CN115784918B

CN115784918B - Preparation method of high-purity ubenimex intermediate

Info

Publication number: CN115784918B
Application number: CN202211484290.2A
Authority: CN
Inventors: 范有平; 卢铁刚; 胡同军; 朱华; 邵波; 王颖
Original assignee: Sichuan Qingmu Pharmaceutical Co ltd
Current assignee: Sichuan Qingmu Pharmaceutical Co ltd
Priority date: 2022-11-24
Filing date: 2022-11-24
Publication date: 2024-10-15
Anticipated expiration: 2042-11-24
Also published as: CN115784918A

Abstract

The present invention provides a method for preparing high-purity intermediate (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid of Wufenmei Si. Compound a is first separated to obtain compound 1a, then hydrogenated and reduced to obtain compound 1b, and finally hydrolyzed to obtain high-purity intermediate c. Using the reaction route of the present invention, the separation yield is increased, the overall yield of intermediate c is increased, the purity is also high, the material usage is reduced, the production cost is lower, and it is more economical and environmentally friendly.

Description

Preparation method of high-purity ubenimex intermediate

Technical Field

The invention relates to the field of organic chemistry, in particular to a preparation method of a high-purity ubenimex intermediate (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid.

Background

Ubenimex (Ubenimex), its chemical name is: n- [ (2S, 3R) -3-amino-2-hydroxy-4-phenylbutyryl ] -L-leucine; the molecular formula: c ₁₆H₂₄N₂O₄; molecular weight: 308.37; the structural formula is as follows:

Ubenimex is a peptide antitumor drug, which is a dipeptide compound isolated from culture solution of Streptomyces olivaceus by Japanese scholares Mei Zebin in 1976, and can competitively inhibit aminopeptidase B, leucine peptidase, caspase and the like, induce apoptosis of tumor cells and promote host immune function. Can be used in combination with chemotherapy, radiotherapy and other solid tumor patients after leukemia, multiple myeloma, myelodysplastic syndrome and hematopoietic stem cell transplantation.

The ubenimex has a complex structure, contains 3 chiral centers and theoretically has 7 stereoisomers, so that how to ensure that 3 chiral centers are correctly formed and the optical purity meets the quality requirement is the primary task of synthesizing ubenimex.

(2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid (compound c) is an important intermediate for the preparation of ubenimex. The route for the preparation of (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid (compound c) is as follows, in view of the reported preparation methods for Wu Benmei s:

The compound a is firstly hydrogenated and reduced, then the compound b is subjected to resolution reaction to obtain salt, then acidolysis is carried out to obtain the compound 1b, and deacetylation is carried out to obtain the intermediate (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid (compound c) of ubenimex.

Journal of Antibiotics,1983, 36 (6): 695-699 reports a practical ubenimex process, which comprises taking acetophenone as raw material, and carrying out bromination, amination, acetylation, aldol condensation, hydrogenation reduction, resolution, deacetylation, amino protection, amide condensation and deprotection reaction to obtain ubenimex. The method also comprises the steps of firstly hydrogenating the compound a to obtain a compound b, then carrying out chiral resolution on the compound b, and carrying out acidolysis and hydrolysis to obtain the ubenimex intermediate (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid (compound c). Wherein this route for compound a to compound c was calculated to yield about 22.32%.

Patent CN101891647 a discloses a method for resolving compound b by using L-lysine, L-arginine and L-histidine, to obtain ubenimex intermediate (2 s,3 r) -3-acetamido-2-hydroxy-4-phenylbutyric acid, which requires multiple recrystallization operations, and preferably adds seed crystals to separate out crystals in the salting-out process, and has complex operation, and the yield of resolved compound b is only about 33.2%, which is not beneficial to industrial production.

Patent CN107098827 a discloses a method for resolving compound b by using S-1-naphthylethylamine, S-1- (2-naphthyl), L-phenylglycinol and L-amphetamine as resolving agents, to obtain ubenimex intermediate (2S, 3 r) -3-acetamido-2-hydroxy-4-phenylbutyric acid, the resolving yield of the method is about 35-37%, and the resolving yield is not high.

The above patents all refer to chiral resolution of the compound b, wherein the compound b is positioned in the intermediate of the sixth step of the ubenimex process chain, and the resolution yield is about 30%, which means that more than 60% of materials and solvents before the intermediate b are ineffective. The route from the compound a to the compound c has the total yield of about 22 percent, low cost, high emission in the production process, low optical purity and no contribution to industrial production. For industrial production, the continuous pursuit of enterprises to reduce cost and reduce environmental pollution caused by waste emission is realized by improving yield and reducing raw material consumption to obtain high-quality products.

Disclosure of Invention

The invention aims to improve the defects of the prior art, and the threo-2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound a) obtained from the fourth step of reaction is split, and is directly hydrolyzed after hydrogenation reduction to obtain (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid. The method has the advantages of early resolution, less material use, improved resolution yield, high intermediate purity and simpler operation.

The invention provides a preparation method of a high-purity ubenimex intermediate (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid (c), which is characterized in that the reaction equation is as follows:

Separating the compound a by a resolution reagent to obtain a compound 1a, then hydrogenating the compound 1a to obtain a compound 1b, and hydrolyzing the compound to obtain an intermediate (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid (c); wherein the resolving agent is selected from N-N-octyl-D-glucosamine, S-alpha-phenylethylamine, L-lysine or L-arginine.

In some embodiments, the resolving agent is preferably N-octyl-D-glucosamine.

In some embodiments, the compound a, threo-2-hydroxy-3-acetamido-4-phenylcarbonylbutyric acid, consists of compound 1a and compound 2 a:

in some embodiments, the molar ratio of compound a to resolving agent is 1: (0.5 to 7), preferably 1: (0.8 to 5), more preferably 1: (1-5).

In some embodiments, the process for preparing intermediate c comprises the steps of:

1) Mixing the compound a with a resolution reagent in an aqueous solvent to form salt, cooling, crystallizing and separating out the salt, and separating to obtain salt of the compound 1a and the resolution reagent; wherein the temperature range at which the compound a and the resolving agent are mixed in the aqueous solvent is 0 to 100 ℃, for example, 50 to 100 ℃,20 to 80 ℃ and the like; the temperature reduction range of the mixture is-20-50 ℃, preferably 0-40 ℃;

2) Dissolving the salt obtained in the step 1) in an aqueous solution, adding a proper amount of acid to enable the compound 1a to be free and separated out, and separating to obtain (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound 1 a) with high purity:

3) Adding the compound obtained in the step 2) into a solvent for hydrogenation to obtain chiral (2S, 3R) -2-hydroxy-3-acetamido-4-phenylbutyric acid (compound 1 b):

4) Hydrolyzing the compound 1b obtained in the step 3) in acid to obtain a chiral compound (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid (compound c):

In some embodiments, the aqueous solvent described in step 1) is selected from one of isopropanol, ethanol, acetone, sec-butanol; the water content of the solvent is in the range of 0.5% to 15%, preferably 1% to 10%, and more preferably 3% to 5%.

In some embodiments, the weight ratio of compound a to the aqueous solvent in step 1) is from 1 (0.5 to 120), preferably from 1 (1 to 100), and more preferably from 1 (4 to 50).

In some embodiments, the acid described in step 2) or 4) is a protic acid, such as hydrochloric acid, nitric acid, sulfuric acid, trifluoroacetic acid, acetic acid, benzoic acid, sulfonic acid, phosphoric acid, and the like.

The preparation process of the invention has the following advantages:

1. compared with the prior art, the method has the advantages that the resolution of the compound b after resolution reduction is generally different, and the method advances the resolution, uses fewer materials, reduces the production cost, improves the yield of the intermediate c by ten percent, and greatly improves the purity of the product.

2. According to the invention, the resolution reagent N-N-octyl-D-glucosamine, S-alpha-phenethylamine, L-lysine or L-arginine is selected for resolution of the compound a, and compared with other resolution reagents, the resolution yield is higher, and the resolution yield is higher than 40%, especially the resolution yield of N-N-octyl-D-glucosamine is higher than 42.5%.

3. The method has the advantages of simpler operation, less resolution times, good resolution effect, better purity of the prepared intermediate c and suitability for industrial production.

Drawings

FIG. 1 is an optical purity HPLC chart of Compound 1a prepared in example 1

FIG. 2 is an optical purity HPLC chart of Compound 1a prepared in example 2

FIG. 3 is a chromatographic purity HPLC chart of Compound c prepared in example 1

FIG. 4 is a chromatographic purity HPLC chart of Compound c prepared in example 2

FIG. 5 is an optical purity HPLC chart of Compound 1b prepared in comparative example 1

Detailed Description

The present invention is further illustrated below with reference to specific examples, but the scope of the present invention is not limited by the following examples.

The room temperature referred to in the present invention means 20.+ -. 5 ℃.

The optical purity in the examples was measured by HPLC and given as area percent.

Liquid phase conditions:

Chromatographic column: OJ-H4.6 x 250mm/5 μm

Mobile phase: n-hexane: ethanol: trifluoroacetic acid=90%: 10%:0.1%

Sample preparation: weighing 10mg of the sample, precisely weighing, placing into a 20ml volumetric flask, adding mobile phase, dissolving, diluting to scale, and shaking. 2 parts were prepared in parallel and the solution was stable for 8 hours after preparation.

Wavelength: 220nm;

Flow rate: 0.6ml/min;

Sample injection amount: 50 μl;

Column temperature: 25 ℃;

Run time: 30min

Example 1

Adding compound a (50.0 g) and N-N-octyl-D-glucosamine (292.0 g) into 2.5kg of acetone with 5% of water content, heating to 50 ℃ with stirring, dissolving, naturally cooling to room temperature after complete dissolution, cooling to-20 ℃ with heat preservation, stirring for 2h, filtering, drying at 50 ℃ under negative pressure to obtain 59.7 g of white solid, namely the lipoamine salt of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound 1 a), adding the salt into purified water (480 g), stirring and dissolving at 20-30 ℃ to obtain a clear solution, dropwise adding hydrochloric acid until the pH value of the system is 2-3 (120 g of concentrated hydrochloric acid is consumed), precipitating a large amount of solids, filtering, drying to obtain 21.3g (compound 1 a) of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid, wherein the optical purity is 98.70% (the optical purity HPLC chart is shown in figure 1), and the yield is 42.6%.

20G of the mixture was charged into a high-pressure hydrogenation reactor, 128g of glacial acetic acid and 2.0g of 5% palladium on carbon were sequentially added, and then nitrogen was replaced three times and hydrogen was replaced three times. Hydrogenation is carried out at the system temperature of 50+/-5 ℃ and the pressure of 1.2MPa to 1.4MPa until the raw materials are completely reacted. Palladium on carbon is filtered, the filtrate is concentrated and dried, then EA 20g is added to pulp for 1h, a large amount of white solid is generated, the white solid is filtered, EA 10g is used for leaching, and a filter cake is dried to obtain 16.7g (compound 1 b) of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylbutyric acid with a yield of 88.45%.

15G of the material is added into 100g of purified water and 20g of concentrated hydrochloric acid, the mixture is heated to reflux under stirring, the reflux reaction is maintained for 8 hours, the reaction is completed, the mixture is concentrated to dryness, 2mol/L sodium hydroxide solution is slowly added to adjust the pH to 5-6, a large amount of white solid is separated out, the temperature is reduced to below 10 ℃ of the system, the mixture is centrifuged and dried, and 11.12g (compound c) of white solid (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid is obtained, and the yield is 90.10%. Chromatographic purity 99.61% (chromatographic purity HPLC profile see fig. 3), single impurity: 0.39%.

Example 2

Adding compound a (50.0 g) and L-lysine (29.09 g) into 200g of 95% ethanol, heating to 80 ℃ with stirring, naturally cooling to room temperature after dissolution, cooling to 20 ℃ and stirring for 2h, filtering, drying at 50 ℃ under negative pressure to obtain 56.8 g of white solid, namely L-lysine salt of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound 1 a), adding the salt into purified water (450 g), stirring and dissolving at 20-30 ℃ to obtain a solution, dropwise adding hydrochloric acid until the pH of the system is 2-3 (180 g of concentrated hydrochloric acid is consumed), precipitating a large amount of solid, filtering, and drying to obtain 20.2g of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound 1 a), wherein the optical purity is 98.71% (the optical purity HPLC chart is shown in figure 2), and the yield is 40.4%.

20G of the mixture was charged into a high-pressure hydrogenation reactor, 128g of glacial acetic acid and 2.0g of 5% palladium on carbon were sequentially added, and then nitrogen was replaced three times and hydrogen was replaced three times. Hydrogenation is carried out at the system temperature of 50+/-5 ℃ and the pressure of 1.2MPa to 1.4MPa until the raw materials are completely reacted. Palladium on carbon is filtered, the filtrate is concentrated and dried, then EA 20g is added to pulp for 1h, a large amount of white solid is generated, the white solid is filtered, EA 10g is used for leaching, and a filter cake is dried to obtain 16.4g (compound 1 b) of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylbutyric acid with the yield of 86.86%.

15G of the material is added into 100g of purified water and 20g of concentrated hydrochloric acid, the mixture is heated to reflux under stirring, the reflux reaction is maintained for 8 hours, the reaction is completed, the mixture is concentrated to dryness, 2mol/L sodium hydroxide solution is slowly added to adjust the pH to 5-6, a large amount of white solid is separated out, the temperature is reduced to below 10 ℃ of the system, the mixture is centrifuged and dried, and 11.29g (compound c) of white solid (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid is obtained, and the yield is 91.46 percent. Chromatographic purity 99.52% (chromatographic purity HPLC profile see fig. 4), single impurity: 0.47%.

Example 3

Adding compound a (50.0 g) and L-arginine (27.73 g) into 100g of isopropanol with 6% of water content, heating to 50 ℃ with stirring, naturally cooling to room temperature after dissolution, keeping the temperature to 0 ℃ and stirring for 2h, filtering, drying at 50 ℃ under negative pressure to obtain 58.5 g of white solid, namely L-arginine salt of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound 1 a), adding the salt into purified water (480 g), stirring and dissolving at 20-30 ℃ to clear, dropwise adding hydrochloric acid until the pH of the system is 2-3 (consuming concentrated hydrochloric acid 120 g), precipitating a large amount of solids, filtering, and drying to obtain 20.8g of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound 1 a), wherein the optical purity is 98.90%, and the yield is 41.6%.

20G of the mixture was charged into a high-pressure hydrogenation reactor, 128g of glacial acetic acid and 2.0g of 5% palladium on carbon were sequentially added, and then nitrogen was replaced three times and hydrogen was replaced three times. Hydrogenation is carried out at the system temperature of 50+/-5 ℃ and the pressure of 1.2MPa to 1.4MPa until the raw materials are completely reacted. Palladium on carbon is filtered, the filtrate is concentrated and dried, then EA 20g is added to pulp for 1h, a large amount of white solid is generated, the white solid is filtered, EA 10g is used for leaching, and a filter cake is dried to obtain 16.6g (compound 1 b) of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylbutyric acid with a yield of 88.29 percent.

15G of the material is added into 100g of purified water and 20g of concentrated hydrochloric acid, the mixture is heated to reflux under stirring, the reflux reaction is maintained for 8 hours, the reaction is completed, the mixture is concentrated to dryness, 2mol/L sodium hydroxide solution is slowly added to adjust the pH to 5-6, a large amount of white solid is separated out, the temperature is reduced to below 10 ℃ of the system, the mixture is centrifuged and dried, and 10.78g (compound c) of white solid, namely (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid, is obtained, and the yield is 87.37 percent. Chromatographic purity 99.75%, single impurity: 0.25%.

Example 4

Adding compound a (50.0 g) and S-alpha-phenethylamine (24.1 g) into 50g of sec-butyl alcohol with 10% of water content, heating to 100 ℃ with stirring, naturally cooling to room temperature after dissolution is completed, preserving heat and stirring for 2h at 50 ℃, filtering, drying at 50 ℃ under negative pressure to obtain 56.2 g of white solid, namely L-arginine salt of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound 1 a), adding the salt into purified water (480 g), stirring and dissolving at 20-30 ℃ until the pH of the system is 2-3 (consuming concentrated hydrochloric acid 120 g), precipitating a large amount of solids, filtering, and drying to obtain 20.1g of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound 1 a), wherein the optical purity is 98.56%, and the yield is 40.2%.

20G of the mixture was charged into a high-pressure hydrogenation reactor, 128g of glacial acetic acid and 2.0g of 5% palladium on carbon were sequentially added, and then nitrogen was replaced three times and hydrogen was replaced three times. Hydrogenation is carried out at the system temperature of 50+/-5 ℃ and the pressure of 1.2MPa to 1.4MPa until the raw materials are completely reacted. Palladium on carbon is filtered, the filtrate is concentrated and dried, then EA 20g is added to pulp for 1h, a large amount of white solid is generated, the white solid is filtered, EA 10g is used for leaching, and a filter cake is dried to obtain 17.2g (compound 1 b) of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylbutyric acid with a yield of 91.48 percent.

15G of the material is added into 100g of purified water and 20g of concentrated hydrochloric acid, the mixture is heated to reflux under stirring, the reflux reaction is maintained for 8 hours, the reaction is completed, the mixture is concentrated to dryness, 2mol/L sodium hydroxide solution is slowly added to adjust the pH to 5-6, a large amount of white solid is separated out, the temperature is reduced to below 10 ℃ of the system, the mixture is centrifuged and dried, and 10.95g (compound c) of white solid, namely (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid, is obtained, and the yield is 88.73%. Chromatographic purity 99.58%, single impurity: 0.42%.

Example 5

Adding compound a (20.0 g) and N-N-octyl-D-glucosamine (23.3 g) into 200g of isopropanol with 3% of water content, heating to 60 ℃ to dissolve the materials completely, naturally cooling to room temperature, cooling to 10 ℃ to keep the temperature and stirring for 2 hours, filtering, drying at 50 ℃ under negative pressure to obtain 23.8 g of white solid, namely the meglumine salt of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound 1 a), adding the salt into purified water (192 g), stirring and dissolving at 20-30 ℃ to obtain a solution, dropwise adding hydrochloric acid until the pH of the system is 2-3 (48 g of concentrated hydrochloric acid is consumed), precipitating a large amount of solids, filtering and drying to obtain 8.50g (compound 1 a) of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid with the optical purity of 98.27% and the yield of 42.5%.

8.0G of the mixture is added into a high-pressure hydrogenation kettle, 51.2g of glacial acetic acid and 0.8g of 5% palladium-carbon are sequentially added, and then nitrogen is replaced three times and hydrogen is replaced three times. Hydrogenation is carried out at the system temperature of 50+/-5 ℃ and the pressure of 1.2MPa to 1.4MPa until the raw materials are completely reacted. Palladium on carbon is filtered, the filtrate is concentrated to dryness, then EA 8.0g is added to pulp for 1h, a large amount of white solid is generated, the mixture is filtered, EA 8.0g is used for leaching, and a filter cake is dried to obtain 6.6g (compound 1 b) of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylbutyric acid, and the yield is 87.41%.

5.0G of the material is added into 30g of purified water and 10g of concentrated hydrochloric acid, the mixture is heated to reflux under stirring, the reflux reaction is maintained for 6 hours, after the reaction is completed, the mixture is concentrated to dryness, 2mol/L sodium hydroxide solution is slowly added to adjust the pH to 5-6, a large amount of white solid is separated out, the temperature is reduced to below 10 ℃ of the system, the mixture is centrifuged and dried, and the white solid, namely 3.57g (compound c) of (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid is obtained, and the yield is 86.89 percent. Chromatographic purity 99.72%, single impurity: 0.28%.

Example 6

Adding compound a (50.0 g) and N-N-octyl-D-glucosamine (116.7 g) into 5.0kg of acetone with 1% of water content, heating to 55 ℃ with stirring to dissolve the mixture completely, naturally cooling to room temperature, cooling to 10 ℃ and preserving heat, stirring for 2 hours, filtering, drying at 50 ℃ under negative pressure to obtain 59.6 g of white solid, namely the meglumine salt of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid (compound 1 a), adding the salt into purified water (480 g), stirring and dissolving at 20-30 ℃ to clear, dropwise adding hydrochloric acid until the pH of the system is 2-3 (118 g of concentrated hydrochloric acid is consumed), precipitating a large amount of solid, filtering and drying to obtain 21.0g (compound 1 a) of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid with optical purity of 98.39% and yield of 42.0%.

20G of the mixture was charged into a high-pressure hydrogenation reactor, 128g of glacial acetic acid and 2.0g of 5% palladium on carbon were sequentially added, and then nitrogen was replaced three times and hydrogen was replaced three times. Hydrogenation is carried out at the system temperature of 50+/-5 ℃ and the pressure of 1.2MPa to 1.4MPa until the raw materials are completely reacted. Palladium on carbon is filtered, the filtrate is concentrated and dried, then EA 20g is added to pulp for 1h, a large amount of white solid is generated, the white solid is filtered, EA 10g is used for leaching, and a filter cake is dried to obtain 16.5g (compound 1 b) of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylbutyric acid with a yield of 87.39%.

15G of the material is added into 100g of purified water and 20g of concentrated hydrochloric acid, the mixture is heated to reflux under stirring, the reflux reaction is maintained for 8 hours, the reaction is completed, the mixture is concentrated to dryness, 2mol/L sodium hydroxide solution is slowly added to adjust the pH to 5-6, a large amount of white solid is separated out, the temperature is reduced to below 10 ℃ of the system, the mixture is centrifuged and dried, and 10.98g (compound c) of white solid, namely (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid, is obtained, and the yield is 88.98 percent. Chromatographic purity 99.66%, single impurity: 0.34%.

Comparative example 1

Adding threo racemate (50.0 g) of a compound b and S-phenethylamine (26.0 g) into 250g of 95% ethanol, heating to 55-60 ℃ to dissolve the material under stirring, naturally cooling to room temperature after dissolving completely, cooling to 0-10 ℃ again, preserving heat and stirring for 24h, filtering to obtain 40.8g of a filter cake wet product, adding the filter cake wet product into 200g of 95% ethanol, heating to 55-60 ℃ to dissolve the material under stirring, naturally cooling to room temperature after dissolving completely, cooling to 0-10 ℃ again, preserving heat and stirring for 24h, filtering, drying at 60 ℃ under negative pressure to obtain 20.3 g of white solid, namely S-phenethylamine salt of (2S, 3R) -2-hydroxy-3-acetamido-4-phenylbutyric acid (compound 1 b), wherein the optical purity is 96.44% (the optical purity HPLC chart is shown in figure 5), and the yield is 26.87%.

15G of the material is added into 100g of purified water and 20g of concentrated hydrochloric acid, the mixture is heated to reflux under stirring, the reflux reaction is maintained for 8 hours, the reaction is completed, the mixture is concentrated to dryness, 2mol/L sodium hydroxide solution is slowly added to adjust the pH to 5-6, a large amount of white solid is separated out, the temperature is reduced to below 10 ℃ of the system, the mixture is centrifuged and dried, and 10.40g (compound c) of white solid, namely (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid, is obtained, and the yield is 83.50 percent.

It is to be understood that the foregoing detailed description and accompanying examples are merely exemplary and are not to be considered limiting the scope of the invention, which is defined solely by the appended claims and their equivalents. Various alterations and modifications to the disclosed embodiments will be readily apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

1. A preparation method of ubenimex intermediate (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid (c), which is characterized by comprising the following steps:

Separating the compound a by a resolution reagent to obtain a compound 1a, then hydrogenating the compound 1a to obtain a compound 1b, and hydrolyzing the compound to obtain an intermediate (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid (c); wherein the resolving agent is selected from N-N-octyl-D-glucosamine.

2. The preparation method according to claim 1, wherein the compound a is composed of a compound 1a and a compound 2 a:

3. The preparation method according to claim 1, wherein the molar ratio of the compound a to the resolving agent is 1: (0.5-7).

4. The preparation method according to claim 1, wherein the molar ratio of the compound a to the resolving agent is 1: (0.8-5).

5. The method of manufacturing according to claim 1, comprising the steps of:

1) Mixing the compound a with a resolution reagent in an aqueous solvent to form salt, and cooling to separate out salt crystals;

2) Dissolving the salt obtained in the step 1) in an aqueous solution, and adding a proper amount of acid to enable the compound 1a to be separated out in a free way;

3) Adding the compound 1a obtained in the step 2) into a solvent for hydrogenation to obtain a compound 1b;

4) And (3) adding acid to hydrolyze the compound 1b obtained in the step (3) to obtain an intermediate (2S, 3R) -2-hydroxy-3-amino-4-phenylbutyric acid (c).

6. The method of claim 5, wherein the aqueous solvent is selected from isopropanol, ethanol, acetone, and sec-butanol; the water content of the aqueous solvent is 0.5-15%.

7. The method according to claim 6, wherein the aqueous solvent has a water content of 1% to 10%.

8. The process according to claim 5, wherein the temperature range at which the compound a and the resolving agent are mixed in the aqueous solvent in step 1) is 50 to 100 ℃.

9. The method according to claim 5, wherein the temperature reduction range in step 1) is-20 to 50 ℃.

10. The process according to claim 5, wherein the weight ratio of the compound a to the aqueous solvent in the step 1) is 1 (0.5 to 120).

11. The process according to claim 10, wherein the weight ratio of the compound a to the aqueous solvent in step 1) is 1 (1-100).

12. The process of claim 5, wherein the acid in step 2) or 4) is a protic acid.