CN103420837A - Preparation method for chiral 4-chloro-3-hydroxybutyrate - Google Patents
Preparation method for chiral 4-chloro-3-hydroxybutyrate Download PDFInfo
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Abstract
The invention discloses a preparation method for chiral 4-chloro-3-hydroxybutyrate. The preparation method specifically comprises: adding chiral chloropropylene oxide, an alcohol, a catalyst into a high-pressure reaction vessel, introducing carbon monoxide, heating for a reaction, and obtaining chiral 4-chloro-3-hydroxybutyrate after the reaction. The preparation method has the advantages of being cheap and easily-available in raw materials, mild in reaction conditions, high in yield, low in cost, and the like. Compared with conventional synthetic methods for chiral 4-chloro-3-hydroxybutyrate, the preparation method employs a reaction with atom economical efficiency of 100%, is environment friendly, low in 'three wastes (waste gas, waste water and industrial residue) ' and applicable to industrial production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to a kind of preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester.
Background technology
4-chloro-3-hydroxybutanoic acid ester (4-chloro-3-hydroxybutanoate esters, CHBE) the extremely wide construction unit as a kind of purposes, owing to containing three multi-functional group (Cl at molecule,-OH,-COOR), can import the multi-medicament intermediate via the replacement(metathesis)reaction of chlorine, reduction reaction etc.Wherein, (R)-CHBE is the crucial chiral intermediate of synthetic L-BETAIN (L-carnitine), (R)-GABOB (GABOB) etc.(S)-CHBE is widely used in the reducing blood-fat statins---(Q.Ye among hydroxymethyl glutaryl CoA (HMG-CoA) reductase inhibitor, alkaloid Slagenins B and C and 4-hydroxyl yrrolidone synthetic, et al.Appl.Microbiol.Biotechnol., 2011,89,513-522; D.S.Karanewsky, et al.J.Med.Chem., 1990,33,2925-2956; B.Zhou, et al.J.Am.Chem.Soc., 1983,105,5925-5926.).Because chirality 4-chloro-3-hydroxybutanoic acid ester provides for pharmaceutical industry the shortcut for preparing various intermediates interested, numerous research institutions has launched cut-throat competition around the production method of exploitation chirality 4-chloro-3-hydroxybutanoic acid ester.At present, the method developed mainly contains (S.Bergeron, et al.Org.Process Res.Dev., 2006,10, the 661-665 such as chemical method, asymmetric catalytic hydrogenation or enzyme process; G..DeSantis, et al.J.Am.Chem.Soc., 2003,125,11476-11477.).
Defect (S.CHO, the et al.US 20060264652 such as it is starting raw material that chemical method adopts chiral epichlorohydrin, passes through the steps such as cyaniding open loop, nitrile hydrolysis, esterification, and hypertoxic sodium cyanide is used in existence, route is long, quantity of three wastes is large; Zhao Chengyu etc., Chinese patent CN 200480007780.7.).The chemical asymmetric catalytic hydrogenation method of 4-chloracetyl acetic ester (H.Mettler, et al.WO 2005049545) and enzyme process (are answered sweat outstanding person etc., Chinese patent CN 200910183017.4; Answer sweat outstanding person etc., WO 2010025607; He Chunmao etc., Chinese patent CN 200810036341.9; Sun Zhihao etc., Chinese patent ZL 200410091114.8.) be the research emphasis of synthesis of chiral 4-chloro-3-hydroxybutanoic acid ester, there are the problems such as the high pressure reactor of anti-strong acid that chiral catalyst is expensive, needs are special in the asymmetric catalytic hydrogenation method.Although enzyme process has reaction conditions gentleness, environmental friendliness, selectivity advantages of higher, but enzyme process is very high to the purity requirement of substrate, hydrogenase is through Derivative repeatedly, just can obtain having in the catalyzer of process efficiency and reaction process needing to add expensive coenzyme, is not suitable with the needs of suitability for industrialized production.Although especially it is worthy of note the domestic production that certain scale is arranged of raw material 4-chloracetyl acetic ester that asymmetric catalytic hydrogenation or enzyme process are required, purity still can not meet the demands.
Therefore, development cost chirality 4-chloro-3-hydroxyl ethyl butyrate new synthesis technology cheap, simple to operate, environmentally friendly, that be applicable to suitability for industrialized production is the focus that academia and industry member are paid close attention to always.In recent years, synthesize the successful experience of 3-hydroxy propionate new technology route by hydroesterification reaction based on oxyethane, the simultaneously development research due to the hydrolytic kinetic resolution of epoxy chloropropane has realized commercialization production basically, and the hydroesterification reaction by chiral epichlorohydrin prepares the first-selection that corresponding chirality 4-chloro-3-hydroxybutanoic acid ester becomes people.In fact, just reported that as far back as McClure in 1967 changing ammonium at glycidyl trimethylammonium chlorine (bromine, iodine) helps under catalysis, Co
2(CO)
8Hydroesterification reaction (the J.D.McClure of Epichlorohydrin, J.Org.Chem., 1967,32,3888-3894), but the condition of operation is harsher, and carbon monoxide pressure need to be more than 12.0MPa, the yield lower (11 ~ 53%) of resulting product 4-chloro-3-hydroxyl methyl-butyrate.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester, this preparation method's raw material is cheap and easy to get, reaction conditions is gentle, yield is high, cost is low, and environmentally friendly, is suitable for suitability for industrialized production.
For solving the problems of the technologies described above, technical scheme of the present invention is achieved in that
A kind of preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester, especially, add autoclave by chiral epichlorohydrin, alcohol, catalyzer, carries out reacting by heating after passing into carbon monoxide, the refining chirality-4-chloro-3-hydroxybutanoic acid ester that obtains after reaction finishes.
Preferably, in the preparation method of above-mentioned chirality 4-chloro-3-hydroxybutanoic acid ester, described catalyzer comprises metallic compound and the nitrogenous compound that contains cobalt-carbonyl.
Preferably, in the preparation method of above-mentioned chirality 4-chloro-3-hydroxybutanoic acid ester, the described metallic compound that contains cobalt-carbonyl is selected from the fatty alcohol solution of pure cobalt octacarbonyl, ten dicarbapentaborane four cobalts, tetracarbonylhydrocobalt and sodium (potassium) salt thereof, cobalt tetracarbonyl negatively charged ion, acetone soln or the synthetic cobalt-carbonyl solution of original position of cobalt tetracarbonyl negatively charged ion.
Preferably, in the preparation method of above-mentioned chirality 4-chloro-3-hydroxybutanoic acid ester, the cobalt source of the cobalt-carbonyl solution that described original position is synthetic is selected from Co (OAc)
22H
2O, CoO, Co
3O
4Or CoCO
3.
Preferably, in the preparation method of above-mentioned chirality 4-chloro-3-hydroxybutanoic acid ester, the described metallic compound that contains cobalt-carbonyl is 0.5 ~ 10% with the amount of substance ratio of described chiral epichlorohydrin, and described nitrogenous compound is 1 ~ 20% with the amount of substance ratio of described chiral epichlorohydrin.
Preferably, in the preparation method of above-mentioned chirality 4-chloro-3-hydroxybutanoic acid ester, described nitrogenous compound is selected from ZnBr
2(pyridine)
2, ZnCl
2(pyridine)
2, ZnI
2(pyridine)
2, 3-Hydroxypyridine, Pyridine, Imidazole, ZnCl
2(3-methylpyridine)
2, ZnBr
2(3-methylpyridine)
2Or ZnI
2(3-methylpyridine)
2.
Preferably, in the preparation method of above-mentioned chirality 4-chloro-3-hydroxybutanoic acid ester, described alcohol is methyl alcohol or ethanol.
Preferably, in the preparation method of above-mentioned chirality 4-chloro-3-hydroxybutanoic acid ester, the pressure of described carbon monoxide is 1 ~ 12MPa, and the temperature of reacting by heating is 40 ~ 140 ° of C, and the reaction times is 1 ~ 16h.
Preferably, in the preparation method of above-mentioned chirality 4-chloro-3-hydroxybutanoic acid ester, the pressure of described carbon monoxide is 4 ~ 8MPa, and the temperature of reacting by heating is 60 ~ 100 ° of C.
Preferably, in the preparation method of above-mentioned chirality 4-chloro-3-hydroxybutanoic acid ester, described chiral epichlorohydrin is R-type or S-type epoxy chloropropane, and the enantiomeric excess value of described chiral epichlorohydrin (ee value) is 70 ~ 100%.
Because technique scheme is used, the present invention compared with prior art has following advantages:
1) by advanced oxo process technology, realize the synthetic of chirality 4-chlorine 3-hydroxybutyrate ester by single step reaction, meet the demand for development of current fine chemistry industry greenization.
2) required raw material chiral epichlorohydrin ring, alcohol, carbon monoxide is bulk chemical, is easy to get, with low cost.
3) racemization (not reducing optical activity) can not occur in the epoxy chloropropane of R-or S-type under reaction conditions, obtains the corresponding chirality 4-chlorine 3-hydroxybutyrate ester of retention of configuration.
4) catalyzer of reaction simply is easy to preparation, and catalytic efficiency is high.
5) reaction conditions is gentle, technological process is easy, convenient operation, and equipment requirements and reaction conditions are easily realized, suitable for mass production.
6) reaction mixture separates, purifies through simple, just can high yield obtain high-purity chiral 4-chlorine 3-hydroxybutyrate ester.
Embodiment
The present invention is described further by the following example: according to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand, the described concrete material ratio of embodiment, processing condition and result thereof be only for the present invention is described, and should also can not limit the present invention described in detail in claims.
The embodiment of the invention discloses a kind of preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester, be specially: chiral epichlorohydrin, alcohol, catalyzer are added to autoclave, carry out reacting by heating after passing into carbon monoxide, the refining chirality-4-chloro-3-hydroxybutanoic acid ester that obtains after reaction finishes.
Above-mentioned preparation method's route can be expressed as follows:
In above-mentioned preparation method, due to the oxo process technology by advanced, by single step reaction, realize the synthetic of chirality 4-chlorine 3-hydroxybutyrate ester, meet the demand for development of current fine chemistry industry greenization; Required raw material chiral epichlorohydrin ring, alcohol, carbon monoxide are bulk chemical, are easy to get, with low cost; Racemization (not reducing optical activity) can not occur in the epoxy chloropropane of R-or S-type under reaction conditions, obtains the corresponding chirality 4-chlorine 3-hydroxybutyrate ester of retention of configuration; Reaction conditions is gentle, technological process is easy, convenient operation, and equipment requirements and reaction conditions are easily realized, suitable for mass production.
In the preparation method of above-mentioned chirality 4-chloro-3-hydroxybutanoic acid ester, catalyzer comprises metallic compound and the nitrogenous compound that contains cobalt-carbonyl.The metallic compound that contains cobalt-carbonyl is preferably from the fatty alcohol solution of pure cobalt octacarbonyl, ten dicarbapentaborane four cobalts, tetracarbonylhydrocobalt and sodium (potassium) salt thereof, cobalt tetracarbonyl negatively charged ion, acetone soln or the synthetic cobalt-carbonyl solution of original position of cobalt tetracarbonyl negatively charged ion.The cobalt source of the cobalt-carbonyl solution that described original position is synthetic is preferably from Co (OAc)
22H
2O, CoO, Co
3O
4Or CoCO
3.The metallic compound that contains cobalt-carbonyl is 0.5 ~ 10% with the amount of substance of described chiral epichlorohydrin ratio.Described nitrogenous compound is 1 ~ 20% with the amount of substance ratio of described chiral epichlorohydrin.Described nitrogenous compound is preferably from ZnBr
2(pyridine)
2, ZnCl
2(pyridine)
2, ZnI
2(pyridine)
2, 3-Hydroxypyridine, Pyridine, Imidazole, ZnCl
2(3-methylpyridine)
2, ZnBr
2(3-methylpyridine)
2Or ZnI
2(3-methylpyridine)
2.The pressure of described carbon monoxide is preferably 1 ~ 12MPa, more preferably 4 ~ 8MPa.The temperature of reacting by heating is 40 ~ 140 ° of C, 60 ~ 100 ° of C more preferably, and the reacting by heating time is preferably 1 ~ 16h.Described chiral epichlorohydrin is R-type or S-type epoxy chloropropane, and the enantiomeric excess value of described chiral epichlorohydrin is 70 ~ 100%.Described alcohol is methyl alcohol or ethanol.
When alcohol is methyl alcohol, the chirality 4-chloro-3-hydroxybutanoic acid ester obtained is chirality 4-chloro-3-hydroxyl methyl-butyrate; When alcohol is ethanol, the chirality 4-chloro-3-hydroxybutanoic acid ester obtained is chirality 4-chloro-3-hydroxyl ethyl butyrate.
In order further to understand the present invention, below in conjunction with embodiment, the preferred embodiment of the invention is described, but should be appreciated that these are described is for further illustrating the features and advantages of the present invention, rather than limiting to the claimed invention.
Embodiment 1:
Add the anhydrous methanol of 200mL, (S)-epoxy chloropropane of 200mmol (ee>99.9%), the cobalt octacarbonyl of 2.5mmol, the ZnBr of 10mmol in the autoclave that is 600mL at volume
2(pyridine)
2.Closed reactor, replace reactor 3 times closed reactor with carbon monoxide.In the Schlenk vacuum line, under room temperature, by CO (carbon monoxide converter) gas, reaction system is replaced three times, being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rises to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 99% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl methyl-butyrate selectivity 94%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl methyl-butyrate 27.5g(yield 97%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value)>99.9%, the nmr analysis data are as follows:
1H NMR (400MHz, CDCl
3, ppm) δ: 4.19-4.27 (m, 1H), 3.69 (s, 3H), 3.58 (d, 1H), 3.56 (d, 1H), 2.62 (d, 1H), 2.60 (d, 1H);
13CNMR (100MHz, CDCl
3, ppm) δ: 172.2,67.9,52.0,48.2,38.3.
Embodiment 2:
Add the anhydrous methanol of 200mL, (R)-epoxy chloropropane of 200mmol (ee>99.9%), the cobalt octacarbonyl of 2.5mmol, the ZnBr of 10mmol in the autoclave that is 600mL at volume
2(pyridine)
2.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 99% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl methyl-butyrate selectivity 96%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl methyl-butyrate 27.8g(yield 96%, purity 99%), gas chromatograph (Chiraldex G-TAcolumn) is analyzed (R)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 3:
Add the dehydrated alcohol of 200mL, (S)-epoxy chloropropane of 200mmol (ee > 99.9%), the cobalt octacarbonyl of 2.5mmol, the 3-Hydroxypyridine of 10mmol in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 95% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 93%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl ethyl butyrate 28.0g(yield 95%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value)>99.9%, nuclear magnetic data is as follows:
1H NMR (400MHz, CDCl
3, ppm) δ: 4.31-4.37 (m, 1H), 4.22 (q, 2H), 3.61-2.67 (m, 4H), 1.27 (t, 3H);
13C NMR (100MHz, CDCl
3, ppm) δ: 171.8,117.4,64.4,61.6,40.3,25.4,14.5.
Embodiment 4:
Add the anhydrous methanol of 200mL, (R)-epoxy chloropropane of 200mmol (ee > 99.9%), the cobalt octacarbonyl of 2.5mmol, the Pyridine of 10mmol in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 89% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl methyl-butyrate selectivity 85%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl methyl-butyrate 21.9g(yield 95%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 5:
Add the anhydrous methanol of 200mL, (S)-epoxy chloropropane of 200mmol (ee > 99.9%), the cobalt octacarbonyl of 2.5mmol, the Imidazole of 5mmol in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 90% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl methyl-butyrate selectivity 85%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl methyl-butyrate 21.7g(yield 93%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 6:
Add the anhydrous methanol of 200mL, (S)-epoxy chloropropane of 200mmol (ee 70.0%), the cobalt tetracarbonyl sodium of 5mmol, the ZnBr of 10mmol in the autoclave that is 600mL at volume
2(pyridine)
2.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 98% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl methyl-butyrate selectivity 83%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl methyl-butyrate 23.8g(yield 96%, purity 99%), it is 70.0% that gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value).
Embodiment 7:
Add the anhydrous methanol of 200mL, (S)-epoxy chloropropane of 200mmol (ee 75.0%), the cobalt tetracarbonyl sodium of 5mmol, the ZnI of 10mmol in the autoclave that is 600mL at volume
2(pyridine)
2.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 94% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl methyl-butyrate selectivity 73%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl methyl-butyrate 19.5g(yield 93%, purity 99%), it is 75.0% that gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value).
Embodiment 8:
Add the anhydrous methanol of 200mL, (R)-epoxy chloropropane of 200mmol (ee>99.9%), the cobalt octacarbonyl of 2.5mmol, the ZnCl of 10mmol in the autoclave that is 600mL at volume
2(3-methylpyridine)
2.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 95% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl methyl-butyrate selectivity 80%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl methyl-butyrate 22.0g(yield 95%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 9:
Add the anhydrous methanol of 200mL, (S)-epoxy chloropropane of 200mmol (ee>99.9%), the cobalt octacarbonyl of 2.5mmol, the ZnBr of 10mmol in the autoclave that is 600mL at volume
2(3-methylpyridine)
2.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 100 ° of C, reacts 6 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 98% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl methyl-butyrate selectivity 70%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl methyl-butyrate 20.1g(yield 96%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 10:
Add the dehydrated alcohol of 200mL, (R)-epoxy chloropropane of 200mmol (ee > 99.9%), the cobalt octacarbonyl of 2.5mmol, the 3-Hydroxypyridine of 10mmol in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid by the reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 96% of (R)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 94%, underpressure distillation obtains (R)-4-chloro-3-hydroxyl ethyl butyrate 28.5g(yield 95%, purity 99%).Gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 11:
Add the dehydrated alcohol of 200mL, (R)-epoxy chloropropane of 200mmol (ee 85.0%), the cobalt octacarbonyl of 2.5mmol, the ZnBr of 10mmol in the autoclave that is 600mL at volume
2(pyridine)
2.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 94% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl ethyl butyrate selectivity 90%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl ethyl butyrate 27.1g(yield 96%, purity 99%), it is 85.0% that gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value).
Embodiment 12:
Add the dehydrated alcohol of 200mL, (S)-epoxy chloropropane of 200mmol (ee 70.0%), 2.5mmol cobalt octacarbonyl, 10mmol3-Hydroxypyridine in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 4.0MPa, controls temperature by temperature controller and slowly rise to 80 ° of C, reacts 6 hours, is cooled to room temperature, unloads still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 99% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 93%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl ethyl butyrate 29.1g(yield 95%, purity 99%), it is 70.0% that gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value).
Embodiment 13:
Add the dehydrated alcohol of 200mL, (R)-epoxy chloropropane of 200mmol (ee > 99.9%), 20mmol cobalt octacarbonyl, 40mmol3-Hydroxypyridine in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 80 ° of C, reacts 2 hours, is cooled to room temperature, unloads still.
Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid by the reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 96% of (R)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 95%, underpressure distillation obtains (R)-4-chloro-3-hydroxyl ethyl butyrate 28.8g(yield 95%, purity 99%).Gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 14:
Add the dehydrated alcohol of 200mL, (R)-epoxy chloropropane of 200mmol (ee > 99.9%), 1mmol cobalt octacarbonyl, 2mmol3-Hydroxypyridine in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 80 ° of C, reacts 12 hours, is cooled to room temperature, unloads still.
Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid by the reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 85% of (R)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 95%, underpressure distillation obtains (R)-4-chloro-3-hydroxyl ethyl butyrate 25.3g(yield 94%, purity 99%).Gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 15:
Add the dehydrated alcohol of 200mL, (R)-epoxy chloropropane of 200mmol (ee > 99.9%), 10mmol cobalt octacarbonyl, 20mmol3-Hydroxypyridine in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 40 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid by the reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 93% of (R)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 98%, underpressure distillation obtains (R)-4-chloro-3-hydroxyl ethyl butyrate 29.2g(yield 96%, purity 99%).Gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 16:
Add the dehydrated alcohol of 200mL, (S)-epoxy chloropropane of 200mmol (ee > 99.9%), 5mmol cobalt octacarbonyl, 10mmol3-Hydroxypyridine in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 100 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid by the reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 97% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 90%, underpressure distillation obtains (S)-4-chloro-3-hydroxyl ethyl butyrate 27.9g(yield 96%, purity 99%).Gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 17:
Add the dehydrated alcohol of 100mL, (S)-epoxy chloropropane of 200mmol (ee > 99.9%), 5mmol cobalt octacarbonyl, 10mmol3-Hydroxypyridine in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid by the reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 95% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 88%, underpressure distillation obtains (S)-4-chloro-3-hydroxyl ethyl butyrate 26.7g(yield 96%, purity 99%).Gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 18:
Add the dehydrated alcohol of 300mL, (S)-epoxy chloropropane of 200mmol (ee > 99.9%), 5mmol cobalt octacarbonyl, 10mmol3-Hydroxypyridine in the autoclave that is 600mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid by the reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 96% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 98%, underpressure distillation obtains (S)-4-chloro-3-hydroxyl ethyl butyrate 29.8g(yield 95%, purity 99%).Gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 19:
Add the anhydrous methanol of 200mL, (R)-epoxy chloropropane of 200mmol (ee>99.9%), 2.5mmol cobalt octacarbonyl, 10mmolZnBr in the autoclave that is 600mL at volume
2(pyridine)
2.Closed reactor, with carbon monoxide, reactor is replaced 3 times, closed reactor, in the Schlenk vacuum line, under room temperature, by CO (carbon monoxide converter) gas, reaction system is replaced three times, being filled with the CO gaseous tension is 6.0MPa, control temperature by temperature controller and slowly rise to 140 ° of C, react 2 hours, be cooled to room temperature, unload still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 99% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl methyl-butyrate selectivity 82%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl methyl-butyrate 23.0g(yield 93%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 20:
Add the anhydrous methanol of 200mL, (R)-epoxy chloropropane of 200mmol (ee>99.9%), 2.5mmol cobalt octacarbonyl, 10mmolZnBr in the autoclave that is 600mL at volume
2(pyridine)
2.Closed reactor, with carbon monoxide, reactor is replaced 3 times, closed reactor, in the Schlenk vacuum line, under room temperature, by CO (carbon monoxide converter) gas, reaction system is replaced three times, being filled with the CO gaseous tension is 2.0MPa, control temperature by temperature controller and slowly rise to 80 ° of C, react 16 hours, be cooled to room temperature, unload still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: (R)-4-chloro-3-hydroxyl methyl-butyrate selectivity 91%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl methyl-butyrate 18.7g(yield 96%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 21:
Add the anhydrous methanol of 200mL, (R)-epoxy chloropropane of 200mmol (ee>99.9%), 2.5mmol cobalt octacarbonyl, 10mmolZnBr in the autoclave that is 600mL at volume
2(pyridine)
2.Closed reactor, with carbon monoxide, reactor is replaced 3 times, closed reactor, in the Schlenk vacuum line, under room temperature, by CO (carbon monoxide converter) gas, reaction system is replaced three times, being filled with the CO gaseous tension is 4.0MPa, control temperature by temperature controller and slowly rise to 80 ° of C, react 12 hours, be cooled to room temperature, unload still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: (R)-4-chloro-3-hydroxyl methyl-butyrate selectivity 93%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl methyl-butyrate 24.5g(yield 96%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 22:
Add the anhydrous methanol of 200mL, (S)-epoxy chloropropane of 200mmol (ee>99.9%), 2.5mmol cobalt octacarbonyl, 10mmolZnBr in the autoclave that is 600mL at volume
2(pyridine)
2.Closed reactor, with carbon monoxide, reactor is replaced 3 times, closed reactor, in the Schlenk vacuum line, under room temperature, by CO (carbon monoxide converter) gas, reaction system is replaced three times, being filled with the CO gaseous tension is 12.0MPa, control temperature by temperature controller and slowly rise to 80oC, react 6 hours, be cooled to room temperature, unload still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 97% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl methyl-butyrate selectivity 96%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl methyl-butyrate 27.0g(yield 95%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 23:
Add the anhydrous methanol of 500mL, (S)-epoxy chloropropane of 500mmol (ee>99.9%), 25mmol cobalt octacarbonyl, 50mmolZnBr in the autoclave that is 2000mL at volume
2(pyridine)
2.Closed reactor, with carbon monoxide, reactor is replaced 3 times, closed reactor, in the Schlenk vacuum line, under room temperature, by CO (carbon monoxide converter) gas, reaction system is replaced three times, being filled with the CO gaseous tension is 6.0MPa, control temperature by temperature controller and slowly rise to 60 ° of C, react 10 hours, be cooled to room temperature, unload still.
By the Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid of reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 99% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl methyl-butyrate selectivity 97%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl methyl-butyrate 71.1g(yield 97%, purity 99%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 24:
Add the dehydrated alcohol of 1000mL, (R)-epoxy chloropropane of 800mmol (ee > 99.9%), 40mmol cobalt octacarbonyl, 80mmol3-Hydroxypyridine in the autoclave that is 2000mL at volume.Closed reactor, in the Schlenk vacuum line, replace reaction system three times by CO (carbon monoxide converter) gas under room temperature, and being filled with the CO gaseous tension is 6.0MPa, controls temperature by temperature controller and slowly rise to 60 ° of C, reacts 10 hours, is cooled to room temperature, unloads still.
Agilent 6890/5973 gas chromatograph-mass spectrometer qualitative analysis for liquid by the reaction gained, Agilent 7890 chromatogram ration analysis: the transformation efficiency 98% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl ethyl butyrate selectivity 98%, underpressure distillation obtains (S)-4-chloro-3-hydroxyl ethyl butyrate 121.6g(yield 95%, purity 99%).Gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
In sum, the present invention compared with prior art has following advantages:
1) by advanced oxo process technology, realize the synthetic of chirality 4-chlorine 3-hydroxybutyrate ester by single step reaction, meet the demand for development of current fine chemistry industry greenization.
2) required raw material chiral epichlorohydrin ring, alcohol, carbon monoxide is bulk chemical, is easy to get, with low cost.
3) racemization (not reducing optical activity) can not occur in the epoxy chloropropane of R-or S-type under reaction conditions, obtains the corresponding chirality 4-chlorine 3-hydroxybutyrate ester of retention of configuration.
4) catalyzer of reaction simply is easy to preparation, and catalytic efficiency is high.
5) reaction conditions is gentle, technological process is easy, convenient operation, and equipment requirements and reaction conditions are easily realized, suitable for mass production.
6) reaction mixture separates, purifies through simple, just can high yield obtain high-purity chiral 4-chlorine 3-hydroxybutyrate ester.
It should be noted that, in this article, relational terms such as the first and second grades only is used for an entity or operation are separated with another entity or operational zone, and not necessarily requires or imply between these entities or operation the relation of any this reality or sequentially of existing.And, term " comprises ", " comprising " or its any other variant are intended to contain comprising of nonexcludability, thereby make the process, method, article or the equipment that comprise a series of key elements not only comprise those key elements, but also comprise other key elements of clearly not listing, or also be included as the intrinsic key element of this process, method, article or equipment.In the situation that not more restrictions, the key element limited by statement " comprising ... ", and be not precluded within process, method, article or the equipment that comprises described key element and also have other identical element.
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
To the above-mentioned explanation of the disclosed embodiments, make professional and technical personnel in the field can realize or use the present invention.Multiple modification to these embodiment will be apparent for those skilled in the art, and General Principle as defined herein can be in the situation that do not break away from the spirit or scope of the present invention, realization in other embodiments.Therefore, the present invention will can not be restricted to these embodiment shown in this article, but will meet the widest scope consistent with principle disclosed herein and features of novelty.
Claims (10)
1. the preparation method of a chirality 4-chloro-3-hydroxybutanoic acid ester, it is characterized in that, chiral epichlorohydrin, alcohol, catalyzer are added to autoclave, carry out reacting by heating after passing into carbon monoxide, the refining chirality-4-chloro-3-hydroxybutanoic acid ester that obtains after reaction finishes.
2. the preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester according to claim 1, is characterized in that, described catalyzer comprises metallic compound and the nitrogenous compound that contains cobalt-carbonyl.
3. the preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester according to claim 2, it is characterized in that, the described metallic compound that contains cobalt-carbonyl is selected from the fatty alcohol solution of pure cobalt octacarbonyl, ten dicarbapentaborane four cobalts, tetracarbonylhydrocobalt and sodium (potassium) salt thereof, cobalt tetracarbonyl negatively charged ion, acetone soln or the synthetic cobalt-carbonyl solution of original position of cobalt tetracarbonyl negatively charged ion.
4. the preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester according to claim 3, is characterized in that, the cobalt source of the cobalt-carbonyl solution that described original position is synthetic is selected from Co (OAc)
22H
2O, CoO, Co
3O
4Or CoCO
3.
5. the preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester according to claim 2, it is characterized in that, the described metallic compound that contains cobalt-carbonyl is 0.5 ~ 10% with the amount of substance ratio of described chiral epichlorohydrin, and described nitrogenous compound is 1 ~ 20% with the amount of substance ratio of described chiral epichlorohydrin.
6. the preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester according to claim 2, is characterized in that, described nitrogenous compound is selected from ZnBr
2(pyridine)
2, ZnCl
2(pyridine)
2, ZnI
2(pyridine)
2, 3-Hydroxypyridine, Pyridine, Imidazole, ZnCl
2(3-methylpyridine)
2, ZnBr
2(3-methylpyridine)
2Or ZnI
2(3-methylpyridine)
2.
7. the preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester according to claim 1, is characterized in that, described alcohol is methyl alcohol or ethanol.
8. the preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester according to claim 1, is characterized in that, the pressure of described carbon monoxide is 1 ~ 12MPa, and the temperature of reacting by heating is 40 ~ 140 ° of C, and the reaction times is 1 ~ 16h.
9. the preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester according to claim 8, is characterized in that, the pressure of described carbon monoxide is 4 ~ 8MPa, and the temperature of reacting by heating is 60 ~ 100 ° of C.
10. the preparation method of chirality 4-chloro-3-hydroxybutanoic acid ester according to claim 1, is characterized in that, described chiral epichlorohydrin is R-type or S-type epoxy chloropropane, and the enantiomeric excess value of described chiral epichlorohydrin (ee value) is 70 ~ 100%.
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