CN108358849A - A kind of synthetic method of Azilsartan process contaminants D - Google Patents
A kind of synthetic method of Azilsartan process contaminants D Download PDFInfo
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- CN108358849A CN108358849A CN201810241851.3A CN201810241851A CN108358849A CN 108358849 A CN108358849 A CN 108358849A CN 201810241851 A CN201810241851 A CN 201810241851A CN 108358849 A CN108358849 A CN 108358849A
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- Prior art keywords
- azilsartan
- synthetic method
- process contaminants
- acid
- organic solvent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
Abstract
The invention discloses provide a kind of synthetic method of Azilsartan process contaminants D.Using Azilsartan methyl esters A1 as raw material, ethyl is taken off in acid condition and generates intermediate A 2, intermediate A 2 generates intermediate A 3 through hydrolysis, and A3 obtains target product impurity D with azanol reaction again.The synthetic route for devising Azilsartan process contaminants D, successfully to obtain Azilsartan impurity D in high yield.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of synthetic method of Azilsartan process contaminants D.
Background technology
Azilsartan (Azilsartan) is angiotensin II receptor antagonist (the husky smooth class) medicine for treating vascular hypertension
Object is researched and developed by Japanese Takeda Pharmaceutical Company Limited (Takeda) and completes phase iii clinical trial, obtains within 2012 U.S. FDA batch for 2010
It is accurate.
The synthesis technology of Azilsartan is as follows：
In Azilsartan synthesis technology, in the building-up process by intermediate B 2 to B3, if esterification is incomplete, B2 compares
It is easy to generate the hydrolysing step generation impurity E for taking final step to
Impurity E, which is easy to slough ethyl in the acidification step of Azilsartan, just produces impurity D.Impurity D can finally influence
The quality of azilsartan crude drug, thus the reference substance of impurity D is needed to carry out technology controlling and process.It is molten since the polarity of impurity D is larger
Solution property is poor, and final product is difficult the reference substance that enriching and purifying obtains purer impurity D.It is then desired to using direct synthesis technique, take
To qualified impurity reference substance D.
Invention content
In order to obtain qualified impurity reference substance, the present invention provides a kind of synthetic methods of Azilsartan process contaminants D.
The synthetic route for devising Azilsartan process contaminants D, successfully to obtain Azilsartan impurity D in high yield.
It is water-soluble big since solubility is poor after Azilsartan decoquinate, so will be taken off as possible in compounding design
Ethyoxyl reacts step progress of putting behind.Impurity D contains a carboxylic acid group simultaneously, and hydroxyl oxime is to acid less stable, because
This purifies and separates cannot use conventional separation methods to carry out.
Based on above-mentioned design philosophy, the technical solution adopted by the present invention is：
A kind of synthetic method of Azilsartan process contaminants D takes off in acid condition using Azilsartan methyl esters A1 as raw material
Ethyl generates intermediate A 2, and intermediate A 2 generates intermediate A 3 through hydrolysis, and A3 obtains target product impurity D with azanol reaction again.
Process route is as follows：
Further, include the following steps：
(1) Azilsartan methyl esters A1 is dissolved in organic solvent, takes off ethyl in acid condition and generates intermediate A 2；
(2) intermediate A 2 is dissolved in organic solvent, adds alkali, reacted 6-20h, be spin-dried for, add water, then acid adding tune pH value, generated
Intermediate A 3；
(3) intermediate A 3 is dissolved in organic solvent, azanol and alkali is added, the reaction was complete, is evaporated under reduced pressure, separation, and freezing is dry
It is dry to obtain product impurity D.
Azanol in the present invention can be azanol or hydroxylamine hydrochloride.
Preferably, the organic solvent in described (1) step is selected from methanol, ethyl alcohol or tetrahydrofuran, increases solubility again
It prevents from intersecting esterification.
Preferably, the acid condition of (1) step reaction refers to that pH value is less than 1.At this ph, it is completeer to take off ethyl
Entirely, and cyan-hydrolysis is prevented.
It is further preferred that acid used is selected from hydrochloric acid, hydrobromic acid or hydroiodic acid, good reaction selectivity, by-product is few, excellent
Select hydrochloric acid.
Preferably, the alkali in described (2) step is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
Carboxylate after hydrolysis is become acid by (2) step elder generation alkaline hydrolysis, then acid adding tune pH value to 2-4.The addition of alkali
For 2 times of equivalents of intermediate A 2.
Preferably, the alkali in described (3) step is selected from triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, hydroxide
Sodium or potassium hydroxide.
For neutralizing the carboxylic acid in hydrochloric acid and intermediate A 3 in hydroxylamine hydrochloride, releases azanol and participate in reaction.
It is further preferred that the alkali in described (3) step is selected from triethylamine.Triethylamine it is fat-soluble good, reaction homogeneously into
Row, reaction speed are fast.
Preferably, the organic solvent in described (3) step is selected from methanol, ethyl alcohol, isopropanol, dimethyl sulfoxide or N, N- bis-
Methylformamide.These solvents are all relatively good to the solubility of hydroxylamine hydrochloride and alkali, can accelerate the progress of hydroxyl oximation reaction.
Preferably, the separation method of described (3) step is that distilled water is added in the residue of vacuum distillation, is prepared through C18
Liquid chromatogram post separation.
Hydroxyl oxime cannot use conventional separation methods to acid less stable, purifies and separates.The present invention uses C18 reversed-phase columns,
Big polarity can be easily separated, and conventional method needs solution adjusting pH to stronger acid extraction and separation again, at this moment in product
Hydroxyl oxime easily decompose.And solution need not be then transferred to using C18 reverse phases post separation by acidity, it can directly upper post separation.
Azilsartan process contaminants D is in the building-up process due to intermediate B 2 to B3, and esterification is incomplete, and B2 is easier
The hydrolysing step generation impurity E for taking final step to is generated, impurity E is easy to slough in the acidification step of Azilsartan ethyl just
Produce impurity D.Azilsartan impurity D has important reference value for synthesising process research and quality research.The present invention
The synthetic route for devising Azilsartan process contaminants D, successfully to obtain Azilsartan impurity D in high yield.
Specific implementation mode
In order to it is clearer, explain purpose of the present invention technical solution in detail, below by related embodiment to this hair
It is bright to be described further.Following embodiment is only to illustrate the implementation of the present invention, does not limit the protection of the present invention
Range.
Embodiment 1
A kind of synthetic method of Azilsartan process contaminants D takes off in acid condition using Azilsartan methyl esters A1 as raw material
Ethyl generates intermediate A 2, and intermediate A 2 generates intermediate A 3 through hydrolysis, and A3 obtains target product impurity D with azanol reaction again.
Embodiment 2
A kind of synthetic method of Azilsartan process contaminants D, includes the following steps：
(1) Azilsartan methyl esters A1 is dissolved in organic solvent, takes off ethyl in acid condition and generates intermediate A 2；
(2) intermediate A 2 is dissolved in organic solvent, adds alkali, reacted 8h, be spin-dried for, add water, then acid adding tune pH value, generated intermediate
Body A3；
(3) intermediate A 3 is dissolved in organic solvent, azanol and alkali is added, the reaction was complete, is evaporated under reduced pressure, separation, and freezing is dry
It is dry to obtain product impurity D.
Embodiment 3
The present embodiment is on the basis of embodiment 2：
The separation method of described (3) step is that distilled water is added in the residue of vacuum distillation, and liquid phase color is prepared through C18
Compose post separation.
Embodiment 4
The present embodiment is on the basis of embodiment 2：
Organic solvent in described (1) step is selected from methanol.
The acid condition of described (1) step reaction refers to that pH value is less than 1, and acid used is selected from hydrochloric acid.
Alkali in described (2) step is selected from sodium carbonate.
Alkali in described (3) step is selected from triethylamine.
Organic solvent in described (3) step is selected from methanol.
Embodiment 5
The present embodiment is on the basis of embodiment 2：
Organic solvent in described (1) step is selected from ethyl alcohol.
The acid condition of described (1) step reaction refers to that pH value is less than 1, and acid used is selected from hydrobromic acid.
Alkali in described (2) step is selected from potassium carbonate.
Alkali in described (3) step is selected from diisopropylethylamine.
Organic solvent in described (3) step is selected from ethyl alcohol.
Embodiment 6
The present embodiment is on the basis of embodiment 2：
Organic solvent in described (1) step is selected from tetrahydrofuran.
The acid condition of described (1) step reaction refers to that pH value is less than 1, and acid used is selected from hydroiodic acid.
Alkali in described (2) step is selected from sodium hydroxide.
Alkali in described (3) step is selected from sodium carbonate.
Organic solvent in described (3) step is selected from isopropanol.
Embodiment 7
The present embodiment is on the basis of embodiment 2：
Organic solvent in described (1) step is selected from methanol.
The acid condition of described (1) step reaction refers to that pH value is less than 1, and acid used is selected from hydrochloric acid.
Alkali in described (2) step is selected from potassium hydroxide.
Alkali in described (3) step is selected from potassium carbonate.
Organic solvent in described (3) step is selected from dimethyl sulfoxide.
Embodiment 8
The present embodiment is on the basis of embodiment 2：
Organic solvent in described (1) step is selected from ethyl alcohol.
The acid condition of described (1) step reaction refers to that pH value is less than 1, and acid used is selected from hydrobromic acid.
Alkali in described (2) step is selected from sodium carbonate.
Alkali in described (3) step is selected from sodium hydroxide.
Organic solvent in described (3) step is selected from N,N-dimethylformamide.
The separation method of described (3) step is that distilled water is added in the residue of vacuum distillation, and liquid phase color is prepared through C18
Compose post separation.
Embodiment 9
The present embodiment is on the basis of embodiment 2：
Organic solvent in described (1) step is selected from tetrahydrofuran.
The acid condition of described (1) step reaction refers to that pH value is less than 1, and acid used is selected from hydroiodic acid.
Alkali in described (2) step is selected from sodium hydroxide.
Alkali in described (3) step is selected from potassium hydroxide.
Organic solvent in described (3) step is selected from methanol.
The separation method of described (3) step is that distilled water is added in the residue of vacuum distillation, and liquid phase color is prepared through C18
Compose post separation.
Embodiment 10
The synthesis of A2
In 500ml round-bottomed flasks, 2g raw material As 1 are dissolved in 100ml methanol, concentrated hydrochloric acid 10ml is added, is stirred at room temperature down 12
Hour, the reaction was complete, boils off methanol, and water 60ml is added, and water phase is extracted with ethyl acetate 100ml, anhydrous sodium sulfate drying, concentration,
Obtain white solid 1.72g, yield 92.4%, purity 97.3%.
1HNMR(DMSO-d6)11.5
(1H,s),7.94(1H,d),7.91-7.76(1H,m),7.74-7.48(4H,m),7.26-7.14(2H,m),
7.11-7.07(4H,m),5.33(2H,s),3.64(3H,s).
LC-MS,cal M(383.1)found 384.2(M+H)
Embodiment 11
The synthesis of A2
In 500ml round-bottomed flasks, 2g raw material As 1 are dissolved in 100ml ethyl alcohol, hydrobromic acid 10ml are added, 50 DEG C, stirring 7 is small
When the reaction was complete, boil off methanol and ethanol, water 60ml be added, water phase is extracted with ethyl acetate 100ml, anhydrous sodium sulfate drying, concentration,
Obtain white solid 1.65g, yield 88.7%, purity 95.3%.
Embodiment 12
The synthesis of A3
In 500ml round-bottomed flasks, 4g intermediate As 2 are dissolved in 80ml methanol, are added with stirring 40mlNaOH (10%),
50 DEG C are reacted 6 hours, are spin-dried for methanol, are added water 50ml, and with dilute HCl tune pH to 2-3, white solid generates, and filters, with a small amount of water
Washing, is dried in vacuo to obtain 3.46g, yield 89.7%, purity 96.2%.
1HNMR(DMSO-d6)13.1(1H,s),11.5(1H,s),7.94(1H,d),7.76-7.60(1H,m),7.58-
7.48(4H,m),7.35-7.32(1H,m),7.24-7.16(3H,m),709-7.06(1H,m),5.47(2H,s).
LC-MS,cal M(369.1)found 369.2(M+H)
Embodiment 13
The synthesis of A3
In 500ml round-bottomed flasks, 4g intermediate As 2 are dissolved in 80ml isopropanols, are added with stirring 40mlKOH (10%),
70 DEG C are reacted 8 hours, are spin-dried for isopropanol, are added water 50ml, and with dilute HCl tune PH to 2-3, white solid generates, and filters, with a small amount of
Water washing is dried in vacuo to obtain 3.23g, yield 83.9%, purity 94%.
Embodiment 14
The synthesis of A3
In 500ml round-bottomed flasks, 4g intermediate As 2 are dissolved in 80ml tetrahydrofurans, are added with stirring 50ml Na2CO3
Saturated aqueous solution, 60 DEG C are reacted 20 hours, are spin-dried for tetrahydrofuran, are added water 50ml, with dilute HCl tune PH to 2-3, white solid production
It is raw, it filters, is washed with a small amount, is dried in vacuo to obtain 1.16g, yield 30.1%, purity 86%.
Embodiment 15
The synthesis of impurity D
In 250ml round-bottomed flasks, 2g A3 are dissolved in 100ml ethyl alcohol, hydroxylamine hydrochloride 9g, triethylamine 15ml is added, are returned
Stream reaction 20 hours, decompression boils off ethyl alcohol.10ml distilled water is added in residue, cold through C18 preparative liquid chromatography column preparative separations
Dry product impurity D is lyophilized.1.12g, yield 53.4%, purity 97.2%.
1HNMR(DMSO-d6)11.2(1H,s),8.17(1H,s),7.43-7.35(6H,m),7.17-7.08(1H,m),
7.05-6.99(3H,m),5.56(2H,S),5.45(2H,S),LC-MS,M(387.1)found388.3(M+H)
LC-MS:cal M(402.1)found 403.3(M+H)
Embodiment 16
The synthesis of impurity D
In 250ml round-bottomed flasks, 2g A3 are dissolved in 100ml methanol, azanol 6g, triethylamine 2ml is added, reflux is anti-
It answers 20 hours, decompression boils off methanol.10ml distilled water is added in residue, and through C18 preparative liquid chromatography column preparative separations, freezing is dry
Dry product impurity D, 1.30g, yield 61.9%, purity 98.5%.
Embodiment 17
The synthesis of impurity D
In 250ml round-bottomed flasks, 2g A3 are dissolved in 60ml n,N-Dimethylformamide, azanol 6g are added, two is different
Propylethylamine 5ml, back flow reaction 20 hours, decompression boil off DMF.10ml distilled water is added in residue, through C18 preparative liquid chromatographies
Column preparative separation is freeze-dried to obtain product impurity D, 0.87g, yield 41.5%, purity 97.6%.
Azilsartan methyl esters A1 is purchased from Mount Emei Hong Noboru medicine companies limited liability company.
Specific implementation mode of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously
Cannot the limitation to the scope of the claims of the present invention therefore be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the guarantor of the present invention
Protect range.
Claims (10)
1. a kind of synthetic method of Azilsartan process contaminants D, it is characterised in that：Using Azilsartan methyl esters A1 as raw material, in acid
Property under the conditions of take off ethyl and generate intermediate A 2, intermediate A 2 generates intermediate A 3 through hydrolysis, and A3 obtains target with azanol reaction again
Impurity in products D；
The structure of impurity D is：
2. the synthetic method of Azilsartan process contaminants D according to claim 1, it is characterised in that：Include the following steps：
(1) Azilsartan methyl esters A1 is dissolved in organic solvent, takes off ethyl in acid condition and generates intermediate A 2；
(2) intermediate A 2 is dissolved in organic solvent, adds alkali, reacted 6-20h, be spin-dried for, add water, then acid adding tune pH value, generated intermediate
Body A3；
(3) intermediate A 3 is dissolved in organic solvent, azanol and alkali is added, the reaction was complete, is evaporated under reduced pressure, and separation is freeze-dried
Product impurity D.
3. the synthetic method of Azilsartan process contaminants D according to claim 2, it is characterised in that：In described (1) step
Organic solvent is selected from methanol, ethyl alcohol or tetrahydrofuran.
4. the synthetic method of Azilsartan process contaminants D according to claim 2, it is characterised in that：Described (1) step is reacted
Acid condition, refer to pH value be less than 1.
5. the synthetic method of Azilsartan process contaminants D according to claim 4, it is characterised in that：It is used acid selected from hydrochloric acid,
Hydrobromic acid or hydroiodic acid.
6. the synthetic method of Azilsartan process contaminants D according to claim 2, it is characterised in that：In described (2) step
Alkali is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
7. the synthetic method of Azilsartan process contaminants D according to claim 2, it is characterised in that：In described (3) step
Alkali is selected from triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
8. the synthetic method of Azilsartan process contaminants D according to claim 7, it is characterised in that：In described (3) step
Alkali is selected from triethylamine.
9. the synthetic method of Azilsartan process contaminants D according to claim 2, it is characterised in that：In described (3) step
Organic solvent is selected from methanol, ethyl alcohol, isopropanol, dimethyl sulfoxide or N,N-dimethylformamide.
10. the synthetic method of Azilsartan process contaminants D according to claim 2, it is characterised in that：Described (3) step
Separation method is that distilled water is added in the residue of vacuum distillation, through C18 preparative liquid chromatography post separations.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102344415A (en) * | 2010-07-29 | 2012-02-08 | 上海医药工业研究院 | Preparation method of azilsartan intermediate |
| CN103664920A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Preparation method of azilsartan intermediate and azilsartan |
| CN103664792A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Azilsartan intermediate and preparation method thereof |
-
2018
- 2018-03-22 CN CN201810241851.3A patent/CN108358849A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102344415A (en) * | 2010-07-29 | 2012-02-08 | 上海医药工业研究院 | Preparation method of azilsartan intermediate |
| CN103664920A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Preparation method of azilsartan intermediate and azilsartan |
| CN103664792A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Azilsartan intermediate and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| SANGEETA SANGWAN ET AL.: "Synthesis and Characterization of Impurities of a Common and Advanced Intermediate of Candesartan and Azilsartan Antihypertensive Drugs", 《INTERNATIONAL RESEARCH JOURNAL OF PURE & APPLIED CHEMISTRY》 * |
| WENTAO ZHOU ET AL.: "Structural Elucidation of Potential Impurities in Azilsartan Bulk Drug by HPLC", 《JOURNAL OF AOAC INTERNATIONAL》 * |
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