CN108947869A - A kind of preparation method of escitalopram process impurity - Google Patents
A kind of preparation method of escitalopram process impurity Download PDFInfo
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- CN108947869A CN108947869A CN201710379949.0A CN201710379949A CN108947869A CN 108947869 A CN108947869 A CN 108947869A CN 201710379949 A CN201710379949 A CN 201710379949A CN 108947869 A CN108947869 A CN 108947869A
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- escitalopram
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- process impurity
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The present invention relates to a kind of preparation methods of escitalopram process impurity, react with 4- flourophenyl magnesium bromide to obtain escitalopram process impurity by 5-Cyano-phthalide, simple process, and yield is higher.
Description
Technical field
The invention belongs to pharmaceutical technology fields.
Background technique
Escitalopram is the d-isomer of Citalopram, it is a kind of well-known antidepressants, it is to select at present
The antidepressant of the strongest serotonin of selecting property (5-HT) reuptaking inhibitor class has very strong parent to serotonin transporter
And power, it is that its commercialized product is mainly escitalopram oxalate, it is listed for the first time in American-European countries such as Switzerland in March, 2002,
FDA approval is obtained in August part, trade name is Lexapro, for the treatment of Serious depression and the maintenance therapy of depression.
Generated process impurity and degradation impurity control the optimization of medicine synthesising process and quality in the synthesis process
Research is all extremely important, so studying impurity of the drug very necessary.
According to the present invention is exactly the impurity very easily occurred in escitalopram process exploitation, structure
It is as follows:
。
Summary of the invention
The present invention is intended to provide a kind of preparation method of escitalopram process impurity, after being hydrolyzed by 5-Cyano-phthalide
It reacts to obtain escitalopram process impurity with grignard reagent 4- flourophenyl magnesium bromide, reaction equation is as follows:
。
It is ether, tetrahydrofuran, toluene that the application 5-Cyano-phthalide, which reacts used solvent with 4- flourophenyl magnesium bromide,.
The application reaction temperature is 0-30 DEG C.
The molar ratio of the application 5-Cyano-phthalide and 4- flourophenyl magnesium bromide is 1:1.0-1:1.5.
Agents useful for same and raw material are commercially available in preparation method of the invention, and wherein 4- flourophenyl magnesium bromide is using commercially available
The tetrahydrofuran solution of specification 1mol/L.
The characteristics of present invention has simple synthetic method, and reaction condition is mild, high income.Preparation method provided by the invention
Can in technique due to raw material reaction not exclusively and generate trace impurity standard reference material is provided.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below, but protection scope of the present invention is not limited to
This.
Embodiment 1
In 100mL there-necked flask, 5-Cyano-phthalide 5.00g(0.031mol, 1.0eq is added), the tetrahydrofuran of 50mL is added,
It stirs and is cooled to 0-5 DEG C, 4- flourophenyl magnesium bromide (1mol/L) (31mL, 1.0eq) is slowly added dropwise, continued to after dripping off anti-
It should be stirred to react 5h at 0-5 DEG C, after completion of the reaction, reaction solution is poured into 100mL ice water, acetic acid is added dropwise into reaction solution and adjusts
Ph=6-7 stirs 5mins, and ammonium hydroxide tune Ph=8-9 is added dropwise, and methylene chloride extraction (50mLx3) is added, and merges organic phase, and use is anhydrous
After sodium sulphate is dry, concentration is filtered, gained crude product passes through column chromatographic purifying, and solvent is petroleum ether: ethyl acetate=5:1 to 3:
1, product stream lease making, which is crossed, is concentrated to get 6.8g white solid, as escitalopram oxalate process impurity (Formula II), yield
85%。
Embodiment 2
In 100mL there-necked flask, 5-Cyano-phthalide 5.00g(0.031mol, 1.0eq is added), the ether of 50mL is added, is stirred
And it is cooled to 0-5 DEG C, 4- flourophenyl magnesium bromide (1mol/L) (38mL, 1.2eq) is slowly added dropwise, reaction is continued to after dripping off and is existed
0-5 DEG C is stirred to react 3h, and reaction solution is warmed to room temperature naturally, and the reaction was continued, and reaction solution is poured into 100mL ice after completion of the reaction by 2h
In water, acetic acid is added dropwise into reaction solution and adjusts Ph=6-7, stirs 5mins, ammonium hydroxide tune Ph=8-9 is added dropwise, ethyl acetate extraction is added
(50mLx3) merges organic phase, after anhydrous sodium sulfate drying, filters concentration, gained crude product passes through column chromatographic purifying, solvent
For petroleum ether: ethyl acetate=5:1 to 3:1, product stream lease making, which is crossed, is concentrated to get 6.1g white solid, as oxalic acid Escitalopram
Pulan process impurity (Formula II), yield 76%.
Embodiment 3
In 100mL there-necked flask, 5-Cyano-phthalide 5.00g(0.031mol, 1.0eq is added), the ether of 50mL is added, is stirred
And it is cooled to 0-5 DEG C, 4- flourophenyl magnesium bromide (1mol/L) (45mL, 1.5eq) is slowly added dropwise, reaction is continued to after dripping off and is existed
0-5 DEG C is stirred to react 3h, and reaction solution is warmed to room temperature naturally, and the reaction was continued, and reaction solution is poured into 100mL ice after completion of the reaction by 2h
In water, acetic acid is added dropwise into reaction solution and adjusts Ph=6-7, stirs 5mins, ammonium hydroxide tune Ph=8-9 is added dropwise, ethyl acetate extraction is added
(50mLx3) merges organic phase, after anhydrous sodium sulfate drying, filters concentration, gained crude product passes through column chromatographic purifying, solvent
For petroleum ether: ethyl acetate=5:1 to 3:1, product stream lease making, which is crossed, is concentrated to get 5.8g white solid, as oxalic acid Escitalopram
Pulan process impurity (Formula II), yield 72%.
Claims (4)
1. a kind of preparation method of Citalopram process impurity, 5-Cyano-phthalide (Formulas I) directly with grignard reagent 4- fluorobenzene bromide
Change magnesium react to obtain Citalopram process impurity reaction equation it is as follows:
。
2. preparation method according to claim 1, which is characterized in that reaction temperature is 0-30 DEG C.
3. preparation method according to claim 1, reaction dissolvent is ether, tetrahydrofuran, toluene.
4. preparation method according to claim 1, which is characterized in that mole of 5-Cyano-phthalide and 4- flourophenyl magnesium bromide
Than for 1:1-1:1.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710379949.0A CN108947869A (en) | 2017-05-25 | 2017-05-25 | A kind of preparation method of escitalopram process impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710379949.0A CN108947869A (en) | 2017-05-25 | 2017-05-25 | A kind of preparation method of escitalopram process impurity |
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| CN108947869A true CN108947869A (en) | 2018-12-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201710379949.0A Pending CN108947869A (en) | 2017-05-25 | 2017-05-25 | A kind of preparation method of escitalopram process impurity |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1761658A (en) * | 2003-03-13 | 2006-04-19 | 阿多凯姆技术有限公司 | Process for the preparation of a cyano-isobenzofuran |
| CN101460448A (en) * | 2006-01-23 | 2009-06-17 | 桑多斯股份公司 | Carbonyl asymmetric alkylation |
-
2017
- 2017-05-25 CN CN201710379949.0A patent/CN108947869A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1761658A (en) * | 2003-03-13 | 2006-04-19 | 阿多凯姆技术有限公司 | Process for the preparation of a cyano-isobenzofuran |
| CN101460448A (en) * | 2006-01-23 | 2009-06-17 | 桑多斯股份公司 | Carbonyl asymmetric alkylation |
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Application publication date: 20181207 |