CN114621221A - Tourtinib key intermediate and preparation method thereof - Google Patents
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Abstract
The embodiment of the invention discloses a preparation method of 4- ([1, 2, 4] triazolo [1, 5-a ] pyridine-7-yloxy) -3-methylaniline, which comprises the following steps: carrying out diazotization reaction on aniline to prepare a diazonium salt solution; carrying out coupling reaction on a compound 2-methylphenol and the diazonium salt solution under alkaline conditions to prepare 2-methyl-4- (phenyl diazenyl) phenol; carrying out nucleophilic substitution reaction on the 2-methyl-4- (phenyl diazenyl) phenol and 7-halogenated- [1, 2, 4] triazolo [1, 5-a ] pyridine to prepare a crude product of the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine; and (2) carrying out hydrogenation reduction reaction on the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine crude product to prepare 4- ([1, 2, 4] triazolo [1, 5-a ] pyridine-7-yloxy) -3-methylaniline. The invention also discloses a corresponding key intermediate of the tocaintinib. The method has the advantages of high economic value of the route, short synthesis step, high yield, stable properties of the prepared intermediate and product, less three wastes and suitability for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of organic synthetic pharmacy, in particular to a key intermediate 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline of tocaintinib and a preparation method thereof.
Background
Tocainib (tucatenib) is an oral inhibitor of HER2+ breast cancer, of the formula:
the chemical formula of a key intermediate 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline of tocaintinib (tucatenib) is as follows:
in the prior art, 2-methyl-4-nitrophenol or 2-methyl-4-aminophenol is used as a starting material to synthesize 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline.
However, the inventor finds that the technical scheme has the following defects in the process of implementing the invention:
the starting raw materials in the prior art are expensive and the production cost is high; and the chemical property is active, and reaction byproducts generated in the production process are many and difficult to purify.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a key intermediate 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline of the tocaininib and a preparation method thereof, so as to reduce the cost of raw materials, shorten the synthesis steps, improve the yield, improve the stability of the properties of the prepared product, reduce the generation of three wastes and be suitable for industrial scale-up production.
In order to solve the technical problem, in a first aspect, the invention discloses a preparation method of a key intermediate of tocaininib, wherein the key intermediate is 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline, and the preparation method comprises the following steps:
carrying out diazotization reaction on aniline to prepare a diazonium salt solution;
carrying out coupling reaction on a compound 2-methylphenol and the diazonium salt solution under alkaline conditions to prepare 2-methyl-4- (phenyl diazenyl) phenol;
carrying out nucleophilic substitution reaction on the 2-methyl-4- (phenyl diazenyl) phenol and 7-halogenated- [1, 2, 4] triazolo [1, 5-a ] pyridine to prepare a crude product of the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine;
and (2) carrying out hydrogenation reduction reaction on the crude product of the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine to prepare the 4- ([1, 2, 4] triazolo [1, 5-a ] pyridine-7-yloxy) -3-methylaniline.
In some possible embodiments, the diazotization reaction specifically comprises:
in an ice salt bath environment, adding hydrochloric acid, deionized water and glacial acetic acid into 1 equivalent of aniline, stirring, and then adding 1.0-1.05 equivalents of NaNO2The aqueous solution reacts to generate diazonium salt solution.
In some possible embodiments, the coupling reaction specifically comprises:
adding 1 equivalent of compound 2-methylphenol into water, dropwise adding NaOH aqueous solution to completely dissolve the compound 2-methylphenol, dropwise adding the diazonium salt solution, dropwise adding the NaOH aqueous solution to make the pH value of the mixed solution alkaline, keeping the temperature of 15-45 ℃ for complete reaction, salting out, filtering, washing and drying to obtain a pure product, namely the compound 2-methyl-4- (phenyl diazenyl) phenol.
In some possible embodiments, the nucleophilic substitution reaction specifically comprises:
under the protection of nitrogen, dissolving the 2-methyl-4- (phenyl diazenyl) phenol in an organic solvent 1, adding 7-halogenated- [1, 2, 4] triazolo [1, 5-a ] pyridine, inorganic base and a catalyst 1, heating to 70-160 ℃, reacting completely, elutriating, filtering and drying to obtain a crude product of the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine.
In some possible embodiments, the hydrogenation reduction reaction specifically comprises:
dissolving the crude 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine in an alcohol solvent, adding a catalyst 2, introducing hydrogen at normal pressure for hydrogenation, filtering the mixture with diatomite after the reaction is completed, concentrating the filtrate under reduced pressure, adding an organic solvent 2, stirring and crystallizing, filtering, and drying in vacuum to obtain the 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline.
In some possible embodiments, the organic solvent 1 is any one of N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone; and/or
The inorganic base is any one of sodium carbonate, potassium carbonate, cesium carbonate and potassium tert-butoxide;
the catalyst 1 is any one of tetrabutylammonium bromide and tetrabutylammonium iodide.
In some possible embodiments, the 7-halo- [1, 2, 4] triazolo [1, 5-a ] pyridine is any one of 7-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridine, 7-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridine, 7-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridine, 7-iodo- [1, 2, 4] triazolo [1, 5-a ] pyridine;
the alcohol solvent is methanol and/or ethanol; and/or
The catalyst 2 is any one of Pd/C and Rey-Ni;
the organic solvent 2 is any one or a mixed solvent of petroleum ether, normal hexane, heptane and methyl tert-butyl ether.
In some possible embodiments, the temperature of the ice bath salt is controlled to be-10 to 5 ℃.
In some possible embodiments, the pH value of the mixed solution is maintained to be 8-10.
In a second aspect, the embodiment of the invention discloses a tocaininib key intermediate which is 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline prepared by the method.
The invention has the beneficial effects that:
according to the embodiment of the invention, the cheap and easily-obtained 2-methylphenol and aniline with relatively inactive chemical properties are used as the starting raw materials to replace the expensive or chemically active raw material 2-methyl-4-nitrophenol 2-methyl-4-aminophenol in the prior art, so that the technical effects of high route economic value, short whole synthesis step, high yield, stable prepared intermediate and product properties, less three wastes and suitability for industrial scale-up production are achieved.
Detailed Description
The preparation method of the key intermediate of the tocaintinib provided by the embodiment of the invention is described in detail below, wherein the key intermediate is 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline, and the preparation method comprises the following steps:
carrying out diazotization reaction on aniline to prepare a diazonium salt solution;
carrying out coupling reaction on a compound 2-methylphenol and the diazonium salt solution under alkaline conditions to prepare 2-methyl-4- (phenyl diazenyl) phenol;
carrying out nucleophilic substitution reaction on the 2-methyl-4- (phenyl diazenyl) phenol and 7-halogenated- [1, 2, 4] triazolo [1, 5-a ] pyridine to prepare a crude product of the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine;
and (2) carrying out hydrogenation reduction reaction on the crude product of the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine to prepare the 4- ([1, 2, 4] triazolo [1, 5-a ] pyridine-7-yloxy) -3-methylaniline.
The chemical equation of each reaction process is as follows:
in some possible embodiments, the diazotization reaction specifically comprises:
in an ice salt bath environment, adding hydrochloric acid, deionized water and glacial acetic acid into 1 equivalent of aniline, stirring, and then adding 1.0-1.05Equivalent NaNO2The aqueous solution reacts to generate diazonium salt solution.
In some possible embodiments, the coupling reaction specifically comprises:
adding 1 equivalent of compound 2-methylphenol into water, dropwise adding NaOH aqueous solution to completely dissolve the compound 2-methylphenol, dropwise adding the diazonium salt solution, dropwise adding the NaOH aqueous solution to make the pH value of the mixed solution alkaline, keeping the temperature of 15-45 ℃ for complete reaction, salting out, filtering, washing and drying to obtain a pure product, namely the compound 2-methyl-4- (phenyldiazenyl) phenol.
In some possible embodiments, the nucleophilic substitution reaction specifically comprises:
under the protection of nitrogen, dissolving the 2-methyl-4- (phenyl diazenyl) phenol in an organic solvent 1, adding 7-halogenated- [1, 2, 4] triazolo [1, 5-a ] pyridine, inorganic base and a catalyst 1, heating to 70-160 ℃, reacting completely, performing elutriation, filtering and drying to obtain a crude product of the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine.
In some possible embodiments, the hydrogenation reduction reaction specifically comprises:
dissolving the crude 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine in an alcohol solvent, adding a catalyst 2, introducing hydrogen at normal pressure for hydrogenation, filtering the mixture with diatomite after the reaction is completed, concentrating the filtrate under reduced pressure, adding an organic solvent 2, stirring and crystallizing, filtering, and drying in vacuum to obtain the 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline.
In some possible embodiments, the organic solvent 1 is any one of N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone; and/or
The inorganic base is any one of sodium carbonate, potassium carbonate, cesium carbonate and potassium tert-butoxide; and/or
The catalyst 1 is any one of tetrabutylammonium bromide and tetrabutylammonium iodide; and/or
The 7-halogenated- [1, 2, 4] triazolo [1, 5-a ] pyridine is any one of 7-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridine, 7-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridine, 7-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridine and 7-iodo- [1, 2, 4] triazolo [1, 5-a ] pyridine.
In some possible embodiments, the alcoholic solvent is methanol and/or ethanol; and/or
The catalyst 2 is any one of Pd/C and Rey-Ni;
the organic solvent 2 is any one or a mixed solvent of petroleum ether, normal hexane, heptane and methyl tert-butyl ether.
In some possible embodiments, the temperature of the ice bath salt is controlled to be-10 to 5 ℃.
In some possible embodiments, the pH value of the mixed solution is maintained to be 8-10.
Compared with the prior art, the invention has the advantages that:
the method for preparing the 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline provided by the embodiment of the invention uses cheap and easily available 2-methylphenol and aniline with relatively inactive chemical properties as starting raw materials, avoids using expensive or chemically active raw materials of 2-methyl-4-nitrophenol or 2-methyl-4-aminophenol, has high route economic value, short whole synthesis step and high yield, and is suitable for industrial large-scale production, and the prepared intermediate and product have stable properties and few three wastes.
To further illustrate the technical means and effects of this example to achieve the intended purpose, the specific steps for preparing 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline, a key intermediate of tocaintinib, are detailed below by way of example data.
Example 1
Diazotization coupling reaction:
adding aniline (23.3g) and water (225mL) into a 1L three-mouth reaction bottle, stirring to prepare a uniform suspension, sequentially dropwise adding hydrochloric acid (65mL) and acetic acid (37.5mL), stirring for 15min to change the reaction solution into light brown yellow, cooling in an ice salt bath to below 5 ℃, and dropwise adding NaNO2(19g in 75mL water), and after the addition was complete, the reaction was stirred for 1.5h, turning brown-green and finally brown-yellow. The o-cresol solution and the NaOH solution were added dropwise at the same time, a yellow solid was gradually produced, and then slowly dissolved, and the solution became brown. And after the o-cresol is dropwise added, continuously dropwise adding a NaOH solution, adjusting the pH value to 8-10, stopping dropwise adding the NaOH solution, stirring at 25 ℃ for reacting for 4 hours, separating out a solid with earthy yellow color, filtering the solid, drying and weighing the 2-methyl-4- (phenyl diazenyl) phenol (49.3g), wherein the yield is 93%.
1H NMR(600MHz，DMSO-d6)δ7.80(d，J＝8.0Hz，2H)，7.69(s，1H)，7.65(d，J＝8.5Hz，1H)，7.55(t，J＝7.5Hz，2H)，7.48(t，J＝7.2Hz，1H)，6.97(d，J＝8.5Hz，1H)，2.21(s，3H)。
Nucleophilic substitution reaction:
in a 500mL three-necked flask, 2-methyl-4- (phenyldiazenyl) phenol (22.1g), 7-chloro- (1, 2, 4) triazolo (1, 5-a) pyridine (12.2g), cesium carbonate (27.6g), DMF (100mL), tetrabutylammonium bromide (1.5g) were added under nitrogen. Stirring and heating to reflux (130-140 deg.C), and reacting for 48 h. After the control reaction is finished, slowly dripping water (300mL) into the reaction liquid, stirring for 1h at the temperature of 5-10 ℃, separating out a yellow-brown solid, filtering to obtain a product, and drying by air blowing to obtain a crude product (23.3g) of 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine, wherein the yield is 89%, and the crude product is directly used for the next reaction.
Hydrogenation reduction reaction:
adding 7- (2-methyl-4- (phenyldiazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine 6(20.0g) into a 500ml single-neck flask, adding ethanol (150ml), stirring to dissolve, adding 5% Pd/C (1.0g), a hydrogen replacement system, protecting a hydrogen balloon, heating to 50 ℃ for reaction for 2h, taking a sample, completely reacting the raw materials, filtering the reaction solution with kieselguhr, concentrating the filtrate to dryness, adding methyl tert-butyl ether (100ml), stirring, pulping, performing suction filtration under reduced pressure to obtain an off-white solid, and performing vacuum drying to obtain 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline (13.3g) with the yield of 91.3%.
1H NMR(600MHz，DMSO-d6)δ8.85(d，J＝7.5Hz，1H)，8.33(s，1H)，6.94(dd，J＝7.5，2.6Hz，1H)，6.81(d，J＝8.5Hz，1H)，6.61(d，J＝2.6Hz，1H)，6.54(d，J＝2.7Hz，1H)，6.49(dd，J＝8.5，2.7Hz，1H)，5.08(s，2H)，1.98(s，3H)。
Example 2
This example replaces the nucleophilic substitution reaction of example 1 with the following under otherwise identical conditions as example 1:
in a 50mL single-necked flask, 2-methyl-4- (phenyldiazenyl) phenol (2.0g), 7-iodo- (1, 2, 4) triazolo (1, 5-a) pyridine (1.0g), potassium carbonate (1.7g), DMF (15mL) was added under nitrogen. Stirring and heating to reflux (140-150 deg.C), and reacting for 36 h. After the control reaction, the reaction solution was slowly dropped into water (30mL), stirred at 5-10 ℃ for 1h to precipitate a yellowish-brown solid, and the product was filtered and air-dried to obtain a crude product (1.1g) of 7- (2-methyl-4- (phenyldiazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine in a yield of 81.8%.
Example 3
This example replaces the nucleophilic substitution reaction of example 1 with the following under otherwise identical conditions as example 1:
in a 50mL single-necked flask, 2-methyl-4- (phenyldiazenyl) phenol (2.2g), 7-fluoro- (1, 2, 4) triazolo (1, 5-a) pyridine (1.0g), sodium carbonate (1.5g), DMF (15mL), tetrabutylammonium iodide (0.1g) were added under nitrogen. Stirring and heating to reflux (100-120 deg.C), and reacting for 30 h. After the control reaction is finished, slowly dripping water (30mL) into the reaction liquid, stirring for 1h at 5-10 ℃, separating out a yellow-brown solid, filtering to obtain a product, and drying by blowing air to obtain a crude product (1.9g) of 7- (2-methyl-4- (phenyldiazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine with the yield of 79.1%.
Example 4
This example replaces the hydrogenation reduction reaction of example 1 with the following steps under the same conditions as in example 1:
adding 7- (2-methyl-4- (phenyldiazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine 6(5.0g) into a 100ml single-neck bottle, adding methanol (35m1), stirring for dissolving, adding Rey-Ni (0.5g), a hydrogen replacement system and a hydrogen balloon for protection, heating to 30-40 ℃ for reaction for 4 hours, taking a sample, completely reacting the raw materials, filtering the reaction solution by using kieselguhr, concentrating the filtrate to dryness, adding n-hexane (20ml), stirring for pulping, carrying out vacuum filtration to obtain an off-white solid, and carrying out vacuum drying to obtain 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline (3.5g) with the yield of 95.9%.
The embodiment of the invention also discloses a key intermediate of the tacrolinib, which is 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline obtained by the preparation method in the embodiment and is not repeated.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all should be considered as belonging to the protection scope of the invention.
Claims (10)
1. A preparation method of a key intermediate of tocaintinib, wherein the key intermediate is 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline, is characterized by comprising the following steps:
carrying out diazotization reaction on aniline to prepare a diazonium salt solution;
carrying out coupling reaction on a compound 2-methylphenol and the diazonium salt solution under alkaline conditions to prepare 2-methyl-4- (phenyl diazenyl) phenol;
carrying out nucleophilic substitution reaction on the 2-methyl-4- (phenyl diazenyl) phenol and 7-halogenated- [1, 2, 4] triazolo [1, 5-a ] pyridine to prepare a crude product of the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine;
and (2) carrying out hydrogenation reduction reaction on the crude product of the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine to prepare the 4- ([1, 2, 4] triazolo [1, 5-a ] pyridine-7-yloxy) -3-methylaniline.
2. The method according to claim 1, wherein the diazotization reaction comprises in particular:
in an ice salt bath environment, adding hydrochloric acid, deionized water and glacial acetic acid into 1 equivalent of aniline, stirring, and then adding 1.0-1.05 equivalents of NaNO2The aqueous solution reacts to generate diazonium salt solution.
3. The method according to claim 1, wherein the coupling reaction comprises in particular:
adding 1 equivalent of compound 2-methylphenol into water, dropwise adding NaOH aqueous solution to completely dissolve the compound 2-methylphenol, dropwise adding the diazonium salt solution, dropwise adding the NaOH aqueous solution to make the pH value of the mixed solution alkaline, keeping the temperature of 15-45 ℃ for complete reaction, salting out, filtering, washing and drying to obtain a pure product, namely the compound 2-methyl-4- (phenyl diazenyl) phenol.
4. The method according to claim 1, characterized in that the nucleophilic substitution reaction comprises in particular:
under the protection of nitrogen, dissolving the 2-methyl-4- (phenyl diazenyl) phenol in an organic solvent 1, adding 7-halogenated- [1, 2, 4] triazolo [1, 5-a ] pyridine, inorganic base and a catalyst 1, heating to 70-160 ℃, reacting completely, elutriating, filtering and drying to obtain a crude product of the 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine.
5. The method according to claim 1, wherein the hydrogenation reduction reaction comprises in particular:
dissolving the crude 7- (2-methyl-4- (phenyl diazenyl) phenoxy) - [1, 2, 4] triazolo [1, 5-a ] pyridine in an alcohol solvent, adding a catalyst 2, introducing hydrogen at normal pressure for hydrogenation, filtering the mixture with diatomite after the reaction is completed, concentrating the filtrate under reduced pressure, adding an organic solvent 2, stirring and crystallizing, filtering, and drying in vacuum to obtain the 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline.
6. The method of claim 4, wherein: the organic solvent 1 is any one of N, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone; and/or
The inorganic base is any one of sodium carbonate, potassium carbonate, cesium carbonate and potassium tert-butoxide; and/or
The catalyst 1 is any one of tetrabutylammonium bromide and tetrabutylammonium iodide; and/or
The 7-halogenated- [1, 2, 4] triazolo [1, 5-a ] pyridine is any one of 7-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridine, 7-fluoro- [1, 2, 4] triazolo [1, 5-a ] pyridine, 7-bromo- [1, 2, 4] triazolo [1, 5-a ] pyridine and 7-iodo- [1, 2, 4] triazolo [1, 5-a ] pyridine.
7. The method of claim 5, wherein: the alcohol solvent is methanol and/or ethanol; and/or
The catalyst 2 is any one of Pd/CRey-Ni;
the organic solvent 2 is any one or a mixed solvent of petroleum ether, normal hexane, heptane and methyl tert-butyl ether.
8. The method of claim 2, wherein: the temperature of the ice bath salt is controlled to be-10-5 ℃.
9. The method of claim 3, wherein: and keeping the pH value of the mixed solution to be 8-10.
10. A key intermediate of the tocaintinib is 4- ([1, 2, 4] triazolo [1, 5-a ] pyridin-7-yloxy) -3-methylaniline, which is characterized in that: the key intermediate of the tocaintinib is prepared by adopting the method as claimed in any one of claims 1 to 9.
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