阅读说明：本技术 一种制备boc-(r)-3-氨基-4-(2,4,5-三氟苯基)丁酸的方法 (Method for preparing BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid ) 是由 卫禾耕 张峰 顾坚雄 黄钦军 夏海建 于 2020-12-14 设计创作，主要内容包括：本发明公开了一种制备BOC-(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸的方法,涉及有机合成药物技术领域。其反应路线如下,其中,所述有机溶剂为与水不混溶的有机溶剂。该方法能够控制缩合杂质产生,得到高纯度、高收率的BOC-(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸,且该方法工艺稳定、操作简便、反应时间短,适合工业化生产。(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 an organic solvent immiscible with water. 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.)

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:

wherein the organic solvent is a water-immiscible organic solvent.

2. The method according to claim 1, characterized by the steps of: and mixing the compound I, water and inorganic base, adding the compound II dissolved by an organic solvent, and reacting to obtain a product compound III.

3. The method according to claim 1 or 2, wherein the organic solvent is selected from at least one of methyl tert-butyl ether, isopropyl acetate, toluene, dichloromethane, n-hexane, petroleum ether, cyclohexane, n-heptane.

4. A process according to claim 3, characterized in that the organic solvent is preferably toluene.

5. The method according to claim 1 or 2, wherein 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.

6. The method of claim 5, wherein the inorganic base is sodium hydroxide.

7. The method according to claim 1 or 2, wherein the reaction is a heat-preserving reaction, the reaction temperature is 0-40 ℃, and the reaction time is 4-18 h.

8. The process according to claim 7, wherein the reaction temperature is 20 ℃ and the reaction time is 10 hours.

9. The method according to claim 1 or 2, wherein the molar ratio of compound I to compound II is 1:1-2.

10. The process according to claim 1 or 2, wherein the molar ratio of compound I to inorganic base is 1: 1-2.2.

Technical Field

The invention relates to the technical field of organic synthetic drugs, and particularly relates 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 of sitagliptin phosphate. The structure is as follows:

the synthetic route of sitagliptin is as follows:

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. The condensed impurity A has the following structure:

the condensation impurities undergo a series of reactions to produce impurity B in the finished sitagliptin product as follows:

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 preparation of BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid by using dichloromethane as a solvent has the disadvantages of large generated condensed impurity A, purification by column chromatography, high cost and difficult industrial production. In patent CN105331651A, the condensation impurity A generated by the method is still large when tetrahydrofuran is used as a solvent to prepare BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid.

In view of this, the application provides a method for preparing high-purity BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid, which has the advantages of simple preparation process, high product purity and low impurity content, effectively solves the above 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 provide 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 achieve the purpose, 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:

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 more preferably sodium hydroxide.

Preferably, the reaction is a heat preservation reaction, the reaction temperature is 0-40 ℃, and the reaction time is 4-18 h; more preferably, the reaction temperature is 20 ℃ and the reaction time is 10 hours.

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 spectrum 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 spectrum 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 must be 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 methods in the following examples are conventional methods unless otherwise specified, and materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

In the following examples, (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid (10g) was purchased from Yongtai science, Inc. under the trade designation 202005006; BOC-anhydride was purchased from GmbH, Inc., having a product number of 4209-.

Example 1

Adding (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid (10g), sodium hydroxide (3.5g) and water (25g) into a reaction bottle, stirring to dissolve the materials, cooling to 20 ℃, controlling the temperature to be 20 ℃, dropwise adding a toluene (20g) solution of BOC-anhydride (10.29g), controlling the temperature to be 20 ℃ after the dropwise adding, and reacting for 10 hours, wherein the purity of a medium-control product is 96.95 percent, and the purity of a condensed impurity is 0.117 percent.

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 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 sodium hydroxide was replaced by potassium carbonate of the same molar mass, the remainder being identical.

The purity of the medium-control product is 96 percent, and the purity of the condensation impurity 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 purity of the condensation impurity 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 reaction was carried out at 20 ℃ for 10 hours with the result of controlling in the reaction liquid to be spectrogram 3, the purity of the product was 83.75%, and the condensed impurity was about 6.23%.

After the reaction was completed, the solid was filtered off, and 3.5(R) -N- (tert-butoxycarbonyl) -3-amino-4- (2,4, 5-trifluorophenyl) was obtained in 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 condensation impurity content 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, with the control result being spectrum 5, the product purity being 81.94%, and the condensation impurity being 13.82%.

Adjusting pH to 2-3, adding ethyl acetate for extraction (50ml x 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 (13.6g), 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 use of toluene solvent as BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid

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 mixture was reacted at 20 ℃ for 10 hours with the control result of spectrogram 7, the product purity was 80.68%, and the condensation impurity was about 15.08%.

After completion of the reaction, the solid was filtered off, and 3.5g of (R) -N- (tert-butoxycarbonyl) -3-amino-4- (2,4, 5-trifluorophenyl) was obtained in a yield of 81.7%. The liquid phase detection spectrogram is shown in figure 8, the purity of the product is 76.95%, and the condensation impurity content 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-C18,4.6 x 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.

Flow rate: 0.6mL/min

Column temperature: 25 deg.C

Detection wavelength: UV,210nm

Sample introduction 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 is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.