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Synthesis method of ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate

A technology of ethyl carboxylate and dioxypyrrole, which is applied in the field of synthesis of R-3-amino-2,5 dioxypyrrole-3-ethyl carboxylate, can solve problems such as difficulty in preparation, and achieve improved chiral induction The effect of realizing asymmetric Michael addition reaction

Inactive Publication Date: 2018-12-21
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The asymmetric catalyst used in this route is formed by the coordination of ligand L and lanthanum nitrate, H-D-Val-OBu-t, which is difficult to prepare and expensive for the catalyst.

Method used

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  • Synthesis method of ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate
  • Synthesis method of ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate
  • Synthesis method of ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate

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Experimental program
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Embodiment 1

[0044] The synthetic method of R-3-amino-2,5-dioxypyrrole-3-carboxylic acid ethyl ester, realizes through the following steps:

[0045] 1) Preparation of R-3-di-tert-butoxyhydrazide-1-benzyl-2,5-dioxypyrrolidine-3-carboxylic acid ethyl ester

[0046] Add 2.61g (0.01mol) of ethyl 1-benzyl-2,5-dioxypyrrolidine-3-carboxylate, square amide (ⅢA) (0.45g, 0.001mol), azodicarboxylate 2.48 g (0.0108 mol) of di-tert-butyl acid and 15 mL of dry dichloromethane were reacted at -20°C. The reaction was followed by TLC for 10 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the residue was directly used in the next reaction.

[0047] Optical purity analysis of the residue: HPLC Chiracel AD-H, λ=254nm

[0048] Mobile phase n-hexane:isopropanol=9:1

[0049] Column temperature: 30°C

[0050] Retention time: 8.5(S) and 11.6min(R)

[0051]ee% of product = 80.8%

[0052] 2) Preparation of R-3-hydrazino-1-benzyl-2,5-dioxypyrrolidine-3...

Embodiment 2

[0061] The synthetic method of R-3-amino-2,5-dioxypyrrole-3-carboxylic acid ethyl ester, realizes through the following steps:

[0062] 1) Preparation of R-3-di-tert-butoxyhydrazide-1-benzyl-2,5-dioxypyrrolidine-3-carboxylic acid ethyl ester

[0063] Add 2.61g (0.01mol) of ethyl 1-benzyl-2,5-dioxypyrrolidine-3-carboxylate, square amide (ⅢB) (0.48g, 0.001mol), azodicarboxylate 2.48 g (0.0108 mol) of di-tert-butyl acid and 15 mL of dry dichloromethane were reacted at -20°C. The reaction was followed by TLC for 10 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the residue was directly used in the next reaction. The optical purity of the residue was analyzed ee% = 87.8%.

[0064] 2) Preparation of R-3-hydrazino-1-benzyl-2,5-dioxypyrrolidine-3-carboxylic acid ethyl ester hydrochloride

[0065] Add ethyl acetate (10mL) to the residue to dissolve, slowly add trifluoroacetic acid (4.56g) in ethyl acetate solution (8mL) dr...

Embodiment 3

[0069] The synthetic method of R-3-amino-2,5-dioxypyrrole-3-carboxylic acid ethyl ester, realizes through the following steps:

[0070] 1) Preparation of R-3-di-tert-butoxyhydrazide-1-benzyl-2,5-dioxypyrrolidine-3-carboxylic acid ethyl ester

[0071] Add 2.61 g (0.01 mol) of ethyl 1-benzyl-2,5-dioxypyrrolidine-3-carboxylate, square amide (ⅢC) (0.49 g, 0.001 mol), azodicarboxy 2.48 g (0.0108 mol) of di-tert-butyl acid and 15 mL of dry dichloromethane were reacted at -20°C. The reaction was followed by TLC for 10 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the residue was directly used in the next reaction. Optical purity analysis of the residue: ee% = 97.5%

[0072] 2) Preparation of R-3-hydrazino-1-benzyl-2,5-dioxypyrrolidine-3-carboxylic acid ethyl ester hydrochloride

[0073] Add dichloromethane (10mL) to the residue to dissolve, slowly add 5M HCL in dichloromethane solution (8mL) dropwise, and react at room ...

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Abstract

The invention relates to a synthesis method of ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate. According to an asymmetric synthesis method of ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate, 1-benzyl-2,5-dioxapyrrolidine-3-carboxylate (I) is used as a raw material, and in the presence of a chiral amide (III) catalyst, the 1-benzyl-2,5-dioxapyrrolidine-3-carboxylate (I) and di-tert-butyl azodicarboxylate (II) are subjected to addition with Michael, so that R-3-di-tert-butoxy-hydrazide-1-benzyl-2,5-dioxopyrrolidine-3-carboxylic acid ethyl ester (IV) is obtained; the IV is directly subjected to BOC removal in the presence of an acid catalyst without separation, so that R-3-mercapto-1-benzyl-2,5-dioxopyrrolidine-3-carboxylic acid ethyl ester hydrochloride (V ) is obtained; and V is subjected toa hydrogenation reaction in the presence of a hydrogenation catalyst, so that the ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate (VI) is obtained. The structure of a chiral amide catalyst (III) is shown as below. The synthesis method is simple, the yield of the asymmetric catalysis product is high, the enantioselectivity of products is 95% or above, the synthesis method is mild in condition, simple to operate and low in production cost, and the synthesis method can be used for industrialized production.

Description

technical field [0001] The invention relates to a synthesis method of ethyl R-3-amino-2,5-dioxypyrrole-3-carboxylate, which belongs to the technical field of organic chemistry and also belongs to the technical field of medicinal chemistry. Background technique [0002] Ethyl R-3-amino-2,5-dioxypyrrole-3-carboxylate is an important intermediate in the synthesis of Ranirestat. Raniresta is currently in clinical research, Ranirestat is a new type of aldose reductase inhibitor for the treatment of diabetic complications. Therefore, the research of this medicine is of great significance. [0003] The preparation method of R-3-amino-2,,5-dioxypyrrole-3-carboxylic acid ethyl ester, the literature report (US20120010405) first prepares the mixed-amino-2,5-dioxypyrrole-3-carboxylic acid ethyl ester , and then use S-camphorsulfonic acid to resolve to obtain R-3-amino-2,5 dioxypyrrole-3-carboxylic acid ethyl ester, the yield is 10-20%, and a large amount of waste is generated; literat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/416
CPCC07B2200/07C07D207/416Y02P20/55
Inventor 申永存邢培阳占雯李天成邹颖陈瑶
Owner WUHAN UNIV OF TECH
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