CN105503774B - A kind of preparation method of S-1574 intermediate - Google Patents
A kind of preparation method of S-1574 intermediate Download PDFInfo
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- CN105503774B CN105503774B CN201511013380.3A CN201511013380A CN105503774B CN 105503774 B CN105503774 B CN 105503774B CN 201511013380 A CN201511013380 A CN 201511013380A CN 105503774 B CN105503774 B CN 105503774B
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Abstract
The invention belongs to chemosynthesis technical fields, and in particular to a kind of preparation method of S-1574 intermediate.This method comprises the following steps：By 2-（N- Methyl-N-phenyls-sulfamic）The chloro- benzoic acid of -4- is added in organic solvent, is heated to reflux after the mixed liquor of chlorinating agent and organic solvent is added, and reaction, which finishes, to be cooled to room temperature；The mixed liquor for adding cyclization reagent and organic solvent is heated to reflux；Reaction solution is added to the water after completion of the reaction and is hydrolyzed, by layering, organic solvent extraction, after combined organic phase is concentrated, other solvents are added to carry out being refining to obtain the chloro- 6- methyl of S-1574 intermediate 3--dibenzo [c, f] [1,2] sulphur azatropylidene -11（6H）-one -5,5- dioxide.This method uses thionyl chloride for chlorinating agent, and titanium tetrachloride is cyclization reagent, and reaction condition is of less demanding, and equipment requirement is simple, and production process is easy to operate, safely controllable, is more suitable for industrialized production.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and in particular to the chloro- 6- methyl of a kind of S-1574 intermediate 3--two
Benzo [c, f] [1,2] sulphur azatropylidene -11（6H）The preparation method of -one -5,5- dioxide.
Background technology
S-1574 trade name Tatinol, [(3- chloro-6,11-dihydro -6- methyldiphenyls are simultaneously [c, f] by the entitled 7- of chemistry
[1,2]-sulphur azatropylidene -11- bases)-amino] enanthic acid S, S- dioxide sodium salt；By controlling for Shiweiya Int'l Co's production
Treat the drug of phrenoblabia.S-1574 in December, 2001, register at home by import, for treat it is light, in or severe depression
Disease, neurogenic and reactive depression, the Anxiety depression etc. of body especially gastrointestinal discomfort, have in human body pair and depression
The anxiety disorder of pass has effect.S-1574 is a kind of 5-HT reuptakes agonist, can adjust hippocampus and almond and cell
The remodeling of dendron, incidence of side effects is low, is safely and effectively antidepressant.
The chloro- 6- methyl of 3--dibenzo [c, f] [1,2] sulphur azatropylidene -11（6H）-one -5,5- dioxide is synthesis thiophene naphthalene
The important intermediate of general spit of fland sodium, molecular formula C14H10ClNO3S, molecular weight 307.75, CAS 26638-53-9, structural formula
For：
。
What the Sun Liang etc. of Wuhan Engineering Univ was delivered《The chloro- 6- methyl of 3--dibenzo [c, f] [1,2] sulphur azatropylidene -11
（6H）The synthesis of -one -5,5- dioxide》（Fine-chemical intermediate, the 3rd phase in 2009, volume 39）In, use polyphosphoric acids
（PPA）Title intermediate is made as dehydration condensation reagent.Patent CN104031005A is disclosed among a kind of S-1574
The preparation method of body, specially：During 339KG intermediate Bs are added in 2000L reaction kettles, it is slowly added to polyphosphoric acids 700KG,
It opens and is steam heated to 40 degree or so, open stirring, be warming up to 75 degree and react 4 hours.Liquid phase monitors intermediate B conversion completely,
30 degree are cooled to, ice water 800KG is squeezed into, continues to be cooled to 10 degree, heat preservation crystallization 2 hours centrifuges to obtain white solid weight in wet base
386KG, HPLC：98.2%.Obtained solid is gone in reaction kettle, has the 95% ethyl alcohol 1300KG squeezed into advance in kettle, is heated
After dissolving completely, be cooled to 5 degree of crystallizations 4 hours, centrifuge 60 degree of drying of fine work there are finished product 292KG, yield 95.1%, HPLC：
99.8%.Polyphosphoric acids is a kind of glutinous thick liquid of water white transparency, has corrosivity, belongs to two pole mineral acid corrosives.Poly
Phosphoric acid room temperature is glassy, and 50 DEG C or more mobility just occur, and reaction temperature need to reach 100 DEG C or more, therefore use
And its it is inconvenient.It is industrial to prepare the chloro- 6- methyl of 3--dibenzo [c, f] [1,2] sulphur azatropylidene -11（6H）-one -5,5- dioxies
Compound, if using polyphosphoric acids（PPA）Title intermediate is made as dehydration condensation reagent but that there are dosages is too big, inconvenient for use
The shortcomings of.
What Wuhan Engineering Univ Cao Shuan etc. was delivered《The chloro- 6,11- dihydrogen-5,5-dioxo-6s -6- methyl of 11- amino -3--two
The synthesis of benzo [c, f] [1,2] sulphur azepine》（Fine-chemical intermediate, the 2nd phase of April in 2010 volume 40）In, use five oxidations
Phosphorus carries out chlorination, and alchlor is reused after processing and does catalyst progress ring-closure reaction, title intermediate is made.Its disadvantage
First, to be hydrolyzed after chlorination, byproduct phosphoric acid, which is difficult to remove in embodying from reaction, causes post-processing more to operate
It is cumbersome.Second is that making catalyst using alchlor, since alchlor is colourless transparent crystal or white and micro-strip is lurid
Crystalline powder, solid, which is added in reaction system, to be dissolved rapidly, and because the unsmooth cause reaction speed of the big stirring of density also can be compared with
Slowly.Therefore, be not suitable for industrialized production, third, being hydrolyzed after ring-closure reaction, hydrolyzate contains a large amount of aluminium salts, environmental protection treatment pressure
Power is big.
Invention content
In order to solve the above technical problem, the present invention provides a kind of chloro- 6- methyl-hexichol of S-1574 intermediate 3-
And [c, f] [1,2] sulphur azatropylidene -11（6H）The preparation method of -one -5,5- dioxide.
The present invention is realized by following technical solutions：
A kind of preparation method of S-1574 intermediate, includes the following steps：
（1）By 2-（N- Methyl-N-phenyls-sulfamic）The chloro- benzoic acid of -4- is added in organic solvent,
（2）It is heated to reflux after the mixed liquor of chlorinating agent and organic solvent is added, reaction, which finishes, to be cooled to room temperature；
（3）The mixed liquor for adding cyclization reagent and organic solvent is heated to reflux；Water is added in reaction solution after completion of the reaction
In be hydrolyzed, by layering, organic solvent extraction is added other solvents and is refining to obtain after concentrating combined organic phase
To the chloro- 6- methyl of S-1574 intermediate 3--dibenzo [c, f] [1,2] sulphur azatropylidene -11（6H）-one -5,5- titanium dioxides
Object.
Reaction equation is as follows：
In the preparation method of above-mentioned S-1574 intermediate, the step（1）Middle organic solvent is dichloromethane,
Weight is 2-（N- Methyl-N-phenyls-sulfamic）8-10 times of the chloro- benzoic acid of -4-.
In the preparation method of above-mentioned S-1574 intermediate, the step（2）Middle chlorinating agent and organic solvent
Mixed liquor is the mixed liquor of thionyl chloride and dichloromethane, wherein thionyl chloride and 2-（N- Methyl-N-phenyls-sulfamic）-
The molar ratio of the chloro- benzoic acid of 4- is 1.5-2.0:1, dichloromethane and 2-（N- Methyl-N-phenyls-sulfamic）The chloro- benzene first of -4-
The weight ratio of acid is 1-3:1.
In the preparation method of above-mentioned S-1574 intermediate, the step（3）Middle cyclization reagent and organic solvent
Mixed liquor is the mixed liquor of titanium tetrachloride and dichloromethane, wherein titanium tetrachloride and 2-（N- Methyl-N-phenyls-sulfamic）-
The molar ratio of the chloro- benzoic acid of 4- is 1.5-2.0:1, dichloromethane and 2-（N- Methyl-N-phenyls-sulfamic）The chloro- benzene first of -4-
The weight ratio of acid is 1-3:1.
In the preparation method of above-mentioned S-1574 intermediate, the step（2）And step（3）Middle reflux temperature is
40 DEG C -44 DEG C, the reaction time is 2-5 hours.
In the preparation method of above-mentioned S-1574 intermediate, the step（3）The middle organic solvent that uses of extracting is
Dichloromethane, with 2-（N- Methyl-N-phenyls-sulfamic）The weight ratio of the chloro- benzoic acid of -4- is 1-5:1.
In the preparation method of above-mentioned S-1574 intermediate, the step（3）In for refined other solvents be
Methanol, with 2-（N- Methyl-N-phenyls-sulfamic）The weight ratio of the chloro- benzoic acid of -4- is 1-3:1.
Preferably, the preparation method of above-mentioned S-1574 intermediate, steps are as follows：By 2-（N- Methyl-N-phenyls-
Sulfamic）The chloro- benzoic acid of -4- is added in dichloromethane, and the weight of dichloromethane used is 2-（N- Methyl-N-phenyls-amine
Sulfonyl）8-10 times of the weight of the chloro- benzoic acid of -4-, thionyl chloride and 2- used（N- Methyl-N-phenyls-sulfamic）-4-
The molar ratio of chloro- benzoic acid is 1.5-2.0:1, dichloromethane and 2-（N- Methyl-N-phenyls-sulfamic）The chloro- benzene first of -4-
The weight ratio of acid is 1-3:0 DEG C -44 DEG C of Isosorbide-5-Nitrae is heated to reflux, and is reacted 2-5 hours, after completion of the reaction, is cooled to room temperature, used four
Titanium chloride and 2-（N- Methyl-N-phenyls-sulfamic）The molar ratio of the chloro- benzoic acid of -4- is 1.5-2.0:1, dichloromethane with
2-（N- Methyl-N-phenyls-sulfamic）The weight ratio of the chloro- benzoic acid of -4- is 1-3:0 DEG C -44 DEG C of Isosorbide-5-Nitrae is heated to reflux, reaction
2-5 hours；Reaction solution is added to the water after completion of the reaction and is hydrolyzed, is layered, water layer is extracted using dichloromethane, is used
Dichloromethane and 2-（N- Methyl-N-phenyls-sulfamic）The weight ratio of the chloro- benzoic acid of -4- is 1-5:1, merge organic layer,
Refining methanol is added after being concentrated to dryness, filter, be dried to obtain the chloro- 6- methyl of tianeptine intermediate 3--dibenzo [c, f] [1,
2] sulphur azatropylidene -11（6H）-one -5,5- dioxide.
Beneficial effects of the present invention are：
The preparation method of the S-1574 intermediate of the present invention, reaction use one kettle way, are continuously finished, reaction condition is wanted
Ask not high, it is easy to operate.This method uses thionyl chloride for chlorinating agent, and titanium tetrachloride is cyclization reagent, is without the use of poly
The reagent inconvenient to use such as phosphoric acid, alchlor, production process is safe, controllable, after post-processing hydrolyzate adjusts pH to neutrality
It is separated by solid-liquid separation, obtains titanium salt and low saline salinity waste water, be easily handled, it is environmentally friendly, it is more suitable for industrialized production.It is prepared
The chloro- 6- methyl of S-1574 intermediate 3--dibenzo [c, f] [1,2] sulphur azatropylidene -11（6H）-one -5,5- dioxide
Yield is 94% or more, liquid phase purity > 99.6%.
Specific implementation mode
The present invention is further described with reference to specific embodiment, so that those skilled in the art knows more about
The present invention, but be not intended to limit the present invention.
Embodiment 1
By 32.6g（0.1mol）2-（N- Methyl-N-phenyls-sulfamic）The chloro- benzoic acid of -4- is added to 260g dichloromethanes
In alkane, 17.8g is added（0.15mol）The mixed liquor of thionyl chloride and 32.6g dichloromethane, 40 DEG C -44 DEG C are heated to reflux, reaction
It 2 hours, after completion of the reaction, is cooled to room temperature, adds 28.4g（0.15mol）The mixing of titanium tetrachloride and 32.6g dichloromethane
Liquid, 40 DEG C -44 DEG C are heated to reflux, and react 2 hours；Reaction solution is added in 326g water after completion of the reaction and is hydrolyzed, is layered, it will
Water layer is extracted using 97.8g dichloromethane, merges organic layer, and 32.6g refining methanols are added after being concentrated to dryness, and is filtered, dry
To the chloro- 6- methyl of tianeptine intermediate 3--dibenzo [c, f] [1,2] sulphur azatropylidene -11（6H）-one -5,5- dioxide
29.0g, molar yield 94.2%, liquid phase purity > 99.6%.
Embodiment 2：
By 32.6g（0.1mol）2-（N- Methyl-N-phenyls-sulfamic）The chloro- benzoic acid of -4- is added to 326g dichloromethanes
In alkane, 17.8g is added（0.15mol）The mixed liquor of thionyl chloride and 32.6g dichloromethane, 40 DEG C -44 DEG C are heated to reflux, reaction
It 4 hours, after completion of the reaction, is cooled to room temperature, adds 28.4g（0.15mol）The mixing of titanium tetrachloride and 32.6g dichloromethane
Liquid, 40 DEG C -44 DEG C are heated to reflux, and react 3 hours；Reaction solution is added in 326g water after completion of the reaction and is hydrolyzed, is layered, it will
Water layer is extracted using 97.8g dichloromethane, merges organic layer, and 32.6g refining methanols are added after being concentrated to dryness, and is filtered, dry
To the chloro- 6- methyl of tianeptine intermediate 3--dibenzo [c, f] [1,2] sulphur azatropylidene -11（6H）-one -5,5- dioxide
29.2g, molar yield 94.9%, liquid phase purity > 99.6%.
Claims (5)
1. a kind of preparation method of S-1574 intermediate, which is characterized in that include the following steps：
（1）By 2-（N- Methyl-N-phenyls-sulfamic）The chloro- benzoic acid of -4- is added in organic solvent,
（2）It is heated to reflux after the mixed liquor of chlorinating agent and organic solvent is added, reaction, which finishes, to be cooled to room temperature；
（3）The mixed liquor for adding cyclization reagent and organic solvent is heated to reflux；After completion of the reaction by reaction solution be added to the water into
Row hydrolysis, by layering, organic solvent extraction is added other solvents and carries out being refining to obtain thiophene after concentrating combined organic phase
The chloro- 6- methyl of Nabumetone spit of fland sodium intermediate 3--dibenzo [c, f] [1,2] sulphur azatropylidene -11（6H）-one -5,5- dioxide；
The step（1）Middle organic solvent is dichloromethane, weight 2-（N- Methyl-N-phenyls-sulfamic）- 4- is chloro-
8-10 times of benzoic acid；
The step（2）The mixed liquor of middle chlorinating agent and organic solvent is the mixed liquor of thionyl chloride and dichloromethane, wherein
Thionyl chloride and 2-（N- Methyl-N-phenyls-sulfamic）The molar ratio of the chloro- benzoic acid of -4- is 1.5-2.0:1, dichloromethane
With 2-（N- Methyl-N-phenyls-sulfamic）The weight ratio of the chloro- benzoic acid of -4- is 1-3:1；
The step（3）The mixed liquor of middle cyclization reagent and organic solvent is the mixed liquor of titanium tetrachloride and dichloromethane, wherein
Titanium tetrachloride and 2-（N- Methyl-N-phenyls-sulfamic）The molar ratio of the chloro- benzoic acid of -4- is 1.5-2.0:1, dichloromethane
With 2-（N- Methyl-N-phenyls-sulfamic）The weight ratio of the chloro- benzoic acid of -4- is 1-3:1.
2. the preparation method of S-1574 intermediate according to claim 1, which is characterized in that the step（2）With
Step（3）Middle reflux temperature is 40 DEG C -44 DEG C, and the reaction time is 2-5 hours.
3. the preparation method of S-1574 intermediate according to claim 1, which is characterized in that the step（3）In
It is dichloromethane to extract the organic solvent used, with 2-（N- Methyl-N-phenyls-sulfamic）The weight of the chloro- benzoic acid of -4-
Than for 1-5:1.
4. the preparation method of S-1574 intermediate according to claim 1, which is characterized in that the step（3）In
It is methanol for refined other solvents, with 2-（N- Methyl-N-phenyls-sulfamic）The weight ratio of the chloro- benzoic acid of -4- is
1-3:1。
5. the preparation method of S-1574 intermediate according to claim 1, which is characterized in that steps are as follows：By 2-
（N- Methyl-N-phenyls-sulfamic）The chloro- benzoic acid of -4- is added in dichloromethane, and the weight of dichloromethane used is 2-
（N- Methyl-N-phenyls-sulfamic）8-10 times of the weight of the chloro- benzoic acid of -4-, addition thionyl chloride and dichloromethane mix
Close thionyl chloride and 2- used in liquid（N- Methyl-N-phenyls-sulfamic）The molar ratio of the chloro- benzoic acid of -4- is 1.5-2.0:1,
Dichloromethane and 2-（N- Methyl-N-phenyls-sulfamic）The weight ratio of the chloro- benzoic acid of -4- is 1-3:0 DEG C of -44 DEG C of heating of Isosorbide-5-Nitrae
Reflux reacts 2-5 hours, after completion of the reaction, is cooled to room temperature, adds the mixed liquor of titanium tetrachloride and dichloromethane, used
Titanium tetrachloride and 2-（N- Methyl-N-phenyls-sulfamic）The molar ratio of the chloro- benzoic acid of -4- is 1.5-2.0:1, dichloromethane
With 2-（N- Methyl-N-phenyls-sulfamic）The weight ratio of the chloro- benzoic acid of -4- is 1-3:0 DEG C -44 DEG C of Isosorbide-5-Nitrae is heated to reflux, instead
It answers 2-5 hours；Reaction solution is added to the water after completion of the reaction and is hydrolyzed, is layered, water layer is extracted using dichloromethane, is made
Dichloromethane and 2-（N- Methyl-N-phenyls-sulfamic）The weight ratio of the chloro- benzoic acid of -4- is 1-5:1, merge organic
Layer, is added refining methanol after being concentrated to dryness, filter, be dried to obtain the chloro- 6- methyl of tianeptine intermediate 3--dibenzo [c, f]
[1,2] sulphur azatropylidene -11（6H）-one -5,5- dioxide.
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| CN110172045B (en) * | 2019-06-05 | 2023-05-12 | 甘肃皓天医药科技有限责任公司 | Preparation method of intermediate for preparing tianeptine sodium |
| CN110862329B (en) * | 2019-11-18 | 2022-09-27 | 山东省化工研究院 | Synthesis method of 7-aminoheptanoic acid hydrochloride |
| CN114507192A (en) * | 2022-02-15 | 2022-05-17 | 上海微巨实业有限公司 | Preparation method of intermediate for preparing tianeptine sodium |
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| WO2015138791A1 (en) * | 2014-03-12 | 2015-09-17 | The Trustees Of Columbia University In The City Of New York | A new class of mu-opioid receptor agonists |
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Denomination of invention: Method for preparing tianeptine sodium intermediate Effective date of registration: 20190715 Granted publication date: 20181106 Pledgee: Qilu bank Limited by Share Ltd. Ji'nan high tech branch Pledgor: JINAN CHENGHUISHUANGDA CHEMICAL INDUSTRY Co.,Ltd. Registration number: 2019370000164 |
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