MXPA01001542A - Improved omeprazole process and compositions thereof - Google Patents
Improved omeprazole process and compositions thereofInfo
- Publication number
- MXPA01001542A MXPA01001542A MXPA/A/2001/001542A MXPA01001542A MXPA01001542A MX PA01001542 A MXPA01001542 A MX PA01001542A MX PA01001542 A MXPA01001542 A MX PA01001542A MX PA01001542 A MXPA01001542 A MX PA01001542A
- Authority
- MX
- Mexico
- Prior art keywords
- further characterized
- omeprazole
- methoxy
- process according
- residual
- Prior art date
Links
- SUBDBMMJDZJVOS-UHFFFAOYSA-N Esomeprazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960000381 omeprazole Drugs 0.000 title claims abstract description 69
- 238000000034 method Methods 0.000 title claims abstract description 49
- 239000000203 mixture Substances 0.000 title claims abstract description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 54
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 48
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims abstract description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- 238000002425 crystallisation Methods 0.000 claims abstract description 23
- 230000005712 crystallization Effects 0.000 claims abstract description 23
- 238000007792 addition Methods 0.000 claims abstract description 22
- 230000001476 alcoholic Effects 0.000 claims abstract description 19
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 19
- 239000000047 product Substances 0.000 claims abstract description 17
- 239000012043 crude product Substances 0.000 claims abstract description 16
- 235000019253 formic acid Nutrition 0.000 claims abstract description 16
- 238000006053 organic reaction Methods 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- XURCIPRUUASYLR-UHFFFAOYSA-N 6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfanyl]-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(OC)=C1C XURCIPRUUASYLR-UHFFFAOYSA-N 0.000 claims abstract description 12
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 alkyl formate Chemical compound 0.000 claims abstract description 8
- 238000010899 nucleation Methods 0.000 claims abstract description 8
- 238000005292 vacuum distillation Methods 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 4
- 238000005406 washing Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 58
- 239000002904 solvent Substances 0.000 claims description 47
- 239000007800 oxidant agent Substances 0.000 claims description 25
- 238000007254 oxidation reaction Methods 0.000 claims description 21
- FVVXWRGARUACNW-UHFFFAOYSA-N 3-methylisoquinoline Chemical compound C1=CC=C2C=NC(C)=CC2=C1 FVVXWRGARUACNW-UHFFFAOYSA-N 0.000 claims description 16
- TZIHFWKZFHZASV-UHFFFAOYSA-N Methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 15
- 230000003647 oxidation Effects 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 11
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 11
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000008346 aqueous phase Substances 0.000 claims description 9
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 150000001204 N-oxides Chemical class 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 230000032683 aging Effects 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229940094025 potassium bicarbonate Drugs 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 230000001105 regulatory Effects 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 239000000546 pharmaceutic aid Substances 0.000 claims 2
- 238000009331 sowing Methods 0.000 claims 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N Peroxybenzoic acid Chemical group OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims 1
- YPKOTWSAVCIFAM-UHFFFAOYSA-N [Na].CCC Chemical compound [Na].CCC YPKOTWSAVCIFAM-UHFFFAOYSA-N 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 238000002955 isolation Methods 0.000 abstract description 9
- 238000000746 purification Methods 0.000 abstract description 9
- 230000001809 detectable Effects 0.000 abstract description 6
- 150000003568 thioethers Chemical class 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 239000003699 antiulcer agent Substances 0.000 abstract description 2
- 238000001953 recrystallisation Methods 0.000 abstract description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- 239000002245 particle Substances 0.000 description 8
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- 238000006386 neutralization reaction Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000002829 reduced Effects 0.000 description 5
- 150000003457 sulfones Chemical class 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 230000001590 oxidative Effects 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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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 2
- USSBDBZGEDUBHE-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O USSBDBZGEDUBHE-UHFFFAOYSA-L 0.000 description 2
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- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
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- 229920002261 Corn starch Polymers 0.000 description 1
- 208000000718 Duodenal Ulcer Diseases 0.000 description 1
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- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical class CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention describes an improved process for the preparation, isolation, and purification of the anti-ulcer agent omeprazole whereby the sulfide precursor pyrmetazole is reacted subsurfacely with exactly one molar equivalent of meta-chloroperoxybenzoic acid in methylene chloride or toluene solution;residual organic solvent is removed from the aqueous layer by vacuum distillation;crude product is obtained by reactive crystallization with an alkyl formate or formic acid solution and seeding;and pure product is isolated by recrystallization in methanol-water containing aqueous NaOH by subsurface addition of aqueous acetic acid to pH 9.0, seeding, filtration, washing, and drying. Compositions of omeprazole containing no chromatographically detectable levels of residual non-alcoholic organic reaction solvent are also described.
Description
IMPROVED PROCEDURE OF OMEPRAZOOL AND COMPOSITIONS OF THE SAME CROSS REFERENCE TO RELATED REQUESTS
The present invention relates to a provisional application of E.U.A with serial No. 60 / 096,037, filed on August 11, 1998, and with a request from E.U.A. not provisional with serial number 09 / 169,231, filed on October 9, 1998, the contents of both being incorporated herein by reference.
FIELD OF THE INVENTION
The present invention provides a novel improved method for the preparation, isolation and purification of the omeprazole anti-ulcer agent. Compositions of omeprazole which do not contain chromatographically detectable levels of residual non-alcoholic organic solvent are also disclosed.
BACKGROUND OF THE INVENTION Omeprazole, the generic name for 5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (represented by Formula I below) is a known gastric proton pump inhibitor and is on the market as LOSEC® or PRILOSE® for the treatment of gastric and duodenal ulcers, gastritis, duodenitis and reflux esophagitis (see Merck Index, 12th Ed., entry 6977, and references cited therein). Omeprazole is commercially prepared through a multiple-step sequence, the last step of which is the oxidation of the sulfide intermediate, 5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridinyl] ) methyl] methylt] -1 H-benzimidazole (indicated as formula II), known generically as pymetazole, which is typically in effect with a peroxide acid, such as meta-chloroperoxybenzoic acid (hereinafter referred to as as MCPBA) (U.S. Patent Nos. 4,255,431 and 5,386,032), magnesium monoperoxyphthalate (MMPP) (U.S. Patent No. 5,391, 752), or peroxyacetic acid (WO 98/09962), in an indicated non-alcoholic organic reaction solvent. The preferred oxidizing agent is usually MCPBA, and suitable non-alcoholic organic reaction solvents include aromatic hydrocarbon solvents such as benzene and toluene, and chlorinated aliphatic hydrocarbon solvents, such as chloroform and methylene chloride, in admixture with a solvent alcohol, such as methanol, ethanol, isopropanol, or 1-butanol. The preferred non-alcoholic organic reaction solvents are usually methylene chloride and toluene, and the preferred alcohol solvent is ethanol. The above procedures for omeprazole have numerous disadvantages that limit both the yield and the purity of the final product.
A significant disadvantage of said prior methods is incomplete oxidative conversion of pymetazole to omeprazole as well as non-chemoselective oxidation. Two aspects of chemoselectivity are important in the oxidation of pirmetazole. First, pyrmetazole contains two tertiary amino groups which can compete with the sulfide group for the oxidizing agent. Although these amino groups are less reactive than the desired sulfides, they nevertheless suffer quantitative oxidation with the MCPBA at room temperature. Second, the product omeprazole (a sulfoxide) can also react with the MCPBA to form a sulfone byproduct. The non-chemoselectivity and over-oxidation, characteristic of the above methods, arose from ineffective controls on the amount of the oxidizing agent as well as the manner in which the oxidizing agent is loaded into the reaction container. The above methods do not use precisely determined amounts of the oxidizing agent and do not provide careful control of their adhesion to the reaction mixture. The chemoselective suboxidation and sobreoxidation contribute to high impurities and loss of performance of the desired final product. Another disadvantage of prior methods is the considerable loss of product in the purification and isolation steps due to the solubility of omeprazole in the mother liquors and the solutions of washing with solvent. Another additional disadvantage refers to the decrease in product quality, result of occlusion of residual solvents and reaction by-products during the steps of crystallization. It is advisable to eliminate residual levels of the organic reaction solvent and impurities of the recrystallization solvent in the final crystalline product, for toxic and safety reasons. Therefore, an object of the present invention is to provide an improved process for the preparation, purification, and isolation of omeprazole that exceeds the yield and purity limitations of the product of the above methods. Also, an object of the invention is to provide omeprazole compositions having low levels of residual non-alcoholic organic reaction solvent after the initial crude reactive crystallization step. Also, another object of the present invention is to provide final omeprazole compositions that do not contain residual non-alcoholic organic reaction solvent within the limits of chromatographic detection and less than 20 p.p.m. of residual crystallization solvent.
BRIEF DESCRIPTION OF THE INVENTION The present invention provides an improved process for the preparation, purification and isolation of omeprazole of formula I. The last chemical transformation in the preparation of omeprazole is the oxidative conversion of the sulfide intermediate, pyrmetazole, of formula II to its sulphoxide derivative, omeprazole, of formula I.
Oxidizing agent toluene or C ^ CI ^ ethanol
I
In one embodiment of the improved process, the oxidizing agent is meta-chloroperoxybenzoic acid (MCPBA), and the non-alcoholic organic reaction solvent is methylene chloride or toluene in admixture with an alcohol solvent, such as methanol, ethanol, isopropanol or 1 -butanol, in particular, ethanol. In this embodiment, the integrity and chemoselectivity of the oxidation have been optimized by a careful control of the amount of MCPBA loaded into the reaction container. The use of a molar equivalent of MCPBA in relation to the number of moles of pyrmetazole, prevents over-oxidation and non-chemoselective suboxidation, resulting in few impurities and high production. In another embodiment of the present invention, the concentration of MCPBA in the solution being loaded is calculated using a new analytical method, based on the oxidation with MCPBA of 3-methylisoquinoline to its N-oxide derivative and the subsequent quantification by CLAR. Without this test, there is no practical way to avoid either over-oxidation or incomplete conversion of pymetazole to omeprazole. In a further embodiment of the present invention, control over localized over-oxidation is achieved by the subsurface addition of MCPBA, provided for the entry of the oxidant solution into the reaction vessel at the tip of the stirrer blades, with simultaneous control of the reaction temperature. The incorporation of these novel features in the procedure ensures the complete conversion of pirmetazole to omeprazole without the formation of sulfone by-products. In another embodiment of the present invention, the isolation of the crude product has been improved by vacuum distillation of the crude aqueous phase after extraction of the reaction mixture before crystallization, to remove most of the methylene chloride or toluene hauled from the oxidation step. The concentration of the alcohol solvent, in particular ethanol, is readjusted in order to promote good growth of the crystal during the crude crystallization step. The crystallization step involves a two-step neutralization with either C un _3 alkyl formate, preferably methyl formate, or a solution of formic acid in aqueous methanol or ethanol, which is added subsurface through a tube. immersion located near and directed perpendicular to the tip of the impeller. This mode of addition of the methyl formate or the formic acid solution ensures the rapid dispersion of the neutralizing agent, which promotes crystal growth upon spontaneous nucleation. While doing this, the occlusion of the mother liquids in the crystals is reduced to a minimum. Decreasing the concentration of ammonia, in relation to that used in the previous procedures, in the ammonia-water solution necessary to remove impurities of color in the raw product, provides additional improvements in the production of omeprazole. A further embodiment of the present invention relates to the final purification phase. A methanol-water mixture is used for the crystallization phase, which is initiated by the addition of the subsurface of aqueous acetic acid and the subsequent application with omeprazole. The same methanol-water mixture is used as a displacement solution to remove the mother liquids and dissolve the impurities while suppressing the loss of solubility. In this way, improvements in production are obtained without any adverse impact on product quality.
The crystalline omeprazole is thus obtained with significant improvements in yield and purity. The isolated material does not contain chromatographically detectable levels of residual non-alcoholic organic reaction solvent and contains less than 20 p.p.m. of residual methanol as the crystallization solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation, purification and isolation of omeprazole proton pump inhibitor and novel compositions thereof. The omeprazole, which has the formula I, is prepared by reacting a solution of pyrmetazole, which has the formula II, cooled between -5 to + 5 ° C and regulated at a pH of about 5 to 6,
MCPBA, toluene or C ^ CI ^ ethanol
with a molar equivalent of an oxidizing agent, relative to the number of moles of pyrmetazole, dissolved in a non-alcoholic organic reaction solvent in admixture with an alcohol solvent. The alcohol solvent is selected from methanol, ethanol, isopropanol, and 1-butanol. In one embodiment of the improved process, the regulated solution comprises potassium bicarbonate, the oxidizing agent is meta-chloroperoxybenzoic acid, and the non-alcoholic, organic reaction solvent is methylene chloride or toluene, either in admixture with ethanol. The reaction is carried out in such a way that both the integrity and the chemoselectivity of the oxidation are optimized. In order to force the reaction to continue in an almost quantitative manner, it is necessary that any excess of the oxidizing agent MCPBA be reduced to a minimum. Therefore, the solution containing the oxidizing agent is accurately tested so that an exact amount of the reagent is charged to the reaction vessel. In previous methods, the amount of MCPBA added was based on the commercial distributor's test number. Since the MCPBA solid contains around 15-25% water for safety reasons, the solid is not homogeneous. Therefore, the manufacturer can only provide the average of the MCPBA test results. If the MCPBA is used by different containers and different distributors, an inaccurate MCPBA charge will result. Therefore, a novel analytical method has been produced to quantify the MCPBA in the charge solution in order to partition an amount of the oxidizing agent. According to the test, an excess of the amount of 3-methylisoquinoline (III) is reacted with the MCPBA in toluene / ethanol solution to form 3-methylisoquinoline (IV) N-oxide, according to the equation:
IV
The reaction is rapid and quantitative. The remaining tertiary amine in the reaction mixture is quantified by reverse phase high-performance liquid chromatography (RP-CLAR). The amount of the amine consumed during the reaction is used to calculate the concentration of the MCPBA solution. It is also important that no excess of oxidizing agent builds up during the reagent addition. This is best achieved by the subsurface addition of MCPBA in such a way that the solution enters the batch through the immersion tube located near and directed perpendicular to the agitator blades. This mode of addition provides immediate dispersion of the oxidant, thereby limiting localized oxidation. The chemoselectivity and the extent of the oxidation are also increased by controlling the reaction temperature without the crystallization of the oxidizing agent. The optimum temperature range is about 0-5 ° C for the oxidizing agent solution and about -5 to + 5 ° C for the reaction mixture through the addition process. Very high temperatures of either the MCPBA solution or the reaction mixture will result in the formation of some sulfones. Likewise, much lower temperatures temporarily suppress the oxidation reaction, which results in a localized accumulation of the oxidizing agent which can direct the over-oxidation products. After the addition of the solution containing the oxidizing agent, an aqueous base of 50% NaOH or KOH is added, the solution is left to age for about 0.5-1.0 hours at 0-5 ° C, and the aqueous phase is separated from the organic phase. To minimize the residual levels of the non-alcoholic organic reaction solvent, in particular toluene or methylene chloride, in the crude product, which results in higher levels of organic, non-alcoholic, volatile reaction solvent in the pure product, it is important to remove both the toluene or methylene chloride formed, as possible from the raw aqueous phase. The source of residual toluene or methylene chloride is an emulsion that is formed when the crude batch is extracted from toluene or methylene chloride with an aqueous base. The removal of the residual solvent can be carried out by vacuum distillation of the aqueous phase at a pressure of about 25-70 mm Hg and temperature of about 15-35 ° C for about 1-4 hours. In a further exemplification, the distillation is carried out with about 50 mm HG and around 15 ° C for 2 hours. The vacuum distillation process reduces the pre-crystallization levels of toluene or methylene chloride to less than 400 p.p.m.
Other options to dissolve the emulsion and better effect the separation phase, are less effective; These include filtration of the raw aqueous phase through a layer of Celite ™, increasing the fixing time, and the addition of a strong electrolyte. Since the distillation process also results in the removal of the alcohol, in particular the ethanol, its concentration must be readjusted to approximately 15%, in order to facilitate crystal growth during the crude crystallization process. A low level of the alcohol solvent, in particular the ethanol, produces fine crystals which are very likely to dissolve during subsequent washes, thereby decreasing the yields of the crude product. At this time, the reactive crystallization of omeprazole is initiated and maintained under controlled conditions. Approximately 40% of a C -? - 3 of alkyl formate, preferably methyl formate, is added in the first 30 minutes to drive the batch from a pH of about 13.5 to near supersaturation, at a pH of about 10.6 at 10.8. The addition of the methyl formate is carried out through a dip tube, which is reduced at one end to create a fine stream, and which is neutralized near and perpendicular to the tip of the impeller. This technique ensures the rapid dispersion of methyl formate so that the occlusion of the impurities is minimized. When a pH of about 10.6-10.8 is reached, the addition of the methyl formate is discontinued, and the batch is aged 10 to 20 minutes to allow the temperature to cool to approximately 20 ° C before planting. It is important to inoculate between a pH of 10.6 and 10.8. Below 10.6 of spontaneous nucleation, if a sufficient seed layer is not present, a small crystal growth occurs. Seeding is carried out with ground, pure omeprazole (100% HPLC), and the rest of methyl formate is added subsuperficially for 6-8 hours to adjust the pH of around 9.0-9.3. This crystallization process improves both the production and the purity of the product. Without being retained in a specific mechanism, it is believed that the increase in purity is mainly due to the prevention of the occlusion of the mother liquors by promoting crystal growth above nucleation. The crude omeprazole in this step contains less than 100 p.p.m. of toluene or residual methylene chloride, as determined in gas-liquid chromatographic analyzes. The reactive crystallization of the crude omeprazole can also be carried out by neutralization of a basic aqueous solution of omeprazole with a solution of formic acid in methanol or aqueous ethanol, preferably a solution of about 20% (v / v) formic acid in about of 25% aqueous methanol, which is added in a subsurface manner as in the one described in the previous paragraph. To adjust the pH from about 13.5 to the supersaturation at a pH of about 10.6 to 10.8, enough formic acid solution is added. In these stages, while the seeding is carried out with ground and pure omeprazole (100% of CLAR), and the rest of the formic acid solution is added superficially of 6-8 hours to adjust the pH to around 9.0-9.3. This alternative neutralization procedure with formic acid solution instead of methyl formate, produces crude crystalline omeprazole with much larger and uniform crystals. The average particle size of the omeprazole crystals obtained with the neutralization of formic acid is approximately 280 μm compared to the average particle size of 180 μm obtained with the neutralization of methyl formate. The larger particle size translates into a more efficient centrifugation or filtration that leads to a significant increase in productivity on a production scale. The crude crystallized product obtained either from the methyl formate or from the neutralization of the formic acid is then filtered, washed with 0.01-1.0%, preferably 0.1%, water-ammonia, and then methanol. The crude wet omeprazole is then purified by dissolving it in 2.1-0.5.1 (v / v) of a water-methanol solution containing an aqueous base, preferably 25% NaOH or KOH, at 20 ° C, cooling the basic solution at around 0.5 ° C, reducing the pH of >11.0 to about 10.5 by subsurface addition through a reduced end of the dip tube (the configuration of the apparatus is the same as in the raw isolation step) of aqueous acetic acid, preferably 25% aqueous acetic acid, over a period of time 30 minutes, while maintaining the temperature at 0-5 ° C. At this point the batch is seeded with pure omeprazole (100% by HPLC), and the subsurface addition of 25% aqueous acetic acid is continued for a period of 2-4 hours until a pH of about 9.0 is reached. The batch is then aged from 0.5 to 1.0, preferably 0.5 hours. Following the aging period, the product is filtered, washed with the same methanol-water mixture to displace the mother liquids containing the impurities, and finally with cold methanol. Pure omeprazole is obtained after vacuum drying with a nitrogen purge at 30-50 mm and 30-35 ° C. The optimum ratio of methanol-water in this last purification step is 1: 1. The above methods used a high proportion of methanol-water. By decreasing the proportion of methanol in the solvent mixture used in the displacement solution, the loss of solubility is reduced and it provides the purification demands, thus improving the performance of the final product without compromising the quality of the product. The crystalline omeprazole obtained using the improvement method of the present invention has a purity by CLAR of 100% with no detectable level of transported residual toluene or methylene chloride from the crude passage, as measured by gas-liquid chromatography, detection limit is 3 ppm The above methods have provided an omeprazole containing 30-100 p.p.m. of residual non-alcoholic organic reaction solvent, namely toluene or methylene chloride. The pure product contains less than 20 p.p.m. of residual methanol than the crystallization solvent.
For the preparation of the pharmaceutical compositions in the form of dosage units for oral administration, omeprazole is prepared according to the process of the present invention either mixed with a solid, a pulverulent carrier, such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives or gelatin, as well as an antifriction agent such as magnesium stearate, calcium stearate, and polyethylene glycol waxes. The mixture is then compressed into tablets. If it is desired to coat the tablets, the central part of them may be coated with a concentrated sugar solution, which could contain, gelatin, talcum, titanium dioxide, or with a plate dissolved in volatile organic solvent or a mixture of solvents. Various dyes can be added to this coating in order to distinguish between tablets with different amounts of active compound present. Soft gelatin capsules containing a mixture of pure omeprazole can be prepared according to the process of the present invention and with vegetable oil. The hard gelatine capsules may contain granules of the active compound in combination with a solid powdery vehicle, such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopeptin, cellulose derivatives or gelatin. Pharmaceutical tablets for oral use are prepared in the following manner. The solids are milled or sieved to a certain particle size and the binder is homogenized and suspended in an appropriate solvent. The solid omeprazole prepared according to the process of the present invention and auxiliary agents are mixed with the binder solution. The resulting mixture is moistened to form a uniform suspension having the consistency of wet snow. The moisture causes the particles to aggregate delicately, and the resulting mass is compressed through a stainless steel screen having a mesh size of about 1 millimeter. The layers of the mixture are dried in carefully controlled drying cabinets for approximately 10 hours, to obtain the desired particle size and consistency. The granules of the dry mix are screened to remove any dust. To this mixture, disintegrating, antifriction and anti-adhesion agents are added. Finally the mixture is compressed into tablets using a machine with appropriate dies and dies to obtain the desired tablet size. The pressure applied affects the size of the tablet, its strength and ability to dissolve in water. The compression pressure used should be in a range of 0.45 to 4.5 tons. Tablets, especially those that are sour or bitter, can be coated with a layer of sugar or some other palatable substance. They are then packed by machines that have electronic counting devices. The following examples illustrate the process of the present invention and are not intended to limit the scope of the invention set forth in the appended claims.
EXAMPLE 1 CLAR test of the loading solution of MCPBA
Step A HPLC operating parameters High performance liquid chromatography was performed using a Waters μBondapak C-18 column (4.6 x 300 mm, particle size 10 μm) with the following additional parameters: Mobile phase: A = acetonitrile; B = 0.1% H3PO4 Method: Socratic 25% A / 75% B at a flow rate of 1.0 ml / min Injection size: 10 μl Wavelength detector: 254 nm Execution time: 32 min. Quantification method: area by electronic integration. Approximate retention time: 3-methylisoquinoline: 3.5 min. N-3-methylisoquinoline oxide: 5.7 min. MCPBA: 11.4 mins. Tolueno: 25.1 mins.
Step B Reagents Acetonitrile (MeCN): CLAR Grade Water: CLAR Grade Phosphoric Acid: CLAR Grade 3-Methylisoquinoline: 98% Solvent Sample: 50/50 (MeCN / H3PO4 0.1%)
Step C Preparation of 3-methylisoquinoline standard The 20 ± 5 mg of 3-methylisoquinoline (98%) was transferred into a 10 ml volumetric flask and dissolved in 1.0 ml of MeCN. 1.0 ml of MCPBA after being heated to a temperature were carefully pipetted into the flask, and the sides of the flask were washed with 1.0 ml of MeCN. The flask was then covered with parafilm film and treated with sound for five minutes. After cooling, the sides of the flask were washed with 1.0 ml of MeCN and the flask was treated with sound for an additional minute. The mixture was carefully diluted to the mark with acetonitrile. 1.0 ml of this solution were pipetted into a 25 ml volumetric flask and diluted to the mark with the solvent sample from step B.
Step D Procedures The CLAR system was balanced for at least 10 minutes in the mobile phase condition given in step A. The standard preparation of step C was injected twice, and the area response average for the peaks of 3- Methylisoquinoline should coincide with ± 1% of the average. Sample preparation was injected once.
Step E Calculations The concentration (mg / ml) of the MCPBA solution was calculated using the following equation:
172. 57 mg / ml of MCPBA solution = (B - (A - As) x Cs x 250) 143.19
where: A = response area of 3-methylisoquinoline for the sample solution. B = weight (mg) of 3-methylisoquinoline in the sample preparation. As = area response average of the 3-methylisoquinoline of the standard solution. Cs = concentration of the standard preparation of 3-methylisoquinoline. 172.57 = weight formula for 3-methylisoquinoline. 143.19 = weight formula for MCPBA As an illustration of the test, a sample of MCPBA of the spectrum was tested (Lot # LF0102, 72.7% MCPBA), and a value of 72.8% (% by weight) was obtained for the MCPBA.
EXAMPLE 2 Preparation of omeprazole with methylene chloride as a solvent
A solution of potassium bicarbonate (14.0 g, 0.140 mol, 1.2 equivalents) in deionized water (115 ml) was added to a solution of pyrmetazole (0.114 mol) in methylene chloride (170 ml) in a three-necked round bottom flask. one liter necks, and the mixture was cooled to 0 ° C. A solution of meta-chloroperoxybenzoic acid (MCPBA) (28 g, 0.114 moles, 1.0 equivalents) in methylene chloride (51 ml) and ethanol (13.3 ml) was prepared and tested by the 3-methylisoquinoline / HPLC procedure described in Example 1, to ensure that exactly one molar equivalent of MCPBA is used. The solution is then cooled between 0-5 ° C and added, subsurface directed to the tip of the impeller, to the rapidly stirred pyrmetazole solution for a period of 2 hours. The oxidation conversion was 99.8% with no over-oxidation to sulfone or N-oxides, as determined by the HPLC analysis. The cold deionized water (115 ml, 5 ° C) and 50% NaOH (15 ml) were then added to the reaction mixture. The solution was allowed to stand at 0-5 ° C for 30 minutes and the phases separated. The methylene chloride layer was discarded and the aqueous layer was concentrated under vacuum (50 mm Hg) for 2 hours at 15 ° C to remove the residual methylene chloride volume. The ethanol level was then adjusted to 15% v / v. At this point the residual methylene chloride level was less than 200 p.p.m., as determined by gas-liquid chromatographic analysis.
The crude product was then isolated by reactive crystallization by the subsurface addition of the methyl formate. Approximately 40% of the charge of the methyl formate (approximately 6 mL) was added during the first 30 minutes to adjust the pH from about 13.5 to 10.8. The mixture was allowed to stand for twenty minutes to allow the internal temperature to cool again to about 20 ° C. The mixture was seeded with a pure omeprazole (0.5 g), and the rest of the methyl formate, (approximately 9 mL) was added subsuperficially for a period of 7 hours at a pH of 9.0. The crude product was filtered, washed with 0.1% water-ammonia (50 mL) followed by methanol (40 mL). The crude product was dissolved in a 1: 1 solution of water-methanol (270 mL) and 50% NaOH (4 mL) in a 3-necked round bottom flask of 500 mL at 20 ° C. The solution was then cooled to 0-5 ° C and the adjusted pH of >; 11.0 to about 10.5 by subsurface addition of 25% acetic acid for a period of 30 minutes, maintaining the temperature at 5 ° C. The batch was seeded with pure omeprazole (0.5 g) and the subsurface addition of 25% acetic acid continued for a period of 4 hours until it reached a pH of 9.0. After 30 minutes, the resulting solid was filtered, washed with a 1: 1 solution of water-methanol (30 mL), and finally with cold methanol (5 ° C) (30 mL). The pure omeprazole (100% as determined by the HPLC analysis) was obtained after vacuum drying (50 mm Hg, 30-35 ° C). The total yield was 92.7%. The residual methanol level was 10 ppm, as determined by gas-liquid chromatography, without detectable levels of methylene chloride (limit of detection of 3 p.p.m.).
EXAMPLE 3 Preparation of omeprazole with toluene as solvent
A solution of potassium bicarbonate (14.0 g, 0.140 mol, 1.2 equivalents) in deionized water (115 mL) was added to a solution of pirmentazole (0.114 mol) in toluene (310 mL) in a three-necked round bottom flask. one liter, and the mixture was cooled to 0 ° C. Following the addition of bicarbonate, a solution of meta-chloroperoxybenzoic acid (0.114 mol, equivalent to 1) in toluene (53 mL) and ethanol (20 mL) was tested and charged to the pyrmetazole solution as in Example 2. The conversion of oxidation was 99.8% without over-oxidation in sulfone or N-oxides. The cold deionized water (145 mL, 5 ° C and 50% NaOH (12 mL) was then added to the reaction mixture, the solution was allowed to stand at 0-5 ° C for 30 minutes and the phases were separated. The toluene layer was discarded and the aqueous layer was concentrated under vacuum (50 mm Hg) for 2 hours at 15 ° C to remove the remaining residual toluene.The ethanol level was then adjusted to 15% v / v. , the residual toluene level was less than 400 ppm, as determined by the gas-liquid chromatographic analysis.
The crude product was then isolated by reactive crystallization by the subsurface addition of methyl formate as in Example 2. This was filtered, washed with 0.1% water-ammonia (50 mL) followed by methanol (40 mL). The crude wet product was then processed to pure omeprazole as in Example 2. The total yield was 93.8% with a purity of CLAR of 100%. The residual methanol level was 10 ppm, as determined by gas-liquid chromatography, without detectable levels of toluene (detection limit 3 p.p.m.).
EXAMPLE 4 Isolation of pure omeprazole by reactive crystallization with formic acid
The basic aqueous solution of omeprazole was prepared exactly as in Example 3 to the crystallization point of the crude product. A solution of formic acid, methanol and water at a ratio of 20:20:60 was then added to the aqueous solution of the crude product in a subsurface manner, at room temperature to effect crystallization. Approximately 40% of the formic acid solution was added in the first 30 minutes to adjust the pH to about 13.5. The batch was then seeded with pure omeprazole (0.5 g), and the rest of the formic acid solution was added subsurfacely over a period of 7 hours at a pH of 9.0. The crude product was then filtered, washed with water-0.1% ammonia (50 mL at 20 ° C) followed by methanol (40 ML at 5 ° C) and vacuum drying (50 mm Hg, 30-35 ° C) . The yield was 95.4% with a purity of HPLC of 99.9% and a median particle size of 285 μm.
EXAMPLE 5
A pharmaceutical composition containing omeprazole prepared according to the method of the present invention as the active ingredient is illustrated in the following formulation. The capsules containing 30 mg of omeprazole of the present invention were prepared from the following ingredients:
The omeprazole of Example 2 or 3 was mixed with the dry and granulated ingredients with a disodium phosphate solution. The wet mass was forced through an extruder and spheronized and dried in a fluid bed dryer. 500 grams of the tablets were coated with a solution of hydroxypropylmethylcellulose (30 grams) in water (750 mL) using a fluidized bed coater. After drying, the tablets were coated with a second coating as follows:
Coating solution:
The final coated tablets were filled into the capsules.
Claims (42)
1. - A procedure for the preparation of omeprazole, which has the formula I, which consists of treating, at around -5 to + 5 ° C, a solution of pyrmetazole with its regulated pH, which has the formula II, in an organic, non-alcoholic reaction solvent, with an equivalent amount of an oxidizing agent in relation to the number of moles of said pyrmetazole, the oxidizing agent dissolved in the non-alcoholic organic reaction solvent in admixture with an alcohol solvent at about 0-5 ° C followed by aging in the presence of a watery base.
2. The process according to claim 1, which further comprises: a) separating the aqueous phase from the aged reaction mixture of the organic phase; and b) removing the organic, non-alcoholic, residual reaction solvent from said aqueous phase followed by a readjustment of the alcohol solvent concentration of about 15% v / v.
3. The process according to claim 1, further characterized in that the alcohol solvent is selected from methanol, ethanol, sodium propane, and 1-butanol.
4. The process according to claim 3, further characterized in that the alcohol solvent is ethanol.
5. The process according to claim 2 which further comprises: a) crystallizing the crude product of said aqueous phase and b) isolating the crude product by filtration and washing with water-ammonia and methanol.
6. The process according to claim 5, further characterized in that said crystallization of crude product is carried out by subsurface addition of a C1-3 alkyl formate to adjust the pH from about 13.5 to 10.6-10.8, aged for about 10-20 minutes, allowing the temperature to reach about 20 ° C, seeding, and adding the remains of said alkyl formate for 6-8 hours to adjust the pH of about 9.0-9.3.
7. The process according to claim 5 further characterized in that said crystallization of crude product is carried out by subsurface addition of a solution of about 20% (v / v) of formic acid in methanol or aqueous ethanol to adjust the pH of about 13.5 to 10.6-10.8, sowing and adding the remainder of said formic acid solution for 6-8 hours to adjust the pH to about 9.0-9.3.
8. The process according to claim 5, which further comprises: a) recrystallizing the crude product in methanol-water containing aqueous sodium hydroxide through cooling of about 0-5 ° C, adjusting the pH to 10.5 by subsurface addition of 25% aqueous acetic acid, sowing, adding 25% aqueous acetic acid at a pH of about 9.0, and aging it for about 0.5 hour; and b) isolating the pure product by filtration, washing with water-methanol and cold methanol, drying under vacuum.
9. The process according to claim 2, further characterized in that the residual, non-alcoholic, organic reaction solvent is removed from the aqueous phase by vacuum distillation at about 25-70 mm Hg and about 15-35 °. C for about 1-4 hours.
10. The process according to claim 1, further characterized in that the oxidizing agent is selected from peroxybenzoic acid, meta-chloroperoxybenzoic acid, magnesium monoperoxylate and peracetic acid.
11. The process according to claim 10, further characterized in that the oxidizing agent is meta-chloroperoxybenzoic acid.
12. The process according to claim 1, further characterized in that the organic, non-alcoholic reaction solvent is selected from an aromatic hydrocarbon solvent and a chlorinated aliphatic hydrocarbon solvent.
13. The process according to claim 12, further characterized in that the aromatic hydrocarbon solvent is toluene.
14. The method according to claim 12, further characterized in that the chlorinated aliphatic hydrocarbon solvent is selected from methylene chloride, 1,2-dichloroethane and chloroform.
15. The process according to claim 14, further characterized in that the chlorinated aliphatic hydrocarbon solvent is methylene chloride.
16. The process according to claim 1, further characterized in that the aging is allowed to continue at about 0-5 ° for a time of about 0.5-1.0 hours.
17. The process according to claim 1, further characterized in that the pH regulator comprises aqueous sodium bicarbonate or aqueous potassium bicarbonate.
18. The process according to claim 1, further characterized in that the aqueous base comprises aqueous sodium hydroxide or aqueous potassium hydroxide.
19. The process according to claim 6, further characterized in that the alkyl formate of C? 3 is methyl formate.
20. The process according to claim 8, further characterized in that the volume ratio of methanol to water in steps (a) and (b) is from 2: 1 to 0.5-1.
21. The process according to claim 20, further characterized in that the ratio by volume of methanol to water is 1: 1.
22. The process according to claim 9, further characterized by the vacuum distillation is carried carried out at a pressure of about 50 mm Hg and at a temperature of about 15-25 ° C.
23. The process according to claim 5, further characterized in that the concentration of water-ammonia in step (b) is 0.01-1.0% (v / v).
24. - The method according to claim 23, further characterized in that the water-ammonia concentration is 0.1% (v / v).
25. The process according to claim 1, further characterized in that the molar amount of oxidizing agent to be added to said pyrmetazole solution is calculated by means of a high performance liquid chromatography test, which quantifies the degree of oxidation of an excess of 3-methylisoquinoline to N-oxide of 3-methylisoquinoline.
26. The process according to claim 1, further characterized in that the oxidizing agent is added subsurfacially in such a way that the solution enters the reaction mixture up to the tip of the agitator blades.
27.- 5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-? Iridinyl) methyl] sulfinyl] -1H-benzimidazole (omeprazole) obtained by the process of claim 8 containing less of 100 parts per million of residual aromatic hydrocarbon solvent.
28.- 5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (omeprazole) obtained by the process of claim 8 containing less than 100 parts per million of the residual chlorinated aliphatic hydrocarbon solvent.
29.- 5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridinyl) methy1] sulfinyl] -1H-benzimidazoi (omeprazole) according to claim 27, further characterized in that the aromatic hydrocarbon solvent is toluene.
30.- 5-Methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (omeprazole) according to claim 28, further characterized in that the hydrocarbon solvent Chlorinated aliphatic is methylene chloride.
31.- 5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole (omeprazole) containing less than 3 parts per million aromatic hydrocarbon solvent residual and 10-20 ppm of residual methanol.
32.- S-methoxy ^ -f ^ -methoxy-S.d-dimethyl-pyridinium methyljsulfinilj-I H-benzimidazole (omeprazole) containing less than three parts per million residual chlorinated aliphatic hydrocarbon solvent and 10-20 p.p.m. of residual methanol.
33.- 5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (omeprazole) according to claim 31, further characterized in that the solvent of aromatic hydrocarbon is toluene.
34.- 5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (omeprazole) according to claim 32, further characterized in that the solvent of Chlorinated aliphatic hydrocarbon is methylene chloride.
35. - A composition comprising 5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfonyl] -1H-benzimidazole (omeprazole) having less than three parts per million residual aromatic hydrocarbon solvent and 10-20 ppm of residual methanol relative to omeprazole. 36.- A composition comprising 5-methoxy-2 - [[4-methoxy-3], 5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (omeprazole) having less than three parts per million of the residual chlorinated aliphatic hydrocarbon solvent and less than 10-20 p.p.m. of residual methanol relative to omeprazole. 37.- The composition according to claim 35, further characterized in that the aromatic hydrocarbon solvent is toluene. 38.- The composition according to claim 36, further characterized in that the chlorinated aliphatic hydrocarbon solvent is methylene chloride. 39.- A pharmaceutical composition comprising 5-methoxy-2- [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (omeprazole) having less than three parts per million of residual aromatic hydrocarbon solvent and 10-20 ppm of methanol in relation to omeprazole, and a pharmaceutically acceptable excipient. 40.- A pharmaceutical composition comprising 5-methoxy-2- [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (omeprazole) having less than three parts per million of the residual chlorinated aliphatic hydrocarbon solvent and 10-20 ppm of residual methanol in relation to omeprazole, and a pharmaceutically acceptable excipient. 41.- The pharmaceutical composition according to claim 39, further characterized in that the aromatic hydrocarbon solvent is toluene. 42.- The pharmaceutical composition according to claim 40, further characterized in that the chlorinated aliphatic hydrocarbon solvent is methylene chloride.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/096,037 | 1998-08-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA01001542A true MXPA01001542A (en) | 2002-03-26 |
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