CN116874436A - Preparation method of letromycin intermediate - Google Patents

Preparation method of letromycin intermediate Download PDF

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CN116874436A
CN116874436A CN202310842229.9A CN202310842229A CN116874436A CN 116874436 A CN116874436 A CN 116874436A CN 202310842229 A CN202310842229 A CN 202310842229A CN 116874436 A CN116874436 A CN 116874436A
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phenyl
preparation
methoxy
trifluoromethyl
methyl acrylate
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肖川
李明丽
师艳秋
杜昕昕
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Jining University
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Jining University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
    • C07C273/1827—X being H
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a preparation method of a letromycin intermediate, belonging to the field of raw material medicine synthesis. The invention mixes 2-bromo-6-fluoroaniline, methyl acrylate, palladium catalyst, acid binding agent and organic solvent for coupling reaction, after obtaining (E) -3- (2-amino-3-fluorophenyl) methyl acrylate, and mixing with 2-methoxy-5-trifluoromethyl phenyl isocyanate for addition reaction, and then mixes the obtained (E) -3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) methyl acrylate with chiral catalyst and organic solvent for intramolecular microphone addition reaction, thus obtaining the letrozole intermediate. The method has only three chemical reaction steps, simple process route, wide commercial sources of all raw materials and auxiliary materials, mild reaction conditions, few byproducts and low cost, and is suitable for industrial production.

Description

Preparation method of letromycin intermediate
Technical Field
The invention relates to the technical field of raw material medicine synthesis, in particular to a preparation method of a letrozole intermediate.
Background
Letermovir (Letermovir) acts on megacytopathyNovel inhibitors of viral (CMV) DNA end enzymes prevent end enzymes from cleaving newly synthesized CMV DNA into individual viral genomes and directing them into empty viral capsids, thereby inhibiting viral replication. Adult human recipients [ R+C ] serologically positive for cytomegalovirus, clinically suitable for receiving allogeneic Hematopoietic Stem Cell Transplantation (HSCT)]Preventing CMV infection or disease. Lenter Mo Weipian developed by the company moesadong (trade name:) The earliest 11 th 2017 was FDA approved for marketing. Clinical experiments show that the letromycin has good safety and effectiveness, after 28 days of treatment, cytomegalovirus is not detected in a patient, and compared with other medicines obtained in batches, the letromycin has no cross drug resistance and has good market prospect.
The compound (S) -2- (8-fluoro-3- (2-methoxy-5-trifluoromethyl) phenyl) -2-oxo-1, 2,3, 4-tetrahydroquinazolin-4-yl) methyl acetate is an important intermediate for preparing letrozole, the structure of which is shown as a formula (I),
the current preparation methods of the compound formula (I) include the following two methods:
in the first method, the reaction process is shown as a formula (II), and the compound shown as a formula (I) is obtained through 6 steps of chemical reactions from the compound II. The initial raw material compound II used in the method is an unconventional reagent and is not easy to be obtained commercially; meanwhile, the reaction steps are too long, the total yield is low, the process is complex, and the method is not suitable for industrial production
The second method is shown in the formula (III), the compound (I) is obtained from the compound III through 5 steps of chemical reaction, and the method also has the defects that the initial raw material is an unconventional reagent, the price is high (about 80000/kg), and the commercial availability is not easy; meanwhile, the second step in the synthesis route requires a temperature condition of 60 ℃ below zero, and workshop equipment requirements are high and are not easy to realize. In addition, the reaction steps are too long, the total yield is low, the process is complex, and the method is not suitable for industrial production.
Disclosure of Invention
In view of the above, the present invention aims to provide a preparation method of an intermediate of letrozole. The preparation method has the advantages of simple reaction steps and process routes, wide commercial sources of all raw materials and auxiliary materials, mild reaction conditions, few byproducts and low cost.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of a letromycin intermediate, which comprises the following steps:
mixing 2-bromo-6-fluoroaniline, methyl acrylate, a palladium catalyst, an acid binding agent and an organic solvent for a coupling reaction to obtain (E) -3- (2-amino-3-fluorophenyl) methyl acrylate;
mixing the (E) -3- (2-amino-3-fluorophenyl) methyl acrylate and 2-methoxy-5-trifluoromethyl phenyl isocyanate for addition reaction to obtain (E) -3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) methyl acrylate;
mixing methyl (E) -3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate, a chiral catalyst and an organic solvent to perform intramolecular microphone addition reaction to obtain the letrozole intermediate, wherein the letrozole intermediate has a structure shown in a specific formula (I):
preferably, the palladium catalyst is 1,1' -bis-diphenylphosphine ferrocene palladium dichloride and/or bis-triphenylphosphine palladium dichloride.
Preferably, the molar equivalent ratio of the 2-bromo-6-fluoroaniline to the palladium catalyst is 100:0.5-1.
Preferably, the acid binding agent is triethylamine and/or diisopropylethylamine.
Preferably, the molar equivalent ratio of the 2-bromo-6-fluoroaniline to the acid-binding agent is 100:2.
Preferably, the temperature of the coupling reaction is 85-90 ℃ and the time is 16-17 h.
Preferably, the temperature of the addition reaction is 80-82 ℃ and the time is 5-6 h.
Preferably, the chiral catalyst is (1R) -trans-N, N-1, 2-cyclohexanediyl (1, 1-trifluoromethanesulfonamide).
Preferably, the molar equivalent ratio of (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate to chiral catalyst is 100:1.
Preferably, the temperature of the intramolecular Michael addition reaction is 50-60 ℃ and the time is 7-8 h.
The invention provides a preparation method of a letromycin intermediate, which comprises the following steps:
mixing 2-bromo-6-fluoroaniline, methyl acrylate, a palladium catalyst, an acid binding agent and an organic solvent for a coupling reaction to obtain (E) -3- (2-amino-3-fluorophenyl) methyl acrylate; mixing the (E) -3- (2-amino-3-fluorophenyl) methyl acrylate and 2-methoxy-5-trifluoromethyl phenyl isocyanate for addition reaction to obtain (E) -3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) methyl acrylate; mixing the (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate, a chiral catalyst and an organic solvent to carry out intramolecular microphone addition reaction to obtain the letrozole intermediate.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a brand-new synthesis strategy of the letrozole intermediate, which provides a reference for industrialization of letrozole bulk drug. The method has only three chemical reaction steps, simple process route, wide commercial sources of all raw materials and auxiliary materials, mild reaction conditions, few byproducts and low cost, and is suitable for industrial production.
Detailed Description
The invention provides a preparation method of a letromycin intermediate, which comprises the following steps:
mixing 2-bromo-6-fluoroaniline, methyl acrylate, a palladium catalyst, an acid binding agent and an organic solvent for a coupling reaction to obtain (E) -3- (2-amino-3-fluorophenyl) methyl acrylate;
mixing the (E) -3- (2-amino-3-fluorophenyl) methyl acrylate and 2-methoxy-5-trifluoromethyl phenyl isocyanate for addition reaction to obtain (E) -3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) methyl acrylate;
mixing methyl (E) -3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate, a chiral catalyst and an organic solvent to perform intramolecular microphone addition reaction to obtain the letrozole intermediate, wherein the letrozole intermediate has a structure shown in a specific formula (I):
in the present invention, all materials used are commercial products in the art unless otherwise specified.
In the invention, the principle of the preparation method is shown as a formula (IV):
the invention mixes 2-bromo-6-fluoroaniline, methyl acrylate, palladium catalyst, acid binding agent and organic solvent for coupling reaction to obtain (E) -3- (2-amino-3-fluorophenyl) methyl acrylate.
In the present invention, the molar ratio of the 2-bromo-6-fluoroaniline to the methyl acrylate is preferably 1:1 to 1.5.
In the present invention, the palladium catalyst is preferably 1,1' -bis-diphenylphosphine ferrocene palladium dichloride and/or bis-triphenylphosphine palladium dichloride, and when the palladium catalyst is a mixture of 1,1' -bis-diphenylphosphine ferrocene palladium dichloride and bis-triphenylphosphine palladium dichloride, the mass ratio of 1,1' -bis-diphenylphosphine ferrocene palladium dichloride and bis-triphenylphosphine palladium dichloride in the mixture is not particularly limited, and any mixture may be used.
In the present invention, the molar equivalent ratio of the 2-bromo-6-fluoroaniline to the palladium catalyst is preferably 100:0.5 to 1.
In the present invention, the acid-binding agent is preferably triethylamine and/or diisopropylethylamine, and when the acid-binding agent is a mixture of triethylamine and diisopropylethylamine, the mass ratio of triethylamine and/or diisopropylethylamine in the mixture is not particularly limited, and any mixture may be used.
In the present invention, the molar equivalent ratio of the 2-bromo-6-fluoroaniline to the acid-binding agent is preferably 100:2.
In the present invention, the organic solvent is preferably N, N-Dimethylformamide (DMF) or 1, 4-dioxane, and the amount of the organic solvent is not particularly limited, and the raw material may be dissolved.
In the present invention, the temperature of the coupling reaction is preferably 85 to 90℃and the time is preferably 16 to 17 hours.
In the present invention, the coupling reaction is preferably carried out in a protective atmosphere, preferably nitrogen.
After the coupling reaction is completed, the obtained coupling product is preferably cooled to room temperature, subjected to solid-liquid separation, subjected to reduced pressure distillation of the obtained liquid, mixed with water, extracted with ethyl acetate, washed with saturated sodium chloride and subjected to reduced pressure distillation of the obtained organic phase, so as to obtain the (E) -3- (2-amino-3-fluorophenyl) methyl acrylate.
In the present invention, the solid-liquid separation is preferably filtration.
In the present invention, the temperature at which the liquid and organic phases are distilled under reduced pressure is preferably 50℃and distilled to no fraction.
After (E) -methyl 3- (2-amino-3-fluorophenyl) acrylate is obtained, the invention mixes the (E) -methyl 3- (2-amino-3-fluorophenyl) acrylate and 2-methoxy-5-trifluoromethyl isocyanate phenyl ester for addition reaction to obtain (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate.
In the present invention, the molar ratio of (E) -methyl 3- (2-amino-3-fluorophenyl) acrylate to 2-methoxy-5-trifluoromethyl phenyl isocyanate is preferably 1:1 to 1.5.
In the present invention, the temperature of the addition reaction is preferably 80 to 82℃and the time is preferably 5 to 6 hours.
In the present invention, the solvent for the addition reaction is preferably acetonitrile, and the amount of acetonitrile used in the present invention is not particularly limited, and the raw material may be dissolved.
After the completion of the addition reaction, the obtained addition product is preferably cooled to room temperature, filtered by suction, and the obtained filter cake is dried in vacuum to obtain the (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate.
In the present invention, the temperature of the vacuum drying is preferably 35 ℃ and the time is drying to constant weight.
After (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) acrylate is obtained, the invention mixes the (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate, a chiral catalyst and an organic solvent for intramolecular microphone addition reaction to obtain the letrovir intermediate.
In the invention, the chiral catalyst is preferably (1R) -trans-N, N-1, 2-cyclohexanediyl (1, 1-trifluoromethanesulfonamide), and the structural formula is shown in the formula (V):
in the present invention, the molar equivalent ratio of (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate to chiral catalyst is preferably 100:1.
In the present invention, the temperature of the intramolecular Michael addition reaction is preferably 50 to 60℃and the time is preferably 7 to 8 hours.
In the present invention, the solvent for the intramolecular microphone addition reaction is preferably toluene, tetrahydrofuran, N-dimethylformamide or acetonitrile, and the amount of the solvent used in the present invention is not particularly limited, and the raw material may be dissolved.
After completion of the intramolecular Michael addition reaction, the present invention preferably subjects the resulting intramolecular Michael addition reaction product to a post-treatment, preferably comprising the steps of: cooling to room temperature, adding aqueous potassium carbonate solution for washing, stirring, standing, discarding the bottom aqueous phase, washing with saturated saline, distilling the obtained organic phase under reduced pressure until no fraction exists, then recrystallizing, and vacuum drying the obtained solid to obtain the letromycin intermediate.
In the invention, the mass percentage of the potassium carbonate in the potassium carbonate aqueous solution is 1%.
In the present invention, the temperature of the reduced pressure distillation is preferably 50 ℃.
In the present invention, ethanol is preferably used for the recrystallization.
In the present invention, the temperature of the vacuum drying is preferably 40 ℃, and preferably the drying is to constant weight.
In order to further illustrate the present invention, the following examples are provided to describe in detail the preparation of the letromycin intermediate provided herein, but they should not be construed as limiting the scope of the invention.
Example 1
Synthesis of Compound (E) -methyl 3- (2-amino-3-fluorophenyl) acrylate
2-bromo-6-fluoroaniline 4 (19 g,0.1 mol), methyl acrylate 2 (12.9 g,0.15 mol), triethylamine (20 g,0.2 mol) and DMF100mL were successively added to a 250mL three-necked flask, stirred well and purged with nitrogen three times. 1,1' -Didiphenylphosphino ferrocene palladium dichloride (0.7 g,1 mmol) was added and nitrogen was replaced once. The oil bath is heated to 85 ℃ and reacted for 16 hours. Cooling to room temperature, stirring for 1h, and suction filtering. The filtrate was distilled under reduced pressure at 50℃until it was substantially free of fractions, 100mL of water was added, extracted with 200mL of ethyl acetate, washed with 100mL of saturated sodium chloride, and the organic phase was distilled under reduced pressure at 50℃until it was substantially free of fractions, to give a brown oil, 18g, which was directly taken into the next reaction.
Synthesis of Compound (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) ureido) acrylate
The prepared compound (E) -methyl 3- (2-amino-3-fluorophenyl) acrylate (18 g) was added to acetonitrile 100mL, all transferred to a 250mL reaction flask, and 2-methoxy-5-trifluoromethylacrylate (21.7 g,0.1 mol) was added. The mixture is heated to reflux 80 ℃ in an oil bath and reacted for 5 hours. Cooling to room temperature, stirring for 1h, and suction filtering. The wet cake was dried under vacuum at 35 ℃ to constant weight to give 33g of white solid in 80% yield in two steps.
Preparation of target product of letromycin intermediate
The compound (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate (20.6 g,0.05 mol) and toluene (150 mL) were added to a 500mL three-necked flask, and the mixture was dissolved in total with stirring, followed by addition of chiral catalyst (1R) -trans-N, N-1, 2-cyclohexanediyl (1, 1-trifluoromethanesulfonamide) (0.19 g,0.5 mmol). Heating to 50 ℃ in a water bath, and reacting for 8 hours. Cooled to room temperature, 50mL of 1wt% potassium carbonate aqueous solution was added to the reaction flask, stirred, left to stand, the bottom aqueous phase was discarded, and the mixture was washed once with 50mL of saturated brine, and the organic phase was distilled under reduced pressure at 50℃until the organic phase was substantially free of fractions, to obtain a white solid. 100mL of ethanol is added for recrystallization, and the filter cake is dried in vacuum at 40 ℃ to obtain 17.5g of target product I. Yield 85%, HPLC purity 99.3%, chiral purity 99.5%.
Example 2
Synthesis of Compound (E) -methyl 3- (2-amino-3-fluorophenyl) acrylate
2-bromo-6-fluoroaniline 4 (19 g,0.1 mol), methyl acrylate 2 (12.9 g,0.15 mol), diisopropylethylamine (25.8 g,0.2 mol) and dioxane 100mL were sequentially added to a 250mL three-necked flask, stirred well, and replaced with nitrogen three times. Bis triphenylphosphine palladium dichloride (0.7 g,1 mmol) was added and nitrogen was displaced once. The oil bath is heated to 85 ℃ and reacted for 16 hours. Cooling to room temperature, stirring for 1h, and suction filtering. The filtrate was distilled at 50℃under reduced pressure until it was substantially free of fractions, and 100mL of water was added. Extracted with 200mL of ethyl acetate and washed with 100mL of saturated sodium chloride. The organic phase was distilled under reduced pressure at 50℃until it was substantially free of fractions, to give a brown oil, 18g, which was directly fed to the next reaction.
Synthesis of Compound (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) ureido) acrylate
The prepared compound (E) -methyl 3- (2-amino-3-fluorophenyl) acrylate (18 g) was added to acetonitrile 100mL, all transferred to a 250mL reaction flask, and 2-methoxy-5-trifluoromethylacrylate (21.7 g,0.1 mol) was added. The mixture was heated to reflux at 82℃in an oil bath and reacted for 5 hours. Cooling to room temperature, stirring for 1h, and suction filtering. The wet cake was dried under vacuum at 35 ℃ to constant weight to give 32g of white solid in 78% yield in two steps.
Preparation of target product of letromycin intermediate
The compound (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate (20.6 g,0.05 mol) and toluene (150 mL) were added to a 500mL three-necked flask, and the mixture was dissolved in total with stirring, followed by addition of chiral catalyst (1R) -trans-N, N-1, 2-cyclohexanediyl (1, 1-trifluoromethanesulfonamide) (0.19 g,0.5 mmol). The mixture was heated to 55℃in a water bath and reacted for 8 hours. Cooling to room temperature, adding 50mL of 1wt% potassium carbonate aqueous solution into the reaction bottle, stirring, standing, and discarding the bottom water phase; the mixture was washed once with 50mL of saturated brine. The organic phase was distilled at 50 ℃ under reduced pressure until essentially no fraction was obtained as a white solid. 100mL of ethanol is added for recrystallization, and the filter cake is dried in vacuum at 40 ℃ to obtain 18.5g of target product I. Yield 90%, HPLC purity 99.2%, chiral purity 99.6%.
The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that modifications and adaptations to the present invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be comprehended within the scope of the present invention.

Claims (10)

1. A preparation method of a letromycin intermediate, which is characterized by comprising the following steps:
mixing 2-bromo-6-fluoroaniline, methyl acrylate, a palladium catalyst, an acid binding agent and an organic solvent for a coupling reaction to obtain (E) -3- (2-amino-3-fluorophenyl) methyl acrylate;
mixing the (E) -3- (2-amino-3-fluorophenyl) methyl acrylate and 2-methoxy-5-trifluoromethyl phenyl isocyanate for addition reaction to obtain (E) -3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) methyl acrylate;
mixing the (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate with a chiral catalyst and an organic solvent to perform intramolecular microphone addition reaction to obtain the letromycin intermediate, wherein the letromycin intermediate has a structure shown in a specific formula (I):
2. the preparation method according to claim 1, wherein the palladium catalyst is 1,1' -bis-diphenylphosphino ferrocene palladium dichloride and/or bis-triphenylphosphine palladium dichloride.
3. The preparation method according to claim 1 or 2, wherein the molar equivalent ratio of the 2-bromo-6-fluoroaniline to the palladium catalyst is 100:0.5-1.
4. The preparation method according to claim 1, wherein the acid binding agent is triethylamine and/or diisopropylethylamine.
5. The process according to claim 1 or 4, wherein the molar equivalent ratio of 2-bromo-6-fluoroaniline to acid-binding agent is 100:2.
6. The preparation method according to claim 1, wherein the coupling reaction is carried out at a temperature of 85-90 ℃ for a time of 16-17 hours.
7. The preparation method according to claim 1, wherein the temperature of the addition reaction is 80-82 ℃ for 5-6 hours.
8. The preparation method according to claim 1, wherein the chiral catalyst is (1R) -trans-N, N-1, 2-cyclohexanediyl (1, 1-trifluoromethanesulfonamide).
9. The process according to claim 1 or 8, wherein the molar equivalent ratio of (E) -methyl 3- (3-fluoro-2- (3- (2-methoxy-5- (trifluoromethyl) phenyl) urea) phenyl) acrylate to chiral catalyst is 100:1.
10. The method according to claim 1, wherein the intramolecular Michael addition reaction is carried out at a temperature of 50 to 60℃for a period of 7 to 8 hours.
CN202310842229.9A 2023-07-11 2023-07-11 Preparation method of letromycin intermediate Pending CN116874436A (en)

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