CN105153110B - A kind of synthetic method of Atorvastatin calcium chiral intermediate - Google Patents
A kind of synthetic method of Atorvastatin calcium chiral intermediate Download PDFInfo
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- CN105153110B CN105153110B CN201510610677.1A CN201510610677A CN105153110B CN 105153110 B CN105153110 B CN 105153110B CN 201510610677 A CN201510610677 A CN 201510610677A CN 105153110 B CN105153110 B CN 105153110B
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- 229960001770 atorvastatin calcium Drugs 0.000 title claims abstract description 24
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 26
- 230000008569 process Effects 0.000 claims abstract description 22
- XKTBBRQXDGKAFW-UHFFFAOYSA-N [Ti].C(C)(C)[O] Chemical compound [Ti].C(C)(C)[O] XKTBBRQXDGKAFW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 95
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- POPHTDTULFTTAM-UHFFFAOYSA-N C(C)(=O)OC(C)(C)C.C(C)(=O)Br Chemical compound C(C)(=O)OC(C)(C)C.C(C)(=O)Br POPHTDTULFTTAM-UHFFFAOYSA-N 0.000 claims description 16
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 230000003197 catalytic effect Effects 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- 239000012074 organic phase Substances 0.000 claims description 13
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 239000011701 zinc Substances 0.000 claims description 11
- 229910052725 zinc Inorganic materials 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- STNJBCKSHOAVAJ-UHFFFAOYSA-N alpha-methyl acrolein Natural products CC(=C)C=O STNJBCKSHOAVAJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 229920002554 vinyl polymer Polymers 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- IOUBNVNWTGKNFM-ZJLYAJKPSA-N C(C=C)(=O)OC(C)(C)C.[N+](=O)([O-])C=C[C@H](C[C@@H](CC)O)O Chemical class C(C=C)(=O)OC(C)(C)C.[N+](=O)([O-])C=C[C@H](C[C@@H](CC)O)O IOUBNVNWTGKNFM-ZJLYAJKPSA-N 0.000 claims description 7
- 229960000583 acetic acid Drugs 0.000 claims description 7
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 6
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- AGUFCHSITKSBOO-UHFFFAOYSA-N 1,1-dimethoxy-3-nitropropan-2-ol Chemical class COC(OC)C(O)C[N+]([O-])=O AGUFCHSITKSBOO-UHFFFAOYSA-N 0.000 claims description 5
- MMEZVPZJQWHNLI-OGFXRTJISA-N C(C=C)(=O)OC(C)(C)C.[N+](=O)([O-])C=C[C@H](CC(CC)=O)O Chemical class C(C=C)(=O)OC(C)(C)C.[N+](=O)([O-])C=C[C@H](CC(CC)=O)O MMEZVPZJQWHNLI-OGFXRTJISA-N 0.000 claims description 5
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 150000002240 furans Chemical class 0.000 claims description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 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 5
- 238000010792 warming Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- -1 suction filtration Substances 0.000 claims description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 2
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 239000005046 Chlorosilane Substances 0.000 claims 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 238000007259 addition reaction Methods 0.000 claims 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 230000007935 neutral effect Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 abstract description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract description 2
- 231100000004 severe toxicity Toxicity 0.000 abstract description 2
- 230000002255 enzymatic effect Effects 0.000 description 6
- 108700016241 Deoxyribose-phosphate aldolases Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000030794 deoxyribose-phosphate aldolase Human genes 0.000 description 5
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000006911 enzymatic reaction Methods 0.000 description 4
- 239000005515 coenzyme Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- XUKUURHRXDUEBC-SVBPBHIXSA-N (3s,5s)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid 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-SVBPBHIXSA-N 0.000 description 2
- 102000007698 Alcohol dehydrogenase Human genes 0.000 description 2
- 108010021809 Alcohol dehydrogenase Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- XJLXINKUBYWONI-NNYOXOHSSA-O NADP(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-O 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- AWLSKYBHCRQPIZ-PHDIDXHHSA-N (3R,5S)-3,5-dihydroxy-7-nitrohept-6-enoic acid Chemical compound [N+](=O)([O-])C=C[C@H](C[C@H](CC(=O)O)O)O AWLSKYBHCRQPIZ-PHDIDXHHSA-N 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 102000003677 Aldehyde-Lyases Human genes 0.000 description 1
- 108090000072 Aldehyde-Lyases Proteins 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 208000002991 Ring chromosome 4 syndrome Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium(II) oxide Chemical compound [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a kind of synthetic method of Atorvastatin calcium chiral intermediate, belong to the synthesis technical field of medicine intermediate.Technical scheme main points are：
Description
Technical field
The invention belongs to the synthesis technical field of medicine intermediate, and in particular to a kind of Atorvastatin calcium chiral intermediate
Synthetic method.
Background technology
Atorvastatin calcium is the potent lipid-lowering medicine that Pfizer Inc. (Pfizer) released in 1997.Atorvastatin
Calcium can be the medicine for reducing T-CHOL and triglycerides simultaneously, category 3- hydroxy-3-methyl-glutaryls-coacetylase (HMG-
CoA) reductase inhibitor.Controlled while increasing suitable for T-CHOL and triglyceride Two indices due to Atorvastatin calcium
Treat, American heart association, palsy association exist within 2008《The secondary prevention guide of Ischemic Stroke and transient ischemic attack》
In emphasize using statins Intensive Lipid-lowing and keypoint recommendation Atorvastatin calcium, this just more established its be big kind and
The big medicine status of market cycle long.Atorvastatin calcium occupies global well selling medicine since two thousand two, always
(blockbuster) umber one position.13,000,000,000 dollars of Atorvastatin calcium global marketing volume in 2014, is the undisputed whole world
Big kind medicine.
2- ((4R, 6R) -6- (2- aminoethyls) -2,2- dimethyl -1,3- dioxane -4- bases) tert-butyl acetate is synthesis
The crucial chiral intermediate of Atorvastatin calcium.Inflammable and explosive butyl is used in the chemical synthesising technology of the current intermediate
Lithium reagent, reaction condition is more harsh, especially to use the potassium cyanide of severe toxicity, and periodic acid used is expensive in addition, from
Industrialization angle says that working condition is harsh, high cost；Said from environmental, it is seriously polluted, therefore by original technique by the kind
Do has great difficulty greatly, seriously hinders the industrialization process of the product.
Chiral intermediate living things catalysis synthetic technology aspect, biological enzyme selectivity is strong, and products obtained therefrom ee values are high, are better than
Chemical method chiral resolution, the chiral intermediate of the ee values high obtained by biological enzyme reduces the difficulty of removal chiral impurity,
And biological enzyme substantially reduces the synthesis technique of product, it is to avoid dangerous or high toxic material and expensive compounds
Use, make operation more terse, cost is substantially reduced, pollutant emission is less, more meets the requirement of Green Chemistry.Current atropic
Cutting down statin calcium key chiral intermediate living things catalysis synthetic method has two kinds, and one kind is to rely on alcohol dehydrogenase using Bacillus acidi lactici (height)
NADP (H)-dependent alcohol dehydrogenase (LBADH) enzymatic, another applies 2- deoxidation-D- cores
Sugar -5- phosphate aldolases are catalyzed deoxyribose phosphate aldolase (DERA).The external existing text of LBADH enzymatics
Report is offered, but coenzyme (NADP+) is needed with LBADH enzymatics, technical program is complicated, and coenzyme is domestic without production, import
It is expensive, it is relatively costly, so this enzymatic is only applicable to laboratory level research, it is impossible to further industrialized production.Closely
In the past few years, reported on a small quantity with DERA enzymatics, compared to LBADH enzymes, the DERA enzymatics efficiency and yield are high, and need not
Coenzyme.But the DERA enzymes of current document report are main to be extracted from wild mushroom, and extraction procedure is complicated, and yield is relatively low, and enzyme is not
It is easy to maintain, easily inactivate, it is difficult to adapt to industrialized production.
The content of the invention
Present invention solves the technical problem that there is provided that a kind of raw material is cheap and easy to get, route is simple to operate, it is reproducible and
The synthetic method of yield Atorvastatin calcium chiral intermediate higher.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of Atorvastatin calcium chiral intermediate
Synthetic method, it is characterised in that concretely comprise the following steps：
A, 1,1,4,4- tetramethoxy -2- butylene prepared by furans and bromine in methyl alcohol；
B, 1,1,4,4- tetramethoxy -2- butylene generate 1,1- dimethoxy acetaldehyde in methyl sulfide through ozone oxidation；
To there is addition in C, 1,1- dimethoxy acetaldehyde anti-under the catalytic action of catalyst anhydrous alumina with nitromethane
1,1- dimethoxy -2- hydroxyl -3- nitropropanes should be generated；
D, 1,1- dimethoxy -2- hydroxyl -3- nitropropanes are under the catalytic action of acetic anhydride and pyridine mixed catalyst
Dehydration obtains 1,1- dimethoxy -3- nitro -2- propylene；
E, with glacial acetic acid as solvent, catalytic action of 1, the 1- dimethoxy -3- nitro -2- propylene in catalyst polyphosphoric acids
Lower hydrolysis obtains 3- nitro -2- methacrylaldehyde；
The catalysis of F, acetyl bromide tert-butyl acetate and zinc powder in glycol dibromide and trim,ethylchlorosilane mixed catalyst
The lower generation acetyl bromide tert-butyl acetate organic zinc reagent of effect；
G, 3- nitro -2- methacrylaldehyde and acetyl bromide tert-butyl acetate organic zinc reagent are in tetra isopropyl oxygen titanium and S- dinaphthols
(5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene tert-butyl acrylates are obtained under the catalytic action of mixed catalyst；
The catalytic action of H, (5S) -7- nitros -5- hydroxyls -3- oxos -6- heptene tert-butyl acrylate in catalyst sodium borohydride
It is lower to obtain (3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene tert-butyl acrylates through carbonyl reduction；
I, (3R, 5S) -7- nitros -3,5- dihydroxy -6- heptene tert-butyl acrylate are made in the catalysis of catalyst p-methyl benzenesulfonic acid
2- ((4R, 6S) -6- (2- nitre vinyl) -2,2- dimethyl -1,3- dioxane -4- bases) acetic acid is obtained with lower reaction with acetone
The tert-butyl ester；
J, 2- ((4R, 6S) -6- (2- nitre vinyl) -2,2- dimethyl -1,3- dioxane -4- bases) tert-butyl acetate exists
Under the catalytic action of palladium-carbon catalyst 2- ((4R, 6R) -6- (2- aminoethyls) -2,2- two are obtained through double bond addition and nitro reduction
Own ring -4- the bases of methyl-1,3-dioxy) tert-butyl acetate.
Further limit, the detailed process of step A is：Furans and methyl alcohol are added in reaction vessel, under nitrogen protection
In -50 DEG C of dropping liquid bromine reactions, reaction is warmed to room temperature after terminating, and the pH that reaction solution is adjusted with saturated sodium bicarbonate solution is 7-8,
Steam methyl alcohol, then steam ethyl acetate after being extracted with ethyl acetate and obtain 1, Isosorbide-5-Nitrae, 4- tetramethoxy -2- butylene.
Further limit, the detailed process of step B is：1,1,4,4- tetramethoxy -2- butylene is added in reaction vessel
And methyl sulfide, under nitrogen protection in -10 DEG C of injection of ozone, controlling reaction temperature is constant, and reaction is warmed to room temperature after terminating, and steams
1,1- dimethoxy acetaldehyde is obtained after solvent.
Further limit, the detailed process of step C is：By 1,1- dimethoxys acetaldehyde, nitromethane in reaction vessel
It is added in DMF with catalyst anhydrous alumina, 130 DEG C of reactions is heated under nitrogen protection, reaction is down to room temperature after terminating,
Saturated nacl aqueous solution is added, then is extracted with dichloromethane, 1,1- dimethoxy -2- hydroxyl -3- nitros are obtained after solvent is evaporated off
Propane.
Further limit, the detailed process of step D is：In 0-5 DEG C by 1,1- dimethoxy -2- hydroxyls in reaction vessel
The dichloromethane solution of base -3- nitropropanes is instilled in the dichloromethane solution of the mixed catalyst containing acetic anhydride and pyridine,
Drip after reaction is stirred at room temperature, reaction obtains 1,1- dimethoxy -3- nitre after terminating through washing, extracting, being evaporated off organic phase
Base -2- propylene.
Further limit, the detailed process of step E is：By 1,1- dimethoxy -3- nitro -2- propylene in reaction vessel
It is placed in solvent glacial acetic acid with catalyst polyphosphoric acids, room temperature reaction, reaction is obtained after terminating through washing, extracting, being evaporated off solvent
3- nitro -2- methacrylaldehyde.
Further limit, the detailed process of step F is：Zinc powder is added in THF solution in reaction vessel, in nitrogen
Protection is lower to add 1,2- Bromofumes and trim,ethylchlorosilane, is added dropwise at room temperature molten dissolved with the THF of acetyl bromide tert-butyl acetate
Liquid, is warming up to 50 DEG C of reaction 10h after dripping, reaction terminates rear filtering reacting liquid, THF is evaporated off and obtains acetyl bromide tert-butyl acetate
Organic zinc reagent.
Further limit, the detailed process of step G is：By 3- nitro -2- methacrylaldehyde and four isopropyls in bottle container is reacted
Base oxygen titanium (Ti (O-i-Pr)4) and S- dinaphthols (S- (-) BINOL) mixed catalyst be added in THF solution, nitrogen protection
Under in -78 DEG C of THF solutions being added dropwise dissolved with acetyl bromide tert-butyl acetate organic zinc reagent, drip rear keeping temperature and continue to stir
Reaction, reaction terminates that rear filtering reacting liquid is scrubbed, extract, solvent is evaporated off obtains (5S) -7- nitro -5- hydroxyl -3- oxos -6-
Heptene tert-butyl acrylate.
Further limit, the detailed process of step H is：In reaction vessel by (5S) -7- nitro -5- hydroxyl -3- oxos -
6- heptene tert-butyl acrylate and sodium borohydride are added in THF solution, room temperature reaction, and reaction is first adjusted after terminating with watery hydrochloric acid reacts
Liquid pH is neutrality, then is extracted with ethyl acetate reaction solution, separates organic phase, after being washed with saturated nacl aqueous solution, acetic acid is evaporated off
Ethyl ester obtains (3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene tert-butyl acrylates.
Further limit, the detailed process of step I is：In reaction vessel by (3R, 5S) -7- nitro -3,5- dihydroxy -
6- heptene tert-butyl acrylate is added in the mixed solution of absolute ethyl alcohol and acetone, adds catalyst p-methyl benzenesulfonic acid, is heated to 55-
60 DEG C of insulation reactions, reaction is cooled down after terminating and separates out white solid, and suction filtration, filter cake absolute ethanol washing obtains 2- after drying
((4R, 6S) -6- (2- nitre vinyl) -2,2- dimethyl -1,3- dioxane -4- bases) tert-butyl acetate.
Further limit, the detailed process of step J is：By 2- ((4R, 6S) -6- (2- nitre vinyl) -2,2- dimethyl -
1,3- dioxane -4- bases) tert-butyl acetate and palladium-carbon catalyst be added in autoclave, using methyl alcohol as solvent, is passed through hydrogen
Gas, controls the pressure in autoclave for 0.3MPa, and after reaction terminates, suction filtration reaction solution is evaporated off solvent and obtains target product 2-
((4R, 6R) -6- (2- aminoethyls) -2,2- dimethyl -1,3- dioxane -4- bases) tert-butyl acetate.
Synthetic route in the synthetic method of Atorvastatin calcium chiral intermediate of the present invention is：
Process route of the invention not only avoid danger, the play such as butyl lithium, potassium cyanide and periodic acid in chemical synthesis
The use of malicious, expensive medicine, and because the use of tetra isopropyl oxygen titanium and S- dinaphthol mixing chiral catalysts makes product
The ee of product is worth to effectively improve, and the synthetic method raw material is cheap and easy to get, and route is simple to operate, and reproducible and yield is very
Height, is adapted to industrialized production.
Specific embodiment
The above of the invention is described in further details by the following examples, but this should not be interpreted as this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
In reaction bulbs of the 2000mL with mechanical agitation and thermometer, furans 50g (0.735mol) and methyl alcohol are added
1000mL, is placed under the conditions of -50 DEG C, displaces nitrogen protection after air, bromine 240g (1.5mol) is slowly added dropwise, after dripping
Reaction 3h, is warming up to 0 DEG C and continues to react 2h, and reaction is warmed to room temperature after terminating, and adjusts anti-with 1000mL saturated sodium bicarbonate solutions
The pH of liquid is answered for 7-8, decompression steams remaining methyl alcohol, then with ethyl acetate 1000mL extractive reactions liquid three times, merge organic phase again
Washed with saturated nacl aqueous solution, separate organic phase, compound 1, Isosorbide-5-Nitrae, 4- tetramethoxy -2- fourths are obtained after steaming ethyl acetate
Alkene 75g.
Embodiment 2
Compound 1,1,4,4- tetramethoxy -2- fourths are added in reaction bulbs of the 1000mL with mechanical agitation and thermometer
Alkene 70g and methyl sulfide 500mL, is placed under the conditions of -10 DEG C, nitrogen is passed through after the displacement hollow gas of bottle outlet, to closed reaction system
In be slowly injected into ozone 30g, controlling reaction temperature maintains -10 DEG C, and raw material reaction completely, is warmed to room temperature after reaction 10h, steams
Compound 1,1- dimethoxy acetaldehyde 32g is obtained after solvent.
Embodiment 3
In reaction bulbs of the 1000mL with mechanical agitation and thermometer, by 1,1- dimethoxy acetaldehyde 30g (0.3mol),
Nitromethane 19g (0.3mol) and anhydrous alumina 3g (0.03mol) is added in DMF 500mL, nitrogen protection, is heated to 130
DEG C, after reaction terminates, room temperature is down to, suction filtration reaction solution adds the saturated nacl aqueous solution of 500mL after concentrating filter liquor, then uses
600mL dichloromethane extractive reactions liquid twice, merges organic phase, and 1,1- dimethoxy -2- hydroxyl -3- nitre is obtained after solvent is evaporated off
Base propane 43g.
Embodiment 4
In reaction bulbs of the 500mL with mechanical agitation and thermometer, under the conditions of 0-5 DEG C, will be dissolved with 1,1- dimethoxies
The dichloromethane solution 200mL of base -2- hydroxyls -3- nitropropanes 30g (0.18mol) is slowly dropped into dissolved with acetic anhydride 38g
In the dichloromethane solution 200mL of (0.36mol) and pyridine 57g (0.72mol), after 4h is stirred at room temperature, ice is added in reactant
Water, stirring, then be extracted twice with chloroform, merge organic phase, neutrality is washed till with saturated sodium bicarbonate solution, organic phase is separated, then
Be washed once with saturated nacl aqueous solution, dried with anhydrous magnesium sulfate, filtered, remove under reduced pressure solvent obtain 1,1- dimethoxys-
3- nitro -2- propylene 31g.
Embodiment 5
In 500mL reaction bulbs, 1,1- dimethoxy -3- nitros -2- propylene 30g and polyphosphoric acids 3g are added to ice second
In sour 200mL, 8h is stirred at room temperature, reaction terminates to add frozen water 100mL in backward reaction solution, polyphosphoric acids is all decomposed,
Then extracted three times with dichloromethane 300mL, anhydrous sodium sulfate drying is used after merging organic phase, filtering is obtained after solvent is evaporated off
3- nitro -2- methacrylaldehyde 17g.
Embodiment 6
In reaction bulbs of the 500mL with thermometer and stirring, zinc powder 7.8g (0.12mol) is added through water removal
In THF50mL, nitrogen protection reaction system is adding 1,2- Bromofumes 0.925g (0.005mol), is warming up to 65 DEG C of stirrings
10min, then room temperature is cooled to, trim,ethylchlorosilane 0.54g (0.005mol) is added, slowly add after 20min is stirred at room temperature
Enter the THF solution 100mL dissolved with acetyl bromide tert-butyl acetate 23.6g (0.1mol), 50 DEG C of reaction 10h be warming up to after dripping,
Reaction terminates rear filtering reacting liquid, and acetyl bromide tert-butyl acetate organic zinc reagent 19g is obtained after THF is evaporated off.
Embodiment 7
In 1000mL reaction bulbs, acetyl bromide tert-butyl acetate organic zinc reagent 20g (0.2mol), chiral catalyst four
Isopropyl oxygen titanium (Ti (O-i-Pr)4) 4g and S- dinaphthols (S- (-) BINOL) 4g is added in THF 200mL, be subsequently placed in-
Under the conditions of 78 DEG C, nitrogen protection is slowly added to molten dissolved with the THF of acetyl bromide tert-butyl acetate organic zinc reagent 40g (0.2mol)
Liquid 200mL, drips rear keeping temperature and continues stirring reaction 5h, and reaction is slowly increased to room temperature, filtering reacting liquid, filtrate after terminating
Washed with saturated nacl aqueous solution 300mL again, separate organic phase, water is mutually extracted three times through dichloromethane 200mL, merged organic again
Phase, is spin-dried for organic phase and obtains (5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene tert-butyl acrylate 29g, and its optical purity is after testing
Reach 98%ee.
Embodiment 8
In reaction bulbs of the 500mL with thermometer, (5S) -7- nitro -5- hydroxyl -3- oxo tertiary fourths of -6- heptenoic acids
Ester 30g (0.11mol) is added in tetrahydrofuran 300mL, and reaction temperature is set to 10 DEG C, is slowly added to dissolved with NaBH4 9g
The tetrahydrofuran solution 50mL of (0.23mol), keeping temperature stirring reaction 4h, stirring is stopped when TLC detection raw materials disappear, and is steamed
Except solvents tetrahydrofurane, saturated nacl aqueous solution 100mL is added, then extracted three times with dichloromethane 100mL, merged organic
Phase, is dried with anhydrous slufuric acid ammonium, and (3R, 5S) -7- nitro -3,5- dihydroxy -6- heptenoic acid uncles are obtained after solvent is steamed after filtering
Butyl ester 24g.
Embodiment 9
(3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene tert-butyl acrylates 26g is sequentially added in 500mL there-necked flasks
(0.1mol), absolute ethyl alcohol 300mL and acetone 35g (0.5mol), stir to complete molten rear addition catalyst p-methyl benzenesulfonic acid 5g, plus
In 55-60 DEG C of insulation reaction 4h, reaction is cooled down and separates out white solid heat after terminating, and suction filtration, filter cake ice absolute ethyl alcohol 20mL is washed
Wash, 2- ((4R, 6S) -6- (2- nitre vinyl) -2,2- dimethyl -1,3- dioxane -4- bases) acetic acid is obtained after filter cake drying
Tert-butyl ester 23g.
Embodiment 10
In 500mL autoclaves, by 2- ((4R, 6S) -6- (2- nitre vinyl) -2,2- dimethyl -1,3- dioxanes -
4- yls) tert-butyl acetate 30g (0.1mol) and palladium-carbon catalyst (content of palladium is 10%) 3g is added in methyl alcohol 200mL, uses
Nitrogen displacement gas reactor 3 times, then replaces gas reactor 3 times with hydrogen again, leads to hydrogen, controls the pressure in autoclave to be
0.3MPa, is progressively warmed up to 60 DEG C, Hydrogen Vapor Pressure is reacted to this understanding and is no longer declined, and continues to keep reaction 2h, after testing
The temperature of material in kettle completely, is then cooled to room temperature by raw material reaction, releases pressure in kettle, opens autoclave, and product is fallen
To enter filtered in funnel, kettle is washed 2 times with methyl alcohol 10mL, filtrate and washing lotion are poured into there-necked flask in the lump, then depressurized
Distillation, when part methyl alcohol is distilled out, cools down material, and product is separated out in there-necked flask, leaches product, is washed with a small amount, will be wet
Filter cake is put on surface plate, and 2- ((4R, 6R) -6- (2- aminoethyls) -2,2- dimethyl -1,3- dioxanes -4- are obtained after drying
Base) tert-butyl acetate 25g.
Embodiment above describes general principle of the invention, principal character and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, simply original of the invention is illustrated described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements each fall within
In the scope of protection of the invention.
Claims (10)
1. a kind of synthetic method of Atorvastatin calcium chiral intermediate, it is characterised in that concretely comprise the following steps：
A, 1,1,4,4- tetramethoxy -2- butylene prepared by furans and bromine in methyl alcohol；
B, 1,1,4,4- tetramethoxy -2- butylene generate 1,1- dimethoxy acetaldehyde in methyl sulfide through ozone oxidation；
There is addition reaction with nitromethane under the catalytic action of catalyst anhydrous alumina and give birth in C, 1,1- dimethoxy acetaldehyde
Into 1,1- dimethoxy -2- hydroxyl -3- nitropropanes；
D, 1,1- dimethoxy -2- hydroxyl -3- nitropropanes are dehydrated under the catalytic action of acetic anhydride and pyridine mixed catalyst
Obtain 1,1- dimethoxy -3- nitro -2- propylene；
E, with glacial acetic acid as solvent, 1,1- dimethoxy -3- nitro -2- propylene water under the catalytic action of catalyst polyphosphoric acids
Solution obtains 3- nitro -2- methacrylaldehyde；
The catalytic action of F, acetyl bromide tert-butyl acetate and zinc powder in glycol dibromide and trim,ethylchlorosilane mixed catalyst
Lower generation acetyl bromide tert-butyl acetate organic zinc reagent；
G, 3- nitro -2- methacrylaldehyde and acetyl bromide tert-butyl acetate organic zinc reagent mix in tetra isopropyl oxygen titanium and S- dinaphthols
(5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene tert-butyl acrylates are obtained under the catalytic action of catalyst；
H, (5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene tert-butyl acrylates are passed through under the catalytic action of catalyst sodium borohydride
Carbonyl reduction obtains (3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene tert-butyl acrylates；
I, (3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene tert-butyl acrylates are under the catalytic action of catalyst p-methyl benzenesulfonic acid
2- ((4R, 6S) -6- (2- nitre vinyl) -2,2- dimethyl -1,3- dioxane -4- bases) tertiary fourth of acetic acid is obtained with acetone reaction
Ester；
J, 2- ((4R, 6S) -6- (2- nitre vinyl) -2,2- dimethyl -1,3- dioxane -4- bases) tert-butyl acetate is in palladium carbon
Under the catalytic action of catalyst through double bond addition and nitro reduction obtain 2- ((4R, 6R) -6- (2- aminoethyls) -2,2- dimethyl -
1,3- dioxane -4- bases) tert-butyl acetate.
2. the synthetic method of Atorvastatin calcium chiral intermediate according to claim 1, it is characterised in that the tool of step A
Body process is：Furans and methyl alcohol are added in reaction vessel, under nitrogen protection in -50 DEG C of dropping liquid bromine reactions, reaction terminates
After be warmed to room temperature, the pH that reaction solution is adjusted with saturated sodium bicarbonate solution is 7-8, steams methyl alcohol, then after being extracted with ethyl acetate
Steam ethyl acetate and obtain 1,1,4,4- tetramethoxy -2- butylene.
3. the synthetic method of Atorvastatin calcium chiral intermediate according to claim 1, it is characterised in that the tool of step B
Body process is：Add 1 in reaction vessel, Isosorbide-5-Nitrae, 4- tetramethoxy -2- butylene and methyl sulfide, under nitrogen protection in -10 DEG C
Injection of ozone, controlling reaction temperature is constant, and reaction is warmed to room temperature after terminating, and 1,1- dimethoxy acetaldehyde is obtained after steaming solvent.
4. the synthetic method of Atorvastatin calcium chiral intermediate according to claim 1, it is characterised in that the tool of step C
Body process is：1,1- dimethoxys acetaldehyde, nitromethane and catalyst anhydrous alumina are added to DMF in reaction vessel
In, 130 DEG C of reactions are heated under nitrogen protection, room temperature is down in reaction after terminating, add saturated nacl aqueous solution, then use dichloro
Methane is extracted, and 1,1- dimethoxy -2- hydroxyl -3- nitropropanes are obtained after solvent is evaporated off.
5. the synthetic method of Atorvastatin calcium chiral intermediate according to claim 1, it is characterised in that the tool of step D
Body process is：Dripped in the 0-5 DEG C of dichloromethane solution by 1,1- dimethoxy -2- hydroxyl -3- nitropropanes in reaction vessel
Enter in the dichloromethane solution of the mixed catalyst containing acetic anhydride and pyridine, drip after reaction is stirred at room temperature, reaction is tied
Shu Houjing washes, extracts, organic phase is evaporated off obtains 1,1- dimethoxy -3- nitro -2- propylene.
6. the synthetic method of Atorvastatin calcium chiral intermediate according to claim 1, it is characterised in that the tool of step E
Body process is：1,1- dimethoxy -3- nitro -2- propylene and catalyst polyphosphoric acids are placed in solvent ice second in reaction vessel
In acid, room temperature reaction, reaction obtains 3- nitro -2- methacrylaldehyde after terminating through washing, extracting, being evaporated off solvent.
7. the synthetic method of Atorvastatin calcium chiral intermediate according to claim 1, it is characterised in that the tool of step F
Body process is：Zinc powder is added in THF solution in reaction vessel, 1,2- Bromofumes and front three are added under nitrogen protection
Base chlorosilane, is added dropwise the THF solution dissolved with acetyl bromide tert-butyl acetate at room temperature, and 50 DEG C of reaction 10h are warming up to after dripping,
Reaction terminates rear filtering reacting liquid, THF is evaporated off and obtains acetyl bromide tert-butyl acetate organic zinc reagent.
8. the synthetic method of Atorvastatin calcium chiral intermediate according to claim 1, it is characterised in that the tool of step G
Body process is：3- nitro -2- methacrylaldehyde is added with tetra isopropyl oxygen titanium and S- dinaphthol mixed catalysts in bottle container is reacted
Enter in THF solution, under nitrogen protection in -78 DEG C of THF solutions being added dropwise dissolved with acetyl bromide tert-butyl acetate organic zinc reagent,
Drip rear keeping temperature and continue stirring reaction, reaction terminates that rear filtering reacting liquid is scrubbed, extract, solvent is evaporated off obtains
(5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene tert-butyl acrylates.
9. the synthetic method of Atorvastatin calcium chiral intermediate according to claim 1, it is characterised in that the tool of step H
Body process is：(5S) -7- nitros -5- hydroxyls -3- oxos -6- heptene tert-butyl acrylate and sodium borohydride are added in reaction vessel
To in THF solution, room temperature reaction, it is neutral that reaction first adjusts reaction solution pH after terminating with watery hydrochloric acid, then is extracted with ethyl acetate
Reaction solution, separates organic phase, after being washed with saturated nacl aqueous solution, ethyl acetate is evaporated off and obtains (3R, 5S) -7- nitro -3,5-
Dihydroxy -6- heptene tert-butyl acrylates.
10. the synthetic method of Atorvastatin calcium chiral intermediate according to claim 1, it is characterised in that step I and J
Detailed process be respectively：(3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene tert-butyl acrylate is added into nothing in reaction vessel
In the mixed solution of water-ethanol and acetone, catalyst p-methyl benzenesulfonic acid is added, be heated to 55-60 DEG C of insulation reaction, reaction knot
Cooled down after beam and separate out white solid, suction filtration, filter cake absolute ethanol washing obtains 2- ((4R, 6S) -6- (2- nitre ethene after drying
Base) -2,2- dimethyl -1,3- dioxane -4- bases) tert-butyl acetate；By 2- ((4R, 6S) -6- (2- nitre vinyl) -2,2-
Dimethyl -1,3- dioxane -4- bases) tert-butyl acetate and palladium-carbon catalyst be added in autoclave, using methyl alcohol as solvent,
Hydrogen is passed through, the pressure in autoclave is controlled for 0.3MPa, after reaction terminates, suction filtration reaction solution is evaporated off solvent and obtains target product
Thing 2- ((4R, 6R) -6- (2- aminoethyls) -2,2- dimethyl -1,3- dioxane -4- bases) tert-butyl acetate.
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| CN106370740A (en) * | 2016-08-23 | 2017-02-01 | 翟梦洋 | Method for analyzing residual quantity of residual solvents in atorvastatin calcium intermediate |
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