Background technology
Domperidone Maleate is a periphery Dopamine Receptors blocade, directly act on gastrointestinal wall, can increase oesophagus bottom sphincter tone, prevent stomach-esophageal reflux, strengthen peristole, promote stomach emptying, coordinate the motion of stomach and duodenum, suppress to feel sick, vomit, and can prevent bile regurgitation effectively, do not influence gastric secretion.Domperidone is difficult for by blood cerebrospinal fluid barrier, and to Dopamine Receptors unrestraint effect in noon, therefore, no extrapyramidal system etc. are neural, spiritual untoward reaction.The oral post-absorption of domperidone is rapid, but 15~30 minutes peaking Plasma Concentrations.Distribution is the highest with the stomach and intestine local drug concentration, and blood plasma takes second place, and does not almost have in the brain.This product is almost all at intrahepatic metabolism, transformation period (t
1/2) be 7 hours, be 31.23% by the urine excretion total amount, the original shape medicine accounts for 0.4%; Defecate total amount 65.7%, the original shape medicine accounts for 10%.Be mainly used in clinically: 1. alleviating is expanded as: epigastrium by stomach emptying delays, gi tract instead flow, esophagitis causes indigestion symptom has or does not have the stomach burning sensation of anti-stream gastric content in vexed sense, abdominal distension, Upper abdominal pain, belch, flatulence, the mouth.2. treat that functional, organic, infectious, diet, radiation treatment or chemotherapy are causedly felt sick, vomiting.At present, it is synthetic for existing two pieces of patents (US04066772, DE 2632870) and many pieces of bibliographical informations, and common operational path has following two kinds:
Method one: with the O-Phenylene Diamine is raw material, at first generate 2 (3H) benzimidazolone with carbonyl chloride reaction cyclization, products therefrom generates 1-(methyl ethylene)-1 with the isopropenyl acetate reaction again, 3-dihydro-2H-benzimidazolyl-2 radicals-ketone, generate 1-(methyl with the reaction of 1-bromo-3-chloropropane again, vinyl)-2H-benzimidazolyl-2 radicals-ketone, further hydrolysis generates 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, with 5-chloro-1,3-dihydro-1-(4-piperidyl)-2H-benzimidazolyl-2 radicals-reactive ketone generates domperidone, and last and toxilic acid reaction generates Domperidone Maleate;
Method two: with 1-benzyl-4-amino-piperadine is raw material, and at first with 2, the reaction of 5-dichloronitrobenzene generates benzyl aminomethyl piperidine derivative.Hydrogenating reduction generates corresponding compound under the condition that Raney nickel exists, generate benzimidizole derivatives with the urea cyclization, under the condition that the carbon palladium exists, take off benzene and generate 5-chloro-1,3 dihydros-1-(4-piperidyl)-2H-benzimidazolyl-2 radicals-ketone, again with 1-(3-chloropropane)-1,3-dihydro-2H-benzimidazolyl-2 radicals-reactive ketone generates domperidone, and methyl alcohol makes solvent and the toxilic acid reaction generates Domperidone Maleate
Above-mentioned two kinds of methods, method one output instability, method two expensive raw material price, yield is low, be not suitable for suitability for industrialized production, thereby causes the complex manufacturing of whole Domperidone Maleate, yield is low, industrial production cost is higher.
Summary of the invention
The technical problem to be solved in the present invention is exactly present Domperidone Maleate complex manufacturing, low, the cost problem of higher of yield.
For solving the problems of the technologies described above, the present invention adopts following simple relatively synthesis technique:
Ortho-diaminobenzene and Vinyl chloroformate reaction generate benzimidazolone, and the latter and the reaction of 1-bromo-3-chloropropane generate 1-(3-chloropropane)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethoxycarbonyl-4-amino piperidine and 2, the reaction of 5-dichloronitrobenzene generates the ethoxycarbonyl aminoderivative, logical hydrogen reduction under the condition that Raney nickel exists again generates 5-chloro-1,3-dihydro-1-(4-piperidyl)-2H-benzimidazolyl-2 radicals-ketone with the last hydrolysis of urea cyclization;
1-(3-chloropropane)-1,3-dihydro-benzimidazolyl-2 radicals-ketone and 5-chloro-1,3-dihydro-1-(4-piperidyl)-2H-benzimidazolyl-2 radicals-reactive ketone generates domperidone;
Domperidone and toxilic acid reaction generate Domperidone Maleate.
The Domperidone Maleate structural formula is as follows:
The reaction equation of whole technology is as follows:
Its concrete reactions steps is as follows:
1,2 (3H) benzimidazolone (I) is synthetic
Charging capacity (mol ratio):
Ortho-diaminobenzene |
Vinyl chloroformate |
Triethylamine |
1 part |
1~3 part |
1~3 part |
Add ortho-diaminobenzene, toluene 1000ml in reaction flask, be warming up to 50~80 ℃, in 6 hours, drip Vinyl chloroformate and triethylamine at leisure simultaneously, control pH value drips off the back under 50~80 ℃ of conditions between 8~11, keep reaction 3~8 hours.Be cooled to 5~30 ℃, separate out solid, filter, washing, dry product 513g, fusing point>300 ℃, yield 92.1%.
2,1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone (II) synthetic
Charging capacity (mol ratio):
I |
1-bromo-3-chloropropane |
10%NaOH solution |
1 part |
1~4 part |
1~3 part |
In reaction flask, add I, 1-bromo-3-chloropropane and 10% sodium hydroxide solution 1340ml, stirring and dissolving at ambient temperature, add methylene dichloride 2000ml and butyl brometo de amonio 5, and react 3~8 hours separate dichloromethane layers down, and wash with distilled water 1000ml at 0~5 ℃, behind the distilled dichloromethane, residue 500ml methanol wash, drying gets crystalline solid 582g, 115~118 ℃ of fusing points, yield 83.0%.
3, ethoxycarbonyl amino piperidine derivatives (III) is synthetic
Charging capacity (mol ratio):
1-ethoxycarbonyl-4-amino piperidine |
2, the 5-dichloronitrobenzene |
Salt of wormwood |
1 part |
1~4 part |
1-5 part |
With 1-ethoxycarbonyl-4-amino piperidine, toluene 2000ml, salt of wormwood and 2,5-dichloronitrobenzene, join in the reaction flask, back flow reaction 3~9 hours is cooled to room temperature, uses distilled water wash, toluene distillation, add 1500ml methyl alcohol, be cooled to 0 ℃, filter, and dry down with the washing of 200ml cold methanol, get product 685g.Fusing point: 162.5~164.5 ℃, yield: 85.0%.
4, the 5-chloro-1,3-dihydro-1-(4-piperidyl)-2H-benzimidazolyl-2 radicals-ketone (IV) synthetic
Charging capacity (mol ratio):
III and 4000ml methyl alcohol are added in the reaction flask that has logical hydrogen production device, add the 68.5g Raney's nickel, guarantee 3kg/cm at hydrogen pressure
2Condition under, logical hydrogen 3~7 hours added the urea back flow reaction 8~15 hours behind the elimination Raney's nickel, then distillating carbinol, add 10%HCl solution, be warming up to 50~60 ℃, stirred 2~5 hours, be cooled to room temperature, transferring pH is 7.5~9.5, is cooled to 5~10 ℃, filters, and washes solid with water.Crude product is added in the reaction flask, add 2000ml ethanol, temperature rising reflux 30min is cooled to 5~10 ℃, filters, and gets product 395g, fusing point: 228~230 ℃, and yield 89.1%.
5, domperidone (V) is synthetic
Charging capacity (mol ratio):
With II, IV, 4-methyl-2 pentanone 3500ml and catalyzer potassiumiodide 23g join in the reaction flask, reflux is divided four times and is added yellow soda ash 280g, and each the maintenance reacted 1 hour, adding the back continues to reflux 8 hours, be cooled to 25~30 ℃ of filtrations, with the washing of 4 premium on currency, filtrate adds in the reaction flask, be warming up to 50~60 ℃, transfer pH=7~7.5 to continue to stir 1 hour at leisure with acetic acid, keep pH constant, cross filter solid 4L water washing, blot, add in the reaction flask, add methyl alcohol 4000ml then, temperature rising reflux is clear to solution becomes, be cooled to 45~55 ℃, the adding gac also kept 0.5 hour, and the filter activity charcoal slowly drips 1000ml water in filtrate under the intense agitation, filter, with 500ml methanol wash secondary, drying, get product 601g.Fusing point: 244~248 ℃, yield 85.0%.
6, Domperidone Maleate (VI) is synthetic
Charging capacity (mol ratio):
V |
Toxilic acid |
1 part |
1~10 part |
3000ml methyl alcohol and toxilic acid are added in the reaction flask, stir and removed by filter unnecessary particle in 15~30 minutes, add purified domperidone then, temperature rising reflux 3~5 hours slowly drips 1000ml and is water-cooled to 35~40 ℃, filters, use the 500ml methanol wash, gained solid and 3000ml methyl alcohol add reaction flask, and temperature rising reflux is transparent to solution, filtered while hot, the filtrate reflux conditions slowly drips 1000ml water down, be cooled to 35~40 ℃, filter, water 500ml washing, dry, product 537g, fusing point: 226~228 ℃, yield 91%.Content 99.3% (HPLC method)
In the process of preparation I, the pH value of reaction solution has material impact to yield, prior art adopts earlier triethylamine to be mixed with reactant and drips the method that the Vinyl chloroformate reaction makes product again, its PH can not get control, we take to drip pH value that the mode of triethylamine controls reaction solution with the preparation product, and yield brings up to 92.1% by 75% of bibliographical information;
Preparing by I in the process of II,, making the yield of product bring up to 83.4% from 74% by temperature of reaction is reduced to 5~10 ℃ by the room temperature condition of document
Prepared by III in the process of IV, prior art adopts ethyl acetate as hydrogenation solvent, then uses methyl alcohol as solvent with the reaction of urea, thus with urea reaction before must steam except that ethyl acetate and just can carry out next step reaction.We have then saved distillation ethyl acetate this step with ethyl acetate as hydrogenation solvent with the methyl alcohol replacement, have shortened the time greatly.With urea reaction after, prior art takes ethyl acetate extraction as means of purification, we then need not purified can carry out next step the reaction, reduced the loss of product.In the purge process of final product, replace Virahol to carry out recrystallization with ethanol.The change of all these methods makes the yield of final product bring up to 89.1% by 75.1% of bibliographical information, and operation has simultaneously also obtained great simplification, and cost also reduces greatly.
Preparing by III in the process of IV, separating out solid for reaction solution after transferring pH=7.0~7.5 handles, prior art takes to use earlier the ethyl acetate purifying, carry out twice recrystallization with methyl alcohol again and obtain product, we directly take dissolve with methanol to this solid, add the method that elutriation goes out again and obtain the good product of purity.The yield of final product brings up to 85.0% by 73.1% of bibliographical information.
In the preparation process of Domperidone Maleate, prior art is carried out activated carbon decolorizing to the reaction solution after refluxing, steam except that after 0.5 times of volumes methanol and separate out the Domperidone Maleate crude product again, and need carry out same activated carbon decolorizing, steam remove the operation of separating out again after 0.5 times of volumes methanol twice this crude product, could obtain content and be the product more than 98.5%, we have then avoided this loaded down with trivial details operation by the mode that adds water, and yield and content also are improved.
By groping of top condition, the whole technology of the preparation of Domperidone Maleate has obtained best optimization, thereby operation is simpler, the reaction safety and reliability, and the cycle is shorter, and yield is higher, and cost is lower, and does not have serious three-waste pollution, is convenient to suitability for industrialized production.
The present invention raw materials used as: methylene dichloride, 1-bromo-3-chloropropane, urea, salt of wormwood, sodium hydroxide, all available technical grade reagent such as ethanol, gac etc.React safe and reliable, simple to operate, products obtained therefrom is through mass spectrum, nucleus magnetic resonance, and infrared spectra, ultimate analysis conclusive evidence structure is errorless.
Domperidone Maleate sample mass spectrum, infrared spectra, ultimate analysis
Domperidone Maleate sample hydrogen nuclear magnetic resonance spectrum and parsing thereof
The organic solvent dichloro that experimentation is used, methyl alcohol, toluene, ethanol etc. are treated can recovery set usefulness, reduces cost; Waste residue, useless siccative can be through the incinerator burning disposal after storing classifiedly, and waste water solution to neutrality, enters unified processing the in the sewage lagoon through acid-base neutralisation, discharge after reaching emission standard, and environmental pollution reduces greatly.
Embodiment
1,2 (3H) benzimidazolone (I) is synthetic
In the reaction flask of 2.5L, add ortho-diaminobenzene 448g, toluene 1000ml, be warming up to 60~70 ℃, in 6 hours, drip Vinyl chloroformate 496g and triethylamine 502g at leisure simultaneously, control pH value drips off the back under 60~70 ℃ of conditions between 8~11, keep reaction 6 hours.Be cooled to 5~-10 ℃, separate out solid, filter, washing, dry product 513g, fusing point>300 ℃, yield 92.1%.
2,1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone (II) synthetic
In reaction flask, add I 446g, 1-bromo-3-chloropropane 577g and 10% sodium hydroxide solution 1340ml, stirring and dissolving adds methylene dichloride 2000ml and butyl brometo de amonio 5, and at room temperature reacted 6 hours at ambient temperature, the separate dichloromethane layer, and with distilled water 1000ml washing, behind the distilled dichloromethane, residue 500ml methanol wash, dry, get product 582g, 115~118 ℃ of fusing points, yield 83.0%.
3, ethoxycarbonyl amino piperidine derivatives (III) is synthetic
With 1-ethoxycarbonyl-4-amino piperidine 423g, toluene 2000ml, salt of wormwood 362g and 2.5-dichloronitrobenzene 519g join in the reaction flask, back flow reaction 6 hours, be cooled to room temperature, use distilled water wash, toluene distillation adds 1500ml methyl alcohol, be cooled to 0 ℃, filter, and dry down with the washing of 200ml cold methanol, get product 685g.Fusing point: 162.5~164.5 ℃, yield: 85.0%.
4, the 5-chloro-1, and the synthetic of 3-dihydro-1-(4-piperidyl)-2H-benzimidazolyl-2 radicals-ketone (IV) adds III685g and 4000ml methyl alcohol in the reaction flask that has logical hydrogen production device, adds the 68.5g Raney's nickel, guarantees 3kg/cm at hydrogen pressure
2Condition under, logical hydrogen 4 hours adds urea backflow 150g reaction 12 hours, then distillating carbinol behind the elimination Raney's nickel, add 10%HCL solution, be warming up to 50~60 ℃, stirred 3 hours, be cooled to room temperature, transferring pH is 8.0~8.5, is cooled to 5~10 ℃, filters, and washes solid with water.Crude product is added in the reaction flask, add 2000ml ethanol, temperature rising reflux 30min is cooled to 5~10 ℃, filters, and gets product 395g, fusing point: 228~230 ℃, and yield 89.1%.
5, domperidone (V) is synthetic
With II378g, IV416g, 4-methyl-2 pentanone 3500ml and catalyzer potassiumiodide 23g join in the reaction flask, reflux is divided four times and is added yellow soda ash 280g, and each the maintenance reacted 1 hour, adding the back continues to reflux 8 hours, be cooled to 25~30 ℃ of filtrations, with the washing of 4 premium on currency, filtrate adds in the reaction flask, be warming up to 50~60 ℃, transfer pH=7~7.5 to continue to stir 1 hour at leisure with acetic acid, keep pH constant, cross filter solid 4L water washing, blot, add in the reaction flask, add methyl alcohol 4000ml then, temperature rising reflux is clear to solution becomes, be cooled to 45~55 ℃, adding gac 20g also kept 0.5 hour, and the filter activity charcoal slowly drips 1000ml water in filtrate under the intense agitation, filter, with 500ml methanol wash secondary, drying, get product 601g.Fusing point: 244~248 ℃, yield 85.0%.
6, Domperidone Maleate (VI) is synthetic
3000ml methyl alcohol and toxilic acid 138g are added in the reaction flask, stir and removed by filter unnecessary particle in 30 minutes, add purified domperidone 463g then, temperature rising reflux 4 hours slowly drips 1000ml water, be cooled to 35~40 ℃, filter, use the 500ml methanol wash, gained solid and 3000ml methyl alcohol add reaction flask, temperature rising reflux is transparent to solution, filtered while hot, filtrate reflux conditions slowly drip 1000ml water down, are cooled to 35~40 ℃, filter, water 500ml washing, drying gets product 537g, fusing point: 226~228 ℃, yield 91%.Content 99.3% (HPLC method)