CN110903240A - Preparation method of broad-spectrum anticancer drug cabozantinib - Google Patents
Preparation method of broad-spectrum anticancer drug cabozantinib Download PDFInfo
- Publication number
- CN110903240A CN110903240A CN201911274743.7A CN201911274743A CN110903240A CN 110903240 A CN110903240 A CN 110903240A CN 201911274743 A CN201911274743 A CN 201911274743A CN 110903240 A CN110903240 A CN 110903240A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- dichloromethane
- cabozantinib
- formula iii
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention belongs to the technical field of synthesis methods of organic compounds, and particularly relates to a preparation method of a broad-spectrum anticancer drug cabozantinib. A preparation method of a broad-spectrum anticancer drug cabozantinib comprises the following steps: the method comprises the following steps: hydrolyzing an ester group of the compound shown in the formula II to obtain a compound shown in the formula III, and condensing the compound shown in the formula III and substituted quinoline to obtain the cabozantinib. The preparation method is simple, convenient and fast to operate, mild in reaction conditions, good in intermediate stability, not easy to generate side reaction, simple in product separation and purification, high in yield and good in purity of the prepared cabozantinib, and very suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of synthesis methods of organic compounds, and particularly relates to a preparation method of a broad-spectrum anticancer drug cabozantinib.
Background
Cabozantinib (Cabozantinib), the chemical name of which is N- [4- [6, 7-dimethoxy-4-quinolyl ] oxy ] phenyl ] -N- (4-fluorophenyl) -1, 1-cyclopropane dicarboxamide, wherein Cabozantinib malate is a tyrosine kinase inhibitor developed by Exelixis pharmaceutical company in the united states, is marketed in the united states in 2012, and is clinically mainly used for treating the thyroid medullary carcinoma in the advanced stage and the metastasis. Meanwhile, the medicine is also a multi-target inhibitor, compared with other targeted medicines, the targeted target is more, and the targeted target mainly comprises MET, VEGFR1/2/3, ROS1, RET, AXL, NTRK and KIT. Therefore, cabozantinib has applications in a variety of solid tumors, such as liver cancer, soft tissue sarcoma, non-small cell lung cancer, prostate cancer, breast cancer, ovarian cancer, intestinal cancer, etc., in addition to approved indications (medullary thyroid cancer and advanced renal cancer).
Since the cabozantinib anticancer drug shows significant clinical efficacy and better safety to various solid tumors, research on preparation methods of cabozantinib is also increasing. The preparation routes can be mainly classified into three types:
1) 1, 1-cyclopropyl dicarboxylic acid and 6, 7-dimethoxy-4-hydroxyquinoline are used as starting raw materials, wherein two carboxyl groups of the 1, 1-cyclopropyl dicarboxylic acid are subjected to condensation reaction with 4-fluoroaniline and 4-hydroxyaniline successively to obtain an amide product, 6, 7-dimethoxy-4-hydroxyquinoline and trifluoromethanesulfonyl chloride are subjected to esterification reaction to obtain an esterification product, and finally, the esterification product and the amide product are reacted at a high temperature of 165 ℃ to obtain cabozantinib (WO 2005030140).
2)1, 1-cyclopropyl dicarboxylic acid is used as a starting material and is subjected to acyl chlorination and then condensed with 4-fluoroaniline to obtain 1- (4-fluoroaniline carbonyl) cyclopropyl-1-carboxylic acid, and then oxalyl chloride acylation is carried out to obtain an acyl chloride intermediate which is subjected to condensation reaction with 4- [ (6, 7-dimethoxy-4-quinoline) oxy ] aniline to obtain cabozantinib (CN 201080012656.5).
3) The method also uses 1, 1-cyclopropyl dicarboxylic acid as a starting material, but the condensation sequence and the method are slightly different from the method reported in the document CN201080012656.5, and the cabozantinib (CN107353246A) is prepared by the steps that the starting material dicarboxylic acid is firstly reacted with 4- [ (6, 7-dimethoxy-4-quinoline) oxy ] aniline after being subjected to acyl chlorination and then is subjected to condensation reaction with 4-fluoroaniline.
Although the three methods can prepare the cabozantinib target product, the synthetic technology has some defects: (1) in the three methods, 1-cyclopropyl dicarboxylic acid is directly used as an initial raw material to carry out condensation reaction, and side reactions are more. (2) All the reagents need to be used with corrosive chlorination reagents such as thionyl chloride and oxalyl chloride, and therefore, the method has the disadvantages of great environmental pollution and high equipment requirement. (3) The method reported in patent WO2005030140 involves high temperature reactions, not only increasing side reactions but also increasing energy consumption. The defects do not meet the environmental-friendly production standard required by the state at present, and are not beneficial to the large-scale preparation of products.
Disclosure of Invention
In order to solve the above problems, the first aspect of the present invention provides a method for preparing a broad spectrum anticancer drug cabozantinib, comprising the steps of: hydrolyzing an ester group of the compound shown in the formula II to obtain a compound shown in the formula III, and condensing the compound shown in the formula III and substituted quinoline to obtain cabozantinib;
formula II:
wherein R is C1-C10 alkyl;
formula III:
as a preferred technical scheme, the substituted quinoline is 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline.
As a preferable technical scheme, the compound shown in the formula III is condensed with 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline in the presence of a condensing agent and an acid-binding agent.
As a preferred technical scheme, the compound of the formula II is formed by condensing a compound of the formula I and para-fluoroaniline;
formula I:
wherein R is C1-C10 alkyl.
As a preferred technical scheme, the compound of the formula I and the para-fluoroaniline are condensed in the presence of a condensing agent and an acid-binding agent.
In a preferred embodiment, the condensing agent is selected from one of HATU, HBTU, HCTU, TBTU, DCC, DIC, EDC, EDCI.
As a preferable technical scheme, the acid-binding agent is an inorganic base and/or an organic base.
As a preferable technical scheme, the condensation reaction temperature of the compound shown in the formula III and 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is-10 ℃ to 50 ℃.
As a preferable technical scheme, the molar ratio of the compound shown in the formula III to the 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is 1 (1-5).
As a preferable technical scheme, the molar ratio of the compound shown in the formula III to the condensing agent is 1 (1-3); the molar ratio of the compound shown in the formula III to the acid-binding agent is 1 (1-3).
Has the advantages that: the preparation method of the broad-spectrum anticancer drug cabozinib provided by the invention is simple, convenient to operate, mild in reaction condition, good in intermediate stability, not easy to generate side reaction, simple in product separation and purification, high in yield and good in purity of the prepared cabozinib, and very suitable for industrial production.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1: a hydrogen spectrum of cabozantinib;
FIG. 2: (ii) a liquid phase spectrum of cabozantinib;
FIG. 3: a mass spectrum of cabozantinib.
Detailed Description
The technical features of the technical solutions provided by the present invention are further clearly and completely described below with reference to the specific embodiments, and the scope of protection is not limited thereto.
The words "preferred", "more preferred", and the like, in the present invention refer to embodiments of the invention that may provide certain benefits, under certain circumstances. However, other embodiments may be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range from "1 to 10" should be considered to include any and all subranges between the minimum value of 1 and the maximum value of 10. Exemplary subranges of the range 1 to 10 include, but are not limited to, 1 to 6.1, 3.5 to 7.8, 5.5 to 10, and the like.
In order to solve the above problems, the first aspect of the present invention provides a method for preparing a broad spectrum anticancer drug cabozantinib, comprising the steps of: hydrolyzing an ester group of the compound shown in the formula II to obtain a compound shown in the formula III, and condensing the compound shown in the formula III and substituted quinoline to obtain cabozantinib;
formula II:
wherein R is C1-C10 alkyl;
formula III:
preferably, the substituted quinoline is 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline.
Examples of the alkyl group in which R is C1 to C10 include C1 to C10 linear, branched or cyclic unsubstituted alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl and the like.
More preferably, R is methyl.
In a specific embodiment, the applicant found that R is different, the product yield and purity are different, and therefore, according to the preparation method of the present invention, it is possible to prepare cabozantinib compound with high yield and purity, which can facilitate the preparation process, so that, when R is methyl, the method can achieve very high yield (91%) and very high purity (99.2%) of the cabozantinib compound.
Preferably, the compound of the formula III is condensed with 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline in the presence of a condensing agent and an acid-binding agent.
The reaction equation is:
preferably, the condensing agent is selected from any one of HATU, HBTU, HCTU, TBTU, DCC, DIC, EDC, EDCI; more preferably, the condensing agent is EDC.
Preferably, the acid scavenger is an inorganic base and/or an organic base.
Examples of inorganic bases that can act as acid scavengers include, but are not limited to: sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, silver carbonate; alkali metal sodium and potassium; and mixtures thereof.
Examples of organic bases that can act as acid scavengers include, but are not limited to: tertiary amines such as trimethylamine, triethylamine and N, N-diisopropylethylamine, N-dimethylaniline, and pyridines which may be substituted with lower alkyl groups such as hydrogen, methyl and ethyl, such as 2-methyl-5 ethylpyridine and pyridine.
More preferably, the acid-binding agent is triethylamine or N, N-diisopropylethylamine.
By selecting proper condensing agent and acid-binding agent and controlling the amount of the condensing agent and the acid-binding agent and the reaction substances, less by-products generated in the reaction process can be ensured, so that the product purity is high.
Preferably, the condensation reaction temperature of the compound shown in the formula III and 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is-10 ℃ to 50 ℃; more preferably, the condensation reaction temperature of the compound of the formula III and 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is 0-30 ℃.
Preferably, the molar ratio of the compound shown in the formula III to the 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is 1 (1-5); more preferably, the molar ratio of the compound shown in the formula III to the 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is 1 (1-2); most preferably, the molar ratio of the compound of formula III to 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is 1 (1-1.5).
Preferably, the molar ratio of the compound of the formula III to the condensing agent is 1 (1-3); the molar ratio of the compound shown in the formula II to the acid-binding agent is 1 (1-3); more preferably, the molar ratio of the compound of formula III to the condensing agent is 1 (1.2-2); the molar ratio of the compound shown in the formula II to the acid-binding agent is 1 (1.3-2.5).
Preferably, the solvent for the reaction of the compound of formula III with 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is selected from N, N-dimethylformamide, diethyl carbonate, dimethyl carbonate, propylene carbonate, ethylene carbonate, ethyl methyl carbonate, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, toluene, xylene, chlorobenzene, dichlorobenzene, trichlorobenzene, tetrachlorobenzene, methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, N-butyl acetate, acetonitrile, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, acetone, diethyl ether, isopropyl ether, butyl ether, anisole, diphenyl ether, 1, 4-dioxane, dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, 1, 1-trichloroethane, 1,2, 2-tetrachloroethane, 1,2, 2-tetrachloroethylene and gamma-butyrolactone.
More preferably, the reaction solvent of the compound of formula III and 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is one or more selected from dichloromethane, chloroform, ethyl acetate, tetrahydrofuran and N, N-dimethylformamide. The amount of the solvent used is not particularly limited.
Preferably, the ester group of the compound of formula II is hydrolyzed to give the compound of formula III.
The compound shown in the formula III is also called 1- (4-fluorophenyl carbamoyl) cyclopropane carboxylic acid.
The reaction equation is:
preferably, the compound of formula II is hydrolyzed in the presence of a base to provide a compound of formula III.
Preferably, the molar ratio of the compound of the formula II to the base is 1 (2-10).
The alkali can be inorganic alkali or organic alkali, and is preferably inorganic alkali with the mass percentage of 30%; examples of the inorganic base include any one of sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, lithium hydroxide; examples of the reaction solvent include aromatic hydrocarbon solvents such as toluene, xylene and mesitylene; aliphatic hydrocarbon solvents such as decane; halogenated aromatic hydrocarbon solvents such as monochlorobenzene; and halogenated aliphatic hydrocarbon solvents such as tetrachloroethane. The amount of the solvent used is not particularly limited.
Preferably, the compound of the formula II is formed by condensing a compound of the formula I and para-fluoroaniline;
formula I:
wherein R is C1-C10 alkyl.
More preferably, R is methyl.
Preferably, the compound of formula I and the para-fluoroaniline are condensed in the presence of a condensing agent and an acid-binding agent.
The reaction equation is:
preferably, the condensing agent and the acid-binding agent used in the condensation reaction of the compound shown in the formula I and the para-fluoroaniline are the same as the condensing agent and the acid-binding agent used in the condensation reaction of the compound shown in the formula III and 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline.
The applicant finds that when the condensing agent and the acid-binding agent adopted in the condensation reaction of the compound shown in the formula I and the para-fluoroaniline are different from those adopted in the condensation reaction of the compound shown in the formula III and the 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline, more by-products are generated in the reaction process, and the purity of the product is influenced.
Preferably, the reaction temperature for the condensation of the compound of the formula I and the para-fluoroaniline is-10 ℃ to 50 ℃; more preferably, the condensation of the compound of formula I and para-fluoroaniline is carried out at a temperature of from 0 ℃ to 30 ℃.
Preferably, the molar ratio of the compound of the formula I to the para-fluoroaniline is 1 (1-5); more preferably, the molar ratio of the compound of formula I to the para-fluoroaniline is 1 (1-2); most preferably, the molar ratio of the compound of formula I to para-fluoroaniline is 1 (1-1.5).
Preferably, the molar ratio of the compound of formula I to the condensing agent is 1 (1-3); the molar ratio of the compound shown in the formula I to the acid-binding agent is 1 (1-3); more preferably, the molar ratio of the compound of formula I to the condensing agent is 1 (1.2-2); the molar ratio of the compound shown in the formula I to the acid-binding agent is 1 (1.3-2.5).
Preferably, the reaction solvent of the compound of formula I and para-fluoroaniline is selected from N, N-dimethylformamide, diethyl carbonate, dimethyl carbonate, propylene carbonate, ethylene carbonate, ethyl methyl carbonate, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, toluene, xylene, chlorobenzene, dichlorobenzene, trichlorobenzene, tetrachlorobenzene, methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, N-butyl acetate, acetonitrile, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, acetone, diethyl ether, isopropyl ether, butyl ether, anisole, diphenyl ether, 1, 4-dioxane, dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, 1,1, 1-trichloroethane, 1,1, 2-trichloroethane, 1,1,2, 2-tetrachloroethane, 1,2, 2-tetrachloroethylene and gamma-butyrolactone.
More preferably, the reaction solvent of the compound of the formula I and the para-fluoroaniline is one or more selected from dichloromethane, chloroform, ethyl acetate, tetrahydrofuran and N, N-dimethylformamide. The amount of the solvent used is not particularly limited.
The present invention will now be described in detail by way of examples, and the starting materials used are commercially available unless otherwise specified.
Examples
Example 1
(1) In a 2000L reactor, 350kg of dichloromethane, 42kg of 1, 1-cyclopropyldicarboxylic acid monomethyl ester (MW: 144.13, 291.4mol, 1eq) and 74kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC hydrochloride, MW: 191.7, 386.0mol, 1.3eq) and 45kg of triethylamine (MW: 101.19, 444.7mol, 1.5eq) were added, stirred at room temperature for 2h, then a solution of 4-fluoroaniline (MW: 111.12, 297.0mol, 1.02eq) in dichloromethane (33kg in 100kg of dichloromethane) was added dropwise, after addition, the reaction was carried out at room temperature for 4h, 50kg of 2N hydrochloric acid was washed, the organic phase was transferred to a 1000L reactor, and dichloromethane was recovered by distillation to give a residue (ready for use).
(2) The residue was dissolved in 400kg of methanol, and 70kg of 30% sodium hydroxide solution (NaOH,875.0mol,3eq) was added dropwise, the mixture was refluxed for 2 hours, cooled, 45kg of concentrated hydrochloric acid was slowly added dropwise, and the solid was precipitated and centrifuged to obtain 56.0kg of intermediate 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (intermediate for short) with a yield of 86% and a purity of 98.5%, 1HNMR (400MHz, DMSO):1.38(2H, m), 1.45(2H, m), 7.06(2H, m), 7.58(2H, m), 10.50(1H, s), and 13.08(1H, s).
(3) In a 1000L reaction kettle, 250kg of dichloromethane and DMF13kg are added, 28kg of intermediate (MW:223.2,125.4mol,1eq), 26kg of EDC hydrochloride (0.135.6mol,1.08eq) and 16kg of triethylamine (158.1mol,1.2eq) are added, 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline (substituted quinoline for short, MW:296.33,128.2mol,1.02eq) in dichloromethane solution (38kg is dissolved in 250kg of dichloromethane) is added dropwise under stirring at room temperature, after the reaction is finished, 46kg of 2N hydrochloric acid is washed, an organic layer is concentrated and dichloromethane is recovered, residual ethanol and water are recrystallized, and centrifugal filtration is carried out to obtain 57kg of cabozantinib free base, the yield is 91%, and the purity is 98.8%. 1HNMR (400MHz, DMSO):1.70(4H, d), 4.05(6H, d), 6.46(1H, s), 7.05(2H, m), 7.16(2H, m), 7.43(3H, m), 7.55(1H, m), 7.63(2H, m), 8.48(1H, m), 8.82(1H, s), 9.43(1H, s).
Example 2
(1) 35kg of dichloromethane, 4.2kg of monomethyl 1, 1-cyclopropyldicarboxylate and 7.4kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 5.6kg of N, N-diisopropylethylamine were added to a 100L reaction vessel, the mixture was stirred at room temperature for 2 hours to 4 hours, a dichloromethane solution of 4-fluoroaniline (3.4kg dissolved in 10kg of dichloromethane) was added dropwise thereto, the mixture was reacted at room temperature for 4 hours to 6 hours, 5kg of 2N hydrochloric acid was washed, the organic phase was transferred to a 100L reaction vessel, and dichloromethane was recovered by distillation to obtain a residue (to be used).
(2) And adding 40kg of methanol into the residue to dissolve, dropwise adding 7.5kg of 30% sodium hydroxide solution, refluxing for 2-4 h, cooling, slowly dropwise adding 5kg of concentrated hydrochloric acid, separating out solid, and performing centrifugal filtration to obtain 5.4kg of intermediate 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (intermediate for short), wherein the yield is 83% and the purity is 98.9%.
(3) In a 100L reaction vessel, 25kg of dichloromethane and 1.3kg of DMF1 were charged, 2.8kg of intermediate, 2.65kg of EDC hydrochloride and 2.5kg of N, N-diisopropylethylamine were added, and a dichloromethane solution of 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline (3.9kg dissolved in 25kg of dichloromethane) was added dropwise under stirring at room temperature, after completion of the reaction, 4.7kg of 2N hydrochloric acid was washed, the organic layer was concentrated to recover dichloromethane, and the residue was recrystallized from ethanol and water, and subjected to centrifugal filtration to obtain 5.5kg of cabozantinib free base with a yield of 88% and a purity of 99.2%.
Example 3
(1) 35kg of dichloromethane, 4.2kg of monomethyl 1, 1-cyclopropyldicarboxylate and 7.4kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 5.6kg of N, N-diisopropylethylamine were added to a 100L reaction vessel, a dichloromethane solution of 4-fluoroaniline (3.4kg dissolved in 10kg of dichloromethane) was added dropwise after stirring at 10 ℃ for 2h to 4h, after the addition, the reaction was carried out at 10 ℃ for 4 to 6h, 5kg of 2N hydrochloric acid was washed, the organic phase was transferred to a 100L reaction vessel, and dichloromethane was recovered by distillation to obtain a residue (to be used).
(2) And adding 40kg of methanol to the residue to dissolve, dropwise adding 7.5kg of 30% sodium hydroxide solution, refluxing for 2-4 h, cooling, slowly dropwise adding 5kg of concentrated hydrochloric acid, separating out a solid, and performing centrifugal filtration to obtain 4.3kg of an intermediate 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (an intermediate for short), wherein the yield is 71% and the purity is 97.5%.
(3) In a 100L reaction vessel, 25kg of dichloromethane and 1.3kg of DMF1 were charged, 2.8kg of intermediate, 2.65kg of EDC hydrochloride and 2.5kg of N, N-diisopropylethylamine were added, and a dichloromethane solution of 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline (3.9kg dissolved in 25kg of dichloromethane) was added dropwise under stirring at 10 ℃ to complete the reaction, 4.7kg of 2N hydrochloric acid was washed, the organic layer was concentrated to recover dichloromethane, and the residue was recrystallized from ethanol and water, and subjected to centrifugal filtration to obtain 4.1kg of cabozantinib free base with a yield of 68% and a purity of 98.2%.
Example 4
(1) 350kg of dichloromethane, 42kg of 1, 1-cyclopropyl dimethyl dicarboxylate monomethyl ester, 85kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC hydrochloride) and 55kg of triethylamine are added into a 2000L reaction kettle, stirred at room temperature for 2 hours, then dropwise added with a dichloromethane solution of 4-fluoroaniline (34kg of the dichloromethane solution is dissolved in 100kg of dichloromethane), reacted at room temperature for 4 hours after the addition is finished, 50kg of 2N hydrochloric acid is washed, an organic phase is transferred to a 1000L reaction kettle, and dichloromethane is distilled and recovered to obtain a residue (for later use).
(2) And adding 400kg of methanol to the residue to dissolve the residue, dropwise adding 70kg of 30% sodium hydroxide solution, refluxing for 2h, cooling, slowly dropwise adding 45kg of concentrated hydrochloric acid, separating out solid, and centrifugally filtering to obtain 48.9kg of intermediate 1- (4-fluorophenyl carbamoyl) cyclopropanecarboxylic acid (intermediate for short), wherein the yield is 75% and the purity is 98.3%.
(3) In a 1000L reaction vessel, 250kg of dichloromethane and DMF13kg were added, 28kg of intermediate (MW:223.2,125.4mol,1eq), 35kg of EDC hydrochloride and 21kg of triethylamine were added, and a dichloromethane solution of 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline (38kg dissolved in 250kg of dichloromethane) was added dropwise with stirring at room temperature, after the reaction was completed, 46kg of 2N hydrochloric acid was washed, the organic layer was concentrated to recover dichloromethane, and the residue was recrystallized from ethanol and water, and was subjected to centrifugal filtration to obtain 50kg of cabozantinib free base, yield 80%, purity 98.7%.
Example 5
(1) 35kg of dichloromethane, 4.6kg of 1, 1-cyclopropyl dicarboxylic acid monoethyl ester and 7.5kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 5.6kg of N, N-diisopropylethylamine are added into a 100L reaction kettle, stirred at room temperature for 2h-4h, then a dichloromethane solution of 4-fluoroaniline (3.3kg of the dichloromethane is dissolved in 10kg of dichloromethane) is dropwise added, after the addition is finished, the reaction is carried out at room temperature for 4-6 h, 5kg of 2N hydrochloric acid is washed, an organic phase is transferred to the 100L reaction kettle, and dichloromethane is distilled and recovered to obtain a residue (for later use).
(2) And adding 40kg of methanol to the residue to dissolve the residue, dropwise adding 7.6kg of 30% sodium hydroxide solution, refluxing for 2-4 h, cooling, slowly dropwise adding 5kg of concentrated hydrochloric acid, separating out solid, and performing centrifugal filtration to obtain 5.1kg of intermediate 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (intermediate for short), wherein the yield is 78% and the purity is 98.3%.
(3) In a 100L reaction vessel, 25kg of dichloromethane and 1.3kg of DMF1 were charged, 2.8kg of intermediate, 2.7kg of EDC hydrochloride and 2.4kg of N, N-diisopropylethylamine were added, and a dichloromethane solution of 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline (3.9kg dissolved in 25kg of dichloromethane) was added dropwise under stirring at room temperature, after completion of the reaction, 5kg of 2N hydrochloric acid was washed, the organic layer was concentrated to recover dichloromethane, and the residue was recrystallized from ethanol and water, and was subjected to centrifugal filtration to obtain 5.0kg of cabozantinib free base, yield 80%, and purity 98.7%.
Example 6
(1) 35kg of dichloromethane, 3.8kg of 1, 1-cyclopropyldicarboxylic acid and 7.4kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 5.6kg of N, N-diisopropylethylamine were added to a 100L reaction kettle, stirred at room temperature for 2h to 4h, then a dichloromethane solution of 4-fluoroaniline (3.4kg dissolved in 10kg of dichloromethane) was added dropwise, after the addition, the reaction was carried out at room temperature for 4 to 6h, 5kg of 2N hydrochloric acid was washed, the organic phase was transferred to a 100L reaction kettle, and dichloromethane was recovered by distillation to obtain a residue (to be used).
(2) And adding 40kg of methanol to the residue to dissolve, dropwise adding 7.5kg of 30% sodium hydroxide solution, refluxing for 2-4 h, cooling, slowly dropwise adding 5kg of concentrated hydrochloric acid, separating out a solid, and performing centrifugal filtration to obtain 3.7kg of an intermediate 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (an intermediate for short), wherein the yield is 57% and the purity is 96.5%.
(2) In a 100L reaction vessel, 25kg of dichloromethane and 2.8kg of intermediate, 2.63kg of EDC hydrochloride and 2.5kg of N, N-diisopropylethylamine were added, and a dichloromethane solution of 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline (3.9kg dissolved in 25kg of dichloromethane) was added dropwise under stirring at room temperature, after completion of the reaction, 4.8kg of 2N hydrochloric acid was washed, the organic layer was concentrated to recover dichloromethane, and the residue was recrystallized from ethanol and water, and subjected to centrifugal filtration to obtain 5.4kg of cabozantinib free base with a yield of 86% and a purity of 97.6%.
Example 7
(1) 35kg of dichloromethane, 4.2kg of monomethyl 1, 1-cyclopropyldicarboxylate and 7.4kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 5.6kg of N, N-diisopropylethylamine were added to a 100L reaction vessel, the mixture was stirred at room temperature for 2 hours to 4 hours, a dichloromethane solution of 4-fluoroaniline (3.4kg dissolved in 10kg of dichloromethane) was added dropwise thereto, the mixture was reacted at room temperature for 4 hours to 6 hours, 5kg of 2N hydrochloric acid was washed, the organic phase was transferred to a 100L reaction vessel, and dichloromethane was recovered by distillation to obtain a residue (to be used).
(2) And adding 40kg of methanol into the residue to dissolve, dropwise adding 7.5kg of 30% sodium hydroxide solution, refluxing for 2-4 h, cooling, slowly dropwise adding 5kg of concentrated hydrochloric acid, separating out solid, and performing centrifugal filtration to obtain 5.4kg of intermediate 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (intermediate for short), wherein the yield is 83% and the purity is 98.9%.
(2) In a 100L reaction vessel, 25kg of dichloromethane and 2.8kg of intermediate, 3.36kg of DCC, 0.16kg of DMAP0.6 kg of N, N-diisopropylethylamine and 2.6kg of 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline in dichloromethane were added under stirring at room temperature (3.9kg of dichloromethane dissolved in 25kg of dichloromethane), after the reaction was completed, 4.7kg of 2N hydrochloric acid was washed, the organic layer was concentrated to recover dichloromethane, the residue was recrystallized from ethanol and water, and the mixture was centrifuged to obtain 4.4kg of cabozantinib free base with a yield of 70% and a purity of 95.2%.
Example 8
(1) 35kg of dichloromethane, 4.2kg of monomethyl 1, 1-cyclopropyldicarboxylate and 22.7kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 15kg of N, N-diisopropylethylamine were added to a 100L reaction vessel, stirred at room temperature for 2h to 4h, then a dichloromethane solution of 4-fluoroaniline (3.4kg dissolved in 10kg of dichloromethane) was added dropwise, after the addition, the reaction was carried out at room temperature for 4 to 6h, 5kg of 2N hydrochloric acid was washed, the organic phase was transferred to a 100L reaction vessel, and dichloromethane was recovered by distillation to obtain a residue (to be used).
(2) And adding 40kg of methanol to the residue to dissolve, dropwise adding 7.5kg of 30% sodium hydroxide solution, refluxing for 2-4 h, cooling, slowly dropwise adding 5kg of concentrated hydrochloric acid, separating out a solid, and performing centrifugal filtration to obtain 4.0kg of an intermediate 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (an intermediate for short), wherein the yield is 61% and the purity is 96.2%.
(3) In a 100L reaction vessel, 25kg of dichloromethane and 1.3kg of DMF1 were charged, 2.8kg of intermediate, 2.65kg of EDC hydrochloride and 2.5kg of N, N-diisopropylethylamine were added, and a dichloromethane solution of 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline (3.9kg dissolved in 25kg of dichloromethane) was added dropwise under stirring at room temperature, after completion of the reaction, 4.7kg of 2N hydrochloric acid was washed, the organic layer was concentrated to recover dichloromethane, and the residue was recrystallized from ethanol and water, and subjected to centrifugal filtration to obtain 5.1kg of cabozantinib free base with a yield of 81.6% and a purity of 97.3%.
Claims (10)
1. A preparation method of a broad-spectrum anticancer drug cabozantinib is characterized by comprising the following steps: hydrolyzing an ester group of the compound shown in the formula II to obtain a compound shown in the formula III, and condensing the compound shown in the formula III and substituted quinoline to obtain cabozantinib;
formula II:
wherein R is C1-C10 alkyl;
formula III:
2. the method of claim 1, wherein the substituted quinoline is 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline.
3. The process of claim 2, wherein the compound of formula iii is condensed with 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline in the presence of a condensing agent and an acid scavenger.
4. The process according to claim 3, wherein the compound of formula II is prepared by condensing a compound of formula I with para-fluoroaniline;
formula I:
wherein R is C1-C10 alkyl.
5. The process according to claim 4, wherein the compound of formula I and para-fluoroaniline are condensed in the presence of a condensing agent and an acid-binding agent.
6. The method according to claim 5, wherein the condensing agent is selected from any one of HATU, HBTU, HCTU, TBTU, DCC, DIC, EDC and EDCI.
7. The preparation method according to claim 5, wherein the acid scavenger is an inorganic base and/or an organic base.
8. The process according to any one of claims 2 to 7, wherein the condensation of the compound of formula III with 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is carried out at a temperature of from-10 ℃ to 50 ℃.
9. The process according to any one of claims 2 to 7, wherein the molar ratio of the compound of formula III to 4- (4-aminophenoxy) -6, 7-dimethoxyquinoline is 1 (1-5).
10. The method according to any one of claims 2 to 7, wherein the molar ratio of the compound of formula III to the condensing agent is 1 (1 to 3); the molar ratio of the compound shown in the formula II to the acid-binding agent is 1 (1-3).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911274743.7A CN110903240A (en) | 2019-12-12 | 2019-12-12 | Preparation method of broad-spectrum anticancer drug cabozantinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911274743.7A CN110903240A (en) | 2019-12-12 | 2019-12-12 | Preparation method of broad-spectrum anticancer drug cabozantinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110903240A true CN110903240A (en) | 2020-03-24 |
Family
ID=69824945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911274743.7A Pending CN110903240A (en) | 2019-12-12 | 2019-12-12 | Preparation method of broad-spectrum anticancer drug cabozantinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110903240A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023222946A1 (en) * | 2022-05-18 | 2023-11-23 | Fermion Oy | Process for the preparation of cabozantinib |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664776A (en) * | 2012-09-26 | 2014-03-26 | 正大天晴药业集团股份有限公司 | Preparation method for tyrosine kinase inhibitor and midbody thereof |
| CN106715397A (en) * | 2014-07-31 | 2017-05-24 | 埃克塞里艾克西斯公司 | Method of preparing fluorine-18 labeled cabozantinib and its analogs |
| CN109836382A (en) * | 2017-11-29 | 2019-06-04 | 江苏豪森药业集团有限公司 | The rich preparation method for replacing Buddhist nun and its intermediate of malic acid card |
| CN109988108A (en) * | 2017-12-29 | 2019-07-09 | 江苏豪森药业集团有限公司 | A kind of rich preparation method for Buddhist nun of card |
-
2019
- 2019-12-12 CN CN201911274743.7A patent/CN110903240A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664776A (en) * | 2012-09-26 | 2014-03-26 | 正大天晴药业集团股份有限公司 | Preparation method for tyrosine kinase inhibitor and midbody thereof |
| CN106715397A (en) * | 2014-07-31 | 2017-05-24 | 埃克塞里艾克西斯公司 | Method of preparing fluorine-18 labeled cabozantinib and its analogs |
| CN109836382A (en) * | 2017-11-29 | 2019-06-04 | 江苏豪森药业集团有限公司 | The rich preparation method for replacing Buddhist nun and its intermediate of malic acid card |
| CN109988108A (en) * | 2017-12-29 | 2019-07-09 | 江苏豪森药业集团有限公司 | A kind of rich preparation method for Buddhist nun of card |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023222946A1 (en) * | 2022-05-18 | 2023-11-23 | Fermion Oy | Process for the preparation of cabozantinib |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2796238C (en) | Process for the preparation of 4-{4-[({[4-chloro-3-trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-n-methylpyridine-2-carboxamide, its salts and monoydyrate | |
| JP4889737B2 (en) | Production of N-substituted isothiazolinone derivatives | |
| CA2775229C (en) | Process for the preparation of sorafenib tosylate | |
| CN106279104B (en) | A kind of process modification method preparing amber love song Ge Lieting | |
| CN104530040A (en) | Novel method for synthesizing 1,2,3-thiadiazole-5-formamidine compound | |
| JP2006232802A (en) | Method for producing (z)-1-phenyl-1-(n,n-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane | |
| CN110903240A (en) | Preparation method of broad-spectrum anticancer drug cabozantinib | |
| CN105051031B (en) | The preparation method of the amine of 1 (ylmethyl of [1,3] dioxolanes 4) 1H pyrazoles 3 | |
| TW200305559A (en) | Process for trans-4-amino-1-cyclohexane carboxylic acid derivatives | |
| CN113416150B (en) | Synthetic method of lobaplatin intermediate | |
| CN105330600A (en) | Preparation method for Regorafenib hydrate | |
| TWI688558B (en) | Method for preparing subtomin (Azoxystyrin) | |
| CN113072436A (en) | Preparation method of benzyl aryl ether | |
| CN110283082A (en) | A kind of preparation method of 3- phenylpropylamine | |
| CN108026017B (en) | Method for producing acid halide solution, mixed solution, and method for producing monoester compound | |
| TWI728077B (en) | Preparation method of deuterated imidazole dione compound | |
| CN108191849B (en) | Preparation method of anti-epidermal growth factor receptor drug resistance mutation inhibitor, related intermediate and application | |
| CN105399668B (en) | A kind of method that " one kettle way " prepares Sorafenib | |
| JP2018090551A (en) | L-carnosine derivative or salt thereof, and process for producing l-carnosine or salt thereof | |
| CN113698375A (en) | Synthesis method of 4-cyclohexylimine methyl substituted benzofuran derivative | |
| Sarrafi et al. | Microwave-assisted chemoselective copper-catalyzed amination of o-chloro and o-bromobenzoic acids using aromatic amines under solvent free conditions | |
| CN112979544A (en) | Preparation method of cabozantinib or salt thereof | |
| CN113336703A (en) | Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives | |
| CN107325078B (en) | Preparation method of cilostazol | |
| CN106831606B (en) | A kind of preparation method of 5- trifluoromethyl -5,6- dihydrouracil |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200324 |
|
| RJ01 | Rejection of invention patent application after publication |