CA2619236A1 - Procede de preparation de la simvastatine et associes produits intermediaires - Google Patents

Procede de preparation de la simvastatine et associes produits intermediaires Download PDF

Info

Publication number: CA2619236A1
Authority: CA; Canada
Prior art keywords: formula; lovastatin; reaction mixture; simvastatin; temperature
Prior art date: 2005-09-13
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Abandoned

Application number

CA002619236A

Other languages

English (en)

Inventor

Ferenc Korodi

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Teva Pharmaceutical Works PLC

Original Assignee

Individual

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2005-09-13

Filing date

2006-09-13

Publication date

2007-09-07

2006-09-13 Application filed by Individual filed Critical Individual

2007-09-07 Publication of CA2619236A1 publication Critical patent/CA2619236A1/fr

Status Abandoned legal-status Critical Current

Links

RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 title claims abstract description 81
229960002855 simvastatin Drugs 0.000 title claims abstract description 80
RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 title claims abstract description 79
238000004519 manufacturing process Methods 0.000 title claims description 5
239000000543 intermediate Substances 0.000 title abstract description 6
229960004844 lovastatin Drugs 0.000 claims abstract description 142
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 claims abstract description 111
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 claims abstract description 104
-1 lovastatin amides Chemical class 0.000 claims abstract description 92
238000000034 method Methods 0.000 claims abstract description 90
150000001408 amides Chemical class 0.000 claims abstract description 25
239000002253 acid Substances 0.000 claims abstract description 21
238000002360 preparation method Methods 0.000 claims abstract description 17
150000001447 alkali salts Chemical class 0.000 claims abstract description 11
239000011541 reaction mixture Substances 0.000 claims description 113
239000000203 mixture Substances 0.000 claims description 60
238000006884 silylation reaction Methods 0.000 claims description 44
FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 43
239000003054 catalyst Substances 0.000 claims description 37
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 claims description 31
150000001412 amines Chemical class 0.000 claims description 26
FFPDWNBTEIXJJF-OKDJMAGBSA-N (3r,5r)-7-[(1s,2s,6r,8s,8ar)-8-(2,2-dimethylbutanoyloxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydroxyheptanoic acid;azane Chemical compound [NH4+].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(C)(C)CC)C[C@@H](C)C=C21 FFPDWNBTEIXJJF-OKDJMAGBSA-N 0.000 claims description 23
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
239000002585 base Substances 0.000 claims description 20
150000001875 compounds Chemical class 0.000 claims description 20
239000003960 organic solvent Substances 0.000 claims description 20
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 18
239000011630 iodine Substances 0.000 claims description 18
229910052740 iodine Inorganic materials 0.000 claims description 18
PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 17
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 16
239000003513 alkali Substances 0.000 claims description 14
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
125000003118 aryl group Chemical group 0.000 claims description 12
239000012022 methylating agents‎ Substances 0.000 claims description 12
CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 12
150000003839 salts Chemical class 0.000 claims description 10
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
238000010791 quenching Methods 0.000 claims description 8
230000000171 quenching effect Effects 0.000 claims description 8
SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical group [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 6
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
YUDRVAHLXDBKSR-UHFFFAOYSA-N [CH]1CCCCC1 Chemical group [CH]1CCCCC1 YUDRVAHLXDBKSR-UHFFFAOYSA-N 0.000 claims description 6
150000003863 ammonium salts Chemical class 0.000 claims description 6
229910052736 halogen Inorganic materials 0.000 claims description 6
150000002367 halogens Chemical class 0.000 claims description 6
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 6
QLJODMDSTUBWDW-BXMDZJJMSA-N mevinolinic acid 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](C)C=C21 QLJODMDSTUBWDW-BXMDZJJMSA-N 0.000 claims description 6
CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 6
229940081974 saccharin Drugs 0.000 claims description 6
235000019204 saccharin Nutrition 0.000 claims description 6
239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 6
125000000217 alkyl group Chemical group 0.000 claims description 5
239000007864 aqueous solution Substances 0.000 claims description 5
229910052739 hydrogen Inorganic materials 0.000 claims description 5
239000001257 hydrogen Substances 0.000 claims description 5
125000003710 aryl alkyl group Chemical group 0.000 claims description 4
150000004678 hydrides Chemical class 0.000 claims description 4
229910017053 inorganic salt Inorganic materials 0.000 claims description 4
JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 4
229910052723 transition metal Inorganic materials 0.000 claims description 4
229910052783 alkali metal Inorganic materials 0.000 claims description 3
HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 3
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
125000005842 heteroatom Chemical group 0.000 claims description 3
150000001340 alkali metals Chemical group 0.000 claims description 2
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
150000007513 acids Chemical class 0.000 abstract 1
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 38
239000000243 solution Substances 0.000 description 19
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
238000007069 methylation reaction Methods 0.000 description 11
238000007112 amidation reaction Methods 0.000 description 9
JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 9
238000006243 chemical reaction Methods 0.000 description 9
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
230000011987 methylation Effects 0.000 description 8
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
239000012074 organic phase Substances 0.000 description 8
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
230000015572 biosynthetic process Effects 0.000 description 7
238000007273 lactonization reaction Methods 0.000 description 7
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
239000007858 starting material Substances 0.000 description 6
238000010511 deprotection reaction Methods 0.000 description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
238000010992 reflux Methods 0.000 description 5
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 5
NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 4
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 4
238000004128 high performance liquid chromatography Methods 0.000 description 4
229910052757 nitrogen Inorganic materials 0.000 description 4
239000012071 phase Substances 0.000 description 4
CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA 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)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 3
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
125000004432 carbon atom Chemical group C* 0.000 description 3
239000012299 nitrogen atmosphere Substances 0.000 description 3
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
239000000047 product Substances 0.000 description 3
239000007787 solid Substances 0.000 description 3
238000003756 stirring Methods 0.000 description 3
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 2
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
102000004190 Enzymes Human genes 0.000 description 2
108090000790 Enzymes Proteins 0.000 description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
125000003342 alkenyl group Chemical group 0.000 description 2
230000009435 amidation Effects 0.000 description 2
235000011114 ammonium hydroxide Nutrition 0.000 description 2
239000008346 aqueous phase Substances 0.000 description 2
150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
239000003610 charcoal Substances 0.000 description 2
NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-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
125000000753 cycloalkyl group Chemical group 0.000 description 2
239000003480 eluent Substances 0.000 description 2
238000001914 filtration Methods 0.000 description 2
AEDIXYWIVPYNBI-UHFFFAOYSA-N heptanamide Chemical compound CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 description 2
150000002431 hydrogen Chemical group 0.000 description 2
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
238000002955 isolation Methods 0.000 description 2
150000002576 ketones Chemical class 0.000 description 2
FJDQVJUXXNIHNB-UHFFFAOYSA-N lithium;pyrrolidin-1-ide Chemical compound [Li+].C1CC[N-]C1 FJDQVJUXXNIHNB-UHFFFAOYSA-N 0.000 description 2
239000000463 material Substances 0.000 description 2
230000001035 methylating effect Effects 0.000 description 2
230000004048 modification Effects 0.000 description 2
238000012986 modification Methods 0.000 description 2
UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
125000001624 naphthyl group Chemical group 0.000 description 2
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
238000000926 separation method Methods 0.000 description 2
239000002002 slurry Substances 0.000 description 2
238000001228 spectrum Methods 0.000 description 2
239000000126 substance Substances 0.000 description 2
125000001424 substituent group Chemical group 0.000 description 2
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical group [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
KJTLQQUUPVSXIM-ZCFIWIBFSA-M (R)-mevalonate Chemical compound OCC[C@](O)(C)CC([O-])=O KJTLQQUUPVSXIM-ZCFIWIBFSA-M 0.000 description 1
150000000185 1,3-diols Chemical group 0.000 description 1
QXDDNRQSWPCCEZ-UHFFFAOYSA-N 1-cyclobutyl-3-ethyl-6-fluoroindazole Chemical compound C12=CC(F)=CC=C2C(CC)=NN1C1CCC1 QXDDNRQSWPCCEZ-UHFFFAOYSA-N 0.000 description 1
PDBMVYIMAMQDCW-UHFFFAOYSA-N 3,5-dihydroxyheptanoic acid Chemical group CCC(O)CC(O)CC(O)=O PDBMVYIMAMQDCW-UHFFFAOYSA-N 0.000 description 1
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
239000004322 Butylated hydroxytoluene Substances 0.000 description 1
QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical class CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 1
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
LXZBFUBRYYVRQJ-UHFFFAOYSA-M Lovastatin hydroxy acid Chemical compound [Na+].C1=CC(C)C(CCC(O)CC(O)CC([O-])=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 LXZBFUBRYYVRQJ-UHFFFAOYSA-M 0.000 description 1
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
GUEULYYYHDURDF-CWZAOXTASA-N [(2r,4r)-2-[2-[(1s,2s,6r,8s,8ar)-8-(2,2-dimethylbutanoyloxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl]-6-oxooxan-4-yl] (3r,5r)-7-[(1s,2s,6r,8s,8ar)-8-(2,2-dimethylbutanoyloxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydro Chemical compound C([C@@H]1C)=CC2=C[C@H](C)C[C@H](OC(=O)C(C)(C)CC)[C@@H]2[C@H]1CC[C@@H](OC(=O)C1)C[C@H]1OC(=O)C[C@H](O)C[C@H](O)CC[C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@H](OC(=O)C(C)(C)CC)[C@H]12 GUEULYYYHDURDF-CWZAOXTASA-N 0.000 description 1
125000003158 alcohol group Chemical group 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
125000003545 alkoxy group Chemical group 0.000 description 1
125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
125000004414 alkyl thio group Chemical group 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
125000006242 amine protecting group Chemical group 0.000 description 1
229910021529 ammonia Inorganic materials 0.000 description 1
239000000908 ammonium hydroxide Substances 0.000 description 1
125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
239000003524 antilipemic agent Substances 0.000 description 1
239000000010 aprotic solvent Substances 0.000 description 1
125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
125000004391 aryl sulfonyl group Chemical group 0.000 description 1
125000005110 aryl thio group Chemical group 0.000 description 1
125000004104 aryloxy group Chemical group 0.000 description 1
AMEDKBHURXXSQO-UHFFFAOYSA-N azonous acid Chemical class ONO AMEDKBHURXXSQO-UHFFFAOYSA-N 0.000 description 1
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
229940095259 butylated hydroxytoluene Drugs 0.000 description 1
235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
239000006227 byproduct Substances 0.000 description 1
125000002837 carbocyclic group Chemical group 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
239000003518 caustics Substances 0.000 description 1
239000007795 chemical reaction product Substances 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
235000012000 cholesterol Nutrition 0.000 description 1
238000001816 cooling Methods 0.000 description 1
SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
125000004093 cyano group Chemical group *C#N 0.000 description 1
125000006165 cyclic alkyl group Chemical group 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
230000003247 decreasing effect Effects 0.000 description 1
238000001514 detection method Methods 0.000 description 1
238000004821 distillation Methods 0.000 description 1
150000002170 ethers Chemical class 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
238000000855 fermentation Methods 0.000 description 1
230000004151 fermentation Effects 0.000 description 1
230000037406 food intake Effects 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
239000012535 impurity Substances 0.000 description 1
238000011065 in-situ storage Methods 0.000 description 1
238000002347 injection Methods 0.000 description 1
239000007924 injection Substances 0.000 description 1
150000002596 lactones Chemical class 0.000 description 1
AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical group [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 description 1
229910001486 lithium perchlorate Inorganic materials 0.000 description 1
UPRXAOPZPSAYHF-UHFFFAOYSA-N lithium;cyclohexyl(propan-2-yl)azanide Chemical compound CC(C)N([Li])C1CCCCC1 UPRXAOPZPSAYHF-UHFFFAOYSA-N 0.000 description 1
AHNJTQYTRPXLLG-UHFFFAOYSA-N lithium;diethylazanide Chemical compound [Li+].CC[N-]CC AHNJTQYTRPXLLG-UHFFFAOYSA-N 0.000 description 1
CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 1
230000014759 maintenance of location Effects 0.000 description 1
238000005259 measurement Methods 0.000 description 1
VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical group COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
229940102396 methyl bromide Drugs 0.000 description 1
229940050176 methyl chloride Drugs 0.000 description 1
MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
238000005580 one pot reaction Methods 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
238000005191 phase separation Methods 0.000 description 1
HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
229910000105 potassium hydride Inorganic materials 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
125000006239 protecting group Chemical group 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
238000009790 rate-determining step (RDS) Methods 0.000 description 1
QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
239000002904 solvent Substances 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
238000003786 synthesis reaction 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
125000003944 tolyl 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
238000005406 washing Methods 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1
239000008096 xylene Substances 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1
229940072168 zocor Drugs 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Chemical Kinetics & Catalysis (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Pyrane Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA002619236A 2005-09-13 2006-09-13 Procede de preparation de la simvastatine et associes produits intermediaires Abandoned CA2619236A1 (fr)

Applications Claiming Priority (5)

Application Number	Priority Date	Filing Date	Title
US71700605P	2005-09-13	2005-09-13
US60/717,006		2005-09-13
US74254105P	2005-12-06	2005-12-06
US60/742,541		2005-12-06
PCT/US2006/035824 WO2007100351A2 (fr)	2005-09-13	2006-09-13	Procede de preparation de la simvastatine et associes produits intermediaires

Publications (1)

Publication Number	Publication Date
CA2619236A1 true CA2619236A1 (fr)	2007-09-07

Family

ID=37898832

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002619236A Abandoned CA2619236A1 (fr)	2005-09-13	2006-09-13	Procede de preparation de la simvastatine et associes produits intermediaires

Country Status (4)

Country	Link
EP (1)	EP1883634A2 (fr)
KR (1)	KR20080034190A (fr)
CA (1)	CA2619236A1 (fr)
WO (1)	WO2007100351A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
WO2007125547A2 (fr)	2006-05-03	2007-11-08	Manne Satyanarayana Reddy	Nouveau procédé faisant intervenir des statines et leurs sels acceptables sur le plan pharmaceutique
EP2086945B1 (fr)	2006-10-09	2016-01-06	MSN Laboratories Private Limited	Nouveau procédé de préparation de statines et leurs sels pharmaceutiquement acceptables
WO2010089770A2 (fr)	2009-01-19	2010-08-12	Msn Laboratories Limited	Procédé amélioré d'élaboration d'acide (3r,5s)-7-[2-cyclopropyl-4-(4-fluorophényl)quinolin-3-yl]-3,5-dihydroxy-6(e)-heptènoïque de haute pureté, y compris ses sels pharmaceutiquement acceptables
US8252829B2 (en)	2009-06-05	2012-08-28	Link Medicine Corporation	Aminopyrrolidinone derivatives and uses thereof
EP2526099B1 (fr)	2010-01-18	2016-03-30	MSN Laboratories Limited	Procédé amélioré pour la préparation d'intermédiaires amides et leur utilisation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4820850A (en) *	1987-07-10	1989-04-11	Merck & Co., Inc.	Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof
US6472542B1 (en) *	2001-11-29	2002-10-29	Fermic S.A. De C.V.	Method for alkylating the alpha carbon of the 2-methylbutyrate secondary chain of lovastatin
US7205415B2 (en) *	2004-01-02	2007-04-17	Hetero Drugs, Ltd.	Process for the preparation of simvastatin

2006
- 2006-09-13 KR KR1020087005349A patent/KR20080034190A/ko not_active Ceased
- 2006-09-13 EP EP06814653A patent/EP1883634A2/fr not_active Withdrawn
- 2006-09-13 WO PCT/US2006/035824 patent/WO2007100351A2/fr not_active Ceased
- 2006-09-13 CA CA002619236A patent/CA2619236A1/fr not_active Abandoned

Also Published As

Publication number	Publication date
KR20080034190A (ko)	2008-04-18
WO2007100351A3 (fr)	2007-12-06
WO2007100351A2 (fr)	2007-09-07
EP1883634A2 (fr)	2008-02-06

Publication	Publication Date	Title
CA2173830C (fr)	1998-04-07	Methode de preparation de simvastatine et de leurs analogues
FI88719B (fi)	1993-03-15	Foerfarande foer -c-alkylering av 8-acylgruppen i mevinolin och dess analoger
AU747219B2 (en)	2002-05-09	Process for the production of semi synthetic statins via novel intermediates
HUP0103021A2 (hu)	2001-12-28	Eljárás szimvasztatinszármazékok előállítására
CZ286576B6 (cs)	2000-05-17	Klíčové meziprodukty při výrobě simvastatinu
US5010105A (en)	1991-04-23	Antihypercholesterolemic compounds
CA2619236A1 (fr)	2007-09-07	Procede de preparation de la simvastatine et associes produits intermediaires
AU619563B2 (en)	1992-01-30	5-oxygenated HMG-CoA reductase inhibitors
US20070129437A1 (en)	2007-06-07	Process for preparing simvastatin and intermediates thereof
WO1999043665A1 (fr)	1999-09-02	Procede de preparation de simvastatine et ses derives
US6307066B1 (en)	2001-10-23	Process for producing simvastatin
WO2004046105A2 (fr)	2004-06-03	Synthese d'acides 3,5-dihydroxy-7-pyrrol-1-yle heptanoiques
JPH03184940A (ja)	1991-08-12	７―置換ＨＭＧ―ＣｏＡ還元酵素阻害剤
CN1283633C (zh)	2006-11-08	制备辛伐他汀的方法
AU2001293726B2 (en)	2005-04-14	Process for preparing discodermolide and analogues thereof
US6573392B1 (en)	2003-06-03	Process for manufacturing simvastatin and the novel intermediates
KR100322630B1 (ko)	2002-08-21	심바스타틴및 이의 중간체 화합물을 제조하는 방법
KR100625346B1 (ko)	2006-09-20	심바스타틴의 제조 방법
EP0306263A2 (fr)	1989-03-08	Inhibiteurs d'HMG-COA réductase
CA2018478A1 (fr)	1990-12-09	Composes antihypercholesterolemiques
WO2002024675A1 (fr)	2002-03-28	Procede de fabrication de simvastatine et nouveaux intermediaires
WO2005069741A2 (fr)	2005-08-04	Procede de production de simvastatine au moyen de nouveaux produits intermediaires d'hydrazide
WO2007096753A2 (fr)	2007-08-30	Procédé de synthèse de simvastatine de pureté élevée
WO2006072963A1 (fr)	2006-07-13	Procédé de synthèse en trois étapes de la simvastatine à partir de sels d'amine de la lovastatine

Legal Events

Date	Code	Title	Description
2008-01-24	EEER	Examination request
2009-09-14	FZDE	Discontinued