Amide ligand and copper-catalyzed amino indazole piperidine compound synthesis method

Abstract

The invention relates to application of an amide ligand and a copper catalyst in preparation of an amino indazole piperidine compound. The indazole piperidine compound is prepared by reacting a halogen-substituted indazole piperidine compound with an ammonia reagent, the reaction is carried out under the action of an amide ligand and a catalyst, the amide ligand is # imgabs0, the structural formula of the amide ligand is # imgabs1 # or L-hydroxyproline, and the catalyst is a cuprous compound.

Description

Technical Field

[0001] The present invention relates to the application of amide ligands and copper catalysis in the synthesis of aminoindazolopiperidine compounds for the preparation of aminoindazolopiperidine compounds. Background Art

[0002] The structural formula of the halo-substituted indazolopiperidine compound is:

[0003]

[0004] A preparation method of this compound is disclosed in Chinese Patent CN110088099A, using Raney nickel as a catalyst to construct the indazole ring.

[0005] The route is as follows:

[0006]

[0007] The main disadvantages of this route are that in the first step, 2-methoxy-5-nitroaniline obtains the target product (2-methoxy-5-nitrophenyl)hydrazine under the conditions of sodium nitrite and stannous chloride. Under these reaction conditions, (2-methoxy-5-nitrophenyl)hydrazine is extremely likely to generate the corresponding nitrosamine impurity under the action of nitrosamine; while in the preparation process of the halo-substituted indazolopiperidine compound, tri-n-butylphosphine is used to prepare indazolopiperidine, avoiding the use of sodium nitrite. The main difficulty of this route lies in the ammonolysis of the halo-substituted indazolopiperidine compound.

[0008] Amide ligands are used in the synthesis of amino-thiophene compounds in Patent Application No. CN202311260534.3. After further research, the inventors found that amide ligands can also be used for aminoindazolopiperidine compounds, with significant technical effects. Summary of the Invention

[0009] The application research of amide ligands in the preparation of aminoindazolopiperidine compounds is still relatively scarce, or lacks breakthrough research results.

[0010] To achieve the above technical objectives, the present invention adopts the following technical solutions:

[0011] The present invention provides an application of an amide ligand and a copper catalyst in the preparation of aminoindazolopiperidine compounds. A method for preparing an aminoindazolopiperidine compound involving an amide ligand provided by the present invention. It is prepared by reacting a halo-substituted indazolopiperidine compound with an ammonia reagent, and its reaction formula is as follows:

[0012]

[0013] Among them, the structural formula of the amide ligand is:

[0014] or L-hydroxyproline,

[0015] Among them, the cuprous catalyst is a cuprous compound;

[0016] R1 is hydrogen, alkyl, alkoxy, nitro, trifluoromethyl, furyl, thienyl, naphthyl, phenyl, ester group, carboxyl group, aldehyde group, cyano group or phenyl substituted by one or more substituents, and the substituents are each independently methyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy or halogen,

[0017] R2 is an amino protecting group,

[0018] X is hydrogen, fluorine, chlorine, bromine or iodine,

[0019] R3 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen,

[0020] R4 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen,

[0021] R5 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen.

[0022] Among them, more preferably, the above reaction is:

[0023]

[0024] Among them, X is bromine, R1 is OEt, Me, NO2 or CF3, and R2 is PhCO or Boc.

[0025] The above ammoniation reaction of the present invention reacts in the presence of an amide ligand. A cuprous catalyst such as a cuprous salt compound also needs to be added in the reaction.

[0026] The cuprous salt compound can be cuprous halide or cuprous oxide, etc.; the cuprous halide can be cuprous bromide, cuprous iodide, etc.

[0027] The specific detailed process of the further ammoniation reaction can be as follows: Add a cuprous catalyst, a ligand, an acid-binding agent, and an organic solvent into a reaction flask. After purging with nitrogen three times, stir at room temperature for 1 hour, then add a halogen-substituted indazolopiperidine compound or an ammonia reagent into the reaction system. Raise the reaction temperature to 20-150 °C and react for 1-48 h. Monitor the reaction by TLC until it is completed. Pour the reaction solution into water, extract with ethyl acetate 2-3 times to obtain an organic phase. After concentrating the organic phase under reduced pressure, separate by column chromatography with ethyl acetate:n-heptane = 1:2-10, and then concentrate and dry to obtain an amino indazolopiperidine compound.

[0028] Among them, the molar ratio range of the halogenated thiophene compound: ammonia reagent: cuprous catalyst: ligand: acid-binding agent is 1:1-10:0.01-0.5:0.01-0.5:1-10.

[0029] More preferably, the molar ratio range of the halogenated thiophene compound: ammonia reagent: cuprous catalyst: ligand: acid-binding agent is 1:2-5:0.01-0.2:0.01-0.3:1-5.

[0030] Furthermore, the ammonia reagent for the reaction is selected from dioxane solution of ammonia, ammonia water, and methanol solution of ammonia.

[0031] Even further, the concentration of the ammonia reagent is 0.5-15 mol / L.

[0032] Furthermore, the organic solvent for the reaction is selected from DMF, DMSO, 1,4-dioxane, or toluene.

[0033] Furthermore, the volume fraction of the organic solvent for the reaction is 5V-15V.

[0034] Furthermore, the cuprous catalyst is preferably cuprous bromide, cuprous iodide, or cuprous oxide.

[0035] Furthermore, the reaction temperature is preferably 40-90 °C.

[0036] Furthermore, the acid-binding agent for the reaction is an inorganic base.

[0037] Even further, the acid-binding agent for the reaction is preferably potassium phosphate, potassium dihydrogen phosphate, potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide.

[0038] Furthermore, the post-treatment method of the reaction solution is as follows: Pour the reaction solution into water, extract with ethyl acetate 2-3 times to obtain an organic phase. After concentrating the organic phase under reduced pressure, separate by column chromatography with ethyl acetate:n-heptane = 1:2-10, and then concentrate and dry to prepare an amino thiophene compound.

[0039] The above amide ligands are prepared according to the following synthesis method:

[0040] An amide compound is prepared by reacting an aniline compound with oxalyl chloride;

[0041] The reaction formula is as follows:

[0042]

[0043] Wherein: R3 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen, etc.; R4 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen, etc.; R5 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen, etc.

[0044] The specific reaction process is as follows:

[0045] The aniline compound is dissolved in 10V of an organic solvent, and then a base is added dropwise at 0 °C, stirred at 0 °C for 5 - 15 minutes, keeping the internal temperature at 0 °C. Oxalyl chloride is slowly added dropwise to the reaction system. After the addition is complete, the reaction is carried out at room temperature for 2 - 5 hours. After monitoring the reaction to completion by TLC, the solvent is removed by distillation under reduced pressure. Water is added and stirred for 1 - 2 hours, and then filtered by suction. The filter cake is washed 3 - 4 times with water or ethyl acetate, and dried in vacuo to obtain the amide ligand. The molar ratio of the aniline compound, the base, and oxalyl chloride is 2.0 - 3.0∶2.5 - 4.0∶1.0.

[0046] Furthermore, the organic solvent is selected from dichloromethane, chloroform, toluene, tetrahydrofuran, ethyl acetate.

[0047] Still further, the volume of the organic solvent is 10 - 30V.

[0048] Furthermore, the base is selected from TEA, DIPEA, DBU.

[0049] Specifically, more preferably, the amide ligand is selected from one of the following:

[0050]

[0051] The beneficial effects of the present invention are as follows:

[0052] The amination reaction involving amide ligands catalyzes halo-substituted indazolopiperidine compounds to prepare aminoindazolopiperidine compounds. The reaction conditions are mild, the yield is high, and it is suitable for industrial production. In the synthesis method of the present invention, on the one hand, aniline compounds are used to prepare novel amide ligands for catalyzing the amination reaction; on the other hand, a cuprous catalyst / amide ligand is used as a catalyst to catalyze the reaction of halo-substituted indazolopiperidine compounds or ammonia reagents, and after post-treatment and separation, aminoindazolopiperidine compounds are obtained. The structure of the aminoindazolopiperidine compounds is an important structural unit and has broad application prospects in the direction of drug research and development. The preparation method provided by the present invention has mild conditions, easily available reaction raw materials, and strong operability. Detailed implementation mode

[0053] The present invention will be described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that those of ordinary skill in the art can make several deformations or improvements without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0054] Example 1:

[0055]

[0056] In a 50 mL round-bottom flask, 2-amino-5-methylbiphenyl (1.83 g, 10 mmol, 2.0 eq.) and 18 mL of tetrahydrofuran were added in sequence and mixed evenly, then placed in an ice bath at 0 °C, and triethylamine (1.23 g, 10 mmol, 2.5 eq.) was added dropwise and stirred for 10 minutes. Oxalyl chloride (0.64 g, 4 mmol, 1.0 eq.) was slowly added dropwise to the reaction system, and a large amount of white smoke was generated. The reaction was carried out at 0 °C for 10 minutes until the white smoke disappeared. The reaction system was transferred to room temperature and reacted for 2 hours. After the reaction was completed, the solvent was desolvated, 20 mL of water was added and stirred for 1 hour. After completion, suction filtration was carried out and washed with water or ethyl acetate 3-4 times. After obtaining the wet product, it was placed in a vacuum drying oven and dried at 55 °C for 12 hours to obtain 1.40 g of dry product, with a yield of 66%. The structure was characterized by hydrogen spectrum and was correct. 1 H-NMR (400 MHz, DMSO-d6): δ 2.34 (s, 6H), 7.08 - 7.48 (m, 14H), 7.76 (d, 2H, J = 8 Hz), 9.86 (s, 2H).

[0057] Taking the same reactants and the same operation steps, amide ligands were prepared with different equivalents of 2-amino-5-methylbiphenyl, different types of bases and different equivalents of bases. The same reaction as above was carried out, and the results are shown in Table 1 below:

[0058] Table 1

[0059]

[0060] In Table 1, the superscript a represents the separation yield.

[0061] Taking the same reactants and under the same operation steps, the intermediates were prepared with different kinds of organic solvents and different volumes of organic solvents respectively. For the same reaction as above, the results are shown in Table 2 below:

[0062] Table 2

[0063] Number Organic solvent Volume of organic solvent Yield (%) a 1 Dichloromethane 10V 45％ 2 Chloroform 15V 44％ 3 Toluene 35V 15％ 4 Toluene 11V 32％ 5 Tetrahydrofuran 30V 57％ 6 Ethyl acetate 12V 36％

[0064] In Table 2, the superscript a represents the separation yield.

[0065] Example 2:

[0066]

[0067] The difference from Reaction Example 1 is that the substrate 2,4,6-trimethoxyaniline was used, and other reaction conditions and operation steps were the same as those in Reaction Example 1 (yield: 65%). 1 1H-NMR (400 MHz, DMSO-d6): δ 3.32 (s, 18H), 6.23 - 6.24 (m, 2H), 6.37 - 6.39 (m, 2H), 9.18 (s, 2H).

[0068] The preparation of the above amide ligand is the same as that in Chinese Patent Application CN202311260534.3.

[0069] Example 3:

[0070]

[0071] CuI (0.14 g, 0.2 eq.), ligand (3)-a (0.64 g, 0.04 eq.), potassium phosphate (14.50 g, 3.0 eq.) and DMSO were added to a reaction flask. After purging with nitrogen three times and stirring at room temperature for 1 hour, compound Ia-1 (1.44 g, 1.0 eq.) and reagent ammonia water (6.49 g) were added to the reaction system. The reaction was heated to 90 °C and reacted for 20 h. After monitoring the reaction by TLC until it was completed, the reaction solution was poured into water, and then extracted with ethyl acetate 2 - 3 times to obtain the organic phase. The organic layer was washed with dilute hydrochloric acid, and the aqueous phase was adjusted to alkaline with sodium hydroxide, followed by filtration and drying to obtain compound Ib-1 (yield: 86%).

[0072] Taking the same reactants and under the same operation steps, with different kinds of cuprous catalysts and different kinds of ligands respectively, the results are shown in Table 3 below:

[0073] Table 3

[0074] Number Copper(I) catalyst Equivalent of copper(I) catalyst Ligand Equivalent of ligand <![CDATA[Yield (%) a > 1 Copper(II) oxide 0.2 e.q L-Proline 0.2 e.q 0 2 Copper(II) oxide 0.2 e.q 3-a 0.2 e.q 32 3 Copper(II) oxide 0.2 e.q 3-b 0.2 e.q 28 4 Copper(I) iodide 0.2 e.q L-Proline 0.2 e.q 86 5 Copper(I) iodide 0.2 e.q 3-a 0.2 e.q 91 6 Copper(I) iodide 0.2 e.q 3-b 0.2 e.q 89

[0075] In Table 3, the superscript a represents the separation yield.

[0076] Example 4:

[0077]

[0078] The difference from Reaction Example 3 is that the substrate used is 1a-2, and other reaction conditions and operation steps are the same as those in Reaction Example 3. The catalyst is copper(I) iodide, and the ligand is L-proline (yield: 75%).

[0079] Example 5:

[0080]

[0081] The difference from Reaction Example 3 is that the substrate used is 1a-3, and other reaction conditions and operation steps are the same as those in Reaction Example 3. The catalyst is copper(I) iodide, and the ligand is L-proline (yield: 76%).

[0082] Example 6:

[0083]

[0084] The difference from Reaction Example 3 is that the substrate used is 1a-4, and other reaction conditions and operation steps are the same as those in Reaction Example 3. The catalyst is copper(I) iodide, and the ligand is L-proline (yield: 69%).

Claims

1. A method for preparing an aminoindazolepiperidine compound, characterized in that, It is prepared by reacting a halo-substituted indazolopiperidine compound with an ammonia reagent, and the reaction is carried out in the presence of an amide ligand and a cuprous catalyst. Among them, the structural formula of the amide ligand is: or L-hydroxyproline, Among them, the cuprous catalyst is a cuprous compound; R1 is hydrogen, alkyl, alkoxy, nitro, trifluoromethyl, furyl, thienyl, naphthyl, phenyl, ester group, carboxyl group, aldehyde group, cyano group or phenyl substituted by one or more substituents, and the said substituents are each independently methyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy or halogen. R2 is an amino protecting group. X is hydrogen, fluorine, chlorine, bromine or iodine. R3 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the said substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen. R4 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the said substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen. R5 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the said substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen.

2. The preparation method according to claim 1, characterized in that, The amide ligand in the said reaction is: The cuprous catalyst is cuprous bromide, cuprous iodide or cuprous oxide.

3. The preparation method according to claim 1 or 2, characterized in that, An acid-binding agent is added in the said reaction.

4. The preparation method according to claim 3, characterized in that, The acid-binding agent is potassium phosphate, potassium dihydrogen phosphate, potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide.

5. The preparation method according to claim 1, 2 or 3, characterized in that, The molar ratio range of the halo-substituted indazolopiperidine compound∶ammonia reagent∶cuprous catalyst∶ligand∶acid-binding agent is 1∶1 - 10∶0.01 - 0.5∶0.01 - 0.5∶1 - 10.

6. The preparation method according to claim 5, characterized in that, The molar ratio range of the halo-substituted indazolopiperidine compound∶ammonia reagent∶cuprous catalyst∶ligand∶acid-binding agent is 1∶2 - 5∶0.01 - 0.2∶0.01 - 0.3∶1 - 5.

7. The preparation method according to claim 1, 2 or 3, characterized in that, The organic solvent for the said reaction is selected from DMF, DMSO, 1,4-dioxane or toluene.

8. The preparation method according to claim 1, 2 or 3, characterized in that The reaction temperature is 40 - 90 °C.

9. The preparation method according to claim 1 or 2, characterized in that, The preparation steps of the amide ligand are as follows. An amide compound is prepared by reacting an aniline compound or oxalyl chloride. Among them: R3 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the said substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen; R4 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the said substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen; R5 is hydrogen, alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents, and the said substituents are each independently methyl, phenyl, methoxy, trifluoromethyl or halogen.

10. A method for preparing an amino indazole piperidine compound, characterized in that, It is prepared by reacting a halo-substituted indazolopiperidine compound with an ammonia reagent under the action of the amide ligand L-hydroxyproline or cuprous iodide. X is bromine, R1 is OEt, Me, R2 is PhCO or Boc.

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