CN114671867A - Preparation method of 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine serving as intermediate of tocainib - Google Patents
Preparation method of 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine serving as intermediate of tocainib Download PDFInfo
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Abstract
The invention relates to the technical field of organic synthesis and preparation of raw material medicines, and discloses a preparation method of a key intermediate 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine of an antitumor medicine, namely tucaninib. The method comprises the following steps: (1) preparation of N-hydroxy-N' - (4-hydroxypyridin-2-yl) -carboxamide: mixing 2-amino-4-hydroxypyridine with an organic solvent, and adding N, N-dimethylformamide dimethyl acetal until the reaction is complete; B. adding hydroxylamine hydrochloride until the reaction is complete; (2) mixing N-hydroxy-N' - (4-hydroxypyridine-2-yl) -formamide with an organic solvent, adding trifluoroacetic anhydride, and performing intramolecular ring closure reaction to obtain a target product. Compared with the prior art, the method has the advantages of easily available raw materials, simple operation and mild reaction conditions; in addition, a protective group is not required to be introduced in the preparation process, the yield is obviously improved, the cost can be reduced, and the preparation method is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the field of organic synthesis and preparation of bulk drugs, in particular to a novel preparation method of 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine, which can be used as a key intermediate of antitumor drug Tukatinib.
Background
Tukatinib, also known as irbinitinib, ARRY-380 or ONT-380, is an oral inhibitor of HER2 (human epidermal growth factor receptor tyrosine kinase ErbB-2), under the trade name Tukysa. Developed by Seattle Genetics and received U.S. FDA approval on day 4/17 of 2020 for the treatment of HER2+ breast cancer. In addition, the compound 1 can be used as an intermediate of other medicines, including HER2 and Erbb inhibitors (WO2021156180, WO2019241715, WO2019214651 and WO2019214634) and glucokinase (GKa) activators (WO2013086397),
the 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine (1) can be used for preparing 4- ([1,2,4] triazolo [1,5-a ] pyridin-7-yloxy) -3-methylaniline (2) which is a key intermediate for preparing antineoplastic drug tocainib (tucatenib), and is shown as a formula I:
currently, two main methods are involved in the preparation of compound 1, as shown in formula II:
the method I (WO 2008072634, WO 2019214651) comprises the steps of taking benzyl alcohol and 2-nitro-4-chloropyridine (3) as raw materials, taking THF as a solvent, and carrying out nucleophilic substitution under the action of strong base NaH to obtain a compound 4- (benzyloxy) -2-nitropyridine (4), wherein the yield is 60%; then using LiHMDS as base to react with NH under the catalysis of Pd3Substituting Cl to obtain a compound 5; reacting the compound 5 with DMF-DMA and hydroxylamine hydrochloride in sequence to obtain 6, reacting with trifluoroacetic anhydride or hydroxylamine sulfonic acid to close a ring to obtain a compound 7, and carrying out Pd/C catalytic hydrogenolysis reaction to generate a compound 1; the total yield of the reaction in the last 3 steps is 20 percent, and the product needs to be purified by column chromatography.
In the second method (WO 2019214634), pyridine-2-formic acid is used as a raw material, the 2-amino-4-methoxypyridine (9) is prepared through 4 steps of reaction, the 2-amino-4-methoxypyridine is sequentially reacted with DMF-DMA and hydroxylamine hydrochloride to obtain 10, the compound is subjected to ring closing through the hydroxylamine sulfonic acid reaction to obtain a compound 11, and the compound 1 is obtained through high-temperature melting and methoxyl removal of pyridine hydrochloride. The starting material 9 has high market price, can be prepared by 4 steps of esterification, chlorination, amination and Hofmann degradation of pyridine-2-formic acid, and has the total yield of 33 percent.
The two synthetic methods have the disadvantages that the route steps are long, a plurality of types of protecting groups are used, part of the steps need column chromatography purification, and the two synthetic methods are not suitable for scale-up preparation. Therefore, it is necessary to improve the prior art to overcome the defects in the prior art, and to provide a preparation method with easily available raw materials, simple process, convenient operation and higher yield, so as to reduce the cost.
Disclosure of Invention
The invention aims to provide a novel method for preparing 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine.
The technical scheme of the invention is as follows:
an organic intermediate, 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine, having the chemical structure of formula 1:
the synthetic route of the organic intermediate 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine (1) is shown as a formula III, and the preparation method comprises the following steps:
(1) Preparation of N-hydroxy-N' - (4-hydroxypyridin-2-yl) -carboxamide:
mixing 2-amino-4-hydroxypyridine with an organic solvent, and adding N, N-dimethylformamide dimethyl acetal (DMF-DMA) until the reaction is complete;
B. adding hydroxylamine hydrochloride until the reaction is complete to obtain N-hydroxy-N' - (4-hydroxypyridine-2-yl) -formamide;
(2) mixing N-hydroxy-N' - (4-hydroxypyridine-2-yl) -formamide with an organic solvent, adding trifluoroacetic anhydride (TFAA), and performing intramolecular ring closure reaction to generate 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine.
In the step (1) A, the organic solvent is alcohol, especially C1-C4 alcohol, and is preferably methanol or ethanol.
The reaction conditions of the step A are as follows: heating at 70-95 deg.c and reflux to complete the reaction.
The reaction temperature in the step B is 20-95 ℃, and preferably 40-60 ℃.
In the step (1), the molar ratio of the 2-amino-4-hydroxypyridine to the N, N-dimethylformamide dimethyl acetal is 1: 1-2, preferably 1: 1.1-1.9. The molar ratio of the hydroxylamine hydrochloride to the 2-amino-4-hydroxypyridine is 1: 1.1-1.5, preferably 1: 1.2-1.3.
In the step (2), the molar ratio of the N-hydroxy-N' - (4-hydroxypyridin-2-yl) -formamide to trifluoroacetic anhydride is 1: 1-2, preferably 1: 1.1-1.3.
The step (2) comprises the following steps:
a.N-hydroxy-N' - (4-hydroxypyridine-2-yl) -formamide is mixed with an organic solvent, and trifluoroacetic anhydride is added at 50-75 ℃ for reaction for 0.5-10 h; or stirring at 5-15 deg.C for 0.5-1 hr, and reflux reacting for 20min-1 hr;
b. removing the solvent, and washing the reaction product to be neutral;
c. and (4) taking the solid, washing and drying.
In step a, the organic solvent is Tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO) or Dimethylformamide (DMF). Tetrahydrofuran is preferred.
Preferably, in step b, after removing the solvent, the reaction product is washed to neutrality with a weak base solution, which is a bicarbonate or carbonate solution, more preferably a saturated solution. Or in the step b, after the solvent is removed, washing the mixture by using a weak base solution and an organic solvent until the mixture is neutral, separating the mixture, taking out the organic phase and drying the organic phase. The organic solvent is dichloromethane, and the weak base solution is bicarbonate or carbonate solution, and is preferably saturated solution.
In the step c, washing and drying by using an organic solvent III, wherein the organic solvent III is alcohol, and methanol or ethanol is preferred.
The 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine with higher purity can be obtained by the method.
In the step (1), 2-amino-4-hydroxypyridine sequentially reacts with N, N-dimethylformamide dimethyl acetal and hydroxylamine hydrochloride, and the N-hydroxy-N' - (4-hydroxypyridine-2-yl) -formamide can be obtained without separation and purification, wherein the purity of the product is more than 99%; in the step (2), the product obtained in the step (1) reacts with trifluoroacetic anhydride to obtain the 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine through intramolecular cyclization, and after washing, the purity of the product is more than 98%, and the post-treatment is simple and convenient. The yield of each step exceeds 80 percent, and the total yield can reach 70 percent.
In addition, the method of the invention only needs two reactions to obtain the high-purity 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine; the steps are few, and the operation is convenient; in addition, the product does not need to be purified in the step (1), so that the process is simpler; the final product has high purity and simple and convenient post-treatment.
Compared with the prior art, the method has the advantages of easily available raw materials, simple operation and mild reaction conditions; in addition, in the preparation process, a protective group is not required to be introduced, the yield is obviously improved, the cost can be reduced, and the method is suitable for process amplification preparation and can be used for industrial large-scale production.
Detailed Description
The technical solution of the present invention will be described below with reference to specific examples.
Example 1 preparation of N-hydroxy-N' - (4-hydroxypyridin-2-yl) -carboxamide (13) (1)
A250 mL three-necked flask is taken, added with 2-amino-4-hydroxypyridine (15g, 0.136mol), added with 90mL EtOH, stirred to form yellow suspension, added with DMF-DMA (33g, 0.245mol), heated and refluxed for 3h at 80 ℃, and the TLC detects that the reaction is complete. Heating is turned off, 12g of hydroxylamine hydrochloride (0.17mol) is added after the reaction liquid is cooled to 40 ℃, the reaction is carried out for 2h at 50 ℃, the suspension turns white, the TLC detection reaction is completed, the heating is stopped, the reaction liquid is cooled to room temperature, and the filtration and drying are carried out at 60 ℃ to obtain off-white solid 13(18.1g, the yield is 87%).
1H NMR(400MHz,DMSO-d6)δ10.29(brs,1H),9.96(s,1H),9.08(d,J＝2.6Hz,1H),7.82(d,J＝5.4Hz,1H),7.78(d,J＝9.6Hz,1H),6.42(d,J＝2.6Hz,1H),6.95(dd,J＝5.2Hz,2.6Hz,1H).
13C NMR(100MHz,DMSO-d6)δ165.8,154.5,148.8,136.5,106.5,96.5.
LC-MS(ESI):154[M+H]+.
HPLC: agilent Eclipse XDB-C18(250 mm. times.4.6 mm. times.5 μm); detecting at 210 nm; the flow rate is 0.8 mL/min; the temperature is 30 ℃; the injection amount is 1 mu L; the solvent is methanol; the concentration is 0.2 mg/mL; the running time is 50 min; the mobile phase A is water; mobile phase B, methanol/triethylamine is 100: 0.1; elution gradient mobile phase a/mobile phase B10/90: tR1.906min, purity 99.69%.
Example 2 preparation of N-hydroxy-N' - (4-hydroxypyridin-2-yl) -carboxamide (13) (2)
2-amino-4-hydroxypyridine (42.9g, 0.39mol) was added to methanol (150mL), DMF-DMA (51.0g, 0.43mol) was added to the reaction solution, and the reaction suspension was stirred and heated to 60-65 ℃ for 2h to give a pale yellow solution. The resulting solution was cooled to about 40 ℃, then hydroxylamine hydrochloride (33.0g, 0.47mol) was added to the reaction, and the reaction solution was stirred and heated to 50-55 ℃ for reaction for 2 h. The reaction solution was cooled to room temperature and then cooled in an ice-water bath for 1h to give a solid, which was filtered, washed with methanol (15 mL. times.1), and dried at 55 ℃ for 8h to give off-white solid 13(49.5g, 83%).
The spectrum was checked to be the same as example 1, and the purity was 99.10%.
EXAMPLE 37 preparation of hydroxy- [1,2,4] triazolo [1,5-a ] pyridine (1)
N-hydroxy-N' - (4-hydroxypyridin-2-yl) -carboxamide (13) (46.0g, 0.3mol) was added to THF (380mL), stirred and heated to 60-65 ℃. TFAA (75.6g, 0.36mol) was added dropwise to the reaction over 30min, controlled at 65-70 ℃. The reaction was stirred at 65-70 ℃ for an additional 1h to give a pale yellow suspension. The solvent was removed under reduced pressure to give a yellow paste, to which was added a saturated sodium bicarbonate solution (600mL) to pH 7 and stirred at 5-10 ℃ for 1 h. The resulting solid was filtered with suction and washed with water (20 mL. times.2) to give 78g of a wet product. It was mixed with methanol (100mL), stirred and heated to reflux for 30min, stirred at 5-10 ℃ for 1 h. The resulting solid was filtered with suction, washed with methanol (15 mL. times.2), and dried at 55 ℃ for 6h to give off-white solid 1(36.7g, 81%).
1H NMR(400MHz,DMSO-d6)δ8.79(d,J＝5.2Hz,1H),8.46(s,1H),7.06(d,J＝2.6Hz,1H),6.84(dd,J＝5.2Hz,2.6Hz,1H).
13C NMR(100MHz,DMSO-d6)δ162.8,150.0,148.6,131.2,110.1,95.5.
LC-MS(ESI):174.1[M+Na]+.
HPLC: column Agilent Eclipse XDB-C18(250 mm. times.4.6 mm. times.5 μm); detecting at 210 nm; the flow rate is 0.8 mL/min; the temperature is 30 ℃; the injection amount is 1 mu L; the solvent is methanol; the concentration is 0.2 mg/mL; the running time is 40 min; the mobile phase A is water; mobile phase B, methanol/triethylamine is 100: 0.1; elution gradient mobile phase a/mobile phase B10/90: tR3.388min, purity 98.39%.
EXAMPLE 47 preparation (2) of hydroxy- [1,2,4] triazolo [1,5-a ] pyridine (1)
N-hydroxy-N' - (4-hydroxypyridin-2-yl) -carboxamide (13) (4.6g, 0.03mol) was added to THF (50mL) and cooled to 5 ℃. TFAA (7.6g, 0.036mol) was added dropwise to the reaction over 10min, controlled at 5-10 ℃. The reaction was stirred at 10-15 ℃ for a further 1h to give a pale yellow suspension which was heated to reflux for 30 min. The solvent was removed under reduced pressure to give a yellow paste, 50mL of methylene chloride and a saturated sodium bicarbonate solution (50mL) were added thereto, liquid separation was performed with stirring, the organic phase was washed with water (50 mL. times.2), and the organic phase was concentrated to dryness to give 7.1g of a crude product. It was mixed with methanol (20mL), stirred and heated to reflux for 30min, stirred at 5-10 ℃ for 1 h. The resulting solid was filtered with suction, washed with methanol (5 mL. times.2), and dried at 55 ℃ for 6h to give 1(2.4g, 53%) as a pale yellow solid.
The spectrum was analyzed as in example 3, and the purity was 97.81%.
It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (8)
- A process for the preparation of 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine, characterized by the steps of:(1) preparation of N-hydroxy-N' - (4-hydroxypyridin-2-yl) -carboxamide:mixing 2-amino-4-hydroxypyridine with an organic solvent, and adding N, N-dimethylformamide dimethyl acetal until the reaction is complete;B. adding hydroxylamine hydrochloride until the reaction is complete to obtain N-hydroxy-N' - (4-hydroxypyridine-2-yl) -formamide;(2) mixing N-hydroxy-N' - (4-hydroxypyridine-2-yl) -formamide with an organic solvent, adding trifluoroacetic anhydride (TFAA), and reacting to generate 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine.
- 2. The method according to claim 1, wherein in step (1) A, the organic solvent is an alcohol.
- 3. The method according to claim 1, wherein the reaction conditions in step (1) A are as follows: heating at 70-95 deg.c and reflux to complete the reaction.
- 4. The method according to claim 1, wherein in the step (1), the molar ratio of the 2-amino-4-hydroxypyridine to the N, N-dimethylformamide dimethyl acetal is 1: 1-2; the molar ratio of the hydroxylamine hydrochloride to the 2-amino-4-hydroxypyridine is 1: 1.1-1.5.
- 5. The process according to claim 1, wherein in step (2), the molar ratio of N-hydroxy-N' - (4-hydroxypyridin-2-yl) -carboxamide to trifluoroacetic anhydride is 1: 1-2.
- 6. The method according to claim 1, wherein the step (2) comprises:a.N-hydroxy-N' - (4-hydroxypyridine-2-yl) -formamide is mixed with an organic solvent, and trifluoroacetic anhydride is added at 50-75 ℃ for reaction for 0.5-10 h; or stirring at 5-15 deg.C for 0.5-1 hr, and reflux reacting for 20min-1 hr;b. removing the solvent, and washing the reaction product to be neutral;c. and (4) taking the solid, washing and drying.
- 7. The method according to claim 6, wherein the organic solvent is tetrahydrofuran, acetonitrile, dimethylsulfoxide or dimethylformamide in step a.
- 8. The method according to claim 6, wherein in the step c, the organic solvent is an alcohol.
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