CN103113306A - Synthesis method of 2,3-benzopyrrole compound NPS-1577 - Google Patents

Abstract

The invention belongs to the technical field of drug synthesis, and specifically relates to a method for synthesizing an indolizine compound NPS-1577, comprising the following steps: a) taking p-fluorobenzoic acid (2) as a raw material, and preparing compound 2 through nitration; b) chlorination Esterification of sulfoxide to obtain compound 3; c) reaction with m-methylbenzylamine to obtain intermediate (4); d) reduction with hydrazine hydrate to obtain intermediate (5); e) aminolysis with piperidine The compound (6) is obtained through the reaction; f) The final product (1) is obtained through acetic anhydride ring closure. Compared with the existing synthetic method, the method of the present invention is shortened to six-step reactions, and the reaction conditions of each step are mild, the yield is high, the operation is simple, the raw materials are cheap and easy to obtain, and the reaction cycle is short, so it is very easy for industrialized large-scale production.

Description

A kind of method for synthesizing the pyrizidine compound NPS-1577

technical field

The invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing an indolizine compound NPS-1577 (compound 1).

Background technique

NPS-1577 (Figure 1.13) is a new drug developed by Korea Neopharm for the treatment of inflammatory skin diseases. At present, as a raw material of cosmetics, it has passed the toxicity test of animals, and the safety verification has been completed. Now NPS-1577 is in clinical trials, and its data show that it has also played a positive role.

Chinese chemical name:

2-methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone;

English chemical name: (2-methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone. the

The molecular structural formula is as follows:

NPS-1577

As the largest organ in the human body, the skin performs important functions of protecting the body, perspiration, and sensing heat, cold, and pressure. It covers the whole body and protects various tissues and organs in the body from physical, mechanical, chemical and pathogenic microorganisms. Therefore, when conditions such as skin inflammation appear, it will have a serious impact on people's health and quality of life. The important clinical manifestation of skin inflammation is skin itching.

Pruritus is a kind of skin sensation with an urgent desire to scratch. It is obviously different from pain in terms of subjective feeling, duration, occurrence site and action behavior. Pruritus can also be understood as the body's defense response to harmful stimuli. Pruritus is the most common clinical manifestation of various skin diseases and systemic diseases, which seriously affects the quality of life of patients and requires timely and effective treatment.

Protease-activated receptors (PARs) belong to G protein-coupled receptors (G

Protein coupled receptor (GPCR) family members, mediate transmembrane signal transduction, can be activated by serine proteases. Protease-activated receptors have a receptor family of seven transmembrane units ^[18] , which play very important roles in blood circulation, respiratory system, nervous system and digestive system.

Protease-activated receptors (PARs) include four members: PAR-1, PAR-2, PAR-3 and PAR-4. Among them, PAR-1, PAR-3 and PAR-4 are thrombin receptors, while PAR-2 is a receptor for insulin, mast cell plasmin, coagulation factors VIIa and Xa and other unknown proteolytic enzymes. PAR-2 does not exist in platelets, and is unevenly distributed in tissues and cells in mammals, and plays a mediating role in inflammatory responses in vivo and in vitro.

Since PAR-2 has dual functions of pro-inflammatory and anti-inflammatory, the inflammatory response mechanism that can be caused includes multiple cascades, increased vascular permeability, cytokine production and expression of adhesion factors, which further cause leukocyte accumulation. PAR-2 can also promote prostanoid production, increase inflammatory response, and activate nerve endings PAR-2 can

Calcitonin gene-related peptide and substance P are released. Therefore, further research on PAR-2 may provide targeted support for the treatment of various inflammations including: allergic dermatitis, rheumatoid arthritis, asthma, gastrointestinal diseases and neuralgia.

Protease-activated receptor (PAR-2) drug research is less, the current representative drug is NPS-1577. NPS-1577 is a new drug developed by Korea Neopharm for the treatment of inflammatory skin diseases. Compared with the original PAR-2 dinitrophenol antagonist, NPS-1577 can achieve a maximum of 200 times the efficacy, and it can play an important role in the treatment of skin inflammation, itching, and skin pigmentation. At present, as the raw material of cosmetics, it has passed the animal toxicity test and completed the safety verification. Now NPS-1577 is in clinical trials, and the data show that it has also played a positive role.

the

Figure 1.14

The current synthesis method of NPS-1577 is generally realized according to the following reaction route (WO2009036404 A2):

 

 

The raw materials used in the existing process are relatively expensive, and the cost of preparing the reaction substrate is also high; the reaction cycle is long, the reaction conditions are difficult to control, and the operation is cumbersome, so it is difficult to apply to scale-up industrial synthesis.

Contents of the invention

The object of the present invention is to provide a new method for synthesizing an indolizine compound (NPS-1577) (compound 1) easily and at low cost in industry.

The technical solution adopted by the present invention to solve the problems of the technologies described above is:

The method for the synthesis of an indolizine compound (NPS-1577) (compound 1) proposed by the present invention, its synthetic route is as follows:

Specific steps are as follows:

(1) Using p-fluorobenzoic acid as a raw material, in the presence of concentrated nitric acid, react with concentrated sulfuric acid as a solvent, the reaction temperature is -5°C to 100°C, and the reaction time is 1-24 hours to generate 4-fluoro-3- Nitrobenzoic acid; wherein: the molar ratio of concentrated nitric acid to p-fluorobenzoic acid is 1:1-3:1;

(2) Under the condition of acidic catalyst, 4-fluoro-3-nitrobenzoic acid is esterified with alcohol solvent to obtain 4-fluoro-3-nitrobenzoic ester compound; wherein: acidic catalyst and 4- The molar ratio of fluoro-3-nitrobenzoic acid is 1:1-5:1; the reaction temperature is -10°C to solvent reflux temperature, and the reaction time is 1-24 hours;

(3) In a solvent, in the presence of a base, 4-fluoro-3-nitrobenzoate reacts with m-methylbenzylamine to generate 3-nitro-4-(3-methylbenzylamine )-3-benzoate; wherein: the molar ratio of base to 4-fluoro-3-nitrobenzoate is 1:1-3:1; m-methylbenzylamine and 4-fluoro-3- The molar ratio of nitrobenzoate is 1:1-5:1; the reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is 1-24 hours;

(4) In a solvent, in the presence of a reducing agent, reduce 3-nitro-4-(3-methylbenzylamino)-3-benzoate to 3-amino-4-(3- Methylbenzylamino)-3-benzoate; wherein, the molar ratio of reducing agent to 3-amino-4-(3-methylbenzylamino)-3-benzoate is 1:1-8 : 1; the reaction temperature is from -5°C to the solvent reflux temperature, and the reaction time is 1-24 hours;

(5) In a solvent, 3-amino-4-(3-methylbenzylamino)-3-benzoate reacts with piperidine to generate (3-amino-4-(3-methylbenzyl amino)phenyl)(piperidin-1-yl)methanone; wherein the molar ratio of piperidine to 3-amino-4-(3-methylbenzylamino)-3-benzoate is 1:1- 5:1; the reaction temperature is from 0°C to the solvent reflux temperature, and the reaction time is 1-24 hours;

(6) In a solvent, (3-amino-4-(3-methylbenzylamino)phenyl)(piperidin-1-yl)methanone reacts with acetic anhydride to generate (2-methyl-1- (3-Methylbenzyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone; where: acetic anhydride and (3-amino-4-(3-methyl The molar ratio of benzylamino)phenyl)(piperidin-1-yl)methanone is 1:1-8:1; the reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is 1-24 hours.

In the present invention, the molar ratio of concentrated nitric acid to p-fluorobenzoic acid in step (1) is 1.3:1-1.7:1.

In the present invention, the reaction temperature in step (1) is 55-60° C., and the reaction time is 2-3 hours.

In the present invention, the acidic catalyst in step (2) is selected from any one of thionyl chloride, concentrated sulfuric acid, p-toluenesulfonic acid, and hydrogen chloride, among which thionyl chloride is preferred.

In the present invention, the solvent in step (2) is selected from any one of methanol, ethanol, isopropanol, n-butanol and propanol, among which methanol is preferred.

In the present invention, the molar ratio of the acidic catalyst to 4-fluoro-3-nitrobenzoic acid in step (2) is 1:1-5:1.

In the present invention, the reaction temperature in step (2) is 60-65°C, and the reaction time is 1-2h.

In the present invention, the alkali described in step (3) is selected from any one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide or sodium ethoxide, wherein the carbonate Potassium is preferred.

In the present invention, the solvent described in step (3) is selected from any one of ethyl acetate, dichloromethane, 1,2-dichloroethane, acetonitrile, acetone or N, N-dimethylformamide, wherein Acetonitrile is preferred.

In the present invention, the molar ratio of the alkali to the 4-fluoro-3-nitrobenzoate in step (3) is 1.5:1-3:1; m-methylbenzylamine and 4-fluoro- The molar ratio of 3-nitrobenzoate is 1.5:1-3:1.

In the present invention, the reaction temperature in step (3) is 70-75° C., and the reaction time is 1-2 hours.

In the present invention, the reducing agent described in step (4) is selected from any one of hydrazine hydrate, hydrogen/palladium carbon, stannous chloride, iron powder/concentrated hydrochloric acid, zinc powder/acetic acid or hydrosulfite, wherein iron powder/ Concentrated hydrochloric acid is preferred.

In the present invention, the solvent in step (4) is selected from concentrated hydrochloric acid, ethyl acetate, dichloromethane, tetrahydrofuran, methanol, ethanol or acetic acid, among which concentrated hydrochloric acid is preferred.

In the present invention, the molar ratio of the reducing agent to 3-amino-4-(3-methylbenzylamino)-3-benzoate in step (4) is 2:1-3:1.

In the present invention, the reaction temperature in step (4) is 15-20° C., and the reaction time is 2-3 hours.

In the present invention, the solvent in step (5) is selected from piperidine, dichloromethane, tetrahydrofuran, methanol, ethanol or ethyl acetate, among which piperidine is preferred.

In the present invention, the molar ratio of piperidine to 3-amino-4-(3-methylbenzylamino)-3-benzoate in step (5) is 2:1-5:1.

In the present invention, the reaction temperature in step (5) is 95-100° C., and the reaction time is 8-10 h.

In the present invention, the solvent in step (6) is selected from acetic anhydride, acetic acid, toluene or xylene, among which acetic anhydride is preferred.

In the present invention, the molar ratio of acetic anhydride to (3-amino-4-(3-methylbenzylamino)phenyl)(piperidin-1-yl)methanone in step (6) is 1: 1-5:1.

Among the present invention, the reaction temperature described in step (6) is 105-115, and the reaction time is 12-16 hours.

Compared with the prior art, the present invention has the advantages that: the present invention shortens the total route to six steps through a new route for synthesizing the pyridine compound (NPS-1577), and the reaction conditions of each step are mild and the yield is stable , simple operation, cheap and easy-to-obtain raw materials, and short reaction cycle, so it is very easy for industrial scale-up production.

Detailed ways

The present invention is further illustrated by the following examples, but the content of the present invention can not be limited.

Example 1:

Add 300ml of concentrated sulfuric acid to the reaction bottle, add 100g of p-fluorobenzoic acid in batches, cool in an ice bath to below 10°C, add 71.5ml of concentrated nitric acid dropwise to control the temperature at 0-5°C, and raise the temperature to 50-55°C for 2.5 hours after dropping. TLC monitors that the reaction of the raw materials is completed and cooled down. The reaction solution is poured into 810ml of ice water, stirred for 0.5h, suction-filtered, and air-dried at 40°C to obtain 120g of intermediate 2 as a pale yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 11.10(s, 1H), 8.83 (dd, J = 2 Hz, 1H), 8.42 (m, 1H), 7.46 (t, 1H).

the

Add 2000ml of methanol and 500g of intermediate 2 to the reaction bottle in turn, cool in an ice bath to 0°C, add 800ml of thionyl chloride dropwise (completely added within 1 hour), and heat up to 65°C for reflux for 1 hour after dropping. TLC shows that the reaction of the raw materials is complete. Evaporate the solvent under reduced pressure, add 50ml of methanol to dissolve, and spin dry to obtain 572g of intermediate 3 crude product, which is directly carried out to the next reaction.

Dissolve 310g of intermediate 3 in 5000ml of acetonitrile, add 325g of potassium carbonate, add 280g of m-methylbenzylamine, raise the temperature to reflux (81°C) for 1h, TLC shows that the reaction is complete, evaporate the solvent under reduced pressure, and dry at 40°C to obtain 450g of yellow solid crude intermediate 4 was directly subjected to the next reaction.

Dissolve 192g of intermediate 4 in 2080ml of concentrated hydrochloric acid, cool in an ice bath to 15°C, add 400g of iron powder in batches to control the temperature at 15-20°C, after the addition is complete, stir for 2 hours, TLC shows that the reaction of the raw materials is complete, add ammonia water in an ice bath to adjust the pH value To 9, add 5000ml ethyl acetate to extract twice, wash once with 2500ml saturated saline, dry with anhydrous sodium sulfate, filter, pass dry hydrogen chloride gas (2h) under ice bath, continue to stir for 1.5h, filter cake with suction Washed with a small amount of ethyl acetate to obtain 159 g of off-white solid Intermediate 5. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.70(s, 1H), 8.57 (s, 1H), 7.80 (m, 1H), 7.26-7.00(m, 6H), 6.69 (d, 1H), 4.50 (d, 2H), 3.92 (s, 3H), 2.36 (s, 3H).

the

Put 2000ml of piperidine and 500g of intermediate 5 into the reaction flask in turn, and after the drop, the temperature was raised to 100°C and refluxed for 8h. TLC showed that the reaction of the raw materials was complete, and the solvent was evaporated under reduced pressure to obtain 480g of the crude intermediate 6, which was directly carried out in the next step.

Put 100g of intermediate 6 into 500ml of acetic anhydride, raise the temperature to 115°C and reflux for 16h, TLC showed that the reaction of the raw materials was complete, and the solvent was evaporated under reduced pressure to obtain the crude product of intermediate 1, which was recrystallized by adding dichloromethane/petroleum ether to obtain 86g of white solid Final product 1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.52(m, 2H), 7.20 (m, 2H), 7.00(s, 1H), 5.48(s, 1H), 3.36 (s, 4H), 2.52 ( s, 3H), 2.25 (s, 3H), 1.57 (m, 6H). LC-MS: m/z 348.2 [M+H] ⁺ .

Example 2

Add 300ml of concentrated sulfuric acid to the reaction bottle, add 100g of p-fluorobenzoic acid in batches, cool in an ice bath to below 10°C, add 71.5ml of concentrated nitric acid dropwise to control the temperature at 5-10°C, and raise the temperature to 25-30°C for 6 hours after dropping, TLC After monitoring the completion of the raw material reaction and cooling, the reaction solution was poured into 810ml of ice water, stirred for 0.5h, suction filtered, and air-dried at 40°C to obtain 118g of intermediate 2 as a pale yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 11.10(s, 1H), 8.83 (dd, J = 2 Hz, 1H), 8.42 (m, 1H), 7.46 (t, 1H).

the

Add 1600ml of methanol and 400g of intermediate 2 to the reaction bottle in turn, cool in an ice bath to 0°C, add 80g of concentrated sulfuric acid dropwise (completely added within 1 hour), heat up to 65°C and reflux for 1 hour after dropping, TLC shows that the reaction of the raw materials is complete, and depressurize The solvent was evaporated to obtain 385 g of intermediate 3 crude product, which was directly carried out to the next reaction.

Dissolve 700g of intermediate 3 in 5000ml of N,N-dimethylformamide, add 305g of sodium carbonate, add 280g of m-methylbenzylamine, raise the temperature to 80°C, and react for 1-1.5h. TLC shows that the reaction is complete. The solvent was removed, and air-dried at 40° C. to obtain 862 g of a yellow solid crude product intermediate 4, which was directly subjected to the next reaction.

Dissolve 210g of intermediate 4 in 2000ml of acetic acid, cool in an ice bath to 0°C, add 380g of zinc powder in batches to control the temperature at 0-5°C, after the addition is complete, stir for 2 hours, TLC shows that the reaction of the raw materials is complete, add sodium hydroxide in an ice bath to adjust the pH value to 9, add 5000ml of dichloromethane to extract twice, wash once with 2500ml of saturated saline, dry over anhydrous sodium sulfate, filter, pass in dry hydrogen chloride gas (2h), continue stirring for 1.5h, and filter the filter cake with a small amount of Dichloromethane was washed to obtain 143 g of off-white solid Intermediate 5. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.70(s, 1H), 8.57 (s, 1H), 7.80 (m, 1H), 7.26-7.00(m, 6H), 6.69 (d, 1H), 4.50 (d, 2H), 3.92 (s, 3H), 2.36 (s, 3H).

the

490ml of piperidine, 500g of intermediate 5, and 2500ml of methanol were successively put into the reaction flask, and the temperature was raised to reflux for 10h. TLC showed that the reaction of the raw materials was complete, and the solvent was evaporated under reduced pressure to obtain 462g of the crude product of intermediate 6, which was directly carried out in the next step.

Put 100g of intermediate 6 into 500ml of acetic anhydride, raise the temperature to 100°C and react for 24 hours. TLC showed that the reaction of the raw materials was complete, and the solvent was evaporated under reduced pressure to obtain the crude product of intermediate 1, which was recrystallized by adding dichloromethane/petroleum ether to obtain 82g of white solid Final product 1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.52(m, 2H), 7.20 (m, 2H), 7.00(s, 1H), 5.48(s, 1H), 3.36 (s, 4H), 2.52 ( s, 3H), 2.25 (s, 3H), 1.57 (m, 6H). LC-MS: m/z 348.2 [M+H] ⁺ .

Example 3

Add 600ml of concentrated sulfuric acid to the reaction bottle, add 200g of p-fluorobenzoic acid in batches, cool in an ice bath to 0-5°C, add 143ml of concentrated nitric acid dropwise to control the temperature at 5-10°C, and raise the temperature to 55-65°C for 1 hour after dropping, TLC After monitoring the completion of the raw material reaction and cooling, the reaction solution was poured into 1620ml of ice water, stirred for 1 hour, suction filtered, and air-dried at 40°C to obtain 240g of intermediate 2 as a pale yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 11.10(s, 1H), 8.83 (dd, J = 2 Hz, 1H), 8.42 (m, 1H), 7.46 (t, 1H).

the

Put 1600ml of ethanol and 400g of intermediate 2 into the reaction bottle in turn, cool in an ice bath to 0°C, add 80g of concentrated sulfuric acid dropwise (completely added within 1 hour), and heat up to 78°C for 1 hour under reflux after dropping. The solvent was evaporated to obtain 392 g of intermediate 3 crude product, which was directly carried out to the next reaction.

Dissolve 700g of intermediate 3 in 5000ml of acetone, add 305g of sodium carbonate, add 280g of m-methylbenzylamine, heat up to 40°C, react for 15h, TLC shows that the reaction is complete, evaporate the solvent under reduced pressure, and dry at 40°C to obtain 830g The yellow solid crude intermediate 4 was directly subjected to the next reaction.

Dissolve 420g of intermediate 4 in 4200ml of acetic acid, cool in an ice bath to 0°C, add 760g of zinc powder in batches and control the temperature at 25-30°C, after the addition is complete, stir for 2 hours, TLC shows that the reaction of the raw materials is complete, add sodium hydroxide in an ice bath to adjust the pH value to 9, add 10L dichloromethane to extract twice, wash once with 5000ml saturated saline, dry over anhydrous sodium sulfate, filter, pass in dry hydrogen chloride gas (2h), continue to stir for 1.5h, and filter the filter cake with a small amount of Dichloromethane was washed to obtain 273 g of off-white solid Intermediate 5. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.70(s, 1H), 8.57 (s, 1H), 7.80 (m, 1H), 7.26-7.00(m, 6H), 6.69 (d, 1H), 4.50 (d, 2H), 3.92 (s, 3H), 2.36 (s, 3H).

the

490ml of piperidine, 500g of intermediate 5, and 2500ml of ethanol were put into the reaction flask successively, and the temperature was raised to reflux for 8h. TLC showed that the reaction of the raw materials was complete, and the solvent was evaporated under reduced pressure to obtain 441g of intermediate 6 crude product, which was directly carried out in the next step.

Put 100g of intermediate 6 into 300ml of acetic anhydride, raise the temperature to 100°C and react for 18h, TLC showed that the reaction of the raw materials was complete, and the solvent was evaporated under reduced pressure to obtain the crude product of intermediate 1, which was recrystallized by adding dichloromethane/petroleum ether to obtain 79g of white solid Final product 1. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.52(m, 2H), 7.20 (m, 2H), 7.00(s, 1H), 5.48(s, 1H), 3.36 (s, 4H), 2.52 ( s, 3H), 2.25 (s, 3H), 1.57 (m, 6H). LC-MS: m/z 348.2 [M+H] ⁺ .

Claims (10)

1. the method for a synthetic nitrogen indene compound NPS-1577 is characterized in that synthetic route is as follows:

Wherein R represents that hydrogen atom, carbonatoms are any alkyl or aryl of 1 ~ 20;

Concrete steps are as follows:

(1) take parafluorobenzoic acid as raw material, under the existence of concentrated nitric acid, to react with the solvent vitriol oil, temperature of reaction is-5 ℃ to 100 ℃, the reaction times is 1-24 hour, generates 4-fluoro-3-nitrobenzoic acid; Wherein: the mol ratio of concentrated nitric acid and parafluorobenzoic acid is 1:1-3:1;

(2) under the condition of an acidic catalyst, 4-fluoro-3-nitrobenzoic acid and alcoholic solvent carry out esterification, obtain 4-fluoro-3-nitrobenzoic acid carboxylate; Wherein: the mol ratio of an acidic catalyst and 4-fluoro-3-nitrobenzoic acid is 1:1-5:1; Temperature of reaction be-10 ℃ to the solvent refluxing temperature, the reaction times is 1-24 hour;

(3) in solvent, under the existence of alkali, 4-fluoro-3-nitrobenzoic acid carboxylate and a methylbenzylamine reaction generate 3-nitro-4-(3-methylbenzylamine base)-the 3-benzoic ether; Wherein: the mol ratio of alkali and 4-fluoro-3-nitrobenzoic acid carboxylate is 1:1-3:1; Between the mol ratio of methylbenzylamine and 4-fluoro-3-nitrobenzoic acid carboxylate be 1:1-5:1; Temperature of reaction be room temperature to the solvent refluxing temperature, the reaction times is 1-24 hour;

(4) in solvent, under the condition that reductive agent exists, with 3-nitro-4-(3-methylbenzylamine base)-the 3-benzoic ether is reduced to 3-amino-4-(3-methylbenzylamine base)-the 3-benzoic ether; The mol ratio of wherein, reductive agent and 3-amino-4-(3-methylbenzylamine base)-3-benzoic ether is 1:1-8:1; Temperature of reaction be-5 ℃ to the solvent refluxing temperature, the reaction times is 1-24 hour;

(5) in solvent, 3-amino-4-(3-methylbenzylamine base)-3-benzoic ether and piperidines react, and generate (3-amino-4-(3-methyl-benzyl is amino) phenyl) (piperidin-1-yl) ketone; The mol ratio of piperidines and 3-amino-4-(3-methylbenzylamine base wherein)-3-benzoic ether is 1:1-5:1; Temperature of reaction be 0 ℃ to the solvent refluxing temperature, the reaction times is 1-24 hour;

(6) in solvent, (3-amino-4-(3-methyl-benzyl is amino) phenyl) (piperidin-1-yl) ketone and aceticanhydride reaction, generate (2-methyl isophthalic acid-(3-methyl-benzyl)-1H-benzo [d] imidazoles-5-yl) (piperidin-1-yl) ketone; Wherein: aceticanhydride and (3-amino-4-(3-methyl-benzyl is amino) phenyl) (piperidin-1-yl) ketone mol ratio is 1:1-8:1; Temperature of reaction be room temperature to the solvent refluxing temperature, the reaction times is 1-24 hour.

2. the method for synthetic nitrogen indene compound NPS-1577 according to claim 1, is characterized in that the mol ratio of concentrated nitric acid described in step (1) and parafluorobenzoic acid is 1.3:1-1.7:1, and temperature of reaction is 55-60 ℃, and the reaction times is 2-3h.

3. the method for synthetic nitrogen indene compound NPS-1577 according to claim 1 is characterized in that an acidic catalyst described in step (2) is selected from sulfur oxychloride, the vitriol oil, tosic acid or hydrogenchloride any; Described solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol or propyl alcohol any.

4. the method for synthetic nitrogen indene compound NPS-1577 according to claim 1, is characterized in that the mol ratio of an acidic catalyst described in step (2) and 4-fluoro-3-nitrobenzoic acid is 1:1-5:1, and temperature of reaction is 60-65 ℃, and the reaction times is 1-2h.

5. the method for synthetic nitrogen indene compound NPS-1577 according to claim 1 is characterized in that alkali described in step (3) is selected from sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate or sodium ethylate any; Described solvent is selected from, and described in step (3), solvent is selected from ethyl acetate, methylene dichloride, 1, in 2-ethylene dichloride, acetonitrile, acetone or DMF any.

6. the method for synthetic nitrogen indene compound NPS-1577 according to claim 1, is characterized in that the mol ratio of alkali described in step (3) and 4-fluoro-3-nitrobenzoic acid carboxylate is 1.5:1-3:1; Between the mol ratio of methylbenzylamine and 4-fluoro-3-nitrobenzoic acid carboxylate be 1.5:1-3:1, temperature of reaction is 70-75 ℃, the reaction times is 1-2 hour.

7. the method for synthetic nitrogen indene compound NPS-1577 according to claim 1 is characterized in that reductive agent described in step (4) is selected from hydrazine hydrate, hydrogen/palladium carbon, tin protochloride, iron powder/concentrated hydrochloric acid, zinc powder/acetic acid or vat powder any; Described solvent is selected from ethyl acetate, methylene dichloride, tetrahydrofuran (THF), methyl alcohol, ethanol or ethyl acetate any.

8. the method for synthetic nitrogen indene compound NPS-1577 according to claim 1, it is characterized in that reductive agent described in step (4) and 3-amino-4-(3-methylbenzylamine base)-mol ratio of 3-benzoic ether is 2:1-3:1, temperature of reaction is 15-20 ℃, and the reaction times is 2-3h.

9. the method for synthetic nitrogen indene compound NPS-1577 according to claim 1, it is characterized in that solvent described in step (5) is selected from piperidines, methylene dichloride, tetrahydrofuran (THF), methyl alcohol, ethanol or ethyl acetate any, the mol ratio of described piperidines and 3-amino-4-(3-methylbenzylamine base)-3-benzoic ether is 2:1-5:1, temperature of reaction is 95-100 ℃, and the reaction times is 8-10h.

10. the method for synthetic nitrogen indene compound NPS-1577 according to claim 1, it is characterized in that solvent described in step (6) is selected from aceticanhydride, acetic acid, toluene or dimethylbenzene any, described aceticanhydride and (3-amino-4-(3-methyl-benzyl amino) phenyl) (piperidin-1-yl) ketone mol ratio is 1:1-5:1, temperature of reaction is 105-115 ℃, and the reaction times is 12-16 hour.