CN103420870A - Preparation method for chiral 4-cyano-3-hydroxybutyrate - Google Patents
Preparation method for chiral 4-cyano-3-hydroxybutyrate Download PDFInfo
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Abstract
The invention discloses a preparation method for chiral 4-cyano-3-hydroxybutyrate. The preparation method specifically comprises that: under the effect of a carbonylation catalyst, chiral chloropropylene oxide is taken as an initial raw material, and reacted with an alcohol and carbon monoxide for a carbonylation reaction, and corresponding chiral 4-chloro-3-hydroxybutyrate with maintained configuration is obtained and then subjected to cyanidation for preparation of chiral 4-cyano-3-hydroxybutyrate with high optical purity. Compared with conventional synthetic methods, the preparation method has the advantages of fewer steps, easily available and cheap raw materials, fewer 'three wastes (waste gas, waste water and industrial residue) ', simple post treatment, low equipment requirements, and applicability to industrial production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of preparation method of chirality 4-cyano-3-hydroxy butyric ester.
Background technology
Statins (statins), i.e. 3-hydroxy-3-methylglutaryl-coenzyme A (3-hydroxy-3-methyglutaryl-coenzyme, HMG-CoA) reductase inhibitor.A large amount of fundamental researchs and clinical trial show, statins not only has powerful effect for reducing fat, also there is " multiple-effect " that be independent of outside its effect for reducing fat, as: improve function of vascular endothelium, inflammation-inhibiting and anti-oxidant reaction, platelet aggregation-against and inhibition thrombosis, stablize atherosclerotic plaque, suppress the myocardial cell and reinvent with apoptosis of cardiac muscle, suppress cardiac electrophysiology and reinvent and regulate a series of effects such as cardiac vegetative nerve function of peripheral.The appearance of statins is an important milestone on the treating cardiovascular disease history, and become at present the main force's blood lipid regulation medicine that is used for the treatment of clinically all kinds of hyperlipidaemias, prevents and treats atherosclerosis and coronary heart disease, be also Global Medicine market famous " cookle " level medicine.Clinical statins antilipemic drugs commonly used is as atorvastatin (Atorvastatin Calcium, Lipitor), Rosuvastatin (claims again rosuvastatin, Rosuvastatin, Crestor), Pravastatin (Pravastatin, Livalo), fluvastatin (Fluvastatin, Losool), Cerivastatin (Cerivastatin, Lipobay), Bervastatin (Bervastatin) etc.According to global medicine marketing data presentation, within 2009, the treating cardiovascular disease consumption sum reaches 352.81 hundred million dollars, and No.1 heavy pound medicine atorvastatin occupies world's situation of selling well medicine the first (wherein home sale reaches 1,800,000,000 yuan) with the sales achievement of 132.88 hundred million dollars, the sales volume in the Rosuvastatin whole world reaches 53.8 hundred million dollars.Along with global Aging Problem aggravation, the market share of the medicine of mainly curing cardiovascular disease will sustainable growth.
Chirality 4-chloro-3-hydroxybutanoic acid ester especially (R)-4-cyano-3-hydroxy ethyl butyrate is key intermediate indispensable in the statins building-up process.Therefore, how the chirality 4-chloro-3-hydroxybutanoic acid ester of the preparation high purity of high yield, high optical activity is the focus of paying close attention to both at home and abroad always.In the synthetic method of having reported, mainly contain two kinds of biological process and chemical methods.
Biological process mainly comprises: 1) take the racemic epoxide chloropropane as starting raw material process cyaniding open loop, cyanogen lytic enzyme catalytic hydrolysis, esterification process production (R)-4-cyano-3-hydroxy ethyl butyrate (S.Bergeron; et al., Org.Process Res.Dev., 2006; 10,661 – 665; M.J.Burk, et al., US 7932064; M.J.Burk, et al., US 20110250657; M.J.Burk, et al., US 20040053378.); 2) bio-transformation of 4-chloroacetyl acetacetic ester is become to (S)-4-chloro-3-hydroxyl ethyl butyrate, then cyaniding obtains (R)-4-cyano-3-hydroxy ethyl butyrate (US 7807423 for S.C.Davis, et al.; S.C.Davis, et al., US 7132267; S.C.Davis, et al., US 7125693; S.C.Davis, et al., US 6884607; Ying Hanjie etc., CN201010213724.6; The CN such as Ou Zhimin 201010108617.7; Ying Hanjie etc., CN200910183017.); 3) (S)-4-chloro-3-hydroxyl ethyl butyrate of take is raw material, utilizes the halogenohydrin dehalogenase through (S)-epoxy ethyl butyrate, produces (R)-4-cyano-3-hydroxy ethyl butyrate (Shi Zhenxiang etc., CN 201110008814.); 4) take racemization 4-cyano group methyl aceto acetate is raw material, through bio-transformation be (R)-4-cyano-3-hydroxy ethyl butyrate (He Chunmao etc., CN200810036341.).
Chemical method mainly comprises: 1) (S)-epoxy chloropropane obtains (S)-4-chloro-3-hydroxyl butyronitrile through the sodium cyanide open loop, obtain (S)-4-chloro-3-hydroxyl ethyl butyrate with the ethanol alcoholysis, again through synthetic (the R)-4-cyano-3-hydroxy ethyl butyrate of the processes such as cyaniding (Zhou Yongjun etc., CN 200910061164; Hong Huabin etc., Chinese Journal of Pharmaceuticals, 2009,40,486-487.); 2) take diketene as the synthetic chloroacetyl acetacetic ester of raw material, and then under ruthenium-phosphine ligand catalysis, selective hydrogenation obtains (S)-4-chloro-3-hydroxyl ethyl butyrate, then cyaniding obtains (R)-4-cyano-3-hydroxy ethyl butyrate (US 5430171. for S.Mitsuhashi, et al.); 3) by oxidation of beta-(1; 4) disaccharides or oligose obtain (S)-3; 4-dihydroxyl butyric acid; then cyclization obtains (S)-3-hydroxyl-gamma-butyrolactone, then through open loop, esterification and cyaniding, is prepared into (R)-4-cyano-3-hydroxy ethyl butyrate (G..Wang, et al.; Tetrahedron:Asymmetry; 1999,10,1895-1901; P.Kumar, et al., Tetrahedron:Asymmetry, 2005,16,2717-2721.); 4) L-(-)-oxysuccinic acid is starting raw material, through esterification, reduction, bromo and cyaniding four-step reaction obtain target compound (R)-4-cyano-3-hydroxy ethyl butyrate (Lv Shixiang etc., organic chemistry, 2009,12,1997-1999.); 5) with (S)-3, the salt of 4-epoxy butyric acid is raw material, and (US 6586616 for D.Hwang, et al. to obtain the purpose compound through steps such as cyaniding, esterifications; K.R.Roh, et al., WO 2000046186.) or with 3,4-epoxy ethyl butyrate is raw material, through synthetic (S)-3 of hydrolytic kinetic resolution, 4-epoxy ethyl butyrate intermediate, then the cyaniding open loop obtain the purpose product (He Guangquan etc., CN201110168082.).
There are the defects such as route is long, quantity of three wastes is large in the chiral epichlorohydrin of clearly take in existing synthetic method as raw material.The asymmetric catalytic hydrogenation method of 4-chloroacetyl acetacetic ester (diketene and chlorine reaction preparation) and enzyme process exist substrate to obtain difficulty, chirality ruthenium-phosphine part or enzyme to be difficult to the problem demanding prompt solutions such as preparation, product purity can not meet the demands, production cost height.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of chirality 4-cyano-3-hydroxy butyric ester, this preparation method's raw material is cheap and easy to get, operation steps is few, 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-cyano-3-hydroxy butyric ester, especially, comprise the steps:
(a) 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;
(b) in chirality 4-chloro-3-hydroxybutanoic acid ester, add cyanating reagent to carry out cyaniding, obtain chirality 4-cyano-3-hydroxy butyric ester.
Preferably, in the preparation method of above-mentioned chirality 4-cyano-3-hydroxy butyric ester, described step (b) is specially: chirality 4-chloro-3-hydroxybutanoic acid ester is dissolved in the pure aqueous solution, under heated and stirred, drip cyanating reagent, drip rear continuation of end and stir, after stopped reaction, underpressure distillation, then add extraction solvent to be extracted, organic layer separates, and merges, drying, obtain chirality 4-cyano-3-hydroxy butyric ester after underpressure distillation.
Preferably, in the preparation method of above-mentioned chirality 4-cyano-3-hydroxy butyric ester, described extraction solvent is ethyl acetate or methylene dichloride.
Preferably, in the preparation method of above-mentioned chirality 4-cyano-3-hydroxy butyric ester, described alcohol is methyl alcohol or ethanol.
Preferably, in the preparation method of above-mentioned chirality 4-cyano-3-hydroxy butyric ester, described chiral epichlorohydrin is (R)-epoxy chloropropane or (S)-epoxy chloropropane, and the enantiomeric excess value of described chiral epichlorohydrin (ee value) is 70 ~ 100%.
Preferably, in the preparation method of above-mentioned chirality 4-cyano-3-hydroxy butyric ester, described catalyzer is Co
2(CO)
8And ZnBr
2(pyridine)
2Mixture, described Co
2(CO)
8With the amount of substance ratio of chiral epichlorohydrin be 0.05 ~ 5.0%, described ZnBr
2(pyridine)
2With the amount of substance ratio of chiral epichlorohydrin be 0.1 ~ 10%.
Preferably, in the preparation method of above-mentioned chirality 4-cyano-3-hydroxy butyric ester, described catalyzer is Co
2(CO)
8With the mixture of 3-hydroxypyridine, described Co
2(CO)
8With the amount of substance ratio of chiral epichlorohydrin be 0.05 ~ 5.0%, described 3-hydroxypyridine is 0.1 ~ 10% with the amount of substance ratio of chiral epichlorohydrin.
Preferably, in the preparation method of above-mentioned chirality 4-cyano-3-hydroxy butyric ester, in described step (a), the temperature of reacting by heating is 30 ~ 90 ° of C, the pressure of carbon monoxide is 4 ~ 9MPa, the time 1 ~ 16h of reacting by heating, and alcohol is 5 ~ 30 with the amount of substance ratio of chiral epichlorohydrin.
Preferably, in the preparation method of above-mentioned chirality 4-cyano-3-hydroxy butyric ester, described cyanating reagent is sodium cyanide solution or potassium cyanide solution.
Preferably, in the preparation method of above-mentioned chirality 4-cyano-3-hydroxy butyric ester, the amount of substance of described cyanating reagent is 1.2 ~ 5 times of chirality 4-chloro-3-hydroxybutanoic acid ester amount of substance.
Because technique scheme is used, the present invention compared with prior art has following advantages:
1) by advanced oxo process technology, realize the one-step synthesis of the essential intermediate chirality 4-chlorine 3-hydroxybutyrate ester of preparation chirality 4-cyano-3-hydroxy butyric ester, meet the demand for development of current fine chemistry industry greenization.
2) required raw material (chiral epichlorohydrin ring, alcohol, carbon monoxide, sodium cyanide or potassium cyanide) is bulk chemical, is easy to get, with low cost.
3) in carbonylation step, 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-chloro-3-hydroxybutanoic acid ester of retention of configuration.
4) by simple conversion chiral epichlorohydrin raw material used, can prepare easily (R)-or (S)-4-cyano-3-hydroxy butyric ester.
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) through carbonylation, two step synthesis of chiral 4-cyano-3-hydroxy butyric esters of cyaniding, operational path is short.
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-cyano-3-hydroxy butyric ester, comprise the steps:
(a) 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;
(b) in chirality 4-chloro-3-hydroxybutanoic acid ester, add cyanating reagent to carry out cyaniding, obtain chirality 4-cyano-3-hydroxy butyric ester.
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 chiral epichlorohydrin 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-cyano-3-hydroxy butyric ester, described step (b) is specially: chirality 4-chloro-3-hydroxybutanoic acid ester is dissolved in the pure aqueous solution, under heated and stirred, drips cyanating reagent, drip and finish the rear stirring that continues, after stopped reaction, underpressure distillation, then add extraction solvent to be extracted, organic layer separates, merge, drying, obtain chirality 4-cyano-3-hydroxy butyric ester after underpressure distillation.Described extraction solvent is preferably ethyl acetate or methylene dichloride.
In the preparation method of above-mentioned chirality 4-cyano-3-hydroxy butyric ester, described alcohol is methyl alcohol or ethanol; Described chiral epichlorohydrin is (R)-epoxy chloropropane or (S)-epoxy chloropropane, and the enantiomeric excess value of described chiral epichlorohydrin is preferably 70 ~ 100%; Described catalyzer is Co
2(CO)
8/ ZnBr
2(pyridine)
2Perhaps Co
2(CO)
8/ 3-hydroxypyridine, wherein CATALYST Co
2(CO)
8Be preferably 0.05～5.0%, ZnBr with the amount of substance ratio of chiral epichlorohydrin
2(pyridine)
2Or 3-hydroxypyridine is preferably 0.1 ~ 10% with the amount of substance ratio of chiral epichlorohydrin; In described step (a), the temperature of reacting by heating is preferably 30 ~ 90 ° of C, and the pressure of carbon monoxide is preferably 4 ~ 9MPa, and the time of reacting by heating is preferably 1 ~ 16h, and alcohol is preferably 5 ~ 30 with the amount of substance ratio of chiral epichlorohydrin; Described cyanating reagent is sodium cyanide solution or potassium cyanide solution; The amount of substance of described cyanating reagent is 1.2 ~ 5 times of chirality 4-chloro-3-hydroxybutanoic acid ester amount of substance.
When alcohol is methyl alcohol, prepared chirality 4-cyano-3-hydroxy butyric ester is chirality 4-cyano-3-hydroxy methyl-butyrate; When alcohol is ethanol, prepared chirality 4-cyano-3-hydroxy butyric ester is chirality 4-cyano-3-hydroxy 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:
(1) carbonylation reaction
The Co that adds the dehydrated alcohol of 400mL, (S)-epoxy chloropropane of 400mmol (ee>99.9%), 5.0mmol in the autoclave that is 1L at volume
2(CO)
8, 10mmol 3-hydroxypyridine.Closed reactor, replace reactor 3 times with carbon monoxide,, 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, controls temperature by temperature controller and slowly rises to 60 ° of C, reacts 10 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 99% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 95%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl ethyl butyrate 60.8g(yield 97%, purity 99%), high performance liquid chromatograph (chial column OB-H) is analyzed (S)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
1H?NMR(400MHz,CDCl
3,ppm)δ:4.33(m,1H),4.20(q,2H),3.62(d,2H),3.51(br,1H),2.63(d,2H),1.29(t,3H);
13C?NMR(100MHz,CDCl
3,ppm)δ:171.9,68.1,61.2,48.6,38.7,14.1。
(2) cyanogenation
In the 500mL there-necked flask, add prepared (the S)-4-of step (1) chloro-3-hydroxyl ethyl butyrate (16.7g, 100mmol) be dissolved in 100mL[V (ethanol): V (water)=4:1] in solution, add sodium cyanide (5.9g under 60 ° of C high degree of agitation conditions, 120mmol), stir 8h, be cooled to room temperature, remove ethanol under reduced pressure, ethyl acetate for remaining liq (50mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (R)-4-cyano-3-hydroxy ethyl butyrate 14.1g(colourless oil liquid, productive rate 89.7%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-cyano-3-hydroxy ethyl butyrate enantiomeric excess value (ee value)>99.9%,
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 2:
(1) carbonylation reaction
The Co that adds the anhydrous methanol of 400mL, (S)-epoxy chloropropane of 400mmol (ee>99.9%), 5.0mmol in the autoclave that is 1L at volume
2(CO)
8, 5.0mmol ZnBr
2(pyridine)
2.Closed reactor, replace reactor 3 times with carbon monoxide,, 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, controls temperature by temperature controller and slowly rises to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 99.5% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl methyl-butyrate selectivity 91%, underpressure distillation obtains (S)-4-chloro-3-hydroxyl methyl-butyrate 51.2g(yield 93%, purity 98%), gas chromatograph (Chiraldex G-TAcolumn) is analyzed (S)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
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);
13C?NMR(100MHz,CDCl
3,ppm)δ:172.2,67.9,52.0,48.2,38.3。
(2) cyanogenation
In the 500mL there-necked flask, add prepared (the S)-4-of step (1) chloro-3-hydroxyl methyl-butyrate (15.3g, 100mmol) be dissolved in 120mL[V (methyl alcohol): V (water)=4:1] in solution, add sodium cyanide (7.4g under 50 ° of C high degree of agitation conditions, 150mmol), stir 8 hours, be cooled to room temperature, remove methyl alcohol under reduced pressure, methylene dichloride for remaining liq (50mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (R)-4-cyano-3-hydroxy methyl-butyrate 12.2g(colourless oil liquid, productive rate 85.2%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-cyano-3-hydroxy methyl-butyrate enantiomeric excess value (ee value)>99.9%,
1H NMR (400MHz, CDCl
3, ppm) δ: 4.30-4.39 (m, 1H), 3.72 (s, 3H), 2.61-2.64 (m, 4H),
13C NMR (100MHz, CDCl
3, ppm) δ: 171.9,117.1,64.0,52.1,39.9,25.1.
Embodiment 3:
(1) carbonylation reaction
Add the dehydrated alcohol of 400mL, (R)-epoxy chloropropane of 400mmol (ee>99.9%), 5.0mmol Co in the autoclave that is 1L at volume
2(CO)
8, 10mmol3-hydroxypyridine.Closed reactor, replace reactor 3 times with carbon monoxide,, 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, controls temperature by temperature controller and slowly rises to 60 ° of C, reacts 10 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 98% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl ethyl butyrate selectivity 95%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl ethyl butyrate 56.2g(yield 96%, purity 99%), high performance liquid chromatograph (chial column OB-H) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
(2) cyanogenation
In the 500mL there-necked flask, add prepared (the R)-4-of step (1) chloro-3-hydroxyl ethyl butyrate (16.7g, 100mmol) be dissolved in 100mL[V (ethanol): V (water)=4:1] in solution, add sodium cyanide (5.9g under 60 ° of C high degree of agitation conditions, 120mmol), stir 8 hours, be cooled to room temperature, remove ethanol under reduced pressure, ethyl acetate for remaining liq (50mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (S)-4-cyano-3-hydroxy ethyl butyrate 13.3g(colourless oil liquid, productive rate 85.0%), gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-cyano-3-hydroxy ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 4:
(1) carbonylation reaction
Add the anhydrous methanol of 400mL, (R)-epoxy chloropropane of 400mmol (ee>99.9%), 5.0mmol Co in the autoclave that is 1L at volume
2(CO)
8, 5.0mmolZnBr
2(pyridine)
2.Closed reactor, replace reactor 3 times with carbon monoxide,, 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, controls temperature by temperature controller and slowly rises to 60 ° of C, reacts 8 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 99% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl methyl-butyrate selectivity 92%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl methyl-butyrate 52.8g(yield 95%, purity 99%), gas chromatograph (Chiraldex G-TAolumn) is analyzed (R)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
(2) cyanogenation
In the 500mL there-necked flask, add prepared (the R)-4-of step (1) chloro-3-hydroxyl methyl-butyrate (15.3g, 100mmol) be dissolved in 120mL[V (methyl alcohol): V (water)=4:1] in solution, add sodium cyanide (7.4g under 50 ° of C high degree of agitation conditions, 150mmol), stir 8 hours, be cooled to room temperature, remove methyl alcohol under reduced pressure, methylene dichloride for remaining liq (50mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (S)-4-cyano-3-hydroxy methyl-butyrate 12.5g(colourless oil liquid, productive rate 87.5%), gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-cyano-3-hydroxy methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 5:
(1) carbonylation reaction
Add the dehydrated alcohol of 400mL, (S)-epoxy chloropropane of 400mmol (ee 70.0%), 5.0mmol Co in the autoclave that is 1L at volume
2(CO)
8, 5.0mmolZnBr
2(pyridine)
2.Closed reactor, replace reactor 3 times with carbon monoxide,, 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, controls temperature by temperature controller and slowly rises to 60 ° of C, reacts 15 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 99.8% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl ethyl butyrate selectivity 90%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl ethyl butyrate 58.1g(yield 97%, purity 98%), it is 70.0% that high performance liquid chromatograph (chial column OB-H) is analyzed (S)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value).
(2) cyanogenation
In the 250mL there-necked flask, add prepared (the S)-4-of step (1) chloro-3-hydroxyl ethyl butyrate (8.4g, 50mmol) be dissolved in 60mL[V (ethanol): V (water)=4:1] in solution, add sodium cyanide (3.4g under 60 ° of C high degree of agitation conditions, 70mmol), stir 10 hours, be cooled to room temperature, remove ethanol under reduced pressure, methylene dichloride for remaining liq (30mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (R)-4-cyano-3-hydroxy ethyl butyrate 7.1g(colourless oil liquid, productive rate 90.5%), it is 70.0% that gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-cyano-3-hydroxy ethyl butyrate enantiomeric excess value (ee value).
Embodiment 6:
(1) carbonylation reaction
Add the anhydrous methanol of 400mL, (R)-epoxy chloropropane of 400mmol (ee 85.0%), 2.5mmol Co in the autoclave that is 1L at volume
2(CO)
8, 5.0mmol3-hydroxypyridine.Closed reactor, replace reactor 3 times with carbon monoxide,, 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, controls temperature by temperature controller and slowly rises to 80 ° of C, reacts 10 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 97% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl methyl-butyrate selectivity 85%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl methyl-butyrate 48.8g(yield 97%, purity 99%), it is 85.0% that gas chromatograph (Chiraldex G-TAcolumn) is analyzed (R)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value).
(2) cyanogenation
In the 250mL there-necked flask, add prepared (the R)-4-of step (1) chloro-3-hydroxyl methyl-butyrate (7.6g, 50mmol) be dissolved in 60mL[V (methyl alcohol): V (water)=4:1] in solution, add sodium cyanide (3.4g under 50 ° of C high degree of agitation conditions, 70mmol), stir 10h, be cooled to room temperature, remove methyl alcohol under reduced pressure, ethyl acetate for remaining liq (30mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (S)-4-cyano-3-hydroxy methyl-butyrate 6.8g(colourless oil liquid, productive rate 96%), it is 85.0% that gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-cyano-3-hydroxy methyl-butyrate enantiomeric excess value (ee value).
Embodiment 7:
(1) carbonylation reaction
Add the dehydrated alcohol of 400mL, (R)-epoxy chloropropane of 400mmol (ee>99.9%), 20mmol Co in the autoclave that is 1L at volume
2(CO)
8, 40mmol3-hydroxypyridine.Closed reactor, replace reactor 3 times with carbon monoxide,, 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, controls temperature by temperature controller and slowly rises to 40 ° of C, reacts 15 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 95% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl ethyl butyrate selectivity 98%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl ethyl butyrate 60.2g(yield 97%, purity 99%), high performance liquid chromatograph (chial column OB-H) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
(2) cyanogenation
In the 500mL there-necked flask, add prepared (the R)-4-of step (1) chloro-3-hydroxyl ethyl butyrate (13.4g, 80mmol) be dissolved in 100mL[V (ethanol): V (water)=4:1] in solution, add sodium cyanide (7.9g under 60 ° of C high degree of agitation conditions, 120mmol), stir 8 hours, be cooled to room temperature, remove ethanol under reduced pressure, ethyl acetate for remaining liq (40mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (S)-4-cyano-3-hydroxy ethyl butyrate 10.8g(colourless oil liquid, productive rate 86.0%), gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-cyano-3-hydroxy ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 8:
(1) carbonylation reaction
Add the anhydrous methanol of 400mL, (S)-epoxy chloropropane of 400mmol (ee>99.9%), 5.0mmol Co in the autoclave that is 1L at volume
2(CO)
8, 5.0mmolZnBr
2(pyridine)
2.Closed reactor, replace reactor 3 times with carbon monoxide,, 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, controls temperature by temperature controller and slowly rises to 80 ° of C, reacts 10 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 99% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl methyl-butyrate selectivity 92%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl methyl-butyrate 52.7g(yield 95%, purity 99%), gas chromatograph (Chiraldex G-TAcolumn) is analyzed (S)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
(2) cyanogenation
In the 500mL there-necked flask, add prepared (the S)-4-of step (1) chloro-3-hydroxyl methyl-butyrate (9.2g, 60mmol) be dissolved in 70mL[V (methyl alcohol): V (water)=4:1] in solution, add sodium cyanide (12.3g under 50 ° of C high degree of agitation conditions, 250mmol), stir 8 hours, be cooled to room temperature, remove methyl alcohol under reduced pressure, methylene dichloride for remaining liq (30mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (R)-4-cyano-3-hydroxy methyl-butyrate 7.6g(colourless oil liquid, productive rate 89%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-cyano-3-hydroxy methyl-butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 9:
(1) carbonylation reaction
Add the dehydrated alcohol of 115mL, (R)-epoxy chloropropane of 400mmol (ee>99.9%), 10mmol Co in the autoclave that is 1L at volume
2(CO)
8, 20mmol3-hydroxypyridine.Closed reactor, replace reactor 3 times with carbon monoxide,, 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, controls temperature by temperature controller and slowly rises to 60 ° of C, reacts 10 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 96% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl ethyl butyrate selectivity 91%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl ethyl butyrate 55.3g(yield 95%, purity 99%), high performance liquid chromatograph (chial column OB-H) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
(2) cyanogenation
In the 500mL there-necked flask, add prepared (the R)-4-of step (1) chloro-3-hydroxyl ethyl butyrate (13.4g, 80mmol) be dissolved in 80mL[V (ethanol): V (water)=4:1] in solution, add sodium cyanide (5.9g under 60 ° of C high degree of agitation conditions, 120mmol), stir 8 hours, be cooled to room temperature, remove ethanol under reduced pressure, ethyl acetate for remaining liq (40mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (S)-4-cyano-3-hydroxy ethyl butyrate 10.9g(colourless oil liquid, productive rate 87%), gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-cyano-3-hydroxy ethyl butyrate enantiomeric excess value (ee value) > 99.9%.
Embodiment 10:
(1) carbonylation reaction
Add the anhydrous methanol of 510mL, (S)-epoxy chloropropane of 400mmol (ee 90.0%), 15mmol Co in the autoclave that is 1L at volume
2(CO)
8, 30mmolZnBr
2(pyridine)
2.Closed reactor, replace reactor 3 times with carbon monoxide,, 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, controls temperature by temperature controller and slowly rises to 60 ° of C, reacts 10 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 98% of (S)-epoxy chloropropane, (S)-4-chloro-3-hydroxyl methyl-butyrate selectivity 98%.Underpressure distillation obtains (S)-4-chloro-3-hydroxyl methyl-butyrate 56.9g(yield 97%, purity 99%), gas chromatograph (Chiraldex G-TAcolumn) is analyzed (S)-4-chloro-3-hydroxyl methyl-butyrate enantiomeric excess value (ee value) 90.0%.
(2) cyanogenation
In the 500mL there-necked flask, add prepared (the S)-4-of step (1) chloro-3-hydroxyl methyl-butyrate (15.3g, 100mmol) be dissolved in 120mL[V (methyl alcohol): V (water)=4:1] in solution, add sodium cyanide (12.3g under 50 ° of C high degree of agitation conditions, 250mmol), stir 8 hours, be cooled to room temperature, remove methyl alcohol under reduced pressure, methylene dichloride for remaining liq (50mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (R)-4-cyano-3-hydroxy methyl-butyrate 12.9g(colourless oil liquid, productive rate 90%), gas chromatograph (Chiraldex G-TA column) is analyzed (R)-4-cyano-3-hydroxy methyl-butyrate enantiomeric excess value (ee value) 90.0%.
Embodiment 11:
(1) carbonylation reaction
Add the dehydrated alcohol of 300mL, (R)-epoxy chloropropane of 400mmol (ee 75.0%), 10mmol Co in the autoclave that is 1L at volume
2(CO)
8, 20mmol3-hydroxypyridine.Closed reactor, replace reactor 3 times with carbon monoxide,, 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 8.0MPa, controls temperature by temperature controller and slowly rises to 90 ° of C, reacts 4 hours, is cooled to room temperature, unloads still.
The reaction gained liquid with Agilent 6890/5973 gas chromatograph-mass spectrometer carry out qualitative analysis, Agilent 7890 gas-chromatographies are carried out quantitative analysis: the transformation efficiency 99% of (R)-epoxy chloropropane, (R)-4-chloro-3-hydroxyl ethyl butyrate selectivity 90%.Underpressure distillation obtains (R)-4-chloro-3-hydroxyl ethyl butyrate 56.4g(yield 95%, purity 99%), high performance liquid chromatograph (chial columnOB-H) is analyzed (R)-4-chloro-3-hydroxyl ethyl butyrate enantiomeric excess value (ee value) 75.0%.
(2) cyanogenation
In the 500mL there-necked flask, add prepared (the R)-4-of step (1) chloro-3-hydroxyl ethyl butyrate (25.0g, 150mmol) be dissolved in 150mL[V (ethanol): V (water)=4:1] in solution, add sodium cyanide (14.8g under 60 ° of C high degree of agitation conditions, 300mmol), stir 8 hours, be cooled to room temperature, remove ethanol under reduced pressure, ethyl acetate for remaining liq (80mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merged, filter, filtrate is concentrated, concentrated crude product underpressure distillation obtains (S)-4-cyano-3-hydroxy ethyl butyrate 20.0g(colourless oil liquid, productive rate 85%), gas chromatograph (Chiraldex G-TA column) is analyzed (S)-4-cyano-3-hydroxy ethyl butyrate enantiomeric excess value (ee value) 75.0%.
In sum, the present invention compared with prior art has following advantages:
1) by advanced oxo process technology, realize the one-step synthesis of the essential intermediate chirality 4-chlorine 3-hydroxybutyrate ester of preparation chirality 4-cyano-3-hydroxy butyric ester, meet the demand for development of current fine chemistry industry greenization.
2) required raw material (chiral epichlorohydrin ring, alcohol, carbon monoxide, sodium cyanide or potassium cyanide) is bulk chemical, is easy to get, with low cost.
3) in carbonylation step, 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-chloro-3-hydroxybutanoic acid ester of retention of configuration.
4) by simple conversion chiral epichlorohydrin raw material used, can prepare easily (R)-or (S)-4-cyano-3-hydroxy butyric ester.
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) through carbonylation, two step synthesis of chiral 4-cyano-3-hydroxy butyric esters of cyaniding, operational path is short.
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-cyano-3-hydroxy butyric ester, is characterized in that, comprises the steps:
(a) 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;
(b) in chirality 4-chloro-3-hydroxybutanoic acid ester, add cyanating reagent to carry out cyaniding, obtain chirality 4-cyano-3-hydroxy butyric ester.
2. the preparation method of chirality 4-cyano-3-hydroxy butyric ester according to claim 1, is characterized in that, described step (b) is specially: chirality 4-chloro-3-hydroxybutanoic acid ester is dissolved in the pure aqueous solution, under heated and stirred, drip cyanating reagent, drip rear continuation of end and stir, after stopped reaction, underpressure distillation, then add extraction solvent to be extracted, organic layer separates, and merges, drying, obtain chirality 4-cyano-3-hydroxy butyric ester after underpressure distillation.
3. the preparation method of chirality 4-cyano-3-hydroxy butyric ester according to claim 2, is characterized in that, described extraction solvent is ethyl acetate or methylene dichloride.
4. the preparation method of chirality 4-cyano-3-hydroxy butyric ester according to claim 1, is characterized in that, described alcohol is methyl alcohol or ethanol.
5. the preparation method of chirality 4-cyano-3-hydroxy butyric ester according to claim 1, it is characterized in that, described chiral epichlorohydrin is (R)-epoxy chloropropane or (S)-epoxy chloropropane, and the enantiomeric excess value of described chiral epichlorohydrin (ee value) is 70 ~ 100%.
6. the preparation method of chirality 4-cyano-3-hydroxy butyric ester according to claim 1, is characterized in that, described catalyzer is Co
2(CO)
8And ZnBr
2(pyridine)
2Mixture, described Co
2(CO)
8With the amount of substance ratio of chiral epichlorohydrin be 0.05 ~ 5.0%, described ZnBr
2(pyridine)
2With the amount of substance ratio of chiral epichlorohydrin be 0.1 ~ 10%.
7. the preparation method of chirality 4-cyano-3-hydroxy butyric ester according to claim 1, is characterized in that, described catalyzer is Co
2(CO)
8With the mixture of 3-hydroxypyridine, described Co
2(CO)
8With the amount of substance ratio of chiral epichlorohydrin be 0.05 ~ 5.0%, described 3-hydroxypyridine is 0.1 ~ 10% with the amount of substance ratio of chiral epichlorohydrin.
8. the preparation method of chirality 4-cyano-3-hydroxy butyric ester according to claim 1, it is characterized in that, in described step (a), the temperature of reacting by heating is 30 ~ 90 ° of C, the pressure of carbon monoxide is 4 ~ 9MPa, time 1 ~ the 16h of reacting by heating, alcohol is 5 ~ 30 with the amount of substance ratio of chiral epichlorohydrin.
9. the preparation method of chirality 4-cyano-3-hydroxy butyric ester according to claim 1, is characterized in that, described cyanating reagent is sodium cyanide solution or potassium cyanide solution.
10. the preparation method of chirality 4-cyano-3-hydroxy butyric ester according to claim 1, is characterized in that, the amount of substance of described cyanating reagent is 1.2 ~ 5 times of chirality 4-chloro-3-hydroxybutanoic acid ester amount of substance.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106966940A (en) * | 2015-07-30 | 2017-07-21 | 新发药业有限公司 | A kind of preparation method of Sitagliptin phosphate intermediate N arylmethyls 2S cyano methyl acridines |
| CN109628511A (en) * | 2019-01-16 | 2019-04-16 | 抚顺顺能化工有限公司 | The environmentally protective preparation method of one kind (R)-(-) -4- cyano-3-hydroxy ethyl butyrate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1506161A1 (en) * | 2002-05-22 | 2005-02-16 | Phoenix Chemicals Limited | Continuous process for the cyanation of hydrogenated beta-ketoesters |
| CN101838221A (en) * | 2009-03-16 | 2010-09-22 | 罗田县华阳生化有限公司 | Manufacturing method of atorvastatin intermediate (R)-(-)-4-nitrile-3-hydroxybutyrate |
-
2012
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1506161A1 (en) * | 2002-05-22 | 2005-02-16 | Phoenix Chemicals Limited | Continuous process for the cyanation of hydrogenated beta-ketoesters |
| CN101838221A (en) * | 2009-03-16 | 2010-09-22 | 罗田县华阳生化有限公司 | Manufacturing method of atorvastatin intermediate (R)-(-)-4-nitrile-3-hydroxybutyrate |
Non-Patent Citations (2)
| Title |
|---|
| HOON SIK KIM ET AL.: "An efficient catalytic system for the carbomethoxylation of ethylene oxide", 《APPLIED CATALYSIS A: GENERAL》, vol. 301, 6 January 2006 (2006-01-06), pages 75 - 78 * |
| KLAUS HINTERDING 等: "Regioselective Carbomethoxylation of Chiral Epoxides: A New Route to Enantiomerically Pure β-Hydroxy Esters", 《 J. ORG. CHEM.》, vol. 64, 11 March 1999 (1999-03-11), pages 2164 - 2165, XP002216881, DOI: doi:10.1021/jo982336l * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106966940A (en) * | 2015-07-30 | 2017-07-21 | 新发药业有限公司 | A kind of preparation method of Sitagliptin phosphate intermediate N arylmethyls 2S cyano methyl acridines |
| CN106966940B (en) * | 2015-07-30 | 2019-03-19 | 新发药业有限公司 | A kind of preparation method of Sitagliptin phosphate intermediate N arylmethyl -2S- cyano methyl acridine |
| CN109628511A (en) * | 2019-01-16 | 2019-04-16 | 抚顺顺能化工有限公司 | The environmentally protective preparation method of one kind (R)-(-) -4- cyano-3-hydroxy ethyl butyrate |
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