JP6244028B2 - 逆転写酵素阻害剤の製造方法 - Google Patents
逆転写酵素阻害剤の製造方法 Download PDFInfo
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- JP6244028B2 JP6244028B2 JP2016536221A JP2016536221A JP6244028B2 JP 6244028 B2 JP6244028 B2 JP 6244028B2 JP 2016536221 A JP2016536221 A JP 2016536221A JP 2016536221 A JP2016536221 A JP 2016536221A JP 6244028 B2 JP6244028 B2 JP 6244028B2
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- 238000004519 manufacturing process Methods 0.000 title description 4
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 66
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000003960 organic solvent Substances 0.000 claims description 27
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 26
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 24
- 239000000543 intermediate Substances 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 21
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical group FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000004215 Carbon black (E152) Substances 0.000 claims description 16
- 229930195733 hydrocarbon Natural products 0.000 claims description 16
- 150000002430 hydrocarbons Chemical class 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003880 polar aprotic solvent Substances 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 150000007524 organic acids Chemical class 0.000 claims description 11
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 11
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 10
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000003586 protic polar solvent Substances 0.000 claims description 9
- 238000001308 synthesis method Methods 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- ZRLVQFQTCMUIRM-UHFFFAOYSA-N potassium;2-methylbutan-2-olate Chemical group [K+].CCC(C)(C)[O-] ZRLVQFQTCMUIRM-UHFFFAOYSA-N 0.000 claims description 8
- 150000003512 tertiary amines Chemical class 0.000 claims description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 6
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 claims description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 6
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 claims description 5
- XRKQMIFKHDXFNQ-UHFFFAOYSA-N n-cyclohexyl-n-ethylcyclohexanamine Chemical compound C1CCCCC1N(CC)C1CCCCC1 XRKQMIFKHDXFNQ-UHFFFAOYSA-N 0.000 claims description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 5
- 125000003944 tolyl group Chemical group 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 150000004703 alkoxides Chemical class 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 3
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 3
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- 239000011698 potassium fluoride Substances 0.000 claims description 3
- 235000003270 potassium fluoride Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 125000002577 pseudohalo group Chemical group 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000011775 sodium fluoride Substances 0.000 claims description 3
- 235000013024 sodium fluoride Nutrition 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 150000003857 carboxamides Chemical class 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 229910052806 inorganic carbonate Inorganic materials 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 description 29
- 239000002002 slurry Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- -1 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl Chemical group 0.000 description 18
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
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- 0 CCC(C)=C1*(C*C2)=C2C1* Chemical compound CCC(C)=C1*(C*C2)=C2C1* 0.000 description 6
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- 239000004322 Butylated hydroxytoluene Substances 0.000 description 3
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- WNWOTMKHOLCHRJ-UHFFFAOYSA-N 1,4-dihydrotriazol-5-one Chemical compound O=C1CN=NN1 WNWOTMKHOLCHRJ-UHFFFAOYSA-N 0.000 description 2
- UTTHWAWJTFTVKE-UHFFFAOYSA-N 1-[(2-hydroxyacetyl)amino]-3-methylurea Chemical group CNC(=O)NNC(=O)CO UTTHWAWJTFTVKE-UHFFFAOYSA-N 0.000 description 2
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- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
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- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
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- 241001430294 unidentified retrovirus Species 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- CWRORZJYSUFYHO-UHFFFAOYSA-N (3z)-3-diazobicyclo[2.2.2]octane Chemical compound C1CC2C(=[N+]=[N-])CC1CC2 CWRORZJYSUFYHO-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- PUJSUOGJGIECFQ-UHFFFAOYSA-N 3,5-dichlorobenzonitrile Chemical compound ClC1=CC(Cl)=CC(C#N)=C1 PUJSUOGJGIECFQ-UHFFFAOYSA-N 0.000 description 1
- JVQISFAXAJZVDE-UHFFFAOYSA-N 3-(hydroxymethyl)-4-methyl-1h-1,2,4-triazol-5-one Chemical compound CN1C(CO)=NNC1=O JVQISFAXAJZVDE-UHFFFAOYSA-N 0.000 description 1
- GHYUOOZZOMUNSY-UHFFFAOYSA-N 3-chloro-5-hydroxybenzonitrile Chemical compound OC1=CC(Cl)=CC(C#N)=C1 GHYUOOZZOMUNSY-UHFFFAOYSA-N 0.000 description 1
- VERWQPYQDXWOGT-LVJNJWHOSA-N 4-amino-5-fluoro-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VERWQPYQDXWOGT-LVJNJWHOSA-N 0.000 description 1
- YKYIFUROKBDHCY-UHFFFAOYSA-N 4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical compound CCOC=CC(=O)C(F)(F)F YKYIFUROKBDHCY-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N Cc1cc(C)cc(C)c1 Chemical compound Cc1cc(C)cc(C)c1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 108010061833 Integrases Proteins 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N NC1CCCC1 Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- 241000577218 Phenes Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 238000006668 aldol addition reaction Methods 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012527 feed solution Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910000032 lithium hydrogen carbonate Inorganic materials 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- CUNPJFGIODEJLQ-UHFFFAOYSA-M potassium;2,2,2-trifluoroacetate Chemical compound [K+].[O-]C(=O)C(F)(F)F CUNPJFGIODEJLQ-UHFFFAOYSA-M 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical compound [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
段階1−第一の低温で炭化水素もしくはエーテル系有機溶媒中、第1の塩基の存在下での、下記式Bのエステル:
段階2−炭化水素もしくはエーテル系有機溶媒(溶媒は段階1でのものと同一であるか異なっていることができる)中、第二の低温で第二の塩基(当該第二の塩基は三級アミン塩基である)の存在下に、有機酸無水物またはスルホニルクロライドと中間体Dを反応させて、中間体Eを生成し、中間体E:
段階3−アルコールおよび有機溶媒の混合物中、第一の高温で、式NH3+nXn(Xn=非配位対アニオンおよびn=0(ゼロ)もしくは1である)を有する窒素源の存在下に中間体Eを環化させることで、式Fの化合物:
を含む方法を包含する。
段階1−第一の低温で、炭化水素またはエーテル系有機溶媒中、第1の塩基の存在下に、式Bのエステル:
段階2−炭化水素またはエーテル系有機溶媒[溶媒は段階1でのものと同一であるか異なっていることができる]中、第二の低温で、第二の塩基[当該第二の塩基は三級アミン塩基である。]の存在下に、中間体Dを有機酸無水物またはスルホニルクロライドと反応させて中間体Eを生成し、中間体E:
段階3−アルコールおよび有機溶媒の混合物中、第一の高温で、式NH3+nXn[Xn=非配位対アニオンであり、n=0または1である。]を有する窒素源の存在下に、中間体Eを環化させて、式Fの化合物を製造すること
を含む方法も包含する。
炭化水素またはエーテル系有機溶媒中の式Bのエステルおよび式Cの化合物を、一つのフローリアクター投入口にポンプで送り;
炭化水素またはエーテル系有機溶媒中の第1の塩基を第2のフローリアクター投入口にポンプで送り;
有機酸無水物またはスルホニルクロライドを連続的に受取容器に加え;そして
第二の塩基を連続的に受取容器に加えた方法を包含する。本発明に従って使用することができるフローリアクターを図1に示してある。
前記第1の塩基がカリウムtert−アミレートまたはナトリウムビス(トリメチルシリル)アミドから選択され;
前記第一の低温が約0℃から約−50℃の範囲であり;
前記炭化水素またはエーテル系有機溶媒がトルエンであり;
前記有機酸無水物またはスルホニルクロライドが無水トリフルオロ酢酸またはメタンスルホニルクロライドから選択され;
前記第二の塩基がトリエチルアミンであり;
前記第二の低温が約0℃から約10℃の範囲であり;
前記窒素源がNH3であり;
前記第一の高温が約60℃から約80℃の範囲であり;
前記アルコールおよび有機溶媒の混合物がメタノールおよびトルエンの混合物であり;
X1がクロロであり;
前記第三の塩基がN,N−ジイソプロピルエチルアミンであり;
前記第一の極性非プロトン性もしくはプロトン性溶媒がtert−アミルアルコールおよびN−メチルピロリジノンの混合物である、上記で記載の式Iの化合物の合成方法も包含する。
℃=摂氏
DMF=ジメチルホルムアミド
NMP=N−メチルピロリジノン
g=グラム
IPA=イソプロピルアルコール
NPA=n−プロピルアルコール
L=リットル
mL=ミリリットル
LC=液体クロマトグラフィー
LCAP=液体クロマトグラフィー面積パーセント
Me=メチル
h=時間
Hz=ヘルツ
t=三重線
d=二重線
s=一重線
brs=広い一重線
IPA=n−プロパノールとも称される2−プロパノール
NMR=核磁気共鳴
wt%=重量パーセント
nm=ナノメートル
ug=ミクログラム
DMF=N,N−ジメチルホルムアミド
ppm=百万分率
Ph=フェニル
L=リットル
HPLC=高速液体クロマトグラフィー
conc.=濃縮された
KOtAm=カリウムtert−アミレート
tAmOH=tert−アミルアルコール
TFAA=無水トリフルオロ酢酸
TEA=トリエチルアミン
mp=融点
GC/MS=ガスクロマトグラフィー/質量分析
BHT=ブチル化ヒドロキシトルエン
MTBE=tert−ブチルメチルエーテル
wt=重量。
アルドール縮合
(2E/Z,4E)−エチル2−(3−クロロ−5−シアノフェノキシ)−5−エトキシ−3−(トリフルオロメチル)ペンタ−2,4−ジエノエート(C):2−(3−クロロ−5−シアノフェノキシ)酢酸エチル(25.01g、104.4mmol、1.00当量)をトルエン(113.43g、131mL)に加え、4−エトキシ−1,1,1−トリフルオロ−3−ブテン−2−オン(26.43g、157.2mmol、1.51当量)を加えた。
3−クロロ−5−((2−オキソ−4−(トリフルオロメチル)−1,2−ジヒドロピリジン−3−イル)オキシ)ベンゾニトリル(E):ジエンのPhMe/MeOH(573mL;40.69g、104.4mmol理論値)中溶液に、メタノール(25mL)を加えた。アンモニア(32g、1.88mol、理論値基準で18当量)を加え、溶液を昇温させて60℃とした。反応液を60℃で18時間熟成させた。温度を35℃から45℃に調節し、圧力を下げて、生産的蒸留速度を維持した。バッチ体積を約300mLまで減らし、メタノール(325mL)を少量ずつ加えて、バッチ体積を250mLから350mLに維持した。加熱を停止し、系を排気した。得られたスラリーを冷却して室温として、終夜熟成させた。
段階1および2:
乾燥機乾燥した250mL丸底フラスコに、ナトリウム2−メチルプロパン−2−オレート(12.85g、134mmol)およびBHT(0.641g、2.91mmol)を加え、次にDMF(30mL)を加えた。10分後、明黄色溶液となった。2−フェニルエタノール(7.66mL、63.9mmol)を加えたところ、溶液は発熱して35℃となった。得られた明黄色溶液を昇温させて55℃とし、次に3,5−ジクロロベンゾニトリル(10g、58.1mmol)のDMF(15mL)中溶液をシリンジポンプによって2時間かけて加えた。得られた赤−橙赤色懸濁液を55から60℃で熟成させた。2時間後、HPLCによって、ナトリウムフェノレートへの変換率>98%が示された。
懸濁液を冷却して10℃とし、次に温度を<20℃に維持しながら、2−ブロモ酢酸エチル(8.70mL、78mmol)を1時間かけて加えた。得られた混合物を環境温度で熟成させた。1時間後、HPLCによって、標題化合物への変換率>99%が示された。
懸濁液に、MTBE(50mL)およびH2O(50mL)を加え、層を分離した。有機層を20%ブライン水溶液(25mL)で洗浄した。有機層は12.5gと定量された(収率90%)。有機層を濃縮して約38mLとし、ヘキサン(12.5mL)で希釈し、冷却して5℃とした。溶液に結晶2−(3−クロロ−5−シアノフェノキシ)酢酸エチル0.28g(2重量%)をシード添加し、5℃で0.5時間熟成させて、自由流動スラリーを得た。ヘキサン(175mL)を、スラリーに0℃から5℃で1時間かけて加えた。スラリーを0℃から5℃で濾過し、ヘキサン(50mL)で洗浄し、窒素気流下に乾燥させて、標題化合物9.8g(収率70%)を白色結晶固体として得た。シードを加えて結晶化を促進したが、溶液を0℃から5℃で少なくとも約2時間熟成させることで、シードなしに結晶生成物を沈澱および単離することが可能である。
Claims (20)
- 式Fの化合物:
[式中、K1およびK2は独立にCH3、CF3、CHF2、CH2CF3、OCH3、Cl、Br、F、CNまたはSCH3であり、R2はCF3、ClまたはBrである。]の合成方法であって、
段階1:−50℃から15℃である第一の低温で炭化水素またはエーテル系有機溶媒中、第1の塩基の存在下での、下記式Bのエステル:
の下記式Cの化合物:
とのアルドール付加[前記第1の塩基は金属アルコキシドまたは金属アミド塩基である。]を行って、中間体D:
を生成する段階であって、任意に中間体Dを単離することを含む、段階;
段階2:炭化水素またはエーテル系有機溶媒(溶媒は段階1でのものと同一であるか異なっていることができる)中、−50℃から15℃である第二の低温で第二の塩基(当該第二の塩基は三級アミン塩基である)の存在下に、有機酸無水物またはスルホニルクロライドと中間体Dを反応させて、中間体E:
を生成する段階であって、任意に中間体Eを単離することを含む、段階;
段階3:アルコールおよび有機溶媒の混合物中、25℃から80℃である第一の高温で、式NH3+nXn(Xn=非配位対アニオンおよびn=0(ゼロ)もしくは1である)を有する窒素源の存在下に中間体Eを環化させることで、式Fの化合物を作る段階を含む方法。 - 前記第1の塩基がカリウムtert−アミレート、ナトリウムビス(トリメチルシリル)アミド、カリウムtert−ブトキシド、ナトリウムtert−ブトキシド、リチウムジイソプロピルアミド、ナトリウムエトキシドまたはカリウムエトキシドから選択される、請求項1または2に記載の式Fまたは式Iの化合物の合成方法。
- 前記炭化水素またはエーテル系有機溶媒がトルエン、テトラヒドロフラン、ジエチルエーテル、メチルtert−ブチルエーテル、2−メチルテトラヒドロフランまたはキシレンから選択される請求項1または2に記載の式Fまたは式Iの化合物の合成方法。
- 前記有機酸無水物またはスルホニルクロライドが無水トリフルオロ酢酸、メタンスルホニルクロライド、無水酢酸、トリフルオロメタンスルホニルクロライド、またはp−トルエンスルホニルクロライドから選択される請求項1または2に記載の式Fまたは式Iの化合物の合成方法。
- 前記第二の塩基がトリメチルアミン、ジメチルエチルアミン、トリエチルアミン、1,4−ジアゾビシクロ−[2,2,2]−オクタン、ジイソプロピルエチルアミンまたはジシクロヘキシルエチルアミンから選択される請求項1または2に記載の式Fまたは式Iの化合物の合成方法。
- 中間体Dおよび中間体Eを単離せず、段階1を受取容器につながる二つの供給液投入口および一つの排出口を有するフローリアクター中で行う、請求項1または2に記載の式Fまたは式Iの化合物の合成方法であって、
炭化水素またはエーテル系有機溶媒中の式Bのエステルおよび式Cの化合物を、一つのフローリアクター投入口にポンプで送り;
炭化水素またはエーテル系有機溶媒中の第1の塩基を第2のフローリアクター投入口にポンプで送り;
有機酸無水物またはスルホニルクロライドを連続的に受取容器に加え;そして
第二の塩基を連続的に受取容器に加える方法。 - 前記窒素源がNH3である請求項1または2に記載の式Fまたは式Iの化合物の合成方法。
- 前記アルコールおよび有機溶媒の混合物において、前記アルコールがメタノール、エタノール、n−プロパノール、イソプロパノール、tert−ブタノール、またはtert−アミルアルコールから選択され、前記有機溶媒がテトラヒドロフラン、ジエチルエーテル、メチルtert−ブチルエーテル、2−メチルテトラヒドロフラン、トルエンまたはキシレンから選択される請求項1または2に記載の式Fまたは式Iの化合物の合成方法。
- X1がハロゲン、OMs、OTs、OBs、OP(O)(ORi)2、OC(O)Ri、OC(O)ORiまたはOC(O)NRiRiiであり、RiおよびRiiが独立にHまたはC1−6アルキルから選択される、請求項2に記載の式Iの化合物の合成方法。
- 前記第三の塩基が水酸化ナトリウム、水酸化リチウム、水酸化カリウム、炭酸ナトリウム、炭酸リチウム、炭酸カリウム、水酸化セシウム、炭酸セシウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウム、フッ化リチウム、フッ化ナトリウム、フッ化カリウム、フッ化セシウム、リチウムtert−ブトキシド、ナトリウムtert−ブトキシド、カリウムtert−ブトキシド、リン酸ナトリウム、リン酸カリウム、トリメチルアミン、ジメチルエチルアミン、トリエチルアミン、1,4−ジアゾビシクロ−[2,2,2]−オクタン、ジイソプロピルエチルアミン、またはジシクロヘキシルエチルアミンから選択される請求項2に記載の式Iの化合物の合成方法。
- 前記極性の非プロトン性もしくはプロトン性溶媒がアルコールおよび有機アミドの混合物である、請求項2に記載の式Iの化合物の合成方法。
- 段階4を25℃から80℃である第二の高温で実施する、請求項2に記載の式Iの化合物の合成方法。
- 前記第二の高温が25℃である請求項13に記載の式Iの化合物の合成方法。
- 前記第1の塩基がカリウムtert−アミレートまたはナトリウムビス(トリメチルシリル)アミドから選択され;
第一の低温が−50℃から0℃の範囲であり;
前記炭化水素またはエーテル系有機溶媒がトルエンであり;
前記有機酸無水物またはスルホニルクロライドが無水トリフルオロ酢酸またはメタンスルホニルクロライドから選択され;
前記第二の塩基がトリエチルアミンであり;
前記第二の低温が0℃から10℃の範囲であり;
前記窒素源がNH3であり;
前記第一の高温が60℃から80℃の範囲であり;
前記アルコールおよび有機溶媒の混合物がメタノールおよびトルエンの混合物であり;
X1がクロロであり;
前記第三の塩基がN,N−ジイソプロピルエチルアミンであり;
前記第一の極性非プロトン性もしくはプロトン性溶媒が、tert−アミルアルコールおよび1−メチル−2−ピロリジノンの混合物である、請求項2に記載の式Iの化合物の合成方法。 - X2がブロモであり;
前記第四の塩基がN,N−ジイソプロピルエチルアミンであり;
前記有機極性非プロトン性溶媒がN,N−ジメチルホルムアミドまたはアセトンである、請求項16に記載の式Fまたは式Iの化合物の合成方法。 - 式Iの化合物において、K1がClであり、K2がCNであり、R1がCH3であり、R2がCF3である、または
式Fの化合物において、K1がClであり、K2がCNであり、R2がCF3である、請求項1〜17のいずれか1項に記載の式Iまたは式Fの化合物の合成方法。
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