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Preparation method of ((1R, 3aR, 4aR, 6R, 8 aR, 9S, 9 aR)-9- formyl group-1-methyl-3-oxa-dodechydrogen naphthalene [2, 3-c]-6-furan group) carboxylic ethyl ester

A technology of ethyl carboxylate and 3-c, which is applied in the field of medicinal chemistry, can solve the problems of unfavorable operator labor protection and environmental protection, low reaction controllability, unsuitable for industrial production, etc., achieves great application value and simple process operation , low cost effect

Inactive Publication Date: 2017-09-05
SHANGHAI SUNTECH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, this method requires high equipment, low reaction controllability, low yield of compound 3 (yield 66%), high cost, and is not conducive to operator's labor protection and environmental protection. It is not suitable for industrial production and needs further improvement.

Method used

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  • Preparation method of ((1R, 3aR, 4aR, 6R, 8 aR, 9S, 9 aR)-9- formyl group-1-methyl-3-oxa-dodechydrogen naphthalene [2, 3-c]-6-furan group) carboxylic ethyl ester
  • Preparation method of ((1R, 3aR, 4aR, 6R, 8 aR, 9S, 9 aR)-9- formyl group-1-methyl-3-oxa-dodechydrogen naphthalene [2, 3-c]-6-furan group) carboxylic ethyl ester
  • Preparation method of ((1R, 3aR, 4aR, 6R, 8 aR, 9S, 9 aR)-9- formyl group-1-methyl-3-oxa-dodechydrogen naphthalene [2, 3-c]-6-furan group) carboxylic ethyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Preparation of Compound 2:

[0026] (Experimental conditions: reduce the amount of lithium tri-tert-butoxy aluminum hydride to 2.6eq)

[0027] (1) 100mg ((1R,3aR,4aR,6R,8aR,9S,9aR)-9-(chlorocarbonyl)-1-methyl-3-oxa dodecahydronaphthalene[2,3-c]- Ethyl 6-furyl)carboxylate (compound 1) was uniformly dispersed in 1ml tetrahydrofuran to prepare a mixed solution;

[0028] (2) Transfer the mixed solution into the reactor, control the temperature at -5°C-0°C, and add lithium tri-tert-butoxyaluminum hydride (185.0mg, 2.6eq);

[0029] (3) Control the temperature at 0°C-10°C for 0.5 hours;

[0030] (4) Add the reaction solution into dilute hydrochloric acid (2.4mol / L, 1.25g), adjust the pH to 4-5, and extract twice with ethyl acetate (5ml each time);

[0031] (5) The organic phase was washed once with 7% sodium bicarbonate (2ml), and 20% sodium chloride solution (2ml);

[0032] (6) The organic phase is dried with anhydrous sodium sulfate (1g);

[0033] (7) The orga...

Embodiment 2

[0034] Example 2 Preparation of compound 2:

[0035] (Experimental conditions: control the amount of lithium tri-tert-butoxy aluminum hydride to the optimal amount of 2.7eq)

[0036] (1) 100mg ((1R,3aR,4aR,6R,8aR,9S,9aR)-9-(chlorocarbonyl)-1-methyl-3-oxa dodecahydronaphthalene[2,3-c]- 6-furyl) ethyl carboxylate is uniformly dispersed in 1ml tetrahydrofuran, and is prepared into a mixed solution;

[0037] (2) Transfer the mixed solution into a parallel reactor, control the temperature at -5-0°C, and add lithium tri-tert-butoxyaluminum hydride (191.9mg, 2.7eq);

[0038] (3) Control the temperature at 0°C-10°C for 0.5 hours;

[0039] (4) Add the reaction solution into dilute hydrochloric acid (2.4mol / L, 1.25g), adjust the pH to 4-5, and extract twice with ethyl acetate (5ml each time);

[0040] (5) The organic phase was washed once with 7% sodium bicarbonate (2ml), and 20% sodium chloride solution (2ml);

[0041] (6) The organic phase is dried with anhydrous sodium sulfate (1...

Embodiment 3

[0043] Example 3 Preparation of compound 2:

[0044] (Experimental conditions: increase the amount of lithium tri-tert-butoxy aluminum hydride to 2.8eq)

[0045] (1) 100mg ((1R,3aR,4aR,6R,8aR,9S,9aR)-9-(chlorocarbonyl)-1-methyl-3-oxa dodecahydronaphthalene[2,3-c]- 6-furyl) ethyl carboxylate is uniformly dispersed in 1ml tetrahydrofuran, and is prepared into a mixed solution;

[0046] (2) Transfer the mixed solution into a parallel reactor, control the temperature at -5-0°C, and add lithium tri-tert-butoxyaluminum hydride (199.0mg, 2.8eq);

[0047] (3) Control the temperature at 0°C-10°C for 0.5 hours;

[0048] (4) Add the reaction solution into dilute hydrochloric acid (2.4mol / L, 1.25g), adjust the pH to 4-5, and extract twice with ethyl acetate (5ml each time);

[0049] (5) The organic phase was washed once with 7% sodium bicarbonate (2ml), and 20% sodium chloride solution (2ml);

[0050] (6) The organic phase is dried with anhydrous sodium sulfate (1g);

[0051] (7) The o...

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Abstract

The invention provides a preparation method of ((1R, 3aR, 4aR, 6R, 8 aR, 9S, 9 aR)-9- formyl group-1-methyl-3-oxa-dodechydrogen naphthalene [2, 3-c]-6-furan group) carboxylic ethyl ester. The method applies lithium tri-tert-butoxyaluminum hydride reduction to prepare ((1R, 3aR, 4aR, 6R, 8 aR, 9S, 9 aR)-9- formyl group-1-methyl-3-oxa-dodechydrogen naphthalene [2, 3-c]-6-furan group) carboxylic ethyl ester (compound 2), and performs sodium hypochlorite oxidization to prepare a target product (compound 3). The method is simple in operation; the heavy metal element palladium in the prior art is removed, so the method has low cost and low equipment requirement; the reaction yield is improved by 20%, and the product quality is stable. The method is suitable for industrial production and has great application value.

Description

technical field [0001] The present invention relates to medicinal chemistry, in particular to the preparation of compounds, especially ((1R, 3aR, 4aR, 6R, 8aR, 9S, 9aR)-9-formyl-1-methyl-3-oxa dodecahydronaphthalene[2 , 3-c] -6-furyl) carboxylic acid ethyl ester preparation method. Background technique [0002] ((1R,3aR,4aR,6R,8aR,9S,9aR)-9-formyl-1-methyl-3-oxadodecahydronaphthalene[2,3-c]-6-furyl)carboxylic acid Ethyl ester (compound 3) is the intermediate of synthetic anticoagulant vorapaxer sulfate, and its structural formula is as follows: [0003] [0004] The method for preparing compound 3 in the prior art: ((1R, 3aR, 4aR, 6R, 8aR, 9S, 9aR)-9-(chlorocarbonyl)-1-methyl-3-oxa dodecahydronaphthalene[2, 3-c]-6-furyl) ethyl carboxylate (compound 1) was dissolved in tetrahydrofuran and 2,6-lutidine, catalyst palladium carbon was added for catalytic hydrogenation, after the reaction, methyl tert-butyl ether was added and phosphoric acid to remove 2,6-lutidine, crystal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/92
CPCC07D307/92
Inventor 刘学军郝璐陈晓冬
Owner SHANGHAI SUNTECH PHARMA