CN1326926A - Preparing D-(-)-Su's 1-R-substituted phenyl-2-difluoro acetoamino-3-fluoro-1-propanol from L type substituted phenyl serine ester - Google Patents

Abstract

The process of the present invention prepares D-(-)-Su's-substituted phenyl-2-dichloro acetoamino-3-fluoro-1-propanol by using L type substituted phenyl serine ester extracted and purified from resolution waste liquid as raw material and through stepped reactions. The process is simple, high in yield, low in cost and complete in configuration and is one effective and simple method of conversion from L type substituted phenyl serine ester to D type fluorothiamphenicol. The present invention solves the problem of disposing waste antimer produced in the resolution process of producing flunikan, and can reduce environmental pollution and has certain practical significance.

Description

A method for preparing D-(-)-threo-1-R-substituted phenyl-2-dichloroacetylamino-3-fluoro-1-propanol from L-substituted phenylserine ester

The invention relates to a method for preparing D-(-)-threo-1-R-substituted phenyl-2-dichloroacetylamino-3-fluoro-1-propanol from L-substituted phenylserine ester. Further speaking, it is a kind of pure L-isomer obtained from the separation waste liquid of substituted phenylserine ester after purification, and D-(-)-threo-1-R-substituted by D-type inversion and fluorination A convenient method for phenyl-2-dichloroacetamido-3-fluoro-1-propanol.

Drugs such as chloramphenicol, thiamphenicol, and fluconyl are a class of broad-spectrum antibiotics, especially for Gram-negative bacteria. Synthesis of this broad class of drugs usually involves resolution of D,L-form-1-R-substituted phenyl-2-aminopropanediols or D,L-form substituted phenylserine esters, of which only the D-form isomer is synthesized above The precursor of the drug, the L-isomer is abandoned (Cutler, R.A., et al, J.Am.Chem.Soc., 74,5475, 1952; Tetra.Letts., 5561, 1988), so far no effective A method utilizing the L-isomer. Worldwide, the amount of such antibiotics and their intermediates is more than 10,000 tons, and tens of thousands of tons of L-isomers are discarded every year, which cannot be rationally utilized, resulting in great waste. So, people are always looking. The method of L-type substituted phenylserine ester is fully and rationally utilized, thereby reducing drug costs and benefiting mankind.

The object of the present invention is to provide a method for preparing D-(-)-threo-1-R-substituted phenyl-2-dichloroacetylamino-3-fluoro-1-propanol from L-substituted phenylserine ester . The L-type substituted phenylserine ester extracted and purified from the separation waste liquid in industrial production is used as a raw material, and the L-type isomer is converted into an oxazoline cyclization product; and then converted into a high value-added D-( -)-threo-1-R-substituted phenyl-2-dichloroacetamido-3-fluoro-1-propanol.

The method of the present invention is to extract and purify L-substituted phenylserine ester 1 from the resolution waste liquid in industrial production, and use 1 as raw material to generate D-(-)-threo formula through acylation, cyclization and isomerization reactions -(4S,5R)-2-R substituted phenyl-4-R ₁ oxyacyl-5-R substituted phenyl-2-oxazoline 2b, 2b can be reduced to obtain D-(-)-threo-(4S ,5R)-2-R ₂ -4-hydroxymethyl-5-R substituted phenyl-2-oxazoline 2c, 2c is fluorinated to give D-(-)-threo-(4S,5R)-2 -R ₂ -4-fluoromethyl-5-R substituted phenyl-2-oxazoline 2d, the hydroxyl group of the above 2c compound can be easily converted into other halogens, ethers, esters and other groups, and the 2d compound can be hydrolyzed The ring can generate D-1-R substituted phenyl-2-amino-3-fluoro-1-propanol 3. Finally, after acylation reaction, D-(-)-threo-1-R substituted phenyl-2-dichloroacetylamino-3-fluoro-1-propanol 4a was synthesized.

其中，R在整个多步反应中是不变的，R＝NO₂，CN，R⁴SO₂，R⁴SO，CF₃，R¹是C_1-8的烷基，R²是芳基或R¹，R³是COOR¹或CH₂Y，Y是羟基或卤素，所述芳基是苯基，卤代苯基，C_1-8的烷基取代苯基，所述R⁴是C_1-8的烷基。Method of the present invention can also represent with following reaction formula:

Wherein, R is constant throughout the multi-step reaction, R=NO ₂ , CN, R ⁴ SO ₂ , R ⁴ SO, CF ₃ , R ¹ is C _1-8 alkyl, R ² is aryl or R ¹ , R ³ is COOR ¹ or CH ₂ Y, Y is hydroxyl or halogen, the aryl is phenyl, halogenated phenyl, C _1-8 alkyl substituted phenyl, the R ⁴ is C ₁ Alkyl of _-8 .

Using the method of the present invention to extract and purify compound 1 from the resolution waste liquid, and synthesize D-(-)-threo-1-R substituted phenyl-2-dichloroacetamido-3-fluoro-1 from compound 1 -propanol, can be realized through the following steps respectively.

In a polar solvent, compound 1 reacts with an acid halide with the molecular formula R ² COX at -20°C to 10°C for 0.2 to 10 hours, and the recommended reaction time is 1 to 5 hours. compounds will facilitate the reaction. After the reaction is complete, drain the solvent and then add a polar solvent, or remove excess acid halide under reduced pressure or without any treatment, add thionyl chloride and continue the reaction at room temperature to 80°C for 0.2-10 hours to obtain compound 2a. The molar ratio of the L-type substituted phenylserine ester 1, the acid halide, the compound containing a lone pair of electrons on the nitrogen atom, and thionyl chloride is 1:0.8～1.5:0～5:0.5～3, and the recommended molar ratios are in order 1:0.8-1.2:0.04-4:0.5-2.

D-(-)-threo-(4R, 5R)-2-R ₂ -4-R ₁ oxyacyl-5-R substituted phenyl-2-oxazoline 2a reacts with alkaline substances for 0.5 to 5 hours, and can Compound D-(-)-threo-(4S,5R)-2-R ₂ -4-R ₁ oxoacyl-5-R substituted phenyl-2-oxazoline 2b was obtained. The molar ratio of 2a to alkaline substance is 1:0.1-10, and the recommended molar ratio is 1:1-3 in turn. In the acid halide, R ² is the aforementioned R ² , and X is halogen. The alkaline substance may be sodium or potassium carbonate, sodium or potassium bicarbonate, ammonium carbonate, diethylamine, triethylamine, sodium or potassium methoxide, sodium or potassium ethoxide, and the like. Compound 2b was reduced to D-(-)-threo-(4S,5R)-2-R ₂ -4-hydroxymethyl-5-R substituted benzene with potassium borohydride or sodium borohydride in a polar solvent Base-2-oxazoline 2c, the reaction temperature is -10°C to 50°C, the reaction time is 1 to 12 hours, the molar ratio of compound 2b to potassium borohydride or sodium in the reaction is 1:1 to 10 in turn, the recommended molar ratio The ratio is 1:1~3. Potassium borohydride or sodium can be directly added to the reaction system in the state of solid particles, or it can be made into a solution and added to the reaction system. The recommended solvent is water.

Compound 2c can also react with fluorinating reagents to prepare D-(-)-threo (4S, 5R)-2-R ₂ -4-fluoromethyl-5-R substituted phenyl-2-oxazoline 2d, 2d After hydrolysis and ring opening under acidic conditions, D-1-R substituted phenyl-2-amino-3-fluoro-1-propanol 3a was obtained, and finally after dichloroacetylation, D-(-)-threo-1 was obtained -R substituted phenyl-2-dichloroacetamido-3-fluoro-1-propanol 4a.

In a polar solvent, compound 2c is reacted with a fluorinating agent to obtain compound 2d. The reaction can be carried out under normal pressure or under closed pressure. The reaction is preferably carried out under an inert atmosphere. When the reaction is carried out under normal pressure, the recommended solvent is acetonitrile, and when carried out in a closed pressure vessel, the recommended solvent is dichloromethane. The reaction temperature is 0-120°C, the recommended temperature is 100-120°C, the reaction time is 0.5-10 hours, the recommended time is 1-3 hours; the molar ratio of compound 2c to fluorinating reagent is 1:0.5-3, the recommended molar ratio It is 1:1~3. Described fluorination reagent can be open and known, and molecular formula is Et _NSF DAST reagent (Nagabhushan, TLUS.4235892,1980), Yarovenko reagent (Shart, CM; Sheppard, WHOrg.Reactions, 1974,21,158-171 ), Ishikawa reagent (Takaoka, A.; Iwagiri, H.; Ishikawa, N. Bull. Chem. Soc. Jpn. 1979, 52, 3377-3380). The recommended reagent is Ishikawa reagent, ie R ₂ ⁵ NCF ₂ CFH(CF ₂ ) _n F, or a mixture of R _f CF=CF ₂ and R ₂ ⁵ NH. Wherein R ⁵ =C _1-8 alkyl, n=1-7, R _f =F or C _1-6 perfluoroalkyl.

Compound 2d can also undergo hydrolytic ring-opening reaction with inorganic acid or organic acid to obtain 3a. The solvent used can be water, methanol, ethanol, isopropanol, glacial acetic acid, etc., and the recommended solvent is water. The molar ratio of compound 2d to inorganic acid or organic acid is 1:1-100. The acid used can be inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or organic acids such as formic acid, glacial acetic acid, p-toluenesulfonic acid and methanesulfonic acid. Hydrochloric acid is recommended. The reaction temperature can be from room temperature to 120°C, the recommended temperature is 80-120°C, the reaction time is 4 hours to 18 hours, and the recommended reaction time is 10-18 hours. The reaction solution hydrolyzed from 2d to 3a needs to be neutralized with alkali and then extracted with an organic solvent. The extraction method can be used to extract 3a by liquid separation extraction or liquid-liquid continuous extractor. It is recommended to use liquid-liquid continuous extractor for extraction. The extraction solution used can be Ether, ethyl acetate, chloroform, dichloromethane, etc. The recommended solvent is dichloromethane.

Compound 3a undergoes an acylation reaction to obtain the target compound 4a, that is, 3a can be acylated with an acylating agent in a polar solvent. If a basic substance is added to the reaction, such as: a compound containing a lone pair of electrons on the nitrogen atom, and a Inorganic bases or sodium alkoxides of valence or divalent metals will facilitate the reaction. The reaction temperature can be 0-100°C, the recommended temperature is room temperature, the reaction time is 5-36 hours, and the recommended reaction time is 10-18 hours. 3a. The molar ratio of the acylating agent to the basic substance is 1:1-10:1-100, and the recommended molar ratio is 1:1.5-3:3-6. The acylating agent used is dichloroacetyl chloride, dichloroacetyl bromide, methyl dichloroacetate or ethyl dichloroacetate, and the recommended acylating agent is methyl dichloroacetate.

The compounds containing a lone pair of electrons on the nitrogen atom in the present invention are tertiary amines, secondary amines, primary amines, pyridine, bipyridine, diethylamine compounds and NH ₃ with C _1-24 hydrocarbon groups.

The polar solvent described in the present invention can be one or more ethers, THF, chloroform, methylene dichloride, ethylene dichloride, trichloroethane, methanol, ethanol, pyridine, triethylamine, toluene, Acetonitrile and water etc.

The method of the present invention can be used to synthesize compound 2 from compound 1 step by step, and compound 2 can also be directly synthesized by a continuous one-pot method, and compound 4a can be synthesized from compound 2 by a step-by-step method. Not only the method is simple, the yield is high, and the cost is low , and the configuration transformation is complete, it is an effective and simple method for transforming from L-substituted phenylserine ester to D-form fluthiamphenicol, thus solving the waste problem of the invalid enantiomer produced by the resolution method , reduce environmental pollution, and have practical economic value.

The following implementation examples will help to understand the present invention, but do not limit the content of the present invention.

Example 1 Extraction and purification of L-(-)-threo-3-(4-methylsulfonyl)phenylserine ethyl ester

Take 500ml of the resolution waste liquid (L-isomer: e.e. > 80%) in industrial production, concentrate under reduced pressure to obtain a viscous liquid, dissolve it in 400ml of water, add 10g of activated carbon, stir at room temperature for 0.5 hours, filter, and the filtrate Use concentrated ammonia water to adjust pH to 8-9, precipitate solids, let stand, filter, wash the filter cake lightly with 100ml of ice-cold water, drain it, mix the solids with 200ml of ethyl acetate and stir for 1 hour, filter, and dry to obtain 32g The off-white solid was recrystallized in 320ml of absolute ethanol, filtered while it was hot, allowed to stand under cooling, and filtered to obtain 21g of white crystals. [α]=-13.4°～-13.6°(c=1, DMF) Example 2 D-(-)-threo-(4S, 5R)-2-phenyl-4-hydroxymethyl-5-( Preparation of 4-methylsulfonyl)phenyl-2-oxazoline

Take 50g of the L-type isomer, put it into a reaction bottle, add 300ml of 1,2-chloroethane, 100ml of absolute ethanol, 37ml of triethylamine, ice-salt bath, control the temperature of the mixture below 5°C, and stir A solution of benzoyl chloride in 1,2-dichloroethane (22 ml of benzoyl chloride, 22 ml of 1,2-dichloroethane) was added dropwise, and the drop was completed in about 1.5 hours. After the addition is complete, stir at room temperature for 2 hours, evaporate the solvent to dryness under reduced pressure, add 300ml of 1,2-dichloroethane, add 27ml of thionyl chloride dropwise at room temperature, drop it in about 1.5 hours, heat to 45°C, and stir for 2 hours. Carefully pour the reaction solution into 300ml of crushed ice, stir until the crushed ice melts, separate the organic phase, wash the organic phase with water (300ml), wash with saturated sodium carbonate solution (300ml), wash with water (300ml×3), and dry over anhydrous sodium sulfate (5g). Filter, evaporate the solvent to dryness under reduced pressure to obtain a viscous liquid, add 500ml of anhydrous methanol, stir well, add sodium methoxide solution (2g sodium, 100ml of anhydrous methanol) dropwise at room temperature, drop it for about 0.5 hours, and continue stirring at room temperature After 2 hours, 5 ml of glacial acetic acid was added to neutralize the reaction solution. Dissolve 25g of potassium borohydride in 100ml of water, add this solution dropwise to the reaction solution, control the reaction temperature below 50°C, after the addition is complete, stir at room temperature for 12 hours, filter to obtain a white solid: 32g, yield 55.6%. mp: 206-209°C, [α] _D ²⁴ = 116.0° (c = 2.5, DMF), MS (CI, NH ₃ ): m/z = 332 (M+ ⁺¹ ). ¹ H NMR (300 MHz, DMSO- d6): δ=3.16 (s, 3H, CCH ₃ ), 3.62 (m, 1H, CH _A H _B ), 3.79 (m, 1H, CH _A H _B ), 4.13 (m, 1H, NCH), 5.12 ( t, 1H, J=5.7Hz, OH), 5.69(d, 1H, J=6.4, OCH), 7.56(m, 5Harom), 7.98(m, 4Harom) Elemental analysis: C ₁₇ H ₁₇ NO ₄ SC61.29 (61.61), H5.08(5.17), N4.16(4.23), S9.83(9.68)

The preparation of example 3D-(-)-threo-2-phenyl-4-fluoromethyl-5-(4-thiamphenicol) phenyl-2-oxazoline gets example 2 gained product 30g (in isopropyl recrystallized in alcohol, and dried _overnight in _P2O5 ), put it into a pressure-resistant sealed bottle, vacuumize the sealed bottle, replace it with nitrogen, add 300ml of dry dichloromethane, and finally add 21.4ml of freshly steamed Ishikawa reagent [A. Takaoka, H. Iwakiri, N. Ishikawa, Bull. Chem. Soc. Jpn. 1979, 52(11), 3377-3380]. Tighten the cap of the bottle, put it into an oil bath preheated to 100-120°C, and react for 2 hours. Cool to room temperature, open the bottle cap, take out the reaction solution, lightly wash the reaction bottle with a small amount of dichloromethane and water, combine the washing solution with the reaction solution, wash the organic phase with water, wash with 0.5N sodium hydroxide solution, and finally wash with water, anhydrous _Na2SO4 dry _. After filtration, the filtrate was evaporated to dryness under reduced pressure. Recrystallized in isopropanol to obtain light yellow or off-white solid: 24.5 g, yield: 82%. For further purification, the product can be recrystallized again to obtain white crystals. Mp: 117-119°C. MS: m/z 334 (M+1)+. ¹ H NMR (300MHZ, DMSO-d6): δ3.23 (s, 3H), 4.3-4.5 (m, 1H), 4.6- 4.9(m, 1H), 5.8(d, 1H, J=6Hz), 7.5-7.7(m, 5H), 7.99(d, 4H, J=9Hz). Elemental analysis: C ₁₇ H ₁₆ NO ₃ SFC61.42 (61.24), H4.83(4.84), N4.15(4.20), F5.34(5.67), S9.68(9.62)

Preparation of Example 4D-(-)-threo-1-(4-thiamphenicol)phenyl-2-amino-3-fluoro-1-propanol

Get 9.07g of the product obtained in Example 3 and suspend it in 150ml of 6N hydrochloric acid, heat to reflux, and react for 12 hours. The suspension is adjusted to pH=11～12 with 2N NaOH solution, and the mixture is transferred to a liquid-liquid continuous extractor. The product was extracted with dichloromethane, heated to reflux for 10 hours, the organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to give a white solid, 6.27 g, with a yield of 93%. Mp: 111～113°C, [α] ²⁴ =-36.5°(c=1, MeOH). MS: m/z248(M+1) ^{+ .1} H NMR (300MHz, DMSO-d6): δ1.54( br s, 2H), 2.9-3.1(m, 1H), 3.2(s, 3H), 4.05-4.5(m, 2H), 4.69(d, 1H, J=6Hz), 5.69(br, s, 1H) , 7.61 (d, 2H, J=9Hz), 7.88 (d, 2H, J=9Hz). Elemental analysis C ₁₀ H ₁₄ NO ₃ SFC48.22 (48.56), H5.48 (5.71), N5.58 (5.67 ), F7.93(7.68), S13.08(12.97)

Preparation of Example 5D-(-)-threo-1-(4-thiamphenicol)phenyl-2-dichloroacetylamino-3-fluoro-1-propanol

Take 5.55 g of the product obtained in Example 4 and dissolve it in 55 ml of dry methanol, add 3.06 ml of triethylamine and 11.4 ml of methyl dichloroacetate, stir at room temperature for 18 hours, evaporate the solvent to dryness, add a mixed solvent of toluene and water, let it stand, and filter , to obtain a crude product, which was recrystallized in isopropanol-water to obtain a white solid, 6.7g, with a yield of 84%. mp: 152-154°C.[α] ₂₄ = 17.9° (c=1, DMF), MS: m/z360(M+1) ⁺ . ¹ H NMR (300MHz, DMSO-d6), δ3.17(s , 3H), 4.2-4.5(m, 2H), 4.55-4.75(m, 1H), 5.00(m, 1H), 6.17(d, 1H, J=9Hz), 6.46(s, 1H), 7.62(d , 2H, J=9Hz), 7.87 (d, 2H, J=9Hz), 8.62 (d, 1H, J=9Hz) Elemental analysis: C ₁₂ H ₁₄ NO ₄ Cl ₂ SFC: 40.48 (40.23), H3.93 (3.94), N3.86(3.91), Cl19.76(19.80), F5.39(5.30), S8.95(8.95)

Example 6

The compound can be prepared according to the method of Example 1 to Example 4, and the product analysis results are as follows: D-threo-(1R, 2S)-1-(4-nitrophenyl)-2-amino-3-fluoro-1-propanol ¹ H 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). Elemental analysis: theoretical value: C (50.47), H (5.14), N (13.08), S (14.95)

Analytical values: C (50.46), H (5.18), N (13.00), S (14.94) D-threo-(1R,2S)-1-(4-methylthiophenyl)-2-amino-3 -Fluoro-1-propionic acid: ¹ H NMR: 1.45 (2H, brs), 2.48 (s, 3H), 2.95-3.15 (m, 1H), 4.05-4.5 (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). Elemental analysis: theoretical value: C(55.81), H( 6.51), N (6.51), S (14.8) Analytical value: C (55.85), H (6.49), N (6.46), S (14.6)

Example 7

D-(-)-threo-1-(4-methylthio)phenyl-2-dichloroacetamido-3-fluoro-1-propanol was prepared according to the method of Example 5, and the product analysis results were as follows: ¹ H NMR: 2.48(s, 3H), 4.2-4.5(m, 2H), 4.55-4.75(m, 1H), 5.00(m, 1H), 6.17(d, 1H, J=9Hz), 6.46(s, 1H ), 7.62 (d, J=9Hz, 2H), 7.87 (d, J=9Hz, 2H), 8.62 (d, 2H, J=9Hz). Elemental analysis: Theoretical value: C (44.18), H (4.33) , N(4.29), Cl(21.73), F(5.82), S(9.83) Analytical values: C(44.12), H(4.30), N(4.23), Cl(21.77), F(5.79), S( 9.79)

Claims (7)

1. one kind prepares the method for D-(-)-Su Shi-1-R substituted-phenyl 2-dichloro acetamino-3-fluoro-1-propyl alcohol from L type substituted benzene serine ester, and described L type substituted benzene serine ester has

Molecular formula, D-(-)-Su Shi-1-R substituted-phenyl 2-dichloro acetamino-3-fluoro-1-propyl alcohol has

Molecular formula, wherein R=NO ₂, CN, R ⁴SO ₂, R ⁴SO, CF ₃, described R ⁴Be C _1-8Alkyl, it is characterized in that making by following reaction respectively:

(1). 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 ²The carboxylic acid halides of COX is in the presence of polar solvent, and-20 ℃～50 ℃ reactions 1 hour to 10 hours add thionyl chloride 1～80 ℃ of reaction 0.2～10 hour, make D-(-)-Su Shi-(4R, 5R)-2-R ₂-4-R ₁Oxygen acyl group-5-R substituted-phenyl-2-oxazoline 2a, R ¹Be C _1-8Alkyl, R ²Be aryl, R ³Be COOR ¹, CH ₂Y, Y are hydroxyl or halogen, and described aryl is a phenyl, halogenophenyl, C _1-4Alkyl-substituted phenyl, described L type substituted benzene serine ester, the mol ratio of nitride, carboxylic acid halides and thionyl chloride is 1: 0.8～1.5: 0～5: 0.5～3, wherein R ²Be aryl, X is a halogen; (2) .D-(-)-Su Shi-(4R, 5R)-2-R ₂-4-R ₁Oxygen acyl group-5-R substituted-phenyl-2-oxazoline 2a and alkali substance reaction 0.5～5 hour, generation D-(-) Su Shi-(4S, 5R)-2-R ₂-4-R ₁Oxygen acyl group-5-R substituted-phenyl-2-Evil

Azoles quinoline 2b, mol ratio is followed successively by 1: 0.1～10, and described alkaline matter is salt of wormwood or sodium, saleratus or sodium, volatile salt, diethylamine, triethylamine, sodium methylate, sodium ethylate;

(3) .D-(-)-Su Shi (4S, 5R)-2-R ₂-4-R ₁Oxygen acyl group-5-R substituted-phenyl-2-oxazoline 2b, polar solvent and POTASSIUM BOROHYDRIDE or sodium-10 ℃ under 50 ℃, reacted 1～12 hour, make D-(-)-Su Shi-(4S, 5R)-2-R ₂-4-methylol-5-R substituted-phenyl-2-oxazoline 2c, the mol ratio of 2c and POTASSIUM BOROHYDRIDE or sodium is 1: 1～10;

(4). in polar solvent, D-(-)-Su Shi-(4R, 5R)-2-R ₂-4-methylol-5-R substituted-phenyl-2-oxazoline 2c and fluorination reagent mol ratio are 1: 0.5～3, and temperature of reaction is 0～120 ℃, reacted 0.5～10 hour, and acquisition D-(-)-Su Shi-(4S, 5R)-2-R ₂-4-methyl fluoride-5-R substituted-phenyl-2-oxazoline 2d, described fluorination reagent are DAST reagent, Yarovenko reagent, Ishikawa reagent;

(5) .D-(-)-Su Shi (4S, 5R)-2-R ₂-4-methyl fluoride-5-R substituted-phenyl-2-oxazoline 2d can also issue unboiled water in solvent and acidity and separate the open loop reaction, temperature of reaction room temperature to 120 ℃, reaction times is to obtain D type-1-R substituted-phenyl-2-amino-3-fluoro-1-propyl alcohol 3a in 4 hours to 18 hours, and D-(-)-Su Shi (4S, 5R)-2-R ₂-4-methyl fluoride-5-R substituted-phenyl-2-oxazoline 2d and mineral acid or organic acid mol ratio are 1: 1～100, and described acid is mineral acid or organic acid, and described solvent is water, methyl alcohol, ethanol, Virahol, glacial acetic acid and water;

(6). in polar solvent and under 0-100 ℃, D type-1-R substituted-phenyl-2-amino-3-fluoro-1-propyl alcohol 3a, alkaline matter and acylating agent carry out obtaining in acylation reaction 5-36 hour D-(-)-Su Shi-1-R substituted-phenyl-2-dichloro acetamino-3-fluoro-1-propyl alcohol, D type-1-R substituted-phenyl-2-amino-3-fluoro-1-propyl alcohol 3a, the mol ratio of acylating agent and alkaline matter is 1: 1～10: 1～100, described alkaline matter is the organic bases that contains lone-pair electron on the nitrogen-atoms, or one or the mineral alkali or the low-carbon (LC) sodium alkoxide of divalent metal, described acylating agent is a dichloroacetyl chloride, two chloro-acetyl bromides, methyl dichloroacetate or ethyl dichloroacetate; The compound that contains lone-pair electron on the above-mentioned nitrogen-atoms is to have C _1-24The tertiary amine of alkyl, secondary amine, primary amine, pyridine, bipyridine, diethylamine compounds and NH ₃

2. as claimed in claim 1ly a kind ofly prepare the method for D-(-)-Su Shi-1-R substituted-phenyl-2-dichloro acetamino-3-fluoro-1-propyl alcohol 4a from L type substituted benzene serine ester, the mol ratio that it is characterized in that containing on described L type substituted benzene serine ester, carboxylic acid halides and the nitrogen-atoms compound of lone-pair electron is 1: 0.8～1.2: 0.04～4: 0.5～2.

3. as claimed in claim 1ly a kind ofly prepare the method for D-(-)-Su Shi-1-R substituted-phenyl-2-dichloro acetamino-3-fluoro-1-propyl alcohol 4a, it is characterized in that described thionyl chloride is 0.5～2: 1 with respect to the mol ratio of L type substituted benzene serine ester from L type substituted benzene serine ester.

4. as claimed in claim 1ly a kind ofly prepare the method for D-(-)-Su Shi-1-R substituted-phenyl-2-dichloro acetamino-3-fluoro-1-propyl alcohol 4a from L type substituted benzene serine ester, it is characterized in that described D-(-)-Su Shi-(4R, 5R)-2-R ₂-4-R ₁The mol ratio of oxygen acyl group-5-R substituted-phenyl-2-oxazoline 2b and POTASSIUM BOROHYDRIDE or sodium is 1: 1～3.

5. as claimed in claim 1ly a kind ofly prepare the method for D-(-)-Su Shi-1-R substituted-phenyl-2-dichloro acetamino-3-fluoro-1-propyl alcohol 4a from L type substituted benzene serine ester, it is characterized in that described D-(-)-Su Shi-(4R, 5R)-2-R ₂The mol ratio of-4-methylol-5-R substituted-phenyl-2-oxazoline 2c and fluorination reagent is 1: 1～3, and this fluorination reagent is Ishikawa reagent, i.e. R ₂ ⁵NCF ₂CFH (CF ₂) _nF, 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.

6. as claimed in claim 1ly a kind ofly prepare the method for D-(-)-Su Shi-1-R substituted-phenyl-2-dichloro acetamino-3-fluoro-1-propyl alcohol 4a, it is characterized in that described polar solvent can be one or more chloroform, dichloromethane gold alkane, ethylene dichloride, trichloroethane, methyl alcohol, ethanol, pyridine, triethylamine, toluene, acetonitrile from L type substituted benzene serine ester.

7. a kind of method for preparing D-(-)-Su Shi-1-R substituted-phenyl-2-dichloro acetamino-3-fluoro-1-propyl alcohol 4a from L type substituted benzene serine ester as claimed in claim 1; it is characterized in that in described (6) method; the mol ratio of D type-1-substituted-phenyl-2-amino-3-fluoro-1-propyl alcohol, acylating agent and alkaline matter is 1: 1.5～3: 3～6; described acylating agent is a methyl dichloroacetate; temperature of reaction is a room temperature, and the reaction times is 10～18 hours.