CN109761835B - Preparation method of tetracaine hydrochloride - Google Patents
Preparation method of tetracaine hydrochloride Download PDFInfo
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- CN109761835B CN109761835B CN201811630115.3A CN201811630115A CN109761835B CN 109761835 B CN109761835 B CN 109761835B CN 201811630115 A CN201811630115 A CN 201811630115A CN 109761835 B CN109761835 B CN 109761835B
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Abstract
The invention discloses a preparation method of tetracaine hydrochloride, which comprises a first step of reaction of p-aminobenzoic acid and N-butyraldehyde, a second step of reaction of a reaction product of the first step and N, N-dimethylethanolamine, and a third step of salt forming reaction; the first step reaction is carried out in the presence of N, N-dimethylethanolamine, and the system after the first step reaction is directly subjected to the second step reaction without concentration. The method adopts the N, N-dimethylethanolamine to replace an alcohol solvent in the aldehyde-amine reaction, not only omits the solvent switching before the second esterification reaction, but also avoids the possibility of impurities caused by incomplete removal of the alcohol solvent, and effectively improves the content of the final product.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of tetracaine hydrochloride.
Background
Tetracaine hydrochloride is a high-efficiency local anesthetic for reversibly blocking nerve functions, is clinically used for infiltration anesthesia, nerve block anesthesia, epidural anesthesia and the like, is one of recognized clinical strong-efficiency anesthetics, and has the advantages of stable physicochemical properties, quick action, long maintenance time and the like.
At present, the most common synthetic method of tetracaine hydrochloride is to use p-aminobenzoic acid as a starting material, and the p-aminobenzoic acid is obtained by respectively carrying out butyl on one end of an amino group and dimethylaminoethyl on one end of a carboxyl group.
For the dimethylaminoethyl group on the carboxyl end, there are currently two main ways: one is esterification with N, N-dimethylethanolamine [ see documents 1 and 3 ], and the other is condensation with N, N-dimethylchloroethylamine [ see documents 2 and 4 ].
For butyl on the amino terminus, there are currently two main approaches: one is reacted with n-butyraldehyde [ see documents 1 and 2 ], and the other is reacted with bromobutane [ see documents 3 and 4 ].
However, the existing tetracaine hydrochloride synthesis method has the main problems that: (1) the synthesis steps are more, and the yield is lower; (2) the aldehyde-amine reaction of p-aminobenzoic acid and n-butyraldehyde needs to adopt a large amount of alcohol solvents, so that the production cost is increased, the environment is not friendly, especially, the alcohol solvents are adopted to be concentrated in advance, the subsequent esterification reaction is influenced, the incomplete concentration is easily caused for the industrial mass production, impurities which are difficult to separate are generated in the subsequent esterification reaction, and the content of tetracaine hydrochloride is influenced.
Document 1: chinese patent document CN102731333A, published 2012, 10 and 17.
Document 2: chinese patent document CN105646261A, 2016, 06, 08.
Document 3: chinese patent document CN106518697A, published 2017, 03 and 22.
Document 4: li Wenli et al, "synthetic process improvement of tetracaine hydrochloride", volume 35, No. 2, 2018, 2 months in Fine chemistry engineering.
Disclosure of Invention
The invention aims to solve the problems and provide a preparation method of tetracaine hydrochloride, which has high yield, does not need to adopt an alcohol solvent in the aldehyde-amine reaction process, and can obtain high-content tetracaine hydrochloride suitable for industrial mass production.
The technical scheme for realizing the purpose of the invention is as follows: a preparation method of tetracaine hydrochloride comprises a first-step reaction of p-aminobenzoic acid and N-butyraldehyde, a second-step reaction of a first-step reaction product and N, N-dimethylethanolamine, and a third-step salt forming reaction; the first step reaction is carried out in the presence of N, N-dimethylethanolamine [ namely, N-dimethylethanolamine as a raw material for the second step reaction is added in advance during the first step reaction ], and a system obtained after the first step reaction is directly subjected to the second step reaction without concentration.
The molar ratio of the p-aminobenzoic acid to the n-butyraldehyde is 1: 1-1: 1.5, preferably 1: 1-1: 1.1.
The weight ratio of the p-aminobenzoic acid to the N, N-dimethylethanolamine is 1: 1 to 1: 10, preferably 1: 4 to 1: 5.
The first step reaction is carried out in the presence of a hydrogenation catalyst; the hydrogenation catalyst is one or more than two (including two) of palladium carbon, platinum carbon and Raney nickel; the dosage of the hydrogenation catalyst is 3-10% of the weight of the p-aminobenzoic acid.
The temperature of the first step reaction is 30-100 ℃, and preferably 40-45 ℃.
The pressure of the first step reaction is 0.2 to 0.8MPa, preferably 0.3 to 0.5 MPa.
The second reaction is catalyzed by 4-dimethylaminopyridine.
The molar amount of the 4-dimethylamino pyridine is 0.5 to 10 percent of the molar number of the para aminobenzoic acid.
The temperature of the second reaction step is the reflux reaction temperature.
The second reaction step can also be carried out in the presence of a water scavenger; the water removing agent is one or more than two (including two) of toluene, xylene, normal hexane, petroleum ether and molecular sieve.
The salt-forming reaction in the third step further comprises a crystallization step.
The crystallization solvent adopted in the crystallization step is one or more than two (including two) of ethanol, methanol, ethyl acetate, acetone, dichloromethane and methyl tert-butyl ether.
The temperature of the crystallization step is 0-10 ℃.
The invention has the following positive effects: the invention unexpectedly discovers that N, N-dimethylethanolamine is one of important raw materials for preparing tetracaine and is an excellent solvent for aldehyde-amine reaction, so that the N, N-dimethylethanolamine is adopted to replace an alcohol solvent in the aldehyde-amine reaction, so that the solvent switching before the second esterification reaction is omitted, the possibility of impurities generated due to incomplete removal of the alcohol solvent is avoided, and the content of a final product is effectively improved.
Detailed Description
(example 1)
The preparation method of tetracaine hydrochloride of this example is specifically as follows:
adding 58kg of p-aminobenzoic acid (0.42 kmol), 260kg of N, N-dimethylethanolamine and 3kg of 3wt% palladium-carbon catalyst into a high-pressure reaction kettle, replacing nitrogen for three times, filling hydrogen, adjusting the temperature to 45-50 ℃, adjusting the pressure to 0.4 +/-0.1 MPa, then slowly dropwise adding 30.5kg of N-butyraldehyde (0.42 kmol) into the high-pressure reaction kettle, and carrying out heat preservation and pressure maintaining reaction for about 3 hours after dropwise adding.
② after the reaction, filtering and recycling the palladium-carbon catalyst, directly adding the filtrate into an esterification reaction kettle, then adding 258.3g of 4-dimethylamino pyridine (2.12 mol), heating to reflux (about 135 +/-2 ℃) and reacting to be complete (about 6 h). And (3) cooling the N, N-dimethylethanolamine distilled in the reaction process by a cooling tower, drying by a 4A molecular sieve drying tower and refluxing to the esterification reaction kettle.
③ after the reaction, decompressing and concentrating to recover the N, N-dimethylethanolamine, adding 80L ethanol and 80L ethyl acetate into the concentrated residues, stirring and dissolving, controlling the temperature to be 45 +/-2 ℃, dropwise adding concentrated hydrochloric acid into the reaction system, adjusting the pH to be 3-4, slowly cooling to 5 ℃, keeping the temperature and crystallizing for 1h, filtering and drying to obtain 93.5kg of white crystalline tetracaine hydrochloride, wherein the yield is 73.5 percent, and the content is 99.8 percent (the titration method is stopped forever).
(examples 2 to 3)
The preparation method of each example is basically the same as that of example 1 except for the differences shown in Table 1.
TABLE 1
| Example 1 | Example 2 | Example 3 | |
| Para aminobenzoic acid | 58kg（0.42kmol） | 66kg（0.48kmol） | 100kg（0.73kmol） |
| N, N-dimethylethanolamine | 260kg | 300kg | 450kg |
| Hydrogenation catalyst | 3kg of 3wt% Palladium on carbon | 3.2kg of 5wt% palladium on carbon | 5kg of 5wt% Palladium on carbon |
| Step (i) reaction temperature | 45～50℃ | 40～45℃ | 40～45℃ |
| Step (i) reaction pressure | 0.4±0.1MPa | 0.7±0.1MPa | 0.3±0.1MPa |
| N-butyraldehyde | 30.5kg（0.42kmol） | 34.7kg（0.48kmol） | 52.6kg（0.73kmol） |
| Step I reaction complete time | About 3h | About 2h | About 4h |
| 4-dimethylaminopyridine | 258.3g（2.1mol） | 610.9g（5mol） | 5kg（41mol） |
| Step II of reaction completion time | About 6h | About 6h | About 6h |
| Crystallization solvent | Ethanol 80L + Ethyl acetate 80L | Methanol 90L + Ethyl acetate 90L | 120L of ethanol + 100L of ethyl acetate |
| White crystal | 93.5kg | 108.6kg | 161.9kg |
| Yield of | 73.5% | 75.0% | 73.8% |
| Content (wt.) | 99.8% | 100.1% | 100.2% |
(example 4)
The preparation method of tetracaine hydrochloride of this example is specifically as follows:
adding 58kg of p-aminobenzoic acid (0.42 kmol), 500kg of N, N-dimethylethanolamine and 3kg of 3wt% palladium-carbon catalyst into a high-pressure reaction kettle, replacing nitrogen for three times, filling hydrogen, adjusting the temperature to 40-45 ℃, adjusting the pressure to 0.3 +/-0.1 MPa, slowly dropwise adding 30.5kg of N-butyraldehyde (0.42 kmol) into the high-pressure reaction kettle, and carrying out heat preservation and pressure maintaining reaction for about 3 hours after dropwise adding.
② after the reaction, filtering and recycling the palladium-carbon catalyst, directly adding the filtrate into an esterification reaction kettle, then adding 1kg of 4-dimethylaminopyridine (8.2 mol) and 50L of toluene, heating to reflux, and reacting completely (about 8 h).
③ after the reaction, decompressing and concentrating to recover the N, N-dimethylethanolamine and toluene, adding 78L ethanol and 78L ethyl acetate into the concentrated residues, stirring and dissolving, controlling the temperature to be 45 +/-2 ℃, dropwise adding concentrated hydrochloric acid into the reaction system, adjusting the pH to be 3-4, slowly cooling to 5 ℃, preserving heat and crystallizing for 1h, filtering and drying to obtain 91.6kg of white crystalline tetracaine hydrochloride, wherein the yield is 72.0 percent and the content is 99.9 percent (the titration method).
(examples 5 to 7)
The preparation method of each example is basically the same as that of example 4 except for the differences shown in Table 2.
TABLE 2
| Example 4 | Example 5 | Example 6 | Example 7 | |
| Para aminobenzoic acid | 58kg（0.42kmol） | 66kg（0.48kmol） | 100kg（0.73kmol） | 100kg（0.73kmol） |
| N, N-dimethylethanolamine | 500kg | 310kg | 458kg | 280kg |
| Hydrogenation catalyst | 3kg of 3wt% Palladium on carbon | 2kg of 5wt% palladium on carbon | Raney nickel 8kg | 10kg of Raney nickel |
| Step (i) reaction temperature | 40～45℃ | 42～47℃ | 40～45℃ | 40～45℃ |
| Step (i) reaction pressure | 0.3±0.1MPa | 0.4±0.1MPa | 0.4±0.1MPa | 0.5±0.1MPa |
| N-butyraldehyde | 30.5kg（0.42kmol） | 34.7kg（0.48kmol） | 52.6kg（0.73kmol） | 52.6kg（0.73kmol） |
| Step I reaction complete time | About 3h | About 2.5h | About 3h | About 3h |
| 4-dimethylaminopyridine | 1kg（8.2mol） | 610.9g（5mol） | 5kg（41mol） | 4.8kg（39mol） |
| Water removing agent | 50L of toluene | Toluene 70L | Xylene 100L | Xylene 110L |
| Step II of reaction completion time | About 8h | About 9h | About 4h | About 5h |
| Crystallization solvent | Ethanol 78L + Ethyl acetate 78L | 95L of ethanol + 95L of methyl tert-butyl ether | Ethanol 120L + methyl tert-butyl ether 110L | Acetone 220L |
| White crystal | 91.6kg | 107.2kg | 164.5kg | 160.1kg |
| Yield of | 72.0% | 74.1% | 75.0% | 73.0% |
| Content (wt.) | 99.9% | 99.8% | 100.0% | 99.9% |
Claims (9)
1. A preparation method of tetracaine hydrochloride comprises a first-step reaction of p-aminobenzoic acid, N-butyraldehyde and hydrogen, a second-step reaction of a first-step reaction product and N, N-dimethylethanolamine, and a third-step salt forming reaction; the method is characterized in that: the first step reaction is carried out in the presence of N, N-dimethylethanolamine, and the system after the first step reaction is directly subjected to the second step reaction without concentration.
2. The method for preparing tetracaine hydrochloride according to claim 1, characterized in that: the molar ratio of the p-aminobenzoic acid to the n-butyraldehyde is 1: 1-1: 1.5.
3. The method for preparing tetracaine hydrochloride according to claim 1, characterized in that: the weight ratio of the p-aminobenzoic acid to the N, N-dimethylethanolamine is 1: 1 to 1: 10.
4. The method for preparing tetracaine hydrochloride according to claim 1, characterized in that: the first step reaction is carried out in the presence of a hydrogenation catalyst; the hydrogenation catalyst is one or more than two of palladium carbon, platinum carbon and Raney nickel; the dosage of the hydrogenation catalyst is 3-10% of the weight of the p-aminobenzoic acid.
5. The method for preparing tetracaine hydrochloride according to claim 1, characterized in that: the temperature of the first step reaction is 40-45 ℃; the pressure of the first step reaction is 0.3-0.5 MPa.
6. The method for preparing tetracaine hydrochloride according to claim 1, characterized in that: the second step reaction is carried out under the catalysis of 4-dimethylamino pyridine; the molar amount of the 4-dimethylamino pyridine is 0.5 to 10 percent of the molar number of the para aminobenzoic acid.
7. The method for preparing tetracaine hydrochloride according to claim 1, characterized in that: the temperature of the second reaction step is the reflux reaction temperature.
8. The method for preparing tetracaine hydrochloride according to claim 1, characterized in that: the second reaction step can also be carried out in the presence of a water scavenger; the water removing agent is one or more than two of methylbenzene, dimethylbenzene, normal hexane, petroleum ether and a molecular sieve.
9. The method for preparing tetracaine hydrochloride according to claim 1, characterized in that: the salt-forming reaction in the third step also comprises a crystallization step; the crystallization solvent adopted in the crystallization step is one or more than two of ethanol, methanol, ethyl acetate, acetone, dichloromethane and methyl tert-butyl ether; the temperature of the crystallization step is 0-10 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5942543A (en) * | 1994-07-15 | 1999-08-24 | Ernst; Amy A. | Topical anesthetic comprising lidocaine, adrenaline, and tetracaine, and its method of use |
| CN102731333A (en) * | 2012-07-13 | 2012-10-17 | 济南诚汇双达化工有限公司 | Method for preparing tetracaine |
| CN105646261A (en) * | 2016-03-24 | 2016-06-08 | 济南诚汇双达化工有限公司 | Tetracaine preparation method |
| CN106518697A (en) * | 2016-09-20 | 2017-03-22 | 北京万全德众医药生物技术有限公司 | Preparation method of tetracaine hydrochloride |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9458102B2 (en) * | 2011-12-16 | 2016-10-04 | Oregon Health & Science University | Derivatives of tetracaine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5942543A (en) * | 1994-07-15 | 1999-08-24 | Ernst; Amy A. | Topical anesthetic comprising lidocaine, adrenaline, and tetracaine, and its method of use |
| CN102731333A (en) * | 2012-07-13 | 2012-10-17 | 济南诚汇双达化工有限公司 | Method for preparing tetracaine |
| CN105646261A (en) * | 2016-03-24 | 2016-06-08 | 济南诚汇双达化工有限公司 | Tetracaine preparation method |
| CN106518697A (en) * | 2016-09-20 | 2017-03-22 | 北京万全德众医药生物技术有限公司 | Preparation method of tetracaine hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| A new method of dicaine synthesis from p-nitrobenzoic acid ethylate;M. G.Abdullaev，等;《Pharmaceutical Chemistry Journal》;20021231;第28-31页 * |
| 盐酸丁卡因的合成工艺研究;李文丽，等;《当代化工研究》;20171231;第36-37页 * |
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