JP2014530901A5 - - Google Patents
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- Publication number
- JP2014530901A5 JP2014530901A5 JP2014537794A JP2014537794A JP2014530901A5 JP 2014530901 A5 JP2014530901 A5 JP 2014530901A5 JP 2014537794 A JP2014537794 A JP 2014537794A JP 2014537794 A JP2014537794 A JP 2014537794A JP 2014530901 A5 JP2014530901 A5 JP 2014530901A5
- Authority
- JP
- Japan
- Prior art keywords
- compound
- alkyl
- dichloro
- bis
- ruthenium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 239000003054 catalyst Substances 0.000 claims description 13
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 12
- -1 acyl halide compound Chemical class 0.000 claims description 10
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 claims description 10
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 8
- RXMRGBVLCSYIBO-UHFFFAOYSA-M tetramethylazanium;iodide Chemical compound [I-].C[N+](C)(C)C RXMRGBVLCSYIBO-UHFFFAOYSA-M 0.000 claims description 8
- GKXDJYKZFZVASJ-UHFFFAOYSA-M tetrapropylazanium;iodide Chemical compound [I-].CCC[N+](CCC)(CCC)CCC GKXDJYKZFZVASJ-UHFFFAOYSA-M 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- RUKVGXGTVPPWDD-UHFFFAOYSA-N 1,3-bis(2,4,6-trimethylphenyl)imidazolidine Chemical group CC1=CC(C)=CC(C)=C1N1CN(C=2C(=CC(C)=CC=2C)C)CC1 RUKVGXGTVPPWDD-UHFFFAOYSA-N 0.000 claims description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- 125000000777 acyl halide group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 claims description 6
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 6
- 125000005207 tetraalkylammonium group Chemical group 0.000 claims description 6
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052707 ruthenium Inorganic materials 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000006343 heptafluoro propyl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- YIQOAVQVXSHEOZ-UHFFFAOYSA-N [Ru].CC1=C(C(=CC(=C1)C)C)N1C(N(CC1)C1=C(C=C(C=C1C)C)C)=C1C(C(C(CC1)(P(C1CCCCC1)C1CCCCC1)Cl)=C1C=C(C2=CC=CC=C12)C1=CC=CC=C1)Cl Chemical compound [Ru].CC1=C(C(=CC(=C1)C)C)N1C(N(CC1)C1=C(C=C(C=C1C)C)C)=C1C(C(C(CC1)(P(C1CCCCC1)C1CCCCC1)Cl)=C1C=C(C2=CC=CC=C12)C1=CC=CC=C1)Cl YIQOAVQVXSHEOZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- CVRYHAXYVVFEDI-UHFFFAOYSA-N [Ru].ClP(C(P(C1CCCCC1)(C1CCCCC1)(C1CCCCC1)Cl)C1=CC=CC=C1)(C1CCCCC1)(C1CCCCC1)C1CCCCC1 Chemical compound [Ru].ClP(C(P(C1CCCCC1)(C1CCCCC1)(C1CCCCC1)Cl)C1=CC=CC=C1)(C1CCCCC1)(C1CCCCC1)C1CCCCC1 CVRYHAXYVVFEDI-UHFFFAOYSA-N 0.000 claims description 2
- FCDPQMAOJARMTG-UHFFFAOYSA-L benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphane Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-L 0.000 claims description 2
- AFOIAAGOVZSFCL-UHFFFAOYSA-N chloro-[1-[chloro(tricyclohexyl)-lambda5-phosphanyl]-3-phenylinden-1-yl]-tricyclohexyl-lambda5-phosphane ruthenium Chemical compound [Ru].ClP(C1(C=C(C2=CC=CC=C12)C1=CC=CC=C1)P(C1CCCCC1)(C1CCCCC1)(C1CCCCC1)Cl)(C1CCCCC1)(C1CCCCC1)C1CCCCC1 AFOIAAGOVZSFCL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- UDWHYAPPVOEOMP-UHFFFAOYSA-L dichloro(phenylsulfanylmethylidene)ruthenium;tricyclohexylphosphane Chemical compound Cl[Ru](Cl)=CSC1=CC=CC=C1.C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 UDWHYAPPVOEOMP-UHFFFAOYSA-L 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 claims description 2
- GHPHCACQRYSXSS-UHFFFAOYSA-N ruthenium;tricyclohexylphosphane Chemical compound [Ru].C1CCCCC1P(C1CCCCC1)C1CCCCC1 GHPHCACQRYSXSS-UHFFFAOYSA-N 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- JTZZSQYMACOLNN-VDWJNHBNSA-N simeprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCN(C)C(=O)[C@H]1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)NS(=O)(=O)C1CC1 JTZZSQYMACOLNN-VDWJNHBNSA-N 0.000 claims 4
- 229960002091 simeprevir Drugs 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- XELFHNUFJMCUIG-UHFFFAOYSA-N [Ru].CC1=C(C(=CC(=C1)C)C)N1C(N(CC1)C1=C(C=C(C=C1C)C)C)=C1C(C(=C(C=C1)P(C1=CC=CC=C1)(C1=CC=CC=C1)=C1C=C(C2=CC=CC=C12)C1=CC=CC=C1)Cl)Cl Chemical compound [Ru].CC1=C(C(=CC(=C1)C)C)N1C(N(CC1)C1=C(C=C(C=C1C)C)C)=C1C(C(=C(C=C1)P(C1=CC=CC=C1)(C1=CC=CC=C1)=C1C=C(C2=CC=CC=C12)C1=CC=CC=C1)Cl)Cl XELFHNUFJMCUIG-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)C(*1)=C*C1=C(*1)C=C(*)c(cc2)c1c(C)c2OC Chemical compound CC(C)C(*1)=C*C1=C(*1)C=C(*)c(cc2)c1c(C)c2OC 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VBJIFLOSOQGDRZ-UHFFFAOYSA-N (2-chloro-2,2-difluoroacetyl) 2-chloro-2,2-difluoroacetate Chemical compound FC(F)(Cl)C(=O)OC(=O)C(F)(F)Cl VBJIFLOSOQGDRZ-UHFFFAOYSA-N 0.000 description 1
- WYKHFQKONWMWQM-UHFFFAOYSA-N 2-sulfanylidene-1h-pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1S WYKHFQKONWMWQM-UHFFFAOYSA-N 0.000 description 1
- JGZVUTYDEVUNMK-UHFFFAOYSA-N 5-carboxy-2',7'-dichlorofluorescein Chemical compound C12=CC(Cl)=C(O)C=C2OC2=CC(O)=C(Cl)C=C2C21OC(=O)C1=CC(C(=O)O)=CC=C21 JGZVUTYDEVUNMK-UHFFFAOYSA-N 0.000 description 1
- NIUATKBQXCFDGT-UHFFFAOYSA-N [4-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-2,3-dichlorocyclohexa-1,5-dien-1-yl]-diphenyl-(3-phenylinden-1-ylidene)-lambda5-phosphane Chemical compound CC1=C(C(=CC(=C1)C)C)N1C(N(CC1)C1=C(C=C(C=C1C)C)C)=C1C(C(=C(C=C1)P(C1=CC=CC=C1)(C1=CC=CC=C1)=C1C=C(C2=CC=CC=C12)C1=CC=CC=C1)Cl)Cl NIUATKBQXCFDGT-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11187025 | 2011-10-28 | ||
| EP11187025.9 | 2011-10-28 | ||
| PCT/IB2012/055900 WO2013061285A1 (en) | 2011-10-28 | 2012-10-26 | Improved process for preparing an intermediate of the macrocyclic protease inhibitor tmc 435 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2014530901A JP2014530901A (ja) | 2014-11-20 |
| JP2014530901A5 true JP2014530901A5 (https=) | 2015-12-17 |
| JP6231482B2 JP6231482B2 (ja) | 2017-11-15 |
Family
ID=47221505
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2014537794A Expired - Fee Related JP6231482B2 (ja) | 2011-10-28 | 2012-10-26 | 大環状プロテアーゼ阻害剤ｔｍｃ４３５の中間体の改善された製造方法 |
Country Status (17)
| Country | Link |
|---|---|
| US (2) | US8981082B2 (https=) |
| EP (1) | EP2771339B1 (https=) |
| JP (1) | JP6231482B2 (https=) |
| KR (1) | KR20140086967A (https=) |
| CN (1) | CN104053658B (https=) |
| AR (1) | AR088568A1 (https=) |
| AU (1) | AU2012327934B2 (https=) |
| BR (1) | BR112014009849A2 (https=) |
| CA (1) | CA2848377A1 (https=) |
| CL (1) | CL2014001043A1 (https=) |
| EA (1) | EA201490892A1 (https=) |
| ES (1) | ES2671732T3 (https=) |
| HK (1) | HK1202120A1 (https=) |
| IL (1) | IL231892A (https=) |
| MX (1) | MX347650B (https=) |
| TW (1) | TWI574960B (https=) |
| WO (1) | WO2013061285A1 (https=) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MA41812A (fr) | 2015-03-27 | 2018-01-30 | Janssen Pharmaceuticals Inc | Procédés et intermédiaires pour la préparation d'un inhibiteur de protéase macrocyclique du vhc |
| WO2017064680A1 (en) * | 2015-10-16 | 2017-04-20 | Lupin Limited | An improved process for the preparation of simeprevir sodium and intermediate thereof |
| CN109846883A (zh) * | 2017-11-30 | 2019-06-07 | 常州寅盛药业有限公司 | 苯并呋喃衍生物与tmc435联合用药物 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2521835A1 (en) * | 2003-04-10 | 2004-10-21 | Boehringer Ingelheim International Gmbh | Process for the preparation of macrocyclic compounds by ruthenium complex catalysed metathesis reaction |
| PE20070211A1 (es) | 2005-07-29 | 2007-05-12 | Medivir Ab | Compuestos macrociclicos como inhibidores del virus de hepatitis c |
| EP1934243B1 (en) | 2005-09-09 | 2011-05-25 | Boehringer Ingelheim International GmbH | Ring-closing metathesis process for the preparation of macrocyclic peptides |
| US8193346B2 (en) | 2007-12-06 | 2012-06-05 | Enanta Pharmaceuticals, Inc. | Process for making macrocyclic oximyl hepatitis C protease inhibitors |
| KR101647520B1 (ko) | 2008-08-07 | 2016-08-10 | 에프. 호프만-라 로슈 아게 | 거대환식 화합물의 제조 방법 |
| JP5687631B2 (ja) * | 2008-12-23 | 2015-03-18 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツドＪａｎｓｓｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． | Ｈｃｖのマクロ環状プロテアーゼ阻害剤を製造するための方法および中間体 |
-
2012
- 2012-10-26 TW TW101139616A patent/TWI574960B/zh not_active IP Right Cessation
- 2012-10-26 WO PCT/IB2012/055900 patent/WO2013061285A1/en not_active Ceased
- 2012-10-26 BR BR112014009849A patent/BR112014009849A2/pt not_active IP Right Cessation
- 2012-10-26 KR KR1020147009887A patent/KR20140086967A/ko not_active Ceased
- 2012-10-26 MX MX2014005070A patent/MX347650B/es active IP Right Grant
- 2012-10-26 AR ARP120104040A patent/AR088568A1/es unknown
- 2012-10-26 AU AU2012327934A patent/AU2012327934B2/en not_active Ceased
- 2012-10-26 US US14/350,138 patent/US8981082B2/en not_active Expired - Fee Related
- 2012-10-26 ES ES12790677.4T patent/ES2671732T3/es active Active
- 2012-10-26 HK HK15102687.7A patent/HK1202120A1/xx unknown
- 2012-10-26 JP JP2014537794A patent/JP6231482B2/ja not_active Expired - Fee Related
- 2012-10-26 EP EP12790677.4A patent/EP2771339B1/en active Active
- 2012-10-26 CN CN201280052692.3A patent/CN104053658B/zh not_active Expired - Fee Related
- 2012-10-26 EA EA201490892A patent/EA201490892A1/ru unknown
- 2012-10-26 CA CA2848377A patent/CA2848377A1/en not_active Abandoned
-
2014
- 2014-04-03 IL IL231892A patent/IL231892A/en not_active IP Right Cessation
- 2014-04-24 CL CL2014001043A patent/CL2014001043A1/es unknown
-
2015
- 2015-02-09 US US14/616,770 patent/US9328108B2/en not_active Expired - Fee Related
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