Process for the asymmetric synthesis of a florfenicol intermediate

Abstract

The application discloses an asymmetric synthesis method of florfenicol intermediate, which comprises the following steps: adding an organic solvent and a substrate I into a dry reaction bottle, adding a catalyst III, then adding a substrate II, controlling temperature, and carrying out post-treatment to obtain a product IV. Through the suitable chiral catalyst, the target product is obtained, the method has mild conditions, high hand type selectivity, the molar yield is more than 80%, the chiral purity can reach more than 99% ee, and the cis-trans selectivity is more than 90% dr.

Description

TECHNICAL FIELD

[0001] The present application relates to an asymmetric synthesis method of florfenicol intermediate, in particular to an asymmetric catalytic synthesis method of florfenicol intermediate by using a chiral catalyst. BACKGROUND

[0002] Florfenicol is a third generation of synthetic chloramphenicol antibiotics, which was developed by Schering-Plough Corporation in 1979. Compared with thiamphenicol, florfenicol uses F atom to replace the hydroxyl group of thiamphenicol according to the electronic isostere rule. The change of the group brings further improvement of the antibacterial activity of florfenicol, and the safety and effectiveness are also greatly improved compared with thiamphenicol and chloramphenicol. The toxic and side effects such as anemia and teratogenicity no longer occur. As a broad-spectrum antibiotic, florfenicol has a strong inhibitory effect on many harmful bacteria, and has been successfully applied in the livestock breeding industry for the prevention and treatment of various bacterial diseases of fish, poultry and livestock such as cattle and sheep.

[0003]

[0004] The key to the synthesis of florfenicol is the construction of two chiral centers. The methods for constructing chiral centers mainly include the following:

[0005] 1. Chemical resolution:

[0006] Chemical resolution method generally uses the form of enantiomeric salt to achieve the purpose of resolution. This method uses the formation of diastereomeric salts with different physical and chemical properties, and then separates the pure enantiomeric salt by crystallization or filtration method according to the physical and chemical properties. Finally, the salt is decomposed by treatment, and the pure enantiomeric salt is obtained.

[0007] Since 1952, the D-tartaric acid has been used to resolve the appropriate chiral intermediates in the preparation process since the Cutler group in the United States first synthesized racemic thiamphenicol.

[0008] This method is simple and convenient to operate under suitable conditions, but due to the existence of isomers, the yield after resolution will not exceed half, causing a certain atomic waste.

[0009] 2. Enzymatic resolution:

[0010] Enzymatic resolution is a method developed in recent decades to directly catalyze the resolution by enzymes or cells. This method generally involves biochemical reactions for resolution. Some microorganisms such as yeast cells, molds, and bacteria can degrade and assimilate one of the two isomers of racemic drug, and the other isomer is not degraded and assimilated and remains in the reaction solution to obtain pure enantiomers.

[0011] In 1990, the Clark group of Schering-Plough Corporation in the United States developed a method for enzymatic hydrolysis to resolve racemic phenylalanine ethyl ester. In 1998, the Kaptein group of DSM Corporation in the Netherlands reported a method for enzymatic resolution of racemic phenylalanine amide. Subsequently, other groups also made corresponding achievements.

[0012] 3. Asymmetric synthesis:

[0013] Asymmetric synthesis has been studied more in recent years. It mainly includes two aspects: one is chiral auxiliary induced asymmetric synthesis. In 1994, Davis et al. reported asymmetric synthesis based on substrate-induced aza-Darzens reaction. In 2006, the Hajra group of the Indian Institute of Technology reported an asymmetric synthesis method of chiral auxiliary induced asymmetric bromohydroxylation reaction.

[0014] In 2014, Myers et al. developed a cis-selective aldol reaction mediated by Pseudoephenamine. Subsequently, many domestic groups have developed research on florfenicol derivatives as chiral auxiliaries to promote their own asymmetric synthesis.

[0015] The other is chiral catalyst catalyzed asymmetric synthesis. In 1994, Dr. Wu of Schering-Plough Corporation in the United States reported a method for synthesizing florfenicol based on Sharpless asymmetric epoxidation reaction. Subsequently, other groups have developed on this basis. In 2006, Academician Lin Guoqiang developed an asymmetric synthesis route of methanamine and florfenicol based on asymmetric cyanation reaction.

[0016] In 2016, Dixon et al. published a chiral catalytic method. This method is a chiral intermediate of chloramphenicol obtained by catalysis of silver ion and cinchona amine derivatives from p-nitrobenzaldehyde and isocyanoacetate. The reaction equation is as follows

[0017]

[0018] When R is benzhydryl, the chiral selectivity of the two carbons of the chiral intermediate is high (ee value 89%, dr selectivity is also above 90).

[0019] After that, Professor Chen Fen'er's research group of Fudan University used a new cinchona alkaloid derivative as a catalyst, 4-substituted benzaldehyde and diethyl isocyanate to obtain an intermediate, and further reacted to obtain a chiral intermediate.

[0020]

[0021] The method does not need to use silver ions, and the chiral selectivity of the reaction is better, but there are more reaction steps, which is still somewhat cumbersome. SUMMARY

[0022] The purpose of the present application is to overcome the problems of harsh process conditions, low selectivity of chiral reagents, and high production cost in the asymmetric synthesis of the existing florfenicol intermediate, and to provide an asymmetric catalytic synthesis method of a florfenicol intermediate using a chiral catalyst. The molar yield of the method is more than 80%, and the chiral purity can reach more than 99% ee, and the cis-trans selectivity is more than 90% dr. Moreover, the reaction method has mild reaction conditions, and the reaction temperature is between-40℃ and 40℃, which is very conducive to the realization in industrial production.

[0023] The technical scheme of the present application is as follows:

[0024] An asymmetric synthesis method for preparing a florfenicol intermediate, comprising the following steps:

[0025] 1) Add organic solvent, substrate I and catalyst III to a dry reaction bottle, and control the reaction system at a certain temperature (-40℃ to 40℃);

[0026] 2) Add substrate II to the reaction bottle under nitrogen protection, and stir for 20-60 hours;

[0027] 3) After the reaction is completed, the solvent is distilled out under reduced pressure, and the distillation residue is column chromatographed to obtain product IV.

[0028] In step 2), substrate II is isocyanate;

[0029] In step 2), the reaction temperature is preferably controlled at-20℃ to 20℃, and more preferably at-10℃ to 10℃.

[0030] In step 1), the catalyst III has the following structure:

[0031]

[0032] In which R1=3,5-(CF3)2C6H3; 4-CF3C6H4; 4-FC6H4;

[0033] In step 1), the molar ratio of catalyst III to substrate I is between 0.01:1 and 0.10:1.

[0034] Step 1) the organic solvent is selected from one or several mixtures of dichloromethane, trichloromethane, toluene;

[0035] The molar ratio of substrate II to substrate I is between 1:1 and 2:1.

[0036] The chemical reaction equation of the present application is shown as follows:

[0037]

[0038] wherein R is C2-C8 branched or straight chain alkyl; 3-8 membered alicyclic group; aryl; heteroaryl; Ar(CH2)n- group, Ar represents aryl or heteroaryl, n = 1-6; n

[0039] The structure of the catalyst III is shown as follows:

[0040]

[0041] wherein R1=3,5-(CF3)2C6H3; 4-CF3C6H4; 4-FC6H4.

[0042] The general preparation method of the catalyst of the present application is as follows:

[0043]

[0044] In a reaction bottle, 3,4-dimethoxycyclobutyl-3-en-1,2-dione, methanol are added, stirred and dissolved, and the temperature is controlled at 25°C. An aromatic amine (R1-NH2) is added to the reaction bottle. The reaction mixture is stirred at 25°C for 48 hours to produce a precipitate, which is filtered to obtain an intermediate, which is dried under reduced pressure. The dried intermediate is added to a reaction bottle, dichloromethane is added and stirred and dissolved, and the temperature is controlled at 25°C. Quinine amine is added, and the reaction mixture is stirred at room temperature for 48 hours. After the reaction is completed, the product is purified by washing with water twice. The organic phase is rotary dried, slurried with methanol for 0.5 hours, filtered, and dried under reduced pressure to obtain the catalyst.

[0045] The principle of catalysis and chiral selectivity of the catalyst is as follows: the catalyst is combined with the isocyanate group. The combination process not only improves the reaction activity of the carbon-nitrogen double bond, but also fixes the position of the isocyanate ester. When the p-toluenesulfonyl benzaldehyde participates in the reaction, the NH on the catalyst is fixed as the space structure of the catalyst itself, so that the substrate II can only react with the substrate I in one direction, thereby obtaining the chiral substituted product we need.

[0046]

[0047] The intermediate of florfenicol in the present application is product VI oxazolidinone ester, and its structural formula is as follows:​

[0048]

[0049] wherein R is C2-C8 branched or straight chain alkyl; 3-8 membered alicycloalkyl; aryl; heteroaryl; Ar(CH2) n - group, Ar represents aryl or heteroaryl, n = 1-6;

[0050] Synthetic route for preparing florfenicol intermediate florfenicol:

[0051]

[0052] Beneficial effects:

[0053] The application selects an effective catalyst, the catalyst has a small amount, which greatly reduces the cost. The molar yield of the method is more than 80%, and the chiral purity can reach more than 90% ee, and the cis-trans selectivity is also more than 90% dr. Moreover, the reaction method has mild reaction conditions, and the reaction temperature is between-40 and 40 DEG C, which is very beneficial to realize in industrial production. DETAILED DESCRIPTION

[0054] In order to better understand the present application, the following will be described in detail through specific examples, it should be noted that the following examples are not limited to the scope of the present application, apparently, those skilled in the art can make various modifications and changes to the present application according to the description herein within the scope of the present application, and these modifications and changes are also included in the scope of the present application.

[0055] General preparation method of catalyst:

[0056]

[0057] wherein R1=3,5-(CF3)2C6H3; 4-CF3C6H4; 4-FC6H4

[0058] In the reaction bottle, 3,4-dimethoxycyclobutyl-3-en-1,2-dione 8 (1.42g, 10.0mmol) is added, 20ml of methanol is stirred and dissolved, and the temperature is controlled at 25 DEG C. The arylamine (R1-NH2) is added to the reaction bottle. The reaction mixture is stirred at 25 DEG C for 48 hours to produce a precipitate, which is filtered to obtain an intermediate, which is dried under reduced pressure.

[0059] The dried intermediate is weighed (1.0mmol) and added to the reaction bottle, 10ml of dichloromethane is stirred and dissolved, and the temperature is controlled at 25 DEG C. The quinine amine is added, and the reaction mixture is stirred at room temperature for 48 hours. After the reaction is completed, 10ml of purified water is washed twice. The organic phase is rotary dried, 5ml of methanol is added to the slurry for 0.5 hours, filtered, and dried under reduced pressure to obtain the catalyst.

[0060] Example 1

[0061]

[0062] The reaction flask was prepared in advance and dried. Chloroform (50 mL), p-tolylsulfonylbenzaldehyde (1.84 g, 10.0 mmol) and catalyst (0.63 g, 1.0 mmol) were added to the reaction flask, and the temperature was lowered to -10 °C. When the temperature reached, the substrate II (2.29 g, 12.0 mmol) solution in chloroform (50 mL) was added dropwise to the reaction flask. The temperature was controlled and stirred for 56 hours, and the reaction was complete. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography, and dried to obtain the product IV (3.15 g. Yield 84%, 99% ee, 97:3 dr).

[0063] 1 H-NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.64-7.38 (m, 7H), 5.72 (d, J = 4.4 Hz, 1H), 5.07 (s, 2H), 4.52 (d, J = 4.4 Hz, 1H), 3.07 (s, 3H).

[0064] Example 2

[0065]

[0066] The reaction flask was prepared in advance and dried. Chloroform (50 mL), p-tolylsulfonylbenzaldehyde (1.84 g, 10.0 mmol) and catalyst (0.63 g, 1.0 mmol) were added to the reaction flask, and the temperature was lowered to -10 °C. When the temperature reached, the substrate II (2.29 g, 12.0 mmol) solution in chloroform (50 mL) was added dropwise to the reaction flask. The temperature was controlled and stirred for 56 hours, and the reaction was complete. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography, and dried to obtain the product IV (3.15 g. Yield 84%, 99% ee, 97:3 dr).

[0067] 1 H-NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.64-7.38 (m, 7H), 5.72 (d, J = 4.4 Hz, 1H), 5.07 (s, 2H), 4.52 (d, J = 4.4 Hz, 1H), 3.07 (s, 3H).

[0068] Example 3

[0069]

[0070] Reaction flask was prepared in advance and dried. Chloroform (50 mL), p-tolylsulfonyl benzaldehyde (1.84 g, 10.0 mmol) and catalyst (0.56 g, 1.0 mmol) were added into the reaction flask, and the temperature was lowered to -10 °C. When the temperature reached, the substrate II (2.29 g, 12.0 mmol) solution in chloroform (50 mL) was added dropwise into the reaction flask. The temperature was controlled and stirred for 56 hours, and the reaction was completed. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography, and dried to obtain the product IV (3.34 g. Yield 89%, 92% ee, 90:10 dr).

[0071] The product IV was taken as an example of oxazolidinone ethyl ester to prepare florfenicol. The method is as follows:

[0072] Example 4

[0073]

[0074] Reaction flask was prepared in advance and dried. Methanol 50 ml, oxazolidinone ethyl ester IV (8.00 g, 25.5 mmol) was added into the reaction flask. After stirring and dissolving, the temperature was controlled at 20 °C, and potassium borohydride (1.95 g, 36.2 mmol) was added in batches. After the addition was completed, the temperature was raised to 50 °C, and the temperature was kept for 1 hour. After the temperature keeping was completed, the temperature was lowered to 35 °C, and acetic acid (1.20 g, 19.8 mmol) was added dropwise, and the temperature was kept for 1 hour. The reaction liquid was distilled under reduced pressure until no solvent was distilled out. 30% Isopropyl alcohol aqueous solution 20 ml was added into the reaction flask, and stirred for 0.5 hour. The temperature was lowered to 10 °C, and the filter was extracted, and dried to obtain the intermediate V (6.37 g, yield 92%).

[0075] Example 5

[0076]

[0077] Reaction flask was prepared in advance and dried. Methanol 50 ml, oxazolidinone ethyl ester IV (8.00 g, 25.5 mmol) was added into the reaction flask. After stirring and dissolving, the temperature was controlled at 20 °C, and potassium borohydride (1.95 g, 36.2 mmol) was added in batches. After the addition was completed, the temperature was raised to 50 °C, and the temperature was kept for 1 hour. After the temperature keeping was completed, the temperature was lowered to 35 °C, and acetic acid (1.20 g, 19.8 mmol) was added dropwise, and the temperature was kept for 1 hour. The reaction liquid was distilled under reduced pressure until no solvent was distilled out. 30% Isopropyl alcohol aqueous solution 20 ml was added into the reaction flask, and stirred for 0.5 hour. The temperature was lowered to 10 °C, and the filter was extracted, and dried to obtain the intermediate V (6.37 g, yield 92%).

[0078] Example 6

[0079]

[0080] The reaction flask was prepared in advance and dried. Tetrahydrofuran 50 ml, intermediate VII (5.00 g, 20.2 mmol), sodium acetate (2.48 g, 30.3 mmol) were added into the reaction flask, and dichloroacetyl chloride (3.13 g, 21.2 mmol) was added dropwise at 20°C. After the addition was completed, the temperature was raised to 30°C and maintained for 1 hour. Distillation was performed under reduced pressure until no solvent was left. Then 30 ml of 35% isopropyl alcohol and 0.20 g of activated carbon were added into the reaction flask, and the temperature was raised to 80°C. The mixture was filtered hot. The filtrate was cooled to 10°C and suction filtered, and dried to obtain florfenicol (6.66 g, yield 92%).

Claims

1. A process for the asymmetric synthesis of florfenicol intermediates characterized in that, Substrate and substrate in the presence of a catalyst The reaction gives the product under catalysis of the catalyst, and the chemical reaction equation is as follows: wherein R is C2-C8 branched or straight chain alkyl; 3-8 membered alicycloalkyl; aryl; Ar(CH2) n - group, Ar represents aryl, n = 1-6; The catalyst The structure is shown below: wherein R1= 3,5-(CF3)2C6H3; 4-CF3C6H4; 4-FC6H4.

2. The process for asymmetric synthesis of florfenicol intermediate according to claim 1, characterized in that, comprising the following steps: 1) Add organic solvent and substrate to a dry reaction flask , catalyst Control the reaction system at -40°C to 40°C. 2) The substrate was added into the reaction bottle under nitrogen protection and stirred for 20-60 hours. 3) After the reaction is completed, the solvent is distilled out under reduced pressure, and the distillation residue is column chromatographed to obtain the product IV.

3. The process for asymmetric synthesis of florfenicol intermediate according to claim 1, characterized in that, Catalyst with the substrate is between 0.01 : 1 and 0.10:

1.

4. The asymmetric synthesis method of a florfenicol intermediate according to claim 2, characterized in that, The organic solvent is selected from one or several mixtures of dichloromethane, trichloromethane, toluene.

5. The asymmetric synthesis method of a florfenicol intermediate according to claim 2, characterized in that, The reaction temperature in step 1) is controlled at -20°C to 20°C.

6. The asymmetric synthesis method of a florfenicol intermediate according to claim 2, characterized in that, Substrate With substrate The molar ratio is between 1:1 and 2:1.

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