CN100368386C - (±)对氟-2-(2-甲基-丙酰基)-4-氧-n,3-二苯基-苯丁酰胺的合成方法以及其中的中间体 - Google Patents
(±)对氟-2-(2-甲基-丙酰基)-4-氧-n,3-二苯基-苯丁酰胺的合成方法以及其中的中间体 Download PDFInfo
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- CN100368386C CN100368386C CNB001080040A CN00108004A CN100368386C CN 100368386 C CN100368386 C CN 100368386C CN B001080040 A CNB001080040 A CN B001080040A CN 00108004 A CN00108004 A CN 00108004A CN 100368386 C CN100368386 C CN 100368386C
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- fluoro
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- methyl
- propionyl
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- 238000000034 method Methods 0.000 title claims description 14
- 230000002194 synthesizing effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- -1 p-4-fluoro-phenylbenzyl ketone Chemical compound 0.000 claims abstract description 10
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 9
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000031709 bromination Effects 0.000 claims abstract description 5
- 238000005893 bromination reaction Methods 0.000 claims abstract description 5
- 238000005917 acylation reaction Methods 0.000 claims abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 4
- NLHNXJPFQDRIKO-UHFFFAOYSA-N BrC(C(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)F)C Chemical compound BrC(C(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)F)C NLHNXJPFQDRIKO-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- HOYCJFDJVJDCCL-UHFFFAOYSA-N FC1=CC=C(C=C1)C1=C(C=CC=C1)C(CC)=O Chemical compound FC1=CC=C(C=C1)C1=C(C=CC=C1)C(CC)=O HOYCJFDJVJDCCL-UHFFFAOYSA-N 0.000 claims 3
- 238000002360 preparation method Methods 0.000 abstract description 8
- ADHRFDCBLJVNFO-UHFFFAOYSA-N 4-methyl-3-oxo-n-phenylpentanamide Chemical compound CC(C)C(=O)CC(=O)NC1=CC=CC=C1 ADHRFDCBLJVNFO-UHFFFAOYSA-N 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract description 4
- 230000005494 condensation Effects 0.000 abstract description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 abstract description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 abstract 4
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 4
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940000635 beta-alanine Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB001080040A CN100368386C (zh) | 2000-05-31 | 2000-05-31 | (±)对氟-2-(2-甲基-丙酰基)-4-氧-n,3-二苯基-苯丁酰胺的合成方法以及其中的中间体 |
Applications Claiming Priority (1)
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CNB001080040A CN100368386C (zh) | 2000-05-31 | 2000-05-31 | (±)对氟-2-(2-甲基-丙酰基)-4-氧-n,3-二苯基-苯丁酰胺的合成方法以及其中的中间体 |
Related Child Applications (1)
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CN2008100067519A Division CN101250133B (zh) | 2000-05-31 | 2000-05-31 | (±)对氟-2-(2-甲基-丙酰基)-4-氧-n,3-二苯基-苯丁酰胺的合成方法以及其中的中间体 |
Publications (2)
Publication Number | Publication Date |
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CN1325844A CN1325844A (zh) | 2001-12-12 |
CN100368386C true CN100368386C (zh) | 2008-02-13 |
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CNB001080040A Expired - Lifetime CN100368386C (zh) | 2000-05-31 | 2000-05-31 | (±)对氟-2-(2-甲基-丙酰基)-4-氧-n,3-二苯基-苯丁酰胺的合成方法以及其中的中间体 |
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Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101306988B (zh) * | 2007-05-15 | 2011-11-30 | 浙江京新药业股份有限公司 | α-溴-4-氟苯基苄基酮的新合成方法 |
CN101768102B (zh) * | 2009-01-05 | 2013-08-21 | 浙江华海药业股份有限公司 | 一种阿托伐他汀钙中间体1h-吡咯衍生物的制备方法 |
CN103724175A (zh) * | 2013-12-12 | 2014-04-16 | 安庆金泉药业有限公司 | 一种阿伐他汀中间体α-溴-4-氟苯基苄基酮的合成方法 |
CN106397296B (zh) * | 2016-08-29 | 2019-03-19 | 江苏阿尔法药业有限公司 | 一种阿托伐他汀钙的制备工艺 |
CN110724123B (zh) * | 2019-11-14 | 2022-03-01 | 扬州工业职业技术学院 | 一种卡格列净中间体的合成方法 |
CN114195670B (zh) * | 2021-12-31 | 2024-03-15 | 河南豫辰药业股份有限公司 | 一种阿托伐他汀母核m4的精制方法 |
CN115260051A (zh) * | 2022-08-26 | 2022-11-01 | 江苏阿尔法药业股份有限公司 | 一种阿托伐他汀钙中间体的制备工艺 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4536517A (en) * | 1983-04-25 | 1985-08-20 | American Cyanamid Company | Method of treating diabetes mellitus using arylglyoxals |
US4829081A (en) * | 1986-01-07 | 1989-05-09 | Sandoz Pharm. Corp. | Analogs of mevalonolactone and derivatives thereof |
US5155251A (en) * | 1991-10-11 | 1992-10-13 | Warner-Lambert Company | Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate |
-
2000
- 2000-05-31 CN CNB001080040A patent/CN100368386C/zh not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4536517A (en) * | 1983-04-25 | 1985-08-20 | American Cyanamid Company | Method of treating diabetes mellitus using arylglyoxals |
US4829081A (en) * | 1986-01-07 | 1989-05-09 | Sandoz Pharm. Corp. | Analogs of mevalonolactone and derivatives thereof |
US5155251A (en) * | 1991-10-11 | 1992-10-13 | Warner-Lambert Company | Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate |
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CN1325844A (zh) | 2001-12-12 |
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C06 | Publication | ||
PB01 | Publication | ||
ASS | Succession or assignment of patent right |
Owner name: ZHEJIANG CHENGYI MEDICINE CO., LTD. Effective date: 20021220 |
|
C41 | Transfer of patent application or patent right or utility model | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20021220 Applicant after: Institute of Materia Medica of Chinese Academy of Medical Sciences Co-applicant after: Zhejiang Chengyi Pharmaceutical Industry Co., Ltd. Applicant before: Institute of Materia Medica of Chinese Academy of Medical Sciences |
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C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C56 | Change in the name or address of the patentee | ||
CP01 | Change in the name or title of a patent holder |
Address after: 100050 Beijing city Xuanwu District Xiannongtan Street No. 1 Patentee after: Institute of Materia Medica of Chinese Academy of Medical Sciences Patentee after: ZHEJIANG CHENG YI PHARMACEUTICAL CO., LTD. Address before: 100050 Beijing city Xuanwu District Xiannongtan Street No. 1 Patentee before: Institute of Materia Medica of Chinese Academy of Medical Sciences Patentee before: Zhejiang Chengyi Pharmaceutical Industry Co., Ltd. |
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CX01 | Expiry of patent term |
Granted publication date: 20080213 |
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CX01 | Expiry of patent term |