Preparation method of indole carboxamide compound

Abstract

The invention belongs to the technical field of medicines, and relates to a preparation method of an indole formamide compound. The preparation method disclosed by the invention is simple in process, easily available in raw materials, stable in intermediate product, high in yield of each step and total yield, few in side reaction and by-product and suitable for industrial production, and the purified compound is high in purity and can better meet the drug application requirements of the compound.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and relates to a method for preparing an indolecarboxamide compound. Background Art

[0002] Classical transient receptor potential canonical channels (TRPCs) are non-selective (Ca 2+ , K + , Na + ) and permeability cation channels. They are widely expressed in various tissues and organs in the human body, play a vital role in various physiological and pathological processes, and are involved in various pathogenesis[TaiY, Yang S, et al. TRPC channels in health and disease. Adv. Exp. Med. Biol., 2017, 976: 35-45.].

[0003] TRPC6 is a member of the classic transient receptor potential cation channel family, composed of 931 amino acids and has a six-transmembrane structure. Current studies have found that TRPC6 is widely distributed in various tissues and organs of mammals, including the brain, heart, kidneys, lungs and other important organs, and plays an important role in many physiological processes such as vascular smooth muscle contraction, podocyte signal transduction, central nervous system development and pain regulation. TRPC6 protein is a component of cell membrane Ca 2+ The molecular basis of the channel, which is mainly involved in receptor-operated Ca 2+ Abnormal expression or gene mutation of receptor-operated calcium entry (ROCE) and store-operated calcium entry (SOCE) can cause intracellular Ca 2+ Changes in signaling pathways are involved in the occurrence and development of many diseases [Li J, Zhang X, Song X, et al. The structure of TRPC ion channels. Cell Calcium, 2019, 80: 25-28.].

[0004] Studies have shown that upregulation of TRPC6 function is the pathological mechanism leading to many diseases; TRPC6 inhibitors have become the therapeutic targets for many of the above-mentioned related diseases. Therefore, the research on TRPC6 small molecule inhibitors has become a research hotspot in related fields, and the development of new specific inhibitors that can target TRPC6 is of great significance for the treatment of diseases.

[0005] Patent document CN2021107574083 relates to an indolecarboxamide compound and a preparation method thereof, which comprises a compound as shown in general formula (I), and the compound is a new specific inhibitor that can target TRPC6.

[0006]

[0007] Patent document CN2021107574083 discloses two synthetic routes of such compounds, one of which is shown in the following synthetic route 1. Compound A is used as the starting material, and reacts with β-alanine ethyl ester in anhydrous dichloromethane (CH2Cl2) under the catalysis of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 4-dimethylaminopyridine (DMAP) to obtain intermediate D. Intermediate D is dissolved in anhydrous tetrahydrofuran (THF) and reduced under the action of diisobutylaluminum hydride (DIBAl-H) to obtain intermediate C. Intermediate C is dissolved in anhydrous CH2Cl2 and esterified with a substituted carboxylic acid RCOOH (or its anhydride (RCO)2O, or its acid chloride RCOCl) under the catalysis of triethylamine (Et3N) and DMAP to obtain intermediate II. Finally, N,N-dimethylformamide (DMF) and phosphorus oxychloride (POCl3) were reacted in an ice bath to obtain a formylation reagent, and then the intermediate II dissolved in DMF was added thereto, and the temperature was gradually raised to continue the reaction. After the reaction was completed, the target product I was purified by a silica gel column to obtain a pure product.

[0008]

[0009] The yields of each step of the synthetic route are shown above, and the total yield is about 14%. The yields of the second and fourth steps are relatively low, which greatly affects the yield of the final target product. At the same time, there are many side reactions and by-products, and DMF is difficult to remove, and subsequent purification is difficult, which makes it impossible to achieve large-scale preparation of such compounds; in addition, a strong reducing agent such as diisobutylaluminum hydride is used in this route, which is very dangerous and has harsh reaction conditions, making this preparation method unable to be applied to industrial production.

[0010] Another synthetic route published in patent document CN2021107574083 is shown in the following synthetic route 2. First, 3-aminopropanol is dissolved in anhydrous CH2Cl2, and reacted with triethylsilyl chloride (TESCl) under the catalysis of imidazole and DMAP to obtain intermediate E. Compound A, EDCI, intermediate E and DMAP are dissolved in anhydrous CH2Cl2 respectively, and then the above three solutions are mixed to react to obtain intermediate F. Intermediate F is dissolved in anhydrous THF, and intermediate C is obtained under the action of tetrabutylammonium fluoride (TBAF). Intermediate C is dissolved in anhydrous CH2Cl2, and esterified with RCOOH (or (RCO)2O, or RCOCl) under the catalysis of Et3N and DMAP to obtain intermediate II. Finally, the formylation reaction reagent is prepared by reacting DMF and POCl3 under ice bath conditions, and then the intermediate II dissolved in DMF is added thereto, and the temperature is gradually increased to continue the reaction. After the reaction is completed, the product is purified by silica gel column to obtain the pure target product I.

[0011]

[0012]

[0013] The yield of each step of this synthetic route 2 is not mentioned in the patent literature, and the total yield is about 30%. Although the total yield of this route is higher than that of synthetic route 1, the number of synthetic steps is increased, there are more side reactions and by-products, the preparation process is more complicated, and the DMF in the reaction is difficult to remove, and the subsequent purification is more difficult, resulting in that this preparation method cannot be applied to the production of industrial pure products.

[0014] In summary, the two synthetic routes disclosed in patent document CN2021107574083 have prominent problems such as harsh reaction conditions, long synthetic routes, complex preparation processes, low preparation yields and compound purity, which make it impossible to achieve large-scale preparation of the compound, and the preparation method cannot be applied to industrial pure product production, limiting the scope of application of the compound as a drug. Summary of the invention

[0015] In view of the outstanding problems existing in the preparation methods of indolecarboxamide compounds provided in the prior art, one of the purposes of the present invention is to propose a new preparation route for such compounds and optimize the preparation method for such compounds so that they can be industrially produced; another purpose is to provide a purification process for such compounds to further improve the purity of the compounds so that they can better meet the requirements of the pharmaceutical application of the compounds.

[0016] To achieve the above-mentioned purpose, the present invention provides a method for preparing indolecarboxamide compound I, which involves safe and readily available raw materials, a short route, a simple process, few side reactions and by-products, and a high yield, and can achieve large-scale industrial production and preparation. The present invention also provides three purification processes for such compounds, and the purity of the compounds after the purification process can reach more than 98%, which can better meet the requirements of the pharmaceutical application of the compounds.

[0017] The present invention provides a method for preparing an indolecarboxamide compound I, comprising the following steps:

[0018]

[0019] (1) Compound A (1-methylindole-2-carboxylic acid) is subjected to chlorination reaction to generate intermediate B (1-methyl-1H-indole-2-carboxylic acid chloride);

[0020] (2) intermediate B undergoes a substitution reaction to generate intermediate C (N-(3-hydroxypropyl)-1-methyl-1H-indole-2-carboxamide);

[0021] (3) Intermediate C undergoes esterification reaction to generate intermediate II (indoleaminopropyl ester compound);

[0022] (4) Intermediate II undergoes Vilsmeier-Haack reaction to generate indolecarboxamide compound I;

[0023] Wherein, R is selected from: hydrogen atom, C 1-10 Alkyl, C 3-10 Cycloalkyl, 6-14 membered aryl, 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, -C(O)-C 1-10 Alkyl, amino, substituted amino, amidino, guanidino or metal ion; the C 1-10 Alkyl, C 3-10 Cycloalkyl, 6-14 membered aryl, 3-10 membered heterocycloalkyl or 5-6 membered heteroaryl are optionally substituted by 1-2 groups selected from hydroxy, nitro, halogen, cyano, trifluoromethyl, C 1-6 Alkoxy, 6- to 8-membered aryloxy, trifluoromethoxy, difluoromethoxy or C 1-6 The 3-10 membered heterocycloalkyl and 5-6 membered heteroaryl groups optionally contain 1-6 heteroatoms selected from N, O and S; preferably, R is selected from: hydrogen atom, C 1-6 Alkyl or phenyl.

[0024] Preferably, in the preparation method:

[0025] In step (1), in the acyl chloride reaction, the acyl chloride reagent is selected from oxalyl chloride (COCl) 2 or thionyl chloride SOCl 2, the solvent is CH 2 Cl 2, and the catalyst is DMF;

[0026] In step (2), the reaction reagent added in the substitution reaction is 3-aminopropanol;

[0027] In step (3), the esterification reaction is carried out by adding RCOOH / (RCO)2O / RCOCl in the presence of DMAP and Et3N using CH2Cl2 as solvent;

[0028] In step (4), in the Vilsmeier-Haack reaction, DMF and POCl3 are used to prepare the formylation reaction reagent.

[0029] Wherein, step (1) comprises: under anhydrous and oxygen-free conditions, adding compound A into a reaction device, using anhydrous CH2Cl2 as a solvent, slowly adding an acyl chloride reaction reagent in an ice bath after dissolution, then dropping a catalytic amount of DMF, and then moving to room temperature to continue the reaction; after the reaction is completed (TLC detection), removing the solvent by rotary evaporation to obtain intermediate B;

[0030] Preferably, the concentration of compound A is 0.10-1.00 mol / L; the acyl chloride reaction reagent is selected from oxalyl chloride or thionyl chloride; the molar ratio of the acyl chloride reaction reagent to compound A is 1.0-2.5:1; the reaction time is 8-20h;

[0031] More preferably, the concentration of compound A is 0.15-0.30 mol / L; the acyl chlorination reaction reagent is oxalyl chloride; the molar ratio of oxalyl chloride to compound A is 1.2-1.5:1; and the reaction time is 10-15 h.

[0032] Wherein, step (2) comprises: placing intermediate B in a reaction device under anhydrous and oxygen-free conditions, adding solvent 1 to dissolve the intermediate B, slowly adding 3-aminopropanol in an ice bath, and then moving the intermediate B to room temperature to continue the reaction (TLC detection); after the reaction is completed, removing the solvent by rotary evaporation to obtain intermediate C;

[0033] Preferably, the concentration of intermediate B is 0.30-2.50 mol / L; the molar ratio of 3-aminopropanol to intermediate B is 1.0-2.5:1; the solvent 1 is selected from 3-aminopropanol, CH2Cl2 or ethyl acetate; the reaction time is 0.5-2.5h;

[0034] More preferably, the concentration of intermediate B is 0.75-1.50 mol / L; the molar ratio of 3-aminopropanol to intermediate B is 1.5-2.0:1; the solvent 1 is CH2Cl2; and the reaction time is 1.0-1.5 h.

[0035] Wherein, step (3) comprises: placing intermediate C and DMAP in a reaction device under anhydrous conditions, using anhydrous CH2Cl2 as a solvent, adding Et3N after dissolution, and finally adding a compound RCOOH or (RCO)2O or RCOCl dropwise to start the reaction; after the reaction is completed (TLC detection), removing the solvent by rotary evaporation to obtain intermediate II;

[0036] Preferably, the concentration of intermediate C is 0.20 mol / L; the molar ratio of compound RCOOH or (RCO)2O or RCOCl to intermediate C is 2:1; and the reaction time is 30 min.

[0037] Wherein, step (4) comprises: first, under anhydrous and oxygen-free conditions, in a 0°C environment, DMF and POCl3 are added successively into a reaction device, mixed and stirred at 0°C for 30 minutes, then moved to room temperature, and continued to mix and stir for 30 minutes to obtain the formylation reaction reagent required for the reaction;

[0038] Then, under anhydrous and oxygen-free conditions, at 0°C, the intermediate II dissolved in solvent 2 is added with a formylation reagent, and then the reaction is continued at room temperature; (TLC detection) after the reaction is completed, saturated brine is added to quench the reaction, the aqueous layer is extracted with CH2Cl2, the organic layers are combined, dried, filtered, the solvent is removed by rotary evaporation, and then purified by silica gel column to obtain indolecarboxamide compound I;

[0039] Preferably, the concentration of intermediate II is 0.10-0.50 mol / L; the molar ratio of the formylation reaction reagent to intermediate II is 1.5-3.0:1; the solvent 2 is selected from DMF, toluene or CH2Cl2; the reaction time is 8-20h; the eluent of silica gel column chromatography is petroleum ether: ethyl acetate = 3:1;

[0040] More preferably, the concentration of intermediate II is 0.20-0.40 mol / L; the molar ratio of the formylation reaction reagent to intermediate II is 1.5-2.0:1; the solvent 2 is CH2Cl2; and the reaction time is 10-15 h.

[0041] Preferably, the total yield of the preparation method of the present invention is higher than 40%.

[0042] The present invention provides a method for purifying an indolecarboxamide compound I, wherein the purification adopts any one of the following three methods:

[0043] Method (1) Recrystallization: Indolecarboxamide compound I is placed in a container, and solvent 3 is slowly added under constant temperature heating conditions to obtain a saturated solution of the compound, and then heating is stopped, and the solution is cooled to room temperature and placed in a 4°C refrigerator to allow crystals to precipitate, and then filtered, washed, and dried to obtain indolecarboxamide compound I crystals;

[0044] Wherein, the solvent 3 is selected from anhydrous EtOH or CH2Cl2, and the heating temperature depends on the solvent selection;

[0045] Preferably, the solvent 3 is anhydrous EtOH, and the heating temperature is 40-60°C.

[0046] Method (2) beating: take indolecarboxamide compound I into a container, then add solvent 4, ultrasonically disperse the compound in the solvent (for example, using an ultrasonic cleaner), stir, filter, wash, dissolve the solid with CH2Cl2, dry the organic phase, and remove the solvent by rotary evaporation to obtain indolecarboxamide compound I crystals;

[0047] Wherein, the solvent 4 is selected from water or petroleum ether;

[0048] Preferably, the solvent 4 is water.

[0049] Method (3) Alcohol-soluble water precipitation: Take indolecarboxamide compound I in a container, slowly add anhydrous ethanol under constant temperature heating conditions to prepare a saturated solution of the compound, then stop heating, wait until it cools to room temperature, then add 5-10 times the volume of water, filter, wash, dissolve the solid with CH2Cl2, dry the organic phase, and remove the solvent by rotary evaporation to obtain indolecarboxamide compound I crystals.

[0050] Those skilled in the art will appreciate that the above three purification processes each have their own advantages and disadvantages, but all can significantly purify the compound, and a suitable purification process should be selected according to actual conditions.

[0051] The preparation method of the present invention has simple process, readily available raw materials, stable intermediate products, high yield in each step and in total, few side reactions and by-products, is suitable for industrial production, and the purity of the compound after the purification process is high, which better meets the requirements of the drug application of the compound. DETAILED DESCRIPTION

[0052] Typical embodiments are listed below to further illustrate the present invention, but are not intended to limit the present invention in any form.

[0053] Example 1: Preparation of 3-[(3-formyl-1-methyl-1H-indole-2-carbonyl)amino]propyl acetate (Compound 1)

[0054]

[0055] Step 1: Preparation of intermediate B

[0056] Under anhydrous and oxygen-free conditions, compound A (17.52 g, 0.10 mol, 1.00 eq.) was placed in a reaction apparatus, dissolved with anhydrous CH2Cl2 (400 mL), and stirring was started; then oxalyl chloride (10.23 mL, 0.12 mol, 1.20 eq.) was added dropwise under ice bath conditions, and then a catalytic amount of anhydrous DMF (1.00 mL) was added dropwise; then the reaction was continued at room temperature; the reaction progress was monitored by TLC (petroleum ether / ethyl acetate = 5:1), and the reaction was complete after about 12 h; then the solvent was removed by rotary evaporation to obtain intermediate B.

[0057] Step 2: Preparation of Intermediate C

[0058] Under anhydrous and oxygen-free conditions, the intermediate B obtained in step 1 is placed in a reaction apparatus, dissolved with anhydrous CH2Cl2 (120 mL), and stirring is started; then 3-aminopropanol (15.29 mL, 0.20 mmol, 2.00 eq.) is added dropwise under ice bath conditions; then the reaction is continued at room temperature; the reaction progress is monitored by TLC (petroleum ether / ethyl acetate = 1:1), and the reaction is complete after about 1 hour; then the solvent is removed by rotary evaporation to obtain intermediate C.

[0059] Step 3: Preparation of Intermediate 2

[0060] Under anhydrous conditions, the intermediate C obtained in step 2 and DMAP (1.22 g, 10.00 mmol, 0.10 eq.) were placed in a reaction apparatus, dissolved with anhydrous CH2Cl2 (500 mL), and stirring was started; Et3N (27.80 mL, 0.20 mmol, 2.00 eq.) was then added, and finally Ac2O (18.90 mL, 0.20 mmol, 2.00 eq.) was added dropwise to start the reaction; the reaction progress was monitored by TLC (petroleum ether / ethyl acetate = 1:1), and the reaction was complete after about 30 min; the solvent was then removed by rotary evaporation to obtain intermediate 2.

[0061] Step 4: Preparation of Compound 1

[0062] First, the formylation reaction reagent is prepared. Under anhydrous and oxygen-free conditions, DMF (15.47 mL, 0.20 mmol, 2.00 eq.) and POCl3 (18.64 mL, 0.20 mmol, 2.00 eq.) are added to the reaction device in succession at 0°C, mixed and stirred for 30 minutes at 0°C, then moved to room temperature, and continued to mix and stir for 30 minutes to obtain the formylation reaction reagent required for the reaction.

[0063] Then, under anhydrous and oxygen-free conditions, at 0°C, CH2Cl2 (300 mL) was added to dissolve the intermediate 2 obtained in step 3; the dissolved raw material was then added dropwise to the prepared formylation reagent; the ice-water bath was removed, and the reaction was continued at room temperature. The reaction progress was monitored by TLC (petroleum ether / ethyl acetate = 1:1), and the reaction was complete after about 12 hours. Then saturated brine (150 mL) was added to quench the reaction, the water layer was extracted with CH2Cl2, the organic phases were combined, and the organic phases were dried with anhydrous Na2SO4, filtered after standing, and the solvent was removed by rotary evaporation to obtain a crude product; the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1), and compound 1 (13.60 g, 44.98 mmol) was obtained after separation and purification.

[0064] The total yield was 44.98%, and the purity of the obtained compound 1 was 94.67% as determined by HPLC.

[0065] Molecular formula: C 16 H 18 N2O4; 1 H NMR, 13 C NMR confirmed that the structure was correct, namely 3-[(3-formyl-1-methyl-1H-indole-2-carbonyl)amino]propyl acetate (Compound 1).

[0066] 1 H NMR (400MHz, CDCl3): δ=10.27(s,1H),9.98(s,1H),8.05(d,J=7.9Hz,1H),7.43(d,J=5.8Hz,2H),7.37(q,J=7.9H z,2.1Hz,1H),4.23(t,J=6.2Hz,2H),4.14(s,3H),3.62(q,J=6.8Hz,2H),2.08(s,3H),2.06(q,J=5.8Hz,2H)ppm.;

[0067] 13 C NMR (100MHz, CDCl3): δ=185.34,171.29,160.68,137.60,127.05,125.31,123.84,119.36,114.04,111.16,36.93,33.05,28.53ppm.

[0068] Example 2: Preparation of 3-[(3-formyl-1-methyl-1H-indole-2-carbonyl)amino]benzoic acid propyl ester (Compound 3)

[0069]

[0070] Referring to Example 1, in step 3, acetic anhydride (Ac2O) was replaced with benzoyl chloride (BzCl), and other conditions were the same as in Example 1 to obtain compound 3.

[0071] The total yield was 42.81%.

[0072] Molecular formula: C 21 H 20 N2O4; Compound 1 H NMR, 13 C NMR confirmed that the structure was correct, namely 3-[(3-formyl-1-methyl-1H-indole-2-carbonyl)amino]benzoic acid propyl ester (Compound 3).

[0073] 1 H NMR (400MHz, CDCl3): δ=10.52(s,1H),9.87(s,1H),8.39-7.97(m,3H),7.72-7.41(m,6 H),4.30(t,J=6.2Hz,2H),4.01(s,3H),3.29(t,J=6.1Hz,2H),2.22-2.18(m,2H)ppm.;

[0074] 13 C NMR (100MHz, CDCl3): δ=185.21,166.50,160.45,145.42,132.84,129.98,128 .64,128.21,124.48,121.71,119.48,109.74,62.47,35.92,32.47,28.78ppm.

[0075] Example 3: Purification of Compound 1 by Recrystallization

[0076] Compound 1 (500 mg, 1.00 eq.) was weighed in a container using an analytical balance, heated in a 45°C constant temperature water bath, and anhydrous ethanol (EtOH, 5 mL) was added to obtain a saturated solution of compound 1; then the heating was stopped, cooled to room temperature, and placed in a 4°C refrigerator to allow the crystals to completely precipitate; after the crystals were completely precipitated, the compound crystals were filtered out, washed with a small amount of cold EtOH, and then dried to remove the residual solvent, to obtain light yellow granular crystals of compound 1. The recovery rate was 85%, and the purity of the obtained compound 1 reached 99.76% as determined by HPLC.

[0077] Example 4: Purification of Compound 1 by Pulping Method

[0078] Compound 1 (500 mg, 1.00 eq.) was weighed into a container using an analytical balance, and 20.00 mL of water was added. The compound was ultrasonicated for 10 min using an ultrasonic cleaner to ensure that the compound was evenly dispersed in the water, and then stirred on a magnetic stirrer for 10 min. The compound solid was filtered out by suction, washed with cold water, and dissolved with CH2Cl2. The obtained organic phase was dried with anhydrous Na2SO4, filtered after standing, and the solvent was removed by rotary evaporation to obtain light yellow granular crystals of compound 1. The recovery rate was 89%, and the purity of the obtained compound reached 97.22% as determined by HPLC.

[0079] Example 5: Purification of Compound 1 by Alcohol-soluble Water-precipitation Method

[0080] Weigh compound 1 (500 mg, 1.00 eq.) in a container using an analytical balance, heat in a 45°C constant temperature water bath, add anhydrous EtOH (5 mL) to obtain a saturated solution of compound 1, then stop heating, wait until cooled to room temperature, and then add water (45.00 mL). At this time, a large amount of solid will precipitate from the solution, and filter to obtain the compound solid, wash the solid with cold water, and dissolve it with CH2Cl2; the obtained organic phase is dried with anhydrous Na2SO4, filtered after standing, and the solvent is removed by rotary evaporation to obtain light yellow granular crystals of compound 1. The recovery rate is 57%, and the purity of the obtained compound reaches 98.49% as determined by HPLC.

[0081] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing an indolecarboxamide compound I, comprising the following steps: (1) Compound A undergoes acyl chlorination reaction to generate intermediate B; (2) Intermediate B undergoes substitution reaction to generate intermediate C; (3) Intermediate C undergoes esterification reaction to generate intermediate II; (4) Intermediate II undergoes Vilsmeier-Haack reaction to generate indolecarboxamide compound I; Wherein, R is selected from: hydrogen atom, C 1-10 Alkyl, C 3-10 Cycloalkyl, 6-14 membered aryl, 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, -C(O)-C 1-10 Alkyl, amino, substituted amino, amidino, guanidino or metal ion; the C 1-10 Alkyl, C 3-10 Cycloalkyl, 6-14 membered aryl, 3-10 membered heterocycloalkyl or 5-6 membered heteroaryl are optionally substituted by 1-2 groups selected from hydroxy, nitro, halogen, cyano, trifluoromethyl, C 1-6 Alkoxy, 6- to 8-membered aryloxy, trifluoromethoxy, difluoromethoxy or C 1-6 The 3-10 membered heterocycloalkyl and 5-6 membered heteroaryl groups optionally contain 1-6 heteroatoms selected from N, O and S; preferably, R is selected from: hydrogen atom, C 1-6 Alkyl or phenyl.

2. The preparation method according to claim 1, wherein In step (1), in the acyl chloride reaction, the acyl chloride reagent is selected from oxalyl chloride or thionyl chloride, the solvent is CH2Cl2, and the catalyst is DMF; In step (2), the reaction reagent added in the substitution reaction is 3-aminopropanol; In step (3), the esterification reaction is carried out by adding RCOOH / (RCO)2O / RCOCl in the presence of DMAP and Et3N using CH2Cl2 as solvent; In step (4), in the Vilsmeier-Haack reaction, DMF and POCl3 are used to prepare the formylation reaction reagent.

3. The preparation method according to claim 1, characterized in that: Step (1) comprises: under anhydrous and oxygen-free conditions, adding compound A into a reaction device, using anhydrous CH2Cl2 as a solvent, slowly adding an acyl chloride reaction reagent in an ice bath after dissolution, then dropping a catalytic amount of DMF, and then moving to room temperature to continue the reaction; after the reaction is completed, removing the solvent by rotary evaporation to obtain an intermediate B; Preferably, the concentration of compound A is 0.10-1.00 mol / L; the acyl chloride reaction reagent is selected from oxalyl chloride or thionyl chloride; the molar ratio of the acyl chloride reaction reagent to compound A is 1.0-2.5:1; the reaction time is 8-20h; More preferably, the concentration of compound A is 0.15-0.30 mol / L; the acyl chlorination reaction reagent is oxalyl chloride; the molar ratio of oxalyl chloride to compound A is 1.2-1.5:1; and the reaction time is 10-15 h.

4. The preparation method according to claim 1, characterized in that: Step (2) comprises: placing intermediate B in a reaction device under anhydrous and oxygen-free conditions, adding solvent 1 to dissolve the intermediate B, slowly adding 3-aminopropanol in an ice bath, and then moving the intermediate B to room temperature to continue the reaction; after the reaction is completed, removing the solvent by rotary evaporation to obtain intermediate C; Preferably, the concentration of intermediate B is 0.30-2.50 mol / L; the molar ratio of 3-aminopropanol to intermediate B is 1.0-2.5:1; the solvent 1 is selected from 3-aminopropanol, CH2Cl2 or ethyl acetate; the reaction time is 0.5-2.5h; More preferably, the concentration of intermediate B is 0.75-1.50 mol / L; the molar ratio of 3-aminopropanol to intermediate B is 1.5-2.0:1; the solvent 1 is CH2Cl2; and the reaction time is 1.0-1.5 h.

5. The preparation method according to claim 1, characterized in that: Step (3) comprises: placing intermediate C and DMAP in a reaction device under anhydrous conditions, using anhydrous CH2Cl2 as a solvent, adding Et3N after dissolution, and finally dropping a compound RCOOH or (RCO)2O or RCOCl to start the reaction; after the reaction is completed, removing the solvent by rotary evaporation to obtain intermediate II; Preferably, the concentration of intermediate C is 0.20 mol / L; the molar ratio of compound RCOOH or (RCO)2O or RCOCl to intermediate C is 2:1; and the reaction time is 30 min.

6. The preparation method according to claim 1, characterized in that: Step (4) comprises: first, under anhydrous and oxygen-free conditions, in a 0°C environment, adding DMF and POCl3 in a reaction device, mixing and stirring them at 0°C for 30 minutes, then moving to room temperature, and continuing to mix and stir for 30 minutes to obtain the formylation reaction reagent required for the reaction; Then, under anhydrous and oxygen-free conditions, in an environment of 0°C, the intermediate II dissolved in solvent 2 is added with a formylation reagent, and then the reaction is continued at room temperature; after the reaction is completed, saturated brine is added to quench the reaction, the aqueous layer is extracted with CH2Cl2, the organic layers are combined, dried, filtered, the solvent is removed by rotary evaporation, and then purified by a silica gel column to obtain indolecarboxamide compound I; Preferably, the concentration of intermediate II is 0.10-0.50 mol / L; the molar ratio of the formylation reaction reagent to intermediate II is 1.5-3.0:1; the solvent 2 is selected from DMF, toluene or CH2Cl2; the reaction time is 8-20h; the eluent of silica gel column chromatography is petroleum ether: ethyl acetate = 3:1; More preferably, the concentration of intermediate II is 0.20-0.40 mol / L; the molar ratio of the formylation reaction reagent to intermediate II is 1.5-2.0:1; the solvent 2 is CH2Cl2; and the reaction time is 10-15 h.

7. The preparation method according to claim 1, characterized in that: The overall yield was above 40%.

8. A method for purifying an indolecarboxamide compound I, using any one of the following three methods: Method (1) Recrystallization: Indolecarboxamide compound I is placed in a container, and solvent 3 is slowly added under constant temperature heating conditions to obtain a saturated solution of the compound, and then heating is stopped, and the solution is cooled to room temperature and placed in a 4°C refrigerator to allow crystals to precipitate, and then filtered, washed, and dried to obtain indolecarboxamide compound I crystals; Method (2) beating: take indolecarboxamide compound I into a container, then add solvent 4, ultrasonically disperse the compound in the solvent (for example, using an ultrasonic cleaner), stir, filter, wash, dissolve the solid with CH2Cl2, dry the organic phase, and remove the solvent by rotary evaporation to obtain indolecarboxamide compound I crystals; Method (3) Alcohol-soluble water precipitation: Indolecarboxamide compound I is placed in a container, and anhydrous ethanol is slowly added under constant temperature heating conditions to obtain a saturated solution of the compound. The heating is then stopped, and the solution is cooled to room temperature, and 5-10 times the volume of water is added. The solution is filtered and washed, and the solid is dissolved with CH2Cl2. The organic phase is dried, and the solvent is removed by rotary evaporation to obtain indolecarboxamide compound I crystals. The general structural formula of the indolecarboxamide compound I is as claimed in claim 1.

9. The purification method according to claim 8, characterized in that In method (1), the solvent 3 is selected from anhydrous EtOH or CH2Cl2, and the heating temperature depends on the solvent selection; preferably, the solvent 3 is anhydrous EtOH, and the heating temperature is 40-60°C; In method (2), the solvent 4 is selected from water or petroleum ether; preferably, the solvent 4 is water.

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