CN106008183B - 麻黄碱或伪麻黄碱及麻黄碱或伪麻黄碱中间体的制备方法 - Google Patents
麻黄碱或伪麻黄碱及麻黄碱或伪麻黄碱中间体的制备方法 Download PDFInfo
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- CN106008183B CN106008183B CN201610396725.6A CN201610396725A CN106008183B CN 106008183 B CN106008183 B CN 106008183B CN 201610396725 A CN201610396725 A CN 201610396725A CN 106008183 B CN106008183 B CN 106008183B
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- Prior art keywords
- phenyl
- reaction
- pseudoephedrine
- acetone
- ephedrine
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- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 title claims abstract description 72
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229960002179 ephedrine Drugs 0.000 title claims abstract description 36
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 title claims abstract description 33
- 229960003908 pseudoephedrine Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 122
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 110
- 238000006243 chemical reaction Methods 0.000 claims abstract description 100
- 238000000034 method Methods 0.000 claims abstract description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 19
- JEQDSBVHLKBEIZ-UHFFFAOYSA-N 2-chloropropanoyl chloride Chemical compound CC(Cl)C(Cl)=O JEQDSBVHLKBEIZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000007858 starting material Substances 0.000 claims abstract description 5
- 238000007171 acid catalysis Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 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 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000001412 amines Chemical group 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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 3
- 239000011230 binding agent Substances 0.000 claims description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
- 239000000920 calcium hydroxide Substances 0.000 claims description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 239000011968 lewis acid catalyst Substances 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 238000011946 reduction process Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- NIOHSOXYJMSVOA-UHFFFAOYSA-N 1-chloro-3-phenylpropan-2-one Chemical compound ClCC(=O)CC1=CC=CC=C1 NIOHSOXYJMSVOA-UHFFFAOYSA-N 0.000 claims 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims 2
- 239000000395 magnesium oxide Substances 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 14
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 12
- 229910052794 bromium Inorganic materials 0.000 abstract description 12
- 239000000010 aprotic solvent Substances 0.000 abstract description 6
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 27
- LPLLVINFLBSFRP-UHFFFAOYSA-N 2-methylamino-1-phenylpropan-1-one Chemical compound CNC(C)C(=O)C1=CC=CC=C1 LPLLVINFLBSFRP-UHFFFAOYSA-N 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
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- 229910052801 chlorine Inorganic materials 0.000 description 6
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- 238000010792 warming Methods 0.000 description 6
- 241000131329 Carabidae Species 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 5
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- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
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- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 description 4
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
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- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
Abstract
Description
Claims (8)
Priority Applications (2)
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CN201610396725.6A CN106008183B (zh) | 2016-06-07 | 2016-06-07 | 麻黄碱或伪麻黄碱及麻黄碱或伪麻黄碱中间体的制备方法 |
PCT/CN2017/080841 WO2017211129A1 (zh) | 2016-06-07 | 2017-04-18 | 麻黄碱或伪麻黄碱及麻黄碱或伪麻黄碱中间体的制备方法 |
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CN201610396725.6A CN106008183B (zh) | 2016-06-07 | 2016-06-07 | 麻黄碱或伪麻黄碱及麻黄碱或伪麻黄碱中间体的制备方法 |
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CN106008183A CN106008183A (zh) | 2016-10-12 |
CN106008183B true CN106008183B (zh) | 2019-05-07 |
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CN106008183B (zh) * | 2016-06-07 | 2019-05-07 | 浙江普洛康裕制药有限公司 | 麻黄碱或伪麻黄碱及麻黄碱或伪麻黄碱中间体的制备方法 |
CN112645829B (zh) * | 2020-12-25 | 2022-10-21 | 浙江普洛康裕制药有限公司 | 麻黄碱关键中间体(s)-2-甲胺基-1-苯基-1-丙酮的手性合成方法 |
CN112939793B (zh) * | 2021-02-03 | 2022-07-08 | 浙江普洛康裕制药有限公司 | 麻黄碱和伪麻黄碱工业生产过程中母液中活性成分的回收利用方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4539420A (en) * | 1981-06-15 | 1985-09-03 | Syntex Pharmaceuticals International Limited | Optically active 1-aromatic-group-substituted-1-alkanones and methods for their manufacture |
CN1706812A (zh) * | 2004-06-07 | 2005-12-14 | 上海医药工业研究院 | (1r,2s)-(-)-麻黄碱或其盐酸盐的制备方法 |
CN101870660A (zh) * | 2010-05-10 | 2010-10-27 | 青海省青海湖药业有限公司 | 一种L-(-)-盐酸麻黄碱和d-(+)-盐酸伪麻黄碱制备方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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GB1423911A (en) * | 1972-03-16 | 1976-02-04 | Monsanto Co | Production of optically active alcohols |
JPWO2003091200A1 (ja) * | 2002-04-26 | 2005-09-02 | 日本曹達株式会社 | 2−アミノケトン類の製造方法 |
CN106008183B (zh) * | 2016-06-07 | 2019-05-07 | 浙江普洛康裕制药有限公司 | 麻黄碱或伪麻黄碱及麻黄碱或伪麻黄碱中间体的制备方法 |
-
2016
- 2016-06-07 CN CN201610396725.6A patent/CN106008183B/zh active Active
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2017
- 2017-04-18 WO PCT/CN2017/080841 patent/WO2017211129A1/zh active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4539420A (en) * | 1981-06-15 | 1985-09-03 | Syntex Pharmaceuticals International Limited | Optically active 1-aromatic-group-substituted-1-alkanones and methods for their manufacture |
CN1706812A (zh) * | 2004-06-07 | 2005-12-14 | 上海医药工业研究院 | (1r,2s)-(-)-麻黄碱或其盐酸盐的制备方法 |
CN101870660A (zh) * | 2010-05-10 | 2010-10-27 | 青海省青海湖药业有限公司 | 一种L-(-)-盐酸麻黄碱和d-(+)-盐酸伪麻黄碱制备方法 |
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WO2017211129A1 (zh) | 2017-12-14 |
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