CN103936702A - Synthetic method of escitalopram impurity J - Google Patents
Synthetic method of escitalopram impurity J Download PDFInfo
- Publication number
- CN103936702A CN103936702A CN201410191633.5A CN201410191633A CN103936702A CN 103936702 A CN103936702 A CN 103936702A CN 201410191633 A CN201410191633 A CN 201410191633A CN 103936702 A CN103936702 A CN 103936702A
- Authority
- CN
- China
- Prior art keywords
- escitalopram
- impurity
- synthetic method
- reaction
- ethyl acetate
- 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.)
- Pending
Links
Classifications
-
- 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
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of an escitalopram impurity J, belonging to the technical field of medicaments. The synthetic route comprises the steps of using escitalopram oxalate as a raw material, adding an acid-binding agent into a solvent in the presence of hydrogen peroxide, and performing hydrolysis reaction to generate the escitalopram impurity J. The method disclosed by the invention uses escitalopram oxalate as a starting material; compared with a raw material required by a conventional method, escitalopram oxalate has the advantages of low cost and easy purchase; the synthetic route is simple, only needs a one-step reaction, is mild in reaction conditions and small in pollution caused by a reagent and the solvent adopted in the reaction, and has the characteristic of environmental friendliness; the escitalopram impurity J synthesized by the synthetic method is high in purity and yield.
Description
Technical field
The invention belongs to medical technical field, be specifically related to the synthetic method of S-escitalopram impurity J.
Background technology
S-escitalopram is the levoisomer of citalopram, its drug effect is 100 times of citalopram dextrorotatory form effect, as thymoleptic of new generation, mainly be applicable to the treatment of the mental diseases such as major depression and generalized anxiety disorder (GAD), there is onset rapid, drug interaction and untoward reaction are less, the fine quality of efficacy stability, and developing prospect is very fine.Thereby, develop high-quality S-escitalopram bulk drug and preparation significant.Because impurity of the drug is studied in medicine technical study, optimization and quality control aspect are extremely important, thereby the research of S-escitalopram impurity is also very necessary.
Be below the structure of S-escitalopram impurity J:
Do not retrieve the synthetic method about S-escitalopram impurity J by By consulting literatures, and the synthetic method of this compound raceme mainly contains following two kinds:
One, the alkaline hydrolysis of cyano group (Journal of Medicinal Chemistry, 2003,56 (23), 9709-9724; Journal of the Brazilian Chemical Society, 2011,22 (5), 836-848.), synthetic route is as follows:
There is following shortcoming in this synthetic method: in synthetic, need high temperature reflux, when the reaction times, long or alkaline mistake was strong, cyano group is easily hydrolyzed into acid; This operation condition is difficult to control, thereby reaction yield is lower, and selectivity is poor, and aftertreatment is loaded down with trivial details; This technology just changes into the citalopram hydrobromate of racemization the amide compound of racemization, does not obtain the S-escitalopram impurity J of S-configuration.
Two, the mainly carboxylic acid by citalopram intermediate and thionyl chloride effect generation acyl chlorides, acyl chlorides again with NH
3effect generates acid amides (European Journal of Medicinal Chemstry, 1977,12,289-295), and synthetic route is as follows:
There is following shortcoming in this synthetic method: be first that reaction raw materials need to be hydrolyzed and be obtained by citalopram, route is longer; In synthetic, use more serious thionyl chloride and the ammonia of environmental pollution, needed vent gas treatment; Acyl chlorides facile hydrolysis and friedel-crafts acylation can occur, produces by product, and reaction preference is bad, makes amidated productive rate only have 45%; Same the method just changes into citalopram hydrobromate the amide compound of racemization, does not also obtain the S-escitalopram impurity J of S-configuration.
In sum, existing method be all utilize the cyano group of citalopram to be hydrolyzed under alkaline condition or the acid of racemization by chloride, amination obtains the acid amides of raceme, does not all obtain single optical isomer, and cyano group is hydrolyzed and is easy to generate excessive hydrolysising by-product carboxylic acid under alkalescence, carboxylic acyloxy chlorination, amination method, agents useful for same toxicity is larger, and by product is also more, reaction preference is bad, and aftertreatment is more difficult.
Summary of the invention
The object of the invention is to overcome the shortcoming of prior art, the synthetic method of a kind of S-escitalopram impurity J is provided, the method has advantages of that synthetic route is brief, reaction conditions is gentle, environmental protection, cost are low.
Object of the present invention is achieved through the following technical solutions: the synthetic method of S-escitalopram impurity J, and synthetic route is:
Taking S-escitalopram oxalate as raw material, under hydrogen peroxide exists, in solvent, add acid binding agent, hydrolysis reaction generates S-escitalopram impurity J.
Further, described solvent is any one of toluene, tetrahydrofuran (THF), methylene dichloride, dioxane, ethyl acetate, methyl-sulphoxide, DMF, methyl alcohol or ethanol.
Further, described acid binding agent is triethylamine, Diisopropylamine, diisopropylethylamine, N, any one of N-diethyl methylamine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide or sodium hydroxide.
Further, the weight ratio of described S-escitalopram oxalate, hydrogen peroxide, acid binding agent, solvent is 1:1～30:1～6:2～40.
Further, temperature of reaction is 20～60 DEG C, and the reaction times is 2～48 hours.
Further, also comprise post-processing step, post-treating method is: after question response completes, add saturated sodium carbonate solution, water is extracted with ethyl acetate, and organic phase, after anhydrous sodium sulfate drying, concentrates; Wherein, the weight ratio of described saturated sodium carbonate solution and ethyl acetate is 1:4～20.
The present invention has the following advantages: the present invention, taking S-escitalopram oxalate as starting raw material, than traditional method desired raw material, has advantages of that cost is low, is easy to buy; Synthetic route simply only needs single step reaction, in the gentle and reaction of reaction conditions agents useful for same and solvent contamination little, there is the characteristic of environmental protection; The synthetic S-escitalopram impurity J purity of the present invention is high, yield is high.
Embodiment
Below in conjunction with embodiment, the present invention will be further described, and protection scope of the present invention is not limited to the following stated.
The synthetic method of S-escitalopram impurity J, taking S-escitalopram oxalate as raw material, under hydrogen peroxide exists, adds acid binding agent in solvent, hydrolysis reaction generates S-escitalopram impurity J.
Embodiment 1: the synthetic method of S-escitalopram impurity J, specific as follows:
Under nitrogen protection, S-escitalopram oxalate, salt of wormwood are suspended in tetrahydrofuran (THF), drip hydrogen peroxide, react 6 hours at 20 DEG C.After question response completes, add saturated sodium carbonate solution, water is extracted with ethyl acetate, organic phase is after anhydrous sodium sulfate drying, concentrate to obtain S-escitalopram impurity J, the weight ratio of described S-escitalopram oxalate, hydrogen peroxide, salt of wormwood, tetrahydrofuran (THF) is 1:1:1:2, and the weight ratio of saturated sodium carbonate solution and ethyl acetate is 1:4.
Embodiment 2: the synthetic method of S-escitalopram impurity J, specific as follows:
Under nitrogen protection, S-escitalopram oxalate, potassium hydroxide are suspended in DMF, drip hydrogen peroxide, 60 DEG C of reaction 48h.After question response completes, add saturated sodium carbonate solution, water is extracted with ethyl acetate, organic phase is after anhydrous sodium sulfate drying, concentrate to obtain S-escitalopram impurity J, the weight ratio of described S-escitalopram oxalate, hydrogen peroxide, potassium hydroxide, DMF is 1:30:6:40, and the weight ratio of saturated sodium carbonate solution and ethyl acetate is 1:20.
Embodiment 3: the synthetic method of S-escitalopram impurity J, specific as follows:
Under nitrogen protection, S-escitalopram oxalate, triethylamine are suspended in methyl-sulphoxide, drip hydrogen peroxide, 25 DEG C of reaction 12h.After question response completes, add saturated sodium carbonate solution, water is extracted with ethyl acetate, organic phase is after anhydrous sodium sulfate drying, concentrate to obtain S-escitalopram impurity J, the weight ratio of described S-escitalopram oxalate, hydrogen peroxide, triethylamine, methyl-sulphoxide is 1:10:3:15, and the weight ratio of saturated sodium carbonate solution and ethyl acetate is 1:15.
Embodiment 4: the synthetic method of S-escitalopram impurity J, specific as follows:
Under nitrogen protection, 2g S-escitalopram oxalate, 0.8g anhydrous sodium carbonate are suspended in 30ml ethanol, drip 0.6ml30% (w/w) hydrogen peroxide, 30 DEG C of reaction 18h.After concentrated, add 100ml saturated sodium carbonate solution, 100ml ethyl acetate extraction for water, organic phase, after anhydrous sodium sulfate drying, concentrates to obtain product 0.80g, productive rate 49.6%, liquid phase purity 98%.
Embodiment 5: the synthetic method of S-escitalopram impurity J, specific as follows:
Under nitrogen protection, 2g S-escitalopram oxalate 1.5ml Diisopropylamine is suspended in 50ml toluene, drips 0.8ml30% (w/w) hydrogen peroxide, 34 DEG C of reaction 23h.After concentrated, add 100ml saturated sodium carbonate solution, 100ml ethyl acetate extraction for water, organic phase, after anhydrous sodium sulfate drying, concentrates to obtain product 0.90g, productive rate 55.8%, liquid phase purity 98%.
Embodiment 6: the synthetic method of S-escitalopram impurity J, specific as follows:
Under nitrogen protection; 2g S-escitalopram oxalate, 1.5ml diisopropylethylamine are suspended in 60ml methylene dichloride; drip 0.8ml30% (w/w) hydrogen peroxide, 42 DEG C of reaction 28h, after concentrating; add 100ml saturated sodium carbonate solution; 100ml ethyl acetate extraction for water, organic phase, after anhydrous sodium sulfate drying, concentrates to obtain product 0.85g; productive rate 52.6%, liquid phase purity 98%.
Embodiment 7: the synthetic method of S-escitalopram impurity J, specific as follows:
Under nitrogen protection; by 2g S-escitalopram oxalate, 1.2mlN, N-diethyl methylamine is suspended in 40ml dioxane, drips 0.8ml30% (w/w) hydrogen peroxide; 48 DEG C of reaction 34h; after concentrated, add 100ml saturated sodium carbonate solution, 100ml ethyl acetate extraction for water; organic phase is after anhydrous sodium sulfate drying; concentrate to obtain product 0.90g, productive rate 55.8%, liquid phase purity 98%.
Embodiment 8: the synthetic method of S-escitalopram impurity J, specific as follows:
Under nitrogen protection; 2g S-escitalopram oxalate, 0.9g sodium bicarbonate are suspended in 80ml ethyl acetate; drip 0.8ml30% (w/w) hydrogen peroxide, 25 DEG C of reaction 40h, after concentrating; add 100ml saturated sodium carbonate solution; 100ml ethyl acetate extraction for water, organic phase, after anhydrous sodium sulfate drying, concentrates to obtain product 1.05g; productive rate 64.9%, liquid phase purity 98%.
Embodiment 9: the synthetic method of S-escitalopram impurity J, specific as follows:
Under nitrogen protection; 2g S-escitalopram oxalate, 0.8g salt of wormwood are suspended in 30ml methyl alcohol; drip 0.8ml30% (w/w) hydrogen peroxide, 45 DEG C of reaction 45h, after concentrating; add 100ml saturated sodium carbonate solution; 100ml ethyl acetate extraction for water, organic phase, after anhydrous sodium sulfate drying, concentrates to obtain product 0.85g; productive rate 52.5%, liquid phase purity 98%.
Embodiment 10: the synthetic method of S-escitalopram impurity J, specific as follows:
Under nitrogen protection; 2g S-escitalopram oxalate, 0.6g sodium hydroxide are suspended in 40ml methyl-sulphoxide; drip 0.8ml30% (w/w) hydrogen peroxide, 30 DEG C of reaction 20h, after concentrating; add 100ml saturated sodium carbonate solution; 100ml ethyl acetate extraction for water, organic phase, after anhydrous sodium sulfate drying, concentrates to obtain product 0.98g; productive rate 60.6%, liquid phase purity 98%.
Claims (6)
1. the synthetic method of S-escitalopram impurity J, is characterized in that, synthetic route is:
Taking S-escitalopram oxalate as raw material, under hydrogen peroxide exists, in solvent, add acid binding agent, hydrolysis reaction generates S-escitalopram impurity J.
2. the synthetic method of S-escitalopram impurity J as claimed in claim 1, it is characterized in that, described solvent is any one of toluene, tetrahydrofuran (THF), methylene dichloride, dioxane, ethyl acetate, methyl-sulphoxide, DMF, methyl alcohol or ethanol.
3. the synthetic method of S-escitalopram impurity J as claimed in claim 1, it is characterized in that, described acid binding agent is triethylamine, Diisopropylamine, diisopropylethylamine, N, any one of N-diethyl methylamine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide or sodium hydroxide.
4. the synthetic method of S-escitalopram impurity J as claimed in claim 1, is characterized in that, the weight ratio of described S-escitalopram oxalate, hydrogen peroxide, acid binding agent, solvent is 1:1～30:1～6:2～40.
5. the synthetic method of S-escitalopram impurity J as claimed in claim 1, is characterized in that, temperature of reaction is 20～60 DEG C, and the reaction times is 2～48 hours.
6. the synthetic method of S-escitalopram impurity J as claimed in claim 1, is characterized in that, also comprises post-processing step, post-treating method is: after question response completes, add saturated sodium carbonate solution, water is extracted with ethyl acetate, organic phase, after anhydrous sodium sulfate drying, concentrates; Wherein, the weight ratio of described saturated sodium carbonate solution and ethyl acetate is 1:4～20.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410191633.5A CN103936702A (en) | 2014-05-07 | 2014-05-07 | Synthetic method of escitalopram impurity J |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410191633.5A CN103936702A (en) | 2014-05-07 | 2014-05-07 | Synthetic method of escitalopram impurity J |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103936702A true CN103936702A (en) | 2014-07-23 |
Family
ID=51184614
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410191633.5A Pending CN103936702A (en) | 2014-05-07 | 2014-05-07 | Synthetic method of escitalopram impurity J |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103936702A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1339435A (en) * | 2000-08-18 | 2002-03-13 | H·隆德贝克有限公司 | Method for preparing xitaipulan |
| WO2003007872A2 (en) * | 2001-07-19 | 2003-01-30 | Ranbaxy Laboratories Limited | Process for the preparation of citalopram hydrobromide |
| WO2003057132A2 (en) * | 2002-01-07 | 2003-07-17 | Sun Pharmaceutical Industries Limited | Process for the preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)- 1,3-dihydro-5-isobenzofuran carbonitrile |
| CN1509279A (en) * | 2002-02-27 | 2004-06-30 | ʵ | Process for production of citalopram |
| CN103360353A (en) * | 2013-08-07 | 2013-10-23 | 中国药科大学 | Preparation methods for impurities of escitalopram oxalate |
-
2014
- 2014-05-07 CN CN201410191633.5A patent/CN103936702A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1339435A (en) * | 2000-08-18 | 2002-03-13 | H·隆德贝克有限公司 | Method for preparing xitaipulan |
| WO2003007872A2 (en) * | 2001-07-19 | 2003-01-30 | Ranbaxy Laboratories Limited | Process for the preparation of citalopram hydrobromide |
| WO2003057132A2 (en) * | 2002-01-07 | 2003-07-17 | Sun Pharmaceutical Industries Limited | Process for the preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)- 1,3-dihydro-5-isobenzofuran carbonitrile |
| CN1509279A (en) * | 2002-02-27 | 2004-06-30 | ʵ | Process for production of citalopram |
| CN103360353A (en) * | 2013-08-07 | 2013-10-23 | 中国药科大学 | Preparation methods for impurities of escitalopram oxalate |
Non-Patent Citations (1)
| Title |
|---|
| ASHWINI K.BANALA，等: "Design and Synthesis of 1-(3-(Dimethylamino)propyl)-1-(4-fluorophenyl)1,3-dihydroisobenzofuran-5-carbonitrile(Citalopram)Analogues as Novel Probes for the Serotonin Transporter S1 and S2 Binding Sites", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 56, no. 23, 15 November 2013 (2013-11-15) * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105294477A (en) | Method for preparing lidocaine hydrochloride | |
| CN104610161A (en) | Preparation method for telmisartan | |
| CN105524044A (en) | Trelagliptin impurity and its composition | |
| CN103694188B (en) | The preparation method of Fu benzene Ni Kao oxazoline intermediate | |
| CN103709023A (en) | Synthesis method for 3,5-dichloro-2-pentanone | |
| CN102964268A (en) | Synthesis method of menthyl amide cooling agent | |
| CN103254087B (en) | Preparation method of efavirenz intermediate | |
| CN103936702A (en) | Synthetic method of escitalopram impurity J | |
| CN102690273B (en) | Preparation method of sildenafil | |
| CN105524042A (en) | Method for preparing trelagliptin | |
| CN104151198A (en) | Synthetic method for N-nitrosobis(cyanomethyl)amino | |
| WO2020134137A1 (en) | Method for synthesizing r-3-chloroalanine methyl ester hydrochloride | |
| CN109232313B (en) | Synthesis method of malononitrile | |
| CN103880756B (en) | The preparation method of a kind of Azilsartan intermediate | |
| CN105367391B (en) | A kind of preparation method of the trimethoxy-ethane of 2 chlorine 1,1,1 | |
| CN105130949B (en) | The preparation method of 1- (2,2- difluoro benzo [D] [1,3] dioxole -5- base) cyclopropanecarbonitrile | |
| CN107954824A (en) | A kind of method with menthol synthesis amide of mint | |
| CN102875415B (en) | Compound and preparation method and application thereof | |
| CN104860936B (en) | A kind of preparation method of razaxaban | |
| CN107382788A (en) | A kind of preparation method of 1,2 dinitro guanidine | |
| CN106946724A (en) | The synthetic method of the benzyl malonic acid mono ethyl ester of 2 acetylamino of monoamine base inhibitor class intermediate 2 | |
| CN105837454B (en) | A kind of synthetic method of 3,3- difiuorocyclohexyls methylamine | |
| CN104591939B (en) | A kind of method preparing xenyl acrylic acid ether compound | |
| CN101328110A (en) | Preparation of butoconazole nitrate intermediate | |
| CN104817482A (en) | 2-substituted pyrrolidine compound, preparation method and application thereof in preparation of vildagliptin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140723 |