CN1093531C - Catalytic synthesis of optical active cyanhydrin compound by using cyanhydrin catenase - Google Patents
Catalytic synthesis of optical active cyanhydrin compound by using cyanhydrin catenase Download PDFInfo
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- CN1093531C CN1093531C CN98110818A CN98110818A CN1093531C CN 1093531 C CN1093531 C CN 1093531C CN 98110818 A CN98110818 A CN 98110818A CN 98110818 A CN98110818 A CN 98110818A CN 1093531 C CN1093531 C CN 1093531C
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- cyanalcohol
- cyanhydrin
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Abstract
本发明是以杏仁为酶源的R-氰醇裂解酶催化分子式为R1COR2的羰基化合物、分子式为R3CN的氰化物在有机溶剂中生成(见式a)，光学活性的氰醇化合物，反应温度为0-50℃，反应时间为0.01-120h，其中R1＝R4Ph，R4OPh，R4OCH2Ph，(见式b)，PhCH＝CH，R5CH＝CH，(见式c)或R5，R2＝H或C1-3的烷基，R3＝H，(CH3)2COH或H2COH，R4＝H或C1-4的烷基，X＝O或S，R5＝C1-8的烷基。所述的有机溶剂可含有微量水。反应底物和溶剂的混合物可以以流动相连续通过固定酶而获高产率、高度立体选择性的产物，尤其适于工业化生产。
The present invention uses almond as the enzyme source R-cyanohydrin lyase to catalyze carbonyl compounds with molecular formula R 1 COR 2 and cyanide with molecular formula R 3 CN in an organic solvent (see formula a), optically active cyanohydrin Compound, the reaction temperature is 0-50°C, the reaction time is 0.01-120h, wherein R 1 =R 4 Ph, R 4 OPh, R 4 OCH 2 Ph, (see formula b), PhCH=CH, R 5 CH=CH , (see formula c) or R 5 , R 2 =H or C 1-3 alkyl, R 3 =H, (CH 3 ) 2 COH or H 2 COH, R 4 =H or C 1-4 alkane group, X=O or S, R 5 =C 1-8 alkyl. The organic solvent may contain a small amount of water. The mixture of the reaction substrate and the solvent can be continuously passed through the immobilized enzyme as a mobile phase to obtain a product with high yield and high stereoselectivity, which is especially suitable for industrial production.
Description
The present invention relates to a kind of enzyme catalysis synthesis of optically active cyanohydrin compound, furtherly with the cyanalcohol lyase at organic solvent or contain catalysis synthesis of optically active cyanohydrin compound in the organic solvent system of little water.
Cyanohydrin compound is important organic synthesis intermediate, can change into compounds such as alpha-alcohol ketone, alpha hydroxy acid, beta-amido alcohol, amido nitrile and aziridine easily.Chemosynthesis product is racemic cyanohydrin compound under the no enzyme catalysis condition, because enzyme develops into enzyme catalysis synthesis of optically active cyanohydrin compound from chemosynthesis to height chemistry, zone and spatial specificity and the enzyme reaction mild condition of reaction.Almond (Almond) is an enzyme source easily, the R-cyanalcohol lyase that is made by the almond source ((R)-oxynitrilase) catalysis synthesis of optically active cyanohydrin compound has carried out studying (Griengl, H etc., J.Chem.Soc., Chem.Commun.1997,1933), with existing (Kiljunen, the E etc. of reporting of the R-cyanalcohol lyase catalyzed reaction of rough enzyme and pure enzyme, Tetrahedron, Asymmetry, 1996,7.1105; 1997,8,1225; 1997,8,1551; Effenberger, F.Angew., Chem.Int.Ed.Engl., 1994,33,1555; Enantiomer., 1996,1,359).Usually the water damping fluid is as the satisfied reaction conditions (Brussee, J etc., Tetrahedron, 1990,46,979) and the water-organic solvent two-phase reaction system of development afterwards.Because carbonyl compound and enzyme have lipophilicity and wetting ability respectively, in the profit two phase reaction, react inhomogeneous, and aqueous phase easily produces the racemization product of chemical addition and cause product ee value low, purification difficult is difficult to suitability for industrialized production.So, seek the focus that new reaction system of R-cyanalcohol lyase and method are still research.
The purpose of this invention is to provide a kind of reaction system and method for preparing the optical active cyanalcohol compound with R-cyanalcohol lyase catalyzed reaction.
Another object of the present invention provides a kind of processing method that adopts above-mentioned reaction system to produce optically active cyanohydrin compound.
The present invention is system and the method that generates the optical active cyanalcohol compound with R-cyanalcohol lyase catalysis of carbonyl compound and prussiate reaction, promptly is R with the molecular formula
1COR
2Carbonyl compound, molecular formula be R
3The prussiate of CN, in organic solvent and 0-50 ℃ the time, R-cyanalcohol lyase catalyzed reaction 0.01-120 hour, 0.05-48 hour recommendation response time, wherein R
1=R
4Ph, R
4OPh, R
4OCH
2Ph,
PhCH=CH, R
5CH=CH,
Or R
5, R
2=H or C
1-3Alkyl, R
3=H, (CH
3)
2COH or HCOH, R
4=H or C
1-4Alkyl, X=O or S, R
5=C
1-8Alkyl.The mol ratio of described carbonyl compound and prussiate is 1: 0.8-20, recommend than being 1: 1-5.The amount ratio of carbonyl compound and R-cyanalcohol lyase is 0.001-100mol carbonyl compound/1 gram R-cyanalcohol lyase, recommends 0.005-20mol carbonyl compound/1 gram R-cyanalcohol lyase.Described solvent can be the solvent commonly used such as ester, ether, aromatic hydrocarbons, substituted arene, alkane, haloalkane, ketone or dimethyl formamide of low carbon chain.As methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, sherwood oil, octane, hexanaphthene, ether, isopropyl ether, ethyl isobutyl ether, isoamyl oxide, methyl-phenoxide, benzene,toluene,xylene, methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride, trichloroethane etc.
Described R-cyanalcohol lyase can adopt rough cellas powder.Above-mentioned organic solvent can contain the water of 0-1% weight.Recommend to contain in the organic solvent water of 0.01-0.8% weight.
Organic solvent described in the present invention can be the water that contains trace in the organic solvent; Also can in water, behind the prepared in reaction HCN, obtain in the organic phase of minor amount of water by acetic acid or mineral acid and NaCN by organic solvent extraction HCN.Usually also contain water in the rough cellas.Cyanidization agent described in the present invention can be HCN, also can be acetone cyanohydrin, formaldehyde cyanalcohol etc.
When adopting method of the present invention to produce optically active cyanohydrin compound, not only can synthesize under these conditions with in the reactor, and can adopt carbonyl compound, prussiate and with the mixture of organic solvent as moving phase, Continuous Flow is crossed the technology of R-cyanalcohol lyase fixed bed, as shown in Figure 1.Fill R-cyanalcohol lyase in reaction column (1), this post can have chuck (2), so that temperature control, mixing tank is equipped with carbonyl compound, prussiate and solvent in (3), and moving phase flows into reaction column (1), can collect product from the other end outlet storage tank (4).Can also be that moving phase enters the preposition constant flow pump of reaction column (1) (5), dispose a valve (6), so that the control flow velocity in the outlet of reaction column the other end moving phase.In order to prevent that the moving phase storage liquid in the mixing tank (3) from chemical addition reaction taking place and cause product ee ratio to descend, the most handy ice bath cooling of mixing tank (3).When adopting constant flow pump (5), moving phase also can flow into from reaction column (1) bottom, and product flows out from the top on the contrary.
Adopt system of the present invention and method, compare with organic-water two-phase system, easy and simple to handle, each substrate is easy to contact with enzyme, easily separated and the purifying of product, enzyme is stablized and is not run off, and can recycle repeatedly, owing to be difficult in this system producing non-zymochemistry addition reaction, improved the stereoselectivity of reaction.Expanded range of reaction temperature, improved speed of response, made enzyme-catalyzed reaction condition more loose.Especially continuous flow phase enzymic catalytic reaction technology is more suitable for need of industrial production.
Following embodiment will help to understand the present invention, but not place restrictions on content of the present invention.
Embodiment 1
Fresh or the old almond of 100 grams is pulverized, stirred 1 hour with 200ml ethyl acetate, acetone or ether, filter, repeated washing is 2-4 time again, and the rough ester Semen Armeniacae Amarum powder that takes off that is obtained is that R-cyanalcohol lyase is stored in the refrigerator standby.
Behind sodium cyanide and Glacial acetic acid or the sulfuric acid reaction, obtain to contain prussic acid organic solvent solution, anhydrous Na with solvent extraction process
2SO
4Use dry back.Perhaps directly HCN reagent is added the organic solvent that contains 0-1% weight water.The above-mentioned rough cellas powder of 500mg (R-cyanalcohol lyase), 2.5mmol carbonyl compound and the 2.5-10mmolHCN in the 10ml solvent are stirred in reaction flask; in temperature shown in the following table and reaction times reaction; the rough enzyme of filtered and recycled then; filtrate concentrates; the crude product purification by silica gel column chromatography; after making the acetic ester or other derivative of O-protection; the asymmetric purity of cyanohydrin compound is carried out chirality high-pressure liquid phase method mensuration with CHI RALPAK AD post, and productive rate and ee% value the results are shown in table 1.
As a comparison, add in the same system 5% (v/v) 0.02M citric acid solution (pH5.5) two-phase system the results are shown in table 2.
Table 1.
Table 2.
* R
1=PhCH=CH, R
2During=H, in aqueous media, can not obtain cyanohydrin compound (Brussee, J etc., Tetrahedron, 1990,46,979).The above-claimed cpd analytical results is as follows: (R)-(+)-and 2-hydroxyl-2-phenylacetonitrile
| Carbonyl compound * | Solvent | Reaction times hour | Temperature ℃ | Productive rate % | ee ％ | |
| R 1 | R 2 | |||||
| Ph 2-furans | H H | Isopropyl ether+buffered soln ethyl acetate+buffered soln isopropyl ether+buffered soln isopropyl ether+buffered soln | 48 24 24 12 | 4 30 30 30 | 92 65 77 70 | 97.5 92 93.9 73 |
[α]
D 20：+50.1°(C.1.89 CHCl
3)；ee＞99％；
1H NMR，δ ppm：3.70(S，1H，OH)，5.50(S，1H，CH)；
7.50(brs，5H)；
IR，cm
-1：3414，3066，3036，2250，1495，1456，1406，1196，
1043，765，701；
MS(m/z)：133(M+，78)，132(M
+-1，50)，116(29)，
115(43)，106(38)，105(92)，91(14)，77(100)，
59(9)，51(45)，43(21)。(R)-(+)-2-hydroxyl-2-(4-p-methoxy-phenyl) acetonitrile
[α]
D 18：+48.5°(C.0.89，CHCl
3)；ee＝92.4％；
1H NMR，δppm：3.18(S，1H，OH)，3.82(S，3H，CH
3O)，
5.46(S，1H，CH)，6.94(d，2H，J＝8.7Hz)，
7.43(d，2H，J＝8.7Hz)；
IR，cm
-1：3398，2248，1613，1515，1023，823；
MS(m/z)：163(M
+，2)，137(11)，136(91)，135(100)，
107(15)，92(14)，77(25)，63(9)，51(5)。(R)-(+)-2-hydroxyl-2-(2-furyl) acetonitrile
[α]
D 21：+50.0°(C.1.60，CHCl
3)；ee＝99％；
1H NMR，δppm：3.17(brs，1H，OH)，5.55(S，1H，CH)，
(6.43 dd, 1H, J=1.9Hz, J=3.3Hz, furans hydrogen),
(6.6 m, 1H, furans hydrogen), 7.49 (m, 1H, furans hydrogen)
IR，cm
-1：3403，2256，1500，1400，1269，1234，1149，1030，750；
MS(m/z)：123(M
+，53)，106(64)，97(27)，96(87)，95
(100)，91(70)，77(28)，68(42)，57(76)，43(52)。(R)-(+)-the 2-hydroxy-4-phenyl-(E)-butylene-3-nitrile
[α]
D 13：+26.1°(0.78，CHCl
3)；ee＝69.3％；
1H NMR，δppm：3.00(d，1H，J＝7Hz，OH)，5.17(t，1H，J＝
5.9Hz，CH)，6.27(dd，1H，J＝5.9Hz，J＝15.9Hz，
＝CH)，6.92(d，1H，J＝15.9Hz，＝CH)，
7.33-7.44(m，5H)；
IR，cm
-1：3358，3030，2253，1654，1492，1415，1300，1088，
1024，976，925，756，695；
MS(m/z)：159(M
+，62)，142(18)，133(96)，132(44)，
131(100)，130(78)，115(35)，105(26)，104(35)，
103(44)，91(35)，78(25)，77(34)，63(15)，
51(24)，43(0.7)。(R)-(+)-2-hydroxy-2-methyl-own nitrile [α]
D 22:+2.2 ° (C 1.33, CHCl
3); Ee=98.6%;
1H NMR, and δ ppm:0.94 (t, 3H, J=7.1Hz, 6-H), 1.24 (t, 2H, J=
7Hz，5-H)，1.35-1.51(m，2H，4-H)，1.59(s，3H，
1-H)，1.73-1.79(m，2H，3-H)； IR，cm
-1：3445，2961，2938，2875，2242，1465，1379，1172，
1143，1063，957，887； MS(m/z)：127(M
+，0.7)，121(0.2)，110(5)，102(13)，
101(100)，94(1)，85(3)，83(5)，71(13)，
68(6)，57(8)，43(14)。(R)-(+)-2-hydroxyl-2-phenyl propionitrile [α]
D 17:+4.6 ° (C 0.47, CHCl
3); Ee=78.1%;
1H NMR, δ ppm:IR, cm
-1: 3421,2927,2856,2250,1494,1451,1371,1226,
1101，764，699； MS(m/z)：149(M
++2，9)，148(M
++1，5)，147(M
+，36)，132
(100)，121(10)，105(55)，91(5)，77(34)，63(4)，
51(20)，43(14)。(S)-2-(2)-(5-thiotolene)-2-hydroxyacetonitrile
1H NMRδppm：1.15(s，3H，CH
3)，3.40(br，s，1H，OH)，
6.59-7.20(m，2H，Ar-H)； MS(m/z)：135(M
+，25)，136(48)，127(100)。(S)-2-(2)-(5-normal-butyl furans)-2-hydroxyacetonitrile
1H NMRδppm：0.89(t，3H，CH3)，1.24-1.70(m，6H，(CH
2)
3)，
3.20(br，s，1H，OH)，5.58(s，1H，CH)，6.45-
(7.21 m, 2H, furans hydrogen); MS (m/z): 179 (M
+, 48), 162 (68), 153 (42), 151 (100).(R)-2-hydroxyl-2-(to methylol) phenylacetonitrile
1H NMR δ ppm:3.35 (s, 1H, OH), 3.98 (s, 1H, OH),
4.68(s，2H，CH
2)，5.43(s，1H，CH)，
6.88(d，2H，Harom)，7.36(d，2H，Harom)；
MS(m/z)：163(M
+，10)，137(21)，135(100)，77(31)。
(R)-2-hydroxyl-2-hexene-2-acetonitrile
1H NMRδppm：0.88(t，3H，CH3)，1.22-1.68(m，6H，(CH
2)
3)，
3.20(d，1H，OH)，5.10(t，1H，CH)，6.05-
6.48(m，2H，CH＝CH)；
MS(m/z)：139(M
+，31)，122(64)，113(100)。
(R)-2-hydroxyl-2-(2-naphthyl) acetonitrile
[α]
D 20：+21°(C.0.78，CHCl
3)；
1H NMRδppm：2.65(brs，1H，OH)，5.72(s，1H，CH)，
7.5-7.7(m，3H，Ar-H)，7.8-8.0(m，4H，Ar-H)，
MS m/z：183(M
+，20)，166(65)，157(100)。
Embodiment 2
In the device as shown in Figure 1, Φ is equipped with 1 described rough Semen Armeniacae Amarum powder enzyme 15 grams with embodiment in the reaction column (1) of 1 * L45cm, use the 10mmol carbonyl compound respectively at every turn, the isopropyl ether of 15mmol HCN and 50ml, at room temperature, flow rate of mobile phase is that 1ml/15min passes through reaction column (1), collect reactant, concentrate, silica gel column chromatography, product change into acetic ester (H.Griengl, Tetrahedron, 52 (23), 7833-7840,1996) make the HPLC chiral separation.The result is as shown in table 3.
Table 3.
| The running number of times | PhCHO mmol | HCN mmol | Isopropyl ether ml | Productive rate % | ee ％ |
| 1 2 3 4 | 10 10 10 10 | 15 15 15 15 | 100 100 100 100 | 98.5 99.6 100 100 | 95 98.3 96.8 97 |
Flow rate of mobile phase changes to 1ml/1min, when temperature of reaction is 20 ℃, the results are shown in table 4.
Table 4.
| Cycle index | PhCHO mmol | HCN mmol | Virahol ml | Productive rate % | ee ％ |
| 4 13 25 32 50 110 150 200 | 10 10 10 10 10 10 10 10 | 15 15 15 15 15 15 15 15 | 50 50 50 50 50 50 50 50 | 91 92 95 94 91 89 90 89 | 98.9 99.5 99.4 ＞99.5 99.6 99.3 99.6 99.5 |
Synthesizing of embodiment 3. (acetone) cyanalcohol
Acetone cyanohydrin and formaldehyde cyanalcohol can be used as the cyano group source of enzyme reaction, replace the bigger HCN of toxicity.With embodiment 2,10 ℃ of temperature of reaction, flow rate of mobile phase is 1ml/15min, the result such as the table 5 of enzyme catalysis phenyl aldehyde and acetone cyanohydrin.
Table 5
Synthesizing of embodiment 4.2-hydroxyl-2-furyl acetonitrile
With embodiment 2,10mmol furfural, 15mmol prussic acid and 100ml benzole soln is mixed, and by reaction column (1), post-treating method is identical with the flow velocity of 0.1ml/min, productive rate 100%, and the ee value is 93%.
Embodiment 5
With embodiment 4, temperature of reaction is 15 ℃, and flow rate of mobile phase is 0.8ml/min, and the results are shown in Table 6.
Table 6
Claims (7)
1. one kind is the method for the R-catalytic synthesis of optical active cyanhydrin compound by using cyanhydrin catenase in enzyme source with the almond, it is characterized in that molecular formula is R
1COR
2Carbonyl compound, molecular formula be R
3The prussiate of CN, in organic solvent and 0-50 ℃ the time, R-cyanalcohol lyase catalyzed reaction 0.01-120 hour, wherein R
1=R
4Ph, R
4OPh, R
4OCH
2Ph,
PhCH=CH, R
5CH=CH,
Or R
5, R
2=H or C
1-
3Alkyl, R
3=H, (CH
3)
2COH or HCOH, R
4=H or C
1-4Alkyl, X=O or S, R
5=C
1-8Alkyl, the mol ratio of described carbonyl compound and prussiate is 1: 0.8-20, the amount ratio of carbonyl compound and R-cyanalcohol lyase are 0.001-100mol carbonyl compound/1 gram R-cyanalcohol lyase, and described organic solvent contains the water of 0-1% weight.
2. the method for R-cyanalcohol lyase catalysis synthesis of optically active cyanalcohol as claimed in claim 1 is characterized in that described carbonyl compound and prussiate mol ratio 1: 1-5.
3. the method for R-cyanalcohol lyase catalysis synthesis of optically active cyanalcohol as claimed in claim 1, the amount ratio that it is characterized in that its compound of described carbonyl and R-cyanalcohol lyase are 0.005-20mol/1 gram R-cyanalcohol lyase.
4. as the method for claims 1 described R-catalytic synthesis of optical active cyanhydrin compound by using cyanhydrin catenase, it is characterized in that described organic solvent contains the water of 0.01-0.8% weight.
5. the method for R-catalytic synthesis of optical active cyanhydrin compound by using cyanhydrin catenase as claimed in claim 1 is characterized in that described R-cyanalcohol lyase is the thick cellas through skimming treatment.
6. the method for R-catalytic synthesis of optical active cyanhydrin compound by using cyanhydrin catenase as claimed in claim 6 is characterized in that the reaction times is 0.05-48 hour.
7. the method for R-catalytic synthesis of optical active cyanhydrin compound by using cyanhydrin catenase as claimed in claim 1, it is characterized in that described carbonyl compound, prussiate and ORGANIC SOLVENT MIXTURES with moving phase by R-cyanalcohol lyase fixed bed.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1970535B (en) * | 2006-12-01 | 2012-05-30 | 中国科学院上海有机化学研究所 | Preparation method of cycloprothrin optical activity isomer |
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|---|---|---|---|---|
| CN1083009C (en) * | 1999-07-16 | 2002-04-17 | 中国科学院上海有机化学研究所 | Process for synthesizing optically active cyanohydrin compound by oxynitrile cracking and enzyme catalysis of new enzyme source |
| CN106032531B (en) * | 2015-08-07 | 2019-11-08 | 上海弈柯莱生物医药科技有限公司 | A kind of cyanalcohol lyases, preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1075166A (en) * | 1991-12-17 | 1993-08-11 | Fmc有限公司 | Method with preparing optically active cyanohydrins with enzymes |
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| CN1075166A (en) * | 1991-12-17 | 1993-08-11 | Fmc有限公司 | Method with preparing optically active cyanohydrins with enzymes |
Cited By (1)
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|---|---|---|---|---|
| CN1970535B (en) * | 2006-12-01 | 2012-05-30 | 中国科学院上海有机化学研究所 | Preparation method of cycloprothrin optical activity isomer |
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