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Synthesis method of chiral N-Boc-3-amino-4-aryl-butyric acid

A synthesis method, n-boc-3-technology, applied in the field of synthesis of chiral N-Boc-3-amino-4-aryl-butyric acid, can solve the problems of difficult industrialization, loss of activity, easy poisoning, etc. Achieve the effect of mild reaction conditions and simple operation

Active Publication Date: 2017-03-08
QUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In summary, in recent decades, although there have been many reports on the synthesis of chiral N-Boc-3-amino-4-aryl-butyric acid, there are unfavorable factors that are difficult to industrialize
In particular, most of the current industrialization is to prepare chiral N-Boc-3-amino-4-aryl- Butyric acid, but this type of catalyst is expensive, and because this type of catalyst is easily poisoned and loses activity after many cycles, the production cost is high

Method used

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  • Synthesis method of chiral N-Boc-3-amino-4-aryl-butyric acid
  • Synthesis method of chiral N-Boc-3-amino-4-aryl-butyric acid

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Embodiment 1

[0032] Example 1: allylbenzene (1.18g, 10mmol), crotonaldehyde (1.4g, 2mmol) and Grubbs second-generation catalyst (9mg, 0.01mol, 0.1mol%) were dissolved in methylene chloride (20mL), and the reaction solution was refluxed After 12 hours, it was cooled to 0°C; the nitrogen atom was Boc-protected hydroxylamine (1.59 g, 12 mmol), and the S-configuration oxygen was trimethylsilane-protected α, α-diphenylprolinol (330 mg, 1 mmol) , 10mol%) and p-nitrobenzoic acid (160mg, 1mmol, 10mol%), the reaction mixture was stirred at 0°C for 15 hours. Remove the solvent dichloromethane;

[0033] Acetonitrile (10mL), NaH 2 PO 4 Aqueous solution (240mg NaH 2 PO 4 , 5ml water) and H 2 o 2 (35W% aqueous solution, 1.4ml, 14mmol) was added to the above residue;

[0034] At 10°C, NaClO 2 Aqueous solution (1.27g NaClO 2 , 14mmol, 14ml water) was added dropwise to the above reaction solution. After 3 hours, dichloromethane (20ml) was added to dilute the reaction solution, the organic phase w...

Embodiment 2

[0036] Embodiment 2: the method similar to embodiment 1. The raw material is allylbenzene (1.18g, 10mmol), and the catalyst is α,α-diphenylprolinol (330mg, 1mmol, 10mol%) protected by trimethylsilane as the oxygen in R configuration. (S)-N-Boc-3-amino-4-phenyl-butyric acid (1.93 g, 92%ee) was obtained in a total yield of 69%.

Embodiment 3

[0037]Embodiment 3: the method similar to embodiment 1. The starting material is 3-fluoroallylbenzene (1.36g, 10mmol), and the reaction is completed to obtain (R)-N-Boc-3-amino-4-(3-fluorophenyl)-butyric acid (1.78g, 87%ee ), total yield 60%.

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Abstract

The invention relates to a synthesis method of chiral N-Boc-3-amino-4-aryl-butyric acid. The method is as below: 1, conducting a cross metathesis reaction, an asymmetric conjugate addition reaction and an oxidation reaction on starting materials including an allyl aromatic compound and crotonaldehyde by a continuous reaction one-pot method to synthesize an N-Boc-3-aryl methyl-5-oxo isoxazole intermediate; or conducting an asymmetric conjugate addition reaction and an oxidation reaction on a starting material (E)-4-aryl-2-crotonaldehyde by a continuous reaction one-pot method to synthesize an N-Boc-3-aryl methyl-5-oxo isoxazole intermediate; and 2, subjecting (3R)-N-Boc-3-aryl methyl-5-oxo isoxazole intermediate by high-pressure hydrogenation to directly prepare the chiral N-Boc-3-amino-4-aryl-butyric acid. The synthesis method provided by the invention has the advantages of simple operation, mild reaction conditions, target product yield reaching 60-69%, and ee value of the target product reaching as high as 96%. The synthetic route has industrialization prospect.

Description

technical field [0001] The invention relates to a synthesis method of chiral N-Boc-3-amino-4-aryl-butyric acid. Background technique [0002] Chiral 3-amino-4-arylbutyric acid is an important intermediate in drug synthesis. For example, (R)-N-Boc-3-amino-4-(2,4,5-trifluorophenyl)butyric acid is a key intermediate of sitagliptin, a drug for treating diabetes. In view of the important use of this amino acid, its synthesis method has been reported in a large number of literatures. In general, there are four types of synthetic methods: (1) preparation of chiral N-Boc-3- Amino-4-aryl-butyric acid (Org.Process Rese.Dev.2005,9,634-639; J.Am.Chem.Soc.2009,131,8798-8804; J.Am.Chem.Soc.2009,131 , 11316-11317; WO patent 2004085661,2004); (2) convert chiral N-Boc-3-amino-4-aryl-butyric acid (Angew.Chem.Int. Ed., 1995,34,471-472; Helv.Chim.Acta 1998,81,187-206; Tetrahedron Lett.1999,40,2629-2632; Tetrahedron 2001,57,7665-7674); (3) Enzymatic catalysis of cyclic amides Hydrolysis (Ad...

Claims

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Application Information

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IPC IPC(8): C07C269/00C07C271/22C07D261/04C07D261/02C07D273/08
CPCC07C269/00C07D261/02C07D261/04C07D273/08C07C271/22
Inventor 葛承胜高浩凌江群翁将森
Owner QUZHOU UNIV