MXPA00007791A - Process for producing simvastatin - Google Patents
Process for producing simvastatinInfo
- Publication number
- MXPA00007791A MXPA00007791A MXPA/A/2000/007791A MXPA00007791A MXPA00007791A MX PA00007791 A MXPA00007791 A MX PA00007791A MX PA00007791 A MXPA00007791 A MX PA00007791A MX PA00007791 A MXPA00007791 A MX PA00007791A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- acid
- simvastatin
- derivative
- give
- Prior art date
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 67
- 238000000034 method Methods 0.000 title claims abstract description 39
- 229960002855 simvastatin Drugs 0.000 title claims abstract description 28
- -1 diol lactone Chemical class 0.000 claims abstract description 49
- 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 abstract description 28
- 229960004844 lovastatin Drugs 0.000 claims abstract description 20
- 150000003509 tertiary alcohols Chemical class 0.000 claims abstract description 14
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 13
- 125000003198 secondary alcohol group Chemical group 0.000 claims abstract description 11
- 150000004072 triols Chemical class 0.000 claims description 67
- 239000002253 acid Substances 0.000 claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- LDJUYMIFFNTKOI-UHFFFAOYSA-N 2,2-dimethylbutanoyl chloride Chemical compound CCC(C)(C)C(Cl)=O LDJUYMIFFNTKOI-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000003586 protic polar solvent Substances 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 230000003247 decreasing Effects 0.000 claims description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- 150000003333 secondary alcohols Chemical class 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims 4
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims 1
- 150000008046 alkali metal hydrides Chemical class 0.000 claims 1
- 230000001681 protective Effects 0.000 abstract description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 abstract 1
- 230000002349 favourable Effects 0.000 abstract 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
- 230000002829 reduced Effects 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000007273 lactonization reaction Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 150000001241 acetals Chemical class 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000003377 acid catalyst Substances 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-Dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 238000005947 deacylation reaction Methods 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000008079 hexane Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 101700067048 CDC13 Proteins 0.000 description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 2
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 2
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- VNLFZVJYRYRAIX-YFKPBYRVSA-N (2S)-2-(tert-butylamino)-3-hydroxypropanoic acid Chemical compound CC(C)(C)N[C@@H](CO)C(O)=O VNLFZVJYRYRAIX-YFKPBYRVSA-N 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-Methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-Methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 1
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-Methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 1
- NUANGSLQWFBVEH-UHFFFAOYSA-N 4-butylcyclohexan-1-ol Chemical compound CCCCC1CCC(O)CC1 NUANGSLQWFBVEH-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- NPOXHVWQQXPCGC-YOXFSPIKSA-N C(C)C1(OCC[C@@H](O1)C(=O)OC)C Chemical compound C(C)C1(OCC[C@@H](O1)C(=O)OC)C NPOXHVWQQXPCGC-YOXFSPIKSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N Cetyl alcohol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O Pyridinium Chemical class C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000005828 desilylation reaction Methods 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- ZLDLVVZTYZSCLC-UHFFFAOYSA-N methyl 2-methyl-1,3-dioxane-2-carboxylate Chemical compound COC(=O)C1(C)OCCCO1 ZLDLVVZTYZSCLC-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
Abstract
A convenient, efficient and industrially favorable process for producing simvastatin which is useful as an HMG-coA reductase inhibitor. This process comprises deacylating lovastatin by treating with an inorganic base and a secondary or tertiary alcohol to thereby form diol lactone, and then selectively protecting, acylating, deblocking and lactonizing the diol lactone by using a ketal or acetal protective group to thereby give simvastatin.
Description
PROCESS TO PRODUCE SIMVASTATIN
Technical Field The present invention relates to a process for producing simvastatin, which comprises the deacylation of lovastatin with an inorganic base and a secondary or tertiary alcohol to give a lactone diol and subjecting it, in series, to selective protection with a group. Cetal or acetal protector, with an acylation and deprotection-lactonization. It is known that simvastatin is a compound that is used as an inhibitor of HMG-CoA reductase.
BACKGROUND OF THE INVENTION The previously known technology, for the production of simvastatin, includes, among others, (1) the process comprising the hydrolysis of lovastatin with lithium hydroxide, the lactonization to give a lactone diol, a silylation? selective with TBDS, acylation and desilylation (USP 4444784), (2) the process in which the potassium salt of lovastatin is methylated directly (USP4582915), and (3) the process in which! REF: 121991 Lovastatin monoalkylamide is methylated directly (USP 4820850). The above process (1) requires high temperatures and a long period of time for the hydrolysis reaction, so that both production and productivity are low. Moreover, the selective silylation and the subsequent steps are not satisfactory enough in terms of reaction selectivity so that the total production is not as high as desired. In the process (2), the lovastatin prima remains partially unreacted so a complicated procedure for purification is required. In the process (3), the reaction must be carried out at an extremely low temperature. Therefore, all processes have much to improve for commercial scale production.
Brief Description of the Invention The inventors of the present invention explore, in search of a technology with which simvastatin can be produced with high efficiency without having to use expensive reagents and under comparatively humble conditions, which leads them to a process novel which comprises the deacylation of lovastatin with an inorganic base and a secondary or tertiary alcohol and subjecting the resulting lactone diol to selective protection with a ketal or acetal protecting group, and to an acylation and deprotection-lactonization to produce simvastatin. The present invention is developed accordingly. The present invention, therefore, relates to a process for producing simvastatin of the formula;
which comprises treating the lovastatin of the formula (1) with an inorganic base and a secondary or tertiary alcohol to give an acid triol of the formula (2);
which acidifies and lactonizes in series the acid triol (2) to give a lactone diol of the formula (3);
and treating the acid triol (2) or the lactone diol (3) with an acid and a compound of the formula (RO? CR ^ 2, wherein R represents a lower alkyl group of 1 to 8 carbon atoms; and R 2 may be the same or different and each represents a hydrogen, a lower alkyl group of 1 to 8 carbon atoms, or an aryl or aralkyl group which may have a substituted group, or R 1 and R 2 may be attached at the ends free to form a ring, to give an acid triol derivative of the formula (4);
wherein R, R1 and R2 are as defined above respectively, treating the acid triol derivative (4) with 2, 2-dimethylbutyryl chloride to give a simvastatin derivative of the formula (5);
wherein R, R1 and R2 are respectively as defined above; and treating the simvastatin derivative (5) with a protic solvent and an acid to simvastatin (6). The present invention, moreover, relates to a process for producing a lactone diol (3) comprising treating lovastatin (1) with an inorganic base and a secondary or tertiary alcohol to give an acid triol (2), acidifying and lactonize in series the acid triol (2) to give a lactone diol (3). The present invention, moreover, relates to a process for producing an acid triol derivative (4), which comprises treating the acid triol (2) or a lactone diol (3) with an acid and a compound of the formula ( RO) 2CR1R2; Where R, R1 and R2 are respectively as defined above, to give a derivative of the acid triol (4). The present invention, moreover, relates to a process for producing a derivative of simvastatin1 (5) which comprises treating a derivative] of the acid triol (4) with 2,2-dimethylbutyryl chloride to give a derivative of the simvastatin (5). The present invention, moreover, relates to a process for producing simvastatin which comprises treating the derivative of simvastatin (5) with a protic solvent and an acid to simvastatin (6). Finally, the present invention relates to a derivative of the acid triol (4) and a derivative of simvastatin (5). The present invention is now described in detail.
Detailed Description of the Invention The lovastatin of the above formula (1), which is the compound of the raw material of the invention, can be produced by a fermentation process employing a strain of a microorganism belonging to the Aspergillus genus (USP 4444784 ). The novel process of the present invention comprises deacylating lovastatin (1) with an inorganic base and a secondary or tertiary alcohol and subjecting the deacylated compound to a lactonization to give a lactone diol (3), a selective protection with a ketal protective group or acetal, an acylation, and a deprotection-lactonization to give, with a high efficiency, the simvastatin of the formula (6).
The process of the present invention is carried out as follows. First, lovastatin (1) is subjected to treatment with an inorganic base and a secondary or tertiary alcohol to give an acid triol (2). More particularly, lovastatin (1) is reacted with an inorganic base in the presence of a secondary or tertiary alcohol solvent in an inert atmosphere such as nitrogen gas to give an acid triol (2). The reaction temperature is from 60 to 100 ° C and the reaction time lasts from 1 to 60 hours. The secondary or tertiary alcohol mentioned above, preferably, is a secondary or tertiary alcohol, of which the hydrocarbon portion is an alkyl group containing from 3 to 8 carbon atoms. This alcohol is not particularly restricted but includes secondary alcohols such as isopropyl alcohol, sec-butyl alcohol and cyclohexanol and tertiary alcohols such as t-butyl alcohol. Preferred is isopropyl alcohol or t-butyl alcohol. The inorganic base mentioned above or is particularly restricted, but includes the alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc .; and alkali metal alkoxides such as potassium t-butoxide, sodium isopropoxide, etc. The most preferred is potassium hydroxide. Normally, the inorganic base is used in a ratio of 1 to 10 molar equivalents for lovastatin (1). Then, the acid triol (2) is acidified and lactonized to give a lactone diol (3). More particularly, the reaction mixture obtainable by the above treatment is concentrated under reduced pressure and the residue is acidified with an inorganic acid such as hydrochloric acid and sulfuric acid and extracted with an organic solvent. The extract is concentrated under reduced pressure to give an acidified acid triol (2). This acidified acid triol (2) is lactonized by heating it in an organic solvent under reflux and the product of the reaction is made to crystallize from an organic solvent. The complex is filtered and dried to give the lactone diol (3). Preferably, as a rule, the acid triol (2) is not isolated but is subjected to a lactonization reaction in the form of a concentrated product in the acidified reaction mixture. The organic solvent for refluxing is not particularly restricted, but includes toluene, hexane, ethyl acetate and isopropyl acetate, among others. The organic solvent for crystallization is not restricted, but includes toluene, hexane, ethyl acetate and isopropyl acetate, among others.
Then, the acid triol (2) or the lactone diol (3) is subjected to treatment with an acid and a ketal or acetal in an organic solvent to give a derivative of the acid triol
(4) . The temperature of the reaction is 20 to 60 ° C and the reaction time lasts from 1 to 10 hours. The formula (RO) 2CR1R2 for this ketal or acetal, means a dialkoxy-ketal or -acetal. In the formula, R represents a lower alkyl group of 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc., and is preferably methyl. R1 and R2 can be the same or different and each represents a hydrogen; an alkyl group decreased from 1 to 8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc .; an aryl group which may have a substituted group, such as phenylp, p-chlorophenyl, etc .; or an aralkyl group such as benzyl, p-chlorobenzyl, etc., or R1 and R2 can be coupled at the free ends to form a ring. Preferably, both R1 and R2, respectively, represent a methyl group. The ketal or acetal should be used theoretically in an equimolar proportion relative to that of the diol lactone (3), but in fact it is used in a ratio of 1 to 10 molar equivalents. The acid mentioned above can, for example, be p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid, and acts as an acid catalyst. The amount of the acid used is 0.01 to 1 molar equivalent in relation to the diol lactone (3). The organic solvent mentioned above must be a solvent which does not adversely affect the reaction, and which is not otherwise particularly restricted, but which includes, for example, methylene chloride, acetone, toluene, hexane, ethyl, t-butyl methyl ether, etc.
After the reaction, normally, the reaction mixture is neutralized with a base, such as a pyridine, and concentrated under a reduced pressure, whereby the acid triol derivative (4) is obtained. This derivative of the acid triol (4), in addition, is reacted with the 2,2-dimethylbutyryl chloride in the presence of an organic base and a tertiary amine to give the derivative of simvastatin (5). The temperature of the reaction is from 40 to 120 ° C and the reaction time lasts from 1 to 100 hours. The organic base mentioned above is not particularly restricted but includes, among others, a pyridine, 2-picoline, 3-picoline and 4-picoline. The tertiary amine mentioned above is not particularly restricted, but includes 4-dimethylaminopyridine, 4-pyrrolidinopyridine and so on. These substances are used in amounts ranging from 10 to 60 moles and from 0.01 to 1 mol, respectively, based on the acid triol derivative (4). The reaction mixture thus obtained is concentrated under a reduced pressure, and added to an organic solvent such as ethyl acetate, washed with an acid, and finally concentrated under a reduced pressure to give the derivative of simvastatin (5). Finally, this derivative of simvastatin (5) is subjected to treatment with an acid catalyst and a protic solvent, preferably with a small amount of water, in an organic solvent, whereby the same is converted to simvastatin (6). ). The temperature of the reaction ranges from 20 to 60 ° C and the time lasts from 1 to 10 hours. The acid catalyst mentioned above is not particularly restricted but includes hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid and trifluoroacetic acid, among others. The acid catalyst is used in a proportion of 0.01 to 1 mol per mol of the simvastatin derivative (5). The amount of water that is used is from 1 to 100% of organic solvent based on a volume-volume.
The organic solvent mentioned above is not particularly restricted, but includes acetonitrile, THF, methanol, etc. The protic solvent mentioned above is also not particularly restricted. Therefore, it is possible to mention not only water, but also methanol, ethanol, n-propanol, i-propanol, etc. The resulting reaction mixture is concentrated under reduced pressure and the residue is crystallized from an organic solvent, such as cyclohexane, filtered, and dried to give simvastatin (6).
BEST METHOD FOR CARRYING OUT THE INVENTION The following examples illustrate the present invention in more detail and under no circumstances should be construed to define the scope of the invention. In the following examples (Examples 7, 8 and 9), the acid triol (2) and / or the lactone diol (3) are determined qualitatively and quantitatively by high performance liquid chromatography under the following conditions (parameter determination TO) .
Determination of parameter A Instrument: LC-10 A, Shimadzu Corporation Column: ODS column, Nakalai-Tesque, Cosmosil 5C18-AR-300 Eluent: Acetonitrile / 0.1% phosphoric acid (aq.) = 100/50 (v / v) Flow rate: 1.5 ml / min. Temperature of 238 nm (UV detector) Detection: 45 ° C
The compounds of formulas (3), (4), (5) and
(6) that are derived from the acid triol are quantified by high performance liquid chromatography under the following conditions (determination of the parameter
B). Determination of parameter B Instrument: LC-10 A, Shimadzu Corporation Column: ODS Column, Nakalai-Tesque, Cosmosil 5C18-AR-300 Eluent: Acetonitrile / 0.1% phosphoric acid (aq.) = 150/50 (v / v) Flow rate: 1.0 ml / min. Temperature of 238 nm (UV detector) Detection: 45 ° C
(Example 1) Process for Producing Diol Lactiona (Compound of Formula (3)) It is added to a solution of KOH (7.92 g) in 300 ml of t-butyl alcohol, 8.09 g (20 mmoles) of lovastatin, and the mixture is stirred under an atmosphere of argon gas at room temperature for 30 minutes. Then, the temperature rises and the mixture is refluxed with stirring for 4 hours. The reaction mixture is concentrated under reduced pressure, and water is added, acidified with phosphoric acid (pH = 3.5), and extracted with ethyl acetate. The extract is concentrated under reduced pressure to give a brown oil. This brown oil is dissolved in 200 ml of isopropyl acetate, and after the addition of 65 μl (1 mmol) of methanesulfonic acid, the solution is concentrated to approximately 1/5 of the volume under reduced pressure. The residue is washed with a saturated aqueous solution of sodium hydrogencarbonate, cooled to -20 C, and stirred. The resulting slurry is filtered and dried in vacuo to give white crystals, this product is identified as the title compound.
(Example 2) Process to produce 2,2-dimethyl-6 (R) - (2- (8- (S) -hydroxy-2 (S), 6 (R) -dimethyl-1, 2, 6.7, 8.8 a (R) -hexahydronaphthyl-1 (S)) ethyl) - (R) - (methyloxycarbonyl) methyl-1,3-dioxane (Compound of Formula (4)) To a solution of diol lactone ( 1.62 g, 5 mmol) in 25 ml of methylene chloride, 3.69 ml (30 mmol) of 2,2-dimethoxypropane and 48 mg (0.25 mmol) of p-toluenesulfonic acid are added, and the mixture is stirred under an atmosphere of argon gas at room temperature for 1 hour. This reaction mixture is neutralized with pyridine and concentrated under reduced pressure, and the concentrated product is purified by column chromatography on silica gel to give a translucent oil. This product is identified as the title compound. NMR (CDC13, 400 MHz) 6: 0.89 (d, 3H), 1.1-1.9 (m, 16H), 1.2 (d, 3H), 2.2-2.6 (m, 5H), 3.65 (s, 3H), 3.85 ( m, 1H), 4.2 (m, 1H), 4.3 (m, 1H), 5.5 (bt, 1H), 5.78 (dd, 1H), 6.0 (d, 1H).
(Example 3) Process to Produce 2,2-dimethyl-6 (R) - (2- (8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (R) -dimethyl- 1,2 , 6,7,8,8 to (R) -hexahydronaphthyl-1 (S)) ethyl) -4 (R) (methyloxycarbonyl) methyl-1,3-dioxane (Compound of Formula (5)) To a solution of 2, 2-dimethyl-6 (R) - (2- (8- (S) -hydroxy-2 (S), 6 (R) -dimethyl-1, 2, 6, 7, 8, 8 a (R) hexahydronaphthyl-1 (S)) ethyl) -4 (R) - (methyloxycarbonyl) methyl-1,3-dioxane (1.96g, 5 mmol) in 16.2 ml (40 mmol) of pyridine, 122 mg (1 mmoles) of 4-dimethylaminopyridine and 2.69 g (20 mmol) of
2, 2-dimethylbutyryl, and the mixture is stirred at 100 ° C for 6 hours. This reaction mixture is concentrated under reduced pressure and ethyl acetate is added. The organic layer is washed with a 10% aqueous solution of citric acid and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give a translucent oil. This product is identified as the title compound. NMR (CDC13, 400 MHz) d: 0.88 (t, 3H), 0.89 (d, 3H), 1.08 (d, 3H), 1.11 (s, 3H), 1.12 (s, 3H), 1.2-1. (m, 11H), 1.35 (s, 3H) 1.45 (s, 3H), 1.88-2.6 (m, 5H), 3.65 (s, 3H), 3.7 (m, 1H), 4.3 (m, 1H), 5.3 (m, 1H), 5.5 (bt, 1H), 5.78 (dd, 1H), 6.0 (d, 1H).
(Example 4) Process for Producing Simvastatin (Compound of Formula (6)) To a solution of 2,2-dimethyl-6 (R) - (2- (8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (R) -dimethyl-1, 2,6,7,8,8a (R) -hexahydronaphthyl) -l (S)) ethyl) -4 (R) - (methyloxycarbonyl) meth1-1,3 dioxane (2.45 g, 5 mmol) in 45 ml of acetonitrile, add 5 ml of 1 N-HC1, and the mixture is stirred at room temperature for 4 hours. This reaction mixture is concentrated under a reduced pressure and extracted with cyclohexane, the product of the extract is crystallized by a concentration. The resulting slurry is filtered and dried in vacuo to give white crystals, this product is identified as the title compound.
(Example 5) Process for Producing Diol Lactone (Compound of Formula (3)) To a solution of KOH (7.92 g) in 100 ml of isopropyl alcohol is added 8.09 g (20 mmol) of lovastatin, the mixture is stirred under an atmosphere of argon gas at room temperature for 30 minutes; The temperature rises, and the mixture is stirred further at the reflux temperature for 4 hours. This reaction mixture is concentrated under reduced pressure and water is added to the residual product, acidified with phosphoric acid (pH = 3.5), and extracted with 200 ml of isopropyl acetate. To the extract is added 65 μl (1 mmol) of methanesulfonic acid, and the mixture 1 is concentrated to about 1/5 of the volume under reduced pressure. The residue is washed with a saturated aqueous sodium hydrogencarbonate solution and allowed to crystallize at -20 ° C. This is followed by filtration and dehydration in vacuo to give white crystals. The product is identified as the compound of the title.
(Example 6) Process for Producing Simvastatin (Compound of Formula (6)) To a solution of white crystals of Idiol lactone (5 mmoles) obtained in Example 5, in 25 ml of methylene chloride, are added 3.69 li (30 mmol) of 2,2-dimethoxypropane and 48 mg (0.25 mmol!) Of p-toluenesulfonic acid, and the mixture is stirred under an atmosphere of argon gas at room temperature for 1 hour. Pyridine is added to this reaction mixture and concentrated under reduced pressure. To a solution of the residue obtained above, in 16.2 ml (40 mmol) of pyridine, 122 mg (1 mmol) of 4-dimethylaminopyridine and 2.69 g (20 mmol) of 2,2-dimethylbutyryl chloride are added thereto, and The mixture is stirred at 100 ° C for 6 hours. This reaction mixture is concentrated under reduced pressure and ethyl acetate is added to the residue. The organic layer is washed with a 10% aqueous solution of citric acid and concentrated under reduced pressure.
To a solution of the residue thus obtained, in 45 ml of acetonitrile, 5 ml of 1 N-HCl is added, and the mixture is stirred at room temperature for 4 hours. This reaction mixture is concentrated under reduced pressure and extracted with cyclohexane and the extract is crystallized by concentration. The resulting slurry is filtered and dried in vacuo to give white crystals. This product is identified as the title compound.
(Example 7) Process to Produce 2, 2-dimethyl-6 (R) - (2- (8 (S) -hydroxy-2 (S), 6 (R) -dimethyl-1, 2, 6, 7, 8 , 8a (R) -hexahydronaphthyl-1 (S)) ethyl) -4 (R) - (methyloxycarbonyl) methyl-1,3-dioxane (Compound of Formula (4)) When using 2-propanol instead of the solvent of the reaction of the deacylation which is used in Example (1), 8.09 g (20 mmoles) of lovastatin are deacylated under the same conditions as in Example (1), and acidified with phosphoric acid to prepare a solution watery The product of the acid triol in the solution is extracted using toluene as an extraction solvent. This toluene extract (305 g) is concentrated under reduced pressure to about 1/3 to remove the concomitant water. Then, 190 g are added
(1 mmole) of p-toluenesulfonic acid, after which 12.5 g (120 mmoles) of 2,2-dimethoxypropane are further added. The resulting mixture is stirred under an atmosphere of nitrogen gas at room temperature for one hour. One hour after the start of the reaction, samples are taken from the reaction mixture and analyzed by HPLC to confirm that the objective derivative of the acid triol (compound of the formula (4) 0 has been formed with a production of not less than 90% This reaction mixture is neutralized with pyrimidine, water is added, and it is stirred to extract the pyridinium salt of p-toluenesulfonic acid, the by-product of methanol and acetone in the aqueous phase. it is separated, concentrated under a reduced pressure to remove the concomitant water and the residual dimethoxyprolpane to give a solution of toluene (80.1 g) of the objective derivative of the acid triol (compound of the formula (4)).
(Example 8) Process to Produce 2,2-dimethyl-6 (R) - (2- (8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (R) -dimethyl- 1, 2 , 6, 7, 8, 8a (R) -hexahydronaphthyl-1 (S)) ethyl-4 (R) - (methyloxycarbonyl) methyl-1,3-dioxane (Compound of Formula (5)) To a solution of toluene (40.0 g) of the derivative: from the acid triol (compound (4)) obtained in Example 7 there are added 15.8 g (200 mmol) of pyridine, 122 mg (1 mmol) of 4-dimethylaminopyridine and 5.38 g (40 mmol) of 2, 2-dimethylbutyryl chloride, and the mixture is stirred under nitrogen at 100 ° C for 6 hours.Six hours after the start of the reaction, a portion of the reaction mixture is quantified by HPLC analysis for confirm that the target derivative of simvastatin (compound (5)) is formed at a conversion rate of not less than 70% after a period of 8 hours of reactionWater is added to the reaction mixture and stirred at room temperature for 3 hours to decompose the residual acid chloride to the carboxylic acid. The aqueous solution is separated to remove the soluble impurity from inclusive water of the carboxylic acid and pyridine. The organic solution is further washed, with water, three times to give 42 g of a toluene solution of the objective compound (compound (5)) with a residual pyridine content of not more than 1%.
(Example 9) Process for Producing Simvastatin (Compound of Formula (6)) To 20 g of the toluene solution of the simvastatin derivative (compound (5)) which is obtained in Example 8, 20 ml of 1 N-HCl, and the mixture is stirred vigorously under an atmosphere of nitrogen gas at room temperature. After a period of 10 hours, it is confirmed by HPLC, that the initial derivative of simvastatin (compound (5)) disappears substantially in its entirety, and after the addition of 200 ml of toluene, the aqueous layer is separated. The organic layer is washed with water and also with a saturated aqueous solution of sodium chloride. Then, 38 mg (0.2 mmoles) of p-toluenesulfonic acid are added and the lactonization reaction is initiated by heating and refluxing ba or nitrogen. After a period of 6 hours, a portion of the reaction mixture is taken and analyzed by HPLC. the result indicates that the simvastatin target has been obtained at a conversion rate of not less than 95%. After cooling, the reaction mixture is added and washed with water under stirring and the toluene is concentrated until the crystals of simvastatin are separated. At the time crystallization is observed, the complex is cooled to 5 ° C and the solid matter resembling a slurry is separated by suction filtration, washed with toluene and dried in vacuo at 50 ° C. Analysis of the dehydrated product by HPLC reveals the formation of simvastatin of 93% purity.
Industrial Application In accordance with the production technology of the present invention, simvastatin can be produced with a high use, and a high efficiency, as an inhibitor of lovastatin HMG-CoA reductase.
It is noted that in relation to this date the best known method for the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.
Claims (11)
1. A process for producing a lactone diol according to formula (3); characterized in that it comprises treating the lovastatin of the formula (1) with an inorganic base and a secondary or tertiary alcohol to give an acid triol of the formula (2); and acidify and lactonize in series the acid triol (2) to give a lactone diol (3).
2. The process to produce a lactone diol of the formula (3) according to claim 1, characterized in that the secondary or tertiary alcohol is i-propanol or t-butanol. 1 .
3. The process for producing a lactone diol of the formula (3) according to claim 1 or 2, characterized in that the inorganic base is an alkali metal hydride or an alkali metal alkoxide.
4. The process for producing a lactone diol of the formula (3), according to claim 3, characterized in that the alkali metal hydroxide is lithium hydroxide, sodium hydroxide or potassium hydroxide.
5. A derivative of the acid triol of the formula (4) wherein R represents a lower alkyl group of 1 to 8 carbon atoms; R1 and R2 may be the same or different and each represents hydrogen, a lower alkyl group of 1 to 8 carbon atoms, or an aryl or aralkyl group which may have a substituted group; or R1 and R2 can be coupled together at their free ends to form a ring, characterized in that it comprises treating an acid triol of the formula (2) or a lactone diol of the formula (3) with an acid and a compound of the formula (R0) 2CR1CR2; wherein R, R1 and R2 are respectively as defined above, to give an acid triol (4).
6. A process for producing a derivative of simvastatin according to formula (5); wherein R represents a lower alkyl group of 1 to 8 carbon atoms; R1 and R2 may be the same or different and each represents hydrogen, an alkyl group decreased from 1 to 8 carbon atoms, or an aryl or aralkyl group which may have a substituted group; or R1 and R2 can be coupled together at their free ends to form a ring, characterized in that it comprises treating a derivative of the acid triol (4) with the 2,2-dimethylbutyryl chloride to give a derivative of simvastatin (5); wherein R, R1 and R2 are respectively as defined above.
7. A process for producing a simvastatin according to formula (6); characterized in that it comprises treating a derivative of simvastatin of the formula (5) with a protic solvent and an acid to give simvastatin (6); wherein R represents an alkyl group decreased from 1 to 8 carbon atoms; R1 and R2 may be the same or different and each represents hydrogen, a lower alkyl group of 1 to 8 carbon atoms, or an aryl or aralkyl group which may have a substituted group; or R1 and R2 can be coupled together at their free ends to form a ring.
8. A process for producing a simvastatin according to formula (6); characterized in that it comprises treating the lovastatin of the formula (1) with an inorganic base and a secondary or tertiary alcohol to give an acid triol of the formula (2); Acidify or lactonize in series the acid triol (2) | to give a lactone diol of the formula (3); treating the diol lactone (3) with an acid and a compound of the formula (RO) 2CR1R '; wherein R represents an alkyl group decreased from 1 to 8 carbon atoms; R "and R2 may be the same or different and 1 each represents hydrogen, an alkyl group decreased from 1 to 8 carbon atoms, or an aryl or aralkyl group which may have a substituted group; or R1 and R2 may be coupled together in its free ends for forming a ring, to give a derivative of the acid triol of the formula (4); wherein R, R1 and R2 are respectively as defined above, treating the acid triol derivative (4) with 2, 2-dimethylbutyryl chloride to give a simvastatin derivative of the formula (5); wherein R, R1 and R2 are respectively as defined above, and subjecting the simvastatin derivative (5) to treatment with a protic solvent and an acid to give a simvastatin (6).
9. The process according to any of claims 5 to 8 characterized in that R = R1 = R2 = methyl.
10. A derivative of the acid triol according to formula (4); characterized in that R, R 1 and R 7 each represent a methyl group.
11. A derivative of simvastatin according to formula (5); characterized in that R, R1 and R2 each represents a methyl group.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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JP10/351865 | 1998-12-10 |
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MXPA00007791A true MXPA00007791A (en) | 2002-05-09 |
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