CN103936702A - Synthetic method of escitalopram impurity J - Google Patents
Synthetic method of escitalopram impurity J Download PDFInfo
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- 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
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- escitalopram
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- ethyl acetate
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- 229960004341 escitalopram Drugs 0.000 title claims abstract description 39
- 239000012535 impurity Substances 0.000 title claims abstract description 38
- 238000010189 synthetic method Methods 0.000 title claims abstract description 28
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 title abstract 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 229960005086 escitalopram oxalate Drugs 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000012141 concentrate Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- KTGRHKOEFSJQNS-BDQAORGHSA-N (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;oxalic acid Chemical compound OC(=O)C(O)=O.C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 KTGRHKOEFSJQNS-BDQAORGHSA-N 0.000 abstract 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000007796 conventional method Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 7
- 229960001653 citalopram Drugs 0.000 description 7
- 238000003810 ethyl acetate extraction Methods 0.000 description 7
- 239000007791 liquid phase Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 230000006340 racemization Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000011688 Generalised anxiety disease Diseases 0.000 description 2
- -1 amide compound Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 208000029364 generalized anxiety disease Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000013456 study Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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.
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| CN201410191633.5A CN103936702A (en) | 2014-05-07 | 2014-05-07 | Synthetic method of escitalopram impurity J |
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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 | Process for preparing citalopram |
| 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 | The production method 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 | Process for preparing citalopram |
| 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 | The production method 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) * |
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Application publication date: 20140723 |