CN1179420A - Method for preparing D-(-) threo -2 -oxazoline derivatives from L-substituted phenyl serine ester - Google Patents
Method for preparing D-(-) threo -2 -oxazoline derivatives from L-substituted phenyl serine ester Download PDFInfo
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- CN1179420A CN1179420A CN 97106492 CN97106492A CN1179420A CN 1179420 A CN1179420 A CN 1179420A CN 97106492 CN97106492 CN 97106492 CN 97106492 A CN97106492 A CN 97106492A CN 1179420 A CN1179420 A CN 1179420A
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Abstract
A process for preparing D-(-)threo -2 -oxazoline derivatives as intermediate of medicines from L-substituted phenylserine ester includes such steps as acylation and cyclization reactions in polar solvent, alkali catalytic transformation, hydrolysis, and optional fluorination, and features simple preparing method, high output rate and high transformation rate of configuration up to 100%. With said process inactive antimer can be transformed into active one.
Description
The present invention relates to a kind of from the short-cut method of L type substituted benzene serine ester to preparation D-(-) the Su-Type-2--oxazoline derivative of D type counter-rotating.
Medicines such as paraxin, thiamphenicol and Florfenicol are class broad-spectrum antibiotics, particularly to the Gram-negative bacteria better effects if, synthetic this big class medicine will inevitably relate to the fractionation of D, L-type-1-substituted-phenyl-2-amino-propanediol and D, L type substituted benzene serine ester, and to have only D-type isomer be the precursor of synthetic said medicine, L-type isomer go out of use (Cutler, R.A.etal, J.Am.Chem.Soc.74,5475,1952; Tetra.Lett, 5561,1988), do not have discovery effectively to utilize the method for L type isomer so far.Worldwide, the consumption of this class microbiotic and intermediate thereof is more than ten thousand tons, annual number goes out of use with ten thousand tons L-isomer, can not rationally be utilized, be caused great waste, so, people are still constantly exploring from the method for L type substituted benzene serine ester to the D configuration inversion, so that fully make rational use of resources, thereby reduce cost of drugs, bring benefit to the mankind.
Method of the present invention is to utilize chemical reaction to make L type substituted benzene serine ester, to the short-cut method of D type conversion.
Method of the present invention is, and to be raw material with L type substituted benzene serine ester 1 generate D-(-) formula (4R of Soviet Union through acidylate and cyclization; 5R)-2-aryl-4-ester group-5-substituted-phenyl-2-oxazoline 2a; alkaline condition generates D-(-) formula (4S of Soviet Union down transition; 5R)-2-aryl-4 ester groups-5-substituted-phenyl-2-oxazoline 2b; 2b can obtain the formula (4S of D-(-) Soviet Union through reduction; 5R)-2-aryl-4 methylols-5-substituted-phenyl-2-oxazoline 2c; 2c obtains D-(-) formula (4S of Soviet Union through fluoridizing; 5R)-and 2-aryl-4-methyl fluoride-5-substituted-phenyl-2-oxazoline 2d, the hydroxyl of above-mentioned 2c compound can also convert other halogen easily to; ether; groups such as ester.All reactions can realize, also can realize continuously by one kettle way in segmentation.Can generate D type-1-substituted-phenyl-2-amino-propanediol and derivative 3 thereof with the inventive method synthetic compound 2 through hydrolysis, be the important intermediate of antibiotic 4 such as synthesizing chloramphenicol, thiamphenicol and fluorine first mycin, thereby realized by the purpose of L type compound to the conversion of D type compound.
Method of the present invention can be represented with following reaction formula:
Wherein, R is constant in entire reaction, R=NO
2, CN, R ' SO
2, R ' SO, CF
3, R
1Be C
1-8Alkyl or aryl, R
2Be aryl, R
3Be COOR
1, CH
2Y, Y are OH or halogen, and described aryl is phenyl, halogenophenyl or R ' C
6H
5, described R ' is C
1-8Alkyl.
, can realize by following step respectively from compound 1 synthetic D-(-) Su-Type-2--oxazoline derivative 2 with method of the present invention.
In polar solvent, compound 1 is R with molecular formula
4The carboxylic acid halides of COX was-20 ℃～10 ℃ reactions 0.2～10 hour, and the recommendation response time is 1～5 hour, will help the carrying out that react if add the nitrogen compound that contains lone-pair electron on the nitrogen-atoms in the reaction.Reaction is finished, and adds polar solvent again after draining solvent, or removes excessive carboxylic acid halides or without any processing through decompression, adds thionyl chloride and ℃ continues reaction 0.2-10 hour in room temperature to 80, obtains compound 2a.2a and alkali substance reaction 0.5-5 hour, obtain 2b.The mol ratio of described L type substituted benzene serine ester 1, carboxylic acid halides, nitrogen compound and thionyl chloride is 1: 0.8-1.5: 0-5: 0.5-3, recommend mol ratio to be followed successively by 1: 0.8-1.2: 0.04-4: 0.5-2.D-(-) Soviet Union formula (4R, 5R)-2-aryl-4-ester group-5-substituted-phenyl-2-oxazoline 2a and alkaline matter mol ratio are 1: 0.1-5, recommend mol ratio to be followed successively by 1: 0.1-5.R in the described carboxylic acid halides
4Be aforesaid R
2, X is a halogen.Described alkaline matter can be yellow soda ash or potassium, sodium bicarbonate or potassium, volatile salt, diethylamine, triethylamine, sodium methylate or potassium, sodium ethylate or potassium etc.
Compound 2b is reduced into D-(-) Soviet Union formula with POTASSIUM BOROHYDRIDE or sodium borohydride with it in polar solvent (4S, 5R)-2-aryl-4 methylols-5-substituted aryl-2-oxazoline 2c, temperature of reaction is-10 ℃ to 50 ℃, reaction times 1-5 hour.The mol ratio of compound 2b and POTASSIUM BOROHYDRIDE or sodium is followed successively by 1 in the reaction: 2-10, recommending mol ratio is 1: 3-8.
Compound 2c can also with fluorination reagent prepared in reaction D-(-) Soviet Union formula (4S, 5R)-obtain D-(-) Su Shi-1-substituted-phenyl-2-amino-3-fluoro-propyl alcohol-13d after 2-aryl-4-methyl fluoride-5-substituted-phenyl-2-oxazoline 2d hydrolysis.Promptly in polar solvent, compound 2c and fluorination reagent reacted 0.5-5 hour to boiling at 40 ℃, and compound 2c and fluorination reagent mol ratio are 1: 0.8-3.Described fluorination reagent is R
2 3NCF
2CFH (CF
2) nF, mol ratio is 1: 1-3 or R
fCF=CF
2And R
2 5The mixture of NH, wherein R
5=C
1-8Alkyl, n=1-7, R
f=F or C
1-6Perfluoroalkyl.
Polar solvent described in the method for the present invention can be one or more polar solvent, and described polar solvent can be toluene, dimethylbenzene, acetonitrile, ethylene dichloride, methylene dichloride, chloroform, methyl alcohol, ethanol, triethylamine, pyridine etc.
Adopt method of the present invention can the substep from compound 1 synthetic compound 2, also can adopt the direct synthetic compound 2 of successive one kettle way, not only method is easy, the productive rate height, cost is low, and the configuration conversion rate is a kind of from the effective simple and easy method of L type substituted benzene serine ester to the D configuration inversion up to 100%.Because compound 2 just can obtain D-2-amino-1-substituted aryl-1 through mineral acid hydrolysis, ammediol and derivative, thereby solved the conversion of the invalid enantiomorph that utilizes method for splitting to prepare to produce in the medicine production process such as optically active paraxin, thiamphenicol, fluorine first mycin, Florfenicol to effective enantiomorph, reduce environmental pollution and utilization of waste material, have practical economic worth.
To help to understand the present invention by following embodiment, but not place restrictions on content of the present invention.Embodiment 1:D-(-) Soviet Union formula (4S, 5R)-2-phenyl-4-methylol-5-is to methylsulfonyl
The preparation of phenyl-2-oxazoline 2c-1:
40-60g compound (R=methylsulfonyl, R
1=CH
3) 1 adding 1,2-ethylene dichloride 300ml, ethanol 100ml, triethylamine or pyridine 40ml stir, and temperature is controlled at-10 ℃-40 ℃, drips acyl chlorides 22ml, drips off, and drips SOCl again
227ml, coreaction time 1-10h uses saturated Na
2CO
3Wash 1 * 300ml time, distillation washing 3 * 300ml time, the organic phase drying, decompression and solvent recovery gets thick thing 2a, adds the 500ml anhydrous methanol, stirs, and adds 0.2-0.5 mole sodium alkoxide, Na under the room temperature
2CO
3, triethylamine, Na
2CO
3, (NH
4)
2CO
3, continuing reaction 2 hours, the purified 2b that obtains is controlled at about 0 ℃, adds 50g KBH
4, stirring at room 2h, reclaim under reduced pressure methyl alcohol is to doing, add ethyl acetate 300ml and water 400ml, stir, filter crowd product 2c-1 that wins, the filtrate layering, and water ethyl acetate extraction 2 times (2 * 200ml), the combined ethyl acetate layer, dry, be evaporated to 50ml, filter second crowd of product 2c-1,46.5g altogether, productive rate 86.7%
1H-NMR (90MHz, DMSO-d6), 3.23 (s, 3H, CH
3SO
2), 3.53-3.86 (m, 2H), 4.00-4.20 (m, 1H), 5.13 (t, 1H, J=6Hz, OH), 5.68 (d.1H, J=6.3Hz), 7.60 (m, 5H), 7.95 (m, 4H) .[α]
D:-110 ℃ of (DMF) embodiment 2:D-(-) Su Shi-1-is to methylsulfonyl phenyl-2-amino-propanediol hydrochloride
The preparation of 3c-1
Get above-mentioned example 1 product 2c-1 50g, add 1-10 N HCl or H
2SO
4100ml-1000ml stirs, backflow 2h, the reactant dichloromethane extraction, the water removal of solvent under reduced pressure, must product 3c-1 (look solid) 40g, productive rate 94%.〔α〕＝-46°(DMF)，1H-NMR(CDCl
3，CD
3COD)，1.4(d，J＝3.0Hz，NH
2)，2.50(M，1H)，3.00(s，3H，CH
3SO
2)，3.2-3.43(m，3H，OH，CH，CHN)，4.60(d，J＝5.7Hz，OCH)，7.46(d，J＝9Hz，2H)，7.77(d，J＝9Hz，2H)。Embodiment 3:D-(-) Soviet Union formula (4S, 5R)-2-phenyl-4-methyl fluoride-5-is (right-methylsulfonyl
The base phenyl)-preparation of 2-oxazoline (2d-1).
In high-pressure-resistant vessel, add example 1 product 2c-130g, CH
2Cl
2Or chloroform 300ml, nitrogen protection under the room temperature adds fluorination reagent 26.3g (0.118ml), is heated to 100 ℃, react after 2 hours, reconcentration adds propyl alcohol and sherwood oil to smaller size smaller, has precipitation to separate out, filtration, with cold isopropanol wash product 2d-1.Productive rate 85%.mp.210-211℃，〔α〕：116.5°(DMF).
1H-NMR (DMSO-d6) δ: 3.23 (s, 3H), 4.3-4.5 (m, 1H), 4.6-4.9 (m, 2H), 5.8 (d, 1H, J=6Hz), 7.5-7.9 (m, 5H), 7.99 (d, 4H, J-9Hz),
13C-NMR (DMSO-d6), δ: 43.4,74.2,74.5,80.3,80.4,82.6,84.8,126.3,126.5,127.6,128.0,128.7,132.0,140.5,146.1,163.1, Ms m/z 334 (M
++ 1). and embodiment 4:D-(-) Soviet Union formula (1R, 2S)-1-(to methylsulfonyl benzene)-2-amino-3-fluorine
The preparation of-propyl alcohol-1 3d-1
Product 2d-1 70.5g adds 6N HCl 100ml, stirs, and backflow 2-6 hour, be chilled to room temperature, filter, use the ethylene dichloride extracting twice, water layer is evaporated to dried, adds the heat of solution of 500ml dehydrated alcohol.Place crystallization, get product 3d-1 54g, yield 94%.
mp：112-113℃
[α]
D：-36.5°(MeOH)
1H-NMR：1.54(2H，brs)，2.9-3.2(m，1H)，4.05-4.5(m，2H)，4.70(d，
1H，J＝6Hz)，5.69(brs，1H)，7.61(d，J＝9Hz，2H)，7.88(d，J＝9Hz，2H)。Embodiment 5:
Respective compound 1 0.11mol adds toluene 300-500ml, bipyridine or Trimethylamine 99 0-0.1mol, and control reaction temperature drips acyl chlorides 0.11mol at-5 ℃-5 ℃, drips SOCl under the room temperature
20.12-0.2mol 40-80 ℃ was reacted 2 hours, desolventized, and added triethylamine 300ml, reacted 1 hour, added KBH in the time of＜5 ℃
40.2-1mol, stirred 3 hours, separate with silica gel column chromatography, obtain compound 2h-k respectively, analytical results such as following table: compound R
1R
2R
3Productive rate physical constant element public affairs are analysed
%
1H-MNR theoretical value analytical value 2h C
16H
14N
2O
4NO
2Ph CH
2OH 81.2 3.5-3.9 (m, 2H)
4.00-4.2(m，1H) C：64.42 64.50
5.10(t，J＝6Hz，OH) H：4.73 4.75
5.70(d，J＝6.3Hz，1H) N：9.39 9.32
7.6-8.00(M，5H)2i?C
16H
13FN
2O
3?NO
2 Ph CH
2F 84 4.3-4.5(m，1H) C：64.00 64.01
4.6-4.9(m，2H) H：4.36 4.41
5.8(d，1H，J＝6Hz) F：6.33 6.29
7.5-8.00(m.9H) N：9.33 9.282j?C
17H
17NO
2S CH
3S Ph CH
2OH?83.1?2.48(s，3H)
3.5-3.65(m，1H) C：68.19 68.15
5.52(d，1H，J＝6Hz) H：5.72 5.73
7.30(s，4H) N：4.68 4.65
7.45-7.65(m，3H) S：10.71 10.74
7.94(d，2H，J＝9Hz)2k?C
17H
16FNOS CH
3S- Ph CH
2F 85 2.46(s，3H)
3.62(m，1H)
3.79(m，1H) C：67.77 67.68
4.13(m，1H) H：5.32 5.36
5.79(d，1H，J＝6.4Hz) N：4.65 4.61
7.30(s，4H) S：10.63 10.62
7.45-7.98 (m, 5H) embodiment 6:
2h, 2i, 2j, 2k compound are used 5-8N HCl back flow reaction 1 hour, remove HCl and H under reduced pressure
2O adds recrystallizing methanol, obtains 3h, 3j, 3k, productive rate 94-97%, and analytical results is as follows:
D-Su-Type-2--amino-1-(4-nitrophenyl)-1.3-propylene glycol 3h
1H-NMR (DMSO-d6) δ: 2.70 (m, 2H, OCH
2), 3.10 (m, 1H, NCH), 3.30 (brs, 4H, 2OH+NH
2), 4.41 (d, 1H, J=5.9Rz, OCH), 7.30 (d, J=8.0Hz, 2H), 8.00 (d, J=8.0Hz, 2H) D-Soviet Union formula (1R, 2S)-1-(4-nitrophenyl)-3-fluoro-propyl alcohol-1 3i
1H-NMR:1.50 (2H, brs), 2.95-3.1 (m, 1H), 4.05-4.4 (m, 2H), 4.60 (d, J=6Hz, 1H), 5.70 (brs, 1H), 7.55 (d, J=9Hz, 2H), 8.10 (d, J=9Hz, 2H). ultimate analysis: C H N S
Theoretical value: 50.47 5.14 13.08 14.95
Analytical value: 50.46 5.18 13.00 14.94D-Soviet Union formula (1R, 2S)-2-amino-1-(4-methylthio group phenyl)-1.3-propylene glycol 3j
mp：150-151℃
〔α〕
D 26：-21(C＝2.0，EtOH)
C
10H
15NO
2S ultimate analysis theoretical value: C 56.31 H7.09 N6.57 S15.04
(213.3) analytical value: C 56,32 H7.08 N6.50 S15.14FAB-MS:(m/z): 214 (M
++ 1)
1H-NMR (DMSO-d6/TMS) δ: 2.46 (s, 4H, 3CH
3), 2.67 (m, 2H, OCH
2), 3.12 (m, H, NCH), 3.30 (brs, 4H, OH+OH+NH
2), 4.41 (d, 1H, J=5.9Hz, OCH), 7.25 (m, 4 aryl) .D-Soviet Union formula (1R, 2S)-1-(4-methylthio group phenyl)-3-fluoro-propyl alcohol-1 3k
1H-NMR (DMSO-d6) δ: 1.45 (2H, brs), 2.48 (s, 3H), 2.95-3.15 (m, 1H), 4.104.5 (m, 2H), 4.60 (d, J=6Hz, 1H), 5.69 (brs, 1H), 7.60 (d, J=8.9Hz, 2H), 7.94 (d, J=8.9Hz, 2H) ultimate analysis: C H N S
Theoretical value: 55.81 6.51 6.51 14.8
Analytical value: 55.85 6.55 6.48 14.80 embodiment 7:
Respective compound 1 0.1mol, trioctylamine or benzylamine 0.15mol, carboxylic acid halides 5ml is in chloroformic solution, and-10 ℃～40 ℃ were reacted 6 hours, adds thionyl chloride 80 ℃ of reactions 6 hours, extract solvent, add salt of wormwood 0.1ml and acetonitrile 200ml, continue reaction 4 hours at 10～30 ℃, column chromatography for separation gets the formula (4S of D-(-) Soviet Union, 5R)-and 2-aryl-4-ester group-5 substituted-phenyls-2-oxazoline, the result is as follows: compound R
1R
2R
3Productive rate physical constant element public affairs are analysed
%
1H-MNR theoretical value analytical value 21 C
19H
16N
2O
3CN COOEt C
6H
582.1 1.27 (3H) (320.35) 4.25 (2H) C:71.24 71.20 for q, J=7.0Hz for t, J=7.0Hz
4.36(d，J＝7.5Hz，1H) H：5.04 5.08
6.05(d，J＝7.5Hz，1H) N：8.74 8.71
7.60(M，5H)
7.98(m，4H)2m?C
20H
18F
3NO
3?CF
3?COOEt CH
3C
6H
4 83.6 1.25(t，J＝6.9Hz，3H)
(377.37) 2.36(s，3H) C：63.66 63.60
4.25(q，J＝6.9Hz，2H) H：4.81 4.90
4.85(d，J＝7.3Hz，1H) N：3.71 3.70
6.05(d，J＝7.3Hz，1H)
7.6-8.10(m，8H)2n?C
19H
19NO
3 CF
3?COOEt CH
2OH 84.1 1.27(t，J＝7.0Hz，3H) (309.37) 2.35(s，3H)
4.25(q，J＝7.0Hz，2H) C：73.77 73.71
4.86(d，J＝7.3Hz，1H) H：6.19 6.22
6.05(d，J＝7.3Hz，1H) N：4.53 4.50
7.62(m，5H)
8.00(m，4H)
Claims (6)
1. one kind prepares the method for D-(-) Su-Type-2--oxazoline from L type substituted benzene serine ester, and described L type substituted benzene serine ester has
Molecular formula, D-(-) Su-Type-2--oxazoline has
Molecular formula, wherein R=NO
2, CN, R ' SO
2, R ' SO, CF
3, R ' or aryl, R
1=C
1-8Alkyl, R
2=aryl, R
3=COOR
1, CH
2OH or CH
2X, R '=C
1-8Alkyl, aryl=benzene, R ' C
6H
5, halogeno-benzene, it is characterized in that making by following reaction respectively:
A. the nitrogen compound and the molecular formula that contain lone-pair electron on described L type substituted benzene serine ester and the nitrogen-atoms are R
4The carboxylic acid halides of COX is in the presence of polar solvent,-20 ℃～50 ℃ were reacted 1 hour to 10 hours, add thionyl chloride 10-80 ℃ of reaction 0.2-10 hour, make D-(-) Su Shi-(4R, 5R)-2-aryl-4-ester group-5-substituted-phenyl-2-oxazoline, the mol ratio of described L type substituted benzene serine ester, nitride, carboxylic acid halides and thionyl chloride is 1: 0.8-1.5: 0-5: 0.5-3, wherein R
4=R ' or R
2, X is a halogen, nitride is to have C
1-24The tertiary amine of alkyl, secondary amine or primary amine, pyridine, bipyridine, diethylamine compounds,
Formula (the 4R of b.D-(-) Soviet Union, 5R)-2-aryl-4 ester groups-5-substituted-phenyl-2-oxazoline and alkali substance reaction 0.5-5 hour, generate D-(-) formula (4S of Soviet Union, 5R)-2-aryl-4 ester groups-5-substituted-phenyl-2-oxazoline, mol ratio is followed successively by 1: 0.1-5, described alkaline matter is that alkaline matter is salt of wormwood or sodium, saleratus or sodium, volatile salt, diethylamine, triethylamine, sodium methylate, sodium ethylate
Formula (the 4S of c.D-(-) Soviet Union, 5R)-2-aryl-4-ester group-5-substituted-phenyl-2-oxazoline, polar solvent and POTASSIUM BOROHYDRIDE or sodium at-10 ℃ under 50 ℃, reacted 1-5 hour, make D-(-) Su-Type-2--aryl-4 methylols-5-substituted-phenyl-2-oxazoline, the mol ratio of D-(-) Su-Type-2--aryl-4-methylol-5-substituted-phenyl-2-oxazoline and POTASSIUM BOROHYDRIDE or sodium is 1: 2-10
D. in polar solvent, formula (the 4S of D-(-) Soviet Union, 5R)-2-aryl-4-methylol-5-substituted-phenyl-2-oxazoline and fluorination reagent mol ratio are 1: 0.8-3, at 40 ℃ to boiling temperature, reacted 0.5-5 hour, acquisition D-(-) Soviet Union formula (4S, 5R)-2-aryl-4-methyl fluoride-5-substituted-phenyl-2-oxazoline, described fluorination reagent is R
2 5NCF
2CFH (CF
2)
nF, or R
2 5N and CF
2=CF (CF
2) the nF mol ratio is 3-1: 1 mixture, n=1-6 wherein, R=C
1-8Alkyl.
2. method as claimed in claim 1 is characterized in that the mol ratio of described L type substituted benzene serine ester, carboxylic acid halides and nitrogen compound is 1: 0.8-1.2: 0.04-4.
3. method as claimed in claim 1 is characterized in that described thionyl chloride is 0.5-2 with respect to the mol ratio of L type substituted benzene serine ester: 1.
4. method as claimed in claim 1, it is characterized in that described D-(-) Soviet Union formula (4S, 5R)-mol ratio of 2-aryl-4-ester group-5-substituted-phenyl-2-oxazoline and POTASSIUM BOROHYDRIDE or sodium is 1: 3-8.
5. method as claimed in claim 1, it is characterized in that described D-(-) Soviet Union formula (4S, 5R)-mol ratio of 2-aryl-4-methylol-5-substituted-phenyl-2-oxazoline and fluorination reagent is 1: 1-3.
6. can one or more chloroform, methylene dichloride, ethylene dichloride, trichloroethane, methyl alcohol, ethanol, pyridine, triethylamine, toluene, acetonitrile as claim 1,2,3 or 4, described polar solvent.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97106492A CN1070188C (en) | 1997-06-27 | 1997-06-27 | Method for preparing D-(-) threo -2 -oxazoline derivatives from L-substituted phenyl serine ester |
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|---|---|---|---|
| CN97106492A CN1070188C (en) | 1997-06-27 | 1997-06-27 | Method for preparing D-(-) threo -2 -oxazoline derivatives from L-substituted phenyl serine ester |
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| Publication Number | Publication Date |
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| CN1070188C CN1070188C (en) | 2001-08-29 |
Family
ID=5168730
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1997
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