CN110981800A - Preparation method of lenvatinib - Google Patents

Preparation method of lenvatinib Download PDF

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CN110981800A
CN110981800A CN201911404054.3A CN201911404054A CN110981800A CN 110981800 A CN110981800 A CN 110981800A CN 201911404054 A CN201911404054 A CN 201911404054A CN 110981800 A CN110981800 A CN 110981800A
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reaction
cyano
methoxy
synthesis
lenvatinib
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刘辉
龚博文
冯成亮
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Anhui Chenglian Medicine Technology Co ltd
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Anhui Chenglian Medicine Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a preparation method of lenvatinib, which is characterized in that 4-nitro-2-chlorobenzonitrile is used as an initial raw material, and nitro group electron-withdrawing is introduced into molecules, so that the electron cloud density of a benzene ring is greatly reduced, nucleophilic substitution reaction is facilitated, and the reaction temperature is greatly reduced; amino protection, namely adopting ZnO as Lewis acid to ensure that the reaction in the step is green; through the processes of acylation, deprotection and intramolecular alkylation, compared with the traditional high-temperature reaction, the synthesis route is novel, the reaction temperature is low, the condition is mild and green, no dangerous step is caused, and the method is suitable for industrial production.

Description

Preparation method of lenvatinib
Technical Field
The invention relates to a preparation method of lenvatinib, in particular to a novel preparation method of oral lenvatinib serving as a tyrosine kinase inhibitor.
Background
Lenvatinib (E7080), chemically known as 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide, is an oral multi-receptor tyrosine kinase inhibitor developed by Euonymus japonicus K.K. (Eisai), and is a potential therapeutic agent for thyroid cancer, liver cancer, non-small cell lung cancer and other solid tumors. In year 2 of 2013, lentitinib was approved by FDA for use in the treatment of follicular, medullary, undifferentiated, metastatic or locally advanced papillary thyroid cancer in year 2015, month 2 and 13, and lentitinib was approved by FDA for use in the treatment of radioiodine refractory differentiated thyroid cancer.
The Levatinib is synthesized by the reaction of an intermediate 6-formamido-7-methoxyl-4-chloroquinoline and 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropyl urea. One of the common schemes in the prior art is that 4-cyano-3-chloroaniline is used as a starting material disclosed in 7253286B2[ P ]. 2007-08-07, firstly, the 4-cyano-3-chloroaniline is reacted with sodium methoxide in a high boiling point solvent NMP to prepare the 4-cyano-3-methoxyaniline, then the 4-cyano-3-methoxyaniline is condensed with Mai de rum acid, then the 4-cyano-3-methoxyaniline is cyclized, oxidized, chlorinated, hydrolyzed, acylchlorinated and aminated in diphenyl ether at high temperature, and finally the product is reacted with 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropyl urea to prepare the compound. The main defects of the scheme are long route, harsh reaction conditions and high requirements on equipment for large-scale production.
The specific route of the scheme is as follows:
Figure BDA0002348144010000021
the other scheme is that 4-aminosalicylic acid is used as a starting raw material, and is firstly reacted with a virulent reagent dimethyl sulfate for methyl esterification, then condensed with acetone produced by malonic acid in the presence of orthoformate, and then cyclized at high temperature under the protection of nitrogen, chlorinated and aminolyzed, and finally prepared with 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropyl urea. (for example: China journal of pharmaceutical chemistry 2015, 25(4): 285- & 288.) the method is still harsh in reaction conditions and uses highly toxic reagents.
The specific route of the scheme is as follows:
Figure BDA0002348144010000031
disclosure of Invention
The invention aims to overcome the defect that the reaction conditions of the preparation method of lenvatinib in the prior art are harsh, and provides a novel preparation method of lenvatinib, which has low cost and is simple and convenient to operate.
In order to solve the technical problems, the invention provides the following technical scheme:
the synthetic route of the invention is as follows:
Figure BDA0002348144010000041
specifically, the method comprises the following steps:
the first step is as follows: synthesis of 4-nitro-2-methoxybenzonitrile (a)
4-nitro-2-chlorobenzonitrile is dissolved in a solvent and undergoes nucleophilic substitution reaction with sodium methoxide to prepare 4-nitro-2-chlorobenzonitrile (a), and the nucleophilic substitution reaction is much easier due to the existence of nitro electron-withdrawing groups in molecules; the specific reaction is as follows:
Figure BDA0002348144010000042
the second step is that: synthesis of 4-cyano-3-methoxyaniline (b)
The 4-nitro-2-methoxy benzonitrile is subjected to catalytic hydrogenation to reduce the nitro group into amino group, and during the reduction process, the temperature of the hydrogenation reaction needs to be well controlled due to the existence of cyano group and methoxy group, otherwise, the yield of the product is reduced. The hydrogenation takes ethanol as a solvent, the reaction temperature is controlled between 30 and 50 ℃, the byproducts of the reduction of the cyano group are minimal, and no demethylation reaction occurs; the specific reaction is as follows:
Figure BDA0002348144010000051
the third step: synthesis of N-t-butoxycarbonyl-4-cyano-3-methoxyaniline (c)
4-cyano-3-methoxyaniline with di-tert-butoxycarbonyldicarbonate ((Boc)2O) reaction, usually a base is chosen as catalyst, while Lewis acids are also used for amino group (Boc)2And (4) protecting by O. In the development of the project, Lewis acid ZnO is found to be capable of effectively catalyzing the reaction to carry out amino protection to prepare N-tert-butoxycarbonyl-4-cyano-3-methoxyaniline (c), ZnO in the reaction is insoluble in a reaction system and water and belongs to heterogeneous reaction, and the catalyst can be effectively recovered and reused, so that the reaction in the step is green; the specific reaction is as follows:
Figure BDA0002348144010000052
the fourth step: synthesis of 4-cyano-3-methoxy-2- (3-chloroacetyl) aniline (d)
Boc-4-cyano-3-methoxyaniline and 3-chloropropionyl chloride in Lewis acid AlCl3Carrying out Friedel-crafts acylation reaction under catalysis, simultaneously removing amino protection from HCl generated in the reaction to prepare 4-cyano-3-methoxy-2- (3-chloroacetyl) aniline (d), wherein in the synthesis of the project, the Friedel-crafts acylation reaction and the amino protection are carried out simultaneously, and due to the nucleophilicity of the amino, the using amount of aluminum trichloride in the reaction is 1.5-2 equivalents; the specific reaction is as follows:
Figure BDA0002348144010000053
the fifth step: synthesis of 6-cyano-7-methoxytetrahydroquinolin-4-one (e)
4-cyano-3-methoxy-2- (3-chloroacetyl) aniline is subjected to intramolecular alkylation reaction under alkaline condition, and cyclization is carried out to form 6-cyano-7-methoxytetrahydroquinoline-4-ketone (e), wherein the specific reaction is as follows:
Figure BDA0002348144010000061
and a sixth step: synthesis of 6-cyano-7-methoxy-4-quinolinone (f)
Oxidative dehydrogenation of 6-cyano-7-methoxytetrahydroquinolin-4-one by DDQ to form 6-cyano-7-methoxy-4-quinolinone (f); the specific reaction is as follows:
Figure BDA0002348144010000062
the seventh step: synthesis (g) of 6-cyano-7-methoxy-4-chloroquinoline
Synthesizing 6-cyano-7-methoxy-4-quinolinone by reacting 6-cyano-7-methoxy-4-quinolinone with thionyl chloride (g); the specific reaction is as follows:
Figure BDA0002348144010000063
eighth step: synthesis (h) of 6-carboxamido-7-methoxy-4-chloroquinoline
Hydrolyzing 6-cyano-7-methoxy-4-chlorolinone under an acidic condition to synthesize 6-formamido-7-methoxy-4-chlorolinone (h); the specific reaction is as follows:
Figure BDA0002348144010000064
the ninth step: synthesis of Levatinib (i)
Nucleophilic substitution reaction of 6-formamido-7-methoxyl-4-chloroquinoline and 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropyl urea in alkaline condition to prepare lenvatinib (i); the specific reaction is as follows:
Figure BDA0002348144010000071
the method comprises the steps of taking 4-nitro-2-chlorobenzonitrile as an initial raw material, forming methyl ether through nucleophilic substitution reaction, reducing nitro, protecting amino, carrying out friedel-crafts acylation reaction with 3-chloropropionyl chloride, simultaneously removing amino protection from acid formed in the reaction, carrying out intramolecular alkylation reaction under an alkaline condition, carrying out oxidative dehydrogenation on DDQ to form 4-quinolinone, forming 4-chloroquinoline under the condition of thionyl chloride, hydrolyzing cyano to form amide under an acidic condition, and directly synthesizing the Levatinib key intermediate 6-formamido-7-methoxy-4-chloroquinoline (i). Then the mixture and 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropyl urea are subjected to alkylation reaction under the action of alkali to prepare the delavatinib.
The invention has the following beneficial effects:
the method takes 4-nitro-2-chlorobenzonitrile as an initial raw material, and introduces nitro electron-withdrawing in molecules, so that the electron cloud density of benzene rings is greatly reduced, nucleophilic substitution reaction is facilitated, and the reaction temperature is greatly reduced; amino protection, namely adopting ZnO as Lewis acid to ensure that the reaction in the step is green; through the processes of acylation, deprotection and intramolecular alkylation, compared with the traditional high-temperature reaction, the synthesis route is novel, the reaction temperature is low, the condition is mild and green, no dangerous step is caused, and the method is suitable for industrial production.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention. In the drawings:
FIG. 1 is a chromatogram of 6-carboxamido-7-methoxy-4-chloroquinoline;
figure 2 is a chromatogram of lenvatinib.
Detailed Description
The preferred embodiments of the present invention will be described in conjunction with the accompanying drawings, and it will be understood that they are described herein for the purpose of illustration and explanation and not limitation.
Examples
S1, Synthesis of 4-nitro-2-methoxybenzonitrile (a)
Dissolving 181g of 4-nitro-2-chlorobenzonitrile in 300g of methanol, heating, refluxing and dissolving, dropwise adding 300g of 30% sodium methoxide solution into the system, finishing dropping for 1h, keeping the temperature of the reaction system for reaction for 12h, after the reaction is finished, recovering most of methanol under reduced pressure, pouring residues into ice water, separating out a large amount of yellow solid, filtering, washing a filter cake to be neutral, recrystallizing the filter cake with isopropanol to obtain 147g of yellow solid, wherein the yield is 83%.
Synthesis of S2, 4-cyano-2-methoxyaniline (b)
Taking 17.8g of 4-nitro-2-methoxybenzonitrile, dissolving in 50 ml of ethanol, firstly replacing air in a system with nitrogen for three times, then replacing a reaction system with hydrogen for three times, adding 1.5g of Pd/C, heating the system to 40 ℃, reacting for 4 hours, cooling the system to room temperature after the reaction is finished, removing a hydrogen source, filtering, decompressing and recovering the solvent, adding 100 ml of ice dilute hydrochloric acid (1mol/L), extracting twice with ethyl acetate, adjusting the pH of a water layer to 9-10 with sodium carbonate, separating out a large amount of yellow solid, recrystallizing with isopropanol to obtain light yellow solid powder, and drying in vacuum to obtain 11.3g with the yield of 76%.
S3 Synthesis of N-t-butyloxycarbonyl-4-cyano-3-methoxyaniline (c)
148g of 4-cyano-2-methoxyaniline is added with 400g of di-tert-butoxycarbonyldicarbonate and 5g of ZnO, the mixture reacts for 2 hours at room temperature, after the reaction is finished, the reaction system is filtered to remove the ZnO, the residue is poured into 300 ml of water, 500 ml of ethyl acetate is used for extraction, an organic layer is dried by anhydrous sodium sulfate, the filtration is carried out, the filtrate is decompressed, the solvent is recovered, 246g of white solid powder is obtained, and the yield is 99%.
S4 Synthesis of 4-cyano-3-methoxy-2- (3-chloroacetyl) aniline (d)
Dissolving 124g of N-tert-butyloxycarbonyl-4-cyano-3-methoxyaniline in 350 ml of tetrachloroethylene, cooling the system to 5 ℃ in ice bath, adding 70g of 3-chloropropionyl chloride, keeping the temperature of the system to 5-10 ℃, adding 120g of anhydrous aluminum trichloride in batches, controlling the temperature of the system to be 5-10 ℃, completing the addition within about 30 minutes, slowly heating the system to room temperature after the completion of the addition, continuing to react for 1.5 hours, slowly pouring the reaction system into ice water after the reaction is completed, stirring for 40-60 minutes, adjusting the pH of the system to be neutral by sodium carbonate, extracting by 400ml of ethyl acetate, washing an organic layer for 2 times by water, drying the anhydrous magnesium sulfate, filtering, recovering the solvent from the filtrate under reduced pressure, and recrystallizing methyl tert-ether to obtain 176g of a light yellow solid with the yield of 74%.
Synthesis of S5, 6-cyano-7-methoxytetrahydroquinolin-4-one (e)
Dissolving 119g of 4-cyano-3-methoxy-2- (3-chloroacetyl) aniline in 400ml of acetonitrile, adding 25g of sodium hydroxide, heating, refluxing for reaction for 7 hours, filtering after the reaction is finished, recovering the solvent from the filtrate under reduced pressure, adding 300 ml of ethyl acetate into the system, stirring uniformly, slowly pouring into ice water, separating, washing an organic layer to be neutral, drying with anhydrous magnesium sulfate, filtering, recovering the solvent under reduced pressure, and recrystallizing tert-methyl ether to obtain 92g with the yield of 91%.
Synthesis of S6, 6-cyano-7-methoxy-4-quinolinone (f)
Dissolving 101g of 6-cyano-7-methoxytetrahydroquinoline-4-ketone in 200 ml of ethyl acetate, adding DDQ200g, carrying out reflux reaction overnight on the system, cooling the system to room temperature after the reaction is finished, adding ice dilute hydrochloric acid into the system until the pH is 2-3, stirring for 30 minutes, separating liquid, adjusting the pH of a water layer to 9-10 by using sodium carbonate, precipitating a large amount of yellow solid, and recrystallizing tert-methyl ether to obtain 91g, wherein the yield is 91%.
Synthesis of S7, 6-cyano-7-methoxy-4-chloroquinoline (g)
Taking 100g of 6-cyano-7-methoxy-4-quinolinone, adding 300g of thionyl chloride, heating the system to reflux, reacting for 6 hours, after the reaction is finished, recovering unreacted thionyl chloride under reduced pressure, adding ethyl acetate into the residue, uniformly stirring, slowly pouring the system into ice water, adjusting the pH value of the system to about 9 by sodium carbonate, stirring for 3 hours, separating liquid, washing an organic layer to be neutral, drying anhydrous magnesium sulfate, filtering, recovering a solvent from the filtrate under reduced pressure, and recovering petroleum ether as the residue: recrystallization from ethyl acetate 1:1 gave 101g of a pale yellow solid powder with a yield of 93%.
S8, 6-carboxamido-7-methoxy-4-chloroquinoline (h)
109g of 6-cyano-7-methoxy-4-chloroquinoline is taken, 100g of acetic acid and 100 ml of 3mol/L diluted hydrochloric acid are added, the system is heated to 60 ℃ for reaction for 3 hours, after the reaction is finished, the system is cooled to room temperature, the pH value of the system is 9-10 under the condition of sodium hydroxide, a large amount of yellow solid is separated out, the yellow solid is filtered, a filter cake is washed to be neutral, and isopropanol-methanol-isopropanol are recrystallized for three times to obtain 102g of white solid with the yield of 87%.
S9 Synthesis of Levatinib (i)
Taking 23.6g of 6-formamido-7-methoxy-4-chloroquinoline and 26g of 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropyl urea, dissolving in 100 ml of DMF, adding 100g of sodium ethoxide, heating the system to 90 ℃, reacting for 12h, cooling the system to room temperature after the reaction is finished, slowly pouring the reaction system into 100 ml of water, precipitating a large amount of solid, filtering, washing the filter cake with water, and recrystallizing the filter cake with isopropanol to obtain 32.5g of white solid with the yield of 77%.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (3)

1. The preparation method of lenvatinib is characterized in that the synthetic route is as follows:
Figure FDA0002348141000000011
2. the process for the preparation of lenvatinib of claim 1, wherein the reaction temperature for the synthesis of product b is from 30 ℃ to 50 ℃.
3. The process for the preparation of lenvatinib of claim 1, wherein the amount of aluminum trichloride used for the synthesis of product d is 1.5-2 equivalents.
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Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN112110856A (en) * 2020-10-25 2020-12-22 南京法恩化学有限公司 Preparation method of 4-chloro-7-methoxyquinoline-6-amide
CN112142662A (en) * 2020-10-27 2020-12-29 南京法恩化学有限公司 Preparation method of lervatinib mesylate
CN112654603A (en) * 2018-09-07 2021-04-13 因德纳有限公司 Preparation method of lenvatinib
CN112654603B (en) * 2018-09-07 2024-05-03 意迪那有限公司 Preparation method of lenvatinib

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CN109734661A (en) * 2018-09-10 2019-05-10 江苏工程职业技术学院 A kind of pleasure cuts down the synthetic method for Buddhist nun
CN110627675A (en) * 2019-08-27 2019-12-31 盐城华钛化学有限公司 Preparation process of high-purity 2, 5-dimethoxy-4-chloro-diethylaniline

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112654603A (en) * 2018-09-07 2021-04-13 因德纳有限公司 Preparation method of lenvatinib
CN112654603B (en) * 2018-09-07 2024-05-03 意迪那有限公司 Preparation method of lenvatinib
CN112110856A (en) * 2020-10-25 2020-12-22 南京法恩化学有限公司 Preparation method of 4-chloro-7-methoxyquinoline-6-amide
CN112110856B (en) * 2020-10-25 2022-09-06 南京法恩化学有限公司 Preparation method of 4-chloro-7-methoxyquinoline-6-amide
CN112142662A (en) * 2020-10-27 2020-12-29 南京法恩化学有限公司 Preparation method of lervatinib mesylate
CN112142662B (en) * 2020-10-27 2022-03-08 南京法恩化学有限公司 Preparation method of lervatinib mesylate

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Application publication date: 20200410