CN111100115A - Method for preparing pantoprazole nitrogen oxide - Google Patents
Method for preparing pantoprazole nitrogen oxide Download PDFInfo
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- CN111100115A CN111100115A CN201911374723.7A CN201911374723A CN111100115A CN 111100115 A CN111100115 A CN 111100115A CN 201911374723 A CN201911374723 A CN 201911374723A CN 111100115 A CN111100115 A CN 111100115A
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- nitrogen oxide
- pantoprazole
- difluoromethoxy
- benzimidazole
- oily substance
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- 229960005019 pantoprazole Drugs 0.000 title claims abstract description 50
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 21
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title claims description 89
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- HJMVPNAZPFZXCP-UHFFFAOYSA-N 5-(difluoromethoxy)-1,3-dihydrobenzimidazole-2-thione Chemical compound FC(F)OC1=CC=C2NC(=S)NC2=C1 HJMVPNAZPFZXCP-UHFFFAOYSA-N 0.000 claims abstract description 10
- YYRIKJFWBIEEDH-UHFFFAOYSA-N 2-(chloromethyl)-3,4-dimethoxypyridine;hydrochloride Chemical compound [Cl-].COC1=CC=[NH+]C(CCl)=C1OC YYRIKJFWBIEEDH-UHFFFAOYSA-N 0.000 claims abstract description 9
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 7
- XYYYTUCWSSREHK-UHFFFAOYSA-N N1=CC=CC=C1.[N]=O Chemical compound N1=CC=CC=C1.[N]=O XYYYTUCWSSREHK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000003647 oxidation Effects 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- -1 pantoprazole nitroxide Chemical class 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- ZWFCXDBCXGDDOM-UHFFFAOYSA-N 2-(chloromethyl)-3,4-dimethoxypyridine Chemical compound COC1=CC=NC(CCl)=C1OC ZWFCXDBCXGDDOM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003759 ester based solvent Substances 0.000 claims description 2
- 239000004210 ether based solvent Substances 0.000 claims description 2
- 239000005453 ketone based solvent Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 33
- 230000001738 genotoxic effect Effects 0.000 abstract description 11
- 231100000024 genotoxic Toxicity 0.000 abstract description 10
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 description 21
- 239000003814 drug Substances 0.000 description 15
- 229940079593 drug Drugs 0.000 description 11
- 229960004048 pantoprazole sodium Drugs 0.000 description 9
- 239000013558 reference substance Substances 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000012827 research and development Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000002574 poison Substances 0.000 description 3
- 231100000614 poison Toxicity 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002500 ions Chemical group 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000007939 sustained release tablet Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 101150044508 key gene Proteins 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a preparation method of Pantoprazole (Pantoprazole) oxynitride, which is realized by the following steps: 2-chloromethyl-3, 4-dimethoxy pyridine hydrochloride is used as a raw material to react with m-chloroperoxybenzoic acid, and pyridine nitrogen oxide is prepared by oxidation; the pyridine nitrogen oxide reacts with 5-difluoromethoxy-2-mercapto-1H-benzimidazole to generate 5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridyl) methyl ] thio-1H-benzimidazole nitrogen oxide. The genotoxic impurity pantoprazole sodium sesquihydrate pantoprazole oxide is prepared by an economic and green method, the operation is simple and convenient, the condition is mild, and the product purity is high.
Description
Technical Field
The invention provides a preparation method of Pantoprazole (Pantoprazole) oxynitride. The method comprises the steps of reacting 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride with 5-difluoromethoxy-2-mercapto-1H-benzimidazole after salt decomposition and oxidation to generate 5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridyl) methyl ] thio-1H-benzimidazole oxynitride.
Background
Pantoprazole sodium sesquihydrate (Pantoprazole sodium sesquihydrate) with the chemical name 5- (difluoromethoxy) -2- [ [ (3, 4-dimethoxy-2-pyridyl) methyl ] benzenesulfinyl ] -1H-benzimidazole sodium and the chemical structural formula is as follows:
pantoprazole sodium is a drug developed by the pharmaceutical works becton, germany for the treatment of gastrointestinal ulcers, a third proton pump inhibitor following omeprazole and lansoprazole. The oral sustained-release tablet is firstly marketed in south Africa in 1994, is approved to be marketed by FDA in 2 months of 2000, and is applied to Wyeth pharmaceutical company Limited, and is in a dosage form of oral sustained-release tablets. The product is currently approved to be marketed in more than 20 countries such as the United states, the United kingdom, Germany and the like. The impurities of pantoprazole sodium included in the united states and european pharmacopoeias are respectively A, B, C, D + F and E, and the chinese pharmacopoeias only include impurities for oxidative degradation.
Based on the general rule of the current consistency evaluation work, the quality control of the bulk drug has a direct influence on the safety of the drug. The research on the gene poison impurities is more and more emphasized by research and development mechanisms and drug production enterprises as one of important components in quality research work, so the gene poison impurities possibly existing in the pantoprazole sodium sesquihydrate raw material drug are analyzed according to the preparation process route (Scheme1) of the pantoprazole sodium sesquihydrate supplied by the current market, and the key gene poison impurities of the pantoprazole sodium sesquihydrate are synthesized by adopting a preparation process which is simple, convenient and feasible in a laboratory, economic and environment-friendly.
Route to pantoprazole sodium sesquihydrate (Scheme 1):
and (3) carrying out a condensation reaction on 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride and 5-difluoromethoxy-2-mercapto-1H-benzimidazole to obtain a thioether intermediate, and oxidizing and salifying to prepare the pantoprazole sodium sesquihydrate.
The potential damage effect of genotoxic impurities on DNA is ensured, potential genotoxic impurities in the pantoprazole sodium process are analyzed to ensure the safety of the medicine, according to the warning structure of genotoxic impurities published by Maliei of the national food and drug administration and drug evaluation center in the New drug journal of China, N atom of pyridine ring in the pantoprazole sodium structure can generate oxidation reaction in the oxidation reaction step to generate pantoprazole nitrogen oxide (shown in the following structural formula), and the compound belongs to genotoxic substances. Based on the requirements of the current national imitation drug research and development on genotoxic impurities, the impurities can not exceed 18ppm according to the calculation method of the maximum daily dose of the ICHM7 on the genotoxicity warning structure. Therefore, the research and evaluation on the impurities are particularly important for ensuring the safety of the pantoprazole sodium raw material medicine.
The 6 known impurities of pantoprazole sodium sesquihydrate, as reported in USP40.0 and EP9.0, are: the impurities of the Chinese pharmacopoeia 2015 version of the Chinese pharmacopoeia are impurity A, impurity B, impurity C, impurity D, impurity E and impurity F, and the detailed structure is shown in scheme 2. The pharmacopoeia does not stipulate pantoprazole nitrogen oxide detection, but as genotoxic impurities, an effective method for detection and the content reduction as much as possible in the synthesis process are urgently needed.
The acquisition way of the impurity reference substance has obvious influence on the development of quality research and the control of the cost of drug research and development, particularly, the generated impurities are measured under certain process conditions, and the conventional column chromatography or crystallization and preparation liquid phase separation preparation usually needs large investment of manpower and material resources, so that the manpower and resource cost is greatly increased, the unit or time limit cannot be guaranteed through the impurity reference substance, or the research and development cost is greatly increased. The invention provides an efficient and green preparation method aiming at the current situation, which has the problems of difficult preparation or low yield of some impurity reference substances, great difficulty in obtaining high-purity reference substances, no particularly good preparation method for pantoprazole nitrogen oxide and difficulty in meeting the reference substance requirement in consistency evaluation.
Disclosure of Invention
The invention aims to prepare the genotoxic impurity pantoprazole nitrogen oxide of the pantoprazole sodium sesquihydrate by an economic and green method, and has the advantages of simple and convenient operation, mild conditions and high product purity.
Based on the cognition of the pantoprazole sodium preparation process, a method which is simple, convenient and easy to implement and can obtain the impurity reference substance with high purity is designed, and a specific reaction route is shown in Scheme 3:
a method for preparing pantoprazole nitrogen oxide is realized according to the following steps:
(1) 2-chloromethyl-3, 4-dimethoxy pyridine hydrochloride is used as a raw material to react with m-chloroperoxybenzoic acid, and pyridine nitrogen oxide is prepared by oxidation;
(2) the pyridine nitrogen oxide reacts with 5-difluoromethoxy-2-mercapto-1H-benzimidazole to generate 5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridyl) methyl ] thio-1H-benzimidazole nitrogen oxide.
Further, the method comprises the following steps:
the preparation method of the pantoprazole nitrogen oxide is characterized by comprising the following steps of:
(1) adding 2-chloromethyl-3, 4-dimethoxy pyridine hydrochloride and sodium hydroxide aqueous solution into a reaction container, stirring for 30 minutes, standing and layering to obtain an oily substance;
(2) dissolving the light yellow oily substance obtained in the step (1) by using a solvent, cooling to a certain temperature, adding m-chloroperoxybenzoic acid, keeping the temperature, stirring and reacting for 2 hours, adding a sodium metabisulfite aqueous solution after the reaction is finished, washing, separating, and distilling a dichloromethane phase under reduced pressure to obtain a brown oily substance;
(3) dissolving the brown oily substance obtained in the step (2) by using a solvent, adding 5-difluoromethoxy-2-mercapto-1H-benzimidazole, adding a sodium hydroxide aqueous solution at 0-10 ℃, and reacting for 2 hours at 0-10 ℃; after the reaction is finished, adjusting the pH value to about 6, crystallizing for 2 hours at 0-10 ℃, and performing suction filtration to obtain pantoprazole nitrogen oxide; refining with organic solvent to obtain white powder.
The preparation method of the pantoprazole nitrogen oxide is characterized in that the reaction temperature in the step (2) is-30-40 ℃, wherein the preferable temperature is-10-20 ℃, and the most preferable temperature is 0-10 ℃;
the preparation method of the pantoprazole nitrogen oxide is characterized in that in the step (2), the molar ratio of the oxidizing agent m-chloroperoxybenzoic acid to the 2-chloromethyl-3, 4-dimethoxypyridine is 0.5-5: 1, preferably 0.9 to 2.0: 1, most preferably 1.5 to 2.0: 1;
the preparation method of the pantoprazole nitrogen oxide is characterized in that the refining solvent in the step (3) is one or a mixture of several of C3-C10 ketone solvents, ether solvents and ester solvents. Among them, C3-C10 ketones are preferable, and acetone and methyl ethyl ketone are most preferable.
Advantageous effects
1. The innovation points of the invention are as follows:
the research of genotoxic impurities is important for evaluating the safety of medicines, and relates to the medicine safety of patients. The invention emphatically researches the preparation process of the pantoprazole nitrogen oxide which is possibly genotoxic impurity in the pantoprazole sodium raw material medicine, designs the simple and easy preparation process route of the pantoprazole sodium nitrogen oxide by utilizing the structural characteristics of the starting material used in the pantoprazole sodium preparation process, avoids the conventional laboratory enriched impurity sample, obtains the impurity reference substance by means of column chromatography or preparation liquid and the like, greatly saves the production cost and improves the acquisition cheapness of the impurity reference substance.
2. The 2-chloromethyl-3, 4-dimethoxy pyridine nitrogen oxide is obtained by oxidation through a simple and feasible oxidation method, then condensed with 5-difluoromethoxy-2-mercapto-1H-benzimidazole, and refined to obtain the pantoprazole nitrogen oxide with higher purity, and the preparation method is simple, convenient and operated. The key steps of the process route are preparation of nitrogen oxides, and the selection of reaction temperature and oxidant has great influence on the purity and yield of the product.
3. The synthesized pantoprazole nitrogen oxide can be used for qualitative and quantitative analysis of pantoprazole sodium sesquihydrate impurities, the limit of the impurities in the pantoprazole sodium sesquihydrate is controlled according to the requirements of ICH M7, and the safety of raw material medicines is ensured.
4. The prior art can know that the pantoprazole nitrogen oxide can only be separated in the preparation process of pantoprazole sodium, and the method has high separation difficulty and high cost, so that the synthesis mode is adopted to meet the market demand; the method has no literature report, the company develops the route for the first time, the route is green and high in yield, the difficulty of acquiring impurities of research and development units is reduced, and enterprises are helped to save research and development cost.
Drawings
FIG. 1 is an MS spectrum of pantoprazole nitroxide obtained in example 1; wherein A is a positive ion signal spectrogram and B is a negative ion signal spectrogram.
FIG. 2 is an HPLC chromatogram of pantoprazole nitroxide obtained in example 1.
FIG. 3 shows the preparation of pantoprazole nitroxide obtained in example 11H-NMR spectrum.
FIG. 4 shows the preparation of pantoprazole nitroxide obtained in example 113C-NMR spectrum.
Detailed Description
Example 1
(1) Adding 20% sodium hydroxide compound (10ml, 5mmol) into a 25ml reaction bottle, adding 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride (1g, 4.4mmol), stirring for 30 min, standing for layering, discarding the upper aqueous phase, and keeping the lower yellowish oily substance;
(2) and (2) dissolving the oily substance in the step (1) by using dichloromethane (20ml), cooling to 2 ℃, adding m-chloroperoxybenzoic acid (1.5g, 7.4mmol) in batches, and reacting for 2 hours at 0-10 ℃ after the addition is finished. After the reaction, the reaction solution was washed with sodium metabisulfite solution and separated into layers. The dichloromethane was distilled off under reduced pressure to obtain a brown oil;
(3) adding methanol (20ml) into the brown oily substance in the step (2), stirring to dissolve, adding 5-difluoromethoxy-2-mercapto-1H-benzimidazole, cooling to 0-10 ℃, adding 20% sodium hydroxide aqueous solution (22ml), and reacting for 2 hours at 0-10 ℃ after the addition is finished. After the reaction is finished, adjusting the pH value to be 6, crystallizing for 2 hours at 0-10 ℃, performing suction filtration to obtain a pantoprazole nitrogen oxide crude product, and drying to obtain 1.60g of white-like powder with the yield of 94.7%.
(4) And (3) adding the pantoprazole nitrogen oxide crude product (500mg) obtained in the step (3) into 20ml of acetonitrile, heating to dissolve, cooling to 20-30 ℃, stirring and crystallizing for 1 hour, performing suction filtration, and drying to obtain a pantoprazole nitrogen oxide refined product 435mg, wherein the yield is 87.0%, the purity is 99.97%, and the mass spectrogram is shown in fig. 1A and B.
Example 2
(1) Adding 10% potassium carbonate aqueous solution (10ml) into a 25ml reaction bottle, adding 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride (0.5g, 2.2mmol), stirring for 30 minutes, standing for layering, removing an upper aqueous phase, and keeping a lower yellowish oily substance;
(2) dissolving the oily substance in the step (1) by using tetrahydrofuran (15ml), cooling to 5 ℃, adding m-chloroperoxybenzoic acid (0.8g, 3.9mmol) in batches, and reacting for 2 hours at 0-10 ℃ after the addition is finished. After the reaction, the reaction solution was washed with a sodium thiosulfate solution and separated into layers. Distilling off tetrahydrofuran under reduced pressure to obtain light yellow oily matter;
(3) adding tetrahydrofuran (15ml) into the light yellow oily substance in the step (2), stirring to dissolve, adding 5-difluoromethoxy-2-mercapto-1H-benzimidazole, adding 20% sodium hydroxide aqueous solution (11ml), and reacting for 2 hours at 20-30 ℃. After the reaction is finished, adjusting the pH value to 6, cooling to 0-10 ℃, crystallizing for 2 hours, performing suction filtration to obtain a pantoprazole nitrogen oxide crude product, and drying to obtain 0.77g of white-like powder, wherein the yield is 91.7%, and the purity is 99.53%.
(4) And (3) adding the pantoprazole nitrogen oxide crude product (500mg) obtained in the step (3) into 10ml of acetone, pulping for 1 hour at the temperature of 20-30 ℃, filtering, and drying to obtain a pantoprazole nitrogen oxide refined product 462mg, wherein the yield is 92.4%, and the purity is 99.56%.
Claims (6)
1. A method for preparing pantoprazole nitrogen oxide is characterized by comprising the following steps:
(1) 2-chloromethyl-3, 4-dimethoxy pyridine hydrochloride is used as a raw material to react with m-chloroperoxybenzoic acid, and pyridine nitrogen oxide is prepared by oxidation;
(2) the pyridine nitrogen oxide reacts with 5-difluoromethoxy-2-mercapto-1H-benzimidazole to generate 5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridyl) methyl ] thio-1H-benzimidazole nitrogen oxide.
2. The method for preparing pantoprazole nitrogen oxide according to claim 1, which comprises the following steps:
(1) mixing 2-chloromethyl-3, 4-dimethoxy pyridine hydrochloride with an aqueous solution of sodium hydroxide, stirring for 30 minutes, standing for layering to obtain an oily substance;
(2) dissolving the light yellow oily substance obtained in the step (1) by using a solvent, cooling, adding m-chloroperoxybenzoic acid, keeping the temperature, stirring and reacting for 2 hours, adding a sodium metabisulfite aqueous solution after the reaction is finished, washing, separating, and carrying out reduced pressure distillation on a dichloromethane phase to obtain a brown oily substance;
(3) dissolving the brown oily substance obtained in the step (2) by using a solvent, adding 5-difluoromethoxy-2-mercapto-1H-benzimidazole, adding a sodium hydroxide aqueous solution at 0-10 ℃, and reacting for 2 hours at 0-10 ℃; after the reaction is finished, adjusting the pH value to about 6, crystallizing for 2 hours at 0-10 ℃, and performing suction filtration to obtain pantoprazole nitrogen oxide; refining with organic solvent to obtain white powder.
3. The method for preparing pantoprazole nitrogen oxide according to claim 2, wherein the reaction temperature in the step (2) is-30 to 40 ℃.
4. The preparation method of pantoprazole nitrogen oxide according to claim 2, wherein the molar ratio of the oxidizing agent m-chloroperoxybenzoic acid to 2-chloromethyl-3, 4-dimethoxypyridine in the step (2) is 0.5-5: 1.
5. the method for preparing pantoprazole nitrogen oxide according to claim 2, wherein the refined organic solvent in step (3) is one or a mixture of several of C3-C10 ketone solvents, ether solvents and ester solvents.
6. The method for preparing pantoprazole nitroxide of claim 5, wherein the refining organic solvent is acetone or butanone.
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| CN201911374723.7A CN111100115A (en) | 2019-12-27 | 2019-12-27 | Method for preparing pantoprazole nitrogen oxide |
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| CN201911374723.7A CN111100115A (en) | 2019-12-27 | 2019-12-27 | Method for preparing pantoprazole nitrogen oxide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114989046A (en) * | 2022-06-22 | 2022-09-02 | 苏州开元民生科技股份有限公司 | Synthetic method of dapoxetine oxidized impurities |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105111186A (en) * | 2015-08-07 | 2015-12-02 | 齐鲁天和惠世制药有限公司 | Method for preparing pantoprazole sodium sulfone-nitrogen oxidized impurity |
| CN105111187A (en) * | 2015-08-07 | 2015-12-02 | 齐鲁天和惠世制药有限公司 | Preparation method for pantoprazole sodium oxynitride impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105111186A (en) * | 2015-08-07 | 2015-12-02 | 齐鲁天和惠世制药有限公司 | Method for preparing pantoprazole sodium sulfone-nitrogen oxidized impurity |
| CN105111187A (en) * | 2015-08-07 | 2015-12-02 | 齐鲁天和惠世制药有限公司 | Preparation method for pantoprazole sodium oxynitride impurity |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114989046A (en) * | 2022-06-22 | 2022-09-02 | 苏州开元民生科技股份有限公司 | Synthetic method of dapoxetine oxidized impurities |
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