CN106831407B - A kind of synthetic method of α-chlorpromazine chloride - Google Patents
A kind of synthetic method of α-chlorpromazine chloride Download PDFInfo
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- CN106831407B CN106831407B CN201710079142.5A CN201710079142A CN106831407B CN 106831407 B CN106831407 B CN 106831407B CN 201710079142 A CN201710079142 A CN 201710079142A CN 106831407 B CN106831407 B CN 106831407B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Abstract
The invention discloses a kind of synthetic methods of α-chlorpromazine chloride, the following steps are included: (1) propionic acid, acyl chlorides catalysts and solvents are added into reactor, it opens and stirs and be passed through chlorine progress substitution reaction, after reaction, it is directly used in by the fraction that α-chloro-propionicacid is collected in distillation and is reacted in next step；(2) α-chloro-propionicacid and catalyst obtained in the previous step are added into reactor, opens stirring, slowly heats up and be passed through phosgene and reacted, after reaction, vacuum distillation obtains α-chlorpromazine chloride.Preparation method of the present invention has the advantages that easy to operate, yield is higher, post-processing does not generate waste water, reaction condition is mild, and the acyl chlorides catalyst that wherein first step chlorination uses can also recycle.
Description
Technical field
The invention belongs to technical field of organic synthesis, the synthetic method of specifically a kind of α-chlorpromazine chloride.
Background technique
α-chlorpromazine chloride is a kind of compound for being widely used in medicine, dyestuff, pesticide field, is to prepare propylamine hydrochloride card
The important intermediate of the drugs such as cause, napropamide, Tiopronin.
The synthetic method of current α-chlorpromazine chloride reported in the literature mainly include the following types:
1) US4051182 is reported with 1,2- dichloropropane as raw material, is replaced under the effect of the catalyst with chlorine
Reaction obtain 1,1,2- trichloropropane, after under alkaline condition dehydrochlorination obtain 1,1- dichloropropylene.Finally and oxygen-containing gas
In the presence of suitable free chlorine and catalyst, reacted to obtain α-chlorpromazine chloride in the liquid phase.Although this method success
Product is obtained, but separation reaction step is longer, conversion ratio is not high, and purification difficulty is larger, and overall yield is low.
2) using propionic acid as raw material, substitution reaction occurs with chlorine under the catalytic action of phosphorus trichloride and obtains α-chloro-propionicacid
(propanoate reaction process improves [J] amino acid magazine, 1991,1:47. in the production of Peng Aiyou alanine)；α-chloro-propionicacid can
α-chlorpromazine chloride is further obtained with phosphorus oxychloride reaction, and (Zeng Pingli, Wang Dong phosphorus oxychloride are in organic synthesis and industrial production
Application [J] Chemical Engineering Technology and exploitation, 2013,42 (2): 31-33.).But benefit can not be recycled by making catalyst using phosphorus trichloride
With post-processing generates phosphorus-containing wastewater, and processing cost is higher, and excessive phosphorus oxychloride can not also recycle, and utilization rate is lower, together
When the phosphorus-containing wastewater that generates it is also more intractable.
3) it using propionic acid as raw material, is reacted with thionyl chloride and directly obtains α-chlorpromazine chloride (general sieve of Wang Dongyang, Zhang Changzheng sulphur
Peaceful new technique for synthesizing [J] China journal of Medicinal Chemistry, 1997,7 (23): 55-56.).It is this that α-chlorine is directly synthesized by propionic acid
The method of propionyl chloride, major defect are to need distilation, cumbersome, higher cost, and yield is lower.And thionyl chloride has
Strong and stimulating smell, it is larger to human injury, during excessive thionyl chloride is applied again facile hydrolysis generate sulfur dioxide and
Hydrogen chloride pollutes environment.
Summary of the invention
To solve the above problems, the present invention provides a kind of synthetic method of α-chlorpromazine chloride, it is easy to operate, yield is higher,
It is mild that post-processing does not generate waste water, reaction condition.
The technical solution adopted by the present invention is that: a kind of synthetic method of α-chlorpromazine chloride, comprising the following steps: (1) to anti-
Addition propionic acid, acyl chlorides catalysts and solvents in device is answered, opens and stirs simultaneously temperature control and be passed through chlorine progress substitution reaction, reaction terminates
Afterwards, it is directly used in by the fraction that α-chloro-propionicacid is collected in distillation and is reacted in next step；The acyl chlorides catalyst has the following structure:, wherein R indicates C1-C18Alkyl, C1-C6Alkylhalide group, phenyl or substituted aryl；It can also be received simultaneously by vacuum distillation
Collect the fraction of the mixture of acyl chlorides catalysts and solvents, recycling；(2) α-chlorine third obtained in the previous step is added into reactor
Acid and catalyst open stirring, and temperature control is simultaneously passed through phosgene and is reacted, and after reaction, vacuum distillation obtains α-chlorpromazine chloride.
In step (1), the molar ratio of propionic acid and acyl chlorides catalyst is 1:0.004 ~ 0.3, and the solvent is dichloromethane
Alkane, 1,2- dichloroethanes, tetrahydrofuran, 2- methyltetrahydrofuran, N,N-dimethylformamide, propionic acid, benzene, chlorobenzene, toluene, two
One of toluene, reaction temperature are 25-130 DEG C, reaction time 4-48 hour.
In step (2), the molar ratio of α-chloro-propionicacid, catalyst and phosgene is 1:0.002 ~ 0.1:1 ~ 3, the catalysis
Agent is pyridine, formamide, n,N-Dimethylformamide, N, one of N- diethylformamide, N-methyl-benzamide, reaction
Temperature is 25-140 DEG C, reaction time 2-16 hour.
Synthetic route of the invention is as follows:
, wherein R indicates C1-C18
Alkyl, C1-C6Alkylhalide group, phenyl or substituted aryl.
The beneficial effects of the present invention are: preparation method of the present invention has, easy to operate, yield is higher, post-processing do not generate it is useless
The advantages that water, mild reaction condition, the acyl chlorides catalyst that wherein first step chlorination uses can also recycle.
Specific embodiment
In order to deepen the understanding of the present invention, the present invention will be described in further detail with reference to the examples below, the embodiment
For explaining only the invention, it is not intended to limit the scope of the present invention..
Embodiment 1:
(1) 74.0 g of propionic acid (1.00 mol), α-chlorine the synthesis of α-chloro-propionicacid: are sequentially added into 250 mL four-hole boiling flasks
1.26 g of propionyl chloride (0.01 mol), 80 mL of toluene open stirring, are to slowly warm up to 65 DEG C, start to be passed through chlorine, temperature control 70-
90 DEG C of reactions stop logical chlorine when chlorine intake reaches 1.10mol.50 DEG C are cooled to, starts to be passed through nitrogen 1h, is removed
Excessive chlorine, vacuum distillation, obtains the mixture of α-chlorpromazine chloride and α-chloro-propionicacid, the content of vapor detection α-chloro-propionicacid is
98.9%, it directly throws in next step；
(2) α-chlorpromazine chloride synthesis: being added 56 g (0.50 mol) α-chloro-propionicacid into 250 mL four-hole boiling flasks, and 0.2
G pyridine opens stirring, starts to stir at 55 DEG C, be passed through phosgene, when phosgene intake reaches 0.55mol, stops light passing
Gas continues after stirring 1h, is passed through nitrogen and removes excess phosgene.67-93 DEG C of fraction α-chlorpromazine chloride 60.5 is collected in vacuum distillation
G, yield 95.4%.
Embodiment 2
(1) 74.0 g of propionic acid (1.00 mol), propionyl the synthesis of α-chloro-propionicacid: are sequentially added into 250 mL four-hole boiling flasks
1.84 g of chlorine (0.02 mol), 80 mL of chlorobenzene open stirring, are to slowly warm up to 75 DEG C, start to be passed through chlorine, and 75-80 DEG C of temperature control
Reaction stops logical chlorine when chlorine intake reaches 1.10mol.Vacuum distillation, collect 70-90 DEG C of fraction be propionyl chloride with
Chlorobenzene mixtures, it is reusable；Collect 98.3 g of tails α-chloro-propionicacid, yield 91%；
(2) α-chlorpromazine chloride synthesis: being added 56 g (0.50 mol) α-chloro-propionicacid into 250 mL four-hole boiling flasks, and 0.2
G n,N-Dimethylformamide opens stirring, starts to stir at 65 DEG C, be passed through phosgene, when phosgene intake reaches 0.60mol
When, stop light passing gas, continue after stirring 1h, is passed through nitrogen and removes excess phosgene.67-93 DEG C of fraction α-chlorine is collected in vacuum distillation
56.7 g of propionyl chloride, yield 89.3%.
Embodiment 3
(1) 74.0 g of propionic acid (1.00 mol), benzene first the synthesis of α-chloro-propionicacid: are sequentially added into 250 mL four-hole boiling flasks
7.02 g of acyl chlorides (0.05 mol), 80 mL of n,N-Dimethylformamide open stirring, are to slowly warm up to 100 DEG C, start to be passed through
Chlorine, 100-120 DEG C of temperature control reaction stop logical chlorine when chlorine intake reaches 1.20mol.105- is collected in vacuum distillation
116 DEG C of 94.8 g of fraction α-chloro-propionicacid, yield 87.4%；Collecting tails is that N,N-dimethylformamide and chlorobenzoyl chloride mix
Object, it is reusable；
(2) α-chlorpromazine chloride synthesis: being added 56 g (0.50 mol) α-chloro-propionicacid into 250 mL four-hole boiling flasks, and 0.3
G N, N- diethylformamide opens stirring, starts to stir at 70 DEG C, be passed through phosgene, when phosgene intake reaches 0.65mol
When, stop light passing gas, continue after stirring 1h, is passed through nitrogen and removes excess phosgene.67-93 DEG C of fraction α-chlorine is collected in vacuum distillation
60.3 g of propionyl chloride, yield 95.1%.
Embodiment 4
(1) 74.0 g of propionic acid (1.00 mol), acetyl the synthesis of α-chloro-propionicacid: are sequentially added into 250 mL four-hole boiling flasks
7.85 g of chlorine (0.10 mol), methylene chloride 80mL open stirring, are to slowly warm up to 50 DEG C, start to be passed through chlorine, temperature control 50-
60 DEG C of reactions stop logical chlorine when chlorine intake reaches 1.30mol.50 DEG C of fraction chloroacetic chlorides and two are collected in air-distillation
Chloromethane mixture, it is reusable；Collect 88.9 g of tails α-chloro-propionicacid, yield 82.2%；
(2) α-chlorpromazine chloride synthesis: being added 56 g (0.50 mol) α-chloro-propionicacid into 250 mL four-hole boiling flasks, and 0.3
G N-methyl-benzamide opens stirring, starts to stir at 45 DEG C, be passed through phosgene, when phosgene intake reaches 0.55mol
When, stop light passing gas, continue after stirring 1h, is passed through nitrogen and removes excess phosgene.67-93 DEG C of fraction α-chlorine is collected in vacuum distillation
59.4 g of propionyl chloride, yield 93.5%.
Embodiment 5
(1) 74.0 g of propionic acid (1.00 mol), 4- tri- synthesis of α-chloro-propionicacid: are sequentially added into 250 mL four-hole boiling flasks
0.83 g of methyl fluoride chlorobenzoyl chloride (0.004 mol), 80 mL of n,N-Dimethylformamide open stirring, are to slowly warm up to 90
DEG C, start to be passed through chlorine, 90-110 DEG C of temperature control reaction stops logical chlorine when chlorine intake reaches 1.10mol.Decompression is steamed
It evaporates, collects 105-116 DEG C of 93.3 g of fraction α-chloro-propionicacid, yield 85.9%；Collecting tails is N,N-dimethylformamide and 4-
The mixture of trifluoromethyl benzoyl chloride, it is reusable；
(2) α-chlorpromazine chloride synthesis: being added 56 g (0.50 mol) α-chloro-propionicacid into 250 mL four-hole boiling flasks, and 0.1
G formamide opens stirring, starts to stir at 65 DEG C, be passed through phosgene, when phosgene intake reaches 0.55mol, stops logical
Phosgene continues after stirring 1h, is passed through nitrogen and removes excess phosgene.67-93 DEG C of fraction α-chlorpromazine chloride 54.2 is collected in vacuum distillation
G, yield 85.3%.
Embodiment 6
(1) 74.0 g of propionic acid (1.00 mol), chloroethene the synthesis of α-chloro-propionicacid: are sequentially added into 250 mL four-hole boiling flasks
22.59 g of acyl chlorides (0.2 mol), 80 mL of toluene, start to stir, are to slowly warm up to 110 DEG C, be passed through chlorine, temperature control at 25 DEG C
110-116 DEG C of reaction stops logical chlorine when chlorine intake reaches 1.30mol.86-103 DEG C of fraction is collected in vacuum distillation
It is reusable for toluene and chloracetyl chloride mixture；Collect 92.1 g of tails α-chloro-propionicacid, yield 84.8%；
(2) α-chlorpromazine chloride synthesis: being added 56 g (0.50 mol) α-chloro-propionicacid into 250 mL four-hole boiling flasks, and 0.2
G formamide opens stirring, starts to stir at 65 DEG C, be passed through phosgene, when phosgene intake reaches 0.55mol, stops logical
Phosgene continues after stirring 1h, is passed through nitrogen and removes excess phosgene.67-93 DEG C of fraction α-chlorpromazine chloride 57.6 is collected in vacuum distillation
G, yield 90.7%.
Claims (1)
1. a kind of synthetic method of α-chlorpromazine chloride, which comprises the following steps: (1) into reactor be added propionic acid,
Acyl chlorides catalysts and solvents, open stirring, and temperature control is simultaneously passed through chlorine progress substitution reaction, after reaction, passes through distillation and collect
The fraction of α-chloro-propionicacid is directly used in react in next step, meanwhile, the mixing of acyl chlorides catalysts and solvents is collected by vacuum distillation
The fraction of object, recycling；The molar ratio of propionic acid and acyl chlorides catalyst is 1:0.004 ~ 0.3, and the acyl chlorides catalyst has
Such as flowering structure:, wherein R indicates C1-C18Alkyl, C1-C6Alkylhalide group, phenyl or substituted aryl；The solvent is
Methylene chloride, 1,2- dichloroethanes, tetrahydrofuran, 2- methyltetrahydrofuran, N,N-dimethylformamide, propionic acid, benzene, chlorobenzene,
One of toluene, dimethylbenzene；
(2) α-chloro-propionicacid and catalyst obtained in the previous step are added into reactor, opens stirring, temperature control is simultaneously passed through phosgene progress
Reaction, after reaction, vacuum distillation obtain α-chlorpromazine chloride；The molar ratio of α-chloro-propionicacid, catalyst and phosgene is 1:0.002
~ 0.1:1 ~ 3, the catalyst are pyridine, formamide, n,N-Dimethylformamide, N, N- diethylformamide, N- methyl
One of benzamide.
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| CN107413380B (en) * | 2017-06-14 | 2020-10-13 | 开封华瑞化工新材料股份有限公司 | Catalyst for synthesizing acyl chloride compounds and application thereof |
| CN107903172A (en) * | 2017-11-01 | 2018-04-13 | 新华制药（寿光）有限公司 | A kind of chlorination reaction temperature control method of 2 chloro-propanoyl chloride |
| CN108752211A (en) * | 2018-07-03 | 2018-11-06 | 浙江禾本科技有限公司 | A method of 99% alpha-chloro methyl propionate is synthesized using micro- reaction method |
| CN115353451B (en) * | 2022-10-20 | 2022-12-27 | 新华制药（寿光）有限公司 | Preparation method of 2-chloro-propionyl chloride |
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| CN1740132A (en) * | 2005-08-29 | 2006-03-01 | 上海华谊丙烯酸有限公司 | Synthesis and purification process of (2-methyl)-3-chloropropionyl chloride |
| CN102190574A (en) * | 2010-03-11 | 2011-09-21 | 通州市诚信氨基酸有限公司 | Method for preparing 2-chloropropionyl chloride with high optical activity |
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