CN109836382B - Preparation method of cabozantinib malate and intermediate thereof - Google Patents
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Abstract
The invention relates to a preparation method of cabozantinib malate and an intermediate thereof, which is characterized in that 4-chloro-6, 7-dimethoxy quinoline (I) is used as a starting material A, and N- (4- { [6, 7-bis (methoxy) quinoline-4-yl ] oxy } phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-diacid amide malate (cabozantinib malate) is obtained through substitution, condensation and salification. Compared with other cabozantinib malate synthesis methods, the synthesis method disclosed by the invention has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, high overall yield and high product purity, avoids high-temperature production, reduces risks, simplifies operation and is more beneficial to industrial production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a synthesis method of cabozantinib malate and an intermediate thereof.
Background
Cabozantinib malate (cabozantinib(s) -malate), chemical name: n- (4- { [6, 7-bis (methoxy) quinolin-4-yl]Oxy } phenyl) -N1- (4-fluorophenyl) cyclopropane-1, 1-diacid amide malate which is a multi-receptor tyrosine kinase inhibitor (tyrosine kinases inhibitor) targets RET, MET, VEGFR-1, -2, -3, KIT, TRKB, FLT-3, AXL, TIE-2 and the like. Tyrosine kinase plays an important role in the process of generating and developing tumors, and the research and development of drugs by taking tyrosine kinase as a target point become a hot spot of the research of antitumor drugs internationally. The tyrosinase inhibitor realizes the anti-tumor effect by inhibiting the damage repair of tumor cells, blocking cell division in a G1 stage, inducing and maintaining apoptosis, resisting neovascularization and other multiple ways; it has wide anticancer spectrum and has become the first-line medicine for treating various kinds of cancer.
The cabozantinib malate has no chiral center, and the structural formula is as follows:
there are many synthesis methods of cabozantinib malate reported in literature, and they can be classified into three types according to the difference of final condensation intermediates:
statistical table of cabozantinib malate synthesis method
Synthetic route 1[1]：
Patent WO2005030140[1]Is a compound patent synthesis method reported by the original research company. The method is to prepare cabozantinib by condensation after preparing 3 and 5 separately in two routes. One route is to prepare 3 by using cyclopropane-1, 1-dicarboxylic acid as a raw material through condensation and substitution. The other route is to prepare 5 by taking 1- (3, 4-dimethoxyphenyl) ethanone as a raw material and carrying out nitration, reduction, cyclization and substitution.
The method has high condensation reaction temperature and low yield, and is not suitable for industrial production.
Synthetic route two[2]：
Patent CN103459373A[2]Is a preparation patent of original research company. The method is to prepare cabozantinib by condensation after preparing 3 and 6 separately in two routes. One route is to prepare 3 by using 4-hydroxy-6, 7-dimethoxyquinoline as a raw material through chlorination and substitution. The other route is to prepare 5 by condensing and chloridizing cyclopropane-1, 1-dicarboxylic acid as a raw material, and then condensing to prepare the cabozantinib.
Compared with the first route, the second route has the advantages of low reaction temperature, high yield, simple operation and the like, but the reaction is required to be carried out for more than 12 hours at 110 ℃ when the 3-form-polymer is prepared, and thionyl chloride with pungent smell is applied when the 6-form-polymer is prepared, which are not beneficial to industrial production.
Synthetic route III[3]：
Patent CN103664776A[3]The synthesis method reported in the publication is very similar to the synthesis route of the first route, and the cabozantinib is prepared by using cyclopropane-1, 1-dicarboxylic acid ethyl ester as a raw material through the steps of hydrolysis, condensation, hydrolysis, condensation and the like.
Compared with the first route, the third route has the characteristics of high reaction temperature, low yield, complex operation and the like, so that the third route is not suitable for industrial production.
Therefore, in the prior art, the preparation process of cabozantinib malate generally has the defects of high reaction temperature, long time and low yield, or the defects of unsuitability for industrial production due to the large use of irritant reagents and the like, and the search for a preparation process which is efficient, simple, convenient, environment-friendly and suitable for industrial production is a technical problem which needs to be solved urgently.
Disclosure of Invention
The invention aims to overcome the defects that the cabozantinib malate synthesis method is not suitable for industrial production, and provides a method for synthesizing cabozantinib malate and intermediates thereof, which is simple and convenient and has high purity.
One of the purposes of the invention is to provide a preparation method of a cabozantinib intermediate shown in a formula (II), which comprises the following steps:
the compound of the formula (I) is substituted with 4-aminophenol under the action of alkali A to prepare a compound of a formula (II);
the base A can be selected from one or more of sodium tert-butoxide, triethylamine, diisopropylethylamine, potassium carbonate, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium hydride and sodium bis (trimethylsilyl) amide, and preferably sodium tert-butoxide or potassium tert-butoxide.
The reaction solvent of the process may be selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide and acetonitrile, preferably N, N-dimethylacetamide or N, N-dimethylformamide.
The molar ratio of the compound of formula (I) to 4-aminophenol may be from 1:1 to 1:3, preferably from 1:1 to 1:1.5, more preferably 1: 1.4.
The weight to volume ratio of the compound of formula (I) to the reaction solvent may be from 150:1g/L to 50:1g/L, preferably 100:1 g/L.
The molar ratio of the compound of formula (I) to the base a may be from 1:1 to 1:3, preferably 1: 2.
The reaction temperature of the method can be 80-120 ℃, and preferably 100-110 ℃.
The invention also aims to provide a method for preparing cabozantinib shown in formula (III), which comprises the steps of condensing a compound shown in formula (II) and a compound shown in formula (VII) under the action of alkali B to obtain a compound shown in formula (III);
r is selected from phenyl substituted or unsubstituted C1-8Alkyl and C0-8Alkyl-substituted phenyl, preferably methyl, ethyl, n-propyl, isopropyl, butyl, phenyl, benzyl or phenethyl.
The base B can be selected from one or more of sodium bis (trimethylsilyl) amide (NaHMDS), triethylamine, diisopropylethylamine, potassium carbonate, potassium hydroxide, sodium carbonate and sodium hydride, and preferably sodium bis (trimethylsilyl) amide.
The reaction solvent of the process may be selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide and acetonitrile, preferably tetrahydrofuran.
The weight to volume ratio of the compound of formula (II) to the reaction solvent may be from 100:1g/L to 20:1g/L, preferably from 60:1g/L to 40:1g/L, more preferably 50:1 g/L.
The molar ratio of the compound of formula (II) to the compound of formula (VII) may be 1:1 to 1:2, preferably 1:1 to 1:1.5, more preferably 1: 1.4.
The molar ratio of the compound of formula (II) to the base B may be 1: 2-10, preferably 1: 6 to 10.
The reaction temperature of the method can be-20 ℃ to 10 ℃, and is preferably-5 ℃ to 5 ℃.
The method of cabozantinib of formula (III) above may further comprise the steps of: the compound of the formula (I) and 4-aminophenol are substituted under the action of alkali A to prepare the compound of the formula (II);
the base A can be selected from one or more of sodium tert-butoxide, triethylamine, diisopropylethylamine, potassium carbonate, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium hydride and sodium bis (trimethylsilyl) amide, and preferably sodium tert-butoxide or potassium tert-butoxide.
The reaction solvent of the process may be selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide and acetonitrile, preferably N, N-dimethylacetamide or N, N-dimethylformamide.
The molar ratio of the compound of formula (I) to 4-aminophenol may be from 1:1 to 1:3, preferably from 1:1 to 1:1.5, more preferably 1: 1.4.
The weight to volume ratio of the compound of formula (I) to the reaction solvent may be from 150:1g/L to 50:1g/L, preferably 100:1 g/L.
The molar ratio of the compound of formula (I) to the base a may be from 1:1 to 1:3, preferably 1: 2.
The reaction temperature of the method can be 80-120 ℃, and preferably 100-110 ℃.
The invention also aims to provide a preparation method of cabozantinib malate, which comprises the following steps:
the compound of the formula (III) reacts with malic acid to obtain N- (4- { [6, 7-bis (methoxy) quinolin-4-yl]Oxy } phenyl) -N1- (4-fluorophenyl) cyclopropane-1, 1-dioic acid amide malate salt (IV);
the reaction solvent may be selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide, methanol, ethanol, isopropanol and acetonitrile, preferably tetrahydrofuran.
The preparation method of cabozantinib malate can further comprise the following steps: condensing a compound shown in a formula (II) and a compound shown in a formula (VII) under the action of alkali B to obtain a compound shown in a formula (III);
r is selected from phenyl substituted or unsubstituted C1-8Alkyl and C0-8Alkyl-substituted phenyl, preferably methyl, ethyl, n-propyl, isopropyl, butyl, phenyl, benzyl or phenethyl.
The base B can be selected from one or more of sodium bis (trimethylsilyl) amide (NaHMDS), triethylamine, diisopropylethylamine, potassium carbonate, potassium hydroxide, sodium carbonate and sodium hydride, and preferably sodium bis (trimethylsilyl) amide.
The reaction solvent of the process may be selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide and acetonitrile, preferably tetrahydrofuran.
The weight to volume ratio of the compound of formula (II) to the reaction solvent may be from 100:1g/L to 20:1g/L, preferably from 60:1g/L to 40:1g/L, more preferably 50:1 g/L.
The molar ratio of the compound of formula (II) to the compound of formula (VII) may be 1:1 to 1:2, preferably 1:1 to 1:1.5, more preferably 1: 1.4.
The molar ratio of the compound of formula (II) to the base B may be 1: 2-10, preferably 1: 6 to 10.
The reaction temperature of the method can be-20 ℃ to 10 ℃, and is preferably-5 ℃ to 5 ℃.
The preparation method of cabozantinib malate can further comprise the following steps: the compound of the formula (I) and 4-aminophenol are substituted under the action of alkali A to prepare the compound of the formula (II);
the base A can be selected from one or more of sodium tert-butoxide, triethylamine, diisopropylethylamine, potassium carbonate, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium hydride and sodium bis (trimethylsilyl) amide, and preferably sodium tert-butoxide or potassium tert-butoxide.
The reaction solvent of the process may be selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide and acetonitrile, preferably N, N-dimethylacetamide or N, N-dimethylformamide.
The molar ratio of the compound of formula (I) to 4-aminophenol may be from 1:1 to 1:3, preferably from 1:1 to 1:1.5, more preferably 1: 1.4.
The weight to volume ratio of the compound of formula (I) to the reaction solvent may be from 150:1g/L to 50:1g/L, preferably 100:1 g/L.
The molar ratio of the compound of formula (I) to the base a may be from 1:1 to 1:3, preferably 1: 2.
The reaction temperature of the method can be 80-120 ℃, and preferably 100-110 ℃.
Compared with other existing methods, the method has the advantages of cheap and easily-obtained raw materials, milder reaction, simple and convenient operation, reaction temperature reduction, reaction time shortening, avoidance of use of thionyl chloride reagent with pungent smell, reduction of risks in industrial production and contribution to industrial production.
Detailed Description
In order to embody the technical solutions and the effects obtained by the technical solutions of the present invention, the present invention will be further described with reference to specific embodiments, but the scope of the present invention is not limited to the specific embodiments.
EXAMPLE one, preparation of Compound (II)
Adding a compound (I) (500g, 2.23mol) and 4-aminophenol (345g, 3.16mol) into a reaction bottle, adding DMA (3L), cooling to 0-5 ℃, dropwise adding DMA (2L) suspension of sodium tert-butoxide (430g), after dropwise adding, heating to 100-110 ℃, and carrying out heat preservation reaction for 4-5 hours. (TLC monitored reaction complete, Rf 0.4 (dichloromethane: methanol: 20: 1)). And cooling to-5-0 ℃, adding ice water (10L), and stirring for crystallization for 15-16 hours. Filtering, washing a filter cake with a small amount of water, and drying by blowing air at 50 ℃ for 15-16 hours to obtain 595g of light yellow solid, wherein the yield is 90 percent, and the HPLC purity is 99.7 percent.
EXAMPLE two preparation of Compound (II)
Adding a compound (I) (500g, 2.23mol) and 4-aminophenol (345g, 3.16mol) into a reaction bottle, adding DMA (3L), cooling to 0-5 ℃, dropwise adding DMA (2L) of potassium tert-butoxide (450g), heating to 100-110 ℃, and carrying out heat preservation reaction for 4-5 hours. (TLC monitored reaction complete, Rf 0.4 (dichloromethane: methanol: 20: 1)). And cooling to-5-0 ℃, adding ice water (1L), and stirring for crystallization for 15-16 hours. Filtering, washing a filter cake with a small amount of water, and drying by air blowing at 50 ℃ for 15-16 hours to obtain 590g of light yellow solid, wherein the yield is 89% and the HPLC purity is 99.3%.
EXAMPLE III Synthesis of Compound (VII)
Adding the compound (V) (200g, 1.39mol) and THF (2L) into a reaction bottle, slowly adding thionyl chloride (50ml) under ice bath, stirring at room temperature for 2 hours after the addition, adding the compound (VI) (154 g), reacting at room temperature for 2 hours, monitoring the reaction by TLC, adding water, extracting with dichloromethane, drying with organic phase anhydrous sodium sulfate, filtering, distilling under reduced pressure to obtain 280g of off-white solid with the yield of 85%.
EXAMPLE four Synthesis of Compound (III)
Adding the compound (II) (200g, 0.67mol), the compound (VII) (220g,0.93mol) and THF (2L) into a reaction bottle, cooling to-5 ℃, dropwise adding a THF (2mol/L)2L solution of NaHMDS, and stirring and reacting for 1-2 hours at-5 ℃ after dropwise adding. (TLC monitored reaction complete, Rf 0.5 (dichloromethane: methanol: 20: 1)). Adding 16L of water into the reaction solution, stirring and crystallizing for 1-2 hours, filtering, and vacuum drying the filter cake at 40-50 ℃ for 23-24 hours to obtain 312g of off-white solid, wherein the yield is 92.9 percent and the HPLC purity is 99.5 percent.
1H NMR(400MHz，d6-DMSO)：δ10.2(s，1H)，10.08(s，1H)，8.4(s，1H)，7.8(m，2H)，7.65(m，2H)，7.5(s，1H)，7.4(s，1H)，7.24(m，2H)，7.15(m，2H)，6.4(s，1H)，4.0(d，6H)，1.5(s，4H)。MS(ESI)：m/z 502[M+H]+.
EXAMPLE five Synthesis of Compound (III)
Adding the compound (II) (200g, 0.67mol), the compound (VII) (285g,0.95mol) and THF (2L) into a reaction bottle, cooling to-5 ℃, dropwise adding a solution of NaHMDS (2mol/L) in THF (2L), and stirring and reacting for 1-2 hours at-5 ℃ after dropwise adding. (TLC monitored reaction complete, Rf 0.5 (dichloromethane: methanol: 20: 1)). Adding water (1.6L) into the reaction solution, stirring and crystallizing for 1-2 hours, filtering, and drying the filter cake at 40-50 ℃ for 23-24 hours in vacuum to obtain 310g of off-white solid, wherein the mass yield is 92.2%, the HPLC purity is 99.3%, and the nuclear magnetic data are basically the same as in the fourth embodiment.
EXAMPLE six Synthesis of Compound (IV)
L-malic acid (76.8g) was dissolved in 1440ml of THF and used. After compound (III) (240g) was dissolved in 1440ml of THF, the mixture was filtered, and the filtrate was added to a reaction flask, and a THF solution of L-malic acid was added dropwise with stirring. After the dripping is finished, stirring for 1-1.5 hours at 20-30 ℃. After slowly adding acetonitrile (3L), stirring for 15-16 hours at 20-30 ℃. And filtering, and drying a filter cake at 40-50 ℃ for 23-24 hours in vacuum to obtain 245g of the compound L-malic acid cabozantinib of the formula (IV) as an off-white solid, wherein the yield is 80%, and the HPLC purity is 99.9%.
1H NMR(400MHz，d6-DMSO)：δ10.2(s，1H)，10.08(s，1H)，8.5(s，1H)，7.8(m，2H)，7.68(m，2H)，7.5(s，1H)，7.4(s，1H)，7.25(m，2H)，7.18(m，2H)，6.5(d，1H)，4.3(m，1H)，4.0(d，6H)，2.6(m，1H)，2.5(m，1H)，1.5(s，4H)。MS：M+H＝502。
Claims (18)
1. The preparation method of cabozantinib comprises the following steps:
condensing the compound of the formula (II) and the compound of the formula (VII) under the action of alkali B to obtain cabozantinib;
wherein R is selected from methyl, ethyl, n-propyl, isopropyl, butyl, phenyl, benzyl or phenethyl;
the alkali B is sodium bis (trimethylsilyl) amide;
the reaction temperature is-20 ℃ to 10 ℃.
2. The method according to claim 1, wherein the reaction solvent is selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, and acetonitrile.
3. The method according to claim 1, wherein the reaction solvent is tetrahydrofuran.
4. The method according to claim 2, wherein the weight/volume ratio of the compound of formula (II) to the reaction solvent is from 100:1g/L to 20:1 g/L.
5. The method according to claim 4, wherein the weight/volume ratio of the compound of formula (II) to the reaction solvent is from 60:1g/L to 40:1 g/L.
6. The method according to claim 4, wherein the weight/volume ratio of the compound of formula (II) to the reaction solvent is 50:1 g/L.
7. The process according to claim 1, wherein the molar ratio of the compound of formula (II) to the compound of formula (VII) is from 1:1 to 1: 2.
8. The process according to claim 7, wherein the molar ratio of the compound of formula (II) to the compound of formula (VII) is from 1:1 to 1: 1.5.
9. The method according to claim 7, wherein the molar ratio of the compound of formula (II) to the compound of formula (VII) is 1: 1.4.
10. The process according to claim 1, wherein the molar ratio of the compound of formula (II) to the base B is 1:2 to 10.
11. The process according to claim 10, wherein the molar ratio of the compound of formula (II) to the base B is 1: 6 to 10.
12. The method of claim 1, wherein the reaction temperature of the method is-5 ℃ to 5 ℃.
13. The preparation method of claim 1, further comprising the step of substituting the compound of formula (I) with 4-aminophenol under the action of a base a to obtain a compound of formula (II);
the alkali A is selected from one or more of sodium tert-butoxide, triethylamine, diisopropylethylamine, potassium carbonate, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium hydride and sodium bis (trimethylsilyl) amide.
14. The method according to claim 13, wherein the reaction solvent for the substitution reaction is selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, and acetonitrile.
15. The method according to claim 14, wherein the substitution reaction is carried out in a solvent selected from the group consisting of N, N-dimethylacetamide and N, N-dimethylformamide.
16. The preparation method of cabozantinib malate, which is characterized by further comprising the following steps on the basis of the steps of any one of claims 1-15:
the compound of the formula (III) reacts with malic acid to obtain N- (4- { [6, 7-bis (methoxy) quinolin-4-yl]Oxy } phenyl) -N1- (4-fluorophenyl) cyclopropane-1, 1-dioic acid amide malate;
17. the process of claim 16, wherein the reaction solvent is selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, methanol, ethanol, isopropanol, and acetonitrile.
18. The process of claim 17, wherein the reaction solvent is tetrahydrofuran.
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