CN111269138B - Method for efficiently preparing propacetamol hydrochloride for injection - Google Patents
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- CN111269138B CN111269138B CN202010121916.8A CN202010121916A CN111269138B CN 111269138 B CN111269138 B CN 111269138B CN 202010121916 A CN202010121916 A CN 202010121916A CN 111269138 B CN111269138 B CN 111269138B
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- WGTYJNGARJPYKG-UHFFFAOYSA-N (4-acetamidophenyl) 2-(diethylamino)acetate;hydron;chloride Chemical compound Cl.CCN(CC)CC(=O)OC1=CC=C(NC(C)=O)C=C1 WGTYJNGARJPYKG-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002347 injection Methods 0.000 title claims abstract description 23
- 239000007924 injection Substances 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 44
- 239000011347 resin Substances 0.000 claims abstract description 28
- 229920005989 resin Polymers 0.000 claims abstract description 28
- 238000003756 stirring Methods 0.000 claims abstract description 27
- 238000002156 mixing Methods 0.000 claims abstract description 25
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims abstract description 20
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000000243 solution Substances 0.000 claims abstract description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 16
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 13
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960005489 paracetamol Drugs 0.000 claims abstract description 10
- 235000011187 glycerol Nutrition 0.000 claims abstract description 9
- 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 claims abstract description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 8
- 239000001540 sodium lactate Substances 0.000 claims abstract description 8
- 229940005581 sodium lactate Drugs 0.000 claims abstract description 8
- 235000011088 sodium lactate Nutrition 0.000 claims abstract description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims abstract description 7
- 238000001291 vacuum drying Methods 0.000 claims abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 23
- 238000001914 filtration Methods 0.000 abstract description 3
- 238000011084 recovery Methods 0.000 abstract description 3
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 41
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000001816 cooling Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- -1 ester hydrochloride Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229960003192 propacetamol Drugs 0.000 description 1
- QTGAJCQTLIRCFL-UHFFFAOYSA-N propacetamol Chemical compound CCN(CC)CC(=O)OC1=CC=C(NC(C)=O)C=C1 QTGAJCQTLIRCFL-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a method for efficiently preparing propacetamol hydrochloride for injection, which mainly comprises the following steps: taking 80-85 parts by weight of acetaminophen, 200-240 parts by weight of PEG-4000 20 parts by weight of sodium lactate and 400-500 parts by weight of ethanol, adjusting pH to 7.2-7.8, mixing and stirring for 15-30 min, dropwise adding 70-85 parts by weight of chloroacetyl chloride at 20-40 ℃, adding 60-80 parts by weight of glycerin, 3-5 parts by weight of sodium carbonate and 70-90 parts by weight of diethylamine after dropwise adding, and mixing and stirring for 15-30 min; treating with macroporous resin; then adding 400-500 parts by weight of ethanol, mixing and stirring to dissolve, dripping hydrogen chloride ethanol solution to pH 1.0-3.5 under mixing and stirring, filtering, and vacuum drying the obtained product to obtain the finished product. The invention can realize the rapid and efficient production of the propacetamol hydrochloride for injection on the basis of keeping good recovery rate and purity.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a method for efficiently preparing propacetamol hydrochloride for injection.
Background
The prodrug of propacetamol (Propacetamol Hydrochloride) hydrochloride which is acetaminophen has chemical name of diethylamine acetic acid-4- (acetamido) phenyl ester hydrochloride and is mainly used for symptomatic treatment of pain, in particular postoperative pain and cancer pain. The existing preparation method of the propacetamol hydrochloride for injection uses acetone as a solvent, potassium carbonate as an acylation catalyst and potassium iodide as an ammonification catalyst for reaction, and the method can obtain higher recovery rate and purity, but has the problems of low solubility of the acetone to the potassium carbonate, difficult removal of the potassium chloride and the like, low catalytic efficiency and the like, so that the reaction and production period is longer. If the reaction time is shortened directly, the yield and purity of the obtained product will be greatly affected, which is obviously not preferable. Therefore, the method can maintain higher recovery rate and purity, and can shorten the production period at the same time, which is a problem to be solved urgently at present.
Disclosure of Invention
Accordingly, the invention provides the propacetamol hydrochloride for injection and the preparation method thereof.
The technical scheme of the invention is as follows:
a method for efficiently preparing propacetamol hydrochloride for injection comprises the following steps:
taking 80-85 parts by weight of acetaminophen, 200-240 parts by weight of PEG-4000 20 parts by weight of sodium lactate and 400-500 parts by weight of ethanol, adjusting pH to 7.2-7.8, mixing and stirring for 15-30 min, dropwise adding 70-85 parts by weight of chloroacetyl chloride at 20-40 ℃, adding 60-80 parts by weight of glycerin, 3-5 parts by weight of sodium carbonate and 70-90 parts by weight of diethylamine after dropwise adding, and mixing and stirring for 15-30 min; treating with macroporous resin; then, dropwise adding an ethanol solution of hydrogen chloride under stirring until the pH value is 1.0-3.5, carrying out suction filtration, and carrying out vacuum drying on the obtained product to obtain a finished product.
Preferably, the addition of chloroacetyl chloride is completed within 10 to 20 minutes.
Preferably, the mixing and stirring speed is 600 to 800rpm.
Preferably, the dripping of the ethanol solution of hydrogen chloride is completed within 5-10 min.
Preferably, the macroporous resins are of the type D900, D113, D4006 and XAD-4.
Preferably, the mass ratio of the macroporous resin is (5-6): (3-2): 1:1.
more preferably, the mass ratio of macroporous resin is 6:2:1:1.
preferably, chloroacetyl chloride is added dropwise at 20-30 ℃.
Preferably, the maximum flow rate of the solution through the macroporous resin is 100ml/min, and too high a flow rate will affect the reduction of the overall yield and purity of the product, and too low a flow rate will extend the production cycle.
Compared with the prior art, the invention has the beneficial effects that:
in order to reduce the reaction time as much as possible and shorten the production period, the inventor performs a great amount of optimization tests on the preparation method of the propacetamol hydrochloride for injection, and finally discovers that the use of certain reaction auxiliary agents (such as sodium lactate, PEG, glycerol and sodium carbonate) has a reaction catalysis effect and has obvious effect on shortening the reaction time. Meanwhile, due to the purification by means of macroporous resin, the subsequent recrystallization operation can be omitted, and good yield and purity can still be maintained.
The yield of the propacetamol hydrochloride for injection obtained by the invention can reach more than 96 percent, and the purity can reach more than 99 percent.
Detailed Description
In order to better understand the technical content of the present invention, the following provides specific examples to further illustrate the present invention.
Example 1
A method for efficiently preparing propacetamol hydrochloride for injection comprises the following steps:
taking 85 parts by weight of acetaminophen, 240 parts by weight of PEG-4000 30 parts by weight of sodium lactate and 500 parts by weight of ethanol, adjusting pH7.8, mixing and stirring (800 rpm) for 15min, dropwise adding 70 parts by weight of chloroacetyl chloride at 30 ℃ within 10-20 min, adding 60 parts by weight of glycerin, 3 parts by weight of sodium carbonate and 90 parts by weight of diethylamine after dropwise adding, and mixing and stirring (800 rpm) for 15min; treatment with macroporous resin (column height 1m, column diameter 50cm, flow rate of solution through macroporous resin 100 mL/min); and (3) dropwise adding an ethanol solution of hydrogen chloride to the product under the condition of mixing and stirring (800 rpm) until the pH is 3.5 (completed within 5-10 min), carrying out suction filtration, and carrying out vacuum drying on the obtained product to obtain a finished product.
The macroporous resin is D900, D113, D4006 and XAD-4, and the mass ratio is 6:2:1:1.
the production of 1kg of products is taken as a standard, 10 batches of products are repeatedly produced, the total yield of each batch of products is more than 96%, the purity is more than 99%, and the production time is reduced by at least 60% compared with the original production process.
Example 2
A method for efficiently preparing propacetamol hydrochloride for injection comprises the following steps:
taking 85 parts by weight of acetaminophen, 240 parts by weight of PEG-4000 30 parts by weight of sodium lactate and 500 parts by weight of ethanol, adjusting pH7.2, mixing and stirring (600 rpm) for 30min, dropwise adding 70 parts by weight of chloroacetyl chloride at 30 ℃ and adding 80 parts by weight of glycerin, 3 parts by weight of sodium carbonate and 90 parts by weight of diethylamine after dropwise adding within 10-20 min, and mixing and stirring (600 rpm) for 30min; treatment with macroporous resin (column height 1m, column diameter 50cm, flow rate of solution through macroporous resin 100 mL/min); then the product is dropwise added with ethanol solution of hydrogen chloride to pH 3.5 (within 5-10 min) under the condition of mixing and stirring (600 rpm), the mixture is filtered, and the obtained product is dried in vacuum to obtain the finished product.
The macroporous resin is D900, D113, D4006 and XAD-4, and the mass ratio is 6:2:1:1.
the production of 1kg of products is taken as a standard, 10 batches of products are repeatedly produced, the total yield of each batch of products is more than 95%, the purity is more than 99%, and the production time is reduced by at least 50% compared with the original production process.
Example 3
A method for efficiently preparing propacetamol hydrochloride for injection comprises the following steps:
taking 80 parts by weight of acetaminophen, 200 parts by weight of PEG-4000 20 parts by weight of sodium lactate and 400 parts by weight of ethanol, adjusting pH7.8, mixing and stirring (600 rpm) for 30min, dropwise adding 85 parts by weight of chloroacetyl chloride at 20 ℃ and adding 60 parts by weight of glycerin, 5 parts by weight of sodium carbonate and 70 parts by weight of diethylamine after dropwise adding within 10-20 min, and mixing and stirring (600 rpm) for 30min; treatment with macroporous resin (column height 1m, column diameter 50cm, flow rate of solution through macroporous resin 100 mL/min); then dripping the product into the ethanol solution of hydrogen chloride to pH 1.0 in 5-10 min under the condition of mixing and stirring (600 rpm), filtering, and vacuum drying the obtained product to obtain the finished product.
The macroporous resin types are D900, D113, D4020 and XAD-4, and the mass ratio of the macroporous resin is 6:2:1:1.
the production of 1kg of products is taken as a standard, 10 batches of products are repeatedly produced, the total yield of each batch of products reaches more than 93 percent, the purity reaches more than 99 percent, and the production time is reduced by at least 50 percent compared with the original production process.
Example 4
Example 4 differs from example 3 in that:
the macroporous resin types are D900, D113, D4006 and XAD-4, and the mass ratio of the macroporous resin is 5:3:1:1.
the production of 1kg of products is taken as a standard, 10 batches of products are repeatedly produced, the total yield of each batch of products is 85-90%, the purity is more than 99%, and the production time is reduced by at least 50% compared with the original production process.
Example 5
Example 5 differs from example 3 in that:
the macroporous resin is prepared from D900, D201, D4020 and XAD-4 by mixing, and the mass ratio is 6:2:1:1.
the production of 1kg of products is taken as standard, 10 batches of products are repeatedly produced, the total yield of each batch of products is 82-85%, the purity is about 96%, and the production time is reduced by at least 50% compared with the original production process.
The original production process comprises the following steps:
the preparation method of the propacetamol hydrochloride for injection comprises the following steps: mixing 80 parts by weight of acetaminophen, 280 parts by weight of potassium carbonate and 400 parts by weight of acetone, dropwise adding 70 parts by weight of chloracetyl chloride at 2 ℃, refluxing for 1h after dropwise adding, adding 4.0 parts by weight of potassium iodide and 80 parts by weight of diethylamine when cooling to 30 ℃, refluxing for 2h, cooling to room temperature, and suction filtering; evaporating acetone and diethylamine from the obtained filtrate under reduced pressure to obtain oily matter, adding 400 parts by weight of acetone, stirring to dissolve the oily matter, dropwise adding an ethanol solution of hydrogen chloride to pH 1.0 under stirring, cooling, carrying out suction filtration, and carrying out vacuum drying on the obtained product to obtain pale yellow crystals, wherein the proportion is 1g:25mL, ethanol was added for recrystallization to give white crystals. And (3) repeatedly producing 10 batches by taking 1kg of produced products as a standard, wherein the total yield of each batch of products is 83%, and the purity is about 99%.
Comparative example 1
A process for preparing propacetamol hydrochloride for injection comprising the steps of:
taking 85 parts by weight of acetaminophen, 240 parts by weight of PEG-4000 30 parts by weight of sodium lactate and 500 parts by weight of ethanol, adjusting pH7.8, mixing and stirring (800 rpm) for 15min, dropwise adding 70 parts by weight of chloroacetyl chloride at 30 ℃ within 10-20 min, adding 60 parts by weight of glycerin, 3 parts by weight of sodium carbonate and 90 parts by weight of diethylamine after dropwise adding, and mixing and stirring (800 rpm) for 15min; suction filtration; the obtained filtrate is dried under reduced pressure, ethanol, glycerol, diethylamine and other substances are removed, 400 parts by weight of ethanol are added and stirred to be dissolved, a hydrogen chloride ethanol solution is added dropwise to the mixture until the pH value is 1.0 under stirring, the mixture is cooled and filtered, the obtained product is dried in vacuum, and the ratio of the obtained product to the ethanol is 1g: and (5) adding ethanol into 25mL to recrystallize to obtain a finished product.
And (3) repeatedly producing 10 batches by taking 1kg of produced products as a standard, wherein the total yield of each batch of products is 83-86%, and the purity is about 90%.
Comparative example 2
The preparation method of the propacetamol hydrochloride for injection comprises the following steps: mixing 80 parts by weight of acetaminophen, 280 parts by weight of potassium carbonate and 400 parts by weight of acetone, dropwise adding 70 parts by weight of chloracetyl chloride at 2 ℃, refluxing for 1h after dropwise adding, adding 4.0 parts by weight of potassium iodide and 80 parts by weight of diethylamine when cooling to 30 ℃, refluxing for 2h, and cooling to room temperature; treatment with macroporous resin (column height 1m, column diameter 50cm, flow rate of solution through macroporous resin 100 mL/min); and (3) dropwise adding an ethanol solution of hydrogen chloride to the product under the condition of mixing and stirring (800 rpm) until the pH is 3.5 (completed within 5-10 min), carrying out suction filtration, and carrying out vacuum drying on the obtained product to obtain a finished product. The macroporous resin is D900, D113, D4006 and XAD-4, and the mass ratio is 6:2:1:1.
and (3) taking 1kg of product as a standard, repeatedly producing 10 batches, prolonging the production time by 60%, wherein the total yield of each batch of product is 85%, and the purity is about 81%.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (7)
1. The method for efficiently preparing the propacetamol hydrochloride for injection is characterized by comprising the following steps of:
taking 80-85 parts by weight of acetaminophen, 200-240 parts by weight of PEG-4000 20 parts by weight of sodium lactate and 400-500 parts by weight of ethanol, adjusting pH to 7.2-7.8, mixing and stirring for 15-30 min, dropwise adding 70-85 parts by weight of chloroacetyl chloride at 20-40 ℃, adding 60-80 parts by weight of glycerin, 3-5 parts by weight of sodium carbonate and 70-90 parts by weight of diethylamine after dropwise adding, and mixing and stirring for 15-30 min; treating with macroporous resin; then dropwise adding an ethanol solution of hydrogen chloride under stirring until the pH value is 1.0-3.5, carrying out suction filtration, and carrying out vacuum drying on the obtained product to obtain a finished product;
the macroporous resin is D900, D113, D4006 and XAD-4; the mass ratio of the macroporous resin is (5-6): (3-2): 1:1.
2. the method for efficiently preparing propacetamol hydrochloride for injection according to claim 1, wherein the dripping of chloroacetyl chloride is completed within 10 to 20 min.
3. The method for efficiently preparing propacetamol hydrochloride for injection according to claim 1, wherein the mixing and stirring speed is 600 to 800rpm.
4. The method for efficiently preparing propacetamol hydrochloride for injection according to claim 1, wherein the dripping of the ethanol solution of hydrogen chloride is completed within 5 to 10 minutes.
5. The method for efficiently preparing the propacetamol hydrochloride for injection according to claim 1, wherein the mass ratio of the macroporous resin is 6:2:1:1.
6. the method for efficiently preparing propacetamol hydrochloride for injection according to claim 1, wherein chloroacetyl chloride is added dropwise at 20 to 30 ℃.
7. The method for efficiently preparing propacetamol hydrochloride for injection according to claim 1, wherein the maximum flow rate of the solution passing through the macroporous resin is 100ml/min.
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