CN100383104C - Synthesis and purification process of (2-methyl)-3-chloropropionyl chloride - Google Patents
Synthesis and purification process of (2-methyl)-3-chloropropionyl chloride Download PDFInfo
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- CN100383104C CN100383104C CNB2005100291737A CN200510029173A CN100383104C CN 100383104 C CN100383104 C CN 100383104C CN B2005100291737 A CNB2005100291737 A CN B2005100291737A CN 200510029173 A CN200510029173 A CN 200510029173A CN 100383104 C CN100383104 C CN 100383104C
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Abstract
The present invention provides a preparation method for (2-methyl) 3-chloropropionyl chloride, which comprises the steps that in a reactor, (2-methyl) 3-chloropropionic acid and acylchloriration reagents carry out an acylchloriration reaction to generate coarse (2-methyl) 3-chloropropionyl chloride products, and the coarse (2-methyl) 3-chloropropionyl chloride products are decompressed and rectified to obtain (2-methyl) 3-chloropropionyl chloride products with high purity. The method provided by the present invention has the advantages of simple operation, mild condition, high selectivity, high yield and high product purity, and can realize industrialization production.
Description
Technical field
The present invention relates to the preparation method of 3-chlorpromazine chloride or (2-methyl)-3-chlorpromazine chloride, relate in particular to the synthetic and method of purification of a kind of high-purity 3-chlorpromazine chloride or (2-methyl)-3-chlorpromazine chloride.
Background technology
3-chlorpromazine chloride or (2-methyl)-3-chlorpromazine chloride are broad-spectrum fine-chemical intermediates, are mainly used in fields such as medicine, agricultural chemicals and organic synthesis.3-chlorpromazine chloride or (2-methyl)-3-chlorpromazine chloride are at the medicine that pharmaceutically is mainly used in synthetic treatment central nervous system, as antiepileptic drug N-benzyl-3-chlorine propionic acid amide, anti-inflammatory analgesic clidanac, spasmolytic propaxoline; The medicine of respiratory system is as the cough medicine Oxolamine; Synthesizing of antiarrhythmics Moracizine (having another name called Moracizine) etc.
JP11-199540 has reported in the presence of organic bases, is the method for feedstock production 3-chlorpromazine chloride with vinylformic acid and sulfur oxychloride.This method is used organic alkali catalyst in reaction process, owing to be homogeneous catalysis system, catalyzer and reaction mass separation difficulty must be brought certain difficulty to aftertreatment, and the effective rate of utilization of catalyzer is low, and loss is big; In addition, a large amount of acrylate chlorides of by-product in this reaction process, the principal product selectivity is low, adopt ordinary method to be difficult to acrylate chloride and 3-chlorpromazine chloride are separated, so the purpose product 3-chlorpromazine chloride purity that this method obtains is low, and total recovery is low.CN1349969A has reported that the 3-chloropropionic acid prepares the method for 3-chlorpromazine chloride through the phosphorus trichloride acidylate.This method is not used catalyzer, does not therefore have the catalyst recovery problem, but the phosphorous acid that produces in the reaction process is difficult to processing, and the product separation difficulty also can be fallen product purity and total recovery.In addition, above-mentioned two patents are purified to the separation of reaction mass system and are not described substantially.
The invention provides a kind of method for preparing high purity 3-chlorpromazine chloride or (2-methyl)-3-chlorpromazine chloride with high yield, synthetic and method of purification are described in detail.Method provided by the invention is simple to operate, mild condition, and the selectivity height, the yield height, product purity height (greater than 99%) can be realized the industrialization product.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of high purity 3-chlorpromazine chloride or (2-methyl)-3-chlorpromazine chloride.
The preparation method of 3-chlorpromazine chloride provided by the invention or (2-methyl)-3-chlorpromazine chloride comprises:
1) with after 3-chloropropionic acid or the thawing of (2-methyl)-3-chloropropionic acid, to wherein dripping chloride reagent, reaction obtains the thick product of 3-chlorpromazine chloride.Chloride reagent is the mixture of any or they in thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, Benzoyl chloride, Acetyl Chloride 98Min. or the chloroacetyl chloride, preferred thionyl chloride or chloroacetyl chloride; Temperature of reaction is 20～150 ℃, preferred 50～100 ℃; The mol ratio of thionyl chloride and 3-chloropropionic acid or (2-methyl)-3-chloropropionic acid is 0.5～5.0: 1, and preferred 1.4～3.0: 1 reaction times was 0.5～10h, preferred 3～8h.
2) reacting the thick product that obtains is 1～10 in theoretical stage number, preferred 2～6; Vacuum tightness is 0.06～100kPa, preferred 1.0～20kPa; Reflux ratio is 1: 1～20: 1, carries out rectification under vacuum under preferred 3: 1～8: 1 conditions.
Embodiment
The following examples are further described content of the present invention, but content of the present invention is not confined to the scope of embodiment.
Product yield is a benchmark with 3-chloropropionic acid or (2-methyl)-3-chloropropionic acid in following examples.
Embodiment 1～6
In the reactor that agitator, thermometer, condenser, exhaust duct are housed, add the 3-chloropropionic acid, rise to 70 ℃ and drip chloride reagent, chloride reagent is respectively thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, Benzoyl chloride, Acetyl Chloride 98Min. and chloroacetyl chloride, chloride reagent: 3-chloropropionic acid mol ratio is 1.2: 1, reaction 6h.The thick product of reacted 3-chlorpromazine chloride is 4 in theoretical stage number, and reflux ratio is 5: 1, and vacuum tightness is to carry out rectifying under the 10kPa, tells light constituent under 28～32 ℃; Temperature rises rapidly and receives product when being stabilized in 78 ℃, and product yield sees Table 1.
Table 1 adopts the yield of 3-chlorpromazine chloride under the different chloride reagents
Embodiment 7～12
With the thionyl chloride is chloride reagent, and the remaining reaction condition is with embodiment 1, the results are shown in Table 2 under the differential responses time.
The yield of 3-chlorpromazine chloride when thionyl chloride is chloride reagent under the table 2 differential responses time
Embodiment 13～18
Reaction conditions is with embodiment 1, changes the mol ratio of thionyl chloride and 3-chloropropionic acid, reacts to the results are shown in Table 3 behind the 5h.
Table 3 thionyl chloride and 3-chloropropionic acid mol ratio are to the influence of 3-chlorpromazine chloride yield
Embodiment 19～24
Reaction conditions changes temperature of reaction with embodiment 14, the results are shown in Table 4.
Table 4 temperature of reaction is to the influence of 3-chlorpromazine chloride yield
Embodiment 25
In the reactor that agitator, thermometer, condenser, exhaust duct are housed, add 2-methyl-3-chloropropionic acid, rise to 70 ℃ of thionyl chloride, thionyl chloride: 2-methyl-3-chloropropionic acid mol ratio is 2, and the yield of 2-methyl-3-chlorpromazine chloride is 84% behind the reaction 6h.
Embodiment 26
With the thick product of reacted 3-chlorpromazine chloride, be 1 in theoretical stage number, reflux ratio is 1: 1, vacuum tightness is to carry out rectifying under the 10kPa, tells light constituent under 28～32 ℃; Temperature rises rapidly and receives product when being stabilized in 78 ℃, and product purity is greater than 97%.
Embodiment 27
With the thick product of reacted 3-chlorpromazine chloride, be 5 in theoretical stage number, reflux ratio is 5: 1, vacuum tightness is to carry out rectifying under the 10kPa, tells light constituent under 28～32 ℃; Temperature rises rapidly and receives product when being stabilized in 78 ℃, and product purity is greater than 99%.
Claims (2)
1. the synthetic and method of purification of a 3-chlorpromazine chloride or (2-methyl)-3-chlorpromazine chloride, it is characterized in that 3-chloropropionic acid or (2-methyl)-3-chloropropionic acid and chloride reagent generation acyl chloride reaction generate 3-chlorpromazine chloride or the thick product of (2-methyl)-3-chlorpromazine chloride, the acyl chloride reaction temperature is that the mol ratio of 20～150 ℃, chloride reagent and 3-chloropropionic acid or (2-methyl)-3-chloropropionic acid is 0.5～5.0: 1, the reaction times is 0.5～10h; The thick product that acyl chloride reaction obtains is 2～6 in theoretical stage number, vacuum tightness is that 1.0～20KPa, reflux ratio are to carry out rectification under vacuum under the condition in 3: 1～8: 1, obtain purity and be higher than 99% 3-chlorpromazine chloride or (2-methyl)-3-chlorpromazine chloride product, chloride reagent is a thionyl chloride, and the adding mode is for dripping.
2. according to the described method of claim 1, it is characterized in that the acyl chloride reaction temperature is that the mol ratio of 50～100 ℃, chloride reagent and 3-chloropropionic acid or (2-methyl)-3-chloropropionic acid is 1.4～3.0: 1, the reaction times is 3～8h.
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| CNB2005100291737A CN100383104C (en) | 2005-08-29 | 2005-08-29 | Synthesis and purification process of (2-methyl)-3-chloropropionyl chloride |
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| CNB2005100291737A CN100383104C (en) | 2005-08-29 | 2005-08-29 | Synthesis and purification process of (2-methyl)-3-chloropropionyl chloride |
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| CN1740132A CN1740132A (en) | 2006-03-01 |
| CN100383104C true CN100383104C (en) | 2008-04-23 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101284772B (en) * | 2008-06-11 | 2010-10-06 | 河北华晨药业有限公司 | Synthetic method of D-(+)-2-chloro-propanoyl chloride |
| CN106831407B (en) * | 2017-02-14 | 2019-08-23 | 江苏快达农化股份有限公司 | A kind of synthetic method of α-chlorpromazine chloride |
| 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 |
| CN109721488B (en) * | 2018-11-23 | 2022-03-15 | 东力（南通）化工有限公司 | Low-temperature synthesis method of isovaleryl chloride |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1348333A1 (en) * | 1986-02-19 | 1987-10-30 | Предприятие П/Я В-2287 | Method of producing chloracetylchloride |
| US4770821A (en) * | 1985-06-05 | 1988-09-13 | Ihara Nikkei Chemical Industry Co., Ltd. | Method for preparing β-chloropivaloyl chloride |
| JPH11199540A (en) * | 1998-01-13 | 1999-07-27 | Sumikin Chemical Co Ltd | Production of 3-chloropropionyl chloride |
| CN1349969A (en) * | 2000-10-20 | 2002-05-22 | 敖枝平 | Prepn of 3-chloropropionyl chloride |
| CN1407964A (en) * | 2000-03-03 | 2003-04-02 | 巴斯福股份公司 | Production of chlorocarboxylic acid chlorides |
-
2005
- 2005-08-29 CN CNB2005100291737A patent/CN100383104C/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4770821A (en) * | 1985-06-05 | 1988-09-13 | Ihara Nikkei Chemical Industry Co., Ltd. | Method for preparing β-chloropivaloyl chloride |
| SU1348333A1 (en) * | 1986-02-19 | 1987-10-30 | Предприятие П/Я В-2287 | Method of producing chloracetylchloride |
| JPH11199540A (en) * | 1998-01-13 | 1999-07-27 | Sumikin Chemical Co Ltd | Production of 3-chloropropionyl chloride |
| CN1407964A (en) * | 2000-03-03 | 2003-04-02 | 巴斯福股份公司 | Production of chlorocarboxylic acid chlorides |
| CN1349969A (en) * | 2000-10-20 | 2002-05-22 | 敖枝平 | Prepn of 3-chloropropionyl chloride |
Non-Patent Citations (2)
| Title |
|---|
| 丙酸及其重要衍生物的生产和应用. 郑旭华.辽宁化工，第1卷. 1996 * |
| 硫普罗宁的合成新工艺. 王东阳等.中国药物化学杂质，第7卷第1期. 1997 * |
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