Synthesis method of 7,8-dihydro-2H-cyclopenta-pyrrolo-pyrazinone compound

Abstract

The present invention relates to a method for synthesizing 7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1(6H)-one compounds and analogs thereof. The method has simple steps, a simple and safe reaction process, and the intermediates involved are easy to separate and purify, making it fully suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical intermediates and medicinal chemistry. More specifically, the present invention relates to a method for synthesizing 7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one compounds and analogs thereof. Background Art

[0002] 7,8-Dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one compounds and their analogues are a new type of pharmaceutical intermediates.

[0003] Chinese patent application CN104125959A provides a variety of active compounds for treating inflammation, immune diseases and cancer, as well as intermediates for preparing these compounds, such as compounds with the following structures:

[0004]

[0005] The patent application also discloses the following preparation method of the above compound:

[0006] Method 1:

[0007]

[0008] This method utilizes the Wittig reaction in the first step of synthesis. This reaction is typically carried out in an aprotic solvent, with a strong base, and in the absence of water and oxygen. The resulting Wittig reagent is extremely unstable and reacts directly with the aldehyde to produce compound 107a without isolation. Due to the harsh conditions of the Wittig reaction, it is not suitable for industrial production. In the second step, sodium azide is used to introduce the amino group (compound 107b). However, since sodium azide is a highly toxic and explosive reagent, this route poses a serious safety hazard in industrial production.

[0009] Method 2:

[0010]

[0011] This method also uses the highly toxic and explosive reagent sodium azide and is not suitable for use in industrial production.

[0012] Moreover, the reaction routes of methods 1 and 2 are long, which is not conducive to industrial production.

[0013] The present invention provides a novel method for synthesizing 7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one compounds and their analogs (compounds of formula (I)). The method has simple steps, a simple and safe reaction process, and the intermediates involved are easily separated and purified, making it fully suitable for large-scale industrial production. The present invention also provides novel intermediate compounds, which can be used to prepare various small molecule inhibitors or their intermediates. Summary of the Invention

[0014] The present invention provides a method for synthesizing 7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one compounds and their analogs (i.e., compounds represented by formula (I)) (hereinafter referred to as the "method of the present invention").

[0015]

[0016] Wherein: R1 and R2 are independently selected from hydrogen, C 1-6 Alkyl or halogen;

[0017] R3 is selected from hydrogen or C 1-6 alkyl;

[0018] m and n are independently 0, 1 or 2, and m+n is 2, 3 or 4; and

[0019] R4 is selected from hydrogen or C 1-6 alkyl.

[0020] On the one hand, the present invention provides the following synthetic route:

[0021]

[0022] The variables are defined as follows.

[0023] On the other hand, the present invention also provides the following specific embodiments.

[0024] Embodiment 1: A method for synthesizing a compound of formula (I),

[0025]

[0026] Wherein: R1 and R2 are independently selected from hydrogen, C 1-6 Alkyl or halogen;

[0027] R3 is selected from hydrogen or C 1-6 alkyl;

[0028] m and n are independently 0, 1 or 2, and m+n is 2, 3 or 4; and

[0029] R4 is selected from hydrogen or C1-6 alkyl;

[0030] The method comprises the following steps:

[0031] a) Compound M1

[0032]

[0033] wherein R1, R2, R3, m and n are as defined above, X is halogen or an active ester group that is easy to leave, such as -OTf, -OTs or -OMs, preferably halogen,

[0034] Carry out cyclization reaction with compound M2,

[0035]

[0036] where R a 、R b and Rx are independently selected from C 1-6 alkyl;

[0037] Obtain compound M3

[0038]

[0039] Among them, R1, R2, R3, m, n, R a 、R b and R c As defined above;

[0040] b) subjecting compound M3 to aminolysis reaction to obtain compound M4

[0041]

[0042] Among them, R1, R2, R3, R4, m, n, R a and R b As defined above;

[0043] c) reacting compound M4 in the presence of an acid to obtain a compound of formula (I).

[0044] Embodiment 2: The method according to embodiment 1, wherein step b) is replaced by the following step b'):

[0045] Compound M3 is subjected to a hydrolysis reaction to generate compound M5,

[0046]

[0047] Among them, R1, R2, R3, m, n, R a and R b As defined above;

[0048] Compound M5 is then reacted with R4NH2 (wherein R4 is selected from hydrogen or C 1-6 alkyl) to produce compound M4.

[0049] Embodiment 3: The method according to embodiment 1 or 2, wherein: R1 and R2 are independently selected from C 1-6 Alkyl or hydrogen, preferably selected from methyl or hydrogen, more preferably methyl.

[0050] Embodiment 4: The method according to any one of the preceding embodiments, wherein: R3 is H.

[0051] Embodiment 5: A method as described in any of the preceding embodiments, wherein: R a and R b are independently selected from methyl or ethyl, preferably selected from methyl.

[0052] Embodiment 6: A method as described in any of the preceding embodiments, wherein: R c It is a methyl group or an ethyl group, preferably an ethyl group.

[0053] Embodiment 7: The method according to any one of the preceding embodiments, wherein m is 0 or 1, and n is 1 or 2; preferably m is 1, and n is 1.

[0054] Embodiment 8: The method according to any one of the preceding embodiments, wherein R4 is H.

[0055] Embodiment 9: A method as described in any of the preceding embodiments, wherein: the cyclization reaction in step a) is carried out in a non-polar solvent, such as N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP) or a mixed solvent thereof; the reaction is carried out under heating conditions, preferably the reaction temperature is controlled at 100-150°C, preferably at 110-130°C, and more preferably at 115-125°C.

[0056] Embodiment 10: The method according to any one of the preceding embodiments, wherein: the aminolysis reaction in step b) uses a corresponding aminolysis agent such as R4NH2, wherein R4 is selected from hydrogen or C 1-6 The alkylation reaction can be carried out under conventional reaction conditions in the art, such as in an organic solvent such as methanol or ethanol. For example, the aminolysis reaction can be carried out in a methanol solution of ammonia.

[0057] Embodiment 11: A method as described in any of the preceding embodiments, wherein: the hydrolysis reaction in step b') can be carried out in the presence of a strong inorganic base, for example, in a reaction solvent (such as an organic solvent and water) at 50-100°C (such as 75-85°C); specifically, the strong inorganic base can be selected from potassium hydroxide, sodium hydroxide or lithium hydroxide.

[0058] Embodiment 12: A method as described in any of the preceding embodiments, wherein: the reaction of compound M5 with R4NH2 in step b') is carried out in the presence of a base, in the presence of an optional condensing agent, and in a solvent; preferably, the base includes but is not limited to triethylamine, pyridine, 4-dimethylaminopyridine or DBU, etc.; preferably, the condensing agent includes but is not limited to HBTU, DCC, EDCI, DIC or CDI.

[0059] Embodiment 13: A method as described in any of the preceding embodiments, wherein: the acid in step c) is selected from an organic acid, such as acetic acid, p-toluenesulfonic acid, etc.; preferably, the reaction temperature is controlled at 70-120°C, such as 95-105°C.

[0060] Embodiment 14: A method for preparing compound M3,

[0061]

[0062] Among them, R1, R2, R3, m, n, R a 、R b and R c As defined above;

[0063] It includes the following steps:

[0064] Compound M1

[0065]

[0066] wherein R1, R2, R3, X, m and n are as defined above,

[0067] Carry out cyclization reaction with compound M2,

[0068]

[0069] where R a 、R b and R c As defined above;

[0070] Compound M3 was obtained.

[0071] Embodiment 15: The method according to Embodiment 14, wherein the cyclization reaction is performed as described in Embodiment 9.

[0072] Embodiment 16: A compound or a salt thereof, wherein the compound is selected from

[0073]

[0074] Among them, R1, R2, R3, R4, m, n, Ra 、R b and R c As defined above.

[0075] Embodiment 17: A compound or a salt thereof, wherein the compound is selected from

[0076]

[0077] Embodiment 18: Use of the compound or salt thereof according to Embodiment 16 or 17 for preparing a compound of formula (I).

[0078] definition:

[0079] The terms and symbols used in this application have the following meanings unless the context indicates otherwise. Technical and scientific terms used herein that are not specifically defined have the meanings commonly understood by those skilled in the art to which this invention belongs.

[0080] The term "alkyl" as used herein refers to a linear or branched saturated monovalent hydrocarbon group having 1 to 6 carbon atoms, for example, 1, 2, 3, 4, 5, or 6 carbon atoms, preferably a linear or branched saturated monovalent hydrocarbon group having 1 to 4 carbon atoms. An alkyl group having 1 to 6 carbon atoms is simply represented by "C 1-6 Alkyl groups with 1 to 4 carbon atoms are simply represented by "C 1-4 Alkyl groups with other numbers of carbon atoms can also be represented in a similar manner. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like.

[0081] As used herein, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably chlorine and bromine, more preferably chlorine.

[0082] The "strong inorganic base" used in step b') herein refers to an inorganic base that can hydrolyze a carboxylate ester to form a carboxylate salt or a carboxylic acid, including but not limited to potassium hydroxide, sodium hydroxide or lithium hydroxide.

[0083] As used herein, the term "easy-to-leave active ester group" refers to an ester group prepared from an alcohol that can be easily displaced by a nucleophilic substance, such as an amine, to form a stable linkage. The "easy-to-leave active ester group" of the present invention is preferably p-CH3-Ph-SO3-(-OTs), CF3SO3-(-OTf), or CH3SO3-(-OMs). Wherein, Ph refers to a phenyl group, Ts refers to a p-toluenesulfonyl group, Tf refers to a trifluoromethanesulfonyl group, and Ms refers to a methylsulfonyl group.

[0084] The term "condensing agent" as used herein refers to common condensing agents that can aid in the formation of amides, including but not limited to HBTU, DCC, EDCI, DIC, or CDI.

[0085] DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0086] HBTU refers to benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0087] DCC refers to N,N'-dicyclohexylcarbodiimide.

[0088] EDCI refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0089] DIC refers to N,N'-diisopropylcarbodiimide.

[0090] CDI refers to N,N'-carbonyldiimidazole.

[0091] It should be understood that, unless otherwise specified or clearly contradicted by the context, when a subsequent embodiment or technical solution refers to a previous embodiment or technical solution and does not further define the variables or features therein, the variables or features in the subsequent embodiment or technical solution have the same meaning or definition as the corresponding variables or features in the previous embodiment or technical solution.

[0092] It should also be understood that the reaction of the present invention can be carried out under conventional reaction conditions known in the art. For example, the reaction temperature and pressure can be controlled according to the characteristics of the reactants until the reaction is complete.

[0093] Usually, the reaction can be carried out in a solvent, and the solvent includes but is not limited to an organic solvent such as methanol, ethanol, isopropyl alcohol, acetonitrile, heptane, toluene, acetone, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, ethyl acetate, ether, isopropyl ether, methyl tert-butyl ether, methylcyclopentyl ether etc. and any combination thereof. Where appropriate, a mixed solvent of an organic solvent and water can be used. In some reactions, other solvents may not be used, and the reaction reagent itself may also be used as a solvent. For example, an acid such as acetic acid may be used as a solvent in step c), or other solvents may be added to react.

[0094] The reaction can be carried out at a suitable temperature, for example, at -78°C to 200°C, such as -78°C to 0°C, -20°C to 20°C, -10°C to 10°C, 10-130°C, 20-100°C, 40-100°C, 50-100°C, 60-100°C, 50-80°C, 70-120°C, 60-90°C, 110-130°C, 110-120°C, 100-150°C or 100-200°C.

[0095] The reaction can be carried out under normal pressure, elevated pressure or reduced pressure, as appropriate.

[0096] It should be understood that those skilled in the art can easily detect the progress of the reaction and thus determine the reaction time or reaction endpoint according to actual conditions.

[0097] In this document, if both the name and structural formula of a compound are given, in the event of a discrepancy between the two, the structure of the compound shall prevail unless the context indicates that the structure of the compound is incorrect and the name is correct.

[0098] The process for synthesizing the compound of formula (I) provided by the present invention has the following beneficial effects:

[0099] 1. There are only three steps in the entire process, each step has a single reaction site, and there are very few side reactions;

[0100] 2. The reaction conditions are mild, the operation is simple, and there are no highly toxic, flammable, or explosive hazardous reagents, making it very suitable for industrial production;

[0101] 3. The production process is simple and the cost is low; and / or

[0102] 4. The intermediates involved are easy to separate and purify, and can even be used directly in subsequent reactions without purification, making them very suitable for large-scale industrial production. DETAILED DESCRIPTION

[0103] The following examples are illustrative of the present invention and should not be construed as limiting the scope of protection of the present invention in any way. The disclosed data (e.g., amount, temperature, etc.) strive to ensure its accuracy, but there will also be some experimental errors and offsets. Unless otherwise stated, the parts in the present invention are parts by weight, the temperature is Celsius, and the pressure is atmospheric pressure or near atmospheric pressure. All hydrogen spectrum data were measured by Varian 400-MR. All reagents used in the examples of the present invention were obtained from commercial channels.

[0104] Example 1

[0105] Synthesis of ethyl 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate

[0106]

[0107] Add compound 1 (50.0 kg) and compound 2 (150.0 kg) and DMF (950 kg of N,N-dimethylformamide) to a 2000 L reactor, stir, and heat at 115-125°C until the reaction is complete. Cool to room temperature, add the reaction mixture to water, add ethyl acetate, stir, and allow to stand for separation, retaining the organic phase. Wash the organic phases with a saturated aqueous NaCl solution, allow to stand for separation, and retain the organic phase. Concentrate the organic phase under reduced pressure until no fraction is left.

[0108] A mixed solvent of n-heptane / ethyl acetate was added to dissolve the distillation residue. A small amount of insoluble matter was removed from the solution by passing through a silica gel pad. The filter cake was washed with a mixed solvent of n-heptane / ethyl acetate, and the filtrates were combined. The filtrate was concentrated under reduced pressure until no liquid was noticeably dripping out, yielding 42.8 kg of a light yellow oil (Compound 3, ethyl 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate). The content was 57.2%, the yield was 26.3%, and the MS (m / z) was 264.0 [M-OMe]. + The product was directly subjected to the next reaction without purification.

[0109] After taking a small amount of sample and purifying it, the product hydrogen spectrum data is measured as follows:

[0110] 1 HNMR (400MHz, CDCl3) δ6.73 (s, 1H), 4.54 (t, J=5.3Hz, 1H), 4.28-4.18 (m, 4H) , 3.35(s, 6H), 2.54(s, 2H), 2.42(s, 2H), 1.32(t, J=7.1Hz, 3H), 1.20(s, 6H).

[0111] Example 2

[0112] Synthesis of 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid

[0113]

[0114] To a 500L reactor, add ethanol (99.0kg), water (125.0kg), compound 3 (25.0kg), and LiOH.H2O (14.2kg), raise the temperature to 75-85°C, and stir at this temperature until the reaction is complete. Concentrate the reaction solution under reduced pressure to remove most of the ethanol. Add methyl tert-butyl ether, stir, and then allow to stand for separation, retaining the lower aqueous phase. Add hydrochloric acid aqueous solution to the aqueous phase to adjust the pH to 5-6, and a large amount of solid precipitates. Filter, wash the filter cake with water, and dry the filter cake to obtain 19.8kg of off-white solid (compound 4, 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid), with a purity of 91.97%, a content of 91%, a yield of 79.6%, and MS (m / z) = 236.0 [M-OMe]. + .

[0115] The product hydrogen spectrum data are as follows:

[0116] 1 HNMR (400MHz, CDCl3) δ6.86 (s, 1H), 4.55 (t, J=5.3Hz, 1H), 4.21 (d, J=5.3Hz, 2H), 3.36 (s, 6H), 2.56 (s, 2H), 2.44 (s, 2H), 1.21 (s, 6H).

[0117] Example 3

[0118] Synthesis of 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxamide

[0119]

[0120] Add DMF (102.6 kg), compound 4 (19.8 kg), and triethylamine (13.6 kg) to the reactor and cool to -5 to 5°C. Control the temperature below 10°C and add HBTU (benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate, 30.6 kg) in batches. After the addition is complete, keep the temperature at -5 to 5°C and stir until the reaction of compound 4 is complete. Control the temperature below 10°C and add ammonia water dropwise to the reaction solution. Keep the temperature at -5 to 5°C and stir until the reaction is complete. Pour the reaction solution into water, add ethyl acetate, stir, and let it stand for separation, retaining the organic phase. Wash the organic phase with a saturated aqueous NaCl solution, let it stand for separation, and retain the organic phase. The organic phase was concentrated under reduced pressure and evaporated until no obvious liquid dripped out to obtain 18.6 kg of light red solid (Compound 5, 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxamide) with a purity of 94.6%, a content of 94.1%, a yield of 97.8%, and MS (m / z) = 235.1 [M-OMe].+ The product was directly used in the next reaction without purification.

[0121] After taking a small amount of sample and purifying it, the product hydrogen spectrum data is measured as follows:

[0122] 1 HNMR (400MHz, CDCl3) δ6.40 (s, 1H), 5.42 (s, 2H), 4.61 (t, J=5.2Hz, 1H), 4.23 (d, J=5.2Hz, 2H), 3.36 (s, 6H), 2.55 (s, 2H), 2.42 (s, 2H), 1.20 (s, 6H).

[0123] Example 4

[0124] 7,7-Dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0125]

[0126] The intermediate compound 5 (17.5 kg) obtained in Example 3 was dissolved in acetic acid (147 kg) and added to a 200 L reactor. The temperature was controlled at 95-105 ° C until the reaction was complete. The reaction mixture was cooled to room temperature and poured into water. A mixed solvent of ethyl acetate and methanol was added with stirring. The mixed solution of the reaction mixture and water was extracted. The mixture was allowed to stand and separate. The organic phases were combined. The organic phase was concentrated under reduced pressure to a small volume. A large amount of solid precipitated. N-heptane and ethyl acetate were added to the reactor, the temperature was raised to 40-50 ° C, and the mixture was stirred. The mixture was filtered hot, and the filter cake was washed with a mixed solvent of n-heptane and ethyl acetate. The filter cake was dried to obtain 11.1 kg of an off-white solid (compound 6,7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) with a purity of 99.8%, a content of 98.4%, and a yield of 83.5%. MS (m / z) = 203.0 [M+H] + .

[0127] The product hydrogen spectrum data are as follows:

[0128] 1 HNMR (400MHz, CDCl3) δ10.92 (s, 1H), 6.89 (s, 1H), 6.74 (d, J=5.6Hz, 1H), 6.51 (t, J=4.5Hz, 1H), 2.63 (s, 2H), 2.60 (s, 2H), 1.26 (s, 6H).

Claims

1. A method for synthesizing a compound of formula (I), in: R1 and R2 are independently selected from hydrogen, C 1-6 Alkyl or halogen; R3 is selected from hydrogen or C 1-6 alkyl; m and n are independently 0, 1 or 2, and m+n is 2, 3 or 4; and R4 is selected from hydrogen or C 1-6 alkyl; The method comprises the following steps: a) Compound M1 wherein R1, R2, R3, m and n are as defined above, X is a halogen or an active ester group that is easily leaving, Carry out cyclization reaction with compound M2, where R a 、R b and R c are independently selected from C 1-6 alkyl; Obtain compound M3 Among them, R1, R2, R3, m, n, R a 、R b and R c As defined above; b) subjecting compound M3 to aminolysis reaction to obtain compound M4 Among them, R1, R2, R3, R4, m, n, R a and R b As defined above; and c) reacting compound M4 in the presence of an acid to obtain a compound of formula (I).

2. The method of claim 1, wherein the easily leaving active ester group is -OTf, -OTs or -OMs.

3. The method of claim 1, wherein X is halogen.

4. The method of claim 1 , wherein step b) is replaced by the following step b′): Compound M3 is subjected to a hydrolysis reaction to generate compound M5, Among them, R1, R2, R3, m, n, R a and R b As defined in claim 1; Compound M5 is then reacted with a molecule wherein R4 is selected from hydrogen or C 1-6 The alkyl group R4NH2 reacts to form compound M4. The method of claim 4 , wherein the easily leaving active ester group is —OTf, —OTs or —OMs. The method of claim 4 , wherein X is halogen.

7. The method according to any one of claims 1 to 6, wherein: R1 and R2 are independently selected from C 1-6 Alkyl or hydrogen.

8. The method of claim 7, wherein R1 and R2 are each independently selected from methyl or hydrogen.

9. The method of claim 8, wherein R1 and R2 are each methyl.

10. The method of any one of claims 1 to 6 and 8 to 9, wherein: R3 is H.

11. The method of claim 7, wherein: R3 is H.

12. The method of any one of claims 1 to 6, 8 to 9 and 11, wherein: R a and R b are independently selected from methyl or ethyl.

13. The method of claim 12, wherein: R a and R b They are methyl groups.

14. The method of any one of claims 1-6, 8-9, 11 and 13, wherein: R c It is methyl or ethyl.

15. The method of claim 14, wherein: R c For ethyl.

16. The method of any one of claims 1-6, 8-9, 11, 13 and 15, wherein m is 0 or 1, and n is 1 or 2. The method of claim 16 , wherein m is 1 and n is 1.

18. The method of any one of claims 1-6, 8-9, 11, 13, 15, and 17, wherein R4 is H.

19. The method of claim 16, wherein R4 is H.

20. The method of any one of claims 1-6, 8-9, 11, 13, 15, 17, and 19, wherein: The cyclization reaction in step a) is carried out in a non-polar solvent; the reaction is carried out under heating conditions.

21. The method of claim 20, wherein the non-polar solvent is N,N-dimethylformamide or N-methylpyrrolidone or a mixed solvent thereof.

22. The method of claim 20, wherein the reaction temperature is controlled at 100-150°C.

23. The method of claim 21, wherein the reaction is carried out at 110-130°C.

24. The method of claim 21, wherein the reaction is carried out at 115-125°C.

25. The method of any one of claims 1-6, 8-9, 11, 13, 15, 17, 19, and 21-24, wherein: The aminolysis reaction in step b) is carried out using a corresponding aminolysis agent.

26. The method of claim 25, wherein the ammonolysis agent is R4NH2, wherein R4 is selected from hydrogen or C 1-6 alkyl.

27. The method of claim 25, wherein the aminolysis reaction is carried out under conventional reaction conditions in the art.

28. The method of claim 25, wherein the aminolysis reaction is carried out in an organic solvent such as methanol or ethanol.

29. The method of claim 25, wherein the aminolysis reaction is carried out in a methanolic ammonia solution.

30. The method of any one of claims 4-6, 8-9, 11, 13, 15, 17, 19, 21-24, and 26-29, wherein: The hydrolysis reaction in step b') is carried out in the presence of a strong inorganic base.

31. The method of claim 30, wherein: The hydrolysis reaction in step b') is carried out in a reaction solvent.

32. The method of claim 31 , wherein: The hydrolysis reaction in step b') is carried out in an organic solvent and water.

33. The method of claim 30, wherein: The hydrolysis reaction in step b') is carried out at 50-100°C.

34. The method of claim 30, wherein: The strong inorganic base is selected from potassium hydroxide, sodium hydroxide or lithium hydroxide.

35. The method of any one of claims 4-6, 8-9, 11, 13, 15, 17, 19, 21-24, 26-29, and 31-34, wherein: The reaction of compound M5 with R4NH2 in step b') is carried out in the presence of a base and optionally a condensing agent in a solvent.

36. The method of claim 35, wherein: The base includes, but is not limited to, triethylamine, pyridine, 4-dimethylaminopyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene.

37. The method of claim 36, wherein the condensing agent includes but is not limited to benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-diisopropylcarbodiimide or N,N'-carbonyldiimidazole.

38. The method of any one of claims 1-6, 8-9, 11, 13, 15, 17, 19, 21-24, 26-29, 31-34, 36, and 37, wherein: The acid in step c) is selected from organic acids.

39. The method of claim 38, wherein the acid is selected from acetic acid and p-toluenesulfonic acid.

40. The method of claim 38, wherein the reaction temperature is controlled at 70-120°C.

41. The method of claim 38, wherein the reaction temperature is controlled at 95-105°C.

42. A method for preparing compound M3, Among them, R1, R2, R3, m, n, R a 、R b and R c As defined in claim 1; It includes the following steps: Compound M1 wherein R1, R2, R3, X, m and n are as defined in claim 1, Carry out cyclization reaction with compound M2, where R a 、R b and R c As defined in claim 1; Compound M3 was obtained.

43. The process of claim 42, wherein the cyclization reaction is performed as described in any one of claims 20-24.

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