CN112375030A - Preparation method of diphenoxylate hydrochloride - Google Patents
Preparation method of diphenoxylate hydrochloride Download PDFInfo
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- CN112375030A CN112375030A CN202011443144.6A CN202011443144A CN112375030A CN 112375030 A CN112375030 A CN 112375030A CN 202011443144 A CN202011443144 A CN 202011443144A CN 112375030 A CN112375030 A CN 112375030A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
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Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of diphenoxylate hydrochloride. According to the method, N-Diisopropylethylamine (DIPEA) is used as an organic base catalyst to catalyze the condensation reaction of bromoethyl diphenylacetonitrile and 4-phenyl-4-ethyl piperidinecarboxylate to prepare the diphenoxylate hydrochloride, the reaction period can be obviously shortened, and the obtained diphenoxylate hydrochloride crude product can be purified to obtain a diphenoxylate hydrochloride refined product with higher yield and higher yield.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of diphenoxylate hydrochloride.
Background
Diphenoxylate hydrochloride with the chemical name: ethyl 1- (3, 3-diphenyl-3-cyanopropyl) -4-phenyl-4-piperidinecarboxylate hydrochloride as a white or almost white powder or as a crystalline powder; the diarrhea-relieving medicine is odorless, belongs to a nonspecific anti-diarrhea medicine, is easy to be absorbed by gastrointestinal tracts after being taken orally, can increase intestinal tension, inhibit or weaken the forward pushing action of gastrointestinal tract peristalsis, and astringe to reduce the secretion of the gastrointestinal tracts, thereby rapidly controlling diarrhea, and is mainly used for symptomatic treatment of acute and chronic functional diarrhea of dogs and cats.
The existing method for preparing diphenoxylate hydrochloride also has the technical problems of low yield and long reaction time.
Disclosure of Invention
The purpose of the invention is: provides a preparation method of diphenoxylate hydrochloride with short production period and high product yield.
(1) Condensation reaction
Adding measured toluene into a reaction kettle, adding bromoethyl diphenylacetonitrile, starting stirring, heating to dissolve the bromoethyl diphenylacetonitrile, standing, dividing water, adding 4-phenyl-4-ethyl piperidinecarboxylate and N, N-Diisopropylethylamine (DIPEA), continuously heating to 110-130 ℃, refluxing for 3-5 hours under heat preservation, and dividing generated water at any time in the heat preservation process. And (3) after heat preservation, cooling to room temperature, discharging, filtering by throwing, washing filter residues to be colorless by using toluene, combining filter solutions, adjusting the pH value to 1-1.5 by using CP hydrochloric acid diluted by drinking water, separating out crystals, and standing overnight. Opening a bottom valve, putting the feed liquid into a centrifuge for spin-drying after rinsing with toluene, washing with drinking water to be neutral, and finally, spin-drying until no water drops out, and discharging. The filtrate is pumped into a recovery pot to recover the toluene. Taking out the materials in the centrifuge, placing the materials in a drying tray, uniformly spreading the materials, placing the drying tray in a hot air circulation drying oven, and drying the materials at 90-110 ℃ for 20-24 hours to obtain a crude product of the diphenoxylate hydrochloride.
Wherein the mass ratio of bromoethyl diphenylacetonitrile to 4-phenyl-4-ethyl piperidinecarboxylate is 1: 0.7-0.9; the mass ratio of the solvent toluene to the bromoethyl diphenylacetonitrile is 1.6-2.0: 1; the amount of N, N-Diisopropylethylamine (DIPEA) is 1-1.5 molar equivalents.
(2) Refining
And (2) sequentially putting absolute ethyl alcohol, the diphenoxylate hydrochloride crude product prepared in the step (1) and activated carbon into a reaction pot, stirring, heating to 70-80 ℃, refluxing, and keeping the temperature for half an hour. And (3) performing filter pressing, wherein the filtrate enters a D-grade clean area, and enters a crystallization kettle after being subjected to fine filtration by a 1-micron precision filter. Starting the crystallization kettle, stirring, cooling to below 10 ℃ with brine ice to fully crystallize, separating out crystals, and standing. And (3) putting the feed liquid into a centrifuge, performing spin-drying, washing with a proper amount of purified water until the filtered water is nearly neutral, and performing spin-drying after washing. And then rinsing the filtrate by using absolute ethyl alcohol until the filtrate is colorless, and drying the filtrate by drying. Drying for 8-10 hours at the temperature of 75-85 ℃ and the vacuum degree of less than or equal to-0.08 MPa to obtain a refined product of the diphenoxylate hydrochloride.
Wherein the mass ratio of the absolute ethyl alcohol to the crude diphenoxylate hydrochloride product is 5-6:1, and the dosage of the active carbon is 5-10% of the mass of the crude diphenoxylate hydrochloride product.
Has the advantages that:
according to the method, N-Diisopropylethylamine (DIPEA) is used as an organic base catalyst to catalyze the condensation reaction of bromoethyl diphenylacetonitrile and 4-phenyl-4-ethyl piperidinecarboxylate to prepare the diphenoxylate hydrochloride, the reaction period can be obviously shortened, and the obtained diphenoxylate hydrochloride crude product can be purified to obtain a diphenoxylate hydrochloride refined product with higher yield and higher yield.
Detailed Description
The present invention is further described below with reference to examples, but is not limited thereto.
Example 1
(1) Condensation reaction
Adding 1.6kg of toluene into a reaction kettle, adding 1kg of bromoethyl diphenylacetonitrile, starting stirring, heating to dissolve the bromoethyl diphenylacetonitrile, standing, dividing water, adding 0.74kg of 4-phenyl-4-ethyl piperidine formate and 1 equivalent of N, N-Diisopropylethylamine (DIPEA), continuously heating to 120 ℃, and carrying out heat preservation and reflux for 4 hours. The water produced is removed at any time during the heat preservation process. And (3) after heat preservation, cooling to room temperature, discharging, filtering by throwing, washing filter residues to be colorless by using toluene, combining filter solutions, adjusting the pH value to 1-1.5 by using CP hydrochloric acid (drinking water: CP hydrochloric acid volume ratio is 1:1) diluted by drinking water, precipitating crystals, and standing overnight. Opening a bottom valve, putting the feed liquid into a centrifuge for spin-drying after rinsing with toluene, washing with drinking water to be neutral, washing for certain time, spin-drying as much as possible when throwing the feed, and finally, discharging after no water drops. The filtrate is pumped into a recovery pot to recover the toluene. Taking out the materials in the centrifuge, placing the materials in a drying tray, uniformly spreading the materials, then placing the drying tray in a hot air circulation drying oven, heating the drying tray to 100 ℃, drying the materials for 24 hours, taking out the dried materials, and weighing the dried materials to obtain the crude product of the diphenoxylate hydrochloride.
(2) Refining
5kg of absolute ethyl alcohol, 1kg of crude diphenoxylate hydrochloride and 100g of active carbon are sequentially put into a reaction pot, stirred and heated to 75 ℃ for reflux, and the temperature is kept for half an hour. And (3) performing filter pressing, wherein the filtrate enters a D-grade clean area, and enters a crystallization kettle after being subjected to fine filtration by a 1-micron precision filter. Starting the crystallization kettle, stirring, cooling to below 10 ℃ with brine ice to fully crystallize, separating out crystals, and standing. And (3) putting the feed liquid into a centrifuge, performing spin-drying, adding a proper amount of purified water until the filtered water is nearly neutral, and performing washing and spin-drying. And then rinsing the filtrate by using absolute ethyl alcohol until the filtrate is colorless, and drying the filtrate by drying. Discharging at 80 deg.C and vacuum degree less than or equal to-0.08 MPa, and drying for 10 hr. The diphenoxylate hydrochloride is obtained with the yield of 93 percent, the purity of 99.7 percent and 0.05 percent of single impurity, and the obtained diphenoxylate hydrochloride is white powder with the drying weight loss not more than 5.0 percent.
Example 2
(1) Condensation reaction
Adding 1.8kg of toluene into a reaction kettle, adding 1kg of bromoethyl diphenylacetonitrile, starting stirring, heating to dissolve the bromoethyl diphenylacetonitrile, standing, dividing water, adding 0.8kg of 4-phenyl-4-ethyl piperidine formate and 1.2 equivalents of N, N-Diisopropylethylamine (DIPEA), continuously heating to 110 ℃, and carrying out heat preservation and reflux for 5 hours. The water produced is removed at any time during the heat preservation process. And (3) after heat preservation, cooling to room temperature, discharging, filtering by throwing, washing filter residues to be colorless by using toluene, combining filter solutions, adjusting the pH value to 1-1.5 by using CP hydrochloric acid diluted by drinking water, separating out crystals, and standing overnight. Opening a bottom valve, putting the feed liquid into a centrifuge for spin-drying after rinsing with toluene, washing with drinking water to be neutral, washing for certain time, spin-drying as much as possible when throwing the feed, and finally, discharging after no water drops. The filtrate is pumped into a recovery pot to recover the toluene. Taking out the materials in the centrifuge, placing the materials in a drying tray, uniformly spreading the materials, then placing the drying tray in a hot air circulation drying oven, heating the drying tray to 100 ℃, drying the materials for 24 hours, taking out the dried materials, and weighing the dried materials to obtain the crude product of the diphenoxylate hydrochloride.
(2) Refining
Putting 6kg of absolute ethyl alcohol, 1kg of crude diphenoxylate hydrochloride and 80g of active carbon into a reaction pot in sequence, stirring, heating to 75 ℃, refluxing, and keeping the temperature for half an hour. And (3) performing filter pressing, wherein the filtrate enters a D-grade clean area, and enters a crystallization kettle after being subjected to fine filtration by a 1-micron precision filter. Starting the crystallization kettle, stirring, cooling to below 10 ℃ with brine ice to fully crystallize, separating out crystals, and standing. And (3) putting the feed liquid into a centrifuge, performing spin-drying, adding a proper amount of purified water until the filtered water is nearly neutral, and performing washing and spin-drying. And then rinsing the filtrate by using absolute ethyl alcohol until the filtrate is colorless, and drying the filtrate by drying. Discharging at 75 deg.C and vacuum degree less than or equal to-0.08 MPa, and drying for 10 hr. The diphenoxylate hydrochloride is obtained with the yield of 93.8 percent, the purity of 99.7 percent and single impurity of 0.05 percent, and the obtained diphenoxylate hydrochloride is white powder with the drying weight loss not more than 5.0 percent.
Example 3
(1) Condensation reaction
Adding 2.0kg of toluene into a reaction kettle, adding 1kg of bromoethyl diphenylacetonitrile, starting stirring, heating to dissolve the bromoethyl diphenylacetonitrile, standing, dividing water, adding 0.9kg of 4-phenyl-4-ethyl piperidine formate and 1.5 equivalents of N, N-Diisopropylethylamine (DIPEA), continuously heating to 130 ℃, and carrying out heat preservation and reflux for 3 hours. The water produced is removed at any time during the heat preservation process. And (3) after heat preservation, cooling to room temperature, discharging, filtering by throwing, washing filter residues to be colorless by using toluene, combining filter solutions, adjusting the pH value to 1-1.5 by using CP hydrochloric acid diluted by drinking water, separating out crystals, and standing overnight. Opening a bottom valve, putting the feed liquid into a centrifuge for spin-drying after rinsing with toluene, washing with drinking water to be neutral, washing for certain time, spin-drying as much as possible when throwing the feed, and finally, discharging after no water drops. The filtrate is pumped into a recovery pot to recover the toluene. Taking out the materials in the centrifuge, placing the materials in a drying tray, uniformly spreading the materials, then placing the drying tray in a hot air circulation drying oven, heating the drying tray to 100 ℃, drying the materials for 24 hours, taking out the dried materials, and weighing the dried materials to obtain the crude product of the diphenoxylate hydrochloride.
(2) Refining
5.5kg of absolute ethyl alcohol, 1kg of crude diphenoxylate hydrochloride and 100g of active carbon are sequentially put into a reaction pot, stirred, heated to 75 ℃ for reflux and kept warm for half an hour. And (3) performing filter pressing, wherein the filtrate enters a D-grade clean area, and enters a crystallization kettle after being subjected to fine filtration by a 1-micron precision filter. Starting the crystallization kettle, stirring, cooling to below 10 ℃ with brine ice to fully crystallize, separating out crystals, and standing. And (3) putting the feed liquid into a centrifuge, performing spin-drying, adding a proper amount of purified water until the filtered water is nearly neutral, and performing washing and spin-drying. And then rinsing the filtrate by using absolute ethyl alcohol until the filtrate is colorless, and drying the filtrate by drying. Discharging at 85 deg.C and vacuum degree less than or equal to-0.08 MPa, and drying for 8 hr. The diphenoxylate hydrochloride is obtained with the yield of 92.9 percent, the purity of 99.3 percent and single impurity of 0.05 percent, and the obtained diphenoxylate hydrochloride is white powder with the drying weight loss of not more than 5.0 percent.
Example 4
(1) Condensation reaction
Adding 1.9kg of toluene into a reaction kettle, adding 1kg of bromoethyl diphenylacetonitrile, starting stirring, heating to dissolve the bromoethyl diphenylacetonitrile, standing, dividing water, adding 0.85kg of 4-phenyl-4-ethyl piperidine formate and 1.3 equivalents of N, N-Diisopropylethylamine (DIPEA), continuously heating to 110 ℃, and carrying out heat preservation and reflux for 5 hours. The water produced is removed at any time during the heat preservation process. And (3) after heat preservation, cooling to room temperature, discharging, filtering by throwing, washing filter residues to be colorless by using toluene, combining filter solutions, adjusting the pH value to 1-1.5 by using CP hydrochloric acid diluted by drinking water, separating out crystals, and standing overnight. Opening a bottom valve, putting the feed liquid into a centrifuge for spin-drying after rinsing with toluene, washing with drinking water to be neutral, washing for certain time, spin-drying as much as possible when throwing the feed, and finally, discharging after no water drops. The filtrate is pumped into a recovery pot to recover the toluene. Taking out the materials in the centrifuge, placing the materials in a drying tray, uniformly spreading the materials, then placing the drying tray in a hot air circulation drying oven, heating the drying tray to 100 ℃, drying the materials for 24 hours, taking out the dried materials, and weighing the dried materials to obtain the crude product of the diphenoxylate hydrochloride.
(2) Refining
5.5kg of absolute ethyl alcohol, 1kg of crude diphenoxylate hydrochloride and 100g of active carbon are sequentially put into a reaction pot, stirred, heated to 80 ℃ for reflux and kept warm for half an hour. And (3) performing filter pressing, wherein the filtrate enters a D-grade clean area, and enters a crystallization kettle after being subjected to fine filtration by a 1-micron precision filter. Starting the crystallization kettle, stirring, cooling to below 10 ℃ with brine ice to fully crystallize, separating out crystals, and standing. And (3) putting the feed liquid into a centrifuge, performing spin-drying, adding a proper amount of purified water until the filtered water is nearly neutral, and performing washing and spin-drying. And then rinsing the filtrate by using absolute ethyl alcohol until the filtrate is colorless, and drying the filtrate by drying. Discharging at 85 deg.C and vacuum degree less than or equal to-0.08 MPa, and drying for 8 hr. The diphenoxylate hydrochloride is obtained with the yield of 92.6 percent, the purity of 99.2 percent and single impurity of 0.05 percent, and the obtained diphenoxylate hydrochloride is white powder with the drying weight loss of not more than 5.0 percent.
Comparative example 1
(1) Condensation reaction
Adding 1.6kg of toluene into a reaction kettle, adding 1kg of bromoethyl diphenylacetonitrile, starting stirring, heating to dissolve the bromoethyl diphenylacetonitrile, standing, dividing water, adding 0.74kg of 4-phenyl-4-ethyl piperidine formate and 1 equivalent of sodium bicarbonate, continuously heating to 120 ℃, and carrying out heat preservation and reflux for 24 hours. The water produced is removed at any time during the heat preservation process. And (3) after heat preservation, cooling to room temperature, discharging, filtering by throwing, washing filter residues to be colorless by using toluene, combining filter solutions, adjusting the pH value to 1-1.5 by using CP hydrochloric acid (drinking water: CP hydrochloric acid volume ratio is 1:1) diluted by drinking water, precipitating crystals, and standing overnight. Opening a bottom valve, putting the feed liquid into a centrifuge for spin-drying after rinsing with toluene, washing with drinking water to be neutral, washing for certain time, spin-drying as much as possible when throwing the feed, and finally, discharging after no water drops. The filtrate is pumped into a recovery pot to recover the toluene. Taking out the materials in the centrifuge, placing the materials in a drying tray, uniformly spreading the materials, then placing the drying tray in a hot air circulation drying oven, heating the drying tray to 100 ℃, drying the materials for 24 hours, taking out the dried materials, and weighing the dried materials to obtain the crude product of the diphenoxylate hydrochloride.
(2) Refining
5kg of absolute ethyl alcohol, 1kg of crude diphenoxylate hydrochloride and 100g of active carbon are sequentially put into a reaction pot, stirred and heated to 75 ℃ for reflux, and the temperature is kept for half an hour. And (3) performing filter pressing, wherein the filtrate enters a D-grade clean area, and enters a crystallization kettle after being subjected to fine filtration by a 1-micron precision filter. Starting the crystallization kettle, stirring, cooling to below 10 ℃ with brine ice to fully crystallize, separating out crystals, and standing. And (3) putting the feed liquid into a centrifuge, performing spin-drying, adding a proper amount of purified water until the filtered water is nearly neutral, and performing washing and spin-drying. And then rinsing the filtrate by using absolute ethyl alcohol until the filtrate is colorless, and drying the filtrate by drying. Discharging at 80 deg.C and vacuum degree less than or equal to-0.08 MPa, and drying for 10 hr. The obtained diphenoxylate hydrochloride has the yield of 75 percent, the purity of 97.9 percent and 0.07 percent of single impurity, and the obtained diphenoxylate hydrochloride is white powder, and the drying weight loss is not more than 5.0 percent.
Comparative example 2
(1) Condensation reaction
Adding 1.6kg of toluene into a reaction kettle, adding 1kg of bromoethyl diphenylacetonitrile, starting stirring, heating to dissolve the bromoethyl diphenylacetonitrile, standing, dividing water, adding 0.74kg of 4-phenyl-4-piperidine ethyl formate and 1 equivalent of triethylamine, continuously heating to 120 ℃, and carrying out heat preservation and reflux for 4 hours. The water produced is removed at any time during the heat preservation process. And (3) after heat preservation, cooling to room temperature, discharging, filtering by throwing, washing filter residues to be colorless by using toluene, combining filter solutions, adjusting the pH value to 1-1.5 by using CP hydrochloric acid (drinking water: CP hydrochloric acid volume ratio is 1:1) diluted by drinking water, precipitating crystals, and standing overnight. Opening a bottom valve, putting the feed liquid into a centrifuge for spin-drying after rinsing with toluene, washing with drinking water to be neutral, washing for certain time, spin-drying as much as possible when throwing the feed, and finally, discharging after no water drops. The filtrate is pumped into a recovery pot to recover the toluene. Taking out the materials in the centrifuge, placing the materials in a drying tray, uniformly spreading the materials, then placing the drying tray in a hot air circulation drying oven, heating the drying tray to 100 ℃, drying the materials for 24 hours, taking out the dried materials, and weighing the dried materials to obtain the crude product of the diphenoxylate hydrochloride.
(2) Refining
5kg of absolute ethyl alcohol, 1kg of crude diphenoxylate hydrochloride and 100g of active carbon are sequentially put into a reaction pot, stirred and heated to 75 ℃ for reflux, and the temperature is kept for half an hour. And (3) performing filter pressing, wherein the filtrate enters a D-grade clean area, and enters a crystallization kettle after being subjected to fine filtration by a 1-micron precision filter. Starting the crystallization kettle, stirring, cooling to below 10 ℃ with brine ice to fully crystallize, separating out crystals, and standing. And (3) putting the feed liquid into a centrifuge, performing spin-drying, adding a proper amount of purified water until the filtered water is nearly neutral, and performing washing and spin-drying. And then rinsing the filtrate by using absolute ethyl alcohol until the filtrate is colorless, and drying the filtrate by drying. Discharging at 80 deg.C and vacuum degree less than or equal to-0.08 MPa, and drying for 10 hr. The diphenoxylate hydrochloride is obtained with the yield of 88 percent, the purity of 98.7 percent and 0.06 percent of single impurity, and the obtained diphenoxylate hydrochloride is white powder with the drying weight loss not more than 5.0 percent.
Comparative example 3
(1) Condensation reaction
Adding 1.6kg of toluene into a reaction kettle, adding 1kg of bromoethyl diphenylacetonitrile, starting stirring, heating to dissolve the bromoethyl diphenylacetonitrile, standing, dividing water, adding 0.74kg of 4-phenyl-4-piperidine ethyl formate and 1 equivalent of piperidine, continuously heating to 120 ℃, and carrying out heat preservation and reflux for 4 hours. The water produced is removed at any time during the heat preservation process. And (3) after heat preservation, cooling to room temperature, discharging, filtering by throwing, washing filter residues to be colorless by using toluene, combining filter solutions, adjusting the pH value to 1-1.5 by using CP hydrochloric acid (drinking water: CP hydrochloric acid volume ratio is 1:1) diluted by drinking water, precipitating crystals, and standing overnight. Opening a bottom valve, putting the feed liquid into a centrifuge for spin-drying after rinsing with toluene, washing with drinking water to be neutral, washing for certain time, spin-drying as much as possible when throwing the feed, and finally, discharging after no water drops. The filtrate is pumped into a recovery pot to recover the toluene. Taking out the materials in the centrifuge, placing the materials in a drying tray, uniformly spreading the materials, then placing the drying tray in a hot air circulation drying oven, heating the drying tray to 100 ℃, drying the materials for 24 hours, taking out the dried materials, and weighing the dried materials to obtain the crude product of the diphenoxylate hydrochloride.
(2) Refining
5kg of absolute ethyl alcohol, 1kg of crude diphenoxylate hydrochloride and 100g of active carbon are sequentially put into a reaction pot, stirred and heated to 75 ℃ for reflux, and the temperature is kept for half an hour. And (3) performing filter pressing, wherein the filtrate enters a D-grade clean area, and enters a crystallization kettle after being subjected to fine filtration by a 1-micron precision filter. Starting the crystallization kettle, stirring, cooling to below 10 ℃ with brine ice to fully crystallize, separating out crystals, and standing. And (3) putting the feed liquid into a centrifuge, performing spin-drying, adding a proper amount of purified water until the filtered water is nearly neutral, and performing washing and spin-drying. And then rinsing the filtrate by using absolute ethyl alcohol until the filtrate is colorless, and drying the filtrate by drying. Discharging at 80 deg.C and vacuum degree less than or equal to-0.08 MPa, and drying for 10 hr. The diphenoxylate hydrochloride is obtained with the yield of 86 percent, the purity of 98.5 percent and 0.05 percent of single impurity, and the obtained diphenoxylate hydrochloride is white powder with the drying weight loss not more than 5.0 percent.
The present invention is not limited to the above-described embodiments, and any obvious improvements, substitutions or modifications can be made by those skilled in the art without departing from the spirit of the present invention.
Claims (8)
1. The preparation method of diphenoxylate hydrochloride is characterized by comprising the following steps:
(1) condensation reaction
Adding measured toluene into a reaction kettle, adding bromoethyl diphenylacetonitrile, starting stirring, heating to dissolve the bromoethyl diphenylacetonitrile, standing, dividing water, adding 4-phenyl-4-ethyl piperidinecarboxylate and N, N-Diisopropylethylamine (DIPEA), continuously heating to reflux reaction, removing generated water at any time in the reaction process, cooling to room temperature after the reaction is finished, discharging, carrying out spin-filtration, washing filter residues to be colorless with toluene, combining filter solutions, adjusting the pH value to 1-1.5 with CP hydrochloric acid diluted by drinking water, separating out crystals, standing overnight, opening a bottom valve of the reaction kettle, putting feed liquid into a centrifugal machine for spin-drying, rinsing with toluene, carrying out spin-drying, washing with drinking water to be neutral, discharging after no water is dripped out, pumping the filtrate into a recovery pot to recover toluene, taking out materials in a centrifugal machine, placing the materials in a drying plate, spreading uniformly, putting the drying plate into a hot air circulation oven for drying, obtaining a crude product of the diphenoxylate hydrochloride;
(2) refining
And (2) sequentially putting absolute ethyl alcohol, the crude diphenoxylate hydrochloride obtained in the step (1) and activated carbon into a reaction pot, stirring, heating to reflux and preserving heat, press-filtering, allowing the filtrate to enter a D-level clean zone, finely filtering by using a 1 mu m precision filter, then allowing the filtrate to enter a crystallization kettle, starting the crystallization kettle, stirring, cooling to below 10 ℃ by using brine ice to fully crystallize the filtrate, standing, putting the feed liquid into a centrifuge, performing spin-filtration, washing by using pure water until the filtrate is nearly neutral, spin-drying, rinsing by using absolute ethyl alcohol until the filtrate is colorless, spin-drying at the temperature of 75-85 ℃ and the vacuum degree is less than or equal to-0.08 MPa, and drying for 8-10 hours to obtain the fine diphenoxylate hydrochloride.
2. The method for preparing diphenoxylate hydrochloride according to claim 1, wherein the mass ratio of bromoethyl diphenylacetonitrile to 4-phenyl-4-piperidinecarboxylic acid ethyl ester in the step (1) is 1: 0.7-0.9.
3. The method for preparing diphenoxylate hydrochloride according to claim 1, wherein the mass ratio of the solvent toluene to bromoethyl diphenylacetonitrile in step (1) is 1.6-2.0: 1.
4. The method for preparing diphenoxylate hydrochloride according to claim 1, wherein the N, N-Diisopropylethylamine (DIPEA) is used in an amount of 1 to 1.5 molar equivalents in step (1).
5. The method for preparing diphenoxylate hydrochloride according to claim 1, wherein the reflux reaction temperature in step (1) is 110-130 ℃ and the reflux reaction time is 3-5 hours.
6. The method for preparing diphenoxylate hydrochloride according to claim 1, wherein the drying temperature in step (1) is 90-110 ℃ and the drying time is 20-24 hours.
7. The method for preparing diphenoxylate hydrochloride according to claim 1, wherein the mass ratio of the absolute ethanol to the crude diphenoxylate hydrochloride in the step (2) is 5-6:1, and the amount of the activated carbon added is 5-10% of the crude diphenoxylate hydrochloride.
8. The method for preparing diphenoxylate hydrochloride according to claim 1, wherein the heating reflux temperature in step (2) is 70-80 ℃, and the temperature is kept for half an hour.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107586275A (en) * | 2017-06-01 | 2018-01-16 | 合肥远志医药科技开发有限公司 | A kind of diphenoxylate hydrochloride industrialized preparing process |
| CN108912041A (en) * | 2018-07-06 | 2018-11-30 | 郑州明泽医药科技有限公司 | A kind of synthetic method of diphenoxylate hydrochloride |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107586275A (en) * | 2017-06-01 | 2018-01-16 | 合肥远志医药科技开发有限公司 | A kind of diphenoxylate hydrochloride industrialized preparing process |
| CN108912041A (en) * | 2018-07-06 | 2018-11-30 | 郑州明泽医药科技有限公司 | A kind of synthetic method of diphenoxylate hydrochloride |
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