WO2021184649A1 - 制备氟苯尼考中间体的方法及由该方法得到的化合物 - Google Patents

制备氟苯尼考中间体的方法及由该方法得到的化合物 Download PDF

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WO2021184649A1
WO2021184649A1 PCT/CN2020/107352 CN2020107352W WO2021184649A1 WO 2021184649 A1 WO2021184649 A1 WO 2021184649A1 CN 2020107352 W CN2020107352 W CN 2020107352W WO 2021184649 A1 WO2021184649 A1 WO 2021184649A1
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compound
acid
reaction
methyl
butyl
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李文森
张文琦
田雷
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和鼎（南京）医药技术有限公司
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
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    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/189—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms containing both nitrogen and phosphorus as complexing atoms, including e.g. phosphino moieties, in one at least bidentate or bridging ligand
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
    • B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C317/50—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
    • B01J2231/341—1,2-additions, e.g. aldol or Knoevenagel condensations
    • B01J2231/342—Aldol type reactions, i.e. nucleophilic addition of C-H acidic compounds, their R3Si- or metal complex analogues, to aldehydes or ketones
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
    • B01J2231/349—1,2- or 1,4-additions in combination with further or prior reactions by the same catalyst, i.e. tandem or domino reactions, e.g. hydrogenation or further addition reactions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
    • B01J2531/16—Copper
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
    • B01J2531/17—Silver
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
    • B01J2531/18—Gold
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2540/00—Compositional aspects of coordination complexes or ligands in catalyst systems
    • B01J2540/40—Non-coordinating groups comprising nitrogen

Definitions

  • the invention belongs to the technical field of drug synthesis, and specifically relates to a method for preparing florfenicol intermediate D-p-methylsulfonyl phenylserine ester, and to a compound obtained in the preparation process of preparing the florfenicol intermediate.
  • Florfenicol is a kind of veterinary chloramphenicol broad-spectrum antibacterial drug successfully developed by Schering-Powell in the late 1980s. It is sensitive to chloramphenicol. The antibacterial activity of the bacteria is similar to that of chloramphenicol and thiamphenicol, but it is still sensitive to chloramphenicol and thiamphenicol resistant bacteria. Florfenicol was registered by the US FDA in 1996. my country has now passed the approval of the drug. Florfenicol has broad application prospects in the prevention and treatment of animal diseases, especially in food animals.
  • the domestically more mature industrial production process uses p-toluenesulfonyl chloride as the starting material, through reduction reaction, methylation reaction, brominated oxidation reaction, and hydrolysis reaction to obtain p-methylsulfonyl benzaldehyde, which is then combined with glycine and copper sulfate.
  • the copper salt is prepared by the reaction, the intermediate D-p-methylsulfone phenylserine ethyl ester is obtained by esterification reaction and tartaric acid resolution, and then undergoes reduction reaction and reacts with dichloroacetonitrile to form oxazoline, which is obtained after fluorination reaction and hydrolysis reaction Florfenicol:
  • the reaction route is as follows:
  • This process involves the resolution of racemic D-type and L-type serine ethyl esters.
  • One of the L-type isomers is discarded, which wastes 50% of raw materials, increases production costs, and when preparing copper salts A large amount of copper sulfate wastewater will be produced, and the cost of wastewater treatment is very high, and environmental protection pressure is great.
  • the ninth item is that the synthesis of chiral drugs requires the use of chiral catalysts, asymmetric catalytic synthesis reactions, and new sources of chirality, etc.
  • Asymmetric synthesis technology is used to improve the technical content of the original products, and also to greatly reduce production costs and enhance market competitiveness.
  • the present invention obtains chiral D-p-methylsulfonyl phenylserine ester by means of direct synthesis, avoiding the shortcomings of the prior art.
  • the preparation method of the intermediate (TM) of florfenicol provided by the present invention includes the following synthetic routes:
  • R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl;
  • the chiral catalyst has a structure shown in Formula 1:
  • M is selected from Au, Ag, Cu;
  • R 1 is selected from methoxy group, chlorine atom or none
  • R 2 is selected from methyl, phenyl or none
  • R 3 is selected from methyl, phenyl or none.
  • examples of the chiral catalyst of the present invention are as follows:
  • M is Au, R 1 is methoxy; R 2 is methyl; R 3 is methyl;
  • M is Au; R 1 is a chlorine atom; R 2 is a methyl group; R 3 is a methyl group.
  • M is Au, Cu; R 1 is none; R 2 is phenyl; R 3 is tolyl.
  • M is Ag; R 1 is methoxy; R 2 is methyl; R 3 is methyl.
  • M is Ag; R 1 is a chlorine atom; R 2 is a methyl group; R 3 is a methyl group.
  • M is Ag; R 1 is none; R 2 is phenyl; R 3 is phenyl.
  • M is Ag; R 1 is no; R 2 is no; R 3 is no.
  • M is Ag; R 1 is a chlorine atom; R 2 is a phenyl group; R 3 is none.
  • M is Cu; R 1 is methoxy; R 2 is methyl; R 3 is methyl.
  • M is Cu; R 1 is a chlorine atom; R 2 is a phenyl group; R 3 is a phenyl group.
  • M is Cu; R 1 is methoxy; R 2 is phenyl; R 3 is methyl.
  • M is Cu; R 1 is no; R 2 is no; R 3 is no.
  • the first step reaction adopts the "one-pot method". Under the catalysis of a chiral catalyst, compound A and compound B undergo a catalytic reaction and react under acidic conditions to produce compound C with two chiral centers. .
  • step (1) of the preparation method of the present invention the molar ratio of compound A to compound B is 1:1.
  • the compound A and the compound B can be completely converted at a molar feed ratio of 1:1, thereby reducing the waste of raw materials.
  • the amount of the catalyst is 0.1-0.5 wt% of the compound A. Thanks to the high-efficiency catalytic performance of the catalyst of the present invention, the amount of the catalyst only occupies a small part of the raw material.
  • the organic solvent 1 is selected from the group consisting of tetrahydrofuran, dichloromethane, tert-butanol, ethyl acetate, acetonitrile, 1,4-dioxane, methyl One or more of butyl tert-butyl ether.
  • the organic solvent can be selected from commonly used organic solvents. The solvent has low cost and low toxicity, and is very suitable for industrial production.
  • the first acid added is not particularly limited, and industrially commonly used acids such as hydrochloric acid, sulfuric acid, etc. can be used.
  • the first acid is selected from one or more of hydrochloric acid, phosphoric acid, boric acid, carbonic acid, sulfuric acid, and nitric acid.
  • the addition of the first acid will make the mixed system acidic, which is conducive to the hydrolysis of the catalytic reaction product to compound C.
  • the temperature after adding the catalyst in step (1) since the catalytic reaction is slightly exothermic, the temperature is controlled within the temperature range of room temperature. Too low temperature is not conducive to the progress of the reaction, too high temperature is easy to produce by-products.
  • step (2) of the preparation method of the present invention the oxidation of compound C to compound D can be accomplished by a mature method in the prior art.
  • compound C is oxidized to compound D through the following process: compound C is dissolved in organic solvent 7, EDTA (ethylenediaminetetraacetic acid) and oxidant are added, and the reaction temperature is controlled at 40-60°C Within the range, compound D is obtained by the reaction.
  • EDTA ethylenediaminetetraacetic acid
  • the organic solvent 2 is selected from one or more of methanol, ethanol, glycerol, and isopropanol.
  • the oxidizing agent is preferably one or more of potassium permanganate, MnO 2 , m-chloroperoxybenzoic acid, and hydrogen peroxide.
  • step (2) the conversion of the methylthio group to the methylsulfone group requires an oxidant to complete.
  • This step of the reaction has a ready-made mature process, so the choice of the oxidant is easier.
  • the oxidant is hydrogen peroxide
  • the mass ratio of compound C, hydrogen peroxide and EDTA is 1:0.85-1.0:0.005-0.01.
  • step (3) of the preparation method of the present invention the removal of the formyl group in compound D can be accomplished by using mature methods in the prior art.
  • the formyl group in compound D is removed by the following operations: compound D is dissolved in organic solvent 3, and a second acid is added to perform the reaction; after the reaction is completed, alkali is added to adjust the pH to precipitate white
  • the solid is florfenicol intermediate TM.
  • the organic solvent 3 is selected from one or more of methanol, ethanol, glycerol, and isopropanol.
  • the mass ratio of compound D to the second acid is 1:0.4-0.8.
  • the second acid is selected from one or more of hydrochloric acid, phosphoric acid, boric acid, carbonic acid, sulfuric acid, and nitric acid.
  • the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and ammonia.
  • the purpose of adding alkali is to adjust the pH value to the range of 7.5-8, so that the product can be precipitated.
  • the base to achieve this goal can be a common base.
  • the pH value adjusted by adding alkali should not be too high, and it is better that the pH reaches 7.5-8 and a large amount of solids are precipitated.
  • the chiral center of florfenicol intermediate TM is directly formed in the first step, and florfenicol intermediate TM does not need to be obtained by chiral resolution in subsequent steps.
  • the yield of chiral compound C is 75-80%, which is significantly higher than the yield (about 40%) obtained by the existing resolution method, and the product has high chiral purity.
  • the method of the present invention does not use anhydrous copper sulfate that pollutes the environment, thereby reducing environmental pressure.
  • the two compounds, compound A and compound B are used as raw materials for the reaction, which has higher material availability and synthesis efficiency than linear synthesis methods, and the overall process operation volume is small.
  • florfenicol can be synthesized by existing common synthetic methods. There are many mature methods for synthesizing florfenicol through florfenicol intermediate TM, and these methods have been reported in many existing literatures.
  • florfenicol intermediate TM For the synthesis of florfenicol by florfenicol intermediate TM, reference can be made to patent documents CN106278964A, CN101265220A and the like.
  • the present invention also provides a compound having a structure represented by formula (2) or formula (3):
  • R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • Figure 1 is a mass spectrum of compound C-1 (methyl ester) obtained by the preparation method of the present invention.
  • Figure 2 is a 1 H NMR spectrum of compound C-1 (methyl ester) obtained by the preparation method of the present invention.
  • Figure 3 is a mass spectrum of compound D-1 (methyl ester) obtained by the preparation method of the present invention.
  • Figure 4 is a 1 H NMR spectrum of compound D-1 (methyl ester) obtained by the preparation method of the present invention.
  • Figure 5 is a mass spectrum of intermediate TM-1 (methyl ester) obtained by the preparation method of the present invention.
  • Figure 6 is a 1 H NMR spectrum of the intermediate TM (methyl ester) obtained by the preparation method of the present invention.
  • Figure 7 is a 1 H NMR spectrum of compound C-2 (ethyl ester) obtained by the preparation method of the present invention.
  • Fig. 8 is an HPLC chart of compound D-2 (ethyl ester) obtained by the preparation method of the present invention.
  • Figure 9 is a 1 H NMR spectrum of compound D-2 (ethyl ester) obtained by the preparation method of the present invention.
  • Figure 10 is a 1 H NMR spectrum of the intermediate TM-2 (ethyl ester) obtained by the preparation method of the present invention.
  • Figure 11 is a mass spectrum of compound C-3 (isopropyl ester) obtained by the preparation method of the present invention.
  • Figure 12 is a 1 H NMR spectrum of compound C-3 (isopropyl ester) obtained by the preparation method of the present invention.
  • Figure 13 is a chiral HPLC chart of compound D-3 (isopropyl ester) obtained by the preparation method of the present invention.
  • Figure 14 is a chiral HPLC chart of the intermediate TM-3 (isopropyl ester) obtained by the preparation method of the present invention.
  • Figure 15 is a 1 H NMR spectrum of intermediate TM-3 (isopropyl ester) obtained by the preparation method of the present invention.
  • Figure 16 is a 1 H NMR spectrum of compound C-4 (tert-butyl ester) obtained by the preparation method of the present invention.
  • Figure 17 is a mass spectrum of compound C-4 (tert-butyl ester) obtained by the preparation method of the present invention.
  • Figure 18 is a 1 H NMR spectrum of compound D-4 (tert-butyl ester) obtained by the preparation method of the present invention.
  • Figure 19 is a 1 H NMR spectrum of intermediate TM-4 (tert-butyl ester) obtained by the preparation method of the present invention.
  • Figure 20 is a 1 H NMR spectrum of florfenicol prepared from the inventive intermediate TM;
  • Figure 21 is the optical detection data of florfenicol prepared from the intermediate TM of the invention.
  • reaction kettle In the reaction kettle, add C-3 1000g, EDTA 8g, methanol 3000g in turn, heat up to 45°C and stir, slowly add 900g manganese dioxide dropwise, control the temperature at 45-55°C, and finish the dripping in about 1h, keep the temperature and react for 6-8h , Sampling and testing, when the raw material is less than or equal to 1%, stop the reaction.
  • the reaction solution was transferred to a concentration kettle, and concentrated under reduced pressure was started, the internal temperature was controlled at 40-60°C, and the concentration was concentrated to almost no methanol, and the distillation was stopped.
  • florfenicol from florfenicol intermediate TM (D-methylsulfonyl phenylserine ethyl ester) refers to CN101265220A, and its synthesis route is as follows.
  • the protective group R’ is one of phthalic anhydride, benzonitrile, and allyl compounds
  • Florfenicol was prepared from Florfenicol IntermediateTM according to the disclosure of CN101265220A.
  • Dissolve compound 5 in 60 ml of dichloromethane add 2-methoxypropene and a catalytic amount of p-toluenesulfonic acid, react compound 5 and 2-methoxypropene at a reaction molar ratio of 1:1.5, and stir at 40°C
  • add 50 ml of saturated sodium bicarbonate solution at room temperature stir for 30 minutes, separate the layers, extract the aqueous phase with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate to obtain 6.8 g of compound 6.
  • the hydrolysis process is: add 20ml of hydrochloric acid with a concentration of 6mol/L, heat to reflux, keep refluxing for 4 hours, cool to room temperature naturally, add 30ml of sodium hydroxide solution with a concentration of 2mol/L to adjust the pH value, use dichloromethane (40ml ⁇ 3) Extract the organic phase, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate to obtain a crude florfenicol.
  • the crude product is recrystallized with ethanol to obtain 0.9 g of a white solid with a purity of 98.5%-florfenicol.
  • the proton nuclear magnetic spectrum and optical rotation detection data of florfenicol are shown in Figure 20 and Figure 21, respectively.
  • Benicol Intermediate TM (D-Methylsulfonyl Phenylserine Ester).
  • the first step in this example is similar to the first step in Example 1, except that p-methylthiobenzaldehyde is replaced with p-methylsulfonylbenzaldehyde.
  • the specific embodiment process is as follows.
  • the preparation method of the florfenicol intermediate TM claimed in the present invention under the catalysis of a chiral catalyst, p-methylthiobenzaldehyde is reacted with isocyanoacetate, and the chiral catalyzed product is Oxidation to obtain the methylsulfone group-substituted product, and the methylsulfone group-substituted product to remove the formyl group to obtain the florfenicol intermediate.
  • the chiral center of the intermediate is directly generated through the first step reaction, and the yield of the first step product reaches 75-80%, which is significantly higher than the yield obtained by the conventional chiral resolution method. And the chiral purity is high.
  • the method of the present invention does not use anhydrous copper sulfate that pollutes the environment, and reduces the environmental pressure.
  • the preparation method of the present invention has good industrial application prospects.

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Abstract

本发明属于化学合成技术领域并提供了一种制备氟苯尼考中间体的方法，所述方法包括：在手性催化剂的催化下，将对甲硫基苯甲醛与异氰基乙酸酯进行反应，将手性催化的产物进行氧化，得到甲砜基取代的产物，将甲砜基取代的产物脱去甲酰基，得到氟苯尼考中间体。在本发明的制备方法中，通过第一步反应直接产生中间体的手性中心，第一步产物的收率达到75-80％，显著高于常规的手性拆分法(其收率为40％左右)获得的收率，产物手性纯度高。本发明的方法不使用到污染环境的无水硫酸铜，减轻了环境压力。另外，采用对甲硫基苯甲醛与异氰基乙酸酯这两个化合物进行反应来合成手性中间体，比线性合成手段的物料利用度和合成效率高。

Description

制备氟苯尼考中间体的方法及由该方法得到的化合物
本申请要求于2020年3月16日提交中国专利局、申请号为202010184089.7、发明名称为“制备氟苯尼考中间体的方法及由该方法得到的化合物”的中国专利申请的优先权，其全部内容通过引用并入本申请中。
技术领域
本发明属于药物合成技术领域，具体地涉及一种制备氟苯尼考中间体D-对甲砜基苯丝氨酸酯的方法，以及涉及制备氟苯尼考中间体的制备过程中得到的化合物。
背景技术
氟苯尼考的中文名称为氟洛芬，氟甲砜霉素是由美国先灵-保雅公司在八十年代末成功研制的一种兽医专用氯霉素类的广谱抗菌药，对敏感菌的抗菌活性与氯霉素和甲砜霉素相似，但对耐氯霉素及甲砜霉素的细菌仍敏感。氟苯尼考于1996年通过美国FDA注册登记，我国目前已经通过了该药的审批，在动物疾病防治上，尤其是在食品动物，氟苯尼考具有广阔的应用前景。
氟苯尼考，分子式：C 12H 14Cl 2FNO 4S，分子量：358.2，其结构式如下：
Figure PCTCN2020107352-appb-000001
目前，国内较成熟的工业化生产工艺是以对甲苯磺酰氯为起始原料，经过还原反应、甲基化反应、溴代氧化反应、水解反应得到对甲砜基苯甲醛，再和甘氨酸、硫酸铜反应制备铜盐后经酯化反应、酒石酸拆分得到中间体D-对甲砜基苯丝氨酸乙酯，再经过还原反应、与二氯乙腈反应生成噁唑啉，氟化反应、水解反应后得到氟苯尼考：
其反应路线如下：
Figure PCTCN2020107352-appb-000002
该工艺路线涉及到外消旋的D-型、L-型丝氨酸乙酯的拆分，其中一个异构体L型被废弃，浪费了50％的原料，增加了生产成本，且制备铜盐时会产生大量的硫酸铜废水，废水处理成本非常高，环保压力大。
在传统的合成工艺中，由于其结构上手性碳官能团的不对称性，造成合成过程中副产品多，转化率低，从而导致原料药成本上升，因而，如何提高转化率是降低成本的关键；我国早已提出了“九五”期间化学医药重要产品关键生产技术开发的总体目标和重点任务，其中第九项为手性药物的合成技术要求采用手性催化剂，不对称催化合成反应，新手性源等不对称合成技术，以此来提高原有产品的技术含量，更以此来大幅降低生产成本，增强市场竞争力。
发明内容
为克服现有技术中合成D-对甲砜基苯丝氨酸酯时存在的手性拆分收率低，原料浪费大，生产成本高，且制备铜盐时会产生大量的硫酸铜废水，废水处理成本非常高，环保压力大的问题，特提出本申请。
本发明通过直接合成的手段，得到手性的D-对甲砜基苯丝氨酸酯，避免现有技术的缺点。
本发明提供的氟苯尼考的中间体(TM)的制备方法包括以下合成路线：
Figure PCTCN2020107352-appb-000003
R选自甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基；
(1)将化合物A(对甲硫基苯甲醛)与化合物B(异氰基乙酸酯)在溶于有机溶剂1中，加入手性催化剂进行催化反应，催化反应结束后，加入第一酸进行处理，处理结束后，将析出的化合物C的异构体进行滤除，滤液经减压蒸馏，得到化合物C；
(2)采用氧化剂将化合物C氧化成化合物D；
(3)将化合物D中的甲酰基脱除，得到氟苯尼考中间体——化合物TM；
其中，所述手性催化剂具有式1所示的结构：
Figure PCTCN2020107352-appb-000004
其中，M选自Au、Ag、Cu；
R 1选自甲氧基、氯原子或无；
R 2选自甲基、苯基或无；
R 3选自甲基、苯基或无。
具体地，本发明的手性催化剂的示例如下所示：
(1)M为Au，R 1为甲氧基；R 2为甲基；R 3为甲基；
(2)M为Au；R 1为氯原子；R 2为甲基；R 3为甲基。
(3)M为Au、Cu；R 1为无；R 2为苯基；R 3为甲苯基。
(4)M为Ag；R 1为甲氧基；R 2为甲基；R 3为甲基。
(5)M为Ag；R 1为氯原子；R 2为甲基；R 3为甲基。
(6)M为Ag；R 1为无；R 2为苯基；R 3为苯基。
(7)M为Ag；R 1为无；R 2无；R 3为无。
(8)M为Ag；R 1为氯原子；R 2为苯基；R 3为无。
(9)M为Cu；R 1为甲氧基；R 2为甲基；R 3为甲基。
(10)M为Cu；R 1为氯原子；R 2为苯基；R 3为苯基。
(11)M为Cu；R 1为甲氧基；R 2为苯基；R 3为甲基。
(12)M为Cu；R 1为无；R 2为无；R 3为无。
在本发明的方法中，第一步反应采用“一锅法”，在手性催化剂的催化下，化合物A与化合物B经催化反应和酸性条件下反应，生成具有两个手性中心的化合物C。
在本发明所述制备方法的步骤(1)中，化合物A与化合物B的摩尔比为1:1。经本发明催化剂的高效催化，化合物A和化合物B可以以1：1的摩尔投料比实现完全转化，从而减少了原料了浪费。
在本发明所述制备方法的步骤(1)中，催化剂的用量为化合物A的0.1-0.5wt％。得益于本发明催化剂的高效催化性能，催化剂的用量只占原料的很小一部分。
优选地，在本发明所述制备方法的步骤(1)中，所述有机溶剂1选自四氢呋喃、二氯甲烷、叔丁醇、乙酸乙酯、乙腈、1,4-二氧六环、甲基叔丁基醚中的一种或多种。在步骤(1)中，有机溶剂可以选自常用的有机溶剂。溶剂成本低、毒性小，非常适于工业化生产。
在本发明所述制备方法的步骤(1)中，对所加入的第一酸并无特别限制，工业上常用的酸例如盐酸、硫酸等均可使用。优选地，所述第一酸选自盐酸、磷酸、硼酸、碳酸、硫酸、硝酸中的一种或多种。加入第一酸将使混合体系呈酸性，有利于中催化反应产物水解为化合物C。
对于步骤(1)中加入催化剂后的反应温度，由于该催化反应轻微放热，因此，温度控制在室温的温度范围内。温度过低不利于反应的进程，温度过高则容易产生副产物。
在本发明所述制备方法的步骤(2)中，将化合物C氧化成化合物D可以采用现有技术中已有的成熟的方法来完成。在本发明的一个实施方式中，通过以下过程将化合物C氧化成化合物D：将化合物C溶于有机溶剂7中，加入EDTA(乙二胺四乙酸)、氧化剂，控制反应温度在40-60℃的范围内，反应得到化合物D。
优选地，在本发明所述制备方法的步骤(2)中，所述有机溶剂2选自甲醇、乙醇、丙三醇、异丙醇中的一种或多种。
优选地，在本发明所述制备方法的步骤(2)中，所述氧化剂优选自高锰酸钾、MnO 2、间氯过氧苯甲酸、双氧水中的一种或多种。
在步骤(2)中，甲硫基转化成甲砜基需要氧化剂的才能完成，这一步反应具有现成的成熟的工艺，因此对氧化剂的选择较为容易。
更优选地，在本发明所述制备方法的步骤(2)中，所述氧化剂为双氧水，且化合物C、双氧水、EDTA的质量比为1:0.85-1.0:0.005-0.01。
在本发明所述制备方法的步骤(3)中，将化合物D中的甲酰基脱除，可以采用现有技术中已有的成熟的方法来完成。在本发明的一个实施方式中，通过以下操作将化合物D中的甲酰基脱除：将化合物D溶解于有机溶剂3中，加入第二酸进行反应；反应结束后，加入碱调节pH至析出白色固体，即为氟苯尼考中间体TM。
优选地，在步骤(3)中，所述有机溶剂3选自甲醇、乙醇、丙三醇、异丙醇中的一种或多种。
优选地，在步骤(3)中，化合物D与第二酸的质量比为1:0.4-0.8。
更优选地，在步骤(3)中，所述第二酸选自盐酸、磷酸、硼酸、碳酸、硫酸、硝酸中的一种或多种。
进一步优选地，在步骤(3)中，所述碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸氢钠、氨水中的一种或多种。加入碱的目的是将pH值调节到7.5-8的范围内，以便产品析出。实现这一目标的碱可以是常见的碱。出于收率和原料成本方面的考虑，加入碱调节得到的pH值不宜过高，以pH达到7.5-8且析出大量固体为宜。
通过采用本发明的氟苯尼考中间体的制备方法，可以取得以下技术效果。
1、氟苯尼考中间体TM的手性中心是通过第一步直接形成的，氟苯尼考中间体TM不需要通过后续步骤的手性拆分而得到。在制备化合物C的第一步反应中，手性化合物C的收率为75-80％，显著高于现有的拆分方法得到的收率(40％左右)，并且产物手性纯度高。此外，本发明的方法不使用污染环境的无水硫酸铜，因此减轻了环境压力。
2、本发明的制备方法中，采用化合物A和化合物B这两个化合物作为原料进行反应，比线性合成手段的物料利用度和合成效率高，并且整个工艺操作量小。
通过本发明的方法制备氟苯尼考的中间体TM后，可以通过现有的常用合成方法来合成氟苯尼考。通过氟苯尼考中间体TM合成氟苯尼考已经很多成熟的方法，这些方法已经在现有的很多文献中报道。通过氟苯尼考中间体TM合成氟苯尼考可以参考专利文献CN106278964A、CN101265220A等。
本发明还提供具有式(2)或式(3)所示的结构的化合物：
Figure PCTCN2020107352-appb-000005
在式2或式3中，R选自甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基。
附图说明
图1是由本发明的制备方法得到的化合物C-1(甲酯)的质谱图；
图2是由本发明的制备方法得到的化合物C-1(甲酯)的 1H NMR谱图；
图3是由本发明的制备方法得到的化合物D-1(甲酯)的质谱图；
图4是由本发明的制备方法得到的化合物D-1(甲酯)的 1H NMR谱图；
图5是由本发明的制备方法得到的中间体TM-1(甲酯)的质谱图；
图6是由本发明的制备方法得到的中间体TM(甲酯)的 1H NMR谱图；
图7是由本发明的制备方法得到的化合物C-2(乙酯)的 1H NMR谱图；
图8是由本发明的制备方法得到的化合物D-2(乙酯)的HPLC谱图；
图9是由本发明的制备方法得到的化合物D-2(乙酯)的 1H NMR谱图；
图10是由本发明的制备方法得到的中间体TM-2(乙酯)的 1H NMR谱图；
图11是由本发明的制备方法得到的化合物C-3(异丙酯)的质谱图；
图12是由本发明的制备方法得到的化合物C-3(异丙酯)的 1H NMR谱图；
图13是由本发明的制备方法得到的化合物D-3(异丙酯)的手性HPLC谱图；
图14是由本发明的制备方法得到的中间体TM-3(异丙酯)的手性HPLC谱图；
图15是由本发明的制备方法得到的中间体TM-3(异丙酯)的 1H NMR谱图；
图16是由本发明的制备方法得到的化合物C-4(叔丁酯)的 1H NMR谱图；
图17是由本发明的制备方法得到的化合物C-4(叔丁酯)的质谱图；
图18是由本发明的制备方法得到的化合物D-4(叔丁酯)的 1H NMR谱图；
图19是由本发明的制备方法得到的中间体TM-4(叔丁酯)的 1H NMR谱图；
图20是由发明的中间体TM制备得到的氟苯尼考的 1H NMR谱图；
图21是由发明的中间体TM制备得到的氟苯尼考的旋光检测数据。
具体实施方式
下面结合实施例对本发明进行详细的说明。
下面的实施例中用到的手性催化剂的结构如下所示：
Figure PCTCN2020107352-appb-000006
实施例1
1.化合物C-1(甲酯)的合成
Figure PCTCN2020107352-appb-000007
在反应釜中，依次加入乙酸乙酯700g、化合物A 100g，式1-1所示催化剂0.1g，搅拌10min左右，控制体系温度15-20℃，将化合物B-1 65g溶于乙酸乙酯中，将B-1的乙酸乙酯溶液缓慢滴加至反应釜中，控制滴加时间为0.5h左右，有轻微放热现象，滴加完毕后继续反应1h，取样检测，后处理，将反应液转加入5％H 2SO 4，加热至45℃，搅拌1h，TLC检测水解 完全，过滤除去不溶物，将滤液通过减压脱除溶剂至干，得到化合物C-1 143g，收率77％。
化合物C-1(甲酯)的质谱图在图1中示出，其 1H NMR图谱在图2中示出。
2.化合物D-1(甲酯)的合成
Figure PCTCN2020107352-appb-000008
在反应釜中，依次加入C-1 100g，EDTA 0.6g，甲醇300g，升温至45℃搅拌，缓慢滴加间氯过氧苯甲酸90g，控制温度45-55℃，约1h滴加完毕，保温反应6-8h，取样检测，原料小于等于1％，停止反应。将反应液转移至浓缩釜，开始减压浓缩，控制內温40-60℃，浓缩至基本无甲醇，停止蒸馏。再向釜内加入自来水，降温至10-20℃，保温析晶1h，放料离心得81g的化合物D-1，收率82％。
化合物D-1(甲酯)的质谱图在图3中示出，其 1H NMR图谱在图4中示出。
3.氟苯尼考中间体TM-1(甲酯)的合成
Figure PCTCN2020107352-appb-000009
在反应釜中，依次加入甲醇300g，D-1 100g，碳酸80g，升温至50℃，保温反应4h，取样检测，原料小于1％，停止反应；减压浓缩，控制內温40～60℃，继续蒸馏至无甲醇，加水与活性炭，除去不溶物，滤液降温至15℃以下，缓慢滴加入氨水，调节pH＝7.5～8，析出大量白色固体，调节完毕后降温至0～5℃，保温析晶2h；放料至刮刀离心机甩滤，滤饼用水漂洗烘干得到78g，收率78％，收率90％。
化合物TM-1(甲酯)的质谱图在图5中示出，其 1H NMR图谱在图6中示出。
实施例2
1.化合物C-2(乙酯)的合成
Figure PCTCN2020107352-appb-000010
在反应釜中，依次加入四氢呋喃7000g、化合物A 1000g，式1-1所示催化剂4g，搅拌 10min左右，控制体系温度15-20℃，将化合物B-2 723g溶于四氢呋喃中，将B-2的四氢呋喃溶液缓慢滴加至反应釜中，控制滴加时间为0.5h左右，有轻微放热现象，滴加完毕后继续反应1h，取样检测，后处理，将反应液转加入5％H 2SO 4，加热至45℃，搅拌1h，TLC检测水解完全，过滤除去不溶物，将滤液通过减压脱除溶剂至干，得到化合物C-2 1563g，收率80％。[MS+H]：284.1； 1H NMR图谱参见图7。
2.化合物D-2(乙酯)的合成
Figure PCTCN2020107352-appb-000011
在反应釜中，依次加入C-2 1000g，EDTA 5g，甲醇3000g，升温至45℃搅拌，缓慢滴加H 2O 2(30wt％)900g，控制温度45-55℃，约1h滴加完毕，保温反应6-8h，取样检测，原料小于等于1％，停止反应。将反应液转移至浓缩釜，开始减压浓缩，控制內温40-60℃，浓缩至基本无甲醇，停止蒸馏。再向釜内加入自来水，降温至10-20℃，保温析晶1h，放料离心得化合物D-2 789g，收率80％(化学纯：98％)。
化合物D-2的表征数据：[MS+Na]:338.1；HPLC图谱见图8； 1H NMR图谱参见图9。
3.氟苯尼考中间体TM-2(乙酯)的合成
Figure PCTCN2020107352-appb-000012
在反应釜中，依次加入甲醇3000g，D-2 1000g，浓盐酸500g，升温至50℃，保温反应4h，取样检测，原料小于1％，停止反应；减压浓缩，控制內温40～60℃，继续蒸馏至无甲醇，加水与活性炭，除去不溶物，滤液降温至15℃以下，缓慢滴加入氨水，调节pH＝7.5～8，析出大量白色固体，调节完毕后降温至0～5℃，保温析晶2h；放料至刮刀离心机甩滤，滤饼用水漂洗烘干得到化合物TM-2 1605g，收率92％。
化合物TM-2的表征数据：[MS+H]：288.2； 1H NMR图谱参见图10。
实施例3
1.化合物C-3(异丙酯)的合成
Figure PCTCN2020107352-appb-000013
在反应釜中，依次加入二氯甲烷7000g、化合物A 1000g，式1-1所示催化剂4.2g，搅拌10min左右，控制体系温度15-20℃，将化合物B-3 835g溶于二氯甲烷中，将B-3的二氯甲烷溶液缓慢滴加至反应釜中，控制滴加时间为0.5h左右，有轻微放热现象，滴加完毕后继续反应1h，取样检测，后处理，将反应液转加入5％H 2SO 4，加热至45℃，搅拌1h，TLC检测水解完全，过滤除去不溶物，将滤液通过减压脱除溶剂至干，得到化合物C-3 1637g，收率80％。
化合物C-3的表征数据：[MS+H]：298.4；质谱在图11中示出， 1H NMR图谱在图12中示出。
2.化合物D-3(异丙酯)的合成
Figure PCTCN2020107352-appb-000014
在反应釜中，依次加入C-3 1000g，EDTA 8g，甲醇3000g，升温至45℃搅拌，缓慢滴加二氧化锰900g，控制温度45-55℃，约1h滴加完毕，保温反应6-8h，取样检测，原料小于或等于1％时，停止反应。将反应液转移至浓缩釜，开始减压浓缩，控制內温40-60℃，浓缩至基本无甲醇，停止蒸馏。再向釜内加入自来水，降温至10-20℃，保温析晶1h，放料离心得化合物D-3 834g，收率85％，[MS+H]:330.1。化合物D-3的手性HPLC图谱如图13所示。
3.氟苯尼考中间体TM-3(异丙酯)的合成
Figure PCTCN2020107352-appb-000015
在反应釜中，依次加入甲醇3000g，D-3 1000g，磷酸600g，升温至50℃，保温反应4h，取样检测，原料小于1％，停止反应；减压浓缩，控制內温40～60℃，继续蒸馏至无甲醇，加水与活性炭，除去不溶物，滤液降温至15℃以下，缓慢滴加入氨水，调节pH＝7.5～8，析出大量白色固体，调节完毕后降温至0～5℃，保温析晶2h，滤饼用水漂洗烘干得到化合的TM-3 1650g，收率94％，手性纯度98.7％。化合物TM-3的表征数据：[MS+H]:302.1；手性HPLC图 谱见图14； 1H NMR图谱参见图15。
实施例4
1.化合物C-4(叔丁酯)的合成
Figure PCTCN2020107352-appb-000016
在反应釜中，依次加入乙腈700g、化合物A 100g，式1-1所示催化剂0.5g，搅拌10min左右，控制体系温度15-20℃，将化合物B-4 93g溶于乙腈中，将B-4的乙腈溶液缓慢滴加至反应釜中，控制滴加时间为0.5h左右，有轻微放热现象，滴加完毕后继续反应1h，取样检测，后处理，将反应液转加入5％H 2SO 4，加热至45℃，搅拌1h，TLC检测水解完全，过滤，过滤除去不溶物，将滤液通过减压脱除溶剂至干，得到C-4 160g，收率75％。化合物C-4的表征数据：[MS+H]:312.4； 1H NMR图谱示于图16中，质谱图示于图17中。
2.化合物D-4(叔丁酯)的合成
Figure PCTCN2020107352-appb-000017
在反应釜中，依次加入C-4 100g、EDTA 0.7，甲醇300g，升温至45℃搅拌，缓慢滴加高锰酸钾95g，控制温度45-55℃，约1h滴加完毕，保温反应6-8h，取样检测，原料小于等于1％，停止反应。将反应液转移至浓缩釜，开始减压浓缩，控制內温40-60℃，浓缩至基本无甲醇，停止蒸馏。再向釜内加入自来水，降温至10-20℃，保温析晶1h，放料离心得化合物D-4 78g。化合物D-4的表征数据：[MS+H]:344.1； 1H NMR图谱在图18中示出。
3.氟苯尼考中间体TM-4(叔丁酯)的合成
Figure PCTCN2020107352-appb-000018
在反应釜中，依次加入甲醇350g，D-4 100g，硼酸60g，升温至50℃，保温反应4h，取样检测，原料小于1％，停止反应；减压浓缩，控制內温40～60℃，继续蒸馏至无甲醇，加水与活性炭，除去不溶物，滤液降温至15℃以下，缓慢滴加入氨水，调节pH＝7.5～8，析出大量 白色固体，调节完毕后降温至0～5℃，保温析晶2h；放料至刮刀离心机甩滤，滤饼用水漂洗烘干得到化合物TM-4 81g。化合物TM-4的表征数据：[MS+H]:316.2； 1H NMR图谱参见图19。
实施例5
由氟苯尼考中间体TM(D-对甲砜基苯丝氨酸乙酯)制备氟苯尼考参考CN101265220A，其合成路线如下。
Figure PCTCN2020107352-appb-000019
保护基R’为苯酐、苯腈、烯丙基类化合物中的一种
根据CN101265220A的公开内容由氟苯尼考中间体TM制备氟苯尼考。
(1)250ml三口瓶中依次加入55ml甲醇、5.5g化合物4(D-对甲砜基苯丝氨酸乙酯，即本发明实施例2中的中间体TM-2)、3.0ml三乙胺以及11ml二氯乙酸甲酯，35℃反应20小时，然后减压浓缩回收甲醇，向浓缩液中加入50ml甲苯，50ml水，搅拌30分钟，过滤，制得化合物5。
将化合物5溶解在60ml二氯甲烷中，加入2-甲氧基丙烯以及催化量的对甲苯磺酸，化合物5与2-甲氧基丙烯以反应摩尔比1∶1.5进行反应，40℃下搅拌3小时，室温下加入50ml碳酸氢钠饱和溶液，搅拌30分钟，分液，水相用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，浓缩得6.8g化合物6。
(2)化合物6经还原制得化合物7
化合物6溶解在20ml甲醇中，2.5g KBH 4溶解在10ml水中，然后将KBH 4溶液滴加到反应体系中，控制滴加速度，保持温度在50℃以下，滴加完毕后室温下搅拌5小时，过滤得化合物7粗品，粗品可用异丙醇重结晶纯化，最后得到3.1g化合物7。
(3)化合物7经氟化制得化合物8，经再水解制得化合物氟苯尼考
将3.0g化合物7与30ml二氯甲烷混合，搅拌，氮气保护，室温下加入2.1ml Ishikawa试剂(石川试剂)，然后，将体系转入高压釜，100℃下反应2小时，自然冷却至室温，将反应体系转入250ml三口瓶中进行再水解。水解过程是：加入20ml浓度为6mol/L的盐酸，加热至回流，保持回流4小时，自然冷却至室温，加入30ml浓度2mol/L的氢氧化钠溶液调pH值，用二氯甲烷(40ml×3)萃取有机相，合并有机相，无水硫酸钠干燥，浓缩得氟苯尼考粗 品，粗品用乙醇重结晶得0.9g，纯度98.5％的白色固体——氟苯尼考。氟苯尼考的核磁氢谱和旋光检测数据分别如图20和图21所示。通过得到的氟苯尼考的旋光值(α＝-18.269°)与CN106349130A公布的旋光值(α＝-18.1°)基本一致，说明了采用本发明的制备方法可以得到预期手性构型的氟苯尼考中间体TM(D-对甲砜基苯丝氨酸酯)。
实施例6
在本实施例的第一步与实施例1中第一步反应类似，不同的是，将对甲硫基苯甲醛替换为对甲砜基苯甲醛。具体的实施例过程如下。
在反应釜中，依次加入二氯甲烷4ml、三乙胺18mg(0.18mmol，0.1eq)、对甲砜基苯甲醛326mg(1.77mmol，1.0eq)、Ag 2O式1-1所示催化剂60mg(0.09mmol，0.05eq)，搅拌2min左右。在室温下将异氰基乙酸乙酯200mg(1.77mmol，1.0eq)、的二氯甲烷溶液缓慢滴加至反应容器中，在反应体系中很快产生固体，导致反应难进继续进行。通过薄层色谱TLC检测，可见反应产物复杂，反应不理想。通过本实施例可知，在第一步反应中，在式1-1催化剂的催化下，通过对甲砜基苯甲醛与异氰基乙酸酯(B)的反应以生成手性化合物(C)的尝试并不成功。
在本发明请求保护的氟苯尼考中间体TM的制备方法中，在手性催化剂的催化下，将对甲硫基苯甲醛与异氰基乙酸酯进行反应，将手性催化的产物进行氧化，得到甲砜基取代的产物，将甲砜基取代的产物脱去甲酰基，得到氟苯尼考中间体。在本发明的制备方法中，通过第一步反应直接产生中间体的手性中心，第一步产物的收率达到75-80％，显著高于常规的手性拆分法获得的收率，且手性纯度高。本发明的方法不使用到污染环境的无水硫酸铜，减轻了环境压力。本发明的制备方法具有很好的工业应用前景。

Claims (8)

  1. 一种制备氟苯尼考的中间体TM的方法，所述方法包括以下合成路线：
    Figure PCTCN2020107352-appb-100001
    其中，R选自甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基；
    所述方法包括以下步骤：
    (1)将化合物A与化合物B在溶于有机溶剂1中，加入催化剂进行催化反应，催化反应结束后，加入第一酸进行处理；处理结束后，将析出的固体滤除，滤液经减压蒸馏，得到化合物C；
    (2)采用氧化剂将化合物C氧化成化合物D；
    (3)将化合物D中的甲酰基脱除，得到氟苯尼考中间体TM；
    其中，在步骤(1)，所述催化剂具有式1所示的结构：
    Figure PCTCN2020107352-appb-100002
    其中，M选自Au、Ag、Cu；
    R 1选自甲氧基、氯原子或无；
    R 2选自甲基、苯基或无；
    R 3选自甲基、苯基或无。
  2. 根据权利要求1所述的方法，其特征在于，在步骤(1)中，化合物A与化合物B的 摩尔比为1:1。
  3. 根据权利要求1所述的方法，其特征在于，在步骤(1)中，催化剂的用量为化合物A的0.1-0.5wt％。
  4. 根据权利要求1所述的方法，其特征在于，在步骤(1)中，所述有机溶剂1选自四氢呋喃、二氯甲烷、叔丁醇、乙酸乙酯、乙腈、1,4-二氧六环、甲基叔丁基醚中的一种或多种；
    优选地，所述第一酸选自盐酸、磷酸、硼酸、碳酸、硫酸、硝酸中的一种或多种。
  5. 根据权利要求1所述的方法，其特征在于，在步骤(2)中，通过以下过程将化合物C氧化成化合物D：将化合物C溶于有机溶剂2中，加入EDTA、氧化剂，控制反应温度在40-60℃的范围内，反应得到化合物D；
    优选地，在步骤(2)中，所述有机溶剂2选自甲醇、乙醇、丙三醇、异丙醇中的一种或多种；
    优选地，在步骤(2)中，所述氧化剂选自高锰酸钾、MnO 2、间氯过氧苯甲酸、双氧水中的一种或多种；
    更优选地，在步骤(2)中，所述氧化剂为双氧水，且化合物C、双氧水、EDTA的质量比1:0.85-1.0:0.005-0.01。
  6. 根据权利要求1所述的方法，其特征在于，在步骤(3)中，通过以下过程将化合物D中的甲酰基脱除：将化合物D溶解于有机溶剂3中，加入第二酸进行反应；反应结束后，加入碱调节pH至析出白色固体，即得氟苯尼考中间体TM；
    优选地，在步骤(3)中，所述有机溶剂3选自甲醇、乙醇、丙三醇、异丙醇中的一种或多种；
    优选地，在步骤(3)中，化合物D与第二酸的质量比为1:0.4-0.8；
    更优选地，在步骤(3)中，所述第二酸选自盐酸、磷酸、硼酸、碳酸、硫酸、硝酸中的一种或多种；
    进一步优选地，在步骤(3)中，所述碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸氢钠、氨水中的一种或多种。
  7. 一种化合物，其具有式(2)所示的结构：
    Figure PCTCN2020107352-appb-100003
    其中，R选自甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基。
  8. 一种化合物，其具有式(3)所示的结构：
    Figure PCTCN2020107352-appb-100004
    其中，R选自甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基。
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