CN1743309A - Synthesis of optical active cyanhydrin compound by enzyme chemical process - Google Patents
Synthesis of optical active cyanhydrin compound by enzyme chemical process Download PDFInfo
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Abstract
The present invention relates to a kind of method of synthesis of optical active cyanhydrin compound by enzyme chemical process.This method is by using the hydroxyl-cyanide HNL catalyzed reaction in almond, loquat seed, apple seed, the Badamu seed, represent as above with reaction formula: pass through the inventive method, obtained a kind of new hydroxyl cyanogen compound, this compound can be used for synthesizing multiple compounds such as thiamphenicol, fluorine Ben Nikao.
Description
Technical field
The present invention relates to a kind of enzyme chemical method synthetic method, especially relate to synthesis of optical active cyanhydrin compound by enzyme chemical process.
Background technology
Thiamphenicol and Florfenicol are the chloromycetin broad-spectrum antibiotics.Thiamphenicol antimicrobial spectrum and anti-microbial effect and paraxin are similar, and owing to thiamphenicol does not combine with glucuronic acid in liver, so antibacterial activity in vivo is higher.Florfenicol (florfenicol) 15 claims Florfenicol again, Sch-25298, it is the novel anti gram-positive microorganism that a special exploitation is used for animal health market, negative bacterium and thiamphenicol Florfenicol (florfenicol, Florfenicol) be the animal specific broad spectrum antibiotic, its structure is similar to thiamphenicol, but anti-microbial activity, antimicrobial spectrum and untoward reaction aspect obviously are better than thiamphenicol, and its antibacterial ability can reach 10 times more than of thiamphenicol.
Thiamphenicol and Florfenicol are the microbiotic of a class chemosynthesis, and two chiral centres are arranged, and four isomer are arranged, and wherein have only one pharmacologically active is arranged.The production of thiamphenicol is taked mostly to first sulfone phenyl aldehyde route, (Tobiki Hisao; Ger Offen, DE 2349496) wherein relate to D, the fractionation of L type substituted benzene Serine, L type isomer wherein goes out of use, and makes the economy of whole route be subjected to discount.
A) NaSO
3, NaHCO
3B) CH
3SO
3ONa; C) Br
2.d) NH
2CH
2COOH, CuSO
4, NH
4OH; E) EtOH, H
2SO
4F) tartrate splits; G) NaBH
4H) MeOH, CHCl
2COOEt.
Scheme 3-2
Florfenicol generally from intermediate D-(-)-2-amino-1-[(of thiamphenicol right-methylsulfonyl) phenyl]-1, ammediol synthesizes, a) Clark J E, Schumacher DP, Wu GZ.Process for preparingflorfenicol, its analogues and oxazoline intermediates.US, 5382673.1995, (CA, 1995; 122:187135a); B) Clark J E, Schumacher DP, Wu GZ.An improved process forflorfenicol, its analogues and oxazoline intermediates.WO, 9207824.1992. (CA, 1992; 117:111273v). (Scheme 3-1).
A) two chloromethyl cyanides, sulfuric acid; B) the saturated Virahol of ammonia, 80 ℃, 2h; C) FPA, THF, 100 ℃, 2h; D) potassium acetate, methyl alcohol, Virahol, water, 10h, pH3.5～4.0;
Scheme 3-1
As above-mentioned, the synthetic route of thiamphenicol and Florfenicol has only half middle physical efficiency to be utilized to the target compound of synthetic required configuration because relate to the fractionation of racemoid, causes very big waste.
So need find the new intermediate of synthetic thiamphenicol of a kind of new method and Florfenicol, thereby being used for efficient, high utilization rate ground synthesizes thiamphenicol and Florfenicol.
Summary of the invention
The present invention is by the generation hydroxyl chirality of enzymatic hydroxyl cyanogenation highly selective.This hydroxyl chirality can be used for the chiral centre of establishing target compound thiamphenicol and Florfenicol efficiently.
The invention provides a kind of: in the enzymatic hydroxyl cyanogenation of key with the catalytic hydroxyl cyanogenation of hydroxyl-cyanide, we are by seeking, screening, find hydroxyl-cyanide in almond, loquat seed, apple seed, the Badamu seed can catalysis should reaction, especially originate in this reaction of hydroxyl-cyanide (HNL) catalysis efficiently in the Badamu in Xinjiang.
Described hydroxyl cyanogenation is expressed as follows with reaction formula:
R1 is recommended as C1～C6 alkyl, and this reaction is recommended in organic solvent such as isopropyl ether, ethyl acetate, and methyl tertiary butyl ether carries out in the toluene, and preferred solvent is an isopropyl ether, ethyl acetate.
Described prussiate is recommended acetone cyanohydrin, HCN,
It is the enzyme source that described hydroxyl-cyanide is recommended to adopt almond, loquat seed, apple seed, Badamu seed, and further recommending to adopt the Badamu seed is the enzyme source.
Table 3-1 enzyme source and reaction conditions screening
| Entry | HNL | Solvent | Yield a(％) | e.e. b(％) |
| 1 2 3 4 | Almond loquat loquat apple | DIPE DIPE EA DIPE | 81 70 13 92 | 39 74 42 65 |
| 5 6 7 | Badamu Badamu Badamu | DIPE TBME EA | 95 89 84 | 93 87 95 |
A) column chromatography for separation productive rate; B) the cyanalcohol acetylize is after chirality HPLC mensuration;
Wherein DIPE represents isopropyl ether, TBME represent methylidene tertbutyl ether, and EA represents ethyl acetate, and R represents alkyl.
Further preferred reaction conditions is by the water-content in the fine setting reaction system hydroxyl cyanogenation of aldehyde 1 to be optimized, and finally can obtain cyanalcohol 2 greater than 95% productive rate and greater than 96% ee value.Cyanalcohol 2 can be greater than 99% by a recrystallization ee value.
Hydroxyl-cyanide of the present invention is to adopt almond, loquat seed, apple seed, Badamu seed as the enzyme source, behind fragmentation, organic solvent degreasing, obtain hydroxyl-cyanide, also can be through broken, water-soluble solvent leaching or extraction, leach liquor or extracting solution through concentrating, perhaps leach liquor or extracting solution reconcentration and making behind reconcentration or organic solvent extraction after dialysis or the column chromatography for separation.The hydroxyl-cyanide that is obtained can be thick product.Concrete preparation method is referring to CN1083009C.
In the method for the present invention, preferred reaction conditions is: described aldehyde 1 is 1: 1.0～5.0 with the mol ratio of HCN, and the weight ratio of hydroxyl-cyanide and aldehyde 1 is 1: 1～100, and reaction is 1～48 hour when room temperature.Water-content in the reaction system is recommended as 0.5～2% (v/v) of organic solvent.
By the inventive method, obtained a kind of new hydroxyl cyanogen compound, its structural formula is as follows:
R1 is recommended as C1～C6 alkyl.
New hydroxyl cyanogen compound of the present invention can be used for compounds such as synthetic thiamphenicol, fluorine Ben Nikao.For example:
Scheme 1 reaction and condition：a)HCN/HNL，＞95％，96％ee，recr.＞99％ee；b)MIP，POCl
3，95％；c)DIBALH；d)BnNH
2；e)NH
4Br，NaCN；f)HCl，H
2O，Ethanol；c，d，e，f，overall 75％；g)(im)
2CO，TEA，91％；h)K
2CO
3，ethanol，then，1N HCl，91％；i)NaBH
4，methanol，85％.
MIP representation methoxy isopropyl ether wherein, DIBALH represents diisobutyl aluminum hydrogen, (im)
2CO represents carbonyl dimidazoles, and TEA represents triethylamine.
Compound 2 acidic conditionss are the protection hydroxyl down, keeps optical activity to get 3, at first with DIBAL cyano reduction is become imines, meets BnNH
2Carry out the displacement of imines, HCN carries out addition to imines then, and hydrochloric acid deprotection base gets compound 4.React with carbonyl dimidazoles 4, the five-ring of formation is with beta-hydroxy and alpha-amino group protection, and cyano group alcohol solves 6 under the alkaline condition, and the sodium borohydride reduction ester group gets compound 7.
Scheme 2 reaction and condition：a)MCPBA，90％；b)2N KOH，relux，85％；c)Pd/C，H
2 90％；MeOH，CHCl
2COOEt，TEA，100％.
Wherein MCPBA represents metachloroperbenzoic acid, and TEA represents triethylamine.
From compound 7, get compound 8 through the metachloroperbenzoic acid oxidation, slough under the 2N potassium hydroxide condition ester protect 9, benzyl is sloughed in 9Pd/C hydrogenation, acetylize gets thiamphenicol 10 in alkaliferous methanol solution again.
Scheme 3 reaction and condition：a)DAST，THF，85％；b)MCPBA，90％；c)8N H
2SO
4，140℃，71％；d)Pd/C，H
2 95％；e)MeOH，CHCl
2COOEt，TEA，100％.
Wherein DAST represents the sulfur trifluoride diethylamide, and THF represents tetrahydrofuran (THF), and MCPBA represents metachloroperbenzoic acid, and TEA represents triethylamine.
From compound 7, we fluoridize it with DAST equally, through condition optimizing, find with the tetrahydrofuran (THF) to be solvent, and reaction can get best result under the room temperature, and its productive rate is greater than 85%.Compound 11 becomes sulfone 12 through metachloroperbenzoic acid sulfur oxide ehter bond; but when hydrolysis oxazolidone ring; discovery is under common KOH condition; hydrolysis can take place in carbon-fluorine bond; screen various alkali; the concentration of alkali; temperature of reaction; carbon-fluorine bond still can not keep; can not realize purpose under the reductive condition, attempt sloughing benzyl earlier and can not realize, obtain 13 with medium productive rate under last 140 ℃ of conditions of 6N sulfuric acid; benzyl is sloughed in 13Pd/C hydrogenation, and acetylize gets Florfenicol 14 in alkaliferous methanol solution again.
The invention provides a kind of hydroxyl-cyanide that obtains from new enzyme source is used for the hydroxyl cyanogenation and obtains a kind of new chiral cyanohydrin compound, solved hydroxyl-cyanide (HNL) that existing document the reports difficult problem of this reaction of catalysis effectively, this cyanohydrin compound can be used for preparing thiamphenicol and Florfenicol etc.
Embodiment
Embodiment 1
1) preparation of Badamu spent meal
50g Badamu kind benevolence is pulverized in tissue mashing machine, used conventional organic solvent degreasing, as the 100mL ethyl acetate, acetone or isopropyl ether stirred 15 minutes to one hour, filter, repeated washing is 2～4 times again, and gained defatting enzyme powder is hydroxyl-cyanide, and to be stored in refrigerator standby.
After sodium cyanide and the Glacial acetic acid reaction, obtain to contain the prussic acid organic solvent solution, use behind the anhydrous sodium sulfate drying with solvent extraction process; Or directly prussic acid is added the organic solvent that contains 0-1% weight water.
Embodiment 2
2) compound 2 is synthetic
25ml egg type bottle adds 400mg compound 1, Badamu spent meal 0.15g, and the isopropyl ether solution 5ml of 1.5eq.HCN, 20 ℃ were reacted 24 hours.Filter, enzyme source powder washs with ethyl acetate, merges organic phase.The saturated FeCl of organic phase
3Solution washing is to FeCl
3The solution nondiscoloration, Na
2SO
4Dry.The clear crystal product, productive rate 90%.
[α]
D 20+50.4(c0.83，CHCl
3)，e.e.＝96％；
1HNMR(CDCl
3，300MHz)：δ，2.50(s，3H，CH
3)，3.00(br，s，1H，OH)，5.49(s，1H，CH)，7.29，7.43(AB，J 8.5Hz，4H)ppm；
EI-MS：m/z(rel.intensty％)：181(M
+，2，5)，179(M
+，79)，162(M
+-OH，39)，153(M
+-CN，55)，152(M
+-HCN，100)，151(M
+-HCN-H，88)，132(29)，123(16)，109(20)，105(17)，91(7)，77(17)；
EA: calculated value: C:60.31%, H:5.06%, N:7.82%
Measured value: C:60.40%, H:5.06%, N:7.73%
Embodiment 3
3) compound 3 is synthetic
250ml egg type bottle adds compound 2 (0.9g), 2-Methoxypropene (20ml), CH
2Cl
2(150ml), POCl
3(20mg), stirring is spent the night under the room temperature.Add Et
3N 3mL stirs 30min, stops.Organic phase is washed (50ml * 3), anhydrous Na with saturated brine
2SO
4Dry.Rapid column chromatography (EA/PE=1/10) gets yellow solid 1.09g, productive rate 96%.Recrystallization gets clear crystal 0.92g, productive rate 77%.
1HNMR(CDCl
3，300MHz)：δ，1.4(s，3H，CH
3)，1.58(s，3H，CH
3)，2.50(s，3H，SCH
3)，3.2(s，3H，OCH
3)，5.42(s，1H，CH)，7.25-7.41(m，4H，Hz，Ar-H)ppm，EI-MS：m/z(rel.intensity％)：251(M
+，1.63)，219(M
+-H-OCH，2.01)，179(100.00)，162(76.27)，151(21.93)，132(82.14)，109(22.98)，105(28.48)，86(49.45)，45(27.76)；
Embodiment 4
4) compound 4 is synthetic
There-necked flask, stirrer, dropping funnel.Device is dry, the Ar protection.Add 3 in the bottle (3.6g, 14mmol), ether (90ml) ,-70 ℃ drip DIBAL-H (1M in toluene) 35mL down, and-70 ℃ were stirred 2.5 hours down.Dropping is dissolved in 50mL CH
3The NH of OH
4Br 3.43g.Remove dry ice-propanone and bathe, add PhCH
2NH
27.5ml, stirred 1 hour under the room temperature.External ice-water bath drips and is dissolved in 90ml CH
3The NH of OH
4Br 4.2g/NaCN 2.1g, 0 ℃ was stirred 1.5 hours down.30 ℃ of backspins remove methyl alcohol, add 100mL 2NNaOH solution, and ether 60mL * 4 extractions merges organic phase, and water 15mL * 2 are washed, and saturated aqueous common salt 15mL * 2 are washed, anhydrous Na
2SO
4Dry.Underpressure distillation or column chromatography (PE/EA=6/1) are removed Bian amine and are got light yellow oil, are dissolved in 100mL ethanol, add 1N HCl 20mL, 45 ℃ of backspins remove ethanol, and toluene band water twice gets faint yellow solid, the white needle-like crystals 3.46g of Virahol recrystallization, productive rate 75%.
1HNMR(CD
3OD，300MHz)：δ2.52(s 3H)，4.47(AB，j＝28Hz，2H)，4.70(d，j＝9Hz，1H)，5.11(d，j＝9Hz，1H)，7.33-7.58(m，9H)ppm；
ESI-MS：m/z(rel.intensity％)：299.0(M
++H)，300.0(M
++2H)；
FT-IR(KBr，cm
-1)：3234，2894，2689，2544，2441，2353，2051，1599，1496，1384，1316，1215，1091，970，920，881，815，746；
Embodiment 5
5) compound 5 is synthetic
Add 4 (0.6g), CH in the 100ml egg type bottle
2Cl
2(7mL), stir adding Et down
3N (0.1mL) stirs 30min, adds im
2CO 0.6g stirs under the room temperature and spends the night.Add water 5ml, stir 10min, stop.Layering, water CH
2Cl
2Extract (20mL * 3), merge organic phase, 0.1N HCl washing, anhydrous Na
2SO
4Dry.Solvent is spin-dried for, and gets white solid 0.32g, CH
2Cl
2/ PE (1/8) recrystallization gets white crystal 276mg.Productive rate 86%.
[α]
D 20+160.1(c0.805，CHCl
3)
1H NMR(300MHz，CDCl
3)δ2.47(s，3H)，4.06(d，j＝6.3Hz，1H)，4.61(AB，j＝252Hz，2H)，5.57(d，j＝6.3Hz，1H)，7.15-7.38(m，9H)
EI-MS：m/z(rel.intensity％)324(M
+，24.23)，286(0.57)，243(0.52)，215(1.81)，175(14.70)，151(2.77)，91(100)，77(4.73)，65(41.498.08)；
Embodiment 6
6) compound 6 is synthetic
Compound 5121mg goes into the egg bottle, and the 3.2ml96% dissolve with ethanol adds 0.23g salt of wormwood stirring at room 6 hours, and elimination salt of wormwood adds 3.5mL hydrochloric acid (1N), stirs 30 minutes, adds the saturated NaHCO of 4mL
3, separate out white precipitate, add the dilution of 30mL methylene dichloride and 30mL water, water dichloromethane extraction twice merges organic phase, washes once dried over sodium sulfate.Filter, be spin-dried for, yellow oil, column chromatography (petrol ether/ethyl acetate=4/1), yellow oil 99mg, productive rate 80%.
1H NMR(300MHz，CDCl
3)δ1.29(t，j＝7.2Hz，3H)，2.47(s，3H)，3.90(d，j＝5.4Hz，1H)，4.21-4.30(m，3H)，4.96(d，j＝14.4Hz，1H)，5.42(d，j＝5.4Hz，1H)，7.14-7.31(m，9H)
EA: calculated value: C:64.67%, H:5.70%, N:3.77%
Measured value: C:64.85%, H:5.76%, N:3.62%
Embodiment 7
7) compound 7 is synthetic
0.95g compound 6 is dissolved in 50mL methyl alcohol, ice-water bath adds NaBH down
40.6g reaction was warming up to stirring at room 2 hours, added 20mL water, revolved methyl alcohol, ethyl acetate 160mL extraction, and organic phase water 10mL * 2 are washed, and saturated aqueous common salt 10mL * 2 are washed, anhydrous Na
2SO
4Dry.Remove desolvate white powder 0.89g, recrystallization gets white needle-like crystals in the methyl alcohol, productive rate 85%.
1H NMR(300MHz，CDCl
3)δ2.45(s，3H)，2.90(br，1H)，3.47-3.50(m，1H)，3.57(dd，j
1＝12.6Hz，j
2＝3.6Hz，1H)，3.81(dd，j
1＝12.6Hz，j
2＝3.6Hz，1H)，4.61(AB，j＝134Hz，2H)，5.36(d，j＝6.3Hz，1H)，7.15-7.32(m，9H)
EA: calculated value: C:65.63%, H:5.81%, N:4.25%
Measured value: C:65.63%, H:5.83%, N:4.17%
HRMS(MALDI)Calcd forC
18H
19NO
3SNa：352.0978，Found：352.097
Embodiment 8
8) compound 8 is synthetic
140mg compound 7 is dissolved in the 15mL tetrahydrofuran (THF), adds the 350mg metachloroperbenzoic acid, and stirring at room 2 hours is revolved tetrahydrofuran (THF), 100mL acetic acid ethyl dissolution, saturated Na
2SO
310mL washes, and water 10mL washes, and saturated NaCl10mL * 2 are washed, anhydrous Na
2SO
4Dry.Column chromatography gets white solid 0.145mg, productive rate 94%.
[α]
D 20+91.3(c1.42，CHCl
3)
1H NMR(300MHz，CDCl
3)δ3.06(s，3H)，2.50(br，1H)，3.49-3.53(m，1H)，3.70(dd，j
1＝12Hz，j
2＝3.0Hz，1H)，3.84(dd，j
1＝12Hz，j
2＝3.0Hz，1H)，4.61(AB，j＝110Hz，2H)，5.50(d，j＝5.7Hz，1H)，7.28-7.37(m，5H)，7.72(AB，j＝125Hz，4H)
13C NMR(75MHz，CDCl
3)δ44.42，46.83，60.15，63.95，126.54，127.93，128.05，128.34，129.09，135.72，140.92，144.94，157.88
ESI-MS：M+Na
+(384.10)
Embodiment 9
9) compound 9 is synthetic
110mg compound 8 is dissolved in 5mL ethanol, adds 4N KOH solution 5mL, and backflow 45min under the argon shield revolves ethanol after the cooling, and methylene dichloride 30mL * 3 extractions merges organic phase, and water 8mL washes, and saturated NaCl8mL * 2 are washed, anhydrous Na
2SO
4Dry.Column chromatography (ethyl acetate) gets white solid 98mg, productive rate 96%.
[α]
D 20-47.1(c1.5，ethanol)
1H NMR(300MHz，CDCl
3)δ2.74-2.76(m，1H)，3.05(s，3H)，3.43(dd，j
1＝11.4Hz，j
2＝3.9Hz，1H)，3.70(AB，j＝44Hz，2H)，3.75(dd，j
1＝11.4Hz，j
2＝3.9Hz，1H)，4.74(d，j＝6.9Hz，1H)，7.22-7.35(m，5H)，7.72(AB，j＝94Hz，
Embodiment 10
9) compound 10 is synthetic
35mg compound 9 is dissolved in 3mL ethanol, adds the 0.05mL concentrated hydrochloric acid, adds 20mg 10%Pd/C, room temperature normal pressure hydrogenation 2 hours, elimination Pd/C removes methyl alcohol, adds anhydrous methanol 1mL, adds the 0.2mL ethyl dichloroacetate, add 25 μ L triethylamines, 30 ℃ were stirred 6 hours, and revolved and desolvate, column chromatography (CH
2Cl
2/ CH
3OH=9/1) get white solid 38mg, productive rate 96%.
[α]
D 2012.5(c0.38，ethanol)
1H NMR(300MHz，CD
3OD)δ3.07(s，3H)，3.59(dd，j
1＝11Hz，j
2＝6Hz，1H)，3.81(dd，j
1＝11Hz，j
2＝7Hz，1H)，4.10-4.14(m，1H)，5.14(d，j＝3.3Hz，1H)，6.23(s，1H)，7.76(AB，j＝69Hz，4H)
13C NMR(75MHz，CD
3OD)δ43.09，57.18，60.87，66.06，70.12，126.76，126.92，139.48，148.99，165.12
ESI-MS：M+Na
+(378.00
Embodiment 11
11) compound 11 is synthetic
255mg compound 7 places the egg bottle, and system is injected anhydrous tetrahydro furan 10mL after being replaced as argon gas, injects DAST 0.3g, stirring at room 12 hours, add 2N NaOH solution 10mL cancellation reaction, ethyl acetate 30mL * 3 extractions merges organic phase, water 8mL washes, and anhydrous Na is washed in saturated NaCl 8mL * 2
2SO
4Dry.Column chromatography (PE/EA=4/1) gets faint yellow solid 260mg, productive rate 90%.
1H NMR(300MHz，CDCl
3)δ2.45(s，3H)，3.57-3.66(m，1H)，4.31-4.62(m，2H)，4.58(AB，j＝181Hz，2H)，5.20(d，j＝6.6Hz，1H)，7.15-7.37(m，9H)
EA: calculated value: C:65.24%, H:5.47%, N:4.23%
Measured value: C:65.04%, H:5.63%, N:4.02%
Embodiment 12
12) compound 12 is synthetic
150mg compound 7 is dissolved in the 6mL tetrahydrofuran (THF), adds the 250mg metachloroperbenzoic acid, and stirring at room 2 hours is revolved tetrahydrofuran (THF), 100mL acetic acid ethyl dissolution, saturated Na
2SO
310mL washes, and water 10mL washes, and saturated NaCl10mL * 2 are washed, anhydrous Na
2SO
4Dry.Column chromatography gets white solid 149mg, productive rate 89%.
[α]
D 2099.0(c1.10，CHCl
3)
1H NMR(300MHz，CDCl
3)δ3.05(s，3H)，3.59-3.68(m，1H)，4.31-4.62(m，2H)，4.58(AB，j＝179Hz，2H)，5.37(d，j＝6.0Hz，1H)，7.25-7.34(m，5H)，7.72(AB，j＝144Hz，4H)
ESIMS(m/z)：(M+Na
+)386.10
Embodiment 13
13) compound 13 is synthetic
60mg compound 12 is dissolved in the 3mL dioxane, add 3mL 8N sulfuric acid, seal after being replaced as argon gas in the tube sealing,, cool off in the rearmounted ice-water bath in 140 ℃ of reactions 6 hours, add 14mL 4N NaOH solution, methylene dichloride 30mL * 3 extractions merges organic phase, and water 8mL washes, anhydrous Na is washed in saturated NaCl 8mL * 2
2SO
4Drying, column chromatography (PE/EA=1/1) gets white solid 42mg. productive rate 75%
[α]
D 20-79.2(c1.10，CHCl
3)
1H NMR(300MHz，CDCl
3)δ2.71-2.83(m，1H)，3.05(s，3H)，3.83(AB，j
AB＝26Hz，2H)，4.10-4.60(m，2H)，4.62(d，j＝110Hz，1H)，7.28-7.35(m，5H)，7.72(AB，j＝110Hz，4H)
13C NMR(75MHz，CDCl
3)δ44.51，51.63，63.30，63.56，71.29，71.35，79.24，81.47，127.58，127.79，128.16，128.68，139.05，140.10，147.95
ESIMS(m/z)：(M+H
+)338.0
HRMS(ESI)Calcd forC
17H
21N
1O
3FS：338.1221，Found：338.1221
Embodiment 14
14) compound 14 is synthetic
22mg compound 13 is dissolved in 3mL ethanol, adds the 0.05mL concentrated hydrochloric acid, adds 12mg 10%Pd/C, room temperature normal pressure hydrogenation 2 hours, elimination Pd/C removes methyl alcohol, adds anhydrous methanol 1mL, add the 0.12mL ethyl dichloroacetate, add 15 μ L triethylamines, 30 ℃ were stirred 6 hours, and revolved and desolvate, column chromatography (PE/EA=1/1) gets white solid 19mg, productive rate 96%.
[α]
D 20-18.0(c0.35，DMF)；
1H NMR(300MHz，DMSO-d
6)δ3.17(s，3H)，4.26-4.33(m，1H)，4.44-4.76(m，2H)，4.99(d，j＝2.4Hz，1H)，6.46(s，1H)，7.74(AB，j＝71Hz，4H)，8.62(d，j＝9Hz，1H)，
13C NMR(75MHz，DMSO-d
6)δ44.10，66.74，69.81，81.64，83.90，126.96，127.63，140.03，148.37，164.21；
ESIMS(m/z)：(M+Na
+)380.00。
Claims (9)
1. new cyanohydrin compound, its structural formula is as follows:
R1 is C1～C6 alkyl in the formula.
2. prepare the hydroxyl cyanogenation method of the compound of claim 1, it is characterized in that being expressed as follows with reaction formula:
Scheme 3-4
R1 is recommended as C1～C6 alkyl, and it is the enzyme source that described hydroxyl-cyanide adopts almond, loquat seed, apple seed, Badamu seed.
3. method according to claim 2 is characterized in that it is the enzyme source that described hydroxyl-cyanide adopts the Badamu seed.
4. method according to claim 2 is characterized in that described prussiate is an acetone cyanohydrin, HCN.
5. method according to claim 2 is characterized in that this is reflected in the organic solvent or buffered soln-organic solvent two-phase is carried out.
6. method according to claim 5 is characterized in that described organic solvent is an isopropyl ether, ethyl acetate, methyl tertiary butyl ether, toluene.
7. method according to claim 2 is characterized in that the described aldehyde 1 and the mol ratio of prussiate are 1: 1.0～5.0, and the weight ratio of hydroxyl-cyanide and aldehyde 1 is 1: 1～100, and reaction is 1～48 hour when room temperature.
8. method according to claim 2 is characterized in that the water-content in the described reaction system is 0.5～2% (v/v) of organic solvent.
9. the purposes of the compound of claim 1 is characterized in that being used for compounds such as synthetic thiamphenicol, fluorine Ben Nikao.
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| CNB2005100287572A CN1309708C (en) | 2005-08-12 | 2005-08-12 | Synthesis of optical active cyanhydrin compound by enzyme chemical process |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187837A (en) * | 2016-07-05 | 2016-12-07 | 和鼎（南京）医药技术有限公司 | A kind of florfenicol midbody, and preparation method thereof and the preparation method of florfenicol |
| CN113248413A (en) * | 2021-04-05 | 2021-08-13 | 复旦大学 | Method for continuously preparing thiamphenicol by using micro-reaction system |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1243879A (en) * | 1999-07-16 | 2000-02-09 | 中国科学院上海有机化学研究所 | Chiral cyanohydrin compound and its derivatives and preparing process |
| CN1268755C (en) * | 2004-09-24 | 2006-08-09 | 浙江大学 | Process for preparing optical active cyanalcohol through enzyme catalysis alcoholysis reaction resolution |
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2005
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187837A (en) * | 2016-07-05 | 2016-12-07 | 和鼎（南京）医药技术有限公司 | A kind of florfenicol midbody, and preparation method thereof and the preparation method of florfenicol |
| CN113248413A (en) * | 2021-04-05 | 2021-08-13 | 复旦大学 | Method for continuously preparing thiamphenicol by using micro-reaction system |
| CN113248413B (en) * | 2021-04-05 | 2022-07-22 | 复旦大学 | Method for continuously preparing thiamphenicol by using micro-reaction system |
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