WO2011141934A1 - An improved process for the preparation of an intermediate of hmg-coa reductase inhibitors - Google Patents
An improved process for the preparation of an intermediate of hmg-coa reductase inhibitors Download PDFInfo
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- WO2011141934A1 WO2011141934A1 PCT/IN2011/000330 IN2011000330W WO2011141934A1 WO 2011141934 A1 WO2011141934 A1 WO 2011141934A1 IN 2011000330 W IN2011000330 W IN 2011000330W WO 2011141934 A1 WO2011141934 A1 WO 2011141934A1
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- Prior art keywords
- formula
- compound
- alkyl
- process according
- viii
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 title claims abstract description 24
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 title claims abstract description 24
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 101
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- -1 Alkalimetal alkoxide Chemical class 0.000 claims description 20
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical group NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 238000007142 ring opening reaction Methods 0.000 claims description 10
- 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 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 9
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229960000672 rosuvastatin Drugs 0.000 claims description 8
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 8
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims description 6
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 6
- 229960000395 phenylpropanolamine Drugs 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- JFKWZVQEMSKSBU-CQSZACIVSA-N benzyl (2r)-2-hydroxy-2-phenylacetate Chemical compound O=C([C@H](O)C=1C=CC=CC=1)OCC1=CC=CC=C1 JFKWZVQEMSKSBU-CQSZACIVSA-N 0.000 claims description 5
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 claims description 5
- 229960002797 pitavastatin Drugs 0.000 claims description 5
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 claims description 5
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 claims description 5
- 229960004796 rosuvastatin calcium Drugs 0.000 claims description 5
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 4
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 claims description 4
- 229960003296 pitavastatin calcium Drugs 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- LTHNHFOGQMKPOV-UHFFFAOYSA-N 2-ethylhexan-1-amine Chemical compound CCCCC(CC)CN LTHNHFOGQMKPOV-UHFFFAOYSA-N 0.000 claims description 3
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 3
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 150000001350 alkyl halides Chemical class 0.000 claims description 3
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 claims description 3
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical compound NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 claims description 3
- SAXHIDRUJXPDOD-SECBINFHSA-N ethyl (2R)-hydroxy(phenyl)acetate Chemical compound CCOC(=O)[C@H](O)C1=CC=CC=C1 SAXHIDRUJXPDOD-SECBINFHSA-N 0.000 claims description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 2
- FMCGSUUBYTWNDP-ONGXEEELSA-O [(1r,2s)-1-hydroxy-1-phenylpropan-2-yl]-dimethylazanium Chemical compound C[NH+](C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-O 0.000 claims description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 2
- 229960002179 ephedrine Drugs 0.000 claims description 2
- 229960003908 pseudoephedrine Drugs 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- FMCGSUUBYTWNDP-GXSJLCMTSA-N (+)-N-methylpseudoephedrine Chemical compound CN(C)[C@@H](C)[C@@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-GXSJLCMTSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 239000012044 organic layer Substances 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 19
- JFCQEDHGNNZCLN-UHFFFAOYSA-L glutarate(2-) Chemical compound [O-]C(=O)CCCC([O-])=O JFCQEDHGNNZCLN-UHFFFAOYSA-L 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000010410 layer Substances 0.000 description 15
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 11
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 150000002431 hydrogen Chemical class 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000008064 anhydrides Chemical class 0.000 description 8
- 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 8
- 229940093499 ethyl acetate Drugs 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000012267 brine Substances 0.000 description 7
- 150000003946 cyclohexylamines Chemical class 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- RXAJGRHLLRGVSB-UHFFFAOYSA-N 4-[tert-butyl(dimethyl)silyl]oxyoxane-2,6-dione Chemical compound CC(C)(C)[Si](C)(C)OC1CC(=O)OC(=O)C1 RXAJGRHLLRGVSB-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- LKFVHFUPNDPFRV-GFCCVEGCSA-N (3r)-3-[tert-butyl(dimethyl)silyl]oxy-6-dimethoxyphosphoryl-5-oxohexanoic acid Chemical compound COP(=O)(OC)CC(=O)C[C@H](CC(O)=O)O[Si](C)(C)C(C)(C)C LKFVHFUPNDPFRV-GFCCVEGCSA-N 0.000 description 2
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 150000003939 benzylamines Chemical class 0.000 description 2
- 150000001934 cyclohexanes Chemical class 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- 0 CCOC(C1CC(C[C@@](*)CC(O)=O)=O)(C1=O)OC*=N Chemical compound CCOC(C1CC(C[C@@](*)CC(O)=O)=O)(C1=O)OC*=N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- RNVCVTLRINQCPJ-UHFFFAOYSA-N Cc(cccc1)c1N Chemical compound Cc(cccc1)c1N RNVCVTLRINQCPJ-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
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- OUWSNHWQZPEFEX-UHFFFAOYSA-N diethyl glutarate Chemical compound CCOC(=O)CCCC(=O)OCC OUWSNHWQZPEFEX-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- NBDQGOCGYHMDSJ-NRFPMOEYSA-M sodium;(e,3r,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound [Na+].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 NBDQGOCGYHMDSJ-NRFPMOEYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- AAAQKTZKLRYKHR-UHFFFAOYSA-N triphenylmethane Chemical compound C1=CC=CC=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 AAAQKTZKLRYKHR-UHFFFAOYSA-N 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/535—Organo-phosphoranes
- C07F9/5352—Phosphoranes containing the structure P=C-
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Definitions
- the present invention relates to an improved process for the preparation of intermediates of HMG-CoA reductase inhibitors and further conversion to HMG-CoA reductase inhibitors and pharmaceutically acceptable salts thereof.
- the HMG-CoA reductase inhibitors have been used in reducing blood levels of LDL cholesterol. Cholesterol is produced via the mevalonic acid pathway. Reducing the formation of mevalonic acid, a precursor to cholesterol, leads to a corresponding decrease in hepatic cholesterol biosynthesis with a reduction in the cellular pool of cholesterol.
- the HMG-CoA reductase inhibitors represented by the following general Formula-I,
- R is a residue of HMG-CoA reductase inhibitor
- M represents hydrogen or pharmaceutically acceptable salts like sodium, potassium, magnesium and calcium.
- Rosuvastatin and its pharmaceutically acceptable salts were first disclosed in European patent publication EP 0,521 ,471. It also discloses process for the preparation of Rosuvastatin calcium.
- Bis ⁇ (3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fiuorophenyl)-3-quinolyl]-3,5-dihydroxy- 6-heptenoate ⁇ monocalcium of Formula-B (Pitavastatin Calcium) is an HMG-CoA reductase inhibitor, developed by Nissan Chemical Industries for the treatment of hyperlipidemia.
- PCT publication No. WO 03/087112 discloses the synthesis of Rosuvastatin from a different intermediate, (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxo- hexanoate.
- US 5,1 17,039 discloses the process for the preparation of (3R)-3-[(tert- Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester by the ring opening of 3-[(tert-Butyldimethylsilyl)oxy] pentanedioic anhydride using benzyl D- mandelate gives by products.
- US 20090076292 discloses process for the preparation of Rosuvastatin by using the intermediates 3(R)-3(tert-butyldimethylsilyloxy)-5-oxo-6-triphenyl-phosphoranylidene hexanoate and (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxo- hexanoate.
- These intermediates are prepared by a novel intermediate i.e. chiral base salt of hydroxy protected diethyl glutarate.
- US 2005/0070605 Al discloses the enantioselective opening of 3-hydroxy protected glutaric anhydride by phenylethylamine to form an amide bond, and further conversion to obtain the HMG-CoA reductase inhibitor.
- HMG-CoA reductase inhibitors obtained by the above processes are having impurities in the final product.
- the present invention provides process for the preparation of HMG-CoA reductase inhibitors with high yield and purity.
- the principle object of the present invention is to provide an improved process for the preparation of compound of Formulae-IXa and IXb having the following structures
- Formula-IXa Formula-IXb wherein P is hydroxy protecting group;
- R 2 is C[-C 5 alkyl or substituted Ci-C 5 alkyl group;
- R 3 , R4 and R 5; each independently, are selected from C 6 -C 10 aryl group, preferably phenyl group or substituted phenyl groups;
- Alk is alkyl preferably Ci-C 5 alkyl.
- Another object of the present invention is to provide a compound of Formula- VI having the following structure
- the base is a non-chiral base; P is hydroxy protecting group and R 2 is Q-C5 alkyl or substituted Q-Cs alkyl group.
- Another object of the present invention is to provide further conversion of compound of Formulae- IXa or IXb into HMG-CoA reductase inhibitors by the conventional methods.
- One aspect of the present invention provides, process for the preparation of the compound of Formulae-IXa or IXb comprising the steps of:
- Another aspect of the present invention provides, a process for the purification of compound of Formula-V comprising: a) reacting a crude compound of Formula-V having the structure
- One more aspect of the present invention provides further conversion of compound of Formula-V into compound of Formula-I by conventional methods.
- the present invention relates to an improved process for the preparation of compound of Formulae- IXa or IXb, by ring opening of the Hydroxyprotected glutaricanhydride by using chiral auxiliary and conversion to monoester, and purification with non chiral amine base and conversion to mixed anhydride which is further converted to compound of formulae IXa or IXb.
- the present invention further relates to conversion of compound of formulae IXa or IXb to HMG-CoA reductase inhibitors.
- the present invention provides a process for the preparation of compound of Formulae- IXa or IXb through the compound of Formula-II is summarized in scheme-I.
- chiral auxiliary used for the ring opening of the compound of Formula-II is selected from N-pyrrolidinyl norephedrine, (1R, 2S)-N- methylephedrine, ephedrine, ⁇ , ⁇ -dibenzylnorephedrine, (lR,2R)-pseudoephedrine, (l S,2S)-N-methylpseudoephedrine, (1R, 2S)-N-piperidinyl norephedrine, preferably N- pyrrolidinyl norephedrine.
- ring opening of the compound of Formula-II is carried out with compound of Formula-Ill, which is selected from benzyl(R)-mandelate, ethyl (R)-mandelate, Trityl (R)-mandelate, preferably benzyl(R)- mandelate.
- compound of Formula-Ill which is selected from benzyl(R)-mandelate, ethyl (R)-mandelate, Trityl (R)-mandelate, preferably benzyl(R)- mandelate.
- the compound of Formula-IV is reacted with Alkalimetal alkoxide.
- Alkalimetal alkoxide used in this reaction is selected from sodiumalkoxide, potassiumalkoxide, preferably sodium methoxide.
- the compound of Formula-V is purified by using base wherein the base is chiral or non-chiral base.
- the non-chiral base is selected from cyclohexylamine, tert-butylamine, cyclopropylamine, cyclopentylamine, benzyl amine, Dicyclohexyl amine, 2-ethyl hexylamine, ethanolamine, methylamine, ethylene amine, preferably cyclohexylamine, tert-butylamine, benzyl amine.
- the compound of formula-VIII can be prepared by reacting the compound of formula-V with ethylchlorocarbonate or pivaloyl chloride, preferably ethylchlorocarbonate.
- the compound of formula-IXa can be prepared by reacting the compound of formula-VIII with triarylphosphonium alkyl halide like methyltriphenyl phosphonium bromide. Alternatively compound of formula VIII is reacted with dialkylmethylphophonate to get compound of formula-IXb. In one more embodiment of the present invention, the compound of Formulae-IXa or IXb are further converted into HMG CoA reductase inhibitors of Formula-I by conventional methods as disclosed in US RE 37,314 and CN 100506796, the disclosers of which are incorporated by reference in their entirety herein.
- the compound of formula-IXa can be converted into the Rosuvastatin calcium by the way as summarized in the following scheme-II.
- Rosuvastatin Calcium For example the compound of formula-IXa can be converted into the Pitavastatin calcium by the way as summarized in the following scheme-Ill.
- the present invention provides, a compound of Formula- VI having the following structure
- Formula- VI wherein the base is a non-chiral base; and P is hydroxy protecting group and R 2 is C 1 -C5 alkyl or substituted C1-C5 alkyl group.
- the present invention provides, a process for the preparation of compound of Formula- VI comprising: reacting a compound of Formula-V having the structure
- the base is a non-chiral base; and P is hydroxy protecting group and R 2 is Ci-C 5 alkyl or substituted Ci-C 5 alkyl group.
- the base used is non-chiral base selected from cyclohexylamine, tert-butylamine, cyclopropylamine, cyclopentylamine, benzyl amine, Dicyclohexylamine, 2-ethylhexylamine, ethanolamine, methylamine, ethylene amine, preferably cyclohexylamine, tert-butylamine, benzyl amine.
- Another aspect of the present invention provides, a process for the purification of compound of Formula-V comprising: a) reacting crude compound of Formula-V having the structure
- the acid used in the above process is selected from hydrochloric acid, acetic acid, formic acid, preferably hydrochloric acid.
- Another aspect of the present invention provides, a process for preparing a compound of Formula-I comprising the steps of:
- R is a residue of HMG-CoA reductase inhibitor ected from
- the present invention provides one-pot synthesis of compound of Formula-XI starting with the compound of Formula-V without isolating the intermediate compounds of Formulae VI, VIII, IXa and X.
- the organic layer was washed with water and sodium chloride solution. The organic layer was concentrated. The concentrated reaction mass taken into 100 ml methanol and to this 100 ml of DM water was added. To this sodium hydroxide (0.55 g) solution in DM water (50 ml) was added and the reaction mass was stirred at room temperature for 2-3 hrs. The reaction mass was concentrated. To the concentrate a mixture of DM water and dichloromethane was added and acidified with Aq hydrochloric acid solution. The Aq layer was extracted with dichloromethane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated.
- Trityl-(R)-mandelate 25 g
- tetrahydrofuran 375 ml
- a solution of 1.6 M BuLi in hexane 40 ml was added drop wise, and the reaction mixture was stirred for 1 hr.
- a solution of 3-[(tert- butyldimethylsilyl)oxy] pentanedioic anhydride (15.5 g) in THF (125 ml) was added, and the resulting reaction mass was stirred for 2-3 Hrs.
- the reaction mixture was acidified with Aq hydrochloric acid and the product was extracted with ethyl acetate.
- the organic layer was washed with water and sodium chloride solution. The organic layer was concentrated. Concentrated reaction mass taken into 100 ml methanol and to this 100 ml DM water added. To this Aq hydrochloric acid solution (50 ml) was added and the reaction mass was stirred at room temperature for 2-3 hrs. The reaction mass was concentrated. To the concentrate a mixture of DM water and dichloromethane was added, Stirred and separated the layers. The Aq layer was extracted with dichloromethane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated.
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Abstract
The present invention relates to an improved process for the preparation of intermediates of HMG-CoA reductase inhibitors of Formulae-IXa or IXb and further conversion to HMG-CoA reductase inhibitors and pharmaceutically acceptable salts thereof.
Description
"An improved process for the preparation of an intermediate of HMG-CoA reductase inhibitors" This application claims priority to Indian patent application 1351 /CHE/2010 filed on May 13, 2010 the contents of which are incorporated by reference in their entity.
FIELD OF THE INVENTION: The present invention relates to an improved process for the preparation of intermediates of HMG-CoA reductase inhibitors and further conversion to HMG-CoA reductase inhibitors and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION:
The HMG-CoA reductase inhibitors (Statins) have been used in reducing blood levels of LDL cholesterol. Cholesterol is produced via the mevalonic acid pathway. Reducing the formation of mevalonic acid, a precursor to cholesterol, leads to a corresponding decrease in hepatic cholesterol biosynthesis with a reduction in the cellular pool of cholesterol. The HMG-CoA reductase inhibitors (Statins) represented by the following general Formula-I,
Formula-I
wherein R is a residue of HMG-CoA reductase inhibitor; M represents hydrogen or pharmaceutically acceptable salts like sodium, potassium, magnesium and calcium..
Bis[(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin- 5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]Calcium Salt of Formula-A (Rosuvastatin Calcium) is an HMG-CoA reductase inhibitor, developed by shionogi for the treatment of hyperlipidemia
Formula-A
Rosuvastatin and its pharmaceutically acceptable salts were first disclosed in European patent publication EP 0,521 ,471. It also discloses process for the preparation of Rosuvastatin calcium.
Bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fiuorophenyl)-3-quinolyl]-3,5-dihydroxy- 6-heptenoate} monocalcium of Formula-B (Pitavastatin Calcium) is an HMG-CoA reductase inhibitor, developed by Nissan Chemical Industries for the treatment of hyperlipidemia.
Formula-B
Pitavastatin and its pharmaceutically acceptable salts were first disclosed in European patent publication EP 0,304,063. It also discloses process for the preparation of Pitavastatin sodium. United States Patent No. 5,260,440 and PCT publication No. WO 03/097614, disclose the synthesis of Rosuvastatin from the intermediate 3(R)-3(tert-butyldimethylsilyloxy)-5- oxo-6-triphenyl-phosphoranylidene hexanoate.
PCT publication No. WO 03/087112 discloses the synthesis of Rosuvastatin from a different intermediate, (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxo- hexanoate.
US 5,1 17,039 discloses the process for the preparation of (3R)-3-[(tert- Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester by the ring opening of 3-[(tert-Butyldimethylsilyl)oxy] pentanedioic anhydride using benzyl D- mandelate gives by products.
US 20090076292 discloses process for the preparation of Rosuvastatin by using the intermediates 3(R)-3(tert-butyldimethylsilyloxy)-5-oxo-6-triphenyl-phosphoranylidene hexanoate and (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxo- hexanoate. These intermediates are prepared by a novel intermediate i.e. chiral base salt of hydroxy protected diethyl glutarate.
US 2005/0070605 Al discloses the enantioselective opening of 3-hydroxy protected glutaric anhydride by phenylethylamine to form an amide bond, and further conversion to obtain the HMG-CoA reductase inhibitor.
Above mentioned processes involves the usage of the expensive and hazardous materials in the preparation of HMG-CoA reductase inhibitors. HMG-CoA reductase inhibitors obtained by the above processes are having impurities in the final product.
Thus the present invention provides process for the preparation of HMG-CoA reductase inhibitors with high yield and purity.
OBJECT AND SUMMARY OF THE INVENTION:
The principle object of the present invention is to provide an improved process for the preparation of compound of Formulae-IXa and IXb having the following structures
Formula-IXa Formula-IXb
wherein P is hydroxy protecting group; R2 is C[-C5 alkyl or substituted Ci-C5 alkyl group; R3, R4 and R5; each independently, are selected from C6-C10 aryl group, preferably phenyl group or substituted phenyl groups; Alk is alkyl preferably Ci-C5 alkyl.
Another object of the present invention is to provide a compound of Formula- VI having the following structure
Formula-VI
wherein the base is a non-chiral base; P is hydroxy protecting group and R2 is Q-C5 alkyl or substituted Q-Cs alkyl group.
Another object of the present invention is to provide further conversion of compound of Formulae- IXa or IXb into HMG-CoA reductase inhibitors by the conventional methods.
One aspect of the present invention provides, process for the preparation of the compound of Formulae-IXa or IXb comprising the steps of:
a) ring opening of hydroxyl protected glutaric anhydride of compound of Formula- II in presence of chiral auxiliary;
b) reacting with alkalimetal alkoxide to get monoester derivative of formula V;
c) optionally purifying the compound of Formula-V by using a base to obtain pure compound of Formula-V;
d) converting the compound of Formula-V to mixed anhydride of Formula- VIII; and e) converting the compound of formula VIII into compound of formulae IXa or IXb.
Another aspect of the present invention provides, a process for the purification of compound of Formula-V comprising: a) reacting a crude compound of Formula-V having the structure
O OP O HO -^-^^OR2
Formula-V
with a non-chiral base to obtain the compound of Formula- VI having the structure
Formula- VI
and; b) reacting the compound of Formula- VI with an acid to obtain pure compound of Formula- V.
One more aspect of the present invention provides further conversion of compound of Formula-V into compound of Formula-I by conventional methods.
DETAILED DESCRIPTION OF THE INVENTION: The present invention relates to an improved process for the preparation of compound of Formulae- IXa or IXb, by ring opening of the Hydroxyprotected glutaricanhydride by using chiral auxiliary and conversion to monoester, and purification with non chiral amine base and conversion to mixed anhydride which is further converted to compound of formulae IXa or IXb. The present invention further relates to conversion of compound of formulae IXa or IXb to HMG-CoA reductase inhibitors.
Accordingly the present invention provides a process for the preparation of compound of Formulae- IXa or IXb through the compound of Formula-II is summarized in scheme-I.
O O OP O O OP o
Y 0 ^ 0R2 AAA AAA
Formula- VI
R,
In one embodiment, the process for the preparation of compound Formulae-IXa or IXb comprising the steps of:
a) ring opening of the compound of Formula-II by using the compound of Formula- Ill in the presence of chiral auxiliary and deprotecting to produce compound of Formula-IV, wherein P is hydroxy protecting group; Ra is alkyl, aryl or optionally substituted aryl and ¾ is hydrogen, optionally substituted alkyl, or optionally substituted aryl alkyl.
b) reacting the compound of Formula-IV with Alkalimetal alkoxide to get the compound of Formula-V, wherein R2 is Ci-C alkyl or substituted Ci-C5 alkyl group.
c) optionally purifying the compound of Formula-V by using a base to obtain pure compound of Formula-V
d) converting the compound of Formula-V into compound of Formula- VIII, wherein Y is an alkoxy or alkyl group of Cj to C5 carbons; and
e) converting the compound of Formula- VIII into compound of Formula-IXa or Formula IXb, wherein R3, R4 and R5> independently, are selected from C6-Ci0 aryl group, preferably phenyl group or substituted phenyl groups.
In one embodiment of the present invention, chiral auxiliary used for the ring opening of the compound of Formula-II is selected from N-pyrrolidinyl norephedrine, (1R, 2S)-N- methylephedrine, ephedrine, Ν,Ν-dibenzylnorephedrine, (lR,2R)-pseudoephedrine, (l S,2S)-N-methylpseudoephedrine, (1R, 2S)-N-piperidinyl norephedrine, preferably N- pyrrolidinyl norephedrine. The prior art US 5117039 discloses ring opening of compound of Formula-II without using chiral auxiliary. If chiral auxiliary is not used, 20 % of the unwanted isomer is formed. By using chiral auxiliary the unwanted isomer is controlled.
In another embodiment of the present invention, ring opening of the compound of Formula-II is carried out with compound of Formula-Ill, which is selected from benzyl(R)-mandelate, ethyl (R)-mandelate, Trityl (R)-mandelate, preferably benzyl(R)- mandelate.
In another embodiment of the present invention, the compound of Formula-IV is reacted with Alkalimetal alkoxide. Alkalimetal alkoxide used in this reaction is selected from sodiumalkoxide, potassiumalkoxide, preferably sodium methoxide.
In another embodiment of the present invention, the compound of Formula-V is purified by using base wherein the base is chiral or non-chiral base. The non-chiral base is selected from cyclohexylamine, tert-butylamine, cyclopropylamine, cyclopentylamine, benzyl amine, Dicyclohexyl amine, 2-ethyl hexylamine, ethanolamine, methylamine, ethylene amine, preferably cyclohexylamine, tert-butylamine, benzyl amine.
In one more embodiment of the present invention, the compound of formula-VIII can be prepared by reacting the compound of formula-V with ethylchlorocarbonate or pivaloyl chloride, preferably ethylchlorocarbonate.
In one more embodiment of the present invention, the compound of formula-IXa can be prepared by reacting the compound of formula-VIII with triarylphosphonium alkyl halide like methyltriphenyl phosphonium bromide. Alternatively compound of formula VIII is reacted with dialkylmethylphophonate to get compound of formula-IXb.
In one more embodiment of the present invention, the compound of Formulae-IXa or IXb are further converted into HMG CoA reductase inhibitors of Formula-I by conventional methods as disclosed in US RE 37,314 and CN 100506796, the disclosers of which are incorporated by reference in their entirety herein.
For example the compound of formula-IXa can be converted into the Rosuvastatin calcium by the way as summarized in the following scheme-II.
Rosuvastatin Calcium
For example the compound of formula-IXa can be converted into the Pitavastatin calcium by the way as summarized in the following scheme-Ill.
SCHEME-III
Pitavastatin Calcium
In one aspect the present invention provides, a compound of Formula- VI having the following structure
Formula- VI
wherein the base is a non-chiral base; and P is hydroxy protecting group and R2 is C1-C5 alkyl or substituted C1-C5 alkyl group.
In another aspect the present invention provides, a process for the preparation of compound of Formula- VI comprising: reacting a compound of Formula-V having the structure
O OP O
H0 ^ 0R2
Formula-V
with a non-chiral base to obtain the compound of Formula-II having the structure
Formula- VI
wherein the base is a non-chiral base; and P is hydroxy protecting group and R2 is Ci-C5 alkyl or substituted Ci-C5 alkyl group.
One embodiment of the present invention provides, the base used is non-chiral base selected from cyclohexylamine, tert-butylamine, cyclopropylamine, cyclopentylamine, benzyl amine, Dicyclohexylamine, 2-ethylhexylamine, ethanolamine, methylamine, ethylene amine, preferably cyclohexylamine, tert-butylamine, benzyl amine.
Another aspect of the present invention provides, a process for the purification of compound of Formula-V comprising: a) reacting crude compound of Formula-V having the structure
O OP O
H0A^^ 0R2
Formula-V
with a non-chiral base to obtain the compound of Formula- VI having the structure
Formula- VI
and; b) reacting the compound of Formula-VI with an acid to obtain pure compound of Formula- V.
In one embodiment of the present invention, the acid used in the above process is selected from hydrochloric acid, acetic acid, formic acid, preferably hydrochloric acid.
Another aspect of the present invention provides, a process for preparing a compound of Formula-I comprising the steps of:
a) reacting a non-chiral base with a compound of formula-V to obtain a salt of formula- VI;
O OP O
II I I ! O OP O
Base + HO A' A- 2 , . Ba.se Λ Ό ΛΛ, OR2
Formula"V Formula-VI wherein P and R2 is defined as above
b) reacting compound of Formula-VI with an acid to obtain pure compound of formula-V;
O OP O O OP O
Formula-VI Formula-V
c) converting the compound of formula-V into compound of formula- VIII by known methods;
Formula-V Formula-VIII d) converting the compound of formula VIII into compound of formula-IXa;
wherein Y, P, R2, R3, R4 and R5 is defined as above
e) converting compound of formula-IXa into compound of formula-X by reacting with an aldehyde compound of Formula R-CHO.
f) deprotecting the compound of Formula-X into compound of Formula-XI; and
Formula-X
Formula-XI
g) converting the compound of Formula-XI into compound of Formula-I by
conventional methods,
wherein R is a residue of HMG-CoA reductase inhibitor ected from
In one embodiment, the present invention provides one-pot synthesis of compound of Formula-XI starting with the compound of Formula-V without isolating the intermediate compounds of Formulae VI, VIII, IXa and X.
O OH O
R OR,
Formula-XI
wherein R and R2 as defined above. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way
Experimental procedure:
Example 1: Process for the preparation of (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester
A solution of N-pyrrolidinyl norephedrine in toluene and catalytic amount of triphenyl methane in tetrahydrofuran (750 ml) was cooled to -78 °C, and to this a solution of 1.6 M BuLi in hexane (257 ml) was added drop wise, and the reaction mixture was stirred for 1 hr. To this reaction mixture a solution of benzyl(R)-mandelate (100 g) in THF (500 ml) was added and stirred for 1 hr. To this a solution of 3-[(tert-butyldimethylsilyl)oxy] pentanedioic anhydride (101 g) in THF (250 ml) was added and the resulting reaction mass was stirred for 2-3 Hrs. The reaction mixture was acidified with Aq hydrochloric acid and the product was extracted with ethylacetate. The organic layer was washed with water and sodium chloride solution and concentrated. The concentrated reaction mass taken into ethyl acetate and to this solution 10 % Palladium on Charcoal was added and the reaction mass was stirred at room temperature in a hydrogen atmosphere. The reaction mass was filtered and the filtrate was extracted with sodium bicarbonate solution .The resulting Aq layer was washed with ethyl acetate, dichloromethane and acidified with Aq hydrochloric acid solution. The Aq layer was extracted with dichloromerthane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated. The concentrated mass was crystallized in toluene to give (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester. The above crude product was purified in Ethylacetate/ hexane to give (3R)-3-[(tert- Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (130 g).
Example 2: Preparation of (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester
A solution of ethyl-(R)-mandelate (25 g) in tetrahydrofuran (375 ml) was cooled to -78 °C, and a solution of 1.6 M BuLi in hexane (87 ml) was added drop wise, and stirred for 1 hr .To this reaction mixture a solution of 3-[(tert-butyldimethylsilyl)oxy] pentanedioic anhydride (33.6 g) in THF (125 ml) was added, and the resulting reaction mass was stirred for 2-3 Hrs. The reaction mixture was acidified with Aq hydrochloric acid and the product was extracted with ethyl acetate. The organic layer was washed with water and
sodium chloride solution. The organic layer was concentrated. The concentrated reaction mass taken into 100 ml methanol and to this 100 ml of DM water was added. To this sodium hydroxide (0.55 g) solution in DM water (50 ml) was added and the reaction mass was stirred at room temperature for 2-3 hrs. The reaction mass was concentrated. To the concentrate a mixture of DM water and dichloromethane was added and acidified with Aq hydrochloric acid solution. The Aq layer was extracted with dichloromethane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated. The concentrated mass was crystallized in toluene to give (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester. The above crude product was purified in Ethyl acetate/ hexane to give (3R)-3-[(tert- Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (45.0 g).
Example 3: Preparation of (3R)-3-[(tert-ButyldimethyIsil I) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester
A solution of Trityl-(R)-mandelate (25 g) in tetrahydrofuran (375 ml) was cooled to -78 °C, and a solution of 1.6 M BuLi in hexane (40 ml) was added drop wise, and the reaction mixture was stirred for 1 hr. To the reaction mixture a solution of 3-[(tert- butyldimethylsilyl)oxy] pentanedioic anhydride (15.5 g) in THF (125 ml) was added, and the resulting reaction mass was stirred for 2-3 Hrs. The reaction mixture was acidified with Aq hydrochloric acid and the product was extracted with ethyl acetate. The organic layer was washed with water and sodium chloride solution. The organic layer was concentrated. Concentrated reaction mass taken into 100 ml methanol and to this 100 ml DM water added. To this Aq hydrochloric acid solution (50 ml) was added and the reaction mass was stirred at room temperature for 2-3 hrs. The reaction mass was concentrated. To the concentrate a mixture of DM water and dichloromethane was added, Stirred and separated the layers. The Aq layer was extracted with dichloromethane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated. The concentrated mass was crystallized in toluene to give (3R)-3- [(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester. The above crude product was purified in Ethyl acetate/ hexane to give (3R)-3-[(tert- Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (22.0 g).
Example 4: Preparation of Hydrogen (3R)-1 -Methyl 3-[(tert-Butyldimethylsilyl)- oxy] pentanedioate
To an ice cold solution of sodium methoxide (80 g) and methanol (300 ml) a solution of (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (100 g) in 150 ml methanol was added drop wise at 0-5 °C. Stirred the reaction mixture for 1-3 hr and the mixture was poured into the mixture of ~ 35 % Aq HC1 (140 ml), Water (500 ml), Dichloromethane (1000 ml). To the organic layer DM water added and pH was adjusted to ~ 6.5 with sodium bicarbonate solution. The organic layer was washed with water, dried the organic layer over sodium sulphate and concentrated to give Hydrogen (3R)-1 -Methyl 3-[(tert-Butyldimethylsilyl)-oxy] pentanedioate (70 g).
Example 5: Preparation of Cyclohexylamine salt of Hydrogen (3R)-l-methyl 3- [(tert-butyldimethylsilyl)-oxy] pentanedioate
To the solution of Hydrogen-(3R)-l -methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (50.0 g) in hexane (375 ml), a solution of cyclohexylamine amine (18 g) in hexane (125 ml) was added drop wise over 20 min. Reaction mixture was Stirred for 1- 3 hr. The solid was filtered and washed with hexane. Solid was dried to give Cyclohexylamine salt of Hydrogen-(3R)-l -methyl 3-[(tert-butyldimethylsilyl)- oxy] pentanedioate (63 g)
Example 6: Preparation of t-butyl amine salt of Hydrogen (3R)-l-methyl 3-[(tert- butyldimethyIsiIyl)-oxy] pentanedioate
To a solution of Hydrogen-(3R)-l -methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (50.0 g) in hexane (375 ml), a solution of t-butyl amine (13.2 g) in hexane (125 ml) was added drop wise over 20 min. Reaction mixture was stirred for 1-3 hr. The reaction mixture was filtered and washed with hexane. The obtained solid was dried to give t-butyl amine salt of Hydrogen-(3R)-l -methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (57.5 g)
Example 7: Preparation of Benzyl amine salt of Hydrogen (3R)-l-methyl 3-[(tert- butyldimethylsilyl)-oxy] pentanedioate
To a solution of Hydrogen-(3R)-l -methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (50.0 g) in hexane (375 ml), a solution of benzyl amine (19.4 g) in hexane (125 ml) was added drop wise over 20 min. Reaction mixture was stirred for 1-3 hr. The reaction mixture was filtered and washed with hexane. The obtained solid was dried to give benzyl amine salt of Hydrogen-(3R)-l -methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (63 g) Example 8: Preparation of Hydrogen (3R)-l-methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate
To cyclohexylamine salt of Hydrogen-(3R)-l-methyl-3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (63 g), mixture of DM water and dichloromethane was added, cooled and acidified with Aq HC1 solution at 15-20 °C. The reaction mass was stirred and layers were separated. The organic layer was washed thrice with DM water, dried the organic layer over sodium sulphate and concentrated to give Hydrogen-(3R)-l-Methyl-3-[(tert- Butyldimethylsilyl)-oxy] pentanedioate (46 g).
Example 9: Preparation of Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6- triphenyl phosphoranylidene hexanoate
A solution of Hydrogen-(3R)-l -Methyl 3-[(tert-Butyldimethylsilyl)-oxy] pentanedioate (25 g), triethylamine (12.0 g) in hexane was cooled to -40 °C, and to this ethylchlorocarbonate (11.0 g) was added drop wise. The reaction mass was stirred for 1-3 hr to give anhydride. In another flask a suspension of methyltriphenyl phosphonium bromide(71 g) in THF was cooled to 0°C, and to this a solution of 1.6 M BuLi solution( 120 ml) in hexane was added drop wise over 60 min. The mixture was cooled to -78 °C and the anhydride obtained in above was added drop wise. The resulting reaction mass was stirred for 1-3 hr. The reaction mass was poured into DM water. The reaction mass was stirred and layers were separated. Organic layer was concentrated under u/v at 40-45 °C. The concentrated mass was taken into diisopropyl ether, washed the diisopropyl ether with DM water and brine solution. The organic layer was dried and concentrated to give
Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidenehexanate (55 g)
Example 10: Preparation of Methyl 7-[4-(4-flouropheny.)-6-isopropyl-2-(N-methyl- N-methylsulfonylamino)-pyrimidin-5-yl] - (3R)-3hydroxy-5-oxo-(E)-6-heptenate (Rosuvastatin intermediate)
A solution of 25 g 4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino)-5-pyrimidine carbaldehyde, 55 g Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo- 6-triphenyl phosphoranylidene hexanoate and acetonitrile was refluxed for about 20 hrs. The reaction mass was concentrated under vacuum. To this cyclohexane was added. The reaction mass was stirred and filtered. Filtrate was Concentrated under u/v and taken into acetonitrile, cooled to 0 °C. To this solution of hydrogen fluoride (100 ml) was added drop wise in acetonitrile under ice cooling, and the mixture was warmed to room temperature and stirred for 1-3 hrs. To this a mixture of DM water and dichloromethane was added and neutralized with sodium bicarbonate solution. The reaction mixture was stirred and layers were separated. The organic layer was washed with water and brine solution. To the concentrated IPA was added, stirred, and filtered. The obtained solid was washed IPE and dried to give Methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-pyrimidin-5-yl] - (3R)-3-hydroxy-5-oxo-(E)-6-heptenate(32 g). Example 11: Preparation of Methyl (E)-7-[2-cyclopropyl-4-(4-flurophenyl)-3- quinolinyl]- 3-hydroxy-5-oxo-6-heptenate (Pitavastatin intermediate)
A solution of 20 g 2-cyclopropyl-4-(4-fluorophenyl)-quinolyl-3-carboxaldehyde, 55 g Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoate and acetonitrile was refluxed for about 20 hrs. The reaction mass was concentrated under vacuum. To this cyclohexane was added, Stirred and filtered. The filtrate was concentrated under u/v. The concentrated mass was taken into acetonitrile and cooled to 0 °C. To this a solution of hydrogen fluoride (100 ml) in acetonitrile was added under ice cooling, and the mixture was warmed to room temperature and stirred for 1-3 hrs. To this a mixture of DM water and dichloromethane was added and neutralized with sodium bicarbonate solution. The reaction mass was stirred and layers were separated. The organic layer was washed with water and brine solution and concentrated. To this
concentrated IPA was added, stirred, and filtered. The obtained solid was washed with hexane and dried to give Methyl (E)-7-[2-cyclopropyl-4-(4-flurophenyl)-3-quinolinyl]-3- hydroxy-5-oxo-6-heptenate (27 g). Example 12: Preparation of Methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl- N-methyl sulfonyIamino)-pyrimidin-5-yl] - (3R)-3-hydroxy-5-oxo-(E)-6-heptenate (Rosuvastatin intermediate)
To a solution of hydrogen (3R)-1 -methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (50.0 g) in hexane (375 ml), cyclohexylamine (18 g) in hexane (125 ml) solution was added drop wise over 20 min. The reaction mixture was stirred, filtered and washed with hexane. The obtained solid was dried to give Cyclohexylamine salt. To the obtained Cyclohexylamine salt a mixture of DM water and dichloromethane added, cooled and acidified with Aq HC1 solution at 15-20 °C. The layers are separated and organic layer was washed thrice with DM water, and dried to give Hydrogen (3R)-1 -Methyl 3-[(tert- Butyldimethylsilyl)-oxy] pentanedioate. The solution of hydrogen (3R)-1 -Methyl 3-[(tert- Butyldimethylsilyl)-oxy] pentanedioate (25 g), triethylamine (12.0 g) in hexane was cooled to -40°C, and to this ethyl chlorocarbonate (1 1.0 g) was added drop wise and stirred for 1-3 hr to give anhydride. A suspension of methyltriphenyl phosphonium bromide(71 g) in THF was cooled to 0 °C, and 1.6 M BuLi solution( 120 ml) in hexane was added drop wise over 60 min. The mixture was cooled to -78 °C and the anhydride obtained in above was added drop wise. The resulting reaction mass was stirred for 1-3 hr. The reaction mass was poured into DM water, stirred and layers were separated. The organic layer was Concentrated under u/v at 40-45 °C. The concentrated mass was taken into diisopropyl ether, washed with DM water and brine solution. The organic layer was concentrated to give Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoate as residue. To this residue 25 g 4-(4-flourophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonyl amino)-5-pyrimidine carbaldehyde and acetonitrile (100 ml) was added and refluxed for about 20 hrs. The reaction mass was concentrated under vacuum. To the concentrated mass cyclohexane was added, stirred and filtered. The concentrated mass was taken into acetonitrile and cooled to 0 °C. To this a solution of hydrogen fluoride (100 ml) in acetonitrile was added under ice cooling,
and the mixture was warmed to room temperature and stirred for 1 -3 hrs. To the reaction mixture a mixture of DM water and dichloromethane was added and neutralized with sodium bicarbonate solution. The layers were separated and the organic layer was washed with water and brine solution. To the concentrated IPA was added, stirred, and filtered. The obtained solid was washed with IPE and dried to give Methyl 7-[4-(4-flourophenyl)- 6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl] - (3R)-3hydroxy-5- oxo-(E)-6-heptenate (34 g).
Example 13: Preparation of Methyl (E)-7-[2-cyclopropyl-4-(4-flurophenyl)-3- quinolinyl]- 3-hydroxy-5-oxo -6-heptenate (Pitavastatin intermediate)
To a solution of hydrogen (3R)-1 -methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (50.0 g) in hexane (375 ml), cyclohexyl amine (18 g) in hexane (125 ml) solution was added drop wise over 20 min. The reaction mixture was for 1-3 hr. The reaction mass was filtered and washed with hexane. The solid was dried to give Cyclohexylamine salt. To the obtained cyclohexyl amine salt a mixture of DM water and dichloromethane was added, cooled and acidified with Aq HC1 solution at 15-20 °C. The layers were separated and the organic layer was washed thrice with DM water. The organic layer was dried over sodium sulphate and concentrated to give residue. The obtained residue and a solution of triethylamine (12.0 g) in hexane was cooled to -40 °C, and to this ethylchlorocarbonate (1 1.0 g) was added drop wise and stirred for 1-3 hr to give anhydride. A suspension of methyltriphenyl phosphonium bromide(71 g) in THF was cooled to 0 °C, and 1.6 M BuLi solution( 120 ml) in hexane was added drop wise over 60 min. The mixture was cooled to -78 °C and to this above obtained anhydride was added drop wise. The resulting reaction mass was stirred for 1-3 hr. The reaction mass was poured into DM water, stirred and layers were separated. The organic layer was concentrated under u/v at 40-45 °C. The concentrated mass was taken into diisopropyl ether, washed with DM water and brine solution. The organic layer was dried and concentrated to give Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoate. To this residue 2-cyclopropyl-4-(4-fluorophenyl)- quinolyl-3-carboxaldehyde (20 g) & acetonitrile was added and refluxed for about 15-24 hrs. The reaction mass was concentrated under vacuum. To the reaction mass
cyclohexane was added, stirred and filtered. The obtained concentrate was taken into acetonitrile and cooled to 0 °C. To this a solution of hydrogen fluoride (100 ml) in acetonitrile was added under ice cooling, and the mixture was warmed to room temperature and stirred for 1-3 hrs. To the reaction mixture a solution of DM water and dichloromethane was added and neutralized with sodium bicarbonate solution. The layers were separated and the organic layer was washed with water and brine solution. To the concentrated IPA was added, stirred, and filtered. The obtained solid was washed with hexane and dried to give Methyl (E)-7-[2-cyclopropyl-4-(4-flurophenyl)-3-quinolinyl]-3- hydroxy-5-oxo-6-heptenate(29g).
Claims
im:
wherein P is hydroxy protecting group; R2 is CrC5 alkyl or substituted C1-C5 alkyl group; R3, R4 and R5, independently, are selected from C6-Ci0 aryl group, preferably phenyl group or substituted phenyl groups; Alk is alkyl preferably Ci- C5 alkyl comprising the steps of:
a) ring opening of the compound of Formula-II by using the compound of Formula-Ill in the presence of chiral auxiliary and deprotecting to produce compound of Formula-IV, wherein P is hydroxy protecting group; Ra is alkyl, aryl or optionally substituted aryl and Rb is hydrogen, optionally substituted alkyl, or optionally substituted aryl alkyl;
b) reacting the compound of Formula-IV with Alkalimetal alkoxide to get the compound of Formula-V, wherein R2 is Q-Cs alkyl or substituted Ci-C5 alkyl group;
O OP O Formula-V
c) optionally purifying the compound of Formula-V by using a base to obtain pure compound of Formula-V;
O OP O
HO
Formula-V
d) converting the compound of Formula-V into compound of Formula- VIII, wherein Y is an alkoxy or alkyl group of Ci to C5 carbons; and O O OP O
YA0X^A^A0R2
Formula-VIII
e) converting the compound of Formula-VIII into compound of Formula-IXa or Formula-IXb by reacting with triarylphosphonium alkyl halide or dialkylmethylphosphonate respectively.
2. The process according to claim 1, wherein chiral auxiliary used for the ring opening of the compound of Formula-II is selected from N-pyrrolidinyl norephedrine, (1R, 2S)-N-methylephedrine, ephedrine, N,N- dibenzylnorephedrine, (lR,2R)-pseudoephedrine, (1S,2S)-N- methylpseudoephedrine and (1R, 2S)-N-piperidinyl norephedrine.
3. The process according to claim 1, wherein ring opening of the compound of Formula-II is carried out with compound of Formula-Ill, which is selected from benzyl(R)-mandelate, ethyl (R)-mandelate and Trityl (R)-mandelate.
4. The process according to claim 1, wherein alkalimetal alkoxide used in step-b is selected from sodiumalkoxide or potassiumalkoxide.
5. The process according to claim 1, wherein the compound of Formula-V is purified in the presence of chiral or non-chiral base.
6. The process according to claim 5, wherein non-chiral base is selected from cyclohexylamine, tert-butylamine, cyclopropylamine, cyclopentylamine, benzyl amine, Dicyclohexyl amine, 2-ethyl hexylamine, ethanolamine, methylamine and ethylene amine.
7. The process according to claim 1, wherein the conversion of compound of formula-V to compound of formula VIII is carried out by reacting the compound of formula-V with ethylchlorocarbonate or pivaloyl chloride.
8. The process according to claim 1, wherein the triarylphosphonium alkyl halide used in the preparation of Formula-IXa is methyltriphenyl phosphonium bromide.
9. The process according to any of the preceding claims, wherein the compounds of Formulae-IXa or IXb is further converted into HMG-CoA reductase inhibitors.
10. The process according to claim 9, wherein the HMG-CoA reductase inhibitor is selected from Rosuvastatin or Pitavastatin.
1 1. The compound of Formula- VI
O OP O
Base
Formula- VI
wherein the base is a non-chiral base; and P is hydroxy protecting group and R2 is C 1 -C5 alkyl or substituted Ci-C5 alkyl group.
12. A process for the preparation of HMG-CoA reductase inhibitors intermediate of the following formula-XI 
Formula-XI
wherein R is Rosuvastatin or Pitavastatin residue of formula
and R2 is Cj-C5 alkyl or substituted Cj-C5 alkyl group comprising the steps of: a) reacting crude compound of formula-V with a non-chiral base to obtain a salt of formula-VI;
o OP o
U I U o OP o
Base + HO >-" -/^ Baee OA A0R,
Formula-V Formula-VI wherein P is hydroxy protecting group and R2 is defined as above
b) reacting compound of Formula-VI with an acid to obtain pure compound of formula-V; 
Formula-VI Formula-V c) converting the compound of formula-V into compound of formula-VIII; 
Formula-V Formula-VIII
wherein Y is an alkoxy or alkyl group of Ci to C5 carbons and P, R2 is defined as above
d) converting the compound of formula VIII into compound of formula-IXa; 
wherein Y, P, R2, and R5 is defined as above and R3, R and R5, independently, are selected from C6-Ci0 aryl group, preferably phenyl group or substituted phenyl groups
e) converting compound of formula-IXa into compound of formula-X by reacting with an aldehyde compound of Formula R-CHO wherein R, P, R2, R3, R4 and R5 are as defined above; and 
f) deprotecting the compound of Formula-X into compound of Formula-XI. 
Formula-X Formula-XI
13. The process according to claim 12, wherein the compound of Formula-XI is further converted into Rosuvastatin calcium.
14. The process according to claim 12, wherein the compound of Formula-XI is further converted into Pitavastatin calcium.
15. The process according to claim 12, wherein the compound of Formula-XI is prepared from the compound of Formula-V without isolating the intermediate compounds of Formulae VI, VIII, IXa and X.
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Cited By (4)
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| CN103408580A (en) * | 2013-06-03 | 2013-11-27 | 南京欧信医药技术有限公司 | Method for synthesizing intermediate through statins |
| CN103483393A (en) * | 2013-09-05 | 2014-01-01 | 江苏兰健药业有限公司 | Preparation method of chiral intermediate for synthesizing statins |
| JP2014533519A (en) * | 2011-11-28 | 2014-12-15 | マイラン ラボラトリーズ リミテッドＭｙｌａｎ Ｌａｂｏｒａｔｏｒｉｅｓ Ｌｉｍｉｔｅｄ | Novel process for producing intermediates of HMG-CoA reductase inhibitors |
| WO2014195965A3 (en) * | 2013-05-27 | 2015-04-30 | Mylan Laboratories Ltd | An improved process for the preparation of hmg-coa reductase inhibitor intermediates |
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| CN103483393B (en) * | 2013-09-05 | 2016-08-17 | 江苏兰健药业有限公司 | A kind of preparation method of the chiral intermediate for statins synthesis |
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