Preparation method of tryptophan derivative

Abstract

The invention discloses a preparation method of a tryptophan derivative, and relates to the field of pharmaceutical chemicals. Comprising the following steps: taking Boc-L-tryptophan methyl ester as a raw material, and introducing methyl through methyl iodide to generate Boc-L-tryptophan (1-Me) methyl ester; the method comprises the following steps: carrying out methyl ester removal on Boc-L-tryptophan (1-Me) methyl ester under an alkaline condition to generate Boc-L-tryptophan (1-Me); boc of Boc-L-tryptophan (1-Me) is removed under the acidic condition, and L-tryptophan (1-Me) is generated; adding a protecting group on the amino group of the L-tryptophan (1-Me) to generate amino-protected L-tryptophan (1-Me); according to the route mode, the side reaction that tryptophan main chain amino or carboxyl is protected is avoided, the yield is high, the reaction temperature is relatively simple, the production cost is relatively low, the refining process is simplified, the yield is also improved, and the production benefit is relatively high.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemicals, and specifically relates to a method for preparing a tryptophan derivative. Background Art

[0002] In the field of peptide synthesis, the artificial synthesis of peptides is controlled by different amino acids in a certain order. Protected amino acids are structural fragments that constitute the target product and are key starting materials. The difficulty lies in the fact that the functional groups of amino acids are easily acted upon by reagents for peptide reactions, which results in an increase in by-products and low synthesis efficiency.

[0003] The current technology for scaling up the production of amino acids with protected side chain amino groups is as follows: amino acids and metal ion compounds, such as copper sulfate, copper sulfide, basic copper carbonate, etc., are dissolved in water and heated to form metal ion chelates of amino acids. The excess metal ion compounds are then filtered out, and the amino acid metal ion chelate aqueous solution is used to form a metal ion chelate protecting the amino acid. The metal ion chelate protecting the amino acid is then filtered and purified, and then decopperized with EDTA.2Na+. After multiple decopperizations, the target product is obtained by filtering.

[0004] Traditional production technology seems simple, but in fact it is complicated to operate. In particular, the step of separating the metal ion chelate that protects the amino acid is particularly difficult and prone to impurities, resulting in impure final products. In addition, traditional processes produce a lot of heavy metal ion wastewater, which is very difficult to treat and has a high cost for reproduction. Under the current situation of great environmental pressure, it is not conducive to the national green production purpose. Summary of the invention

[0005] In order to solve the technical problems of high production cost and low production efficiency of the prior art for preparing tryptophan derivatives, and also to reduce the pollution and harm to the environment during the production process, the present invention provides a method for preparing tryptophan acid derivatives.

[0006] The present invention provides a tryptophan derivative, the structural formula of which is shown in Formula I.

[0007]

[0008] Where R represents an amino protecting group

[0009] More preferably, the R is represented by Boc, Fmoc, or Cbz.

[0010] The present invention provides a method for preparing a tryptophan derivative, and the synthetic route thereof is:

[0011]

[0012] Further preferably, the method for preparing the tryptophan derivative is characterized in that the preparation comprises the following steps:

[0013] Step A: Dissolve Boc-L-tryptophan methyl ester compound 1 in a reaction solution, and carry out a methylation reaction with CH3I under the action of NaH to obtain compound 2.

[0014] Step B: Compound 2 is dissolved in a reaction solution, and a saponification reaction is carried out under alkaline conditions of sodium hydroxide to obtain compound 3.

[0015] Step C: Compound 3 is dissolved in the reaction solution, and Boc is removed under acidic conditions of hydrochloric acid to obtain compound 4.

[0016] Step D: Compound 4 is dissolved in the reaction solution, and a protecting group is added under alkaline conditions to obtain compound 5.

[0017] Further preferably, in the step A, the methyl group on the amino acid side chain, the reaction solvent used is dichloromethane, the amount of NaH used is 1.1-1.2 equivalents of compound 1, and the amount of CH3I used is 1.1-1.2 times the equivalent of compound 1.

[0018] Further preferably, in the step B, the methyl ester is saponified, the reaction solvent used is a mixed solvent of water and tetrahydrofuran, and the amount of sodium hydroxide used is the same equivalent to compound 2.

[0019] Further preferably, in the step C, the Boc protecting group of compound 2 is removed, and the reaction solvent used is a mixed solvent of ethyl acetate and water, and the amount of hydrochloric acid used is twice the equivalent of compound 3.

[0020] Further preferably, in the step D, the protecting group is prepared by using a reaction solvent of a mixed solvent of ethyl acetate and water, and the amount of the protecting agent used is 1.1-1.2 times the equivalent of compound 4.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. The present invention uses Boc-L-tryptophan methyl ester as a raw material, and successfully introduces a methyl group into the side chain primary amine through step A, thereby avoiding the occurrence of a main chain side reaction. Then, step B, step C, and step D are performed to prepare a tryptophan derivative with a content of more than 99%, with a high yield and low production cost.

[0023] 2. The process of the present invention does not involve heavy metal ions, is environmentally friendly, does not involve cumbersome handling, is simple to operate, and is safer and more effective. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 A flow chart for preparing tryptophan derivatives according to the present invention;

[0025] Figure 2 is a flow chart of the preparation of Fmoc-L-tryptophan (1-Me) in Example 1 of the present invention;

[0026] Figure 3 is a flow chart of the preparation of Cbz-L-tryptophan (1-Me) in Example 2 of the present invention;

[0027] Figure 4 This is a schematic diagram of the HPLC test results of Example 4 of the present invention;

[0028] Figure 5 Schematic diagram of HPLC test results of Example 2 of the present invention DETAILED DESCRIPTION

[0029] In order to make the purpose, technical solution and advantages of the embodiments of the present application clearer, the technical solution in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. The components of the embodiments of the present application described and shown in the drawings here can be arranged and designed in various different configurations.

[0030] Therefore, the following detailed description of the embodiments of the present application provided in the accompanying drawings is not intended to limit the scope of the present application for which protection is sought, but merely represents selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.

[0031] Embodiment 1:

[0032] A tryptophan derivative, the structure of which is shown in Formula I:

[0033]

[0034] wherein R represents a protecting group for an amino group.

[0035] The preparation of Fmoc-L-tryptophan (1-Me) is as follows:

[0036]

[0037] The preparation comprises the following steps:

[0038] Step A: Weigh compound 1, i.e. Boc-L-tryptophan methyl ester (318.37 g, 1 mol), and dissolve it in a reaction solution, i.e. dichloromethane (1 L), to form a mixed solution. Under nitrogen protection and with the temperature controlled to be maintained in the range of 0°C-5°C, NAH (23.39 g, 1.1 mol) and CH3I (170.33 g, 1.2 mol) were added respectively, and under the action of NaH, the mixed solution and CH3I were subjected to methylation reaction, and the reaction was stirred for 4 hours. After the reaction was complete as monitored by TLC, the mixture was washed once with 1N hydrochloric acid (200 ml) and twice with saturated brine (2×200 ml), and then dried, concentrated and filtered to finally obtain compound 2.

[0039] Step B: Weigh compound 2 (305.78 g, 0.92 mol), dissolve it in 400 ml of water and 500 ml of tetrahydrofuran, add sodium hydroxide (36.8 g, 0.92 mol), and saponify the reaction system for 1 hour. After the saponification reaction is basically complete as monitored by TLC, add 400 ml of ethyl acetate and adjust the pH range to 2-3 with 5N hydrochloric acid, separate the water layer, concentrate the ester layer to dryness, add an appropriate amount of petroleum ether for pulping, and finally filter with suction to obtain compound 3.

[0040] Step C: Weigh compound 3 (254.69 g, 0.8 mol), add ethyl acetate (500 ml) and 5N hydrochloric acid (200 ml) in sequence, stir and react for 2 hours to precipitate the product, filter the product to obtain compound 4.

[0041] Step D: Weigh compound 4 (203.89 g, 0.8 mol), sodium carbonate (169.6 g, 1.6 mol), add ethyl acetate (500 ml) and water (500 ml), slowly add Fmoc-Osu (323.83 g, 0.96 mol) during stirring, and stir for 5 hours. The reaction is basically complete when monitored by TLC. 5N hydrochloric acid is added to the reaction system to adjust the pH to 2-3, stand for stratification, separate the water layer, concentrate the ester layer to dryness, add an appropriate amount of petroleum ether to slurry, and filter to obtain compound 5a (Fmoc-L-tryptophan (1-Me)). The total yield of Fmoc-L-tryptophan (1-Me) is 76.9%. Figure 4 As shown, HPCL showed a purity of 99.51%

[0042] Embodiment 2:

[0043] The preparation of Cbz-L-tryptophan (1-Me) is as follows:

[0044]

[0045] Step A: Weigh Boc-L-tryptophan methyl ester (318.37 g, 1 mol) and dissolve it in dichloromethane (1 L), and control the temperature in the range of 0°C-5°C under nitrogen protection. Add NAH (23.39 g, 1.1 mol) and CH3I (170.33 g, 1.2 mol) respectively, and stir to react for 4 hours. After the reaction is complete by TLC monitoring, wash once with 1N hydrochloric acid (200 ml) and twice with saturated brine (2×200 ml), and then dry, concentrate and filter to finally obtain compound 2.

[0046] Step B: Weigh compound 2 (305.78 g, 0.92 mol), dissolve it in 400 ml of water and 500 ml of tetrahydrofuran, add sodium hydroxide (36.8 g, 0.92 mol), and saponify the reaction system for 1 hour. After the saponification reaction is basically complete as monitored by TLC, add 400 ml of ethyl acetate and adjust the pH to between 2 and 3 with 5N hydrochloric acid, separate the water layer, concentrate the ester layer to dryness, then add an appropriate amount of petroleum ether for pulping and suction filtration to finally obtain compound 3.

[0047] Step C: Weigh compound 3 (254.69 g, 0.8 mol), add ethyl acetate (500 ml) and 5N hydrochloric acid (200 ml) respectively, stir and react for 2 hours to precipitate the product, then filter the product to obtain compound 4.

[0048] Step D: Weigh compound 4 (203.89 g, 0.8 mol), sodium carbonate (169.6 g, 1.6 mol), add ethyl acetate (400 ml) and water (600 ml), slowly add Cbz-Osu (239.25 g, 0.96 mol) during stirring, and stir for 4 hours. After the reaction is basically complete as monitored by TLC, 5N hydrochloric acid is added to the reaction system to adjust the pH to between 2-3, stand for stratification, separate the water layer, concentrate the ester layer to dryness, add an appropriate amount of petroleum ether for pulping and suction filtration, and finally obtain compound 5b (Cbz-L-tryptophan (1-Me)). The total yield of Cbz-L-tryptophan (1-Me) is 73.5%. Figure 5 As shown, HPCL showed a purity of 99.65%.

[0049] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A tryptophan derivative, the structure of which is shown in Formula I: wherein R represents a protecting group for an amino group.

2. A tryptophan derivative according to claim 1, characterized in that: R represents Boc, Fmoc, Cbz.

3. A method for preparing a tryptophan derivative as claimed in claims 1 and 2, characterized in that: The synthetic route is:

4. The method for preparing a tryptophan derivative according to claim 3, characterized in that: The preparation comprises the following steps: Step A: dissolving Boc-L-tryptophan methyl ester compound 1 in a reaction solution, and reacting with CH3I under the action of NaH to obtain compound 2; Step B: dissolving compound 2 in a reaction solution, and subjecting the compound 2 to saponification reaction under alkaline conditions of sodium hydroxide to obtain compound 3; Step C: Compound 3 is dissolved in the reaction solution, and Boc is removed under acidic conditions of hydrochloric acid to obtain compound 4; Step D: Compound 4 is dissolved in the reaction solution, and a protecting group is added under alkaline conditions to obtain compound 5.

5. The method for preparing a tryptophan derivative according to claim 4, characterized in that: The reaction solvent used in step A is dichloromethane, the amount of NaH used is 1.1-1.2 times the equivalent of compound 1, and the amount of CH3I used is 1.1-1.2 times the equivalent of compound 1.

6. The method for preparing a tryptophan derivative according to claim 4, characterized in that: The reaction solvent used for saponification in step B is a mixed solvent of water and tetrahydrofuran, and the amount of sodium hydroxide used is the same equivalent amount as compound 2.

7. The method for preparing a tryptophan derivative according to claim 4, characterized in that: The reaction solvent used for removing the Boc protecting group of compound 2 in step C is a mixed solvent of ethyl acetate and water, and the amount of hydrochloric acid used is twice the equivalent of compound 3.

8. The method for preparing a tryptophan derivative according to claim 4, characterized in that: The reaction solvent used for adding the protective group in step D is a mixed solvent of ethyl acetate and water, and the amount of the protective agent used is 1.1-1.2 times the equivalent of compound 4.

9. A method for preparing a tryptophan derivative according to claim 4, characterized in that: The reaction temperature of steps AD is 0-80°C.

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