Semi-continuous method for preparing (S) -acetoxy propionyl chloride
阅读说明：本技术 一种制备（s）-乙酰氧基丙酰氯的半连续方法 (Semi-continuous method for preparing (S) -acetoxy propionyl chloride ) 是由 高梦 张秋华 陈熠 罗良豪 周中平 于 2021-08-05 设计创作，主要内容包括：一种制备(S)-乙酰氧基丙酰氯的半连续方法,该方法包括以下步骤：(1)向反应瓶中加入L-乳酸溶液,在氮气保护下,分批次加入碱,加完后搅拌,得到乳酸钠溶液；(2)将乳酸钠溶液进行降温至10～(o)C以下,开始滴加酯化剂,滴完后自然升至室温,之后逐渐升温,之后再保温反应得到酯化物混合液；(3)向酯化物混合液中滴入氯化剂,滴完后保温反应得到(S)-乙酰氧基丙酰氯。该方法具有操作简便,工艺稳定,成本低,产物收率高,三废易处理,环境污染小,适合工业化大规模生产的特点。(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.C o C, 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.)
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。
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:
with regard to the synthesis of the intermediate (S) -acetyloxypropionyl chloride, there have been many reports, for example, US20150329464a1 reports the following synthesis:
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:
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:
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:
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.
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