CN1562940A - New technique for preparing alpha halogenate acid in class of optical purity - Google Patents
New technique for preparing alpha halogenate acid in class of optical purity Download PDFInfo
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Abstract
This invention relates alpha-halogenated acid (R-CHXOOR) prepn. using low cost raw material of metals complex of tartaric acid or additives thereof; using splitting agent with ratio of 0.5:1 to 2.0:1 (product to agent), and 1:1 to 1:2.0 (metal complex to agent). They are mixed in solvent and violent stirring at temp. of 10 deg.C-50 deg.C, then compounding matter is separated. Said matter is then dissociated is acid water to obtain a crude optical active alpha-halogenated acid. Final product having optical pureness of 95% ee is obtd. by recrystallization or being dissociated in acid water after being salt with amine. Mother liquor and filter cake from up steps are mixed and then proceeding splitting procedure. Above-mentioned steps can operated for several times. Splitting agent and divalent metal compounds can be recovery and reused. The advantages are: no waste liquid and commercialization can be realized easily.
Description
Technical field
The invention belongs to the organic synthesis field, specifically is to utilize to cooperate Split Method, uses a kind of configuration resolving agent to obtain a kind of optical purity alpha-halogen acid (R-CHXCOOH) of configuration.Chemical kinetics having taken place simultaneously split and to make another configuration alpha-halogen acid that racemization take place in split process, do not needed to carry out racemization again and handle, makes the resolution yield can be greater than 50% (in raceme).
Background technology
Alpha-halogen acid (R-CHXCOOH) is a kind of important intermediate, being widely used in a plurality of fields such as medicine, agricultural chemicals and chemical industry, is the active intermediate that is used to prepare multiple medicine such as thiazole compound with antiulcer action and agricultural chemicals as alpha-brominated o-chlorobenzene acetic acid.So the application of optical purity alpha-halogen acid has broad prospects.Especially can be applied to the preparation of multiple chiral drug with the alpha-brominated o-chlorobenzene acetic acid of optical purity, make it have huge exploitation and be worth.Its preparation method has caused people's attention in recent years.At present, the report of the alpha-brominated o-chlorobenzene acetic acid of relevant preparation optical activity only is a method for splitting, (JP 2,000 34 as Japanese Patent, 256), it is used chirality fragrance methylamine and splits alpha-halogen virtue acetate as resolving agent, its optical purity can reach 96%, but yield only is 22.25%, and resolving agent costs an arm and a leg.(Chem.Eur.J.1998 such as Andras Mravik, 4,1621) reported and utilized optical purity O that the metal complex of O '-two sweet-smelling formacyl tartrate (DBTA) splits alpha-halogen lipid acid under the condition of alcohols, carboxylic acid compound coexistence as resolving agent; Its resolution yield can reach 17%-43%, but optical purity lower (11%ee-60%ee), and be only applicable to minority alpha-halogen fatty acid compound, there is not actual application value.
Summary of the invention
The invention provides the new preparation process of a kind of optical purity alpha-halogen acid; adopt the tartrate and the derivative O thereof of a kind of configuration cheap and easy to get first; O '-two sweet-smelling formacyl tartrate; with venus crystals, alpha-halogen acid in solvent; form title complex under 10-50 ℃ of following vigorous stirring, split and obtain optically active alpha-halogen acid, the alpha-halogen that is not split acid can be recycled; the fractionation that circulates again makes the resolution yield can be greater than 50%.
The present invention utilizes the cooperation Split Method, adopts a kind of tartrate of configuration or tartaric acid derivatives that it is split, and presses resolving agent: alpha-halogen acid (mol ratio)=0.5: 1-2.0: 1; Resolving agent: bivalent metallic compound (mol ratio)=1: 1-1: 2 mixed is in solvent, in 10-50 ℃ of vigorous stirring, separate out title complex, use acid hydrolysis from this title complex this title complex, obtain the certain optically active alpha-halogen acid crude of having of a kind of configuration, through recrystallization, filter, recrystallization mother liquor concentrates and obtains the alpha-halogen acid of optical purity greater than 95%ee; The alpha-halogen acidleach cake that reclaims the alpha-halogen acid that obtains and above-mentioned recrystallization gained from the above-mentioned mother liquor of removing behind the title complex merges, and need not carry out racemization, just can split, and can obtain the optical purity alpha-halogen acid with a kind of configuration.Also above-mentioned alpha-halogen acid crude and amine salify can be used again acid hydrolysis from, obtain of the alpha-halogen acid of a kind of optical purity of configuration greater than 96%ee.Because above-mentioned split process related to the chemical kinetics fractionation, the alpha-halogen acid of recovery does not need to carry out the racemization fractionation that just can circulate again, so can be greater than 50% with a kind of resolution yield of isomer.
This method for splitting can be used for alpha-halogen acid (R-CHXCOOH):
X is fluorine, chlorine, bromine or iodine.
R is C
1-C
10Alkyl,
Wherein: R
1, R
2Be H, F, Cl, Br, I or NO
2Fractionation;
The resolving agent that this method for splitting uses can be the optically pure tartrate and the derivative thereof of arbitrary configuration:
The sweet-smelling formacyl that R=H or any position replace is preferably optical purity D-O, O '-dibenzoyl wine
Stone acid and L-O, O '-dibenzoyl tartaric acid.
Recrystallization is above-mentioned in this method for splitting has the used recrystallization solvent of certain optically active alpha-halogen acid crude and is: mixed systems such as benzene and substituted benzene series, alkane-ester, naphthenic hydrocarbon-ester, sherwood oil-acetone;
Ester is that acid has certain solubility lower aliphatic ester to alpha-halogen for methyl acetate, ethyl acetate, propyl acetate, butylacetate etc. in the above-mentioned recrystallization solvent mixed system.Be preferably petroleum ether-ethyl acetate.
Have the used aminated compounds of certain optically active alpha-halogen acid crude salt-forming reaction and be with above-mentioned in this method for splitting:
Chiral amine compound: D or mould amine of L-chlorine and aminomethylation derivative thereof
Non chiral amine compound: RNH
2, R
1NHR
2
Wherein, R can be C
1-C
15Alkyl, phenyl, benzyl or styroyl;
R
1And R
2Can be C
1-C
15Alkyl, C
3-C
8Cycloalkyl, phenyl, benzyl or styroyl;
Wherein, R
1=R
2Or R
1≠ R
2(R
1, R
2Can arbitrary combination).Be preferably aniline.
Above-mentioned and amine are reacted into salt solvent can be: ester class (manthanoate, acetic ester, propionic ester etc.), alcohols (methyl alcohol, ethanol, propyl alcohol etc.), ketone (acetone, butanone etc.), toluene, methylene dichloride, acetonitrile and wherein above two or more mixed solvent.
The bivalent metallic compound that this method for splitting uses can for: calcium oxide, calcium hydroxide, zinc acetate, ventilation breather, venus crystals etc. are preferably venus crystals.
The recycling step of resolving agent of the present invention is: add among the 10%HCl splitting the fine ground gradation of gained title complex, vigorous stirring is fully dissociated title complex, and resolving agent is separated out from reaction solution, filters, and the resolving agent that obtains can recycle once more.
The recycling step of venus crystals of the present invention is: gained acid waste liquid after reclaiming raw material is regulated the pH value to there being a large amount of blue solids to separate out with NaOH, filter, in filter cake, add acetic acid solution and be stirred to dissolving, leave standstill, venus crystals is separated out, filter, recovery obtains venus crystals and can recycle once more, and the acetate raffinate can be used for the recovery of venus crystals repeatedly.
The invention has the advantages that: technology is simple, raw material is easy to get, and resolution yield can be greater than 50%.Resolving agent tartrate and derivative thereof that this split process is used are cheap and easy to get, and can obtain fine recovery, recycle; Because this fractionation relates to chemical kinetics and splits, reclaim the alpha-halogen acid that obtains the mother liquor after removing title complex, do not need to carry out again racemization, can split once more, make the resolution yield can be greater than 50%; The venus crystals that uses in the fractionation can reclaim preferably, and the acetate waste liquid behind the recovery venus crystals can be used for the recovery of venus crystals once more, recycles, and has avoided discharging of waste liquid, has reduced preparation cost and the protection that has realized environment; Help realizing industrialized production.Therefore, we can say, the invention solves the difficult problem of the inapplicable industrialized production of prior art.
Embodiment:
Be embodiments of the invention below.
Embodiment one:
With 45.12 gram D-DBTAH
2O, the alpha-brominated o-chlorobenzene acetic acid of 30.0 grams is dissolved in 300 milliliters of acetonitriles, adds 48 and restrains venus crystalss, and stirring at room is added 150 milliliters of acetonitriles to separating out title complex, continues to stir 5 days, filters, and filter cake washs with minor amounts of acetonitrile, and oven dry gets 117 gram title complexs.This title complex is fine ground, with 1200 milliliters of 10%HCl hydrolysis, filter D-DBTAH
2The O crude product is again at this D-DBTAH
2Added 100 milliliters of toluene vigorous stirring in the O crude product 15 minutes, filter the pure product D-DBTAH of 38 grams
2O (rate of recovery 84.2%).Hydrochloric acid filtrate is extracted 3 times with 100 milliliters of ethyl acetate extraction, and extracting solution and above-mentioned toluene layer merge, use saturated NaCl solution washing 2 times again, anhydrous sodium sulfate drying removes by filter sodium sulfate, evaporate to dryness gets (+)-alpha-brominated o-chlorobenzene acetic acid crude product 28.5 grams, and optical purity is 60.3%ee.Be somebody's turn to do (+)-alpha-brominated o-chlorobenzene acetic acid crude product petroleum ether-ethyl acetate recrystallization, filter, recrystallization mother liquor concentrates and obtains 4.95 gram (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 15%, and optical purity is 97.0%ee.
Acetonitrile is removed in resulting mother liquor underpressure distillation after will removing by filter title complex, add the residual acid solution after previous step is extracted product, stirred 1 hour, with 100 milliliters of ethyl acetate extraction, extract the extracting solution anhydrous sodium sulfate drying No. 3 times, remove by filter sodium sulfate, evaporate to dryness, the resulting filter cake merging of residue and recrystallization obtains the alpha-brominated o-chlorobenzene acetic acid of about 25 grams altogether, carries out next step circulation and splits.
Under ice bath stirs, in the aqueous solution after reclaiming alpha-brominated o-chlorobenzene acetic acid and resolving agent, add solid NaOH to there being a large amount of blue solids to produce, leave standstill, filter, obtain Cu (OH)
2Wet product add 480 milliliters of 40%HAc and are stirred to dissolving in these wet product, stirring at room 1 hour, and standing over night is filtered, and must contain 460 milliliters of the filtrates (being used for the recovery of next venus crystals) of acetate, the air-dry 40.56 gram venus crystalss that obtain of filter cake.
Embodiment two:
In embodiment one, reclaim in the alpha-brominated o-chlorobenzene acetic acid of gained, add the 37.6 gram D-DBTAH that reclaim
2O, 40 gram venus crystals and 375 milliliters of acetonitriles of recovery are stirred to after the dissolving and separate out title complex, and vigorous stirring is 5 days again, filters, and filter cake washs with minor amounts of acetonitrile, oven dry.This title complex is fine ground, dissociate with 800 milliliters of 10%HCl, filter D-DBTAH
2The O crude product is again at this D-DBTAH
2Add 100 milliliters of toluene vigorous stirring in the O crude product and filtered in 15 minutes, get the pure product D-DBTAH of 28.59 grams
2O (rate of recovery 76.3%).Hydrochloric acid filtrate is with 100 milliliters of ethyl acetate extraction, extract 3 times, extracting solution and above-mentioned toluene layer merge, use saturated NaCl solution washing 2 times again, anhydrous sodium sulfate drying, remove by filter sodium sulfate, evaporate to dryness obtains (+)-alpha-brominated o-chlorobenzene acetic acid 13.5 grams, optical purity is 86.5%ee, be somebody's turn to do (+)-alpha-brominated o-chlorobenzene acetic acid crude product petroleum ether-ethyl acetate recrystallization, filter, recrystallization mother liquor concentrates and obtains 8.136 gram (+)-alpha-brominated o-chlorobenzene acetic acid, yield is 26%, and optical purity is 95.5%ee.
Acetonitrile is removed in resulting mother liquor underpressure distillation after will removing by filter title complex, add the residual acid solution after previous step is extracted product, stirred 1 hour, with 100 milliliters ethyl acetate extraction, extract 3 times, the extracting solution anhydrous sodium sulfate drying removes by filter sodium sulfate, evaporate to dryness, the resulting filter cake merging of residue and recrystallization obtain alpha-brominated o-chlorobenzene acetic acid 30 gram (warps
1HMNR analyzes, wherein: the alpha-brominated o-chlorobenzene acetic acid of 17 grams, 13 gram D-DBTAH
2O), carrying out next step circulation splits.
Under ice bath stirs, in the aqueous solution after reclaiming alpha-brominated o-chlorobenzene acetic acid and resolving agent, add solid NaOH to there being a large amount of blue solids to produce, leave standstill, filter, obtain Cu (OH)
2Wet product add 460 milliliters of the acetic acid filtrate described in the embodiment one in these wet product, stirring at room 1 hour, and standing over night is filtered, and must contain 450 milliliters of the filtrates (being used for the recovery of next venus crystals) of acetate, the air-dry 28.8 gram venus crystalss that obtain of filter cake.
Embodiment three:
In embodiment two, reclaim in the alpha-brominated o-chlorobenzene acetic acid of gained, add the 10 gram D-DBTAH that reclaim
2O, 27.2 gram venus crystals and 300 milliliters of acetonitriles of recovery are stirred to after the dissolving and separate out title complex, vigorous stirring is 5 days again, filters, filter cake washs with minor amounts of acetonitrile, dry 31 gram title complexs, this title complex is fine ground, with 350 milliliters of 10%HCl filter D-DBTAH
2The O crude product is again at this D-DBTAH
2Added 50 milliliters of toluene vigorous stirring in the O crude product 15 minutes, filter the pure product D-DBTAH of 13.5 grams
2O.Hydrochloric acid filtrate is with 50 milliliters of ethyl acetate extraction, extract 3 times, extracting solution and above-mentioned toluene layer merge, use saturated NaCl solution washing 2 times again, anhydrous sodium sulfate drying, remove by filter sodium sulfate, evaporate to dryness obtains 2.5 gram (+)-alpha-brominated o-chlorobenzene acetic acid, optical purity is 81.2%ee, be somebody's turn to do (+)-alpha-brominated o-chlorobenzene acetic acid crude product petroleum ether-ethyl acetate recrystallization, filter, recrystallization mother liquor concentrates and obtains 2.02 gram (+)-alpha-brominated o-chlorobenzene acetic acid, yield is 6%, and optical purity is 96.2%ee.
Acetonitrile is removed in mother liquid obtained underpressure distillation after will removing by filter title complex, add the residual acid solution after previous step is extracted product, stirred 1 hour, with 100 milliliters of ethyl acetate extraction, extract 3 times, the extracting solution anhydrous sodium sulfate drying removes by filter sodium sulfate, and evaporate to dryness obtains alpha-brominated o-chlorobenzene acetic acid 26.25 gram (warps
1HMNR analyzes, wherein: the alpha-brominated o-chlorobenzene acetic acid of 10.48 grams, 15.77 gram D-DBTAH
2O), optical purity is 1.25%ee.
Under ice bath stirs, in the aqueous solution after reclaiming alpha-brominated o-chlorobenzene acetic acid and resolving agent, add solid NaOH to there being a large amount of blue solids to produce, leave standstill, filter, obtain Cu (OH)
2Wet product add 250 milliliters and the 20 milliliters Glacial acetic acid of acetic acid filtrate described in the embodiment two in these wet product, stirring at room 1 hour, and standing over night, filtration must contain 240 milliliters of the filtrates of acetate, and filter cake is air-dry to be obtained 20.15 and restrains venus crystalss.
Merge the alpha-brominated o-chlorobenzene acetic acid of the optical purity of gained among the embodiment one, two and three greater than 95%ee, obtain product 15.1 grams altogether, total recovery is 50.3%.
Embodiment four:
With 45.12 gram D-DBTAH
2O, the alpha-brominated o-chlorobenzene acetic acid of 30 grams is dissolved in 300 milliliters of acetonitriles, adds 48 gram venus crystalss, and stirring is 2 days under 30 ℃, separates out solid, adds 150 milliliters of acetonitriles again, continues to stir 5 days again, filters, and filter cake washs with minor amounts of acetonitrile, dries, and gets 91 gram title complexs.This title complex is fine ground, with 1000 milliliters of 10%HCl hydrolysis, filter and obtain D-DBTAH
2The O crude product is again at this D-DBTAH
2Added 100 milliliters of toluene vigorous stirring in the O crude product 15 minutes, filter the pure product D-DBTAH of 37.25 grams
2O (rate of recovery 84.2%).Hydrochloric acid filtrate is with 100 milliliters of ethyl acetate extraction, extract 3 times, extracting solution and above-mentioned toluene layer merge, and use saturated NaCl solution washing 2 times again, anhydrous sodium sulfate drying, remove by filter sodium sulfate, evaporate to dryness gets 28 gram (+)-alpha-brominated o-chlorobenzene acetic acid crude products, is somebody's turn to do (+)-alpha-brominated o-chlorobenzene acetic acid crude product petroleum ether-ethyl acetate recrystallization, remove by filter DBTA, recrystallization mother liquor concentrates and obtains 24 gram (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 80%, and optical purity is 79.4%ee.
Embodiment five:
With 7.5 gram D-DBTAH
2O, 5 grams, alpha-brominated o-chlorobenzene acetic acid is dissolved in 75 milliliters of acetonitriles, under 40 ℃ of stirrings, add 16 gram venus crystalss, insulated and stirred is to separating out solid, and insulated and stirred is 3 days again, filters, filter cake washs with minor amounts of acetonitrile, oven dry gets 17.7 gram title complexs, and this title complex is fine ground, with 180 milliliters of 10%HCl hydrolysis, filter D-DBTAH
2The O crude product is again at this D-DBTAH
2Add 50 milliliters of toluene vigorous stirring in the O crude product and filtered in 15 minutes, get the pure product D-DBTAH of 6.68 grams
2O (rate of recovery 87.6%).Hydrochloric acid filtrate is with 50 milliliters of ethyl acetate extraction, extract 3 times, extracting solution and above-mentioned toluene layer merge, and use saturated NaCl solution washing 2 times again, anhydrous sodium sulfate drying, remove by filter sodium sulfate, evaporate to dryness gets 4.43 gram (+)-alpha-brominated o-chlorobenzene acetic acid crude products, is somebody's turn to do (+)-alpha-brominated o-chlorobenzene acetic acid crude product petroleum ether-ethyl acetate recrystallization, filter, recrystallization mother liquor concentrates and obtains 3.7 gram (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 74%, and optical purity is 90.2%ee.
Embodiment six:
With 7.5 gram L-DBTAH
2O, the alpha-brominated o-chlorobenzene acetic acid of 5 grams is dissolved in 75 milliliters of acetonitriles, adds 16 gram venus crystalss under 40 ℃ of stirrings, insulated and stirred, separate out solid after 2 days, insulated and stirred is 3 days again, filters, filter cake washs with minor amounts of acetonitrile, oven dry gets 17.7 gram title complexs, and this title complex is fine ground, with 180 milliliters of 10%HCl hydrolysis, filter L-DBTAH
2The O crude product is again at this L-DBTAH
2Add in the O crude product 50 milliliters of toluene vigorous stirring filtered in 15 minutes the pure product L-DBTAH of 6.68 grams
2O (rate of recovery 89.0%).Hydrochloric acid filtrate is with 50 milliliters of ethyl acetate extraction, extract 3 times, extracting solution and above-mentioned toluene layer merge, and use saturated NaCl solution washing 2 times again, anhydrous sodium sulfate drying, remove by filter sodium sulfate, evaporate to dryness gets 4.33 gram (-)-alpha-brominated o-chlorobenzene acetic acid crude products, is somebody's turn to do (-)-alpha-brominated o-chlorobenzene acetic acid crude product petroleum ether-ethyl acetate recrystallization, filter, recrystallization mother liquor concentrates and obtains 3.5 gram (-)-alpha-brominated o-chlorobenzene acetic acid, and yield is 70%, and optical purity is 91.2%ee.
Embodiment seven:
Get 125 milligrams of embodiment five gained (+)-alpha-brominated o-chlorobenzene acetic acid crude product, be dissolved in 0.8 milliliter of ethyl acetate, add 64 milligrams of Di-n-Butyl Amines, stir, separate out white solid, filter 95 milligrams of salt, this salt is dissociated with 10 milliliters of 10%HCl, with 5 milliliters of ethyl acetate extraction, extract the extracting solution anhydrous sodium sulfate drying No. 3 times, remove by filter sodium sulfate, evaporate to dryness gets 62.5 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 50%, and optical purity is 94.17%ee.
Embodiment eight:
Get 125 milligrams of embodiment five gained (+)-alpha-brominated o-chlorobenzene acetic acid crude product, be dissolved in 0.8 milliliter of Virahol, add 64 milligrams of Di-n-Butyl Amines, stir, separate out white solid, filter 50 milligrams of salt, this salt is dissociated with 10 milliliters of 10%HCl, with 5 milliliters of ethyl acetate extraction, extract the extracting solution anhydrous sodium sulfate drying No. 3 times, remove by filter sodium sulfate, evaporate to dryness gets 33.07 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 26.4%, and optical purity is 97.17%ee.
Embodiment nine:
Get 125 milligrams of embodiment five gained (+)-alpha-brominated o-chlorobenzene acetic acid crude product, be dissolved in 0.8 milliliter of ethanol, add 47 milligrams of aniline, stir, separate out white solid, filter 80 milligrams of salt, this salt is dissociated with 10 milliliters of 10%HCl, with 5 milliliters of ethyl acetate extraction, extract the extracting solution anhydrous sodium sulfate drying No. 3 times, remove by filter sodium sulfate, evaporate to dryness gets 58.1 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 46.5%, and optical purity is 97.01%ee.
Embodiment ten:
Get 125 milligrams of embodiment five gained (+)-alpha-brominated o-chlorobenzene acetic acid crude product, be dissolved in 0.8 milliliter of ethyl acetate, add 47 milligrams of aniline, stir, separate out white solid, filter 105 milligrams of salt, this salt is dissociated with 10 milliliters of 10%HCl, with 5 milliliters of ethyl acetate extraction, extract the extracting solution anhydrous sodium sulfate drying No. 3 times, remove by filter sodium sulfate, evaporate to dryness gets 73.2 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 61.04%, and optical purity is 96.07%ee.
Embodiment 11:
Get 500 milligrams of embodiment five gained (+)-alpha-brominated o-chlorobenzene acetic acid crude product, add 425 milligrams of mould amine of D-chlorine, add 3 milliliters of ethanol, stir, separate out white solid, filter 600 milligrams of salt, this salt is dissociated with 10 milliliters of 10%HCl, with 8 milliliters of ethyl acetate extraction, extract the extracting solution anhydrous sodium sulfate drying No. 3 times, remove by filter sodium sulfate, evaporate to dryness gets 300 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 60.5%, and optical purity is 98.0%ee.
Embodiment 12:
Get 500 milligrams of embodiment five gained (+)-alpha-brominated o-chlorobenzene acetic acid crude product, add 425 milligrams of mould amine of D-chlorine, add 3 milliliters of ethanol, stir, separate out white solid, heating for dissolving is reduced to room temperature, separate out white solid, filter 450 milligrams of salt, this salt is dissociated with 10 milliliters of 10%HCl, with 8 milliliters of ethyl acetate extraction, extract 3 times, the extracting solution anhydrous sodium sulfate drying removes by filter sodium sulfate, and evaporate to dryness gets 231 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, yield is 46.2%, and optical purity is 99.0%ee ([α]
D 28=+107 ° (C=1.026, ethanol); Fusing point=59-61 ℃).
Embodiment 13:
Get 500 milligrams of embodiment six gained (-)-alpha-brominated o-chlorobenzene acetic acid crude product, add 425 milligrams of mould amine of L-chlorine, add 3 milliliters of ethanol, stir, separate out white solid, heating for dissolving is reduced to room temperature, separate out white solid, filter 450 milligrams of salt, this salt is dissociated with 15 milliliters of 10%HCl, with 8 milliliters of ethyl acetate extraction, extract 3 times, the extracting solution anhydrous sodium sulfate drying removes by filter sodium sulfate, and evaporate to dryness gets 225 milligrams (-)-alpha-brominated o-chlorobenzene acetic acid, yield is 45.0%, and optical purity is 99.1%ee ([α]
D 28=-109 ° (C=1.030, ethanol)).
Embodiment 14:
Get 500 milligrams of embodiment five gained (+)-alpha-brominated o-chlorobenzene acetic acid crude product, add 425 milligrams of mould amine of D-chlorine, add 3 milliliter of 75% aqueous ethanolic solution, stir, separate out white solid, heating for dissolving is reduced to room temperature, separate out white solid, filter 361 milligrams of salt, this salt is dissociated with 15 milliliters of 10%HCl, with 8 milliliters of ethyl acetate extraction, extract 3 times, the extracting solution anhydrous sodium sulfate drying removes by filter sodium sulfate, and evaporate to dryness gets 195 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, yield is 39.0%, and optical purity is 96.8%ee.
Embodiment 15:
Get 500 milligrams of embodiment five gained (+)-alpha-brominated o-chlorobenzene acetic acid crude product, with 3 ml n-hexanes-butylacetate heating for dissolving, freezing, separate out small amount of solid, filter, the evaporate to dryness mother liquor gets 348 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, yield is 69.6%, and optical purity is 95.9%ee.
Embodiment 16:
Get 500 milligrams of embodiment five gained (+)-alpha-brominated o-chlorobenzene acetic acid crude product, with 3 milliliters of toluene heating for dissolving, freezing, separate out small amount of solid, filter, the evaporate to dryness mother liquor gets 225 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, yield is 45%, and optical purity is 93.6%ee.
Embodiment 17:
With 150 milligrams of D-tartrate., 250 milligrams of alpha-brominated o-chlorobenzene acetic acid are dissolved in 1 milliliter of acetone and the 0.3 ml water mixed system, under 30 ℃ of stirrings, add 200 milligrams of venus crystalss, insulated and stirred is to separating out solid, and insulated and stirred is 1 day again, filters, get 250 milligrams of solids, this solid with 20 milliliters of 10%HCl hydrolysis, is filtered, and mother liquor is with 8 milliliters of ethyl acetate extraction, extract 3 times, the extracting solution anhydrous sodium sulfate drying removes by filter sodium sulfate, and evaporate to dryness gets 65 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, yield is 26%, and optical purity is 10.2%ee.
Embodiment 18:
With 376 milligrams of D-DBTAH
2O, 250 milligrams of alpha-brominated o-chlorobenzene acetic acid are dissolved in 2 milliliters of ethanol and the 1 ml water mixed system, under 30 ℃ of stirrings, add 200 milligrams of venus crystalss, insulated and stirred is to separating out solid, and insulated and stirred is 1 day again, filters, get 425 milligrams of solids, this solid with 20 milliliters of 10%HCl hydrolysis, is filtered, and mother liquor is with 10 milliliters of ethyl acetate extraction, extract 3 times, the extracting solution anhydrous sodium sulfate drying removes by filter sodium sulfate, and evaporate to dryness gets 100 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, yield is 40%, and optical purity is 12.2%ee.
Embodiment 19:
With 601.6 milligrams of D-DBTAH
2O, 500 milligrams of alpha-brominated o-chlorobenzene acetic acid are dissolved in 2.5 milliliters of acetonitriles, add 320 milligrams of venus crystalss under 30 ℃ of stirrings, insulated and stirred is to separating out solid, and insulated and stirred is 1 day again, filters, get solid 1.02 grams, this solid with 20 milliliters of 10%HCl hydrolysis, is filtered, mother liquor extracts the extracting solution anhydrous sodium sulfate drying No. 3 times with 10 milliliters of ethyl acetate extraction, remove by filter sodium sulfate, evaporate to dryness gets 297 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 59.4%, and optical purity is 46.94%ee.
Embodiment 20:
With 564 milligrams of D-DBTAH
2O, 250 milligrams of alpha-brominated o-chlorobenzene acetic acid are dissolved in 2 milliliters of acetonitriles, add 200 milligrams of venus crystalss under 30 ℃ of stirrings, insulated and stirred is to separating out solid, and insulated and stirred is 1 day again, filters, get 900 milligrams of solids, this solid with 20 milliliters of 10%HCl hydrolysis, is filtered, mother liquor extracts the extracting solution anhydrous sodium sulfate drying No. 3 times with 10 milliliters of ethyl acetate extraction, remove by filter sodium sulfate, evaporate to dryness gets 136 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 55%, and optical purity is 35.6%ee.
Embodiment 21:
With 376 milligrams of D-DBTAH
2O, 500 milligrams of alpha-brominated o-chlorobenzene acetic acid are dissolved in 2.5 milliliters of acetonitriles, add 200 milligrams of venus crystalss under 30 ℃ of stirrings, insulated and stirred is to separating out solid, and insulated and stirred is 1 day again, filters, get 936 milligrams of solids, this solid with 20 milliliters of 10%HCl hydrolysis, is filtered, mother liquor extracts the extracting solution anhydrous sodium sulfate drying No. 3 times with 10 milliliters of ethyl acetate extraction, remove by filter sodium sulfate, evaporate to dryness gets 225 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 45%, and optical purity is 25.94%ee.
Embodiment 22:
With 376 milligrams of D-DBTAH
2O, 250 milligrams of alpha-brominated o-chlorobenzene acetic acid are dissolved in 2.5 milliliters of acetonitriles, add 200 milligrams of venus crystalss under 30 ℃ of stirrings, insulated and stirred is to separating out solid, and insulated and stirred is 4 days again, filters, get 705 milligrams of solids, this solid with 20 milliliters of 10%HCl hydrolysis, is filtered, mother liquor extracts the extracting solution anhydrous sodium sulfate drying No. 3 times with 10 milliliters of ethyl acetate extraction, remove by filter sodium sulfate, evaporate to dryness gets 104 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 41.8%, and optical purity is 88.2%ee.
Embodiment 23:
With 45.12 gram D-DBTAH
2O, the alpha-brominated 4-Chlorophenylacetic acid of 30 grams is dissolved in 300 milliliters of acetonitriles, adds 48 gram venus crystalss, stirring at room is to separating out solid, add 150 milliliters of acetonitriles, continue to stir 5 days, filter, filter cake washs with minor amounts of acetonitrile, oven dry gets 120 gram title complexs, and this title complex is fine ground, use 1200 milliliters of 10%HCl hydrolysis again, filter D-DBTAH
2The O crude product is again at this D-DBTAH
2Add 100 milliliters of toluene vigorous stirring in the O crude product and filtered in 15 minutes, get the pure product D-DBTAH of 39.5 grams
2O (rate of recovery 87.5%).Hydrochloric acid filtrate is with 100 milliliters of ethyl acetate extraction, extract 3 times, extracting solution and above-mentioned toluene layer merge, use saturated NaCl solution washing 2 times again, anhydrous sodium sulfate drying removes by filter sodium sulfate, and evaporate to dryness gets 24.5 gram (+)-alpha-brominated 4-Chlorophenylacetic acid crude products, yield is 82%, and optical purity is 75.2%ee.
Acetonitrile is removed in mother liquid obtained underpressure distillation after will removing by filter title complex, add the residual acid solution after previous step is extracted product, stirred 1 hour, with 100 milliliters of ethyl acetate extraction, extract 3 times, the extracting solution anhydrous sodium sulfate drying removes by filter sodium sulfate, and evaporate to dryness gets the alpha-brominated 4-Chlorophenylacetic acid (warp of 10.2 grams
1HMNR analyzes, wherein: the alpha-brominated 4-Chlorophenylacetic acid of 4.2 grams, 6.0 gram D-DBTAH
2O).
Embodiment 24:
With 37.6 gram D-DBTAH
2O, the alpha-brominated propionic acid of 15.3 grams is dissolved in 200 milliliters of acetonitriles, adds 40 gram venus crystalss, stirring at room 2 days is separated out solid, adds 190 milliliters of acetonitriles, continue to stir 5 days, filter, filter cake washs with minor amounts of acetonitrile, oven dry, get 51 gram title complexs, this title complex is fine ground, use 600 milliliters of 10%HCl hydrolysis again, filter D-DBTAH
2The O crude product is again at this D-DBTAH
2Added 100 milliliters of toluene vigorous stirring in the O crude product 15 minutes, filter the pure product D-DBTAH of 33.5 grams
2O (rate of recovery 90.1%).Hydrochloric acid filtrate is extracted 3 times with 100 milliliters of ethyl acetate extraction, and extracting solution and above-mentioned toluene layer merge, use saturated NaCl solution washing 2 times again, anhydrous sodium sulfate drying removes by filter sodium sulfate, evaporate to dryness gets 8.3 gram (+)-alpha-brominated propionic acid crude products, and yield is 54%, and optical purity is 45%ee.
Acetonitrile is removed in mother liquid obtained underpressure distillation after will removing by filter title complex, adds the raffinate (acid) after previous step is extracted product, stirs 1 hour, with 100 milliliters of ethyl acetate extraction, extract the extracting solution anhydrous sodium sulfate drying No. 3 times, remove by filter sodium sulfate, evaporate to dryness gets the alpha-brominated propionic acid (warp of 9.8 grams
1HMNR analyzes, wherein: the alpha-brominated propionic acid of 4.5 grams, 5.3 gram D-DBTAH
2O).
Embodiment 25:
With 376 milligrams of D-DBTAH
2O, 205 milligrams of alpha-chloro propionic acid are dissolved in 3 milliliters of acetonitriles, add 400 milligrams of venus crystalss under 30 ℃ of stirrings, insulated and stirred is to separating out solid, and insulated and stirred is 4 days again, filters, get 435 milligrams of solids, this solid with 20 milliliters of 10%HCl hydrolysis, is filtered, mother liquor extracts the extracting solution anhydrous sodium sulfate drying No. 3 times with 10 milliliters of ethyl acetate extraction, remove by filter sodium sulfate, evaporate to dryness gets 123 milligrams (+)-alpha-chloro propionic acid, and yield is 60%, and optical purity is 35.2%ee.
Embodiment 26:
With 376 milligrams of D-DBTAH
2O, 250 milligrams of alpha-brominated o-chlorobenzene acetic acid are dissolved in 3 milliliters of acetonitriles, under 30 ℃ of stirrings, add 240 milligrams of ventilation breathers, insulated and stirred is to separating out solid, insulated and stirred is 4 days again, filter, 105 milligrams of solids, with this solid with 20 milliliters of 10%HCl hydrolysis, filter, mother liquor extracts the extracting solution anhydrous sodium sulfate drying No. 3 times with 10 milliliters of ethyl acetate extraction, remove by filter sodium sulfate, evaporate to dryness gets 30.3 milligrams (+)-alpha-brominated o-chlorobenzene acetic acid, and yield is 12.1%, and optical purity is 65.2%ee.
Embodiment 27:
With 188 milligrams of D-DBTAH
2O, 115 milligrams of alpha-brominated o-fluoro-acids are dissolved in 1.5 milliliters of acetonitriles, under 40 ℃ of stirrings, add 200 milligrams of venus crystalss, insulated and stirred is to separating out solid, insulated and stirred is 5 days again, filter, 325 milligrams of solids, with this solid with 20 milliliters of 10%HCl hydrolysis, filter, mother liquor extracts the extracting solution anhydrous sodium sulfate drying No. 3 times with 10 milliliters of ethyl acetate extraction, remove by filter sodium sulfate, evaporate to dryness gets 58.9 milligrams (+)-alpha-brominated o-fluoro-acid, and yield is 51.2%, and optical purity is 91.5%ee.
Claims (9)
1. the new preparation process of optical purity alpha-halogen acid (R-CHXCOOH) adopts a kind of tartrate of configuration or tartaric acid derivatives that it is split, and presses resolving agent: alpha-halogen acid (mol ratio)=0.5: 1-2.0: 1; Resolving agent: bivalent metallic compound (mol ratio)=1: 1-1: 2 mixed is in solvent, in 10-50 ℃ of following vigorous stirring, separate out title complex, with this title complex with acid hydrolysis from, obtain the certain optically active alpha-halogen acid crude of having of a kind of configuration, use acid dissociation again through recrystallization or with the amine salify again, obtain a kind of alpha-halogen acid of configuration, its optical purity is greater than 95%ee.The alpha-halogen acidleach cake that reclaims the alpha-halogen acid that obtains and above-mentioned recrystallization gained from the above-mentioned mother liquor of removing behind the title complex merges, and need not carry out racemization, splits again, can obtain the optical purity alpha-halogen acid with a kind of configuration.This process can repeat repeatedly, so the total recovery of optical purity alpha-halogen acid can be greater than 50% (in raceme).It is characterized in that, except that above-mentioned splitting step, also comprise the steps:
A. the hydrolytic process of above-mentioned title complex is: title complex is fine ground, and gradation adds among the 10%HCl, and vigorous stirring is fully dissociated title complex, and resolving agent is separated out, and filters the mother liquor ethyl acetate extraction;
B. this split process relates to the chemical kinetics fractionation, the acid of the described recovery mother liquor of step 1 gained alpha-halogen is raceme, need not to carry out again racemization, merge into raw material with the alpha-halogen acidleach cake of the described recrystallization gained of step 1, repeat to split, so circulation can obtain a kind of optical purity alpha-halogen acid of configuration;
C. in the above-mentioned recrystallization process, higher optically active alpha-halogen acid is stayed in the mother liquor, and impurity and the acid of raceme alpha-halogen are then preferentially separated out in recrystallization process.
2. as claims 1 described optical purity alpha-halogen acid new preparation process, it is characterized in that, described alpha-halogen acid: R-CHXCOOH, wherein, X is fluorine, chlorine, bromine or iodine.
R is C
1-C
10Alkyl,
Wherein: R
1, R
2Be H, F, Cl, Br, I or NO
2
3. as claims 1 described optical purity alpha-halogen acid new preparation process, it is characterized in that described resolving agent is the optically pure tartrate and the derivative thereof of arbitrary configuration:
The sweet-smelling formacyl that R=H or any position replace is preferably optical purity D-O, O '-dibenzoyl tartaric acid and L-O, O '-dibenzoyl tartaric acid.
4. as claims 1 described optical purity alpha-halogen acid new preparation process, it is characterized in that described bivalent metallic compound is: calcium oxide, calcium hydroxide, zinc acetate, ventilation breather, venus crystals etc. are preferably venus crystals.
5. as claims 1 described optical purity alpha-halogen acid new preparation process, it is characterized in that the used solvent of described split process is: acetonitrile, 25%-50% aqueous ethanolic solution, ethanol/acetone, ethanol/acetate equal solvent are preferably acetonitrile.
6. as claims 1 described optical purity alpha-halogen acid new preparation process, it is characterized in that described recrystallization solvent is: mixed systems such as benzene and substituted benzene series, alkane-ester, naphthenic hydrocarbon-ester, alkane-acetone, naphthenic hydrocarbon-acetone; Wherein, alkane, naphthenic hydrocarbon are normal hexane, sherwood oil, hexanaphthene etc., and ester is that acid has certain solubility lower aliphatic ester to alpha-halogen for methyl acetate, ethyl acetate, propyl acetate, butylacetate etc.; Be preferably petroleum ether-ethyl acetate.
7. as claims 1 described optical purity alpha-halogen acid new preparation process, it is characterized in that the described and aminated compounds amine salt-forming reaction is:
Chiral amine compound: D or mould amine of L-chlorine and aminomethylation derivative thereof
Non chiral amine compound: RNH
2, R
1NHR
2
Wherein, R is C
1-C
15Alkyl, phenyl, benzyl or styroyl;
R
1And R
2Be C
1-C
15Alkyl, C
3-C
8Cycloalkyl, phenyl, benzyl or styroyl; Wherein, R
1=R
2Or R
1≠ R
2(R
1, R
2Can arbitrary combination), be preferably aniline.
8. as claims 1 described optical purity alpha-halogen acid new preparation process, it is characterized in that, described and the solvent amine salt-forming reaction are: ester class (manthanoate, acetic ester, propionic ester, butyric ester etc.), alcohols (methyl alcohol, ethanol, propyl alcohol, Virahol, butanols etc.), ketone (acetone, butanone etc.), toluene, methylene dichloride, acetonitrile or wherein above two or more mixed solvent.
9. as claims 1 described optical purity alpha-halogen acid new preparation process, it is characterized in that the recycling step of described resolving agent and bivalent metallic compound:
D. the resolving agent that steps A is described to be separated out after dissociating is filtered, add toluene again in filter cake, vigorous stirring is filtered, and filter cake obtains the pure product of resolving agent with toluene wash, can be used for recycling;
E. remove and desolvate removing behind the title complex mother liquid obtained evaporate to dryness, residue dissociates under acidic conditions, with toluene or ethyl acetate extraction recovery part resolving agent, can be used for recycling again;
F. steps A and the acid raffinate liquid of E gained are regulated the pH value to there being a large amount of blue solids to separate out with NaOH, leave standstill filtration, filter cake leaves standstill with 30-40% acetic acid solution stirring and dissolving, and venus crystals is separated out, and filters, and the air-dry venus crystals that gets can be used for recycling; Mother liquor can be used for the recovery of venus crystals once more.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102344355A (en) * | 2011-08-25 | 2012-02-08 | 上海科利生物医药有限公司 | Method for preparing chiral (S)-2-propionic acid |
| CN102516002A (en) * | 2011-12-09 | 2012-06-27 | 中原工学院 | Preparation technology of optically pure alpha-hydroxy acid and derivatives of the optically pure alpha-hydroxy acid |
| CN112358398A (en) * | 2020-11-19 | 2021-02-12 | 山东新华制药股份有限公司 | Recovery preparation method of D- (+) -di-p-toluoyl tartaric acid |
-
2004
- 2004-03-25 CN CN 200410039895 patent/CN1274656C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102344355A (en) * | 2011-08-25 | 2012-02-08 | 上海科利生物医药有限公司 | Method for preparing chiral (S)-2-propionic acid |
| CN102344355B (en) * | 2011-08-25 | 2014-01-01 | 上海科利生物医药有限公司 | Method for preparing chiral (S)-2-propionic acid |
| CN102516002A (en) * | 2011-12-09 | 2012-06-27 | 中原工学院 | Preparation technology of optically pure alpha-hydroxy acid and derivatives of the optically pure alpha-hydroxy acid |
| CN112358398A (en) * | 2020-11-19 | 2021-02-12 | 山东新华制药股份有限公司 | Recovery preparation method of D- (+) -di-p-toluoyl tartaric acid |
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| Publication number | Publication date |
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