CN113717049A - Semi-continuous method for preparing (S) -acetoxy propionyl chloride - Google Patents
Semi-continuous method for preparing (S) -acetoxy propionyl chloride Download PDFInfo
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- 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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- 238000011437 continuous method Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 14
- 238000010924 continuous production Methods 0.000 claims abstract description 13
- 239000008156 Ringer's lactate solution Substances 0.000 claims abstract description 12
- 239000000243 solution Substances 0.000 claims abstract description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000011259 mixed solution Substances 0.000 claims abstract description 9
- 238000004321 preservation Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 229910019213 POCl3 Inorganic materials 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 12
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 4
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 description 4
- 229960004647 iopamidol Drugs 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000011552 falling film Substances 0.000 description 3
- 239000010408 film Substances 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000011017 operating method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- 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
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.
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。
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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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