Synthesis method of cartinib and intermediate product thereof
阅读说明：本技术 一种图卡替尼及其中间产物的合成方法 (Synthesis method of cartinib and intermediate product thereof ) 是由 王郁萱 李智 温进富 姚志刚 于 2019-04-16 设计创作，主要内容包括：本发明公开了一种图卡替尼的合成方法,包括以式VI所示的化合物的卤酸盐或是其游离碱为原料,在碱性条件下,与式VII所示的化合物进行取代反应得到式VIII所示的化合物的步骤。本发明的整个合成路线用到的原料均易获得,且无需昂贵的催化剂,适合放大生产,有利于工业化生产图卡替尼。(The invention discloses a method for synthesizing Tucotinib, which comprises the step of taking halate of a compound shown as a formula VI or free alkali thereof as a raw material to perform substitution reaction with a compound shown as a formula VII under an alkaline condition to obtain the compound shown as the formula VIII. The raw materials used in the whole synthesis route are easy to obtain, expensive catalysts are not needed, and the method is suitable for large-scale production and beneficial to industrial production of the cartinib.)
1. A method for synthesizing a compound shown as a formula VIII is characterized in that halate of the compound shown as the formula VI or free alkali of the halate is used as a raw material to perform substitution reaction with the compound shown as the formula VII under an alkaline condition to obtain the compound shown as the formula VIII,
2. the method for synthesizing the compound represented by the formula VIII in claim 1, wherein the base used in the substitution reaction is selected from one or a combination of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, N-methylpiperidine and N-methylmorpholine.
3. The method of claim 2, wherein the base is a combination of one selected from potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate and one selected from triethylamine, diisopropylethylamine, pyridine, N-methylpiperidine and N-methylmorpholine.
4. The method for synthesizing the compound represented by the formula VIII in claim 3, wherein the base is a composition of potassium hydroxide and triethylamine, and the ratio of the equivalent weight of the potassium hydroxide to the equivalent weight of the triethylamine is 1: 1-3: 1.
5. The method for synthesizing the compound represented by the formula VIII in claim 4, wherein the concentration of the potassium hydroxide is 1-3 equivalents, and the concentration of the triethylamine is 1-3 equivalents.
6. The method for synthesizing the compound shown in the formula VIII as claimed in claim 2, wherein the base is potassium hydroxide or potassium carbonate, and the amount of the potassium hydroxide or the potassium carbonate is 1-5 equivalents.
7. The method for synthesizing the compound represented by the formula VIII as claimed in claim 1, wherein the equivalent ratio of the halide salt or the free base of the compound represented by the formula VI to the compound represented by the formula VII is 1: 1-2.
8. The method for synthesizing the compound represented by the formula VIII in claim 7, wherein the amount of the halide salt or the free base thereof in the compound represented by the formula VI is 1-2 equivalents, and the amount of the compound represented by the formula VII is 1-2 equivalents.
9. The method of claim 1, wherein Y in the compound of formula VII is halogen, OMs, OTf or OTs.
10. The method of claim 9, wherein Y in the compound of formula VII is fluorine.
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing Tucotinib and an intermediate product thereof.
Background
Tucaninib is a potent selective oral HER2 tyrosine kinase inhibitor and HER2 is a growth factor receptor that is overexpressed in a variety of cancers, including breast, colorectal, esophageal, gastric, lung and ovarian cancers. It is overexpressed in about 20% of breast cancers, and standard therapy is safe and effective for patients with advanced HER2 positive breast cancer and those with brain metastases due to primary disease. Tucaninib has been evaluated as a single drug and associated with other HER 2-directed drugsIn combination, these targeted agents include
Chemical name of Charcotinib
N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy) -3-methylphenyl) -N6- (5,5-dimethyl-2,5-dihydrooxazol-2-yl) quinazoline-4, 6-diamine. Has an empirical formula of C26H24N8O2And a molecular weight of 480.52 g/mol. The chemical structure is as follows:
the synthesis method of the compound of the cartinib is reported in documents and patents to be few, and patent WO2007059257A2 reports that a key intermediate (the compound shown in formula I) is obtained only by taking 2-chloro-4-nitropyridine as a starting material and carrying out eight-step lengthy reaction path. The route is long, the total yield is only 5.7%, an expensive catalyst Pd2dba3 and hexamethyldisilazane lithium amide LiHDMS which are not suitable for industrial production are needed in the synthetic route, and the scale-up production is difficult and not suitable for industrial production.
Therefore, those skilled in the art have made efforts to develop a method for obtaining a key intermediate (the compound shown in formula I) by using the halide salt of the compound shown in formula VI or the free base thereof as a raw material through a simple reaction route, wherein the raw material used in the whole synthesis route is easily available, does not need expensive catalysts, is suitable for scale-up production, and is beneficial to industrial production of the cartinib.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the technical problem to be solved by the present invention is how to scale up the production process of synthetic cartinib.
In order to achieve the purpose, the invention provides a synthesis method of a compound shown as a formula VIII, which takes a halate shown as a formula VI or free alkali thereof as a raw material to perform substitution reaction with a compound shown as a formula VII under an alkaline condition to obtain the compound shown as the formula VIII,
further, the base used in the substitution reaction is selected from one or a combination of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, N-methylpiperidine and N-methylmorpholine.
Further, the base is one selected from the group consisting of potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate and is in combination with one of triethylamine, diisopropylethylamine, pyridine, N-methylpiperidine and N-methylmorpholine.
Further, the base is a composition of potassium hydroxide and triethylamine, and the ratio of the equivalent weight of the potassium hydroxide to the equivalent weight of the triethylamine is 1: 1-3: 1.
Further, the concentration of potassium hydroxide is 1 to 3 equivalents, and the concentration of triethylamine is 1 to 3 equivalents.
Further, the alkali is potassium hydroxide or potassium carbonate, and the amount of the potassium hydroxide or potassium carbonate is 1-5 equivalents.
Furthermore, the equivalent ratio of the halide salt or the free base of the compound shown in the formula VI to the compound shown in the formula VII is 1: 1-2.
Furthermore, the amount of the halide salt or the free base of the compound represented by formula VI is 1-2 equivalents, and the amount of the compound represented by formula VII is 1-2 equivalents.
Further, Y in the compound represented by formula VII is halogen, OMs, OTf or OTs.
Further, Y in the compound represented by formula VII is fluorine.
Further, HX in the halide salt of the compound represented by formula VI is HCl, HBr, HF or HI.
Further, the reaction time of the substitution reaction is less than 18 hours, and the reaction temperature is 25-120 ℃.
Further, the reaction time is 16-18h, and the reaction temperature is 20-70 ℃.
Further, the reaction solvent of the substitution reaction is a protic solvent or an aprotic solvent, the protic solvent is selected from one of methanol, ethanol, N-propanol, isopropanol, N-butanol, tert-butanol and water, and the aprotic solvent is selected from one of tetrahydrofuran, acetonitrile, methyl sulfoxide, N-dimethylformamide and ethyl acetate.
The invention also provides a synthesis method of the halide salt of the compound shown in the formula VI, wherein the pressure of the compound shown in the formula V is 3-8 kg/cm2Under the conditions of (1) reacting with alkali liquor to obtain a middle product, and reacting the middle product with acid liquor to obtain the halate of the compound shown in the formula VI
Further, the pressure is 5-6 kg/cm2。
Further, the amount of the compound represented by the formula V is 1 to 2 equivalents.
Further, the alkali liquor is derived from one of sodium hydroxide, potassium hydroxide and lithium hydride.
Further, the equivalent weight of the alkali liquor is 2-5N.
Further, the equivalent ratio of the compound shown as the formula V to the alkali liquor is 1: 1-1: 3.
Further, the reaction temperature is 150-200 ℃, and the reaction time is 12-24 h.
Furthermore, the reaction temperature is 170-180 ℃, and the reaction time is 16-18 h.
Further, the acid solution is halogen acid, and the halogen acid is HCl, HBr, HF or HI.
Further, the equivalent ratio of the medium product to the halogen acid is 1: 1-1: 2
Further, the reaction temperature of the medium product and the acid solution is 0-25 ℃, and the reaction time is 30-180 min.
Further, the compound shown in the formula VI is obtained by taking the compound shown in the formula II as a raw material and carrying out the following steps:
(1) the compound shown in the formula II is subjected to sulfoxide chloride and salt to obtain the compound shown in the formula III, and the compound shown in the formula III is subjected to ammonia to obtain the compound shown in the formula IV
(2) Carrying out Hofmann amide degradation reaction on the compound shown in the formula IV to obtain a compound shown in a formula V,
(3) the compound shown as the formula V is under the pressure of 3-8 kg/cm2The compound shown in VI is obtained by reacting with alkali liquor and then with acid liquor.
The invention also provides a synthesis method of the compound shown in the formula I, which comprises the following steps:
(i) taking halide of the compound shown in the formula VI or free alkali thereof as raw material, and carrying out substitution reaction with the compound shown in the formula VII under alkaline condition to obtain the compound shown in the formula VIII,
(ii) carrying out condensation reaction on the compound shown in the formula VIII and the compound shown in the formula IX to obtain a compound shown in the formula X, carrying out cyclization reaction on the compound shown in the formula X and hydroxylamine-O-sulfonic acid to obtain a compound shown in the formula XI,
(iii) subjecting the compound of formula XI to hydrogenation reaction to obtain the compound of formula I
Further, the condensation reaction in the step (ii) is carried out at the temperature of 40-120 ℃ for 2-5 h.
Further, the temperature of the cyclization reaction in the step (ii) is-10 to 40 ℃, and the reaction time is 12 to 24 hours.
Further, in the step (iii), the compound shown in the formula XI is obtained by hydrogenation reaction under the action of a catalyst and hydrogen gas.
Further, the pressure of the hydrogen is 1 to 3 atm.
Further, the hydrogenation temperature is 25-100 ℃.
Further, the hydrogenation time is 2-5 h.
Further, the catalyst is selected from palladium carbon, Raney nickel, Pd (OAc)2、PtO2And Pd (OH)2One kind of (1).
Further, in the hydrogenation reaction in the step (iii), iron powder or zinc powder is used as a reducing agent, and the compound shown in the formula XI is hydrogenated under an acidic condition to obtain the compound shown in the formula I.
Further, the reaction temperature of the hydrogenation is 40-120 ℃, and the reaction time is 15-30 min.
Further, the acid used in the acidic condition is selected from one of hydrochloric acid, ammonium chloride and acetic acid.
Further, the reaction solvent in steps (ii) and (iii) is a protic solvent or an aprotic solvent, the protic solvent is selected from one of methanol, ethanol, N-propanol, isopropanol, N-butanol, tert-butanol and water, and the aprotic solvent is selected from one of tetrahydrofuran, acetonitrile, methyl sulfoxide, N-dimethylformamide and ethyl acetate.
The invention provides a method for synthesizing cartinib, which comprises the following steps:
(i) taking halide shown in formula VI or free alkali thereof as raw material, carrying out substitution reaction with a compound shown in formula VII under alkaline condition to obtain a compound shown in formula VIII,
(ii) condensing the compound shown in the formula VIII with the compound shown in the formula IX to obtain a compound shown in the formula X, carrying out cyclization reaction on the compound shown in the formula X and hydroxylamine-O-sulfonic acid to obtain a compound shown in the formula XI,
(iii) hydrogenating a compound of formula XI to obtain a compound of formula I,
(iv) reacting the compound shown in the formula I with the compound shown in the formula XII under an acidic condition to obtain a compound shown in the formula XIV,
(v) the compound shown in the formula XIV is subjected to the action of alkaline 4-toluene sulfonyl chloride to obtain the Tucanitinib.
Further, the acid used in the acidic condition of step (iv) is one of acetic acid, hydrochloric acid and sulfuric acid.
Further, the reaction time of the step (iv) is 16-18h, and the reaction temperature is 20-50 ℃.
Further, the alkali used in the alkaline condition of step (v) is one of sodium hydroxide, potassium hydroxide and lithium hydroxide.
Further, the reaction time of the step (v) is 3-7 hours, and the reaction temperature is 20-70 ℃.
Compared with the prior art, the method takes the halate of the compound shown in the formula VI or the free alkali thereof as a raw material to synthesize the compound shown in the formula VIII by a one-step method under the alkaline condition, the yield reaches more than 60 percent, the purity reaches more than 90 percent, and the impurity content is low; however, in WO2007059257a2, 4- (2-methyl-4-nitrophenoxy) pyridin-2-amine is obtained by using 2-chloro-4-nitropyridine as a starting material and performing six steps under an expensive catalyst, and in addition, in order to prevent substitution reaction of an amino group on pyridine and fluorine, in the prior art, the amino group is protected by using a protecting group, the reaction is complicated, and the steps are long, so that the final yield of 4- (2-methyl-4-nitrophenoxy) pyridin-2-amine is only 30% and impurities are more;
the halide salt of the compound shown in the formula VI or the free alkali of the compound is used as a raw material, so that the raw material is convenient to obtain, and the production cost is low; in the invention, the compound shown in the formula VI is obtained by performing Hofmann degradation reaction on the compound shown in the formula II and reacting with alkali liquor under high pressure; the synthetic route has low cost and strong economic effect; the reaction can be effectively promoted under high pressure, so that the yield of the product is over 80 percent, and the purity reaches 99 percent.
Compared with the synthetic route mentioned in WO2007059257A2, the synthetic route of the cartinib is simpler, the reaction condition is not harsh, no expensive catalyst is needed, and the preparation method is suitable for large-scale production; green and environment-friendly, and is suitable for industrial production.
The conception, the specific structure and the technical effects of the present invention will be further described with reference to the accompanying drawings to fully understand the objects, the features and the effects of the present invention.
Drawings
FIG. 1 is a synthetic roadmap for Charcotinib of the present invention;
FIG. 2 is a diagram of the synthetic scheme of the compounds of formula VI according to the invention.
Detailed Description
The technical contents of the preferred embodiments of the present invention will be more clearly and easily understood by referring to the drawings attached to the specification. The invention can be embodied in many different forms of embodiments and the scope of the invention is not limited to the embodiments set forth herein.
The halide salt of the compound of formula VI mentioned in the present invention includes, but is not limited to, the hydrochloride salt of formula VI in the present embodiment. The halide salt of formula VI or its free base is available from a wide variety of sources including, but not limited to, the synthetic route shown in figure 2.
Figure 1 shows a composite roadmap for cartinib. Taking halide of the compound shown in the formula VI or free alkali thereof as a raw material, and carrying out five-step reaction to finally obtain the Tucotinib. Step (I) halide salt of the compound shown in the formula VI or free base thereof is subjected to substitution reaction with the compound shown in the formula VII under the alkaline condition to obtain the compound shown in the formula VIII, step (ii) the compound shown in the formula VIII is condensed with the compound shown in the formula IX to obtain the compound shown in the formula X, the compound shown in the formula X is subjected to cyclization reaction with hydroxylamine-O-sulfonic acid to obtain the compound shown in the formula XI, step (iii) the compound shown in the formula XI is subjected to hydrogenation reduction to obtain the compound shown in the formula I, step (iv) the compound shown in the formula I is subjected to reaction with the compound shown in the formula XII under the acidic condition to obtain the compound shown in the formula XIV, and step (v) the compound shown in the formula XIV is subjected to the action of alkalinity and 4-toluene sulfonyl chloride to obtain the Tukatinib.
Figure 2 shows a synthetic scheme for the hydrochloride salt of the compound shown in formula VI. Is represented by the formula IIThe compound of the formula VI is used as a raw material, and the compound shown as the formula VI is obtained through three steps. The method comprises the following specific steps: (1.1) obtaining a compound shown as a formula III by a compound shown as a formula II in the presence of thionyl chloride and salt, (1.2) obtaining a compound shown as a formula IV by a compound shown as a formula III in the presence of ammonia, (2) obtaining a compound shown as a formula V by a Hofmann amide degradation reaction of the compound shown as a formula IV, and (3) obtaining a compound shown as a formula V under the pressure of 5-6 kg/cm2Under the condition (1), the intermediate product is firstly reacted with alkali liquor to obtain a product, and then the product is reacted with hydrochloric acid to obtain hydrochloride of the compound shown in the formula VI.
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