A method for the synthesis of a florfenicol key intermediate

Abstract

The application provides a synthesis method of a key intermediate of florfenicol, and particularly relates to a preparation method of (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol. The application utilizes the selectivity of ketoreductase to the substrate carbonyl ortho position chirality, realizes dynamic kinetic resolution (DKR) while reducing the carbonyl group to obtain a pure chiral compound, and then reduces the chiral compound to obtain a target product. The method is simple in process, high in selectivity, and greatly improves the product yield.

Description

Technical Field

[0001] This invention belongs to the fields of biopharmaceutical and biochemical technology, specifically a method for synthesizing a key intermediate of florfenicol. Background Technology

[0002] Florfenicol is a synthetic monofluoro derivative of thiamphenicol, a veterinary chloramphenicol antibiotic developed by Schering-Plough in the late 1980s. It is primarily used for the prevention and treatment of animal diseases and systemic infections in livestock, poultry, and aquatic animals, and shows promising application prospects.

[0003] (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol is a key intermediate in the synthesis of florfenicol. Therefore, the development of synthetic routes for (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol has attracted increasing attention from researchers.

[0004] To address the limiting challenges in its development, pharmaceutical researchers have developed various methods for synthesizing (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol. Currently, the main method for synthesizing (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol is the reduction of D-p-methylsulfonylbenzylserine ethyl ester or D-p-methylsulfonylbenzylserine using a reducing agent.

[0005] Chinese patent CN101550110B describes the reduction of D-p-methylsulfonylbenzylserine ethyl ester with potassium borohydride to obtain (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol.

[0006] Chinese patent application CN114634459A uses D-p-methylsulfonylbenzylserine ethyl ester as a raw material and anhydrous ethanol as a solvent to reduce it with sodium to obtain (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol.

[0007] Chinese patent application CN111704564A prepared (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol using D-p-methylsulfonylbenzylserine as a raw material, DMSO as a solvent, sodium borohydride as a reducing agent, and iodine as a reducing aid.

[0008] As can be seen from the above-disclosed synthesis methods, (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol is basically prepared from D-p-methylsulfonylbenzylserine ethyl ester, which is prepared from p-methylsulfonyltoluene or p-methylsulfonylbenzaldehyde. This invention directly starts from p-methylsulfonylbenzoic acid and provides a new method for synthesizing (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol. Summary of the Invention

[0009] To address the above problems, this invention provides a method for preparing (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol. This method is simple, has high selectivity, and greatly improves the product yield.

[0010] The preparation method of (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol according to the present invention comprises the following reaction route:

[0011]

[0012] The preparation method of (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol according to the present invention includes the following steps:

[0013] Step 1: Compound D is reacted with ketone reductase to yield compound E;

[0014] Step 2: Compound E undergoes a reduction reaction to yield compound A (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol.

[0015] Preferably, the trade name of the ketone reductase is YH2027.

[0016] Preferably, compound D is prepared by the following steps:

[0017] Step a: Compound B reacts with CDI to give intermediate B1;

[0018] Step b: Intermediate B1 reacts with nitromethane in the presence of sodium methoxide or sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, etc., to obtain compound C;

[0019] Step c: Compound C reacts with formaldehyde to give compound D.

[0020] Preferably, the solvent in step a is selected from one or a combination of tetrahydrofuran, 1,4-dioxane, DMSO, and DMF.

[0021] Preferably, in step b, intermediate B1 is reacted directly without purification.

[0022] Preferably, the ketone reductase in step 1 is selected from:

[0023] Preferably, the coenzyme cycle system for the enzyme reaction in step 1 is a glucose dehydrogenation, isopropanol dehydrogenation, or formic acid dehydrogenation system.

[0024] Preferably, the coenzyme for the enzyme reaction in step 1 is selected from NAD. + or NAPD +

[0025] Preferably, the reduction conditions in step 2 are a Pd / C and H2 system.

[0026] In the present invention, compound D has a strong acidity due to the presence of a strongly electron-withdrawing nitro group at the carbonyl position, which causes it to undergo rapid carbonyl-enol tautomerism. The reduced product does not have this characteristic. The present invention utilizes the selectivity of ketone reductase for the chirality of the substrate carbonyl position to achieve dynamic kinetic resolution (DKR) to obtain pure chiral compound E while reducing the carbonyl group. Compound E is then reduced to obtain the target product A. Detailed Implementation

[0027] To provide a clearer understanding of the technical features, objectives, and effects of the present invention, specific embodiments of the present invention are now described.

[0028] Example 1: Synthesis of Compound C

[0029]

[0030] In a 500 mL four-necked flask, p-methylsulfonylbenzoic acid (25 g, 0.125 mol) and 1,1-carbonyldiimidazole (24.3 g, 0.150 mol) were added to anhydrous THF (150 mL), and the mixture was stirred under reflux for 2 h. The resulting mixture was concentrated to obtain a pale yellow oily crude product B1, which could be used for the next step without further purification. CH3NO2 (15.26 g, 0.250 mol) was added dropwise to an anhydrous THF (50 mL) solution of sodium methoxide (8.10 g, 0.150 mol), and the resulting mixture was stirred at room temperature for 2 h. At this time, a THF solution of crude product B1 was added dropwise, and the mixture was stirred at room temperature for 2 h after the addition was complete. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with THF (100 mL) and dissolved in cold water (200 mL). The aqueous solution was slowly acidified to pH 3-4 with 6 M HCl and extracted with CH2Cl2 (3 × 100 mL). The combined organic phases were dried with anhydrous Na2SO4 and then concentrated to give 28.49 g of pale yellow solid C with a liquid phase purity of 98.82% and a yield of 93.8%.

[0031] Example 2: Synthesis of Compound D

[0032]

[0033] Water (80 mL) and sodium hydroxide (4.52 g, 0.113 mol) were added to a 500 mL four-necked flask. The mixture was stirred and cooled to 0 °C. Compound C (25 g, 0.103 mol) was slowly added to the system. After stirring for 2 h, a prepared 37% formaldehyde aqueous solution (formaldehyde: 3.40 g, 0.113 mol) was slowly added dropwise to the system, with the temperature controlled at 0-5 °C. After the addition was complete, the mixture was stirred for 0.5 h, then heated to 25 °C and stirred for 2 h. The mixture was then cooled to 0 °C, and acetic acid (7.41 g, 0.123 mol) was slowly added. After the addition was complete, the mixture was heated to 25 °C and extracted with 3 x 100 mL ethyl acetate. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated to give 26.85 g of pale yellow solid D. The liquid phase purity was 98.4%, and the yield was 95.6%.

[0034] Example 3: Synthesis of Compound E

[0035]

[0036] Under nitrogen protection, add 52 mL of a 0.4 mol / L buffer solution of sodium dihydrogen phosphate and disodium hydrogen phosphate (pH 6.5) to a 500 mL four-necked flask. Add 18 g of glucose and stir to dissolve. Then add 25 g of compound D and 50 mL of water. Insert a pH meter and control the pH between 6.4 and 6.6. Maintain the temperature of the system at 35°C. Take 1 g of ketone reductase YH2027 enzyme powder, 2 g of glucose dehydrogenase YH1901 enzyme powder, 100 mg of magnesium chloride hexahydrate, and 25 mg of NAD+. + In a 50 mL reaction flask, the mixture was thoroughly mixed and heated to 35 °C, then added to the four-necked flask mentioned above. The reaction temperature was maintained at 35 °C, and stirring continued. Titration with 4 M NaOH solution was used to maintain the pH between 6.4 and 6.6. After 5 hours, the reaction was complete. The mixture was extracted with 3 x 100 mL ethyl acetate. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated to yield 24.48 g of off-white solid E, with a liquid phase purity of 99.12% and a yield of 97.2%. The ketone reductase and glucose dehydrogenase used in the reaction were purchased from Suzhou Yinhang Biotechnology Co., Ltd., with product codes YH2027 and YH1901, respectively.

[0037] Example 4: Synthesis of Compound A

[0038]

[0039] Under a hydrogen atmosphere, 100 mL of methanol and 20 g of compound E were added to a 500 mL four-necked flask. After stirring and dissolving, 2 g of Pd / C was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was filtered, washed with 20 x 2 mL of methanol, and the total weight of the filtrate was weighed to be 123.28 g. A sample solution was taken for external standard detection. Based on the standard, compound A was calculated to be 17.13 g. Based on the mass of the reducing agent, the reaction yield was calculated to be 96.1%, and the liquid phase purity was 99.45%. NMR data: 1H NMR (400MHz, DMSO) δ 8.15 (s, 2H), 7.93 (d, J = 8.4Hz, 2H), 7.68 (d, J = 8.4Hz, 2H), 6.48 (d, J = 4.4Hz, 1H), 5.43 (t, J = 5.0Hz, 1H), 4.86 (dd, J = 7.8, 4.0Hz, 1H), 3.51–3.44 (m, 1H), 3.34–3.25 (m, 1H), 3.22 (s, 3H); 13C NMR (101MHz, DMSO) δ 147.24 (s), 140.26 (s), 127.91 (s), 127.05 (s), 69.40 (s), 58.28 (s), 58.03 (s), 43.54 (s).

[0040] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0041] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol, characterized in that, Includes the following steps: Step 1: Compound D is reacted with ketone reductase to yield compound E; Step 2: Compound E undergoes a reduction reaction to yield compound A (1R,2R)-2-amino-1-(4-methylsulfonyl)phenyl-1,3-propanediol.

2. The method according to claim 1, characterized in that, Compound D was prepared by the following steps: Step a: Compound B reacts with CDI to give intermediate B1; Step b: Intermediate B1 reacts with nitromethane in the presence of sodium methoxide or sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, etc., to obtain compound C; Step c: Compound C reacts with formaldehyde to give compound D.

3. The method as described in claim 2, characterized in that, The solvent in step a is selected from one or a combination of tetrahydrofuran, 1,4-dioxane, DMSO, and DMF.

4. The method as described in claim 2, characterized in that, In step b, intermediate B1 is reacted directly without purification.

5. The method as described in claim 1, characterized in that, The ketone reductase used in step 1 is commercially known as YH2027.

6. The method as described in claim 2, characterized in that, The enzyme reaction coenzyme cycle system in step 1 is a glucose dehydrogenation, isopropanol dehydrogenation, or formic acid dehydrogenation system.

7. The method as described in claim 2, characterized in that, The coenzyme for the enzyme reaction in step 1 is selected from: NAD. + or NADP + .

8. The method as described in claim 2, characterized in that, The reduction conditions in step 2 are a Pd / C and H2 system.

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