CN113666861A - Preparation method of non-natural L-tryptophan derivative - Google Patents

Preparation method of non-natural L-tryptophan derivative Download PDF

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CN113666861A
CN113666861A CN202111081935.3A CN202111081935A CN113666861A CN 113666861 A CN113666861 A CN 113666861A CN 202111081935 A CN202111081935 A CN 202111081935A CN 113666861 A CN113666861 A CN 113666861A
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tryptophan
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贺志良
夏建胜
林嘉伟
潘子扬
杨莹莹
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Changxing Yisheng Pharmaceutical Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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Abstract

The invention discloses a preparation method of non-natural L-tryptophan derivatives, which adopts cheap and easily obtained substituted indole compounds as raw materials, and obtains the non-natural L-tryptophan derivatives, namely N-fluorenylmethoxycarbonyl-R through a series of reactions of formylation, cyclization, ring opening, asymmetric hydrogenation, hydrolysis deprotection and Fmoc protecting group application in sequence1-L-tryptophan. Compared with the existing chemical resolution and enzymatic synthesis, the method has the advantages of simple reaction process route, simple and quick operation, greatly improved yield, total yield of 65-70 percent, reduced cost, less three wastes, easy realization of large-scale production, small safety risk, higher advantage and suitability for popularization and application.

Description

Preparation method of non-natural L-tryptophan derivative
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of an unnatural L-tryptophan derivative for synthesizing polypeptides and bioactive small molecules.
Background
Tryptophan is an essential amino acid for biosynthesis and is also a precursor for many natural non-ribosomal peptides, as well as an important raw material for alkaloids. Due to its remarkable physiological properties, non-natural L-tryptophan is used for synthesizing various polypeptide drugs and plays an increasingly important role in medicine, and many compounds with medicinal value, such as anticancer drugs Rebeccamycin and diazanamide A, contain a chlorinated tryptophan parent nucleus; the antifungal drug pyrrolnitrin is obtained by cleavage of 7-chlorotryptophan. The tryptophan aromatic ring is substituted by halogen or alkane, so that a brand new natural product analogue can be synthesized, the bioactivity and bioavailability of the tryptophan aromatic ring can be greatly changed, and the tryptophan aromatic ring becomes a structural unit which is frequently appeared in the research and development of new drugs, so that the tryptophan aromatic ring has important significance for the research of a non-natural tryptophan derivative synthesis method.
Journal of medicinal Chemistry 2014,57,15,6861-6866. the opioid endorphins mentioned in this article contain non-natural L-tryptophan derivative structural fragments.
The opioid peptides endorphin-1 (EM1: H-Tyr-Pro-TrpPhenH2) and endorphin-2 (EM2: H-Tyr-Pro-phenh2) found in endogenous neurotransmitters in the brain of mammals have led to great expectations, the structural formulae of which are shown below; there is an opportunity to develop analgesic morphine and other mu-opioid receptor (MOR) agonists without long-term side effects, with acute tolerance, physical dependence, respiratory depression, nausea and other gastrointestinal reactions to reduce side effects.
Figure BDA0003264304440000021
In the year 2006,Philip L.A.et al propose a method for producing non-natural tryptophan by using tryptophan synthase (Chemical Communications,2006,47, 4924) -4925), which comprises the following reaction steps:
Figure BDA0003264304440000022
in the synthesized target product, when 7-chloroindole is used for preparing 7-chloro-L-tryptophan, the yield is only 9 percent; when 7-bromo-L-tryptophan is prepared from 7-bromoindole, the yield is only 8%; when 4-bromo-L-tryptophan was prepared from 4-bromoindole, the yield was only 3%. In 2016, there was a report of 5, 6-dichloroindole production of 5, 6-dichloro-L-tryptophan in only 7% yield (Tetrahedron,2016, vol.72, #46, p.7306-7310), according to the following reaction scheme:
Figure BDA0003264304440000023
in 2014, a method for preparing 4 bromo-L-tryptophan by 4-bromoindole is reported, but the yield is only 9% (Organic Letters, 2014,16,10, 2622-one 2625.) because the specificity and the conversion rate of the enzyme are extremely low, and the directed evolution of the enzyme needs a lot of manpower and financial resources to induce so as to adapt to a special substrate structure, namely a different substituted indole structure.
Therefore, the development of a general synthetic method for non-natural tryptophan is urgently needed, and the existing method for synthesizing non-natural tryptophan derivatives needs to be improved so as to solve the problem of low yield.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a preparation method of a non-natural L-tryptophan derivative, which has the advantages of cheap and easily-obtained raw materials, simple process route and simple and quick operation, greatly improves the yield and ee value compared with the existing chemical resolution and enzymatic synthesis, reduces the cost and the three wastes, is easy to realize large-scale production, has small safety risk and has higher industrial prospect advantage, and the total yield reaches 65-70%.
The invention discloses a preparation method of a non-natural L-tryptophan derivative, which has a structural formula shown in a formula (VIII), and is obtained by taking an indole compound shown in a formula (I) as a raw material and sequentially carrying out a series of reactions of formylation, cyclization, ring opening, asymmetric hydrogenation, hydrolysis deprotection and Fmoc protection, and is characterized by specifically comprising the following steps:
1) taking an indole compound shown in a formula (I) as a starting material, carrying out formylation reaction in the presence of a Vilesmeier reagent and a solvent A, adding water to quench the reaction after the reaction is finished, and adjusting the pH value with an alkaline substance A to separate out a material to obtain a 3-formylindole compound shown in a formula (II);
2) taking the 3-formyl indole compound shown in the formula (II) obtained in the step 1) as a raw material, adding a solvent B and a glycine derivative shown in the formula (III), carrying out oxazolone synthesis reaction under the action of a catalyst, cooling and separating materials after the reaction is finished, and filtering to obtain an indoxazolone compound shown in the formula (IV);
3) adding an indoxazolone compound shown in a formula (IV) into a solvent C, stirring at room temperature in the presence of an alkaline substance B for ring-opening reaction, adding water for precipitation after the reaction is finished, filtering and drying to obtain a compound shown in a formula (V);
4) adding the compound shown in the formula (V) into a solvent D, adding an asymmetric catalyst, introducing hydrogen, carrying out asymmetric hydrogenation reaction under the conditions that the pressure is 0.2-1 MPa and the temperature is 30-60 ℃, concentrating to remove part of the solvent after the reaction is finished, cooling, crystallizing, filtering and drying to obtain the compound shown in the formula (VI);
5) adding a compound shown as a formula (VI) into acid A, heating for hydrolysis, extracting a byproduct, namely benzoic acid by using ethyl acetate after the reaction is finished, adjusting the pH value to be 5.0-6.0 by using an alkaline substance C, separating materials, filtering, and drying to obtain a compound shown as a formula (VII);
6) adding a compound shown as a formula (VII) and an alkaline reagent E into a solvent D, adding 9-fluorenylmethyl-N-succinimidyl carbonate for amidation reaction, layering after the reaction is finished, concentrating to remove part of the solvent, adjusting the pH to 3-4 with an acid B, and carrying out aftertreatment to obtain the non-natural L-tryptophan derivative shown as a formula (VIII), namely N-fluorenylmethoxycarbonyl-R1-L-tryptophan;
Figure BDA0003264304440000051
wherein: in the formulae (I), (II) (IV), (V), (VI), (VII), (VIII), the substituents R1Is C1-C9 alkyl, halogen or C1-C9 oxygen alkyl substituent, the substituent is mono-substituted or multi-substituted, and the position of the substituent is 4,5, 6, 7 positions of the indole; substituent R2Is C1-C9 alkyl or phenyl, R3Hydrogen or C1-C9 alkyl.
Furthermore, the invention limits that the solvent A in the step 1) is DMF or a mixed solvent of DMF and any one of toluene, THF and xylene, and the Vilesmeier reagent is an intermediate generated by the reaction of phosphorus oxychloride and DMF; the alkaline substance A for adjusting the pH value is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate.
Further, the invention defines that the solvent B in the step 2) is acetic anhydride or a mixed solution of the acetic anhydride and any one of toluene, xylene and tetrahydrofuran; the glycine derivative is acetyl glycine or hippuric acid; the catalyst is sodium acetate, potassium acetate, lithium acetate or calcium acetate.
Further, the invention defines the solvent C in the step 3) as an alcohol solvent, preferably methanol, ethanol, isopropanol, n-butanol or n-propanol; the alkaline substance B is sodium methoxide, sodium ethoxide, sodium propoxide or sodium hydroxide.
Further, the invention defines that the solvent D in the step 4) is methanol, ethanol or isopropanol; the asymmetric hydrogenation catalyst was (-) -1, 2-bis ((2R,5R) -2, 5-dimethylphosphosoap) benzene (cyclooctadiene) rhodium (I) tetrafluoroborate.
Further, the invention defines that the acid A in the step 5) is hydrochloric acid, acetic acid, formic acid or sulfuric acid; the alkaline substance C is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
Further, the invention defines the alkaline reagent D in the step 6) as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, DBU or DIPEA; the acid B is hydrochloric acid, acetic acid, formic acid or sulfuric acid; the solvent E is ethyl acetate, tetrahydrofuran, methyl acetate, chloroform, dichloromethane, 1, 2-dichloroethane, toluene, acetone, butyl acetate or methyl tert-butyl ether.
The invention relates to a preparation method of a non-natural L-tryptophan derivative, which adopts a cheap and easily obtained substituted indole compound as a raw material to obtain the non-natural L-tryptophan derivative, namely N-fluorenylmethyloxycarbonyl-R through a series of reactions of formylation, cyclization, ring opening, asymmetric hydrogenation, hydrolysis deprotection and Fmoc protection1The method has the advantages of simple process route, simple and quick operation, greatly improved yield compared with the prior chemical resolution and enzymatic synthesis, total yield of 65-70 percent, reduced cost, less three wastes and easy realization of scale productionThe method is a synthesis method with small safety risk and higher advantages, and is suitable for popularization and application.
Detailed Description
The invention is further illustrated by the following specific examples, which are not intended to limit the invention thereto.
Example 1: starting with 7-methylindole as a specific example, Fmoc-7-methyl-L-tryptophan was prepared according to the following synthetic route:
Figure BDA0003264304440000071
to collect the product of each step, each step can be repeated several times.
1) Preparation of 7-methyl-3-formylindole (II-a)
DMF (12.26g) was weighed into a 100mL three-necked flask, transferred to a water bath and stirred at 10 ℃. Extracting phosphorus oxychloride (6.43g) by using a needle cylinder, slowly adding the phosphorus oxychloride into a three-neck flask, discharging heat (controlling the temperature to be less than 35 ℃) in the reaction process (the phosphorus oxychloride and DMF form an intermediate, namely Vilesmeier reagent), removing the mixture out of a water bath, continuously stirring, heating to 40 ℃, and stirring for 1h (nitrogen protection reaction) to obtain a reaction solution; weighing raw material I-a (5g), adding DMF (4.25g) for dissolving, dropwise adding into the reaction solution after dissolving (the temperature is controlled between 10 and 25 ℃, the reaction has exothermic phenomenon), washing with DMF (1.75g), deepening the color of the solution into yellow green, heating to 35 ℃, changing to a three-neck flask, inserting a thermometer, and mechanically stirring. After 1 hour at 35 ℃ a large white solid precipitated and was monitored by a sample TLC plate. After the reaction is finished, ice water is added to quench excessive phosphorus oxychloride, then the alkaline pH value is adjusted to 10-12 by using sodium hydroxide aqueous solution, the mixture is heated to 70 ℃, cooled to room temperature, filtered and dried to obtain 7-methyl-3-formylindole (II-a, 5.8g), and the yield is 95.6%.1H NMR(400MHz,DMSO-d6)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).
2) Preparation of 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-a)
Weighing hippuric acid (1.5g), sodium acetate (0.01g) and anhydride (6g) and adding into a single-mouth bottle (50mL), heating to 60 ℃, preserving heat for 30 minutes, and changing white turbid liquid into light yellow clear liquid; slowly adding 7-methyl-3-formylindole (1g) serving as a raw material into the reaction bottle, preserving the temperature for one hour at 60-65 ℃, generating yellow solid in the process of preserving the temperature, cooling to room temperature, adding 10mL of acetic acid, mechanically stirring for 15min, filtering, drying at 60 ℃ to obtain 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-a, 1.8g), wherein the yield is 94.8%, and the step can be repeated for multiple experiments and collects the product;1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.69(s,1H),7.92-8.03(m,3H),7.61-7.71(m,4H),7.10-7.20(d,2H),2.53(s,3H).
3) preparation of methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) acrylate (V-a)
Weighing 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyl oxazole-5 (4H) -ketone (3.5g), placing the mixture into a 50mL single-neck flask, adding 17.5mL of methanol and sodium methoxide (0.1g) into the single-neck flask to clarify (have an exothermic phenomenon), quickly heating to 55-60 ℃, keeping the temperature for 1H, sampling a sample point plate (adding 6mL of methanol during the reaction), cooling the reaction liquid to 10-25 ℃, adding 23.5mL of ice water into the three-neck flask, stirring in an ice bath for 10min, performing suction filtration at 15 ℃ to obtain a wet product, and drying to obtain 2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl acrylate (V-a, 3.7g) with the yield of 95.6%.
1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.88(s,1H),8.07-8.09(d,2H),7.87(s,1H),7.73(s,1H),7.58-7.64(m,4H),7.02-7.07(m,2H),3.78(s,3H)，2.47(s,3H).
4) Preparation of (S) -2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl propionate (VI-a)
Weighing 2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl acrylate (20g), placing the weighed methyl acrylate in a 500mL autoclave, adding 200mL of anhydrous methanol, replacing the mixture with nitrogen for 3 times, adding a catalyst (-) -1, 2-bis ((2R,5R) -2, 5-dimethyl phosphorus soap) benzene (cyclooctadiene) rhodium (I) tetrafluoroborate (0.01g), replacing the mixture with hydrogen for 3 times, starting pressurizing to 0.5Mpa, heating to 40-50 ℃, preserving the heat for 4 hours, and after the reaction is finished, concentrating the mixture to the concentration of the mixture until the pressure is 0.5Mpa150mL, cooling, separating, filtering and drying to obtain a product (S) -methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) propionate (VI-a, 19g), wherein the ee value is more than 99.0 percent and the yield is 94.43 percent.1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.81-8.83(d,1H),7.85-7.87(d,2H),7.41-7.58(m,4H),7.24(s,1H),6.89-6.96(m,2H),4.70-4.75(m,1H),3.68(s,3H)，3.23-3.30(m,2H),2.45(s,3H).
5) Preparation of 7-methyl-L-tryptophan (VII-a)
Weighing (S) -2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl propionate (10g), adding 80mL of concentrated hydrochloric acid, heating to 90-100 ℃, preserving heat for 18 hours, after the reaction is finished, extracting a byproduct benzoic acid by using ethyl acetate, then adjusting the pH value to 5.0-6.0 by using an aqueous solution of sodium hydroxide, controlling the temperature to 15-20 ℃, preserving heat for 1 hour, filtering to obtain a gray solid, and drying to obtain 7-methyl-L-tryptophan (VII-a, 6.1g) with the yield of 94.02%.1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.43(s,3H),7.43-7.45(d,1H),7.27-7.28(d,1H),6.90(m,2H)，4.11(m,1H),3.31-3.33(d,2H),2.47(s,3H).
6) Preparation of Fmoc-7-methyl-L-tryptophan (VIII-a)
Weighing 7-methyl-L-tryptophan (50g), placing the weighed 7-methyl-L-tryptophan in a 1L reaction bottle, adding 250g of ethyl acetate, 500g of water and 36.4g of sodium carbonate, stirring the mixture for 30 minutes at room temperature of 20-25 ℃, then adding 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-OSu) (73.4g), keeping the temperature controlled at 20-25 ℃, stirring the mixture for 4 hours, separating a water layer after the reaction is finished, then adding dilute hydrochloric acid, adjusting the pH value to 3-4, separating the water layer, concentrating the ethyl acetate to the residual 50-70 g, cooling the mixture to 10-15 ℃, preserving the temperature for 1 hour, filtering and drying to obtain a product (Fmoc-7-methyl-L-tryptophan VIII-a, 91g), wherein the ee value is not less than 99.0%, the yield is 90.18%, and the purity HPLC is not less than 99.0%.1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.83(s,1H),7.70-7.91(m,2H),7.45-7.68(m,3H),7.20-7.42(m,6H)，6.88-6.92(m,2H),4.10(m,4H),3.19-3.24(m,1H)，3.01-3.07(m,1H),2.46(s,3H).
Example 2: preparation of Fmoc-7-methyl-L-tryptophan starting from 7-methylindole following the synthetic route of example 1
1) Preparation of 7-methyl-3-formylindole (II-a)
DMF (10g) and THF (2.54g) were weighed into a 100mL three-necked flask, transferred to a water bath and stirred at 10 ℃ in water. Extracting phosphorus oxychloride (6.43g) by using a needle cylinder, slowly adding the phosphorus oxychloride into a three-neck flask, discharging heat (controlling the temperature to be less than 35 ℃) in the reaction process (the phosphorus oxychloride and DMF form an intermediate, namely Vilesmeier reagent), removing the mixture out of a water bath, continuously stirring, heating to 40 ℃, and stirring for 1h (nitrogen protection reaction) to obtain a reaction solution; weighing raw material I-a (5g), adding DMF (4.25g) for dissolving, dropwise adding into the reaction solution after dissolving (the temperature is controlled between 10 and 25 ℃, the reaction has exothermic phenomenon), washing with DMF (1.75g), deepening the color of the solution into yellow green, heating to 35 ℃, changing to a three-neck flask, inserting a thermometer, and mechanically stirring. After 1 hour at 35 ℃ a large white solid precipitated and was monitored by a sample TLC plate. After the reaction is finished, ice water is added to quench excessive phosphorus oxychloride, then the alkaline pH value is adjusted to 10-12 by using a sodium carbonate aqueous solution, the mixture is heated to 70 ℃, cooled to room temperature, filtered and dried to obtain 7-methyl-3-formylindole (II-a, 5.75g), and the yield is 94.8%.
2) Preparation of 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-a)
Weighing hippuric acid (1.5g), lithium acetate (0.01g), anhydride (4g) and tetrahydrofuran (2g) and adding into a single-mouth bottle (50mL), heating to 60 ℃, preserving heat for 30 minutes, and changing white turbid liquid into light yellow clear liquid; slowly adding the raw material 7-methyl-3-formylindole (1g) into the reaction bottle, preserving the temperature for one hour at 60-65 ℃, generating yellow solid in the process of preserving the temperature, cooling to room temperature, adding 10mL of acetic acid, mechanically stirring for 15min, filtering, and drying at 60 ℃ to obtain 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-a, 1.75g) with the yield of 92.17%.
3) Preparation of methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) acrylate (V-a)
Weighing 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyl oxazole-5 (4H) -ketone (3.5g), placing the mixture into a 50mL single-neck flask, adding 17.5mL of methanol and sodium methoxide (0.1g) into the single-neck flask to clarify (have an exothermic phenomenon), quickly heating to 55-60 ℃, keeping the temperature for 1H, sampling a sample point plate (adding 6mL of methanol during the reaction), cooling the reaction liquid to 10-25 ℃, adding 23.5mL of ice water into the three-neck flask, stirring in an ice bath for 10min, performing suction filtration at 15 ℃ to obtain a wet product, and drying to obtain 2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl acrylate (V-a, 3.62g) with the yield of 93.5%.
4) Preparation of (S) -2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl propionate (VI-a)
Weighing 20g of methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) acrylate, placing the methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) acrylate in a 500mL autoclave, adding 200mL of absolute ethanol, replacing with nitrogen for 3 times, adding 0.01g of catalyst (-) -1, 2-bis ((2R,5R) -2, 5-dimethyl phosphorus soap) benzene (cyclooctadiene) rhodium (I) tetrafluoroborate, replacing with hydrogen for 3 times, starting pressurizing to 0.5Mpa, heating to 40-50 ℃, preserving heat for 4 hours, after the reaction is finished, starting to concentrate to 150mL, cooling, separating out materials, filtering and drying to obtain a product (S) -methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) propionate (VI-a, 19.13g), ee > 99.0% and yield 95.10%.
5) Preparation of 7-methyl-L-tryptophan (VII-a)
Weighing (S) -2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl propionate (10g), adding 63mL of concentrated sulfuric acid and 120mL of water, heating to 90-100 ℃, preserving heat for 18 hours, after the reaction is finished, extracting a byproduct benzoic acid by using ethyl acetate, then adjusting the pH to 5.0-6.0 by using a potassium carbonate aqueous solution, controlling the temperature to 15-20 ℃, preserving heat for 1 hour, filtering to obtain a gray solid, and drying to obtain 7-methyl-L-tryptophan (VII-a, 6.16g) with the yield of 94.94%.
6) Preparation of Fmoc-7-methyl-L-tryptophan (VIII-a)
Weighing 7-methyl-L-tryptophan (50g), placing the weighed 7-methyl-L-tryptophan in a 1L reaction bottle, adding 250g of ethyl acetate, 500g of water and 36.4g of sodium carbonate, stirring the mixture for 30 minutes at room temperature of 20-25 ℃, then adding 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-OSu) (73.4g), keeping the temperature controlled at 20-25 ℃, stirring the mixture for 4 hours, separating a water layer after the reaction is finished, then adding dilute hydrochloric acid, adjusting the pH value to 3-4, separating the water layer, concentrating the ethyl acetate to the residual 50-70 g, cooling the mixture to 10-15 ℃, preserving the temperature for 1 hour, filtering and drying to obtain a product (Fmoc-7-methyl-L-tryptophan VIII-a, 91.86g), wherein the ee value is not less than 99.0%, the yield is 91.03% and the purity is not less than 99.0% by HPLC.
Example 3: preparation of Fmoc-7-methyl-L-tryptophan starting from 7-methylindole following the synthetic route of example 1
1) Preparation of 7-methyl-3-formylindole (II-a)
DMF (9g) and toluene (3g) were weighed into a 100mL three-necked flask, transferred to a water bath and stirred at 10 ℃. Extracting phosphorus oxychloride (6.43g) by using a needle cylinder, slowly adding the phosphorus oxychloride into a three-neck flask, discharging heat (controlling the temperature to be less than 35 ℃) in the reaction process (the phosphorus oxychloride and DMF form an intermediate, namely Vilesmeier reagent), removing the mixture out of a water bath, continuously stirring, heating to 40 ℃, and stirring for 1h (nitrogen protection reaction) to obtain a reaction solution; weighing raw material I-a (5g), adding DMF (4.25g) for dissolving, dropwise adding into the reaction solution after dissolving (the temperature is controlled between 10 and 25 ℃, the reaction has exothermic phenomenon), washing with DMF (1.75g), deepening the color of the solution into yellow green, heating to 35 ℃, changing to a three-neck flask, inserting a thermometer, and mechanically stirring. After 1 hour at 35 ℃ a large white solid precipitated and was monitored by a sample TLC plate. After the reaction is finished, ice water is added to quench excessive phosphorus oxychloride, then the alkaline pH value is adjusted to 10-12 by using potassium hydroxide aqueous solution, the mixture is heated to 70 ℃, cooled to room temperature, filtered and dried to obtain 7-methyl-3-formylindole (II-a, 5.78g), and the yield is 95.3%.
2) Preparation of 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-a)
Weighing hippuric acid (1.5g), lithium acetate (0.01g), anhydride (4g) and tetrahydrofuran (2g) and adding into a single-mouth bottle (50mL), heating to 60 ℃, preserving heat for 30 minutes, and changing white turbid liquid into light yellow clear liquid; slowly adding the raw material 7-methyl-3-formylindole (1g) into the reaction bottle, preserving the temperature for one hour at 60-65 ℃, generating yellow solid in the process of preserving the temperature, cooling to room temperature, adding 10mL of acetic acid, mechanically stirring for 15min, filtering, and drying at 60 ℃ to obtain 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-a, 1.85g) with the yield of 97.4%.
3) Preparation of methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) acrylate (V-a)
Weighing 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyl oxazole-5 (4H) -ketone (3.5g), placing the mixture into a 50mL single-neck flask, adding 17.5mL of methanol and sodium methoxide (0.1g) into the single-neck flask to clarify (have heat release phenomenon), quickly heating to 55-60 ℃, keeping the temperature for 1H, sampling a sample point plate (adding 6mL of methanol during the reaction), cooling the reaction liquid to 10-25 ℃, adding 23.5mL of ice water into the three-neck flask, stirring in an ice bath for 10min, performing suction filtration at 15 ℃ to obtain a wet product, and drying to obtain 2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl acrylate (V-a, 3.8g) with the yield of 98.18%.
4) Preparation of (S) -2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl propionate (VI-a)
Weighing 20g of methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) acrylate, placing the methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) acrylate in a 500mL autoclave, adding 200mL of ethanol, replacing the mixture with nitrogen for 3 times, adding 0.01g of catalyst (-) -1, 2-bis ((2R,5R) -2, 5-dimethyl phosphorus soap) benzene (cyclooctadiene) rhodium (I) tetrafluoroborate, replacing the mixture with hydrogen for 3 times, starting pressurizing to 0.5Mpa, heating to 40-50 ℃, preserving the temperature for 4 hours, after the reaction is finished, starting concentrating the mixture to 150mL, cooling, separating out materials, filtering and drying to obtain a product (S) -methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) propionate (VI-a, 18.9g), ee value > 99.0%, yield 93.9%.
5) Preparation of 7-methyl-L-tryptophan (VII-a)
Weighing (S) -2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl propionate (10g), adding 100mL of acetic acid and 30mL of water, heating to 90-100 ℃, preserving heat for 18 hours, after the reaction is finished, extracting a byproduct benzoic acid by using ethyl acetate, then adjusting the pH to 5.0-6.0 by using an aqueous solution of sodium hydroxide, controlling the temperature to 15-20 ℃, preserving heat for 1 hour, filtering to obtain a gray solid, and drying to obtain 7-methyl-L-tryptophan (VII-a, 6.18g), wherein the yield is 95.25%.
6) Preparation of Fmoc-7-methyl-L-tryptophan (VIII-a)
Weighing 7-methyl-L-tryptophan (50g), placing the weighed 7-methyl-L-tryptophan in a 1L reaction bottle, adding 180g of acetone and 70g of ethyl acetate, 500g of water and 52.2g of DBU, stirring the mixture for 30 minutes at room temperature of 20-25 ℃, then adding 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-OSu) (73.4g), keeping the temperature controlled at 20-25 ℃, stirring the mixture for 4 hours, separating a water layer after the reaction is finished, then adding acetic acid, adjusting the pH value to 3-4, separating the water layer, concentrating the acetone to the residual 50-70 g, cooling the mixture to 10-15 ℃, preserving the temperature for 1 hour, filtering and drying to obtain a product (Fmoc-7-methyl-L-tryptophan VIII-a, 92.64g), wherein the ee value is not less than 99.0%, the yield is 91.8% and the HPLC purity is not less than 99.0%.
Example 4: preparation of Fmoc-7-methyl-L-tryptophan starting from 7-methylindole following the synthetic route of example 1
1) Preparation of 7-methyl-3-formylindole (II-a)
DMF (9g) and xylene (3g) were weighed into a 100mL three-necked flask, transferred to a water bath and stirred at 10 ℃. Extracting phosphorus oxychloride (6.43g) by using a needle cylinder, slowly adding the phosphorus oxychloride into a three-neck flask, discharging heat (controlling the temperature to be less than 35 ℃) in the reaction process (the phosphorus oxychloride and DMF form an intermediate, namely Vilesmeier reagent), removing the mixture out of a water bath, continuously stirring, heating to 40 ℃, and stirring for 1h (nitrogen protection reaction) to obtain a reaction solution; weighing raw material I-a (5g), adding DMF (4.25g) for dissolving, dropwise adding into the reaction solution after dissolving (the temperature is controlled between 10 and 25 ℃, the reaction has exothermic phenomenon), washing with DMF (1.75g), deepening the color of the solution into yellow green, heating to 35 ℃, changing to a three-neck flask, inserting a thermometer, and mechanically stirring. After 1 hour at 35 ℃ a large white solid precipitated and was monitored by a sample TLC plate. After the reaction is finished, ice water is added to quench excessive phosphorus oxychloride, then the alkaline pH value is adjusted to 10-12 by using potassium hydroxide aqueous solution, the mixture is heated to 70 ℃, cooled to room temperature, filtered and dried to obtain 7-methyl-3-formylindole (II-a, 5.73g), and the yield is 94.5%.
2) Preparation of 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-a)
Weighing hippuric acid (1.5g), calcium acetate (0.02g), anhydride (4g) and xylene (2g) and adding into a single-mouth bottle (50mL), heating to 60 ℃, preserving heat for 30 minutes, and changing white turbid liquid into light yellow clear liquid; slowly adding the raw material 7-methyl-3-formyl indole (1g) into the reaction bottle, preserving the temperature for one hour at 60-65 ℃, generating yellow solid in the heat preservation process, cooling to room temperature, adding 10mL of acetic acid, mechanically stirring for 15min, filtering, and drying at 60 ℃ to obtain 4-
((7-methyl-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-a, 1.81g) in 95.3% yield.
3) Preparation of methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) acrylate (V-a)
Weighing 4- ((7-methyl-1H-indol-3-yl) methylene) -2-phenyl oxazole-5 (4H) -ketone (3.5g) and placing the mixture into a 50mL single-neck flask, adding 17.5mL of methanol and sodium methoxide (0.1g) into the single-neck flask to clarify (have heat release phenomenon), quickly heating to 55-60 ℃, keeping the temperature for 1H, sampling a sample point plate (adding 6mL of methanol during the reaction), cooling the reaction liquid to 10-25 ℃, adding 23.5mL of ice water into the three-neck flask, stirring in an ice bath for 10min, performing suction filtration at 15 ℃ to obtain a wet product, and drying to obtain 2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl acrylate (V-a, 3.6g) with the yield of 93.0%.
4) Preparation of (S) -2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl propionate (VI-a)
Weighing 20g of methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) acrylate, placing the methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) acrylate in a 500mL autoclave, adding 200mL of anhydrous isopropanol, replacing with nitrogen for 3 times, adding a catalyst (-) -1, 2-bis ((2R,5R) -2, 5-dimethyl phosphorus soap) benzene (cyclooctadiene) rhodium (I) tetrafluoroborate (0.01g), replacing with hydrogen for 3 times, starting pressurizing to 0.5Mpa, heating to 40-50 ℃, preserving heat for 4 hours, after the reaction is finished, starting concentrating to 150mL, cooling, separating out materials, filtering and drying to obtain a product (S) -methyl 2-benzamido-3- (7-methyl-1H-indol-3-yl) propionate (VI-a, 19.13g), ee > 99.0% and yield 95.10%.
5) Preparation of 7-methyl-L-tryptophan (VII-a)
Weighing (S) -2-benzamido-3- (7-methyl-1H-indol-3-yl) methyl propionate (10g), adding 63mL of concentrated sulfuric acid and 30mL of water, heating to 90-100 ℃, preserving heat for 18 hours, after the reaction is finished, extracting a byproduct benzoic acid by using ethyl acetate, then adjusting the pH to 5.0-6.0 by using a potassium carbonate aqueous solution, controlling the temperature to 15-20 ℃, preserving heat for 1 hour, filtering to obtain a gray solid, and drying to obtain 7-methyl-L-tryptophan (VII-a, 6.16g) with the yield of 94.92%.
6) Preparation of Fmoc-7-methyl-L-tryptophan (VIII-a)
Weighing 7-methyl-L-tryptophan (50g), placing the weighed 7-methyl-L-tryptophan in a 1L reaction bottle, adding 250g of ethyl acetate, 500g of water and 36.4g of sodium carbonate, stirring the mixture for 30 minutes at room temperature of 20-25 ℃, then adding 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-OSu) (73.4g), keeping the temperature controlled at 20-25 ℃, stirring the mixture for 4 hours, separating a water layer after the reaction is finished, then adding dilute hydrochloric acid, adjusting the pH value to 3-4, separating the water layer, concentrating the ethyl acetate to the residual 50-70 g, cooling the mixture to 10-15 ℃, preserving the temperature for 1 hour, filtering and drying to obtain a product (Fmoc-7-methyl-L-tryptophan VIII-a, 92g), wherein the ee value is not less than 99.0%, the yield is 91.17%, and the purity HPLC is not less than 99.0%.
Example 5: starting with 4-bromoindole as a specific example, Fmoc-4-bromo-L-tryptophan was prepared according to the following synthetic route:
Figure BDA0003264304440000191
1) preparation of 4-bromo-3-formylindole (II-b)
DMF (20g) was weighed into a 100mL three-necked flask, transferred to a water bath and stirred at 10 ℃. And (3) pumping the phosphorus oxychloride (9.38g) by using a syringe, slowly adding the phosphorus oxychloride into the three-neck flask, discharging heat in the reaction process (controlling the temperature to be less than 35 ℃), removing the phosphorus oxychloride from the water bath, continuously stirring, heating to 40 ℃, and stirring for 1h (nitrogen protection reaction). Raw material I-b (10g) was weighed and dissolved in DMF (10 g). After dissolution, the solution was added dropwise to the reaction mixture (the temperature was controlled between 10 ℃ and 25 ℃ and the reaction was exothermic), washed with DMF (5g), heated to 35 ℃ and stirred mechanically with a three-necked flask, in which a thermometer was inserted. After 1 hour at 35 ℃ a large white solid precipitated and was monitored by a sample TLC plate. After the reaction is finished, adding ice water to quench excessive phosphorus oxychloride, adjusting the pH value to be 10-12, heating to 70 ℃ and keeping the pH value to be 10-12. After cooling to room temperature and filtration and drying, 4-bromo-3-formylindole (II-b, 11g) was obtained with a yield of 96.2%.
2) Preparation of 4- ((4-bromo-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-b)
8.8g of hippuric acid is weighed and added into a single-mouth bottle (200mL), 0.01g of sodium acetate is weighed and added into a reaction bottle, and 50g of anhydride is weighed and added into the reaction bottle. Heating to 60 deg.C, and maintaining for 30 min to obtain yellowish clear liquid. The starting material, 4-bromo-3-formylindole (10g), was slowly charged into the reaction flask. Keeping the temperature for one hour at 60-65 ℃. (yellow solid is generated in the heat preservation process) cooling to room temperature, adding 10mL of acetic acid, and mechanically stirring for 15 min. Filtration and drying gave 4- ((4-bromo-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-b, 15.7g) in 95.8% yield.
3) Preparation of 2-benzamido-3- (4-bromo-1H-indol-3-yl) acrylic acid ethyl ester (V-b)
4- ((4-bromo-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (7.2g) was weighed into a 100mL single-neck flask and 40mL of ethanol was added. 0.1g of sodium ethoxide is weighed and put into the reaction liquid, the heat release phenomenon occurs, and the reaction liquid becomes clear. And (4) rapidly heating to 55-60 ℃, preserving the heat for 1h, and sampling the sample point plate. And cooling the reaction liquid to 10-25 ℃, adding 40.5mL of ice water into the three-neck flask, and stirring for 10min in an ice bath. After suction filtration and drying, (V-b, 7.8g) was obtained with a yield of 96.2%.
4) Preparation of (S) -2-benzamido-3- (4-bromo-1H-indol-3-yl) ethyl propionate (VI-b)
Weighing 2-benzamido-3- (4-bromo-1H-indol-3-yl) ethyl acrylate (15g), placing the weighed ethyl acrylate in a 500mL autoclave, adding 150mL of anhydrous methanol, replacing the anhydrous methanol with nitrogen for 3 times, adding a catalyst (-) -1, 2-bis ((2R,5R) -2, 5-dimethyl phosphorus soap) benzene (cyclooctadiene) rhodium (I) tetrafluoroborate (0.01g), replacing the anhydrous methanol with hydrogen for 3 times, starting pressurizing to 0.5Mpa, heating to 40-50 ℃, preserving the heat for 4 hours, after the reaction is finished, concentrating the mixture to 70mL of methanol, cooling, separating out the materials, filtering and drying to obtain a product (VI-b, 14g), wherein the ee value is more than 99.0%, and the yield is 92.8%.
5) Preparation of 4-bromo-L-tryptophan (VII-b)
Weighing (S) -2-benzamido-3- (4-bromo-1H-indol-3-yl) ethyl propionate (8g), adding 80mL of concentrated hydrochloric acid, heating to 90-100 ℃, preserving heat for 19 hours, and after the reaction is finished, extracting a byproduct by using ethyl acetateBenzoic acid, then adjusting the pH value to 5.0-6.0 by using an aqueous solution of sodium hydroxide, controlling the temperature to 15-20 ℃, preserving the heat for 1 hour, filtering and drying to obtain (VII-b, 8g) with the yield of 91.6%.1H NMR(400MHz,D2O)δ7.44-7.47(m,1H),7.29-7.32(m,1H),7.05-7.10(m,1H),4.39-4.44(m,1H),3.85-3.90(m,1H),3.16-3.24(m,1H).
6) Preparation of Fmoc-4-bromo-L-tryptophan (VIII-b)
Weighing 4-bromo-L-tryptophan (40g), placing the 4-bromo-L-tryptophan into a 1L reaction bottle, adding 400g of ethyl acetate, 400g of water and 22.4g of sodium carbonate, stirring the mixture at room temperature of 20-25 ℃ for 30 minutes, then adding Fmoc-OSu (45.2g), keeping the temperature controlled at 20-25 ℃, stirring the mixture for 4 hours, after the reaction is finished, removing a water layer, then adding dilute hydrochloric acid, adjusting the pH value to 3-4, removing the water layer, concentrating the ethyl acetate to be 100g, cooling the mixture to 10-15 ℃, preserving the temperature for 1 hour, filtering, and drying to obtain a product (VIII-b, 68g), wherein the ee value is more than or equal to 99.0%, the yield is 95.2%, and the HPLC purity is more than or equal to 99.0%.
Example 6: starting with 5, 6-dichloro-indole as a specific example, Fmoc-5, 6-dichloro-L-tryptophan was prepared according to the following synthetic route:
Figure BDA0003264304440000221
1) preparation of 5, 6-dichloro-3-formylindole (II-c)
Adding 50g of DMF (dimethyl formamide) into a 100mL three-neck flask, moving the three-neck flask into a water bath, stirring at the water temperature of 10 ℃, extracting 17.2g of phosphorus oxychloride by using a needle cylinder, slowly adding the phosphorus oxychloride into the three-neck flask, discharging heat in the reaction process (controlling the temperature to be less than 35 ℃), removing the three-neck flask out of the water bath, continuously stirring, heating to 40 ℃, and stirring for 1h (nitrogen protection reaction). The starting material I-c (20g) was weighed out and DMF (20g) was added to the solution. After dissolution, the mixture was added dropwise to the reaction mixture (the temperature was controlled between 10 ℃ and 25 ℃ and the reaction was exothermic), washed with DMF (10g), heated to 35 ℃ and stirred mechanically with a three-necked flask, equipped with a thermometer. After 1 hour at 35 ℃ a large white solid precipitated and was monitored by a sample TLC plate. After the reaction is finished, adding ice water to quench excessive phosphorus oxychloride, adjusting the pH value to be 10-12, heating to 70 ℃ and keeping the pH value to be 10-12. After cooling to room temperature and filtration and drying, 5, 6-dichloro-3-formylindole (II-c, 22g) was obtained with a yield of 95.6%.
2) Preparation of 4- ((5, 6-dichloro-1H-indol-3-yl) methylene) -2-methyloxazol-5 (4H) -one (IV-c)
Acetylglycine (6g) was weighed into a single-neck flask (100mL), and sodium acetate (0.01g) was weighed into the reaction flask. Weigh anhydride 40g and put into the reaction flask. Heating to 60 deg.C, and maintaining for 30 min to obtain yellowish clear liquid. The starting material, 5, 6-dichloro-3-formylindole (10g), was slowly charged into the reaction flask. Keeping the temperature for one hour at 60-65 ℃. (yellow solid is generated in the heat preservation process) cooling to room temperature, adding 10ml acetic acid, and mechanically stirring for 15 min. Filtration and drying (60 ℃ C.) gave 4- ((5, 6-dichloro-1H-indol-3-yl) methylene) -2-phenyloxazol-5 (4H) -one (IV-c, 13g) in 94.2% yield.
3) Preparation of ethyl 2-acetamide-3- (5, 6-dichloro-1H-indol-3-yl) acrylate (V-c)
4- ((5, 6-dichloro-1H-indol-3-yl) methylene) -2-methyloxazol-5 (4H) -one (8g) was weighed into a 100mL single-neck flask and 40mL of ethanol (insoluble) was added. 0.1g of sodium ethoxide is weighed and put into the reaction liquid, the heat release phenomenon occurs, and the reaction liquid becomes clear. And (4) rapidly heating to 55-60 ℃, preserving the heat for 1h, and sampling the sample point plate. And cooling the reaction liquid to 10-25 ℃, adding 40.5mL of ice water into the three-neck flask, and stirring for 10min in an ice bath. The mixture was filtered, filtered and dried in an oven to obtain (V-c, 9g) in 97.3% yield.
4) Preparation of ethyl (S) -2-acetamide-3- (5, 6-dichloro-1H-indol-3-yl) propionate (VI-c)
Weighing 2-acetamide-3- (5, 6-dichloro-1H-indol-3-yl) ethyl acrylate (20g), placing the weighed ethyl acrylate in a 500mL autoclave, adding 150mL of anhydrous methanol, replacing the anhydrous methanol with nitrogen for 3 times, adding a catalyst (-) -1, 2-bis ((2R,5R) -2, 5-dimethylphosphosoap) benzene (cyclooctadiene) rhodium (I) tetrafluoroborate (0.02g), replacing the anhydrous methanol with hydrogen for 3 times, starting pressurizing to 0.5Mpa, heating to 40-50 ℃, preserving the heat for 4 hours, after the reaction is finished, concentrating the mixture to 70mL of methanol, cooling, separating out the materials, filtering and drying to obtain a product (VI-c, 18.5g), wherein the ee value is more than 99.0%, and the yield is 92%.
5) Preparation of 5, 6-dichloro-L-tryptophan (VII-c)
Weighing (S) -2-acetamide-3- (5, 6-dichloro-1H-indol-3-yl) ethyl propionate (15g), adding 120mL of concentrated hydrochloric acid, heating to 90-100 ℃, preserving heat for 18 hours, after the reaction is finished, firstly extracting impurities by using ethyl acetate, then adjusting the pH value to 5.0-6.0 by using a sodium hydroxide aqueous solution, controlling the temperature to 15-20 ℃, preserving heat for 1 hour, filtering, and drying to obtain (VII-c, 11g) with the yield of 92.1%.1HNMR(400MHz,D2O)δ7.57(m,1H),7.44(m,1H),7.18(m,1H),4.13(d,1H),3.28(m,1H),3.21(m,1H).
6) Preparation of Fmoc-5, 6-dichloro-L-tryptophan (VIII-c)
Weighing 5, 6-dichloro-L-tryptophan (10g), placing the weighed 5, 6-dichloro-L-tryptophan into a 1L reaction bottle, adding 100g of ethyl acetate, 100g of water and 5.82g of sodium carbonate, stirring the mixture at room temperature of 20-25 ℃ for 30 minutes, then adding Fmoc-OSu (11.73g), keeping the temperature controlled at 20-25 ℃, stirring the mixture for 4 hours, removing a water layer after the reaction is finished, then adding dilute hydrochloric acid, adjusting the pH value to 3-4, removing the water layer, concentrating the ethyl acetate to the residual 30g, cooling the temperature to 10-15 ℃, preserving the temperature for 1 hour, filtering, and drying to obtain a product (VIII-c, 17g), wherein the ee value is more than or equal to 99.0%, the yield is 93.7%, and the HPLC purity is more than or equal to 99.0%.
Although the invention has been described and illustrated in some detail by the inventor, it should be understood that modifications and alterations to the above-described embodiments, or equivalent alterations thereto, will become apparent to those skilled in the art without departing from the spirit of the invention, and that no limitation to the invention is intended by the terms of the present invention as set forth herein.

Claims (9)

1. The preparation method of the non-natural L-tryptophan derivative is characterized by comprising the following steps of taking an indole compound shown in a formula (I) as a raw material, and sequentially carrying out formylation, cyclization, ring opening, asymmetric hydrogenation, hydrolysis deprotection and Fmoc protection, wherein the structural formula of the non-natural L-tryptophan derivative is shown in a formula (VIII):
1) taking an indole compound shown in a formula (I) as a starting material, carrying out formylation reaction in the presence of a Vilesmeier reagent and a solvent A, adding water to quench the reaction after the reaction is finished, and adjusting the pH value with an alkaline substance A to separate out a material to obtain a 3-formylindole compound shown in a formula (II);
2) taking the 3-formyl indole compound shown in the formula (II) obtained in the step 1) as a raw material, adding a solvent B and a glycine derivative shown in the formula (III), carrying out oxazolone synthesis reaction under the action of a catalyst, cooling and separating materials after the reaction is finished, and filtering to obtain an indoxazolone compound shown in the formula (IV);
3) adding an indoxazolone compound shown in a formula (IV) into a solvent C, stirring at room temperature in the presence of an alkaline substance B for ring-opening reaction, adding water for precipitation after the reaction is finished, filtering and drying to obtain a compound shown in a formula (V);
4) adding the compound shown in the formula (V) into a solvent D, adding an asymmetric catalyst, introducing hydrogen, carrying out asymmetric hydrogenation reaction under the conditions that the pressure is 0.2-1 MPa and the temperature is 30-60 ℃, concentrating to remove part of the solvent after the reaction is finished, cooling, crystallizing, filtering and drying to obtain the compound shown in the formula (VI);
5) adding a compound shown as a formula (VI) into acid A, heating for hydrolysis, extracting a byproduct, namely benzoic acid by using ethyl acetate after the reaction is finished, adjusting the pH value to be 5.0-6.0 by using an alkaline substance C, separating materials, filtering, and drying to obtain a compound shown as a formula (VII);
6) adding a compound shown as a formula (VII) and an alkaline reagent D into a solvent E, adding 9-fluorenylmethyl-N-succinimidyl carbonate for amidation reaction, layering after the reaction is finished, concentrating to remove part of the solvent, adjusting the pH to 3-4 with an acid B, and carrying out aftertreatment to obtain the non-natural L-tryptophan derivative shown as a formula (VIII), namely N-fluorenylmethoxycarbonyl-R1-L-tryptophan;
Figure FDA0003264304430000021
wherein: in the formulae (I), (II) (IV), (V), (VI), (VII), (VIII), the substituents R1Is C1-C9 alkyl, halogen or C1-C9 oxygen alkyl substituent, the substituent is mono-substituted or multi-substituted, and the position of the substituent is 4,5, 6, 7 positions of the indole; substituent R2Is C1-C9 alkyl or phenyl, R3Hydrogen or C1-C9 alkyl.
2. The method for preparing a non-natural L-tryptophan derivative according to claim 1, wherein the solvent A in the step 1) is DMF or a mixed solvent of DMF and any one of toluene, THF and xylene, and the Vilesmeier reagent is an intermediate generated by the reaction of phosphorus oxychloride and DMF.
3. The method of claim 1, wherein the basic substance A for adjusting pH in step 1) is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate.
4. The method for preparing a non-natural L-tryptophan derivative according to claim 1, wherein the solvent B in the step 2) is acetic anhydride or a mixed solution of acetic anhydride and any one of toluene, xylene and tetrahydrofuran; the glycine derivative is acetyl glycine or hippuric acid.
5. The method of claim 1, wherein the catalyst used in step 2) is sodium acetate, potassium acetate, lithium acetate, or calcium acetate.
6. The method for preparing a non-natural L-tryptophan derivative according to claim 1, wherein the solvent C in the step 3) is an alcohol solvent, preferably methanol, ethanol, isopropanol, n-butanol or n-propanol; the alkaline substance B is sodium methoxide, sodium ethoxide, sodium propoxide or sodium hydroxide.
7. The method for preparing a non-natural L-tryptophan derivative according to claim 1, wherein the solvent D in the step 4) is methanol, ethanol or isopropanol; the asymmetric hydrogenation catalyst was (-) -1, 2-bis ((2R,5R) -2, 5-dimethylphosphosoap) benzene (cyclooctadiene) rhodium (I) tetrafluoroborate.
8. The method of claim 1, wherein the acid A in step 5) is hydrochloric acid, acetic acid, formic acid or sulfuric acid; the alkaline substance C is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
9. The method of claim 1, wherein the basic reagent D in step 6) is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, DBU, or DIPEA; the acid B is hydrochloric acid, acetic acid, formic acid or sulfuric acid; the solvent E is ethyl acetate, tetrahydrofuran, methyl acetate, chloroform, dichloromethane, 1, 2-dichloroethane, toluene, acetone, butyl acetate or methyl tert-butyl ether.
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