CN106699737A - Refining method of candesartan - Google Patents
Refining method of candesartan Download PDFInfo
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- CN106699737A CN106699737A CN201611243249.0A CN201611243249A CN106699737A CN 106699737 A CN106699737 A CN 106699737A CN 201611243249 A CN201611243249 A CN 201611243249A CN 106699737 A CN106699737 A CN 106699737A
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- candesartan
- crude product
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a refining method of candesartan. The refining method includes the step of refining a candesartan crude product in a tetrahydrofuran or acetonitrile solvent with an acid-base crystallization method. The refining method is high in yield, low in cost, good in refining effect and very suitable for industrial production.
Description
Technical field
The present invention relates to a kind of process for purification of the intermediate Candesartan of candesartan Cilexetil.
Background technology
Candesartan Cilexetil is selective angiotensin-ii-receptor (ATl) antagonist, by with vascular smooth muscle ATl acceptors
With reference to and the vasoconstrictor effects of antagonizing angiotensin II, so as to reduce peripheral vascular resistance.Candesartan is Candesartan
Important intermediate in Lipase absobed technique, its structural formula is shown in formula I：
At present, the synthesis of Candesartan is main with cyclocomplex (VI) and Sodium azide as raw material, and the cycloaddition by [3+2] is anti-
Tetrazolium structure should be formed, then is obtained using sodium hydroxide solution saponification-crystallization.
Contain substantial amounts of candy ketone (II), Candesartan isomers in synthesizing the Candesartan crude product for obtaining by the route
(III) and the impurity such as other impurity (such as impurity IV, V), concrete structure formula is as follows：
Known refined system is carried out to Candesartan crude product mainly to have dimethyl sulfoxide (DMSO), DMF, the system exists organic
The problems such as high, the refined yield of solvent usage amount is low, feed liquid difficulty in filtration is big, drying is difficult, these problems greatly cause life
Produce the problems such as high cost, material waste and environmental pollution.
The content of the invention
A kind of process for purification of Candesartan of the present invention, comprises the steps of：
A the aqueous solution that Candesartan crude product is added to organic solvent and inorganic base is completely dissolved it by (), described organic
Solvent is selected from acetonitrile or tetrahydrofuran；
B () is lowered the temperature, add sour regulation system pH value to acidity to separate out Candesartan；
C () filtering drying obtains Candesartan highly finished product.
Used as preferred scheme, wherein step (a) organic solvent is relative to Candesartan crude product weight using volume
0.5~2mL/g, preferably 1~1.5mL/g.
The inorganic base is preferably NaOH, potassium hydroxide or their mixture；The consumption of the wherein inorganic base
It is 4-9 with the mol ratio of Candesartan crude product:1；The concentration range of alkali lye is preferably 1mol/L-3mol/L.
The acid is acetic acid or hydrochloric acid, preferably uses acetic acid.
Step b) is preferably finally cooled to 0~5 DEG C, and adds after acid system final ph to 5.0-5.5.
Step b) is more preferably fractional crystallization, and specific method is：10-15 DEG C is first cooled to, acid for adjusting pH value is added
Start to separate out to 6.0-6.5；Continue to be cooled to 0~5 DEG C, add acid for adjusting pH value to 5.0-5.5 completion crystallizations.
One or more comprising following compound in Candesartan crude product of the present invention：
The Candesartan highly finished product that the present invention is obtained can be further converted to Candesartan according to the method for prior art
Ester.
The Candesartan process for purification that the present invention is provided has advantages below：
A. refining effect is good, can be effectively reduced the impurity such as Candesartan ketone (II) and candy ethyl ester (IV)；
B. product easily filtering and drying, simple to operate, is especially suitable for industrialized production；
C. solvent usage amount is low, high income, effectively reduces production cost.
Specific embodiment
Embodiment 1
Candesartan crude product 20g is taken, the NaOH 200mL, tetrahydrofuran 20mL, stirring and dissolving of 2mol/L is added.Drop
Temperature is added dropwise glacial acetic acid to after 15 DEG C, adjusts pH to 6.5, and stirring and crystallizing continues to be cooled to 5 DEG C, is added dropwise glacial acetic acid, regulation pH to
5.5, stirring and crystallizing 1 hour, suction filtration, drying obtain solid white product 17.6g, Candesartan purity (HPLC) 97.6%.
Embodiment 2
Candesartan crude product 20g is taken, the NaOH 160mL, tetrahydrofuran 40mL, stirring and dissolving of 2mol/L is added.Drop
Temperature is added dropwise glacial acetic acid to after 10 DEG C, adjusts pH to 6.0, and stirring and crystallizing continues to be cooled to 0 DEG C, is added dropwise glacial acetic acid, regulation pH to
5.0, stirring and crystallizing 1 hour, suction filtration, drying obtain solid white product 16.7g, Candesartan purity (HPLC) 98.2%.
Embodiment 3
Candesartan crude product 20g is taken, the potassium hydroxide 100mL, tetrahydrofuran 30mL, stirring and dissolving of 2mol/L is added.Drop
Temperature is added dropwise glacial acetic acid to after 13 DEG C, adjusts pH to 6.2, and stirring and crystallizing continues to be cooled to 3 DEG C, is added dropwise glacial acetic acid, regulation pH to
5.3, stirring and crystallizing 2 hours, suction filtration, drying obtain solid white product 16.0g, Candesartan purity (HPLC) 97.3%.
Embodiment 4
Candesartan crude product 20g is taken, the NaOH 100mL, tetrahydrofuran 10mL, stirring and dissolving of 2mol/L is added.Drop
Temperature is added dropwise glacial acetic acid to after 15 DEG C, adjusts pH to 6.4, and stirring and crystallizing continues to be cooled to 3 DEG C, is added dropwise glacial acetic acid, regulation pH to
5.2, stirring and crystallizing 1 hour, suction filtration, drying obtain solid white product 17.2g, Candesartan purity (HPLC) 97.7%.
Embodiment 5
Candesartan crude product 20g is taken, the NaOH 160mL, tetrahydrofuran 10mL, stirring and dissolving of 2mol/L is added.Drop
Temperature is added dropwise glacial acetic acid to after 15 DEG C, adjusts pH to 6.2, and stirring and crystallizing continues to be cooled to 0 DEG C, is added dropwise glacial acetic acid, regulation pH to
5.0, stirring and crystallizing 1 hour, suction filtration, drying obtain solid white product 16.9g, Candesartan purity (HPLC) 97.1%.
Embodiment 6
Candesartan crude product 20g is taken, the NaOH 160mL, tetrahydrofuran 20mL of 2mol/L is added.Stirring and dissolving, drop
Temperature is added dropwise glacial acetic acid to after 15 DEG C, adjusts pH to 6.5, and stirring and crystallizing continues to be cooled to 2 DEG C, is added dropwise glacial acetic acid, regulation pH to
5.2, stirring and crystallizing 1 hour, suction filtration, drying obtain solid white product 17.1g, Candesartan purity (HPLC) 98.5%.
Embodiment 7
Candesartan crude product 20g is taken, the NaOH 200mL, tetrahydrofuran 40mL of 1mol/L is added.Stirring and dissolving, drop
Temperature is added dropwise glacial acetic acid to after 10 DEG C, adjusts pH to 6.5, and stirring and crystallizing continues to be cooled to 0 DEG C, is added dropwise glacial acetic acid, regulation pH to
5.0, stirring and crystallizing 1 hour, suction filtration, drying obtain solid white product 17.5g, Candesartan purity (HPLC) 98.2%.
Embodiment 8
Candesartan crude product 20g is taken, the NaOH 100mL, tetrahydrofuran 20mL of 3mol/L is added.Stirring and dissolving, drop
Temperature is added dropwise glacial acetic acid to after 15 DEG C, adjusts pH to 6.5, and stirring and crystallizing continues to be cooled to 0 DEG C, is added dropwise glacial acetic acid, regulation pH to
5.0, stirring and crystallizing 1 hour, suction filtration, drying obtain solid white product 18.0g, Candesartan purity (HPLC) 97.5%.
Embodiment 9
Candesartan crude product 20g is taken, the NaOH 160mL, tetrahydrofuran 30mL of 2mol/L is added.Stirring and dissolving, drop
After warm to 10 DEG C, the hydrochloric acid of 2mol/L is added dropwise, adjusts pH to 6.2, stirring and crystallizing continues to be cooled to 0 DEG C, and the salt of 2mol/L is added dropwise
Acid, regulation pH to 5.3, stirring and crystallizing 1 hour, suction filtration, drying obtain solid white product 17.7g, Candesartan purity (HPLC)
97.9%.
Embodiment 10
Candesartan crude product 20g is taken, the NaOH 160mL, acetonitrile 20mL of 2mol/L is added.Stirring and dissolving, is cooled to
After 12 DEG C, glacial acetic acid is added dropwise, adjusts pH to 6.0, stirring and crystallizing continues to be cooled to 0 DEG C, and glacial acetic acid is added dropwise, and pH is to 5.0 for regulation,
Stirring and crystallizing 1 hour, suction filtration, drying obtain solid white product 18.5g, Candesartan purity (HPLC) 98.0%.
Embodiment 11
Candesartan crude product 20g is taken, the NaOH 200mL, acetonitrile 30mL of 2mol/L is added.Stirring and dissolving, is cooled to
After 15 DEG C, glacial acetic acid is added dropwise, adjusts pH to 6.2, stirring and crystallizing continues to be cooled to 2 DEG C, and glacial acetic acid is added dropwise, and pH is to 5.0 for regulation,
Stirring and crystallizing 1 hour, suction filtration, drying obtain solid white product 17.8g, Candesartan purity (HPLC) 98.3%.
Table one be Candesartan crude product in experimental example 1-11 and it is refined after product HPLC test experience Comparative results
Collect：
Table one
Claims (10)
1. a kind of process for purification of Candesartan, comprises the steps of：
A the aqueous solution that Candesartan crude product is added to organic solvent and inorganic base is completely dissolved it by (), the organic solvent
Selected from acetonitrile or tetrahydrofuran；
B () is lowered the temperature, add sour regulation system pH value to acidity to separate out Candesartan；
C () filtering drying obtains Candesartan highly finished product.
2. method according to claim 1, it is characterised in that：Wherein step (a) organic solvent uses volume phase
It is 0.5~2mL/g, preferably 1~1.5mL/g for Candesartan crude product weight.
3. a method according to claim 1, it is characterised in that：Described inorganic base is selected from：NaOH, potassium hydroxide
Or their mixture.
4. method according to claim 1, it is characterised in that：The consumption of the wherein inorganic base and Candesartan crude product
Mol ratio is 4-9:1.
5. method according to claim 4, it is characterised in that：The concentration range of described alkali lye is 1mol/L-3mol/L.
6. the method described in claim 1, the acid is acetic acid or hydrochloric acid, preferably acetic acid.
7. method according to claim 1, wherein step b) is finally cooled to 0~5 DEG C, and system is final after adding acid
PH value is to 5.0-5.5.
8. method according to claim 6, wherein step b) specific methods are：
10-15 DEG C is first cooled to, adds acid for adjusting pH value to start to separate out to 6.0-6.5；
Continue to be cooled to 0~5 DEG C, add acid for adjusting pH value to 5.0-5.5 completion crystallizations.
9. method according to claim 1, includes one or more of following compound wherein in Candesartan crude product：
10. a kind of preparation method of candesartan Cilexetil, including the candy that the method according to claim 1-9 is prepared
Sha Tan is further converted to candesartan Cilexetil.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611119010 | 2016-12-07 | ||
| CN2016111190102 | 2016-12-07 |
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| Publication Number | Publication Date |
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| CN106699737A true CN106699737A (en) | 2017-05-24 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201611243249.0A Pending CN106699737A (en) | 2016-12-07 | 2016-12-28 | Refining method of candesartan |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040215023A1 (en) * | 2001-08-03 | 2004-10-28 | Hideo Hashimoto | Crystal and process for producing the same |
| CN1800179A (en) * | 2005-12-22 | 2006-07-12 | 浙江天宇药业有限公司 | Method for preparing candestartan |
| CN101941965A (en) * | 2010-09-14 | 2011-01-12 | 青岛黄海制药有限责任公司 | Preparation method of candesartan cilexetil |
| WO2013186390A9 (en) * | 2012-06-15 | 2014-05-08 | Farma Grs, D.O.O. | Selective crystallization processes using reverse micelle and w/o microemulsion systems - multitask emulsion crystallization (mec) |
| CN104098550A (en) * | 2014-07-17 | 2014-10-15 | 浙江华海药业股份有限公司 | Method for refining trityl-candesartan |
| CN105153124A (en) * | 2015-08-26 | 2015-12-16 | 山西皇城相府药业有限公司 | Preparation method of candesartan cilexetil |
| CN105198863A (en) * | 2015-10-30 | 2015-12-30 | 浙江华海药业股份有限公司 | Method for preparing high-purity losartan |
-
2016
- 2016-12-28 CN CN201611243249.0A patent/CN106699737A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040215023A1 (en) * | 2001-08-03 | 2004-10-28 | Hideo Hashimoto | Crystal and process for producing the same |
| CN1800179A (en) * | 2005-12-22 | 2006-07-12 | 浙江天宇药业有限公司 | Method for preparing candestartan |
| CN101941965A (en) * | 2010-09-14 | 2011-01-12 | 青岛黄海制药有限责任公司 | Preparation method of candesartan cilexetil |
| WO2013186390A9 (en) * | 2012-06-15 | 2014-05-08 | Farma Grs, D.O.O. | Selective crystallization processes using reverse micelle and w/o microemulsion systems - multitask emulsion crystallization (mec) |
| CN104098550A (en) * | 2014-07-17 | 2014-10-15 | 浙江华海药业股份有限公司 | Method for refining trityl-candesartan |
| CN105153124A (en) * | 2015-08-26 | 2015-12-16 | 山西皇城相府药业有限公司 | Preparation method of candesartan cilexetil |
| CN105198863A (en) * | 2015-10-30 | 2015-12-30 | 浙江华海药业股份有限公司 | Method for preparing high-purity losartan |
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