CN101417986A - Method for preparing 2-chlorophenothiazine - Google Patents
Method for preparing 2-chlorophenothiazine Download PDFInfo
- Publication number
- CN101417986A CN101417986A CNA2008101363971A CN200810136397A CN101417986A CN 101417986 A CN101417986 A CN 101417986A CN A2008101363971 A CNA2008101363971 A CN A2008101363971A CN 200810136397 A CN200810136397 A CN 200810136397A CN 101417986 A CN101417986 A CN 101417986A
- Authority
- CN
- China
- Prior art keywords
- chloro
- phenothiazine
- preparation
- pentanoic
- reaction
- 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.)
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- KFZGLJSYQXZIGP-UHFFFAOYSA-N 2-chloro-10h-phenothiazine Chemical compound C1=CC=C2NC3=CC(Cl)=CC=C3SC2=C1 KFZGLJSYQXZIGP-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title abstract description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 230000003197 catalytic effect Effects 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000011630 iodine Substances 0.000 claims abstract description 3
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 3
- 229910052742 iron Inorganic materials 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 11
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 claims description 6
- 239000005864 Sulphur Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- OHHIBZKYXJDQEU-UHFFFAOYSA-N 3-chloro-n-phenylaniline Chemical compound ClC1=CC=CC(NC=2C=CC=CC=2)=C1 OHHIBZKYXJDQEU-UHFFFAOYSA-N 0.000 abstract 2
- QEWKYTGBJVAKSE-UHFFFAOYSA-N 3-amino-2-(3-chlorophenyl)benzoic acid Chemical compound ClC=1C=C(C=CC=1)C1=C(C(=O)O)C=CC=C1N QEWKYTGBJVAKSE-UHFFFAOYSA-N 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- JONFYSWOLCTYFK-UHFFFAOYSA-N 2-(2,3-dichloroanilino)benzoic acid Chemical group OC(=O)C1=CC=CC=C1NC1=CC=CC(Cl)=C1Cl JONFYSWOLCTYFK-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000031361 Hiccup Diseases 0.000 description 1
- ZGUGWUXLJSTTMA-UHFFFAOYSA-N Promazinum Chemical compound C1=CC=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZGUGWUXLJSTTMA-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- -1 fen thiophene class Chemical class 0.000 description 1
- 230000006266 hibernation Effects 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 230000002557 soporific effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The invention relates to a method for preparing 2-chloro-phenothiazine, which comprises the following steps: (1) performing deacidification reaction on 2-(3-chlorphenyl)-amino benzoic acid in the presence of a catalytic amount of iron at a temperature of between 160 and 180 DEG C to generate m-chloro diphenylamine; and (2) performing cyclization reaction on the obtained m-chloro diphenylamine and sulfur in the presence of a catalytic amount of iodine at a temperature of between 110 and 150 DEG C to obtain the 2-chloro-phenothiazine. The method has a short synthetic route and a simple process; and based on the target product 2-chloro-phenothiazine, the total mol yield is more than 70 percent, the purity is more than 99.7 percent, and the production cost is low.
Description
Technical field
The present invention relates to a kind of preparation method of 2-chloro phenothiazine.
Background technology
Torazina is the representative drugs in the fen thiophene class medicine, is mainly used in antipsychotic, strengthens soporific, narcotic, analgesic agent and anticonvulsive agent, also can be used for the town of vomiting and intractable singultus is told and causes artificial hibernation etc.
The 2-chloro phenothiazine is the important intermediate of synthetic hydrochloric acid chlorpromazine, and its structural formula is:
At present, in patent documentation, do not see the play-by-play of preparation 2-chloro phenothiazine as yet, and the price of 2-chloro phenothiazine is generally higher on the market.
Summary of the invention
Technical problem to be solved by this invention is in order to overcome the deficiencies in the prior art and provide a kind of preparation method of 2-chloro phenothiazine, and this method yield height, cost are low.
For solving above technical problem, the present invention takes following technical scheme:
A kind of preparation method of 2-chloro phenothiazine comprises the steps:
(1), 2-(3-chloro-phenyl-) benzaminic acid is in the presence of the iron of catalytic amount, in 160～180 ℃ of following depickling reaction generation m-chloro pentanoic that take place;
(2), by step (1) gained m-chloro pentanoic in the presence of the iodine of catalytic amount, at 110～150 ℃ ring-closure reactions taking place down with sulphur makes described 2-chloro phenothiazine.
Aforesaid method is expressed as follows with synthetic route:
Described 2-(3-chloro-phenyl-) benzaminic acid is made with 0-chloro-benzoic acid generation condensation reaction in pH7.5～8 time by m-chloro aniline, and the temperature of condensation reaction is 90～110 ℃, and the reaction times is 4～6 hours.
The molar ratio of m-chloro aniline and 0-chloro-benzoic acid is preferably 1～1.2:1.
The molar ratio of described m-chloro pentanoic and sulphur is preferably 1.05～1.1:1.
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
1, synthetic route is short, technology is easy;
2, in target product 2-chloro phenothiazine, total molar yield is more than 70%, and purity is more than 99.7%, and production cost is low.
Embodiment
Below the specific embodiment of the present invention is described, but be not limited to these embodiment.
Embodiment 1
Preparation method according to the 2-chloro phenothiazine of present embodiment comprises the steps:
(1), the m-chloro pentanoic is synthetic: add 24 kilograms of 0-chloro-benzoic acids in the 100L reactor of reflux distillation condenser is housed, 21.5 kilograms of 30% sodium hydroxide solutions, slowly drip 21.6 kilograms of m-chloro anilines, keep about 100 ℃ of temperature, drip and finish, stir insulation 5 hours, add an amount of 30% hydrochloric acid and separate out the grey crystallization and be 2-(3-chloro-phenyl-) benzaminic acid (another name is acidum clofenamicum).Put in the decarboxylation still after with whizzer crystallization being dried, add 1 kilogram of iron powder, be warming up to 170 ℃, slowly decarboxylize distill 28 kilograms of m-chloro pentanoic, analysis content 99.56%, molar yield 90% is used for next step reaction.
(2), the 2-chloro phenothiazine is synthetic: drop into 28 kilograms of m-chloro pentanoic in the cyclization still of 100L, 4.2 kilograms in sulphur, add 0.5 kilogram of iodine, slowly be warming up to 120 ℃, hydrogen sulfide is progressively emitted in reaction, sodium hydroxide solution with 30% absorbs, be incubated 5 hours, treat the hydrogen sulfide postcooling that no longer comes out, add chlorobenzene, the decolouring of less investment carbon content active, the suction filtration crystallisation by cooling gets product 2-chloro phenothiazine, with the whizzer water dumping dry about 25 kilograms of dry products, molar yield 77.8%, HPLC analyzes content 99.75%.
Embodiment 2
Preparation method according to the 2-chloro phenothiazine of present embodiment comprises the steps:
(1), the m-chloro pentanoic is synthetic: add 24 kilograms of 0-chloro-benzoic acids in the 100L reactor of reflux distillation condenser is housed, 41.2 kilograms of 30% sodium hydroxide solutions, slowly drip 21.6 kilograms of m-chloro anilines, keep about 100 ℃ of temperature, drip and finish, stir insulation 5 hours, add an amount of 30% hydrochloric acid and separate out the grey crystallization and be acidum clofenamicum.Put in the decarboxylation still after with whizzer crystallization being dried, add 1 kilogram of iron powder, be warming up to 180 ℃, slowly decarboxylize distill 27.5 kilograms of m-chloro pentanoic, analysis content is more than 99.60%, molar yield 88.4% is used for next step reaction.
(2), the 2-chloro phenothiazine is synthetic: drop into 27.5 kilograms of m-chloro pentanoic in the cyclization still of 100L, 4.1 kilograms in sulphur, add 0.5 kilogram of iodine, slowly be warming up to 150 ℃, hydrogen sulfide is progressively emitted in reaction, sodium hydroxide solution with 30% absorbs, be incubated 5 hours, treat the hydrogen sulfide postcooling that no longer comes out, add chlorobenzene, the decolouring of less investment carbon content active, the suction filtration crystallisation by cooling gets product 2-chloro phenothiazine, with the whizzer water dumping dry about 25.5 kilograms of dry products, molar yield 80.8%, HPLC analyzes content 99.80%.
Claims (4)
1, a kind of preparation method of 2-chloro phenothiazine is characterized in that: comprise the steps:
(1), 2-(3-chloro-phenyl-) benzaminic acid is in the presence of the iron of catalytic amount, in 160～180 ℃ of following depickling reaction generation m-chloro pentanoic that take place;
(2), by step (1) gained m-chloro pentanoic in the presence of the iodine of catalytic amount, at 110～150 ℃ ring-closure reactions taking place down with sulphur makes described 2-chloro phenothiazine.
2, the preparation method of a kind of 2-chloro phenothiazine according to claim 1, it is characterized in that: described 2-(3-chloro-phenyl-) benzaminic acid is made at pH 7.5～8 times and 0-chloro-benzoic acid generation condensation reaction by m-chloro aniline, the temperature of condensation reaction is 90～110 ℃, and the reaction times is 4～6 hours.
3, the preparation method of a kind of 2-chloro phenothiazine according to claim 2 is characterized in that: the molar ratio of m-chloro aniline and 0-chloro-benzoic acid is 1～1.2:1.
4, according to the preparation method of any described a kind of 2-chloro phenothiazine in the claim 1 to 3, it is characterized in that: the molar ratio of described m-chloro pentanoic and sulphur is 1.05～1.1:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101363971A CN101417986A (en) | 2008-12-01 | 2008-12-01 | Method for preparing 2-chlorophenothiazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101363971A CN101417986A (en) | 2008-12-01 | 2008-12-01 | Method for preparing 2-chlorophenothiazine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101417986A true CN101417986A (en) | 2009-04-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008101363971A Pending CN101417986A (en) | 2008-12-01 | 2008-12-01 | Method for preparing 2-chlorophenothiazine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101417986A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103951636A (en) * | 2014-04-21 | 2014-07-30 | 江苏飞亚化学工业有限责任公司 | Method for synthesizing phenothiazine by using fixed bed |
| CN104311508A (en) * | 2014-09-29 | 2015-01-28 | 苏州大学 | Synthetic method of iron-catalyzed phenothiazine compound |
| CN105524016A (en) * | 2015-11-11 | 2016-04-27 | 中国科学院宁波材料技术与工程研究所 | Synthetic method and application of phenothiazine and/or derivative thereof |
| CN107245062A (en) * | 2017-07-17 | 2017-10-13 | 启东市瑞丰化工有限公司 | A kind of 2 chloro phenothiazine preparation technologies |
| CN113429366A (en) * | 2021-05-21 | 2021-09-24 | 常州康普药业有限公司 | Preparation method of chlorpromazine hydrochloride |
-
2008
- 2008-12-01 CN CNA2008101363971A patent/CN101417986A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103951636A (en) * | 2014-04-21 | 2014-07-30 | 江苏飞亚化学工业有限责任公司 | Method for synthesizing phenothiazine by using fixed bed |
| CN104311508A (en) * | 2014-09-29 | 2015-01-28 | 苏州大学 | Synthetic method of iron-catalyzed phenothiazine compound |
| CN105524016A (en) * | 2015-11-11 | 2016-04-27 | 中国科学院宁波材料技术与工程研究所 | Synthetic method and application of phenothiazine and/or derivative thereof |
| CN105524016B (en) * | 2015-11-11 | 2018-07-06 | 中国科学院宁波材料技术与工程研究所 | The synthetic method and application of phenthazine and/or its derivative |
| CN107245062A (en) * | 2017-07-17 | 2017-10-13 | 启东市瑞丰化工有限公司 | A kind of 2 chloro phenothiazine preparation technologies |
| CN113429366A (en) * | 2021-05-21 | 2021-09-24 | 常州康普药业有限公司 | Preparation method of chlorpromazine hydrochloride |
| CN113429366B (en) * | 2021-05-21 | 2022-03-08 | 常州康普药业有限公司 | Preparation method of chlorpromazine hydrochloride |
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| C06 | Publication | ||
| PB01 | Publication | ||
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
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Open date: 20090429 |