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Preparation method of non-natural L-tryptophan derivative

A technology of derivatives and tryptophan, applied in the field of preparation of non-natural L-tryptophan derivatives, can solve the problems of low yield, specificity, low conversion rate, etc., and achieves simple process route and low safety risk. , the effect of simple and quick operation

Pending Publication Date: 2021-11-19
长兴宜生药物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In 2014, a method for preparing 4-bromo-L-tryptophan from 4-bromoindole was reported in the literature, but the yield was only 9% (Organic Letters, 2014, 16, 10, 2622-2625.). Because of the specificity of the enzyme One sex, the conversion rate is extremely low, and the directed evolution of the enzyme requires a lot of manpower and financial resources to induce to adapt to the special substrate structure, that is, the indole structure of different substitutions
[0011] Therefore, it is of great significance to urgently develop a general synthetic method for unnatural tryptophan, and it is necessary to improve the current method for synthesizing unnatural tryptophan derivatives to solve the above-mentioned low yield problem

Method used

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  • Preparation method of non-natural L-tryptophan derivative
  • Preparation method of non-natural L-tryptophan derivative
  • Preparation method of non-natural L-tryptophan derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Starting with 7-methylindole as a specific example, Fmoc-7-methyl-L-tryptophan was prepared according to the following synthetic route:

[0031]

[0032] In order to collect the products of each step, each step can be repeated many times.

[0033] 1) Preparation of 7-methyl-3-formylindole (Ⅱ-a)

[0034] Weigh DMF (12.26g) into a 100mL three-neck flask, move to a water bath, and stir at a water temperature of 10°C. Extract phosphorus oxychloride (6.43g) with a syringe, and slowly add it into a three-necked flask. During the reaction (the formation of an intermediate between phosphorus oxychloride and DMF, that is, the Vilesmeier reagent), phosphorus oxychloride will be exothermic (control temperature1 H NMR (400MHz, DMSO-d 6 )δ12.18(s,1H),9.96(s,1H),8.30-8.31(d,1H),7.93-7.95(d,1H),7.08-7.16(m,2H),2.52(s,3H) .

[0035] 2) Preparation of 4-((7-methyl-1H-indol-3-yl)methylene)-2-phenyloxazol-5(4H)-one (Ⅳ-a)

[0036] Weigh hippuric acid (1.5g), sodium acetate ...

Embodiment 2

[0046] Example 2: Starting with 7-methylindole as a specific example, Fmoc-7-methyl-L-tryptophan was prepared according to the synthetic route of Example 1

[0047] 1) Preparation of 7-methyl-3-formylindole (Ⅱ-a)

[0048] Weigh DMF (10g) and THF (2.54g) into a 100mL three-neck flask, move to a water bath, and stir at a water temperature of 10°C. Extract phosphorus oxychloride (6.43g) with a syringe, and slowly add it into a three-necked flask. During the reaction (the formation of an intermediate between phosphorus oxychloride and DMF, that is, the Vilesmeier reagent), phosphorus oxychloride will be exothermic (control temperature<35°C). After the addition, remove the water bath and continue to stir, heat up to 40°C and stir for 1h (nitrogen protection reaction) to obtain the reaction solution; weigh I-a raw material (5g), add DMF (4.25g) to dissolve, dissolve and add dropwise to the reaction solution (the temperature is controlled between 10-25°C, the reaction has exothermic...

Embodiment 3

[0059] Example 3: Starting with 7-methylindole as a specific example, Fmoc-7-methyl-L-tryptophan was prepared according to the synthetic route of Example 1

[0060] 1) Preparation of 7-methyl-3-formylindole (Ⅱ-a)

[0061] Weigh DMF (9g) and toluene (3g) into a 100mL three-neck flask, move to a water bath, and stir at a water temperature of 10°C. Extract phosphorus oxychloride (6.43g) with a syringe, and slowly add it into a three-necked flask. During the reaction (the formation of an intermediate between phosphorus oxychloride and DMF, that is, the Vilesmeier reagent), phosphorus oxychloride will be exothermic (control temperature<35°C). After the addition, remove the water bath and continue to stir, heat up to 40°C and stir for 1h (nitrogen protection reaction) to obtain the reaction solution; weigh I-a raw material (5g), add DMF (4.25g) to dissolve, dissolve and add dropwise to the reaction solution (the temperature is controlled between 10-25°C, the reaction has exothermic...

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Abstract

The invention discloses a preparation method of a non-natural L-tryptophan derivative, the preparation method comprises the following steps: taking a cheap and easily available substituted indole compound as a raw material, and sequentially carrying out formylation, cyclization, ring opening, asymmetric hydrogenation, hydrolysis deprotection and Fmoc protecting group loading to obtain the non-natural L-tryptophan derivative, namely N-fluorenylmethoxycarbonyl-R1-L-tryptophan. According to the present invention, the reaction process route is simple, the operation is simple and rapid, compared with the existing chemical resolution and enzymatic synthesis, the yield is substantially improved, the total yield reaches 65-70%, the cost is reduced, the three wastes are less, the large-scale production is easily achieved, and the method is the synthesis method with characteristics of low safety risk and high advantages, and is suitable for promotion and application.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a preparation method for unnatural L-tryptophan derivatives used for synthesizing polypeptides and biologically active small molecules. Background technique [0002] Tryptophan is an essential amino acid for biosynthesis, a precursor of many natural non-ribosomal peptides, and an important raw material for alkaloids. Due to its remarkable physiological properties, non-natural L-tryptophan is used to synthesize a variety of polypeptide drugs, and it is playing an increasingly important role in medicine. Many medicinal compounds, such as anticancer drugs Rebeccamycin and Diazonamide A contains the nucleus of tryptophan chloride; the antifungal drug pyrrolnitrin is obtained by cleavage of 7-chlorotryptophan. Halogen substitution or alkane substitution on the aromatic ring of tryptophan can synthesize a new natural product analog, and it...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/20
CPCC07D209/20C07B2200/07Y02P20/55
Inventor 贺志良夏建胜林嘉伟潘子扬杨莹莹
Owner 长兴宜生药物科技有限公司
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