CN103408416B - Synthesis method of high-purity D-2-chloropropionyl chloride - Google Patents
Synthesis method of high-purity D-2-chloropropionyl chloride Download PDFInfo
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- CN103408416B CN103408416B CN201310385621.1A CN201310385621A CN103408416B CN 103408416 B CN103408416 B CN 103408416B CN 201310385621 A CN201310385621 A CN 201310385621A CN 103408416 B CN103408416 B CN 103408416B
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Abstract
The invention provides a synthesis method of high-purity D-2-chloropropionyl chloride. A process path of chlorination, hydrolysis and chloroacylation of L-methyl lactate is adopted. Specifically, the synthesis method sequentially comprises the following steps: (1) the synthesis of D-methyl-2-chloropropionate: dropwise adding thionyl chloride into the mixed solution of the L-methyl lactate and pyridine, carrying out vacuum stirring, increasing the temperature to 55-90 DEG C, reacting for 1-5h, reducing the temperature to 25-35 DEG C, exhausting air, washing and separating, wherein the L-methyl lactate and the thionyl chloride are used as raw materials and the pyridine is used as a catalyst; (2) the synthesis of D-2-chloropropionic acid: hydrolyzing methyl-2-chloropropionate under the action of a sodium hydroxide solution, and carrying out chloroform extraction; and (3) the synthesis of D-2-chloropropionyl chloride: dropwise adding the thionyl chloride into the mixed solution of D-2-chloropropionic acid and the catalyst, increasing the temperature to 70-80 DEG C, reacting for 3-5 hours, and carrying out vacuum rectification to obtain a target product. The process path has the advantages that raw materials are easily available; synthesis steps are simple, safe and reliable; the waste gas generated in the production can be easily disposed; therefore, the process path is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of high purity organic synthesis intermediate D-2-chlorpromazine chloride.
Background technology
Chlorpromazine chloride is the important intermediate of synthesizing amino acid derivative-glutamine dipeptide, is mainly used in body-care industry, is the ideal substitute of the abundantest amino acid, glutamine of body burden.Relative to glutamine, the solubleness of glutamine dipeptide is 20 times of glutamine, also very stable in storage and heat sterilization, directly can be prepared into infusion preparation for clinical, healthy human body long-term intravenous injection instillation glutamine dipeptide, without any side effect and untoward reaction, does not affect normal renal function.In known technology, the synthetic method of existing D-2 chlorpromazine chloride uses food grade Pfansteihl and sulfur oxychloride one pot synthesis under catalyst action to obtain D-2 chlorpromazine chloride, it is many that this method produces amount of by-products, product and by product are not easily separated, the a large amount of superpolymer produced cannot recycle, thus be not suitable for chemical plant economic circulation to use, and last D-2-chlorpromazine chloride purity is not high.
Summary of the invention
The object of this invention is to provide a kind of raw material simple and easy to get, material economic circulation, yield is high, the D-2-chlorpromazine chloride synthetic method that purity is high.
The synthetic method of described high purity D-2-chlorpromazine chloride, have employed the route of Pfansteihl methyl esters chloro-hydrolysis-chlorine acidylate, step comprises successively:
(1) D-2-methyl chloropropionate is synthesized
Sulfur oxychloride is added drop-wise in the mixing solutions of Pfansteihl methyl esters and pyridine, vacuum stirring, reacts 1 ~ 5h at being warming up to 55 ~ 90 DEG C, be cooled to 25 ~ 35 DEG C, bleed, washing, be separated;
(2) D-2-chloropropionic acid is synthesized
2-methyl chloropropionate is hydrolyzed under sodium hydroxide solution effect, chloroform extraction;
(3) D-2-chlorpromazine chloride is synthesized
Be added drop-wise to by sulfur oxychloride in the mixing solutions of D-2-chloropropionic acid and catalyzer, be warming up to 70 ~ 80 DEG C of reaction 3 ~ 5h, rectification under vacuum obtains product;
Wherein:
In step (1), the mass ratio of Pfansteihl methyl esters, pyridine, sulfur oxychloride is 1: 0.005 ~ 0.015: 1.2 ~ 1.8; Vacuum stirring temperature is-10 ~ 0 DEG C, and the vacuum stirring time is 1 ~ 5h; The mol ratio 1: 1 ~ 2 of methyl chloropropionate and sodium hydroxide, hydrolysis temperature is 0 ~ 10 DEG C, and hydrolysis time is 1 ~ 4h; Sulfur oxychloride dropping temperature is-10 ~ 0 DEG C, and time for adding is 1 ~ 3h; The catalyzer that synthesis D-2 chlorpromazine chloride is selected is the one in DMF, N,N-dimethylacetamide or triethylamine; The weight ratio of step (3) D-2-chloropropionic acid, sulfur oxychloride and catalyzer is 1: 1.2 ~ 1.4: 0.005 ~ 0.015.
The present invention compared with prior art, has following beneficial effect:
1, selected temperature of reaction system easily reaches, and does not relate to High Temperature High Pressure, low for equipment requirements, operates safer.
2, after Pfansteihl methyl esters chlorination terminates, adopt pulling vacuum insulation, prevent lower one-step hydrolysis from reacting and produce a large amount of salt, hydrolysis reaction is more thorough.
3, employ catalyzer, improve reaction yield and the purity of D-2-chlorpromazine chloride.
4, organic solvent can recycle, and decreases the consumption of solvent, and the waste gas produced easily processes, and is the friendly process route of a safety and environmental protection.
Embodiment
Below in conjunction with embodiment, the present invention is described further, but scope of the present invention is not by any restriction of embodiment.
Embodiment 1
Step a, synthesis D-2-methyl chloropropionate
Dry with stir and condensation reaction flask in add Pfansteihl methyl esters 110g and pyridine 1.5g, cryosel bath is cooled to-7 DEG C, drip sulfur oxychloride 140g, hierarchy of control temperature less than 0 DEG C, 2h dropwises, and drop-down vacuum stirring 1h bathed by cryosel, after be warming up to 80 DEG C, backflow 4h, question response liquid is down to 35 DEG C, and decompression pumps gas SOCl
2, SO
2deng gas, treat that gas exhausts substantially, add 30g tap water washing 10min, get methyl chloropropionate 128g, yield 99.2%, purity 99.6%.
Step b, synthesis D-2-chloropropionic acid
With in the reaction flask stirred, add methyl chloropropionate 120g, the sodium hydroxide solution of less than 10 DEG C dropping 228g massfractions 20%, 2h dropwises, and less than 10 DEG C are incubated 1h, add chloroform 200ml, concentrated hydrochloric acid is acidified to pH=1, with chloroform extraction three times, merge organic phase, after decompression is steamed and do not gone out cut to liquid phase 90 DEG C, open large vacuum (more than-0.095MPa), collect 90 ~ 100 DEG C of cuts, yield 82.5%, purity 98.5%.
Step c, synthesis D-2-chlorpromazine chloride
Dry with stir and condensation reaction flask in add D-2 chloropropionic acid 100g, catalyst n, dinethylformamide 0.5g, is down to-5 DEG C, drip sulfur oxychloride 120g,-7 DEG C reaction 3h, dropwise continue reaction 2h, after be warming up to 75 DEG C backflow 5h, stopped reaction, be cooled to 30 DEG C, 30 ~ 35 DEG C of cuts are collected in rectification under vacuum, more than vacuum-0.095MPa.Yield 82.2%, purity 99.4%.
Embodiment 2
Step a, synthesis D-2-methyl chloropropionate
Dry with stir and condensation reaction flask in add Pfansteihl methyl esters 150g and pyridine 1.5g, cryosel bath is cooled to-2 DEG C, dropping sulfur oxychloride 190g, hierarchy of control temperature less than 0 DEG C, 3h dropwises, and drop-down vacuum stirring 2h bathed by cryosel, after be warming up to 60 DEG C, backflow 5h, question response liquid is down to 35 DEG C, decompression pumps the gases such as gas SOCl2, SO2, treat that gas exhausts substantially, add 30g tap water washing 10min, get methyl chloropropionate 174.6g, yield 99.2%, purity 99.4%.
Step b, synthesis D-2-chloropropionic acid
With in the reaction flask stirred, add methyl chloropropionate 135g, the sodium hydroxide solution of less than 5 DEG C dropping 400g massfractions 20%, 2h dropwises, and less than 5 DEG C are incubated 3h, add chloroform 200ml, concentrated hydrochloric acid is acidified to pH=1.5, with chloroform extraction three times, merge organic phase, after decompression is steamed and do not gone out cut to liquid phase 90 DEG C, open large vacuum (more than-0.095MPa), collect 90 ~ 100 DEG C of cuts, yield 80%, purity 98.6%.
Step c, synthesis D-2-chlorpromazine chloride
Dry with stir and condensation reaction flask in add D-2 chloropropionic acid 100g, catalyst n, N-N,N-DIMETHYLACETAMIDE 0.5g is down to-2 DEG C, drips sulfur oxychloride 140g ,-7 DEG C of reaction 4h, dropwise and continue reaction 1h, after be warming up to 75 DEG C backflow 3h, stopped reaction, is cooled to 30 DEG C, 30 ~ 35 DEG C of cuts are collected in rectification under vacuum, more than vacuum-0.095MPa.Yield 81.6%, purity 99.2%.
Embodiment 3
Step a, synthesis D-2-methyl chloropropionate
Dry with stir and condensation reaction flask in add Pfansteihl methyl esters 150g and pyridine 1.5g, cryosel bath is cooled to-10 DEG C, dropping sulfur oxychloride 190g, hierarchy of control temperature less than 0 DEG C, 3h dropwises, and drop-down vacuum stirring 2h bathed by cryosel, after be warming up to 55 DEG C, backflow 5h, question response liquid is down to 35 DEG C, decompression pumps the gases such as gas SOCl2, SO2, treat that gas exhausts substantially, add 30g tap water washing 10min, get methyl chloropropionate 174.6g, yield 99.2%, purity 99.4%.
Step b, synthesis D-2-chloropropionic acid
With in the reaction flask stirred, add methyl chloropropionate 135g, the sodium hydroxide solution of less than 5 DEG C dropping 270g massfractions 20%, 2h dropwises, and less than 5 DEG C are incubated 3h, add chloroform 200ml, concentrated hydrochloric acid is acidified to pH=1.5, with chloroform extraction three times, merge organic phase, after decompression is steamed and do not gone out cut to liquid phase 90 DEG C, open large vacuum (more than-0.095MPa), collect 90 ~ 100 DEG C of cuts, yield 80%, purity 98.6%.
Step c, synthesis D-2-chlorpromazine chloride
Dry with stir and condensation reaction flask in add D-2 chloropropionic acid 100g, catalyst of triethylamine 0.5g, be down to-10 DEG C, drip sulfur oxychloride 133g ,-10 DEG C of reaction 4h, dropwise and continue reaction 1h, after be warming up to 75 DEG C backflow 3h, stopped reaction, is cooled to 30 DEG C, 30 ~ 35 DEG C of cuts are collected in rectification under vacuum, more than vacuum-0.095MPa.Yield 81.6%, purity 99.2%.
Claims (5)
1. a synthetic method for high purity D-2-chlorpromazine chloride, is characterized in that, comprises the following steps successively:
(1) D-2-methyl chloropropionate is synthesized
Sulfur oxychloride is added drop-wise in the mixing solutions of Pfansteihl methyl esters and pyridine, vacuum stirring, reacts 1 ~ 5h at being warming up to 55 ~ 90 DEG C, be cooled to 25 ~ 35 DEG C, bleed, washing, be separated;
(2) D-2-chloropropionic acid is synthesized
2-methyl chloropropionate is hydrolyzed under sodium hydroxide solution effect, chloroform extraction;
(3) D-2-chlorpromazine chloride is synthesized
Be added drop-wise to by sulfur oxychloride in the mixing solutions of D-2-chloropropionic acid and catalyzer, be warming up to 70 ~ 80 DEG C of reaction 3 ~ 5h, rectification under vacuum obtains product;
The temperature of vacuum stirring is-10 ~ 0 DEG C, and the vacuum stirring time is 1 ~ 5h;
The temperature that sulfur oxychloride drips is-10 ~ 0 DEG C, and time for adding is 1 ~ 3h.
2. the synthetic method of high purity D-2-chlorpromazine chloride according to claim 1, is characterized in that, in step (1), the mass ratio of Pfansteihl methyl esters, pyridine and sulfur oxychloride is 1: 0.005 ~ 0.015: 1.2 ~ 1.8.
3. the synthetic method of high purity D-2-chlorpromazine chloride according to claim 1, is characterized in that, the mol ratio of 2-methyl chloropropionate and sodium hydroxide is 1: 1 ~ 2, and hydrolysis temperature is 0 ~ 10 DEG C, and hydrolysis time is 1 ~ 4h.
4. the synthetic method of high purity D-2-chlorpromazine chloride according to claim 1, is characterized in that, the catalyzer described in step (3) is the one in DMF, N,N-dimethylacetamide or triethylamine.
5. the synthetic method of high purity D-2-chlorpromazine chloride according to claim 4, is characterized in that, in step (3), the mass ratio of D-2-chloropropionic acid, sulfur oxychloride and catalyzer is 1: 1.2 ~ 1.4: 0.005 ~ 0.015.
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| 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 |
| CN110845351A (en) * | 2019-10-08 | 2020-02-28 | 安徽生源化工有限公司 | Production process of chloropropylglutamine |
| CN112479853B (en) * | 2020-11-19 | 2023-05-02 | 四川新迪医药化工有限公司 | Preparation method of D-2-chloropropionyl chloride and D-2-chloropropionyl chloride |
| CN113773190A (en) * | 2021-07-28 | 2021-12-10 | 苏州永诺泓泽生物科技有限公司 | Preparation method of D- (+) -2-chloropropionyl chloride |
Citations (3)
| 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 |
| CN1786019A (en) * | 2005-10-14 | 2006-06-14 | 邢将军 | Manufacturing method of proglu-dipeptide |
| CN101284772A (en) * | 2008-06-11 | 2008-10-15 | 河北华晨药业有限公司 | Synthetic method of D-(+)-2-chloro-propanoyl chloride |
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| JP3952569B2 (en) * | 1998-01-13 | 2007-08-01 | エア・ウォーター株式会社 | Method for producing 3-chloropropionic acid chloride |
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| 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 |
| CN1786019A (en) * | 2005-10-14 | 2006-06-14 | 邢将军 | Manufacturing method of proglu-dipeptide |
| CN101284772A (en) * | 2008-06-11 | 2008-10-15 | 河北华晨药业有限公司 | Synthetic method of D-(+)-2-chloro-propanoyl chloride |
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Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: SHANDONG JINCHENG PHARMACEUTICAL GROUP CO.,LTD. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL CO.,LTD. Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: SHANDONG JINCHENG PHARMACEUTICAL CO.,LTD. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL & CHEMICAL Co.,Ltd. |