CN113717049A - Semi-continuous method for preparing (S) -acetoxy propionyl chloride - Google Patents

Semi-continuous method for preparing (S) -acetoxy propionyl chloride Download PDF

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Publication number
CN113717049A
CN113717049A CN202110895524.1A CN202110895524A CN113717049A CN 113717049 A CN113717049 A CN 113717049A CN 202110895524 A CN202110895524 A CN 202110895524A CN 113717049 A CN113717049 A CN 113717049A
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semi
preparing
continuous process
reaction
temperature
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高梦
张秋华
陈熠
罗良豪
周中平
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Jiangxi Xiongdi Pharmaceutical Co ltd
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Jiangxi Xiongdi Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A semi-continuous process for the preparation of (S) -acetoxypropionyl chloride, the process comprising the steps of: (1) adding an L-lactic acid solution into a reaction bottle, adding alkali in batches under the protection of nitrogen, and stirring to obtain a sodium lactate solution; (2) cooling the sodium lactate solution to 10 deg.CoC, starting to drip an esterifying agent, naturally raising the temperature to room temperature after dripping, gradually raising the temperature, and then carrying out heat preservation reaction to obtain an esterified product mixed solution; (3) dripping a chlorinating agent into the esterified product mixed solution, and carrying out heat preservation reaction after dripping to obtain the (S) -acetoxy propionyl chloride. The method has the operationsSimple and convenient preparation, stable process, low cost, high product yield, easy treatment of three wastes and little environmental pollution, and is suitable for industrialized large-scale production.

Description

Semi-continuous method for preparing (S) -acetoxy propionyl chloride
Technical Field
The present invention relates to a semi-continuous process for the preparation of (S) -acetoxypropionyl chloride.
Background
Iopamidol is a non-ionic water-soluble contrast agent, belongs to an image diagnosis medicament, has low toxicity to vascular wall-based nerves, good local and systemic tolerance, low osmotic pressure and low viscosity, and is suitable for spinal cord radiography and patients with high risk factors of contrast agent reaction.
In therapy, iopamidol is administered by intravenous injection and has the following structural formula:
Figure DEST_PATH_IMAGE002
with regard to the synthesis of the intermediate (S) -acetyloxypropionyl chloride, there have been many reports, for example, US20150329464a1 reports the following synthesis:
Figure DEST_PATH_IMAGE004
the method generates a large amount of waste acid acetic acid, and sulfur dioxide gas with high toxicity and environmental harmfulness is generated in the chlorination reaction, so that the method is not beneficial to popularization and production.
The reported route of WO201292880 is as follows:
Figure DEST_PATH_IMAGE006
the method uses amino acid as raw material, and the amino acid is subjected to diazotization, esterification and chlorination to obtain a product intermediate, and the method has the advantages of low yield (35%) in the esterification step, high diazotization reaction risk and no contribution to popularization and production.
Disclosure of Invention
The invention aims to provide a semi-continuous method for preparing (S) -acetoxy propionyl chloride, which solves the problems in the background art, and has the advantages of simple and convenient operation, stable process, cheap and easily obtained raw materials, high product yield, easy treatment of three wastes, small environmental pollution and low preparation cost, and is suitable for industrial large-scale production.
The technical scheme adopted for achieving the purpose is thatA semi-continuous process for preparing (S) -acetoxypropionyl chloride, the process comprising the steps of: (1) adding an L-lactic acid solution into a reaction bottle, adding alkali in batches under the protection of nitrogen, and stirring to react to obtain a sodium lactate solution; (2) cooling the sodium lactate solution to 10 deg.CoC, starting to drip an esterifying agent, naturally raising the temperature to room temperature after dripping, gradually raising the temperature, and then carrying out heat preservation reaction to obtain an esterified product mixed solution; (3) dripping a chlorinating agent into the esterified product mixed solution, and carrying out heat preservation reaction after dripping to obtain the (S) -acetoxy propionyl chloride.
Further, the mass fraction of the L-lactic acid solution in the step (1) is 80% or more.
Further, the base in the step (1) is K2CO3, Na2CO3, KHCO3, NaHCO3, KOH or NaOH.
Further, the temperature of the sodium lactate solution obtained by the reaction in the step (1) is 20 oC-100oC, preferably 40 oC-60oC。
Further, the step (2) is performed in a continuous manner.
Further, the esterifying agent in the step (2) is acetic anhydride or acetyl chloride.
Further, the step (2) is carried out by adopting a continuous pipeline reactor, and the reaction temperature is 20 DEG oC-120oC, preferably 50 oC-90oC; the residence time is 10min to 1h, preferably 0.5 h.
Further, the chlorinating agent in the step (3) is POCl3, PCl5, oxalyl chloride and a combination thereof.
Further, the reaction temperature in the step (3) is 30 DEG oC-100oC, preferably 55 oC-60 oC。
Advantageous effects
Compared with the prior art, the invention has the following advantages.
The method provided by the invention is suitable for industrial production requirements, optimizes synthesis conditions, reasonably selects the reactor and the reagent, avoids the adverse problems of low yield, complex operation procedures, high-pollution sulfur dioxide and the like, and is more beneficial to realizing industrialization.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to examples below.
A semi-continuous process for the preparation of (S) -acetoxypropionyl chloride, the process comprising the steps of: (1) adding an L-lactic acid solution into a reaction bottle, adding alkali in batches under the protection of nitrogen, and stirring to react to obtain a sodium lactate solution; (2) cooling the sodium lactate solution to 10 deg.CoC, starting to drip an esterifying agent, naturally raising the temperature to room temperature after dripping, gradually raising the temperature, and then carrying out heat preservation reaction to obtain an esterified product mixed solution; (3) dripping a chlorinating agent into the esterified product mixed solution, and carrying out heat preservation reaction after dripping to obtain the (S) -acetoxy propionyl chloride.
The mass fraction of the L-lactic acid solution in the step (1) is more than 80%.
The alkali in the step (1) is K2CO3, Na2CO3, KHCO3, NaHCO3, KOH or NaOH.
The temperature of sodium lactate solution obtained by the reaction in the step (1) is 20 oC-100oC, preferably 40 oC-60oC。
The step (2) is carried out in a continuous manner.
The esterifying agent in the step (2) is acetic anhydride or acetyl chloride.
The step (2) is carried out by adopting a continuous pipeline reactor, and the reaction temperature is 20 DEG oC-120oC, preferably 50 oC-90oC; the residence time is 10min to 1h, preferably 0.5 h.
The chlorinating agent in the step (3) is POCl3, PCl5, oxalyl chloride and a combination of the two.
The reaction temperature in the step (3) is 30 DEG oC-100oC, preferably 55 oC-60 oC。
The reaction route of the invention is as follows:
Figure DEST_PATH_IMAGE008
examples
(1) Adding 90% L-lactic acid solution (50 g, 0.5mol, 1 equivalent weight) into a reaction bottle, adding solid sodium hydroxide (22 g, 0.55mol, 1.1 equivalent weight) in batches under the protection of nitrogen, and stirring for 0.5h to obtain sodium lactate water solution.
The effect of the selection of the amount, temperature and time of sodium hydroxide on the reaction was investigated according to the actual operating method and the results are shown in table 1:
table 1 effect of different conditions on yield:
equivalent of sodium hydroxide Reaction temperature Reaction time/h Yield of
1.01 30 3 Undissolved residue
1.01 40 3 95%
1.01 50 3 95%
1.01 60 3 95%
1.01 70 3 95%
1.01 80 3 95%
Water content ratio Reaction temperature Reaction time/h Dissolution behavior
10% 60 3 Undissolved residue
15% 60 6 Long dissolving time
20% 60 3 Soluble clear
25% 60 3 Soluble clear
Reaction time/h Reaction temperature Amount of water Yield of
0.5 60 20% 85%
1 60 20% 95%
1.5 60 20% 95%
2 60 20% 95%
(2) Cooling the sodium lactate solution in the step (1) to 10 DEGoAdding dropwise acetic anhydride (150 g, 1.47mol, 2.94 equiv) below C, naturally heating to room temperature, and slowly heating to 90%oC, and keeping the temperature for 0.5h at the temperature to obtain the compound shown in the formula III, wherein the yield is 90 percent (based on the feeding amount of the lactic acid). After discharging, most of acetic anhydride and acetic acid are removed by a falling film and wiped film evaporator to obtain the mixed solution of the esterified substance.
The effect of feed ratio, temperature, residence time on the reaction was investigated according to the operating method and the results are shown in table 2:
table 2 effect of different reaction conditions on the reaction:
residence time Reaction temperature Feed (lactic acid: acetic anhydride) Yield of
10min 80 1:3.1 65%
0.5h 80 1:3.1 92%
1h 80 1:3.1 92%
1.5h 80 1:3.1 90%
2h 80 1:3.1 90%
Feed (lactic acid: acetic anhydride) Reaction temperature Residence time/h Yield of
1:3.1 80 0.5 92%
1:3.3 80 0.5 92%
1:3.5 80 0.5 91.8%
Reaction temperature Feed ratio Residence time/h Yield of
40 1:3.1 0.5 80%
50 1:3.1 0.5 85%
60 1:3.1 0.5 87%
70 1:3.1 0.5 90%
80 1:3.1 0.5 92%
Dropping the mixture of the esterified compound (0.5 mol) of (2) into PCl5(0.5 mol) of POCl3In the solution, the temperature is kept between 55 and 60 DEGoC, arranging a tail gas absorption device, preserving heat for 1.5 hours after dripping, and recovering POCl through a falling film and a wiped film evaporator3And then the product is processed by a falling film evaporator and a wiped film evaporator to obtain the formula IV with the yield of 90 percent.
According to the operating method, the influence of the material ratio, the reaction temperature and the reaction time on the reaction was investigated, and the results are shown in Table 3:
table 3 effect of different reaction conditions on the reaction:
Figure DEST_PATH_IMAGE010
Figure DEST_PATH_IMAGE012
Figure DEST_PATH_IMAGE014
the invention uses L-lactic acid with 80 percent or higher concentration as raw material to prepare (S) -acetoxy propionyl chloride, which is an intermediate compound necessary for preparing iopamidol, has high quality due to the necessity of industrialized production, and is used for producing iopamidol with pharmacopoeia requirements.

Claims (9)

1. A semi-continuous process for the preparation of (S) -acetoxypropionyl chloride, characterized in that it comprises the following steps: (1) adding an L-lactic acid solution into a reaction bottle, adding alkali in batches under the protection of nitrogen, and stirring to react to obtain a sodium lactate solution; (2) cooling the sodium lactate solution to 10 deg.CoC, starting to drip an esterifying agent, naturally raising the temperature to room temperature after dripping, gradually raising the temperature, and then carrying out heat preservation reaction to obtain an esterified product mixed solution; (3) dripping a chlorinating agent into the esterified product mixed solution, and carrying out heat preservation reaction after dripping to obtain the (S) -acetoxy propionyl chloride.
2. The semi-continuous process for preparing (S) -acetyloxypropionyl chloride according to claim 1, wherein the mass fraction of the L-lactic acid solution in the step (1) is 80% or more.
3. The semi-continuous process for preparing (S) -acetoxypropionyl chloride according to claim 1, wherein the base in step (1) is K2CO3、Na2CO3、KHCO3、NaHCO3KOH or NaOH.
4. The semi-continuous process for preparing (S) -acetoxypropionyl chloride according to claim 1, wherein the temperature of the reaction to obtain sodium lactate solution in step (1) is 20 deg.CoC-100 oC, preferably 40 oC-60oC。
5. The semi-continuous process for preparing (S) -acetyloxypropionyl chloride according to claim 1, wherein the step (2) is carried out in a continuous manner.
6. The semi-continuous process for preparing (S) -acetoxypropionyl chloride according to claim 1, wherein the esterifying agent in step (2) is acetic anhydride or acetyl chloride.
7. The semi-continuous process for preparing (S) -acetoxypropionyl chloride according to claim 1, wherein the step (2) is carried out using a continuous pipeline reactor, and the reaction temperature is 20 deg.C oC-120oC, preferably 50 oC-90oC; the residence time is 10min to 1h, preferably 0.5 h.
8. The semi-continuous process for preparing (S) -acetyloxypropionyl chloride according to claim 1, wherein the chlorinating agent in the step (3) is POCl3, PCl5, oxalyl chloride and a combination thereof.
9. The semi-continuous process for preparing (S) -acetyloxypropionyl chloride according to claim 1, wherein the reaction temperature in the step (3) is 30 ℃ oC-100oC, preferably 55oC-60oC。
CN202110895524.1A 2021-08-05 2021-08-05 Semi-continuous method for preparing (S) -acetoxy propionyl chloride Pending CN113717049A (en)

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Cited By (1)

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CN115974804A (en) * 2023-02-03 2023-04-18 内蒙古莱科作物保护有限公司 Synthesis process of novel arylpyrrole compound pesticide

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CN106831475A (en) * 2017-01-19 2017-06-13 沈阳药科大学 The preparation method of 2 lacto benzoic acid and application
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115974804A (en) * 2023-02-03 2023-04-18 内蒙古莱科作物保护有限公司 Synthesis process of novel arylpyrrole compound pesticide

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