Preparation method of (2R, 3S)-2-Boc amino-3-hydroxy-3-(pyridine-4-yl) alanine

Abstract

The invention discloses a preparation method of (2R, 3S)-2-Boc amino-3-hydroxy-3-(pyridine-4-yl) alanine, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: by taking glycine ester hydrochloride as a raw material, carrying out benzophenone dimethyl ketal reaction to generate a glycine ester imine intermediate; then, the 2-amino-3-hydroxyl-3-(pyridine-4-yl) alanine and pyridine-4-formaldehyde are subjected to acidolysis, and 2-amino-3-hydroxyl-3-(pyridine-4-yl) alanine is generated; then, the 2-Boc amino-3-hydroxyl-3-(pyridine-4-yl) alanine is subjected to a reaction with Boc2O, and a 2-Boc amino-3-hydroxyl-3-(pyridine-4-yl) alanine racemate is generated; and finally, salifying and resolving by adopting a cyclohexanedibenzylamine resolving agent, and then dissociating to obtain a target product. The raw materials are available in the market, direct condensation reaction is performed between pyridine-4-formaldehyde and amino acid imine, effective resolution can be performed by adopting 0.5 eq of a resolution reagent, and the whole route is simple and convenient to operate and suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The application relates to a preparation method of (2R, 3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl) alanine and belongs to the technical field of medical intermediates. BACKGROUND

[0002] Beta-hydroxy acids are widely present in molecules with biological activity, and a synthesis method thereof is of great significance to drug research and development. Common beta-hydroxy amino acids mainly include serine, threonine, tyrosine and the like, and are widely applied in the fields of medicine, food, cosmetics and the like. 2-amino-3-hydroxy-3-(pyridin-4-yl) alanine, as a beta-hydroxy amino acid containing a pyridine ring, is a high-dose candidate drug raw material [WO20080011478].

[0003] As to the synthesis route of 2-amino-3-hydroxy-3-(pyridin-4-yl) alanine, the existing literatures are searched, and the literatures [Organic Process Research and Development, 2015, 19, 1308; Organic Process Research and Development, 2015, 19, 1317] report that pyridine-4-formaldehyde is used as a raw material, reacts with glycine under the catalysis of an enzyme to generate 2-amino-3-hydroxy-3-(pyridin-4-yl) alanine.

[0004] In the synthesis method reported at present, the synthesis route is relatively single, and an enzyme catalysis reaction is needed, the reaction is not easy to control, and the enzyme catalyst is not easy to prepare and preserve, so it is necessary to research and explore the synthesis method of Boc-protected (2R, 3S)-2-amino-3-hydroxy-3-(pyridin-4-yl) alanine and develop a new process route. SUMMARY

[0005] The application is carried out in order to solve the above problems, and aims to provide a preparation method with high yield and economical route.

[0006] In order to solve the above technical problems, the application adopts the following technical scheme: glycine ester hydrochloride is used as a raw material, diphenyl ketone dimethyl ketal reaction is carried out to generate a glycine ester imine intermediate; then, the intermediate reacts with pyridine-4-formaldehyde under an alkaline condition, and then is subjected to acidolysis to generate 2-amino-3-hydroxy-3-(pyridin-4-yl) alanine; then, the 2-amino-3-hydroxy-3-(pyridin-4-yl) alanine reacts with Boc2O to generate 2-Boc amino-3-hydroxy-3-(pyridin-4-yl) alanine racemate; finally, the racemate is subjected to salt resolution by using a resolution agent, and then is dissociated to obtain (2R, 3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl) alanine.

[0007] The application provides a preparation method of (2R, 3S)-2-Boc amino-3-hydroxy-3-(pyridine-4-yl) alanine, which comprises the following steps:

[0008]

[0009] A, glycine ester hydrochloride is mixed with triethylamine in methanol, then pyridine p-toluenesulfonate (PPTS) and benzophenone dimethyl ketal are added to react to obtain a glycine imine intermediate;

[0010] B, the glycine imine intermediate, pyridine-4-formaldehyde and a base are mixed in a solvent to react under reflux conditions to obtain 2-amino-3-hydroxy-3-(pyridine-4-yl) alanine;

[0011] C, 2-amino-3-hydroxy-3-(pyridine-4-yl) alanine, Boc2O and a base are mixed in a solvent to react at room temperature to obtain 2-Boc amino-3-hydroxy-3-(pyridine-4-yl) alanine racemate.

[0012] D, 2-Boc amino-3-hydroxy-3-(pyridine-4-yl) alanine racemate and a resolving agent are salted in isopropanol to obtain (2R, 3S)-2-Boc amino-3-hydroxy-3-(pyridine-4-yl) alanine after dissociation by adding hydrochloric acid.

[0013] Further, preferably, in step A, the glycine ester hydrochloride is selected from glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride.

[0014] Further, preferably, in step A, the molar ratio of the glycine ester hydrochloride, the base, PPTS and benzophenone dimethyl ketal is 1:1-1.1:0.02-0.06:1-1.1.

[0015] Further, preferably, in step B, the base is selected from NaOH, KOH or Cs2CO3.

[0016] Further, preferably, in step B, the solvent is selected from dichloromethane, toluene or acetonitrile.

[0017] Further, preferably, in step B, the molar ratio of the glycine imine intermediate, pyridine-4-formaldehyde and the base is 1:1-1.2:1-1.3.

[0018] Further, preferably, in step C, the base is selected from NaOH, Na2CO3 or 4-DMAP (4-dimethylaminopyridine).

[0019] Further, preferably, in step C, the solvent is selected from acetonitrile or dichloromethane.

[0020] Further, preferably, in step C, the molar ratio of the 2-amino-3-hydroxy-3-(pyridin-4-yl)alanine, Boc20 and the base is 1:1-1.2:1-1.2.

[0021] Further, preferably, in step D, the resolving agent is (1S,2S)-N,N'-dibenzylcyclohexane-1,2-diamine.

[0022] Further, preferably, in step D, the molar ratio of the racemate and the resolving agent is 1:0.45-0.55.

[0023] The present application has the following beneficial effects:

[0024] 1. The present application uses cheap and readily available glycine ester hydrochloride as raw material, and through four-step reaction, (2R,3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine intermediate is prepared, which is good in operability and high in overall yield.

[0025] 2. In step A of the present application, benzophenone dimethyl ketal is used to protect the amino group, the reaction speed is fast, and the conversion rate is high.

[0026] 3. In step B of the present application, pyridine-4-formaldehyde is directly condensed with the amino acid imine intermediate; in step D, 0.5 eq of cyclohexanediamine is used for resolution, which can effectively resolve, is simple to operate, and is suitable for scale-up production. Specific embodiments

[0027] The present application will be further described below through specific examples. These examples should be understood as only for illustrating the present application and not for limiting the protection scope of the present application. After reading the content described in the present application, those skilled in the art can make various changes or modifications to the present application, and these equivalent changes and modifications also fall within the scope defined by the claims of the present application.

[0028] Example 1

[0029]

[0030] Glycine methyl ester hydrochloride (8.9 g, 0.1 mol) and triethylamine (10.1 g, 0.1 mol) were mixed in 80 mL of methanol under nitrogen protection, stirred at room temperature for 20 min, then PPTS (1 g, 0.004 mol) and benzophenone dimethyl ketal (24 g, 0.105 mol) were added, and reacted at room temperature for 3 hours, concentrated, and the crude product was purified by column chromatography, eluent ethyl acetate / petroleum ether (v / v=80 / 20), to obtain glycine imine intermediate 24.8 g, yield 98%, HPLC 99.5%. 1HNMR (400 MHz, CDC13): 7.76-7.65 (m, 2H), 7.57-7.47 (m, 3H), 7.45-7.34 (m, 3H), 7.26-7.20 (m, 2H), 4.25 (s, 2H), 3.79 (s, 3H) ppm.

[0031] Example 2

[0032]

[0033] Glycine methyl ester hydrochloride (8.9 g, 0.1 mol) and benzophenone (20 g, 0.11 mol) were mixed in 80 mL of toluene under nitrogen protection, then DIPEA (11.1 g, 0.11 mol) was added, and the reaction was dehydrated at reflux for 4 h. After cooling, the crude product was purified by column chromatography using ethyl acetate / petroleum ether (v / v = 80 / 20) as eluent to give glycine imine intermediate 21.8 g in 86% yield, HPLC 98.8%.

[0034] Example 3

[0035]

[0036] Glycine methyl ester hydrochloride (8.9 g, 0.1 mol) and benzophenone imine (18.1 g, 0.1 mol) were mixed in 100 mL of dichloromethane under nitrogen protection, and stirred at room temperature for 12 h. After concentration, the crude product was purified by column chromatography using ethyl acetate / petroleum ether (v / v = 80 / 20) as eluent to give glycine imine intermediate 23.1 g in 91% yield, HPLC 99.1%.

[0037] Example 4

[0038]

[0039] Glycine imine intermediate (25.3 g, 0.1 mol), pyridine-4-carboxaldehyde (11.8 g, 0.11 mol) and Cs2CO3(35.8 g, 0.11 mol) were mixed in 200 mL of acetonitrile under nitrogen protection, and the reaction was carried out at reflux for 3 h. After cooling to room temperature, the acetonitrile was concentrated, 60 mL of sodium hydroxide (2 M) was added and heated to 40-50 °C, and the reaction was carried out for 5 h. Then, hydrochloric acid (2 M) was added to adjust pH = 1-2, and the mixture was stirred at room temperature for 3 h. After extraction with 60 mL of toluene twice, the water layer was adjusted to pH = 8 with saturated sodium bicarbonate solution, and the solid product was precipitated by cooling to 0-5 °C. After filtration, the filter cake was washed with petroleum ether twice and dried to give 2-amino-3-hydroxy-3-(pyridin-4-yl)alanine dihydrate 19.6 g in 90% yield, HPLC 99.2%.1 H NMR (400 MHz, D20): 8.52 (d, 2H), 7.51 (d, 2H), 5.34 (d, 1H), 3.92 (d, 1H) ppm.

[0040] Example 5

[0041]

[0042] Glycine imine intermediate (25.3 g, 0.1 mol), pyridine-4-carboxaldehyde (11.8 g, 0.11 mol) and KOH (6.2 g, 0.11 mol) were mixed in 200 mL dichloromethane under nitrogen protection, refluxed for 5 hours, TLC detected that the raw material was reacted completely, cooled to room temperature, concentrated dichloromethane, added 60 mL sodium hydroxide (2M) and heated to 40-50°C, reacted for 5 hours, then added hydrochloric acid (2M) to adjust pH = 1-2, stirred at room temperature for 3 hours, extracted twice with 60 mL toluene, added saturated sodium bicarbonate solution to the water layer, adjusted pH = 7-8, cooled to 0-5°C, the solid product precipitated, filtered, the filter cake was washed twice with petroleum ether and dried to obtain 2-amino-3-hydroxy-3-(pyridin-4-yl) proline dihydrate 17 g, yield 78%, HPLC 98.6%.

[0043] Example 6

[0044]

[0045] Glycine imine intermediate (25.3 g, 0.1 mol), pyridine-4-carboxaldehyde (11.8 g, 0.11 mol) and KOH (6.2 g, 0.11 mol) were mixed in 200 mL dichloromethane under nitrogen protection, refluxed for 5 hours, TLC detected that the raw material was reacted completely, cooled to room temperature, concentrated dichloromethane, added 60 mL sodium hydroxide (2M) and heated to 40-50°C, reacted for 5 hours, then added hydrochloric acid (2M) to adjust pH = 1-2, stirred at room temperature for 3 hours, extracted twice with 60 mL toluene, added saturated sodium bicarbonate solution to the water layer, adjusted pH = 7-8, cooled to 0-5°C, the solid product precipitated, filtered, the filter cake was washed twice with petroleum ether and dried to obtain 2-amino-3-hydroxy-3-(pyridin-4-yl) proline dihydrate 17 g, yield 78%, HPLC 98.6%. 1 H NMR (400 MHz, DMSO-d6): 8.51 (d, 2H), 7.39 (d, 2H), 6.25 (d, 1H), 5.11 (s, 1H), 4.29 (d, 1H), 4.02 (d, 1H), 1.18 (s, 9H) ppm.

[0046] Example 7

[0047]

[0048] To a reaction flask was added 2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine racemate (28.2 g, 0.1 mol) and 140 mL of isopropanol under nitrogen protection, after stirring well, a solution of (1S,2S)-N,N'-dibenzylcyclohexane-1,2-diamine (14.7 g, 0.05 mol) and 120 mL of isopropanol was added dropwise, after the dropwise addition was completed, the reaction was stirred at room temperature for 3 hours, then the temperature was increased to 30-40 °C and stirred for 4 hours, the temperature was slowly decreased to 10-20 °C, filtered, the filter cake was washed with cold isopropanol, the solid was re-added to the reaction flask, 200 mL of dichloromethane was added, while stirring, a hydrochloric acid (1 M) solution was added to adjust the pH to 5.5-6.0, the layers were separated, the aqueous layer was extracted with 100 mL of dichloromethane, the combined organic layers were concentrated to obtain 11.3 g of (2R,3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine with a yield of 40%, 98.2% ee, HPLC 99.7%. 1 HNMR (400 MHz, DMSO-d6): 8.48 (d, 2H), 7.36 (d, 2H), 6.43 (d, 1H), 5.15 (s, 1H), 4.34 (d, 1H), 4.26 (d, 1H), 1.22 (s, 9H) ppm.

[0049] The above description is only the preferred specific embodiments of the present application, but the protection scope of the present application is not limited thereto, any person skilled in the art can make equivalent replacements or changes to the technical solutions and the inventive concept of the present application within the technical scope disclosed by the present application, which should be covered within the protection scope of the present application.

Claims

1. A method for preparing (2R,3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine, characterized in that, Includes the following steps: A. Glycine ester hydrochloride and triethylamine were mixed in methanol, followed by the addition of pyridine p-toluenesulfonate and benzophenone dimethyl ketal to give glycine imine intermediate; B. Glycine imine intermediate, pyridine-4-carboxaldehyde and base are mixed in a solvent and reacted under reflux to give 2-amino-3-hydroxy-3-(pyridin-4-yl)alanine; C. Mix 2-amino-3-hydroxy-3-(pyridin-4-yl)alanine, Boc2O and a base in a solvent and react at room temperature to obtain the racemic mixture of 2-Bocamino-3-hydroxy-3-(pyridin-4-yl)alanine. D. The racemic mixture of 2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine and the resolving agent were separated by salt formation in isopropanol, and after dissociation with hydrochloric acid, (2R,3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine was obtained.

2. The method for preparing (2R,3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine according to claim 1, characterized in that: In step A, glycine ester hydrochloride is selected from glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride.

3. The method for preparing (2R,3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine according to claim 1, characterized in that: In step A, the molar ratio of glycine ester hydrochloride, base, pyridine p-toluenesulfonate and benzophenone dimethyl ketal is 1:1-1.1:0.02-0.06:1-1.

1.

4. The method for preparing (2R,3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine according to claim 1, characterized in that: In step B, the alkali is selected from NaOH, KOH, or Cs2CO3.

5. The method for preparing (2R,3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine according to claim 1, characterized in that: In step B, the solvent is selected from dichloromethane, toluene, or acetonitrile.

6. The method for preparing (2R,3S)-2-Bocamino-3-hydroxy-3-(pyridin-4-yl)alanine according to claim 1, characterized in that: In step B, the molar ratio of the glycine imine intermediate, pyridine-4-carboxaldehyde, and base is 1:1-1.2:1-1.

3.

7. The method for preparing (2R,3S)-2-Bocamino-3-hydroxy-3-(pyridin-4-yl)alanine according to claim 1, characterized in that: In step C, the alkali is selected from NaOH, Na2CO3, or 4-DMAP.

8. The method for preparing (2R,3S)-2-Boc amino-3-hydroxy-3-(pyridin-4-yl)alanine according to claim 1, characterized in that: In step C, the solvent is selected from acetonitrile or dichloromethane.

9. The method for preparing (2R,3S)-2-Bocamino-3-hydroxy-3-(pyridin-4-yl)alanine according to claim 1, characterized in that: In step C, the molar ratio of 2-amino-3-hydroxy-3-(pyridin-4-yl)alanine, Boc2O, and base is 1:1-1.2:1-1.

2.

10. The method for preparing (2R,3S)-2-Bocamino-3-hydroxy-3-(pyridin-4-yl)alanine according to claim 1, characterized in that: In step D, the resolving agent is (1S,2S)-N,N'-dibenzylcyclohexane-1,2-diamine; the molar ratio of the racemic mixture to the resolving agent is 1:0.45-0.55.

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