METHODS FOR PREPARING FLORFENIOL AND INTERMEDIATE THEREOF

Abstract

The present invention discloses a method for preparing florfenicol and its intermediate (V), comprising an addition reaction, a ring closure reaction, a hydrolysis reaction, a ring opening reaction, a reduction reaction, a ring reaction, a fluorination reaction and a ring opening reaction. In the present method for preparing florfenicol, respective reaction steps can be continuously operated, therefore the methods of the present invention features simplified process and shorter synthetic route, and obtained florfenicol has high chiral purity and is of high yield. The method of the present invention for preparing florfenicol (TM) using the intermediate (V) avoids waste water pollution and reduces the cost for treating wastewater and alleviates environmental pollution. At the same time, the methods of the present invention eliminates a chiral resolution procedure, thus increasing the utilization rate of atoms in the reaction. As a result, cost is reduced and process is simplified.

Claims

1. A method for preparing an intermediate (V) of florfenicol, comprising: step (1): addition reaction adding source material SM, compound (I) and tetraethyl titanate to a solvent of tetrahydrofuran, heating the resulting mixture and allowing the mixture to react under an atmosphere of nitrogen and under reflux to form compound (II); step (2): ring closure reaction adding compound (II), ethyl bromoacetate and lithium bis(trimethylsilyl)amide to a solvent of tetrahydrofuran, allowing the resulting mixture to react at a temperature in a range from −50° C. to −78° C. to form compound (III); step (3): hydrolysis reaction adding compound (III) to an ethanol-mixed solvent, and adding hydrochloric acid to hydrolyze compound (III) to form compound (IV); step (4): ring opening reaction subjecting compound (IV) to a ring opening reaction in the presence of an acid to form intermediate (V); wherein the synthetic route for preparing the intermediate (V) of florfenicol is shown in route (1): ##STR00012##

2. The method according to claim 1, wherein in step (1), the molar ratio of the source material SM:compound (I):tetraethyl titanate is 1:1.0-1.5:1.5-2.5.

3. The method according to claim 1, wherein in step (2), the molar ratio of compound (II):ethyl bromoacetate:lithium bis(trimethylsilyl)amide is 1:1.1-1.5:1.1-1.5.

4. The method according to claim 1, wherein in step (3), the ethanol-mixed solvent is selected from a tetrahydrofuran-ethanol mixed solvent, an n-hexane-ethanol mixed solvent, a methyl tert-butyl ether-ethanol mixed solvent and a toluene-ethanol mixed solvent.

5. The method according to claim 1, wherein in step (4), the acid is selected from the group consisting of glacial acetic acid, hydrochloric acid, sulfuric acid and nitric acid.

6. A method for preparing florfenicol using an intermediate (V) of florfenicol, comprising: step (1): addition reaction adding source material SM, compound (I) and tetraethyl titanate to a solvent of tetrahydrofuran, heating the mixture and allowing the resulting mixture to react under an atmosphere of nitrogen and under reflux to form compound (II); step (2): ring closure reaction adding compound (II), ethyl bromoacetate and lithium bis(trimethylsilyl)amide to a solvent of tetrahydrofuran, allowing the resulting mixture to react at a temperature in a range from −50° C. to −78° C. to form compound (III); step (3): hydrolysis reaction adding compound (III) to an ethanol-mixed solvent, and adding hydrochloric acid to hydrolyze compound (III) to form compound (IV); step (4): ring opening reaction subjecting compound (IV) to a ring opening reaction in the presence of an acid to form intermediate (V); step (5): reduction reaction reducing intermediate (V) to compound (VI) by using a reducing agent of sodium borohydride in a solvent of ethanol; step (6): cyclization reaction cyclizing compound (VI) with dichloroacetonitrile in an alcohol to form an intermediate (VII); step (7): fluorination reaction fluorinating intermediate (VII) by using an Ishikawa reagent to form intermediate (VIII); step (8): ring opening reaction hydrolyzing intermediate (VIII) in an acid-containing alcohol solution to form florfenicol (TM); wherein the synthetic route for preparing florfenicol (TM) is shown in route (2): ##STR00013## ##STR00014##

7. The method according to claim 6, wherein in step (1), the molar ratio of the source material SM:compound (I):tetraethyl titanate is 1:1.0-1.5:1.5-2.5; and in step (2), the molar ratio of compound (II):ethyl bromoacetate:lithium bis(trimethylsilyl)amide is 1:1.1-1.5:1.1-1.5.

8. The method according to claim 6, wherein in step (3), the ethanol-mixed solvent is selected from a tetrahydrofuran-ethanol mixed solvent, an n-hexane-ethanol mixed solvent, a methyl tert-butyl ether-ethanol mixed solvent and a toluene-ethanol mixed solvent; and in step (4), the acid is selected from the group consisting of glacial acetic acid, hydrochloric acid, sulfuric acid and nitric acid.

9. The method according to claim 6, wherein in step (5), the molar ratio of compound (V):sodium borohydride is 1:1.1-1.5; and in step (6), the molar ratio of compound (VI):dichloroacetonitrile is 1:1.1-1.5, and the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, propylene glycol and glycerol.

10. The method according to claim 6, wherein in step (7), the molar ratio of compound (VII):Ishikawa reagent is 1:1.1-1.5; and in step (8), the acid in the acid-containing alcohol solution is selected from the group consisting of halogenated acid and trifluoroacetic acid, and the alcohol in the acid-containing alcohol solution is selected from the group consisting of methanol, ethanol, isopropanol, propylene glycol and glycerol.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1 is a .sup.1HNMR spectrum of the intermediate of Formula (V) prepared using the method for preparing the intermediate (V) according to the present invention;

[0056] FIG. 2 is a HPLC spectrum indicating the purity of the intermediate of Formula (V) prepared using the method for preparing the intermediate (V) according to the present invention;

[0057] FIG. 3 is a HPLC spectrum indicating the purity of the compound of Formula (VII) prepared using the method for preparing florfenicol according to the present invention;

[0058] FIG. 4 is a .sup.1HNMR spectrum of the compound of Formula (VII) prepared using the method for preparing florfenicol according to the present invention;

[0059] FIG. 5 a .sup.1HNMR spectrum of the compound of Formula (TM) prepared using the method for preparing florfenicol according to the present invention;

[0060] FIG. 6 is a .sup.1HNMR spectrum of the compound of Formula (II) prepared using the method for preparing the intermediate of Formula (V) according to the present invention;

[0061] FIG. 7 is a .sup.1HNMR spectrum of the compound of Formula (III) prepared using the method for preparing intermediate of Formula (V) according to the present invention;

[0062] FIG. 8 is a .sup.1HNMR spectrum of the compound of Formula (IV) prepared using the method for preparing the intermediate (V) according to the present invention;

[0063] FIG. 9 is a chiral HPLC spectrum of the intermediate of Formula (V) prepared using the method for preparing the intermediate (V) according to the present invention;

[0064] FIG. 10 is a chiral HPLC spectrum of the compound of Formula (TM) prepared using the method for preparing florfenicol according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0065] In order to make the technical solutions of the present invention clearer and definite, the present invention will be further described in detail below with reference to the embodiments and the accompanying drawings, but the embodiments of the present invention are not limited thereto.

[0066] A method for preparing an intermediate (V) of florfenicol, comprising the following steps:

[0067] step (1): addition reaction

[0068] adding source material SM, compound (I) and tetraethyl titanate to a solvent of tetrahydrofuran, heating the resulting mixture and allowing the mixture to react under an atmosphere of nitrogen and under reflux to form compound (II);

[0069] step (2): ring closure reaction

[0070] adding compound (II), ethyl bromoacetate and lithium bis(trimethylsilyl)amide to a solvent of tetrahydrofuran, allowing the resulting mixture to react at a temperature in a range from −50° C. to −78° C. to form compound (III);

[0071] step (3): hydrolysis reaction

[0072] adding compound (III) to an ethanol-mixed solvent, and adding hydrochloric acid to hydrolyze compound (III) to form compound (IV);

[0073] step (4): ring opening reaction

[0074] subjecting compound (IV) to a ring opening reaction in the presence of an acid to form intermediate (V);

[0075] wherein the synthetic route for preparing the intermediate (V) of florfenicol is shown in route (1):

##STR00009##

[0076] In some embodiments, in step (1), the molar ratio of the source material SM:compound (I):tetraethyl titanate is 1:1.0-1.5:1.5-2.5.

[0077] In some embodiments, in step (2), the molar ratio of compound (II):ethyl bromoacetate:lithium bis(trimethylsilyl)amide is 1:1.1-1.5:1.1-1.5.

[0078] In some embodiments, in step (3), the ethanol-mixed solvent is selected from a tetrahydrofuran-ethanol mixed solvent, an n-hexane-ethanol mixed solvent, a methyl tert-butyl ether-ethanol mixed solvent and a toluene-ethanol mixed solvent.

[0079] In some embodiments, in step (4), the acid is selected from the group consisting of glacial acetic acid, hydrochloric acid, sulfuric acid and nitric acid.

[0080] A method for preparing florfenicol using the intermediate (V), of florfenicol, comprising the following steps:

[0081] step (1): addition reaction

[0082] adding source material SM, compound (I) and tetraethyl titanate to a solvent of tetrahydrofuran, heating the mixture and allowing the resulting mixture to react under an atmosphere of nitrogen and under reflux to form compound (II);

[0083] step (2): ring closure reaction

[0084] adding compound (II), ethyl bromoacetate and lithium bis(trimethylsilyl)amide to a solvent of tetrahydrofuran, allowing the resulting mixture to react at a temperature in a range from −50° C. to −78° C. to form compound (III);

[0085] step (3): hydrolysis reaction

[0086] adding compound (III) to an ethanol-mixed solvent, and adding hydrochloric acid to hydrolyze compound (III) to form compound (IV);

[0087] step (4): ring opening reaction

[0088] subjecting compound (IV) to a ring opening reaction in the presence of an acid to form intermediate (V);

[0089] step (5): reduction reaction

[0090] reducing intermediate (V) to compound (VI) by using a reducing agent of sodium borohydride in a solvent of ethanol;

[0091] step (6): cyclization reaction

[0092] cyclizing compound (VI) with dichloroacetonitrile in an alcohol to form an intermediate (VII);

[0093] step (7): fluorination reaction

[0094] fluorinating intermediate (VII) by using an Ishikawa reagent to form intermediate (VIII);

[0095] step (8): ring opening reaction

[0096] hydrolyzing intermediate (VIII) in an acid-containing alcohol solution to form florfenicol (TM);

[0097] wherein the synthetic route for preparing florfenicol (TM) is shown in route (2):

##STR00010## ##STR00011##

[0098] In some embodiments, in step (1), the molar ratio of the source material SM:compound (I):tetraethyl titanate is 1:1.0-1.5:1.5-2.5; and in step (2), the molar ratio of the compound (II):ethyl bromoacetate:lithium bis(trimethylsilyl)amide is 1:1.1-1.5:1.1-1.5.

[0099] In some embodiments, in step (3), the ethanol-mixed solvent is selected from a tetrahydrofuran-ethanol mixed solvent, an n-hexane-ethanol mixed solvent, a methyl tert-butyl ether-ethanol mixed solvent and a toluene-ethanol mixed solvent; and in step (4), the acid is selected from the group consisting of glacial acetic acid, hydrochloric acid, sulfuric acid and nitric acid.

[0100] In some embodiments, in step (5), molar ratio of compound (V):sodium borohydride is 1:1.1-1.5; and in step (6), the molar ratio of compound (VI):dichloroacetonitrile is 1:1.1-1.5, and the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, propylene glycol and glycerol.

[0101] In some embodiments, in step (7), the molar ratio of compound (VII):Ishikawa reagent is 1:1.1-1.5; and in step (8), the acid in the acid-containing alcohol solution is selected from the group consisting of halogenated acid and trifluoroacetic acid, and the alcohol in the acid-containing alcohol solution is selected from the group consisting of methanol, ethanol, isopropanol, propylene glycol and glycerol.

Example 1

[0102] 1. Preparation of Compound (II)

[0103] In a 500 ml three-necked flask purged with nitrogen were added compound (SM) (20 g, 110 mmol), compound (I) (14.7 g, 121 mmol), tetraethyl titanate (50.2 g, 220 mmol), and THF (tetrahydrofuran) (200 ml), and the resulting mixture was heated and allowed to react under reflux for 6 hours. And the reaction was detected by liquid chromatography, after the reaction was completed, the reaction mixture was cooled to room temperature, and 60 ml of an icy solution of sodium chloride, 100 ml of ethyl acetate, 20 g of diatomaceous earth were added, then the resulting mixture was stirred for about 1 hour. Suction filtration was performed and the filtrate was extracted, and the organic phase was concentrated to afford a crude product of compound (II) (30 g) in a yield of 95%.

[0104] MS: [M+1] 288. .sup.1HNMR (400 MHz, CDCl.sub.3) δ1.284 (s, 9H), 3.090 (s, 3H), 8.051-8.054 (s, 4H), 8.658 (s, 1H).

[0105] 2. Preparation of Compound (III)

[0106] In a 500 ml three-necked flask were added ethyl bromoacetate (20.8 g, 125 mmol), lithium bis(trimethylsilyl)amide (20.9 g, 125 mmol), and THF (100 ml), and the resulting mixture was stirred at a temperature in the range from −50° C. to −78° C. After stirring for 30 minutes, a solution of compound (II) (30 g, 104 mmol) in tetrahydrofuran (100 ml) was added, and the temperature was controlled within the range from −50° C. to −78° C. After stirring for 1 hour, the reaction mixture was slowly warmed to room temperature, and the reaction was stirred for another 1 hour. The reaction was monitored and after completion of the reaction, water was added to quench the reaction. Ethyl acetate was added and the aqueous layer and the organic layers were separated and extraction was performed. The organic phase was washed with a solution of saturated sodium chloride, and dried over anhydrous sodium sulfate. The organic solvent was removed by rotary evaporation to give compound (III) (35 g) in a yield of 90%.

[0107] MS: [M+1] 374. .sup.1HNMR (300 MHz, DMSO-d.sub.6), δ 0.906-0.953 (t, 3H), 1.495 (s, 9H), 3.219 (s, 3H).

[0108] 3. Preparation of Compound (IV)

[0109] In a 500 ml three-necked flask, compound III (30 g, 80 mmol) was dissolved in a solution obtained by mixing 200 ml of tetrahydrofuran and a hydrochloric acid solution (4M) in 60 ml of ethanol, the resulting mixture was stirred at 0° C. for 5 minutes, and at 25° C.-35° C. for 1.5 hours. The reaction was monitored to the end of the reaction, and a reduced pressure distillation was carried out to give a crude product. The crude product was washed with a small amount of diethyl ether, and suction filtration was followed to give compound (IV) (18.3 g of) in a yield of 85%.

[0110] MS: [M+K] 308. .sup.1HNMR (300 MHz, DMSO-d.sub.6), δ 0.967-1.013 (m, 3H), 3.26 (s, 3H), 4.004-4.095 (m, 2H), 4.986-5.014 (m, 1H), 5.207-5.236 (m, 1H), 7.902-7.919 (d, 2H), 8.022-8.049 (d, 2H), 9.021 (s, 1H).

[0111] 4. Preparation of Compound (V)

[0112] In a 1000 ml three-necked flask were added compound (IV) (50 g, 186 mmol), glacial acetic acid (50 wt %, 350 ml), and dichloromethane (200 ml), the resulting mixture was stirred at 40° C.-60° C. for 3 hours and was cooled to 0° C.-10° C. The mixture was diluted with water and pH was adjusted to a value of 10. The mixture system was separated, and the aqueous phase was extracted with dichloromethane. The organic phase was collected and washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give a crude product, and the crude product was washed with a small amount of diethyl ether to give compound (V) (47.5 g) in a yield of 95%.

[0113] .sup.1H NMR (300 MHz, DMSO-d.sub.6), δ 1.088-1.136 (t, 3H), 1.623 (s, 2H), 3.168 (s, 3H), 3.499 (d, 1H), 4.006-4.077 (m, 2H), 4.914 (t, 1H), 5.730-5.747 (d, 1H), 7.569-7.597 (d, 2H), 7.832-7.860 (d, 2H).

[0114] 5. Preparation of Compound (VII)

[0115] In a 1000 ml three-necked flask were added compound (V) (50 g, 174 mmol) and ethanol (400 ml). When compound (V) was dissolved completely, sodium borohydride (7.6 g) was slowly added in batches, and the resulting mixture was heated to react under reflux for 0.5 hour. The reaction was monitored by TLC until compound (V) was completely reacted, and the reaction was terminated. Distillation was followed to distilled off 80% of the ethanol, and then glycerol (100 g) and glacial acetic acid (7.8 g) were added. After stirring for 15 minutes, dichloroacetonitrile (21.9 g) was added, and the reaction temperature was controlled at 40° C.-60° C. The mixture was reacted for 3 hours under stirring, a solid precipitated and was filtered. The solid was stirred in water to form a slurry, and the slurry was filtered to give a solid of compound (VII) (52.8 g) in a yield of 90%.

[0116] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 3.228 (s, 3H), 3.55-3.61 (m, 1H), 3.68-3.78 (m, 1H), 4.05-4.11 (m, 1H), 5.17 (t, 1H), 5.75 (d, 2H), 7.257 (s, 1H), 7.589-7.609 (d, 2H), 7.979-8.000 (d, 2H).

[0117] 6. Preparation of Compound (TM)

[0118] In a 1000 ml three-necked flask were added compound (VII) (50 g, 148 mmol), DCM (dichloromethane) (500 ml), and Ishikawa reagent (46.3 g, 208 mmol), and the resulting mixture was reacted for 3 hours under a pressure of 5-6 kPa. Workup was followed and organic phase was washed and concentrated to give a crude product which was directly used in the next step. In the crude product obtained in the previous step were added isopropanol (120 ml) and water (80 ml), and hydrochloric acid was added to adjust the pH value to 3-4, and the resulting mixture was reacted at a temperature of 40° C.-60° C. for 2 hours. The reaction was monitored by HPLC, after completion of the reaction, 100 ml of water was added to precipitate a solid, and suction filtration was performed to give a solid of compound (TM) (46.6 g) in a yield of 88%.

[0119] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ3.162 (s, 3H), 4.25-4.462 (m, 2H), 4.577-4.729 (m, 1H), 4.97 (d, 1H), 6.13 (d, 1H), 6.44 (s, 1H), 7.59 (d, 2H), 7.83 (d, 2H), 8.60 (d, 1H).

Example 2

[0120] 1. Preparation of Compound (II)

[0121] In a 1000 ml three-necked flask purged with nitrogen were added compound (SM) (40 g, 220 mmol), compound (I) (29.4 g, 242 mmol), tetraethyl titanate (100.4 g, 440 mmol), and THF (400 ml), and the resulting mixture was heated and allowed to react under reflux for 6 hours. And the reaction was detected by liquid chromatography, after the reaction was completed, the reaction mixture was cooled to room temperature, and 120 ml of an icy solution of sodium chloride, 200 ml of ethyl acetate, 50 g of diatomaceous earth were added, then the resulting mixture was stirred for about 1 hour. Suction filtration was performed and the filtrate was extracted, and the organic phase was concentrated to afford compound (II) (60 g) in a yield of 93%.

[0122] 2. Preparation of Compound (III)

[0123] In a 1000 ml three-necked flask were added ethyl bromoacetate (41.6 g, 250 mmol), lithium bis(trimethylsilyl)amide (41.8 g, 250 mmol), and n-hexane (300 ml), and the resulting mixture was stirred at a temperature in the range from −50° C. to −78° C. After stirring for 30 minutes, a solution of compound (II) (60 g, 208 mmol) in n-hexane (180 ml) was added, and the temperature was controlled within the range from −50° C. to −78° C. After stirring for 1 hour, the reaction mixture was slowly warmed to room temperature, and the reaction was stirred for another 1 hour. The reaction was monitored and after completion of the reaction, water was added to quench the reaction. Ethyl acetate was added and the aqueous layer and the organic layers were separated and extraction was performed. The organic phase was washed with a solution of saturated sodium chloride, and dried over anhydrous sodium sulfate. The organic solvent was removed by rotary evaporation to give compound (III) (71.8 g) in a yield of 92%.

[0124] 3. Preparation of Compound (IV)

[0125] In a 1000 ml three-necked flask, compound (III) (60 g, 160 mmol) was dissolved in a solution obtained by mixing 200 ml of tetrahydrofuran and a hydrochloric acid solution (4M) in 200 ml of ethanol, the resulting mixture was stirred at 0° C. for 5 minutes, and at 25° C.-35° C. for 1.5 hours. The reaction was monitored to the end of the reaction, and a reduced pressure distillation was carried out to give a crude product. The crude product was washed with a small amount of diethyl ether, and suction filtration was followed to give compound (IV) (43 g) in a yield of 100%.

[0126] 4. Preparation of Compound (V)

[0127] In a 2000 ml three-necked flask were added compound (IV) (100 g, 372 mmol), 1 M hydrochloric acid (500 ml), and dichloromethane (400 ml), the resulting mixture was stirred at 40° C.-60° C. for 3 hours and was cooled to 0° C.-10° C. The mixture was diluted with water and pH was adjusted to a value of 10. The mixture system was separated, and the aqueous phase was extracted with dichloromethane. The organic phase was collected and washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give a crude product, and the crude product was washed with a small amount of diethyl ether to give compound (V) (99.4 g) in a yield of 93%.

[0128] 5. Preparation of Compound (VII)

[0129] In a 2000 ml three-necked flask were added compound (V) (100 g, 348 mmol) and ethanol (800 ml) when compound (V) was dissolved completely, sodium borohydride (15.2 g) was slowly added in batches, and the resulting mixture was heated to react under reflux for 0.5 hour. The reaction was monitored by TLC until compound (V) was completely reacted, and the reaction was terminated. Distillation was followed to distilled off 80% of the ethanol, and then isopropanol (200 g) and glacial acetic acid (15.6 g) were added. After stirring for 15 minutes, dichloroacetonitrile (43.8 g) was added, and the reaction temperature was controlled at 40° C.-60° C. The mixture was reacted for 3 hours under stirring, a solid precipitated and was filtered. The solid was stirred in water to form a slurry, and the slurry was filtered to give a solid of compound (VII) (112.9 g) in a yield of 96%.

[0130] 6. Preparation of Compound (TM)

[0131] In a 2000 ml three-necked flask were added compound (VII) (100 g 296 mmol), DCM (1000 ml), and Ishikawa reagent (92.6 g, 416 mmol), and the resulting mixture was reacted for 3 hours under a pressure of 5-6 kPa. Workup was followed and organic phase was washed and concentrated to give a crude product which was directly used in the next step. In the crude product obtained in the previous step were added glycerol (250 ml) and water (160 ml), and hydroiodic acid was added to adjust the pH value to 3-4, and the resulting mixture was reacted at a temperature of 40° C.-60° C. for 2 hours. The reaction was monitored by HPLC, after completion of the reaction, 200 ml of water was added to precipitate a solid, and suction filtration was performed to give a solid of compound (TM) (99.7 g) in a yield of 94%.

Example 3

[0132] 1. Preparation of Compound (II)

[0133] In a 250 ml three-necked flask purged with nitrogen were added compound (SM) (10 g, 55 mmol), compound (I) (7.4 g, 60.5 mmol), tetraethyl titanate (25.1 g, 110 mmol), and THF (100 ml), and the resulting mixture was heated and allowed to react under reflux for 6 hours. And the reaction was detected by liquid chromatography, after the reaction was completed, the reaction mixture was cooled to room temperature, and 30 ml of an icy solution of sodium chloride, 50 ml of ethyl acetate, 10 g of diatomaceous earth were added, then the resulting mixture was stirred for about 1 hour. Suction filtration was performed and the filtrate was extracted, and the organic phase was concentrated to afford compound (II) (15.2 g) in a yield of 96%.

[0134] 2. Preparation of Compound (III)

[0135] In a 250 ml three-necked flask were added ethyl bromoacetate (10.4 g, 62.5 mmol), lithium bis(trimethylsilyl)amide (10.5 g, 62.5 mmol), and methyl tert-butyl ether (100 ml), and the resulting mixture was stirred at a temperature in the range from −50° C. to −78° C. After stirring for 30 minutes, a solution of compound (II) (15 g, 52 mmol) in methyl tert-butyl ether (15 ml) was added, and the temperature was controlled within the range from −50° C. to −78° C. After stirring for 1 hour, the reaction mixture was slowly warmed to room temperature, and the reaction was stirred for another 1 hour. The reaction was monitored and after completion of the reaction, water was added to quench the reaction. Ethyl acetate was added and the aqueous layer and the organic layers were separated and extraction was performed. The organic phase was washed with a solution of saturated sodium chloride, and dried over anhydrous sodium sulfate. The organic solvent was removed by rotary evaporation to give compound (III) (17.7 g) in a yield of 91%.

[0136] 3. Preparation of Compound (IV)

[0137] In a 500 ml three-necked flask, compound III (15 g, 40 mmol) was dissolved in a solution obtained by mixing 150 ml of tetrahydrofuran and a hydrochloric acid solution (4M) in 30 ml of ethanol, the resulting mixture was stirred at 0° C. for 5 minutes, and at 25° C.-35° C. for 1.5 hours. The reaction was monitored to the end of the reaction, and a reduced pressure distillation was carried out to give a crude product. The crude product was washed with a small amount of diethyl ether, and suction filtration was followed to give compound (IV) (21.5 g) in a yield of 100%.

[0138] 4. Preparation of Compound (V)

[0139] In a 500 ml three-necked flask were added compound (IV) (50 g, 186 mmol), sulfuric acid (1 mol/L, 150 ml), and dichloromethane (100 ml), the resulting mixture was stirred at 40° C.-60° C. for 3 hours and was cooled to 0° C.-10° C. The mixture was diluted with water and pH was adjusted to a value of 10. The mixture system was separated, and the aqueous phase was extracted with dichloromethane. The organic phase was collected and washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give a crude product, and the crude product was washed with a small amount of diethyl ether to give compound (V) (44 g) in a yield of 88%.

[0140] 5. Preparation of Compound (VII)

[0141] In a 1000 ml three-necked flask were added compound (V) (50 g, 174 mmol), ethanol (400 ml), when compound (V) was dissolved completely, sodium borohydride (7.6 g) was slowly added in batches, and the resulting mixture was heated to react under reflux for 0.5 hour. The reaction was monitored by TLC until compound (V) was completely reacted, and the reaction was terminated. Distillation was followed to distilled off 80% of the ethanol, and the 1,3-propanediol (100 g) and glacial acetic acid (7.8 g) were added. After stirring for 15 minutes, dichloroacetonitrile (21.9 g) was added, and the reaction temperature was controlled within a range of 40° C.-60° C. The mixture was reacted for 3 hours under stirring, a solid precipitated and was filtered. The solid was stirred in water to form a slurry, and the slurry was filtered to give a solid of compound (VII) (53.9 g) in a yield of 92%.

[0142] 6. Preparation of Compound (TM))

[0143] In a 1000 ml three-necked flask were added compound (VII) (50 g 148 mmol), DCM (500 ml), and Ishikawa reagent (46.3 g, 208 mmol), and the resulting mixture was reacted for 3 hours under a pressure of 5-6 kPa. Workup was followed and organic phase was washed and concentrated to give a crude product which was directly used in the next step. In the crude product obtained in the previous step were added 1,3-propanediol (120 ml) and water (80 ml), and hydrobromic acid was added to adjust the pH value to 3-4, and the resulting mixture was reacted at a temperature of 40° C.-60° C. for 2 hours. The reaction was monitored by HPLC, after completion of the reaction, 100 ml of water was added to precipitate a solid, and suction filtration was performed to give a solid of compound (TM) (47.7 g) in a yield of 90%.

[0144] In the above examples, FIG. 1 is the .sup.1HNMR spectrum of the compound of Formula (V); FIG. 2 is the HPLC spectrum illustrating the purity of the compound of Formula (V); FIG. 3 is the HPLC spectrum illustrating the purity of the compound of Formula (VII); FIG. 4 is the .sup.1HNMR spectrum of the compound of Formula (VII); FIG. 5 is the .sup.1HNMR spectrum of the compound of Formula (TM); FIG. 6 is the .sup.1HNMR spectrum of the compound of Formula (II); FIG. 7 is the .sup.1HNMR spectrum of the compound of Formula (III); FIG. 8 is the .sup.1HNMR spectrum of the compound of Formula (IV); FIG. 9 is the chiral HPLC spectrum of the compound of Formula (V); and FIG. 10 is the chiral HPLC spectrum of the compound of Formula (TM).

[0145] As described above, according to the method for preparing the intermediate (V) of florfenicol and according to the method for preparing florfenicol (TM) in this example, the reactions from step a through step c, the reactions from step e through step f, and the reactions from step g through step h, as shown in synthetic route (2), can be continuously operated, so that the whole process has only a total of 4 steps of reaction. Therefore the process of the present invention features simplified reactions and shorter synthetic route, and florfenicol prepared as such has high chiral purity and high yield, with a total yield up to 50-60%.

[0146] According to the method for preparing the intermediate (V) of florfenicol and according to the method for preparing florfenicol (TM) in this example, a chiral synthesis method is used to synthesize a chiral center of the florfenicol, which avoids waste water pollution caused by existing processes, and reduces the cost for treating wastewater and environmental pollution. At the same time, the methods of the present invention eliminates a chiral resolution procedure, thus increasing the utilization rate of atoms in the reaction. As a result, cost is reduced and process is simplified.

[0147] The above descriptions are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereto. Any technical person skilled in the art may make substitutions or alterations according to the disclosure of the present invention, and any equivalent substitutions or alterations within the scope of the present disclosure, and those equivalent substitutions or alterations according to the technical solution and conception of the present invention should be deemed to fall within the scope of the present invention.