CN109384807B - 一种安塞曲匹中间体的制备方法 - Google Patents
一种安塞曲匹中间体的制备方法 Download PDFInfo
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- CN109384807B CN109384807B CN201710685373.0A CN201710685373A CN109384807B CN 109384807 B CN109384807 B CN 109384807B CN 201710685373 A CN201710685373 A CN 201710685373A CN 109384807 B CN109384807 B CN 109384807B
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- Prior art keywords
- fluoro
- licl
- isopropyl
- methoxyphenyl
- catalyst
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- MZZLGJHLQGUVPN-HAWMADMCSA-N anacetrapib Chemical compound COC1=CC(F)=C(C(C)C)C=C1C1=CC=C(C(F)(F)F)C=C1CN1C(=O)O[C@H](C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)[C@@H]1C MZZLGJHLQGUVPN-HAWMADMCSA-N 0.000 title claims abstract description 15
- 229950000285 anacetrapib Drugs 0.000 title claims abstract description 14
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 32
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- HIMPTPIZYRIPFV-UHFFFAOYSA-N (4-fluoro-2-methoxy-5-propan-2-ylphenoxy)boronic acid Chemical compound FC1=CC(=C(C=C1C(C)C)OB(O)O)OC HIMPTPIZYRIPFV-UHFFFAOYSA-N 0.000 claims abstract description 14
- CPPYOHQHPFTBON-UHFFFAOYSA-N 1-bromo-4-fluoro-2-methoxy-5-propan-2-ylbenzene Chemical compound COC1=CC(F)=C(C(C)C)C=C1Br CPPYOHQHPFTBON-UHFFFAOYSA-N 0.000 claims abstract description 14
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 8
- RULNRPPZHIOZEC-UHFFFAOYSA-L [Cl-].[Li+].CC1=C(C(=CC(=C1)C)C)[Mg]Br Chemical compound [Cl-].[Li+].CC1=C(C(=CC(=C1)C)C)[Mg]Br RULNRPPZHIOZEC-UHFFFAOYSA-L 0.000 claims abstract description 7
- 239000011777 magnesium Substances 0.000 claims abstract description 5
- JOWQNXIISCPKBK-UHFFFAOYSA-M magnesium;1,3,5-trimethylbenzene-6-ide;bromide Chemical compound [Mg+2].[Br-].CC1=CC(C)=[C-]C(C)=C1 JOWQNXIISCPKBK-UHFFFAOYSA-M 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- QNRUKMBLUVIEBO-UHFFFAOYSA-L lithium;magnesium;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-] QNRUKMBLUVIEBO-UHFFFAOYSA-L 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- XKZRGAGBWCJQMW-UHFFFAOYSA-M [Cl-].[Li+].C(C)(C)[Mg]C(C)C Chemical group [Cl-].[Li+].C(C)(C)[Mg]C(C)C XKZRGAGBWCJQMW-UHFFFAOYSA-M 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 abstract description 4
- ULKSWZAXQDJMJT-UHFFFAOYSA-M magnesium;2,2,6,6-tetramethylpiperidin-1-ide;chloride Chemical compound [Cl-].CC1(C)CCCC(C)(C)N1[Mg+] ULKSWZAXQDJMJT-UHFFFAOYSA-M 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 2
- 229910052744 lithium Inorganic materials 0.000 abstract description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 abstract description 2
- DQZLQYHGCKLKGU-UHFFFAOYSA-N magnesium;propane Chemical compound [Mg+2].C[CH-]C.C[CH-]C DQZLQYHGCKLKGU-UHFFFAOYSA-N 0.000 abstract description 2
- OSNYCIBBCFDLQQ-UHFFFAOYSA-N [B]C1=CC(C(C)C)=C(F)C=C1OC Chemical compound [B]C1=CC(C(C)C)=C(F)C=C1OC OSNYCIBBCFDLQQ-UHFFFAOYSA-N 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- 239000012071 phase Substances 0.000 description 27
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- HMRRCUXJGOSJJA-UHFFFAOYSA-N (4-fluoro-2-methoxy-5-propan-2-ylphenyl)boronic acid Chemical compound COC1=CC(F)=C(C(C)C)C=C1B(O)O HMRRCUXJGOSJJA-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- -1 small molecule oxazolidinones Chemical class 0.000 description 7
- 201000001320 Atherosclerosis Diseases 0.000 description 5
- 150000001840 cholesterol esters Chemical class 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 3
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 description 3
- 108010028554 LDL Cholesterol Proteins 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 108090001030 Lipoproteins Proteins 0.000 description 2
- 102000004895 Lipoproteins Human genes 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002632 lipids Chemical group 0.000 description 2
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 108010069201 VLDL Cholesterol Proteins 0.000 description 1
- MWVGKTUELQKXEN-UHFFFAOYSA-K [Li+].[Mg++].[Cl-].[Cl-].[Cl-] Chemical compound [Li+].[Mg++].[Cl-].[Cl-].[Cl-] MWVGKTUELQKXEN-UHFFFAOYSA-K 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 1
- 229940125881 cholesteryl ester transfer protein inhibitor Drugs 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims (2)
Priority Applications (1)
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CN201710685373.0A CN109384807B (zh) | 2017-08-11 | 2017-08-11 | 一种安塞曲匹中间体的制备方法 |
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CN201710685373.0A CN109384807B (zh) | 2017-08-11 | 2017-08-11 | 一种安塞曲匹中间体的制备方法 |
Publications (2)
Publication Number | Publication Date |
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CN109384807A CN109384807A (zh) | 2019-02-26 |
CN109384807B true CN109384807B (zh) | 2021-08-03 |
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CN201710685373.0A Active CN109384807B (zh) | 2017-08-11 | 2017-08-11 | 一种安塞曲匹中间体的制备方法 |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2468735A1 (en) * | 2010-12-23 | 2012-06-27 | LEK Pharmaceuticals d.d. | Synthesis of intermediates for preparing anacetrapib and derivates thereof |
CN102516237A (zh) * | 2011-12-05 | 2012-06-27 | 成都苑东药业有限公司 | 一种恶唑烷酮类化合物 |
CN103384663A (zh) * | 2010-12-23 | 2013-11-06 | 力奇制药公司 | 用于制备安塞曲匹及其衍生物的中间体的合成 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2681628C (en) * | 2007-03-16 | 2016-10-18 | Concert Pharmaceuticals, Inc. | Inhibitors of cholesterol ester transfer protein |
US9145348B2 (en) * | 2011-10-31 | 2015-09-29 | Merck Sharpe & Dohme Corp. | Process for synthesizing a CETP inhibitor |
-
2017
- 2017-08-11 CN CN201710685373.0A patent/CN109384807B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2468735A1 (en) * | 2010-12-23 | 2012-06-27 | LEK Pharmaceuticals d.d. | Synthesis of intermediates for preparing anacetrapib and derivates thereof |
CN103384663A (zh) * | 2010-12-23 | 2013-11-06 | 力奇制药公司 | 用于制备安塞曲匹及其衍生物的中间体的合成 |
CN102516237A (zh) * | 2011-12-05 | 2012-06-27 | 成都苑东药业有限公司 | 一种恶唑烷酮类化合物 |
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CN109384807A (zh) | 2019-02-26 |
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TR01 | Transfer of patent right |
Effective date of registration: 20221128 Address after: 276006 No. 209 Hongqi Road, Shandong, Linyi Patentee after: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Address before: 276005 No. 209 Hongqi Road, Shandong, Linyi Patentee before: LUNAN PHARMACEUTICAL Group Corp. |
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PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of the intermediate of ansetrapine Effective date of registration: 20230117 Granted publication date: 20210803 Pledgee: Industrial and Commercial Bank of China Limited Linyi Shizhong Sub-branch Pledgor: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980031096 |