CN103936614A - Preparation method of tiopronin intermediate alpha-chloropropionylglycine - Google Patents
Preparation method of tiopronin intermediate alpha-chloropropionylglycine Download PDFInfo
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- CN103936614A CN103936614A CN201410185275.7A CN201410185275A CN103936614A CN 103936614 A CN103936614 A CN 103936614A CN 201410185275 A CN201410185275 A CN 201410185275A CN 103936614 A CN103936614 A CN 103936614A
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Abstract
The invention discloses a preparation method of a tiopronin intermediate alpha-chloropropionylglycine. The preparation method comprises the following steps: mixing glycine and a NaOH aqueous solution, cooling and respectively dropwise adding alpha-chloropropionyl chloride and the NaOH aqueous solution, wherein the concentration of the NaOH aqueous solution is controlled at 8-25%, crystals are directly separated out after cooling, and the dropwise addition time of the alpha-chloropropionyl chloride and the NaOH aqueous solution is 1.5-3 hours; adjusting the pH value of the solution to 1-2 by using hydrochloric acid, cooling to -5 DEG C to 5 DEG C to directly separating out crystals. The preparation method has the advantages that the reaction product alpha-chloropropionylglycine can be directly separated out under the condition of the appropriate concentration of reaction liquid, an ethyl acetate extraction process is omitted, so that the cost is reduced, and the environmental protection is facilitated.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to the preparation method of tiopronin intermediate, say more specifically a kind of preparation method of tiopronin intermediate α-chlorine Propionylglycine.
Background technology
Tiopronin is a kind of novel glycine derivative containing free sulfhydryl groups.It is mainly used in viral hepatitis, alcoholic hepatitis, and drug induced hepatitis, heavy metal poisoning hepatitis, fatty liver and liver cirrhosis are early stage; The toxic side effect that reduces 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 due to can preventive radiotherapy; Early senile cataract and vitreous opacity are had to remarkable therapeutic action; Prevention and treatment urinary system cystine stone; There is anti-inflammatory anti-allergic effects, dermatitis, eczema, acne and urticaria are had to good therapeutic effect.α-chlorine Propionylglycine is the important intermediate of producing tiopronin; Luo Yucheng etc. the improvement of Preparation of Tiopronin. fine-chemical intermediate; 2007; 37 (5): the reports such as 43-45; taking 2-chloro-propanoyl chloride as starting raw material, carry out amino acylation reaction with glycine and can obtain alpha-chloro Propionylglycine.It is neutralizing agent that this technique is used sodium hydroxide, and reaction finishes repeatedly to extract by ethyl acetate afterwards, and dry, underpressure distillation is concentrated into after certain volume, cooling crystallization.The shortcoming of its existence is that the α-chlorine Propionylglycine finally obtaining need to extract by ethyl acetate.
Summary of the invention
The shortcoming that the object of the invention is to overcome prior art, with not enough, provides a kind of preparation method of tiopronin intermediate α-chlorine Propionylglycine.The present invention is investigating after the concentration of alkali, and ethyl acetate extraction process is improved to after acid neutralizes and is directly separated out.So not only improved yield, and saved manpower, equipment, has lowered cost, has also reduced 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, cooling lower α-chlorpromazine chloride and the NaOH aqueous solution of dripping respectively, is characterized in that the concentration of the NaOH aqueous solution is controlled at 8-25%(w/w), preferably 8-16%(w/w), particularly preferably 10-16%(w/w), most preferably 12%(w/w), stir cooling rear direct crystallization.
The time that drips respectively α-chlorpromazine chloride and the NaOH aqueous solution of the present invention is 1.5-3 hour, is then 1-2 with hydrochloride adjusted solution pH, stirs cooling rear direct crystallization.Particularly preferred example is: the NaOH concentration of dissolving glycine is 12%(w/w); While dripping respectively α-chlorpromazine chloride and the NaOH aqueous solution, NaOH concentration is also controlled at 12%(w/w); Dropping temperature is controlled at-5 to 5 DEG C, and time for adding is controlled at 2-2.5 hour, then direct crystallization.
The positively effect that compared to the prior art preparation method disclosed by the invention had is:
(1) the present invention finds that by comparative experiments the concentration of sodium hydroxide is the principal element that affects yield in reaction; and be revised as the sodium hydroxide of 10-16%; particularly preferably 12%; overcome like this shortcoming that former document needs 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 reduce cost, be conducive to environment protection.
(2), due to without ethyl acetate abstraction process, also just naturally omitted being dried of acetic acid ethyl acetate extract, underpressure distillation, cooling crystallization, filtration and in mother liquor, reclaimed the operations such as solvent ethyl acetate.
High spot reviews of the present invention the 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 is when too high, solid sodium chloride can be separated out in the lump with product, affects quality product, need re-refine, and result has reduced yield.Naoh concentration the results are shown in following table to the impact of yield:
The impact of naoh concentration on 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 separating out is little, its detection method: get 10 grams, the prepared intermediate of 12% concentration hydrogen sodium oxide, with acetic acid ethyl dissolution, after insolubles is dry, be weighed as 0.5 gram, product purity is 95%; Get 8 grams, the prepared intermediate of 14% concentration hydrogen sodium oxide, with acetic acid ethyl dissolution, after insolubles is dry, be weighed as 0.5 gram, product purity is 93.75%.The product that use 12% and lower naoh concentration obtain need not be processed and can be directly used in next step reaction; And the one-tenth branch that naoh concentration contains sodium-chlor in 12% product when above significantly increases, need can be used for next step reaction after re-crystallizing in ethyl acetate.
Embodiment
In order to explain more fully enforcement of the present invention, provide following preparation method's embodiment.These embodiments are only to explain instead of limit the scope of the invention.The glycine that wherein reaction is used, α-chlorpromazine chloride all has commercially available.
Embodiment 1
In 1L four-hole bottle, add 50g(0.67mol) glycine, 8%NaOH 220mL, cooling lower stirring makes dissolution of solid, then under agitation drips respectively α-chlorpromazine chloride 85g(0.67mol in-5 DEG C simultaneously) and the 8%NaOH aqueous solution, time for adding approximately 1.5 hours, pH remains at 8 left and right.Dropping finishes rear continuation stirring reaction 2 hours.Then be 1 with hydrochloride adjusted solution pH, continue to stir crystallization.To be crystallized separate out completely after, filter, obtain white crystals 60.4g, yield 54.5%, mp101-103 DEG C of (H
2o). the crystallization obtaining is alpha-chloro Propionylglycine.
Embodiment 2
In 1L four-hole bottle, add 50g(0.67mol) glycine, 12%NaOH110mL, cooling lower stirring 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 approximately 1.5 hours, pH remains at 8 left and right.Dropping finishes rear continuation stirring reaction 2 hours.Then be 1 with hydrochloride adjusted solution pH, continue to stir crystallization.To be crystallized separate out completely after, filter, obtain white crystals 89.7g, yield 80.9%, mp101-103 DEG C of (H
2o) crystallization, obtaining is alpha-chloro Propionylglycine.
Embodiment 3
In 1L four-hole bottle, add 50g(0.67mol) glycine, 12%NaOH110mL, cooling lower stirring 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 approximately 2 hours, pH remains at 8 left and right.Dropping finishes rear continuation stirring reaction 2 hours.Then be 1 with hydrochloride adjusted solution pH, continue to stir crystallization.To be crystallized separate out completely after, filter, obtain white crystals 89.3g, yield 80.5%, mp101-103 DEG C of (H
2o) crystallization, obtaining is alpha-chloro Propionylglycine.
Embodiment 4
In 1L four-hole bottle, add 50g(0.67mol) glycine, 16%NaOH110mL, cooling lower stirring 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 approximately 3 hours, pH remains at 8 left and right.Dropping finishes rear continuation stirring reaction 2 hours.Then be 2 with hydrochloride adjusted solution pH, continue to stir crystallization.To be crystallized separate out completely after, 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) crystallization, obtaining is alpha-chloro Propionylglycine.
Embodiment 5
Application Example
The alpha-chloro Propionylglycine that adopts the present invention to prepare is prepared 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 and can obtain tiopronin under acidity through zinc powder again
Step:
In 200L glassed steel reaction vessels, add nine water cure sodium 14 kg(58.3mol), 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 of reactions 1 hour, obtain sodium disulfide solution, added in test tank.
In 200L glassed steel reaction vessels, add alpha-chloro Propionylglycine 10.2 kg (61.6 mol), water 60 kg, slowly add anhydrous sodium carbonate 3.1 kg (29.2 mol) under stirring, and reaction solution is cooled to 10 DEG C, drip sodium disulfide solution.Dropwise, rise to room temperature, continue reaction 10 hours, be cooled to 5 DEG C, regulate PH=2, suction filtration with sulfuric acid, filtrate is squeezed in reactor, controls 10 DEG C of temperature, 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 concentrating, and is cooled to-10 DEG C, material crystallization, centrifuging, filter cake vacuum-drying, obtains tiopronin crude product 6.2 kg, yield 62%, 95-98 DEG C of fusing points.
In 100L glassed steel reaction vessels, add tiopronin 6.2 kg(38 mol), ethyl acetate 50L, is heated to 50 DEG C under stirring, solid all dissolves, in reactor, add gac 20 g, keep 50 DEG C of reactions 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 present invention has improved the preparation method of tiopronin intermediate alpha-chloro Propionylglycine, save operation steps, reduce conversion unit, reduce production cost, stop environmental pollution. the alpha-chloro Propionylglycine obtaining is through curing, reduction two-step reaction has successfully synthesized final product tiopronin, and product meets the drug standard completely.
Claims (5)
1. the preparation method of tiopronin intermediate α-chlorine Propionylglycine, it is by glycine, NaOH aqueous solution, cooling lower α-chlorpromazine chloride and the NaOH aqueous solution of dripping respectively, is characterized in that the concentration of the NaOH aqueous solution is controlled at 8-25%(w/w), cooling rear direct crystallization.
2. preparation method claimed in claim 1, wherein the concentration of the NaOH aqueous solution is controlled at 8-16%(w/w).
3. preparation method claimed in claim 1, the time that wherein drips respectively α-chlorpromazine chloride and the NaOH aqueous solution is 1.5-3 hour, is then 1-2 with hydrochloride adjusted solution pH, stirs cooling rear direct crystallization.
4. preparation method claimed in claim 3, wherein said NaOH concentration of aqueous solution is 10-14%(w/w), the time is 2-2.5 hour, be controlled at-5-5 DEG C of dropping temperature.
5. preparation method claimed in claim 4, wherein said NaOH concentration of aqueous solution is 12%(w/w), dropping temperature control-5-5 DEG C.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111217727A (en) * | 2019-12-09 | 2020-06-02 | 湖北美林药业有限公司 | Preparation method of tiopronin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102898339A (en) * | 2012-10-29 | 2013-01-30 | 苏州二叶制药有限公司 | Method for preparing tiopronin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102898339A (en) * | 2012-10-29 | 2013-01-30 | 苏州二叶制药有限公司 | Method for preparing tiopronin |
Non-Patent Citations (1)
| Title |
|---|
| 罗愉城等: "硫普罗宁合成工艺的改进", 《精细化工中间体》, vol. 37, no. 5, 31 October 2007 (2007-10-31), pages 43 - 45 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217727A (en) * | 2019-12-09 | 2020-06-02 | 湖北美林药业有限公司 | Preparation method of tiopronin |
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