Synthesis method of 1H-indazole-7-tert-butyl formate

Abstract

The invention discloses a synthesis method of 1H-indazole-7-tert-butyl formate, and belongs to the technical field of organic synthesis. The synthesis method of the 1H-indazole-7-tert-butyl formate comprises the following steps: dissolving 7-carboxyl-1H-indazole in an organic solvent I, then adding 1, 1-di-tert-butoxy-N, N-dimethyl methylamine, heating, and carrying out a stirring reaction to obtain a reaction solution; and performing post-treatment. According to the synthesis method, one-step conversion of indazole carboxylic acid into indazole tert-butyl formate is achieved, reaction conditions are mild, aftertreatment and purification are simple, cost is low, and manufacturability amplification can be achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing tert-butyl 1H-indazole-7-carboxylate. Background Art

[0002] Tert-butyl indazole carboxylates are an important class of organic compounds with widespread applications in fields such as synthesis, pesticides, and pharmaceuticals. For example, patent WO2018 / 234354 discloses the synthesis of novel substituted 3-indole and 3-indazole compounds used as phosphodiesterase inhibitors, using tert-butyl 1H-indazole-5-carboxylate as a key intermediate. Patent WO2024 / 088351 also discloses the synthesis of drugs for BAF complex-related diseases using tert-butyl 1H-indazole-6-carboxylate as a key intermediate. Tert-butyl indazole carboxylates hold great potential for application in drug development.

[0003] In this type of compounds, tert-butyl 1H-indazole-7-carboxylate serves as an important molecular building block. For example, in the article "Process Development of C-NCross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib" published by Cheol K. Chung et al., tert-butyl 1H-indazole-7-carboxylate was used as a key intermediate for the synthesis of the orally active poly(adenosine ribose) polymerase inhibitor niraparib.

[0004] In the prior art, the synthesis route of tert-butyl 1H-indazole-7-carboxylate has not been reported. Further research on its synthesis method will not only be beneficial to the development of this compound, but will also contribute to the development and utilization of tert-butyl indazolecarboxylate compounds. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention provides a method for synthesizing tert-butyl 1H-indazole-7-carboxylate. This method utilizes 1,1-di-tert-butoxy-N,N-dimethylmethylamine to convert 7-carboxyl-1H-indazole into tert-butyl indazole formate. The reaction conditions are mild, the operation is simple, and the yield is high.

[0006] The technical solutions of the present invention are as follows:

[0007] The first aspect of the present invention provides a method for synthesizing tert-butyl 1H-indazole-7-carboxylate, comprising the following steps:

[0008] 7-Carboxyl-1H-indazole is dissolved in organic solvent I, and 1,1-di-tert-butoxy-N,N-dimethylmethylamine is added. The temperature is raised and the reaction is stirred to obtain a reaction solution. After post-treatment, the target compound, i.e., tert-butyl 1H-indazole-7-carboxylate, is obtained.

[0009] Preferably, the organic solvent I is selected from one or more of toluene, cyclohexane and xylene.

[0010] Preferably, the mass volume ratio of the 7-carboxy-1H-indazole to the organic solvent I is 1:5-40 (g / mL).

[0011] Preferably, the molar ratio of the 7-carboxy-1H-indazole to the 1,1-di-tert-butoxy-N,N-dimethylmethylamine is 1:1-3.

[0012] Preferably, the reaction temperature is 60-200° C. and the reaction time is 10-40 h.

[0013] Preferably, the specific process of the post-processing is:

[0014] After the reaction is complete, the reaction solution is cooled, concentrated under reduced pressure, extracted with organic solvent II-alkali solution, and then the aqueous phase is extracted with organic solvent II. The organic phases are combined, dried, filtered, and concentrated to obtain a crude product. The crude product is purified to obtain the target compound, i.e., tert-butyl 1H-indazole-7-carboxylate.

[0015] Preferably, in the organic solvent II-alkali solution, the volume ratio of the organic solvent II to the alkali solution is 1 to 1.5:1.

[0016] Preferably, the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane;

[0017] The alkali solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, and potassium hydroxide solution;

[0018] Preferably, the concentration of the alkali solution is 4 to 6 mol / L.

[0019] Preferably, the purification method includes one or more of beating, column chromatography, recrystallization, and distillation.

[0020] The beneficial technical effects of the present invention are:

[0021] The invention uses 7-carboxyl-1H-indazole as a raw material and synthesizes 1H-indazole-7-tert-butyl carboxylate under the action of 1,1-di-tert-butoxy-N,N-dimethylmethylamine.

[0022] The synthesis method of the present invention realizes the one-step conversion of indazole carboxylic acid into indazole tert-butyl formate, has mild reaction conditions, simple post-treatment and purification, low cost, and can achieve process scale-up. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the H NMR spectrum of tert-butyl 1H-indazole-7-carboxylate prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0024] The present invention will be described in detail below with reference to the embodiments.

[0025] The first aspect of the present invention provides a method for synthesizing tert-butyl 1H-indazole-7-carboxylate, comprising the following steps:

[0026] 7-Carboxyl-1H-indazole is dissolved in organic solvent I, and 1,1-di-tert-butoxy-N,N-dimethylmethylamine is added. The temperature is raised and the reaction is stirred to obtain a reaction solution. After post-treatment, the target compound, i.e., tert-butyl 1H-indazole-7-carboxylate, is obtained.

[0027] In some embodiments, the synthesis method of tert-butyl 1H-indazole-7-carboxylate includes the following steps: dissolving raw material 1, i.e., 7-carboxyl-1H-indazole, in organic solvent I, then adding raw material 2, i.e., 1,1-di-tert-butoxy-N,N-dimethylmethylamine, heating, stirring, and reacting to obtain a reaction solution; after the reaction is complete, the reaction solution is post-treated to obtain target compound 3, i.e., tert-butyl 1H-indazole-7-carboxylate. The corresponding synthesis route is as follows:

[0028]

[0029] In some embodiments, the organic solvent I is selected from one or more of toluene, cyclohexane, and xylene.

[0030] In some embodiments, the mass volume ratio of the 7-carboxy-1H-indazole to the organic solvent I is 1:5-40 g / mL.

[0031] In some embodiments, the molar ratio of 7-carboxy-1H-indazole to 1,1-di-tert-butoxy-N,N-dimethylmethylamine is 1:1 to 3, including but not limited to 1:1, 1:2, and 1:3.

[0032] In some embodiments, the reaction temperature is 60-200°C, including but not limited to 60°C, 90°C, 100°C, 120°C, 150°C, 180°C, and 200°C, and the reaction time is 10-40h, including but not limited to 10h, 20h, 30h, and 40h.

[0033] In some embodiments, the specific process of the post-processing is:

[0034] After the reaction is complete, the reaction solution is cooled, concentrated under reduced pressure, extracted with organic solvent II-alkali solution, and then the aqueous phase is extracted with organic solvent II. The organic phases are combined, dried, filtered, and concentrated to obtain a crude product. The crude product is purified to obtain the target compound, i.e., tert-butyl 1H-indazole-7-carboxylate.

[0035] In some embodiments, in the organic solvent II-alkali solution, the volume ratio of the organic solvent II to the alkali solution is 1 to 1.5:1, including but not limited to 1:1, 1.2:1, and 1.5:1.

[0036] In some embodiments, the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0037] The alkali solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution and potassium hydroxide solution.

[0038] In some embodiments, the concentration of the alkali solution is 4 to 6 mol / L, including but not limited to 4 mol / L, 5 mol / L, and 6 mol / L.

[0039] In some embodiments, the purification method includes one or more of beating, column chromatography, recrystallization, and distillation.

[0040] The following are specific embodiments.

[0041] Example 1

[0042] A method for synthesizing tert-butyl 1H-indazole-7-carboxylate comprises the following steps:

[0043] (1) Raw material 1, i.e., 7-carboxyl-1H-indazole (200.00 g, 1.23 mol, 1.00 eq) was dissolved in toluene (2.0 L), and raw material 2, i.e., 1,1-di-tert-butoxy-N,N-dimethylmethylamine (376.19 g, 1.85 mol, 1.50 eq) was added dropwise. After the addition, the temperature was raised to 100°C and the reaction was stirred at 100°C for 12 h.

[0044] (2) After the reaction is complete, the reaction solution is cooled and concentrated under reduced pressure to remove toluene. Ethyl acetate (3.0 L) and 5M sodium hydroxide aqueous solution (3.0 L) are added for extraction. The aqueous phase is then extracted twice with ethyl acetate (2.0 L × 2). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product is purified by beating with methyl tert-butyl ether (4.0 L) to obtain the target compound 3, i.e., tert-butyl 1H-indazole-7-carboxylate (weight 261.60 g, purity 98%, yield 95%).

[0045] The H NMR spectrum of the obtained compound 2 (tert-butyl 1H-indazole-7-carboxylate) is as follows: Figure 1 The characterization data are as follows:

[0046] 1 H NMR (400MHz, CDCl3) δ11.25(s,1H),8.14(s,1H),8.03(dd,J=7.3,0.8Hz,1H),7.96(dd,J=8.0,0.7Hz,1H),7.22(t,J=7.7Hz,1H),1.67(d,J=8.8Hz,9H).

[0047] Example 2-3

[0048] The synthesis method of Example 2-3 is basically the same as that of Example 1, except that the molar amounts of raw material 2, i.e., 1,1-di-tert-butoxy-N,N-dimethylmethylamine, in step (1) of Example 2-3 are adjusted to 1.23 mol and 3.08 mol, respectively, and the rest of the contents remain unchanged. The yield of tert-butyl 1H-indazole-7-carboxylate in Example 2-3 is shown in Table 1.

[0049] Examples 4-5

[0050] The synthesis method of Example 4-5 is basically the same as that of Example 1, except that the organic solvent I in step (1) of Example 4-5 is adjusted to cyclohexane and xylene, respectively, and the rest of the contents remain unchanged. The yield of tert-butyl 1H-indazole-7-carboxylate in Example 4-5 is shown in Table 1.

[0051] Examples 6-7

[0052] The synthesis method of Example 6-7 is basically the same as that of Example 1, except that the temperature of the stirring reaction in step (1) of Example 6-7 is adjusted to 90°C and 110°C, respectively, and the rest of the contents remain unchanged. The yield of tert-butyl 1H-indazole-7-carboxylate in Example 6-7 is shown in Table 1.

[0053] Examples 8-9

[0054] The synthesis method of Example 8-9 is basically the same as that of Example 1, except that the stirring reaction time in step (1) of Example 8-9 is adjusted to 10 h and 14 h, respectively, and the rest of the contents remain unchanged. The yield of tert-butyl 1H-indazole-7-carboxylate in Example 8-9 is shown in Table 1.

[0055] Table 1 Synthesis conditions and yield of tert-butyl 1H-indazole-7-carboxylate in each example

[0056]

[0057]

[0058] As shown in Table 1, compared with Examples 1-3, when the molar ratio of raw material 1 (7-carboxy-1H-indazole) to raw material 2 (1,1-di-tert-butoxy-N,N-dimethylmethylamine) was 1.0:1.00-2.50, the yield of the target compound, tert-butyl 1H-indazole-7-carboxylate, was high. The product yields were essentially equivalent when the molar ratio of raw material 1 to raw material 2 was 1.00:1.50 and 1.00:2.50. The results of Examples 1 and 4-5 indicate that the reactions proceeded smoothly using toluene, cyclohexane, and xylene as solvents, and the yields of the target compound, tert-butyl 1H-indazole-7-carboxylate, were high. The highest yield was achieved when toluene was used. The results of Examples 1 and 6-7 indicate that the reaction performance was optimal when conducted at 100°C. The results of Examples 1 and 8-9 indicate that the reaction performance was optimal when the reaction was conducted for 12 hours.

[0059] The above description is merely a preferred embodiment of the present invention, and the present invention is not limited to the above embodiment. It is understood that other improvements and variations directly derived or imagined by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing tert-butyl 1H-indazole-7-carboxylate, characterized in that: The steps include: 7-Carboxyl-1H-indazole is dissolved in organic solvent I, and 1,1-di-tert-butoxy-N,N-dimethylmethylamine is added. The temperature is raised and the reaction is stirred to obtain a reaction solution. After post-treatment, the target compound, i.e., tert-butyl 1H-indazole-7-carboxylate, is obtained.

2. The synthesis method according to claim 1, wherein The organic solvent I is selected from one or more of toluene, cyclohexane and xylene.

3. The synthesis method according to claim 1, wherein The mass volume ratio of the 7-carboxyl-1H-indazole to the organic solvent I is 1:5-40 g / mL.

4. The synthesis method according to claim 1, characterized in that The molar ratio of the 7-carboxyl-1H-indazole to the 1,1-di-tert-butoxy-N,N-dimethylmethylamine is 1:1-3.

5. The synthesis method according to claim 1, characterized in that The reaction temperature is 60-200° C. and the reaction time is 10-40 hours.

6. The synthesis method according to claim 1, characterized in that The specific process of the post-processing is: After the reaction is complete, the reaction solution is cooled, concentrated under reduced pressure, extracted with organic solvent II-alkali solution, and then the aqueous phase is extracted with organic solvent II. The organic phases are combined, dried, filtered, and concentrated to obtain a crude product. The crude product is purified to obtain the target compound, i.e., tert-butyl 1H-indazole-7-carboxylate.

7. The synthesis method according to claim 6, characterized in that In the organic solvent II-alkali solution, the volume ratio of the organic solvent II to the alkali solution is 1 to 1.5:

1.

8. The synthesis method according to claim 6, characterized in that The organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

9. The synthesis method according to claim 6, characterized in that The alkali solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, and potassium hydroxide solution; Preferably, the concentration of the alkali solution is 4-6 mol / L.

10. The synthesis method according to claim 6, characterized in that The purification method includes one or more of beating, column chromatography, recrystallization, and distillation.

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