CN106810524A - The preparation method of escitalopram process contaminants - Google Patents
The preparation method of escitalopram process contaminants Download PDFInfo
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- CN106810524A CN106810524A CN201710072534.9A CN201710072534A CN106810524A CN 106810524 A CN106810524 A CN 106810524A CN 201710072534 A CN201710072534 A CN 201710072534A CN 106810524 A CN106810524 A CN 106810524A
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- preparation
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- acid amides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
Abstract
The present invention relates to a kind of preparation method of escitalopram process contaminants, by 5 cyanophthalides hydrolyze after with N methyl Ns Methoxyamine formed weinreb acid amides, then with N, N dimethylamino chloropropanes grignard reagent reaction obtain escitalopram process contaminants, process is simple, yield is higher.
Description
Technical field
This method belongs to pharmaceutical technology field.
Background technology
Escitalopram is the d-isomer of Citalopram, and it is a kind of well-known antidepressants, is selection at present
The most strong serotonin of property（5-HT）The antidepressant of reuptaking inhibitor class, has very strong affine to serotonin transporter
Power, in March, 2002 is listed in American-European countries such as Switzerland in escitalopram oxalate form first, and FDA batches is obtained in August part
Standard, trade name is Lexapro, treatment and depressed maintaining treatment for Serious depression.
Process contaminants to being produced during pharmaceutical synthesis are studied great to Control of drug quality Research Significance, therefore
With this end in view, the preparation method of the one of which process contaminants produced to escitalopram building-up process is carried out the application
Research.
Involved by the application is exactly the impurity for being very easy to occur in escitalopram process exploitation, and structure is such as
Under：
。
The content of the invention
A kind of we's pharmaceutical technology field owned by France, and in particular to preparation method of escitalopram process contaminants：5- cyanogen
Form weinreb acid amides after the hydrolysis of base phthalide with N- methyl-N-methoxies amine, then with N, the form of N- dimethylamino chloropropanes tries
Agent reaction obtains escitalopram process contaminants.
。
This method has the characteristics that：
（1）5-Cyano-phthalide（Formula II）Hydrolysis solvent for use be water, methyl alcohol, ethanol, tetrahydrofuran, dioxane, dichloromethane,
One or more solvents mixing in toluene；Reaction alkali used is NaOH, lithium hydroxide, potassium hydroxide, sodium carbonate, carbonic acid
Potassium, calcium carbonate；
（2）The hydrolysate 4- cyano group -2- hydroxymethyl-benzoic acids of 5-Cyano-phthalide（Formula III）It is anti-with N- methyl-N-methoxy amine
Corresponding weinreb acid amides should be generated, the reaction solvent for use is dichloromethane, ethyl acetate, toluene, tetrahydrofuran, dioxy
Six rings, DMF, DMA；Institute the condensing agent that uses for CDI, EDCI, HOBt, HATU, DCC, DIC, HBTU in one or more mixing make
With；Alkali used is triethylamine, DIEA；
（3）The grignard reagent of N, N- dimethylamino chloropropane is THF, ether, first with weinreb amide addition reactions solvent for use
Benzene, n-hexane；
（4）Temperature used is 0-50 DEG C in 5-Cyano-phthalide hydrolysis；Alkali used is 1 with the mol ratio of 5-Cyano-phthalide:
1-5:1；
（5）In the synthesis of weinreb acid amides, reaction temperature is 0-30 DEG C；N- methyl-N-methoxies amine is hydrolyzed with 5-Cyano-phthalide
The mol ratio of product is 1:1-5:1；Condensing agent is 1 with the mol ratio of 5-Cyano-phthalide hydrolysate:1-3:1；
（6）In addition reaction, grignard reagent is 1 with the mol ratio of weinreb acid amides:1-3:1；Reaction temperature is 0-65 DEG C.
The application has a simple synthetic method, and reaction condition is gentle, the characteristics of high income.The preparation method that the application is provided
Standard reference material can be provided for the trace impurity produced because raw material reaction is incomplete in technique.
Specific embodiment
With reference to specific embodiment, the present invention is further illustrated, but the protection domain of the application is not limited to
This：
Embodiment 1
A. in 100mL there-necked flasks, 5-Cyano-phthalide 5.00g is added（0.031mol,1.0eq）, sequentially add 40mL methyl alcohol
With 10mL water, LiOH 1.13g are eventually adding（0.047mol, 1.5eq）, stirring reaction 5h, reaction completely after, be concentrated under reduced pressure, to
The HCl solution tune system pH=4-6 that dichloromethane 50mL and water 10mL is stirred at room temperature lower use 1N, suction filtration are separately added into concentrate
White solid is obtained, drying is taken out and is obtained product 4- cyano group -2- hydroxymethyl-benzoic acids（Formula III）4.86g, yield 87.3%.
B. in 100mL there-necked flasks, addition a step gained 4- cyano group -2- hydroxymethyl-benzoic acids 4.18g (0.024mol,
1.0eq), dichloromethane 40mL is added, is stirred at room temperature down and is added N in batches, N'- carbonyl dimidazoles（CDI）5.74g
（0.035mol, 1.5eq）, continue to stir 10mins after adding, to addition N- methyl-N-methoxy amine 2.88g in reaction
（0.047mol, 2.0eq）Continue to stir 3h, after reaction completely, add 10mLNH4Cl saturated solutions to stir to reaction system
5mins, stratification, take it is organic be added to anhydrous sodium sulfate drying, suction filtration, mother liquor concentrations obtain weinreb acid amides（Formula IV）
4.28g, yield 82.3%.
C. the preparation of grignard reagent：In 100mL single port bottles, magnesium rod 0.79g is sequentially added（0.033mol, 1.8eq）, it is anhydrous
Tetrahydrofuran 10mL, dropwise addition contains N, N- dimethylamino chloropropanes 3.30g（0.027mol, 1.5eq）Tetrahydrofuran 9mL it is molten
Liquid.Plus 1, the 2- Bromofume initiation reactions of several drops, continue vigorous reaction 3h, it is stand-by.
D. in 100mL there-necked flasks, b step gained weinreb acid amides 4.00g (0.018mol, 1.0eq) is added, then add
Enter anhydrous tetrahydro furan 40mL, stirring and dissolving, to the grignard reagent being slowly added dropwise in system prepared by step c, after adding, room temperature
Stirring reaction 12h, after reaction completely, reaction solution is poured into 50mL 1NH4Cl solution, is extracted with 50mL ethyl acetate, organic
Mutually with anhydrous sodium sulfate drying after saturated common salt water washing, filtering, concentration gained off-white powder is product（Formulas I）3.58g, receives
Rate 80.1%.
Embodiment 2
A. in 100mL there-necked flasks, 5-Cyano-phthalide 5.00g is added（0.031mol,1.0eq）, sequentially add 40mLTHF and
10mL water, is eventually adding NaOH 1.51g（0.038mol, 1.2eq）, stirring reaction 5h, reaction completely after, be concentrated under reduced pressure, to dense
The HCl solution tune system pH=4-6 that dichloromethane 50mL and 10mL are stirred at room temperature lower use 1N is separately added into contracting liquid, suction filtration is obtained
White solid, takes out drying and obtains product 4- cyano group -2- hydroxymethyl-benzoic acids（Formula III）4.18g, yield 75.0%.
B. in 100mL there-necked flasks, addition a step gained 4- cyano group -2- hydroxymethyl-benzoic acids 4.18g (0.024mol,
1.0eq), ethyl acetate 40mL is added, is stirred at room temperature down and is added N in batches, N'- carbonyl dimidazoles（CDI）4.59g
（0.028mol, 1.2eq）, continue to stir 10mins after adding, to addition N- methyl-N-methoxy amine 2.16g in reaction
（0.035mol, 1.5eq）Continue to stir 3h, after reaction completely, add 10mLNH4Cl saturated solutions to stir to reaction system
5mins, stratification, take it is organic be added to anhydrous sodium sulfate drying, suction filtration, mother liquor concentrations obtain weinreb acid amides solids（Formula
IV）4.42g, yield 85.0%.
C. the preparation of grignard reagent：In 100mL single port bottles, magnesium rod 0.96g is sequentially added（0.040mol, 2.2eq）, it is anhydrous
Ether 10mL, dropwise addition contains N, N- dimethylamino chloropropanes 4.40g（0.036mol, 2.0eq）Tetrahydrofuran 9mL solution.Plus
1, the 2- Bromofume initiation reactions of a few drops, continue vigorous reaction 3h, stand-by.
D. in 100mL there-necked flasks, b step gained weinreb acid amides 4.00g (0.018mol, 1.0eq) is added, then add
Enter absolute ether 40mL, stirring and dissolving, to the grignard reagent being slowly added dropwise in system prepared by step c, after adding, is stirred at room temperature
Reaction 12h, after reaction completely, reaction solution is poured into 50mL 1NH4Cl solution, is extracted with 50mL ethyl acetate, and organic phase is used
Anhydrous sodium sulfate drying after saturated common salt water washing, filtering, concentration gained off-white powder is product（Formulas I）3.80g, yield
85.0%。
Embodiment 3
A. in 100mL there-necked flasks, 5-Cyano-phthalide 5.00g is added（0.031mol,1.0eq）, sequentially add 30mL ethanol
With 20mL water, NaCO36.66g is eventually adding（0.063mol, 2.0eq）, 50 DEG C of stirring reaction 5h, after reaction completely, decompression is dense
Contracting, to be separately added into concentrate dichloromethane 50mL and water 10mL be stirred at room temperature lower use 1N HCl solution adjust system pH=4-6,
Suction filtration obtains white solid, takes out drying and obtains product 4- cyano group -2- hydroxymethyl-benzoic acids（Formula III）4.00g, yield 71.8%.
B. in 100mL there-necked flasks, addition a step gained 4- cyano group -2- hydroxymethyl-benzoic acids 4.00g (0.023mol,
1.0eq), dichloromethane 40mL is added, is stirred at room temperature down and is sequentially added EDCI 5.20g（0.027mol, 1.2eq）, HOBT
4.58g（0.034mol, 1.5eq）, triethylamine 8.57g（0.085mol, 3.0eq）, N- methyl-N-methoxy amine 2.76g
（0.045mol, 2.0eq）Continue to stir 5h, after reaction completely, add 10mLNH4Cl saturated solutions to stir to reaction system
5mins, stratification, take it is organic be added to anhydrous sodium sulfate drying, suction filtration, mother liquor concentrations obtain weinreb acid amides（Formula IV）
4.16g, yield 83.8%.
C. the preparation of grignard reagent：In 100mL single port bottles, magnesium rod 1.31g is sequentially added（0.054mol, 3.0eq）, it is anhydrous
Tetrahydrofuran 20mL, dropwise addition contains N, N- dimethylamino chloropropanes 5.50g（0.045mol, 2.5eq）Tetrahydrofuran 15mL it is molten
Liquid.Plus 1, the 2- Bromofume initiation reactions of several drops, continue vigorous reaction 5h, it is stand-by.
D. in 100mL there-necked flasks, b step gained weinreb acid amides 4.00g (0.018mol, 1.0eq) is added, then add
Enter anhydrous tetrahydro furan 40mL, stirring and dissolving, to the grignard reagent being slowly added dropwise in system prepared by step c, after adding, 40 DEG C
Stirring reaction 12h, after reaction completely, reaction solution is poured into 50mL 1NH4Cl solution, is extracted with 50mL ethyl acetate, organic
Mutually with anhydrous sodium sulfate drying after saturated common salt water washing, filtering, concentration gained off-white powder is product（Formulas I）3.39g, receives
Rate 75.8%.
Embodiment 4
A. in 100mL there-necked flasks, 5-Cyano-phthalide 5.00g is added（0.031mol,1.0eq）, sequentially add 30mL dichloros
Methane and 20mL water, are eventually adding NaOH 1.51g（0.038mol, 1.2eq）, stirring reaction 5h, after reaction completely, system is used
The HCl solution of 1N adjusts system pH=4-6, suction filtration to obtain white solid, takes out drying and obtains product 4- cyano group -2- hydroxymethyl-benzoic acids
（Formula III）4.44g, yield 79.8%.
B. in 250mL there-necked flasks, addition a step gained 4- cyano group -2- hydroxymethyl-benzoic acids 4.00g (0.023mol,
1.0eq), DMF 40mL are added, is stirred at room temperature down and is sequentially added HATU12.9g（0.034mol, 1.5eq）, DIEA 8.76g
（0.085mol, 3.0eq）, N- methyl-N-methoxy amine 2.76g（0.045mol, 2.0eq）Continue to stir 5h, after reaction completely,
50mLNH4Cl saturated solutions and 50mL dichloromethane are sequentially added to reaction system, 5mins is stirred, stratification takes organic phase
Anhydrous sodium sulfate drying is added, suction filtration, mother liquor concentrations obtain weinreb acid amides（Formula IV）4.31g, yield 86.8%.
C. the preparation of grignard reagent：In 100mL single port bottles, magnesium rod 1.44g is sequentially added（0.059mol, 3.3eq）, it is anhydrous
Toluene 30mL, dropwise addition contains N, N- dimethylamino chloropropanes 6.54g（0.054mol, 3.0eq）Tetrahydrofuran 15mL solution.
Plus 1, the 2- Bromofume initiation reactions of several drops, continue vigorous reaction 5h, it is stand-by.
D. in 100mL there-necked flasks, b step gained weinreb acid amides 4.00g (0.018mol, 1.0eq) is added, then add
Enter dry toluene 40mL, stirring and dissolving, to the grignard reagent being slowly added dropwise in system prepared by step c, after adding, 50 DEG C of stirrings
Reaction 12h, after reaction completely, reaction solution is poured into 50mL 1NH4Cl solution, is extracted with 50mL ethyl acetate, and organic phase is used
Anhydrous sodium sulfate drying after saturated common salt water washing, filtering, concentration gained off-white powder is product（Formulas I）4.47g, yield
88.8%。
Claims (7)
1. a kind of preparation method of Citalopram process contaminants, comprises the following steps：
(1) 5-Cyano-phthalide (II) hydrolyzes to obtain compound III；
(2) compound III forms weinreb acid amides with N- methyl-N-methoxies amine；
(3) the grignard reagent reaction of weinreb acid amides and N, N- dimethylamino chloropropane obtains Citalopram process contaminants.
2. preparation method according to claim 1, step（1）Solvent for use is water, methyl alcohol, ethanol, tetrahydrofuran, dioxy
One or more solvents mixing in six rings, dichloromethane, toluene；Reaction alkali used is NaOH, lithium hydroxide, hydroxide
Potassium, sodium carbonate, potassium carbonate, calcium carbonate.
3. preparation method according to claim 1, step（2）Solvent for use is dichloromethane, ethyl acetate, toluene, four
Hydrogen furans, dioxane, DMF, DMA；Condensing agent used is CDI, EDCI, HOBt, HATU, DCC, DIC, HBTU；Alkali used is
Triethylamine, DIEA.
4. preparation method according to claim 1, step（3）Addition reaction solvent for use is THF, ether, toluene, dioxy
Six rings, n-hexane, hexamethylene.
5. preparation method according to claim 1, step（1）Hydrolysising reacting temperature is 0-50 DEG C；Alkali used and 5- cyano group
The mol ratio of phthalide is 1:1-5:1.
6. preparation method according to claim 1, step（2）Reaction temperature is 0-30 DEG C；N- methyl-N-methoxies amine with
Compound III mol ratios are 1:1-5:1；Condensing agent is 1 with compound III mol ratios:1-3:1.
7. preparation method according to claim 1, step（3）Middle grignard reagent is 1 with the mol ratio of weinreb acid amides:
1-3:1；Reaction temperature is 0-65 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114761004A (en) * | 2019-12-06 | 2022-07-15 | 细胞基因公司 | Process for the preparation of 2- (4-chlorophenyl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 2-difluoroacetamide |
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|---|---|---|---|---|
| EP1736550A1 (en) * | 2005-06-22 | 2006-12-27 | Adorkem Technology SpA | Chemoenzymatic process for the synthesis of escitalopram |
| CN104529736A (en) * | 2014-12-18 | 2015-04-22 | 青岛无为保温材料有限公司 | Preparation method of p-fluorophenyl butanone |
| CN106324141A (en) * | 2016-08-30 | 2017-01-11 | 山东京卫制药有限公司 | HPLC (high-performance liquid chromatography) detection method for escitalopram oxalate related substances |
-
2017
- 2017-02-10 CN CN201710072534.9A patent/CN106810524A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1736550A1 (en) * | 2005-06-22 | 2006-12-27 | Adorkem Technology SpA | Chemoenzymatic process for the synthesis of escitalopram |
| CN104529736A (en) * | 2014-12-18 | 2015-04-22 | 青岛无为保温材料有限公司 | Preparation method of p-fluorophenyl butanone |
| CN106324141A (en) * | 2016-08-30 | 2017-01-11 | 山东京卫制药有限公司 | HPLC (high-performance liquid chromatography) detection method for escitalopram oxalate related substances |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114761004A (en) * | 2019-12-06 | 2022-07-15 | 细胞基因公司 | Process for the preparation of 2- (4-chlorophenyl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 2-difluoroacetamide |
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Application publication date: 20170609 |