CN104031023A - Method for synthesizing zotepine - Google Patents
Method for synthesizing zotepine Download PDFInfo
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- CN104031023A CN104031023A CN201410255773.4A CN201410255773A CN104031023A CN 104031023 A CN104031023 A CN 104031023A CN 201410255773 A CN201410255773 A CN 201410255773A CN 104031023 A CN104031023 A CN 104031023A
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- CN
- China
- Prior art keywords
- zotepine
- heptanone
- thiophene
- reaction
- acetic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/14—[b,f]-condensed
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for synthesizing zotepine. The method comprises the following steps: with sulfo-phenylacetic acid as a raw material, firstly, performing cyclization in the presence of polyphosphoric acid and P2O5 to prepare an intermediate thia-heptanone; and with methyl isobutyl ketone as a solvent, performing condensation reaction on thia-heptanone and chloroethyl dimethylamine to prepare the zotepine. The method has the technical benefits that the product yield can be 86.4%, which is increased by 51.4% when being compared with 35% in the prior art, and the effects are very remarkable. The purity of a primary product is as high as 99.8%, which is qualitatively improved when being compared with the 95% in the prior art, and the cost is lowered. The preparation process conditions are reduced, normal pressure and intermediate temperate reactions are adopted, the highest reaction temperature is only 90 DEG C, the reaction danger is greatly degraded, and meanwhile three-waste pollution is reduced.
Description
Technical field:
The present invention relates to a kind of synthetic method of zotepine.
Background technology:
Zotepine is a kind of metitepine class Psychotolytic, English name: Zolepine, and zotepine has another name called Zotepine, and CAS accession number is: 26615-21-4
At present, the existing synthetic method of zotepine has two kinds:
First method is to take thio phenyl acetic acid as raw material, first carries out ring-closure reaction with polyphosphoric acid, and then carries out condensation reaction with dimethylamino monochloroethane, can obtain zotepine.(the chemistry 2-by name of thio phenyl acetic acid is to chlorobenzene sulfenyl toluylic acid.)
Its synthesis technique is as follows: thio phenyl acetic acid and polyphosphoric acid carry out ring-closure reaction between 120 ℃～130 ℃, carry out condensation and generate zotepine at 110 ℃～120 ℃ with dimethylamino monochloroethane again, specific solution is shown in Ueda I et, al, Chem pham bull1978,26:3058.
The defect that this synthetic method exists is: the yield of product is too low, only 35% left and right; The purity of product is not high, below 92%; The temperature requirement of building-up reactions is high, and three-waste pollution is large.
The second is that to take chloro thiophene heptanone be raw material, directly carries out condensation with dimethylamine, can obtain zotepine.The chemistry 8-chlorodiphenyl by name of chloro thiophene heptanone is [b, f] thiotropilium-10 (11H)-chloroethyl ketone also.
Its synthesis technique is as follows: chloro thiophene heptanone passes into dimethylamine under 8～10kg pressure, direct reaction and zotepine.Concrete preparation method has full and accurate record in US3704245.
The defect that this synthetic method exists is: raw materials used price ten costlinesses, so just must cause holding at high price of zotepine, and the expense of patient's medication is too high, and many patients can only abandon the use of this medicine, thereby directly have influence on the generally use of this medicine.
Summary of the invention:
The synthetic method that the object of this invention is to provide a kind of zotepine, it take thio phenyl acetic acid as raw material, not only the purity of disposable products is up to more than 99.8%, and product yield is up to more than 86%, and prior art is only 35%, working condition is gentle, needs only normal pressure, middle temperature, production process potential safety hazard is extremely low, is particularly suitable for low-cost industrial and produces.
The technical solution used in the present invention is:
The synthetic method of a kind of zotepine of the present invention, take thio phenyl acetic acid as raw material, first at polyphosphoric acid and P
2o
5under condition, carry out cyclization and make intermediate thiophene heptanone, then take methyl iso-butyl ketone (MIBK) as solvent, at cold condition, make thiophene heptanone and dimethylamino monochloroethane carry out condensation reaction and make zotepine.
Concrete synthetic method of the present invention is as follows:
The first step, ring-closure reaction: in reaction vessel, first add polyphosphoric acid and P
2o
5, both weight ratios are polyphosphoric acid: P
2o
5=3:1～10:1, is warming up to 80 ℃～90 ℃, adds thio phenyl acetic acid, thio phenyl acetic acid add weight and P
2o
5weight identical, be incubated 2 hours, discharging is poured in frozen water and is stirred 1 hour, filters, water cleans, and dries to obtain thiophene heptanone, yield 98.4%;
Second step, condensation reaction: in reaction vessel, first drop into methyl iso-butyl ketone (MIBK), then the thiophene heptanone that adds the first step to obtain under whipped state, be warming up to 50 ℃～60 ℃ and start to drip dimethylamino monochloroethane, drip and finish rear insulation 3 hours, be then refrigerated to-5 ℃～5 ℃, washing after filtration,, drying get final product to obtain zotepine, yield 90%;
Adopt the effect of acquisition of technology of the present invention:
According to this zotepine synthetic method, there is following beneficial effect:
1. product yield reaches 86.4%, than 35% of prior art, improves 51.4%, and effect is very remarkable.
2. the purity of first product, up to 99.8%, has had the lifting of matter than 95% of prior art, has reduced cost.
3. reduced preparation process condition, adopted normal pressure, the reaction of middle temperature, maximum temperature is only 90 ℃, has greatly reduced reactivity hazard, has reduced three-waste pollution simultaneously.
Accompanying drawing explanation:
Fig. 1 is synthetic Engineering Route figure of the present invention.
Embodiment:
Below in conjunction with specific examples, the invention will be further described:
Take thio phenyl acetic acid as raw material, first at polyphosphoric acid and P
2o
5under condition, carry out cyclization, make intermediate (thiophene heptanone), then be that solvent bends down gentle dimethylamino monochloroethane and carries out condensation reaction and obtain zotepine in methyl iso-butyl ketone (MIBK).
Embodiment 1:
The first step, ring-closure reaction: in 1000ml four-hole boiling flask, first drop into 300g polyphosphoric acid and 100gP
2o
5, be warming up to 80 ℃～90 ℃, add thio phenyl acetic acid 100g, be incubated 2 hours, for stirring in frozen water 2000g 1 hour, filter, water cleans, and dries to obtain 90g thiophene heptanone, yield 96.2%;
Second step, condensation reaction: in 1000ml four-hole boiling flask, first drop into 500g methyl iso-butyl ketone (MIBK), under stirring, add 90g thiophene heptanone to be warming up to 50 ℃～60 ℃, drip 120g dimethylamino monochloroethane, rear equality of temperature keeps 3 hours, be refrigerated to below 5 ℃, filter, wash and to obtain zotepine wet product 127g; Dry to obtain dry product 112g, yield 95.6%.
Embodiment 2:
The first step, ring-closure reaction: in 1000ml four-hole boiling flask, first drop into 600g polyphosphoric acid and 100gP
2o
5, be warming up to 80 ℃～90 ℃, add thio phenyl acetic acid 100g, be incubated 2 hours, for stirring in frozen water 2000g 1 hour, filter, water cleans, and dries to obtain 90.5g thiophene heptanone, yield 96.4%;
Second step, condensation reaction: in 1000ml four-hole boiling flask, first drop into 500g methyl iso-butyl ketone (MIBK), under stirring, add 92g thiophene heptanone to be warming up to 50 ℃～60 ℃, drip 120g dimethylamino monochloroethane, rear equality of temperature keeps 3 hours, be refrigerated to below 5 ℃, filter, wash and to obtain wet product zotepine 130g; Dry to obtain dry product 113g, yield 95.8%.
Embodiment 3:
The first step, ring-closure reaction: in 1000ml four-hole boiling flask, first drop into 1000g polyphosphoric acid and 100gP
2o
5, be warming up to 80 ℃～90 ℃, add thio phenyl acetic acid 100g, be incubated 2 hours, for stirring in frozen water 2000g 1 hour, filter, water cleans, and dries to obtain 89.5g thiophene heptanone, yield 95.8%;
Second step, condensation reaction: in 1000ml four-hole boiling flask, first drop into 500g methyl iso-butyl ketone (MIBK), under stirring, add 89g thiophene heptanone to be warming up to 50 ℃～60 ℃, drip 120g dimethylamino monochloroethane, rear equality of temperature keeps 3 hours, be refrigerated to below 5 ℃, filter, wash and to obtain wet product zotepine 125g; Dry to obtain dry product 110g, yield 95.5%.
Claims (1)
1. a synthetic method for zotepine, take thio phenyl acetic acid as raw material, first at polyphosphoric acid and P
2o
5under condition, carry out cyclization and make intermediate thiophene heptanone, then take methyl iso-butyl ketone (MIBK) as solvent, make thiophene heptanone and dimethylamino monochloroethane carry out condensation reaction make zotepine at cold condition, concrete synthetic method is as follows:
The first step, ring-closure reaction: in reaction vessel, first add polyphosphoric acid and P
2o
5, both weight ratios are polyphosphoric acid: P
2o
5=3:1～10:1, is warming up to 80 ℃～90 ℃, adds thio phenyl acetic acid, thio phenyl acetic acid add weight and P
2o
5weight identical, be incubated 2 hours, discharging is poured in frozen water and is stirred 1 hour, filters, water cleans, and dries to obtain thiophene heptanone, yield 98.4%;
Second step, condensation reaction: in reaction vessel, first drop into methyl iso-butyl ketone (MIBK), then the thiophene heptanone that adds the first step to obtain under whipped state, be warming up to 50 ℃～60 ℃ and start to drip dimethylamino monochloroethane, drip and finish rear insulation 3 hours, be then refrigerated to-5 ℃～5 ℃, washing after filtration,, drying get final product to obtain zotepine, yield 90%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410255773.4A CN104031023A (en) | 2014-06-10 | 2014-06-10 | Method for synthesizing zotepine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410255773.4A CN104031023A (en) | 2014-06-10 | 2014-06-10 | Method for synthesizing zotepine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104031023A true CN104031023A (en) | 2014-09-10 |
Family
ID=51462044
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410255773.4A Pending CN104031023A (en) | 2014-06-10 | 2014-06-10 | Method for synthesizing zotepine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104031023A (en) |
-
2014
- 2014-06-10 CN CN201410255773.4A patent/CN104031023A/en active Pending
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| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140910 |
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| WD01 | Invention patent application deemed withdrawn after publication |