CN1562961A - Method for preparing procaine - Google Patents
Method for preparing procaine Download PDFInfo
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- CN1562961A CN1562961A CN 200410014538 CN200410014538A CN1562961A CN 1562961 A CN1562961 A CN 1562961A CN 200410014538 CN200410014538 CN 200410014538 CN 200410014538 A CN200410014538 A CN 200410014538A CN 1562961 A CN1562961 A CN 1562961A
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- cacaine
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- procaine hcl
- raney
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Abstract
This invention relates to a process for preparing procaine, by using p-nitrobenzoic acid and diethylamino ethanol as raw materials, by esterification to produce nitrocaine, which is then reduced by reductant of hydrogenin xylene solvent with catalyst of nicket compound (Leininie) in suitable temp. and pressure to produce final product-procaine. Advantages are simple process, high transforming rate, high yield, high pureness, short process, reutilization of catalyst, no three wastes.
Description
Technical field
The present invention relates to a kind of preparation method of ester class narcotic, prepare the method for PROCAINE HCL, PHARMA GRADE more specifically to a kind of shortening.
Background technology
PROCAINE HCL, PHARMA GRADE (para-amino benzoic acid-β-diethylin ethyl ester) is a kind of common ester class local anesthetic, is one of essential drugs of domestic and international wide clinical application.Pungency and side effect are all less in the clinical application, and effect is better, and absorb fast and the anesthesia duration weak point.In recent years, its novel clinical use constantly increases, and it is prosperous that the market requirement becomes, and day by day causes concern.
The PROCAINE HCL, PHARMA GRADE synthetic method mainly contains direct esterification method and indirect esterification process.
In producing, PROCAINE HCL, PHARMA GRADE adopts the direct esterification method at present mostly.Concrete route is as follows:
The direct esterification method is a raw material with p-nitrobenzoic acid and diethylin ethanol, is the band aqua with dimethylbenzene, azeotropic dehydration, and esterification obtains nitro cacaine (p-nitrobenzoic acid-β-diethylin ethyl ester).Unreacted p-nitrobenzoic acid extracts with aqueous sodium hydroxide solution, and organic phase is alkali and analyses nitro cacaine (nitro cacaine xylene solution).Alkali is analysed nitro cacaine hcl as extraction agent, be acid out nitro cacaine (nitro cacaine hydrochloric acid soln).With the iron powder reducing method acid out nitro cacaine is reduced to PROCAINE HCL, PHARMA GRADE.
The iron powder reducing legal system is equipped with the PROCAINE HCL, PHARMA GRADE technical maturity, low for equipment requirements, yield is higher, but its purity is lower, residual iron, the sulfonium ion plasma that has in the treating processes in product, and produce waste water and the iron mud that contains arylamine in a large number in the production process, the serious and etching apparatus of environmental pollution, and physical labor intensity is big.
United States Patent (USP) (US3728376) has reported that catalytic hydrogenating reduction prepares PROCAINE HCL, PHARMA GRADE in the direct esterification method.Adopt the direct reducine of noble metal catalyst Pd/C to analyse the nitro cacaine.Reduction effect is good, and yield height, the three wastes are few, the recyclable utilization of solvent xylene.But Pd/C catalyzer market value is more expensive, has limited its application on industrial production.And this process using added nitro cacaine xylene solution continuously in autoclave in 7 hours, and Operating Pressure has increased the danger of operation and to the requirement of equipment in the reinforced process.
Summary of the invention
The present invention has overcome shortcoming of the prior art, the preparation method of the PROCAINE HCL, PHARMA GRADE of provide that a kind of catalyzer is cheap, production cost is low, the technology simple operations is convenient, transformation efficiency and yield height and product purity are high.
The preparation method's of PROCAINE HCL, PHARMA GRADE of the present invention technical scheme may further comprise the steps: (a) take by weighing alumel, 1～1.5h add one by one in the time in batches temperature be 55～65 ℃, concentration be 18～20% NaOH solution in, reinforced finishing is warming up to 85～95 ℃, and keep discharging after 2～3 hours, leave standstill then, the solution that inclines is earlier with 70～80 ℃ of washings, be washed till pH value 8～9 with normal-temperature water again, obtain Raney's nickel catalyst and preserve with dehydrated alcohol; (b) be that raw material esterification in xylene solvent obtains the nitro cacaine with p-nitrobenzoic acid and diethylin ethanol; (c) with the Raney's nickel be catalyzer, hydrogen is reductive agent, reduction nitro cacaine in xylene solvent, hydrogen pressure is 2.0～3.0MPa, and temperature of reaction is 80～130 ℃, 5～8 hours reaction times, cooling discharging then, filter through extraction, filtrate is regulated pH value, will get the solid PROCAINE HCL, PHARMA GRADE after sedimentation and filtration, the drying.
Raney's nickel catalyst weight in wet base consumption described in the step (c) is 5～15% of a nitro cacaine.
Compared with prior art, the invention has the beneficial effects as follows:
Catalyst activity used in the present invention is good, low price, preparation activation is easy, and can recycle or directly stay in the reactor and apply mechanically, and production cost is greatly reduced; Reduction of the present invention is that the alkali after esterification is analysed in the nitro cacaine xylene solution and realized, need not introduce other solvents, saved in the iron powder reducing method and gone out one step of nitro cacaine with acid out, and owing to there is not the introducing of iron ion, product quality is greatly improved, and do not have a large amount of to contain arylamine waste water and iron mud produces, operational path is short, the no three wastes; The present invention simultaneously adopts feed way one time, and does not need to be with press operation, makes more convenient to operate; Hydrogenating reduction transformation efficiency of the present invention can reach 99.4%, and the PROCAINE HCL, PHARMA GRADE product purity can reach 98%, and yield reaches 83.5%.
Embodiment
Embodiment 1
Take by weighing the 20g alumel, in the time of 1.2h, add temperature one by one at 60 ℃ in batches, concentration is in 19% the 160mLNaOH solution, and reinforced finishing is warming up to 90 ℃, and keep discharging after 2.5 hours, leave standstill then, the solution that inclines is with twice of 75 ℃ of washing, be washed till pH value 8.5 with normal-temperature water again, obtain Raney's nickel catalyst and preserve with dehydrated alcohol.
In the 500ml three-necked flask of agitator, thermometer, water trap is housed, add 46.4g (0.278mol) p-nitrobenzoic acid successively, 150ml dimethylbenzene, 31g (0.264mol) N, the N-diethylethanolamine, reflux is divided water.Stop behind the reaction 19h, be cooled to about 60 ℃, transfer in the separating funnel, add the 100ml5%NaOH solution that is preheated to about 60 ℃, standing demix is cast out water layer, obtains nitro cacaine xylene solution 184ml, the nitro cacaine that contains 0.204mol, productive rate 73.4% (in p-nitrobenzoic acid).
Nitro cacaine xylene solution 120mL, the dimethylbenzene 130mL and the Raney's nickel catalyst weight in wet base 3.4g that obtain are added reactor, airtight, use nitrogen replacement three times earlier, use hydrogen exchange again three times, under agitation be heated to 80 ℃, hydrogen pressure 3.0MPa, keep 7h, temperature is cooled to 50 ℃, release, discharging; Recording the hydrogenating reduction transformation efficiency is 92.6%, is 10% hydrochloric acid soln extraction filtrate with concentration, and the water intaking layer adds the 0.4g gac, is warming up to 60 ℃, keeps 10min, filters; Filtrate transfers to pH value 10.0～10.5 with saturated sodium carbonate solution, with sedimentation and filtration, weighs after the drying, gets faint yellow solid PROCAINE HCL, PHARMA GRADE 24.7g, and yield is 78.5%, and purity is 97.6%.
Embodiment 2
Nitro cacaine xylene solution 120mL, the dimethylbenzene 130mL and the Raney's nickel catalyst weight in wet base 4.2g that obtain among the embodiment 1 are added reactor, airtight, 100 ℃ of holding temperatures, hydrogen pressure 3.0MPa, other is operated with embodiment 1; Recording the hydrogenating reduction transformation efficiency is 93.1%, gets faint yellow solid PROCAINE HCL, PHARMA GRADE 24.9g, and yield is 79.2%, and purity is 97.8%.
Embodiment 3
Nitro cacaine xylene solution 120mL, the dimethylbenzene 130mL and the Raney's nickel catalyst weight in wet base 1.8g that obtain among the embodiment 1 are added reactor, airtight, 130 ℃ of holding temperatures, hydrogen pressure 2.0MPa, other operation is with embodiment 1, and recording the hydrogenating reduction transformation efficiency is 90.3%, gets faint yellow solid PROCAINE HCL, PHARMA GRADE 24.5g, yield is 77.8%, and purity is 97.6%.
Embodiment 4
Nitro cacaine xylene solution 120mL, the dimethylbenzene 130mL and the Raney's nickel catalyst weight in wet base 1.8g that obtain among the embodiment 1 are added reactor, airtight, 130 ℃ of holding temperatures, hydrogen pressure 2.5MPa, other operation is with embodiment 1, and recording the hydrogenating reduction transformation efficiency is 92.6%, gets faint yellow solid PROCAINE HCL, PHARMA GRADE 24.6g, yield is 78.4%, and purity is 97.6%.
Embodiment 5
Nitro cacaine xylene solution 120mL, dimethylbenzene 130mL and Raney's nickel catalyst weight in wet base 5.3g that embodiment 1 is obtained add reactor, airtight, 130 ℃ of holding temperatures, hydrogen pressure 3.0MPa, other operation is with embodiment 1, and recording the hydrogenating reduction transformation efficiency is 98.2%%, gets faint yellow solid PROCAINE HCL, PHARMA GRADE 26.3g, yield is 83.5%, and purity is 98.0%.
Embodiment 6
Leave in embodiment 1 and add nitro cacaine xylene solution 120mL and the dimethylbenzene 130mL that embodiment 1 obtains in the reactor of catalyzer, airtight, other is operated with embodiment 5, and recording the hydrogenating reduction transformation efficiency is 99.4%.Faint yellow solid PROCAINE HCL, PHARMA GRADE 27.4g, yield are 87.3%, and purity is 97.4%.
Claims (2)
1, a kind of preparation method of PROCAINE HCL, PHARMA GRADE, may further comprise the steps: (a) take by weighing alumel, 1～1.5h add one by one in the time in batches temperature be 55～65 ℃, concentration be 18～20% NaOH solution in, reinforced finishing is warming up to 85～95 ℃, and keeps discharging after 2～3 hours, leaves standstill then, solution inclines, earlier, be washed till pH value 8～9 with normal-temperature water again, obtain Raney's nickel catalyst and preserve with dehydrated alcohol with 70～80 ℃ of washings; (b) be that raw material esterification in xylene solvent obtains the nitro cacaine with p-nitrobenzoic acid and diethylin ethanol; (c) with the Raney's nickel be catalyzer, hydrogen is reductive agent, reduction nitro cacaine in xylene solvent, hydrogen pressure is 2.0～3.0MPa, and temperature of reaction is 80～130 ℃, 5～8 hours reaction times, cooling discharging then, filter through extraction, filtrate is regulated pH value, will get the solid PROCAINE HCL, PHARMA GRADE after sedimentation and filtration, the drying.
2, the preparation method of PROCAINE HCL, PHARMA GRADE according to claim 1 is characterized in that the Raney's nickel catalyst weight in wet base consumption described in the step (c) is 5～15% of a nitro cacaine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410014538 CN1233620C (en) | 2004-04-02 | 2004-04-02 | Method for preparing procaine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410014538 CN1233620C (en) | 2004-04-02 | 2004-04-02 | Method for preparing procaine |
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| Publication Number | Publication Date |
|---|---|
| CN1562961A true CN1562961A (en) | 2005-01-12 |
| CN1233620C CN1233620C (en) | 2005-12-28 |
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| CN 200410014538 Expired - Fee Related CN1233620C (en) | 2004-04-02 | 2004-04-02 | Method for preparing procaine |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101823928A (en) * | 2010-05-17 | 2010-09-08 | 无锡宏瑞生物医药科技有限公司 | Clean production process for derivatives of para aminobenzoic acid by reactor coupled simulated moving bed |
| CN114591190A (en) * | 2022-03-29 | 2022-06-07 | 浙江辰阳化工有限公司 | Method for synthesizing procaine by catalytic hydrogenation |
| CN115504892A (en) * | 2022-11-09 | 2022-12-23 | 浙江工业大学 | Method for synthesizing procaine by continuous catalytic hydrogenation |
-
2004
- 2004-04-02 CN CN 200410014538 patent/CN1233620C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101823928A (en) * | 2010-05-17 | 2010-09-08 | 无锡宏瑞生物医药科技有限公司 | Clean production process for derivatives of para aminobenzoic acid by reactor coupled simulated moving bed |
| CN101823928B (en) * | 2010-05-17 | 2013-10-23 | 无锡宏瑞生物医药科技有限公司 | Clean production process for derivatives of para aminobenzoic acid by reactor coupled simulated moving bed |
| CN114591190A (en) * | 2022-03-29 | 2022-06-07 | 浙江辰阳化工有限公司 | Method for synthesizing procaine by catalytic hydrogenation |
| CN114591190B (en) * | 2022-03-29 | 2024-04-09 | 浙江辰阳化工有限公司 | Method for synthesizing procaine through catalytic hydrogenation |
| CN115504892A (en) * | 2022-11-09 | 2022-12-23 | 浙江工业大学 | Method for synthesizing procaine by continuous catalytic hydrogenation |
| CN115504892B (en) * | 2022-11-09 | 2023-04-07 | 浙江工业大学 | Method for synthesizing procaine by continuous catalytic hydrogenation |
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| Publication number | Publication date |
|---|---|
| CN1233620C (en) | 2005-12-28 |
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