CN112824417A - Preparation method of Laolatinib - Google Patents

Preparation method of Laolatinib Download PDF

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CN112824417A
CN112824417A CN201911149484.5A CN201911149484A CN112824417A CN 112824417 A CN112824417 A CN 112824417A CN 201911149484 A CN201911149484 A CN 201911149484A CN 112824417 A CN112824417 A CN 112824417A
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compound
formula
reaction
another preferred
solvent
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李函璞
李勇刚
王卓
殷保胜
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SHANGHAI TIANCI INTERNATIONAL PHARMACEUTICAL CO LTD
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SHANGHAI TIANCI INTERNATIONAL PHARMACEUTICAL CO LTD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Abstract

The invention relates to a preparation method of Laolatinib. Specifically, the invention provides a preparation method of Laolatinib. The preparation method comprises the steps of taking 1-methyl-3- ((methyl-tert-butoxycarbonyl-amino) methyl) -1H-pyrazole-4-bromine-5-nitrile of a compound shown in a formula VII and 2- (tert-butoxycarbonyl-amino) -3-hydroxy-5-bromopyridine of a compound shown in a formula VI as raw materials, and carrying out coupling reaction, Williamson reaction, hydrolysis reaction, acidolysis reaction and condensation reaction to prepare the loratinib. The preparation method of loratinib has the advantages of short synthesis route, simple and convenient operation, mild reaction conditions, high yield and the like, and is suitable for industrial production of loratinib.

Description

Preparation method of Laolatinib
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of Laolatinib.
Background
Laolatinib (PF-06463922) is an ALK inhibitor modified by Crizotinib (Crizotinib) by Pfizer, U.S. A., and the drug enters clinical trials in 2014 and is used for treating lung cancer, mainly aiming at non-small cell lung cancer patients with Crizotinib resistance as a first generation ALK inhibitor and Ceritinib (Ceritinib) and aletinib (Alectinib) resistance as a second generation ALK inhibitor. However, the synthesis method of loratinib in the prior art has many disadvantages, such as long synthesis route, high cost, long time consumption, low yield and the like, which causes the synthesis efficiency of loratinib to be reduced, and is not beneficial to industrial production, thereby limiting the application of loratinib.
Therefore, there is a need in the art to develop a simple, efficient synthesis method for loratinib.
Disclosure of Invention
The invention aims to provide a preparation method of Laolatinib, which has the advantages of short synthetic route, simple and convenient operation, mild reaction conditions and high yield and is suitable for industrial production.
The invention provides a preparation method of Laolatinib, which comprises the following steps:
(1) in a first solvent, under the catalysis of a first alkaline reagent, carrying out a coupling reaction on a compound shown in a formula VI and a compound shown in a formula VII under the catalysis of a palladium catalyst to obtain a compound shown in a formula V;
Figure BDA0002283142530000011
(2) in a second solvent, carrying out Williamson reaction on the compound of the formula V and the compound of the formula IV in a second alkaline reagent to obtain a compound of a formula III;
Figure BDA0002283142530000021
(3) the compound of the formula III is subjected to hydrolysis reaction and acidolysis reaction in sequence to obtain a compound of a formula II;
Figure BDA0002283142530000022
(4) carrying out condensation reaction on the compound of the formula II to obtain a compound of a formula I;
Figure BDA0002283142530000023
in another preferred embodiment, in said step (1), the molar ratio of said compound of formula VI to said compound of formula VII is from 0.5 to 1.5:0.5 to 1.5, preferably from 0.8 to 1.2:0.8 to 1.2, more preferably from 0.9 to 1.1:0.9 to 1.1.
In another preferred embodiment, in said step (1), the molar ratio of said compound of formula VI to said first basic agent is 1:0.5-10, preferably 1:0.8 to 8, more preferably 1:1-5, more preferably 1:1.5-3.5, most preferably 1: 2-3.
In another preferred embodiment, in said step (1), the molar ratio of said compound of formula VII to said first alkaline agent is 1:0.5-10, preferably 1:0.8 to 8, more preferably 1:1-5, more preferably 1:1.5-3.5, most preferably 1: 2-3.
In another preferred embodiment, in the step (1), the molar ratio of the first alkaline agent to the palladium catalyst is 200-.
In another preferred embodiment, in the step (1), the palladium catalyst is selected from the group consisting of: 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium acetate, or a combination thereof.
In another preferred embodiment, the palladium catalyst is 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride.
In another preferred embodiment, in the step (1), the first solvent is selected from the group consisting of: 1, 4-dioxane, toluene, water, tetrahydrofuran, or a combination thereof.
In another preferred example, in the step (1), the first solvent is a mixed solvent of 1, 4-dioxane and water.
In another preferred embodiment, the volume ratio of 1, 4-dioxane to water is 1-10:1, preferably 1-8:1, more preferably 2-6:1, most preferably 3-5: 1.
In another preferred embodiment, in the step (1), the first solvent is a mixed solvent of 1, 4-dioxane and water, and the molar ratio of the water to the first alkaline agent is 2-10:0.1-0.5, preferably 3-8:0.1-0.4, more preferably 4.5-6.5: 0.2-0.3.
In another preferred embodiment, in the step (1), the first solvent is a mixed solvent of 1, 4-dioxane and water, and the weight ratio of the water to the first alkaline agent is 1-6:1, preferably 1-5:1, preferably 2-4:1, and most preferably 2.5-3.2: 1.
In another preferred embodiment, in the step (1), the first alkaline agent is selected from the group consisting of: potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or combinations thereof.
In another preferred embodiment, in the step (1), the first alkaline agent is potassium carbonate.
In another preferred embodiment, in the step (1), the coupling reaction is performed under the protection of nitrogen.
In another preferred embodiment, in the step (1), the reaction temperature is 50-90 ℃, preferably 60-80 ℃, and more preferably 65-75 ℃.
In another preferred embodiment, in the step (1), the reaction time is 2 to 24 hours, preferably 2 to 12 hours, more preferably 2 to 8 hours, more preferably 2 to 6 hours, more preferably 2 to 5 hours, and most preferably 2 to 4 hours.
In another preferred example, in the step (1), the reaction solution generated by the coupling reaction is filtered, the filtrate is concentrated under reduced pressure, ethyl acetate is added for extraction, the ethyl acetate layer is washed with water, and the ethyl acetate layer is concentrated to be dry, so as to obtain the compound of the formula V.
In another preferred embodiment, in said step (1), the compound of formula V is obtained in a molar yield of 60% or more, preferably 70% or more, more preferably 80% or more, more preferably 90% or more, more preferably 95% or more, more preferably 99% or more, most preferably 95-99%.
In another preferred embodiment, in said step (2), the molar ratio of said compound of formula V to said compound of formula IV is 1:1 to 5, preferably 1:1 to 3, more preferably 1:1 to 2, more preferably 1:1 to 1.5, more preferably 1:1 to 1.3, more preferably 1:1 to 1.2, most preferably 1:1.05 to 1.10.
In another preferred embodiment, in said step (2), the molar ratio of said compound of formula V to said second basic agent is 1:0.2-15, preferably 1:0.5-15, more preferably 1:0.5-10, more preferably 1:1-5, most preferably 1: 1-3.
In another preferred embodiment, in said step (2), the molar ratio of said compound of formula IV to said second basic agent is 1:0.2-15, preferably 1:0.5-15, more preferably 1:0.5-10, more preferably 1:1-5, most preferably 1: 1-3.
In another preferred embodiment, in the step (2), the molar ratio of the second solvent to the second basic reagent is 10 to 150: 1, preferably 10-100: 1, more preferably 20-90:1, more preferably 40-80:1, more preferably 50-70: 1, most preferably 55-65: 1.
In another preferred embodiment, in the step (2), the second alkaline reagent is selected from the group consisting of: potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, morpholine, triethylamine, pyridine, or combinations thereof.
In another preferred embodiment, in the step (2), the second basic reagent is potassium carbonate.
In another preferred embodiment, in the step (2), the second solvent is selected from the group consisting of: n, N-dimethylformamide, N-dimethylacetamide, acetone, 1, 4-dioxane, tetrahydrofuran, 1-methyl-tetrahydrofuran, dichloromethane, dichloroethane, chloroform, or a combination thereof.
In another preferred embodiment, in the step (2), the second solvent is acetone.
In another preferred embodiment, in the step (2), the temperature of the reaction is 0 to 80 ℃, preferably 0 to 70 ℃, more preferably 20 to 70 ℃, more preferably 40 to 70 ℃, more preferably 45 to 65 ℃, more preferably 50 to 60 ℃, and most preferably 55 to 60 ℃.
In another preferred embodiment, in the step (2), the reaction time is 6-36h, preferably 12-36h, more preferably 15-30h, more preferably 18-25h, and most preferably 18-20 h.
In another preferred embodiment, in the step (2), the reaction solution generated after the Williamson reaction is filtered, the filtrate is concentrated (preferably to dryness), n-hexane and ethyl acetate are added, and the mixture is filtered, so as to obtain the compound of the formula III.
In another preferred embodiment, the volume ratio of the n-hexane to the ethyl acetate is 1-10:1, preferably 1-8:1, more preferably 2-6:1, most preferably 3-5: 1.
In another preferred embodiment, in said step (2), the compound of formula III is obtained in a molar yield of 80% or more, preferably 850% or more, more preferably 90% or more, more preferably 95% or more, more preferably 99% or more, most preferably 95-99%.
In another preferred embodiment, in the step (3), the hydrolysis reaction is performed in the presence of a third solvent, and the third solvent is selected from the group consisting of: methanol, ethanol, isopropanol, tetrahydrofuran, 1-methyl-tetrahydrofuran, or a combination thereof.
In another preferred embodiment, in the step (3), the hydrolysis reaction is performed in the presence of a third alkaline agent selected from the group consisting of: sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, or combinations thereof.
In another preferred embodiment, in the step (3), the molar ratio of the compound of formula III to the third alkaline agent is 1:0.5-10, preferably 1:0.8-8, more preferably 1:1-5, most preferably 1: 2-4.
In another preferred embodiment, in the step (3), the ratio (g: ml) of the third alkaline agent to the third solvent is 1-30:100-500, preferably 1-20:200-400, more preferably 1-10: 250-350, optimally 4-8: 280-320.
In another preferred embodiment, in the step (3), the temperature of the hydrolysis reaction is 40 to 80 ℃, preferably 50 to 80 ℃, more preferably 55 to 75 ℃, and most preferably 55 to 65 ℃.
In another preferred embodiment, in the step (3), the hydrolysis reaction time is 2 to 12 hours, preferably 3 to 12 hours, more preferably 3 to 8 hours, and most preferably 3 to 6 hours.
In another preferred embodiment, in the step (3), the acidolysis reaction is performed in the presence of a fourth solvent, and the fourth solvent is selected from the group consisting of: ethyl acetate, isopropyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, or combinations thereof.
In another preferred embodiment, in the step (3), the acidolysis reaction is performed in the presence of a first acidic reagent, and the acidic reagent is selected from the group consisting of: trifluoroacetic acid, hydrochloric acid, sulfuric acid, or a combination thereof.
In another preferred example, in the step (3), after completion of the hydrolysis reaction, the reaction solution is concentrated, water (preferably, water adjusted to pH 6 to 7 with an acidic reagent) and a fourth solvent are added and mixed to obtain an aqueous phase and a fourth solvent phase, the fourth solvent phase is separated, and the first acidic reagent is added to the fourth solvent phase to perform an acidolysis reaction, thereby obtaining the compound II.
In another preferred embodiment, the volume ratio of water to the fourth solvent is 0.5-3:0.5-5, preferably 0.5-2:0.5-4, preferably 0.5-1.5:0.8-3, more preferably 0.8-1.2:1-3, most preferably 0.8-1.2: 1.5-2.5.
In another preferred embodiment, the water is water having a pH of 6 to 7.
In another preferred embodiment, the water is water adjusted to pH 6-7 by acid (such as hydrochloric acid).
In another preferred embodiment, in the step (3), the reaction temperature of the acidolysis reaction is 0 to 20 ℃, preferably 0 to 10 ℃, and more preferably 0 to 5 ℃.
In another preferred embodiment, in the step (3), the hydrolysis reaction and the acidolysis reaction are continuous processes.
In another preferred embodiment, in the step (3), after the acidolysis reaction is completed, water (preferably, water adjusted to pH 7-8 by an alkaline agent) is added to the reaction solution, and then the fourth solvent phase is separated and concentrated under reflux to obtain the compound of formula II.
In another preferred embodiment, in said step (3), the compound of formula II is obtained in a molar yield of 60% or more, preferably 70% or more, more preferably 80% or more, more preferably 90% or more, more preferably 95% or more, more preferably 99% or more, most preferably 95-99%.
In another preferred embodiment, in the step (4), the condensation reaction is performed in the presence of a fifth solvent, and the fifth solvent is selected from the group consisting of: ethyl acetate, dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide, or a combination thereof.
In another preferred embodiment, in the step (4), the condensation reaction is performed in the presence of a condensing agent selected from the group consisting of: DCC, EDCI, DIC, HATU, HBTU, or combinations thereof.
In another preferred embodiment, in the step (4), the condensation reaction is carried out under catalysis of DMAP.
In another preferred embodiment, the molar ratio of said compound of formula II to said condensing agent is 0.2-5:1, preferably 0.2-3:1, more preferably 0.3-2: 1, more preferably 0.5-1.5:1, most preferably 0.7-1.3: 1.
In another preferred embodiment, the molar ratio of the condensing agent to the DMAP is 1-10:0.1-0.8, preferably 3-7: 0.2-0.4.
In another preferred embodiment, in the step (4), the temperature of the reaction is 50 to 90 ℃, preferably 60 to 80 ℃, and more preferably 65 to 75 ℃.
In another preferred embodiment, in the step (4), the reaction time is 2 to 24 hours, preferably 5 to 12 hours, and more preferably 5 to 8 hours.
In another preferred embodiment, in the step (4), after the condensation reaction is completed, water is added to the reaction solution, the fifth solvent phase is separated, and the compound of formula I is separated from the fifth solvent phase.
In another preferred embodiment, in said step (4), the compound of formula I is obtained in a molar yield of 60% or more, preferably 70% or more, more preferably 80% or more, more preferably 90% or more, more preferably 95% or more, more preferably 99% or more, most preferably 95-99%.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is a schematic representation of Lauratinib synthesized in example 41H-NMR spectrum.
Detailed Description
The present inventors have conducted extensive and intensive studies and, as a result, have developed a process for producing loratinib by using 1-methyl-3- ((methyl-tert-butoxycarbonyl-amino) methyl) -1H-pyrazole-4-bromo-5-carbonitrile of the formula vii and 2- (tert-butoxycarbonyl-amino) -3-hydroxy-5-bromopyridine of the formula vi as starting materials through coupling reaction, Williamson reaction, hydrolysis reaction, acidolysis reaction, and condensation reaction. The preparation method of loratinib has the advantages of short synthetic route, simple and convenient operation, mild reaction conditions, high yield and the like, and is suitable for industrial production of loratinib. The present invention has been completed based on this finding.
Term(s) for
As used herein, the terms "comprising," "including," and "containing" are used interchangeably and include not only open-ended definitions, but also semi-closed and closed-ended definitions. In other words, the term includes "consisting of … …", "consisting essentially of … …".
The following description abbreviations the indicated reagents, DCC, EDCI, DIC, HATU, HBTU, DMAP:
DCC: dicyclohexylcarbodiimide
EDCI: 1-Ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride
DIC: diisopropylcarbodiimide
HATU: 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
HABU: o-benzotriazole-tetramethylurea hexafluorophosphate
DMAP: 4-dimethylaminopyridine
Preparation method of Laolatinib
The invention provides a preparation method of Laolatinib, which comprises the following steps:
(1) in a first solvent, under the catalysis of a first alkaline reagent, carrying out a coupling reaction on a compound shown in a formula VI and a compound shown in a formula VII under the catalysis of a palladium catalyst to obtain a compound shown in a formula V;
Figure BDA0002283142530000081
(2) in a second solvent, carrying out Williamson reaction on the compound of the formula V and the compound of the formula IV in a second alkaline reagent to obtain a compound of a formula III;
Figure BDA0002283142530000082
(3) the compound of the formula III is subjected to hydrolysis reaction and acidolysis reaction in sequence to obtain a compound of a formula II;
Figure BDA0002283142530000083
(4) carrying out condensation reaction on the compound of the formula II to obtain a compound of a formula I;
Figure BDA0002283142530000091
preparation of Compounds of formula V
The present invention provides a process for the preparation of a compound of formula V, said process comprising the steps of:
(1) in a first solvent, under the catalysis of a first alkaline reagent, carrying out a coupling reaction on a compound shown in a formula VI and a compound shown in a formula VII under the catalysis of a palladium catalyst to obtain a compound shown in a formula V;
Figure BDA0002283142530000092
in a preferred embodiment, in said step (1), the molar ratio of said compound of formula VI to said compound of formula VII is 0.5-1.5:0.5-1.5, preferably 0.8-1.2:0.8-1.2, more preferably 0.9-1.1: 0.9-1.1.
In another preferred embodiment, in said step (1), the molar ratio of said compound of formula VI to said first basic agent is 1:0.5-10, preferably 1:0.8 to 8, more preferably 1:1-5, more preferably 1:1.5-3.5, most preferably 1: 2-3.
In another preferred embodiment, in said step (1), the molar ratio of said compound of formula VII to said first alkaline agent is 1:0.5-10, preferably 1:0.8 to 8, more preferably 1:1-5, more preferably 1:1.5-3.5, most preferably 1: 2-3.
In another preferred embodiment, in the step (1), the molar ratio of the first alkaline agent to the palladium catalyst is 200-.
In another preferred example, in the step (1), the palladium catalyst includes (but is not limited to): 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium acetate, or a combination thereof.
Typically, the palladium catalyst is 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride.
In another preferred example, in the step (1), the first solvent includes (but is not limited to): 1, 4-dioxane, toluene, water, tetrahydrofuran, or a combination thereof.
Typically, in the step (1), the first solvent is a mixed solvent of 1, 4-dioxane and water.
In another preferred embodiment, the volume ratio of 1, 4-dioxane to water is 1-10:1, preferably 1-8:1, more preferably 2-6:1, most preferably 3-5: 1.
In another preferred embodiment, in the step (1), the first solvent is a mixed solvent of 1, 4-dioxane and water, and the molar ratio of the water to the first alkaline agent is 2-10:0.1-0.5, preferably 3-8:0.1-0.4, more preferably 4.5-6.5: 0.2-0.3.
In another preferred embodiment, in the step (1), the first solvent is a mixed solvent of 1, 4-dioxane and water, and the weight ratio of the water to the first alkaline agent is 1-6:1, preferably 1-5:1, preferably 2-4:1, and most preferably 2.5-3.2: 1.
In another preferred embodiment, in the step (1), the first alkaline agent includes (but is not limited to): potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or combinations thereof.
Typically, in the step (1), the first alkaline agent is potassium carbonate.
In another preferred embodiment, in the step (1), the coupling reaction is performed under the protection of nitrogen.
In another preferred embodiment, in the step (1), the reaction temperature is 50-90 ℃, preferably 60-80 ℃, and more preferably 65-75 ℃.
In another preferred embodiment, in the step (1), the reaction time is 2 to 24 hours, preferably 2 to 12 hours, more preferably 2 to 8 hours, more preferably 2 to 6 hours, more preferably 2 to 5 hours, and most preferably 2 to 4 hours.
In another preferred example, in the step (1), the reaction solution generated by the coupling reaction is filtered, the filtrate is concentrated under reduced pressure, ethyl acetate is added for extraction, the ethyl acetate layer is washed with water, and the ethyl acetate layer is concentrated to be dry, so as to obtain the compound of the formula V.
In another preferred embodiment, in said step (1), the compound of formula V is obtained in a molar yield of 60% or more, preferably 70% or more, more preferably 80% or more, more preferably 90% or more, more preferably 95% or more, more preferably 99% or more, most preferably 95-99%.
Preparation of Compounds of formula III
The present invention provides a process for the preparation of a compound of formula III, said process comprising the steps of:
(2) in a second solvent, carrying out Williamson reaction on the compound of the formula V and the compound of the formula IV in a second alkaline reagent to obtain a compound of a formula III;
Figure BDA0002283142530000111
in a preferred embodiment, in said step (2), the molar ratio of said compound of formula V to said compound of formula IV is 1:1 to 5, preferably 1:1 to 3, more preferably 1:1 to 2, more preferably 1:1 to 1.5, more preferably 1:1 to 1.3, more preferably 1:1 to 1.2, most preferably 1:1.05 to 1.10.
In another preferred embodiment, in said step (2), the molar ratio of said compound of formula V to said second basic agent is 1:0.2-15, preferably 1:0.5-15, more preferably 1:0.5-10, more preferably 1:1-5, most preferably 1: 1-3.
In another preferred embodiment, in said step (2), the molar ratio of said compound of formula IV to said second basic agent is 1:0.2-15, preferably 1:0.5-15, more preferably 1:0.5-10, more preferably 1:1-5, most preferably 1: 1-3.
In another preferred embodiment, in the step (2), the molar ratio of the second solvent to the second basic reagent is 10 to 150: 1, preferably 10-100: 1, more preferably 20-90:1, more preferably 40-80:1, more preferably 50-70: 1, most preferably 55-65: 1.
In another preferred embodiment, in the step (2), the second alkaline reagent includes (but is not limited to): potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, morpholine, triethylamine, pyridine, or combinations thereof.
Typically, in the step (2), the second basic reagent is potassium carbonate.
In another preferred example, in the step (2), the second solvent includes (but is not limited to): n, N-dimethylformamide, N-dimethylacetamide, acetone, 1, 4-dioxane, tetrahydrofuran, 1-methyl-tetrahydrofuran, dichloromethane, dichloroethane, chloroform, or a combination thereof.
Typically, in the step (2), the second solvent is acetone.
In another preferred embodiment, in the step (2), the temperature of the reaction is 0 to 80 ℃, preferably 0 to 70 ℃, more preferably 20 to 70 ℃, more preferably 40 to 70 ℃, more preferably 45 to 65 ℃, more preferably 50 to 60 ℃, and most preferably 55 to 60 ℃.
In another preferred embodiment, in the step (2), the reaction time is 6-36h, preferably 12-36h, more preferably 15-30h, more preferably 18-25h, and most preferably 18-20 h.
In another preferred embodiment, in the step (2), the reaction solution generated after the Williamson reaction is filtered, the filtrate is concentrated (preferably to dryness), n-hexane and ethyl acetate are added, and the mixture is filtered, so as to obtain the compound of the formula III.
In another preferred embodiment, the volume ratio of the n-hexane to the ethyl acetate is 1-10:1, preferably 1-8:1, more preferably 2-6:1, most preferably 3-5: 1.
In another preferred embodiment, in said step (2), the compound of formula III is obtained in a molar yield of 80% or more, preferably 850% or more, more preferably 90% or more, more preferably 95% or more, more preferably 99% or more, most preferably 95-99%.
Preparation of Compounds of formula II
The present invention provides a process for the preparation of a compound of formula II, said process comprising the steps of:
(3) the compound of the formula III is subjected to hydrolysis reaction and acidolysis reaction in sequence to obtain a compound of a formula II;
Figure BDA0002283142530000121
in another preferred embodiment, in the step (3), the hydrolysis reaction is performed in the presence of a third solvent, and the third solvent includes (but is not limited to): methanol, ethanol, isopropanol, tetrahydrofuran, 1-methyl-tetrahydrofuran, or a combination thereof.
In another preferred embodiment, in the step (3), the hydrolysis reaction is performed in the presence of a third alkaline agent, and the third alkaline agent includes (but is not limited to): sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, or combinations thereof.
In another preferred embodiment, in the step (3), the molar ratio of the compound of formula III to the third alkaline agent is 1:0.5-10, preferably 1:0.8-8, more preferably 1:1-5, most preferably 1: 2-4.
In another preferred embodiment, in the step (3), the ratio (g: ml) of the third alkaline agent to the third solvent is 1-30:100-500, preferably 1-20:200-400, more preferably 1-10: 250-350, optimally 4-8: 280-320.
In another preferred embodiment, in the step (3), the temperature of the hydrolysis reaction is 40 to 80 ℃, preferably 50 to 80 ℃, more preferably 55 to 75 ℃, and most preferably 55 to 65 ℃.
In another preferred embodiment, in the step (3), the hydrolysis reaction time is 2 to 12 hours, preferably 3 to 12 hours, more preferably 3 to 8 hours, and most preferably 3 to 6 hours.
In another preferred embodiment, in the step (3), the acidolysis reaction is performed in the presence of a fourth solvent, and the fourth solvent includes (but is not limited to): ethyl acetate, isopropyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, or combinations thereof.
In another preferred embodiment, in the step (3), the acidolysis reaction is performed in the presence of a first acidic reagent, and the acidic reagent includes (but is not limited to): trifluoroacetic acid, hydrochloric acid, sulfuric acid, or a combination thereof.
In another preferred example, in the step (3), after completion of the hydrolysis reaction, the reaction solution is concentrated, water (preferably, water adjusted to pH 6 to 7 with an acidic reagent) and a fourth solvent are added and mixed to obtain an aqueous phase and a fourth solvent phase, the fourth solvent phase is separated, and the first acidic reagent is added to the fourth solvent phase to perform an acidolysis reaction, thereby obtaining the compound II.
In another preferred embodiment, the volume ratio of water to the fourth solvent is 0.5-3:0.5-5, preferably 0.5-2:0.5-4, preferably 0.5-1.5:0.8-3, more preferably 0.8-1.2:1-3, most preferably 0.8-1.2: 1.5-2.5.
In another preferred embodiment, the water is water having a pH of 6 to 7.
In another preferred embodiment, the water is water adjusted to pH 6-7 by acid (such as hydrochloric acid).
In another preferred embodiment, in the step (3), the reaction temperature of the acidolysis reaction is 0 to 20 ℃, preferably 0 to 10 ℃, and more preferably 0 to 5 ℃.
In another preferred embodiment, in the step (3), the hydrolysis reaction and the acidolysis reaction are continuous processes.
In another preferred embodiment, in the step (3), after the acidolysis reaction is completed, water (preferably, water adjusted to pH 7-8 by an alkaline agent) is added to the reaction solution, and then the fourth solvent phase is separated and concentrated under reflux to obtain the compound of formula II.
In another preferred embodiment, in said step (3), the compound of formula II is obtained in a molar yield of 60% or more, preferably 70% or more, more preferably 80% or more, more preferably 90% or more, more preferably 95% or more, more preferably 99% or more, most preferably 95-99%.
Preparation of Compounds of formula I
The present invention provides a process for the preparation of a compound of formula I, said process comprising the steps of:
(4) carrying out condensation reaction on the compound of the formula II to obtain a compound of a formula I;
Figure BDA0002283142530000141
in another preferred embodiment, in the step (4), the condensation reaction is performed in the presence of a fifth solvent, and the fifth solvent includes (but is not limited to): ethyl acetate, dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide, or a combination thereof.
In another preferred embodiment, in the step (4), the condensation reaction is performed in the presence of a condensing agent, and the condensing agent includes (but is not limited to): DCC, EDCI, DIC, HATU, HBTU, or combinations thereof.
In another preferred embodiment, in the step (4), the condensation reaction is carried out under catalysis of DMAP.
In another preferred embodiment, the molar ratio of said compound of formula II to said condensing agent is 0.2-5:1, preferably 0.2-3:1, more preferably 0.3-2: 1, more preferably 0.5-1.5:1, most preferably 0.7-1.3: 1.
In another preferred embodiment, the molar ratio of the condensing agent to the DMAP is 1-10:0.1-0.8, preferably 3-7: 0.2-0.4.
In another preferred embodiment, in the step (4), the temperature of the reaction is 50 to 90 ℃, preferably 60 to 80 ℃, and more preferably 65 to 75 ℃.
In another preferred embodiment, in the step (4), the reaction time is 2 to 24 hours, preferably 5 to 12 hours, and more preferably 5 to 8 hours.
In another preferred embodiment, in the step (4), after the condensation reaction is completed, water is added to the reaction solution, the fifth solvent phase is separated, and the compound of formula I is separated from the fifth solvent phase.
In another preferred embodiment, in said step (4), the compound of formula I is obtained in a molar yield of 60% or more, preferably 70% or more, more preferably 80% or more, more preferably 90% or more, more preferably 95% or more, more preferably 99% or more, most preferably 95-99%.
The main advantages of the invention include:
the preparation method of Laolatinib has the advantages of short synthetic route, simple and convenient operation, mild reaction conditions, environmental friendliness, low cost, good purity of the synthesized Laolatinib and high yield, thereby being suitable for industrial production
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Examples
1,1' -bis (diphenylphosphino) ferrocene Palladium dichloride 98% Sahn chemical technology (Shanghai) Co., Ltd
Example 1
Preparation of Compound (V)
Figure BDA0002283142530000151
28.8g (0.1mol) of the compound (VI) and 32.9g (0.1mol) of the compound (VII), 400ml of 1, 4-dioxane and 100ml of water were charged into a 1L reaction flask, and under nitrogen protection, 0.3g of 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium and 34.6g (0.25mol) of potassium carbonate were added, and the temperature was raised to 70 ℃ to react for 3 hours. Cooling to room temperature, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure, extracting with ethyl acetate, washing the ethyl acetate layer with water, and concentrating the ethyl acetate layer to dryness to obtain 40.3g of a yellow solid, in 88% molar yield, ms (esi): and M is 458.51.
Example 2
Preparation of Compound (III)
Figure BDA0002283142530000161
27.5g (0.06mol) of compound (V), 400ml of acetone, 16.6g (0.12mol) of powdered potassium carbonate, 17.4g (0.063mol) of compound (IV) were charged into a 1L reaction flask, and the reaction was carried out at 55 ℃ for 18 hours, cooled to room temperature, and filtered. The filtrate was concentrated to dryness, and 80ml of n-hexane and 20ml of ethyl acetate were added thereto, followed by stirring, filtration and drying to obtain 36.4g of compound (III) with a molar yield of 95%. Ms (esi): and M is 638.69.
Example 3
Preparation of Compound (II)
Figure BDA0002283142530000162
Adding 32.2g (0.05mol) of compound (III) and 300ml of methanol into a 1L reaction bottle, stirring to dissolve the compound, dropwise adding a sodium hydroxide aqueous solution (6g of sodium hydroxide is dissolved in 20g of water), heating to 60 ℃ to react for 3 hours, finishing the reaction, concentrating the reaction solution, adding 100ml of water, dropwise adding diluted hydrochloric acid to adjust the pH value to 6-7, adding 200ml of ethyl acetate, stirring, separating out an ethyl acetate solution, drying the sodium sulfate in the ethyl acetate solution, dropwise adding 17.1g (0.15mol) of trifluoroacetic acid at 0-5 ℃, detecting the reaction end point by TLC, adding 100ml of water, dropwise adding ammonia water to adjust the pH value of a water layer to 7-8, separating, concentrating an ethyl acetate phase, recovering ethyl acetate to obtain 19.1g of a yellow solid, and obtaining the molar yield of 90%. Ms (esi): and M is 424.73.
Example 4
Preparation of loratinib
Figure BDA0002283142530000171
A1L reaction flask was charged with 300ml of 19.1g (0.045mol) of compound (II) dichloroethane, stirred to dissolve it, charged with HATU19.0g (0.05mol) and 0.4g of DMAP, heated to 70 ℃ to react for 5 hours, cooled to room temperature, charged with 100ml of water, separated, washed with dichloroethane, and concentrated in dichloroethane. 18.3g of Laratinib was obtained with a molar yield of 90%. Ms (esi): [ M + H ]]407.16. Laolatinib1The H-NMR spectrum is shown in figure 1,1H-NMR(300MHz,DMSO-d6):δ7.57(2H，m)，7.46(1H，m)，7.18(1H，m)，6.81(1H，d)，6.20(2H，s)，5.60(1H,m)，4.42(1H,d)，4.17(1H,d)，4.04(3H,s)，2.99(3H,s)，1.67(3H,d)。
in conclusion, the preparation method of loratinib in example 1 has the advantages of short synthetic route, simple and convenient operation, mild reaction conditions, environmental friendliness, low cost, good purity of synthesized loratinib and high yield, and is suitable for industrial production.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A method of preparing loratinib, comprising the steps of:
(1) in a first solvent, under the catalysis of a first alkaline reagent, carrying out a coupling reaction on a compound shown in a formula VI and a compound shown in a formula VII under the catalysis of a palladium catalyst to obtain a compound shown in a formula V;
Figure FDA0002283142520000011
(2) in a second solvent, carrying out Williamson reaction on the compound of the formula V and the compound of the formula IV in a second alkaline reagent to obtain a compound of a formula III;
Figure FDA0002283142520000012
(3) the compound of the formula III is subjected to hydrolysis reaction and acidolysis reaction in sequence to obtain a compound of a formula II;
Figure FDA0002283142520000013
(4) carrying out condensation reaction on the compound of the formula II to obtain a compound of a formula I;
Figure FDA0002283142520000014
2. the method as claimed in claim 1, wherein in the step (1), the molar ratio of the first alkaline agent to the palladium catalyst is 200-.
3. The method of claim 1, wherein in step (1), the palladium catalyst is selected from the group consisting of: 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium acetate, or a combination thereof.
4. The method of claim 1, wherein in step (1), the first solvent is selected from the group consisting of: 1, 4-dioxane, toluene, water, tetrahydrofuran, or a combination thereof.
5. The method of claim 1, wherein in step (1), the first alkaline agent is selected from the group consisting of: potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or combinations thereof.
6. The method of claim 1, wherein in step (2), the molar ratio of the second solvent to the second basic agent is from 10 to 150: 1, preferably 10-100: 1, more preferably 20-90:1, more preferably 40-80:1, more preferably 50-70: 1, most preferably 55-65: 1.
7. The method of claim 1, wherein in step (2), the second basic reagent is selected from the group consisting of: potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, morpholine, triethylamine, pyridine, or combinations thereof.
8. The method of claim 1, wherein in step (2), the second solvent is selected from the group consisting of: n, N-dimethylformamide, N-dimethylacetamide, acetone, 1, 4-dioxane, tetrahydrofuran, 1-methyl-tetrahydrofuran, dichloromethane, dichloroethane, chloroform, or a combination thereof.
9. The method of claim 1, wherein in step (3), the hydrolysis reaction is carried out in the presence of a third solvent selected from the group consisting of: methanol, ethanol, isopropanol, tetrahydrofuran, 1-methyl-tetrahydrofuran, or a combination thereof.
10. The method of claim 1, wherein in step (4), the condensation reaction is carried out in the presence of a condensing agent selected from the group consisting of: DCC, EDCI, DIC, HATU, HBTU, or combinations thereof.
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