JP2016519669A5 - - Google Patents
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- Publication number
- JP2016519669A5 JP2016519669A5 JP2016502940A JP2016502940A JP2016519669A5 JP 2016519669 A5 JP2016519669 A5 JP 2016519669A5 JP 2016502940 A JP2016502940 A JP 2016502940A JP 2016502940 A JP2016502940 A JP 2016502940A JP 2016519669 A5 JP2016519669 A5 JP 2016519669A5
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- compound
- formula
- alkylene
- phenyl
- 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
- 150000001875 compounds Chemical class 0.000 claims description 87
- 125000000217 alkyl group Chemical group 0.000 claims description 68
- 238000000034 method Methods 0.000 claims description 58
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
- -1 bromo, chloro, iodo Chemical group 0.000 claims description 44
- 229910052799 carbon Inorganic materials 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 125000001188 haloalkyl group Chemical group 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000002947 alkylene group Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 125000004450 alkenylene group Chemical group 0.000 claims description 14
- 125000004419 alkynylene group Chemical group 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 12
- 125000000232 haloalkynyl group Chemical group 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 12
- 239000012025 fluorinating agent Substances 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 150000008052 alkyl sulfonates Chemical class 0.000 claims description 6
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 6
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 5
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 5
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 5
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000003729 cation exchange resin Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 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 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 description 32
- 0 *C1(CC=C)OC(*N=C)*(CCCC=C)C1 Chemical compound *C1(CC=C)OC(*N=C)*(CCCC=C)C1 0.000 description 7
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical group C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- 239000007800 oxidant agent Substances 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- RWFPXJAUVOBOLJ-UHFFFAOYSA-N acetic acid;ethyl acetate;heptane Chemical compound CC(O)=O.CCOC(C)=O.CCCCCCC RWFPXJAUVOBOLJ-UHFFFAOYSA-N 0.000 description 2
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- YXHBJJHMEZLEAR-RMFXVYADSA-N (5R)-3,3-difluoro-5-[(E,3S,4R)-3-hydroxy-4-methyl-7-phenylhept-1-enyl]-1-(3-thiophen-2-ylpropyl)pyrrolidin-2-one Chemical compound C[C@H](CCCC1=CC=CC=C1)[C@@H](/C=C/[C@H]2CC(C(=O)N2CCCC3=CC=CS3)(F)F)O YXHBJJHMEZLEAR-RMFXVYADSA-N 0.000 description 1
- CMRXZAKSZIVSCC-UHFFFAOYSA-N OCC(CC1(F)F)NC1=O Chemical compound OCC(CC1(F)F)NC1=O CMRXZAKSZIVSCC-UHFFFAOYSA-N 0.000 description 1
- JUZIBPFPQSPBAX-GSVOUGTGSA-N OC[C@@H](CC(C1=O)(F)F)N1I Chemical compound OC[C@@H](CC(C1=O)(F)F)N1I JUZIBPFPQSPBAX-GSVOUGTGSA-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
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361799334P | 2013-03-15 | 2013-03-15 | |
| US61/799,334 | 2013-03-15 | ||
| PCT/US2014/028933 WO2014144500A2 (en) | 2013-03-15 | 2014-03-14 | Methods of synthesizing a difluorolactam analog |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2016519669A JP2016519669A (ja) | 2016-07-07 |
| JP2016519669A5 true JP2016519669A5 (enExample) | 2017-04-20 |
| JP6368351B2 JP6368351B2 (ja) | 2018-08-01 |
Family
ID=50693998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016502940A Active JP6368351B2 (ja) | 2013-03-15 | 2014-03-14 | ジフルオロラクタムアナログを合成する方法 |
Country Status (7)
| Country | Link |
|---|---|
| US (3) | US9914725B2 (enExample) |
| EP (1) | EP2970234B1 (enExample) |
| JP (1) | JP6368351B2 (enExample) |
| AU (1) | AU2014229065B2 (enExample) |
| CA (1) | CA2903314C (enExample) |
| IL (1) | IL241042B (enExample) |
| WO (1) | WO2014144500A2 (enExample) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3176162B1 (en) * | 2012-07-19 | 2020-05-27 | Cayman Chemical Company, Inc. | Difluorolactam compounds as ep4 receptor-selective agonists for use in the treatment of ep4-mediated disease and conditions |
| HU231033B1 (hu) * | 2016-03-22 | 2019-12-30 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Eljárás 3-as kötést tartalmazó optikailag aktív karbonsavak, karbonsav sók és karbonsav származékok előállítására |
| CN106699604B (zh) * | 2017-01-09 | 2019-01-01 | 四川同晟生物医药有限公司 | 一种沙库比曲及其中间体的制备方法 |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3975399A (en) | 1974-08-06 | 1976-08-17 | E. I. Du Pont De Nemours And Company | 1,5-Disubstituted-2-pyrrolidinones, -3-pyrrolin-2-ones, and -4-pyrrolin-2-ones |
| DE2517771A1 (de) | 1975-04-18 | 1976-10-28 | Schering Ag | Neue prostaglandin-acetylen-analoga und verfahren zu ihrer herstellung |
| DE2528664A1 (de) | 1975-06-27 | 1977-01-13 | Hoechst Ag | Pyrrolidone und verfahren zu ihrer herstellung |
| CA1085859A (en) | 1975-06-27 | 1980-09-16 | Wilhelm Bartmann | Pyrrolidones and process for their manufacture |
| DE2619638A1 (de) | 1976-05-04 | 1977-11-17 | Hoechst Ag | Pyrrolidone und verfahren zu ihrer herstellung |
| US4177346A (en) | 1976-08-06 | 1979-12-04 | Pfizer Inc. | 1,5-Disubstituted-2-pyrrolidones |
| US4320136A (en) | 1980-08-11 | 1982-03-16 | E. I. Du Pont De Nemours And Company | 8-Aza-16,16-difluoroprostanoids |
| US4311644A (en) * | 1981-01-30 | 1982-01-19 | E. R. Squibb & Sons, Inc. | Method for preparing 10,10-difluoro prostacyclin intermediates and new compounds produced thereby |
| US4456613A (en) | 1982-12-27 | 1984-06-26 | E. I. Du Pont De Nemours And Company | 6-Keto- and 6-hydroxy-8-azaprostanoids and anti-ulcer use thereof |
| IL155368A0 (en) | 2000-11-27 | 2003-11-23 | Pfizer Prod Inc | Ep4 receptor selective agonists in the treatment of osteoporosis |
| AU2002226035A1 (en) * | 2000-12-07 | 2002-06-18 | Michael P Doyle | Lewis acid catalysis using chiral metal complexes |
| AU2002328855B2 (en) | 2001-07-16 | 2005-11-24 | F. Hoffmann-La Roche Ag | Prostaglandin Analogues As EP4 Receptor Agonists |
| JP4211605B2 (ja) | 2001-07-16 | 2009-01-21 | 小野薬品工業株式会社 | プロスタノイドアゴニストとしての２ピロリドン誘導体 |
| US7608637B2 (en) * | 2001-07-23 | 2009-10-27 | Ono Pharmaceutical Co., Ltd. | Pharmaceutical composition for treatment of diseases associated with decrease in bone mass comprising EP4 agonist as the active ingredient |
| JP2005514378A (ja) | 2001-12-03 | 2005-05-19 | メルク エンド カムパニー インコーポレーテッド | 高眼圧症の治療方法 |
| DE60307607T2 (de) | 2002-03-18 | 2007-08-09 | Pfizer Products Inc., Groton | Verwendung von selektiven ep4 rezeptor agonisten zur behandlung von krankheiten |
| WO2003103772A1 (en) | 2002-06-06 | 2003-12-18 | Merck Frosst Canada & Co. | 1,5-distributed pyrrolid-2-one derivatives for use as ep4 receptor agonists in the teatment of eye diseases such as glaucoma |
| CA2483555A1 (en) | 2002-06-10 | 2003-12-18 | Applied Research Systems Ars Holding N.V. | Gamma lactams as prostaglandin agonists and use thereof |
| WO2004037786A2 (en) | 2002-10-25 | 2004-05-06 | Merck Frosst Canada & Co. | 2-pyrrolidones as ep4 receptor agonists |
| ATE394372T1 (de) | 2003-03-03 | 2008-05-15 | Serono Lab | G-lactamderivate als prostaglandinagonisten |
| WO2009023193A1 (en) * | 2007-08-15 | 2009-02-19 | Cytokinetics, Incorporated | Certain chemical entities, compositions, and methods |
| BRPI0820410A2 (pt) | 2007-10-23 | 2015-05-19 | Allergan Inc | Lactans substituídos terapêuticos |
| WO2011003058A1 (en) | 2009-07-03 | 2011-01-06 | Concert Pharmaceuticals, Inc. | Prostacyclin derivatives |
| JP5847830B2 (ja) | 2010-11-10 | 2016-01-27 | アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ | オレキシン受容体拮抗薬として有用なラクタム誘導体 |
| US9181279B2 (en) * | 2011-07-04 | 2015-11-10 | Rottapharm Biotech S.R.L. | Cyclic amine derivatives as EP4 receptor antagonists |
| EP3176162B1 (en) | 2012-07-19 | 2020-05-27 | Cayman Chemical Company, Inc. | Difluorolactam compounds as ep4 receptor-selective agonists for use in the treatment of ep4-mediated disease and conditions |
-
2014
- 2014-03-14 US US14/775,591 patent/US9914725B2/en not_active Expired - Fee Related
- 2014-03-14 JP JP2016502940A patent/JP6368351B2/ja active Active
- 2014-03-14 CA CA2903314A patent/CA2903314C/en active Active
- 2014-03-14 AU AU2014229065A patent/AU2014229065B2/en not_active Ceased
- 2014-03-14 WO PCT/US2014/028933 patent/WO2014144500A2/en not_active Ceased
- 2014-03-14 EP EP14723569.1A patent/EP2970234B1/en active Active
-
2015
- 2015-09-02 IL IL241042A patent/IL241042B/en unknown
-
2018
- 2018-01-30 US US15/883,724 patent/US20180170918A1/en not_active Abandoned
-
2019
- 2019-03-12 US US16/299,916 patent/US11345690B2/en active Active
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