CN108373436A - The preparation method of acetyl captopril - Google Patents
The preparation method of acetyl captopril Download PDFInfo
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- CN108373436A CN108373436A CN201710445229.XA CN201710445229A CN108373436A CN 108373436 A CN108373436 A CN 108373436A CN 201710445229 A CN201710445229 A CN 201710445229A CN 108373436 A CN108373436 A CN 108373436A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07B2200/07—Optical isomers
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Abstract
The present invention relates to pharmaceutical technology fields, provide a kind of preparation method of acetyl captopril.Using after thioacetic acid and methacrylic acid addition through splitting, the technique for preparing captopril intermediate " 2 methyl propionyl chloride of D acetylthios " with thionyl chloride chloride again, pass through test of many times, organic solvent-acetone is substituted using inorganic solvent water, the safety of preparation process is improved, environmental pollution is reduced.In addition, screening resolving agent by the method that half amount (or full dose) is split, screening efficiency is improved, reduces screening number.Furthermore modification and recovery system reduces material input, improves the utilization rate of valuable raw material, and significantly reduce the discharge of pollutant.Furthermore the process conditions such as the temperature in process control procedure, pressure, reaction time are determined, so that it is guaranteed that the quality stability of industrialization production.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of preparation method of acetyl captopril.
Background technology
Captopril (I, captopril) is angiotensin converting enzyme (ACE) inhibitor of first clinical application, main
It is used for the treatment of the diseases such as hypertension, heart failure.Product captopril intermediate " 3- acetylthio -2- methyl propionyl of the present invention
Chlorine " abbreviation " acetyl captopril " is the key intermediate for preparing captopril bulk pharmaceutical chemicals, mainly for the preparation of captopril original
Expect medicine.
The preparation of captopril intermediate generally uses organic solvent-acetone as solvent both at home and abroad at present, and acetone is inflammable
Substance, danger is high and be easy to cause environmental pollution.It is inflammable that acetone belongs to the 3.1st class low-flash in Classification of Dangerous Chemicals
Liquid, highly volatile set off an explosion burning, and use is very dangerous.Acetone still belongs to precursor chemicals simultaneously, and national regulatory is strict
Evil.Using conventionally produced acetyl captopril, dangerous height, environmental pollution is serious, production cost is corresponding also higher.
Invention content
The purpose of the invention is to overcome above-mentioned technical problem, a kind of preparation method of acetyl captopril is provided.It adopts
It is substituted in traditional acetyl captopril production technology with the extensive inorganic solvent of nontoxic, pollution-free, safe to use, resource-water
Organic solvent-acetone, the problems such as solving dangerous height in conventional preparation techniques, cause serious pollution to the environment, production cost reduces by 30%,
Securely and reliably, energy conservation and environmental protection.
The technical problem of the present invention is mainly addressed by following technical proposals：
Acetyl captopril, i.e. 3- acetylthios -2- methyl propionyl chlorides are medicine intermediate, mainly for the production of Kato
Puli's bulk pharmaceutical chemicals etc., technological process includes the following steps：
1) addition of acid synthesizes
The thioacetic acid and methacrylic acid calculated is put into reaction kettle, is stirred under normal pressure and is warming up to 45~50 DEG C,
Stop heating after initiation reaction, exothermic heat of reaction automatic heating is to 90~98 DEG C, back flow reaction, by remaining methyl after reaction 1 hour
Acrylic acid added in six times, every 0.5 hour plus 1 time.120~130 DEG C are kept the temperature after adding to react 4 hours, are then cooled to 50
DEG C, boiling object (excessive thioacetic acid etc.) before the removing of water pump negative pressure is opened, and be gradually heating to 140 DEG C, stops heating.After cooling
Addition acid product barrelling.
Preceding boiling object send wastewater treatment after being absorbed with lye.
Reaction equation is：
2) it splits
Resolving agent water is prepared into 15% ± 0.2 solution, 15~20 DEG C is cooled to, addition of acid is added dropwise, drips off within 4 hours, drip
30min is kept the temperature after complete, is cooled to 0~-5 DEG C, is crystallized 12 hours, rejection filter, filter cake is washed with ice water, obtains wet product D salt.
Reaction equation is：
3) D salt is free
Process water and 31% hydrochloric acid are added into reaction kettle, is cooled to 20 DEG C hereinafter, input D salt wet products, stir simultaneously temperature control
It is reacted 1 hour under the conditions of 15~20 DEG C, surveys pH value, should be less than 3.0, otherwise added hydrochloric acid to regulation pH value, dichloromethane is added
Alkane extracts, and stirs 15min, stands 30min, and layering is so extracted 3 times with dichloromethane again.
Oil reservoir merges precipitation, obtains D- addition of acid, dichloroethane solvent recycling, and water layer recycles resolving agent after going alkalization.
Reaction equation is：
4) mother liquor is free
A batch is put into reaction kettle and splits mother liquor, is cooled to 15~20 DEG C, 31% hydrochloric acid is added dropwise, and drop finishes, and surveys pH value, answers small
In 3.0, hydrochloric acid is otherwise added to regulation pH value.
Dichloromethane extraction is added, stirs 15min, stands 30min, layering is so extracted 3 times again.
Oil reservoir merges precipitation, obtains L- addition of acid, solvent recovery.
Reaction equation is：
5) racemization
L- acid and catalyst are put into reaction kettle, stirring is warming up to 90~100 DEG C, and insulation reaction 5~6 hours is sampled
After detection is qualified, 20~30 DEG C are cooled to, after water agitator treating 30min is added, adds dichloromethane stirring extraction 15min,
30min, layering are stood, water phase is extracted three times with dichloromethane again.
Oil reservoir merges precipitation, obtains racemization addition of acid, solvent recovery, water phase decontamination water process.
Reaction equation is：
6) resolving agent is recycled
A collection of free water layer is added in reaction kettle, puts into piece alkali, stirs and react 1 hour under room temperature, survey pH value, should be greater than
10, piece alkali is otherwise added to regulation pH value.
It is original 1/2 or so that alkaline solution elder generation atmospheric distillation, which is dehydrated to volume, rectifying obtain the fractionation agent content in water≤
0.1%, as process water recovery.
Concentrate removes vacuum distillation resolving agent aqueous solution, uses process water stripping after being evaporated again 3 times, and last time detection steams
Agent content≤2.0% is split in aqueous.
Merge the fractionation agent solution steamed, detection level should be 15% ± 0.2.
Fractionation agent solution, which is applied mechanically, to be split, and vinasse goes wastewater treatment.
Reaction equation is：
7) chloride
D- acid is put into reaction kettle, and SOCl2 is added dropwise under room temperature, drips off within 1 hour, insulation reaction 16 hours under room temperature, reacts
Tail gas (HCl, SO2) is absorbed with ammonium hydroxide.
After completion of the reaction, excess SOCl2 and HCl is removed with water stream injection pump decompression (- 0.095MPa), kettle temperature is to slowly warm up to
80 DEG C or so, then 50 DEG C are cooled to hereinafter, using combination vacuum pump instead, vacuum distillation acetyl captopril is to substantially without product steaming
Go out, obtains product (S)-acetyl mercapto -2- methyl propionyl chlorides.
It is discharged after a small amount of vinasse cooling, burning disposal.
Reaction end gas is after weak aqua ammonia absorbs, then concentrated, crystallization, centrifugal filtration, recycles NH4Cl and NH4HSO3 by-products
Product.It mother liquor and steams water deallocation ammonia circulation and applies mechanically.
Reaction equation is：
8) acetyl captopril synthesizes
1200kg purified waters are put into reaction kettle, stir lower input L-PROLINE 195kg, dissolving is stirred at room temperature, then drops
Temperature starts while being added dropwise D- acyl chlorides and aqueous slkali (140kg pieces alkali soluble is in 800kg water), control dropwise addition process PH=to -5~0 DEG C
8~9, about 70~90min is dripped off, and dropping temperature is -5~0 DEG C, rear -5~0 DEG C of insulation reaction is added dropwise 1 hour, then is risen to
Room temperature starts that hydrochloric acid (31% hydrochloric acid 260kg is dissolved in 150kg water) is added dropwise, and control terminal pH value is 0.5~1.0, about 2 hours
It drips off.Then -5~-3 DEG C of crystallizations are cooled to 1 hour, take advantage of cold centrifugal filtration, filter cake is washed twice with 2 × 200kg ice water, obtains second
Acyl captopril wet product about 520kg, give money as a gift 420kg.
Product is not soluble in water, be centrifuged, wash after obtain crude product, then dry, obtain product.
Reaction equation is：
The process generates washings and filtrated stock, while there is condensed water in while being dried in vacuo, send at Sewage Disposal together
Reason.
The beneficial effects of the invention are as follows：
(1) it uses inorganic solvent water to substitute traditional captopril intermediate " D- acetylthio -2- methyl propionyl chloride " to prepare
Organic solvent-acetone in technique solves the problems such as dangerous height in conventional preparation techniques, cause serious pollution to the environment, reduces life
Produce cost.Traditional process route is improved, using after thioacetic acid and methacrylic acid addition through splitting, then with chlorine
Change the technique that sulfoxide chloride prepares captopril intermediate " D- acetylthio -2- methyl propionyl chloride ", it is first by test of many times
First using pollution-free, safe to use, source is sufficient, inorganic solvent --- water is not only greatly reduced and is produced into as solvent
This, and reduce pollution and safe and reliable.
(2) it proposes a kind of in the fixed method to screen resolving agent of solvent, raising screening efficiency, reduction sieve
Select number.Use half amount (or full dose) fractionation method, i.e. the dosage of resolving agent be the amount for being split compound half (or
All).Racemic compound with single chiral center is containing there are two enantiomters.Any of which individual isomer accounts for
The 1/2 of total amount selects specific resolving agent, the dosage of molal quantity identical with individual isomer (or 2 times) is pressed, in specific solvent
In be quantitatively combined into and salt out with it.The isomers of another configuration because in the solvent without resolving agent in combination with (Resolution) or
The salt formed with resolving agent is dissolved in the solvent (full dose fractionation), to achieve the purpose that separation.It is fixed next in solvent
Resolving agent is screened, mainly compares different △ Rf values with yield, specific rotation, optical purity, final determine splits use
Best resolving agent, improve screening efficiency, reduce screening number.
(3) recovery process is improved, reuse after solvent for use and resolving agent can recycle reduces solvent and resolving agent storage
Fortune and consumption, realize all solvents and fractionation and recycling, reduce solvent and resolving agent storing and consumption, reduce
Environmental pollution reduces material and puts into production cost, improves the utilization rate of valuable raw material, and significantly reduce the discharge of pollutant,
Production cost compares with current domestic advanced enterprises declines 30% or more.
Description of the drawings
Fig. 1 is present invention process flow chart.
Specific implementation mode
The technical solutions of the present invention will be further described below in conjunction with the accompanying drawings, rather than limits the present invention.
Embodiment 1：
Acetyl captopril, i.e. 3- acetylthios -2- methyl propionyl chlorides are medicine intermediate, mainly for the production of Kato
Puli's bulk pharmaceutical chemicals etc., technological process includes the following steps：
1) addition of acid synthesizes
The thioacetic acid and methacrylic acid calculated is put into reaction kettle, is stirred under normal pressure and is warming up to 45~50 DEG C,
Stop heating after initiation reaction, exothermic heat of reaction automatic heating is to 90~98 DEG C, back flow reaction, by remaining methyl after reaction 1 hour
Acrylic acid added in six times, every 0.5 hour plus 1 time.120~130 DEG C are kept the temperature after adding to react 4 hours, are then cooled to 50
DEG C, boiling object (excessive thioacetic acid etc.) before the removing of water pump negative pressure is opened, and be gradually heating to 140 DEG C, stops heating.After cooling
Addition acid product barrelling.
Preceding boiling object send wastewater treatment after being absorbed with lye.
Reaction equation is：
2) it splits
Resolving agent water is prepared into 15% ± 0.2 solution, 15~20 DEG C is cooled to, addition of acid is added dropwise, drips off within 4 hours, drip
30min is kept the temperature after complete, is cooled to 0~-5 DEG C, is crystallized 12 hours, rejection filter, filter cake is washed with ice water, obtains wet product D salt.
Reaction equation is：
3) D salt is free
Process water and 31% hydrochloric acid are added into reaction kettle, is cooled to 20 DEG C hereinafter, input D salt wet products, stir simultaneously temperature control
It is reacted 1 hour under the conditions of 15~20 DEG C, surveys pH value, should be less than 3.0, otherwise added hydrochloric acid to regulation pH value, dichloromethane is added
Alkane extracts, and stirs 15min, stands 30min, and layering is so extracted 3 times with dichloromethane again.
Oil reservoir merges precipitation, obtains D- addition of acid, dichloroethane solvent recycling, and water layer recycles resolving agent after going alkalization.
Reaction equation is：
4) mother liquor is free
A batch is put into reaction kettle and splits mother liquor, is cooled to 15~20 DEG C, 31% hydrochloric acid is added dropwise, and drop finishes, and surveys pH value, answers small
In 3.0, hydrochloric acid is otherwise added to regulation pH value.
Dichloromethane extraction is added, stirs 15min, stands 30min, layering is so extracted 3 times again.
Oil reservoir merges precipitation, obtains L- addition of acid, solvent recovery.
Reaction equation is：
5) racemization
L- acid and catalyst are put into reaction kettle, stirring is warming up to 90~100 DEG C, and insulation reaction 5~6 hours is sampled
After detection is qualified, 20~30 DEG C are cooled to, after water agitator treating 30min is added, adds dichloromethane stirring extraction 15min,
30min, layering are stood, water phase is extracted three times with dichloromethane again.
Oil reservoir merges precipitation, obtains racemization addition of acid, solvent recovery, water phase decontamination water process.
Reaction equation is：
6) resolving agent is recycled
A collection of free water layer is added in reaction kettle, puts into piece alkali, stirs and react 1 hour under room temperature, survey pH value, should be greater than
10, piece alkali is otherwise added to regulation pH value.
It is original 1/2 or so that alkaline solution elder generation atmospheric distillation, which is dehydrated to volume, rectifying obtain the fractionation agent content in water≤
0.1%, as process water recovery.
Concentrate removes vacuum distillation resolving agent aqueous solution, uses process water stripping after being evaporated again 3 times, and last time detection steams
Agent content≤2.0% is split in aqueous.
Merge the fractionation agent solution steamed, detection level should be 15% ± 0.2.
Fractionation agent solution, which is applied mechanically, to be split, and vinasse goes wastewater treatment.
Reaction equation is：
7) chloride
D- acid is put into reaction kettle, and SOCl2 is added dropwise under room temperature, drips off within 1 hour, insulation reaction 16 hours under room temperature, reacts
Tail gas (HCl, SO2) is absorbed with ammonium hydroxide.
After completion of the reaction, excess SOCl2 and HCl is removed with water stream injection pump decompression (- 0.095MPa), kettle temperature is to slowly warm up to
80 DEG C or so, then 50 DEG C are cooled to hereinafter, using combination vacuum pump instead, vacuum distillation acetyl captopril is to substantially without product steaming
Go out, obtains product (S)-acetyl mercapto -2- methyl propionyl chlorides.
It is discharged after a small amount of vinasse cooling, burning disposal.
Reaction end gas is after weak aqua ammonia absorbs, then concentrated, crystallization, centrifugal filtration, recycles NH4Cl and NH4HSO3 by-products
Product.It mother liquor and steams water deallocation ammonia circulation and applies mechanically.
Reaction equation is：
8) acetyl captopril synthesizes
1200kg purified waters are put into reaction kettle, stir lower input L-PROLINE 195kg, dissolving is stirred at room temperature, then drops
Temperature starts while being added dropwise D- acyl chlorides and aqueous slkali (140kg pieces alkali soluble is in 800kg water), control dropwise addition process PH=to -5~0 DEG C
8~9, about 70~90min is dripped off, and dropping temperature is -5~0 DEG C, rear -5~0 DEG C of insulation reaction is added dropwise 1 hour, then is risen to
Room temperature starts that hydrochloric acid (31% hydrochloric acid 260kg is dissolved in 150kg water) is added dropwise, and control terminal pH value is 0.5~1.0, about 2 hours
It drips off.Then -5~-3 DEG C of crystallizations are cooled to 1 hour, take advantage of cold centrifugal filtration, filter cake is washed twice with 2 × 200kg ice water, obtains second
Acyl captopril wet product about 520kg, give money as a gift 420kg.
Product is not soluble in water, be centrifuged, wash after obtain crude product, then dry, obtain product.
Reaction equation is：
The process generates washings and filtrated stock, while there is condensed water in while being dried in vacuo, send at Sewage Disposal together
Reason.
In the present embodiment：
(1) it uses inorganic solvent water to substitute traditional captopril intermediate " D- acetylthio -2- methyl propionyl chloride " to prepare
Organic solvent-acetone in technique solves the problems such as dangerous height in conventional preparation techniques, cause serious pollution to the environment, reduces life
Produce cost.Traditional process route is improved, using after thioacetic acid and methacrylic acid addition through splitting, then with chlorine
Change the technique that sulfoxide chloride prepares captopril intermediate " D- acetylthio -2- methyl propionyl chloride ", it is first by test of many times
First using pollution-free, safe to use, source is sufficient, inorganic solvent --- water is not only greatly reduced and is produced into as solvent
This, and reduce pollution and safe and reliable.
(2) it proposes a kind of in the fixed method to screen resolving agent of solvent, raising screening efficiency, reduction sieve
Select number.Use half amount (or full dose) fractionation method, i.e. the dosage of resolving agent be the amount for being split compound half (or
All).Racemic compound with single chiral center is containing there are two enantiomters.Any of which individual isomer accounts for
The 1/2 of total amount selects specific resolving agent, the dosage of molal quantity identical with individual isomer (or 2 times) is pressed, in specific solvent
In be quantitatively combined into and salt out with it.The isomers of another configuration because in the solvent without resolving agent in combination with (Resolution) or
The salt formed with resolving agent is dissolved in the solvent (full dose fractionation), to achieve the purpose that separation.It is fixed next in solvent
Resolving agent is screened, mainly compares different △ Rf values with yield, specific rotation, optical purity, final determine splits use
Best resolving agent, improve screening efficiency, reduce screening number.
(3) recovery process is improved, reuse after solvent for use and resolving agent can recycle reduces solvent and resolving agent storage
Fortune and consumption, realize all solvents and fractionation and recycling, reduce solvent and resolving agent storing and consumption, reduce
Environmental pollution reduces material and puts into production cost, improves the utilization rate of valuable raw material, and significantly reduce the discharge of pollutant,
Production cost compares with current domestic advanced enterprises declines 30% or more.
The present embodiment is the exemplary embodiment of the present invention, for those skilled in the art, in the present invention
On the basis of disclosing application process and principle, it is easy to make various types of improvement or deformation, be not limited solely to the present invention
Structure described in above-mentioned specific implementation mode, therefore previously described mode is preferred embodiment, and it is not restrictive
Meaning, it is every according to equivalence changes made by the present invention with modification, all in the range protection domain of claims of the present invention.
Claims (9)
1. the preparation method of acetyl captopril, i.e. 3- acetylthios -2- methyl propionyl chlorides are medicine intermediate, are mainly used for
Produce captopril bulk pharmaceutical chemicals etc., which is characterized in that include the following steps：
1) addition of acid synthesizes
Thioacetic acid and methacrylic acid are put into reaction kettle, are stirred under normal pressure and are warming up to 45~50 DEG C, stopped after initiation reaction
It only heats, exothermic heat of reaction automatic heating is to 90~98 DEG C, back flow reaction, after reaction 1 hour in six times by remaining methacrylic acid
It adds, every 0.5 hour plus 1 time；120~130 DEG C are kept the temperature after adding to react 4 hours, is then cooled to 50 DEG C, and it is negative to open water pump
Pressure-off removes preceding boiling object, and is gradually heating to 140 DEG C, stops heating；Addition acid product barrelling after cooling, preceding boiling object are absorbed with lye
After send wastewater treatment；
2) it splits
Resolving agent water is prepared into 15% ± 0.2 solution, 15~20 DEG C is cooled to, addition of acid is added dropwise, drips off within 4 hours, after dripping off
30min is kept the temperature, is cooled to 0~-5 DEG C, is crystallized 12 hours, rejection filter, filter cake is washed with ice water, obtains wet product D salt；
3) D salt is free
Process water and 31% hydrochloric acid are added into reaction kettle, is cooled to 20 DEG C hereinafter, input D salt wet products, stir and temperature control is 15
It is reacted 1 hour under the conditions of~20 DEG C, surveys pH value, should be less than 3.0, otherwise added hydrochloric acid to regulation pH value, dichloromethane is added and carries
It takes, stirs 15min, stand 30min, layering is so extracted 3 times with dichloromethane again；Oil reservoir merges precipitation, obtains D- addition of acid,
Dichloroethane solvent recycles, and water layer recycles resolving agent after going alkalization；
4) mother liquor is free
A batch is put into reaction kettle and splits mother liquor, is cooled to 15~20 DEG C, 31% hydrochloric acid is added dropwise, and drop finishes, and surveys pH value, should be less than
3.0, hydrochloric acid is otherwise added to regulation pH value；Dichloromethane extraction is added, stirs 15min, stands 30min, layering so carries again
It takes 3 times；Oil reservoir merges precipitation, obtains L- addition of acid, solvent recovery；
5) racemization
L- acid and catalyst are put into reaction kettle, stirring is warming up to 90~100 DEG C, insulation reaction 5~6 hours, sampled detection
After qualification, 20~30 DEG C are cooled to, after water agitator treating 30min is added, dichloromethane stirring extraction 15min is added, stands
30min, layering, water phase are extracted three times with dichloromethane again；Oil reservoir merges precipitation, obtains racemization addition of acid, solvent recovery, water phase
Decontamination water process；
6) resolving agent is recycled
A collection of free water layer is added in reaction kettle, puts into piece alkali, stirs and react 1 hour under room temperature, survey pH value, should be greater than 10,
Otherwise piece alkali is added to regulation pH value；It is original 1/2 or so that alkaline solution elder generation atmospheric distillation, which is dehydrated to volume, and rectifying obtains in water
Agent content≤0.1% is split, as process water recovery；Concentrate removes vacuum distillation resolving agent aqueous solution, is used again after being evaporated
Process water stripping 3 times, last time detection steam fractionation agent content≤2.0% in aqueous；Merge the fractionation agent solution steamed, inspection
Surveying content should be 15% ± 0.2；Fractionation agent solution, which is applied mechanically, to be split, and vinasse goes wastewater treatment；
7) chloride
D- acid is put into reaction kettle, and SOCl2 is added dropwise under room temperature, drips off within 1 hour, insulation reaction 16 hours, reaction end gas under room temperature
HCl, SO2 are absorbed with ammonium hydroxide；After completion of the reaction, it being depressurized with water stream injection pump, pressure -0.095MPa removes excess SOCl2 and HCl,
Kettle temperature is to slowly warm up to 80 DEG C or so, then is cooled to 50 DEG C hereinafter, using combination vacuum pump instead, and vacuum distillation acetyl captopril is extremely
Substantially it is steamed without product, obtains product (S)-acetyl mercapto -2- methyl propionyl chlorides；It is discharged after a small amount of vinasse cooling, at burning
Reason；Reaction end gas is after weak aqua ammonia absorbs, then concentrated, crystallization, centrifugal filtration, recycles NH4Cl and NH4HSO3 byproducts；It is female
It liquid and steams water deallocation ammonia circulation and applies mechanically；
8) acetyl captopril synthesizes
1200kg purified waters are put into reaction kettle, stir lower input L-PROLINE 195kg, dissolving is stirred at room temperature, be then cooled to-
5~0 DEG C, start while being added dropwise D- acyl chlorides and aqueous slkali, control dropwise addition process PH=8~9, about 70~90min is dripped off, and temperature is added dropwise
Degree is -5~0 DEG C, rear -5~0 DEG C of insulation reaction is added dropwise 1 hour, then rises to room temperature, starts that hydrochloric acid, control terminal PH is added dropwise
Value dripped off for 0.5~1.0,2 hours；Then -5~-3 DEG C of crystallizations are cooled to 1 hour, take advantage of cold centrifugal filtration；Product is not soluble in water,
Be centrifuged, wash after obtain crude product, then dry, obtain product；The process generates washings and filtrated stock, while vacuum is dry
There is condensed water when dry, send Sewage Disposal to handle together.
2. the preparation method of acetyl captopril according to claim 1, which is characterized in that step 1 reaction equation is：
3. the preparation method of acetyl captopril according to claim 1, which is characterized in that step 2 reaction equation is：
4. the preparation method of acetyl captopril according to claim 1, which is characterized in that step 3 reaction equation is：
5. the preparation method of acetyl captopril according to claim 1, which is characterized in that step 4 reaction equation is：
6. the preparation method of acetyl captopril according to claim 1, which is characterized in that step 5 reaction equation is：
7. the preparation method of acetyl captopril according to claim 1, which is characterized in that step 6 reaction equation is：
8. the preparation method of acetyl captopril according to claim 1, which is characterized in that step 7 reaction equation is：
9. the preparation method of acetyl captopril according to claim 1, which is characterized in that step 8 reaction equation is：
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