CN103936614B - A kind of preparation method of tiopronin intermediate α-chlorine Propionylglycine - Google Patents
A kind of preparation method of tiopronin intermediate α-chlorine Propionylglycine Download PDFInfo
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- CN103936614B CN103936614B CN201410185275.7A CN201410185275A CN103936614B CN 103936614 B CN103936614 B CN 103936614B CN 201410185275 A CN201410185275 A CN 201410185275A CN 103936614 B CN103936614 B CN 103936614B
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- aqueous solution
- propionylglycine
- naoh aqueous
- chlorine
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Abstract
The invention discloses a kind of preparation method of tiopronin intermediate α-chlorine Propionylglycine, it is by glycine, NaOH aqueous solution, α-chlorpromazine chloride and the NaOH aqueous solution is dripped respectively under cooling, wherein the concentration of the NaOH aqueous solution controls at 8-25%, direct crystallization after cooling, described dropping α-chlorpromazine chloride and the time of the NaOH aqueous solution are 1.5-3 hour, are then 1-2 ,-5-5 DEG C with hydrochloride adjusted solution pH and cool rear directly crystallization.The present invention is under suitable reaction solution concentration, and reaction product α-chlorine Propionylglycine can directly be separated out, and eliminates ethyl acetate abstraction process, reduces to make cost and is more conducive to environment protection.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to the preparation method of tiopronin intermediate, is a kind of preparation method of tiopronin intermediate α-chlorine Propionylglycine in particular.
Background technology
Tiopronin is a kind of novel glycine derivative containing free sulfhydryl groups.It is mainly used in viral hepatitis, alcoholic hepatitis, drug induced hepatitis, heavy metal poisoning hepatitis, fatty liver and liver cirrhosis early stage; Reduce the toxic side effect of radiotherapy, chemotherapy, leukocyte increasing also accelerates hepatocellular recovery, reduces the generation of bone marrow chromosome aberration rate and skin ulcer, and the generation of secondary tumour caused by energy preventive radiotherapy; Remarkable therapeutic action is had to early senile cataract and vitreous opacity; Prevention and therapy urinary system cystine stone; There is anti-inflammatory anti-allergic effects, have good therapeutic effect to dermatitis, eczema, acne and urticaria.α-chlorine Propionylglycine is the important intermediate of producing tiopronin; Luo Yucheng etc. the improvement of Preparation of Tiopronin. fine-chemical intermediate; 2007; the reports such as 37 (5): 43-45; with 2-chloro-propanoyl chloride for starting raw material, carry out amino acylation reaction with glycine and can obtain alpha-chloro Propionylglycine.This technique uses sodium hydroxide to be neutralizing agent, and reaction terminates rear ethyl acetate and repeatedly extracts, dry, after underpressure distillation is concentrated into certain volume, and cooling crystallization.Its shortcoming existed is that the α-chlorine Propionylglycine finally obtained needs to extract by ethyl acetate.
Summary of the invention
The object of the invention is to overcome the shortcoming of prior art and deficiency, a kind of preparation method of tiopronin intermediate α-chlorine Propionylglycine is provided.The present invention, after having investigated paper mill wastewater, directly separates out after ethyl acetate extraction process being improved to acid neutralization.This not only increases yield, and save manpower, equipment, reduce cost, decrease environmental pollution simultaneously.
For achieving the above object, the invention provides a kind of preparation method of tiopronin intermediate α-chlorine Propionylglycine, it is by glycine and NaOH aqueous solution, drip α-chlorpromazine chloride and the NaOH aqueous solution under cooling respectively, it is characterized in that the concentration of the NaOH aqueous solution controls at 8-25%(w/w), preferred 8-16%(w/w), particularly preferably 10-16%(w/w), most preferably 12%(w/w), stir, direct crystallization after cooling.
The time dripping α-chlorpromazine chloride and the NaOH aqueous solution respectively of the present invention is 1.5-3 hour, is then 1-2 with hydrochloride adjusted solution pH, to stir after cooling directly crystallization.Particularly preferred example is: the NaOH concentration of dissolving glycine is 12%(w/w); When dripping α-chlorpromazine chloride and the NaOH aqueous solution respectively, NaOH concentration also controls at 12%(w/w); Dropping temperature controls at-5 to 5 DEG C, and time for adding controls at 2-2.5 hour, then direct crystallization.
The positively effect that preparation method disclosed by the invention is compared to the prior art had is:
(1) by comparative experiments, the present invention finds that the concentration of sodium hydroxide is in the reaction the principal element affecting yield; and be revised as the sodium hydroxide of 10-16%; particularly preferably 12%; this overcome original text and offer the shortcoming needing ethyl acetate to extract; reaction product α-chlorine Propionylglycine can directly be separated out; the product yield of gained significantly improves. and omit ethyl acetate abstraction process and can be reduced cost, be conducive to environment protection.
(2) due to without ethyl acetate abstraction process, the drying of acetic acid ethyl acetate extract, underpressure distillation, cooling crystallization, filtration and the operation such as recycling design ethyl acetate in mother liquor is also just naturally eliminated.
The high spot reviews of the present invention impact of naoh concentration on α-chlorine Propionylglycine yield.Result shows, when naoh concentration is low, product α-chlorine Propionylglycine crystallization is few; And naoh concentration too high time, solid sodium chloride can be separated out in the lump with product, affects quality product, need re-refine, and result reduces yield.The impact of naoh concentration on yield the results are shown in following table:
Naoh concentration is on the impact of α-chlorine Propionylglycine yield:
| Naoh concentration (%) | 8 | 10 | 12 | 14 | 16, 25 |
| Chlorine Propionylglycine yield (%) | 54.5 | 69.7 | 80.9 | 79.2 | 70.9 57.8 |
We experimental studies have found that:
Under 12% naoh concentration, yield is higher, and the sodium-chlor of precipitation is little, its detection method: get 10 grams, intermediate prepared by 12% sodium hydroxide, with acetic acid ethyl dissolution, be weighed as 0.5 gram after insolubles drying, namely product purity is 95%; Get 8 grams, intermediate prepared by 14% sodium hydroxide, with acetic acid ethyl dissolution, be weighed as 0.5 gram after insolubles drying, namely product purity is 93.75%.The product that use 12% and lower naoh concentration obtain need not process and namely can be directly used in next step reaction; And naoh concentration more than 12% time product in significantly increase containing the one-tenth branch of sodium-chlor, next step reaction can be used for after needing re-crystallizing in ethyl acetate.
Embodiment
In order to explain enforcement of the present invention more fully, provide following preparation method's embodiment.These embodiments are only explain instead of limit the scope of the invention.Wherein react the glycine used, α-chlorpromazine chloride all has commercially available.
Embodiment 1
50g(0.67mol is added in 1L four-hole bottle) glycine, 8%NaOH 220mL, the lower stirring of cooling makes dissolution of solid, then under agitation drip α-chlorpromazine chloride 85g(0.67mol respectively in-5 DEG C simultaneously) and the 8%NaOH aqueous solution, time for adding about 1.5 hours, pH remains at about 8.Dropping terminates rear continuation stirring reaction 2 hours.Then be 1 with hydrochloride adjusted solution pH, continue to stir crystallization.After precipitation to be crystallized completely, filter, obtain white crystals 60.4g, yield 54.5%, mp101-103 DEG C of (H
2o). the crystallization obtained is alpha-chloro Propionylglycine.
Embodiment 2
50g(0.67mol is added in 1L four-hole bottle) glycine, 12%NaOH110mL, the lower stirring of cooling makes dissolution of solid, then under agitation-2 DEG C drip α-chlorpromazine chloride 85g(0.67mol simultaneously) and the 12%NaOH aqueous solution, time for adding about 1.5 hours, pH remains at about 8.Dropping terminates rear continuation stirring reaction 2 hours.Then be 1 with hydrochloride adjusted solution pH, continue to stir crystallization.After precipitation to be crystallized completely, filter, obtain white crystals 89.7g, yield 80.9%, mp101-103 DEG C of (H
2o), the crystallization obtained is alpha-chloro Propionylglycine.
Embodiment 3
50g(0.67mol is added in 1L four-hole bottle) glycine, 12%NaOH110mL, the lower stirring of cooling makes dissolution of solid, then under agitation drips α-chlorpromazine chloride 85g(0.67mol in 0 DEG C simultaneously) and the 12%NaOH aqueous solution, time for adding about 2 hours, pH remains at about 8.Dropping terminates rear continuation stirring reaction 2 hours.Then be 1 with hydrochloride adjusted solution pH, continue to stir crystallization.After precipitation to be crystallized completely, filter, obtain white crystals 89.3g, yield 80.5%, mp101-103 DEG C of (H
2o), the crystallization obtained is alpha-chloro Propionylglycine.
Embodiment 4
50g(0.67mol is added in 1L four-hole bottle) glycine, 16%NaOH110mL, the lower stirring of cooling makes dissolution of solid, then under agitation drips α-chlorpromazine chloride 85g(0.67mol in 5 DEG C simultaneously) and the 16%NaOH aqueous solution, time for adding about 3 hours, pH remains at about 8.Dropping terminates rear continuation stirring reaction 2 hours.Then be 2 with hydrochloride adjusted solution pH, continue to stir crystallization.After precipitation to be crystallized completely, filter. obtain white crystals through re-crystallizing in ethyl acetate, obtain white crystalline solid 78.6g, yield 70.9%, mp101-103 DEG C of (H
2o), the crystallization obtained is alpha-chloro Propionylglycine.
Embodiment 5
Application Example
The alpha-chloro Propionylglycine adopting the present invention to prepare prepares tiopronin
Method: gained alpha-chloro Propionylglycine of the present invention is through obtaining α-dithio Propionylglycine with sodium disulfide reactant aqueous solution, and the latter reduces can obtain tiopronin through zinc powder again under acidity
Step:
Nine water cure sodium 14 kg(58.3mol are added) in 200L glassed steel reaction vessels, water 16.5 kg, stir, dissolution of solid, adds sublimed sulphur 1.9 kg (59.4 mol), is heated to 50 DEG C, solid all dissolves, keep 50 DEG C to react 1 hour, obtain sodium disulfide solution, added in test tank.
Add alpha-chloro Propionylglycine 10.2 kg (61.6 mol) in 200L glassed steel reaction vessels, water 60 kg, slowly add anhydrous sodium carbonate 3.1 kg (29.2 mol) under stirring, reaction solution is cooled to 10 DEG C, drips sodium disulfide solution.Dropwise, rise to room temperature, continue reaction 10 hours, be cooled to 5 DEG C, regulate PH=2 with sulfuric acid, suction filtration, filtrate is squeezed in reactor, control temperature 10 DEG C, and gradation adds zinc powder 8.7 kg (133.8 mol), add room temperature reaction 6 hours, suction filtration, filtrate is extracted by ethyl acetate, by 1 kg anhydrous sodium sulfate drying organic phase, filter, filtrate has been concentrated into crystal and has separated out, and stops concentrated, is cooled to-10 DEG C, material crystallization, centrifuging, filter cake vacuum-drying, obtains tiopronin crude product 6.2 kg, yield 62%, fusing point 95-98 DEG C.
Tiopronin 6.2 kg(38 mol is added in 100L glassed steel reaction vessels), ethyl acetate 50L, is heated to 50 DEG C under stirring, solid all dissolves, in reactor, add gac 20 g, keep 50 DEG C to react 1 hour, suction filtration, filtrate enters in crystallization kettle, be cooled to-5 DEG C, centrifuging, filter cake vacuum-drying obtains tiopronin 5.3 kg, yield 85%, fusing point 96-98 DEG C.
Result: the preparation method that present invention improves over tiopronin intermediate alpha-chloro Propionylglycine, save operation steps, decrease conversion unit, reduce production cost, stop environmental pollution. the alpha-chloro Propionylglycine obtained is through curing, reduction two-step reaction has successfully synthesized final product tiopronin, and product meets the drug standard completely.
Claims (2)
1. the preparation method of tiopronin intermediate α-chlorine Propionylglycine, it is by glycine, NaOH aqueous solution, α-chlorpromazine chloride and the NaOH aqueous solution is dripped respectively under cooling, it is characterized in that the concentration of the NaOH aqueous solution controls in 10-14% w/w, direct crystallization after cooling; The time wherein dripping α-chlorpromazine chloride and the NaOH aqueous solution is respectively 1.5-3 hour, is then 1-2 with hydrochloride adjusted solution pH, to stir after cooling directly crystallization.
2. preparation method according to claim 1, wherein said NaOH concentration of aqueous solution is 12% w/w, and the time is 2-2.5 hour, and dropping temperature controls at-5-5 DEG C.
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| 硫普罗宁合成工艺的改进;罗愉城等;《精细化工中间体》;20071031;第37卷(第5期);第43-45页 * |
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