CN105111187A - Preparation method for pantoprazole sodium oxynitride impurity - Google Patents
Preparation method for pantoprazole sodium oxynitride impurity Download PDFInfo
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- CN105111187A CN105111187A CN201510483592.1A CN201510483592A CN105111187A CN 105111187 A CN105111187 A CN 105111187A CN 201510483592 A CN201510483592 A CN 201510483592A CN 105111187 A CN105111187 A CN 105111187A
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention discloses a preparation method for a pantoprazole sodium oxynitride impurity. The preparation method comprises the following steps: 2-chloromethyl-3,4-dimethoxypyridine hydrochloride is used as a raw material to react with 5-difluoromethoxy-2-mercapto-1H-benzimidazole and produce 5-difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulphur}-1H-benzimidazole; then in a presence of hydrogen peroxide and acetic acid, with copper hydroxyphosphate as a catalyst, oxidation is performed to obtain an oxynitride product of the pantoprazole; and finally a sodium salt is obtained by a reaction with sodium hydroxide, and pantoprazole sodium oxynitride impurity is obtained. According to the preparation method, no extreme reaction condition is needed, and raw materials are easy to obtain; the oxidant is capable of selective oxidations, which can not only oxidate pyridine ring, but also can oxidate thioether to sulfoxide, and by controlling the dosage of the catalyst, i.e., copper hydroxyphosphate, a peroxidation is less likely to occur (oxidate thioether to sulphone); and a post-treatment is simple and easy in operation, and the resulting product is high in purity and high in yield.
Description
Technical field
The invention belongs to medical art, relate to the preparation method of the nitrogen oxidation impurities that a kind of Pantoprazole Sodium preparation process produces in particular.
Background technology
Pantoprazole Sodium is national four kind new medicines, is the first-line treatment medicine of peptic ulcer disease, has 20 countries such as Britain, Germany, Mexico so far and gets permission to use.Pantoprazole Sodium is developed by German BykGulden company, and preparation is developed by U.S. Hui Shi, in 1994 in Sweden's listing, is the third generation proton pump inhibitor after Omeprazole Sodium and lansoprazole.In order to ensure drug safety and the quality of Pantoprazole Sodium, with regard to needing, rigorous research is carried out to relevant impurity, by Control of Impurities within safety, reasonably limits.The structural formula of Pantoprazole Sodium is as follows.
5-difluoro-methoxy-2-[(3; 4-dimethoxy-2-pyridinyl) methyl] sulfinyl-1H-benzoglyoxaline sodium salt oxynitride (is popularly at present called Pantoprazole Sodium nitrogen oxidation impurities; hereinafter referred nitrogen oxidation impurities), CAS:953787-60-5, molecular formula: C
16h
14f
2n
3naO
5s, molecular weight: 421.35; Chemical structural formula is as follows.
The generation of Pantoprazole Sodium nitrogen oxidation impurities is that the oxidizability of oxidants owing to using in the building-up process of pantoprazole is strong, the pyridine ring snperoxiaized product-nitrogen oxidation impurities produced while sulfide oxidation is become sulfoxide.And if produce this nitrogen oxidation impurities, be difficult in follow-up treating process removing.This impurity or genotoxicity impurity simultaneously, needs strict to control its content in Pantoprazole Sodium finished product.
Summary of the invention
The object of this invention is to provide a kind of preparation method of Pantoprazole Sodium nitrogen oxidation impurities.The method is without the need to the reaction conditions of harshness, and starting material are simple and easy to get; Oxygenant alternative used is oxidized, both can pyridine oxide ring, can oxidizing sulfur ether be also sulfoxide, and by controlling catalyzer (hydroxyl cupric phosphate) consumption, peroxidation (sulfide oxidation is become sulfone) not easily occurs; Aftertreatment is simple to operation, and products therefrom purity is high, and yield is high.The nitrogen oxidation impurities of synthesis may be used for the Qualitative and quantitative analysis of pantoprazole sodium impurity, thus can improve the drug safety of Pantoprazole Sodium.
Technical scheme of the present invention is: a kind of preparation method of Pantoprazole Sodium nitrogen oxidation impurities, is characterized in that,
(1) with 2-chloromethyl-3, to be raw material (compound 1) with 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline (compound 2) react 4-dimethoxy pyridine hydrochloride generates 5-difluoro-methoxy-2-{ [(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-1H-benzoglyoxaline (intermediate 3);
(2) then intermediate 3, under hydrogen peroxide and acetic acid existent condition, makees catalyzer with hydroxyl cupric phosphate, and the nitrogen oxidation products (intermediate 4) of pantoprazole is produced in oxidation;
(3) intermediate 4 is reacted into sodium salt again and obtains Pantoprazole Sodium nitrogen oxidation impurities with sodium hydroxide.Chemical reaction mode is as follows.
Concrete steps are as follows:
(1) 2-chloromethyl-3 is added in reaction vessel, 4-dimethoxy pyridine hydrochloride (compound 1), 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline (compound 2) and methylene chloride, then drip sodium hydroxide solution; After dropwising, 20-30 DEG C of stirring reaction 1 ~ 2h; Then stratification, dichloromethane layer obtains yellow oil (intermediate 3) after washing, underpressure distillation;
(2) by the yellow oil acetic acid that step (1) obtains, add hydrogen peroxide and catalyzer hydroxyl cupric phosphate, be warming up to 40 ~ 50 DEG C, reaction 5 ~ 6h; After having reacted, reaction solution is poured into water, adjusts pH neutral with sodium hydroxide solution; Then through dichloromethane extraction, yellow oil (intermediate 4) after underpressure distillation, is obtained; Refine through organic solvent again, obtain faint yellow solid;
(3) by the faint yellow solid acetone solution that step (2) obtains, add sodium hydroxide solution and react; Then be cooled to-5 ~ 5 DEG C, crystallization 30-60min, suction filtration obtains Pantoprazole Sodium nitrogen oxidation impurities.
The mol ratio of the compound 1 of described step (1), compound 2 and sodium hydroxide is 1:1.0 ~ 1.2:5 ~ 10.
In described step (2), the mol ratio of hydrogen peroxide and compound 1 is 4 ~ 6:1, and the mol ratio of catalyzer hydroxyl cupric phosphate and compound 1 is 0.005 ~ 0.01:1.The consumption of acetic acid, for dissolving intermediate 3, can form Peracetic Acid with hydrogen peroxide after adding acetic acid.
The preferred first benzene and heptane of organic solvent that in described step (2), organic solvent is refining, and the volume ratio of toluene and normal heptane is 1:4 ~ 8, preferred 1:6.
The intermediate 4 of described step (3) is 1:1.0 ~ 1.5 with the mol ratio of sodium hydroxide.
The invention has the beneficial effects as follows:
(1) preparation method of the present invention is simple, and reaction conditions requires low, and starting material are cheaply simple and easy to get, and aftertreatment is simple to operation, and suitability for industrialized is produced;
(2) oxygenant alternative used is oxidized, both can pyridine oxide ring, can be also sulfoxide by sulfide oxidation, and by controlling catalyzer hydroxyl cupric phosphate consumption, peroxidation (sulfide oxidation is become sulfone) not easily occurs;
(3) products therefrom purity is high, and yield is high; The nitrogen oxidation impurities of synthesis may be used for the Qualitative and quantitative analysis of pantoprazole sodium impurity, thus can improve the drug safety of Pantoprazole Sodium.
Embodiment
Below in conjunction with specific embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited thereto:
Embodiment 1
(1) in reaction flask, 10g2-chloromethyl-3 is added, 4-dimethoxy pyridine hydrochloride (compound 1), 10g5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline (compound 2), 100ml methylene dichloride, stirs, drip the sodium hydroxide solution 130g that concentration is 10%, 20-30 DEG C is stirred 2h, stratification, and dichloromethane layer washes 2 times, each water 30ml, then underpressure distillation obtains yellow oil 16.6g (intermediate 3);
(2) the yellow oil 40ml acetic acid of step (1), adds 14.4g50% hydrogen peroxide, 0.06g hydroxyl cupric phosphate, is warming up to 45 DEG C, reaction 5h; After having reacted, reaction solution is poured in 100ml water, adjust pH neutral with 10% sodium hydroxide solution, water layer 50ml (each consumption) dichloromethane extraction 3 times, subtract steaming methylene dichloride and obtain yellow oil.Dissolved by oily matter with 20ml toluene, add 120ml normal heptane, stir 1h, suction filtration, obtains faint yellow solid 12.7g (intermediate 4), purity 97.8%, molar yield 71.2%;
(3) by 12.7g intermediate 4 20ml acetone solution, add 8.5g20% sodium hydroxide solution and react, be then cooled to 0 DEG C and stir 30min, suction filtration obtains faint yellow solid 12.2g, purity 98.9%, molar yield 91.1%.The spectral data of product after testing, MS-ESI (m/z): 422 [M+H]
+; 1HNMR (600MHz, DMSO): 3.72 (s, 3H ,-OCH
3), 3.90 (s, 3H ,-OCH
3), 4.79 (s, 2H ,-CH
2), 7.01-8.21 (m, 6H, Ar-5Hand-OCHF
2).
Embodiment 2
(1) by the 16.6g yellow oil 45ml acetic acid of embodiment 1 step (1), add 12.6g50% hydrogen peroxide, 0.08g hydroxyl cupric phosphate, be warming up to 50 DEG C, reaction 6h; After having reacted, reaction solution is poured in 100ml water, adjust pH neutral with 10% sodium hydroxide solution, water layer 50ml (each consumption) dichloromethane extraction 3 times, subtract steaming methylene dichloride and obtain yellow oil.Dissolved by oily matter with 18ml toluene, add 126ml normal heptane, stir 1h, suction filtration, obtains faint yellow solid 13.0g (intermediate 4), purity 97.4%, molar yield 72.9%;
(2) by 13.0g intermediate 4 18ml acetone solution, add 7.0g20% sodium hydroxide solution and react, be then cooled to 0 DEG C and stir 30min, suction filtration obtains faint yellow solid 12.4g, purity 98.5%, molar yield 90.1%.
Embodiment 3
(1) by the 16.6g yellow oil 50ml acetic acid of embodiment 1 step (1), add 17.2g50% hydrogen peroxide, 0.1g hydroxyl cupric phosphate, be warming up to 40 DEG C, reaction 5.5h; After having reacted, reaction solution is poured in 100ml water, adjust pH neutral with 10% sodium hydroxide solution, water layer 50ml (each consumption) dichloromethane extraction 3 times, subtract steaming methylene dichloride and obtain yellow oil.Dissolved by oily matter with 25ml toluene, add 200ml normal heptane, stir 1h, suction filtration, obtains faint yellow solid 13.4g (intermediate 4), purity 98.1%, molar yield 75.2%;
(2) by 13.4g intermediate 4 25ml acetone solution, add 7.0g20% sodium hydroxide solution and react, be then cooled to 0 DEG C and stir 30min, suction filtration obtains faint yellow solid 13.0g, purity 98.9%, molar yield 92.0%.
Claims (7)
1. a preparation method for Pantoprazole Sodium nitrogen oxidation impurities, is characterized in that,
(1) with 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride be raw material and 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline react generate 5-difluoro-methoxy-2-{ [(3,4-dimethoxy-2-pyridinyl) methyl] sulphur-1H-benzoglyoxaline;
(2) then 5-difluoro-methoxy-2-{ [(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-1H-benzoglyoxaline is under hydrogen peroxide and acetic acid existent condition, make catalyzer with hydroxyl cupric phosphate, the nitrogen oxidation products of pantoprazole is produced in oxidation;
(3) the nitrogen oxidation products of pantoprazole is reacted into sodium salt again and obtains Pantoprazole Sodium nitrogen oxidation impurities with sodium hydroxide.
2. the preparation method of a kind of Pantoprazole Sodium nitrogen oxidation impurities as claimed in claim 1, is characterized in that, specifically comprise the following steps:
(1) add 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline and methylene chloride in reaction vessel, then drip sodium hydroxide solution; After dropwising, 20-30 DEG C of stirring reaction 1 ~ 2h; Then stratification, dichloromethane layer obtains yellow oil after washing, underpressure distillation;
(2) by the yellow oil acetic acid that step (1) obtains, add hydrogen peroxide and catalyzer hydroxyl cupric phosphate, be warming up to 40 ~ 50 DEG C, reaction 5 ~ 6h; After having reacted, reaction solution is poured into water, adjusts pH neutral with sodium hydroxide solution; Then through dichloromethane extraction, after underpressure distillation, yellow oil is obtained; Refine through organic solvent again, obtain faint yellow solid;
(3) by the faint yellow solid acetone solution that step (2) obtains, add sodium hydroxide solution and react; Then be cooled to-5 ~ 5 DEG C, crystallization 30-60min, suction filtration obtains Pantoprazole Sodium nitrogen oxidation impurities.
3. the preparation method of a kind of Pantoprazole Sodium nitrogen oxidation impurities as claimed in claim 1 or 2, is characterized in that, in described step (2), the mol ratio of hydrogen peroxide and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride is 4 ~ 6:1.
4. the preparation method of a kind of Pantoprazole Sodium nitrogen oxidation impurities as claimed in claim 1 or 2, is characterized in that, the mol ratio of described catalyzer hydroxyl cupric phosphate and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride is 0.005 ~ 0.01:1.
5. the preparation method of a kind of Pantoprazole Sodium nitrogen oxidation impurities as claimed in claim 2, is characterized in that, the organic solvent that in described step (2), organic solvent is refining is first benzene and heptane, and wherein the volume ratio of toluene and normal heptane is 1:4 ~ 8.
6. the preparation method of a kind of Pantoprazole Sodium nitrogen oxidation impurities as claimed in claim 5, is characterized in that, the volume ratio of described toluene and normal heptane is 1:6.
7. as the preparation method of a kind of Pantoprazole Sodium nitrogen oxidation impurities in claim 2,5-6 as described in any one, it is characterized in that, the mol ratio of the 2-chloromethyl-3,4-dimethoxypyridine hydrochloride of described step (1), 5-difluoro-methoxy-2-sulfydryl-1H-benzoglyoxaline and sodium hydroxide is 1:1.0 ~ 1.2:5 ~ 10.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111100115A (en) * | 2019-12-27 | 2020-05-05 | 北京新领先医药科技发展有限公司 | Method for preparing pantoprazole nitrogen oxide |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998040378A1 (en) * | 1997-03-07 | 1998-09-17 | A/S Gea Farmaceutisk Fabrik | Process for the preparation of 2-[[(2-pyridinyl)methyl]sulfinyl]-1h-benzimidazoles and novel compounds of use for such purpose |
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2015
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998040378A1 (en) * | 1997-03-07 | 1998-09-17 | A/S Gea Farmaceutisk Fabrik | Process for the preparation of 2-[[(2-pyridinyl)methyl]sulfinyl]-1h-benzimidazoles and novel compounds of use for such purpose |
Non-Patent Citations (3)
| Title |
|---|
| GANTA MADHUSUDHAN REDDY，ET AL.，: "Structural identification and characterization of potential impurities of pantoprazole sodium", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| 于锐: "双氧水体系选择性氧化硫醚的研究", 《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》 * |
| 徐宝财，等: "(R)-2-{[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基亚硫酰基}-1H-苯并咪唑的合成", 《有 机 化 学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111100115A (en) * | 2019-12-27 | 2020-05-05 | 北京新领先医药科技发展有限公司 | Method for preparing pantoprazole nitrogen oxide |
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Effective date of registration: 20200225 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Patentee after: Shandong Anxin Pharmaceutical Co., Ltd Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |