proceeds, and for example, THF, aromatic hydrocarbons, etc. can be used.
- the reducing agent is not limited to this, but typically a combination of LiAlH 4 and aluminum chloride (AlCl 3 ), Red-Al, DIBAL, BH 3 , Et 3 SiH, etc. can be used, and are suitable.
- a combination of LiAlH 4 and aluminum chloride (AlCl 3 ) can be used.
- the present invention provides the following formula: From the compound represented by the following formula: The method may include a step of obtaining a compound represented by or a salt such as its hydrochloride (C-300).
- the invention provides the following formula: From the compound represented by the following formula: After obtaining a compound represented by or a salt such as its hydrochloride (C-200), the compound is reduced to form the following formula:
- the method may include a step of obtaining a compound represented by or a salt such as its hydrochloride (C-300).
- 6-(1-hydroxy-4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (A-300) to 1-[6-(4,4-dimethylcyclohexyl) Reactions to obtain salts such as -1-en-1-yl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or its hydrochloride (C-200) include, but are not limited to, The cyano group is reduced using a nickel catalyst such as Raney nickel or a palladium catalyst such as Pd, Pd(OH) 2 in a reaction-inert solvent under a hydrogen atmosphere, followed by MeOH hydrochloric acid solution, hydrochloric acid, sulfuric acid, etc.
- the cycloalkene can be obtained by dehydration using .
- the reaction conditions are not particularly limited, but can be, for example, typically cooling to heating, preferably at 0° C. to 50° C., for 0.1 hour to 3 days.
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF, or mixed solvents thereof can be used.
- cyano group reduction and Boc protection of the primary amine are performed at once using Raney nickel in the presence of (Boc) 2 O, and then dehydration and Boc removal are simultaneously performed with MeOH hydrochloric acid solution, thereby converting the primary amine into The reaction can proceed while suppressing side reactions derived from the nucleophilicity of .
- the step of obtaining it may be a hydrogenation reaction.
- This reaction can be carried out, for example, by stirring the compound (C-200) with a metal catalyst in a hydrogen atmosphere, in a solvent inert to the reaction, by cooling to heating, preferably at room temperature, usually for 1 hour to 5 days. , but not limited to.
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF and CPME, etc.
- EtOH can be preferably used.
- metal catalyst include, but are not limited to, palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , and rhodium catalysts such as Wilkinson's catalyst.
- hydrogen source formic acid, ammonium formate, etc. can also be used instead of hydrogen gas.
- the present invention provides the following formula: By reducing the compound represented by the following formula: You may obtain a compound represented by 6-(4,4-dimethylcyclohex-1-en-1-yl)-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (D-200) is reduced to 1-[6- The process of obtaining (4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine or its salt such as hydrochloride (C-300) may be carried out by hydrogenation reaction. .
- This reaction is carried out, for example, by combining compound D-200 with a metal catalyst in a hydrogen atmosphere, in a solvent inert to the reaction, typically between cooling and heating, preferably between 0°C and 80°C, usually for 1 hour to 80°C. It may be stirred for 5 days, but is not limited thereto.
- the solvent is not particularly limited as long as it does not interfere with the reaction, but typically alcohols such as MeOH and EtOH, ethers such as THF and CPME, etc. can be used, and MeOH or EtOH is preferably used. can.
- metal catalysts include, but are not limited to, typically palladium catalysts such as Pd and Pd(OH) 2 , platinum catalysts such as PtO 2 , and rhodium catalysts such as Wilkinson's catalyst.
- a hydrogen source formic acid, ammonium formate, etc. can also be used instead of hydrogen gas.
- catalytic reduction using a palladium catalyst such as Pd(OH) 2 is carried out under heating conditions of 70°C, for example, but not limited thereto, to simultaneously convert the alkene into the cyano group of compound D-200. Since the reduction can be performed in one pot, the synthesis process can be shortened.
- the invention provides the following formula:
- the compound represented by is reacted with divinyl sulfone to form the following formula:
- the method may include a step of obtaining a compound represented by:
- the target compound is obtained by reacting 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanamine-hydrogen chloride (C-300) with divinyl sulfone.
- the solvent is not particularly limited as long as the reaction proceeds, but typically includes alcohols such as MeOH and EtOH, aromatic hydrocarbons such as toluene and xylene, Et 2 O, Ethers such as THF, DME, and dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, DMF, DMSO, EtOAc, MeCN, and mixed solvents thereof can be used, and MeOH is preferably used. be able to.
- a base for example, typically an organic amine such as TEA, DIPEA, DBU, NMI, etc. can be used, preferably DIPEA.
- the reaction can proceed favorably by slowly dropping a MeOH solution of C-300 and DIPEA into a reaction solution in which divinyl sulfone is dissolved in MeOH.
- the compounds described in this specification may exist as tautomers or geometric isomers depending on the type of substituent. Although only one isomer form of a compound may be described herein, it is understood that the present invention includes other isomers as well as separated isomers or mixtures thereof. Should. Similarly, the compounds described in this specification may have asymmetric carbon atoms or axial asymmetry, and optical isomers based on this may exist. In such cases, the present invention also includes separated optical isomers of the compound or mixtures thereof.
- concentrations and the like are based on weight, and numerical ranges include the end points.
- Reference example International Publication 2015/056771A1 contains 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]- based on the scheme below.
- the synthesis of 2-methylthieno[2,3-d]pyrimidine has been described.
- Process 1 DMSO (50 mL) and TEA (100 mL) were added to a mixture of 2-(4,4-dimethylcyclohexyl)EtOH (25.3 g) and DCM (200 mL) under an argon atmosphere, and the mixture was further cooled on ice.
- reaction mixture was allowed to cool to room temperature, and then concentrated under reduced pressure. Chloroform and saturated aqueous sodium bicarbonate were added to the residue and stirred. The organic layer was washed successively with water and brine. MgSO 4 , activated carbon (10 g), and silica gel (100 mL) were added to the organic layer, stirred, filtered through Celite, concentrated under reduced pressure, and 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[ 2,3-d]pyrimidine (31.3 g) was obtained.
- Process 8 Calcium chloride was added to a mixture of ethyl 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (13.0 g), THF (150 mL) and EtOH (150 mL). (6.6 g) was added thereto, and after stirring at room temperature for 30 minutes, NaBH 4 (1.8 g) was added in small portions over 15 minutes under ice cooling. After stirring at room temperature for 4.5 h, water (100 mL) and EtOAc (100 mL) were added to the reaction mixture under ice-cooling, and 1M HCl (100 mL) was added until the suspension became a solution, followed by vacuum reduction.
- Step 10 Methanesulfonic acid [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4 was added to a mixture of thiomorpholine-1,1-dioxide (70 mg) and DMF (4 mL). -yl]methyl (120 mg) and TEA (150 ⁇ L) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , and concentrated under reduced pressure.
- the yield is about 68%, and many raw materials are required to synthesize the target substance (Bioorganic & Medicinal Chemistry Letters (2011), 21(15), pp. 4409- 4415).
- step 1 the oxidation reaction using SO 3 pyridine/DMSO generates toxic and foul-smelling dimethyl sulfide, and in step 5, In this process, phosphoryl chloride (POCl 3 ), which is a poisonous substance under the Poisonous and Deleterious Substances Control Law, will be used for chlorination. From the perspective of green chemistry, it is desirable to establish a method for synthesizing target substances without using as many harmful substances as possible.
- Organic layers 1 to 3 were mixed, activated carbon (purified Shirasagi W50, manufactured by Osaka Gas Chemical Co., Ltd., 63.0 kg) and THF (82.0 kg) were charged into reaction tank 3, and the mixture was stirred at an internal temperature of 23°C to 26°C for 3 hours.
- the suspension was filtered and the solution was transferred to reaction tank 2.
- Reaction tank 3 was washed with THF (112.5 kg) and transferred to reaction tank 2 via a filter.
- the solution was concentrated under reduced pressure at an external temperature of 50°C or less until the remaining volume was 252 L.
- THF 224.4 kg was charged and concentrated under reduced pressure at an external temperature of 50°C or lower until the remaining volume was 252 L.
- the suspension containing the crystals was filtered, and the crystals were washed with an aqueous MeCN solution (25 v/v%, 238.5 kg).
- the crystals were dried under reduced pressure at an external temperature of 50° C. or less for 43 hours to obtain 92.17 kg of Compound A-200.
- the yield of compound A-200 based on compound A-100 charged as a raw material was 86.6%.
- the suspension was filtered, and the crystals were washed with an aqueous MeCN solution (50 v/v%, 408.8 kg), and then with ordinary water (457.9 kg).
- the washed crystals (total amount) and an aqueous MeCN solution (33 v/v%, 510.4 kg) were charged into a reaction tank 1 purged with nitrogen, and stirred at an internal temperature of 40°C to 45°C for 2 hours.
- the suspension was cooled and stirred for 30 minutes at an internal temperature of 27°C to 30°C.
- the suspension was filtered and the crystals were washed with an aqueous MeCN solution (33 v/v%, 256.7 kg).
- the suspension was filtered and the crystals were washed with aqueous EtOH (67 v/v%, 282.9 kg).
- the crystals were washed three times with ordinary water (244.8 kg) and dried under reduced pressure at an external temperature of 50° C. or lower for 27 hours to obtain 80.81 kg of Compound A-400.
- the yield of compound A-400 based on the charged compound A-300 was 90.5%.
- reaction tank 3 Isopropyl acetate (353.8 kg) was charged into reaction tank 3 at an internal temperature of 6°C, and the reaction solution in reaction tank 2 was dropped into reaction tank 3 at an internal temperature of 4°C to 5°C.
- Reaction tank 2 was washed with isopropyl acetate (353.1 kg) and transferred to reaction tank 3. After stirring the reaction solution in reaction tank 3 for 30 minutes, it was allowed to stand still, and the aqueous layer was separated.
- An aqueous potassium carbonate solution (10 v/v%, 440.2 kg) was added to the organic layer, and after stirring for 10 minutes, the mixture was allowed to stand, and the aqueous layer was separated. The organic layer was concentrated under reduced pressure at an external temperature of 50°C or lower until the remaining volume was 310 L.
- EtOH (317.8 kg) was charged and concentrated under reduced pressure at an external temperature of 50°C or lower until the remaining volume was 310 L.
- EtOH (316.8 kg) was charged and concentrated under reduced pressure at an external temperature of 50°C or less until the remaining volume was 280 L.
- EtOH (95.7 kg) was charged, and then ordinary water (480.0 kg) was charged at 24°C to 30°C. The suspension was stirred at an internal temperature of 24°C to 25°C for 12 hours.
- the suspension was filtered and the crystals were washed with an aqueous EtOH solution (40 v/v%, 221.0 kg).
- the crystals were dried under reduced pressure at an external temperature of 50°C or less for 15 hours to obtain 63.1 kg of Compound A-500.
- the yield of compound A-500 based on the charged compound A-400 was 90.4%.
- reaction solution After increasing the hydrogen pressure to 0.7 MPa, the reaction solution was heated and stirred at an internal temperature of 65°C to 70°C for 5 hours. After the reaction solution was cooled and the pressure was released, the atmosphere was replaced with nitrogen four times.
- Pd(OH) 2 /C (palladium content 20 w/w%, water wet product, 6.6 kg) was suspended in purified water (19.1 kg) and charged into reaction tank 1 at an internal temperature of 28°C. Reaction tank 1 was purged with nitrogen three times and further with hydrogen three times, and the reaction solution was heated and stirred at an internal temperature of 65°C to 70°C for 6 hours. After confirming the completion of the reaction, the reaction solution was cooled, the pressure was released, and the atmosphere was replaced with nitrogen three times.
- reaction tank 2 was purged with nitrogen.
- Reaction tank 1 was washed with EtOH (151.1 kg) and transferred to reaction tank 2 via a filter.
- the solution was stirred and ordinary water (283.2 kg) was charged at an internal temperature of 24°C to 25°C. Seed crystals (63 g) of compound A-600 were charged at an internal temperature of 25°C, and stirred for 1 hour at an internal temperature of 23°C to 25°C. Further, ordinary water (628.8 kg) was charged at an internal temperature of 22°C to 27°C, and the mixture was stirred for 1 hour at an internal temperature of 25°C to 27°C. The suspension was filtered and the crystals were washed with aqueous EtOH (33 v/v%, 177.8 kg).
- reaction tank 3 purged with nitrogen and stirred to prepare an EtOH/AcOH aqueous solution.
- Reaction tank 2 was purged with nitrogen, the washed crystals (total amount) and the prepared EtOH/AcOH aqueous solution (531.1 kg) were charged, and the mixture was stirred at an internal temperature of 35°C to 41°C for 2 hours and an internal temperature of 26°C to 30°C for 2 hours. did.
- the suspension was filtered and the crystals were washed with aqueous EtOH (33 v/v%, 175.8 kg).
- MeCN 297.5 kg
- ordinary water 853.8 kg
- the suspension was stirred for 1 hour at an internal temperature of 25°C to 26°C.
- the suspension was filtered and the crystals were washed with an aqueous MeCN solution (40 v/v%, 215.1 kg).
- Reaction tank 1 was purged with nitrogen, washed crystals (total amount) and MeCN aqueous solution (30 v/v%, 1330 kg) were charged, and the mixture was stirred at an internal temperature of 22°C to 23°C for 1 hour.
- the suspension was filtered and the crystals were washed with an aqueous MeCN solution (30 v/v%, 221.7 kg).
- the crystals were dried under reduced pressure for 30 hours at an external temperature of 50°C or less.
- the vacuum-dried crystals (total amount) and a mixed solution of MEK (114.7 kg) and n-heptane (548.5 kg) were charged into reaction tank 2, which was purged with nitrogen, and stirred.
- the suspension was heated to 40°C to 45°C and stirred for 1 hour. It was then cooled and stirred at -3°C to 5°C for 15 hours.
- the suspension was filtered and the crystals were washed with MEK/n-heptane solution (15 v/v%, 63.5 kg).
- the crystals were dried under reduced pressure at an external temperature of 50° C. or lower for 15 hours to obtain 54.9 kg of unpurified compound A-800.
- the yield of unpurified compound A-800 relative to the charged compound A-600 was 82.6%.
- reaction tank 1 unpurified compound A-800 (54.6 kg) and MEK (265.9 kg) were charged into reaction tank 1 which was purged with nitrogen and stirred. The temperature of the suspension was raised, dissolution was confirmed at an internal temperature of 71°C, and the suspension was transferred to reaction tank 2 which was purged with nitrogen via a cartridge filter.
- MEK (22.4 kg) and n-heptane (18.9 kg) were charged into reaction tank 1 and stirred. The solution was heated to an internal temperature of 73° C. and transferred to reaction tank 2, which was purged with nitrogen via a cartridge filter.
- N-heptane (632.9 kg) was charged into reaction tank 2 at an internal temperature of 68°C to 71°C, and stirred for 1 hour at an internal temperature of 69°C to 70°C. The suspension was cooled and stirred at an internal temperature of -1°C to 5°C for 1 hour. N-heptane (633.1 kg) was charged at an internal temperature of -3°C to 1°C, and stirred for 1 hour at an internal temperature of 0°C to 1°C. MEK (22.1 kg) and n-heptane (93.4 kg) were placed in another container purged with nitrogen and stirred to prepare a MEK/n-heptane solution.
- the suspension was filtered, and the crystals were washed with the entire amount of the prepared MEK/n-heptane solution.
- the crystals were dried under reduced pressure at an external temperature of 50°C or lower for 12 hours to obtain 49.3 kg of Compound A-800.
- the yield in this purification step that is, the yield of compound A-800 based on the charged unpurified compound A-800, was 90.3%.
- the total yield (total yield) in Example 1 that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 36.8%.
- the suspension was filtered, the crystals were washed with ordinary water (50 mL), ordinary water (150 mL) was added, and the mixture was stirred at room temperature for 1 hour.
- the suspension was filtered and the crystals were washed with ordinary water (50 mL).
- the crystals were dried under reduced pressure at an external temperature of 50°C to obtain 3.93 g of Compound B-100.
- the yield of compound B-100 based on the charged compound A-400 was 85.5%.
- the suspension was filtered and the crystals were washed with an appropriate amount of MEK/n-heptane solution (1:2 v/v).
- the crystals were dried under reduced pressure at an external temperature of 50°C to obtain 800.7 mg of Compound B-300.
- the yield of compound B-300 based on the charged compound B-100 was 54.2%.
- LiAlH 4 (90 mg) and THF (5 mL) were mixed in a container purged with nitrogen, and AlCl 3 (474 mg) was added at an internal temperature of 0°C. 500 ⁇ L of this solution was added dropwise to a solution of compound B-300 (50 mg) in THF (1 mL), and the mixture was stirred at room temperature for 2 hours.
- An aqueous ammonium chloride solution (15 w/w%) and t-butyl methyl ether were added to the reaction mixture, and the organic layer was washed with water and concentrated.
- MEK (234 ⁇ L) and n-heptane (630 ⁇ L, 612 ⁇ L) were added, and the mixture was stirred at 0° C. for 3 hours.
- Example 2 The suspension was filtered and the crystals were washed with MEK/n-heptane solution (15 v/v%). The crystals were dried under reduced pressure to obtain 36.64 mg of Compound A-800.
- the yield of compound A-800 relative to compound B-300 was 75.8%.
- the total yield (total yield) in Example 2 that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 25.4%.
- the inside of the reactor was purged with nitrogen, and Pd(OH) 2 /C was filtered through Celite and washed twice with MeOH (50 mL).
- the solution was concentrated, purified water (20 mL) was added, and the mixture was stirred at 25°C for 30 minutes.
- the suspension was filtered, and the crystals were dried under reduced pressure at room temperature for 1 hour and at an external temperature of 40°C for 4 hours to obtain 3.4 g of compound C-300.
- the yield of compound C-300 based on the charged compound C-100 was 68.0%.
- Divinylsulfone (0.15 mL) and MeOH (3.5 mL) were charged into Container 1 and stirred.
- Compound C-300 (0.5 g), DIPEA (0.32 mL), and MeOH (3 mL) were placed in another container, and added dropwise to Container 1 over 1 hour at an internal temperature of 0°C to 5°C. After the dropwise addition was completed, the sample was washed with MeOH (0.5 mL). The mixture was stirred for 1.5 hours at an internal temperature of 5°C or less, and ordinary water (7 mL) was slowly added dropwise at the same temperature, followed by stirring for 1.5 hours.
- the suspension was filtered and the crystals were washed with an aqueous MeOH solution (50 v/v%, 2 mL). Subsequently, the crystals were dried under reduced pressure. In a separate container, the crystals (total amount) dried under reduced pressure, MEK (1.5 mL), and n-heptane (8.5 mL) were charged, and the mixture was stirred at an internal temperature of 45°C for 1 hour. The mixture was cooled to an internal temperature of 5°C and further stirred at the same temperature for 1 hour. The suspension was filtered and the crystals were washed with MEK/n-heptane solution (25 v/v%, 1 mL).
- Example 3 the total yield (total yield) in Example 3, that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 38.2%.
- the washed crystals (total amount) and MeCN aqueous solution (33 v/v%, approximately 60 mL) were charged, and after stirring at an internal temperature of 45°C for 2 hours, it was cooled and stirred for 30 minutes at an internal temperature of 25°C. .
- the suspension was filtered and the crystals were washed with an aqueous MeCN solution (33 v/v%, 30 mL).
- the crystals were dried under reduced pressure to obtain 7.84 g of Compound D-200.
- the yield of compound D-200 based on the charged compound D-100 was 81.0%.
- EtOAc Further EtOAc (10 mL) was added, and the mixture was again concentrated under reduced pressure to 5 mL. EtOAc (5 mL) was added to the concentrated solution, stirred, and cooled to 3°C. A 4 M hydrogen chloride ethyl acetate solution (1.3 mL) was added dropwise to this over 1 hour, and the mixture was stirred at the same temperature for 3 hours. The suspension was filtered and the crystals were washed with an EtOH/THF solution (1:2 v/v, 6 mL) prepared by mixing EtOH (2 mL) and THF (4 mL) in a separate container.
- the mixture was stirred for 1.5 hours at an internal temperature of 5°C or less, and ordinary water (7 mL) was slowly added dropwise at the same temperature, followed by stirring for 1.5 hours.
- the suspension was filtered and the crystals were washed with an aqueous MeOH solution (50 v/v%, 2 mL). Subsequently, the crystals were dried under reduced pressure. In a separate container, the crystals (total amount) dried under reduced pressure, MEK (1.5 mL), and n-heptane (8.5 mL) were charged, and the mixture was stirred at an internal temperature of 45°C for 1 hour. The mixture was cooled to an internal temperature of 5°C and further stirred at the same temperature for 1 hour.
- Example 4 the yield of Compound A-800 based on the charged compound C-300 was 85.4%. Further, the total yield (total yield) in Example 4, that is, the yield of Compound A-800, which was the target compound, with respect to Compound A-100, which was charged as a starting material, was 23.9%. Discussion Regarding the reference example (method described in WO2015/056771A1) and the methods described in Examples 1 to 4, the yield (total yield) of the compound of formula I, which is the target compound, is shown below.
- the present invention provides 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxo-1 ⁇ 6 -thiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine and its A more preferable synthesis method from the viewpoint of efficient and green chemistry regarding salts is provided.
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Abstract
La présente invention aborde le problème de la fourniture d'un nouveau procédé de synthèse de 6-(4,4-diméthylcyclohexyl)-4-[(1,1-dioxo-1λ6-thiomorpholin-4-yl)méthyl]-2-méthylthiéno[2,3-d]pyrimidine et d'un de ses sels, qui est efficace et préférable du point de vue de la chimie verte. Le 6-(4,4-diméthylcyclohexyl)-4-[(1,1-dioxo-1λ6-thiomorpholin-4-yl)méthyl]-2-méthylthiéno[2,3-d]pyrimidine est synthétisé de manière sûre et efficace par un procédé comprenant une étape d'ajout de 4,4-diméthyl-cyclohexanone à la position 6 dans un composé représenté par la formule présentée ci-dessous [dans la formule, Hal représente un atome d'halogène].
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PCT/JP2023/031795 WO2024048714A1 (fr) | 2022-09-01 | 2023-08-31 | PROCÉDÉ DE PRODUCTION DE 6-(4,4-DIMÉTHYLCYCLOHEXYL)-4-[(1,1-DIOXO-1λ6-THIOMORPHOLIN-4-YL)MÉTHYL]-2-MÉTHYLTHIÉNO[2,3-D]PYRIMIDINE OU D'UN DE SES SELS |
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WO2015056771A1 (fr) * | 2013-10-17 | 2015-04-23 | アステラス製薬株式会社 | Composé bicyclique contenant du soufre |
JP2022522777A (ja) * | 2019-03-01 | 2022-04-20 | レボリューション メディシンズ インコーポレイテッド | 二環式ヘテロアリール化合物及びその使用 |
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WO2015056771A1 (fr) * | 2013-10-17 | 2015-04-23 | アステラス製薬株式会社 | Composé bicyclique contenant du soufre |
JP2022522777A (ja) * | 2019-03-01 | 2022-04-20 | レボリューション メディシンズ インコーポレイテッド | 二環式ヘテロアリール化合物及びその使用 |
Non-Patent Citations (1)
Title |
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TABER DOUGLASS F., SCHUCHARDT JONATHAN L.: "Intramolecular carbon-hydrogen insertion: synthesis of (.+-.)-pentalenolactone E methyl ester", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 107, no. 18, 1 September 1985 (1985-09-01), pages 5289 - 5290, XP009552929, ISSN: 0002-7863, DOI: 10.1021/ja00304a052 * |
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