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CN112500316B - Method for preparing BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid - Google Patents

Method for preparing BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid Download PDF

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CN112500316B
CN112500316B CN202011481999.8A CN202011481999A CN112500316B CN 112500316 B CN112500316 B CN 112500316B CN 202011481999 A CN202011481999 A CN 202011481999A CN 112500316 B CN112500316 B CN 112500316B
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trifluorophenyl
amino
boc
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butyric acid
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CN112500316A (en
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卫禾耕
张峰
顾坚雄
黄钦军
夏海建
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ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Zhejiang Yongtai Handxin Pharmaceutical Technology Co ltd
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ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Zhejiang Yongtai Handxin Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a method for preparing BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid, and relates to the technical field of organic synthetic drugs. The reaction route is as follows, wherein the organic solvent is a water-immiscible organic solvent. The method can control the generation of condensation impurities, obtain the BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid with high purity and high yield, and has the advantages of stable process, simple and convenient operation, short reaction time and suitability for industrial production.
Figure DDA0002834406670000011

Description

Method for preparing BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid
Technical Field
The invention relates to the technical field of organic synthetic drugs, in particular to a method for preparing high-purity BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid.
Background
Sitagliptin phosphate (Sitagliptin phosphate) developed by Merck company in the United states, the first dipeptidyl peptidase (DPP-IV) inhibitor approved by FDA to be on the market in 2006 and 10 months is mainly used for treating type II diabetes, and the single use or the combination with metformin has obvious hypoglycemic effect compared with the combination of glitazone, and the Sitagliptin phosphate is safe to take, good in tolerance and less in adverse reaction. The drug for treating type II diabetes by sitagliptin phosphate is one of hot drugs, and is expensive in market at present. BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid is a key intermediate for sitagliptin phosphate. The structure is as follows:
Figure BDA0002834406650000011
the synthetic route of sitagliptin is as follows:
Figure BDA0002834406650000012
the condensation impurity A is inevitably generated in the process of synthesizing the BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid, and the generation and the content of the impurity directly influence the quality of the BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid and the quality of the synthesized sitagliptin phosphate subsequently. The condensed impurity A has the following structure:
Figure BDA0002834406650000021
the condensation impurities undergo a series of reactions to produce impurity B in the finished sitagliptin product as follows:
Figure BDA0002834406650000022
if the content of the condensed impurity A in liquid phase detection is more than 0.20%, the single known impurity of BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid is high, and the impurity B generated in the subsequent synthesis of sitagliptin exceeds the standard, so that the product quality of the sitagliptin is unqualified. It is difficult to remove the condensed impurities by recrystallization, resulting in a decrease in yield and an increase in cost, which is not favorable for industrial production.
Patent CN109824546A discloses the structure and preparation method of the condensation impurity A and the influence on the quality of the raw material drug sitagliptin phosphate. Patent CN102199102B mentions that the BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid is prepared by using dichloromethane as a solvent, and the condensation impurity A generated by the method is large, needs to be purified by a column chromatography method, is high in cost and is not beneficial to industrial production. In patent CN105331651A, BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid is prepared by using tetrahydrofuran as a solvent, and a condensation impurity A generated by the method is still large.
In view of this, the application provides a method for preparing high-purity BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid, which has the advantages of simple preparation process, high product purity and small impurity content, effectively solves the problems in the prior art, and is suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a method for preparing high-purity BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid. The method has the advantages of simple preparation process, high product purity, low impurity content, short reaction time and suitability for industrial production.
In order to realize the purpose of the invention, the technical scheme of the invention is as follows:
a method for preparing high-purity BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid comprises the following synthetic route:
Figure BDA0002834406650000031
the organic solvent is an organic solvent immiscible with water, preferably at least one of methyl tert-butyl ether, isopropyl acetate, toluene, dichloromethane, n-hexane, petroleum ether, cyclohexane and n-heptane, and more preferably toluene.
Preferably, the preparation method comprises the following steps:
mixing the compound I, water and inorganic base, adding the compound II dissolved by an organic solvent, and reacting to obtain the product.
Preferably, the inorganic base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, and is more preferably sodium hydroxide.
Preferably, the reaction is a heat preservation reaction, the reaction temperature is 0-40 ℃, and the reaction time is 4-18h; more preferably, the reaction temperature is 20 ℃ and the reaction time is 10h.
Preferably, the molar ratio of the compound I to the compound II is 1:1-2.
Preferably, the molar ratio of compound I to inorganic base is 1:1-2.2.
Compared with the prior art, the invention has the following beneficial effects:
the method can control the generation of condensation impurities, obtain the BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid with high purity and high yield, and has the advantages of stable process, simple and convenient operation, short reaction time and suitability for industrial production.
Drawings
FIG. 1 is a liquid phase spectrum of a reaction solution of example 1;
FIG. 2 is a liquid phase spectrum of the solid product of example 1;
FIG. 3 is a liquid phase chromatogram of the reaction solution of comparative example 1;
FIG. 4 is a liquid phase spectrum of the solid product of comparative example 1;
FIG. 5 is a liquid phase spectrum of the reaction solution of comparative example 2;
FIG. 6 is a liquid phase spectrum of the solid product of comparative example 2;
FIG. 7 is a liquid phase chromatogram of the reaction solution of comparative example 3;
FIG. 8 is a liquid phase spectrum of the solid product of comparative example 3.
Detailed Description
The present invention will be further explained with reference to specific examples in order to make the technical means, the technical features, the technical objectives and the effects of the present invention easier to understand, but the following examples are only preferred embodiments of the present invention, and not all embodiments of the present invention. In the interest of clarity, not all features of an actual implementation are described. In the following description, well-known functions or constructions are not described in detail since they would obscure the invention in unnecessary detail. It will of course be appreciated that in the development of any such actual embodiment, numerous implementation-specific details are set forth in order to achieve the developer's specific goals. Based on the embodiments in the implementation, other embodiments obtained by those skilled in the art without any creative efforts belong to the protection scope of the present invention.
The experimental procedures in the following examples were carried out in a conventional manner unless otherwise specified, and materials, reagents and the like used in the following examples were commercially available unless otherwise specified.
In the following examples, (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid (10 g) was purchased from Yongtai science, inc. under the code 202005006; BOC-anhydrides were purchased from Ghan pharmaceuticals, inc., changzhou under the product number 4209-0001-20002.
Example 1
Adding (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid (10 g), sodium hydroxide (3.5 g) and water (25 g) into a reaction bottle, stirring to dissolve the materials, cooling to 20 ℃, controlling the temperature to be 20 ℃, dropwise adding a toluene (20 g) solution of BOC-acid anhydride (10.29 g), controlling the temperature to be 20 ℃ after dropwise adding, and reacting for 10 hours, wherein the purity of a medium-control product is 96.95%, and the purity of a condensed impurity is 0.117%.
And (3) layering and separating a toluene layer after the reaction is finished, dropwise adding hydrochloric acid into the water layer to adjust the pH value to be 1-2, separating out a large amount of solid, performing suction filtration and drying to obtain a product, wherein the yield is 90%. The purity of the product was 99.87% and the condensed impurities were 0.12%.
Example 2
In contrast to example 1, the molar mass of potassium carbonate used was the same as that used in the preparation of sodium hydroxide.
The purity of the medium control product is 96 percent, and the content of the condensation impurities is 0.15 percent.
The yield after the reaction was 89%. The purity of the product is 99.7 percent, and the condensation impurities are 0.15 percent.
Example 3
In contrast to example 1, the same mass of methyl tert-butyl ether was used instead of toluene, the rest being identical.
The purity of the medium-control product is 96.5 percent, and the purity of the condensation impurity is 0.14 percent.
The yield after the reaction is finished is 90 percent. The purity of the product is 99.8 percent, and the condensation impurities are 0.13 percent.
Example 4
The reaction temperature was controlled at 40 ℃ and the reaction time was controlled at 4 hours, which was the same as in example 1.
The purity of the medium-control product is 95 percent, and the purity of the condensation impurity is 0.15 percent.
The yield after the reaction was 91%. The purity of the product is 99.8 percent, and the condensation impurities are 0.15 percent.
Example 5
The reaction temperature was controlled at 0 ℃ and the reaction time was controlled at 18 hours, which was the same as in example 1.
The purity of the medium control product is 96 percent, and the content of the condensation impurities is 0.15 percent.
The yield after the reaction is finished is 90 percent. The purity of the product is 99.8 percent, and the condensation impurity is 0.14 percent.
Comparative example 1
3g of (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid was dissolved in 200ml of methyl t-butyl ether, 3.5g of BOC-anhydride and 2g of triethylamine were added, and the reaction was carried out at 20 ℃ for 10 hours with the result of controlling in the reaction solution to spectrogram 3, the product purity was 83.75%, and the condensation impurity was about 6.23%.
After the reaction was complete, the solid was filtered off, 3.5 (R) -N- (tert-butoxycarbonyl) -3-amino-4- (2,4,5-trifluorophenyl) with a yield of 81.7%. The liquid phase detection spectrogram is shown in figure 4, the purity of the product is 92.66%, and the concentration impurity is 5.96%.
Comparative example 2
10g of (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid, 11.2g of BOC-anhydride, 7.9g of sodium bicarbonate, 50ml of tetrahydrofuran and 50ml of water were charged into a reaction flask and reacted at room temperature for 24 hours, the control result was spectrum 5, the product purity was 81.94%, and the condensed impurity was 13.82%.
Adjusting pH to 2-3, adding ethyl acetate for extraction (50ml × 3), combining extract liquids, adding anhydrous sodium sulfate for drying treatment, filtering and concentrating to obtain (R) -N-tert-butoxycarbonyl-3-amino-4- (2,4,5-trifluorophenyl) butyric acid (13.6 g), wherein the yield is 75%, the liquid phase detection spectrogram is 6, the product purity is 83.24%, and the condensation impurity is 12.78%.
COMPARATIVE EXAMPLE 3 BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid using toluene solvent
3g of (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid was dissolved in 200ml of toluene, 3.5g of BOC-anhydride and 2g of triethylamine were added, and the reaction was carried out at 20 ℃ for 10 hours with the control result of spectrogram 7 in the reaction solution, the product purity was 80.68%, and the condensation impurity was about 15.08%.
After the reaction was completed, the solid was filtered off, and 3.5g of (R) -N- (tert-butoxycarbonyl) -3-amino-4- (2,4,5-trifluorophenyl) was obtained in 81.7% yield. The liquid phase detection spectrogram is shown in figure 8, the purity of the product is 76.95%, and the concentration impurity is 16.97%.
Liquid chromatography analysis
The liquid chromatography analysis of example 1 and comparative examples 1-3 was as follows:
instruments and parameters instruments: agilent Technologies 1260Infinity II (or suitable HPLC, equipped with UV detector) chromatography column: infinityLab Poroshell 120EC-C18, 4.6X 100mm,2.7 μm (or equivalent column)
Parameters of the instrument
Mobile phase A: measuring 1.0mL perchloric acid, putting the perchloric acid into a 500mL volumetric flask, shaking up, diluting the perchloric acid to a scale with sleep, shaking up, and ultrasonically degassing.
Mobile phase B: acetonitrile
The gradient program is shown in table 1:
table 1.
Figure BDA0002834406650000061
Flow rate: 0.6mL/min
Column temperature: 25 deg.C
Detection wavelength: UV,210nm
Sample injection amount: 5 μ L
The control spectrum of example 1 is shown in fig. 1, the liquid phase detection spectrum of the product is shown in fig. 2, the control spectrum of comparative example 1 is shown in fig. 3, the liquid phase detection spectrum of the product is shown in fig. 4, the control spectrum of comparative example 1 is shown in fig. 5, the liquid phase detection spectrum of the product is shown in fig. 6, the control spectrum of comparative example 1 is shown in fig. 7, and the liquid phase detection spectrum of the product is shown in fig. 8.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.

Claims (5)

1. A method for preparing high-purity BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid is characterized in that the reaction route is as follows:
Figure FDA0003768911120000011
adding 10g of (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid, 3.5g of inorganic base and 25g of water, stirring to dissolve the materials, cooling to 20 ℃, controlling the temperature to be 20 ℃, dropwise adding 20g of organic solvent solution of 10.29g of BOC-anhydride, and controlling the temperature to react after the dropwise adding is finished;
layering and separating out an organic solvent layer after the reaction is finished, dripping hydrochloric acid into the water layer to adjust the pH value to be 1-2, separating out a large amount of solid, and performing suction filtration and drying to obtain a product;
wherein the organic solvent is toluene;
the inorganic base is sodium hydroxide;
the temperature-controlled reaction is controlled at 20 ℃ and is carried out for 10 hours.
2. The process for the preparation of high purity BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid according to claim 1, characterized in that, unlike claim 1, potassium carbonate of the same molar mass is used instead of sodium hydroxide.
3. The process for preparing high purity BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid according to claim 1, characterized in that, unlike claim 1, toluene is replaced by methyl t-butyl ether of the same quality.
4. The method for preparing high-purity BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid according to claim 1, wherein the temperature-controlled reaction is controlled at 40 ℃ for 4 hours, which is different from claim 1.
5. The process for preparing high purity BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid according to claim 1, wherein the temperature controlled reaction is controlled at 0 ℃ for 18 hours, which is different from claim 1.
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CN105331651B (en) * 2015-11-25 2018-11-13 尚科生物医药（上海）有限公司 The enzyme-chemically preparation method of sitagliptin and its intermediate
CN107501112B (en) * 2017-09-15 2019-06-11 苏州爱玛特生物科技有限公司 A kind of Chiral Synthesis of chiral beta-amino acids and the synthetic method of medicine intermediate
CN111039900B (en) * 2019-02-28 2023-12-22 弈柯莱生物科技(集团)股份有限公司 Preparation method of 1-morpholine-4- (2, 4, 5-trifluoro-phenyl) butane-1, 3-dione
CN109824546B (en) * 2019-03-19 2021-07-02 浙江永太科技股份有限公司 BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid condensation impurity and preparation method thereof

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