MX2007006596A - Diastereomeric purification of rosuvastatin - Google Patents
Diastereomeric purification of rosuvastatinInfo
- Publication number
- MX2007006596A MX2007006596A MXMX/A/2007/006596A MX2007006596A MX2007006596A MX 2007006596 A MX2007006596 A MX 2007006596A MX 2007006596 A MX2007006596 A MX 2007006596A MX 2007006596 A MX2007006596 A MX 2007006596A
- Authority
- MX
- Mexico
- Prior art keywords
- process according
- rosuvastatin
- ester
- solvent
- water
- Prior art date
Links
- 229960000672 rosuvastatin Drugs 0.000 title claims abstract description 116
- BPRHUIZQVSMCRT-VEUZHWNKSA-N Rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 title claims abstract description 111
- 238000000746 purification Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 88
- 239000000203 mixture Substances 0.000 claims description 125
- -1 diol ester Chemical class 0.000 claims description 105
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 93
- 239000000243 solution Substances 0.000 claims description 75
- 239000011541 reaction mixture Substances 0.000 claims description 70
- 239000002904 solvent Substances 0.000 claims description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 59
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 50
- 239000003960 organic solvent Substances 0.000 claims description 45
- 239000011780 sodium chloride Substances 0.000 claims description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000012535 impurity Substances 0.000 claims description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 31
- 230000002829 reduced Effects 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 28
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 26
- 239000000725 suspension Substances 0.000 claims description 26
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 claims description 24
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 24
- 238000002425 crystallisation Methods 0.000 claims description 23
- 230000005712 crystallization Effects 0.000 claims description 23
- 150000002148 esters Chemical class 0.000 claims description 22
- 150000002576 ketones Chemical class 0.000 claims description 22
- 238000004519 manufacturing process Methods 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- FESAXEDIWWXCNG-UHFFFAOYSA-N diethyl(methoxy)borane Chemical compound CCB(CC)OC FESAXEDIWWXCNG-UHFFFAOYSA-N 0.000 claims description 20
- 239000012074 organic phase Substances 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 230000001603 reducing Effects 0.000 claims description 16
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 claims description 16
- 238000006722 reduction reaction Methods 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- 150000001298 alcohols Chemical class 0.000 claims description 11
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 11
- 150000002170 ethers Chemical class 0.000 claims description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 11
- 230000001965 increased Effects 0.000 claims description 9
- 239000002826 coolant Substances 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 7
- 235000019270 ammonium chloride Nutrition 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 claims description 7
- WQOXQRCZOLPYPM-UHFFFAOYSA-N Dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutic aid Substances 0.000 claims description 6
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 claims description 6
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 5
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- 239000012448 Lithium borohydride Substances 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 3
- NZTNZPDOBQDOSO-UHFFFAOYSA-N lithium;boron(1-) Chemical compound [Li+].[B-] NZTNZPDOBQDOSO-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- HHUJLKPGQMFFMS-UHFFFAOYSA-N potassium;boron(1-) Chemical compound [B-].[K+] HHUJLKPGQMFFMS-UHFFFAOYSA-N 0.000 claims description 3
- 239000003586 protic polar solvent Substances 0.000 claims description 3
- 238000011084 recovery Methods 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- QYPUTBKHHRIDGS-UHFFFAOYSA-N octane-1,1-diol Chemical compound CCCCCCCC(O)O QYPUTBKHHRIDGS-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N Hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N Glyoxalate, Glyoxylate Chemical group OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims 1
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 235000002639 sodium chloride Nutrition 0.000 description 24
- 239000007787 solid Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 239000003826 tablet Substances 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
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- 239000002552 dosage form Substances 0.000 description 10
- 229960005069 Calcium Drugs 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 9
- 229910052791 calcium Inorganic materials 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000008187 granular material Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- 239000002775 capsule Substances 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
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- 239000000047 product Substances 0.000 description 6
- 238000007907 direct compression Methods 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 5
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- SOEGVMSNJOCVHT-VEUZHWNKSA-N Rosuvastatin 5 S-lactone Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC(N(C)S(C)(=O)=O)=NC=1C1=CC=C(F)C=C1 SOEGVMSNJOCVHT-VEUZHWNKSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 3
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Abstract
The invention relates to diastereomerically pure rosuvastatin and processes for preparing diastereomerically pure rosuvastatin and its intermediates. Formula (I).
Description
DIASTEREOMERIC PURIFICATION OF ROSUVASTATINA
Field of the invention
The invention relates to an intermediate of rosuvastatin having low levels of diastereomeric impurities, and to a process for preparing them.
BACKGROUND OF THE INVENTION The calcium of Rosuvastatin (bis (+) 7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-methylsulfonylaminopyrimidin) -5-yl] - (3R, 5S) - monocalcium dihydroxy- (E) -6-heptanoate) is an inhibitor of HMG-CoA reductase, developed by Shionogi for the daily oral treatment of hyperlipidemia (Ann Rep, Shionogi, 1996; Direct Communications, Shionogi, February 8, 1999 and February 25, 2000). The calcium of rosuvastatin is a supersetin, which can lower LDL cholesterol and triglycerides more effectively than first-generation drugs. The calcium of rosuvastatin has the following chemical formula:
The calcium of rosuvastatin is marketed under the trademark CRESTOR for the treatment of a mammal such as a human. According to the manufacturer of CRESTOR, it is administered in a daily dose of 5 mg to 40 mg. For patients who require less reductions of LDL-C less aggressive or who have predisposing factors to myopathy, a dose of 5 mg is recommended, while a dose of 10 mg is recommended for the average patient, the dose of 20 mg for patients with marked hypercholesterolemia and aggressive target lipids (> 190 mg / dL), and the 40 mg dose for patients who have not responded to lower doses.
Rosuvastatin is a compound that has two chiral centers at positions 3 and 5 of the molecule. Two of the four calcium diastereomers of Rosuvastatin are those derived from (3R, 5R) and (3R, 5S). These diastereomers can be detected by reverse phase HPLC.
The synthetic process disclosed in US RE37,314E for rosuvastatin consists in the reduction of a keto-ester of a rosuvastatin at carbon 5 to obtain a diol ester. This reduction in position 5 is a typical standard step in the synthesis of statins. This reduction step, however, can lead to diastereomeric impurities.
WO 2005/040134 discloses a process that is reported to reduce the diastereomer content of rosuvastatin through lactonization, or through the conversion of amorphous rosuvastatin into crystalline rosuvastatin and subsequent conversion to the amorphous form.
A preparation of a diastereomerically pure rosuvastatin and its intermediates is needed in the art.
Extract of the invention
In one embodiment, the present invention provides a rosuvastatin intermediate of the following structure:
Where Rx is a C1-C alkyl group, which has diastereomeric impurities of less than 0.37%, measured in percent area by HPLC.
In another embodiment, the present invention provides a process for preparing an intermediate of rosuvastatin diol ester having the structure:
Where ¾ is a C1-C4 alkyl group, which comprises: a) combining MeO-9 - ??? with an organic solvent and a source of hydride ions; b) adding to the combination a solution of a keto-ester of rosuvastatin in an organic solvent, wherein the keto-ester of rosuvastatin has the following formula:
wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and ¾ is a carboxy protecting group, to obtain a reaction mixture; and c) maintaining the reaction mixture to obtain the diol ester.
In another embodiment, the present invention provides a process of a container for preparing rosuvastatin or a pharmaceutically acceptable salt thereof comprising: a) combining MeO-9 - ??? an organic solvent and a source of hydride ions; b) adding to the combination a solution of an intermediate keto-ester of rosuvastatin in an organic solvent, wherein the keto-ester intermediate of rosuvastatin has the following formula:
wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and ¾ is a carboxy protecting group to obtain a reaction mixture; c) maintaining the reaction mixture to reduce the intermediate; and d) converting the reduced intermediate to rosuvastatin or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a process for preparing an intermediate diol ester having the structure:
wherein Ri is a carboxy protecting group comprising the steps of: a) combining diethylmethoxy borane (DEMB) with an organic solvent and a source of hydride ions; b) adding to the combination a solution of a keto-ester of rosuvastatin in an organic solvent, wherein the keto-ester of rosuvastatin has the following formula:
wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and Ri is a carboxy protecting group, to obtain a reaction mixture wherein the total of the solvent from the keto-ester solution and the solvent that is combined with the DEMB is 30 to 80 volumes (ml per gram of the keto ester) in the reaction mixture; and c) maintaining the reaction mixture.
In another embodiment, the present invention provides a process for isolating a diol ester of rosuvastatin having the following structure:
wherein ¾ is a carboxy protecting group, which comprises crystallizing the diol ester from an organic solvent or a mixture of water and an organic solvent.
In another embodiment, the present invention provides a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, prepared by converting the rosuvastatin ester of C3-C4, preferably t-butyl ester, having less than 0.3% of diastereomeric impurities, measured by percentage of HPLC area, in rosuvastatin or a pharmaceutically acceptable salt thereof, and combining rosuvastatin with a pharmaceutically acceptable excipient.
In another embodiment, the present invention provides the use of rosuvastatin t-butyl ester having less than 0.3% diastereomeric impurities, measured, by HPLC, in the manufacture of a pharmaceutical composition.
Detailed Description of the Invention Diastereomeric impurities in a rosuvastatin composition can reduce the biological activity of the composition, and therefore rosuvastatin having low levels of diastereomeric impurities is desirable for formulating rosuvastatin pharmaceutical compositions. The invention provides a process for preparing rosuvastatin having low levels of diastereomeric impurities through the reduction of a C1-C ester intermediate of rosuvastatin, such as the t-butyl ester of rosuvastatin (TBRE), with 9-methoxymethyl ester. 9-bora-bicyclo [3.3.1] nonane PMeO-9 - ??? ").
The reduction of a keto ester of rosuvastatin with MeO-9 - ??? provides a diol ester of rosuvastatin having high diastereomeric purity. The diastereomer purity of the diol ester can be increased further by crystallizing the diol ester from an organic solvent. The diasteromerically pure diol ester can be used to prepare rosuvastatin and salts thereof which also have low levels of diastereomeric impurities.
As used herein, "normal aggregate" generally refers to adding a reducing agent to a mixture of an ester that must be reduced (see, for example, US RE37,314E).
As used herein, the term "inverted aggregate" generally refers to adding a compound that must be reduced, i.e. a keto-ester of rosuvastatin, to a mixture of a reducing agent (see, e.g., Patent United States No. 5,189,164).
As used herein, the term "diastereomeric impurity" refers to the total amount of any diastereomer of rosuvastatin or its intermediates other than the preferred diastereomer (3R, 5S), and specifically refers to the (3R, 5S) diastereomer of rosuvastatin. or its intermediates.
As used herein, the term "diastereomerically pure TBRE" refers to TBRE that has a total level of diastereomeric impurities of less than 0.37% as measured by HPLC area percentage.
An embodiment of the invention provides an intermediate of rosuvastatin having the following structure:
wherein Ri is a carboxy protecting group.
Preferably, the intermediate is TBRE, which has the following structure:
and having diastereomeric impurities at a level of less than 0.37%, more preferably less than 0.13% and more preferably less than 0.11%, as measured by percent HPLC area.
The invention provides a process for preparing the rosuvastatin diol ester intermediate having the following structure:
where ¾. is a carboxy protecting group, which includes an inverted aggregate process, in which a keto-ester of rosuvastatin is added to a mixture of MeO-9 - ??? and a reducing agent. The use of MeO-9 - ??? as a complex former in the inverted aggregate process of the invention allows the preferred stereoselective reduction and increased diastereomeric purity of the TBRE product.
The process includes the steps of: providing a keto-ester solution of rosuvastatin of the following formula:
wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and Ri is a carboxy protecting group, in an organic solvent; to combine Metoxi-9 - ??? with an organic solvent and a source of hydride ions; add the keto-ester solution of rosuvastatin to the mixture of Methoxy-9 - ??? to obtain a reaction mixture; and maintaining the reaction mixture to obtain an intermediate diol ester having the following structure:
wherein Ri is a carboxy protecting group. Preferably, R x is a C 1 -C 4 alkyl group. More preferably, Ri is a t-butyl group (i.e., TBRE).
Preferably, the keto-ester of rosuvastatin has a ketone at the fifth carbon (eg, TB21). The structure of TB21 is shown below:
Preferably, the obtained diol ester has less than 0.37% or less than 0.30%, more preferably less than 0.13%, more preferably less than 0.11% diastereomeric impurities, as measured by percent HPLC area .
Preferably, the keto-ester solution of rosuvastatin is prepared by combining the keto-ester of rosuvastatin with a suitable organic solvent. A suitable organic solvent is a solvent that does not pass through a reduction in the presence of hydride ions. Preferably, the organic solvent is selected from the group consisting of: a C 1 to C 1 alcohol, a non-polar hydrocarbon solvent, a C 2 to C 3 ether, a chlorinated solvent, a non-protic solvent and mixtures thereof. More preferably, the organic solvent is selected from the group consisting of: methylene chloride, toluene, methyl t-butyl ether, diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, and n-butanol. More preferably, the solvent is a mixture of methanol and THF in a THF / MeO ratio of 3.5 / 1, by volume per gram of the ester.
The mixture of methoxy-9 - ??? in an organic solvent and a source of hydride ions is prepared by combining a source of hydride ions with Methoxy-9 - ??? in a soluble organic solvent that was provided above. Preferably, the source of hydride ions is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride and sodium triacetoxy borohydride. More preferably, the hydride is sodium borohydride. In general, 1.5 to 4 equivalents can be used for each gram of keto-ester.
Preferably, the same solvent is used in the preparation of the mixture of Methoxy-9 - ??? and the hydride ions that in the preparation of the keto-ester solution of rosuvastatin. A mixture of tetrahydrofuran and methanol is a preferred solvent. Preferably, the mixture is cooled to a temperature of -70 ° C to -80 ° C, more preferably to a temperature of -70 ° C.
The solution of the keto-ester of rosuvastatin is added to the mixture of Methoxy-9 - ??? and hydride ions, which provides a mixture of the reaction. Preferably, the keto-ester is added dropwise. Preferably, the keto-ester is added over a period of time of at least 30 minutes, more preferably from 1.5 to 2 hours.
Preferably, the solvent of the keto-ester solution and the solvent that is combined with the Methoxy-9 - ??? they are present in a total amount of 30 to 80 volumes (me per gram of the keto ester) in the reaction mixture.
Preferably, the solvent of the keto-ester solution constitutes 10% to 40% of the total amount of the solvent in the reaction mixture, more preferably 15%.
Preferably, the reaction mixture is maintained, preferably while stirring, for a sufficient time to obtain a diol ester of rosuvastatin. The reaction is almost immediate. Preferably, the reaction mixture is maintained for at least 5 minutes, more preferably for at least 30 minutes, more preferably for at least 0.5-3 hours.
Preferably, a cooling agent is combined with the reaction mixture to terminate the reaction. Preferably, the cooling agent is selected from the group consisting of: hydrogen peroxide, 3-chloroperbenzoic acid, ammonium chloride, aqueous solution of HC1, acetic acid, oxone, sodium hypochlorite, dimethyl disulfide, diethanolamine, O-sulfonic acid of hydroxylamine. More preferably, the cooling agent is hydrogen peroxide.
Another embodiment of the invention provides a process for preparing an intermediate diol ester having the following structure:
where ¾. is a carboxy protecting group, comprising the steps of: providing a keto-ester solution of rosuvastatin of the following formula:
wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and Rx is a carboxy protecting group, in an organic solvent; combine DEMB with an organic solvent and a source of hydride ions to obtain a mixture; add the keto-ester solution of rosuvastatin to the DEMB mixture to obtain a reaction mixture, in. where the total amount of the solvent of the keto-ester solution and the solvent which is combined with the DEMB is from 30 to 80 volumes (ml per gram of the keto ester) in the reaction mixture; and keep the reaction mixture.
Preferably, Ri is a C1-C alkyl group. More preferably, Ri is a t-butyl group (i.e., TBRE).
Preferably, the keto-ester of rosuvastatin has ketone at the fifth carbon (ie, TB21). The TB21 structure is shown below:
Preferably, the obtained diol ester has less than 0.37%, more preferably less than 0.13%, more preferably less than 0.11% of the total level of diastereomeric impurities, as measured by percentage of HPLC area.
Preferably, the keto-ester solution of rosuvastatin is prepared by combining the ceto-ester of rosuvastatin with a suitable organic solvent. A suitable organic solvent is a solvent that does not pass through a reduction in the presence of hydride ions. Preferably, the organic solvent is selected from the group consisting of: Ci to C alcohol, non-polar hydrocarbon solvent, C2 to Ce ether, chlorinated solvent, non-protic solvent and mixtures thereof. More preferably, the organic solvent is selected from the group consisting of: methylene chloride, toluene, methyl t-butyl ether, diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, and n-butanol. More preferably, the solvent is a mixture of methanol and THF.
Preferably, the solvent of the keto-ester solution and the solvent that is combined with the DEMB are present in a total amount of 30 to 60 volumes (ml per gram of the keto ester) in the reaction mixture.
Preferably, the source of hydride ions is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, and sodium triacetoxy borohydride. More preferably, the hydride is sodium borohydride. Preferably, the source of hydride ions is present in an amount of 1.5 to 4 equivalents (per gram of the keto ester), more preferably, of 2.7 equivalents (per gram of the keto ester). Preferably, the solvent of the keto-ester solution constitutes 10% to 40% of the total amount of the solvent in the reaction mixture.
Preferably, the solvent is used in the preparation of the mixture of DEMB and hydride ions as used in the preparation of the keto-ester solution of rosuvastatin. A mixture of tetrahydrofuran and methanol is a preferred solvent. Preferably, the mixture is cooled to a temperature of -50 ° C to -80 ° C, more preferably to a temperature of -70 ° C.
The solution of the rostovastatin keto-ester is added to the DEMB mixture of hydride ions, which provides a reaction mixture. Preferably, the keto-ester is added dropwise. Preferably, the keto-ester is added over a period of time of at least 30 minutes, more preferably from 1.5 to 2 hours.
Preferably, the reaction mixture is maintained, preferably while stirring, for a sufficient time to obtain the diol ester of rosuvastatin. The reaction is almost immediate. Preferably, the reaction mixture is maintained for at least 5 minutes, more preferably for at least 30 minutes, more preferably for 0.5-3 hours.
Preferably, a cooling agent is combined with the reaction mixture to terminate the reaction. Preferably, the cooling agent is selected from the group consisting of: hydrogen peroxide, 3-chloroperbenzoic acid, ammonium chloride, aqueous solution of HC1, acetic acid, oxone, sodium hypochlorite, dimethyl disulfide, diethanolamine, acetone and O-acid. -hydroxylamine sulfonic acid. More preferably, the cooling agent is hydrogen peroxide.
The following table summarizes the results obtained from the examples:
The obtained diol ester can be recovered, or converted into rosuvastatin in a container. Recovery can be done by evaporating the reaction mixture to obtain a residue.
Preferably, the diol ester is recovered by combining the reaction mixture with a mixture of an organic solvent immiscible with water and water; Separate the organic phase from the two-phase system that is formed; and remove the solvent.
The use of ammonium chloride during the final treatment of the reaction is illustrated in Example 6. The use of ammonium chloride facilitates the dissolution of the salts formed after cooling of the reaction with H202. The use of ammonium chloride allows partial dissolution of the salts in the aqueous layer. The rest of the salts can then be removed by filtration. Washing with a mixture of water and brine allows the removal of the octane diol impurity, which is formed after cooling (rupture of the OMe-9-BBN complex) of the reaction with H202. The ratio of H20 / NaCl is preferably 10/10 volumes relative to TB21 or another ester. Preferably a second wash is carried out with a preferable ratio of 10/2 volumes relative to TB21 or another ester.
Preferably, the organic solvent immiscible with water is selected from the group consisting of C4 to C7 esters and C6 to C6 aromatic hydrocarbons. Preferably, the solvent is selected from the group consisting of: ethyl acetate, toluene, methyl ethyl ketone, and mixtures thereof. from them. More preferably, the solvent is ethyl acetate. The diol ester moves in the organic phase of the biphasic system, and the organic phase is separated, and then washed under basic conditions and in brine, more preferably, with a mixture of H20 / saturated NaCl. The solvent can be removed by any technique known in the art, for example, by evaporation.
Another embodiment of the invention provides a process for increasing the diastereomeric purity of TBRE by crystallizing TBRE from a solution of the diol ester. In another embodiment the present invention provides a process for increasing the diastereomeric purity of TBRE by suspending the diol ester.
The TBRE crystallization process comprises the steps of: providing a TBRE solution in a solvent selected from the group consisting of: C1-C4 alcohols, C3-C3 esters, C3-C8 ketones, C3-C8 ethers, hydrocarbons Ce aromatics. a Cio, PGME (propylene glycol monomethyl ether), water, acetonitrile, and mixtures thereof; cool the solution to crystallize the TBRE; and recover the crystallized TBRE.
The process of suspending TBRE comprises: combining TBRE with a solvent selected from the group consisting of: - C4 alcohols, C3-C8 esters, C3-C8 ketones, C3-C8 ethers, Cg to Cio aromatic hydrocarbons, PGME (propylene glycol monomethyl ether), water, acetonitrile, and mixtures thereof, to obtain a suspension; and recover TBRE. Preferably, the recovery comprises filtering the suspension to obtain a precipitate. Preferably, the filtration is under reduced pressure. Preferably, the precipitate obtained is dried further.
Preferably, the solvent used in the crystallization or the suspension is selected from the group consisting of methanol, PGME, acetonitrile: water, acetone: water, acetone: MTBE (methyl tere-butyl ether), methanol: water, ethanol: water, ethanol : TBE, acetonitrile: MTBE, methanol: MTBE, MEK (methyl ethyl ketone): TBE and toluene. More preferably, the solvent is toluene, a mixture of methanol and water, or a mixture of acetonitrile and water. More preferably, the solvent is toluene.
Preferably, the crystallization or suspension is carried out with preferred solvents and solvent mixtures under selected conditions to increase purification. For example, crystallization with methanol is preferably carried out with 3 volumes at 10 volumes (ml per gram of TBRE) of MeOH. In one embodiment, the ratio of MeOH: H20 preferably is less than 5: 1 by volume. In another embodiment, ACN: TBE or MeOH: MTBE is used with a ratio less than 2:10 by volume.
Crystallization or suspension is usually carried out by heating the TBRE solution or suspension to a temperature of 50 ° C, and then cooling. The cooling is preferably carried out at a temperature of 40 ° C to 0 ° C, more preferably at a temperature of 30 ° C to 0 ° C, and more preferably from 5 ° C to 0 ° C.
A suspension can also be made by suspending the ester in an organic solvent at room temperature as performed in Example 10.
After crystallization or suspension, the diol ester can be recovered by conventional techniques, such as filtration, and can be dried. Drying can be accelerated by reducing the pressure or raising the temperature. The diol ester is preferably dried at a temperature of 40 ° C to 50 ° C under ambient pressure.
As will be appreciated by an expert in the art, any of the methods of the invention, such as the. use of MeO-9 - ??? or DEMB, inverted aggregate, and crystallization of TBRE, can be combined to further reduce the level of diastereomeric impurities. In one embodiment, the combination of the reduction with MeO-9 - ??? through the inverted aggregate of reagents and the crystallization of TBRE. or
In another embodiment, the invention comprises a process for preparing rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt of rosuvastatin, which comprises preparing diol ester of rosuvastatin by a process defined by any of the embodiments mentioned above, and converting the diol ester of rosuvastatin in rosuvastatin or a pharmacologically acceptable salt of rosuvastatin. The intermediate can be converted to rosuvastatin, which includes a pharmaceutically acceptable salt of rosuvastatin, as illustrated for TBRE in the following scheme:
TBRE Rosuvastatin Calcium
The conversion of the diol ester to rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt thereof can be carried out in accordance with US Patent Publication No. 2005/080134. The conversion can be carried out with basic hydrolysis of the ester. The basic hydrolysis of the statin diol ester can be carried out with one or more equivalents of an alkali metal or alkaline earth metal base such as NaOH or Ca (OH) 2, in organic solvents such as C3 to Cs ethers (tetrahydrofuran, isopropyl ether), ACN (acetonitrile), Ci to C4 alcohols (MeOH, EtOH, IPA (isopropyl alcohol), propanol, butanol, etc.), C3 to C8 ketones (acetone, methyl ethyl ketone, methyl isopropyl ketone, ethyl). The hydrolysis can also be carried out with water, a mixture of the preceding solvents, or a mixture of water and the preceding solvents, preferably at room temperature or by heating. In one embodiment, the obtained diol ester is reacted with sodium or calcium hydroxide to obtain the sodium or calcium salt. In another embodiment, the diol ester is reacted with sodium hydroxide and then converted to the calcium salt. A source of calcium such as calcium chloride or calcium acetate can be used for that conversion.
The rosuvastatin calcium obtained from the diastereomerically pure TBRE is also diastereomerically pure. Then, another embodiment of the invention provides rosuvastatin, rosuvastatin lactone and salts thereof having low levels of diastereomeric impurities. An embodiment of the invention provides rosuvastatin, rosuvastatin lactone and salts thereof having less than 0.2% diastereomeric impurities, more preferably less than 0.15% and even more preferably, less than 0.1%, measured as a percentage of HPLC area.
The invention also comprises a pharmaceutical composition comprising the rosuvastatin salt of the present invention and at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical compositions comprise rosuvastatin and salts thereof having less than 0.2% diastereomeric impurities, more preferably less than 0.15%, and more preferably, less than 0.1%, as measured by percent HPLC area . '"
The invention also comprises a process for preparing a pharmaceutical composition comprising combining the rosuvastatin salt of the present invention with at least one pharmaceutically acceptable excipient.
The invention also provides a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof prepared by converting TBRE having less than 0.3% diastereomeric impurities, as measured by percent HPLC area, into rosuvastatin or a pharmaceutically acceptable salt thereof, and combining rosuvastatin with a pharmaceutically acceptable excipient.
The pharmaceutical compositions can be prepared as medicaments that must be administered orally, parenterally, rectally, transdermally, buccally or nasally. The pharmaceutical compositions of the present invention are preferably forms suitable for oral administration include tablets, compressed or coated tablets, dragees, sachets, hard or gelatin capsules, sublingual tablets, syrups and suspensions. Suitable forms for parenteral administration include an aqueous solution or emulsion, while for rectal administration suitable forms include suppositories with a hydrophilic or hydrophobic carrier. For topical administration, the invention provides suitable transdermal delivery systems known in the art, and for nasal administration, suitable aerosol delivery systems known in the art are provided.
In addition to the active ingredient (s), the pharmaceutical compositions of the invention contain one or more excipients or adjuvants. The selection of excipients and the quantities to be used can be easily determined by the formula scientist based on experience and consideration of procedures and reference works of art.
The diluents increase the volume of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier to handle for the patient and caregiver. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, calcium phosphate dibasic dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (for example, EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted in a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., LUCEL®) , hydroxypropyl methyl cellulose (eg, METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (eg, KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a solid pharmaceutical composition compacted in the stomach of the patient can be increased by adding a disintegrator to the composition. Disintegrators include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (eg, Ac-Di-Sol®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (eg, KOLLIDON®, POLYPLASDONE®), gum guar, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (for example, EXPLO ®) and starch.
Glidants can be added to improve the flowability of a non-compacted solid composition and to improve dosing precision. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
When a dosage form such as a tablet is made by compaction of a powder composition, the composition is pressurized by a punch and die. Some excipients and active ingredients have a tendency to adhere to punch and die surfaces, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate the release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmito-stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc fumarate.
Flavoring agents and flavor improvers make the dosage form more palatable to the patient. Flavoring and flavoring agents common for pharmaceuticals that can be included in the composition of the present invention include maltol, vanilla, ethyl vanilla, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
The solid and liquid compositions can also be stained using any pharmaceutically acceptable dye to improve their appearance and / or facilitate the identification of the product and the unit dosage level by the patient.
In the liquid pharmaceutical compositions of the present invention, the nateglimide and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
The liquid pharmaceutical compositions may contain emulsifying agents to uniformly disperse throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetoestaryl alcohol, and cetyl alcohol.
The liquid pharmaceutical compositions of the invention may also contain a viscosity enhancing agent to improve the mouthfeel of the product and / or coat the gastrointestinal tract lining. These agents include acacia, alginic acid bentonite, carbomer, calcium or sodium of carboxymethylcellulose, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, tragacanth starch, and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve flavor.
Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at safe levels for ingestion to improve storage stability.
In accordance with the invention, a liquid composition may also contain an ampon such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
The selection of excipients and the quantities used can be determined quickly by the scientist formulator based on experience and on the consideration of the standard procedures and reference works of the field.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. Dosages include suitable dosages for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ophthalmic administration. Although the most appropriate administration in any given case depends on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages can conveniently be presented in a unit dosage form and prepared by any of the methods known in the pharmaceutical art.
Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, bits and capsules, as well as liquid syrups, suspensions and elixirs. The dosage form of the present invention can be a capsule containing the composition, preferably a solid or powder composition (granulated of the invention, within a hard or soft capsule) The capsule can be made with gelatin and optionally can contain a plasticizer such as glycerin or sorbitol, and an opacifying or coloring agent.
The active ingredient and the excipients can be formulated into compositions and dosage forms according to methods known in the art.
A composition for the manufacture of tablets or for the filling of capsules can be prepared by wet granulation. In wet granulation, some or all of the ingredients and excipients in powder form are mixed and then further mixed in the presence of a liquid, generally water, which causes the powders to be grouped into granules. The granulate is screened and / or milled, dried and then sieved and / or milled to the desired particle size. With the granulate tablets can then be made or other excipients, such as a glidant and / or a lubricant, can be added prior to the manufacture of tablets.
A composition for making tablets can be prepared conventionally by dry blending. For example, the mixed composition of the active ingredients and excipients can be compacted into a piece or a sheet and then comminuted into compacted granules. The compacted granules can then be compressed into a tablet.
As an alternative for dry granulation, a blended composition can be directly compressed into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. The excipients that are particularly well suited for the manufacture of tablets by direct compression include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate and colloidal silica. The correct use of these and other excipients in the manufacture of tablets by direct compression is known to those who belong to the art and have experience and expertise in the challenge of particular formulation of the manufacture of tablets by direct compression.
A capsule filler of the present invention may comprise any of the mixtures and granulates that were described with reference to the manufacture of tablets, although they do not undergo the final step of tablet manufacture. A preferred dosage form is from 5 mg to 80 mg per day, more preferably from 5 mg to 40 mg per day, where the tablets of 5 mg, 10 mg, 20 mg, 40 mg and 80 mg once a day are a preferred method of administration. These tablets can have the following inactive ingredients: microcrystalline cellulose NF, lactose monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF, hypromellose NF, triacetin NF and titanium dioxide NF.
A method is also provided for treating an animal that needs inhibition of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A ("H G-CoA") reductase which comprises administering to the mammal a pharmaceutical composition prepared to from TBRE that has less than 0.3% diastereomeric impurities.
EXAMPLES HPLC method for the content of diastereomers in the tere-butyl ester of Rosuvastatin HPLC conditions: Column: BDS Hypersil C18 Mobile phase: Buffer gradient and organic modifier Ampon: Ammonium acetate buffer Organic modifier: Acetonitrile and Ethanol Detection: Ultraviolet radiation - 245 nm Injection: ?? μ? Column temperature: 5 ° C Diluent: Acetonitrile / Water
Preparation of 0.5mg / ml samples in diluent Calculations:% of 3R isomer, 5R = 3R isomer area, 5R in sample x 100%. ? All Areas HPLC Method for the Content of Diastereomers in Calcium from Rosuvas to ina HPLC Conditions: Column: C18 Mobile Phase: Buffer Gradient and Organic Modifier Buffer: Ammonium Acetate Buffer Organic Modifier: Acetonitrile and Ethanol Detection: Radiation ultraviolet - 243 nm Injection: ?? μ? Column temperature: 20 ° C Diluent: Acetonitrile / Water
Sample preparation 0.2 mg / ml in diluent Calculations:% of 3R isomer, 5R = 3R isomer area, 5R in sample x 100%? all areas
Reduction of TB-21 to TBRE (Examples 1-5)
Example 1: Inverted aggregate with DEMP according to the
U.S. Patent No. 5,189,164
A 25 ml flask equipped with a nitrogen booster and a magnetic stir bar was charged with TB21 (1.0 g), tetrahydrofuran (0.35 ml) and methanol (0.1 ml) and a suspension formed. The suspension was stirred at room temperature to obtain a clear solution.
A 3-neck flask of 50 ml equipped with a mechanical stir bar and a nitrogen blender was charged with tetrahydrofuran (4.4 ml) and methanol (1.2 ml) and cooled to -78 ° C. NaBH 4 (0.192 g), and then diethylmethoxybenzene (2.05 ml, 1M in THF) were added to form a mixture which was stirred at -78 ° C for 10 minutes.
The TB-21 solution was added to the mixture of NaBH4 and diethylmethoxybenzene through a syringe over a period of 1.5 hours, and a reaction mixture was formed. The reaction mixture was stirred at -78 ° C for 30 minutes. H2O2 (0.8 ml, 30%) was added and the reaction mixture was allowed to come to room temperature, and then evaporated to dryness and a residue was obtained.
Ethyl acetate (5 ml) was added to the residue, and washed with water (5 ml) and saturated NaCl (3.5 ml). The organic phase was separated, and washed again and separated 3 times each with NaHCO3, Na2SC > 3 and NaCl (4 mi x 3). The organic phase was then evaporated to dryness and an oily residue of TBRE (1.05 g, 26.7%) was obtained.
Example 2: Inverted aggregate with DEMB in 60 volumes of solvent A 50 ml flask equipped with a nitrogen booster and a magnetic stir bar was loaded with TB-21 (1.0 g), tetrahydrofuran (3.5 ml) and methanol (1.0 ml). The suspension was stirred at room temperature and a clear solution was obtained. A 50 ml 3 neck flask equipped with a mechanical stir bar and a nitrogen blender was charged with tetrahydrofuran (44.0 ml) and methanol (12.0 ml) and a mixture was obtained. The mixture was cooled to -78 ° C and NaB¾ (0.192 g), and then diethylmethoxyborane (2.05 mL, 1M in THF) was added. The mixture was stirred at -78 ° C for 10 minutes.
The TB-21 solution was added to the mixture through a syringe for 1.5 hours, a reaction mixture was formed and then the reaction mixture was stirred at -78 ° C for 30 minutes. ¾C > 2 (0.8 ml, 30%) and the reaction mixture was allowed to come to room temperature. The reaction mixture was evaporated to dryness and a residue was obtained.
Ethyl acetate (5 ml) was added to the residue and washed with water (5 ml) and saturated NaCl (3.5 ml). The organic phase was separated, and washed again and separated 3 times each with NaHCC > 3, a2SÜ3 and NaCl (4 mi x 3). The organic phase was then evaporated to dry to obtain an oily residue of TBRE (1.06 g, 90.1%). The content of diastereomers is 0.76%.
Example 3: Reduction with DEMB, normal aggregate
A 3-neck flask of 100 ml equipped with a mechanical stir bar, a rubber septum and a nitrogen booster was loaded with TB-21 (1.0 g), THF (47 ml) and methanol (13.5 ml). ) and a mixture was obtained. The mixture was stirred at room temperature until, that TB-21 dissolved. The resulting solution was then cooled to -78 ° C.
Diethylmethoxyborane (1M in THF, 2.80 ml) was added to the solution through a syringe and the solution was stirred again for 30 minutes at -78 ° C. NaB¾ (0.106 g) was added to the solution, and a reaction mixture was formed which was stirred for 3 hours at -78 ° C. ¾ (¾ (0.8 mL, 30% in water) was added at -78 ° C. The reaction mixture was allowed to come to room temperature and was evaporated to dryness and a residue was obtained.
Ethyl acetate (5 mL), water (5 mL) and saturated NaCl (3.5 mL) were added to the residue and the organic phase was separated and washed again with saturated NaHCO3 (4 mL), Na2SC > 3 saturated (4 mL) and saturated NaCl (4 mL). The combined organic layers were concentrated under reduced pressure and a residue of TB E diol (1.08 g, 81.6%) was obtained. The content of diastereomers is 0.64%.
Example 4: Inverted aggregate with MeO-9 - ???
A 100 ml flask equipped with a nitrogen booster and a magnetic stir bar was charged with TB-ROSU-21 (5.0 g), tetrahydrofuran (17.5 ml) and methanol (5 ml). The suspension was stirred at room temperature and a clear solution was obtained.
A 250 ml 3-necked flask equipped with a magnetic stir bar and a nitrogen blender was charged with tetrahydrofuran (100 ml) and methanol (29 ml) and a mixture formed. The mixture was cooled to -78 ° C. NaBH4 (1.0 g) and then 'Metoxi-9 - ??? (11.2 ml, 1M in hexanes) and the mixture was stirred at -78 ° C for 10 minutes.
The TB-21 solution was added to the mixture of Methoxy-9 - ??? and NaBH4 through a syringe at a rate of 2 ml per 5 minutes, and a reaction mixture was formed. The reaction mixture was stirred at -78 ° C for 30 minutes. Then H2O2 (4 mL, 30%) was added and the reaction mixture was allowed to come to room temperature. The reaction mixture was then evaporated to dryness and a residue was obtained.
Ethyl acetate (25 ml) was added to the residue and washed with water (25 ml) and saturated NaCl (17 ml). The organic phase was separated, and washed again and separated 3 times each with NaHCC > 3, a2S03 and NaCl (20 ml x 3). The organic phase was then evaporated to dryness and an oily residue of TBRE (4.57 g, 91.1%) was obtained. The content of diastereomers is 0.11%.
Example 5: Inverted aggregate with MeO-9 - ???
A 500 ml flask equipped with a nitrogen booster and a magnetic stir bar was charged with TB-21 (50.0 g), tetrahydrofuran (175 ml) and methanol (50 ml). The suspension was stirred at room temperature and a clear solution was obtained.
A 3-neck, 2-L flask equipped with a mechanical stir bar and a nitrogen blender was charged with tetrahydrofuran (1000 ml) and methanol (290 ml) and a mixture formed. The mixture was cooled to -78 ° C. NaBH4 (10.0 g) and then Metoxy-9 - ??? (107 mL, 1M in hexanes) and the mixture was stirred at -78 ° C for 10 minutes.
The TB-21 solution was added to the mixture through a dropping funnel for 2 hours and a reaction mixture was obtained. The reaction mixture was stirred at -78 ° C for 1 hour. Then ¾ (¾ (40 ml, 30%) was added and the reaction mixture was allowed to come to room temperature The reaction mixture was then evaporated to dryness and a residue was obtained Ethyl acetate ( 250 ml) to the residue and washed with water (400 ml) and saturated NaCl (170 ml) The organic phase was separated and washed again and separated 3 times each with aHC03, Na2SO3 and NaCl (200 ml × 3). The organic phase was then evaporated to dryness and an oily TBRE residue was obtained (42.1 g, 83.9%) The content of diastereomers is 0.13%.
Example 6: Termination treatment with NH4C1
A 500 ml flask equipped with a nitrogen booster and a mechanical stir bar was loaded with TB-21 (18.60 g, assay = 62.9%), tetrahydrofuran (40.5 ml) and methanol (11.5 g). my) . The suspension was stirred at room temperature and a clear solution was obtained.
A 1000 ml 3-necked flask equipped with a mechanical stir bar and a nitrogen blender was charged with tetrahydrofuran (232 ml) and methanol (66.5 ml) and a mixture formed. The mixture was cooled to -78 ° C. NaBH4 (2.22 g, 2.7 equivalents) and then Metoxy-9 - ??? (24 mL, 1.1 equivalent, 1M in hexanes) and the mixture was stirred at -78 ° C for 10 minutes.
The solution of TB-21 was added dropwise to the mixture of Methoxy-9 - ??? for 1.5 hours, and a reaction mixture was formed, and the reaction mixture was allowed to stir further at -78 ° C for 1 hour. Then ¾ (¾ (9.3 ml, 30%) was added and the reaction mixture was allowed to come to room temperature.
Ethyl acetate (58 ml) and NH 4 Cl (174 ml) were slowly added to the reaction mixture with stirring at room temperature. The phases were filtered and separated. The organic phase was washed and separated each time with saturated a2SO3 (46 mL) with H20 (116 mL) + saturated NaCl (116 mL), then with ¾0 (116 mL) + NaCl (23 mL) and finally with saturated NaCl ( 58 mi). The organic phase was then evaporated to dryness and an oily residue of TB-22 (19.02 g, 99.7%) was obtained. The content of diastereomers is 0.17%.
Example 7: Reduction in CH2Cl2
A 3-neck 100-ml flask equipped with a mechanical stirring bar, a rubber septum and a nitrogen booster was charged with TB-21 (1.0 g), CH2C12 (47 ml) and methanol (13.5 ml). ). The resulting mixture was stirred at room temperature until TB-21 dissolved and a solution was obtained. The solution was then cooled to -78 ° C.
Diethylmethoxyborane (1M in THF, 2.80 mL) was added to the solution through a syringe and the solution was stirred for 30 minutes at -78 ° C. NaBH (0.106 g) was added, and a reaction mixture was formed which was stirred for 3 hours at -78 ° C. H20 (0.8 ml, 30% in water) was added. Then the reaction mixture was allowed to come to room temperature and evaporated to dryness and a residue was obtained.
Ethyl acetate (5 mL), water (5 mL) and saturated NaCl (3.5 mL) were added to the residue. The organic phase was separated and washed again with saturated NaHCO 3 (4 mL), saturated a 2 SO 3 (4 mL) and saturated NaCl (4 mL). The combined organic layers were concentrated- under reduced pressure and a residue of the TBRE diol (1.15 g, 83.6%) was obtained. The content of diastereomers is 7.5%.
Example 8: Reduction in toluene
A 3-neck 100-ml flask equipped with a mechanical stirring bar, a rubber septum and a nitrogen booster was loaded with TB-21 (1.0 g), toluene (47 mL) and methane! (13.5 mL). The resulting mixture was stirred at room temperature until TB-21 dissolved and. A solution was obtained. The solution was then cooled to -78 ° C.
Diethylmethoxyborane (1M in THF, 2.80 mL) was added to the solution through a syringe and the solution was stirred for 30 minutes at -78 ° C. NaBH 4 (0.106 g) was added and a reaction mixture was formed which was stirred for 3 hours at -78 ° C. ¾02 (0.8 mL, 30% in water) was added at -78 ° C. Then the reaction mixture was allowed to come to room temperature and evaporated to dry to obtain a residue.
Ethyl acetate (5 mL), water (5 mL) and saturated NaCl (3.5 mL) were added to the residue. The organic phase was separated and washed again with saturated NaHCO 3 (4 mL), saturated a 2 SO 2 (4 mL) and saturated NaCl (4 mL). The combined organic layers were concentrated under reduced pressure to obtain a residue of the TBRE diol (1.19 g, 80.3%). The content of diastereomers is 11.7%.
Examples of Crystallization (Examples 9-21)
Example 9: Crystallization of TBRE in MeOH
TBRE (1 g, 1.1% diastereomers) was dissolved in MeOH (5 mL) by heating. The solution was then allowed to cool to room temperature, and stirred at this temperature overnight. The solid was then filtered under reduced pressure, washed and dried at 45 ° C under atmospheric pressure for 18 hours and TBRE (0.52% diastereomers) was obtained.
Example 10: Suspension of TBRE in MeOH
TBRE (1 g, 1.1% diastereomers) was suspended in MeOH (5 mL) while stirring at room temperature overnight. The solid was then filtered under reduced pressure, washed and dried at 45 ° C under atmospheric pressure for 18 hours and 0.60 g of TBRE (diastereomers 0.51%) was obtained.
Example 11: Crystallization of TBRE from 2 mi of PGME
TBRE (lg, 1.1% diastereomers) was dissolved in PGME (2 mL) by heating to 100 ° C. The solution was then allowed to cool to room temperature and stirred at this temperature overnight. The solid was then filtered under reduced pressure, washed and dried at 45 ° C under atmospheric pressure for 18 hours and 0.67 g of TBRE (0.62% diastereomers) was obtained.
Example 12: Crystallization of TBRE from ACN: H2Q TBRE (lg, 1.1% diastereomers) was dissolved in a mixture of 5.5 ml of ACN and 4 ml of 0 by heating under reflux. The solution was allowed to cool to room temperature and was stirred at this temperature for 72 hours. The solid was then filtered under reduced pressure, washed and dried at 45 ° C under atmospheric pressure for 18 hours and 0.84 g of TBRE (0.55% diastereomers) was obtained.
Example 13. Crystallization of TBRE from Acetone: H20 (6: 2)
TBRE (lg, 1.1% diastereomers) was dissolved in a mixture of 6 ml of acetone and 2 ml of H20 under reflux. The solution was allowed to cool to room temperature, and stirred at this temperature overnight. The solid was then filtered under reduced pressure, washed and dried at 45 ° C under atmospheric pressure for 18 hours and 0.68 g of TBRE (0.50% diastereomers) was obtained.
Example 14: Crystallization of TBRE from Acetone: MTBE
TBRE (lg, 0.79% diastereomers) was dissolved in a mixture of 2 ml of acetone and 10 ml of MTBE under reflux. The solution was then allowed to cool to room temperature, and stirred at this temperature overnight. The solid was then filtered under reduced pressure, washed and dried at 45 ° C under reduced pressure for 18 hours and 0.46 g of TBRE (0.38% diastereomers) was obtained.
Example 15: Crystallization of TBRE from MeOH: H20 (5: 0.5) TBRE (lg, 0.79% diastereomers) was dissolved in a mixture of 5 ml of MeOH and 0.5 ml of H20 under reflux. Then the solution was allowed to cool to room temperature and was stirred at this temperature overnight. The solid was then filtered, under reduced pressure, washed and dried at 45 ° C under atmospheric pressure for 18 hours and 0.84 g of TBRE (0.45% diastereomers) was obtained.
Example 16: Crystallization of TBRE from EtOH: H20 (5: 0.5) TBRE (lg, 0.79% diastereomers) was dissolved in a mixture of 5 ml of EtOH and 0.5 ml of 0 by heating under reflux. The solution was then allowed to cool to room temperature and was stirred at this temperature overnight. The solid was then filtered under reduced pressure, washed and dried at 45 ° C under reduced pressure for 18 hours and 0.77 g of TBRE (0.43% diastereomers) was obtained.
Example 17: Crystallization of TBRE from EtOH: TBE
TBRE (lg, 0.79% diastereomers) was dissolved in a mixture of 2 ml of EtOH and 10 ml of MTBE heating under reflux. The solution was then allowed to cool to room temperature, and stirred at this temperature overnight. The solid was then filtered under reduced pressure, washed and dried at 45 ° C under reduced pressure for 18 hours and 0.55 g of TBRE (0.42% diastereomers) was obtained.
Example 18: Crystallization of TBRE from ACN: MTBE TBRE (1 g, 0.79% diastereomers) was dissolved in a mixture of 0.5 ml of ACN and 10 ml of MTBE heating at reflux. The solution was allowed to cool to room temperature. The mixture was stirred at this temperature overnight. The solid was then filtered under reduced pressure, washed and dried at 45 ° C under atmospheric pressure for 18 hours and 0.61 g of TBRE (0.42% diastereomers) was obtained.
Example 19: Crystallization of TBRE from MeOH: MTBE TBRE (lg, 0.79% diastereomers) was dissolved in a mixture of 0.5 ml of MeOH and 10 ml of MTBE under reflux. The solution was allowed to cool to room temperature and stirred at this temperature overnight. The solid was then filtered under reduced pressure, washed and dried at 45 ° C under atmospheric pressure for 18 hours and 0.61 g of TBRE (0.34% diastereomers) was obtained.
Example 20: Crystallization of TBRE from MEK: MTBE TBRE (lg, 1.1% diastereomers) was dissolved in 2 ml of MEK at reflux temperature. MTBE (6 ml) was added at this temperature. It was observed that there was no precipitation. The solution was allowed to cool to room temperature and an additional amount of MTBE (10 mL) was added. The aggregate of MTBE did not induce any precipitation. After stirring at room temperature for 72 hours, precipitation was observed. The solid was filtered under reduced pressure, washed and dried at 45 ° C under atmospheric pressure for 18 hours and 0.62 g of TBRE (0.47% diastereomers) was obtained.
Example 21: Crystallization of TBRE from Toluene
TBRE (2g, 0.23% diastereomers) was dissolved in Toluene (7 ml) by heating to about 60 ° C. The solution was then allowed to cool to room temperature, and then cooled in an ice bath at 09C. The resulting mixture was stirred at this temperature overnight. The solid was then filtered under reduced pressure, washed and dried at 50 ° C under reduced pressure for 18 hours and 1.59 g of TBRE (0.08% diastereomers) was obtained.
Example 22: Calcium of rosuvastatin with less than 0.1% diastereomers
A 25 ml flask equipped with a mechanical stir bar was charged with EtOH (6 mL), water (3.6 mL) and TBRE (1.2 g, 0.19% diastereomers). To this suspension, 47% of 1.2 equivalent NaOH (0.23 g) was added dropwise at 25 ° C ± 5 ° C. The resulting mixture was stirred at 25 ° C ± 5 ° C for three hours. The mixture was carefully acidified to pH = 10 by adding 0.01N HC1 and then washed with toluene (6 mL). The aqueous layer was isolated and concentrated under reduced pressure at 40 ° C at 2/3 of the initial volume.
Example 23: Preparation of Rosuvastatin Calcium from Rosuvastatin Ester
A 100 ml reactor equipped with a mechanical stir bar was charged with EtOH (100 mL), water (60 mL), t-butyl-Rosuvastatin (20 g) and NaBH 4 (0.1 g). To this suspension, 47% of 1.1 equivalent NaOH (3.5 g) was added dropwise at 25 ° C ± 5 ° C and the mixture was stirred at 25 ° C ± 5 ° C for two hours. The mixture was then filtered under reduced pressure with a Sinter to remove the activated carbon present in the solution.
Water (140 ml) was added to this suspension and the reaction mixture was acidified with 0.1 M HC1 to pH 8-10. The mixture was then washed with toluene (100 ml) and stirred at 25 ° C ± 5 ° C for half an hour. The aqueous layer was then isolated. Activated carbon was added to the aqueous phase and the suspension was stirred at 25 ° C ± 5 ° C for 30 minutes. The mixture was filtered under reduced pressure with Sinter and Hyflo to remove the activated carbon present in the solution. Then the reaction mixture was concentrated under reduced pressure at 40 ° C to half the volume of the solution. The treatment of completion of the solution was made to 10 volumes of water with respect to TBRE. -The solution was heated to a temperature of 40 ° C-45 ° C. CaCl 2 (4.13 g) was added dropwise to this solution for 30-90 minutes at a temperature of 38 ° C-45 ° C. The suspension was then cooled to 25 ° C ± 5 ° C, stirred at 25 ° C ± 5 ° C for 1 hour, filtered and washed with water (4x20 ml) and a powdery compound was obtained (17.3 g. dry g, 92%).
The resulting solution was placed in a flask and heated to 40 ° C. Solid CaCl 2 portion (0.25 g) was added per portion to this solution while stirring. The resulting mixture was then cooled to 25 ° C ± 5 ° C, stirred at 25 ° C ± 5 ° C for 1 hour, filtered and washed with water and a powder product was obtained, which was dried in vacuo at 50 ° C.
Having described the invention with reference to particular preferred embodiments and having it illustrated with Examples, those skilled in the art will appreciate modifications of the described and illustrated invention which do not depart from the spirit and scope of the invention disclosed in the specification. The Examples are set forth to assist in understanding the invention but are not intended or construed to limit its scope in any way. The examples do not include the detailed description of conventional methods. All references mentioned herein are incorporated in their entirety.
Claims (73)
- The rosuvastatin intermediate according to claim 1, having diastereomeric impurities of less than 0.13%, as measured by percentage of HPLC area.
- The rosuvastatin intermediate according to claim 1, which has diastereomeric impurities of less than 0.11% measured by percent HPLC area.
- The rosuvastatin intermediate according to claims 1-3, wherein Ri is a t-butyl group.
- A process for preparing an intermediate diol ester of rosuvastatin that has the structure wherein ¾ is a carboxy protecting group, comprising: a) combining MeO-9 - ??? with an organic solvent and a source of hydride ions; b) adding to the combination a solution of a keto-ester of rosuvastatin in an organic solvent, wherein the keto-ester of rosuvastatin has the following formula: wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and ¾ is a carboxy protecting group, and a reaction mixture is obtained; c) maintaining the reaction mixture to obtain the diol ester.
- A process of a container for preparing rosuvastatin or a pharmaceutically acceptable salt thereof, comprising: a) combining MeO-9 - ??? with an organic solvent and a source of hydride ions; b) adding to the combination a solution of an intermediate keto-ester of rosuvastatin in an organic solvent, wherein the keto-ester intermediate of rosuvastatin has the following formula: wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and ¾ is a carboxy protecting group, to obtain a reaction mixture; c) maintaining the reaction mixture to reduce the intermediate; and d) converting the reduced intermediate to rosuvastatin or a pharmaceutically acceptable salt thereof.
- A process for preparing an intermediate diol ester having the structure wherein ¾ is a carboxy protecting group, comprising the steps of: a) combining diethylmethoxy borane (DEMB) with an organic solvent and a source of hydride ions; b) adding to the combination a solution of a keto-ester of rosuvastatin in an organic solvent, wherein the rosuvastatin ester has the following formula: wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and ¾ is a carboxy protecting group, to obtain a reaction mixture, wherein the The total amount of the solvent from the keto ester solution and the solvent that is combined with the DEMB is 30 to 80 volumes (ml per gram of the keto ester) in the reaction mixture; and c) maintaining the reaction mixture.
- The process according to any of claims 5-7, wherein the organic solvent is selected from the group consisting of a non-polar hydrocarbon solvent, a chlorinated solvent, an alcohol of
- Ci to C, a non-protic solvent, an ether of C2 to Cg and mixtures of them.
- The process according to any of claims 5-8, wherein the organic solvent is selected from the group consisting of methylene chloride, toluene, methyl t-butyl ether, diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, isopropanol and n-butanol.
- . The process according to any of claims 5-9, wherein the organic solvent is a mixture of methanol and THF. ·
- . The process according to claim 10, wherein the ratio of THF / MeOH is 3.5 / 1 by volume for each gram of the ester.
- . The process according to any of claims 7-9, wherein the reaction mixture contains from 1.5 to 4 equivalents of hydride ion for each gram of rostovastatin keto ester.
- . The process according to any of claims 7-12, wherein the ratio in the reaction mixture of the solvent in the keto-ester solution of rosuvastatin to the solvent combined with DEMB or MeO-9-BBN is 10/85. .
- . The process according to any of claims 7-13, wherein the solvent of the keto-ester solution constitutes from 10% to 50% of the total amount of the solvent in the reaction mixture.
- . The process according to claim 14, wherein the solvent of the keto-ester solution constitutes up to 15% of the total amount of the solvent in the reaction mixture.
- . The process according to any of claims 5-15, wherein the source of hydride ions is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, and sodium triacetoxy borohydride.
- . The process according to any of claims 5-16, wherein the source of hydride ions is sodium borohydride.
- . The process according to any of claims 5-17, wherein the keto-ester is added dropwise.
- . The process according to any of claims 5-18, wherein the keto-ester is added over a period of at least thirty minutes.
- . The process according to any of claims 5-6, 16-19, wherein the reaction mixture has a total amount of the solvent from the keto-ester solution and the solvent that is combined with the Methoxy-9- ??? from '30 to 80 volumes (mi per gram of the keto ester).
- . The process according to any of claims 5-20, wherein the source of hydride ions is present in an amount- from 1.5 to 4 equivalents (per gram of keto ester).
- . The process according to any of claims 5-21, wherein the source of hydride ions is present in an amount of 2.7 equivalents (per gram of keto ester).
- . The process according to any of claims 5-22, wherein the reaction mixture is maintained for at least 5 minutes.
- . The process according to any of claims 5-23, wherein the reaction mixture is maintained for 0.5-3 hours.
- . The process according to any of claims 5-24, wherein the process also comprises cooling the combination containing the hydride ions at a temperature of -70 ° C to -80 ° C.
- The process according to claim 25, wherein the cooling is at a temperature of -70 ° C.
- 27. The process according to any of claims 5-26, wherein the process also comprises cooling the reaction mixture.
- 28. The process according to claim 27, wherein the cooling comprises combining the reaction mixture with a cooling agent selected from the group consisting of 3-chloroperbenzoic acid, ammonium chloride, aqueous solution of HC1, acetic acid, oxo, hypochlorite of sodium, dimethyl disulfide, diethanolamine, acetone 'and hydroxylamine O-sulfonic acid.
- 29. The process according to claim 28, wherein the cooling agent is hydrogen peroxide.
- 30. The process according to any of claims 5, 7-29, which also comprises recovering the diol ester of rosuvastatin.
- 31. The process according to claim 30, wherein the recovery of the diol ester of rosuvastatin comprises the steps of: a) combining the reaction mixture with a mixture of an organic solvent immiscible with water; b) separating the organic phase of the two-phase system that is formed; and c) removing the solvent to obtain the diol ester.
- . The process according to claim 31, wherein the organic solvent immiscible with water is selected from the group consisting of esters of C4 to C7, aromatic hydrocarbons of Ce to Cio and ketones.
- The process according to claim 32, wherein the organic solvent immiscible with water is selected from the group consisting of ethyl acetate, toluene, methyl ethyl ketone, and mixtures thereof.
- . The process according to any of claims 31-33, wherein the process also comprises adding ammonium chloride to the reaction mixture of step a).
- . The process according to any of claims 31-34, wherein the organic phase is washed with a saturated mixture of E ^ O / NaCl.
- . The process according to claim 35, wherein the ratio of ¾0 / NaCl is preferably 10/10 volumes relative to the ester.
- . The process according to claim 36, wherein a second wash is carried out with a ratio of H20 / NaCl of 10/10 volumes in relation to the ester.
- . The process according to any of claims 35-37, wherein the process results in the reduction in the amount of octanediol.
- . A process for increasing the diastereomeric purity of the diol ester of rosuvastatin of the formula: which comprises crystallizing the diol ester of a solvent selected from the group consisting of: Ci-Ca alcohols, C3-C8 esters, C3-C8 ketones, C3-C8 ethers, aromatic hydrocarbons from Ce to Cio, PGME ( propylene glycol monomethyl ether), water, acetonitrile and mixtures thereof.
- . The process according to claim 39, wherein the crystallization of the diol ester comprises: a) dissolving the diol ester in a solvent selected from the group consisting of: C1-C4 alcohols, C3-C8 esters, C3 ketones -C8, C3-C8 ethers, Cg to Cio aromatic hydrocarbons, PGME (propylene glycol monomethyl ether), water, acetonitrile, and mixtures thereof, mixtures of organic solvents, and mixtures of water and organic solvents; b) cooling the solution to crystallize the diol ester; and c) recovering the crystalline diol ester.
- . A process for increasing the diastereomeric purity of the diol ester of rosuvastatin of the formula: which comprises suspending the diol ester from a solvent selected from the group consisting of: C1-C alcohols, C3-C8 esters, C3-C8 ketones, C3-C8 ethers, aromatic hydrocarbons of Cío, PGME ( propylene glycol monomethyl), water, acetonitrile, and mixtures thereof.
- . The process according to claim 41, wherein the suspension of the diol ester comprises: combining TBRE with a solvent selected from the group consisting of C3-C4 alcohols, C3-C3 esters, C3-C3 ketones, ethers of C3-C8, aromatic hydrocarbons from Cs to C10, PGME (propylene glycol monomethyl ether), water, acetonitrile, and mixtures thereof, to obtain a suspension; and recover.
- . The process according to any of claims 39-42, wherein the organic solvent is selected from the group consisting of methanol, PGME, acetonitrile: water, acetone: water, acetone: MTBE (methyl tere-butyl ether), methanol: water, ethanol ragua, ethanolrMTBE, acetonitrile rMTBE, methanol rMTBE, MEK (methyl ethyl ketone) rMTBE and toluene.
- . The process according to any of claims 5, 7-43, which also comprises increasing the diastereomeric purity of the diol ester of rosuvastatin of the formula: . crystallizing the diol ester of the formula from a solvent selected from the group consisting of: C1-C4 alcohols, C3-Ca esters, C3-C8 ketones, C3-C8 ethers, Ce aCio aromatic hydrocarbons, PGME ( propylene glycol monomethyl ether), water, acetonitrile, and mixtures thereof.
- .Four. Five. The process according to claim 44, wherein the crystallization of the diol ester comprises: a) dissolving the diol ester in a solvent selected from the group consisting of: C1-C4 alcohols, C3-C8 esters, C3 ketones -C8, C3-C8 ethers, C6 to C14 aromatic hydrocarbons, PGME (propylene glycol monomethyl ether), water, acetonitrile, and mixtures thereof, mixtures of organic solvents, and mixtures of water and organic solvents; b) cooling the solution to crystallize the diol ester; and c) recovering the crystalline diol ester.
- . The process according to any of claims 5, 7-45, which also comprises increasing the diastereomeric purity of the diol ester of rosuvastatin of the formula: suspending the diol ester of a solvent selected from the group consisting of: C1-C4 alcohols, C3-C8 esters, C3-C8 ketones, C3-C8 ethers, C6 to C10 aromatic hydrocarbons, PGME ( propylene glycol monomethyl), water, acetonitrile, and mixtures thereof.
- . The process according to claim 46, wherein the suspension of the diol ester comprises: combining TBRE with a solvent selected from the group consisting of: C1-C4 alcohols, C3-Cs esters, C3-C8 ketones, ethers of C3-C8, aromatic hydrocarbons from Ce to Cío, PGME (propylene glycol monomethyl ether), water, acetonitrile, and mixtures thereof, to obtain a suspension; and recover.
- 48. The process according to claim 39-47, wherein the organic solvent is selected from the group consisting of methanol, PGME, acetonitrile: water ,. acetone: water, acetonarMTBE (methyl tere-butyl ether), methanol: water, ethanol, water, ethanol: MTBE, acetonitrile: MTBE, methanol: MTBE, MEK (methyl ethyl ketone): TBE and toluene.
- 49. The process according to claim 48, wherein the solvent is PGME.
- 50. The process according to claim 48, wherein the solvent is a mixture of acetonitrile and water.
- 51. The process according to claim 48, wherein the solvent is a mixture of acetone and water.
- 52. The process according to claim 48, wherein the solvent is a mixture of acetone and MTBE.
- 53. The process according to claim 48, wherein the solvent is a mixture of methanol and water.
- 54. The process according to claim 48, wherein the solvent is a mixture of ethanol and water.
- . The process according to claim 48, wherein the solvent is a mixture of ethanol and MTBE.
- . The process according to claim 48, wherein the solvent is a mixture of methanol and MTBE.
- . The process according to claim 48, wherein the solvent is a mixture of 'MEK and MTBE.
- • The process according to claim 48, wherein the solvent is toluene.
- . The process according to any of claims 40-58, wherein the cooling in step b) is a temperature of '40 ° C to 0 ° C.
- . The process according to claim 59, wherein the cooling in step b) is at a temperature of 30 ° C to G! OC.
- . The process according to claim 60, wherein the cooling in step b) is at a temperature of 5 ° C to 0 ° C.
- . The process according to any of claims 5-61, wherein Ri is a group of C3-C4.
- . The process according to any of claims 5-61, wherein Ri is a t-butyl group.
- . The process according to any of claims 5-63, wherein the process derives in that the intermium has less than 0.37% of diastereomeric impurities, measured by percentage of area of HPLC.
- . The process according to any of claims 5-64, wherein the process results in the intermediate having less than 0.13% diastereomeric impurities, measured by percent HPLC area.
- . The process according to any of claims 5-65, wherein the process results in the intermediate having less than 0.11% diastereomeric impurities, measured by percent HPLC area.
- . A process for preparing rosuvastatin or a pharmaceutically acceptable salt thereof, comprising converting the diol ester prepared by any of claims 5, 0-66 into rosuvastatin or a pharmaceutically acceptable salt thereof.
- . The process according to claim 67, wherein the rosuvastatin or a pharmaceutically acceptable salt thereof has less than 0.2% diastereomeric impurities, as measured by percent HPLC area.
- . The process according to claim 68, wherein the rosuvastatin or a pharmaceutically acceptable salt thereof, has less than 0.1% diastereomeric impurities, as measured by percent HPLC area.
- . The process according to claim 68, wherein the rosuvastatin or pharmaceutically acceptable salt thereof has less than 0.15% diastereomeric impurities, measured as a percentage of HPLC area.
- . A process for preparing a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, wherein the process comprises converting the t-butyl ester of rosuvastatin having less than 0.3% diastereomeric impurities, measured by percentage of area of HPLC, in rosuvastatin or a pharmaceutically acceptable salt thereof, and combining rosuvastatin with a pharmaceutically acceptable excipient.
- 72. A pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof prepared by converting t-butyl ester of rosuvastatin having less than 0.3% diastereomeric impurities, as measured by percentage of HPLC area, into rosuvastatin or a pharmaceutically acceptable salt of and combining rosuvastatin with a pharmaceutically acceptable excipient.
- 73. The use of rosuvastatin t-butyl ester having less than 0.3% diastereomeric impurities, as measured by HPLC, in the manufacture of a pharmaceutical composition.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US60/723,491 | 2005-10-03 | ||
US60/732,979 | 2005-11-02 |
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MX2007006596A true MX2007006596A (en) | 2008-10-03 |
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