CN113121540B - Synthesis method of sitagliptin free alkali - Google Patents

Synthesis method of sitagliptin free alkali Download PDF

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CN113121540B
CN113121540B CN202010044086.3A CN202010044086A CN113121540B CN 113121540 B CN113121540 B CN 113121540B CN 202010044086 A CN202010044086 A CN 202010044086A CN 113121540 B CN113121540 B CN 113121540B
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butoxycarbonyl
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trifluorophenyl
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CN113121540A (en
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李亚洲
冯启国
刘忠
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Lunan Pharmaceutical Group Corp
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to the field of organic chemistry, and particularly discloses a method for synthesizing sitagliptin free alkali, which comprises the following specific steps of: (1) Dissolving (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butyric acid and organic alkali in an organic solvent, adding a phosphorus-containing condensing agent, and then adding 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4, 3-alpha ] pyrazine hydrochloride to prepare a compound of a formula II; (2) Removing tert-butoxycarbonyl from the compound of the formula II under the action of acid to obtain a compound I sitagliptin free base; the method has the advantages of mild reaction conditions, easy control, short reaction time, no extraction, simple operation, contribution to industrial production and reduction of process cost; the prepared compound of the formula I has high yield and purity, and the product has no heavy metal residue.

Description

Synthesis method of sitagliptin free alkali
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a method for synthesizing sitagliptin free alkali.
Background
Sitagliptin phosphate (Sitagliptin Phosphate), chemical name (2R) -4-oxo-4- [ 3-trifluoromethyl-5, 6-dihydro [1,2,4] triazolo [4,3- α ] pyrazin-7 (8H) -yl ] -1- (2, 4, 5-trifluorophenyl) -butan-2-amine phosphate (1:1) monohydrate, is a dipeptidyl peptidase-IV (DPP-IV) inhibitor developed by Merck corporation in the United states, and has the following structural formula:
10 months 2006, the U.S. FDA approved sitagliptin for use alone or in combination with metformin, thiazolidinediones, for improving glycemic control in type 2 diabetics; for 10 months 2007, FDA approved the use of sitagliptin in combination with metformin for the initial treatment of diabetes and as an additional therapy for the inability of sulfonylureas or sulfonylurea+metformin to control blood glucose; 2 months 2010, FDA approved sitagliptin as an additive to insulin; 5 months 2011, sitagliptin was approved for use in combination with an α -glucosidase inhibitor; the 9 th 2011 month, the japan approved the use of sitagliptin in combination with insulin; 10 months 2011, the FDA approved the sitagliptin+simvastatin compound formulation for patients suffering from both diabetes and hyperlipidemia; 3 months 2014, sitagliptin was approved in japan for the treatment of type II diabetes mellitus with severe renal insufficiency; 5 months 2014, sitagliptin was approved in japan for the treatment of type II diabetes in combination with other oral medications. The sitagliptin has the function characteristics that the sitagliptin can reduce hunger sense while stimulating insulin secretion, does not increase body weight, and does not cause hypoglycemia and edema.
At present, the synthesis of sitagliptin phosphate, especially the synthesis of free alkali thereof, has the defects of high cost, complex operation, low yield and the like, and cannot realize large-scale production. The sitagliptin free base has the following structural formula:
the synthesis of sitagliptin free base reported at present mainly comprises the following steps:
Med.chem.Lett.,2007,17,5934-5939 reports the condensation reaction of (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid and 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3- α ] pyrazine as starting materials with 1-hydroxybenzotriazole (HOBt)/1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDCI) system with β -amino acid and cyclic amine to give the amide, followed by deprotection to give the final product, sitagliptin free base, with the following reaction equation:
the condensation catalysis reagent used in the route is expensive, the operation is complex and complicated when the condensation is carried out to form the amide, the pH value needs to be regulated and the extraction is needed when the post-treatment is carried out, the intermediate product is difficult to refine, and the method is not suitable for industrial production.
Organic Process Research & Development,2005,9,634-639 reported that starting from (3R) -N-benzyloxy-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid and 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3- α ] pyrazine hydrochloride, the same condensation reaction of β -amino acids with cyclic amines was carried out using 1-hydroxybenzotriazole (HOBt)/1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) to give amides, which were then deprotected by palladium-catalyzed hydrogenation to give the final product, sitagliptin free base, with the following reaction equation:
the condensation catalyst reagent used in the route is also relatively expensive, and the last step needs to use noble metal palladium as a catalyst, so that the problem of heavy metal residue in the final product is caused.
WO2011/135586 (2004) reports the use of phenethyl protected β -amino acid and pivaloyl chloride to give a mixed anhydride, which is then condensed with an amine to give an amide, followed by palladium-catalyzed hydrogenation to remove phenethyl to give sitagliptin free base, the reaction equation is as follows:
the disadvantage of this route is that the amino group in the phenethyl-protected β -amino acid also participates in the reaction, resulting in more reaction byproducts and difficulty in purification; the last step needs noble metal palladium as a catalyst, and has high cost, so that the final product has the problem of heavy metal residue.
Patent CN104693207a reports that, after reaction with (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid using hydrocarbyl sulfonyl chloride as the acylating agent to form a mixed anhydride intermediate, the mixed anhydride intermediate is reacted with 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3- α ] pyrazine to give the corresponding amide, which is then deprotected to give the sitagliptin free base, the reaction equation is as follows:
the method has the defects that the post-treatment needs extraction, the operation is complex, the product yield is low, the process cost is high, racemization products are easy to generate, and the product quality is influenced.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention provides a method for synthesizing sitagliptin free alkali. The technical scheme of the invention is as follows:
a method for synthesizing sitagliptin free base, comprising the steps of:
(1) Dissolving (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butyric acid and organic alkali in an organic solvent, adding a phosphorus-containing condensing agent, and then adding 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4, 3-alpha ] pyrazine hydrochloride to prepare a compound of a formula II;
(2) Removing tert-butoxycarbonyl from the compound of the formula II under the action of acid to obtain a compound I sitagliptin free base;
preferably, the phosphorus-containing condensing agent in step (1) is selected from one of phenyl dichlorophosphate, diphenyl hypophosphorous acid chloride and diethyl cyanophosphate.
Preferably, the organic base in step (1) is selected from one of diisopropylethylamine, triethylamine, pyridine and N-methylmorpholine.
Preferably, the organic solvent in step (1) is selected from one of acetonitrile, tetrahydrofuran, N-dimethylformamide, acetone, N-methylpyrrolidone and dioxane.
Preferably, the reaction temperature in step (1) is from-5 to 10 ℃.
Further preferably, the reaction temperature in step (1) is 1 to 5 ℃.
Preferably, the molar ratio of (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butyric acid to phosphorous-containing condensing agent in step (1) is 1:1.0 to 1.5.
Preferably, the molar ratio of (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid to base in step (1) is 1:2 to 4.
Preferably, in the step (1), the mass volume ratio of the (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butyric acid to the organic solvent is 1:2 to 5, wherein the mass is in g and the volume is in ml.
Preferably, the acid in step (2) is selected from one of trifluoroacetic acid and hydrochloric acid.
Preferably, the reaction temperature in step (2) is room temperature.
The invention has the following beneficial effects:
the invention adopts better coupling reaction conditions, has simple process and low cost, improves the yield and the purity of the product, and is suitable for industrial production.
(1) The reaction condition is mild, the control is easy, the reaction time is short, the extraction is not needed, the operation is simple, the industrial production is facilitated, and the process cost is reduced.
(2) The yield of the prepared compound of the formula II is higher than 98.36 percent.
(3) The prepared compound of the formula I has high yield and high purity; the yield is up to 98.8%, the HPLC purity is up to 99.9%, and the optical purity is 100%.
(4) Heavy metal catalyst is not needed in the reaction, the product has no heavy metal residue, the purity of the product is improved, and the production cost is reduced.
Detailed Description
The advantages of the invention will now be further described by the following examples, which are given for illustrative purposes only and do not limit the scope of the invention, while variations and modifications apparent to those skilled in the art in light of the present disclosure are included within the scope of the invention.
EXAMPLE 1 preparation of Compound II
(3R) -N-t-Butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butyric acid (40 g,120.01 mmol) and triethylamine (33.36 mL,240.02 mmol) are added into 90mL of N-methylpyrrolidone in sequence at the temperature of 5-0 ℃ for reaction for 0.5h, diethyl cyanophosphate (23.49 g,144.01 mmol) is added dropwise, and 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4, 3-alpha ] pyrazine hydrochloride (32.92 g,144.01 mmol) is added in portions for stirring reaction for 4h; TLC detection reaction is complete, and 360mL of water is slowly added into the reaction solution; after the addition, a large amount of white solid is precipitated, suction filtration and drying are carried out to obtain 60.41g of white solid of the compound II, the yield is 99.25%, and the HPLC purity is 99.55%.
EXAMPLE 2 preparation of Compound II
(3R) -N-t-Butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid (40 g,120.01 mmol) and N-methylmorpholine (39.6 mL,360.03 mmol) are added to 80mL of N, N-dimethylformamide in sequence at 1-5 ℃, phenyl dichlorophosphate (25.32 g,120.01 mmol) is added dropwise and stirred for 1h, and 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4, 3-alpha ] pyrazine hydrochloride (32.92 g,144.01 mmol) is added in portions and stirred for 3h; TLC detection reaction is complete, and 300mL of water is slowly added into the reaction solution; after the addition, a large amount of white solid is precipitated, the white solid of the compound II is obtained by suction filtration and drying, and the yield is 99.12 percent and the HPLC purity is 98.62 percent.
EXAMPLE 3 preparation of Compound II
(3R) -N-t-Butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid (40 g,120.01 mmol) and diisopropylethylamine (79.3 mL,480.05 mmol) were added sequentially to 200mL of tetrahydrofuran at 5-10deg.C, and then diphenylphosphinoyl chloride (42.6 g,180.02 mmol) was added dropwise and stirred for 1.5h; after that, 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4, 3-alpha and ] pyrazine hydrochloride (32.92 g,144.01 mmol) were added in portions and stirred for 2.5h, TLC detection reaction was complete, and 300mL of water was slowly added to the reaction solution; after the addition, a large amount of white solid is precipitated, suction filtration and drying are carried out to obtain 60.66g of white solid of the compound II, the yield is 99.60%, and the HPLC purity is 98.75%.
EXAMPLE 4 preparation of Compound II
(3R) -N-t-Butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid (40 g,120.01 mmol) and pyridine (48.1 mL,600.06 mmol) were added sequentially to 80mL of acetonitrile at room temperature, diethyl cyanophosphate (36.42 mL,240.02 mmol) was added dropwise and stirred for 30min, followed by the addition of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3- α ] pyrazine hydrochloride (32.92 g,144.01 mmol) in portions and stirred for 3h; TLC detection reaction is complete, 400mL of water is slowly added into the reaction solution; after the addition, a large amount of white solid is precipitated, suction filtration and drying are carried out to obtain 60.02g of white solid of the compound II, the yield is 98.57%, and the HPLC purity is 98.10%.
EXAMPLE 5 preparation of Compound II
(3R) -N-t-Butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid (40 g,120.01 mmol) and DBU (26.92 mL,180.02 mmol) were added sequentially to 100mL of acetone at room temperature, phenyl dichlorophosphate (22.8 g,108.01 mmol) was added dropwise and stirred for 20min, then 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3- α ] pyrazine hydrochloride (32.92 g,144.01 mmol) was added in portions and stirred for 4h; TLC detection reaction is complete, 400mL of water is slowly added into the reaction solution; after the addition, a large amount of white solid is precipitated, suction filtration and drying are carried out to obtain 59.89g of white solid of the compound II, the yield is 98.36%, and the HPLC purity is 97.88%.
EXAMPLE 6 preparation of Compound II
(3R) -N-Boc-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid (40 g,120.01 mmol) and tetramethyl ethylenediamine (15.0 mL,100.0 mmol) were added sequentially to 220mL dioxane at-15-10deg.C, diphenyl phosphinyl chloride (31.24 g,132.01 mmol) was added dropwise and stirred for 30min, after which 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3- α and ] pyrazine hydrochloride (32.92 g,144.01 mmol) were added portionwise and stirred for 3.5h; TLC detection reaction is complete, and 300mL of water is slowly added into the reaction solution; after the addition, a large amount of white solid is precipitated, filtered by suction, and dried to obtain 59.95g of compound II white solid with the yield of 98.46% and the HPLC purity of 98.40%.
EXAMPLE 7 preparation of Compound I
7- [ (3R) -N-tert-Butoxycarbonyl-3-amino-1-oxo-4- (2, 4, 5-trifluorophenyl) butyl ] -5,6,7, 8-tetrahydro-3- (trifluoromethyl) -1,2, 4-triazolone [4, 3-alpha ] pyrazine (10 g,19.71 mmol) was added to 70mL of methanol, stirred at room temperature and then reacted with hydrogen chloride gas for 5h (TLC confirmed the completion of the reaction), the reaction solution was concentrated, dissolved in water, neutralized with 20% NaOH solution, extracted with ethyl acetate, the organic phase was concentrated, and N-heptane was slurried to give 7.88g of sitagliptin free base, yield 98.20%, HPLC purity 99.90, and optical purity 100%.
EXAMPLE 8 preparation of Compound I
7- [ (3R) -N-t-Butoxycarbonyl-3-amino-1-oxo-4- (2, 4, 5-trifluorophenyl) butyl ] -5,6,7, 8-tetrahydro-3- (trifluoromethyl) -1,2, 4-triazolone [4, 3-alpha ] pyrazine (10 g,19.71 mmol) was added to 30mL of dichloromethane, trifluoroacetic acid was added with stirring at room temperature for 4h (TLC confirmed the completion of the reaction), the reaction solution was concentrated, dissolved in water, neutralized with 20% NaOH solution, extracted with ethyl acetate, the organic phase was concentrated, and N-heptane was slurried to give 7.90g of sitagliptin free base, yield 98.51%, HPLC purity 99.95%, optical purity 100%.
EXAMPLE 9 preparation of Compound I
7- [ (3R) -N-t-Butoxycarbonyl-3-amino-1-oxo-4- (2, 4, 5-trifluorophenyl) butyl ] -5,6,7, 8-tetrahydro-3- (trifluoromethyl) -1,2, 4-triazolone [4, 3-alpha ] pyrazine (10 g,19.71 mmol) was reacted with 50mL 4N hydrochloric acid solution for 4.5h (TLC confirmed reaction completion), 20% NaOH solution neutralization, ethyl acetate extraction, organic phase concentration, N-heptane beating to give 7.90g of sitagliptin free base, yield 99.02%, HPLC purity 99.92%, optical purity 100%.
Comparative example 1 preparation of Compound I
100g of (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid and 67g of triethylamine are added into 700mL of methylene chloride in sequence and stirred for 10min, 68g of DCC and 44.6g of HOBt are then added and stirred for 10-20min, 77.5g of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4, 3-alpha ] pyrazine hydrochloride is then added into the reaction solution, the mixture is heated to 25-30 ℃ and stirred for 4h, after the reaction, the reaction mass is filtered and the filtrate is washed with 2.5% sodium bicarbonate solution (2X 350 mL) and water (2X 500 mL). The dichloromethane phase was cooled directly to 0-1 ℃, 400mL of 16% hydrochloric acid methanol solution was added, the temperature was raised to 25-30 ℃, and stirring was carried out for 4 hours. After the reaction was completed, 1000mL of aqueous phase was added, the dichloromethane phase was extracted with water (2X 300 mL) and the aqueous phase was washed with 300mL of dichloromethane. The aqueous phase was adjusted to pH 10-11 with 10% NaOH, then 1000mL of dichloromethane was added and stirred for 10min, the phases were separated, the aqueous phase was extracted twice with 300mL of dichloromethane, the combined organic phases were washed with 300mL of water and 300mL of 5% NaCl, and the organic layer was dried over anhydrous sodium sulfate. Filtering and vacuum distilling to remove solvent. 100mL of isopropanol was added to the concentrate, and after again vacuum distillation 800mL of heptane was added. The crystals were filtered and dried at 50℃for 12-15 hours under vacuum to give the yield: 94.2% of sitagliptin free base, HPLC purity 98.12% and optical purity 99.00%.
Comparative example 2 preparation of Compound II
4.02g of (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid and 2.77g of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1, 7,8 ] triazolo [4,3- α ] pyrazine hydrochloride were added sequentially to 25mL of pyridine at 0deg.C, followed by 2.73g of EDC, stirred at room temperature for 16h, 100mL of ethyl acetate and 1000mL of water were added, the phases were separated, and the aqueous phase was extracted with 100mL of ethyl acetate. The collected organic phase was washed with 100mL of water, and then 100mL of water was added to the organic phase to adjust the pH of the mixture to about 3. Phase separation, concentration and drying of the organic phase gave 5.70g of Compound II in 92.1% yield, 95.22% purity by HPLC and 98.32% optical purity.
Comparative example 3 preparation of Compound II
Into a 500mL four port round bottom flask with dean stark trap were charged 25g of (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid and 200mL of toluene, 25mL of Hunig base was added at room temperature followed by 25g of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4, 3-alpha ]]The pyrazine hydrochloride was stirred for 5min. 11.5g of 2-chlorophenyl boric acid was added to the reaction, stirred at reflux temperature for 48 hours, the reaction was completed, cooled to room temperature, and 250mL of water was added. The organic layer was separated and washed twice with 125mL 1N HC1. The organic layer was separated and washed successively with 125ml water, 6% NaHCO 3 The solution was washed with 125mL of water. The organic layer was then separated and the solvent was distilled off in vacuo. The resulting solid was stirred with 125mL diisopropyl ether for 2 hours, filtered and dried at 50℃for 12-15 hours under vacuum. 35.13g of Compound II was obtained in a yield of 92.31%, with an HPLC purity of 97.82% and an optical purity of 98.51%.
Comparative example 4 preparation of Compound II
(R) -3- (((R) -1-phenethyl) amino) -4- (2, 4, 5-trifluorophenyl) butanoic acid (25 g,0.074 mol) and triethylamine (26 mL,0.187 mol) were added sequentially to dichloromethane (250 mL), and a mixture of pivaloyl chloride solution (11.4 mL,0.093 mol) and dichloromethane (25 mL) was added dropwise at 3.+ -. 2 ℃ followed by HOBt (2.0 g,0.015 mol). 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3- α ] pyrazine hydrochloride (21 g,0.092 mol) was added in portions at-8.+ -. 2 ℃ and stirring continued for 3 hours, then at 25 ℃ for 8 hours. The reaction solution was washed with 5% sodium hydroxide solution and water in this order, and then concentrated. Recrystallizing the 2-propanol to obtain a compound II, and obtaining the yield: 82.40%, HPLC purity: 96.88% and optical purity 100%.
Comparative example 5 preparation of Compound II
Trifluoromethanesulfonyl chloride (4.71 g,28 mmol), na 2 CO 3 (3.18 g,30 mmol) was addedTo tetrahydrofuran (60 mL) was stirred at-10℃and (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid (9.33 g,28 mmol) was added to the reaction solution and stirred for 2h. 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4, 3-alpha ]]Pyrazine hydrochloride (5.76 g,30 mmol) was added to the prepared mixed anhydride solution, and after stirring at-10℃for 30min, TLC detection was performed, and the reaction of the starting materials was completed. Water washing was added, stirring was performed, and the aqueous phase was extracted 2 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 12.60g of compound II in 88.6% yield, HPLC purity: 90.35%, optical purity: 98.26%.

Claims (5)

1. A method for synthesizing sitagliptin free base, comprising the steps of:
(1) Dissolving (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butyric acid and organic alkali in an organic solvent, adding a phosphorus-containing condensing agent, and then adding 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4, 3-alpha ] pyrazine hydrochloride to prepare a compound of a formula II;
(2) Removing tert-butoxycarbonyl from the compound of the formula II under the action of acid to obtain a compound I sitagliptin free base;
wherein, the phosphorus-containing condensing agent in the step (1) is selected from one of phenyl dichlorophosphate, diphenyl hypophosphorous acid chloride and diethyl cyanophosphate; the organic base is selected from one of diisopropylethylamine, triethylamine, pyridine and N-methylmorpholine; the organic solvent is selected from one of dichloromethane, acetonitrile, tetrahydrofuran, N-dimethylformamide, acetone, N-methylpyrrolidone and dioxane; the acid in the step (2) is selected from one of trifluoroacetic acid and hydrochloric acid; the reaction temperature in step (2) was room temperature.
2. The method according to claim 1, wherein the reaction temperature in the step (1) is-5 to 10 ℃.
3. The synthesis according to claim 2, wherein the reaction temperature in step (1) is 1 to 5 ℃.
4. The synthesis method according to claim 1, wherein in the step (1), the molar ratio of (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butyric acid to the phosphorous-containing condensing agent is 1:1.0 to 1.5.
5. The method according to claim 1, wherein the molar ratio of (3R) -N-t-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) butanoic acid to organic base in step (1) is 1:2 to 4.
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