ITMI20100753A1 - PROCEDURE FOR THE PREPARATION OF STATINES - Google Patents
PROCEDURE FOR THE PREPARATION OF STATINES Download PDFInfo
- Publication number
- ITMI20100753A1 ITMI20100753A1 IT000753A ITMI20100753A ITMI20100753A1 IT MI20100753 A1 ITMI20100753 A1 IT MI20100753A1 IT 000753 A IT000753 A IT 000753A IT MI20100753 A ITMI20100753 A IT MI20100753A IT MI20100753 A1 ITMI20100753 A1 IT MI20100753A1
- Authority
- IT
- Italy
- Prior art keywords
- formula
- compound
- salt
- group
- statin
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 36
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 8
- -1 β-ketoacid compound Chemical class 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 238000006114 decarboxylation reaction Methods 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910003074 TiCl4 Inorganic materials 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 2
- 150000002602 lanthanoids Chemical class 0.000 claims description 2
- 239000011968 lewis acid catalyst Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 229910052723 transition metal Inorganic materials 0.000 claims description 2
- 150000003624 transition metals Chemical class 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000003480 eluent Substances 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 6
- 101150041968 CDC13 gene Proteins 0.000 description 6
- 239000007832 Na2SO4 Substances 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
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 229960003765 fluvastatin Drugs 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229960002797 pitavastatin Drugs 0.000 description 4
- 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 description 4
- 229960000672 rosuvastatin Drugs 0.000 description 4
- 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 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- PDBMVYIMAMQDCW-UHFFFAOYSA-N 3,5-dihydroxyheptanoic acid Chemical compound CCC(O)CC(O)CC(O)=O PDBMVYIMAMQDCW-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LJIZUXQINHXGAO-ITWZMISCSA-N HR 780 Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 LJIZUXQINHXGAO-ITWZMISCSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229950005357 bervastatin Drugs 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229960005110 cerivastatin Drugs 0.000 description 2
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- ZADJRRFMOOACHL-WQICJITCSA-N ethyl (e,3s,5r)-7-[4-(4-fluorophenyl)spiro[chromene-2,1'-cyclopentane]-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound C12=CC=CC=C2OC2(CCCC2)C(/C=C/[C@H](O)C[C@H](O)CC(=O)OCC)=C1C1=CC=C(F)C=C1 ZADJRRFMOOACHL-WQICJITCSA-N 0.000 description 2
- 229950000806 glenvastatin Drugs 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 229960002965 pravastatin Drugs 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- UQTAMVHWXCJSIR-LLVKDONJSA-N (5r)-5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-3,7-dioxoheptanoic acid Chemical compound COC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)CC(O)=O UQTAMVHWXCJSIR-LLVKDONJSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JAHBIRPTCXOGLB-UHFFFAOYSA-N 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde Chemical compound C1=CC(F)=CC=C1C1=C(C=O)C(C2CC2)=NC2=CC=CC=C12 JAHBIRPTCXOGLB-UHFFFAOYSA-N 0.000 description 1
- ZHEVDQXUHZWVTE-UHFFFAOYSA-N 3-hydroxyoxane-2,6-dione Chemical compound OC1CCC(=O)OC1=O ZHEVDQXUHZWVTE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 241000228153 Penicillium citrinum Species 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- JFKWZVQEMSKSBU-AWEZNQCLSA-N benzyl (2s)-2-hydroxy-2-phenylacetate Chemical compound O=C([C@@H](O)C=1C=CC=CC=1)OCC1=CC=CC=C1 JFKWZVQEMSKSBU-AWEZNQCLSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010596 desymmetrization reaction Methods 0.000 description 1
- 238000011917 diastereoselective reduction Methods 0.000 description 1
- FESAXEDIWWXCNG-UHFFFAOYSA-N diethyl(methoxy)borane Chemical compound CCB(CC)OC FESAXEDIWWXCNG-UHFFFAOYSA-N 0.000 description 1
- 235000010300 dimethyl dicarbonate Nutrition 0.000 description 1
- 239000004316 dimethyl dicarbonate Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- WGJJZRVGLPOKQT-UHFFFAOYSA-K lanthanum(3+);trifluoromethanesulfonate Chemical compound [La+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F WGJJZRVGLPOKQT-UHFFFAOYSA-K 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- HFOVTPILZMOMQW-GFCCVEGCSA-N methyl (3r)-3-[tert-butyl(dimethyl)silyl]oxy-5-imidazol-1-yl-5-oxopentanoate Chemical compound COC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1C=CN=C1 HFOVTPILZMOMQW-GFCCVEGCSA-N 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- 229950009116 mevastatin Drugs 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 238000013048 microbiological method Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000006772 olefination reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- VBQCHPIMZGQLAZ-UHFFFAOYSA-N phosphorane Chemical class [PH5] VBQCHPIMZGQLAZ-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 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
- 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 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“PROCEDIMENTO PER LA PREPARAZIONE DI STATINE” "PROCEDURE FOR THE PREPARATION OF STATINS"
CAMPO DELL’INVENZIONE FIELD OF THE INVENTION
La presente invenzione riguarda un nuovo procedimento per la preparazione di intermedi sintetici a struttura β-chetoesterea utili nella preparazione di statine. The present invention relates to a new process for the preparation of synthetic intermediates with β-ketoesterea structure useful in the preparation of statins.
STATO DELLA TECNICA STATE OF THE TECHNIQUE
Le statine sono una classe di composti farmaceutici utili nel trattamento della colesterolemia. Il loro meccanismo d’azione è legato alla capacità di queste molecole di agire come inibitori dell’attività della 3-idrossi-3-metilglutarico Coenzima A reduttasi (HMG-CoA), che si traduce nella inibizione a livello epatico della biosintesi del colesterolo. La struttura molecolare delle statine è normalmente costituita da una porzione A e da una catena laterale come sotto riportato. Statins are a class of pharmaceutical compounds useful in the treatment of cholesterolemia. Their mechanism of action is linked to the ability of these molecules to act as inhibitors of the activity of 3-hydroxy-3-methylglutaric Coenzyme A reductase (HMG-CoA), which results in the hepatic inhibition of cholesterol biosynthesis. The molecular structure of statins is normally made up of a portion A and a side chain as reported below.
dove il legame in grassetto \ rappresenta un legame semplice \ o doppio where the bold link \ represents a simple \ or double link
La loro attività è attribuita proprio alla presenza della catena laterale, costituita essenzialmente da un residuo di acido 3,5-diidrossi eptanoico che mima il raggruppamento 3-idrossi-3metilglutarico del HMG-CoA. Their activity is attributed precisely to the presence of the side chain, essentially consisting of a residue of 3,5-dihydroxy heptanoic acid which mimics the 3-hydroxy-3methylglutaric grouping of HMG-CoA.
La configurazione (R) al C-3 e la configurazione relativa syn tra gli ossidrili è stata dimostrata essere essenziale per ottenere una alta attività inibitoria. In tutte le statine sviluppate e commercializzate fino ad oggi il problema chimico principale da risolvere era rappresentato proprio dalla sintesi del residuo di acido 3,5-diidrossi eptanoico otticamente attivo. Il problema è stato fino ad ora risolto impiegando le metodologie più diverse, come metodi enzimatici e microbiologici, (si veda Angew. Chem. Ini. Ed. The (R) configuration at C-3 and the relative syn configuration between the hydroxyls was shown to be essential to obtain a high inhibitory activity. In all the statins developed and marketed to date, the main chemical problem to be solved was represented precisely by the synthesis of the optically active 3,5-dihydroxy heptanoic acid residue. The problem has so far been solved by using the most diverse methodologies, such as enzymatic and microbiological methods, (see Angew. Chem. Ini. Ed.
2005, 44, 362-365), ma anche sintetici (Helvetica Chimica Acta, 2007, 1069-1081). Tra i metodi sintetici attualmente disponibili ci sono sia processi che prevedono la sintesi enantio selettiva dell’acido, che quelli che portano alla formazione del racemo e successiva risoluzione. Tutte queste metodologie hanno permesso di ottenere intermedi sintetici otticamente attivi, ormai reperibili anche in commercio, che una volta inseriti nella struttura della statina portano alla sintesi della catena laterale in forma otticamente attiva. 2005, 44, 362-365), but also synthetics (Helvetica Chimica Acta, 2007, 1069-1081). Among the synthetic methods currently available there are both processes that involve the selective enantium synthesis of the acid, and those that lead to the formation of the racemic and subsequent resolution. All these methodologies have made it possible to obtain optically active synthetic intermediates, now also available on the market, which once inserted in the statin structure lead to the synthesis of the side chain in an optically active form.
La prima statina è stata la mevastatina, isolata dal Penicillium citrinum, e impiegata successivamente nella sintesi della statina semisintetica pravastatina. Le statine oggigiorno presenti in commercio, ad esempio sia la pravastatina semisintetica che la lovastatina, di origine completamente naturale, sono caratterizzate dall’avere la catena laterale legata al nucleo A con un legame singolo C-C o C-N (il legame in grassetto nella formula sopra riportata). Recentemente invece si sono imposte sul mercato delle statine di origine completamente sintetica come ed esempio la rosuvastatina, la fluvastatina e la pitavastatina, dotate di altissima attività biologica. Queste statine sono caratterizzate da una catena laterale legata tramite un doppio legame C=C a geometria rigorosamente (E) (legame in grassetto della formula sopra riportata) al nucleo A della statina, normalmente avente una complessa struttura aromatica. Anche in questo caso gli approcci alla risoluzione del problema della configurazione assoluta del doppio legame sono stati i più vari e le sintesi proposte sono state sia consecutive che convergenti. In particolare però sono stati sviluppati ed ottimizzati i metodi per ottenere in maniera convergente la formazione della statina col doppio legame a geometria (E). Questi metodi si basano sulle metodologie classiche della formazione dei doppi legami (E) mediante reazioni di olefinazione su opportune aldeidi, presenti indifferentemente o sulla porzione aromatica o sulla catena laterale della statina, attraverso reazioni di Wittig, Horner-Emmons o Julia, come ben riassunto in Organic Process Research & Development 2001, 5, 519-527 per la fluvastatina. The first statin was mevastatin, isolated from Penicillium citrinum, and subsequently used in the synthesis of the semisynthetic statin pravastatin. Statins present on the market today, for example both semi-synthetic pravastatin and lovastatin, of completely natural origin, are characterized by having the side chain linked to nucleus A with a single C-C or C-N bond (the link in bold in the above formula ). Recently, however, statins of completely synthetic origin such as rosuvastatin, fluvastatin and pitavastatin, with very high biological activity, have established themselves on the market. These statins are characterized by a side chain linked by a C = C double bond with a strictly (E) geometry (link in bold of the above formula) to the A nucleus of the statin, normally having a complex aromatic structure. Also in this case the approaches to solving the problem of the absolute configuration of the double bond have been the most varied and the proposed syntheses have been both consecutive and convergent. In particular, however, methods have been developed and optimized to obtain the formation of the statin with the double bond with geometry (E) in a convergent manner. These methods are based on the classical methodologies of the formation of double bonds (E) by means of olefination reactions on suitable aldehydes, present indifferently or on the aromatic portion or on the side chain of the statin, through reactions of Wittig, Horner-Emmons or Julia, as well summarized. in Organic Process Research & Development 2001, 5, 519-527 for fluvastatin.
Sebbene queste metodiche abbiano portato all’ ottenimento di diverse statine di grande successo commerciale, queste sintesi soffrono ancora in molti casi di problemi di regioselettività, legate alla formazione della statina impurezza col doppio legame a configurazione (Z), di problemi di costi legati all’uso di basi organiche e reattivi costosi, delicati o da preparare in situ in condizioni sofisticate di reazione, e nel caso di fosforani e fosfonati, impiegati per la Wittig, pure del problema dello smaltimento dei reflui contenenti fosforo organico. Although these methods have led to the obtaining of several highly commercially successful statins, these syntheses still suffer in many cases from regioselectivity problems, linked to the formation of the impurity statin with the double bond at configuration (Z), from problems of costs related to the use of expensive, delicate or reactive organic bases and reactives to be prepared in situ under sophisticated reaction conditions, and in the case of phosphoranes and phosphonates, used for Wittig, also the problem of disposing of waste containing organic phosphorus.
Esiste quindi la necessità di un metodo alternativo più vantaggioso per preparare le statine, in particolare quelle di formula (I), qui riportate, contenenti un doppio legame -C=C- a configurazione (E) tra la catena laterale ed in nucleo A, ed intermedi utili per la loro sintesi. Tale nuovo metodo dovrebbe in particolare essere più semplicemente scalabile industrialmente, prevedere l’impiego di reagenti possibilmente più stabili ed economici, allo stesso tempo fornire alte rese e reflui di processo più ecocompatibili e facilmente smaltibili. There is therefore a need for a more advantageous alternative method to prepare statins, in particular those of formula (I), reported here, containing a double bond -C = C- with configuration (E) between the side chain and in nucleus A, and intermediates useful for their synthesis. This new method should in particular be more simply industrially scalable, provide for the use of possibly more stable and economical reagents, at the same time providing high yields and more environmentally friendly and easily disposable process waste.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
E stato qui sorprendentemente trovato che è possibile preparare statine di formula (I) contenenti un doppio legame -C=C- a configurazione (E), da intermedi di formula (Π), ottenuti mediante condensazione di Knoevenagel. Gli intermedi di formula (II) così ottenute presentano un contenuto di isomero a configurazione (Z) inferiore all’ 1% valutato mediante HPLC. It has been surprisingly found here that it is possible to prepare statins of formula (I) containing a double bond -C = C- with configuration (E), from intermediates of formula (Π), obtained by Knoevenagel condensation. The intermediates of formula (II) thus obtained have a configuration isomer content (Z) lower than 1% evaluated by HPLC.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Oggetto della presente invenzione è un procedimento per la preparazione di un composto di formula (II), o un suo sale, The object of the present invention is a process for the preparation of a compound of formula (II), or a salt thereof,
dove A è il gruppo residuo di una statina, P è un gruppo protettivo, e Ri è idrogeno, un gruppo Ci-C12alchile opzionalmente sostituito, cicloalchile, arile, oppure un gruppo arile-Ci-C^ alchile opzionalmente sostituito; comprendente la condensazione di una aldeide di formula (III) ^ CHO where A is the residual group of a statin, P is a protecting group, and R1 is hydrogen, an optionally substituted C 1 -C12alkyl group, cycloalkyl, aryl, or an optionally substituted aryl-C1-C 2 alkyl group; comprising the condensation of an aldehyde of formula (III) ^ CHO
dove A è come prima definito, con un composto β-chetoacido di formula (IV), o un suo sale, where A is as defined above, with a β-ketoacid compound of formula (IV), or a salt thereof,
dove P e Ri sono come prima definiti, in presenza di un catalizzatore, se necessario in un solvente, e successiva spontanea decarbossilazione. where P and Ri are defined as before, in the presence of a catalyst, if necessary in a solvent, and subsequent spontaneous decarboxylation.
Ad esempio A può essere il gruppo residuo di una statina scelta tra Pitavastatina, Fluvastatina, Glenvastatina, Rosuvastatina, Cerivastatina e Bervastatina. Tale residuo può essere rappresentato da una delle strutture cicliche riportate di seguito. For example A can be the residual group of a statin chosen from Pitavastatin, Fluvastatin, Glenvastatin, Rosuvastatin, Cerivastatin and Bervastatin. This residue can be represented by one of the cyclical structures shown below.
Pitavastatina Fluvastatina Glenvastatina Pitavastatin Fluvastatin Glenvastatin
Rosuvastatina Cerivastatina Bervastatina dove la linea tratteggiata indica il punto d’aggancio della catena laterale sul residuo della statina. Preferibilmente il gruppo residuo A è il nucleo della pitavastatina, della fluvastatina o della rosuvastatina. Rosuvastatin Cerivastatin Bervastatin where the dotted line indicates the attachment point of the side chain on the statin residue. Preferably the residual group A is the core of pitavastatin, fluvastatin or rosuvastatin.
P come un gruppo protettivo della funzione ossidrilica, esso può essere ad esempio scelto tra quelli utilizzati nella chimica degli zuccheri, preferibilmente è il gruppo tert-butil dimetilsilile. P as a protecting group of the hydroxyl function, it can be selected for example from those used in sugar chemistry, preferably it is the tert-butyl dimethylsilyl group.
Un gruppo Ci-C12alchile, può essere lineare o ramificato, non sostituito o sostituito da uno o due sostituenti scelti indipendentemente tra idrossi, acetossi e Ci-C4alcossi, preferibilmente è un gruppo Ci-C4alchile, più preferibilmente metile e tert-butile. A C1-C12alkyl group can be linear or branched, unsubstituted or substituted by one or two substituents independently selected from hydroxy, acetoxy and C1-C4alkoxy, preferably it is a C1-C4alkyl group, more preferably methyl and tert-butyl.
Un gruppo cicloalchile può essere ad esempio un gruppo C3-C8cicloalchilico, ad esempio cicloesile. A cycloalkyl group can be for example a C3-C8cycloalkyl group, for example cyclohexyl.
Un gruppo arile è ad esempio un gruppo C6-C12arile, preferibilmente fenile o naftile, in particolare fenile. An aryl group is for example a C6-C12aryl group, preferably phenyl or naphthyl, in particular phenyl.
Un gruppo arile-C6-C12alchile, dove Falchile è non sostituito o sostituito da uno o due sostituenti scelti indipendentemente tra idrossi, acetossi e Ci-C4alcossi, è ad esempio benzile o feniletile, preferibilmente benzile. An aryl-C6-C12alkyl group, where Falkyl is unsubstituted or substituted by one or two substituents independently selected from hydroxy, acetoxy and C1-C4alkoxy, is for example benzyl or phenylethyl, preferably benzyl.
La condensazione di Knoevenagel può essere condotta in accordo a metodi noti, ad esempio in presenza di uno dei catalizzatori noti dalla letteratura per questa reazione. In particolare il catalizzatore può essere un catalizzatore basico o acido, organico o inorganico. Knoevenagel condensation can be carried out according to known methods, for example in the presence of one of the catalysts known from the literature for this reaction. In particular, the catalyst can be a basic or acidic, organic or inorganic catalyst.
Un catalizzatore basico organico può essere scelto tra una ammina secondaria ed una ammina terziaria, sia debole che forte, ciclica o aciclica, o un suo sale, ad esempio piperidina o un suo sale, tipicamente sale acetato. An organic basic catalyst can be selected from a secondary amine and a tertiary amine, either weak or strong, cyclic or acyclic, or a salt thereof, for example piperidine or a salt thereof, typically acetate salt.
Un catalizzatore basico inorganico può essere scelto ad esempio tra un carbonato di un metallo alcalino ed un idrossido di un metallo alcalino, preferibilmente sodio o potassio. An inorganic basic catalyst can be selected, for example, between a carbonate of an alkali metal and a hydroxide of an alkali metal, preferably sodium or potassium.
Alternativamente la condensazione di Knoevenagel può essere effettuata con un catalizzatore acido di Lewis. Un acido di Lewis può essere ad esempio scelto tra ZnCl2, FeCl3, TiCl4, Ti tetraisopropossido, A1C13, BF3eterato, un alogenuro, ad esempio un cloruro o un trifluorometansolfonato di un metallo di transizione della serie dei lantanidi, preferibilmente lantanio trifluorometansolfonato in forma sia anidra che idrata. Alternatively, the Knoevenagel condensation can be carried out with a Lewis acid catalyst. A Lewis acid can be selected for example from ZnCl2, FeCl3, TiCl4, Ti tetraisopropoxide, A1C13, BF3eterate, a halide, for example a chloride or a trifluoromethanesulfonate of a transition metal of the lanthanide series, preferably lanthanum trifluoromethanesulfonate in both anhydrous form that hydrates.
La condensazione di Knoevenagel, se necessario, può essere condotta in un solvente, ad esempio un solvente polare aprotico, tipicamente un’ammide, ad esempio dimetilformammide, dimetilacetammide o N-metilpirrolidone, preferibilmente dimetilacetammide; acetonitrile; dimetilsolfossido; oppure in un solvente scelto tra un etere, ad esempio tetraidrofurano o diossano; un solvente clorurato, ad esempio, diclorometano, dicloroetano, cloroformio o clorobenzene; un estere, ad esempio acetato di etile o di metile; un solvente apolare aprotico tipicamente toluene; oppure un solvente polare protico, ad esempio acqua o un Ci-C5alcanolo, preferibilmente metanolo; od una miscela di due o più, preferibilmente di due o tre, di detti solventi. The condensation of Knoevenagel, if necessary, can be carried out in a solvent, for example an aprotic polar solvent, typically an amide, for example dimethylformamide, dimethylacetamide or N-methylpyrrolidone, preferably dimethylacetamide; acetonitrile; dimethyl sulfoxide; or in a solvent selected from an ether, for example tetrahydrofuran or dioxane; a chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or chlorobenzene; an ester, for example ethyl or methyl acetate; a non-polar aprotic solvent typically toluene; or a polar protic solvent, for example water or a C 1 -C 5 alkanol, preferably methanol; or a mixture of two or more, preferably two or three, of said solvents.
La reazione può essere condotta ad una temperatura compresa tra circa 0°C e la temperatura di riflusso del solvente, preferibilmente tra circa 25°C e 85°C. The reaction can be carried out at a temperature comprised between about 0 ° C and the reflux temperature of the solvent, preferably between about 25 ° C and 85 ° C.
Il composto di formula (II) grezzo così ottenuto presenta il doppio legame in configurazione (E) ed un contenuto di isomero a configurazione (Z) inferiore all’ 1%, valutato mediante HPLC. The crude compound of formula (II) thus obtained has the double bond in configuration (E) and an isomer content in configuration (Z) lower than 1%, evaluated by HPLC.
Un ulteriore oggetto dell’ invenzione è una statina di formula (I), o un suo sale, con un contenuto di isomero a configurazione (Z) inferiore all’ 1%, preferibilmente compreso tra circa 0,01 e 0,1%, valutato mediante HPLC. A further object of the invention is a statin of formula (I), or a salt thereof, with a content of configuration isomer (Z) lower than 1%, preferably between about 0.01 and 0.1%, evaluated by HPLC.
Un composto di formula (II), o un suo sale, così ottenuto, può essere convertito in una statina di formula (I), o un solo sale, in accordo a metodiche note, ad esempio secondo il seguente schema riportato in WO 03064392. A compound of formula (II), or a salt thereof, thus obtained, can be converted into a statin of formula (I), or a single salt, according to known methods, for example according to the following scheme reported in WO 03064392.
1 ) deprotezione 1) deprotection
2) riduzione diastereoselettiva 2) diastereoselective reduction
3) saponificazione 3) saponification
(II) (II)
dove A, P e Ri sono come prima definiti. where A, P and Ri are defined as above.
Pertanto l’invenzione fornisce inoltre un procedimento comprendente la conversione di un composto di formula (II), o un suo sale, ottenuto a partire da un composto di formula (IV), in una statina di formula (I), o un suo sale, Therefore, the invention also provides a process comprising the conversion of a compound of formula (II), or a salt thereof, obtained starting from a compound of formula (IV), into a statin of formula (I), or a salt thereof. ,
dove A è il gruppo residuo di una statina. where A is the residual group of a statin.
Un sale di un composto di formula (I) è ad esempio un sale farmaceuticamente accettabile, preferibilmente il sale di calcio. A salt of a compound of formula (I) is for example a pharmaceutically acceptable salt, preferably the calcium salt.
I composti di formula (III) possono essere preparati come descritto ad esempio in Organic Process Research & Development 2001, 5, 519-527, per il caso della fluvastatina e sono commercialmente disponibili. The compounds of formula (III) can be prepared as described for example in Organic Process Research & Development 2001, 5, 519-527, for the case of fluvastatin and are commercially available.
Un composto di formula (IV), o un suo sale, può essere preparato a partire da un composto di formula (V), o un suo sale, per rimozione selettiva del gruppo estereo R2, A compound of formula (IV), or a salt thereof, can be prepared starting from a compound of formula (V), or a salt thereof, by selective removal of the ester group R2,
(V) (IV) (V) (IV)
dove P è come sopra definito; R2è un gruppo CrC12alchile, cicloalchile, arile, oppure arile-Ci-C^ alchile; ed Ri è come prima definito. In un composto di formula (V), quando Ri è diverso da idrogeno, Ri e R2possono essere uguali o diversi. Preferibilmente R2è benzile e Ri è metile. where P is as defined above; R 2 is a CrC12alkyl, cycloalkyl, aryl, or aryl-C 1 -C6 alkyl group; and Ri is as defined above. In a compound of formula (V), when Ri is different from hydrogen, Ri and R2 can be the same or different. Preferably R2 is benzyl and R1 is methyl.
Preferibilmente R2può essere rimosso a dare l’acido carbossilico libero di formula (V) in maniera selettiva rispetto alla protezione P ed eventualmente al gruppo Ri quando questo è diverso da idrogeno. Ad esempio, in accordo ad un aspetto preferito dell’ invenzione, quando in un composto di formula (V) Ri è metile, R2è benzile, la rimozione del gruppo benzile può essere effettuata mediante idrogenazione catalitica con i metodi noti alla persona esperta dell’ arte. Preferably R2 can be removed to give the free carboxylic acid of formula (V) in a selective manner with respect to the protection P and possibly to the group Ri when this is different from hydrogen. For example, according to a preferred aspect of the invention, when in a compound of formula (V) Ri is methyl, R2 is benzyl, the removal of the benzyl group can be carried out by catalytic hydrogenation with the methods known to the person skilled in the art. .
I composti di formula (IV) e (V), o un loro sale, sono nuovi e costituiscono un ulteriore oggetto della presente invenzione. The compounds of formula (IV) and (V), or a salt thereof, are new and constitute a further object of the present invention.
Un ulteriore oggetto dell’invenzione è l’uso di un composto di formula (IV) in un procedimento per la preparazione di una statina di formula (I)· A further object of the invention is the use of a compound of formula (IV) in a process for the preparation of a statin of formula (I) ·
Un composto di formula (V), o un suo sale, può essere preparato per reazione tra un composto di formula (VI), o un suo sale, ed un composto di formula (VII), o un suo sale, in presenza di un solvente A compound of formula (V), or a salt thereof, can be prepared by reaction between a compound of formula (VI), or a salt thereof, and a compound of formula (VII), or a salt thereof, in the presence of a solvent
(VI) (VII) (V) (VI) (VII) (V)
dove P, Ri ed R2sono come sopra definiti ed X è un gruppo uscente, preferibilmente un alogeno, in particolare cloro, o imidazolo. Il solvente è preferibilmente un solvente etereo ad esempio tetraidro furano. where P, Ri and R2 are as defined above and X is a leaving group, preferably a halogen, in particular chlorine, or imidazole. The solvent is preferably an ethereal solvent, for example tetrahydro furan.
L’acido maionico monoestere (VI) dove R2, essendo come prima definito, è preferibilmente benzile può essere prima convertito nel suo sale di magnesio per trattamento con almeno 2 equivalenti di un reattivo di Grignard, ad esempio isopropilmagnesio cloruro, e poi fatto reagire con un composto di formula (VII), a fornire, dopo spontanea decarbossilazione, il composto di formula (V). Monoester (VI) mayionic acid where R2, being defined as above, is preferably benzyl can first be converted into its magnesium salt by treatment with at least 2 equivalents of a Grignard reagent, for example isopropylmagnesium chloride, and then reacted with a compound of formula (VII), to yield, after spontaneous decarboxylation, the compound of formula (V).
Un composto di formula (VI) è commercialmente disponibile o può essere preparato con metodologie note per mono esterificazione dell’acido maionico. A compound of formula (VI) is commercially available or can be prepared with known methods for monoesterification of mayionic acid.
Un composto di formula (VII), o un suo sale, a sua volta può essere preparato per attivazione della funzione carbossilica di un composto di formula (Vili), o un suo sale, A compound of formula (VII), or a salt thereof, can in turn be prepared by activating the carboxyl function of a compound of formula (VIII), or a salt thereof,
(Vili) (VII) (VIII) (VII)
dove P, Ri ed X sono come sopra definiti. where P, Ri and X are as defined above.
Quando X è cloro, l’attivazione dell’acido carbossilico di formula (Vili) può essere effettuata impiegando ad esempio cloruro di tionile, quando X è imidazolo, si può ad esempio impiegare il carbonildiimidazolo. When X is chlorine, the activation of the carboxylic acid of formula (VIII) can be carried out using for example thionyl chloride, when X is imidazole, for example, carbonyldiimidazole can be used.
Un composto di formula (Vili) è commercialmente disponibile o può essere preparato ad esempio mediante desimmetrizzazione chimica dell’ anidride idrossiglutarica protetta con il gruppo protettivo P, definito precedentemente, come riportato ad esempio in /. Org. Chem. 1994, 59, 7849-7854, o desimmetrizzazione enzimatica, come riportato in Angew. Chem. Int. Ed. 2005, 44, 362-365. A compound of formula (VIII) is commercially available or can be prepared for example by chemical desymmetrization of the hydroxyglutaric anhydride protected with the protective group P, defined previously, as reported for example in /. Org. Chem. 1994, 59, 7849-7854, or enzymatic desymmetry, as reported in Angew. Chem. Int. Ed. 2005, 44, 362-365.
Un sale di un composto di formula (II), (IV), (V), (VI), (VII) o (Vili) è ad esempio un sale farmaceuticamente accettabile. A salt of a compound of formula (II), (IV), (V), (VI), (VII) or (VIII) is for example a pharmaceutically acceptable salt.
Se desiderato, un composto di formula (I), (II), (IV), (V), (VI), (VII) o (VIII) può essere convertito in un suo sale, oppure un sale di un composto di formula (I), (II), (IV), (V), (VI), (VII) o (Vili) può essere convertito nell’acido libero, in accordo a metodi noti. If desired, a compound of formula (I), (II), (IV), (V), (VI), (VII) or (VIII) can be converted into a salt thereof, or a salt of a compound of formula (I), (II), (IV), (V), (VI), (VII) or (VIII) can be converted into free acid according to known methods.
I seguenti esempi illustrano l’invenzione. The following examples illustrate the invention.
Esempio 1. Sintesi di un composto di formula (VII): (R)-metil 3-(ter-butildimetilsililossi)-5-(lH-imidazol-l-il)-5-ossopentanoato Example 1. Synthesis of a compound of formula (VII): (R) -methyl 3- (tert-butyldimethylsilyloxy) -5- (1H-imidazol-1-yl) -5-oxopentanoate
Una soluzione di (S)-benzil mandelato (6 g, 24,79 mmol) in THF anidro (100 mL) in atmosfera di N2 viene portata a -78°C ed una soluzione di BuLi 2.5 M in esano (10,9 mL, 27,27 mmol) viene aggiunta goccia a goccia. La miscela è tenuta sotto agitazione a -78°C per 20 minuti, poi viene aggiunta una soluzione di anidride 3-[(ter-butildimetilsilil)ossi]pentandioica (6,05 g, 24,79 mmol) in THF anidro (25 mL) e la miscela risultante è mantenuta sotto agitazione magnetica a -78°C per 2 ore. La reazione viene acidificata con HC1 1 N ed estratta con EtOAc. La fase organica è lavata con HC1 1 N e brine, anidrificata su Na2S04, filtrata ed evaporata a pressione ridotta. Il grezzo di reazione è purificato tramite cromatografia flash su gel di silice (eluente: EtPet/EtOAc 4:1) ed il prodotto ottenuto è disciolto in THF anidro (150 mi) e trattato con dimetil dicarbonato (2,47 mL, 23,04 mmol) e DMAP (201 mg, 1,65 mmol). La miscela viene mantenuta in agitazione a 25 °C per 20 minuti, quindi il solvente è evaporato a pressione ridotta ed il residuo purificato tramite cromatografia flash (eluente: EtPet/EtOAc 9:1). L’olio incolore ottenuto è disciolto in etile acetato (90 mL) e la soluzione ottenuta viene mantenuta sotto agitazione in atmosfera di H2in presenza di Pd(OH)2/C 20% (652 mg, 0,93 mmol) a 20°C per 10 ore. La miscela è filtrata su celite ed il solvente viene evaporato a pressione ridotta. Il grezzo di reazione (contenente acido fenilacetico come impurezza) è solubilizzato in THF anidro in atmosfera di N2e si trattato con Ι,Γ-carbonildiimidazolo (3,02 g, 18,68 mmol). La miscela viene lasciata sotto agitazione a 20°C per 3 ore. Il solvente è evaporato a pressione ridotta ed il residuo è purificato tramite cromatografia flash su gel di silice (eluente: EtPet/EtOAc 30:70). Si ottengono 2,85 g di un olio giallo chiaro (Resa 41,6% su 4 passaggi). A solution of (S) -benzyl mandelate (6 g, 24.79 mmol) in anhydrous THF (100 mL) in an N2 atmosphere is brought to -78 ° C and a solution of 2.5 M BuLi in hexane (10.9 mL , 27.27 mmol) is added dropwise. The mixture is stirred at -78 ° C for 20 minutes, then a solution of 3 - [(tert-butyldimethylsilyl) oxy] pentanedioic anhydride (6.05 g, 24.79 mmol) in anhydrous THF (25 mL ) and the resulting mixture is kept under magnetic stirring at -78 ° C for 2 hours. The reaction is acidified with 1 N HCl and extracted with EtOAc. The organic phase is washed with 1 N HC1 and brine, anhydrified on Na2SO4, filtered and evaporated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: EtPet / EtOAc 4: 1) and the product obtained is dissolved in anhydrous THF (150 ml) and treated with dimethyl dicarbonate (2.47 mL, 23.04 mmol) and DMAP (201 mg, 1.65 mmol). The mixture is kept under stirring at 25 ° C for 20 minutes, then the solvent is evaporated under reduced pressure and the residue purified by flash chromatography (eluent: EtPet / EtOAc 9: 1). The colorless oil obtained is dissolved in ethyl acetate (90 mL) and the resulting solution is kept under stirring in an H2 atmosphere in the presence of 20% Pd (OH) 2 / C (652 mg, 0.93 mmol) at 20 ° C for 10 hours. The mixture is filtered on celite and the solvent is evaporated under reduced pressure. The reaction crude (containing phenylacetic acid as impurity) is solubilized in anhydrous THF in an N2 atmosphere and treated with Ι, Γ-carbonyldiimidazole (3.02 g, 18.68 mmol). The mixture is left under stirring at 20 ° C for 3 hours. The solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel (eluent: EtPet / EtOAc 30:70). 2.85 g of a light yellow oil are obtained (yield 41.6% over 4 passages).
1H NMR (400 MHz, CDC13) δ: 8.06 (s, IH); 7.37 (s, IH), 6.92 (s, IH); 4.54-5.52 (m, IH); 3.53 (s, 3H); 3.04-2.96 (s, 2H); 2.50-2.40 (m, 2H); 0.62 (s, 9H); -0.1 (s, 3H), -0.21 (s, 3H).<13>C NMR (100 MHz, CDC13) δ: 170.36; 167.19; 136.06; 130.47; 115.68; 65.69; 51.11; 42.35; 41.41; 24.95; 17.17; -5.58; -5.79. MS(ES<+>): m/z 349 [M+Na]<+>. 1H NMR (400 MHz, CDC13) δ: 8.06 (s, 1H); 7.37 (s, 1H), 6.92 (s, 1H); 4.54-5.52 (m, 1H); 3.53 (s, 3H); 3.04-2.96 (s, 2H); 2.50-2.40 (m, 2H); 0.62 (s, 9H); -0.1 (s, 3H), -0.21 (s, 3H). <13> C NMR (100 MHz, CDC13) δ: 170.36; 167.19; 136.06; 130.47; 115.68; 65.69; 51.11; 42.35; 41.41; 24.95; 17.17; -5.58; -5.79. MS (ES <+>): m / z 349 [M + Na] <+>.
Esempio 2 Sintesi di un composto di formula (V): (Zf)-l-benzil 7-metil 5-(fer-butildimetilsililossi)-3-ossoeptandioato Example 2 Synthesis of a compound of formula (V): (Zf) -1-benzyl 7-methyl 5- (fer-butyldimethylsilyloxy) -3-oxoheptanedium
Isopropil magnesio cloruro (2 M in THF, 15,10 mL, 30,20 mmol) viene aggiunto goccia a goccia ad una soluzione di monobenzil maionato (2,93 g, 15,10 mmol) in THF anidro (28 mL) mantenuta a 0°C in atmosfera di N2. Dopo 30 minuti a 0°C la soluzione viene scaldata a 50°C per 30 minuti, poi raffreddata di nuovo a 0°C e si aggiunge lentamente una soluzione di (VII) preparato come in Esempio 1 (4,1 g, 12,58 mmol) in THF anidro (28 mL). La miscela viene lasciata sotto agitazione a 20°C per 12 ore, poi si aggiunge HC1 1 M e si estrae con Et20. La fase organica viene lavata con HC1 1 M e salamoia, anidrificata su Na2S04, filtrata e concentrata a pressione ridotta. Il grezzo di reazione viene purificato tramite cromatografia flash su gel di silice (eluente: EtPet/EtOAc 9: 1). Si ottengono 3,74 g di un olio giallo con una resa del 73%. Isopropyl magnesium chloride (2 M in THF, 15.10 mL, 30.20 mmol) is added dropwise to a solution of monobenzyl mayionate (2.93 g, 15.10 mmol) in anhydrous THF (28 mL) maintained at 0 ° C in N2 atmosphere. After 30 minutes at 0 ° C the solution is heated to 50 ° C for 30 minutes, then cooled again to 0 ° C and a solution of (VII) prepared as in Example 1 (4.1 g, 12, 58 mmol) in anhydrous THF (28 mL). The mixture is left under stirring at 20 ° C for 12 hours, then 1 M HCl is added and extracted with Et20. The organic phase is washed with 1 M HCl and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: EtPet / EtOAc 9: 1). 3.74 g of a yellow oil are obtained with a yield of 73%.
1H NMR (400 MHz, CDC13) δ: 7.32-7.28 (m, 5H); 5.12 (s, 2H); 4.57-4.52 (m, IH); 3.60 (s, 3H); 3.47 (s, 2H); 2.75 (d, J = 6, 2H); 2.51-2.37 (m, 2H); 0.81 (s, 9H); 0.03 (d, J = 10, 3H).<13>C NMR (100 MHz, CDC13) δ: 200.23; 170.76; 166.24; 134.93; 128.14; 127.95; 127.83; 127.66; 66.61; 65.06; 51.04; 49.89; 49.54; 41.65; 25.26; 17.42; -5.29; -5.45. MS(ES<+>): m/z 431 [M+Na]<+>. 1H NMR (400 MHz, CDC13) δ: 7.32-7.28 (m, 5H); 5.12 (s, 2H); 4.57-4.52 (m, 1H); 3.60 (s, 3H); 3.47 (s, 2H); 2.75 (d, J = 6.2H); 2.51-2.37 (m, 2H); 0.81 (s, 9H); 0.03 (d, J = 10, 3H). <13> C NMR (100 MHz, CDC13) δ: 200.23; 170.76; 166.24; 134.93; 128.14; 127.95; 127.83; 127.66; 66.61; 65.06; 51.04; 49.89; 49.54; 41.65; 25.26; 17.42; -5.29; -5.45. MS (ES <+>): m / z 431 [M + Na] <+>.
Esempio 3. Sintesi di un composto di formula (IV): Acido ( R)-5-(ter -butildimetilsililossi)-7-metossi-3,7-diossoeptanoico. Example 3. Synthesis of a compound of formula (IV): (R) -5- (t-butyldimethylsilyloxy) -7-methoxy-3,7-dioxoheptanoic acid.
Una soluzione del composto (V) preparato come in esempio 2 (1,1 g, 2,70 mmol) in EtOAc (30 mL) viene tenuta sotto agitazione in atmosfera di H2in presenza di Pd/C 10% (287 mg, 0,27 mmol) a temperatura ambiente per 2 ore. La miscela è filtrata su celite ed il solvente viene evaporato a pressione ridotta a 30°C. Il grezzo di reazione (885 mg) viene utilizzato senza ulteriore purificazione nella preparazione successiva. A solution of compound (V) prepared as in example 2 (1.1 g, 2.70 mmol) in EtOAc (30 mL) is kept under stirring in an H2 atmosphere in the presence of 10% Pd / C (287 mg, 0, 27 mmol) at room temperature for 2 hours. The mixture is filtered on celite and the solvent is evaporated under reduced pressure at 30 ° C. The reaction crude (885 mg) is used without further purification in the subsequent preparation.
MS(ES<+>): m/z 341 [M+Na]<+>. MS (ES <+>): m / z 341 [M + Na] <+>.
Esempio 4. Sintesi di un composto di formula (II): (/?,E)-metil 3-(ter-butildimetilsililossi)-7-(2-ciclopropil-4-(-4-fluorofenil)chinolin-3-il)-5-ossoept-6-enoato Example 4. Synthesis of a compound of formula (II): (/ ?, E) -methyl 3- (tert-butyldimethylsilyloxy) -7- (2-cyclopropyl-4 - (- 4-fluorophenyl) quinolin-3-yl) -5-oxoept-6-enoate
Il composto (IV) ottenuto come in Esempio 3 (885 mg, 2,78 mmol) viene solubilizzato in DMF (4 mL) in atmosfera di N2e si aggiungono 2-ciclopropil-4-(4-fluorofenil)chinolina-3-carbaldeide (271 mg, 0,93 mmol) e piperidina (46 pL, 0,46 mmol). La miscela viene lasciata sotto agitazione magnetica a temperatura ambiente per 15 minuti, poi è scaldata a 40°C per 10 ore. La soluzione viene diluita con EtOAc e lavata con HC1 1 N e salamoia, anidrificata su Na2S04, filtrata e concentrata a pressione ridotta. Il grezzo di reazione è purificato tramite cromatografia flash su gel di silice (eluente: EtPet/EtOAc 9:1). Si ottengono 280 mg di un olio giallo chiaro con una resa del 55% The compound (IV) obtained as in Example 3 (885 mg, 2.78 mmol) is solubilized in DMF (4 mL) in an atmosphere of N2 and 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde are added ( 271 mg, 0.93 mmol) and piperidine (46 pL, 0.46 mmol). The mixture is left under magnetic stirring at room temperature for 15 minutes, then it is heated to 40 ° C for 10 hours. The solution is diluted with EtOAc and washed with 1 N HC1 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: EtPet / EtOAc 9: 1). 280 mg of a light yellow oil are obtained with a yield of 55%
1H NMR (400 MHz, CDC13) δ: 7.93 (d, / = 8, IH); 7.63-7.57 (m, 2H); 7.36-7.29 (m, 2H); 7.19-7.16 (m, 4H); 6.31 (d, J = 16, IH); 4.57-4.54 (m, IH); 3.63 (s, 3H); 2.74-2.62 (m, 2H); 2.50-2.38 (m, 2H); 2.34-2.30 (m, IH); 1.38-1.36 (m, 2H); 1.05-1.03 (m, 2H); 0.79 (s, 9H); 0.03 (s, 3H); -0.02 (s, 3H).<13>C NMR (100 MHz, CDC13) δ: 196.80; 170.89; 163.40; 160.93; 159.51; 146.96; 145.57; 139.70; 133.72; 131.86; 131.27; 131.21; 129.35; 128.57; 126.63; 125.80; 125.46; 125.25; 115.39; 115.18; 65.47; 51.03; 47.61; 41.95; 25.23; 17.43; 15.89; 10.23; 10.16; -5.20; -5.42. MS(ES<+>): m/z 570 [M+Na]<+>. 1H NMR (400 MHz, CDC13) δ: 7.93 (d, / = 8, 1H); 7.63-7.57 (m, 2H); 7.36-7.29 (m, 2H); 7.19-7.16 (m, 4H); 6.31 (d, J = 16, 1H); 4.57-4.54 (m, 1H); 3.63 (s, 3H); 2.74-2.62 (m, 2H); 2.50-2.38 (m, 2H); 2.34-2.30 (m, 1H); 1.38-1.36 (m, 2H); 1.05-1.03 (m, 2H); 0.79 (s, 9H); 0.03 (s, 3H); -0.02 (s, 3H). <13> C NMR (100 MHz, CDC13) δ: 196.80; 170.89; 163.40; 160.93; 159.51; 146.96; 145.57; 139.70; 133.72; 131.86; 131.27; 131.21; 129.35; 128.57; 126.63; 125.80; 125.46; 125.25; 115.39; 115.18; 65.47; 51.03; 47.61; 41.95; 25.23; 17.43; 15.89; 10.23; 10.16; -5.20; -5.42. MS (ES <+>): m / z 570 [M + Na] <+>.
Esempio 5. Sintesi di un composto di formula (I): (3/?,5S,E)-7-(2-ciclopropil-4-(4-fluorofenil)chinolin-3-il)-3,5-diidrossiept-6-enoico sale di calcio (Pitavastatin sale di calcio) Example 5. Synthesis of a compound of formula (I): (3 / ?, 5S, E) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyept- 6-enoic calcium salt (Pitavastatin calcium salt)
Una soluzione di (II) preparato come in Esempio 4 (735 mg, 1,34 mmol) in MeOH (12 mL) viene portata a 0°C e si aggiunge HC1 2 M (1 mL, 2,01 mmol) goccia a goccia. La miscela viene lasciata sotto agitazione a 20°C per 4 ore. La soluzione viene diluita con EtOAc e lavata con una soluzione satura di NaHC03, anidrificata su Na2S04, filtrata e concentrata a pressione ridotta. Il grezzo di reazione è purificato tramite cromatografia flash su gel di silice (eluente: EtPet/EtOAc 3:2). Si ottiene un solido che è disciolto in THE anidro (1,5 mL) e MeOH (1,5 mL). La soluzione è quindi aggiunta goccia a goccia ad una sospensione di NaBH4(55 mg, 1,45 mmol) e dietilmetossiborano 1 M in THL (1,04 mL, 1,04 mmol) in THL anidro (6 mL) mantenuta -78°C. La miscela di reazione è mantenuta in agitazione a -78°C e dopo 30 min è trattata con una soluzione satura di NaHC03ed estratta con EtOAc. La fase organica è lavata con acqua, anidrificata su Na2S04, filtrata e concentrata a pressione ridotta. Il residuo ottenuto è disciolto in EtOAc (6 mL) e la soluzione è scaldata a 50°C. Si aggiunge una soluzione acquosa al 35% di H202(286 pL, 3,33 mmol) e la miscela è lasciata sotto agitazione magnetica a 50°C per 1 ora. Poi si aggiunge salamoia (6 mL) e si lascia a 50°C per 20 minuti; infine si aggiunge una soluzione acquosa di Na2S03(223 mg in 6 mL di H20) e la miscela è tenuta sotto agitazione a 50°C per ulteriori 5 minuti. La fase organica è lavata con acqua, anidrificata su Na2S04, filtrata e concentrata a pressione ridotta. Il grezzo di reazione è purificato tramite cromatografia flash su gel di silice (eluente: EtPet/EtOAc 3:2). Si ottiene un solido giallo che è disciolto in MeOH (7 mL) e trattato con NaOH 1 M. La miscela è mantenuta sotto agitazione a 20°C per 2 ore, poi il solvente viene evaporato a pressione ridotta a 40°C. Il residuo è disciolto in H20 e trattato goccia a goccia una soluzione acquosa di CaCl2(103 mg, 0,93 mmol). Si forma istantaneamente un solido bianco, che è mantenuto sotto agitazione a 20°C per 10 ore. Il precipitato viene filtrato, lavato con H20 ed asciugato a pressione ridotta a 40°C per 4 ore. Si ottengono 348 mg di pitavastatin sale di calcio come solido bianco. A solution of (II) prepared as in Example 4 (735 mg, 1.34 mmol) in MeOH (12 mL) is brought to 0 ° C and 2 M HCl (1 mL, 2.01 mmol) is added drop by drop . The mixture is left under stirring at 20 ° C for 4 hours. The solution is diluted with EtOAc and washed with a saturated solution of NaHC03, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: EtPet / EtOAc 3: 2). A solid is obtained which is dissolved in anhydrous THE (1.5 mL) and MeOH (1.5 mL). The solution is then added dropwise to a suspension of NaBH4 (55 mg, 1.45 mmol) and 1 M diethylmethoxyborane in THL (1.04 mL, 1.04 mmol) in anhydrous THL (6 mL) maintained at -78 ° C. The reaction mixture is kept under stirring at -78 ° C and after 30 min it is treated with a saturated solution of NaHC03 and extracted with EtOAc. The organic phase is washed with water, anhydrified on Na2SO4, filtered and concentrated under reduced pressure. The residue obtained is dissolved in EtOAc (6 mL) and the solution is heated to 50 ° C. A 35% aqueous solution of H202 (286 pL, 3.33 mmol) is added and the mixture is left under magnetic stirring at 50 ° C for 1 hour. Then brine (6 mL) is added and left at 50 ° C for 20 minutes; finally an aqueous solution of Na2SO3 (223 mg in 6 mL of H20) is added and the mixture is kept under stirring at 50 ° C for a further 5 minutes. The organic phase is washed with water, anhydrified on Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash chromatography on silica gel (eluent: EtPet / EtOAc 3: 2). A yellow solid is obtained which is dissolved in MeOH (7 mL) and treated with 1 M NaOH. The mixture is kept under stirring at 20 ° C for 2 hours, then the solvent is evaporated under reduced pressure at 40 ° C. The residue is dissolved in H2 O and treated drop by drop with an aqueous solution of CaCl2 (103 mg, 0.93 mmol). A white solid is instantly formed, which is kept under stirring at 20 ° C for 10 hours. The precipitate is filtered, washed with H2 O and dried under reduced pressure at 40 ° C for 4 hours. 348 mg of pitavastatin calcium salt are obtained as a white solid.
1H NMR (400 MHz, DMSO) δ: 7.80 (d, / = 8, IH); 7.58 (t, / = 8, IH); 7.36-7.20 (m, 6H); 6.44 (d, / = 16, IH); 6.03 (bs, IH); 5.56 (dd, = 5, J2= 16, IH); 4.86 (bs, IH); 4.11-4.07 (m, IH); 3.58-3.56 (s, IH); 2.04-2.00 (m, IH); 1.89-1.83 (m, IH); 1.38-1.33 (m, IH); 1.19-1.04 (m, 2H); 1.00-0.97 (m, 2H); 0.83-0.77 (m, 2H).<13>C NMR (100 MHz, DMSO) δ: 178.13; 163.04; 160.59; 160.50; 145.94; 143.68; 142.28; 133.12; 132.19; 131.89; 129.67; 128.81; 128.39; 125.71; 123.10; 115.36; 115.15; 68.85; 65.67; 44.50; 43.79; 15.38; 10.75. MS(ES<+>): m/z 444 [M+Na]<+>. 1H NMR (400 MHz, DMSO) δ: 7.80 (d, / = 8, 1H); 7.58 (t, / = 8, 1H); 7.36-7.20 (m, 6H); 6.44 (d, / = 16, 1H); 6.03 (bs, 1H); 5.56 (dd, = 5, J2 = 16, 1H); 4.86 (bs, 1H); 4.11-4.07 (m, 1H); 3.58-3.56 (s, 1H); 2.04-2.00 (m, 1H); 1.89-1.83 (m, 1H); 1.38-1.33 (m, 1H); 1.19-1.04 (m, 2H); 1.00-0.97 (m, 2H); 0.83-0.77 (m, 2H). <13> C NMR (100 MHz, DMSO) δ: 178.13; 163.04; 160.59; 160.50; 145.94; 143.68; 142.28; 133.12; 132.19; 131.89; 129.67; 128.81; 128.39; 125.71; 123.10; 115.36; 115.15; 68.85; 65.67; 44.50; 43.79; 15.38; 10.75. MS (ES <+>): m / z 444 [M + Na] <+>.
Claims (10)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000753A ITMI20100753A1 (en) | 2010-04-30 | 2010-04-30 | PROCEDURE FOR THE PREPARATION OF STATINES |
| EP11162992A EP2383260A3 (en) | 2010-04-30 | 2011-04-19 | Process for the preparation of statins |
| US13/092,171 US20110269962A1 (en) | 2010-04-30 | 2011-04-22 | Process for preparing statins |
| JP2011100741A JP2011236212A (en) | 2010-04-30 | 2011-04-28 | Process for preparing statin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000753A ITMI20100753A1 (en) | 2010-04-30 | 2010-04-30 | PROCEDURE FOR THE PREPARATION OF STATINES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ITMI20100753A1 true ITMI20100753A1 (en) | 2011-10-31 |
Family
ID=42848999
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT000753A ITMI20100753A1 (en) | 2010-04-30 | 2010-04-30 | PROCEDURE FOR THE PREPARATION OF STATINES |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | ITMI20100753A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003087112A1 (en) * | 2002-04-09 | 2003-10-23 | Cls Laboratories, Inc. | Chiral intermediate and process for the production thereof |
| EP1365029A1 (en) * | 2001-02-02 | 2003-11-26 | Mitsubishi Chemical Corporation | Process for producing (3r,5s)-(e)-7- 2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3,5-dihydroxyhept-6-enic acid esters |
| WO2007040940A1 (en) * | 2005-10-03 | 2007-04-12 | Teva Pharmaceutical Industries Ltd. | Diastereomeric purification of rosuvastatin |
| WO2009121066A1 (en) * | 2008-03-28 | 2009-10-01 | The Regents Of The University Of California | Producing dicarboxylic acids using polyketide synthases |
-
2010
- 2010-04-30 IT IT000753A patent/ITMI20100753A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1365029A1 (en) * | 2001-02-02 | 2003-11-26 | Mitsubishi Chemical Corporation | Process for producing (3r,5s)-(e)-7- 2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3,5-dihydroxyhept-6-enic acid esters |
| WO2003087112A1 (en) * | 2002-04-09 | 2003-10-23 | Cls Laboratories, Inc. | Chiral intermediate and process for the production thereof |
| WO2007040940A1 (en) * | 2005-10-03 | 2007-04-12 | Teva Pharmaceutical Industries Ltd. | Diastereomeric purification of rosuvastatin |
| WO2009121066A1 (en) * | 2008-03-28 | 2009-10-01 | The Regents Of The University Of California | Producing dicarboxylic acids using polyketide synthases |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100208867B1 (en) | Diastereomer salt of optically active quinolinemevalonic acid | |
| WO2007072529A2 (en) | Process for the synthesis of intermediates for the preparation of astaxanthin | |
| RU2335500C2 (en) | Method of production of mevalonic acid derivatives inhibiting hmg-coa reductase | |
| EP2914574B1 (en) | New process | |
| JP2011236212A (en) | Process for preparing statin | |
| EP4121408B1 (en) | Synthesis of capsaicin derivatives | |
| WO2008103016A1 (en) | Atorvastatin intermediates and method for producing the same | |
| KR100980379B1 (en) | Method for preparing 5-hydroxy-3-oxoheptanoate derivative having optical activity | |
| Li et al. | PhI (OAc) 2-mediated additions of 2, 4-dinitrophenylsulfenamide with methylenecyclopropanes (MCPs) and a methylenecyclobutane (MCB) | |
| JPH083138A (en) | Cleavage reaction with ozone | |
| AU2018340858B2 (en) | Chiral auxiliaries and uses thereof | |
| ITMI20100753A1 (en) | PROCEDURE FOR THE PREPARATION OF STATINES | |
| JP2003335756A (en) | Method for producing aromatic aldehyde and chiral diol | |
| EP1615879B1 (en) | Process for the production of 9-cis retinoic acid | |
| ITMI20110397A1 (en) | PROCEDURE FOR THE PREPARATION OF PYAVASTATIN AND ANALOGUES | |
| EP1833798B1 (en) | A process for the preparation of (s)-(+)-10,11-dihydro-10-hydroxy-5h-dibenz[b,f]azepine-5-carboxamide | |
| CA2835459C (en) | New process for synthesizing 3-(2-bromo-4,5-dimethoxyphenyl) propanenitrile, and application in the synthesis of ivabradine and its addition salts to a pharmaceutically acceptableacid. | |
| EP1060159A2 (en) | SYNTHESIS OF CHIRAL $g(b)-AMINO ACIDS | |
| US20100076199A1 (en) | Process for the preparation of substituted pyridone carboxylic acids | |
| EP1375467B1 (en) | 2-Bromomethyl-6-methyl-benzoic acid and a process for the preparation thereof | |
| EP2880008B1 (en) | Process for preparing spiro[2.5]octane-5,7-dione | |
| KR100226622B1 (en) | Novel synthetic intermediate of muscone and the preparation thereof | |
| Nagano et al. | Synthesis of unsymmetrically and highly substituted thiophenes utilizing regioselective ring-expansion of gem-dichlorocyclopropyl ketones with Lawesson’s reagent | |
| KR950003333B1 (en) | α, β-unsaturated ketones and ketooxime derivatives | |
| JPH02290830A (en) | Production method of glutaric acid derivatives |