CN107652268A - The preparation method of 4 5-Hydroxyomeprazoles - Google Patents
The preparation method of 4 5-Hydroxyomeprazoles Download PDFInfo
- Publication number
- CN107652268A CN107652268A CN201710647903.2A CN201710647903A CN107652268A CN 107652268 A CN107652268 A CN 107652268A CN 201710647903 A CN201710647903 A CN 201710647903A CN 107652268 A CN107652268 A CN 107652268A
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- CN
- China
- Prior art keywords
- compound
- acid
- preparation
- omeprazole
- hydroxyomeprazoles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- XURCIPRUUASYLR-UHFFFAOYSA-N Cc1cnc(CSc2nc3cc(OC)ccc3[nH]2)c(C)c1OC Chemical compound Cc1cnc(CSc2nc3cc(OC)ccc3[nH]2)c(C)c1OC XURCIPRUUASYLR-UHFFFAOYSA-N 0.000 description 1
- RUGQJBJNYIHOIW-UHFFFAOYSA-O Cc1cnc(C[SH+](c2nc3cc(OC)ccc3[n]2C)=O)c(C)c1OC Chemical compound Cc1cnc(C[SH+](c2nc3cc(OC)ccc3[n]2C)=O)c(C)c1OC RUGQJBJNYIHOIW-UHFFFAOYSA-O 0.000 description 1
Classifications
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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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 present invention relates to a kind of impurity in medicine esomeprazole or Omeprazole technical field：The preparation method of 4 5-Hydroxyomeprazoles.Specifically include：Omeprazole thioether acids are hydrolyzed into demethylating, then phenolic hydroxyl group is protected with acetic anhydride, metachloroperbenzoic acid oxidizing sulfur ether, last hydrolyzed under basic conditions deacetylate, obtains target product.The present invention has that synthetic route is short, and easy to operate, gained impurity product purity is high, the features such as can be applied to Omeprazole and esomeprazole impurity research of the chemical standard product.
Description
Technical field：
The present invention relates to medicine Omeprazole and esomeprazole, more particularly to a kind of preparation side of 4- 5-Hydroxyomeprazoles
Method.
Technical background：
Esomeprazole (Esomeprazole) chemistry is entitled：5- methoxyl groups -2- [(S)-[(4- methoxyl group -3,5- diformazans
Base -2- pyridine radicals) methyl] sulfinyl] -1H- benzimidazoles, Cas No：161796-78-7, there is the chemistry shown in following formula
Structure：
Esomeprazole is a kind of proton pump inhibitor, by the H for suppressing parietal cell+/K+- ATP enzyme is divided to reduce hydrochloric acid in gastric juice
Secrete, prevent the formation of hydrochloric acid in gastric juice.Esomeprazole is researched and developed by AstraZeneca and in the multinational listing such as Sweden, the U.S., disappears for treating
Change bad, peptic ulcer, GERD and soft woods lattice syndrome.The formulation of domestic listing mainly has Esso beautiful at present
Draw azoles magnesium enteric coatel tablets, injection Esomeprazole sodium and esomeprazole capsulae enterosolubilis.
Reported according to patent WO2011140446, esomeprazole has following A, B, C, D, E, F and N- methyl Esso are beautiful to draw
Azoles totally 7 known impurities：
Wherein, compound F and compound G is the catabolite of esomeprazole, and mechanism of degradation is：Two molecule Essos are beautiful to be drawn
Azoles is degraded, and a molecule pyridine ring 4- positions methoxyl group takes off methyl, is transferred on the imidazoles N of another molecule, obtains 4- hydroxyls
Omeprazole and N- methyl esomeprazole impurity (referring to following formula).
Although patent WO2011140446 has delivered the structure of 4- 5-Hydroxyomeprazoles first, its preparation method is domestic
It is outer to there is no open report.
Because this degradation reaction generally occurs in esomeprazole preparation and storage process, therefore 4- hydroxyls Aomei is drawn
The Qualitative and quantitative analysis for the impurity that the correlative study of azoles impurity can be used in esomeprazole production, so as to rear
The quality research of continuous esomeprazole provides technical support, to improve the quality standard of esomeprazole, ensures the people
Safe medication has positive meaning.
The content of the invention
In order to solve the above technical problems, the invention provides a kind of preparation method of 4- 5-Hydroxyomeprazoles.
The present invention provides a kind of preparation method of 4- 5-Hydroxyomeprazoles (compound 1), and this method comprises the following steps：
(1) Omeprazole thioether (compound 2) is placed in aqueous acid and be stirred at reflux 12 hours, filtered, after water washing
Obtain demethylation thioether (compound 3).
(2) demethylation thioether (compound 3) is dissolved in acetic anhydride, heats 60 DEG C, reacted 3 hours.Decompression boils off solvent,
Product methanol-acetone recrystallization purifying.
(3) compound 4 is dissolved in chloroform, is cooled to 0 DEG C, oxidant is slowly added dropwise under stirring.After reaction completely, decompression
Boil off and be more than solvent, crude product direct plunges into the next step.
(4) compound 5 being dissolved in sodium hydrate aqueous solution, 40 DEG C of heating stirrings 2 hours, middle acetic acid is neutralized to pH=7-8,
Extracted with chloroform, decompression boils off chloroform, obtains crude product, then ethyl acetate/petroleum ether system silica gel column chromatography, obtains product and exist again
Recrystallized in acetone/petroleum ether, obtain target product (compound 1).
Further, the acid described in step (1) can be the one or several kinds in hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid
Mixed acid.Wherein preferred hydrochloric acid.
Further, the protection group reagent described in step (2) can be acetic anhydride or propionic andydride either phenylacetic acid
The one of which of acid anhydride.Wherein preferred acetic anhydride.
Further, the oxidant described in step (3) can be metachloroperbenzoic acid, hydrogen peroxide and sodium hypochlorite
One of which.Wherein preferred metachloroperbenzoic acid
Further, the preparation method of the 4- 5-Hydroxyomeprazoles (compound 1) described in step (3), it is characterised in that
The volume ratio of ethyl acetate and petroleum ether described in step (4) is 1:1.
Further, the preparation method of the 4- 5-Hydroxyomeprazoles (compound 1) described in step (3), it is characterised in that
The volume ratio of recrystallization solvent acetone and petroleum ether described in step (4) is 2:1.
Beneficial effects of the present invention are：
The invention provides the new method of compound shown in formula 1, this method is simple, and easily operation, products obtained therefrom are pure
Degree is high, up to more than 99.5%, can be used directly to make impurity reference substance.
Brief description of the drawings
Accompanying drawing 1 is the chromatogram of 4- 5-Hydroxyomeprazoles prepared by this method.
Embodiment：
With embodiment, the invention will be further described below, but the invention is not limited in the present embodiment.
Embodiment
Take Omeprazole 13g to be placed in 250ml three-neck flasks, add 25% aqueous hydrochloric acid solution, oil bath stirring is warming up to back
Stream.Reaction 12 hours, TLC displays react complete, stop reaction, filter reactant, and it is in neutrality that filter cake, which is washed with water to solid,
Dry filter cake product.The product after drying, it is added in 100ml single-necked flasks, stirring adds 50ml acetic anhydride, and heating is anti-
Should be to 60 DEG C, after reacting 4 hours, decompression rotation removes unnecessary acetic anhydride, product methanol-acetone (1:1) recrystallization purifying.
Compound 4 is dissolved with chloroform-methanol, stirring is cooled to 0 DEG C, 11g metachloroperbenzoic acid chloroformic solutions is slowly added dropwise, instead
Answer 2 hours, TLC detections reaction is to close to reaction completely, is stopped, and decompression is boiled off more than solvent, and it is anti-that crude product direct plunges into lower step
Should.
Compound 5 is dissolved in sodium hydrate aqueous solution, 40 DEG C of heating stirrings 2 hours, middle acetic acid is neutralized to pH=7-8, uses
Chloroform extracts, and decompression boils off chloroform, obtains crude product, then ethyl acetate/petroleum ether (1：1) system silica gel column chromatography, product is obtained again
Recrystallized in acetone/petroleum ether, obtain target product 3g (compound 1), HPLC detection chemical purities 99.2%.
Claims (6)
1. a kind of preparation method of 4- 5-Hydroxyomeprazoles, it is characterised in that comprise the following steps：
(1) Omeprazole thioether (compound 2) is placed in aqueous acid and be stirred at reflux 12 hours, filtered, obtained after water washing
Demethylation thioether (compound 3).
(2) demethylation thioether (compound 3) is dissolved in acetic anhydride, heats 60 DEG C, reacted 3 hours.Decompression boils off solvent, product
With methanol-acetone recrystallization purifying.
(3) 4- acetoxyl group Omeprazole thioethers (compound 4) are dissolved in chloroform, are cooled to 0 DEG C, oxygen is slowly added dropwise under stirring
Agent.After reaction completely, decompression boils off direct plunges into the next step more than solvent, crude product.
(4) 4- acetoxyl groups Omeprazole (compound 5) is dissolved in sodium hydrate aqueous solution, 40 DEG C of heating stirrings 2 hours, middle vinegar
Acid is neutralized to pH=7-8, is extracted with chloroform, and decompression boils off chloroform, obtains crude product, then ethyl acetate/petroleum ether system silica gel column layer
Analysis, obtains product and is recrystallized again in acetone/petroleum ether, obtain target product (compound 1).
The route that chemically reacts is as follows：
2. the preparation method of 4- 5-Hydroxyomeprazoles thioether (compound 3) according to claim 1, it is characterised in that step
Suddenly the acid described in (1) can be one or several kinds of mixed acid in hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
3. the preparation method of 4- acetoxyl groups Omeprazole thioether (compound 4) according to claim 1, its feature exist
In the protection group reagent described in step (2) can be the one of which of acetic anhydride or propionic andydride either phenylacetic anhydride.
4. the preparation method of 4- acetoxyl groups Omeprazole (compound 5) according to claim 1, it is characterised in that step
Suddenly the oxidant described in (3) can be the one of which of metachloroperbenzoic acid, hydrogen peroxide and sodium hypochlorite.
5. the preparation method of 4- 5-Hydroxyomeprazoles (compound 1) according to claim 1, it is characterised in that step (4)
Described in ethyl acetate and petroleum ether volume ratio be 1:1.
6. the preparation method of 4- 5-Hydroxyomeprazoles (compound 1) according to claim 1, it is characterised in that step (4)
Described in recrystallization solvent acetone and petroleum ether volume ratio be 2:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710647903.2A CN107652268A (en) | 2017-08-01 | 2017-08-01 | The preparation method of 4 5-Hydroxyomeprazoles |
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| CN201710647903.2A CN107652268A (en) | 2017-08-01 | 2017-08-01 | The preparation method of 4 5-Hydroxyomeprazoles |
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| CN107652268A true CN107652268A (en) | 2018-02-02 |
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| CN201710647903.2A Pending CN107652268A (en) | 2017-08-01 | 2017-08-01 | The preparation method of 4 5-Hydroxyomeprazoles |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358439A (en) * | 2020-11-26 | 2021-02-12 | 成都百泉生物医药科技有限公司 | Omeprazole process impurity and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999063940A3 (en) * | 1998-06-08 | 2001-06-07 | Advanced Medicine Inc | INHIBITORS OF H+K+-ATPase |
-
2017
- 2017-08-01 CN CN201710647903.2A patent/CN107652268A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999063940A3 (en) * | 1998-06-08 | 2001-06-07 | Advanced Medicine Inc | INHIBITORS OF H+K+-ATPase |
Non-Patent Citations (1)
| Title |
|---|
| PHARMACOPOEIALIMPURITIESSUSHANT BHIMRAO JADHAV, ET AL.: "Development of RP UPLC-TOF/MS, stability indicating method for omeprazole and its related substances by applying two level factorial design factorialdesign; and identification and synthesis of non-pharmacopoeial impurities", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358439A (en) * | 2020-11-26 | 2021-02-12 | 成都百泉生物医药科技有限公司 | Omeprazole process impurity and preparation method thereof |
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Application publication date: 20180202 |