Method for preparing florfenicol intermediate through chiral auxiliary agent mediated asymmetric aldol reaction

Abstract

The invention discloses a method for preparing a florfenicol intermediate through chiral auxiliary agent mediated asymmetric aldol reaction, which comprises the following steps: reacting a chiral auxiliary agent I with N-Boc-glycine to obtain an intermediate II, performing enolization on the intermediate II, performing aldol condensation on the intermediate II and p-methylsulfonyl benzaldehyde to obtain an intermediate III, and performing reduction reaction on the intermediate III to obtain a target product IV. According to the method, raw materials are easy to obtain, reaction conditions are mild, and the chiral auxiliary can be repeatedly utilized.

Description

Technical Field

[0001] The invention relates to the field of synthesis of florfenicol intermediates, and in particular to a method for preparing a florfenicol intermediate by a chiral auxiliary-mediated asymmetric aldol reaction. Background Art

[0002] Florfenicol is a synthetic third-generation chloramphenicol antibiotic with the structural formula shown below:

[0003]

[0004] It was developed by Schering-Plough Company in the United States in 1979. Compared with thiamphenicol, florfenicol uses F atoms to replace the hydroxyl group of thiamphenicol according to the electronic isostere rule. The change of the group has brought about a further improvement in the antibacterial activity of florfenicol, and its safety and effectiveness have also been greatly improved compared with thiamphenicol and chloramphenicol. Toxic side effects such as aplastic anemia and teratogenicity have never occurred. As a broad-spectrum antibiotic, florfenicol has a strong inhibitory effect on many harmful bacteria. It has been successfully used in animal husbandry to prevent and treat a variety of bacterial diseases in livestock such as fish, poultry, cattle and sheep.

[0005] The key to the synthesis of florfenicol is the construction of two chiral centers. There are mainly the following methods for constructing chiral centers:

[0006] 1. Chemical separation:

[0007] Chemical separation methods generally use enantiomeric salts to achieve separation purposes. This method uses the fact that it can form diastereomeric salts with different physical and chemical properties, and then uses the physical and chemical properties to separate them into pure enantiomeric salts through crystallization or filtration. Finally, the salts are further decomposed by treatment to obtain pure enantiomers.

[0008] Since the first synthesis of racemic thiamphenicol by the American Cutler group in 1952, D-tartaric acid has been used to split and obtain suitable chiral intermediates in the preparation process. This method is simple and convenient to operate under appropriate conditions, but due to the existence of isomers, the maximum yield after splitting will not exceed half, resulting in a certain amount of atomic waste.

[0009] 2. Enzymatic separation:

[0010] Enzymatic splitting is a method developed in recent decades that uses enzymes or cells to directly catalyze splitting. This method generally involves a certain biochemical reaction to split. Some microorganisms such as yeast cells, molds, and bacteria can degrade and assimilate one of the two isomers of the racemic drug through their own enzymatic reactions, while the other is not degraded and assimilated and remains in the reaction solution, thus obtaining a pure enantiomer.

[0011] In 1990, the Clark team of Schering-Plough Company in the United States developed a method for enzymatic hydrolysis of racemic phenylserine ethyl ester. In 1998, the Kaptein team of DSM Company in the Netherlands reported a method for enzymatic hydrolysis of racemic phenylserine amide. Other groups have also made corresponding achievements subsequently.

[0012] 3. Asymmetric synthesis:

[0013] Asymmetric synthesis methods have been studied extensively in recent years. They are mainly divided into two aspects:

[0014] One is asymmetric synthesis catalyzed by chiral catalysts. In 1994, Dr. Wu of Schering-Plough Company in the United States reported a synthesis of florfenicol based on the Sharpless asymmetric epoxidation reaction. Other groups have subsequently developed on this basis. In 2006, Academician Lin Guoqiang of my country developed an asymmetric synthesis route of methacycline and florfenicol based on asymmetric light cyanation reaction.

[0015] In 2016, Dixon et al. published a chiral catalytic method. This method is to obtain a chiral intermediate of chloramphenicol by reacting p-nitrobenzaldehyde with isocyanoacetate under the catalysis of silver ions and cinchona amine derivatives. The reaction equation is as follows

[0016]

[0017] When R is benzhydryl, the chiral selectivity of the two carbon atoms of the chiral intermediate is high (ee value 89%, dr selectivity is also above 90).

[0018] Afterwards, Professor Chen Fener's research group at Fudan University used new cinchona amine derivatives as catalysts to react 4-substituted benzaldehyde with diethyl isocyanate to obtain an intermediate, which was further reacted to obtain a chiral intermediate.

[0019]

[0020] This method does not require silver ions as a catalyst and the chiral selectivity of the reaction is better, but it has additional reaction steps and is still somewhat cumbersome.

[0021] The other is chiral auxiliary-induced asymmetric synthesis. In 1994, Davis et al. reported an asymmetric synthesis based on substrate-induced aza-Darzens reaction. In 2006, the Hajra group at the Indian Institute of Technology reported an asymmetric synthesis method using chiral auxiliary-induced asymmetric bromohydroxylation reaction.

[0022] In 1984, Meyers and his colleagues pioneered the use of pseudoephedrine as a chiral auxiliary in the asymmetric alkylation of amide enolates. The products of asymmetric alkylation gave corresponding chiral carboxylic acids with good enantiomeric excess (51-86%), which opened a new chapter in the use of pseudoephedrine as a chiral auxiliary. Ephedrine compounds contain a β-amino alcohol skeleton, with the phenyl and methyl groups located at the two ends of the ethyl chain. The presence of hydroxyl and methylamino groups makes ephedrine compounds contain two chiral centers and four isomers, which provides a wider range of options for using ephedrine as a chiral auxiliary.

[0023]

[0024] Because of its structural similarity to the controlled psychotropic drug methamphetamine, pseudoephedrine is strictly controlled in many countries, which greatly limits its promotion and application. In 2012, Pseudoephenamine was developed by Myers' research team. Compared with ephedrine, Pseudoephenamine uses a phenyl group instead of the original methyl group. Although this solves the limitation of pseudoephedrine as a controlled drug, it brings a complex structure and makes it no longer competitive in price. At present, this chiral auxiliary still needs to be obtained through asymmetric synthesis.

[0025]

[0026] In 2022, a research team from Beijing University of Chemical Technology discovered that the key chiral structure of florfenicol is similar to the structure of ephedrines, and developed and studied florfenicol derivatives as chiral auxiliary agents to promote its own asymmetric synthesis.

[0027]

[0028] Although the chiral auxiliary agent is not difficult to obtain in this method and the chiral selectivity can reach a maximum of dr=62.44:1, the reaction yield is very low, with a maximum of only 22%, and further optimization is needed. Summary of the invention

[0029] The purpose of the present invention is to overcome the problems of harsh process conditions, low selectivity of chiral reagents and low yield of the existing chiral auxiliary-mediated asymmetric synthesis of florfenicol intermediates, and to provide a new chiral auxiliary for mediating asymmetric aldol reaction to prepare florfenicol intermediates. After using the new chiral auxiliary, the molar yield is above 80%, and the cis-trans selectivity is also above 95% dr. In addition, the reaction method has mild reaction conditions and a reaction temperature between -40 and 40°C, which is very conducive to implementation in industrial production.

[0030] The technical solution of the present invention is as follows:

[0031] A method for preparing a florfenicol intermediate IV by a chiral auxiliary-mediated asymmetric aldol reaction, wherein a chiral auxiliary I and N-Boc-glycine are first reacted to obtain an intermediate II, and the intermediate II is first enolized and then subjected to aldol condensation with p-methylsulfonylbenzaldehyde to obtain an intermediate III, and the intermediate III is subjected to a reduction reaction to obtain a target product IV and a chiral auxiliary I, and the chiral auxiliary I can be recycled for the next reaction, and the chemical reaction equation is as follows:

[0032]

[0033] The structure of the chiral auxiliary agent I is shown below:

[0034]

[0035] Wherein R1 is H, C2-C8 branched or straight chain alkyl or halogenated alkyl, aryl; R2 is C2-C8 straight chain halogenated alkyl, C2-C8 straight chain alkene alkyl.

[0036] The specific steps include:

[0037] 1) Chiral auxiliary I reacts with N-Boc-glycine to obtain intermediate II;

[0038] 2) Intermediate II is first enolized and then subjected to aldol condensation with p-methylsulfonylbenzaldehyde to obtain intermediate III;

[0039] 3) The intermediate III is subjected to reduction reaction to obtain the target product IV and the chiral auxiliary agent I;

[0040] In step 1), the molar ratio of chiral auxiliary agent I to N-Boc-glycine is 0.5-1:1, the solvent is dichloromethane, or any one of DMF and toluene, and the reaction temperature is 10-20°C.

[0041] In step 2), the enolation is carried out using base catalysis, the base catalyst is LiHMDS (lithium bistrimethylsilylamide) or LDA (lithium diisopropylamide), and the molar ratio of the base catalyst to the intermediate II is 1 to 5:1.

[0042] In step 2), the molar ratio of intermediate II to p-methylsulfonylbenzaldehyde is 1:1-2.

[0043] The reducing agent for the reduction reaction in step 3) is sodium borohydride or potassium borohydride.

[0044] More specifically, the following steps are included:

[0045] 1) N-Boc-glycine is added to a solvent and an acid-binding agent system at a temperature of 0 to 20°C, and then chiral auxiliary agent I is added to the reaction system, and the reaction is kept warm until the reaction is complete, quenched, extracted with an organic solvent, spin-dried, and crystallized to obtain intermediate II;

[0046] 2) Add solvent and anhydrous lithium chloride to the dried reaction system, cool down and slowly add catalytic base to the system, keep the temperature and continue to drop the intermediate II solution to the system, keep warm for half an hour after the addition, drop the p-methylsulfonylbenzaldehyde solution to the reaction system, keep warm until the reaction is complete, quench, extract with organic solvent, spin dry, and crystallize to obtain intermediate III;

[0047] 3) Add methanol and intermediate III to the dry reaction system, add sodium borohydride in batches at a temperature below 25°C, heat to 50-55°C and keep the reaction for 2-5 hours until the reaction is complete, quench, distill until no solvent is evaporated, control the temperature at 30°C and slowly add 30% ethanol aqueous solution to the system, keep the temperature and stir for 1 hour, then cool to 0°C and keep the temperature for 1 hour, filter to obtain a crude mixture. The crude product is placed in toluene, heated to 70°C, and washed with water 3 times. Combine the aqueous phases, cool to 3°C for crystallization, and filter to obtain the target product IV. Distill the toluene phase under reduced pressure to evaporate most of the solvent, cool and crystallize to obtain chiral auxiliary I for recycling.

[0048] In step 1), the solvent is dichloromethane, DMF, or toluene; the acid binding agent is at least one of triethylamine, DIEA, pyridine, sodium carbonate, potassium carbonate, etc.

[0049] In step 1), the molar ratio of N-Boc-glycine, acid binding agent and pivaloyl chloride is 1:1:1 to 1:2:2

[0050] The reaction time in step 1) is 5 to 10 hours, and the reaction can also be carried out overnight; the reaction temperature in step 1) is preferably 10 to 20°C.

[0051] In step 2), the reaction temperature is controlled at -40°C to 40°C, preferably at -20°C to 20°C.

[0052] The organic solvent in step 2) is selected from the following: tetrahydrofuran, diethyl ether, MTBE;

[0053] Step 2) The molar ratio of intermediate II to p-methylsulfonylbenzaldehyde is 1:1-2.

[0054] The present invention has comprehensively studied and believed that the chiral auxiliary agents that can be used for the preparation of florfenicol intermediates are mainly of the following structures:

[0055]

[0056] The X group mainly plays the role of inducing the structure, while if the Y group and the Z group have too much steric hindrance, it is not conducive to the formation of enolate and the subsequent aldol reaction.

[0057] From a structural point of view, the chiral structure of this structure is also very similar to that of cinchona alkaloids. The structure of cinchona alkaloids is as follows:

[0058]

[0059] Based on the structure of cinchona alkaloid, we deconstructed it and optimized the Y and Z groups to obtain chiral auxiliary I, considering the formation of enolate and the subsequent hydroxyaldehyde reaction.

[0060]

[0061] Wherein R1 is H, C2-C8 branched or straight chain alkyl or halogenated alkyl, aryl; R2 is C2-C8 straight chain halogenated alkyl, C2-C8 straight chain alkene alkyl.

[0062] Typical additives are as follows:

[0063]

[0064] The synthetic route of the intermediate IV prepared in the present invention to florfenicol is as follows:

[0065]

[0066] Beneficial effects:

[0067] The present invention selects an effective chiral auxiliary agent, which is very beneficial to the aldol reaction. The molar yield of the method is above 80%, and the chiral selectivity is also above 95% dr. In addition, the reaction method has mild reaction conditions and the reaction temperature is between -40 and 40°C, which is very beneficial to the realization in industrial production. DETAILED DESCRIPTION

[0068] In order to better understand the present invention, the following will be described in detail through specific examples. It should be noted that the following examples are not intended to limit the scope of the present invention. Obviously, ordinary technicians in the field can make various modifications and changes to the present invention within the scope of the present invention based on the description herein, and these modifications and changes are also included in the scope of the present invention.

[0069] Example 1

[0070]

[0071] Add N-Boc-glycine (2.58g, 14.72mmol) and 40ml of dichloromethane to the reaction flask, cool to 0℃, add triethylamine (2.04mL, 14.72mmol), slowly add pivaloyl chloride (1.77g, 14.72mmol) dropwise under temperature control, and keep the temperature for 30 minutes. Then add triethylamine (2.04mL, 14.72mmol) to the mixture, and add a dichloromethane (20ml) solution of chiral auxiliary I (3.19g, 11.30mmol) dropwise under temperature control. After the addition is completed, heat to 25℃ and keep warm. When the reaction is complete, add 20mL of saturated NaHCO3 solution to the reaction system to quench the reaction. The aqueous phase was extracted with dichloromethane (15 mL x 3 times), the dichloromethane phases were combined and washed with saturated NaCl solution, the phases were separated, dried over anhydrous Na2SO4, and concentrated to obtain a white solid crude product, which was crystallized from MTBE to obtain Intermediate II (4.86 g, yield 98%).

[0072] Example 2

[0073]

[0074] Anhydrous LiCl (0.67 g, 15.77 mmol) and 20 ml THF were added to the dry reaction bottle under nitrogen protection. Cool down to 0°C and add LDA (3.54 mL, 7.07 mmol). Add the THF (20 ml) solution of intermediate II (0.88 g, 2.00 mmol) dropwise under heat preservation, and keep the temperature for 30 minutes after the addition is complete. Then cool down to -20°C, and add the THF (20 ml) solution of p-methylsulfonylbenzaldehyde (0.48 g, 2.60 mmol) dropwise under temperature control, and keep the temperature for complete reaction. Add 10 mL of saturated NH4Cl solution to the reaction system to quench the reaction. Extract the reaction solution with ethyl acetate (15 mL × 3 times), combine the organic phases and wash with saturated NaCl solution, dry, concentrate, and recrystallize from MTBE to obtain intermediate III (1.12 g. Yield 90%).

[0075] Example 3

[0076]

[0077] Add intermediate III (1.00 g, 1.60 mmol) and 20 ml of methanol to the dry reaction bottle and control the temperature to 25°C. Add sodium borohydride (0.24 g, 6.34 mmol) to the reaction bottle in batches, raise the temperature to 50°C, keep warm for 3 hours, and confirm that the reaction is complete. Cool down to room temperature and slowly add 5 mL of saturated NH4Cl solution to the reaction system to quench the reaction.

[0078] Control the temperature below 50°C and distill under reduced pressure until no solvent is evaporated. After the distillation is completed, control the temperature at 30°C and add 20 ml of 30% ethanol aqueous solution to the reaction bottle. After the addition is completed, keep warm and stir for 1 hour. Cool to 0°C and keep warm and stir for 1 hour. Filter by suction and rinse with a small amount of water to obtain a crude mixture.

[0079] The crude mixture was added to a reaction flask, 10 ml of toluene was added, the temperature was raised to 70°C, and the mixture was washed with purified water (15 mL x 3 times). The aqueous phases were combined, the temperature was lowered to 3°C and kept warm for 30 minutes, filtered, and dried to obtain the target product IV (0.504 g, yield 91%, 95:5 dr).

[0080] The organic phase was distilled under reduced pressure until there was no solution, and the chiral auxiliary I (0.43 g, yield 95%) was obtained by recrystallization from MTBE.

[0081] Example 4

[0082] Preparation of Florfenicol by Reaction of Product IV

[0083]

[0084] Add intermediate IV (1.74 g, 5 mmol) to a dry reaction bottle, add 15 ml of isopropanol, raise the temperature to 39°C, add dichloroacetonitrile (0.55 g, 5 mmol) dropwise, raise the temperature to 49°C, keep the temperature for 5 h, cool, filter, and dry to obtain a crude cyclocompound.

[0085] Prepare the fluorination reagent, add 4.1 g of dichloromethane and 0.5 g of diethylamine into a dry reaction bottle, cool to -20°C, and slowly introduce 0.9 g of hexafluoropropylene to obtain the fluorination reagent.

[0086] Add the cyclocompound (1.69 g, 5 mmol) and 4.5 ml of dichloromethane to a dry reaction flask, stir and dissolve. Add the prepared fluorination reagent, heat to 105-110°C and 0.75 MPa to react for 1 hour, cool down to evaporate the dichloromethane, add potassium acetate (0.26 g, 3 mmol) and 10 ml of water, stir and heat to 80°C to react for 6 hours to completely hydrolyze. Cool down to 10°C, filter, and dry to obtain florfenicol (1.6 g, yield of about 90%).

Claims

1. A method for preparing a florfenicol intermediate by a chiral auxiliary-mediated asymmetric aldol reaction, characterized in that: The steps include: 1) Chiral auxiliary agent I reacts with N-Boc-glycine to obtain intermediate II; 2) Intermediate II is first enolized and then subjected to aldol condensation with p-methylsulfonylbenzaldehyde to obtain intermediate III; 3) The intermediate III is subjected to reduction reaction to obtain the target product IV and the chiral auxiliary agent I; The chemical reaction equation is as follows: Wherein R1 is H, C2-C8 branched or straight chain alkyl or halogenated alkyl, aryl; R2 is C2-C8 straight chain halogenated alkyl, C2-C8 straight chain alkene alkyl.

2. The method for preparing a florfenicol intermediate by a chiral auxiliary-mediated asymmetric aldol reaction according to claim 1, characterized in that: In the step 1), the molar ratio of the chiral auxiliary agent I to N-Boc-glycine is 0.5 to 1:

1.

3. The method for preparing a florfenicol intermediate by a chiral auxiliary-mediated asymmetric aldol reaction according to claim 1, characterized in that: In the step 1), the reaction temperature is 10-20°C.

4. The method for preparing a florfenicol intermediate by a chiral auxiliary-mediated asymmetric aldol reaction according to claim 1, characterized in that: In the step 2), the enolization is catalyzed by base, and the base catalyst is lithium bistrimethylsilylamide or lithium diisopropylamide.

5. The method for preparing a florfenicol intermediate by a chiral auxiliary-mediated asymmetric aldol reaction according to claim 1, characterized in that: The reaction temperature in step 2) is between -40°C and 40°C.

6. The method for preparing a florfenicol intermediate by a chiral auxiliary-mediated asymmetric aldol reaction according to claim 1, characterized in that: In the step 2), the molar ratio of intermediate II to p-methylsulfonylbenzaldehyde is 1:1-2.

7. The method for preparing a florfenicol intermediate by a chiral auxiliary-mediated asymmetric aldol reaction according to claim 4, characterized in that: In the step 2), the molar ratio of the base catalyst to the intermediate II is 1 to 5:

1.

8. The method for preparing a florfenicol intermediate by a chiral auxiliary-mediated asymmetric aldol reaction according to claim 1, characterized in that: The reducing agent for the reduction reaction in step 3) is sodium borohydride or potassium borohydride.

9. A chiral auxiliary agent I for mediating an asymmetric aldol reaction, characterized in that: The structure is as follows: Wherein R1 is H, C2-C8 branched or straight chain alkyl or halogenated alkyl, aryl; R2 is C2-C8 straight chain halogenated alkyl, C2-C8 straight chain alkene alkyl.

10. The chiral auxiliary agent I according to claim 9, characterized in that The chiral auxiliary agent I is any one of the following

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