CN112262121A - 用于制备他喷他多的新方法 - Google Patents
用于制备他喷他多的新方法 Download PDFInfo
- Publication number
- CN112262121A CN112262121A CN201980039041.2A CN201980039041A CN112262121A CN 112262121 A CN112262121 A CN 112262121A CN 201980039041 A CN201980039041 A CN 201980039041A CN 112262121 A CN112262121 A CN 112262121A
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- salt
- formula
- derivatives
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- KWTWDQCKEHXFFR-SMDDNHRTSA-N tapentadol Chemical compound CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-SMDDNHRTSA-N 0.000 title claims abstract description 14
- 229960005126 tapentadol Drugs 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 239000002253 acid Substances 0.000 claims description 69
- 150000003839 salts Chemical class 0.000 claims description 43
- 239000000203 mixture Substances 0.000 claims description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 17
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 16
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 13
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 12
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 12
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 9
- 239000002841 Lewis acid Substances 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 8
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- 150000007517 lewis acids Chemical class 0.000 claims description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 8
- 239000011976 maleic acid Substances 0.000 claims description 8
- 229910017604 nitric acid Inorganic materials 0.000 claims description 8
- 235000002906 tartaric acid Nutrition 0.000 claims description 8
- 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 8
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 7
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 7
- 239000011975 tartaric acid Substances 0.000 claims description 7
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 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 claims description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 5
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 5
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 5
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 5
- 235000015165 citric acid Nutrition 0.000 claims description 5
- 238000006392 deoxygenation reaction Methods 0.000 claims description 5
- 239000001530 fumaric acid Substances 0.000 claims description 5
- 239000001630 malic acid Substances 0.000 claims description 5
- 235000011090 malic acid Nutrition 0.000 claims description 5
- 229960002510 mandelic acid Drugs 0.000 claims description 5
- 235000006408 oxalic acid Nutrition 0.000 claims description 5
- 235000019260 propionic acid Nutrition 0.000 claims description 5
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- 229910021623 Tin(IV) bromide Inorganic materials 0.000 claims description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 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 claims description 3
- LTSUHJWLSNQKIP-UHFFFAOYSA-J tin(iv) bromide Chemical compound Br[Sn](Br)(Br)Br LTSUHJWLSNQKIP-UHFFFAOYSA-J 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- JKVBTSJLQLSTHJ-SWLSCSKDSA-N (2r,3r)-3-(3-methoxyphenyl)-n,n,2-trimethylpentan-1-amine Chemical compound CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(OC)=C1 JKVBTSJLQLSTHJ-SWLSCSKDSA-N 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- OIKHZBFJHONJJB-UHFFFAOYSA-N dimethyl(phenyl)silicon Chemical compound C[Si](C)C1=CC=CC=C1 OIKHZBFJHONJJB-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 claims description 2
- 229920001843 polymethylhydrosiloxane Polymers 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 2
- 239000005052 trichlorosilane Substances 0.000 claims description 2
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 claims description 2
- AKQNYQDSIDKVJZ-UHFFFAOYSA-N triphenylsilane Chemical compound C1=CC=CC=C1[SiH](C=1C=CC=CC=1)C1=CC=CC=C1 AKQNYQDSIDKVJZ-UHFFFAOYSA-N 0.000 claims description 2
- SCHZCUMIENIQMY-UHFFFAOYSA-N tris(trimethylsilyl)silicon Chemical compound C[Si](C)(C)[Si]([Si](C)(C)C)[Si](C)(C)C SCHZCUMIENIQMY-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- 230000001335 demethylating effect Effects 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 150000007513 acids Chemical class 0.000 description 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- -1 palladium/carbon hydride Chemical class 0.000 description 8
- 235000011054 acetic acid Nutrition 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 229940098895 maleic acid Drugs 0.000 description 6
- 235000011007 phosphoric acid Nutrition 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- PZNRRUTVGXCKFC-SWLSCSKDSA-N (2s,3r)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol Chemical compound CN(C)C[C@H](C)[C@](O)(CC)C1=CC=CC(OC)=C1 PZNRRUTVGXCKFC-SWLSCSKDSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 229960005261 aspartic acid Drugs 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 4
- 238000010520 demethylation reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229960001367 tartaric acid Drugs 0.000 description 4
- XKSJVTDZSYZBGF-SBKWZQTDSA-N (2r,3r)-3-(3-methoxyphenyl)-n,n,2-trimethylpentan-1-amine;hydrochloride Chemical compound Cl.CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(OC)=C1 XKSJVTDZSYZBGF-SBKWZQTDSA-N 0.000 description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 3
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 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 3
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 230000017858 demethylation Effects 0.000 description 3
- 235000011087 fumaric acid Nutrition 0.000 description 3
- 229960002598 fumaric acid Drugs 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 229960000448 lactic acid Drugs 0.000 description 3
- 229940099690 malic acid Drugs 0.000 description 3
- 229940116315 oxalic acid Drugs 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000003460 sulfonic acids Chemical class 0.000 description 3
- GAWAYYRQGQZKCR-UWTATZPHSA-N (2r)-2-chloropropanoic acid Chemical compound C[C@@H](Cl)C(O)=O GAWAYYRQGQZKCR-UWTATZPHSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 229960004365 benzoic acid Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 150000004672 propanoic acids Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 150000003892 tartrate salts Chemical class 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- PZNRRUTVGXCKFC-WFASDCNBSA-N (2s,3s)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol Chemical compound CN(C)C[C@H](C)[C@@](O)(CC)C1=CC=CC(OC)=C1 PZNRRUTVGXCKFC-WFASDCNBSA-N 0.000 description 1
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
- GAWAYYRQGQZKCR-REOHCLBHSA-N (S)-2-chloropropanoic acid Chemical compound C[C@H](Cl)C(O)=O GAWAYYRQGQZKCR-REOHCLBHSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 1
- ISPHOSMFKNAQQV-OZIFAFRSSA-N 3-[(1R,6R)-5-(dimethylamino)-1-ethyl-6-methylcyclohexa-2,4-dien-1-yl]phenol hydrochloride Chemical compound Cl.CN(C=1[C@@H]([C@](C=CC1)(CC)C=1C=C(C=CC1)O)C)C ISPHOSMFKNAQQV-OZIFAFRSSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ZKCUKJDEBHPCTF-CYBMUJFWSA-N C[C@H](C1=CC=CC2=CC=CC=C12)NC1=CC=CC=C1C(O)=O Chemical compound C[C@H](C1=CC=CC2=CC=CC=C12)NC1=CC=CC=C1C(O)=O ZKCUKJDEBHPCTF-CYBMUJFWSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 229910052692 Dysprosium Inorganic materials 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 229910021576 Iron(III) bromide Inorganic materials 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 229910052769 Ytterbium Inorganic materials 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-OMNKOJBGSA-N [(4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-OMNKOJBGSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000003635 deoxygenating effect Effects 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 229910052733 gallium Inorganic materials 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229940074355 nitric acid Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940098695 palmitic acid Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- UBZYKBZMAMTNKW-UHFFFAOYSA-J titanium tetrabromide Chemical compound Br[Ti](Br)(Br)Br UBZYKBZMAMTNKW-UHFFFAOYSA-J 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
本发明涉及制备他喷他多和中间体化合物(2R,3R)‑3‑(‑甲氧基苯基)‑N,N,2‑三甲基戊胺(式IIa的化合物)的新方法。
Description
技术领域
本发明涉及制备他喷他多(Tapentadol)及其中间体的新型方法。
背景技术
他喷他多是3-[(1R,2R)-3-(二甲氨基)-1-乙基-2-甲基苯基]苯酚单盐酸盐的INN(国际非专有名称),其由下式表示:
他喷他多的化学结构已在EP-A-0693475中公开为化合物(+21)。实施例1以及实施例24步骤1至3中描述了他喷他多的合成。
除上述之外,现有技术中还公开了许多用于制备他喷他多或其关键中间体——式IIa的化合物的合成步骤。
PCT公开WO2008012283A1公开了用于制备(2R,3R)-3-(-甲氧基苯基)-N,N,2-三甲基戊胺(式II的化合物)的方法,其通过用三氟乙酸酐或乙酰氯或草酰氯乙酯处理式IIIa的相应羟基化合物并且随后用过渡金属催化剂比如钯/碳氢化,从而产生(2R,3R)-3-(3-甲氧基苯基)-N,N,2-三甲基戊胺(表示为式IIa的化合物)或其酸加成盐(式IIa’的化合物),如方案1中所显示。然后根据现有技术中公开的方法(见例如EP-A-0693475)通过脱甲基将式IIa’的化合物转化为他喷他多。
印度专利申请IN201641017954公开了替代合成,其利用式IIIb的化合物来制备式IIa的化合物。根据现有技术中的方法,特别是USRE39593、US6344558B2和WO2012101649中公开的那些来制备式IIIb的化合物。
根据本申请,在合适的酸的存在下(2S,3S)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基-戊-3-醇(式III的化合物的S,S-异构体,表示为IIIb)与氢硅烷试剂在合适的酸的存在下根据方案2反应以产生2R,3R和2R,3S-[3-(3-甲氧基苯基)-2-甲基戊基]二甲胺盐酸盐的非对映混合物(表示为式IIa和IIb的化合物)。将非对映混合物转变转化为各自的盐酸盐,这使得能够分离出期望的2R,3R非对映体IIa。分离公开为优选地通过分步结晶的方式进行,该分步结晶可以进行多次以便实现期望的非对映体纯度。然后脱甲基提供作为游离碱或作为药学上可接受的盐的他喷他多。值得注意的是,该策略采用式IIIb的化合物作为起始原料,其是式III的化合物的S,S-非对映体。这种非对映体,虽然根据以上提及的现有技术步骤可获得,但是与允许获得非对映体IIIa的步骤相比,其通过更复杂且产率大大降低的步骤制备。
因而,期望的是,在不需要使用昂贵的试剂比如氢化所需要的那些的情况下或者在不需要使用昂贵的起始原料的情况下制备他喷他多。
定义
出于本申请(包括所附的权利要求)的目的,以下术语应具有如下所述的各自含义。当本文提及通用术语,比如酸、碱、盐等时,本领域技术人员可从以下定义中给出的试剂中,以及从以下说明书中叙述的附加试剂中,或从本领域文献参考中发现的试剂中,对这种试剂进行适当的选择。
“酸”是指含有氢并在水或溶剂中分解以产生正氢离子的任何化合物,以及路易斯酸,包括但不限于酸比如盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三卤代乙酸(例如,三氟乙酸)、马来酸、磺酸比如甲磺酸、甲苯磺酸和樟脑磺酸、丙酸比如(R)-氯丙酸、邻氨甲酰苯甲酸比如N-[(R)-l-(l-萘基)乙基]邻氨甲酰苯甲酸、扁桃酸、酒石酸比如D-或L-酒石酸,以及其衍生物比如二芳酰基酒石酸、乳酸、樟脑酸、天冬氨酸、香茅酸等。因而,该术语包括弱酸比如乙酸和硫化氢;强有机酸比如甲磺酸、三氟乙酸等。
“质子酸(protic acid)”是指当溶解在水中时释放出H+离子的酸。
“手性酸(chiral acid)”是指也作为手性化合物的酸,即,含有不对称中心(手性原子或手性中心)并且因而可以以两个不可重叠的镜像形式(对映体)出现的化合物。手性酸的常见实例是(1R)-和(1S)-樟脑磺酸、(R)-和(S)-氯丙酸、N-[(R)-和(S)-1-(1-萘基)乙基]邻氨甲酰苯甲酸、R)-和(S)-扁桃酸、D-和L-酒石酸和其衍生物,比如二芳酰基酒石酸、D-和L-乳酸、樟脑酸的所有非对映体、D-和L-天冬氨酸等。
因此,“非手性酸(achiral acid)”是指不是手性化合物的以上通常定义的酸,例如,盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三卤代乙酸(例如,三氟乙酸)、马来酸、磺酸比如甲磺酸、甲苯磺酸等。
“路易斯酸”在本文中定义为作为电子对受体的任何化学物质,即,能够无限制地接收电子对的任何化学物质。路易斯酸(也称为路易斯酸催化剂)可以是基于过渡金属、镧系金属以及元素周期表第4、5、13、14和15族中的金属的任何路易斯酸,该金属包括硼、铝、镓、铟、钛、锆、锡、钒、砷、锑、铋、镧、镝和镱。路易斯酸的非限制性实例是四氯化钛、四溴化钛、异丙醇钛、氯化铝、溴化铝、异丙醇铝、三氟化硼、三溴化硼、四氯化锡、四溴化锡、氯化锌、三氯化铁、三溴化铁及其配合物。
本文制备的化合物的可接受的盐包括其合适的酸加成盐。它们被称为“酸加成盐”或简称为“盐”。用如下酸形成盐,例如,强酸比如无机酸,例如,硫酸、磷酸、硝酸、硼酸或氢卤酸;强有机羧酸,比如未取代的或(例如,被卤素)取代的1至4个碳原子的烷羧酸,比如乙酸和三氟乙酸;用饱和或不饱和二羧酸,例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或四苯二甲酸;羟基羧酸,例如,抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸及其酯,例如,二芳酰基酒石酸;氨基酸,例如天冬氨酸或谷氨酸;苯甲酸;或者有机磺酸,比如取代的或未取代的(例如,被卤素)(C1-4)-烷基-或芳基-磺酸,比如甲烷-或对甲苯磺酸。
药学上可接受的盐是保留母体化合物的期望的生物活性并且不会产生不期望的毒理效应的盐。这种盐的实例是(a)用无机酸,例如盐酸、氢溴酸、硫酸、磷酸、硝酸等形成的酸加成盐;和用有机酸比如例如乙酸、草酸、酒石酸、琥珀酸、马来酸、富马酸、葡萄糖酸、柠檬酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、棕榈酸、藻酸、聚谷氨酸、萘磺酸、甲磺酸,对甲苯磺酸、萘二甲磺酸、聚半乳糖醛酸等形成的盐;(b)由元素阴离子比如氯、溴和碘等形成的盐,和(c)源自碱的盐,比如铵盐、碱金属盐比如钠和钾盐、碱土金属盐比如钙和镁盐,以及与有机碱比如二环己胺和N-甲基-D-葡萄糖胺的盐。在Berge等人,J.Pharm.Sci.,66,1,19(1977)中可找到合适的药学上可接受的盐的综述。
具体实施方式
在第一实施方式中,本发明涉及由式IIIa的化合物或其盐制备式IIa的化合物或其盐的方法,其包括以下步骤:
a)在氢硅烷试剂和酸的存在下对式IIIa的化合物或其盐进行脱氧以提供式IIa的化合物——其任选地为非对映混合物的形式;
b)用手性或非手性酸或其混合物任选地处理步骤a)的产物,经由胺基形成酸加成盐,并且分离期望的(2R,3R)-[3-(3-甲氧基苯基)-2-甲基-戊基]二甲胺(式IIa的化合物)的盐。
根据现有技术步骤制备式IIIa的化合物或其盐,如例如在EP2046724(或相应的WO2008012047)中所公开的。式IIIa的化合物,即,式III的化合物的2S,3R非对映体,以可靠且可再现的方式可获得,如现有技术公开内容中所广泛显示的。它还可以以游离碱或者酸加成盐的形式在商业上获得。
步骤a中进行的脱氧通常采用氢硅烷还原剂,其可以选自三乙基硅烷、三甲基硅烷、二甲基苯基硅烷、苯基硅烷、三苯基硅烷、三氯硅烷、三(三甲基甲硅烷基)硅烷、聚甲基氢硅氧烷。
为了进行脱氧,氢硅烷还原剂还需要存在酸(以下称为步骤a的酸)。步骤a的酸可以是能够活化式IIIa的化合物的任何酸。该酸可以是路易斯酸或质子酸。在路易斯酸的情况下,该酸可以选自四氯化钛、氯化铝、溴化铝、三氟化硼、三溴化硼、四氯化锡、四溴化锡、氯化亚锡、氯化铁、氯化锌。在质子酸的情况下,该酸可以选自三氟乙酸、对甲苯磺酸或甲磺酸。
反应的溶剂可以选自烃,比如甲苯、二甲苯,卤代烃,比如二氯甲烷、1,2-二氯乙烷、氯仿、氯苯、二氯苯。优选的是二氯甲烷。
温度可以在大约(-50)℃至反应溶剂的沸点的范围内。优选的温度范围为(-10)-50℃。更优选地为0-25℃。甚至更优选地为5-10℃。
所使用的氢硅烷可以在1.5至10当量范围内。优选地,所使用的当量可以是2.0。
所使用的酸可以在2至10当量范围内。优选地,所使用的当量可以是2.1。
脱氧反应将式IIIa的化合物转化为式IIa的化合物。式IIa的化合物可以任选地形成为非对映混合物的一部分,即,式IIa的化合物和其非对映体(式IIb的化合物)的混合物。
两种非对映体的比率取决于各种因素,比如反应温度和溶剂。
当非对映体纯度不令人满意时,非对映混合物可以用酸进行处理,通过该酸所形成的酸加成盐使得能够分离两种非对映体。
步骤b中所使用的酸选自手性或非手性酸并且可以是如下的任一种:盐酸、氢溴酸、硝酸、草酸、琥珀酸、马来酸、富马酸、硫酸、磷酸、乙酸、丙酸、苯磺酸、甲苯磺酸、柠檬酸、酒石酸及其衍生物、苹果酸、扁桃及其衍生物、樟脑磺酸及其衍生物。优选的酸是盐酸、氢溴酸、硫酸、苯磺酸、甲苯磺酸、酒石酸及其衍生物和扁桃酸。
选择以实现非对映体分离的酸可以变化,并且取决于步骤a中产生的非对映混合物的非对映体比率。另外,步骤b可以进行多次,并且每个循环中使用的酸不一定相同。
步骤b中可以使用的溶剂取决于用于实现非对映体分离的酸的选择。一般地,通常使用的极性有机溶剂或水是合适的,比如酮、醇、酯、醚、卤代烃及其混合物。在氢卤酸盐的情况下,酮溶剂是优选的,比如丙酮、丁酮、甲基异丁酮。另一方面,在酒石酸衍生物的加成盐的情况下,水性醇溶剂是优选的。
步骤b中的合适的溶剂取决于用于实现非对映体分离的酸的选择。例如,对于IIa的HCl加成盐的非对映混合物的分离,在丙酮、丁酮-2、甲基异丁酮及相关酮中选择溶剂。另一方面,对于酒石酸衍生物加成盐的混合物的分离,最合适的溶剂是含水甲醇、含水乙醇或类似溶剂。
非对映混合物的解析通常可以根据完善的现有技术步骤进行,比如WO2008012047中使用盐酸盐的步骤或者WO2016023913中或根据本发明使用二芳酰基酒石酸衍生物的步骤。
在优选的实施方式中,如步骤a中所述,式IIIa的化合物脱氧反应成式IIa的化合物产生非对映混合物,然后如步骤b中所述,对其进行分离以提供式IIa的化合物。
式IIIa的化合物可以被用作游离胺碱,或者可以用作其酸加成盐。在优选的实施方式中,式IIIa的化合物为其酸加成盐的形式。酸加成盐的抗衡离子可以源自如上所定义的酸。优选地,酸选自盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三卤代乙酸(例如,三氟乙酸)、马来酸,磺酸比如甲磺酸、甲苯磺酸和樟脑磺酸、丙酸比如(R)-氯丙酸、邻氨甲酰苯甲酸比如N-[(R)-1-(1-萘基)乙基]邻氨甲酰苯甲酸、酒石酸比如L-酒石酸和二苄基-L-酒石酸、乳酸、樟脑酸、天冬氨酸、香茅酸。更优选的是盐酸和氢溴酸。
在本发明的第二实施方式中,提供了制备他喷他多或其药学上可接受的盐的方法,其包括如先前的实施方式中所限定的步骤a和b,并且进一步包括对式IIa的化合物进行脱甲基,以提供式I的化合物并且任选地将式I的化合物转化成其药学上可接受的盐。
脱甲基反应可以根据现有技术中公开的方法进行。其中使用的试剂包括但不限于氢溴酸、甲磺酸、盐酸、三氟乙酸、氯化铝、溴化铝或其组合。氢溴酸是优选的。
实施例
实施例1:
将50mg的(2S,3R)-1-(二甲氨基)-3-(3-甲氧基苯基)-2-甲基戊-3-醇连同1.0ml二氯甲烷进料到10ml RB烧瓶中。在搅拌下添加0.32ml三乙基硅烷并且将混合物冷却至0-5℃。在该温度下添加67mg三氯化铝并且在0-5℃下将混合物搅拌2小时。然后使得混合物达到环境温度,并且进一步搅拌2小时。
将混合物再次冷却至0-5℃并且用3.0ml的乙酸乙酯稀释,用2.0ml的10%w/v氢氧化钠水溶液淬灭并且使其再次达到环境温度。分离有机相并且将水相用另一部分的3.0ml乙酸乙酯萃取。再次分离有机相并且与第一个有机相组合,以经硫酸钠干燥。在过滤之后,将溶剂蒸发掉以提供55mg的粗产物。
实施例2:
将50mg的(2S,3R)-1-(二甲氨基)-3-(3-甲氧基苯基)-2-甲基戊-3-醇连同1.0ml甲苯进料到10ml RB烧瓶中。在搅拌下添加0.32ml三乙基硅烷并且将混合物冷却至0-5℃。在该温度下添加67mg三氯化铝,并且在0-5℃下将混合物搅拌2小时。然后使得混合物达到环境温度并且进一步搅拌2小时。
对混合物进行如上加工,以提供57mg的粗产物。
实施例3:
将250mg的(2S,3R)-1-(二甲氨基)-3-(3-甲氧基苯基)-2-甲基戊-3-醇连同10ml二氯甲烷进料到10ml RB烧瓶中。然后在搅拌下将混合物冷却至0-5℃。在该温度下,添加0.5ml三乙基硅烷,接着添加0.76ml三氟乙酸。将混合物温热至室温并且继续搅拌1小时。在大约50℃下加热混合物并且维持该温度2小时。
对混合物进行如上加工,以提供223mg的粗产物。
实施例4:
将250mg的(2S,3R)-1-(二甲氨基)-3-(3-甲氧基苯基)-2-甲基戊-3-醇连同10ml二氯甲烷进料到10ml RB烧瓶。然后在搅拌下将混合物冷却至0-5℃。在该温度下,添加0.5ml三乙基硅烷,接着添加1.23ml三氟化硼乙醚络合物。将混合物温热至室温并且继续搅拌1小时。在大约50℃下加热混合物并且将温度保持2小时。对混合物进行如上处理,以提供238mg的粗产物。
实施例5:
在装配有搅拌棒和温度计的1L三颈RB烧瓶中进料10.0g的(2S,3R)-1-(二甲氨基)-3-(3-甲氧基苯基)-2-甲基戊-3-醇,接着进料80ml DCM和12.7ml三乙基氯硅烷。然后在搅拌下将混合物冷却至0-5℃。按份添加10.61g的三氯化铝。在0-5℃下将反应混合物搅拌1-2小时。在反应(TLC)完成后,添加100ml的DM水并且在环境温度下将混合物搅拌30分钟。分离有机相并且除去溶剂。将残留物在50ml叔丁基甲基醚与10ml HCl 1.0N之间分配。将水相转移至500ml RB烧瓶中并且添加7.0ml NaOH 50%w/v,接着添加50ml DCM。将有机相分离,经硫酸钠干燥并过滤。除去溶剂以提供8.53g的粗产物。HPLC:两种非对映体(IIa和IIb)为81.2%。
实施例6:
在装配有搅拌棒和温度计的250ml三颈RB烧瓶中进料10.0g的(2S,3R)-1-(二甲氨基)-3-(3-甲氧基苯基)-2-甲基戊-3-醇盐酸盐,接着进料80ml DCM和22.2ml三乙基氯硅烷。然后在搅拌下将混合物冷却至0-5℃。按份添加11.58g的三氯化铝。在环境温度下将反应混合物搅拌1-2小时。在反应(TLC)完成后,将反应混合物倒入100ml酒石酸钾钠的水溶液(20%w/v)中并且搅拌几分钟。然后添加25ml的50%w/v氢氧化钠水溶液并且过滤混合物。收集有机相。用50ml DCM萃取水相。将有机相分离,与先前的有机相组合并且除去溶剂。向残留物添加50ml叔丁基甲基醚,接着添加80ml的1.0N HCl。收集水相,添加9.0ml的50%w/v氢氧化钠水溶液并且用50ml二氯甲烷萃取水相两次。将组合的有机相经硫酸钠干燥,过滤并除去溶剂以提供7.9g的粗产物。HPLC:两种非对映体(IIa和IIb)为98.1%。
实施例7:
在环境温度下,在装配有磁力棒的25ml RB烧瓶中进料1.0g的实施例6中的粗产物,接着进料5.0ml丁酮。添加0.59mL的氯三甲基硅烷,接着添加84μL的DM水。将混合物进一步搅拌1-2小时并且通过布氏漏斗过滤。用1.0ml丁酮洗涤湿滤饼(wet cake)两次并且干燥,以提供378mg的(2R,3R)-3-(3-甲氧基苯基)-N,N,2-三甲基戊烷-1-胺盐酸盐。HPLC:74.8%IIa,23.7%的式IIb的化合物。
实施例8:
在环境温度下,在装配有磁力棒的25ml RB烧瓶中进料1.07g的实施例6中的粗产物,接着进料8.0ml丁酮。添加40μL的DM水,接着逐滴添加280μL的氯三甲基硅烷。将混合物进一步搅拌2小时并且通过布氏漏斗过滤。用2.0ml丁酮洗涤湿滤饼,并且干燥以提供290mg的(2R,3R)-3-(3-甲氧基苯基)-N,N,2-三甲基戊烷-1-胺盐酸盐。HPLC:87.0%的IIa,10.6%的IIb。
实施例9:
在环境温度下,在装配有磁力棒的25ml RB烧瓶中进料550mg的实施例6中的粗产物,接着进料2.2ml丙酮。添加21μL的DM水,接着逐滴添加148μL的氯三甲基硅烷。将混合物进一步搅拌24小时。添加2.2ml的叔丁基甲基醚并且形成悬浮液。将混合物搅拌2小时并且然后通过布氏漏斗过滤。将湿滤饼用2.0ml叔丁基甲基醚洗涤并干燥以提供190mg的(2R,3R)-3-(3-甲氧基苯基)-N,N,2-三甲基戊烷-1-胺盐酸盐。HPLC:91.2%的式IIa的化合物和7.7%的式IIb的化合物。
实施例10:
在装配有温度计和搅拌棒的50ml RB烧瓶中进料1.0g的实施例6中的粗产物,接着进料1.5ml含水甲醇10%。将1.8g二-对甲苯基-酒石酸-L添加至所得的溶液。将混合物加热至回流30分钟。然后逐渐冷却至5-10℃并且进一步搅拌1.5小时。在真空下过滤混合物,并且将滤饼用2.0ml甲醇水溶液10%洗涤,以提供1.78g的(2R,3R)-3-(3-甲氧基苯基)-N,N,2-三甲基戊烷-1-胺盐酸盐,其中式IIa的化合物的非对映体纯度为75.8%并且式IIb的化合物为22.0%,呈白色固体。
Claims (7)
2.根据权利要求1所述的方法,其中所述氢硅烷试剂选自三乙基硅烷、三甲基硅烷、二甲基苯基硅烷、苯基硅烷、三苯基硅烷、三氯硅烷、三(三甲基甲硅烷基)硅烷、聚甲基氢硅氧烷。
3.根据权利要求1或2所述的方法,其中步骤a中的所述酸选自四氯化钛、氯化铝、溴化铝、三氟化硼、三溴化硼、四氯化锡、四溴化锡、氯化亚锡、氯化铁、氯化锌、三氟乙酸、对甲苯磺酸或甲磺酸。
4.根据前述权利要求中任一项所述的方法,其中步骤b中的所述酸选自盐酸、氢溴酸、硝酸、草酸、琥珀酸、马来酸、富马酸、硫酸、磷酸、乙酸、丙酸、苯磺酸、甲苯磺酸、柠檬酸、酒石酸及其衍生物、苹果酸、扁桃酸及其衍生物、樟脑磺酸及其衍生物。
5.根据前述权利要求中任一项所述的方法,其中式IIIa的化合物为酸加成盐的形式。
6.根据权利要求5所述的方法,其中所述酸加成盐为盐酸盐或氢溴酸盐。
7.一种制备他喷他多或其药学上可接受的盐的方法,其包括前述权利要求中任一项所述的步骤a和步骤b,并且进一步包括对式IIa的化合物进行脱甲基,以提供式I的化合物并且任选地将式I的化合物转化成其药学上可接受的盐。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN201831022432 | 2018-06-15 | ||
IN201831022432 | 2018-06-15 | ||
PCT/EP2019/025173 WO2019238267A1 (en) | 2018-06-15 | 2019-06-10 | A novel process for the preparation of tapentadol |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112262121A true CN112262121A (zh) | 2021-01-22 |
Family
ID=66999774
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980039041.2A Pending CN112262121A (zh) | 2018-06-15 | 2019-06-10 | 用于制备他喷他多的新方法 |
Country Status (4)
Country | Link |
---|---|
US (1) | US20210253513A1 (zh) |
EP (1) | EP3807243A1 (zh) |
CN (1) | CN112262121A (zh) |
WO (1) | WO2019238267A1 (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1930135A (zh) * | 2004-03-05 | 2007-03-14 | 弗·哈夫曼-拉罗切有限公司 | 作为p2x3和p2x2/3拮抗剂的二氨基嘧啶 |
CN101495445A (zh) * | 2006-07-24 | 2009-07-29 | 格吕伦塔尔有限公司 | (1r,2r)-3-(3-二甲胺基-1-乙基-2-甲基丙基)苯酚的制备方法 |
CN106349241A (zh) * | 2015-07-15 | 2017-01-25 | 上海翰森生物医药科技有限公司 | 具有hsp90抑制活性的三唑衍生物及其制备方法和应用 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9315148D0 (en) * | 1993-07-22 | 1993-09-08 | Smithkline Beecham Plc | Novel compounds |
DE4426245A1 (de) | 1994-07-23 | 1996-02-22 | Gruenenthal Gmbh | 1-Phenyl-3-dimethylamino-propanverbindungen mit pharmakologischer Wirkung |
DE10328316A1 (de) * | 2003-06-23 | 2005-01-20 | Grünenthal GmbH | Verfahren zur Herstellung von Dimethyl-(3-aryl-buthyl)-aminverbindungen als pharmazeutische Wirkstoffe |
CN101495447B (zh) | 2006-07-24 | 2013-05-29 | 詹森药业有限公司 | (2r,3r)-3-(3-甲氧苯基)-n,n,2-三甲基戊胺的制备 |
EP2545028A4 (en) | 2011-01-27 | 2013-07-03 | Symed Labs Ltd | STEREOSPECIFIC SYNTHESIS OF (-) (2S, 3S) -1-DIMETHYLAMINO-3- (3-METHOXYPHENYL) -2-METHYLPENTAN-3-OLE |
WO2014180305A1 (zh) * | 2013-05-09 | 2014-11-13 | 四川海思科制药有限公司 | 苯酚衍生物及其制备方法和在医药上的应用 |
US20170233330A1 (en) | 2014-08-11 | 2017-08-17 | Sandoz Ag | Process for the preparation of 3-[(1R,2R)-3-(Dimethylamino)-1-ethyl-2-methylpropyl]-phenol |
-
2019
- 2019-06-10 US US17/252,097 patent/US20210253513A1/en active Pending
- 2019-06-10 CN CN201980039041.2A patent/CN112262121A/zh active Pending
- 2019-06-10 EP EP19732261.3A patent/EP3807243A1/en active Pending
- 2019-06-10 WO PCT/EP2019/025173 patent/WO2019238267A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1930135A (zh) * | 2004-03-05 | 2007-03-14 | 弗·哈夫曼-拉罗切有限公司 | 作为p2x3和p2x2/3拮抗剂的二氨基嘧啶 |
CN101495445A (zh) * | 2006-07-24 | 2009-07-29 | 格吕伦塔尔有限公司 | (1r,2r)-3-(3-二甲胺基-1-乙基-2-甲基丙基)苯酚的制备方法 |
CN106349241A (zh) * | 2015-07-15 | 2017-01-25 | 上海翰森生物医药科技有限公司 | 具有hsp90抑制活性的三唑衍生物及其制备方法和应用 |
Non-Patent Citations (3)
Title |
---|
KASTURI LAI ET AL.: "Robustadials.2.Total synthesis of the bicyclo[3.2.0]heptane structure proposed for robustadials A and B", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
ROMAIN COFFINIER ET AL.: "Total Synthesis of (-)-Bacchopetiolone via an Asymmetric Hydroxylative Phenol Dearomatization/[4+2]-Dimerization Cascade Promoted by a Novel Salen-Type Chiral Iodane", 《ORGANIC LETTERS》 * |
TAO ZHANG ET AL.: "A facile synthesis of (±)-heliannuol-D", 《NATURAL PRODUCT COMMUNICATIONS》 * |
Also Published As
Publication number | Publication date |
---|---|
EP3807243A1 (en) | 2021-04-21 |
US20210253513A1 (en) | 2021-08-19 |
WO2019238267A1 (en) | 2019-12-19 |
JP2021527096A (ja) | 2021-10-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20020120005A1 (en) | Method for the preparation of pure citalopram | |
JP2009503035A (ja) | 3,3−ジフェニルプロピルアミンを得る方法 | |
US20130096321A1 (en) | Crystalline rotigotine base and preparation process therefor | |
WO2015007897A1 (en) | Method of racemisation of undesired enantiomers | |
KR20030059206A (ko) | 결정질 벤라팍신 염기 및 벤라팍신 히드로클로라이드의신규한 다형태, 이의 제조 방법 | |
CN112262121A (zh) | 用于制备他喷他多的新方法 | |
US6262270B1 (en) | Enantioselective synthesis | |
JP7486438B2 (ja) | タペンタドールの調製のための新規な方法 | |
US6635773B2 (en) | Process for preparing citalopram | |
JP4461048B2 (ja) | エナンチオ選択的合成 | |
EP3044215B1 (en) | Processes for preparing medicaments for the treatment of cardiovascular diseases and intermediates for use therein | |
US20020151596A1 (en) | Novel process to prepare 2-aminoindan derivatives | |
JP2008531510A (ja) | 6−ジメチルアミノメチル−1−(3−メトキシフェニル)−1,3−ジヒドロキシ−シクロヘキサン化合物のリン酸塩 | |
WO2009027766A2 (en) | New crystalline solid forms of o-desvenlafaxine base | |
EP2739610B1 (en) | Process for the manufacture of ivabradine and of intermediates of synthesis thereof | |
JP2007519660A (ja) | 2−(エトキシメチル)トロパン誘導体の製造方法 | |
AU2003278409A1 (en) | Improved process for the manufacture of citalopram hydrobromide | |
WO2011147576A1 (en) | Process for the preparation of substituted 1-aminomethyl-2-phenyl-cyclohexane compounds | |
CN104159902A (zh) | 制备(1r,4r)-6’-氟-(N,N-二甲基-和N-甲基)-4-苯基-4’,9’-二氢-3’H-螺[环己烷-1,1’-吡喃并[3,4,b]吲哚]-4-胺的方法 | |
CA2769765A1 (en) | Polymorphic form of toremifene citrate and process for its preparation | |
WO2015117576A1 (en) | A solid form of tapentadol maleate and a method of its preparation | |
CZ303627B6 (cs) | Zpusob výroby Cinacalcetu | |
CZ2012508A3 (cs) | Nový oxalát TAPENTADOLU a zpusob jeho prípravy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40044927 Country of ref document: HK |