CN102675246A - Preparation method of pramoxine hydrochloride - Google Patents
Preparation method of pramoxine hydrochloride Download PDFInfo
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- CN102675246A CN102675246A CN2012101555677A CN201210155567A CN102675246A CN 102675246 A CN102675246 A CN 102675246A CN 2012101555677 A CN2012101555677 A CN 2012101555677A CN 201210155567 A CN201210155567 A CN 201210155567A CN 102675246 A CN102675246 A CN 102675246A
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Abstract
The invention relates to a preparation method of pramoxine hydrochloride. The preparation method comprises the following steps of: dissolving salt of strong alkali weak acid into water, preparing into a weakly alkaline solution, adding morpholine and 1-bromine-3-chloropropane into the weakly alkaline solution to carry out thermostatic reaction, standing and layering, and rectifying an oily matter at the upper layer to obtain intermediate N-(3-chloropropyl) morpholine; adding absolute ethyl alcohol and sodium hydroxide into a reaction kettle, then adding 4-butoxyphenol and N-(3-chloropropyl) morpholine, refluxing to obtain the oily matter, adding hydrochloric acid and methylbenzene into the oily matter, and layering to obtain an organic layer at the upper layer; adding a sodium hydroxide solution into a water layer at the lower layer to regulate the solution to be alkaline, then adding ethyl acetate and water and layering, and concentrating the solution at the upper layer to obtain a pramoxine basic group; and dissolving the pramoxine basic group into ethyl alcohol, and adding hydrochloric acid to obtain pramoxine dydrochloride. The preparation process disclosed by the invention requires no chlorination, production steps are reduced, the operation process is simple, the production cost is reduced, the environmental pollution problem is avoided, and large-scale industrial production can be realized.
Description
Technical field
The present invention relates to a kind of toponarcosis medicine, exactly is a kind of preparation method of Pramoxine HCL.
Background technology
Pramoxine HCL is a kind of local anaesthesia similar drug.Because Pramoxine HCL has special chemical structure, can the danger of cross allergy reaction be reduced.Pramoxine HCL produces can produce surface anesthesia, and little to skin and not tender and lovely mucous membrane irritation, can not surpass the scope of standing.The preparation method of Pramoxine HCL is at present: the product that morphine quinoline and the reaction of 3-propylene chlorohydrin obtain carries out chlorination again; Be prepared into N-(3-chloropropyl) morphine quinoline, N-(3-chloropropyl) morphine quinoline becomes Pramoxine HCL with 4-butoxy phenol prepared in reaction.This reaction must have chlorinating step, and preparation process is longer, and production cost is higher, and production efficiency is low.When chlorination, adopt sulfur oxychloride, produce strong impulse property gas---hydrogenchloride, sulfurous gas, these waste gas are serious to contaminate environment, and administering pollution needs higher production cost, is unfavorable for large-scale industrial production.And the Pramoxine HCL purity of preparation is about 98%, and purity is not high.Because high production cost and small-scale suitability for industrialized production causes this drug price expensive, can't satisfy the demand of modern medicine, each state is all in the working method of studying this toponarcosis medicine.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method of Pramoxine HCL, do not have chlorinating step, can not produce irritant gas, step only needed for two steps, can reduce production costs, and overcame the deficiency of prior art.
The present invention is for realizing above-mentioned purpose, and realize through following technical scheme: a kind of preparation method of Pramoxine HCL may further comprise the steps:
1. strong base-weak acid salt is soluble in water, be configured to weakly alkaline solution; In weakly alkaline solution, add morphine quinoline and 1-bromo-3-chloropropane; Stir after 30-40 minute, isothermal reaction 4-6h in 55-65 ℃ hot water bath opens cooling bath again and is cooled to room temperature; Standing demix at room temperature; Get upper strata oily matter and carry out rectifying, obtain intermediate N (3-chloropropyl) morphine quinoline, morphine quinoline, 1-bromo-3-chloropropane and strong base-weak acid salt weight ratio are 1:1.57-2.0:0.52-1.27;
2. absolute ethyl alcohol and sodium hydroxide are added in the reaction kettle; Stirring and dissolving adds 4-butoxy phenol and N-(3-chloropropyl) morphine quinoline, temperature rising reflux 24-26h again in reaction kettle; Reduce to the room temperature after-filtration; Filtrating is concentrated into no ethanol flows out, obtain oily matter, the weight ratio of N-(3-chloropropyl) morphine quinoline and 4-butoxy phenol is 1:0.9-1.3; Adding concentration is 20% hydrochloric acid in oily matter, regulates pH=2-3, adds toluene and stirs mixing down, leaves standstill, and tells the upper strata organic layer; The sodium hydroxide solution of lower aqueous layer adding 20% is regulated pH=9-10, add ETHYLE ACETATE and water again and extract 2 times, get upper solution and concentrate, obtain the Pramoxine base; The Pramoxine base is dissolved in the ethanol, adds concentration again and be 30% hydrochloric acid, regulate and carry out freezing crystallization behind the pH=1-3, centrifugally get rid of filter, obtain Pramoxine HCL.
Described strong base-weak acid salt is yellow soda ash, sodium hydrogencarbonate, salt of wormwood or saleratus.
The invention has the advantages that: in preparation N-(3-chloropropyl) the morphine quinoline process, only need to accomplish, need not to carry out chlorination once going on foot.Production stage reduces, and operating process is simple, reduces production costs; Can not produce hydrogenchloride and sulfurous gas irritant gas, avoid occurring problem of environmental pollution, save and administer the cost that pollutes, can carry out large-scale industrial production.Through the detection to preparation finished product Pramoxine HCL, purity is greater than 99.5%.The strong acid weak base salt performance is gentle, and accurately the pH value of regulator solution is simple to operation.
Embodiment
The preparation method of a kind of Pramoxine HCL of the present invention may further comprise the steps:
1. strong base-weak acid salt is soluble in water, be configured to weakly alkaline solution; In weakly alkaline solution, add morphine quinoline and 1-bromo-3-chloropropane; Stir after 30-40 minute, isothermal reaction 4-6h in 55-65 ℃ hot water bath opens cooling bath again and is cooled to room temperature; Standing demix at room temperature; Get upper strata oily matter and carry out rectifying, obtain intermediate N (3-chloropropyl) morphine quinoline, morphine quinoline, 1-bromo-3-chloropropane and strong base-weak acid salt weight ratio are 1:1.57-2.0:0.52-1.27;
2. absolute ethyl alcohol and sodium hydroxide are added in the reaction kettle; Stirring and dissolving adds 4-butoxy phenol and N-(3-chloropropyl) morphine quinoline, temperature rising reflux 24-26h again in reaction kettle; Reduce to the room temperature after-filtration; Filtrating is concentrated into no ethanol flows out, obtain oily matter, the weight ratio of N-(3-chloropropyl) morphine quinoline and 4-butoxy phenol is 1:0.9-1.3; Adding concentration is 20% hydrochloric acid in oily matter, regulates pH=2-3, adds toluene and stirs mixing down, leaves standstill, and tells the upper strata organic layer; The sodium hydroxide solution of lower aqueous layer adding 20% is regulated pH=9-10, add ETHYLE ACETATE and water again and extract 2 times, get upper solution and concentrate, obtain the Pramoxine base; The Pramoxine base is dissolved in the ethanol, adds concentration again and be 30% hydrochloric acid, regulate and carry out freezing crystallization behind the pH=1-3, centrifugally get rid of filter, obtain Pramoxine HCL.
Described strong base-weak acid salt is yellow soda ash, sodium hydrogencarbonate, salt of wormwood or saleratus.
One of preparing method's embodiment of the present invention is: concrete steps are following:
1. 4.82 kilograms of salt of wormwood are soluble in water, be configured to solution of potassium carbonate; In solution of potassium carbonate, add 6.5 kilograms of morphine quinolines and 11 kilograms of 1-bromo-3-chloropropanes; Stir after 30 minutes; Isothermal reaction 4h in 55 ℃ hot water bath opens cooling bath again and is cooled to room temperature, at room temperature standing demix; Get upper strata oily matter and carry out rectifying, obtain 9.8 kilograms of intermediate N (3-chloropropyl) morphine quinolines;
2. 71 kilograms of absolute ethyl alcohols and 4.1 kilograms of sodium hydroxide are added in the reaction kettle; Stirring and dissolving; In reaction kettle, add 10.6 kilograms of 4-butoxy phenol and 9.8 kilograms of N-(3-chloropropyl) morphine quinoline again, temperature rising reflux 24h reduces to the room temperature after-filtration; Filtrating is concentrated into no ethanol flows out, obtain oily matter; Adding concentration is 20% hydrochloric acid in oily matter, regulates pH=3, adds 30 kilograms of toluene and stirs mixing down, leaves standstill, and tells the upper strata organic layer; The sodium hydroxide solution of lower aqueous layer adding 20% is regulated pH=9-10, add 50 kilograms of ETHYLE ACETATE and 30 kg of water again and carry out layering, get upper solution and concentrate, obtain the Pramoxine base; The Pramoxine base being dissolved in 30 kilograms of ethanol, adding concentration again and be 30% hydrochloric acid, regulate and carry out freezing crystallization behind the pH=1, centrifugally get rid of filter, obtain 16.6 kilograms of Pramoxine HCLs, is 99.8% through detecting purity.
Two of preparing method's embodiment of the present invention is: concrete steps are following:
1. 8.63 kilograms of yellow soda ash are soluble in water, be configured to sodium carbonate solution; In sodium carbonate solution, add 16.2 kilograms of morphine quinolines and 25.5 kilograms of 1-bromo-3-chloropropanes; Stir after 35 minutes; Isothermal reaction 5h in 60 ℃ hot water bath opens cooling bath again and is cooled to room temperature, at room temperature standing demix; Get upper strata oily matter and carry out rectifying, obtain 22.5 kilograms of intermediate N (3-chloropropyl) morphine quinolines;
2. 130 kilograms of absolute ethyl alcohols and 9 kilograms of sodium hydroxide are added in the reaction kettle; Stirring and dissolving; In reaction kettle, add 25 kilograms of 4-butoxy phenol and 22.5 kilograms of N-(3-chloropropyl) morphine quinoline again, temperature rising reflux 25h reduces to the room temperature after-filtration; Filtrating is concentrated into no ethanol flows out, obtain oily matter; Adding concentration is 20% hydrochloric acid in oily matter, regulates pH=2, adds 70 kilograms of toluene and stirs mixing down, leaves standstill, and is divided into the upper strata organic layer; The sodium hydroxide solution of lower aqueous layer adding 20% is regulated pH=9-10, add 180 kilograms of ETHYLE ACETATE and 55 kg of water again and carry out 2 extractions, 90 kilograms of ETHYLE ACETATE of each extraction adding are got upper solution and are concentrated,, obtain the Pramoxine base; The Pramoxine base being dissolved in 55 kilograms of ethanol, adding concentration again and be 30% hydrochloric acid, regulate and carry out freezing crystallization behind the pH=2, centrifugally get rid of filter, obtain 38 kilograms of Pramoxine HCLs, is 99.5% through detecting purity.
Three of preparing method's embodiment of the present invention is: concrete steps are following:
1. 25.4 kilograms of saleratus are soluble in water, be configured to potassium bicarbonate solution; In solution of potassium carbonate, add 20 kilograms of morphine quinolines and 40 kilograms of 1-bromo-3-chloropropanes; Stir after 40 minutes; Isothermal reaction 6h in 65 ℃ hot water bath opens cooling bath again and is cooled to room temperature, at room temperature standing demix; Get upper strata oily matter and carry out rectifying, obtain 32 kilograms of intermediate N (3-chloropropyl) morphine quinolines;
2. 220 kilograms of absolute ethyl alcohols and 12.5 kilograms of sodium hydroxide are added in the reaction kettle; Stirring and dissolving; In reaction kettle, add 39 kilograms of 4-butoxy phenol and 32 kilograms of N-(3-chloropropyl) morphine quinoline again, temperature rising reflux 26h reduces to the room temperature after-filtration; Filtrating is concentrated into no ethanol flows out, obtain oily matter; Adding concentration is 20% hydrochloric acid in oily matter, regulates pH=2.5, adds 100 kilograms of toluene and stirs mixing down, leaves standstill, and tells the upper strata organic layer; The sodium hydroxide solution of lower aqueous layer adding 20% is regulated pH=9-10, add 310 kilograms of ETHYLE ACETATE and 90 kg of water again and carry out 2 extractions, 155 jin of ETHYLE ACETATE of each extraction adding are got upper solution and are concentrated, and obtain the Pramoxine base; The Pramoxine base being dissolved in 85 kilograms of ethanol, adding concentration again and be 30% hydrochloric acid, regulate and carry out freezing crystallization behind the pH=3, centrifugally get rid of filter, obtain 54 kilograms of Pramoxine HCLs, is 99.8% through detecting purity.
Strong base-weak acid salt of the present invention also can adopt sodium hydrogencarbonate.
Technical scheme of the present invention is not restricted in the scope of embodiment of the present invention.The present invention not technology contents of detailed description is known technology.
Claims (3)
1. the preparation method of a Pramoxine HCL is characterized in that: may further comprise the steps:
1. strong base-weak acid salt is soluble in water, be configured to weakly alkaline solution; In weakly alkaline solution, add morphine quinoline and 1-bromo-3-chloropropane; Stir after 30-40 minute, isothermal reaction 4-6h in 55-65 ℃ hot water bath opens cooling bath again and is cooled to room temperature; Standing demix at room temperature; Get upper strata oily matter and carry out rectifying, obtain intermediate N (3-chloropropyl) morphine quinoline, morphine quinoline, 1-bromo-3-chloropropane and strong base-weak acid salt weight ratio are 1:1.57-2.0:0.52-1.27;
2. absolute ethyl alcohol and sodium hydroxide are added in the reaction kettle; Stirring and dissolving adds 4-butoxy phenol and N-(3-chloropropyl) morphine quinoline, temperature rising reflux 24-26h again in reaction kettle; Reduce to the room temperature after-filtration; Filtrating is concentrated into no ethanol flows out, obtain oily matter, the weight ratio of N-(3-chloropropyl) morphine quinoline and 4-butoxy phenol is 1:0.9-1.3; Adding concentration is 20% hydrochloric acid in oily matter, regulates pH=2-3, adds toluene and stirs mixing down, leaves standstill, and tells the upper strata organic layer; The sodium hydroxide solution of lower aqueous layer adding 20% is regulated pH=9-10, add ETHYLE ACETATE and water again and extract 2 times, get upper solution and concentrate, obtain the Pramoxine base; The Pramoxine base is dissolved in the ethanol, adds concentration again and be 30% hydrochloric acid, regulate and carry out freezing crystallization behind the pH=1-3, centrifugally get rid of filter, obtain Pramoxine HCL.
2. the preparation method of a kind of Pramoxine HCL according to claim 1, it is characterized in that: described strong base-weak acid salt is yellow soda ash, sodium hydrogencarbonate, salt of wormwood or saleratus.
3. the preparation method of a kind of Pramoxine HCL according to claim 1, it is characterized in that: its concrete steps are following:
1. 4.82 kilograms of salt of wormwood are soluble in water, be configured to solution of potassium carbonate; In solution of potassium carbonate, add 6.5 kilograms of morphine quinolines and 11 kilograms of 1-bromo-3-chloropropanes; Stir after 30 minutes; Isothermal reaction 4h in 55 ℃ hot water bath opens cooling bath again and is cooled to room temperature, at room temperature standing demix; Get upper strata oily matter and carry out rectifying, obtain 9.8 kilograms of intermediate N (3-chloropropyl) morphine quinolines;
2. 71 kilograms of absolute ethyl alcohols and 4.1 kilograms of sodium hydroxide are added in the reaction kettle; Stirring and dissolving; In reaction kettle, add 10.6 kilograms of 4-butoxy phenol and 9.8 kilograms of N-(3-chloropropyl) morphine quinoline again, temperature rising reflux 24h reduces to the room temperature after-filtration; Filtrating is concentrated into no ethanol flows out, obtain oily matter; Adding concentration is 20% hydrochloric acid in oily matter, regulates pH=3, adds 30 kilograms of toluene and stirs mixing down, leaves standstill, and tells the upper strata organic layer; The sodium hydroxide solution of lower aqueous layer adding 20% is regulated PH=9-10, add 100 kilograms of ETHYLE ACETATE and 30 kg of water again and carry out 2 extractions, 50 kilograms of ETHYLE ACETATE of each extraction adding are got upper solution and are concentrated, and obtain the Pramoxine base; The Pramoxine base is dissolved in 30 kilograms of ethanol, adds concentration again and be 30% hydrochloric acid, regulate and carry out freezing crystallization behind the pH=1, centrifugally get rid of filter, obtain 16.6 kilograms of Pramoxine HCLs.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104059029A (en) * | 2014-07-07 | 2014-09-24 | 北京石草溪医药技术有限公司 | Preparation method of pramoxine hydrochloride |
| CN106045942A (en) * | 2016-06-30 | 2016-10-26 | 山东诚汇双达药业有限公司 | Preparation method of pramoxine hydrochloride |
| CN112521347A (en) * | 2020-12-31 | 2021-03-19 | 山东诚汇双达药业有限公司 | Method for preparing pramoxine hydrochloride by one-pot method |
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| GB710511A (en) * | 1950-09-29 | 1954-06-16 | Abbott Lab | Improvements in or relating to aryl ethers of morpholino-alkanols and methods for the production thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104059029A (en) * | 2014-07-07 | 2014-09-24 | 北京石草溪医药技术有限公司 | Preparation method of pramoxine hydrochloride |
| CN106045942A (en) * | 2016-06-30 | 2016-10-26 | 山东诚汇双达药业有限公司 | Preparation method of pramoxine hydrochloride |
| CN112521347A (en) * | 2020-12-31 | 2021-03-19 | 山东诚汇双达药业有限公司 | Method for preparing pramoxine hydrochloride by one-pot method |
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