CN108864036A - The method for preparing D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride - Google Patents
The method for preparing D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride Download PDFInfo
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Abstract
To solve complex process and technical problem at high cost, that yield is low in tradition D- (+)-α-(2- thienylethyl)-α-(2- chlorphenyl) methyl acetate hydrochloride synthesis technology, the present invention provides a kind of new method for preparing D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride.Include the following steps：1) preparation of 2- bromothiophene, 2) preparation of 2- thiophene ethanol, 3) preparation of 2- thiophene ethanol p-methyl benzenesulfonic acid ester, 4) L- (+)-preparation of O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt, 5) preparation of D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride, preparation method of the invention is at low cost, high income, highly-safe, is suitble to industrialized production.
Description
Technical field
D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride is prepared the invention discloses a kind of
Method.
Background technique
Clopidogrel is a kind of adp receptor retarding agent, can make fibrinogen in conjunction with platelet membrane surface A DP receptor
, so that blood platelet be inhibited mutually to assemble, pre- anti-stroke and heart attack can not be reached in conjunction with II b/ of glycoprotein GP, III a receptor
Curative effect, and can effectively treat and prevent atherosclerosis.
Wherein D- (+)-α-(2- thienylethyl)-α-(2- chlorphenyl) methyl acetate hydrochloride is synthesize clopidogrel one
Kind important intermediate.It is in the prior art, most strong with corrosivity using thiophene and Chloro-O-Phenyl glycine methyl ester as starting material
Bromine or hydrogen peroxide-hydrobromic acid acetate system are bromo agent, and reaction generates a large amount of more bromothiophenes of impurity, and product 2- bromothiophene is received
Rate is not high, causes to prepare 2- thiophene ethanol high expensive, and operability is more difficult.
In addition during splitting O-chlorobenzene glycine methyl ester in the prior art, resolution yield only has 50% or so, resolving agent
Tartaric acid does not find suitable recovery method, causes to waste a large amount of raw material O-chlorobenzene glycine methyl ester, tartaric acid, so that
Production cost is higher.To need to find one kind, cost is relatively low, highly-safe, is suitble to the method for industrialized production.
Summary of the invention
To solve work in tradition D- (+)-α-(2- thienylethyl)-α-(2- chlorphenyl) methyl acetate hydrochloride synthesis technology
The technical problem that skill is complex and costly, yield is low, the present invention, which provides, a kind of prepares D- (+)-α-(2 thiophene ethyl amine base)-α-
The new method of (2- chlorphenyl) methyl acetate hydrochloride.
Synthetic route of the present invention is as follows：
1, prepared by 2- thiophene ethanol p-methyl benzenesulfonic acid ester
2, L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt preparation
3, prepared by D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride
Specific technical solution of the present invention is as follows：
A method of D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride is prepared, including
Following steps：
1) prepared by 2- bromothiophene：By thiophene, phenyltrimethyl-ammonium tribromide (PTT) structural formula：Stirring solvent mixing, is cooled to -10-0 DEG C, insulation reaction 3-4h, and water is added into system, is layered,
Water layer is extracted with this step aforementioned solvents, merges solvent layer, and rectification under vacuum obtains 2- bromothiophene；
2) prepared by 2- thiophene ethanol：Solvent and zinc powder is added, takes 1/100~1/ of 2- bromothiophene mass ratio obtained by step 1)
50 instill, and iodine grain is added to cause, and after causing successfully, the 2- bromothiophene of remaining step 1) preparation are added dropwise, flow back insulation reaction, reaction
To the basic dissolved clarification of zinc powder, then the mixed solution of ethylene oxide He this step aforementioned solvents is added dropwise, 1~2h is kept the temperature after being added dropwise；
It is cooled to 0~20 DEG C, sulfuric acid tune pH=1~2, stratification are added dropwise, organic layer washing by organic layer rectification under vacuum, obtains 2- thiophene
Pheno ethyl alcohol；
3) prepared by 2- thiophene ethanol p-methyl benzenesulfonic acid ester：By 2- thiophene ethanol obtained by step 2) and organic solvent and to toluene
Sulfonic acid chloride (PTSC) structural formula：It is stirred, is cooled to 0~5 DEG C, sodium hydroxide solution, heat preservation 12h reaction is added dropwise
Terminate, hydrochloric acid is added dropwise and adjusts pH=1~2, stratification, water layer are extracted using this step aforementioned organic solvents, merged organic molten
Oxidant layer water washing, organic solvent layer are distilled to doing, and obtain 2- thiophene ethanol p-methyl benzenesulfonic acid ester；
4) L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt preparation：L- (+)-tartaric acid is mixed with solvent, is heated up
To reflux, Chloro-O-Phenyl glycine methyl ester is added dropwise, is added dropwise and is warming up to reflux, and keep the temperature 12-16h, be cooled to 0-5 DEG C of progress
It filters for the first time, filter cake is beaten with polar solvent, is filtered to obtain L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID for the second time
Salt；
5) prepared by D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride：It will be obtained by step 4)
L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt is added to the water, and sodium bicarbonate is slowly added to, after stirring to bubble-free generates
Organic solvent is added to extract for the first time, stirring, stratification, takes organic layer, water layer continues to be extracted with second of organic solvent, have
Machine is laminated simultaneously, dry, is evaporated under reduced pressure to dry；3) -2 second of gained p-methyl benzenesulfonic acid thiophene is added in resulting grease after distilling
Ester, ethyl acetate, sodium bicarbonate are warming up to reflux, keep the temperature 45-55h, are cooled to room temperature, add water and stir and carry out first time washing,
Stratification, organic layer add water to carry out second of washing, dry, filtering, and filtrate added drop-wise hydrochloric acid analysis of material is cooled to 0-5 DEG C, mistake
Filter, filter cake ethyl acetate and methanol mixed solution purification, obtain product D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorobenzene
Base) methyl acetate hydrochloride.
Further, solvent described in step 1) is chloroform, methylene chloride, carbon tetrachloride, tetrahydrofuran, 2- methyl tetrahydro
One of furans, ether.
Further, thiophene in step 1), phenyltrimethyl-ammonium tribromide, solvent mass ratio be 1.0:2.3:2.0~
1.0:3.6:10.0, preferentially select mass ratio for 1.0:2.3:2.0~1.0:2.8:4.0.
Further, the mass ratio of the step 1) water and solvent is 0.8:1.0~10.0:1.0.
Further, the mass ratio of the step 1) extractant and water is 0.5:1.0~10.0:1.0.
Further, step 1) further includes the steps that recycling phenyltrimethyl-ammonium tribromide, and the step is, to extraction institute
It obtains in water layer, hydrobromic acid is added, is added dropwise 0-20 DEG C of temperature of dioxygen water management, generates Orange red solid, filters to obtain phenyl trimethicone
Tribromide ammonium.
Further, in step 2), the solvent is tetrahydrofuran or 2- methyltetrahydrofuran.This step grignard reaction,
It need to be carried out in ether solvent, tetrahydrofuran or 2- methyltetrahydrofuran can guarantee that this step yield is higher than 94%, and advantageous
In improving final whole yield, using other ethers, yield is significantly reduced.
Further, in step 2), the molar ratio of the zinc powder and the resulting 2- bromothiophene of step 1) is 1.0:1.0~
1.0:3.0 preferentially select molar ratio for 1.0:1.0~1.0:1.5；
The mass ratio 2.0 of the solvent and zinc powder:1.0~10.0:1.0；
In the ethylene oxide and the mixed solution of this step aforementioned solvents, ethylene oxide and the aforementioned 2- bromothiophene of this step
Molar ratio be 1.05:1.0~3.0:1.0, preferentially select molar ratio for 1.05:1.0~2.0:1.0.
Further, after the washing of step 2) organic layer, include the steps that sodium sulphate is added or magnesium sulfate is dry.
Further, the step 3) organic solvent is methylene chloride, chloroform, one in toluene, 2- methyltetrahydrofuran
Kind.
Further, the molar ratio of PTSC described in step 3) and step 2) gained 2- thiophene ethanol is 1.05:1.0~
5.0:1.0, preferentially select molar ratio for 1.05:1.0~1.5:1.0；
The mass ratio of the organic solvent and PTSC are 1.5:1.0~5.0:1.0；
The mass percent concentration of the sodium hydroxide solution is 10~40%, in the sodium hydroxide solution of the dropwise addition
The molar ratio of 2- thiophene ethanol obtained by sodium hydroxide and step 2) is 1.5:1.0~3.0:1.0.
Further, the step 4) solvent is one of isopropanol, acetone, butanone, espeleton.
Further, the mass ratio of L- (+) described in step 4)-tartaric acid and solvent is 1.0:5.0~1.0:20.0；
The molar ratio of the Chloro-O-Phenyl glycine methyl ester and L- (+)-tartaric acid is 1.0:1.0~1.0:5.0 preferential choosing
Selecting molar ratio is 1.0:1.0~1.0:2.0.
Further, after step 4) the first time suction filtration, further include the steps that filtrate recycling design.
Further, the step 5) organic solvent is methylene chloride, dichloroethanes, chloroform, ethyl acetate, acetic acid isopropyl
Ester, one of toluene.
Further, the step 5) water and the L- (+) of addition-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt mass ratio
It is 3.0:1.0~10.0:1.0；
The sodium bicarbonate in the mixed liquor of L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt and water and step 4) is added
Gained L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt molar ratio is 2.5:1.0~4.0:1.0；
The organic solvent and L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt is wherein added to when extracting for the first time
In water mass ratio be 1.0:1.0~1.0:5.0；
Second organic solvent when extracting and wherein it is added to L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt
In water mass ratio be 0.4:1.0~5.0:1.0；
The mass ratio of the grease and the sodium bicarbonate being wherein added is 1.0:1.2~1.0:2.0；
The grease is 1.0 with the ethyl acetate mass ratio being wherein added:4.0~1.0:10.0；
The first time washing water is 0.8 with the ethyl acetate mass ratio being wherein added in grease:1.0~5.0:
1.0；
Second of washing water is 0.5 with the ethyl acetate mass ratio being wherein added in grease:1.0~5.0:
1.0；
Further, after step 5) second of extraction, further include the steps that water layer recycles tartaric acid, the step
For hydrochloric acid is added into water layer to pH in calcium chloride is added after acidity, generates precipitating, stirring cooling crystallization filters to obtain tartaric acid
Calcium stirs the solvent of solvable tartaric acid together with calcium tartrate, and sulfuric acid is added dropwise to pH=1~2, heating cooling filtering, filtrate
Distillation to thick shape, cooling filters and dries to obtain tartaric acid.The solvent of the solvable tartaric acid does not include alcohols, can be dichloromethane
One of alkane, chloroform, dichloroethanes, acetone.
Compared with the existing technology, the invention has the advantages that：
1, prepare 2- bromothiophene has used bromating agent PTT instead of traditional bromine or hydrobromic acid-dioxygen water body in the process
System, PTT just have with respect to other bromo agent：2- bromos of thiophene are selectively good, and stability is good, and solid is easy to use, in addition PTT
Recovery scheme is simple and the rate of recovery is up to 93% or more, so that not only yield and quality are high outer for 2- bromothiophene, also having can
Strong operability, the features such as safety is good, production cost is low are particularly suitable for industrialized production.
2, during preparing 2- thiophene ethanol, traditional magnesium chips is replaced using zinc powder, so that the 2- thiophene second of step synthesis
Alcohol has 5% or more raising with respect to magnesium chips yield, and purity is up to 99% or more, so that the step cost reduces.
3, Chloro-O-Phenyl glycine methyl ester is split using L- (+) tartaric acid, has studied specific solvent as resolution reaction
Solvent (isopropanol, acetone, butanone, espeleton), first back flow reaction, then the slow crystallization that cools down make invalid Chloro-O-Phenyl
Glycine methyl ester is converted into effective L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt, so that the step yield reaches
92%.It is significantly improved relative to other document yields, in addition resolving agent tartaric acid has excellent recovery scheme, winestone acid recovery
Rate is up to 90% or more, and the tartaric acid recycled is applied in resolution reaction, the quality and yield of final products is not influenced, to make
The step production cost is substantially reduced, and has very big practical value, is suitable for industrial amplification production.
4, in preparation and refined products (D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride)
In the process, the expensive acetonitrile of other document utilizations is as preparing solvent, when purification need to use the water of acetonitrile and methanol as
Mixed solvent purification, replaces acetonitrile using ethyl acetate herein, and not only cost of material reduces, and recovered solvent can directly cover
With (acetonitrile and methanol azeotropic are difficult to separate, and ethyl acetate and methanol are convenient for separately), it is very effective that cost is reduced for industrialization.
5, integrated artistic supplementary material is easy to get, and operating procedure is short, strong operability, and not only production cost is low and produces for final product
Product yield is with respect to other techniques height, and five step entirety yield of preparation method provided by the invention is up to 63.8%, and purity is up to 99.5%.Separately
Outer auxiliary material (tartaric acid) recycling, the recycling of solvent (ethyl acetate, methanol, methylene chloride, isopropanol etc.) are especially suitable for industry
Metaplasia produces.
Specific embodiment
The present invention is made combined with specific embodiments below and further being elaborated, the embodiment is served only for explaining this
Invention, is not intended to limit the scope of the present invention.Test method as used in the following examples is normal unless otherwise specified
Rule method；Used material, reagent etc., unless otherwise specified, for the reagent and material commercially obtained.
Embodiment 1
1, prepared by 2- bromothiophene：Methylene chloride 252g, thiophene 84g, PTT 225g, stirring cooling are put into reaction flask
To -10-0 DEG C, insulation reaction 4h, water 200g is added into system and is stirred at room temperature, is layered, methylene chloride 135g extraction is added in water layer
1 time, merge dichloromethane layer, rectifying obtains 2- bromothiophene：150.6g yield：92.4%, gas phase purity 99.5%.
Water layer is transferred in another reaction flask and recycles PTT：System is cooled down, hydrobromic acid 202g is added, 30% hydrogen peroxide is added dropwise
136g, temperature control are no more than 20 DEG C, and cooling is added dropwise and filters, and dry to obtain recycling PTT 214g, the rate of recovery 95%.
2, prepared by 2- thiophene ethanol：Tetrahydrofuran 180g is put into reaction flask, puts into zinc powder 80g, instills 2- bromothiophene
Then 2 iodine grains are added in 2g, after initiation, the 2- bromothiophene of remaining above-mentioned preparation, control ground acceleration, reaction is added dropwise
Liquid maintains the reflux for, and reaction to the basic dissolved clarification of zinc powder is added dropwise the mixed solution of ethylene oxide 49g+ tetrahydrofuran 45g, is added dropwise
Insulation reaction 1h, cooling are added dropwise dilute sulfuric acid and adjust pH=1~2, and stratification, organic layer is primary with 300g water washing, organic layer
Rectification under vacuum collects 1.73kPa, 108~110 DEG C of fractions, obtains 2- thiophene ethanol：111.4g yield 94%, purity 99.2%.
3, prepared by 2- thiophene ethanol p-methyl benzenesulfonic acid ester：2- thiophene ethanol is walked in investment into reaction flask：111.4g, dichloro
Methane 600g, PTSC 211.5g, stirring are cooled to 0-5 DEG C, and the sodium hydroxide solution 278g of 30% mass fraction, control is added dropwise
0-5 DEG C of temperature, heat preservation 12h is added dropwise, dropwise addition hydrochloric acid to pH=1~2, layering, water layer is used to be extracted with 300g methylene chloride,
Merging dichloromethane layer, 100g water washing, organic layer distill to dry to obtain 2- thiophene ethanol p-methyl benzenesulfonic acid ester：233.2g yield
95%, purity 99.4%.
4, L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt preparation：Isopropanol 1000g, L- are put into reaction flask
(+)-tartaric acid 102g is warming up to reflux, and Chloro-O-Phenyl glycine methyl ester 136g is added dropwise, is added dropwise and is warming up to reflux, keeps the temperature
12h is reacted, heat preservation terminates slow cooling, is cooled to 0-5 DEG C, filters, and filter cake 500g methanol room temperature is beaten, 0-5 is cooled to
DEG C filter, dry to obtain L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt：216g yield 91%.
5, prepared by D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride：It is thrown into reaction flask
Enter upper step solid：216g, water 700g is added, stirring is slowly added to sodium bicarbonate 156g, after stirring to bubble-free generates, is added
Methylene chloride 1000g, stirring, stratification, water layer are extracted 1 time with 300g methylene chloride, merge dichloromethane layer, with 40g sulphur
Sour magnesium dries, filters, and distilled dichloromethane obtains grease 135g to doing.
Winestone acid recovery：This step water layer hydrochloric acid is adjusted into PH=3-4, adjusts and finishes addition calcium chloride 79.4g, stirring,
Be cooled to 0-10 DEG C, filter to obtain calcium tartrate, will filter calcium tartrate and 370g methylene chloride investment reaction flask in, stirring
Sulfuric acid 69.2g is added dropwise, is added dropwise, cools down 5-15 DEG C, filtering filter cake is abraum salt, and filtrate is distilled to system in thick shape, is cooled to
0-5 DEG C, filtering, drying filter cake must recycle L- (+) tartaric acid 92g, the rate of recovery 90.2%.
Grease 135g, ethyl acetate 540g, 2- thiophene ethanol after being evaporated to another reaction flask investment methylene chloride
P-methyl benzenesulfonic acid ester 233.2g, sodium bicarbonate 190g are warming up to reflux, and flow back insulation reaction 45h, are cooled to room after heat preservation
Water 480g washing is added in temperature, stands, layering, and organic layer adds 135g water washing, organic layer magnesium sulfate 40g drying, filtering, filter
Drop adds hydrochloric acid 163g, and stirring is cooled to 0-5 DEG C, filters to obtain crude product, crude product, methanol 109g, ethyl acetate 434g is put into anti-
It answers in bottle, is warming up to reflux heat preservation 1h, is cooled to 0-5 DEG C, product is dried to obtain in filtering：181.2g, yield 85%, purity
99.5%.
Embodiment 2
1, prepared by 2- bromothiophene：Methylene chloride 500g, thiophene 84g, PTT 302g, stirring cooling are put into reaction flask
To -10-0 DEG C, insulation reaction 4h, 200ml water is added into system and is stirred at room temperature, is layered, methylene chloride 135g extraction is added in water layer
It takes 1 time, merges dichloromethane layer, rectifying obtains 2- bromothiophene：151g yield：92.6%, gas phase purity 99.5%.
Water layer is transferred in another reaction flask and recycles PTT：System is cooled down, hydrobromic acid 202g is added, 30% hydrogen peroxide is added dropwise
136g, temperature control are no more than 20 DEG C, and cooling is added dropwise and filters, and dry to obtain recycling PTT 287.4g, the rate of recovery 95.1%.
2, prepared by 2- thiophene ethanol：2- methyltetrahydrofuran 450g is put into reaction flask, puts into zinc powder 90g, instills 2-
Then 2 iodine grains are added in bromothiophene 1.5g, after initiation, the 2- bromothiophene of remaining above-mentioned preparation is added dropwise, control ground accelerates
Degree, reaction solution maintain the reflux for, and the mixing of ethylene oxide 49g+2- methyltetrahydrofuran 45g is added dropwise in reaction to the basic dissolved clarification of zinc powder
Insulation reaction 1h is added dropwise in solution, and cooling is added dropwise dilute sulfuric acid and adjusts pH=1~2, stratification, and organic layer is washed with 300g
Primary, organic layer rectification under vacuum is washed, collection 1.73kPa, 108~110 DEG C of fractions obtain 2- thiophene ethanol：112g yield 94.5%,
Purity 99.2%.
3, prepared by 2- thiophene ethanol p-methyl benzenesulfonic acid ester：2- thiophene ethanol is walked in investment into reaction flask：112g, chloroform
600g, PTSC 249.4g, stirring are cooled to 0-5 DEG C, and the sodium hydroxide solution 834g of 10% mass fraction is added dropwise, and control temperature
0-5 DEG C, heat preservation 12h is added dropwise, hydrochloric acid is added dropwise to pH=1~2, layering, water layer is used to be extracted with 300g chloroform, merges chloroform
Layer, 100g water washing, organic layer distills to dry to obtain 2- thiophene ethanol p-methyl benzenesulfonic acid ester：235.1g yield 95.3%, purity
99.5%.
4, L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt preparation：Butanone 1000g, L- (+)-is put into reaction flask
Tartaric acid 204g is warming up to reflux, and Chloro-O-Phenyl glycine methyl ester 136g is added dropwise, is added dropwise and is warming up to reflux, insulation reaction
12h, heat preservation terminate slow cooling, are cooled to 0-5 DEG C, filter, and filter cake 500g methanol room temperature is beaten, 0-5 DEG C of pumping is cooled to
Filter, dries to obtain L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt：216.5g yield 91.2%.
5, prepared by D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride：It is thrown into reaction flask
Enter upper step solid：216.5g, water 2000g is added, stirring is slowly added to sodium bicarbonate 156g and adds after stirring to bubble-free generates
Enter chloroform 1000g, stir, stratification, water layer is extracted 1 time with 300g chloroform, merges chloroform layer, mistake dry with 40g magnesium sulfate
Filter, distillation chloroform obtain grease 134g to doing.
Winestone acid recovery：This step water layer hydrochloric acid is adjusted into PH=3-4, adjusts and finishes addition calcium chloride 79.4g, stirring,
Be cooled to 0-10 DEG C, filter to obtain calcium tartrate, will filter calcium tartrate and 700g chloroform investment reaction flask in, agitation and dropping
Sulfuric acid 138.4g, is added dropwise, and cools down 5-15 DEG C, and filtering filter cake is abraum salt, and filtrate is distilled to system in thick shape, is cooled to 0-5
DEG C, filtering, drying filter cake must recycle L- (+) tartaric acid 185g, the rate of recovery 90.6%.
Grease 134g, ethyl acetate 540g, 2- thiophene ethanol after being evaporated to another reaction flask investment chloroform is to first
Benzene sulfonate 235.1g, sodium bicarbonate 190g are warming up to reflux, and flow back insulation reaction 55h, are cooled to room temperature after heat preservation,
Water 480g washing is added, stands, layering, organic layer adds 270g water washing, organic layer magnesium sulfate 40g drying, filtering, filtrate
Hydrochloric acid 163g is added dropwise, stirring is cooled to 0-5 DEG C, filters to obtain crude product, by crude product, methanol 109g, ethyl acetate 434g investment reaction
In bottle, it is warming up to reflux heat preservation 1h, is cooled to 0-5 DEG C, product is dried to obtain in filtering：181.5g, yield 85.1%, purity
99.5%.
Embodiment 3
1, prepared by 2- bromothiophene：2- methyltetrahydrofuran 250g, thiophene 84g, PTT 252g, stirring are put into reaction flask
- 10-0 DEG C, insulation reaction 4h are cooled to, water 500g is added into system and is stirred at room temperature, is layered, 2- methyl tetrahydro furan is added in water layer
The 500g that mutters is extracted 1 time, merges 2- methyltetrahydrofuran layer, and rectifying obtains 2- bromothiophene：150.3g yield：92.2%, gas phase purity
99.5%.
Water layer is transferred in another reaction flask and recycles PTT：System is cooled down, hydrobromic acid 202g is added, 30% hydrogen peroxide is added dropwise
136g, temperature control are no more than 20 DEG C, and cooling is added dropwise and filters, and dry to obtain recycling PTT 240g, the rate of recovery 95.2%.
2, prepared by 2- thiophene ethanol：Tetrahydrofuran 126g is put into reaction flask, puts into zinc powder 71.6g, instills 2- bromine thiophene
Then 2 iodine grains are added in pheno 3g, after initiation, the 2- bromothiophene of remaining above-mentioned preparation is added dropwise, and control ground acceleration, instead
Liquid is answered to maintain the reflux for, the mixed solution of ethylene oxide 69.3g+ tetrahydrofuran 45g is added dropwise in reaction to the basic dissolved clarification of zinc powder, is added dropwise
Insulation reaction 1h is finished, cooling is added dropwise dilute sulfuric acid and adjusts pH=1~2, and stratification, organic layer is primary with 300g water washing, has
Machine layer rectification under vacuum collects 1.73kPa, 108~110 DEG C of fractions, obtains 2- thiophene ethanol：111.5g yield 94%, purity
99.3%.
3, prepared by 2- thiophene ethanol p-methyl benzenesulfonic acid ester：2- thiophene ethanol is walked in investment into reaction flask：111.5g, 2- first
Base tetrahydrofuran 500g, PTSC 211.5g, stirring are cooled to 0-5 DEG C, and the sodium hydroxide solution of 20% mass fraction is added dropwise
417g controls 0-5 DEG C of temperature, and heat preservation 12h is added dropwise, and hydrochloric acid is added dropwise to pH=1~2, layering, water layer 300g 2- first
The extraction of base tetrahydrofuran, merges 2- methyltetrahydrofuran layer, 100g water washing, and organic layer is distilled to dry 2- thiophene ethanol to first
Benzene sulfonate：233.8g yield 95.2%, purity 99.5%.
4, L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt preparation：Butanone 1000g, L- (+)-is put into reaction flask
Tartaric acid 102g is warming up to reflux, and Chloro-O-Phenyl glycine methyl ester 136g is added dropwise, is added dropwise and is warming up to reflux, insulation reaction
16h, heat preservation terminate slow cooling, are cooled to 0-5 DEG C, filter, and filter cake 500g methanol room temperature is beaten, 0-5 DEG C of pumping is cooled to
Filter, dries to obtain L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt：217g yield 91.4%.
5, prepared by D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride：It is thrown into reaction flask
Enter upper step solid：217g, water 1500g is added, stirring is slowly added to sodium bicarbonate 156g, after stirring to bubble-free generates, is added
Isopropyl acetate 1000g, stirring, stratification, water layer are extracted 1 time with 300g isopropyl acetate, merge isopropyl acetate layer,
It is dried, filtered with 40g magnesium sulfate, distillation isopropyl acetate obtains grease 136g to doing.
Winestone acid recovery：This step water layer hydrochloric acid is adjusted into PH=3-4, adjusts and finishes addition calcium chloride 79.4g, stirring,
Be cooled to 0-10 DEG C, filter to obtain calcium tartrate, will filter calcium tartrate and 500g methylene chloride investment reaction flask in, stirring
Sulfuric acid 69.2g is added dropwise, is added dropwise, cools down 5-15 DEG C, filtering filter cake is abraum salt, and filtrate is distilled to system in thick shape, is cooled to
0-5 DEG C, filtering, drying filter cake must recycle L- (+) tartaric acid 92g, the rate of recovery 90.2%.
Grease 136g, ethyl acetate 1360g, 2- thiophene second after being evaporated to another reaction flask investment isopropyl acetate
Alcohol p-methyl benzenesulfonic acid ester 233.8g, sodium bicarbonate 272g are warming up to reflux, and flow back insulation reaction 50h, are cooled to after heat preservation
Room temperature, addition water 1100g washing, stands, layering, and organic layer adds 680g water washing, and organic layer is dry with magnesium sulfate 40g, filters,
Filtrate added drop-wise hydrochloric acid 163g, stirring are cooled to 0-5 DEG C, filter to obtain crude product, and crude product, methanol 109g, ethyl acetate 434g are put into
In reaction flask, it is warming up to reflux heat preservation 1h, is cooled to 0-5 DEG C, product is dried to obtain in filtering：181.1g, yield 85.0%, purity
99.5%.
Embodiment 4
1, prepared by 2- bromothiophene：Tetrahydrofuran 250g, thiophene 84g, PTT 225g, stirring cooling are put into reaction flask
To -10-0 DEG C, insulation reaction 4h, water 500g is added into system and is stirred at room temperature, is layered, tetrahydrofuran 840g extraction is added in water layer
1 time, merge tetrahydrofuran layer, rectifying obtains 2- bromothiophene：149.8g yield：91.9%, gas phase purity 99.5%.
Water layer is transferred in another reaction flask and recycles PTT：System is cooled down, hydrobromic acid 202g is added, 30% hydrogen peroxide is added dropwise
136g, temperature control are no more than 20 DEG C, and cooling is added dropwise and filters, and dry to obtain recycling PTT 213.8g, the rate of recovery 95%.
2, prepared by 2- thiophene ethanol：Tetrahydrofuran 126g is put into reaction flask, puts into zinc powder 71.6g, instills 2- bromine thiophene
Then 2 iodine grains are added in pheno 1.5g, after initiation, the 2- bromothiophene of remaining above-mentioned preparation is added dropwise, and control ground acceleration,
Reaction solution maintains the reflux for, reaction to the basic dissolved clarification of zinc powder, and the mixed solution of ethylene oxide 58.8g+ tetrahydrofuran 45g, drop is added dropwise
Complete insulation reaction 1h is added, cooling is added dropwise dilute sulfuric acid and adjusts pH=1~2, and stratification, organic layer is primary with 300g water washing,
Organic layer rectification under vacuum collects 1.73kPa, 108~110 DEG C of fractions, obtains 2- thiophene ethanol：111.1g yield 93.7%, purity
99.5%.
3, prepared by 2- thiophene ethanol p-methyl benzenesulfonic acid ester：2- thiophene ethanol is walked in investment into reaction flask：111.1g, toluene
500g, PTSC 198g, stirring are cooled to 0-5 DEG C, and the sodium hydroxide solution 209g of 40% mass fraction is added dropwise, and control temperature 0-
5 DEG C, heat preservation 12h is added dropwise, dropwise addition hydrochloric acid to pH=1~2, layering, water layer is used to be extracted with 300g toluene, combining methylbenzene layer,
100g water washing, organic layer distill to dry to obtain 2- thiophene ethanol p-methyl benzenesulfonic acid ester：232.6g yield 95.2%, purity
99.5%.
4, L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt preparation：Espeleton 1000g, L- are put into reaction flask
(+)-tartaric acid 153g is warming up to reflux, and Chloro-O-Phenyl glycine methyl ester 136g is added dropwise, is added dropwise and is warming up to reflux, keeps the temperature
14h is reacted, heat preservation terminates slow cooling, is cooled to 0-5 DEG C, filters, and filter cake 500g methanol room temperature is beaten, 0-5 is cooled to
DEG C filter, dry to obtain L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt：215.5g yield 90.7%.
5, prepared by D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride：It is thrown into reaction flask
Enter upper step solid：215.5g, water 646.5g being added, stirring is slowly added to sodium bicarbonate 156g, after stirring to bubble-free generates,
Ethyl acetate 1000g, stirring, stratification, water layer 300g ethyl acetate extraction 1 time, combined ethyl acetate layer, use is added
40g magnesium sulfate dries, filters, and distillation ethyl acetate obtains grease 135.5g to doing.
Winestone acid recovery：This step water layer hydrochloric acid is adjusted into PH=3-4, adjusts and finishes addition calcium chloride 119.4g, stirring,
Be cooled to 0-10 DEG C, filter to obtain calcium tartrate, will filter calcium tartrate and 500g methylene chloride investment reaction flask in, stirring drop
Add sulfuric acid 103.8g, be added dropwise, cool down 5-15 DEG C, filtering filter cake is abraum salt, and filtrate is distilled to system in thick shape, is cooled to 0-
5 DEG C, filtering, drying filter cake must recycle L- (+) tartaric acid 139.3g, the rate of recovery 91%.
Grease 135.5g, ethyl acetate 1084g, 2- thiophene after being evaporated to another reaction flask investment isopropyl acetate
Ethyl-4-methylbenzenesulfonate 232.6g, sodium bicarbonate 203g are warming up to reflux, and flow back insulation reaction 50h, cool down after heat preservation
To room temperature, water 1100g washing is added, stands, layering, organic layer adds 542g water washing, organic layer dry, mistake with magnesium sulfate 40g
Filter, filtrate added drop-wise hydrochloric acid 163g, stirring are cooled to 0-5 DEG C, filter to obtain crude product, and crude product, methanol 109g, ethyl acetate 434g are thrown
Enter in reaction flask, is warming up to reflux heat preservation 1h, is cooled to 0-5 DEG C, product is dried to obtain in filtering：181.4g, yield 85.1% are pure
Degree 99.5%.
Embodiment 5
1, prepared by 2- bromothiophene：Into reaction flask, investment chloroform 250g, thiophene 84g, PTT 252g, stirring are cooled to -10-
0 DEG C, insulation reaction 4h, water 500g is added into system and is stirred at room temperature, is layered, water layer is added chloroform 500g and extracts 1 time, merges chlorine
Imitative layer, rectifying obtain 2- bromothiophene：150.8g yield：92.5%, gas phase purity 99.5%.
Water layer is transferred in another reaction flask and recycles PTT：System is cooled down, hydrobromic acid 202g is added, 30% hydrogen peroxide is added dropwise
136g, temperature control are no more than 20 DEG C, and cooling is added dropwise and filters, and dry to obtain recycling PTT 239.8g, the rate of recovery 95.1%.
2, prepared by 2- thiophene ethanol：2- methyltetrahydrofuran 126g is put into reaction flask, puts into zinc powder 71.6g, is instilled
Then 2 iodine grains are added in 2- bromothiophene 1.5g, after initiation, the 2- bromothiophene of remaining above-mentioned preparation is added dropwise, control ground adds
Speed, reaction solution maintain the reflux for, reaction to the basic dissolved clarification of zinc powder, and the mixed of ethylene oxide 49g+2- methyltetrahydrofuran 45g is added dropwise
Solution is closed, insulation reaction 1h is added dropwise, cooling is added dropwise dilute sulfuric acid and adjusts pH=1~2, stratification, organic layer 300g water
It washed once, organic layer rectification under vacuum, collect 1.73kPa, 108~110 DEG C of fractions, obtain 2- thiophene ethanol：111.2g yield
93.7%, purity 99.4%.
3, prepared by 2- thiophene ethanol p-methyl benzenesulfonic acid ester：2- thiophene ethanol is walked in investment into reaction flask：111.2g, dichloro
Methane 500g, PTSC 165g, stirring are cooled to 0-5 DEG C, and the sodium hydroxide solution 417g of 20% mass fraction, control temperature is added dropwise
Heat preservation 12h is added dropwise in 0-5 DEG C of degree, hydrochloric acid is added dropwise to pH=1~2, layering, water layer is used to be extracted with 300g methylene chloride, is merged
Dichloromethane layer, 100g water washing, organic layer distill to dry to obtain 2- thiophene ethanol p-methyl benzenesulfonic acid ester：233.2g yield
95.2%, purity 99.5%.
4, L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt preparation：Acetone 1000g, L- (+)-is put into reaction flask
Tartaric acid 102g is warming up to reflux, and Chloro-O-Phenyl glycine methyl ester 136g is added dropwise, is added dropwise and is warming up to reflux, insulation reaction
16h, heat preservation terminate slow cooling, are cooled to 0-5 DEG C, filter, and filter cake 500g methanol room temperature is beaten, 0-5 DEG C of pumping is cooled to
Filter, dries to obtain L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt：215g yield 90.6%.
5, prepared by D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride：It is thrown into reaction flask
Enter upper step solid：215g, water 1500g is added, stirring is slowly added to sodium bicarbonate 156g, after stirring to bubble-free generates, is added
Dichloroethanes 1000g, stirring, stratification, water layer are extracted 1 time with 300g dichloroethanes, merge dichloroethanes layer, with 40g sulphur
Sour magnesium dries, filters, and distillation dichloroethanes obtains grease 135g to doing.
Winestone acid recovery：This step water layer hydrochloric acid is adjusted into PH=3-4, adjusts and finishes addition calcium chloride 79.4g, stirring,
Be cooled to 0-10 DEG C, filter to obtain calcium tartrate, will filter calcium tartrate and 500g methylene chloride investment reaction flask in, stirring
Sulfuric acid 69.2g is added dropwise, is added dropwise, cools down 5-15 DEG C, filtering filter cake is abraum salt, and filtrate is distilled to system in thick shape, is cooled to
0-5 DEG C, filtering, drying filter cake must recycle L- (+) tartaric acid 92g, the rate of recovery 90.2%.
Grease 135g, ethyl acetate 540g, 2- thiophene ethanol after being evaporated to another reaction flask investment dichloroethanes
P-methyl benzenesulfonic acid ester 233.2g, sodium bicarbonate 270g are warming up to reflux, and flow back insulation reaction 55h, are cooled to room after heat preservation
Water 1100g washing is added in temperature, stands, layering, and organic layer adds 540g water washing, organic layer magnesium sulfate 40g drying, filtering, filter
Drop adds hydrochloric acid 163g, and stirring is cooled to 0-5 DEG C, filters to obtain crude product, crude product, methanol 109g, ethyl acetate 434g is put into anti-
It answers in bottle, is warming up to reflux heat preservation 1h, is cooled to 0-5 DEG C, product is dried to obtain in filtering：181.1g, yield 85.0%, purity
99.5%.
Embodiment 6
1, prepared by 2- bromothiophene：Carbon tetrachloride 250g, thiophene 84g, PTT 252g, stirring cooling are put into reaction flask
To -10-0 DEG C, insulation reaction 4h, water 500g is added into system and is stirred at room temperature, is layered, carbon tetrachloride 500g extraction is added in water layer
1 time, merge carbon tetrachloride layer, rectifying obtains 2- bromothiophene：150.3g yield：92.2%, gas phase purity 99.5%.
Water layer is transferred in another reaction flask and recycles PTT：System is cooled down, hydrobromic acid 202g is added, 30% hydrogen peroxide is added dropwise
136g, temperature control are no more than 20 DEG C, and cooling is added dropwise and filters, and dry to obtain recycling PTT 241g, the rate of recovery 95.6%.
2, prepared by 2- thiophene ethanol：2- methyltetrahydrofuran 126g is put into reaction flask, puts into zinc powder 86g, instills 2-
Then 2 iodine grains are added in bromothiophene 2g, after initiation, the 2- bromothiophene of remaining above-mentioned preparation is added dropwise, control ground accelerates
Degree, reaction solution maintain the reflux for, reaction to the basic dissolved clarification of zinc powder, and the mixed of ethylene oxide 73.5g+2- methyltetrahydrofuran 45g is added dropwise
Solution is closed, insulation reaction 1h is added dropwise, cooling is added dropwise dilute sulfuric acid and adjusts pH=1~2, stratification, organic layer 300g water
It washed once, organic layer rectification under vacuum, collect 1.73kPa, 108~110 DEG C of fractions, obtain 2- thiophene ethanol：111.8g yield
94.5%, purity 99.4%.
3, prepared by 2- thiophene ethanol p-methyl benzenesulfonic acid ester：2- thiophene ethanol is walked in investment into reaction flask：111.8g, chloroform
500g, PTSC 198g, stirring are cooled to 0-5 DEG C, and the sodium hydroxide solution 417g of 20% mass fraction is added dropwise, and control temperature 0-5
DEG C, heat preservation 12h is added dropwise, dropwise addition hydrochloric acid to pH=1~2, layering, water layer is used to be extracted with 300g chloroform, merging chloroform layer,
100g water washing, organic layer distill to dry to obtain 2- thiophene ethanol p-methyl benzenesulfonic acid ester：234g yield 95%, purity 99.5%.
4, L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt preparation：Acetone 1000g, L- (+)-is put into reaction flask
Tartaric acid 102g is warming up to reflux, and Chloro-O-Phenyl glycine methyl ester 136g is added dropwise, is added dropwise and is warming up to reflux, insulation reaction
16h, heat preservation terminate slow cooling, are cooled to 0-5 DEG C, filter, and filter cake 500g methanol room temperature is beaten, 0-5 DEG C of pumping is cooled to
Filter, dries to obtain L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt：215g yield 90.6%.
5, prepared by D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride：It is thrown into reaction flask
Enter upper step solid：215g, water 1500g is added, stirring is slowly added to sodium bicarbonate 156g, after stirring to bubble-free generates, is added
Dichloroethanes 1000g, stirring, stratification, water layer are extracted 1 time with 300g dichloroethanes, merge dichloroethanes layer, with 40g sulphur
Sour magnesium dries, filters, and distillation dichloroethanes obtains grease 135g to doing.
Winestone acid recovery：This step water layer hydrochloric acid is adjusted into PH=3-4, adjusts and finishes addition calcium chloride 79.4g, stirring,
Be cooled to 0-10 DEG C, filter to obtain calcium tartrate, will filter calcium tartrate and 500g methylene chloride investment reaction flask in, stirring
Sulfuric acid 69.2g is added dropwise, is added dropwise, cools down 5-15 DEG C, filtering filter cake is abraum salt, and filtrate is distilled to system in thick shape, is cooled to
0-5 DEG C, filtering, drying filter cake must recycle L- (+) tartaric acid 92g, the rate of recovery 90.2%.
Grease 135g, ethyl acetate 540g, 2- thiophene ethanol after being evaporated to another reaction flask investment dichloroethanes
P-methyl benzenesulfonic acid ester 234g, sodium bicarbonate 270g are warming up to reflux, and flow back insulation reaction 55h, are cooled to room after heat preservation
Water 1100g washing is added in temperature, stands, layering, and organic layer adds 540g water washing, organic layer magnesium sulfate 40g drying, filtering, filter
Drop adds hydrochloric acid 163g, and stirring is cooled to 0-5 DEG C, filters to obtain crude product, crude product, methanol 109g, ethyl acetate 434g is put into anti-
It answers in bottle, is warming up to reflux heat preservation 1h, is cooled to 0-5 DEG C, product is dried to obtain in filtering：181.1g, yield 85.0%, purity
99.5%.
Claims (17)
1. a kind of method for preparing D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride, feature
It is, includes the following steps：
1) prepared by 2- bromothiophene：Thiophene, phenyltrimethyl-ammonium tribromide, stirring solvent are mixed, are cooled to -10-0 DEG C, heat preservation
3-4h is reacted, into system plus water, layering, water layer are extracted with this step aforementioned solvents, merge solvent layer, rectification under vacuum obtains 2- bromine
Thiophene；
2) prepared by 2- thiophene ethanol：Solvent and zinc powder is added, takes 1/100~1/50 drop of 2- bromothiophene mass ratio obtained by step 1)
Enter, iodine grain is added to cause, after causing successfully, the 2- bromothiophene of remaining step 1) preparation is added dropwise, flow back insulation reaction, reaction to zinc
The basic dissolved clarification of powder, then the mixed solution of ethylene oxide He this step aforementioned solvents is added dropwise, 1~2h is kept the temperature after being added dropwise；Cooling
To 0~20 DEG C, sulfuric acid tune pH=1~2, stratification are added dropwise, organic layer washing by organic layer rectification under vacuum, obtains 2- thiophene second
Alcohol；
3) prepared by 2- thiophene ethanol p-methyl benzenesulfonic acid ester：2- thiophene ethanol obtained by step 2) and the stirring of organic solvent and PTSC is mixed
It closes, is cooled to 0~5 DEG C, sodium hydroxide solution is added dropwise, keeping the temperature 12h reaction terminates, and hydrochloric acid is added dropwise and adjusts pH=1~2, stands and divides
Layer, water layer are extracted using this step aforementioned organic solvents, merge organic solvent layer water washing, and organic solvent layer is distilled to doing, obtained
2- thiophene ethanol p-methyl benzenesulfonic acid ester；
4) L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt preparation：L- (+)-tartaric acid is mixed with solvent, is warming up to back
Stream is added dropwise Chloro-O-Phenyl glycine methyl ester, is added dropwise and is warming up to reflux, and keep the temperature 12-16h, is cooled to 0-5 DEG C and carries out first
Secondary suction filtration, filter cake are beaten with polar solvent, are filtered to obtain L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt for the second time；
5) prepared by D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl) methyl acetate hydrochloride：By L- obtained by step 4)
(+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt is added to the water, and is slowly added to sodium bicarbonate, and stirring to bubble-free adds after generating
Enter organic solvent to extract for the first time, stirring, stratification, takes organic layer, water layer continues to be extracted with second of organic solvent, organic
It is laminated simultaneously to dry, it is evaporated under reduced pressure to dry；Will after distillation resulting grease be added 3) -2 ethyl ester of gained p-methyl benzenesulfonic acid thiophene,
Ethyl acetate, sodium bicarbonate are warming up to reflux, keep the temperature 45-55h, are cooled to room temperature, add water and stir and carry out first time washing, quiet
Layering is set, organic layer, which adds second of water progress, to be washed, and dry, filtering, filtrate added drop-wise hydrochloric acid analysis of material is cooled to 0-5 DEG C, it filters,
Filter cake ethyl acetate and methanol mixed solution purification, obtain product D- (+)-α-(2 thiophene ethyl amine base)-α-(2- chlorphenyl)
Methyl acetate hydrochloride.
2. the method according to claim 1, wherein solvent described in step 1) is chloroform, methylene chloride, tetrachloro
Change one of carbon, tetrahydrofuran, 2- methyltetrahydrofuran, ether.
3. the method according to claim 1, wherein thiophene, phenyltrimethyl-ammonium tribromide, solvent in step 1)
Mass ratio be 1.0:2.3:3.0~1.0:3.6:10.0, preferentially select mass ratio for 1.0:2.3:2.0~1.0:2.8:4.0.
4. the method according to claim 1, wherein the mass ratio of water described in step 1) and solvent is 0.8:
1.0~10.0:1.0.
5. the method according to claim 1, wherein extracting the quality of the water of solvent for use and addition in step 1)
Than being 0.5:1.0~10.0:1.0.
6. the method according to claim 1, wherein step 1) further includes recycling phenyltrimethyl-ammonium tribromide
Step, the step are, into extraction gained water layer, hydrobromic acid to be added, is added dropwise 0-20 DEG C of temperature of dioxygen water management, generates orange red
Color solid filters to obtain phenyltrimethyl-ammonium tribromide.
7. the method according to claim 1, wherein the solvent is tetrahydrofuran or 2- methyl in step 2)
Tetrahydrofuran.
8. the method according to claim 1, wherein in step 2), the zinc powder and the resulting 2- bromine of step 1)
The molar ratio of thiophene is 1.0:1.0~1.0:3.0, preferentially select molar ratio for 1.0:1.0~1.0:1.5；
The mass ratio 2.0 of the solvent and zinc powder:1.0~10.0:1.0；
In the ethylene oxide and the mixed solution of this step aforementioned solvents, ethylene oxide and this step 2- bromothiophene above-mentioned rub
You are than being 1.05:1.0~3.0:1.0, preferentially select molar ratio for 1.05:1.0~2.0:1.0.
9. the method according to claim 1, wherein further including that sodium sulphate is added after the washing of step 2) organic layer
Or the step that magnesium sulfate is dry.
10. the method according to claim 1, wherein the step 3) organic solvent be methylene chloride, chloroform,
One of toluene, 2- methyltetrahydrofuran.
11. the method according to claim 1, wherein 2- thiophene obtained by PTSC described in step 3) and step 2)
The molar ratio of ethyl alcohol is 1.05:1.0~5.0:1.0, preferentially select molar ratio for 1.05:1.0~1.5:1.0；
The mass ratio of the organic solvent and PTSC are 1.5:1.0~5.0:1.0；
The mass percent concentration of the sodium hydroxide solution is 10~40%, the hydrogen-oxygen in the sodium hydroxide solution of the dropwise addition
Changing 2- thiophene ethanol molar ratio obtained by sodium and step 2) is 1.5:1.0~3.0:1.0.
12. the method according to claim 1, wherein the step 4) solvent is isopropanol, acetone, butanone, first
One of base butanone.
13. the method according to claim 1, wherein the body of L- (+) described in step 4)-tartaric acid and solvent
Product is than being 1.0:5.0~1.0:20.0；
The molar ratio of the Chloro-O-Phenyl glycine methyl ester and L- (+)-tartaric acid is 1.0:1.0~1.0:5.0, preferential selection rubs
You are than being 1.0:1.0~1.0:2.0.
14. the method according to claim 1, wherein further including filter after the step 4) first time filters
The step of liquid recycling design.
15. the method according to claim 1, wherein the step 5) organic solvent is methylene chloride, two chloroethenes
Alkane, chloroform, ethyl acetate, isopropyl acetate, one of toluene.
16. the method according to claim 1, wherein the step 5) water and the adjacent chlorobenzene of the L- (+)-of addition are sweet
The mass ratio of propylhomoserin methyl esters L-TARTARIC ACID salt is 3.0:1.0~10.0:1.0；
It is added obtained by the sodium bicarbonate in the mixed liquor of L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt and water and step 4)
L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt molar ratio is 2.5:1.0~4.0:1.0；
It the organic solvent and is wherein added in L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt when extracting for the first time
The mass ratio of water is 1.0:1.0~1.0:5.0；
It second organic solvent when extracting and is wherein added in L- (+)-O-chlorobenzene glycine methyl ester L-TARTARIC ACID salt
The mass ratio of water is 0.4:1.0~5.0:1.0；
The mass ratio of the grease and the sodium bicarbonate being wherein added is 1.0:1.2~1.0:2.0；
The grease is 1.0 with the ethyl acetate mass ratio being wherein added:4.0~1.0:10.0；
The first time washing water is 0.8 with the ethyl acetate mass ratio being wherein added in grease:1.0~5.0:1.0；
Second of washing water is 0.5 with the ethyl acetate mass ratio being wherein added in grease:1.0~5.0:1.0.
17. the method according to claim 1, wherein further including that water layer returns after described second of step 5) extracts
The step of receiving tartaric acid, the step are that hydrochloric acid is added into water layer to pH in calcium chloride is added after acidity, generate precipitating, stir
Cooling crystallization is mixed, calcium tartrate is filtered to obtain, the solvent of solvable tartaric acid is stirred together with calcium tartrate, sulfuric acid is added dropwise to pH=
1~2, heating cooling filtering, filtrate is distilled to thick shape, and cooling filters and dries to obtain tartaric acid.
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|---|---|---|---|---|
| CN110229069A (en) * | 2019-07-16 | 2019-09-13 | 重庆医药高等专科学校 | The recoverying and utilizing method of trimethylphenyl tribromide ammonium in preparation method and the naproxen production of trimethylphenyl tribromide ammonium |
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