CN1243879A

CN1243879A - Chiral cyanohydrin compound and its derivatives and preparing process

Info

Publication number: CN1243879A
Application number: CN 99113883
Authority: CN
Inventors: 林国强; 韩世清; 李祖义
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 1999-07-16
Filing date: 1999-07-16
Publication date: 2000-02-09

Abstract

The present invention relates to a chiral cyanohydrin compound and its derivatives, part of which are prepared mainly by the addition reaction of ACHO on HCN under the catalysis of oxynitrilase. Its advantages are simple process and continuous industrial production.

Description

Chiral cyanohydrin compound and derivative thereof and preparation method

The present invention relates to a class chiral cyanohydrin compound and a derivative thereof.Specifically comprising optically active nitrogen heterocyclic cyanalcohol, fluorine substituted aroma aldehyde cyanalcohol and derivative thereof etc., is by R-oxynitrilase catalysis aldehydes or ketones and HCN reaction and synthesize.

Optical active cyanalcohol and derivative thereof are the important intermediates of a class, functional group in the molecule easily is converted into many chiral compounds that have, as Alpha-hydroxy alcohol, Alpha-hydroxy aldehydes or ketones, alpha hydroxy acid, a-amino acid, beta-alkamine, cyanamide, nitrogen pyridine, imidazolyl heterocycles etc. are the important source material of synthesis of chiral medicine and intermediate.The structural unit that all contains chiral cyanohydrin and relevant derivative in many chiral drugs and the pesticide structure.Usually the synthetic of optical active cyanalcohol is to utilize HCN that the chemical addition reaction of aldehydes or ketones is realized, what obtain is a mapping isomer, needs to split.Inducing cyano group that aldehydes or ketones is carried out asymmetric reduction reaction with enzyme catalysis develops along with the synthetic needs of chiral drug and agricultural chemicals and imitation biochemistry compound thereof with the method that obtains optical active cyanalcohol and derivative thereof, woods Guoqiang etc. had once reported the method (CN98110818.0) with the oxynitrilase catalysis synthesis of optically active cyanohydrin compound of extraction separation in the almond, had developed a kind of industrial continuous production method that is suitable for.Though a lot of medicines have the modular construction of chirality nitrogen heterocyclic or fluorine substituted aroma aldehyde cyanalcohol, no matter still be enzyme catalysis synthesis of chiral pyrroles cyanalcohol, contain two heteroatoms five-ring aldehyde cyanalcohols, all manque report of fluorine substituted aroma aldehyde cyanalcohol so far from chemosynthesis.In order to satisfy people's continuous needs, still need constantly provide new chiral cyanohydrin and derivative thereof.

The purpose of this invention is to provide new chiral cyanohydrin of a class and derivative thereof, specifically R-cyanalcohol and derivative thereof.

The object of the invention also provides a kind of method for preparing above-mentioned chiral cyanohydrin and derivative thereof, this method be utilize that raw material is easy to get, R-oxynitrilase that preparation and the easy enzyme of purification process source make, carry out asymmetric reduction reaction by enzyme catalysis HCN and aldehydes or ketones and make.

Chiral cyanohydrin provided by the invention and derivative thereof have following structural formula: A=

B=H or

, n=1-5, m=1-2, R=H, C _1-4Alkyl,

(being called for short Ts),

(simplifying Boc), CH ₃OCH ₂-(being called for short MOM), as

The preparation method of above-mentioned chiral nitriles alcohol of the present invention and derivative, be with thick nitrile alcoholase as catalyzer, being ACHO with molecular formula in solvent is arranged makes as raw material and HCN reaction

This product and acetic acid reaction can obtain Wherein A as previously mentioned.

Aldehyde described in the present invention and HCN mol ratio are 1: 0.8-20, and the weight ratio of thick nitrile alcoholase and aldehyde is 1: 0.001-200, react above-mentioned substance 0.01-120 hour in organic solvent and under 0-45 ℃.Adopt more HCN or thick nitrile alcoholase to not influence of reaction.Recommending aldehyde and HCN mol ratio is 1: 1-5, the weight ratio of thick oxynitrilase and aldehyde is 0.005-20.Temperature of reaction is 0-35 ℃, and the reaction times is 0.05-48 hour.

The solvent that adopts in the reaction can be the common solvent such as ester, ether, aromatic hydrocarbons, substituted arene, alkane, haloalkane, alcohol or dimethyl formamide of low carbon chain.As methyl-formiate, ethyl formate, ethyl acetate, sherwood oil, kerosene, hexanaphthene, ether butyl ether, isopropyl ether, different octyl ether, isoamyl oxide, methyl alcohol, ethanol, Virahol, methyl-phenoxide, benzene, toluene, trichloromethane, trichloromethane, tetracol phenixin, trichloroethane etc.

Can contain water in reaction system, water content is the water of 0-10% weight.For favourable reaction is carried out, recommend to contain the water of 0.01-2% weight.The moisture content that contains in the reaction system also can be in the contained water belt body system of solvent, reagent or thick nitrile alcoholase.

This reaction not only can be finished under these conditions with in reaction flask, pipe or the pot, also can adopt aldehyde cpd, HCN and organic solvent as moving phase, and Continuous Flow is crossed thick pure cyanogen enzyme fixed bed, and reaction is constantly carried out rapidly, continuously.

Thick pure cyanogen enzyme of the present invention means the thick pure cyanogen enzyme that is obtained as the enzyme source by Semen Armeniacae Amarum, peach kernel, loquat benevolence or Herba Viviae Sativae seed, above-mentioned kernel or seed is broken in historrhexis's machine, the organic solvent washing of doubly measuring with 1-10 takes off ester 1-9 time, promptly obtains thick oxynitrilase.It is standby that this enzyme powder preferably places refrigerator to store, and described kernel or seed are preferably cleaned in advance, dried and allowance for bark.Described organic solvent can be the common solvent such as alcohol, ether, ester, ketone, ethyl ester, sherwood oil, haloalkane, benzene or acetonitrile of low carbon bond.

Make with aforesaid method

With the aceticanhydride mol ratio be 1: during 1-10, in the presence of organic solvent room temperature reaction 0.5-5 hour, can generate

Compound of the present invention can be used for further synthesizing asymmetric medicine, agricultural chemicals and imitation biochemistry compound.Adopt oxynitrilase catalysis process of the present invention, help with N-protected base strategy, synthesized the azepine pyrrole ring cyanohydrin compound of (R)-configuration, when using the MOM blocking group, the cyanalcohol stereoselectivity of acquisition is up to 81%.Obtained 98% productive rate and 66.4%ee when being substrate with 3-(5 cyano group-N-methyl) pyrrole aldehyde.Obtain R-2-hydroxyl-2-(2-thiazole) cyanalcohol of 99% productive rate and 67% ratio when containing two heteroatomic 2-(1,3-thiazoles) formaldehyde for substrate.Pyridine-3-aldehyde has obtained R-2-hydroxyl-2-(3-pyridine) cyanalcohol of 94% productive rate and 50%ee value during for substrate, chirality fluorine or nitro substituted aroma alcohol have been synthesized, for the asymmetric hydroxyl cyanogenation of 4-fluorobenzaldehyde substrate, obtained R-2-hydroxyl-2-(4-fluorophenyl) cyanalcohol of 90% productive rate and 94.2%ee value.

Adopt method of the present invention, not only simple and easy, in little aqueous systems, suppressed chemical addition reaction, improved the ee value of reaction, need not regulate and control pH value, the temperature of reaction scope of application is looser, and make carrier with natural cellulose in the thick oxynitrilase, the Semen Armeniacae Amarum powder of degreasing, the Radix Eriobotryae powder, peach kernel powder or Herba Viviae Sativae seed meal are natural immobilized oxynitrilase, overcome enzyme purification, immobilized tired latching operation, realized the stable repeated use of enzyme under the high production flux (reaching 3630g/ days), the enzyme column performance is not seen any decline, obtains high yield, the optical purity product of highly-solid selectively.Method of the present invention is a kind of method of the convenient and practical asymmetric synthesis optical active cyanalcohol that is easy to suitability for industrialized production.

The present invention will be helped further to understand by following embodiment, but content of the present invention can not be limited.

Embodiment 1 thick oxynitrilase powder preparation

Historrhexis's crusher machine is cleaned, allowances for bark, dries, used to Semen Armeniacae Amarum, Radix Eriobotryae, peach kernel or Herba Viviae Sativae seed 100 grams, and the conventional skimming treatment of solvent is filtered, and sieves with 100 orders, obtains thick oxynitrilase powder, is stored in the refrigerator stand-by.

Embodiment 2

The ethyl acetate solution 10ml that adds the thick oxynitrilase powder of 0.5 gram, 10mmol aldehyde, 11-15mmol HCN in this reaction flask, stirring reaction, filtering the thick enzyme powder that obtains can reuse.Rapid column chromatography purifying (ethyl acetate/petroleum ether, 1/6) desolventizes and obtains product, and it is as shown in the table for the result: sequence number aldehyde temperature ℃ reaction times product productive rate ^*Ee ^*

(hour) % %1 Semen Armeniacae Amarum

30 46

95 592 30 24

85 623

30 72

90 684 Semen Armeniacae Amarums 20 168

96 70.35 Radix Eriobotryaes

25 84

94 786 big nest elements

30 46 90 697 peach kernels

20 96

96 40.18 Radix Eriobotryaes

25 300 90 21.49 Herba Viviae Sativaes 45 24

83 17.310 peach kernels 20 168

86 5811

30 24 87 8112

45 24

92 22.3 ^*Column chromatography chromatogram separation and purification productive rate.Productive rate calculates by the conversion thing that breaks off the base. ^*The ee value splits through the chiral column high-pressure liquid phase and measures.(R)-(+)-the light yellow oily liquid of 2-hydroxyl-2-(2-N-Ts) pyrroles acetonitrile.Ts-p-toluenesulfonyl [α] _D ²⁵+ 60 (c 0.83, CHCl ₃), ee=59%. ¹H NMR: δ, 2.42 (s, 3H, CH ₃); 3.50 (br, s, 1H, OH), 5.92 (s, 1H, CH); 6.30 (t, 1H, J=3.5Hz, Pyrr-H); 6.66 (ddd, 1H, J1=3.5Hz, J2=1.7Hz, J3=0.5Hz, Pyrr-H); 7.30 (dd, 1H, J1=3.3Hz, J2=1.7Hz, Pyrr-H); 7.33 (ABX, 2H, J1=8.5Hz, J2=0.5Hz, Ar-H); 7.77 (ABX, 2H, J1=8.5Hz, J2=0.5Hz, Ar-H); 7.77 (ABX, 2H, J1=8.5Hz, J2=1.9Hz, Ar-H). ¹³C NMR: δ, 146.01 (t-C-Ph); 135.40 (t-C-Ph); 130.28 (C-Ph); 129.10 (t-C-Pyrr); 127.07 (C-Ph); 125.37 (C-Pyrr); 117.23 (CN); 116.97 (C-Pyrr); 112.13 (C-Pyrr); 56.57 (CHOH); 21.69 (CH ₃). IR:3429,3150,2927,1597,1495,1471,1403,1371,1175,1151,672,591.MS:m/z (intensity %): 277 (M ⁺+ 1,2), 276 (M ⁺, 12), 259 (16), 250 (25), 195 (2), 185 (9), 155 (41), 139 (7), 121 (12), 105 (18), 91 (100), 65 (26) .HRMS:C ₁₃H ₁₂N ₂O ₃S (M): measured value 276.0561, calculated value 276.0569 (+)-2-hydroxyl-2-(2-N-Boc) pyrroles acetonitrile light yellow oil.Boc-tert-butoxy formyl radical [α] _D ²⁵+ 44 (c1.0, CHCl ₃), ee=62%. ¹H?NMR：δ，1.64(s，9H，t-Bu)；4.95(br，s，1H，OH)；5.65(s，1H，CH)；6.16(m，1H，Pyrr-H)；6.45(m，1H，Pyrr-H)；7.24(m，1H，Pyrr-H)。IR:3444,3159,2984,2938,1743,1480,1460,1416,1353,1327,1129,7436.MS:m/z (intensity %): 222 (M ⁺, 2), 205 (6), 196 (5), 167 (4), 149 (3), 140 (60), 122 (40), 105 (20), 95 (9), 57 (100), 41 (32) .HRMS:C ₁₁H ₁₄N ₂O ₃(M): measured value 222.1003, calculated value 222.1004.2-(3-N-Boc indoles)-2-hydroxyl-acetonitrile oily liquids.[α] _D ²⁰+ 19.4 (c0.333, CHCl ₃), ee=68%. ¹H NMR: δ, 1.68 (s, 9H, t-Bu); 3.22 (br, s, 1H, OH); 5.75 (s, 1H, CH); 7.26-7.41 (m.2H, Ar-H); 7.70 (d, 1H, J=7.4Hz, Ar-H); 7.80 (s, 1H, Ar-H); 8.49 (d, 1H, J=8.2Hz, Ar-H) .IR:3491,3123,2987,2932,2243,1730,1597,1573,1451,1370,1160,749.MS:m/z (intensity %): 272 (M ⁺, 2), 245 (12), 216 (12), 189 (49), 172 (17), 145 (43), 116 (20), 89 (11), 57 (100) .HRMS:C ₁₅H ₁₆N ₂O ₃: measured value: 272.1179, calculated value: 272.1161. (+)-2-hydroxyl-2-(2-(N-methoxyl methyl) pyrroles) the light yellow oily liquid of acetonitrile.[α] _D ²⁰+ 104.9 (c0.667, CHCl ₃), ee=81%. ¹H NMR: δ, 3.30 (s, 3H, CH ₃); 3.92 (br, s, 1H, OH); 5.08,5.68 (AB, 2H, J=10.9Hz, CH ₂); 5.56 (s, 1H, CH); 6.13 (dd, 1H, J1=3.5Hz, J2=3.0Hz, Pyrr-H); 6.47 (dd, 1H, J1=3.6Hz, J2=1.7Hz, Pyrr-H); 6.83 (dd, 1H, J1=2.9Hz, J2=1.7Hz, Pyrr-H). ¹³C NMR: δ, 126.38 (t-C-Pyrr); 125.59 (C-Pyrr); 118.01 (CN); 113.18 (C-Pyrr); 108.01 (C-Pyrr); 78.63 (NCH ₂O); 56.55 (CHOH); 55.995 (OCH ₃) .IR:3402,3117,2934,2851,2247,1486,1464,1444,1400,1277,1097,1025,732.MS:m/z (intensity %): 166 (M ⁺, 5), 149 (4), 139 (9), 124 (31), 108 (17), 94 (7), 80 (10), 71 (9), 57 (13), 45 (100), 41 (12) .HRMS:C ₈H ₁₀N ₂O ₂: measured value, 166.742, calculated value, 166.742. (R)-(+)-2-(2-(N-methyl) the pyrroles)-light yellow oily liquid of 2-hydroxyl-acetonitrile.[α] _D ²⁰+35.7(c1.15，EtoH)，ee＝40.1％ ¹HNMR：δ，2.90(br，s，1H，OH)；3.72(s，3H，CH ₃)；5.50(s，1H，CH)；6.09(m，1H，Pyrr-H)；6.38(m，1H，Pyrr-H)；6.67(m，1H，Pyrr-H).

Synthesizing of embodiment 3. chirality methyl pyrroles alcohol nitrile compound

Under the condition that is same as embodiment 2, investigated when making catalyzer with the thick oxynitrilase in synaptase source, during the different substituting group of 5 bit strips of N-methylpyrrole aldehyde to the influence of reaction, reaction temperature product productive rate when the results are shown in table 2 sequence number aldehyde reaction ^*Ee ^*

Between hour the degree ℃ % %1

70 20

78 552

70 20

84 66.43

70 20

99 34.1 (R)-2-hydroxyl-2-[2-(5-ethanoyl-N-methyl) pyrroles] m.p.96-97 ℃ of acetonitrile white solid [α] _D ²⁰+ 38.8 (c0.80, EtOH), ee=34.1% ¹H NMR: δ, (D6-acetone/TMS): 2.40 (s, 3H, CH ₃CO); 3.30 (s, 1H, OH); 3.96 (s, 3H, N-CH ₃); 5.93 (s, 1H, CH); 6.37 (d, 1H, J=4Hz, Pyrr-H); 7.03 (d, 1H, J=4Hz, Pyrr-H) .IR:3337,3200 (w), 3127,2966,2918,2846,2246,1645,1625,1531,1492,1458,1385,1250,1027,768.MS:m/z (intensity %): 179 (M ⁺+ 1,5), 178 (M ⁺, 16), 163 (M ⁺-CH ₃, 15) and .151 (M ⁺-HCN, 100), 136 (M ⁺-CH ₃-HCN, 78), 123 (14), 108 (19), 80 (22), 53 (23), 43 (19). and ultimate analysis: C ₉H ₁₀N ₂O ₂: measured value: C:60.55%, H:5.57%, N:15.78%; Calculated value: C:60.55%, H:5.66%, N:15.73%. (R)-2-hydroxyl-2-(2-(5-itrile group-N-methyl) pyrroles) acetonitrile white solid.M.p.104-105 ℃ of .[α] _D ²⁰+ 24.7 (c0.75, EtOH), ee=66.4%. ¹H NMR: δ (D6-acetone/TMS): 3.30 (s, 1H, OH): 3.82 (s, 3H, N-CH ₃); 5.62 (s, 1H, CH); 6.96 (d, 1H, J=1.8Hz, Pyrr-H); 7.26 (d, 1H, J=1.8Hz, Pyrr-H) .IR:3406,3125,3093,2954,2881,2225 (s, CN), 1561,1484,1414,1398,1214,1135,1052,845,600.MS:m/z (intensity %): 162 (M ⁺+ 1.8), 161 (M ⁺, 34), 144 (M ⁺-OH, 32), 135 (M ⁺-CN, 52), 134 (M ⁺-HCN, 65), 133 (M ⁺-HCN-H, 100), 117 (3), 105 (14), 78 (9), 64 (9) .HRMS:C ₈H ₇N ₃O: measured value: 161.0596, calculated value: 161.0589. (R)-2-hydroxyl-2-[2-(5-chloro-N-methyl) pyrroles] the acetonitrile white solid.Mp 80-81 ℃ of .[α] _D ²⁰+ 45.1 (C0.92, EtOH), ee=70% ¹H NMR: δ, (D6-acetone/TMS): 3.34 (s, 1H, OH); 3.90 (s, 3H, N-CH ₃), 5.81 (s, 1H, CH); 6.56 (d, 1H, J=3Hz, Pyrr-H); 7.00 (d, 1H, J=3Hz, Pyrr-H) .IR:3330,3150,3098,2955,2878,2230,1581,1495,1420,1390,1210,1130,1030,700. ultimate analyses: C ₇H ₇NOCl: measured value: C:53.59%, H:4.61%, N:9.10%, Cl:23.01%; Calculated value: C:53.85%, H:4.49%, N:8.97%, Cl:22.76%.

With (R)-2-hydroxyl-[2-(2-(5-ethanoyl-N-methyl) pyrroles] acetonitrile 1mmol, pyridine 0.1ml, CH ₂Cl ₄3ml, DMAP 1mg, acetic anhydride 0.1-0.2ml, stirring at room 1 hour adds the ether dilution, saturated Na ₂SO ₄Solution washing, anhydrous Na ₂SO ₄Drying concentrates, rapid column chromatography (ethyl acetate/petroleum ether=1: 4 washing composition), and it is as follows to obtain product: (R)-and 2-acetoxyl group-2-(2-5-ethanoyl-N-methyl) pyrroles) the acetonitrile white solid.M.p.94-95 ℃ of .[α] _D ²⁰+ 3.8 (c1.48, CHCl ₃), ee=34.1% ¹H NMR: δ, 2.18 (s, 3H, CH ₃CO ₂); 2.46 (s, 3H, CH ₃CO); 3.97 (s, 3H, CH ₃-N); 6.48 (AB, 1H, J=4Hz, Pyrr-H); 6.51 (s, 1H, CH); 6.92 (AB, 1H, J=4Hz, Pyrr-H) .IR:3130,3113,2928,1764,1661,1533,1486,1460,1382,1209,1024,772.MS:m/z (intensity %): 221 (M ⁺+ 1,15), 220 (M ⁺, 30), 205 (M ⁺-CH ₃, 5), 178 (M ⁺+ 1-CH ₃CO, 89), 161 (100), 150 (6), 132 (16), 119 (45), 117 (44), 43 (64). and ultimate analysis: C ₁₁H ₁₂N ₂O ₃: measured value: C:60.07%, H:5.54%, N:12.71%; Calculated value: C:59.98%, H:5.50%, N:12.73%.

Embodiment 4 contains the chirality of 2 heteroatoms five-ring cyanalcohols and synthesizes

1mmol

Thick almond oxynitrilase powder 0.3 gram, the isoamyl oxide solution 5ml of 1mmol HCN, 15 ℃ were reacted 16-20 hour, filter, with 3 * 10ml washing with acetone enzyme powder, above-mentioned solution for vacuum concentration, must be colourless to light yellow crystal, with 2 * 10ml ether and 3 * 10ml hexane wash crystal, obtain respectively (productive rate 94%) and (productive rate 97), record the ee value to be followed successively by＜5% and 67%.(R)-2-hydroxyl-2-(2-N-Methylimidazole) acetonitrile is colourless to light yellow crystal.Decompose .124 ℃ of .[α] _D ²⁰-2 (c0.30, CH ₃OH), ee＜5%. ¹H NMR: δ, (CD ₃OD/TMS): 4.0 (s, 4H, CH ₃, OH); 6.03 (s, 1H, CH); 7.13 (d, 1H, J=1.0Hz, Im-H); 7.35 (d, 1H, J=1.0Hz, Im-H) .IR:2500-3300 (w), 3148,3062,2817,2693,2065 (CN), 1681,1666,1504,1468,1427,1392,1280,1035,925,748,719.MS:m/z (intensity %): 138 (M ⁺+ 1,11), 137 (M ⁺, 33), 120 (M ⁺-OH, 35), 111 (M ⁺-CN, 36), 111 (M ⁺-HCN, 83), 97 (11), 82 (100), 81 (72), 54 (61), 42 (66). and ultimate analysis: C ₆H ₇N ₃O: measured value: C:52.23%, H:5.12%, N:30.72%, calculated value: C:52.55%, H:5.15%, N:30.64%. (R)-2-hydroxyl-2-(2-thiazole) acetonitrile faint yellow solid.M.p.133-134 ℃ of .[α] _D ²⁰+ 13 (c0.038, EtOH), ee=67%. ¹H NMR: δ, (CD ₃OD/TMS): 6.17 (s, 1H, CH); 7.89 (AB, 1H, Ar-H, J=3.3Hz); 8.03 (AB, 1H, Ar-H, J=3.3Hz) .IR:3125 (w), 2843,2725,1508,1454,1408,1187,1123,1046,909,753.MS:m/z (intensity %): 142 (M ⁺+ 2,4), 141 (M ⁺+ 1,15), 140 (M ⁺, 30), 123 (M ⁺-OH, 13), 114 (M ⁺-CN, 20), 113 (M ⁺-HCN, 26), 95 (8), 86 (68), 85 (51), 58 (100), 45 (21). and ultimate analysis: C ₅H ₄N ₂OS: measured value: C:42.87%, H:2.78%, N:20.03%; Calculated value: C:42.85%, H:2.88%, N:19.98%.

Synthesizing of embodiment 5 chirality fluorine substituted aroma aldehyde cyanalcohols

With 1-2mmol substrate aldehyde, thick oxynitrilase powder 0.2-0.5g, the ethyl acetate of the HCN of mol ratios such as 1-1.5, ether or isoamyl oxide solution 10ml, 10-20 ℃ was reacted rapid column chromatography purifying (ethyl acetate: sherwood oil=1: 4-6) 24-48 hour, obtain product, result such as following table.

Product productive rate during sequence number aldehyde temperature ℃ reaction ^*Ee ^*

Between hour % %1 almond

20 24

90 94.22 Radix Eriobotryaes

4 24

36 77.33 peach kernels 20 24

96 844 peach kernels

28 24 71 84.35 Radix Eriobotryaes

4 24

40 40.16 Herba Viviae Sativae seeds

20 24

92.1 46.17 Herba Viviae Sativae seeds

12 24

70 418 Herba Viviae Sativae seeds

20 24 91 599 almonds

30 3

28.4 3010 peach kernels

12 48

90 35

^*, ^*With table 2.(R)-2-hydroxyl-2-(4-fluoro phenyl) acetonitrile colourless oil liquid.[α] _D ²⁰+ 36.4 (c6.38, CHCl ₃), ee=94.2%. ¹H NMR: δ, 3.39 (br, s, 1H, OH); 5.52 (s, 1H, CH); 7.13 (m, 2H, Ar-H); 7.49 (m, 2H, Ar-H). ¹³F-NMR (CDCl ₃/ TFA, δ ppm) :-33.93 (m, Ar-F) .IR:3410 (w), 2252,1606,1511,1421,1235,1038,837.MS:m/z (intensity %): 151 (M ⁺, 11), 133 (M ⁺-H ₂O, 8), 124 (M ⁺-HCN, 85), 123 (M ⁺-1-HCN, 100), 109 (11), 95 (81), 75 (30) .HRMS, C ₈H ₆FNO: measured value: 151.0413, calculated value: 151.0433. (R)-2-hydroxyl-2-(2-fluoro phenyl) acetonitrile colourless oil liquid.[α] _D ²⁰+ 21.85 (c3.60, CHCl ₃), ee=84%. ¹H NMR: δ, 3.40 (br, s, 1H, OH); 5.78 (s, 1H, CH); 7.14 (m, 1H, Ar-H), 7.24 (td, 1H, J1=7.6Hz, J2=1.1Hz, Ar-H), 7.43 (m, 1H, Ar-H); 7.62 (td, 1H, J1=7.5Hz, J2=1.8Hz, Ar-H). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-41.02 (m, Ar-F) .IR:3412 (w), 3080,2928,2255,1618,1592,1494,1460,1234,1043,759.MS:m/z (intensity %): 151 (M ⁺, 6), 124 (M ⁺-HCN, 67), 123 (M ⁺-1-HCN, 100), 109 (18), 95 (50), 75 (20), 70 (8), 50 (12) .HRMS:C ₈H ₆FNO: measured value: 151.0417, calculated value: 151.0434. (R)-2-hydroxyl-2-(3,4-trifluoro-benzene base) acetonitrile colourless oil liquid.[α] _D ²⁰+ 22.5 (c2.55, CHCl ₃), ee=84.3%. ¹H NMR: δ, 3.00 (br, s, 1H, OH); 5.54 (s, 1H, CH); 7.27 (m, 3H, Ar-H). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-58.3 (m, Ar-F) .IR:3412 (w), 3086,2928,2254 (CN), 1616,1522,1438,1289,1120,1042,875,825,772.MS:m/z (intensity %): 170 (M ⁺+ 1,5), 169 (M ⁺, 49), 158 (3), 152 (24), 142 (74), 141 (100), 123 (26), 114 (26), 113 (67), 63 (35). ultimate analysis C ₈H ₅F ₂NO: calculated value: C:56.81; H:2.98; N, 8.28. measured value: C:57.02; H:3.14; N:8.16. (R)-2-hydroxyl-2-(2,3-phenyl-difluoride base) acetonitrile colourless oil liquid.[α] _D ²⁰+ 10.7 (c3.50, CHCl ₃), ee=46.1%. ¹H NMR: δ, 3.25 (br, s, 1H, OH); 5.81 (s, 1H, CH); 7.17-7.23 (m, 2H, Ar-H); 7.42 (m, 1H, Ar-H). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-59.50 (m, 1F, Ar-F);-65.68 (m, 1F, Ar-F) .IR:3413,2930,2250,1629,1602,1494,1408,1286,1046,794,759.MS:m/z (intensity %): 169 (M ⁺, 53), 152 (M ⁺-OH, 26), 143 (M ⁺-CN, 100), 141 (M ⁺-1-HCN, 50), 123 (40), 115 (12), 114 (15), 63 (20) .HRMS:C ₈H ₅F ₂NO-H ⁺: measured value: 168.0288, calculated value: 168.0261. (R)-2-hydroxyl-2-(2,5-phenyl-difluoride base) acetonitrile colourless oil liquid.[α] _D ²⁰+ 6.7 (c1.90, CHCl ₃), ee=41%. ¹HNMR: δ, 3.37 (d, 1H, J=6.4Hz, OH); 5.77 (d, 1H, J=6.4Hz, CH); 7.12 (m, 2H, Ar-H); 7.35 (m, 1H, Ar-H). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-39.34 (m, 1F, Ar-F);-46.73 (m, 1F, Ar-F) .IR:3437 (w), 3092,2910,2254,1491,1437,1404,1187,1135,1063,877,817,799,745.MS:m/z (intensity %): 170 (M ⁺+ 1,6), 169 (M ⁺, 61), 152 (M ⁺-OH, 27), 149 (30), 142 (80), 141 (100), 125 (19), 123 (59), 115 (21), 114 (31), 113 (57), 95 (20), 63 (40). and ultimate analysis C ₈H ₅F ₂NO: calculated value C, 56.81; H, 2.98, N, 8.28. measured value: C, 57.00; H, 2.96; N, 8.45.HRMS:C ₈H ₅F ₂NO: calculated value: 169.0313, measured value: 169.0340. (R)-2-hydroxyl-2-(3,4,5-trifluoro-benzene base) acetonitrile colourless oil liquid [α] _D ²⁰+ 28.90 (C, 1.50, CHCl ₃), ee=59% ¹HNMR: δ, 3.10 (br, s, 1H, OH); 5.65 (s, 1H, CH); 7.15 (s, 2H, Ar-H). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-58.6 (m, 2F, Ar-F);-49.5 (m, 1F, Ar-F) .IR:3415,2931,2248,1610,1545,1428,1400,1280,1042,810,796,760. ultimate analysis: C ₈H ₄F ₃NO: measured value: C:51.08%, H:2.12%, N:7.28%; Calculated value: C:51.34%, H:2.14%, N:7.49%. (R)-2-hydroxyl-2-phenyl-pentafluoride base acetonitrile clear crystal.M.p.55-56 ℃ of .[α] _D ¹⁸+ 10 (c0.655, CHCl ₃), ee=35%. ¹HNMR: δ, 3.95 (s, 1H, OH); 5.83 (s, 1H, CH). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-82.5 (m, 2F, F-Ar);-72.3 (t, 1F, F-Ar);-64.7 (m, 2F, F-Ar) .IR:3494,2953,2266,1660,1515,1137,1052,1002,894,787,658cm ^-1.MS:m/z (intensity %): 224 (M ⁺+ 1,12), 223 (M ⁺, 100), 206 (78), 203 (31), 197 (43), 196 (32), 195 (43), 177 (41), 168 (20), 167 (21), 149 (10), 117 (23), 99 (19), 56 (7), 43 (0.8). ultimate analysis C ₈H ₂F ₅NO: calculated value C:43.05; H:0.90; N:6.28. measured value: C:42.97; H:0.82; N:6.12.

Embodiment 6

In the dry reaction bottle, add 50mg,

Pyridine 0.1ml, CH ₂Cl ₂3ml, DMAP1mg, acetic anhydride 0.2ml, stirring at room 1-2 hour.Add CH ₂Cl ₂Dilution, saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure, rapid column chromatography (ethyl acetate: sherwood oil=1: it is as follows 10-15) to obtain the product result:

Sequence number product productive rate % ee%1

99 94.22 94 77.33

100 67.14 98 46.15

93 416

96 35 (R)-2-acetoxyl group-2-(4-fluoro phenyl)-acetonitrile colourless oil liquid.[α] _D ²⁰+ 3.83 (c3.40, CHCl ₃), ee=94.2%. ¹H NMR: δ, 2.18 (s, 3H, CH ₃); 6.39 (s, 1H, CH); 7.14 (m, 2H, Ar-H); 7.52 (m, 2H, Ar-H). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-32.6 (m, Ar-F) .IR:3076,2949,1756,1608,1513,1424,1373,1218,1025,835.MS:m/z (intensity %): 194 (M ⁺+ 1,4), 193 (M ⁺, 25), 167 (M ⁺-CN, 1), 151 (M ⁺+ 1-CH ₃CO, 74), 134 (M ⁺-CH ₃CO ₂, 81), 133 (M ⁺-HOAc, 100), 123 (31), 107 (24), 95 (12), 43 (81). and ultimate analysis: C ₁₀H ₈FNO ₂: measured value: C:61.91%, H:4.16%, N:7.20%; Calculated value: C:62.16%, H:4.18%, N:7.25%. (R)-2-acetoxyl group-2-(2-fluoro phenyl) acetonitrile colourless oil liquid .[α] _D ²⁰+ 17.5 (c0.90, CHCl ₃), ee=77.3%. ¹H NMR: δ, 2.18 (s, 3H, CH ₃); 6.63 (s, 1H, CH); 7.16 (m, 1H, Ar-H); 7.26 (m, 1H, Ar-H); 7.47 (m, 1H, Ar-H); 7.64 (m, 1H, Ar-H). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-39.4 (m, Ar-F) .IR:2946,1759,1619,1594,1496,1460,1373,1214,1025,761.MS:m/z (intensity %): 194 (M ⁺+ 1,2), 193 (M ⁺, 5), 167 (M ⁺-CN, 2), 151 (M ⁺+ 1-CH ₃CO, 100), 134 (74), 133 (78), 123 (31), 107 (26), 95 (8), 75 (8), 57 (8), 43 (84) .HRMS:C ₁₀H ₈FNO ₂: measured value: 193.0531, calculated value: 193.0539. (R)-2-acetoxyl group-2-(3,4-phenyl-difluoride base) acetonitrile colourless oil liquid.[α] _D ²⁰+ 3.1 (c1.20, CHCl ₃), 33=67.1%. ¹H NMR: δ, 2.35 (s, 3H, CH ₃); 6.74 (s, 1H, CH); 7.62 (m, 2H, Ar-H); 7.72 (m, 1H, Ar-H). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-57.0 (m, 1F, Ar-F);-57.6 (m, 1F, Ar-F) .IR:3066,2946,1756,1616,1523,1439,1374,1294,1214,1027,825,771cm ^-1.MS:m/z (intensity %): 212 (M ⁺+ 1,5), 211 (M ⁺, 7), 185 (M ⁺-CN, 5), 169 (M ⁺+ H-CH ₃CO, 64), 152 (90), 151 (79), 141 (27), 125 (28), 113 (14), 101 (6), 75 (11), 63 (11), 43 (100) .HRMS:C ₁₀H ₇F ₂NO ₂: measured value: 211.0442, calculated value: 211.0445. (R)-2-acetoxyl group-2-(2,3-phenyl-difluoride base) acetonitrile colourless oil liquid [α] _D ²⁰+ 11.2 (c3.00, CHCl ₃), ee=46.1%. ¹H NMR: δ, 2.18 (s, 3H, CH ₃); 6.62 (s, 1H, CH); 7.21-7.43 (m, 3H, Ar-H). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-63.6 (m, 1F, Ar-F);-59.0 (m, 1F, Ar-F) .IR:3105,3063,2951,1763,1631,1602,1497,1433,1374,1214,1024,790,722.MS:m/z (intensity %): 212 (M ⁺+ 1,0.8), 211 (M ⁺, 3), 185 (M ⁺-CN, 0.7), 169 (M ⁺+ 1-CH ₃CO, 75), 152 (53), 151 (37), 141 (18), 125 (17), 113 (6), 43 (100) .HRMS:C ₁₀H ₇F ₂NO ₂: measured value: 211.0447; Calculated value: 211.0445. (R)-2-acetoxyl group-2-(2,6-phenyl-difluoride base) acetonitrile colourless oil liquid [α] _D ²⁰+ 7.7 (c1.60, CHCl ₃), ee=41%. ¹H NMR: δ, 2.20 (s, 3H, CH ₃CO); 6.59 (s, 1H, CH); 7.16 (m, 2H, Ar-H); 7.35 (m, 1H, Ar-H). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-39.20 (m, 1F, Ar-F);-45.07 (m, 1F, Ar-F) .IR:3088,2940,1761 (CO), 1502,1433,1373,1214,1028,873,825,737.MS:m/z (intensity %): 212 (M ⁺+ 1,1), 211 (M ⁺, 7), 185 (M ⁺-CN, 1), 169 (M ⁺+ 1-CH ₃CO, 99), 152 (55), 151 (55), 141 (26), 125 (23), 113 (7), 43 (100) .HRMS:C ₁₀H ₇F ₂NO ₂: measured value: 211.0448, calculated value: 211.0445. (±)-2-acetoxyl group-2-phenyl-pentafluoride base acetonitrile colourless oil liquid.[α] _D ¹⁸+ 20.3 (c1.28, CHCl ₃), ee=35%. ¹H NMR: δ, 2.19 (s, 1H, CH ₃); 6.68 (s, 1H, CH). ¹⁹F-NMR (CDCl ₃/ TFA, δ ppm) :-82.2 (m, 2F, F-Ar);-70.9 (m, 1F, F-Ar);-62.1 (m, 2F, F-Ar) .IR:2963,1770,1659,1515,1211,1030,908cm ^-1.MS:m/z (intensity %): 266 (M ⁺+ 1,6), 265 (M ⁺, 4), 239 (2), 223 (99), 206 (100), 195 (12), 179 (28), 167 (7), 155 (7), 117 (9), 106 (5), 93 (6), 69 (4), 43 (75) .HRMS:C ₁₀H ₄F ₅NO ₂: measured value: 265.0159, calculated value: 265.0162. ultimate analysis: measured value: F:35.62, calculated value: F:35.83.

Embodiment 7 continuous flow on stationary phase enzyme post is synthetic

Adopt diameter phi 0.7cm, the thick oxynitrilase in dress Radix Eriobotryae enzyme source in the reaction column of length 80cm, the enzyme column volume equals 29ml, with the p-Fluorobenzenecarboxaldehyde that is respectively 1mmol concentration is substrate and HCN, in the time of 15 ℃, pass through the enzyme post with the 3ml/min flow velocity, continuous operation 200 times, sampling analysis the results are shown in table 6 respectively.

The running number of times flows through substrate substrate overall yield at every turn ^???ee ^*?????????????mmol????????mmol??????％???????％
	????1????????10??????????10????????90??????94.5 ????4????????10??????????40????????91??????95.1 ????25???????10??????????250???????89??????94.8 ????50???????10??????????500???????90??????95.7 ????100??????10??????????1000??????90??????95.2 ????150??????10??????????1500??????91??????94.4 ????200??????10??????????2000??????90??????94.6

^*, ^*With table 2.

Claims

1. chiral cyanohydrin compound and derivative thereof is characterized in that having following molecular formula:

A=

B=H or

N=1-5, m=1-2, R=H, C _1-4Alkyl, Or CH ₃OCH ₂-

2. chiral cyanohydrin compound as claimed in claim 1 and derivative thereof is characterized in that having following molecular formula: Wherein B according to claim 1.

3. the preparation method of chiral cyanohydrin compound as claimed in claim 1 and derivative thereof, it is characterized in that making respectively by following reaction: (1) is in organic solvent and 0-45 ℃ the time, molecular formula is that aldehyde and the HCN mol ratio of ACHO is 1: 0.8-20, the weight ratio of thick nitrile alcoholase and aldehyde is 1: 0.001-200, the water that contains 0-10% in the reaction system, 0.05-48 is little in reaction

(2) in organic solvent and under the room temperature,

With the aceticanhydride mol ratio be 1: reaction generated in 0.5-5 hour during 1-10

Wherein A according to claim 1.

4. preparation method as claimed in claim 3 is characterized in that described thick oxynitrilase is the thick oxynitrilase that is obtained through broken, degreasing by Semen Armeniacae Amarum, peach kernel, Radix Eriobotryae or Herba Viviae Sativae seed.

5. preparation method as claimed in claim 3 is characterized in that described thick oxynitrilase contains the moisture content of 8-10%.

6. preparation method as claimed in claim 3 is characterized in that described aldehyde and HCN mol ratio are 1: 1-5.

7. preparation method as claimed in claim 3, the weight ratio that it is characterized in that described thick oxynitrilase and aldehyde is 0.005-20.

8. preparation method as claimed in claim 3 is characterized in that described organic solvent is ester, ether, alcohol, aromatic hydrocarbons, substituted arene, alkane, haloalkane or the dimethyl formamide of low carbon chain.

9. preparation method as claimed in claim 3 is characterized in that thick oxynitrilase as stationary phase, described aldehyde, HCN and ORGANIC SOLVENT MIXTURES be flowing reactive mutually.