CA2619236A1 - Process for preparing simvastatin and intermediates thereof - Google Patents
Process for preparing simvastatin and intermediates thereof Download PDFInfo
- Publication number
- CA2619236A1 CA2619236A1 CA002619236A CA2619236A CA2619236A1 CA 2619236 A1 CA2619236 A1 CA 2619236A1 CA 002619236 A CA002619236 A CA 002619236A CA 2619236 A CA2619236 A CA 2619236A CA 2619236 A1 CA2619236 A1 CA 2619236A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- lovastatin
- reaction mixture
- simvastatin
- temperature
- Prior art date
- 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
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)
Abstract
Novel processes for the preparation of simvastatin and intermediates of such processes. Preferred embodiments include the preparation of lovastatin amides, protected lovastatin amide derivatives, simvastatin dihydroxy acid amide derivatives, alkali salts, simvastatin dihydroxy acids, simvastatin ammonium salts, and simvastatin.
Description
PROCESS FOR PREPARING SIMVASTATIN AND INTERMEDIATES THEREOF
[0001] This application claims the benefit of U.S. Provisional Patent Applications Ser. Nos. 60/717,006, filed September 13, 2005, and 60/742,541, filed December 6, 2005, which are incorporated herein by reference, in their entirety.
FIELD OF INVENTION
[0001] This application claims the benefit of U.S. Provisional Patent Applications Ser. Nos. 60/717,006, filed September 13, 2005, and 60/742,541, filed December 6, 2005, which are incorporated herein by reference, in their entirety.
FIELD OF INVENTION
[0002] The invention relates to processes for preparing simvastatin and intennediates of such processes.
BACKGROUND OF THE INVENTION
BACKGROUND OF THE INVENTION
[0003] Simvastatin, marketed under the name ZOCOR by Merck & Co., is a lipid-lowering agent. After oral ingestion, it is believed that simvastatin, an inactive lactone, is hydrolyzed to the corresponding 3,5-dihydroxy acid form, which then inhibits the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA) reductase. This enzyme is believed to catalyze the conversion of HMG-CoA to mevalonate, an early rate-limiting step in the biosynthesis of cholesterol.
[0004] Simvastatin is also known as butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl- 8- [2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl] -1-naphthalenyl ester, [1S-[1(alpha),3(alpha),7(beta),8(beta)(2S*,4S*),-8(alpha)(beta)].
Simvastatin (m.w. 418.57) has the structure represented in formula I below.
O
O
O
simvastatin [0005] Simvastatin can be synthetically prepared from the fermentation product lovastatin, shown in formula II, by "methylation" processes.
O
O
O
II
lovastatin [0006] For example, U.S. Patent No. 4,582,915 describes a process for preparing simvastatin by first converting lovastatin to an alkali metal salt, preferably the potassium salt, of the dihydroxycarboxylate, then methylating the 2-methylbutyryloxy group at the C2-position.
Simvastatin (m.w. 418.57) has the structure represented in formula I below.
O
O
O
simvastatin [0005] Simvastatin can be synthetically prepared from the fermentation product lovastatin, shown in formula II, by "methylation" processes.
O
O
O
II
lovastatin [0006] For example, U.S. Patent No. 4,582,915 describes a process for preparing simvastatin by first converting lovastatin to an alkali metal salt, preferably the potassium salt, of the dihydroxycarboxylate, then methylating the 2-methylbutyryloxy group at the C2-position.
[0007] Acidity of the a-protons of the 3,5-dihydroxyheptanoic acid moiety can be decreased by formation of a lovastatin hydroxy acid amide. This dihydroxy amide derivative can be methylated without further protection, as disclosed in U.S.
Patent No.
5,763,646, or after protection of the 1,3-diol moiety by (1) tert-butyldimethylsilylation, as disclosed in U.S. Patent No. 4,820,850; (2) the formation of phenylboronic acid derivatives, as disclosed in U.S. Patent No. 5,393,893; (3) the formation of acetonides as disclosed in U.S. Patent No. 6,100,407; or (4) protection using hexamethyldisilazane (HMDS), as disclosed in U.S. Patent No. 6,472,542.
Patent No.
5,763,646, or after protection of the 1,3-diol moiety by (1) tert-butyldimethylsilylation, as disclosed in U.S. Patent No. 4,820,850; (2) the formation of phenylboronic acid derivatives, as disclosed in U.S. Patent No. 5,393,893; (3) the formation of acetonides as disclosed in U.S. Patent No. 6,100,407; or (4) protection using hexamethyldisilazane (HMDS), as disclosed in U.S. Patent No. 6,472,542.
[0008] The above processes, however, suffer from several disadvantages. Thus, there is a continuing need for processes for preparing simvastatin.
SUMMARY OF THE INVENTION
SUMMARY OF THE INVENTION
[0009] In one aspect, the present invention provides a process for the preparation of simvastatin and intermediates useful in making simvastatin.
[00010] In one embodiment, the invention relates to a process for the preparation of lovastatin amide of formula III, N, R2 OH
j <:OH
H CH H CH
HC\"
a which includes:
(a) combining a lovastatin compound selected from the group consisting of (i) lovastatin of formula II, HO O O
O
= H
O
H3C"
(ii) lovastatin acid of formula VII, OH
OH
O OH
H CH - H VII
H C ", (iii) a salt of lovastatin of formula II, (iv) a salt of lovastatin acid of formula VII, and (v) mixtures thereof, an inert organic solvent, and an amine of formula HNR1R2 to obtain a first reaction mixture; and (b) obtaining a second reaction mixture comprising the lovastatin amide of formula III by maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin compound to the lovastatin amide of formula III.
j <:OH
H CH H CH
HC\"
a which includes:
(a) combining a lovastatin compound selected from the group consisting of (i) lovastatin of formula II, HO O O
O
= H
O
H3C"
(ii) lovastatin acid of formula VII, OH
OH
O OH
H CH - H VII
H C ", (iii) a salt of lovastatin of formula II, (iv) a salt of lovastatin acid of formula VII, and (v) mixtures thereof, an inert organic solvent, and an amine of formula HNR1R2 to obtain a first reaction mixture; and (b) obtaining a second reaction mixture comprising the lovastatin amide of formula III by maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin compound to the lovastatin amide of formula III.
[00011] In such a process, the molar ratio of the amine of formula HNR1R2 to the lovastatin compound is no more than about 1.5, and R' and R2 are independently selected from hydrogen, straight or branched C2_$ alkyl, aryl, aryalkyl, and C3_$
cycloalkyl groups, or together form a ring optionally containing a heteroatom.
cycloalkyl groups, or together form a ring optionally containing a heteroatom.
[00012] The period of time can be, e.g., from about 3 hours to about 5 hours and the temperature can be from about 60 C to about 120 C. The amine of formula can be, e.g., selected from the group consisting of n-butylamine, diethylamine, cyclohexylamine, morpholine, benzylamine and mixtures thereof, e.g., cyclohexylamine, benzylamine or mixtures thereof. In certain embodiments, the molar ratio of the amine of formula HNRiR2 to the lovastatin compound is no more than about 1.2, or from about 1 to about 1.2.
[00013] The lovastatin compound can be, e.g., an ammonium salt of formula VIII.
OH
O
In certain embodiments, the process can further comprise:
(c) converting the lovastatin amide of formula III to simvastatin of formula I.
HO O
O
O
= H
H CH
H3C~
OH
O
In certain embodiments, the process can further comprise:
(c) converting the lovastatin amide of formula III to simvastatin of formula I.
HO O
O
O
= H
H CH
H3C~
[00014] In certain embodiments, the process can further comprise:
(c) combining the lovastatin amide of forinula III, a silylation catalyst and hexamethyldisilazane (HMDS) to obtain a third reaction mixture; and (d) maintaining the third reaction mixture at a temperature and for a period of time sufficient to convert substantially of the lovastatin amide of formula III to the bis (TMS)-lovastatin amide derivative of formula IV;
' R2 OSiMe3 0 OSiMe3 H
14 Me Me Me' IV
wherein Rl and R2 are as defined previously.
(c) combining the lovastatin amide of forinula III, a silylation catalyst and hexamethyldisilazane (HMDS) to obtain a third reaction mixture; and (d) maintaining the third reaction mixture at a temperature and for a period of time sufficient to convert substantially of the lovastatin amide of formula III to the bis (TMS)-lovastatin amide derivative of formula IV;
' R2 OSiMe3 0 OSiMe3 H
14 Me Me Me' IV
wherein Rl and R2 are as defined previously.
[00015] In a certain embodiment, the second reaction mixture comprising the lovastatin amide of formula III of step (b) is directly combined with the silylation catalyst and the HMDS. In such a process, the period of time in step (b) is, e.g., from about 3 to about 5 hours, the period of time in step (d) is from about 0.5 to about 10 hours, the temperature of step (b) is'from about 60 to about 120 C and the temperature of step (d) is from about 0 C to about 40 C. The molar ratio of the silylation catalyst to the lovastatin compound can be, e.g., from about 0.0001 to about 0.05. The silylation catalyst can be, e.g., silylhalide or iodine and the molar ratio of the silylhalide or iodine to the lovastatin compound can be, e.g., about 0.02 (if silylhalide), or about 0.004 (if iodine).
The molar ratio of the HMDS to the lovastatin compound can be, e.g., from about 1 to about 1.7. In a certain embodiment, this process can further comprise:
(e) combining the bis (TMS)-lovastatin amide derivative of formula IV with an aprotic organic solvent to obtain a fourth reaction mixture;
(f) combining the fourth reaction mixture with a strong base at a temperature of from about -10 C to about -80 C to obtain a fifth reaction mixture;
(g) maintaining the fifth reaction mixture at a temperature of from about 0 C
to about -40 C for a period of time of at least about 1 hour (e.g. about 1-5 hours) to obtain a sixth reaction mixture;
(h) combining the sixth reaction mixture with a methylating agent at a temperature of from about 0 C to about -60 C to obtain a seventh reaction mixture;
(i) maintaining the seventh reaction mixture at a temperature of from about -20 C to about -40 C for a period of time of at least about 0.5 hours (e.g.
about 0.5-3 hours) to obtain an eighth reaction mixture;
(j) quenching the eighth reaction mixture at a temperature of from about 0 C
to about -20 C; and, optionally (k) recovering simvastatin dihydroxy acid amide derivative of formula V;
wherein Rl and Ra are as defined in formula III.
OH
O OH
H
Nle Me Me Me"
v [00016] In one embodiment, the above process further comprises:
(1) combining the simvastatin dihydroxy acid amide derivative of formula V, a water miscible organic solvent and an aqueous solution of an alkali base to obtain a ninth reaction mixture; and (m) maintaining the ninth reaction mixture at a temperature of from about 50 C
to about 100 C for a period of time of at least about 2 hours (e.g. about 2-8 hours) to obtain an alkali salt of formula IX;
0 M+
OH
0 _ OH
/ ='1 ~ H
H3C CH _ CH3 lX
H3C~ ~
wherein M is alkali metal atom.
The molar ratio of the HMDS to the lovastatin compound can be, e.g., from about 1 to about 1.7. In a certain embodiment, this process can further comprise:
(e) combining the bis (TMS)-lovastatin amide derivative of formula IV with an aprotic organic solvent to obtain a fourth reaction mixture;
(f) combining the fourth reaction mixture with a strong base at a temperature of from about -10 C to about -80 C to obtain a fifth reaction mixture;
(g) maintaining the fifth reaction mixture at a temperature of from about 0 C
to about -40 C for a period of time of at least about 1 hour (e.g. about 1-5 hours) to obtain a sixth reaction mixture;
(h) combining the sixth reaction mixture with a methylating agent at a temperature of from about 0 C to about -60 C to obtain a seventh reaction mixture;
(i) maintaining the seventh reaction mixture at a temperature of from about -20 C to about -40 C for a period of time of at least about 0.5 hours (e.g.
about 0.5-3 hours) to obtain an eighth reaction mixture;
(j) quenching the eighth reaction mixture at a temperature of from about 0 C
to about -20 C; and, optionally (k) recovering simvastatin dihydroxy acid amide derivative of formula V;
wherein Rl and Ra are as defined in formula III.
OH
O OH
H
Nle Me Me Me"
v [00016] In one embodiment, the above process further comprises:
(1) combining the simvastatin dihydroxy acid amide derivative of formula V, a water miscible organic solvent and an aqueous solution of an alkali base to obtain a ninth reaction mixture; and (m) maintaining the ninth reaction mixture at a temperature of from about 50 C
to about 100 C for a period of time of at least about 2 hours (e.g. about 2-8 hours) to obtain an alkali salt of formula IX;
0 M+
OH
0 _ OH
/ ='1 ~ H
H3C CH _ CH3 lX
H3C~ ~
wherein M is alkali metal atom.
[00017] In an embodiment, the above process further comprises:
(n) converting the alkali salt of formula IX to simvastatin dihydroxy acid of formula X.
OH
OH
H C.=1CH : H
O
HC~
(n) converting the alkali salt of formula IX to simvastatin dihydroxy acid of formula X.
OH
OH
H C.=1CH : H
O
HC~
[00018] Once the simvastatin dihydroxy acid of formula X is obtained, it may be, e.g., further converted into simvastatin ammonium salt of formula VI, which is then recovered.
0- NH4+
OH
O _ OH
O
H3C CH ' H CH VI
H C,, [00019] In various embodiments, the simvastatin ammonium salt of formula VI
can be converted to simvastatin of formula I.
0- NH4+
OH
O _ OH
O
H3C CH ' H CH VI
H C,, [00019] In various embodiments, the simvastatin ammonium salt of formula VI
can be converted to simvastatin of formula I.
[00020] Certain embodiments relate to a process for the preparation of bis (TMS)-lovastatin amide derivative of formula IV, which may comprise:
(a) combining lovastatin amide of formula III, a silylation catalyst and hexamethyldisilazane (HMDS) to obtain a first reaction mixture; and (b) obtaining a second reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV by maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin anlide of formula III to the bis (TMS)-lovastatin amide derivative of formula IV.
(a) combining lovastatin amide of formula III, a silylation catalyst and hexamethyldisilazane (HMDS) to obtain a first reaction mixture; and (b) obtaining a second reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV by maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin anlide of formula III to the bis (TMS)-lovastatin amide derivative of formula IV.
[00021] The period of time can be, e.g., from about 0.5 to about 10 hours and the temperature can be from about 0 C to about 40 C. The silylation catalyst can be, e.g., selected from the group consisting of silylhalide, molecular halogen, inorganic salt, organic salt, transition metal phosphonic acid derivative, saccharin and mixtures thereof, e.g., silylhalide, molecular halogen, saccharin or mixtures thereof, e.g., trimethylsilyl iodide, iodine or mixtures thereof.
[00022] The molar ratio of the silylation catalyst to the lovastatin amide of formula III can be, e.g., from about 0.0001 to about 0.06. The silylation catalyst can be, e.g., silylhalide and the molar ratio of silylhalide to the lovastatin amide of formula III can be from about 0.02 to about 0.025. The silylation catalyst can be, e.g., iodine and the molar ratio of the iodine to the lovastatin amide of formula III can be from about 0.004 to about 0.005. The molar ratio of the HMDS to the lovastatin amide of formula III can be, e.g., from about 1 to about 2.
[00023] If desired, the bis (TMS)-lovastatin amide derivative of formula IV
can be converted to simvastatin of formula I using any suitable method.
can be converted to simvastatin of formula I using any suitable method.
[00024] Certain embodiments relate to a process for the preparation of simvastatin dihydroxy acid amide derivative of formula V, which may comprise:
(a) combining the bis (TMS)-lovastatin amide derivative of formula IV, an aprotic organic solvent, and an amine derivative to obtain a third reaction mixture;
(b) combining the third reaction mixture and a strong base at a temperature of from about -10 C to about -80 C to obtain a fourth reaction mixture;
(c) maintaining the fourth reaction mixture at a temperature of from about 0 C
to about -40 C for a period of time of at least about 1 hour (for example, about 1-5 hours) to obtain a fifth reaction mixture;
(d) combining the fifth reaction mixture with a methylating agent at a temperature of from about 0 C to about -60 C to obtain a sixth reaction mixture;
(e) maintaining the sixth reaction mixture at a temperature of from about -20 C to about -40 C for a period of time of at least about 0.5 hours (for example, about 0.5-3 hours) to obtain a seventh reaction mixture; and (f) quenching the seventh reaction mixture at a temperature of from about 0 C
to about -20 C to obtain the simvastatin dihydroxy acid amide derivative of formula V.
Preferably, the process also includes:
(g) recovering the simvastatin dihydroxy acid amide derivative of formula V.
(a) combining the bis (TMS)-lovastatin amide derivative of formula IV, an aprotic organic solvent, and an amine derivative to obtain a third reaction mixture;
(b) combining the third reaction mixture and a strong base at a temperature of from about -10 C to about -80 C to obtain a fourth reaction mixture;
(c) maintaining the fourth reaction mixture at a temperature of from about 0 C
to about -40 C for a period of time of at least about 1 hour (for example, about 1-5 hours) to obtain a fifth reaction mixture;
(d) combining the fifth reaction mixture with a methylating agent at a temperature of from about 0 C to about -60 C to obtain a sixth reaction mixture;
(e) maintaining the sixth reaction mixture at a temperature of from about -20 C to about -40 C for a period of time of at least about 0.5 hours (for example, about 0.5-3 hours) to obtain a seventh reaction mixture; and (f) quenching the seventh reaction mixture at a temperature of from about 0 C
to about -20 C to obtain the simvastatin dihydroxy acid amide derivative of formula V.
Preferably, the process also includes:
(g) recovering the simvastatin dihydroxy acid amide derivative of formula V.
[00025] Any suitable methylating agent may be used. Examples of methylating agents include methyl halide (e.g., methyl iodide, etc.), methyl sulfate and mixtures thereof. The seventh reaction mixture can be quenched, for example, with water. If desired, the simvastatin dihydroxy acid amide derivative of formula V can be converted to simvastatin of formula I.
[00026] In certain embodiments, the bis (TMS)-lovastatin amide derivative of formula IV is prepared by a process comprising:
(aa) combining lovastatin amide of formula III, a silylation catalyst and hexamethyldisilazane (HMDS) to obtain a first reaction mixture; and (bb) obtaining a second reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV by maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin amide of fonnula III to the bis (TMS)-lovastatin amide derivative of formula IV.
(aa) combining lovastatin amide of formula III, a silylation catalyst and hexamethyldisilazane (HMDS) to obtain a first reaction mixture; and (bb) obtaining a second reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV by maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin amide of fonnula III to the bis (TMS)-lovastatin amide derivative of formula IV.
[00027] The period of time can be, e.g., about 0.5-10 hours and the temperature can be from about 0 C to about 40 C.
[00028] If desired, the second reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV can be directly combined with the aprotic organic solvent and the amide derivative.
[00029] The process may further comprise:
(h) combining the simvastatin dihydroxy acid ainide derivative of formula V, a water miscible organic solvent and an aqueous solution of an alkali base to obtain an eighth reaction mixture;
(i) maintaining the eighth reaction mixture at a temperature of from about 50 C to about 100 C for a period of time of at least about 2 hours (e.g., about 2-8 hours) to obtain an alkali salt of formula IX;
(j) converting the alkali salt of formula IX to simvastatin dihydroxy acid of formula X; and (k) converting the simvastatin dihydroxy acid of formula X to simvastatin ammonium salt of formula VI.
The process can also comprise:
(1) recovering the simvastatin ammonium salt of formula VI.
(h) combining the simvastatin dihydroxy acid ainide derivative of formula V, a water miscible organic solvent and an aqueous solution of an alkali base to obtain an eighth reaction mixture;
(i) maintaining the eighth reaction mixture at a temperature of from about 50 C to about 100 C for a period of time of at least about 2 hours (e.g., about 2-8 hours) to obtain an alkali salt of formula IX;
(j) converting the alkali salt of formula IX to simvastatin dihydroxy acid of formula X; and (k) converting the simvastatin dihydroxy acid of formula X to simvastatin ammonium salt of formula VI.
The process can also comprise:
(1) recovering the simvastatin ammonium salt of formula VI.
[00030] The alkali base can be, e.g., sodium hydroxide, potassium hydroxide or mixtures thereof.
[00031] The invention also relates to certain novel compounds, which are useful as synthetic intermediates in the preparation of simvastatin. For example, such compounds include a compound of formula IV-a:
' R2 OSi Me3 0 OSiMe3 lq Me ' Me Me IV-a wherein one of Rl and R2 is H and the other of R' and Ra is selected from the group consisting of benzyl radical and cyclohexyl radical; for example, one of R' and R2 is H
and the other of Rl and R2 is benzyl radical, or one of R' and Ra is H and the other of Rl and R2 is cyclohexyl radical.
' R2 OSi Me3 0 OSiMe3 lq Me ' Me Me IV-a wherein one of Rl and R2 is H and the other of R' and Ra is selected from the group consisting of benzyl radical and cyclohexyl radical; for example, one of R' and R2 is H
and the other of Rl and R2 is benzyl radical, or one of R' and Ra is H and the other of Rl and R2 is cyclohexyl radical.
[00032] Certain embodiments of the invention also relate to a process for the preparation of simvastatin of formula I, the process comprising:
(a) providing a compound of formula IV-a; and (b) converting the compound of formula IV-a to simvastatin of formula I.
DETAILED DESCRIPTION OF THE INVENTION
(a) providing a compound of formula IV-a; and (b) converting the compound of formula IV-a to simvastatin of formula I.
DETAILED DESCRIPTION OF THE INVENTION
[00033] As used herein, the phrase "at a temperature and for a period of time sufficient to convert substantially all of ' a particular starting material to another compound means that at least about 80%, preferably at least about 85%, more preferably at least about 90%, even more preferably at least about 95%, of the starting material is converted to the another compound.
[00034] In one embodiment, the invention relates to a synthesis of simvastatin (I) from lovastatin (II) according to the following general scheme. (It will be appreciated that the invention also relates to the individual steps and compounds involved therein).
HO 0 fl- NR2 NR2 OH O-S/~
O O
H O = OH O
O'S", ~O ~
CHO H CHa H CH = H CHa -~ H H~ H CH
a '= / / / /
H3C HaC' HaC
ii iii iV
N, R2 O NH4+
OH OH
O OH O OH
O
Ha = H CHa Ha'~ - H
CHa HaC./ H Cr v vi HO~
O
= H
O
HaC,=
HO 0 fl- NR2 NR2 OH O-S/~
O O
H O = OH O
O'S", ~O ~
CHO H CHa H CH = H CHa -~ H H~ H CH
a '= / / / /
H3C HaC' HaC
ii iii iV
N, R2 O NH4+
OH OH
O OH O OH
O
Ha = H CHa Ha'~ - H
CHa HaC./ H Cr v vi HO~
O
= H
O
HaC,=
[00035] In preferred embodiments, this process affords a simple and economical way for commercial scale production of simvastatin in high yield and purity.
In one embodiment, the first four steps of the process may be combined in a "one-pot"
process in which the simvastatin ammonium salt (VI) is the first isolated intermediate.
Antidatiota ofLovastatiya [00036] The amidation of lovastatin includes combining a lovastatin compound, an inert organic solvent, and an amine of formula HNR'R2 to obtain a first reaction mixture, which is then converted to a second reaction mixture comprising the lovastatin amide of formula III by maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin compound to the lovastatin compound of formula III.
In one embodiment, the first four steps of the process may be combined in a "one-pot"
process in which the simvastatin ammonium salt (VI) is the first isolated intermediate.
Antidatiota ofLovastatiya [00036] The amidation of lovastatin includes combining a lovastatin compound, an inert organic solvent, and an amine of formula HNR'R2 to obtain a first reaction mixture, which is then converted to a second reaction mixture comprising the lovastatin amide of formula III by maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin compound to the lovastatin compound of formula III.
[00037] For example, the temperature can be from about 60 C to about 120 C and the period of time of can be at least about 3 hours (preferably about 3-5 hours). In certain embodiments, the temperature is from about 80 C to about 110 C, more preferably from about 80 C to about 90 C.
[00038] Preferably, a Dean-Stark apparatus is used to remove water, which is a by-product.
[00039] The lovastatin compound can be selected from the group consisting of (i) lovastatin of formula II, HO O
O
O
H
H CH = H CH3 II
H3C~
(ii) lovastatin acid of formula VII, OH
OH
H' CH H VII
HC, (iii) a salt of lovastatin of formula II, (iv) a salt of lovastatin acid of formula VII (e.g. the ammonium salt of formula VIII), and (v) mixtures thereof.
OH
H CH = H CH3 VIII
HCa' [00040] In the amidation reaction, preferably the inert organic solvent is benzene, toluene, xylene, tetrahydrofuran (TBF), or mixtures thereof. More preferably, the inert organic solvent is toluene.
O
O
H
H CH = H CH3 II
H3C~
(ii) lovastatin acid of formula VII, OH
OH
H' CH H VII
HC, (iii) a salt of lovastatin of formula II, (iv) a salt of lovastatin acid of formula VII (e.g. the ammonium salt of formula VIII), and (v) mixtures thereof.
OH
H CH = H CH3 VIII
HCa' [00040] In the amidation reaction, preferably the inert organic solvent is benzene, toluene, xylene, tetrahydrofuran (TBF), or mixtures thereof. More preferably, the inert organic solvent is toluene.
[00041] The R' and R2 groups of HNR1R2 are independently selected in each instance from hydrogen, straight or branched CZ_g alkyl, aryl, arylalkyl, and C3_$
cycloalkyl groups, or together form a ring optionally containing a heteroatom such as 0, S, or N.
cycloalkyl groups, or together form a ring optionally containing a heteroatom such as 0, S, or N.
[00042] "Aryl", "aryl group" or "Ar" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7yl, and the like) provided that the point of attachment is through an aromatic ring atom.
Preferably, the aryl is phenyl, naphthyl or 5,6,7,8-tetrahydronaphth-2-yl. The aryl may be substituted or unsubstituted. The substituents may be, for example, an alkyl group, an alkenyl group, a cyclic alkyl group, an aralkyl group, a cyclic alkenyl group, a cyano group, an aryl group, an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, an alkylsulfonyl group, or an arylsulfonyl group.
Preferably, the aryl is phenyl, naphthyl or 5,6,7,8-tetrahydronaphth-2-yl. The aryl may be substituted or unsubstituted. The substituents may be, for example, an alkyl group, an alkenyl group, a cyclic alkyl group, an aralkyl group, a cyclic alkenyl group, a cyano group, an aryl group, an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, an alkylsulfonyl group, or an arylsulfonyl group.
[00043] "Arylalkyl" refers to an aryl group with at least one alkyl substituent, such as a linear or branched alkyl group preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. The substituent is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.
[00044] Preferably, the amine of formula HNR1R2 is n-butylamine, diethylamine, cyclohexylamine, morpholine, benzylamine, or mixtures thereof. More preferably, the amine of formula HNR1R2 is cyclohexylamine, benzylamine or mixtures thereof.
Indeed, the inventor has surprisingly discovered that the amidation reaction works well with amines having relatively large groups - i.e. cyclohexyl and benzyl groups.
Indeed, the inventor has surprisingly discovered that the amidation reaction works well with amines having relatively large groups - i.e. cyclohexyl and benzyl groups.
[00045] The molar ratio of the amine of formula HNR1R2 to the lovastatin compound is no more than about 1.5, more preferably, no more than about 1.2, e.g., a molar ratio of from about 1 to about 1.2 or about 1 to about 1.5. Indeed, the use of no or a slight excess of amine is advantageous, because, e.g., the silylation reaction can be performed without the need to first remove the excess amine by, e.g., distillation, a time-consuming operation that can lead to formation of impurities.
[00046] Preferably, the lovastatin of formula II and the amine of formula HNRiRa are commercially available. Preferably, the lovastatin compound is the ammonium salt of formula VIII.
[00047] Preferably, the lovastatin amide of formula III is converted to simvastatin of formula I by a suitable process, e.g., the silylation, methylation, deprotection, and/or lactonization reactions of the general scheme.
Silylation Reaction [00048] In the silylation reaction, the alcohol groups of the lovastatin amide of formula III are protected. In a preferred embodiment, bis (TMS)-lovastatin amide derivative of formula IV is prepared. The silylation reaction is carried out by:
(a) combining lovastatin amide of formula III, a silylation catalyst and hexamethyldisilazane (HMDS) to obtain a reaction mixture; and (b) maintaining the reaction mixture at a teinperature and for a period of time sufficient to convert substantially all of the lovastatin amide of formula III
to the bis (TMS)-lovastatin amide of formula IV (wherein R' and Ra are as defined in formula III):
' 2 OSiMe3 O OSiMe3 9 H =
14 Me Me Me"0 IV
Silylation Reaction [00048] In the silylation reaction, the alcohol groups of the lovastatin amide of formula III are protected. In a preferred embodiment, bis (TMS)-lovastatin amide derivative of formula IV is prepared. The silylation reaction is carried out by:
(a) combining lovastatin amide of formula III, a silylation catalyst and hexamethyldisilazane (HMDS) to obtain a reaction mixture; and (b) maintaining the reaction mixture at a teinperature and for a period of time sufficient to convert substantially all of the lovastatin amide of formula III
to the bis (TMS)-lovastatin amide of formula IV (wherein R' and Ra are as defined in formula III):
' 2 OSiMe3 O OSiMe3 9 H =
14 Me Me Me"0 IV
[00049] For example, the temperature can be from about 0 C to about 40 C
(preferably about room temperature to about 40 C) and the period of time can be at least about 0.5 hours (preferably about 0.5-10 hours, more preferably about 1-4 hours).
(preferably about room temperature to about 40 C) and the period of time can be at least about 0.5 hours (preferably about 0.5-10 hours, more preferably about 1-4 hours).
[00050] Preferably, the silylation catalyst is silylhalide, molecular halogen, inorganic salt, organic salt, transition metal phosphonic acid derivative, saccharin or mixtures thereof. Preferably, the silylhalide is trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride, or mixtures thereof, more preferably, trimethylsilyl iodide. Preferably, the molecular halogen is iodine, bromine, or mixtures thereof, more preferably, iodine. Preferably, the inorganic salt is zinc chloride, tetrabutylammonium fluoride, lithium perchlorate, copper triflate, or mixtures thereof. Preferred transition metal phosphonic acid derivative include phosphonomolybdenic acid, tungstenophosphonic acid, and mixtures thereof. The more preferred silylation catalysts are iodine, trimethylsilyl iodide, saccharin and mixtures thereof. The most preferred silylation catalyst is iodine. Surprisingly, the inventor has discovered that silylation catalysts not only improve the rate of reaction, but also decrease the amount of starting material necessary, which is both unexpected and advantageous.
[00051] Preferably, the bis (TMS)-lovastatin amide derivative of formula IV is subsequently converted to simvastatin of formula I by a suitable process, e.g., the methylation, deprotection, and/or lactonization steps of the general scheme.
[00051] Preferably, the bis (TMS)-lovastatin amide derivative of formula IV is subsequently converted to simvastatin of formula I by a suitable process, e.g., the methylation, deprotection, and/or lactonization steps of the general scheme.
[00052] Preferably, the molar ratio of the silylation catalyst to the lovastatin amide of formula III is from about 0.0001 to about 0.06. More preferably, the silylation catalyst is silylhalide and the molar ratio of silylhalide to the lovastatin amide of formula III is from about 0.02 to about 0.025, or the silylation catalyst is iodine and the molar ratio of the iodine to the lovastatin amide of formula III is from about 0.004 to about 0.005.
Preferably, the molar ratio of the HMDS to the lovastatin amide of formula III
is from about 1 to about 2. Thus, in a preferred embodiment, the silylation reaction of the present invention is performed with no or a slight excess of HMDS. This is advantageous because, for example, 1) HMDS can decompose to ammonia; 2) the excess HMDS
does not have to be removed by isolation steps; and 3) isolation steps to remove the excess HMDS can expose the trimethyl-silyl protecting groups to water, which can remove the protecting groups and also lead to insufficient conversion in the methylation step.
Preferably, the molar ratio of the HMDS to the lovastatin amide of formula III
is from about 1 to about 2. Thus, in a preferred embodiment, the silylation reaction of the present invention is performed with no or a slight excess of HMDS. This is advantageous because, for example, 1) HMDS can decompose to ammonia; 2) the excess HMDS
does not have to be removed by isolation steps; and 3) isolation steps to remove the excess HMDS can expose the trimethyl-silyl protecting groups to water, which can remove the protecting groups and also lead to insufficient conversion in the methylation step.
[00053] Preferably, the lovastatin amide of formula III is prepared by an amidation reaction, e.g., the amidation reaction discussed above. More preferably, the lovastatin of formula III is prepared by the amidation reaction discussed above, and the reaction mixture comprising the amidation reaction product (i.e., the lovastatin amide of formula III) is directly combined with the silylation catalyst and HMDS. That is, the reaction mixture comprising the lovastatin amide of formula III is combined with the silylation catalyst and the HMDS without recovering or purifying the lovastatin amide of formula III from the reaction mixture comprising the lovastatin amide of formula III.
[00054] In this preferred embodiment, preferably, the molar ratio of the silylation catalyst to the lovastatin compound is 0.0001 to about 0.05, depending on the catalyst.
More preferably, silylhalide is the silylation catalyst and the molar ratio of the silyl halide to the lovastatin compound is about 0.02. More preferably, iodine is the silylation catalyst and the molar ratio of the iodine to the lovastatin compound is about 0.004.
More preferably, silylhalide is the silylation catalyst and the molar ratio of the silyl halide to the lovastatin compound is about 0.02. More preferably, iodine is the silylation catalyst and the molar ratio of the iodine to the lovastatin compound is about 0.004.
[00055] Preferably, the molar ratio of the HMDS to the lovastatin compound is from about 1 to about 1.7, more preferably, from about 1 to about 1.2.
[00056] In another aspect, the present invention relates to 2 novel compounds:
N-cyclohexyl-7-[ 1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)-naphtyl]-3(R),5(R)-bis(trimethylsilyloxy)heptanamide;
and N-benzyl-7-[ 1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)-naphtyl]-3(R),5(R)-bis(trimethylsilyloxy)heptanamide.
These compounds are embraced by formula IV-a:
R' N'R2 OSiMe3 0 OSiMe3 II o H =
14'' Me Me Me' IV-a wherein one of Rl and R2 is H and the other of R' and R- is benzyl radical or cyclohexyl radical.
N-cyclohexyl-7-[ 1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)-naphtyl]-3(R),5(R)-bis(trimethylsilyloxy)heptanamide;
and N-benzyl-7-[ 1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)-naphtyl]-3(R),5(R)-bis(trimethylsilyloxy)heptanamide.
These compounds are embraced by formula IV-a:
R' N'R2 OSiMe3 0 OSiMe3 II o H =
14'' Me Me Me' IV-a wherein one of Rl and R2 is H and the other of R' and R- is benzyl radical or cyclohexyl radical.
[00057] The compound of formula IV-a wherein one of Rl and R2 is H and the other of R' and R~ is cyclohexyl radical can be characterized by data selected from an 1H-NMR spectrum having hydrogen chemical shifts at about 0.05, 0.73, 0.76, 0.93, 0.97, 1.01-1.09, 1.13, 1.20-1.31, 1.38-1.59, 1.72-1.81, 1.85, 2.05, 2.10, 2.19, 2.25, 2.31, 3.49, 3.63, 4.09, 5.15, 5.37, 5.65, 5.85 and 6.07 ppm, and MS (ESI) spectrum having peaks at about 648.44 (MH+).
[00058] Meanwhile, the compound of fonnula IV-a wherein one of Rt and Ra is H
and the other of Rl and R2 is benzyl radical can be characterized by data selected from an 1H-NMR spectrum having hydrogen chemical shifts at about 0.06, 0.11, 0.84, 0.86, 1.05, 1.07, 1.12, 1.14, 1.33, 1.39, 1.52, 1.62-1.64, 1.89, 1.96, 2.19-2.45, 3.58, 4.16, 4.41, 5.31, 5.48, 5.76, 5.95, 6.60 and 7.18-7.33 ppm; and MS (ESI) spectrum having peaks at about 656.42 (MH+).
and the other of Rl and R2 is benzyl radical can be characterized by data selected from an 1H-NMR spectrum having hydrogen chemical shifts at about 0.06, 0.11, 0.84, 0.86, 1.05, 1.07, 1.12, 1.14, 1.33, 1.39, 1.52, 1.62-1.64, 1.89, 1.96, 2.19-2.45, 3.58, 4.16, 4.41, 5.31, 5.48, 5.76, 5.95, 6.60 and 7.18-7.33 ppm; and MS (ESI) spectrum having peaks at about 656.42 (MH+).
[00059] The compounds of formula IV-a can be prepared by any suitable process, e.g., the arnidation reaction and silylation reaction described above.
[00060] Preferably, the compound of formula IV-a is converted to simvastatin by a suitable process, e.g., the methylation, deprotection and/or lactonization steps of the general scheme.
Metlzylation Reaction [00061] In one embodiment, a methylation reaction involving the bis (TMS)-lovastatin amide derivative of formula IV can be carried out as follows:
(a) combining the bis (TMS)-lovastatin amide derivative of formula IV with an aprotic organic solvent to obtain a third reaction mixture;
(b) combining the third reaction mixture and a strong base at a temperature of from about -10 C to about -80 C to obtain a fourth reaction mixture;
(c) maintaining the fourth reaction mixture at a temperature of from about 0 C
to about -40 C for a period of time of at least about 1 hour (preferably about 1-5 hours) to obtain a fifth reaction mixture;
(d) combining the fifth reaction mixture with a methylating agent at a temperature of from about 0 C to about -60 C to obtain a sixth reaction mixture;
(e) maintaining the sixth reaction mixture at a temperature of from about -20 C to about -40 C for a period of time at least about 0.5 hours (preferably about 0.5-3 hours) to obtain a seventh reaction mixture;
(f) quenching the seventh reaction mixture at a temperature of from about 0 C
to about -20 C; and, optionally, (g) recovering the simvastatin dihydroxy acid amide derivative of formula V
(wherein Rl and Ra are as defined in formula III):
OH
Nle Me Me Me""
V
Metlzylation Reaction [00061] In one embodiment, a methylation reaction involving the bis (TMS)-lovastatin amide derivative of formula IV can be carried out as follows:
(a) combining the bis (TMS)-lovastatin amide derivative of formula IV with an aprotic organic solvent to obtain a third reaction mixture;
(b) combining the third reaction mixture and a strong base at a temperature of from about -10 C to about -80 C to obtain a fourth reaction mixture;
(c) maintaining the fourth reaction mixture at a temperature of from about 0 C
to about -40 C for a period of time of at least about 1 hour (preferably about 1-5 hours) to obtain a fifth reaction mixture;
(d) combining the fifth reaction mixture with a methylating agent at a temperature of from about 0 C to about -60 C to obtain a sixth reaction mixture;
(e) maintaining the sixth reaction mixture at a temperature of from about -20 C to about -40 C for a period of time at least about 0.5 hours (preferably about 0.5-3 hours) to obtain a seventh reaction mixture;
(f) quenching the seventh reaction mixture at a temperature of from about 0 C
to about -20 C; and, optionally, (g) recovering the simvastatin dihydroxy acid amide derivative of formula V
(wherein Rl and Ra are as defined in formula III):
OH
Nle Me Me Me""
V
[00062] Preferably, the bis (TMS)-lovastatin amide derivative of formula IV is prepared according to the silylation reaction, and the reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV is directly combined with the aprotic organic solvent. That is, the reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV is combined with the aprotic organic solvent without recovering or purifying the bis (TMS)-lovastatin amide derivative of formula IV.
[00063] Preferably, the aprotic solvent is aromatic hydrocarbon, ether, or mixtures thereof. Preferably, the aromatic hydrocarbon is toluene. Preferably, the ether is tetrahydrofuran (THF), diethyl ether, diisopropyl ether, dioxane, or mixtures thereof.
More preferably, the ether is THF. A preferred mixture is that of toluene and THF.
More preferably, the ether is THF. A preferred mixture is that of toluene and THF.
[00064] Preferably, if methylation is preceded by amidation of lovastatin, the amount of the strong base used in the methylation reaction is such that the molar ratio of the strong base to the lovastatin compound is from about 3 to about 6.
[00065] Preferably, the strong base is commercially available. More preferably, the strong base is an alkali amide. Preferably, the alkali amide is lithium amide, sodium amide, lithium diethylamide, lithium N-isopropyl-N-cyclohexylamide, lithium diisopropylamide (LDA), lithium pyrrolidide, or mixtures thereof. More preferably, the base is LDA, lithium pyrrolidide or mixtures thereof.
[00066] In a particularly preferred embodiment, the strong base is prepared in-situ by adding alkyllithium, alkali hydride, or mixtures thereof to a third reaction mixture that includes, in this embodiment, the bis (TMS)-lovastatin amide derivative and an amine derivative. Preferably, the alkali hydride is sodium hydride, potassium hydride or mixtures thereof. Preferred alkyllithiums include n-butyllithium, n-hexyllithium and mixtures thereof. More preferably, n-butyllithium is used to prepare the strong base.
Preferably, the amine derivative is pyrrolidine. Thus, in this preferred einbodiment, the alkyllithium, the alkali hydride or mixtures thereof is directly added to the bis (TMS)-lovastatin amide derivative of formula IV, instead of preparing the strong base in a work-up reaction and then combining it witli the bis (TMS)-lovastatin amide derivative of formula IV.
Preferably, the amine derivative is pyrrolidine. Thus, in this preferred einbodiment, the alkyllithium, the alkali hydride or mixtures thereof is directly added to the bis (TMS)-lovastatin amide derivative of formula IV, instead of preparing the strong base in a work-up reaction and then combining it witli the bis (TMS)-lovastatin amide derivative of formula IV.
[00067] Preferably, the temperature of step (b) is from about -30 C to about -60 C, more preferably, from about -40 C to about -60 C. Preferably, the temperature of step (c) is from about -30 C to about -40 C.
[00068] Preferably, the methylating agent is methyl halide, methyl sulfate or mixtures thereof. Preferably, the methyl halide is methyl iodide, methyl bromide, methyl chloride or mixtures thereof. A preferred methylsulfate is methyl tosylate, methyl mesylate or mixtures thereof. The more preferred methylating agent is methyl iodide.
[00069] Preferably, the methylation reaction is preceded by the amidation reaction described above. In this preferred embodiment, preferably, the amount of the methylating agent used is such that the molar ratio of the methylating agent to the lovastatin compound is from about 1.5 to about 3.
[00070] Preferably, the temperature of step of step (d) is from about -30 C to about -50 C. Preferably, the temperature of step (f) is from about -10 C to about -20 C.
[00071] Preferably, in step (f), the step of quenching the seventh reaction mixture includes the use of water as a quenching reagent. Preferably, the water also removes the silyl groups to produce the desired product, simvastatin dihydroxy acid amide derivative of formula V.
[00072] Preferably, simvastatin dihydroxy acid arnide derivative of formula V
is recovered in step (g) by acidifying the organic phase followed by washing with water and evaporating the solvents.
is recovered in step (g) by acidifying the organic phase followed by washing with water and evaporating the solvents.
[00073] Preferably, simvastatin dihydroxy acid amide derivative of formula V
is subsequently converted to simvastatin by a suitable process, e.g., the deprotection and/or lactonization steps disclosed in the general scheme.
Deprotection Step [00074] In certain embodiments, the amine protecting group of the simvastatin dihydroxy acid amide derivative of formula V can be removed to provide the simvastatin ammonium salt of formula VI. For example, such a process can include:
(a) combining simvastatin dihydroxy acid amide derivative of formula V, a water miscible organic solvent and an aqueous solution of an alkali base to obtain a first reaction mixture;
(b) maintaining the first reaction mixture at a temperature of from about 50 C
to about 100 C (preferably about 75-80 C) for a period of time of at least about 2 hours (preferably about 2-8 hours, more preferably 4-8 hours) to obtain second reaction mixture comprising an allcali salt of formula IX;
(c) converting the alkali salt of formula IX to simvastatin dihydroxy acid of formula X; and (d) converting the simvastatin dihydroxy acid of formula X to simvastatin ammonium salt of formula VI.
is subsequently converted to simvastatin by a suitable process, e.g., the deprotection and/or lactonization steps disclosed in the general scheme.
Deprotection Step [00074] In certain embodiments, the amine protecting group of the simvastatin dihydroxy acid amide derivative of formula V can be removed to provide the simvastatin ammonium salt of formula VI. For example, such a process can include:
(a) combining simvastatin dihydroxy acid amide derivative of formula V, a water miscible organic solvent and an aqueous solution of an alkali base to obtain a first reaction mixture;
(b) maintaining the first reaction mixture at a temperature of from about 50 C
to about 100 C (preferably about 75-80 C) for a period of time of at least about 2 hours (preferably about 2-8 hours, more preferably 4-8 hours) to obtain second reaction mixture comprising an allcali salt of formula IX;
(c) converting the alkali salt of formula IX to simvastatin dihydroxy acid of formula X; and (d) converting the simvastatin dihydroxy acid of formula X to simvastatin ammonium salt of formula VI.
[00075] Preferably, the process also includes: (e) recovering the simvastatin ammonium salt of formula VI.
[00076] Preferably, the simvastatin dihydroxy acid amide derivative of formula V
is prepared according to a process set forth previously.
is prepared according to a process set forth previously.
[00077] Preferably, the water miscible organic solvent is C1-4 alcohol, ketone, ether or mixtures thereof. Preferred C1-4 alcohols are methanol, ethanol and mixtures thereof.
The more preferred water miscible organic solvent is methanol. Preferably, the ketone is acetone. A preferred ethers include THF, dioxane and mixtures thereof.
The more preferred water miscible organic solvent is methanol. Preferably, the ketone is acetone. A preferred ethers include THF, dioxane and mixtures thereof.
[00078] Preferably, the alkali base is sodium hydroxide, potassium hydroxide or mixtures thereof.
[00079] The alkali salt of formula IX can be converted to simvastatin dihydroxy acid of formula X
OH
OH
H CH
H3C r"
by, e.g., concentrating the second reaction mixture, then adding an acid to adjust the pH
of the organic phase to a range of about 2 to about 6, preferably from about 3 to about 5.
OH
OH
H CH
H3C r"
by, e.g., concentrating the second reaction mixture, then adding an acid to adjust the pH
of the organic phase to a range of about 2 to about 6, preferably from about 3 to about 5.
[00080] Simvastatin dihydroxy acid of formula X can be converted to simvastatin ammonium salt of formula VI
O- NH4+
OH
0 _ OH
O
H= H =
3 CH3 vi by, e.g., adding ammonium hydroxide to simvastatin dihydroxy acid of formula X.
O- NH4+
OH
0 _ OH
O
H= H =
3 CH3 vi by, e.g., adding ammonium hydroxide to simvastatin dihydroxy acid of formula X.
[00081] Simvastatin ammonium salt of formula VI can be recovered by any suitable method, such as cooling to induce precipitation followed by filtering to obtain a wet solid that is then washed.
Lactonization Step [00082] In certain embodiments, the lactonization of simvastatin ammonium salt of formula VI to simvastatin of formula I, may be performed by, for example, a thermally-induced lactonization process, as disclosed in PCT Publication No. WO
2004/071456 A2, which is incorporated herein by reference.
Lactonization Step [00082] In certain embodiments, the lactonization of simvastatin ammonium salt of formula VI to simvastatin of formula I, may be performed by, for example, a thermally-induced lactonization process, as disclosed in PCT Publication No. WO
2004/071456 A2, which is incorporated herein by reference.
[00083] Simvastatin of formula I can be further purified by, e.g., a process involving crystallization from a mixture of an aromatic hydrocarbon and a C5_$
aliphatic hydrocarbon.
EXAMPLES
General [00084] In the examples below, the HPLC chromatographic measurements were made on an AGILENT 1100 with a ZORBAX SB C18 4,6*'75mm' 3,5 m, or Hypersil ODS 100*4 mm column, and eluted with a 0.1 % aqueous phosphoric acid solution (eluant A)/acetonitrile (eluant B) mixture as described below, with detection at 240 mn, a flow rate of 1.2mL/min, and an injection volume of 10 l. The colunm temperature was 25 C and the sample temperature was 5 C.
aliphatic hydrocarbon.
EXAMPLES
General [00084] In the examples below, the HPLC chromatographic measurements were made on an AGILENT 1100 with a ZORBAX SB C18 4,6*'75mm' 3,5 m, or Hypersil ODS 100*4 mm column, and eluted with a 0.1 % aqueous phosphoric acid solution (eluant A)/acetonitrile (eluant B) mixture as described below, with detection at 240 mn, a flow rate of 1.2mL/min, and an injection volume of 10 l. The colunm temperature was 25 C and the sample temperature was 5 C.
[00085] The following gradient program was used with the HPLC:
Time (min) eluent A(%) eluent B(%) 0.0 50.0 50.0 5.0 50.0 50.0 25.0 5.0 95.0 34.0 5.0 95.0 35.0 50.0 50.0 40.0 50.0 50.0 [00086] Retention times under these conditions are the following:
RT/min RRT
Simvastatin hidroxy acid 5.8 0.55 Lovastatin 8.3 0.78 Simvastatin 10.5 1.00 Anhidro-Simvastatin 16.3 1.55 Simvastatin-dimer 27.3 2.59 Example 1:Prenaration of lovastatin cyclohexylamide [00087] Lovastatin (10.1 g, 25 mmol) was suspended in a mixture of cyclohexylamine (2.6 g, 3.0 ml, 26.3 mmol) and toluene (25 ml) and the reaction mixture was heated to a temperature of 80 - 90 C to obtain a solution. The solution was stirred at this temperature for 5 hours under nitrogen atmosphere to complete the reaction and obtain a solution including lovastatin cyclohexamide.
Example 2: Preparation of bis(TMS)-lovastatin cyclohexylamide [00088] Trimethylsilyl iodide (100 mg, 0.5 mmol) and hexamethyldisilazane (HMDS) (6.03 g, 7.8 ml, 37 mmol) were added to the solution including lovastatin cyclohexamide obtained in Example 1. The resulting reaction mixture was stirred at a temperature of 30-40 C for 4 hours, to complete the reaction and obtain a reaction mixture including bis(TMS)-lovastatin cyclohexamide.
Example 3: Methylation of bis(TMS)-lovastatin cyclohexylamide [00089] The reaction mixture including bis(TMS)-lovastatin cyclohexamide obtained in Example 2 was diluted with THF (100 ml) and cooled to a temperature of-30 to -40 C. Lithium diisopropylamide (60 m12 molar solution, 120 mmol) was added to the reaction mixture while stirring at the above temperature under nitrogen.
After the addition, the reaction mixture was aged at a temperature of -30 to -35 C for 1.5 hours.
The mixture was then cooled to -50 C and methyl iodide (8.9 g, 3.8 ml, 62.5 mmol) was added (after which the temperature increased to 14 C). Then, the reaction mixture was stirred at a temperature of -30 to -35 C for 1 hour. The temperature was allowed to increase to -10 C and the reaction mixture was stirred at this temperature for 30 min followed by the addition of water (50 ml). Toluene (50 ml) was added after the water and the organic phase were separated. 1M solution of hydrochloric acid (150 ml) was added to the organic phase to obtain a mixture, which was stirred for 15 min and the phases were separated again. After separation of the aqueous phase, the organic phase was washed twice with water (2x 50 ml). The organic phase was concentrated in vacuum to give an oil (about 14 g) containing a simvastatin dihydroxy acid amide derivative.
Example 4 :Preparation of lovastatin benzylamide [00090] Lovastatin (10.1 g, 25 mmol) was suspended in a mixture of benzylamine (2.94 g, 3 ml, 27.5 mmol) and toluene (25 ml) and the resulting mixture was heated to 80 - 90 C to obtain a solution. The solution was stirred at this temperature for 4 hours under nitrogen atmosphere to complete the reaction and obtain a solution including lovastatin benzylamide.
Example 5: Preparation of bis(TMS)-lovastatin-benzylamide [00091] Iodine (25 mg, 0.1 mmol) and hexamethyldisilazane (H1VIDS) (6.03 g, 7.8 ml, 37 mmol) were added to the reaction mixture including lovastatin benzylamide obtained in Example 4. The reaction mixture then was stirred at room temperature for 1 hour. After the 1 hour period, there was no starting material detected by TLC
in the reaction mixture.
Example 6: Methylation of bis(TMS)-lovastatin benzylamide [00092] The reaction mixture obtained in Example 5 was diluted with THF (50 ml) and toluene (50 ml) followed by addition of pyrrolidine (8.9 g, 10.3 ml; 125 mmol) under nitrogen to give a mixture. The mixture was then cooled to -60 C. A solution of n-butyl lithium (78 ml; 125 mmol) was added over 60 minutes while the temperature was kept at -50 to -60 C. After the addition, the reaction mixture was aged at a temperature of -30 to about -40 C for 2 hours. The mixture was then cooled to -50 to -60 C, methyl iodide (8.9 g, 3.8 ml; 62.5 mmol) was added over about 10 min at the above temperature, and then the reaction mixture was stirred at -30 to -35 C for 1 hour. The temperature was allowed to increase to -10 C and the reaction mixture was stirred at this temperature for 30 min followed by the addition of water (50 ml) to give two phases. After phase separation, 1M
solution of sulfuric acid (100 ml) was added to the organic phase and the mixture was stirred for 30 min. Then, the phases were separated again. After separation of the aqueous phase, the organic layer was washed with water (50 ml) and concentrated under vacuum to give an oil (about 15 g) containing a simvastatin dihydroxy acid amide derivative.
Example 7: Caustic hydrolysis and preparation of ammonium salt [00093] The oil of Example 6 was dissolved in methanol (120 ml). Sodium hydroxide (6.4 g, 160 mmol) in water (80 ml) was added to this solution followed by stirring at reflux temperature (75 - 80 C) for 4 hours. The obtained solution was then concentrated under vacuum to about half of its original volume. The concentrated mixture was cooled to 5 C and the pH was adjusted to about 7 by addition of aqueous hydrochloric acid solution. Ethyl acetate (175 ml) was added and the pH was adjusted to 3-5. Then, the water phase was separated and the organic phase was diluted with methanol (50 ml) and the pH was adjusted to 9-11 by adding aqueous ammonia solution (6 ml).
Time (min) eluent A(%) eluent B(%) 0.0 50.0 50.0 5.0 50.0 50.0 25.0 5.0 95.0 34.0 5.0 95.0 35.0 50.0 50.0 40.0 50.0 50.0 [00086] Retention times under these conditions are the following:
RT/min RRT
Simvastatin hidroxy acid 5.8 0.55 Lovastatin 8.3 0.78 Simvastatin 10.5 1.00 Anhidro-Simvastatin 16.3 1.55 Simvastatin-dimer 27.3 2.59 Example 1:Prenaration of lovastatin cyclohexylamide [00087] Lovastatin (10.1 g, 25 mmol) was suspended in a mixture of cyclohexylamine (2.6 g, 3.0 ml, 26.3 mmol) and toluene (25 ml) and the reaction mixture was heated to a temperature of 80 - 90 C to obtain a solution. The solution was stirred at this temperature for 5 hours under nitrogen atmosphere to complete the reaction and obtain a solution including lovastatin cyclohexamide.
Example 2: Preparation of bis(TMS)-lovastatin cyclohexylamide [00088] Trimethylsilyl iodide (100 mg, 0.5 mmol) and hexamethyldisilazane (HMDS) (6.03 g, 7.8 ml, 37 mmol) were added to the solution including lovastatin cyclohexamide obtained in Example 1. The resulting reaction mixture was stirred at a temperature of 30-40 C for 4 hours, to complete the reaction and obtain a reaction mixture including bis(TMS)-lovastatin cyclohexamide.
Example 3: Methylation of bis(TMS)-lovastatin cyclohexylamide [00089] The reaction mixture including bis(TMS)-lovastatin cyclohexamide obtained in Example 2 was diluted with THF (100 ml) and cooled to a temperature of-30 to -40 C. Lithium diisopropylamide (60 m12 molar solution, 120 mmol) was added to the reaction mixture while stirring at the above temperature under nitrogen.
After the addition, the reaction mixture was aged at a temperature of -30 to -35 C for 1.5 hours.
The mixture was then cooled to -50 C and methyl iodide (8.9 g, 3.8 ml, 62.5 mmol) was added (after which the temperature increased to 14 C). Then, the reaction mixture was stirred at a temperature of -30 to -35 C for 1 hour. The temperature was allowed to increase to -10 C and the reaction mixture was stirred at this temperature for 30 min followed by the addition of water (50 ml). Toluene (50 ml) was added after the water and the organic phase were separated. 1M solution of hydrochloric acid (150 ml) was added to the organic phase to obtain a mixture, which was stirred for 15 min and the phases were separated again. After separation of the aqueous phase, the organic phase was washed twice with water (2x 50 ml). The organic phase was concentrated in vacuum to give an oil (about 14 g) containing a simvastatin dihydroxy acid amide derivative.
Example 4 :Preparation of lovastatin benzylamide [00090] Lovastatin (10.1 g, 25 mmol) was suspended in a mixture of benzylamine (2.94 g, 3 ml, 27.5 mmol) and toluene (25 ml) and the resulting mixture was heated to 80 - 90 C to obtain a solution. The solution was stirred at this temperature for 4 hours under nitrogen atmosphere to complete the reaction and obtain a solution including lovastatin benzylamide.
Example 5: Preparation of bis(TMS)-lovastatin-benzylamide [00091] Iodine (25 mg, 0.1 mmol) and hexamethyldisilazane (H1VIDS) (6.03 g, 7.8 ml, 37 mmol) were added to the reaction mixture including lovastatin benzylamide obtained in Example 4. The reaction mixture then was stirred at room temperature for 1 hour. After the 1 hour period, there was no starting material detected by TLC
in the reaction mixture.
Example 6: Methylation of bis(TMS)-lovastatin benzylamide [00092] The reaction mixture obtained in Example 5 was diluted with THF (50 ml) and toluene (50 ml) followed by addition of pyrrolidine (8.9 g, 10.3 ml; 125 mmol) under nitrogen to give a mixture. The mixture was then cooled to -60 C. A solution of n-butyl lithium (78 ml; 125 mmol) was added over 60 minutes while the temperature was kept at -50 to -60 C. After the addition, the reaction mixture was aged at a temperature of -30 to about -40 C for 2 hours. The mixture was then cooled to -50 to -60 C, methyl iodide (8.9 g, 3.8 ml; 62.5 mmol) was added over about 10 min at the above temperature, and then the reaction mixture was stirred at -30 to -35 C for 1 hour. The temperature was allowed to increase to -10 C and the reaction mixture was stirred at this temperature for 30 min followed by the addition of water (50 ml) to give two phases. After phase separation, 1M
solution of sulfuric acid (100 ml) was added to the organic phase and the mixture was stirred for 30 min. Then, the phases were separated again. After separation of the aqueous phase, the organic layer was washed with water (50 ml) and concentrated under vacuum to give an oil (about 15 g) containing a simvastatin dihydroxy acid amide derivative.
Example 7: Caustic hydrolysis and preparation of ammonium salt [00093] The oil of Example 6 was dissolved in methanol (120 ml). Sodium hydroxide (6.4 g, 160 mmol) in water (80 ml) was added to this solution followed by stirring at reflux temperature (75 - 80 C) for 4 hours. The obtained solution was then concentrated under vacuum to about half of its original volume. The concentrated mixture was cooled to 5 C and the pH was adjusted to about 7 by addition of aqueous hydrochloric acid solution. Ethyl acetate (175 ml) was added and the pH was adjusted to 3-5. Then, the water phase was separated and the organic phase was diluted with methanol (50 ml) and the pH was adjusted to 9-11 by adding aqueous ammonia solution (6 ml).
[00094] The basic mixture was cooled in a refrigerator and the precipitated material was collected, washed with ethyl acetate and dried to yield simvastatin ammonium salt (9.3 g, 82 % yield based on the starting material, lovastatin), in a purity of 97% area by HPLC.
Example 8: Preparation of simvastatin [00095] Simvastatin ammonium salt (6.0 g) in toluene (300 ml) in the presence of butylhydroxytoluene (BHT) (0.08 g) was refluxed for 2 hours, under nitrogen, using a Dean-Stark condenser for removing water. After reflux, the reaction mixture was stirred at 85-90 C for 3 hours. The reaction mixture was then evaporated to dryness to form a solid residue.
Example 8: Preparation of simvastatin [00095] Simvastatin ammonium salt (6.0 g) in toluene (300 ml) in the presence of butylhydroxytoluene (BHT) (0.08 g) was refluxed for 2 hours, under nitrogen, using a Dean-Stark condenser for removing water. After reflux, the reaction mixture was stirred at 85-90 C for 3 hours. The reaction mixture was then evaporated to dryness to form a solid residue.
[00096] The solid residue was then dissolved in toluene (20 ml) at about 60 C.
The solution was treated with charcoal (0.3 g). The charcoal was removed by filtration, and the solution was washed with toluene (4 ml). The solution was then charged into a four-necked round bottomed flask fitted with nitrogen inlet, thermometer, dropping funnel and reflux condenser. The solution was heated to about 60 C and n-hexane (55 ml) was added in a dropwise manner for 1 hour, while stirring. The reaction mixture was then cooled to 0 - 5 C in 1.5 hours and a new portion of hexane (41 ml) was added to the slurry over an hour. The slurry was then stirred at this temperature for another hour and the product was collected, washed with the mixture of toluene (4 ml) and hexane (16 ml) containing BHT (butylated hydroxytoluene) (0.007 g) and dried at 48 C in a vacuum oven to yield simvastatin (5.0 g, 90 % yield, based on the starting material, simvastatin ammonium salt) in a purity of 98 %(HPLC).
Example 9: Preparation of lovastatin benzylamide [00097] Lovastatin ammonium salt (11.0 g, 25 mmol) was suspended in a mixture of benzylamine (3.2 g, 3.3 ml, 30 mmol) and toluene (30 ml) and the mixture was heated to reflux temperature. The mixture was stirred at reflux temperature for 3 hours under nitrogen atmosphere using a Dean-Stark water separator to complete the formation of the lovastatin benzylamide.
The solution was treated with charcoal (0.3 g). The charcoal was removed by filtration, and the solution was washed with toluene (4 ml). The solution was then charged into a four-necked round bottomed flask fitted with nitrogen inlet, thermometer, dropping funnel and reflux condenser. The solution was heated to about 60 C and n-hexane (55 ml) was added in a dropwise manner for 1 hour, while stirring. The reaction mixture was then cooled to 0 - 5 C in 1.5 hours and a new portion of hexane (41 ml) was added to the slurry over an hour. The slurry was then stirred at this temperature for another hour and the product was collected, washed with the mixture of toluene (4 ml) and hexane (16 ml) containing BHT (butylated hydroxytoluene) (0.007 g) and dried at 48 C in a vacuum oven to yield simvastatin (5.0 g, 90 % yield, based on the starting material, simvastatin ammonium salt) in a purity of 98 %(HPLC).
Example 9: Preparation of lovastatin benzylamide [00097] Lovastatin ammonium salt (11.0 g, 25 mmol) was suspended in a mixture of benzylamine (3.2 g, 3.3 ml, 30 mmol) and toluene (30 ml) and the mixture was heated to reflux temperature. The mixture was stirred at reflux temperature for 3 hours under nitrogen atmosphere using a Dean-Stark water separator to complete the formation of the lovastatin benzylamide.
[00098] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the invention.
Claims (48)
- I Claim:
l. A process for preparing lovastatin amide of formula III, the process comprising:
(a) reacting a lovastatin compound selected from the group consisting of (i) lovastatin of formula II, (ii) lovastatin acid of formula VII, (iii) a salt of lovastatin of formula II, (iv) a salt of lovastatin acid of formula VII, and (v) mixtures thereof, with an amine of formula HNR1R2 to form the lovastatin amide of formula III;
wherein R1 and R2 are independently selected from hydrogen, straight or branched C2-8 alkyl, aryl, arylalkyl, and C3-8 cycloalkyl groups, or together form a ring optionally containing a heteroatom; and wherein the molar ratio of the amine of formula HNR1R2 to the lovastatin compound is no more than about 1.5. - 2. The process of claim 1 wherein the reacting step comprises reacting the lovastatin compound and the amine for about 3 hours to about 5 hours at a temperature of from about 60°C to about 120°C.
- 3. The process as in either claim 1 or claim 2 wherein the amine of formula is selected from the group consisting of n-butylamine, diethylamine, cyclohexylamine, morpholine, benzylamine and mixtures thereof.
- 4. The process as in either claim 1 or claim 2 wherein the amine of formula is selected from the group consisting of cyclohexylamine, benzylamine and mixtures thereof.
- 5. The process as in one of claims 1-4 wherein the molar ratio of the amine of formula HNR1R2 to the lovastatin compound is no more than about 1.2.
- 6. The process as in one of claims 1-4 wherein the molar ratio of the amine of formula HNR1R2 to the lovastatin compound is from about 1 to about 1.2.
- 7. The process as in one of claims 1-6 wherein the lovastatin compound is an ammonium salt of formula VIII:
- 8. The process as in one of claims 1-7 further comprising:
converting the lovastatin amide of formula III to simvastatin of formula I.
- 9. The process as in one of claims 1-8 further comprising:
reacting the lovastatin amide of formula III with hexamethyldisilazane (HMDS) in the presence of a silylation catalyst to form the bis (TMS)-lovastatin amide derivative of formula IV;
wherein R1 and R2 are as defined in claim 1. - 10. The process of claim 9 wherein the lovastatin amide of formula III is directly combined with the silylation catalyst and the HMDS.
- 11. The process as in either claim 9 or claim 10 wherein the reacting the lovastatin compound with the amine is from about 3 to about 5 hours at about 60°C
to about 120°C, and the reacting the lovastatin amide with the HMDS is from about 0.5 to about 10 hours at about 0°C to about 40°C. - 12. The process as in one of claims 9-11 wherein the molar ratio of the silylation catalyst to the lovastatin compound is from about 0.0001 to about 0.05.
- 13. The process as in one of claims 9-11 wherein the silylation catalyst is silylhalide and the molar ratio of the silylhalide to the lovastatin compound is about 0.02.
- 14. The process as in one of claims 9-11 wherein the silylation catalyst is iodine and the molar ratio of the iodine to the lovastatin compound is about 0.004.
- 15. The process as in one of claims 9-14 wherein the molar ratio of the HMDS
to the lovastatin compound is from about 1 to about 1.7. - 16. The process as in one of claims 9-15 further comprising:
(e) combining the bis (TMS)-lovastatin amide derivative of formula IV with an aprotic organic solvent to obtain a fourth reaction mixture;
(f) combining the fourth reaction mixture with a strong base at a temperature of from about -10°C to about -80°C to obtain a fifth reaction mixture;
(g) maintaining the fifth reaction mixture at a temperature of from about 0°C
to about -40°C for a period of time of at least about 1 hour to obtain a sixth reaction mixture;
(h) combining the sixth reaction mixture with a methylating agent at a temperature of from about 0°C to about -60°C to obtain a seventh reaction mixture;
(i) maintaining the seventh reaction mixture at a temperature of from about -20°C to about -40°C for a period of time of at least about 0.5 hours to obtain an eighth reaction mixture;
(j) quenching the eighth reaction mixture at a temperature of from about 0°C
to about -20°C; and, optionally, (k) recovering simvastatin dihydroxy acid amide derivative of formula V;
wherein R1 and R2 are as defined in claim 1.
- 17. The process of claim 16 further comprising:
(1) combining the simvastatin dihydroxy acid amide derivative of formula V, a water miscible organic solvent and an aqueous solution of an alkali base to obtain a ninth reaction mixture; and (m) maintaining the ninth reaction mixture at a temperature of from about 50°C
to about 100°C for a period of time of at least about 2 hours to obtain an alkali salt of formula IX;
wherein M is alkali metal atom.
- 18. The process of claim 17 further comprising:
(n) converting the alkali salt of formula IX to simvastatin dihydroxy acid of formula X.
- 19. The process of claim 18 further comprising:
(o) converting the simvastatin dihydroxy acid of formula X to simvastatin ammonium salt of formula VI; and (p) recovering the simvastatin ammonium salt of formula VI.
- 20. The process of claim 19 further comprising:
(q) converting the simvastatin ammonium salt of formula VI to simvastatin of formula I. - 21. The process as in one of claims 17-20 wherein the reacting the lovastatin compound with the amine is from about 3 to about 5 hours, the reacting the lovastatin amide with the HMDS is from about 0.5 to about 10 hours, the period of time in step (g) is from about 1 to about 5 hours, the period of time in step (i) is from about 0.5 to about 3 hours, and the period of time in step (m) is from about 2 to about 8 hours.
- 22. A process for the preparation of bis (TMS)-lovastatin amide derivative of formula IV, the process comprising:
(a) combining lovastatin amide of formula III, a silylation catalyst and hexamethyldisilazane (HMDS) to obtain a first reaction mixture; and (b) maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin amide of formula III to the bis (TMS)-lovastatin amide derivative of formula IV. - 23. The process of claim 22 wherein the period of time is from about 0.5 to about 10 hours and the temperature is from about 0°C to about 40°C.
- 24. The process as in either claim 22 or claim 23 wherein the silylation catalyst is selected from the group consisting of silylhalide, molecular halogen, inorganic salt, organic salt, transition metal phosphonic acid derivative, saccharin and mixtures thereof.
- 25. The process as in either claim 22 or claim 23 wherein the silylation catalyst is selected from the group consisting of silylhalide, molecular halogen, saccharin and mixtures thereof.
- 26. The process as in either claim 22 or claim 23 wherein the silylation catalyst is selected from the group consisting of trimethylsilyl iodide, iodine and mixtures thereof.
- 27. The process as in one of claims 22-26 wherein the molar ratio of the silylation catalyst to the lovastatin amide of formula III is from about 0.0001 to about 0.06.
- 28. The process as in either claim 22 or claim 23 wherein the silylation catalyst is silylhalide and the molar ratio of silylhalide to the lovastatin amide of formula III is from about 0.02 to about 0.025.
- 29. The process as in either claim 22 or claim 23 wherein the silylation catalyst is iodine and the molar ratio of the iodine to the lovastatin amide of formula III is from about 0.004 to about 0.005.
- 30. The process as in one of claims 22-29 wherein the molar ratio of the HMDS
to the lovastatin amide of formula III is from about 1 to about 2. - 31. The process as in one of claims 22-29 further comprising:
(c) converting the bis (TMS)-lovastatin amide derivative of formula IV to simvastatin of formula I. - 32. A process for the preparation of simvastatin dihydroxy acid amide derivative of formula V, comprising:
(a) combining a bis (TMS)-lovastatin amide derivative of formula IV, an aprotic organic solvent, an amine derivative to obtain a third reaction mixture;
(b) combining the third reaction mixture and a compound selected from the group consisting of alkyllithium, alkali hydride, and mixtures thereof at a temperature of from about -10°C to about -80°C to obtain a fourth reaction mixture;
(c) maintaining the fourth reaction mixture at a temperature of from about 0°C
to about -40°C for a period of time of at least about 1 hour to obtain a fifth reaction mixture;
(d) combining the fifth reaction mixture with a methylating agent at a temperature of from about 0°C to about -60°C to obtain a sixth reaction mixture;
(e) maintaining the sixth reaction mixture at a temperature of from about -20°C to about -40°C for a period of time at least about 0.5 hours to obtain a seventh reaction mixture; and (f) quenching the seventh reaction mixture at a temperature of from about 0°C
to about -20°C to obtain the simvastatin dihydroxy acid amide derivative of formula V. - 33. The process of claim 32 further comprising:
(g) recovering the simvastatin dihydroxy acid amide derivative of formula V. - 34. The process as in one of claims 32-33 wherein the methylating agent is selected from the group consisting of methyl halide and methyl sulfate.
- 35. The process as in one of claims 32-33 wherein the methylating agent is methyl iodide.
- 36. The process as in one of claims 32-35 wherein the step of quenching the seventh reaction mixture comprises the use of water.
- 37. The process as in one of claims 32-35 further comprising:
converting the simvastatin dihydroxy acid amide derivative of formula V to simvastatin of formula I. - 38. The process as in one of claims 32-37 further comprising preparing the bis (TMS)-lovastatin amide derivative of formula IV by a process comprising:
(aa) combining lovastatin amide of formula III, a silylation catalyst and hexamethyldisilazane (HMDS) to obtain a first reaction mixture; and (bb) obtaining a second reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV by maintaining the first reaction mixture at a temperature and for a period of time sufficient to convert substantially all of the lovastatin amide of formula III to the bis (TMS)-lovastatin amide derivative of formula IV. - 39. The process of claim 38 wherein the period of time in step (bb) is from about 0.5 to about 10 hours, the period of time in step (c) is from about 1 to about 5 hours, the period of time in step (e) is from about 0.5 to about 3 hours, and the temperature of step (bb) is of from about 0°C to about 40°C.
- 40. The process as in one of claims 38-39 wherein the second reaction mixture comprising the bis (TMS)-lovastatin amide derivative of formula IV is directly combined with the aprotic organic solvent and the amine derivative.
- 41. The process as in one of claims 33-39 further comprising:
(h) combining the simvastatin dihydroxy acid amide derivative of formula V, a water miscible organic solvent and an aqueous solution of an alkali base to obtain an eighth reaction mixture;
(i) maintaining the eighth reaction mixture at a temperature of from about 50°C to about 100°C for a period of time of at least about 2 hours to obtain an alkali salt of formula IX;
(j) converting the alkali salt of formula IX to simvastatin dihydroxy, acid of formula X; and (k) converting the simvastatin dihydroxy acid of formula X to simvastatin ammonium salt of formula VI. - 42. The process of claim 41 further comprising (l) recovering the simvastatin ammonium salt of formula VI.
- 43. The process as in either claim 41 or claim 42 wherein the period of time of step (i) is from about 2 to about 8 hours.
- 44. The process as in one of claims 41-43 wherein the alkali base is selected from the group consisting of sodium hydroxide, potassium hydroxide and mixtures thereof.
- 45. A compound of formula IV-a:
wherein one of R1 and R2 is H and the other of R1 and R2 is selected from the group consisting of benzyl radical and cyclohexyl radical. - 46. The compound of formula IV-a of claim 45 wherein one of R1 and R2 is H and the other of R1 and R2 is benzyl radical.
- 47. The compound of formula IV-a of claim 45 wherein one of R1 and R2 is H and the other of R1 and R2 is cyclohexyl radical.
- 48. A process for the preparation of simvastatin of formula I, the process comprising:
(a) providing a compound of formula IV-a; and (b) converting the compound of formula IV-a to simvastatin of formula I.
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 (en) | 2005-09-13 | 2006-09-13 | Process for preparing simvastatin and intermediates thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2619236A1 true CA2619236A1 (en) | 2007-09-07 |
Family
ID=37898832
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002619236A Abandoned CA2619236A1 (en) | 2005-09-13 | 2006-09-13 | Process for preparing simvastatin and intermediates thereof |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1883634A2 (en) |
KR (1) | KR20080034190A (en) |
CA (1) | CA2619236A1 (en) |
WO (1) | WO2007100351A2 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI2024341T1 (en) | 2006-05-03 | 2016-04-29 | Msn Laboratories Private Limited | Novel process for statins and its pharmaceutically acceptable salts thereof |
EP2086945B1 (en) | 2006-10-09 | 2016-01-06 | MSN Laboratories Private Limited | Novel process for the preparation of statins and their pharmaceutically acceptable salts thereof |
WO2010089770A2 (en) | 2009-01-19 | 2010-08-12 | Msn Laboratories Limited | Improved process for the preparation of highly pure (3r,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-3,5-dihydroxy-6(e)-heptenoic acid and pharmaceutically acceptable salts thereof |
US8252829B2 (en) | 2009-06-05 | 2012-08-28 | Link Medicine Corporation | Aminopyrrolidinone derivatives and uses thereof |
WO2011086584A2 (en) | 2010-01-18 | 2011-07-21 | Msn Laboratories Limited | Improved process for the preparation of amide intermediates and their use thereof |
Family Cites Families (3)
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 |
EP1699774A1 (en) * | 2004-01-02 | 2006-09-13 | Hetero Drugs Limited | A novel process for the preparation of simvastatin |
-
2006
- 2006-09-13 KR KR1020087005349A patent/KR20080034190A/en not_active Application Discontinuation
- 2006-09-13 CA CA002619236A patent/CA2619236A1/en not_active Abandoned
- 2006-09-13 WO PCT/US2006/035824 patent/WO2007100351A2/en active Application Filing
- 2006-09-13 EP EP06814653A patent/EP1883634A2/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
EP1883634A2 (en) | 2008-02-06 |
WO2007100351A3 (en) | 2007-12-06 |
KR20080034190A (en) | 2008-04-18 |
WO2007100351A2 (en) | 2007-09-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2173830C (en) | Process for producing simvastatin and analogs thereof | |
FI88719B (en) | FOERFARANDE FOER -C-ALKYLERING AV 8-ACYLGRUPPEN I MEVINOLIN OCH DESS ANALOGER | |
AU747219B2 (en) | Process for the production of semi synthetic statins via novel intermediates | |
CA2619236A1 (en) | Process for preparing simvastatin and intermediates thereof | |
US20070129437A1 (en) | Process for preparing simvastatin and intermediates thereof | |
CZ286576B6 (en) | Lovastatin cyclopropyl amide and process of its preparation | |
US5010105A (en) | Antihypercholesterolemic compounds | |
AU619563B2 (en) | 5-oxygenated HMG-CoA reductase inhibitors | |
WO1999043665A1 (en) | Process for the preparation of simvastatin and derivatives thereof | |
JP2002505327A (en) | Method for producing simvastatin and / or its derivative | |
US6307066B1 (en) | Process for producing simvastatin | |
WO2004046105A2 (en) | Synthesis of 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids | |
CA2435371A1 (en) | Process for preparing intermediates for the manufacture of discodermolide and discodermolide analogues | |
JPH03184940A (en) | 7-substituted hmg-coa reductase inhibiting agent | |
AU2001293726B2 (en) | Process for preparing discodermolide and analogues thereof | |
EP0137444A2 (en) | Processes for preparing 6(R)-[2-[8(S)(2,2-dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-Decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one | |
US6573392B1 (en) | Process for manufacturing simvastatin and the novel intermediates | |
WO2003057684A1 (en) | Process for the preparation of simvastatin | |
CA2040530A1 (en) | Fluorinated derivatives of mevinic acids | |
US20020198389A1 (en) | Process for preparing discodermolide and analogues thereof | |
KR100625346B1 (en) | Process for preparation of Simvastatin | |
CA2018478A1 (en) | Antihypercholesterolemic compounds | |
WO2002024675A1 (en) | Process for manufacturing simvastatin and the novel intermediates | |
WO2006072963A1 (en) | Process for preparing simvastatin from lovastatin amine salts in three steps | |
WO2007096753A2 (en) | Process for preparing highly pure simvastatin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Discontinued |