Novel efficient method for synthesizing chiral beta-amino acid

An amino acid and chirality technology, applied in organic chemistry methods, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of difficult removal of heavy metal residues, high cost, limited production capacity, etc., to overcome microbial residues and reaction conditions. Gentle, easy-to-use results

Active Publication Date: 2018-12-11
深圳市茵诺圣生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of these three methods are obvious: they are not suitable for large-scale industrial production, there are microbial residues, especially as starting raw materials, it is not easy to pass the GMP audit; there may be heavy metal residues that are difficult to remove, expensive, and limited production capacity; high disassembly costs, low optical purity

Method used

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  • Novel efficient method for synthesizing chiral beta-amino acid
  • Novel efficient method for synthesizing chiral beta-amino acid
  • Novel efficient method for synthesizing chiral beta-amino acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Synthesis of S-type β-amino acid (I-1) (where R is meta-nitro).

[0031]

[0032] The implementation route is as follows:

[0033]

[0034] Preparation of intermediate (III-1):

[0035]

[0036] 3-Nitrobenzaldehyde (500g, 3.31mol, 1eq), R-tert-butyl sulfinamide (401g, 3.31mol, 1eq), tetraethyl titanate (1.5kg, 6.62mol, 2eq), and then added THF (2.5L), heated to 70°C under reflux overnight while stirring. After TLC showed that the reaction was complete, the reaction solution was poured into 1L saturated brine, extracted twice with ethyl acetate (1L*2), the combined organic phases were dried and concentrated to obtain a yellow thick liquid (610g, crude product), which was directly carried out without further purification. One step reaction.

[0037] Intermediate (IV-1) preparation:

[0038]

[0039] Zinc powder (270g, 4.13mol, 3.5eq) was added into anhydrous THF (1L), under N 2 Heated to 40°C and stirred for 1h in a protected and light-proof environment. ...

Embodiment 2

[0048] Synthesis of R-type β-amino acid (I-2) (where R is p-benzyl ether).

[0049]

[0050] The implementation route is as follows:

[0051]

[0052] Intermediate (III-2) preparation:

[0053]

[0054] 4-Benzyloxybenzaldehyde (200g, 0.94mol, 1eq), S-tert-butyl sulfinamide (113g, 0.94mol, 1eq), tetraethyl titanate (541g, 1.88mol, 2eq) were added to THF (1L), heated to 70°C and refluxed overnight. After TLC showed that the reaction was complete, the reaction solution was added to 1L saturated brine, extracted twice with ethyl acetate (500mL*2), the organic phases were combined, dried and concentrated to obtain a yellow thick liquid (250g, crude product), and proceeded to the next step without purification reaction.

[0055] Preparation of intermediate (IV-2):

[0056]

[0057]Zinc powder (214g, 3.29mol, 3.5eq) was added to anhydrous THF (1L), heated to 40°C and stirred for 1h. After cooling to room temperature, ethyl bromoacetate (314g, 1.88mol, 2eq) was added d...

Embodiment 3

[0066] Synthesis of S-type β-amino acid ester (I-3) (where R is meta-trifluoromethyl).

[0067]

[0068] The implementation route is as follows:

[0069]

[0070] Preparation of intermediate (III-3):

[0071]

[0072] 3-trifluoromethylbenzaldehyde (500g, 2.87mol, 1eq), R-tert-butyl sulfinamide (347g, 2.87mol, 1eq), tetraethyl titanate (1.3kg, 5.74mol, 2eq), Then THF (2.5 L) was added, and heated to 70° C. under reflux overnight while stirring. After TLC showed that the reaction was complete, the reaction solution was poured into 1L saturated brine, extracted twice with ethyl acetate (1L*2), the combined organic phases were dried and concentrated to obtain a yellow thick liquid (713g, crude product), which was directly carried out without further purification. One step reaction.

[0073] Preparation of intermediate (IV-3):

[0074]

[0075] Zinc powder (588g, 9.0mol, 3.5eq) was added to anhydrous THF (2L), heated to 40°C and stirred for 1h. After cooling to room...

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Abstract

The invention relates to a synthesis method of a compound as shown by the formula (I), namely chiral beta-amino acid: an aromatic aldehyde compound. An aromatic aldehyde compound and a chiral amine auxiliary form Schiff base, and then the Schiff base is reduced to prepare an intermediate compound as shown by the formula (IV); an ester group and an acyl group are removed, and crystallization is performed to finally obtain an optically active product. The method is simple in process, high in yield and high in purity; the product is high in optical purity; no harsh reaction conditions exist; different corresponding isomers are obtained by selecting different chiral auxiliaries; the synthesis method has small pollution and is very suitable for industrial production. The formula (I) and the formula (IV) are respectively as follows: as shown in the specification.

Description

technical field [0001] The invention relates to the technical field of chiral compound synthesis, in particular to a novel method for efficiently synthesizing chiral β-amino acids. Background technique [0002] Due to the special biological activity of chiral β-amino acids, its structure has been reflected in many drugs or lead drug molecules, such as DPP-4 inhibitor type diabetes drugs. [0003] Table 1 [0004] [0005] Referring to Table 1, there are mainly two methods for the synthesis of chiral β-amino acids that are commonly used at present: one is to use the method of biological fermentation to prepare, for example, Kadota, Yosuke et al. discussed the method of biological fermentation to achieve chiral The synthesis of β-amino acids; the second is to use precious metal catalysts such as Rh to perform asymmetric hydrogenation to synthesize chiral β-amino acids, such as "DpenPhos / Rh(I) Catalytic The Asymmetric Hydrogenation of β-Amino Acid Esters" discusses in deta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/34
CPCC07B2200/07C07C227/18C07C313/06C07C229/34
Inventor 林文泉邱学辉巫江钦
Owner 深圳市茵诺圣生物科技有限公司
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