MXPA06000926A - Process and intermediate compounds useful in the preparation of statins, particularly atorvastatin - Google Patents
Process and intermediate compounds useful in the preparation of statins, particularly atorvastatinInfo
- Publication number
- MXPA06000926A MXPA06000926A MXPA/A/2006/000926A MXPA06000926A MXPA06000926A MX PA06000926 A MXPA06000926 A MX PA06000926A MX PA06000926 A MXPA06000926 A MX PA06000926A MX PA06000926 A MXPA06000926 A MX PA06000926A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- compound
- group
- hydrogen
- protecting
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 143
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 17
- XUKUURHRXDUEBC-KAYWLYCHSA-N atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title description 5
- 229960005370 atorvastatin Drugs 0.000 title description 5
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 title description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 48
- 239000001257 hydrogen Substances 0.000 claims abstract description 48
- 125000006239 protecting group Chemical group 0.000 claims abstract description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 17
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 15
- 125000001424 substituent group Chemical group 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000011780 sodium chloride Substances 0.000 claims abstract description 13
- 230000001808 coupling Effects 0.000 claims abstract description 9
- 238000010168 coupling process Methods 0.000 claims abstract description 9
- 238000005859 coupling reaction Methods 0.000 claims abstract description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 9
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 230000003647 oxidation Effects 0.000 claims description 11
- 238000007254 oxidation reaction Methods 0.000 claims description 11
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 7
- 238000007333 cyanation reaction Methods 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 230000001681 protective Effects 0.000 claims description 4
- -1 trifluoromethylphenyl Chemical group 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 8
- 150000002596 lactones Chemical class 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 6
- 125000004432 carbon atoms Chemical group C* 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N Dess–Martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- 229940002661 Lipitor Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical compound [Ca+2].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.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 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2-Pyrone Chemical class O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 229910003827 NRaRb Inorganic materials 0.000 description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N Sodium cyanide Chemical class [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 229910000090 borane Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- DMJZZSLVPSMWCS-UHFFFAOYSA-N diborane Chemical compound B1[H]B[H]1 DMJZZSLVPSMWCS-UHFFFAOYSA-N 0.000 description 2
- KQTXIZHBFFWWFW-UHFFFAOYSA-L disilver;carbonate Chemical compound [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- SBANJZXICHSWIF-JEAXJGTLSA-N (2S,4R)-2-(chloromethyl)-6-methoxyoxan-4-ol Chemical compound COC1C[C@H](O)C[C@@H](CCl)O1 SBANJZXICHSWIF-JEAXJGTLSA-N 0.000 description 1
- XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-Bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 description 1
- VOLMSPGWNYJHQQ-UHFFFAOYSA-N 3,5-dihydroxy-6-methyl-2,3-dihydropyran-4-one Chemical compound CC1=C(O)C(=O)C(O)CO1 VOLMSPGWNYJHQQ-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- 241000981924 Juniperus oxycedrus Species 0.000 description 1
- MZPAQCAPWLAKSD-UHFFFAOYSA-N N-phenyl-1H-pyrrole-2-carboxamide Chemical compound C=1C=CNC=1C(=O)NC1=CC=CC=C1 MZPAQCAPWLAKSD-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N Ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N Potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 229910006095 SO2F Inorganic materials 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000004799 bromophenyl group Chemical group 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
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- LQQCGEGRINLHDP-UHFFFAOYSA-L carboxyphosphate Chemical compound OC(=O)OP([O-])([O-])=O LQQCGEGRINLHDP-UHFFFAOYSA-L 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- RBBOWEDMXHTEPA-UHFFFAOYSA-N hexane;toluene Chemical compound CCCCCC.CC1=CC=CC=C1 RBBOWEDMXHTEPA-UHFFFAOYSA-N 0.000 description 1
- KLGZELKXQMTEMM-UHFFFAOYSA-N hydride Chemical compound [H-] KLGZELKXQMTEMM-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Abstract
There is provided a process for the preparation of a compound of formula (7) or salts thereof:wherein R1 represents a hydrogen or a hydrocarbyl group, R2 represents a hydrogen or substituent group, R3 represents a hydrogen or a hydrocarbyl group, and X represents a hydrogen or substituent group which comprises a) cyanating a compound of formula (1):wherein Y represents a halo group, preferably CI or Br;P1 represents hydrogen or a protecting group, and W represents=0 or -OP2, in which P2 represents hydrogen or a protecting group, to give a compound of formula (2):b) reducing the compound of formula (2) to give a compound of formula (3):coupling the compound of formula (3) with a compound of formula (4):to give a compound of formula (5):when W represents -OP2, deprotecting and then oxidising the compound of formula (5) to give a compound of formula (6):and e) subjecting the compound of formula (5) when W represents=O, or compound of formula (6) to ring-opening, and removal of any remaining protecting groups, to give a compound of formula (7) or salts thereof.
Description
Published: For two-lettering cades and olher abbrevialions, referto thc "Guid- - with inlcniational scarch report anee Noles on Codes and? Bbrevialions" appiiring to the ihe begin- - before the expiration of the time limil for amending the ning of each regular issue of the PCT Gazette. claims and to be republishcd in the event of receipt of ameiulments
PROCEDURE AND USEFUL INTERMEDIATE COMPOUNDS IN THE PREPARATION OF STATINES, PARTICULARLY ATORVASTATIN
DESCRIPTIVE MEMORY
The present invention relates to a process and intermediates useful in the preparation of statins, particularly atorvastatin. According to the present invention, there is provided a process for the preparation of a compound of formula (7) or salts thereof:
wherein R1 represents a hydrogen or a hydrocarbyl group, R2 represents a hydrogen or a substituent group, R3 represents a hydrogen or a hydrocarbyl group, X represents a hydrogen or a substituent group comprising a) cyanation of a compound of formula (1) ): wherein Y represents a halogen group, preferably Cl or Br; P1 represents hydrogen or a protective group, and W represents = O or -OP2, wherein P2 represents hydrogen or a protecting group, to provide a compound of formula (2):
b) reducing the compound of formula (2) to provide a compound of formula (3):
c) coupling the compound of formula (3) with a compound of formula
to provide a compound of formula (5):
d) when W represents -OP? 2, deprotection and then oxidation of the compound of formula (5) to provide a compound of formula (6): e) subjecting the compound of formula (5) when W represents = O, or a compound of formula (6) to a ring opening, and removal of any of the remaining protecting groups, to provide a compound of formula (7) or its salts:
The hydrocarbyl groups that can be represented by R 1 and R 3 independently include alkyl, alkenyl and aryl groups, and any combination thereof, such as the aralkyl and alkaryl groups, for example benzyl groups. The alkyl groups which may be represented by R1 and R3 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups sometimes comprise up to 10 branched chain carbon atoms, preferably up to 4 branched carbon atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the longer ring and optionally having one or more rings with bridges. Examples of alkyl groups that may be represented by R1 and R3 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups. Ayanyl groups that can be represented by R1 and R3 include C2.20 alkenyl groups, and preferably C2.6. One or more carbon-carbon double bonds may be present. The alkenyl group can carry one or more substituents, particularly phenyl substituents.
Examples of alkenyl groups include vinyl, styryl, and indenyl groups. The aryl groups that may be represented by R 1 and R 3 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of the aryl group that can be represented by R 1 and R 3 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups. When any of R1 and R3 is a substituted hydrocarbyl group, the substituent (s) must be such that they do not adversely affect the proportion or selectivity of any of the reaction steps or the process as a whole. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbyl, esters, carbamates, carbonates, amides, sulfonyl and sulfonamido groups wherein the hydrocarbyl groups are as was defined for R1 above. One or more substituents may be present. Examples of groups R1 or R3 having more than one substituent present include -CF3 and C2F5.
Substituent groups that can be represented by X and R 2 independently include hydrocarbyl groups as defined for R 1 above, electron donating groups, electron extraction groups, halogens and heterocyclic groups. Substituent groups are commonly selected from the group consisting of optionally substituted alkoxy (preferably C? -4 alco alkoxy), optionally substituted aryl (preferably phenyl), optionally substituted aryloxy (preferably phenoxy), polyalkylene oxide (preferably polyethylene oxide or oxide) polypropylene), carboxy, phosphate, sulfo, nitro, cyano, halo, ureido, -SO2F, hydroxy, ester, -NRaRb, -CORa, -CONRaRb- -NHCOR3, -OCONRaRb, carboxester, sulfone and -SO2NRaRb wherein Ra and Rb each are independently H, optionally substituted aryl, especially phenyl or optionally substituted alkyl (especially CM alkyl) OR, in the case of -NRaRb, CONRaRb, -CONRaRb, -OCONRaRb and -S02NRaRb, Ra and R may be together as well with the nitrogen atom to which they are attached, they represent an aliphatic or aromatic ring system; or a combination thereof. Preferably, a process for the preparation of a compound of formula (7) or its salts is provided:
R1 represents an alkyl group, such as an alkyl group of C -? - 6, and preferably an isopropyl group, R2 represents an aryl group, preferably a phenyl group, R3 represents an aryl group, preferably a 4-fluorophenyl group, X represents a group of formula -COZ, wherein Z represents -OR4, wherein R4 represents an alkyl, preferably a methyl or ethyl group, or -NR5R6, wherein R5 and R6 each independently represent H, alkyl or aryl, and preferably R5 is H and R6 is phenyl, which comprises a) cyanation of a compound of formula (1):
wherein Y represents a halogen group, preferably Cl or Br; P 1 represents hydrogen or a protecting group, and W represents = O or -OP 2, wherein P 2 represents hydrogen or a protecting group, to provide a compound of formula (2):
b) reducing the compound of formula (2) to provide a compound of formula (3):
c) coupling the compound of formula (3) with a compound of formula (4):
to provide a compound of formula (5):
d) when W represents -OP2, deprotection and then oxidation of the compound of formula (5) to provide a compound of formula (6):
e) subjecting the compound of formula (5) when W represents
= O, or a compound of formula (6) at ring opening, and removal of any of the remaining protecting groups, to provide a compound of formula (7) or its salts: More preferably R1 is an isopropyl group, R2 is a phenyl group, R3 is a 4-fluorophenyl group and X is a group -CO2Me, -CO2Et or -CONHPh. The protection groups that may be represented by P1 and P2 include alcohol protection groups, examples of which are well known in the art. Particular examples include tetrahydropyranyl groups. Preferred protection groups are silyl groups, for example triaryl- and especially trialkylsilyl groups, and hydrocarbyl groups. Especially preferred are benzyl, methyl, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. The protection groups that can be represented by P1 and P2 can be the same or different. When the protection groups P1 and P2 are different, they can conveniently allow selective removal only P1 or P2. Preferably, when the protecting groups P1 and P2 are different, P1 is a benzyl or silyl group and P2 is a methyl group. The cyanation of compounds of formula (1) can be achieved by methods known in the art for displacement of a halogen group with a cyanide. Preferably, the process comprises contacting the compound of formula (1) with a source of cyanide. Preferred sources of cyanide include cyanide salts, especially ammonium or alkali metal cyanides, particularly sodium or potassium cyanide. A particularly preferred process comprises contacting the compound of formula (1) with 5 molar equivalents of KCN in the presence of dimethyl sulfoxide solvent at a temperature of, for example, 50 to 120 ° C, preferably 60 to 100 ° C and more preferably from 70 to 90 ° C, normally close to 80 ° C. The reduction of the compounds of formula (2) can be achieved using reduction systems known in the art for the reduction of nitrile groups. Preferred reduction systems include reduction with Raney nickel and hydrogen, reduction with hydrogen in the presence of a catalyst, such as palladium in carbon, reduction using hydride reagents, such as LYAH4. More preferred is the reduction using boranes such as borane -THF. When the palladium-on-carbon catalyzed hydrogenation is employed, the preferred conditions comprise the use of methanol solvent at elevated temperature, such as about 40 ° C, in the presence of about 0.01 to 100 molar equivalents of ammonia. The coupling of the compound of formula (3) with the compound of formula (4) can employ conditions analogous to those provided in WO89 / 07598 for the corresponding coupling. The conditions preferably comprise heating at reflux of the compounds of formula (3) and (4) in a hydrocarbon solvent, such as toluene or cyclohexane, or mixtures thereof, followed by contact with aqueous acid, such as aqueous HCl.
When W represents OP2, the protection group can be removed to form a hydroxy group by methods known in the art for the removal of the given protection group. For example, silyl protecting groups can be removed by contact with a source of fluoride ion, such as tetrabutylammonium fluoride, and benzyl groups can be removed by hydrogenolysis, such as reaction with hydrogen in the presence of palladium on carbon. Oxidation of compounds formed by deprotection of compounds wherein W represents -OP2 may employ conditions known in the art for the oxidation of pyranones to pyranones, and include those that are provided in "Comprehensive Organic Transformations," R.C. Larock, 2nd Ed (1999) p 1670, published by Wiley VCH, incorporated herein by reference. Preferred oxidation systems include Ag2C? 3 / Celite, especially Celite J2 (with Ag2CO3), bromine, Swern oxidation or Dess-Martin periodinane oxidation. The ring opening of the compounds of formula (5), when
W represents = O or formula (6) can employ conditions known in the art to open the ring of a pyranone. Preferably, the ring is opened by contact with a base, such as sodium hydroxide. Methanol is conveniently used as the solvent. The remaining protection groups can be removed by methods known in the art for the removal of the given protection group. For example, silyl protecting groups can be removed through contact with a fluoride ion source, such as tetrabutylammonium fluoride, benzyl ethers can be removed by hydrogenolysis, and methyl acetals can be removed by acid treatment. diluted aqueous. It will be recognized that when X represents a group of formula -COOR4, this can be converted to a group where X represents -CONR5R6 at any stage during the process, for example through the reaction of the corresponding compounds of formulas (4), (5), (6) or (7) with a compound of formula HNR5R6. It will also be recognized that the compounds of formulas (2) and (3) can be subjected to oxidation (when W represents -OH) or deprotection or oxidation (when W represents a protecting group -O-) to form the corresponding compound in where W represents = O. Preferred compounds of formula (1) are compounds of formula:
where W, P1 and Y are as described above. Preferred compounds of formula (2) are compounds of formula:
where W and P1 are as defined above. Preferred compounds of formula (3) are compounds of formula:
where W and P1 are as described above. The preferred compounds of formula (5) are of the formula:
wherein R1, R2, R3, W, X and P1 are as previously described. The preferred compounds of formula (6) are of the formula:
wherein R1, R2, R3, and X are as described above. The preferred compounds of formula (7) are of the formula: wherein R1, R2, R3, and X are as previously described. The compounds of formula (7) are conveniently converted to pharmaceutically acceptable salts, especially their calcium salts. The compounds of formula (4) are conveniently prepared by methods provided in J. Med. Chem., 1991, 34, pp357-366. Particularly preferred compounds of formula (4) are compounds of formula:
The compounds of formula (I) are conveniently prepared through enzyme-catalyzed condensation of acetaldehyde and 2-haloacetaldehyde, for example using the method described in the U.S.A. 5, 795,749. The compounds of formulas (2) and (3) and, when W is OP2, formula (5) form additional aspects of the present invention.
In preferred compounds of the formula (2) and (3) P1 is a protecting group and preferably W represents -OP2. When P1 is a protective group and W represents -OP2, preferably P1 and P2 are different. More preferred compounds of formulas (2) and (3) are compounds wherein P1 is a benzyl or silyl group and W represents OP2, where P2 is a methyl group. Preferred compounds of formula (5) are compounds wherein P1 is hydrogen, benzyl or silyl and W represents = O or OP2 where P2 is a methyl group. More preferred compounds of formula (5) are compounds wherein R1 is an alkyl group of C -? - 6, R2 is an aryl group, R3 is an aryl group, X is COZ where Z is OR4, where R4 is an alkyl group or Z is NR5R6 where R5 and R6 are each independently hydrogen, alkyl or aryi, P1 is hydrogen, benzyl or a silyl group and W represents = O or OP2 where P2 is a methyl group. The most preferred compounds of formula (5) are compounds wherein R1 is an isopropy group, R2 is a phenyl group, R3 is a 4-fluorophenyl aryl group, X is COZ where Z is OR4, where R4 is a methyl or ethyl group or Z is NR5R6 where R5 is hydrogen and R6 is phenyl, P1 is hydrogen, benzyl or a silyl group and W represents = O or OP2 where P2 is a methyl group. The invention is illustrated through the following examples.
EXAMPLE 1 Preparation of ((2S, 4R) -2- (chloromethyl) -6-methoxytetrahydro-2H-pyran-4-ol) clorolactol methyl acetal. a compound of formula 1 where Y = Cl, P1 = H v W = -OP2, where P2 = Me
The crude clorolactol (15 g) is dissolved in methanol (150 ml) and heated at 40 ° C for 2 hours in the presence of 0.1 ml of sulfuric acid. The solvent is removed by ry evaporation to produce the product as an oil with dark brown fluidity. The product is dissolved in DCM and washed with sodium bicarbonate solution. The solvent is removed by ry evaporation to produce the product as an oil with dark brown fluidity, which is purified by column chromatography (16.1g) m / z 179, 149 and 113; 1 H NMR CDCl 3 3.6-3.7 (m, 2 H), 4.1 (m 1 H), 1.5-1.6 (m, 2 H), 4.0 (m 1 H), 1.3-1.6 (m 2 H), 4.9 (m 1 H), 3.3 & 3.5 (s 3H); 13C NMR CDCl 3 32, 36, 45 55 &56, 64, 65, 94.
EXAMPLE 2 Preparation of ((2S.4R) -4- (benzyloxy) -2- (chloromethyl) -6-methoxytetrahydro-2H-pyran O-benzyl-clorolactol methyl acetal, a compound of formula 1 wherein Y = Cl, P1 = Bz and W - -OP2, where P2 = Me
Clorolactol methyl acetal (1 g) is dissolved in THF (5 ml) and charged to sodium hydride (0.33 g 60% in mineral oil) in THF (5 ml) at room temperature. The benzyl bromide (1.9 g) is added dropwise and the mass is heated at 80 ° C for 2 hours. Methanol (2 ml) is added and the mass is partitioned between DCM / water, and then washed with water. The organic phase is dried and the solvent is removed by ry evaporation to yield an oil with orange fluidity (2.1g). m / z 270; 238; 203; 132; 91; 1 H NMR CDCl 3 1.6-2.0 (m 4 H), 3.4 & 3.5 (s 3 H), 3.6 (m, 2 H), 3.8 (m 1 H), 4.0 (m 1 H), 4.5 (m 2 H), 4.7 (m 1 H), 7.3-7.5 (m 5 H); 13C NMR CDCI3 32 &33, 46, 55 &56, 58, 66, 74, 96 &98, 128-131.
EXAMPLE 3 Preparation of (I? 2R. 4R) -4- (benzyloxy) -β-methoxytetrahydro-2H-pyran-2-nacetonitrile) cyano-O-benzyl lactol methyl acetal. a compound of formula 2 wherein P1 = Bz v W = -OP2. where P2 = Me
The O-benzyl-chloro-Iactol methyl acetal (5 g) is dissolved in DMSO (50 ml) containing psium cyanide (5 g) and heated for 4 days at 80 ° C. The mass is then divided between diethyl ether (50 ml) and water (5 ml). The organic phase is removed, dried, and the solvent is removed by ry evaporation to yield a dark oil, which has been purified by column chromatography m / z 261, 229, 184, 123, 107, 91; 1 H NMR CDCl 3 1.6-1.9 (m 4 H), 2.5 (m, 2 H), 3.4 & 3.5 (s 3 H), 3.6 (m 1 H), 3.8 (m 1 H), 4.5 (s 2 H); 13C NMR CDCl324, 34, 36, 54, 56, 58, 68, 73, 98 &100, 117, 122-128.
EXAMPLE 4 Preparation of (2-r (2R, 4R) -4- (benzyloxy) -6-methoxytetrahydro-2H-pyran-2-iPetanamine) aminoethyl-O-benzyl lactol methyl acetal, a compound of formula 3 where P1 = Bz and W = -OP2, where P2 = Me
The borane-THF complex (1 molar solution) (1.19 mis) is charged to a flask purged with nitrogen at 10 ° C and diluted with THF (2.5 mis). The cyano-O-benzyl lactol methyl acetal (0.05 g) is dissolved in THF (7.5.5 mis) at 10 ° C and charged to the borane. The resulting mixture is then heated to reflux for 9 hours. The mixture is cooled, quenched with methanol (10 ml) and concentrated in vacuo. Two additional portions of methanol (2 x 10 mis) are added, and the mixture is concentrated twice until dried. The final concentration produces an oil (45 mg). TLC (CH2CI2): New spot in Rf = 0.05, positive ninhydrin stain, without residual nitrile. m / z 265, 233, 107, 91; 1 H NMR CDCl 3 1.6-1.9 (m 6H), 3.4 & 3.45 (s, 3H), 3.5 (2H), 3.6
(m, 1H), 3.8 (m, 1H), 4.5 (s, 2H), 4.7 (m, 1 H), 7.1 (m, 5H). 13C NMR CDCl 3 24, 26, 34, 36, 54, 56, 58, 68, 73, 98 & 100, 122-128.
EXAMPLE 5 Preparation of O-benzyl lactol methyl ester of pyrrolo ester, a compound of formula wherein R1 = iPr, R2 = Ph, R3 = 4-FCfiHt, X = CO2Et, P1 = Bz and W = -OP2, where P2 = Me
The aminoethyl-O-benzyl lactol methyl acetal (1.00 g) is dissolved in
THF (10 ml). Esdiol ester (1.12 g) is added, followed by acetic acid (2 ml) and the mixture is heated at 80 ° C for 2 days. After concentration in vacuo the reaction mass is divided between diethyl ether (10 ml) and water (10 ml). The organic phase is collected, dried (MgSO), and the solvent is removed in vacuo to yield a brown oil which is purified through column chromatography (0.38 g). M / z: 599, 567, 460, 107, 91; 1 H NMR CDCl 3 1.15 (t, 3 H), 1.3 (d, 6 H), 1.6-1.9 (m, 6 H), 3.4 & 3.45 (s, 3H), 3.5 (2H), 3.6 (m, 2H) 3.8 (m, 1 H), 4.1 (q, 2H), 4.5 (s, 2H), 4.7 (m, 1 H), 7.1 ( m, 14H). 19G NMR: Displacement of 106 ppm (dike ester) at 115 ppm (product).
EXAMPLE 6 Preparation of O-benzyl lactol methyl acetal of pyrrolo anuide, a compound of formula 5 wherein R 1 = iPr, R 2 = Ph. R3 = 4-FCsHU, X = CíO) NHPh, Pi = Bz and W = -OP2, where P2 = Me
The O-benzyl lactol methyl ester of pyrrolo ester (0.30 g) is dissolved in DMF (5 ml). The aniline (1.0 g) is added and the mixture is heated at 80 ° C for 18 hours. After cooling and concentration in vacuo, the reaction mass is divided between diethyl ether (5 ml) and water (5 ml). The organic phase is collected, further washed with water (5 ml), dried (MgSO) and the solvent removed in vacuo to yield a brown oil which is purified by column chromatography (0.26 g). M / z 646, 614, 507, 107, 91;
1 H NMR CDCl 3 1.3 (d, 6 H), 1.6-1.9 (m, 6 H), 3.4 & 3.45 (s, 3H), 3.5 (2H), 3.6 (m, 2H), 3.8 (m, 1H), 4.5 (s, 2H), 4.7 (m, 1 H), 6.8 (br.s 1H), 7.1 (m, 19H).
EXAMPLE 7 Preparation of OH-lactol methyl acetal of pyrrolo anilide (Lipitor Lactol-OMe) a compound of formula 5 wherein R1 = iPr. R2s = Ph, R3s4-FCfiH¿. X = C (O) NHPh, P1 = H v W = -OP2, where P2-Me
The O-benzyl lactol methyl acetal of pyrrolo anuide (0.15 g) is dissolved in methanol (5 ml). 10% Pd / C (0.1 g) is added under nitrogen. The system is cleaned with hydrogen, heated under a hydrogen atmosphere for 6 hours. After removal of Pd / c by filtration, and concentration of the reaction mass in vacuo, the residual brown oil is purified by column chromatography. M / z 556, 524, 506; 1 H NMR CDCl 3 1.3 (d, 6 H), 1.6-1.9 (m, 6 H), 3.4 & 3.45 (s, 3H), 3.5 (2H), 3.6 (m, 2H), 3.8 (m, 1 H), 4.7 (m, 1H), 6.8 (br.s 1 H), 7.1 (m, 14H).
EXAMPLE 8 Preparation of OH lactol from pyrrolo anuide (Lipitor Lactol). a compound -OP2, where P2 = H
The OH-lactol methyl acetal of pyrrolo anuide (0.050 g) is dissolved in methanol (2 ml), and water (2 ml) is added, followed by 0.1 N HCl (1 ml). After stirring at room temperature for 2 hours, the mixture is concentrated in vacuo to yield the product as a colorless oil. M / z 542, 524, 506, 1H NMR CDCl 3 1.3 (d, 6H), 1.6-1.9 (m, 6H), 3.45 (2H), 3.6 (m, 2H), 3.8 (m, 1H), 5.0 (m , 1 H), 6.8 (br.s 1 H), 7.1 (m, 14H); 13C NMR CDCl 3 91. dppm (Lactol C); FTIR: 1652cm "1 (amide)
EXAMPLE 9 Preparation of lactone. a compound of formula 6 wherein R1 = iPr,
The OH lactol of anilide pyrrolo (35 mg, 0.065 mmol) in dichloromethane (0.5 ml) is added to Dess-Martin periodinone (30 mg, 0.07 mmol) and the mixture is stirred at room temperature for 2.5 hours. The reaction is partitioned between 1M sodium hydroxide and diethyl ether. The phases are then separated and the organic volume is reduced in vacuo to produce the crude product oil. 1H NMR 500MHz CDCI3: 9.8, 7.5, 7.28, 7.2, 7.08, 7.02, 6.98, 5.2, 4.5, 4.1, 4.0, 3.9, 3.2, 2.6, 2.4, 1.6, 1.4. 13C NMR 125.72 MHz DMSO: 169.6, 165.9, 139.3, 135.9, 134.7,
133. 3, 129.4, 128.8, 128.4, 127.5, 127.2, 125.3, 122.9, 120.7, 119.3, 117.6,
115. 4, 25.5, 22.1, 22.3, 39.5, 34.5, 72.8, 36.8, 61.0, 38.3.
EXAMPLE 10 Preparation of atorvastatin (hydrolysis of lactone), a compound of formula 7 wherein R1 = iPr, R2 = Ph, R3 = 4-FCgH. X = C (O) NHPh
The lactone (1.1 g) is dissolved in ethanol (10 ml). Water (2 ml) and Ca (OH) 2 (0.15 g) are added and the suspension is heated at 60 ° C for 3 hours. An additional 10 ml of hot water is added, then the mixture is allowed to cool slowly to room temperature. The formed precipitate is filtered and dried to provide calcium salt of atorvastatin (0.3 g). The material is identical to an authentic sample mixed by mixed melting point, NMR and mass spectrometry.
Independent preparation of OH lactol from pyrrolo anuide (lipitor
Lactol), a compound of formula 5 wherein R1 = iPr, R2 = Ph, R3 = 4-FCgH4,
X = C (O) NHPh, P1 = H v W -OP2, where P2 = H, from an authentic source of lactone An authentic sample of lactone (530 mg) is dissolved in DMF
(5 ml) anhydrous, followed by imidazole (174 mg), and then TBDMS chloride
(371 mg). The mixture is stirred at room temperature. After 6 hours, the reaction is worked up by the addition of Et2O (30 ml) and water (30 ml). The separated organic phase is further washed with water (2 x 20 ml), dried and concentrated in vacuo to yield silylated lactone as a white powder (470 mg, 73%). The silylated lactone (233 mg) is dissolved in anhydrous dichloromethane (5 ml), then cooled to -78 ° C under nitrogen. DIBAL is added
(0.31 ml, 1M in toluene) dropwise and the mixture is stirred for 10 minutes at
-78 ° C. The mixture is then quenched by the addition of 1 ml of 10% aqueous Rochelle's salt and allowed to warm to room temperature. After the addition of additional dichloromethane (10 ml) and water (10 ml), the phases are separated and the organic phase is dried and concentrated in vacuo. The residual oil is purified by column chromatography (50% Et2O in hexane). FTIR: 1668 cm "1 (amide) interval in 1735cm" 1 (Lactone) is no longer present. The silylated alcohol (100 mg) is dissolved in anhydrous THF. HF Pyridine is added (0.1 ml) at 0 ° C and allowed to warm to room temperature. The mass is annealed with ether / and sodium bicarbonate solution. The phases are separated and the aqueous phase is counter-extracted with ether. The organic phases are combined, dried and evaporated to yield an oil (75mg). M / z 542, 524, 506; 1H NMR CDCI3 1.3 (d, 6H), 1.6-1.9 (m, 6H), 3.45 (2H), 3.6 (m, 2H), 3.8 (m, 1 H), 5.0 (m, 1 H), 6.8 (br .s 1 H), 7.1 (m, 14H); 13 C NMR CDCl 3 91.6 ppm (lactol C); FTIR: 1652cm-1 (amide).
Claims (14)
1. - A process for the preparation of a compound of formula (7) or salts thereof: wherein R1 represents a hydrogen or a hydrocarbyl group, R2 represents a hydrogen or a substituent group, R3 represents a hydrogen or a hydrocarbyl group, X represents a hydrogen or a substituent group, comprising a) cyanation of a compound of formula ( 1): wherein Y represents a halogen group, preferably Cl or Br; P1 represents hydrogen or a protective group, and W represents = O or -OP2, wherein P2 represents hydrogen or a protecting group, to provide a compound of formula (2): b) reducing the compound of formula (2) to provide a compound of formula (3): c) coupling the compound of formula (3) with a compound of formula to provide a compound of formula (5): d) when W represents -OP, deprotection and then oxidation of the compound of formula (5) to provide a compound of formula (6): and e) subjecting the compound of formula (5) when W represents = O, or a compound of formula (6) to a ring opening, and removing any of the remaining protecting groups, to provide a compound of formula (7) or its salts:
2. - The method according to claim 1, further characterized in that it is for the preparation of a compound of formula (7) or its salts: wherein R1 represents an alkyl group, such as an alkyl group of C6-6, and preferably an isopropyl group, R2 represents an aryl group, preferably a phenyl group, R3 represents an aryl group, preferably a 4-fluorophenyl group, X represents a group of formula -COZ, wherein Z represents -OR4, wherein R4 represents an alkyl, preferably a methyl or ethyl group, or -NR5R6, wherein R5 and R6 each independently represent H, alkyl or aryl, and preferably R5 is H and R6 is phenyl, which comprises a) cyanation of a compound of formula (1): wherein Y represents a halogen group, preferably Cl or Br; P represents hydrogen or a protecting group, and W represents = O or -OP2, wherein P2 represents hydrogen or a protecting group, to provide a compound of formula b) reducing the compound of formula (2) to provide a compound of formula (3): c) coupling the compound of formula (3) with a compound of formula (4): to provide a compound of formula (5): d) when W represents -OP2, deprotection and then oxidation of the compound of formula (5) to provide a compound of formula (6): and e) subjecting the compound of formula (5) when W represents = O, or a compound of formula (6) to ring opening, and removing any of the remaining protecting groups, to provide a compound of formula (7) or its salts:
3. The process according to claim 2, further characterized in that R1 is an isopropyl group, R2 is a phenyl group, R3 is a 4-fluorophenyl group and X is a group -CO2Me, -CO2Et or -CONHPh.
4. A process for the preparation of a compound of formula (2): comprising the cyanation of a compound of formula (1): wherein Y represents a halogen group, preferably Cl or Br; P1 represents hydrogen or a protecting group, and W represents = O or -OP2, where P2 represents hydrogen or a protecting group.
5. A process for the preparation of a compound of formula (3): comprising the reduction of a compound of formula (2): wherein P1 represents hydrogen or a protecting group; and W represents = O or -OP2, wherein P2 represents hydrogen or a protecting group.
6. The process according to claim 4 or 5, further characterized in that P1 represents a benzyl or silyl group; and W represents = O or -OP2, wherein P2 represents a methyl group.
7. - A process for the preparation of a compound of formula (5): comprising the coupling of the compound of formula (3): with a compound of formula (4): wherein R1 represents an alkyl group, such as an alkyl group of C -? - 6, and preferably an isopropyl group, R2 represents an aryl group, preferably a phenyl group, R3 represents an aryl group, preferably a 4-fluorophenyl group, X represents a group of formula -COZ, wherein Z represents -OR4, wherein R4 represents an alkyl, preferably a methyl or ethyl group, or -NR5R6, wherein R5 and R6 each independently represents H, alkyl or aryl, and preferably R5 is H and R6 is phenyl, P1 represents hydrogen or a protecting group, preferably a benzyl or silyl group; and W represents = O or -OP2, wherein P2 represents hydrogen or a protecting group, preferably OP2 where P2 is a methyl group.
8. A compound of formula (2): wherein P1 represents hydrogen or a protecting group; and W represents = O or -OP2, wherein P2 represents hydrogen or a protecting group.
9. The compound according to claim 8, further characterized in that P1 is a protecting group and preferably W represents -OP2, and more preferably P1 and P2 are different.
10. The compound according to claim 9, further characterized in that P1 is a benzyl or silyl group and W represents OP2 where P2 is a methyl group.
11. A compound of formula (3): wherein P1 represents hydrogen or a protecting group; and W represents = O or -OP2, wherein P2 represents hydrogen or a protecting group.
12. The compound according to claim 11, further characterized in that P1 is a protecting group and preferably W represents -OP2, and more preferably P1 and P2 are different.
13. The compound according to claim 12, further characterized in that P1 is a benzyl or silyl group and W represents OP2 where P2 is a methyl group.
14. A compound of formula (5): wherein R1 represents an alkyl group, such as an alkyl group of C6-6, and preferably an isopropyl group, R2 represents an aryl group, preferably a phenyl group, R3 represents an aryl group, preferably a 4-fluorophenyl group, X represents a group of formula -COZ, wherein Z represents -OR4, wherein R4 represents an alkyl, preferably a methyl or ethyl group, or -NR5R6, wherein R5 and R6 each independently represent H, alkyl or aryl, and preferably R5 is H and R6 is phenyl, P1 represents hydrogen or a protecting group; and W represents -OP2, wherein P2 represents hydrogen or a protecting group. SUMMARY OF THE INVENTION A process for the preparation of a compound of formula (7) or salts thereof is provided: wherein R1 represents a hydrogen or a hydrocarbyl group, R2 represents a hydrogen or a substituent group, R3 represents a hydrogen or a hydrocarbyl group, and X represents a hydrogen or a substituent group, comprising a) cyanation of a compound of formula (1): wherein Y represents a halogen group, preferably Cl or Br; P1 represents hydrogen or a protective group, and W represents = O or -OP2, wherein P2 represents hydrogen or a protecting group, to provide a compound of formula (2): b) reducing the compound of formula (2) to provide a compound of formula (3): c) coupling the compound of formula (3) with a compound of formula to provide a compound of formula (5): d) when W represents -OP 52, deprotection and then oxidation of the compound of formula (5) to provide a compound of formula (6): and e) subjecting the compound of formula (5) when W represents = O, or a compound of formula (6) to a ring opening, and removing any of the remaining protecting groups, to provide a compound of formula (7) or its salts: 7A / mmf * nsh * ecj * gcg * P05 / 2105F
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0317393.7 | 2003-07-25 | ||
GB0406760.9 | 2004-03-26 |
Publications (1)
Publication Number | Publication Date |
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MXPA06000926A true MXPA06000926A (en) | 2006-12-13 |
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