CN114230568A - Preparation method of HER2 small-molecule inhibitor picatinib - Google Patents
Preparation method of HER2 small-molecule inhibitor picatinib Download PDFInfo
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- CN114230568A CN114230568A CN202111657884.4A CN202111657884A CN114230568A CN 114230568 A CN114230568 A CN 114230568A CN 202111657884 A CN202111657884 A CN 202111657884A CN 114230568 A CN114230568 A CN 114230568A
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention provides a preparation method of HER2 small-molecule inhibitor picatinib. Compared with the prior art, the inventor of the invention innovatively adopts a catalyst Pd (acac) in the step (4)2And the amination reaction is carried out on the ligand L, the reaction site is single, and the method has the advantage of high yield. The synthetic route and the preparation method have the advantages of short reaction steps, single reaction site in each step and high yield, and meanwhile, the preparation method has simple post-treatment of the reaction, only adopts pulping purification in the purification step, avoids expensive column chromatography purification, directly reduces the reaction cost, and effectively improves the total yield of the reaction and the industrial operability.
Description
Technical Field
The invention relates to the technical field of biological medicines, and in particular relates to a preparation method of HER2 small-molecule inhibitor picatinib.
Background
Tucatinib (Tucatenib, research and development code ARRY-380, ONT-380, trade name Tukysa) is a small molecule oral tyrosine kinase inhibitor, and has excellent targeting selectivity to HER 2. At 18/4/2020, the selective HER2 inhibitor, tucatinib, developed by FDA approved Seattle Genetics (Seattle Genetics) is marketed for use in combination with trastuzumab and capecitabine in the treatment of adult patients with surgically unresectable or metastatic advanced HER2 positive breast cancer.
The chemical structure of the Tucaninib is shown as formula I:
however, the preparation method for the cartinib still needs to be improved.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a preparation method of a HER2 small molecule inhibitor, namely, Tucanitinib. Compared with the prior art, the inventor of the invention innovatively adopts a catalyst Pd (acac) in the step (4)2And the amination reaction is carried out on the ligand L, the reaction site is single, and the method has the advantage of high yield. The synthetic route and the preparation method have the advantages of short reaction steps, single reaction site in each step and high yield, and meanwhile, the preparation method has simple post-treatment of the reaction, only adopts pulping purification in the purification step, avoids expensive column chromatography purification, directly reduces the reaction cost, and effectively improves the total yield of the reaction and the industrial operability.
In one aspect of the invention, the invention provides a preparation method of the compound of formula I, namely, the cartinib. According to an embodiment of the invention, the preparation process comprises:
(1) reacting a compound represented by the formula 1 with K2CO3A compound of formula 2, so as to obtain a compound of formula 3;
(2) contacting the compound represented by formula 3 with palladium/carbon and hydrogen to obtain a compound represented by formula 4;
(3) reacting a compound represented by the formula 4 with K2CO3A compound of formula 5, to obtain a compound of formula 6;
(4) reacting a compound represented by the formula 6, a compound represented by the formula 7 and K3PO4·3H2O、Pd(acac)2And a compound of formula 8, to obtain a compound of formula I,
the inventor finds that the compound of the formula I, namely the Tukatinib, can be quickly and effectively prepared by using the preparation process disclosed by the invention and using a low-price commercial compound as a starting material through halogenation reaction, nitro reduction, halogenation reaction and amination.
The term "contacting" as used herein is to be understood broadly and can be any means that enables a chemical reaction of at least two reactants, such as mixing the two reactants under appropriate conditions. The reactants to be contacted may be mixed with stirring as necessary, and thus, the type of stirring is not particularly limited, and may be, for example, mechanical stirring, that is, stirring under the action of a mechanical force.
The terms "first", "second" and "first" are used herein for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
According to embodiments of the present invention, the above-described method for preparing the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 6, the compound represented by formula I may further have at least one of the following additional technical features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the starting materials for preparing the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 6, and the compound represented by formula I is not particularly limited, and it may be prepared by any known method or may be commercially available.
According to an embodiment of the present invention, in step (1), a compound represented by formula 1 and K2CO3The contact manner of the compound represented by formula 2 is not particularly limited. Thus, the compound represented by the formula 1, K, can be promoted2CO3And the efficiency of the contact reaction of the compound shown in the formula 2 is improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 3 by using the method is further improved.
According to an embodiment of the present invention, in the step (1), the following steps are included: reacting a compound represented by formula 1 with K at room temperature2CO3Adding the mixture into stirred DMF, mixing, slowly dropwise adding a mixed solution containing the compound shown in the formula 2 and DMF, heating and stirring for reaction, carrying out post-treatment after the reaction is finished, filtering and collecting precipitated solid, stirring, pulping and purifying, filtering the solid, and drying to obtain the compound shown in the formula 3. Thus, the compound represented by the formula 1, K, can be promoted2CO3The efficiency of the contact reaction with the compound shown in the formula 2 is improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 3 by using the method is further improved.
According to an embodiment of the present invention, in step (1), the compound represented by formula 1, K2CO3The molar ratio of the compound represented by the formula 2 is 1 (1-1.3) to 1-1.2, preferably the compound represented by the formula 1 and K2CO3The molar ratio of the compound represented by formula 2 is 1:1.1: 1.1. Thus, the efficiency of preparing the compound represented by formula 3 using this method can be further improved.
According to an embodiment of the present invention, in step (1), the compound represented by formula 1, K2CO3The reaction time of the contact stirring of the compound shown as the formula 2 is 1.5-2.5 h, and the compound shown as the formula 1 and K are preferably selected2CO3The reaction time for contacting and stirring the compound represented by the formula 2 was 2 hours. Thus, the compound represented by the formula 1, K, can be promoted2CO3And the efficiency of the contact reaction of the compound shown in the formula 2 further improves the efficiency of preparing the compound shown in the formula 3 by using the method.
According to an embodiment of the present invention, in step (1), the compound represented by formula 1, K2CO3The reaction temperature for heating the compound represented by the formula 2 by contact stirring is 90 to 105 ℃, and the compound represented by the formula 1 and K are preferably selected2CO3And heating the compound shown in the formula 2 to 100 ℃, and stirring for reaction. Thus, the compound represented by the formula 1, K, can be promoted2CO3And the efficiency of the contact reaction of the compound shown in the formula 2 further improves the efficiency of preparing the compound shown in the formula 3 by using the method.
According to the embodiment of the invention, in the step (1), the mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 3:1 is adopted for pulping and purification.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: a compound represented by the formula 1 (15.36g,100mmol) and K are reacted at room temperature2CO3(15.20g,110mmol) is added into DMF (240mL) which is stirred for mixing, then the mixed solution containing the compound shown in the formula 2 (16.85g,110mmol) and DMF (40mL) is slowly dropped, the temperature is raised to 100 ℃, stirring is carried out for 2h, after the reaction is finished, the reaction solution is poured into water (300mL), the precipitated solid is filtered and collected, the mixed solvent (150mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 3:1 is used for stirring, pulping and purifying for 30min, the solid is filtered, and the compound shown in the formula 3 is obtained after drying, the yield is 24.89g, and the yield is 92.1%.
According to an embodiment of the present invention, the contacting manner of the compound represented by formula 3 with Pd/C in step (2) is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 3 and Pd/C can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to an embodiment of the present invention, in the step (2), the following steps are included: adding Pd/C into the compound shown in the formula 3 and an organic solvent, replacing the compound with hydrogen for several times under vacuum, keeping the reaction liquid at 20-30 ℃ under the hydrogen atmosphere, stirring for 1-2 h, filtering the reaction liquid to remove Pd/C after TLC shows that the raw materials are completely consumed, and concentrating the filtrate to dryness to obtain the compound shown in the formula 4. Therefore, the efficiency of the contact reaction of the compound shown in the formula 3 and Pd/C can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to the embodiment of the invention, in the step (2), the mass ratio of the compound represented by the formula 3 to Pd/C is 1 (0.025-0.1), and preferably the mass ratio of the compound represented by the formula 3 to Pd/C is 1: 0.1. Thus, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to an embodiment of the present invention, in the step (2), the organic solvent is a linear or branched alcohol selected from C1-C3, and preferably the organic solvent is at least one selected from methanol and ethanol.
According to an embodiment of the present invention, in the step (2), the mass-to-volume ratio of the compound represented by formula 3 to the organic solvent is 1: (8-50).
According to a specific embodiment of the present invention, in the step (2), the following steps are included: Pd/C (10%, 750mg) was added to the compound represented by formula 3 (7.5g) and methanol (75ml), and after several replacements with hydrogen under vacuum, the reaction solution was kept at 20 to 30 ℃ under a hydrogen atmosphere and stirred for 1 hour, after TLC showed complete consumption of the raw material, the reaction solution was filtered to remove Pd/C, and the filtrate was concentrated to dryness to obtain 6.30g of a solid which is the compound represented by formula 4, with a yield of 94.5%.
According to an embodiment of the present invention, in step (3), the compound represented by formula 4 is reacted with K2CO3The contact manner of the compound represented by formula 5 is not particularly limited. Thus, the compound represented by the formula 4 and K can be promoted2CO3And the efficiency of the contact reaction of the compound shown as the formula 5 is improved, the reaction speed is increased, and the efficiency of preparing the compound shown as the formula 6 by using the method is further improved.
According to an embodiment of the present invention, in the step (3), the following steps are included: reacting a compound represented by the formula 4 with K at room temperature2CO3Adding the mixture into stirred DMF, mixing, slowly dropwise adding a mixed solution containing the compound shown in the formula 5 and DMF, heating and stirring for reaction, carrying out post-treatment after the reaction is finished, filtering and collecting precipitated solid, stirring, pulping and purifying, filtering the solid, and drying to obtain the compound shown in the formula 6. Thus, the compound represented by the formula 4, K, can be promoted2CO3The efficiency of the contact reaction with the compound shown as the formula 5 is improved, the reaction speed is accelerated, and the preparation by the method is further improvedEfficiency of the compound represented by formula 6.
According to an embodiment of the present invention, in step (3), the compound represented by formula 4 is reacted with K2CO3The molar ratio of the compound represented by the formula 5 is 1 (1.0-1.3) to 1.0-1.2, preferably the compound represented by the formula 4 and K2CO3The molar ratio of the compound represented by formula 5 is 1:1.2: 1.0. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in step (3), the compound represented by formula 4 is reacted with K2CO3The reaction time of the compound shown as the formula 5 in contact stirring is 45 minutes to 1.5 hours, and the compound shown as the formula 4 and K are preferably selected2CO3And the reaction time of the compound represented by the formula 5 with contact stirring was 1 hour. Thus, the compound represented by the formula 4 and K can be promoted2CO3And the efficiency of the contact reaction of the compound shown in the formula 5, and the efficiency of preparing the compound shown in the formula 6 by using the method is further improved.
According to an embodiment of the present invention, in step (3), the compound represented by formula 4 is reacted with K2CO3The reaction temperature for the contact, stirring and heating of the compound shown as the formula 5 is 70-90 ℃, and preferably the compound shown as the formula 4 and K2CO3And heating the compound shown in the formula 5 to 80 ℃, and stirring for reaction. Thus, the compound represented by the formula 4 and K can be promoted2CO3And the efficiency of the contact reaction of the compound shown in the formula 5, and the efficiency of preparing the compound shown in the formula 6 by using the method is further improved.
According to an embodiment of the invention, in the step (3), the pulping purification adopts a mixed solvent of petroleum ether/ethyl acetate with a volume ratio of 1:1.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: a compound represented by the formula 4 (24.03g,100mmol) and K are reacted at room temperature2CO3(16.58g,120mmol) was added to DMF (250mL) while stirring and mixed, and then a mixture containing the compound represented by the formula 5 (20.96g,100mmol) and DMF (50mL) was slowly added dropwise thereto, the mixture was heated to 80 ℃ and stirred for reaction for 1 hour, after completion of the reaction, the reaction mixture was poured into water (500mL), and the precipitated solid was collected by filtration,stirring and pulping the mixture (200mL) of petroleum ether and ethyl acetate according to the volume ratio of 1:1 for 30min, filtering the solid, and drying to obtain the compound shown in the formula 6, wherein the yield is 37.58g and 90.9%.
According to an embodiment of the present invention, in the step (4), the compound represented by formula 6, the compound represented by formula 7, K3PO4·3H2O、Pd(acac)2The contact manner with the compound represented by formula 8 is not particularly limited. Thus, the compound represented by the formula 6, the compound represented by the formula 7, and K can be promoted3PO4·3H2O、Pd(acac)2The efficiency of the contact reaction with the compound shown as the formula 8 is improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown as the formula I by using the method is further improved.
According to an embodiment of the present invention, in the step (4), the following steps are included: adding the compound represented by the formula 7 and K to a mixture of the compound represented by the formula 6 and dioxane under stirring3PO4·3H2O、Pd(acac)2And a ligand L (a compound represented by formula 8), wherein the reaction solution is substituted for N at room temperature under vacuum2Heating and stirring for reaction for several times, cooling after the reaction is finished, concentrating the reaction solution at low temperature to remove half of the solvent, pouring the solution into water (60mL), filtering and collecting the precipitated solid, stirring and pulping the solid by using an organic solvent for purification, filtering and drying to obtain the solid which is the compound shown in the formula I. Therefore, the efficiency of preparing the compound of formula I, namely the Tucotinib, by the method can be further improved.
According to an embodiment of the present invention, in the step (4), the compound represented by formula 6, the compound represented by formula 7, K3PO4·3H2O、Pd(acac)2And the compound represented by the formula 8 is in a molar ratio of 1 (1.0-1.5): 1.1-1.6): 0.025-0.1): 0.05-0.2, preferably the compound represented by the formula 6, the compound represented by the formula 7, and K3PO4·3H2O、Pd(acac)2And the compound of formula 8 in a molar ratio of 1:1.2:1.5:0.05: 0.1. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
In accordance with an embodiment of the present invention,in the step (4), a compound represented by the formula 6, a compound represented by the formula 7, K3PO4·3H2O、Pd(acac)2The reaction time of the compound shown as the formula 8 and the contact stirring is 18-32 h, and the compound shown as the formula 6, the compound shown as the formula 7 and the compound K are preferable3PO4·3H2O、Pd(acac)2The reaction time with contact stirring of the compound represented by the formula 8 was 24 hours. Thus, the compound represented by the formula 6, the compound represented by the formula 7, and K can be promoted3PO4·3H2O、Pd(acac)2And the efficiency of the contact reaction of the compound shown as the formula 8, and the efficiency of preparing the compound shown as the formula I by using the method is further improved.
According to an embodiment of the present invention, in the step (4), the compound represented by formula 6, the compound represented by formula 7, K3PO4·3H2O、Pd(acac)2The reaction temperature for contacting with the compound represented by the formula 8, stirring and raising the temperature is 75 to 95 ℃, and the compound represented by the formula 6, the compound represented by the formula 7 and K are preferably selected3PO4·3H2O、Pd(acac)2And the compound shown in the formula 8 is heated to 90 ℃ and stirred for reaction. Thus, the compound represented by the formula 6, the compound represented by the formula 7, and K can be promoted3PO4·3H2O、Pd(acac)2And the efficiency of the contact reaction of the compound shown as the formula 8, and the efficiency of preparing the compound shown as the formula I by using the method is further improved.
According to a specific embodiment of the present invention, in the step (4), the following steps are included: to a stirred mixture of the compound represented by formula 6 (41.34g,100mmol) and dioxane (410ml), the compound represented by formula 7 (17.12g,150mmol) and K were added in this order3PO4·3H2O(39.35g,150mmol)、Pd(acac)2(1.52g,5mmol) and ligand L (Compound represented by formula 8) (5.06g,10mmol), and the reaction mixture was subjected to vacuum displacement of N at room temperature2Heating to 90 ℃ for reaction for 24 hours after a plurality of times, cooling after-treatment after the reaction is finished, concentrating the reaction liquid at low temperature to remove half of the solvent, pouring the concentrated reaction liquid into water (400mL), filtering and collecting the precipitated solid, stirring and pulping for purification for 30min by using a mixed solvent (200mL) consisting of petroleum ether/ethyl acetate with the volume ratio of 1:1, filtering and drying to obtain a solid 44.11g of the compound is the compound shown in the formula I, namely the Tucotinib, the yield is 91.8 percent, and the HPLC purity is 99.7 percent.
According to an embodiment of the present invention, the synthetic route of the compound of formula I, picatinib, can be as follows:
compared with the prior art, the preparation method of the HER2 small molecule inhibitor, namely the Tucotinib, has the following beneficial effects: the method adopts a low-price commercial compound as an initial raw material, and synthesizes a target compound, namely the tic catinib, through halogenation reaction, nitro reduction, halogenation reaction and amination, wherein the total step is 4 steps of reaction. Wherein, the step (1) and the step (3) both adopt halogenation reaction, the reaction sites in the raw materials of the two steps are single, the yield is high, and the purification method is simple. The Pd/C reduction is adopted in the step (2), and the first three steps of reaction have the advantages of simple operation and high yield. The conventional route of step (4) is to reduce the nitro group in compound 6 to amino group and then perform halogenation reaction with the halide (amino group is replaced by halogen) of compound 7, and this route has the disadvantages of one more step, relatively more reaction sites, and low reaction yield due to the substitution reaction with halogen if imino group exists in compound 6. The inventors of the present invention innovatively employed the catalyst Pd (acac) in step (4)2And the amination reaction is carried out on the ligand L, the reaction site is single, and the method has the advantage of high yield. In a word, the synthetic route and the preparation method have the advantages of short reaction steps, single reaction site in each step and high yield, and meanwhile, the preparation method has simple post-treatment of the reaction, only adopts pulping purification in the purification step, avoids expensive column chromatography purification, directly reduces the reaction cost, and effectively improves the total yield of the reaction and the industrial operability.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 Synthesis of Compound represented by formula 3
A compound represented by the formula 1 (15.36g,100mmol) and K are reacted at room temperature2CO3(15.20g,110mmol) is added into DMF (240mL) which is stirred for mixing, then the mixed solution containing the compound shown in the formula 2 (16.85g,110mmol) and DMF (40mL) is slowly dropped, the temperature is raised to 100 ℃, stirring is carried out for 2h, after the reaction is finished, the reaction solution is poured into water (300mL), the precipitated solid is filtered and collected, the mixed solvent (150mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 3:1 is used for stirring, pulping and purifying for 30min, the solid is filtered, and the compound shown in the formula 3 is obtained after drying, the yield is 24.89g, and the yield is 92.1%.
LC-MS(APCI):m/z＝271.2(M+1)+。
EXAMPLE 2 Synthesis of Compound represented by formula 3
A compound represented by the formula 1 (15.36g,100mmol) and K are reacted at room temperature2CO3(13.82g,100mmol) is added into DMF (240mL) which is stirred for mixing, then the mixed solution containing the compound shown in the formula 2 (15.31g,100mmol) and DMF (40mL) is slowly dropped, the temperature is raised to 90 ℃, stirring is carried out for reaction for 2.5h, after the reaction is finished, the reaction solution is poured into water (300mL), the precipitated solid is filtered and collected, then the mixed solvent (150mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 3:1 is used for stirring, pulping and purifying for 30min, the solid is filtered, and the compound shown in the formula 3 is obtained after drying, the yield is 23.97g, and the yield is 88.7%.
EXAMPLE 3 Synthesis of Compound represented by formula 3
A compound represented by the formula 1 (15.36g,100mmol) and K are reacted at room temperature2CO3(17.97g,130mmol) was added to DMF (240mL) while stirring and mixed, and then a mixture of the compound represented by formula 2 (15.31g,120mmol) and DMF (40mL) was slowly added dropwise thereto, the temperature was raised to 105 ℃ and the reaction was stirred for 1.5 hours, after the reaction was completed, the reaction solution was poured into water (300mL), the precipitated solid was collected by filtration, and then the mixture was used in a volume ratio of 3:1Stirring and pulping a mixed solvent (150mL) consisting of petroleum ether/ethyl acetate for 30min, filtering the solid, and drying to obtain the compound shown in the formula 3, wherein the yield is 24.59g and 91.0%.
Example 4 Synthesis of Compound represented by formula 4
Pd/C (10%, 750mg) was added to a solution of the compound represented by formula 3 (7.5g) and methanol (75ml), the mixture was replaced with hydrogen gas several times under vacuum, the reaction solution was kept at 20 to 30 ℃ under a hydrogen atmosphere and stirred for 1 hour, after TLC showed complete consumption of the raw material, the Pd/C was removed by filtration from the reaction solution, and the filtrate was concentrated to dryness to obtain 6.30g of a solid which was the compound represented by formula 4 with a yield of 94.5%.
LC-MS(APCI):m/z＝241.2(M+1)+。
EXAMPLE 5 Synthesis of Compound represented by formula 4
Pd/C (5%, 375mg) was added to a solution of the compound represented by formula 3 (7.5g) and methanol (375ml), the mixture was replaced with hydrogen gas several times under vacuum, the reaction solution was kept at 20 to 30 ℃ under a hydrogen atmosphere and stirred for 1.5 hours, after TLC showed complete consumption of the raw material, the Pd/C was removed by filtration from the reaction solution, and the filtrate was concentrated to dryness to obtain 6.13g of a solid which is the compound represented by formula 4 with a yield of 92.0%.
EXAMPLE 6 Synthesis of Compound represented by formula 4
Pd/C (2.5%, 188mg) was added to a solution of the compound represented by formula 3 (7.5g) and ethanol (60ml), the mixture was replaced with hydrogen under vacuum several times, the reaction solution was stirred at 20 to 30 ℃ for 2 hours under a hydrogen atmosphere, after TLC showed complete consumption of the raw material, the Pd/C was removed by filtration from the reaction solution, and the filtrate was concentrated to dryness to obtain a solid 5.96g as the compound represented by formula 4 with a yield of 89.4%.
Example 7 Synthesis of Compound represented by formula 6
A compound represented by the formula 4 (24.03g,100mmol) and K are reacted at room temperature2CO3(16.58g,120mmol) is added into DMF (250mL) which is stirred for mixing, then the mixed solution containing the compound shown in the formula 5 (20.96g,100mmol) and DMF (50mL) is slowly dropped, the temperature is raised to 80 ℃, stirring is carried out for reaction for 1h, after the reaction is finished, the reaction solution is poured into water (500mL), the precipitated solid is filtered and collected, then the mixed solvent (200mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1 is stirred, pulped and purified for 30min,the solid was filtered and dried to obtain 37.58g of the compound represented by formula 6 in a yield of 90.9%.
LC-MS(APCI):m/z＝414.2(M+1)+。
EXAMPLE 8 Synthesis of Compound represented by formula 6
A compound represented by the formula 4 (24.03g,100mmol) and K are reacted at room temperature2CO3(13.82g,100mmol) is added into DMF (250mL) which is stirred for mixing, then the mixed solution containing the compound shown in the formula 5 (23.06g,110mmol) and DMF (50mL) is slowly dropped, the temperature is raised to 70 ℃, stirring is carried out for 1.5h, after the reaction is finished, the reaction solution is poured into water (500mL), the precipitated solid is filtered and collected, then the mixed solvent (200mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1 is used for stirring and pulping for purification for 30min, the solid is filtered, and the compound shown in the formula 6 is obtained after drying, the yield is 36.67g, and the yield is 88.7%.
Example 9 Synthesis of Compound represented by formula 6
A compound represented by the formula 4 (24.03g,100mmol) and K are reacted at room temperature2CO3(17.97g,130mmol) is added into DMF (250mL) which is stirred for mixing, then a mixed solution containing a compound shown as a formula 5 (25.15g,120mmol) and DMF (50mL) is slowly dropped, the temperature is raised to 90 ℃, stirring is carried out for 45 minutes, after the reaction is finished, the reaction liquid is poured into water (500mL), precipitated solid is filtered and collected, mixed solvent (200mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1 is used for stirring, pulping and purifying for 30 minutes, the solid is filtered, and the compound shown as a formula 6 is obtained after drying, the yield is 37.21g, and the yield is 90.0%.
EXAMPLE 10 Synthesis of the Compound of formula I, illustrated in Tucanitinib
To a stirred mixture of the compound represented by formula 6 (41.34g,100mmol) and dioxane (410ml), the compound represented by formula 7 (13.70g,120mmol) and K were added in this order3PO4·3H2O(39.35g,150mmol)、Pd(acac)2(1.52g,5mmol) and ligand L (Compound represented by formula 8) (5.06g,10mmol), and the reaction mixture was subjected to vacuum displacement of N at room temperature2Heating to 90 deg.C for 24 hr, reacting, cooling, concentrating the reaction solution at low temperature to remove half of solvent, pouring into water (400mL), filtering, collecting the solid, and concentrating by volumeStirring and pulping a mixed solvent (200mL) consisting of petroleum ether and ethyl acetate in a ratio of 1:1 for 30min, filtering and drying to obtain 44.1g of solid which is the compound of the formula I, namely the Tucotinib, with the yield of 91.8 percent and the HPLC purity of 99.7 percent.
LC-MS(APCI):m/z＝481.3(M+1)+。
EXAMPLE 11 Synthesis of the Compound of formula I, illustrated by Charcotinib
To a stirred mixture of the compound represented by formula 6 (41.34g,100mmol) and dioxane (400ml), the compound represented by formula 7 (11.42g,100mmol) and K were added in this order3PO4·3H2O(29.29g,110mmol)、Pd(acac)2(760mg,2.5mmol) and ligand L (compound represented by formula 8) (2.53g,5mmol), and the reaction mixture was subjected to vacuum displacement of N at room temperature2After several times, heating to 95 ℃ for reaction for 18h, after the reaction is finished, cooling and post-treating, concentrating the reaction liquid at low temperature to remove half of the solvent, pouring the concentrated reaction liquid into water (400mL), filtering and collecting the precipitated solid, stirring and pulping the solid for purification for 30min by using a mixed solvent (200mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1, filtering and drying to obtain 42.0g of solid, namely the compound of formula I, namely the cartilaginib, the yield is 87.4%, and the HPLC purity is 99.1%.
Example 12 Synthesis of the Compound of formula I, Tucanitinib
To a stirred mixture of the compound represented by formula 6 (41.34g,100mmol) and dioxane (600ml), the compound represented by formula 7 (17.12g,150mmol) and K were added in this order3PO4·3H2O(42.61g,160mmol)、Pd(acac)2(3.04g,10mmol) and ligand L (Compound represented by formula 8) (10.12g,20mmol), and the reaction mixture was subjected to vacuum displacement of N at room temperature2After several times, heating to 75 ℃ for reaction for 36 hours, after the reaction is finished, cooling and post-treating, concentrating the reaction liquid at low temperature to remove half of the solvent, pouring the concentrated reaction liquid into water (400mL), filtering and collecting the precipitated solid, stirring and pulping the solid for purification for 30 minutes by using a mixed solvent (200mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1, filtering and drying to obtain 43.3g of solid, namely the compound of formula I, namely the cartilaginib, the yield is 90.1%, and the HPLC purity is 99.4%.
Example 13 Synthesis of the Compound of formula I, Tucanitinib
Example 13 is a comparative example, and in this example, the inventors adjusted a compound represented by formula 6, a compound represented by formula 7, and K3PO4·3H2O、Pd(acac)2And a compound represented by formula 8 in a molar ratio of 1:2:2.5:0.2:0.4, and according to formula 6, a compound represented by formula 7, and K3PO4·3H2O、Pd(acac)2The reaction time of contacting and stirring the compound shown as the formula 8 is 15 h. The results show that example 13 is more effective than the compounds represented by the formula 6, the compounds represented by the formula 7 and K described in examples 10 to 12 of the present invention in terms of technical effects3PO4·3H2O、Pd(acac)2And the final product obtained when the molar ratio of the compound represented by the formula 8 is 1 (1.0-1.5): (1.1-1.6): (0.025-0.1): 0.05-0.2), the purity of the product obtained in example 13 is reduced, impurities are increased, the raw materials of the reactants are actually wasted in example 13, and the yield of the obtained target compound is not improved.
To a stirred mixture of the compound represented by formula 6 (41.34g,100mmol) and dioxane (600ml), the compound represented by formula 7 (22.83g,200mmol) and K were added in this order3PO4·3H2O(66.58g,250mmol)、Pd(acac)2(6.08g,20mmol) and ligand L (Compound represented by formula 8) (20.24g,40mmol), and the reaction mixture was subjected to vacuum displacement of N at room temperature2After several times, heating to 95 ℃ for reaction for 15 hours, after the reaction is finished, cooling and post-treating, concentrating the reaction liquid at low temperature to remove half of the solvent, pouring the concentrated reaction liquid into water (400mL), filtering and collecting the precipitated solid, stirring and pulping the solid for purification for 30 minutes by using a mixed solvent (200mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1, filtering and drying to obtain 41.9g of solid which is the compound of formula I, namely the cartilaginib, the yield is 87.2%, and the HPLC purity is 98.0%.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A preparation method of a compound of formula I, namely, Tucotinib, is characterized by comprising the following steps:
(1) reacting a compound represented by the formula 1 with K2CO3A compound of formula 2, so as to obtain a compound of formula 3;
(2) contacting the compound represented by formula 3 with palladium/carbon and hydrogen to obtain a compound represented by formula 4;
(3) reacting a compound represented by the formula 4 with K2CO3A compound of formula 5, to obtain a compound of formula 6;
(4) reacting a compound represented by the formula 6, a compound represented by the formula 7 and K3PO4·3H2O、Pd(acac)2And a compound of formula 8, to obtain a compound of formula I,
2. the method according to claim 1, wherein in step (1), the following steps are included: reacting a compound represented by formula 1 with K at room temperature2CO3Adding into DMF under stirring, mixing, and slowly adding dropwise compound containing compound shown in formula 2 and DMAnd F, heating the mixed solution, stirring and reacting, carrying out post-treatment after the reaction is finished, filtering and collecting the precipitated solid, stirring, pulping and purifying, filtering the solid, and drying to obtain the compound shown in the formula 3.
3. The method according to claim 2, wherein in step (1), the compound represented by formula 1, K2CO3The molar ratio of the compound represented by the formula 2 is 1 (1-1.3) to 1-1.2, preferably the compound represented by the formula 1 and K2CO3The molar ratio of the compound shown in the formula 2 is 1:1.1: 1.1;
optionally, in step (1), a compound represented by formula 1, K2CO3The reaction time of the contact stirring of the compound shown as the formula 2 is 1.5-2.5 h, and the compound shown as the formula 1 and K are preferably selected2CO3The reaction time of the contact stirring of the compound shown in the formula 2 is 2 hours;
optionally, in step (1), a compound represented by formula 1, K2CO3The reaction temperature for heating the compound represented by the formula 2 by contact stirring is 90 to 105 ℃, and the compound represented by the formula 1 and K are preferably selected2CO3Heating the compound shown in the formula 2 to 100 ℃, and stirring for reaction;
optionally, in the step (1), the pulping purification adopts a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 3: 1.
4. The method of claim 1, wherein in step (2), the following steps are included: adding Pd/C into the compound shown in the formula 3 and an organic solvent, replacing the compound with hydrogen for several times under vacuum, keeping the reaction liquid at 20-30 ℃ under the hydrogen atmosphere, stirring for 1-2 h, filtering the reaction liquid to remove Pd/C after TLC shows that the raw materials are completely consumed, and concentrating the filtrate to dryness to obtain the compound shown in the formula 4.
5. The method according to claim 1, wherein in the step (2), the mass ratio of the compound represented by the formula 3 to Pd/C is 1 (0.025-0.1), preferably the mass ratio of the compound represented by the formula 3 to Pd/C is 1: 0.1;
optionally, in the step (2), the organic solvent is a linear or branched alcohol selected from C1-C3, preferably the organic solvent is at least one selected from methanol and ethanol;
optionally, in the step (2), the mass-to-volume ratio of the compound represented by the formula 3 to the organic solvent is 1: (8-50).
6. The method of claim 1, wherein in step (3), the following steps are included: reacting a compound represented by the formula 4 with K at room temperature2CO3Adding the mixture into stirred DMF, mixing, slowly dropwise adding a mixed solution containing the compound shown in the formula 5 and DMF, heating and stirring for reaction, carrying out post-treatment after the reaction is finished, filtering and collecting precipitated solid, stirring, pulping and purifying, filtering the solid, and drying to obtain the compound shown in the formula 6.
7. The method according to claim 6, wherein in step (3), the compound represented by formula 4 is reacted with K2CO3The molar ratio of the compound represented by the formula 5 is 1 (1.0-1.3) to 1.0-1.2, preferably the compound represented by the formula 4 and K2CO3The molar ratio of the compound shown in the formula 5 is 1:1.2: 1.0;
optionally, in step (3), the compound of formula 4 is reacted with K2CO3The reaction time of the compound shown as the formula 5 in contact stirring is 45 minutes to 1.5 hours, and the compound shown as the formula 4 and K are preferably selected2CO3The reaction time of the compound shown in the formula 5 for contact stirring is 1 hour;
optionally, in step (3), the compound of formula 4 is reacted with K2CO3The reaction temperature for the contact, stirring and heating of the compound shown as the formula 5 is 70-90 ℃, and preferably the compound shown as the formula 4 and K2CO3Heating the compound shown in the formula 5 to 80 ℃, and stirring for reaction;
optionally, in the step (3), the pulping purification adopts a mixed solvent of petroleum ether/ethyl acetate with a volume ratio of 1:1.
8. The method of claim 1The method is characterized in that the step (4) comprises the following steps: adding the compound represented by the formula 7 and K to a mixture of the compound represented by the formula 6 and dioxane under stirring3PO4·3H2O、Pd(acac)2And a compound represented by the formula 8, wherein N is replaced with a reaction solution at room temperature under vacuum2Heating and stirring for reaction for several times, cooling after the reaction is finished, concentrating the reaction solution at low temperature to remove half of the solvent, pouring the solution into water (60mL), filtering and collecting the precipitated solid, stirring and pulping the solid by using an organic solvent for purification, filtering and drying to obtain the solid which is the compound shown in the formula I.
9. The method according to claim 8, wherein in the step (4), the compound represented by the formula 6, the compound represented by the formula 7, K3PO4·3H2O、Pd(acac)2And the compound represented by the formula 8 is in a molar ratio of 1 (1.0-1.5): 1.1-1.6): 0.025-0.1): 0.05-0.2, preferably the compound represented by the formula 6, the compound represented by the formula 7, and K3PO4·3H2O、Pd(acac)2And the compound of formula 8 in a molar ratio of 1:1.2:1.5:0.05: 0.1;
optionally, in step (4), a compound represented by formula 6, a compound represented by formula 7, K3PO4·3H2O、Pd(acac)2The reaction time of the compound shown as the formula 8 and the contact stirring is 18-32 h, and the compound shown as the formula 6, the compound shown as the formula 7 and the compound K are preferable3PO4·3H2O、Pd(acac)2The reaction time of the contact stirring of the compound shown as the formula 8 and the compound is 24 hours;
optionally, in step (4), a compound represented by formula 6, a compound represented by formula 7, K3PO4·3H2O、Pd(acac)2The reaction temperature for contacting with the compound represented by the formula 8, stirring and raising the temperature is 75 to 95 ℃, and the compound represented by the formula 6, the compound represented by the formula 7 and K are preferably selected3PO4·3H2O、Pd(acac)2And the compound shown in the formula 8 is heated to 90 ℃ and stirred for reaction.
10. According to claim1-9, wherein in step (1), the method comprises the steps of: a compound represented by the formula 1 (15.36g,100mmol) and K are reacted at room temperature2CO3(15.20g,110mmol) is added into DMF (240mL) which is stirred for mixing, then mixed liquid containing a compound (16.85g,110mmol) shown in the formula 2 and DMF (40mL) is slowly dripped, the temperature is raised to 100 ℃, stirring is carried out for 2h, after the reaction is finished, reaction liquid is poured into water (300mL), precipitated solid is filtered and collected, mixed solvent (150mL) consisting of petroleum ether/ethyl acetate with the volume ratio of 3:1 is used for stirring, pulping and purifying for 30min, the solid is filtered, and the compound shown in the formula 3 is obtained after drying, the yield is 24.89g, and the yield is 92.1%;
in the step (2), the method comprises the following steps: adding Pd/C (10%, 750mg) into a compound (7.5g) shown in formula 3 and methanol (75ml), replacing the mixture with hydrogen for several times under vacuum, keeping the reaction liquid at 20-30 ℃ under a hydrogen atmosphere, stirring for 1h, filtering the reaction liquid to remove the Pd/C after TLC shows that the raw materials are completely consumed, and concentrating the filtrate to dryness to obtain a solid 6.30g which is a compound shown in formula 4 with the yield of 94.5%;
in the step (3), the method comprises the following steps: a compound represented by the formula 4 (24.03g,100mmol) and K are reacted at room temperature2CO3(16.58g,120mmol) is added into DMF (250mL) which is stirred for mixing, then the mixed solution containing the compound shown in the formula 5 (20.96g,100mmol) and DMF (50mL) is slowly dripped, the temperature is raised to 80 ℃, stirring is carried out for 1h, after the reaction is finished, the reaction solution is poured into water (500mL), the precipitated solid is filtered and collected, the mixed solvent (200mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1 is used for stirring, pulping and purifying for 30min, the solid is filtered, and the compound shown in the formula 6 is obtained after drying, the yield is 37.58g, and the yield is 90.9%;
in the step (4), the method comprises the following steps: to a stirred mixture of the compound represented by formula 6 (41.34g,100mmol) and dioxane (410ml), the compound represented by formula 7 (17.12g,150mmol) and K were added in this order3PO4·3H2O(39.35g,150mmol)、Pd(acac)2(1.52g,5mmol) and ligand L (Compound represented by formula 8) (5.06g,10mmol), and the reaction mixture was subjected to vacuum displacement of N at room temperature2Heating to 90 deg.C for 24 hr, cooling, concentrating the reaction solution at low temperatureRemoving half of the solvent, pouring into water (400mL), filtering and collecting the precipitated solid, stirring and pulping by using a mixed solvent (200mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1 for 30min, purifying, filtering and drying to obtain 44.11g of solid which is the compound of the formula I, namely the Tucotinib, with the yield of 91.8% and the HPLC purity of 99.7%.
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| CN109422755A (en) * | 2017-09-01 | 2019-03-05 | 上海医药集团股份有限公司 | A kind of nitrogen-containing heterocycle compound, preparation method, intermediate, composition and application |
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