CN106831407A - A kind of synthetic method of α chlorpromazine chlorides - Google Patents
A kind of synthetic method of α chlorpromazine chlorides Download PDFInfo
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- CN106831407A CN106831407A CN201710079142.5A CN201710079142A CN106831407A CN 106831407 A CN106831407 A CN 106831407A CN 201710079142 A CN201710079142 A CN 201710079142A CN 106831407 A CN106831407 A CN 106831407A
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- 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
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Abstract
The invention discloses a kind of synthetic method of α chlorpromazine chlorides, comprise the following steps：（1）To propionic acid, acyl chlorides catalysts and solvents are added in reactor, unlatching is stirred and is passed through chlorine carries out substitution reaction, after reaction terminates, is directly used in next step by the cut for distilling collection α chloropropionic acids and reacts；（2）To α chloropropionic acids obtained in the previous step and catalyst is added in reactor, stirring is opened, slowly heat up and be passed through phosgene and reacted, after reaction terminates, vacuum distillation obtains α chlorpromazine chlorides.Preparation method of the present invention possesses the advantages of easy to operate, yield is higher, post processing does not produce waste water, reaction condition is gentle, and the acyl chlorides catalyst that wherein first step chlorination is used can also be recycled.
Description
Technical field
The invention belongs to technical field of organic synthesis, specifically a kind of synthetic method of α-chlorpromazine chloride.
Background technology
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 medicines such as cause, napropamide, Tiopronin.
The synthetic method of the α-chlorpromazine chloride of current document report mainly has following several：
1）US4051182 is reported with 1,2- dichloropropanes as raw material, and substitution reaction is carried out with chlorine in the presence of catalyst
Obtain 1,1,2- trichloropropane, after in the basic conditions dehydrochlorination obtain 1,1- dichloropropylenes.Finally with oxygen-containing gas suitable
In the presence of the free chlorine and catalyst of amount, carry out reacting in the liquid phase obtaining α-chlorpromazine chloride.Although the method is successfully obtained
Product, but separate that reactions steps are more long, conversion ratio is not high, and purification difficulty is larger, and overall yield is low.
2）With propionic acid as raw material, α-chloro-propionicacid is obtained with chlorine generation substitution reaction under the catalytic action of phosphorus trichloride
(propanoate reaction process improves [J] amino acid magazines, 1991,1 during Peng's love has alanine to produce:47.)；α-chloro-propionicacid can
α-chlorpromazine chloride is further obtained with phosphorus oxychloride reaction, and (Zeng Pingli, king east POCl3s are in organic synthesis and industrial production
Application [J] Chemical Engineering Technologies with exploitation, 2013,42 (2):31-33.).But making catalyst using phosphorus trichloride cannot reclaim profit
With post processing produces phosphorus-containing wastewater, and processing cost is higher, and the POCl3 of excess cannot also be reclaimed, and utilization rate is relatively low, together
When the phosphorus-containing wastewater that produces it is also more intractable.
3）With propionic acid as raw material, α-chlorpromazine chloride (general sieve of Wang Dongyang, Zhang Changzheng sulphur is directly obtained with thionyl chloride reaction
Peaceful new technique for synthesizing [J] China pharmaceutical chemistry magazine, 1997,7 (23):55-56.).It is this that α-chlorine is directly synthesized by propionic acid
The method of propionyl chloride, major defect is to need distilation, cumbersome, and relatively costly, yield is relatively low.And thionyl chloride has
Strong and stimulating smell, it is larger to human injury, excessive thionyl chloride apply mechanically again during facile hydrolysis generation sulfur dioxide and
Hydrogen chloride, pollutes environment.
The content of the invention
To solve the above problems, the present invention provides a kind of synthetic method of α-chlorpromazine chloride, easy to operate, yield is higher,
Post processing does not produce waste water, reaction condition gentle.
The technical solution adopted by the present invention is：A kind of synthetic method of α-chlorpromazine chloride, comprises the following steps：（1）To anti-
Addition propionic acid, acyl chlorides catalysts and solvents in device are answered, opening to stir simultaneously temperature control and be passed through chlorine carries out substitution reaction, and reaction terminates
Afterwards, the cut that α-chloro-propionicacid is collected by distilling is directly used in next step reaction；Described acyl chlorides catalyst has following structure：, wherein, R represents C1-C18Alkyl, C1-C6Alkylhalide group, phenyl or substituted aryl；Can also be received by vacuum distillation simultaneously
Collect the cut of the mixture of acyl chlorides catalysts and solvents, recycling；（2）To adding α-chlorine third obtained in the previous step in reactor
Acid and catalyst, open stirring, and temperature control is simultaneously passed through phosgene and is reacted, and after reaction terminates, vacuum distillation obtains α-chlorpromazine chloride.
Step（1）In, propionic acid is 1 with the mol ratio of acyl chlorides catalyst:0.004 ~ 0.3, described solvent is dichloromethane
Alkane, 1,2- dichloroethanes, tetrahydrofuran, 2- methyltetrahydrofurans, N,N-dimethylformamide, propionic acid, benzene, chlorobenzene, toluene, two
One kind in toluene, reaction temperature is 25-130 DEG C, reaction time 4-48 hours.
Step（2）In, the mol ratio of α-chloro-propionicacid, catalyst and phosgene is 1:0.002 ~0.1:1 ~ 3, described catalysis
Agent is pyridine, formamide, DMF, N, the one kind in N- DEFs, N-methyl-benzamide, reaction
Temperature is 25-140 DEG C, reaction time 2-16 hours.
Synthetic route of the invention is as follows：
, wherein, R represents C1-C18Alkane
Base, C1-C6Alkylhalide group, phenyl or substituted aryl.
The beneficial effects of the invention are as follows：Preparation method of the present invention possess easy to operate, yield it is higher, post processing do not produce it is useless
The advantages of water, gentle reaction condition, the acyl chlorides catalyst that wherein first step chlorination is used can also be recycled.
Specific embodiment
In order to deepen the understanding of the present invention, below in conjunction with embodiment, the invention will be further described, the embodiment
It is only used for explaining the present invention, is not intended to limit the scope of the present invention..
Embodiment 1：
（1）The synthesis of α-chloro-propionicacid：To sequentially adding the g of propionic acid 74.0 (1.00 mol), α-chlorine propionyl in 250 mL four-hole boiling flasks
The g of chlorine 1.26 (0.01 mol), the mL of toluene 80, open stirring, are to slowly warm up to 65 DEG C, start to be passed through chlorine, 70-90 DEG C of temperature control
Reaction, when chlorine intake reaches 1.10mol, stops logical chlorine.50 DEG C are cooled to, start to be passed through nitrogen 1h, removed excessive
Chlorine, vacuum distillation obtains the mixture of α-chlorpromazine chloride and α-chloro-propionicacid, and the content of vapor detection α-chloro-propionicacid is
98.9%, directly throw next step；
（2）The synthesis of α-chlorpromazine chloride：To adding 56 g (0.50 mol) α-chloro-propionicacid, 0.2 g pyrroles in 250 mL four-hole boiling flasks
Pyridine, opens stirring, in stirring is started at 55 DEG C, is passed through phosgene, when phosgene intake reaches 0.55mol, stops thang-kng gas, after
After continuous stirring 1h, it is passed through nitrogen and removes excess phosgene.Vacuum distillation, collects 67-93 DEG C of cut α-g of chlorpromazine chloride 60.5, yield
95.4%。
Embodiment 2
（1）The synthesis of α-chloro-propionicacid：To sequentially adding the g of propionic acid 74.0 (1.00 mol), propionyl chloride in 250 mL four-hole boiling flasks
1.84 g (0.02 mol), the mL of chlorobenzene 80, 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 is anti-
Should, when chlorine intake reaches 1.10mol, stop logical chlorine.Vacuum distillation, it is propionyl chloride and chlorine to collect 70-90 DEG C of cut
Benzol mixture, repeats and utilizes；Collect the g of tails α-chloro-propionicacid 98.3, yield 91%；
（2）The synthesis of α-chlorpromazine chloride：To adding 56 g (0.50 mol) α-chloro-propionicacid, 0.2 g in 250 mL four-hole boiling flasks
DMF, opens stirring, in stirring is started at 65 DEG C, phosgene is passed through, when phosgene intake reaches 0.60mol
When, stop thang-kng gas, after continuing to stir 1h, it is passed through nitrogen and removes excess phosgene.Vacuum distillation, collects 67-93 DEG C of cut α-chlorine
The g of propionyl chloride 56.7, yield 89.3%.
Embodiment 3
（1）The synthesis of α-chloro-propionicacid：To sequentially adding the g of propionic acid 74.0 (1.00 mol), chlorobenzoyl chloride in 250 mL four-hole boiling flasks
7.02 g (0.05 mol), the mL of DMF 80, open stirring, are to slowly warm up to 100 DEG C, start to be passed through chlorine,
100-120 DEG C of reaction of temperature control, when chlorine intake reaches 1.20mol, stops logical chlorine.Vacuum distillation, collects 105-116 DEG C
The g of cut α-chloro-propionicacid 94.8, yield 87.4%；Tails is collected for DMF and chlorobenzoyl chloride mixture, can
Recycling；
（2）The synthesis of α-chlorpromazine chloride：To adding 56 g (0.50 mol) α-chloro-propionicacid, 0.3 g in 250 mL four-hole boiling flasks
N, N- DEF, open stirring, in stirring is started at 70 DEG C, phosgene are passed through, when phosgene intake reaches 0.65mol
When, stop thang-kng gas, after continuing to stir 1h, it is passed through nitrogen and removes excess phosgene.Vacuum distillation, collects 67-93 DEG C of cut α-chlorine
The g of propionyl chloride 60.3, yield 95.1%.
Embodiment 4
（1）The synthesis of α-chloro-propionicacid：To sequentially adding the g of propionic acid 74.0 (1.00 mol), chloroacetic chloride in 250 mL four-hole boiling flasks
7.85 g (0.10 mol), dichloromethane 80mL, open stirring, are to slowly warm up to 50 DEG C, start to be passed through chlorine, temperature control 50-60
DEG C reaction, when chlorine intake reaches 1.30mol, stops logical chlorine.Air-distillation, collects 50 DEG C of cut chloroacetic chlorides and dichloro
Methane mixture, repeats and utilizes；Collect the g of tails α-chloro-propionicacid 88.9, yield 82.2%；
（2）The synthesis of α-chlorpromazine chloride：To adding 56 g (0.50 mol) α-chloro-propionicacid, 0.3 g in 250 mL four-hole boiling flasks
N-methyl-benzamide, opens stirring, in stirring is started at 45 DEG C, is passed through phosgene, when phosgene intake reaches 0.55mol,
Stop thang-kng gas, after continuing to stir 1h, be passed through nitrogen and remove excess phosgene.Vacuum distillation, collects 67-93 DEG C of cut α-chlorine propionyl
The g of chlorine 59.4, yield 93.5%.
Embodiment 5
（1）The synthesis of α-chloro-propionicacid：To sequentially adding the g of propionic acid 74.0 (1.00 mol), 4- fluoroforms in 250 mL four-hole boiling flasks
The g of base chlorobenzoyl chloride 0.83 (0.004 mol), the mL of DMF 80, open stirring, are to slowly warm up to 90 DEG C, open
Beginning is passed through chlorine, and 90-110 DEG C of reaction of temperature control, when chlorine intake reaches 1.10mol, stops logical chlorine.Vacuum distillation, receives
The 105-116 DEG C of g of cut α-chloro-propionicacid 93.3 of collection, yield 85.9%；It is N,N-dimethylformamide and 4- trifluoros to collect tails
The mixture of methyl benzoyl chloride, repeats and utilizes；
（2）The synthesis of α-chlorpromazine chloride：To adding 56 g (0.50 mol) α-chloro-propionicacid, 0.1 g in 250 mL four-hole boiling flasks
Formamide, opens stirring, in stirring is started at 65 DEG C, is passed through phosgene, when phosgene intake reaches 0.55mol, stops thang-kng
Gas, after continuing to stir 1h, is passed through nitrogen and removes excess phosgene.Vacuum distillation, collects 67-93 DEG C of cut α-chlorpromazine chloride 54.2
G, yield 85.3%.
Embodiment 6
（1）The synthesis of α-chloro-propionicacid：To sequentially adding the g of propionic acid 74.0 (1.00 mol), chloracetyl chloride in 250 mL four-hole boiling flasks
22.59 g (0.2 mol), the mL of toluene 80, in stirring is started at 25 DEG C, are to slowly warm up to 110 DEG C, are passed through chlorine, temperature control 110-
116 DEG C of reactions, when chlorine intake reaches 1.30mol, stop logical chlorine.Vacuum distillation, it is first to collect 86-103 DEG C of cut
Benzene and chloracetyl chloride mixture, repeat and utilize；Collect the g of tails α-chloro-propionicacid 92.1, yield 84.8%；
（2）The synthesis of α-chlorpromazine chloride：To adding 56 g (0.50 mol) α-chloro-propionicacid, 0.2 g in 250 mL four-hole boiling flasks
Formamide, opens stirring, in stirring is started at 65 DEG C, is passed through phosgene, when phosgene intake reaches 0.55mol, stops thang-kng
Gas, after continuing to stir 1h, is passed through nitrogen and removes excess phosgene.Vacuum distillation, collects 67-93 DEG C of cut α-chlorpromazine chloride 57.6
G, yield 90.7%.
Claims (5)
1. a kind of synthetic method of α-chlorpromazine chloride, it is characterised in that comprise the following steps：（1）To in reactor add propionic acid,
Acyl chlorides catalysts and solvents, open stirring, and temperature control is simultaneously passed through chlorine and carries out substitution reaction, after reaction terminates, is collected by distilling
The cut of α-chloro-propionicacid is directly used in next step reaction；（2）To adding α-chloro-propionicacid obtained in the previous step and catalysis in reactor
Agent, opens stirring, and temperature control is simultaneously passed through phosgene and is reacted, and after reaction terminates, vacuum distillation obtains α-chlorpromazine chloride.
2. a kind of synthetic method of α-chlorpromazine chloride according to claim 1, it is characterised in that step（1）In, propionic acid with
The mol ratio of acyl chlorides catalyst is 1:0.004 ~ 0.3, described solvent is dichloromethane, 1,2- dichloroethanes, tetrahydrofuran,
One kind in 2- methyltetrahydrofurans, N,N-dimethylformamide, propionic acid, benzene, chlorine benzene,toluene,xylene.
3. a kind of synthetic method of α-chlorpromazine chloride according to claim 1 and 2, it is characterised in that step（1）In, institute
The acyl chlorides catalyst stated has following structure：, wherein, R represents C1-C18Alkyl, C1-C6Alkylhalide group, phenyl or substituted
Aryl.
4. a kind of synthetic method of α-chlorpromazine chloride according to claim 1, it is characterised in that step（1）In, substitution is anti-
After should terminating, the cut of the mixture of acyl chlorides catalysts and solvents, recycling are collected by vacuum distillation.
5. a kind of synthetic method of α-chlorpromazine chloride according to claim 1, it is characterised in that step（2）In, α-chlorine third
The mol ratio of acid, catalyst and phosgene is 1:0.002 ~0.1:1 ~ 3, described catalyst is pyridine, formamide, N, N- diformazans
Base formamide, N, the one kind in N- DEFs, N-methyl-benzamide.
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Cited By (4)
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| CN107413380A (en) * | 2017-06-14 | 2017-12-01 | 开封华瑞化工新材料股份有限公司 | A kind of catalyst and its application for being used to synthesize acyl chloride compound |
| 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 |
| CN115353451A (en) * | 2022-10-20 | 2022-11-18 | 新华制药（寿光）有限公司 | Preparation method of 2-chloro propionyl chloride |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107413380A (en) * | 2017-06-14 | 2017-12-01 | 开封华瑞化工新材料股份有限公司 | A kind of catalyst and its application for being used to synthesize acyl chloride compound |
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| 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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