Preparation method of a therapeutic drug for ulcerative colitis

Abstract

The present invention discloses a preparation method of methyl carteolol, a therapeutic drug for ulcerative colitis: Step 1, 5-(dimethylamino)-2-(methylamino)benzoic acid reacts with Nα-Boc-4-amino-L-phenylalanine methyl ester to first obtain an intermediate compound, and then the boc group is removed to obtain the intermediate 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalanine methyl ester; Step 2, the product of Step 1 and 2,6-dichlorobenzoic acid are subjected to a docking reaction to obtain methyl carteolol. The new synthesis method of methyl carteolol described in the present invention has obvious advantages over the prior art, with high yield, environmental friendliness, complete reaction and fewer by-products.

Description

Field of the Invention

[0001] The present invention belongs to the field of chemical drug synthesis, and particularly relates to a new preparation method of a drug for treating ulcerative colitis, Carotegrast methyl. Background Art

[0002] Inflammatory bowel disease (IBD) is a group of chronic intestinal inflammatory diseases with unclear pathogenesis and etiology, mainly including ulcerative colitis (UC) and Crohn's disease (CD). Currently, genetic susceptibility, abnormal intestinal mucosal immunity, abnormal intestinal microecology, external environment, etc. are considered possible inducing factors for IBD.

[0003] Traditional drugs for treating IBD include aminosalicylate preparations, corticosteroids, and immunosuppressants. These drugs have limited efficacy and numerous adverse reactions. The emergence of biological agents (such as the anti-TNF-α agent infliximab) has alleviated the above situation to a certain extent, but there are still certain deficiencies. The induction and maintenance remission rates are both less than 50%. 20% of patients need to undergo intestinal resection surgery 2 - 5 years after taking the drug, and there are also serious infusion reactions and systemic infection adverse reactions.

[0004] Integrin is a heterodimer transmembrane receptor composed of an α subunit and a β subunit, which plays an important role in the proliferation, signal transduction, and transportation of immune cells. Integrin mediates the specific migration and homing of inflammatory cells to the gastrointestinal tract, which is a new target for the treatment of IBD and an effective therapeutic drug for treating IBD. Monoclonal antibody integrin inhibitors have been on the market for many years, such as natalizumab and vedolizumab. However, monoclonal antibody drugs need to be injected for a long time, and they have the deficiencies of infusion adverse reactions, immunogenicity, and reduced efficacy due to the appearance of anti-drug antibodies. Moreover, natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). In June 2022, Carotegrast methyl was approved in Japan for the treatment of moderate ulcerative colitis (only in cases where the treatment effect of 5-aminosalicylic acid preparations is insufficient), opening the era of small molecule integrin inhibitors for the treatment of IBD.

[0005] Carotegrast methyl is an ester prodrug of an oral small molecule α4 integrin inhibitor. It can simultaneously act on the α4β1 and α4β7 heterodimer transmembrane receptors expressed on immune cells, and inhibit the interaction between α4β7 and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on intestinal endothelial cells and between α4β1 and vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells, preventing the transportation of inflammatory cells to intestinal lymphoid tissue. Its mechanism of action is the same as that of natalizumab.

[0006] Carotegrast methyl is the first approved oral small molecule integrin inhibitor for the treatment of IBD, which can improve patient compliance and reduce the burden on medical workers. From the existing data, carotegrast methyl in the treatment of UC can improve the clinical remission rate, response rate and mucosal healing rate. In terms of safety, carotegrast methyl has good tolerance, its serum half-life and clearance time are shorter than those of natalizumab, and the drug can be rapidly cleared from the body. Therefore, the safety of PML may be improved, and no PML cases have been found at present. This drug will benefit a large number of patients.

[0007] The Chinese chemical name of Carotegrast methyl: Methyl (2S)-2-(2,6-dichlorobenzamido)-3-{4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]phenyl}propionate, molecular formula: C 28 H 26 Cl2N4O5, molecular weight: 569.44, CAS registration number: 401905-67-7, and its chemical structural formula is as follows:

[0008]

[0009] Carotegrast methyl

[0010] The prior art document patent CN200480010615 reported the synthesis route 1 of carotegrast methyl as follows:

[0011]

[0012] In the above route 1, carotegrast methyl is synthesized in 5 to 6 steps, in which a precious metal catalyst pt / C is used, and finally a methylation reaction is carried out. Due to the long route, the overall yield is relatively low.

[0013] The prior art document patent CN200780050294 reported two preparation methods of the key intermediate formula a of carotegrast methyl as follows:

[0014] Method 1:

[0015]

[0016] Method 2:

[0017]

[0018] In this technical document, Compound A is prepared through four steps of reaction, and finally methyl carotegrast is obtained through methylation reaction; in Method 2, Compound A is prepared through two steps of reaction, and methyl carotegrast is obtained through methylation reaction of Compound A according to Route 1. However, the above still has problems of a relatively long route and low yield. Therefore, it is necessary to develop a new preparation method for methyl carotegrast with a shorter route, simple and safe operation, low cost, and environmental friendliness. Summary of the Invention

[0019] The present invention provides a new preparation method for the ulcerative colitis treatment drug methyl carotegrast, and the specific route is as follows:

[0020]

[0021] Step 1: 5-(Dimethylamino)-2-(methylamino)benzoic acid reacts with methyl Nα-Boc-4-amino-L-phenylalaninate to obtain an intermediate (N-boc-Compound C), and then the boc group is removed to obtain the intermediate methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (Compound C);

[0022] Step 2: The intermediate methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (Compound C) reacts with 2,6-dichlorobenzoic acid to obtain methyl carotegrast.

[0023] Among them, the starting material N α -Boc-4-amino-L-phenylalaninate is synthesized in the following manner.

[0024]

[0025] The route of the present invention is different from the synthesis routes of methyl carotegrast reported in the prior art patents CN200480010615 and CN200780050294. The present invention provides a new method for obtaining methyl carotegrast through two steps of reaction using 1,5-(dimethylamino)-2-(methylamino)benzoic acid, N α -Boc-4-amino-L-phenylalaninate and 2,6-dichlorobenzoic acid as starting materials. This method has the advantages of inexpensive and easily available starting materials, simple and safe operation, low cost, and environmental friendliness.

[0026] In Step 1 of the present invention, 1,5-(dimethylamino)-2-(methylamino)benzoic acid, N α-Boc-4-amino-L-phenylalanine methyl ester is used as the starting material, in which 5-(dimethylamino)-2-(methylamino)benzoic acid has its methyl group introduced in advance, avoiding the methylation reaction in the last step; N α In the -Boc-4-amino-L-phenylalanine methyl ester material, the Boc group is used to protect the primary amino group, avoiding the generation of by-products at the amino position, which is the biggest highlight of the present invention different from the prior art documents.

[0027] In step 1 of the present invention, in the reaction, the starting material 1, 5-(dimethylamino)-2-(methylamino)benzoic acid first cyclizes with the acylating agent to form the intermediate 5-dimethylamino-N-methylisatoic anhydride, and then reacts with the starting material N α -Boc-4-amino-L-phenylalanine methyl ester to form the intermediate N α -Boc-4-{2-amino-5-dimethylaminobenzoyl amino}-L-phenylalanine methyl ester, and then cyclizes with the acylating agent to form N α -Boc-4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalanine methyl ester (compound of formula c). The acylating agent used in this process is selected from triphosgene or carbonyldiimidazole, both of which can achieve good reaction effects.

[0028] In the present invention, the reaction solvent for step 1 is selected from dimethylformamide or dimethylacetamide. The above solvents can ensure the dissolution of the main materials and products, and the homogeneous system reaction can ensure the smooth progress of the reaction. In the reaction of step 1 of the present invention, the excess of any main material will cause an increase in by-products and is difficult to purify and remove in the post-treatment. However, a slightly excessive acylating agent is beneficial to the two cyclization reactions. After final optimization and confirmation, the molar feeding ratio of 5-(dimethylamino)-2-(methylamino)benzoic acid, N α -Boc-4-amino-L-phenylalanine methyl ester and the acylating agent is 1:0.9-1.1:2-2.4, preferably 1:0.95-1.05:2.1-2.3, and the reaction can proceed smoothly, and the by-products can be controlled to the minimum.

[0029] The key conditions for the reaction in step 1 of the present invention are: 5-(dimethylamino)-2-(methylamino)benzoic acid first reacts with half of the amount of N,N'-carbonyldiimidazole at a controlled temperature of 15-25°C for 2-3 hours, then N α -Boc-4-amino-L-phenylalanine methyl ester is added and the reaction continues at a controlled temperature of 60-70°C for 2-3 hours. Finally, the remaining amount of N,N'-carbonyldiimidazole is added, and the reaction continues at a controlled temperature of 60-70°C for 8-10 hours. The above reaction condition control can ensure the complete reaction of each stage and less by-products.

[0030] In the reaction of step 2 of the present invention, 2,6-dichlorobenzoic acid needs to react with an acylating agent first and then dock with methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (compound of formula c), wherein the acylating agent is selected from thionyl chloride or carbonyldiimidazole; our company has tried other acylation conditions, such as using DCC as the acylating agent, but there are more by-products. When thionyl chloride or carbonyldiimidazole is used as the acylating agent, there are fewer by-products. However, when the acylating agent is thionyl chloride, an organic base needs to be added as an acid-binding agent in the docking reaction, and the organic base is selected from N,N-diisopropylethylamine or triethylamine.

[0031] In the reaction of step 2 of the present invention, when the acylating agent is thionyl chloride, the molar feeding ratio of methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (compound of formula c), 2,6-dichlorobenzoic acid, thionyl chloride, and organic base is 1:0.9-1.1:1-2:1-3, preferably 1:0.95-1.05:1.2-1.8:1.5-2.5, and particularly preferably 1:1:1.5:2, with fewer by-products.

[0032] In the reaction of step 2 of the present invention, when the acylating agent is carbonyldiimidazole, since the material methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (compound of formula c) is relatively expensive, a slightly excessive amount of 2,6-dichlorobenzoic acid and the acylating agent N,N'-carbonyldiimidazole are used to make methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (compound of formula c) react as completely as possible, and the above-mentioned excessive materials are easy to remove. After final optimization and confirmation, the molar feeding ratio of methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (compound of formula c), 2,6-dichlorobenzoic acid, and N,N'-carbonyldiimidazole is 1:1-1.2:1-1.2, preferably 1:1.05-1.15:1.05-1.15, and particularly preferably 1:1.1:1.1, with the best reaction effect.

[0033] The key condition in the reaction of step 2 of the present invention when the acylating agent is carbonyldiimidazole is: 2,6-dichlorobenzoic acid and N,N'-carbonyldiimidazole are first controlled at 15-25°C for 1-2 h, and then methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate is added and the temperature is controlled at 50-60°C for continuous reaction for 5-6 h, which can ensure complete reaction and fewer by-products.

[0034] The present invention provides a preparation method of methyl carteolol with high yield and environmental friendliness, which has obvious advantages over the existing technical documents. Specific implementation method

[0035] Next, in combination with the embodiments of the present invention, the technical solutions in the embodiments of the present invention will be described in detail. However, the following embodiments are only for understanding the present invention and cannot limit the present invention. The present invention can be implemented in many different ways defined and covered by the claims.

[0036] The following will further illustrate the new synthesis method of methyl carbestrol and the advantages of this method in combination with Embodiments 1-7 of the present invention. Specifically as follows:

[0037] Example 1, N α -Boc-4-nitro-L-phenylalanine

[0038]

[0039] Put 4-nitro-L-phenylalanine (105.1 g, 0.5 mol), 300 ml of water, 200 ml of acetone and 100 ml of 5 mol / L sodium hydroxide aqueous solution into a three-necked flask, stir to dissolve, control the temperature below 10 °C and slowly add dropwise BOC anhydride (109.1 g, 0.5 mol). After the addition, continue to control the temperature at 15-25 °C and react for 1 h. Adjust the pH to neutral with 200 ml of 5 mol hydrochloric acid, precipitate a solid, filter, wash with water, and dry the filter cake to obtain N α -Boc-4-nitro-L-phenylalanine (148.9 g, yield 96%), Ms m / z 311.1 (M+1).

[0040] Example 2, N α -Boc-4-nitro-L-phenylalanine methyl ester

[0041]

[0042] Put N α -Boc-4-nitro-L-phenylalanine (124.0 g, 0.4 mol), 300 ml of water and 200 ml of acetone into a three-necked flask, heat to 40-50 °C with stirring, control the temperature and add dropwise 160 ml of 5 mol / L sodium hydroxide solution and dimethyl sulfate (50.4 g, 0.4 mol). After the addition, continue to control the temperature and react for 0.5 h. Cool to room temperature, add 500 ml of ethyl acetate, stir and separate the liquid. Extract the aqueous phase with 300 ml of ethyl acetate. Combine the organic phases, wash successively with 500 ml of water and 400 ml of saturated sodium chloride. Dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to remove most of the solvent, add 200 ml of n-hexane to the residue, stir and disperse, filter, and dry the filter cake to obtain N α -Boc-4-nitro-L-phenylalanine methyl ester (107.6 g, yield 83%), Ms m / z 325.1 (M+1).

[0043] Example 3, N α Methyl - Boc - 4 - amino - L - phenylalaninate

[0044]

[0045] Place N α -Boc-4-nitro-L-phenylalanine (97.3 g, 0.3 mol), 1000 ml of absolute ethanol and 5% Pd / C (31.9 g, 15 mmol) into a pressure reactor, displace the air, pressurize to 0.5 - 1 MPa, control the temperature at 30 - 40 °C and react for 10 h, relieve the pressure, and filter. Concentrate the filtrate to remove 4 / 5 of the solvent, cool the residue, filter, wash the filter cake with an appropriate amount of ethanol, and dry the filter cake to obtain N α -Boc-4-amino-L-phenylalanine methyl ester (71.5 g, 81%, purity 98.2%), Ms m / z 295.2 (M + 1). 1 HNMR(300MHz d6 - DMSO): δ1.45(s, 9H), 3.67(s, 3H), 2.88~3.13(m, 2H), 4.70(t, 1H), 6.46(d, 2H), 6.94(d, 2H), 7.40(d, 1H).

[0046] Example 4: Synthetic method 1 of 4-(6 - dimethylamino - 1 - methylquinazoline - 2,4[1H,3H]-dione - 3 - yl)-L - phenylalanine methyl ester (Compound of formula c)

[0047]

[0048] Add 5-(dimethylamino)-2-(methylamino)benzoic acid (38.8 g, 0.2 mol), N,N'-carbonyldiimidazole (35.6 g, 0.22 mol) and 250 ml of dimethylformamide into a three - necked flask, control the reaction at 15 - 25 °C for 3 h; add N α-Boc-4-amino-L-phenylalanine methyl ester (58.8 g, 0.2 mol), continue the reaction at 60 - 70 °C for 2 h, then add N,N'-carbonyldiimidazole (CDI, 35.6 g, 0.22 mol), continue the reaction at 60 - 70 °C for 10 h, cool to room temperature, add 300 ml of water and 300 ml of dichloromethane, stir and separate the layers. The aqueous phase is extracted again with 300 ml of dichloromethane. The organic phases are combined, and then the organic phase is washed with 300 ml of saturated brine, and separated. The organic phase is added with trifluoroacetic acid (25.1 g, 0.22 mol) and stirred at room temperature for 2 h. Add 300 ml of water, adjust the pH to 7 - 8 with 10% sodium bicarbonate solution, separate the layers. The organic phase is washed again with 300 ml of water. The organic phase is added with 30 g of anhydrous sodium sulfate and dried for 2 h, filtered, and the filtrate is concentrated to dryness under reduced pressure. The residue is added with 400 ml of absolute ethanol, heated to reflux for dissolution, and naturally cooled to room temperature for crystallization. Filtered, the filter cake is dried in vacuo to obtain the title compound methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (Compound of Formula c, 65.0 g, yield 82%, chemical purity 98.6%). Ms m / z 397.2 (M+1). 1 HNMR(300MHz d6-DMSO): δ3.10(s, 6H), 3.16 and 3.44(m, 2H), 3.68(s, 3H), 3.91(s, 3H), 4.15(t, 1H), 7.16(d, 1H), 7.19(d, 2H), 7.33(d, 2H), 7.38(s, 1H), 7.52(m, 1H).

[0049] Example 5: Synthesis Method 2 of Methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (Compound of Formula c)

[0050]

[0051] Add 5-(dimethylamino)-2-(methylamino)benzoic acid (19.4 g, 0.1 mol), triphosgene (BTC, 32.6 g, 0.11 mol) and 150 ml of dimethylacetamide to a three-necked flask, control the reaction at 15 - 25 °C for 2 h; add N αMethyl (2S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (29.4 g, 0.1 mol) was reacted at 60 - 70 °C for 2 h. Then trichloromethyl chloroformate (BTC, 32.6 g, 0.112 mol) was added and the reaction was continued at 60 - 70 °C for 8 h. After cooling to room temperature, 150 ml of water and 200 ml of dichloromethane were added. The mixture was stirred and separated. The aqueous phase was extracted with 150 ml of dichloromethane. The organic phases were combined, washed with 150 ml of saturated brine, and separated. The organic phase was added with trifluoroacetic acid (12.5 g, 0.11 mol) and stirred at room temperature for 2 h. 150 ml of water was added and the pH was adjusted to 7 - 8 with 10% sodium bicarbonate solution. The mixture was separated. The organic phase was washed with 150 ml of water again. 10 g of anhydrous sodium sulfate was added to the organic phase and dried for 2 h. Then it was filtered. The filtrate was concentrated under reduced pressure to dryness. The residue was added with 200 ml of absolute ethanol, heated to reflux for dissolution, and then naturally cooled to room temperature for crystallization. After filtration, the filter cake was dried in vacuo to obtain the title compound methyl 4-(6-(dimethylamino)-1-methylquinazoline-2,4(1H,3H)-dione-3-yl)-L-phenylalaninate (Compound of Formula c, 31.3 g, yield 79%, chemical purity 97.8%). Ms m / z 397.2 (M + 1).

[0052] Example 6: Synthesis Method 1 of Methyl Catecoster

[0053]

[0054] 2,6-Dichlorobenzoic acid (21.0 g, 0.11 mol), N,N'-carbonyldiimidazole (CDI, 17.8 g, 0.11 mol) and 120 ml of dimethylformamide were added to a three-necked flask. The reaction was carried out at 15 - 25 °C for 1 - 2 h. Then methyl 4-(6-(dimethylamino)-1-methylquinazoline-2,4(1H,3H)-dione-3-yl)-L-phenylalaninate (Formula c, 39.6 g, 0.1 mol) was added and the reaction was continued at 50 - 60 °C for 6 h. After cooling to room temperature, 300 ml of water was added to precipitate a large amount of solid. The solid was filtered, washed with water, and the filter cake was dried to obtain methyl catecoster (47.3 g, yield 83%, chemical purity 99.1%, optical purity 99.5%). Ms m / z 569.2 (M + 1). 1 HNMR(300MHz d6-DMSO): δ2.92(s, 6H), 3.00(q, 1H), 3.20(q, 1H), 3.45(s, 3H), 3.68(s, 3H), 4.80(m, 1H), 7.13 - 7.18(m, 2H), 7.21(d, 1H), 7.28(q, 1H), 7.33 - 7.45(m, 6H), 9.28(d, 1H).

[0055] Example 7: Synthesis Method 2 of Methyl Catecoster

[0056]

[0057] 2,6-Dichlorobenzoic acid (7.0 g, 50 mmol) and 50 ml of dichloromethane were added to a three-necked flask, and thionyl chloride (8.9 g, 75 mmol) was slowly added dropwise. After the addition, the mixture was refluxed for 1 h, and the solvent was evaporated under reduced pressure. The residue was dissolved in 30 ml of dichloromethane and used as a dichloromethane solution of 2,6-dichlorobenzoyl chloride for standby.

[0058] Methyl carteolol (19.8 g, 50 mmol) of formula c compound, triethylamine (10.1 g, 0.1 mol) and 60 ml of dichloromethane were added to a three-necked flask and cooled to below 10 °C. The dichloromethane solution of 2,6-dichlorobenzoyl chloride was added dropwise while controlling the temperature below 10 °C. After the addition, the reaction was continued at room temperature for 2 h. 100 ml of 5% sodium bicarbonate solution was added, and the mixture was stirred and separated. The organic phase was washed with 100 ml of water again, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, the residue was added with 50 ml of absolute ethanol, filtered, the filter cake was washed with water, and the filter cake was dried to obtain methyl carteolol (21.62 g, yield 76%, chemical purity 98.8%, optical purity 99.3%), Ms m / z 569.2 (M+1).

[0059] Compared with the prior art documents, Examples 1-7 of the present invention have a higher yield, reduce the health damage to production operators, and are more environmentally friendly.

[0060] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various changes and modifications. 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 preparation method of a therapeutic drug for ulcerative colitis, characterized in that, The method is as follows: Among them, in Step 1, 5-(dimethylamino)-2-(methylamino)benzoic acid first reacts with an acylating agent and then reacts with N α -Boc-4-amino-L-phenylalanine methyl ester to obtain an intermediate state (N-Boc-form c compound), and then the Boc group is removed to obtain the intermediate 4-(6-dimethylamino-1-methylquinazoline-2,4-[1 H ,3 H -dione-3-yl)-L-phenylalanine methyl ester (form c compound); The acylating agent is selected from triphosgene or carbonyldiimidazole; In the reaction, the molar feed ratio of 5-(dimethylamino)-2-(methylamino)benzoic acid, N α methyl -Boc-4-amino-L-phenylalaninate and the acylating agent is 1:0.9~1.1:2~2.4; Step 2: 2,6-Dichlorobenzoic acid first reacts with the acylating agent, and then undergoes a docking reaction with the intermediate methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (Compound of Formula c) to obtain methyl catestat, wherein the acylating agent is selected from thionyl chloride or carbonyldiimidazole; When the acylating agent is thionyl chloride, an organic base as an acid-binding agent needs to be added to the docking reaction, and the organic base is selected from N,N-diisopropylethylamine or triethylamine; the molar feeding ratio of Compound of Formula c, 2,6-dichlorobenzoic acid, thionyl chloride and the organic base is 1:0.9 - 1.1:1 - 2:1 - 3; When the acylating agent is carbonyldiimidazole, the molar feeding ratio of Compound of Formula c, 2,6-dichlorobenzoic acid and carbonyldiimidazole is 1:1 - 1.2:1 - 1.

2.

2. The preparation method according to claim 1, characterized in that, Starting material N α -Boc-4-amino-L-phenylalanine methyl ester is synthesized as follows: 。 3. The preparation method according to claim 1, wherein The acylating agent described in Step 1 is selected from carbonyldiimidazole.

4. The preparation method according to claim 1, wherein In the reaction of step 1, the molar feeding ratio of 5-(dimethylamino)-2-(methylamino)benzoic acid, N α methyl -Boc-4-amino-L-phenylalaninate and the acylating agent is 1:0.95 to 1.05:2.1 to 2.

3.

5. The preparation method according to claim 1, wherein When the acylating agent is thionyl chloride, the molar feeding ratio of methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (Compound of Formula c), 2,6-dichlorobenzoic acid, thionyl chloride and the organic base is 1:0.95 - 1.05:1.2 - 1.8:1.5 - 2.

5.

6. The preparation method according to claim 5, characterized in that, When the acylating agent is thionyl chloride, the molar feeding ratio of methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (Compound of Formula c), 2,6-dichlorobenzoic acid, thionyl chloride and the organic base is 1:1:1.5:

2.

7. The preparation method according to claim 1, characterized in that, When the acylating agent is carbonyldiimidazole, the molar feeding ratio of methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (Compound of Formula c), 2,6-dichlorobenzoic acid and N,N'-carbonyldiimidazole is 1:1.05 - 1.15:1.05 - 1.

15.

8. The preparation method according to claim 7, characterized in that, When the acylating agent is carbonyldiimidazole, the molar feeding ratio of methyl 4-(6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dione-3-yl)-L-phenylalaninate (Compound of Formula c), 2,6-dichlorobenzoic acid and N,N'-carbonyldiimidazole is 1:1.1:1.1.

Images