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Preparation method of edoxaban intermediate

A technology for edoxaban and intermediates, which is applied in the field of preparation of edoxaban intermediates, can solve the problem of high production risk of explosive dangerous reagent sodium azide, low diastereomer selectivity, and conversion steps. Cumbersome and other problems, to achieve the effect of reducing production risks, reducing costs, and simplifying operation steps

Active Publication Date: 2020-09-01
CANGZHOU SENARY CHEM SCI TEC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In summary, the existing synthesis process still has low yield of azidation of ester group or para-position of amide, low diastereoselectivity, and high production risk of using explosive and dangerous reagent sodium azide And the deficiencies in aspects such as comparatively loaded down with trivial details of conversion steps, it is necessary to improve the synthetic technique of edoxaban intermediate, improve yield, reduce production cost

Method used

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  • Preparation method of edoxaban intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0043] A preparation method of an edoxaban intermediate, specifically comprising the following reaction steps:

[0044] S1: Add 100.0g (1.00eq.) of compound II thiophene derivative, 31.5g (1.05eq.) of acrylic acid and 500mL (5.0vol.) of diethylene glycol dimethyl ether into a 1L four-necked flask, and raise the temperature to 135°C. Insulate the reaction, and stop the reaction after detecting that the content of the raw compound II is ≤1.0% (6h). Cool down to 5°C, keep warm for 1h, crystallize, filter the system, wash and filter with 50mL (0.5vol.) of pre-cooled diethylene glycol dimethyl ether at 5°C, and dry the filter cake at 50°C to obtain 119.6g Compound III, the yield is 92%, the purity (HPLC) is 99.0%, 1 HNMR (MeOD) 3.98 (d, J = 12.2 Hz, 1H), 3.60 (t, J = 12.4 Hz, 1H), 2.80 (m, 1H), 2.11 (m, 2H).

[0045]The above compound III was subjected to chiral resolution, 500mL (5.0vol.) methanol was added to the reaction flask, the temperature was raised to 25°C, stirring was ...

Embodiment 2

[0053] A preparation method of an edoxaban intermediate, specifically comprising the following reaction steps:

[0054] S1: Add 100.0g (1.00eq.) of compound II thiophene derivative, 32.4g (1.08eq.) of acrylic acid and 500mL (5.0vol.) of diethylene glycol dimethyl ether into a 1L four-necked flask, and raise the temperature to 130°C. Insulate the reaction, and stop the reaction after detecting that the content of the raw compound II is ≤1.0% (8h). Cool down to 0°C, keep warm for 1h, crystallize, filter the system, wash and filter with 50mL (0.5vol.) of diethylene glycol dimethyl ether pre-cooled at 0°C, and dry the filter cake at 45°C to obtain 122.2g Compound III, the yield is 94%, the purity (HPLC) is 99.3%, 1 HNMR (MeOD) 3.98 (d, J = 12.2 Hz, 1H), 3.60 (t, J = 12.4 Hz, 1H), 2.80 (m, 1H), 2.11 (m, 2H).

[0055] The above compound III was subjected to chiral resolution, 500mL (5.0vol.) methanol was added to the reaction flask, the temperature was raised to 20°C, stirring was...

Embodiment 3

[0063] A preparation method of an edoxaban intermediate, specifically comprising the following reaction steps:

[0064] S1: Add 100.0g (1.00eq.) of compound II thiophene derivative, 33.0g (1.10eq.) of acrylic acid and 500mL (5.0vol.) of diethylene glycol dimethyl ether into a 1L four-necked flask, and raise the temperature to 140°C. Insulate the reaction, and stop the reaction after detecting that the content of the raw compound II is ≤1.0% (4h). Cool down to 10°C, keep warm for 1h, crystallize, filter the system, wash and filter with 50mL (0.5vol.) of diethylene glycol dimethyl ether pre-cooled at 10°C, and dry the filter cake at 55°C to obtain 120.9g Compound III, the yield is 93%, the purity (HPLC) is 99.1%, 1 HNMR (MeOD) 3.98 (d, J = 12.2 Hz, 1H), 3.60 (t, J = 12.4 Hz, 1H), 2.80 (m, 1H), 2.11 (m, 2H).

[0065] The above compound III was subjected to chiral resolution, 500mL (5.0vol.) methanol was added to the reaction flask, the temperature was raised to 30°C, stirring w...

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Abstract

The invention relates to the technical field of medicines, and particularly discloses a preparation method of an edoxaban intermediate. The preparation method comprises the following steps: carrying out diene synthesis on a thiophene derivative of a compound II and acrylic acid, and carrying out chiral resolution to obtain a compound IV; carrying out amidation reaction with dimethylamine hydrochloride to obtain a compound V; reacting with di-tert-butyl dicarbonate in a hydrogen atmosphere to obtain a compound VI and a compound VI'; and carrying out amino deprotection and chiral resolution to obtain a compound I, namely the edoxaban intermediate. The preparation method provided by the invention has the advantages of concise operation steps, high diastereomer selectivity, facilitation of improvement of the product yield and reduction of the production cost, no use of a dangerous reagent sodium azide, no involvement of a low-temperature reaction, reduction of the production risk, and guarantee of the safety and the operability of the reaction.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of an edoxaban intermediate. Background technique [0002] Edoxaban, the first orally administered anticoagulant drug, is a factor X (FXa) blocker. The chemical name of Edoxaban is N-(5-chloropyridin-2-yl)-N′-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)]-2 -[(5-Methyl-4,5,6,7-tetrahydro-1,3-thiazolo[5,4-c]-pyridine-2-carboxamido)cyclohexyl]oxamide, commercially available drug The active ingredient is edoxaban tosylate monohydrate. [0003] At present, edoxaban is mostly passed through several steps through the intermediate [(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate tert-butyl ester shown in compound I. Made synthetically. The existing synthetic techniques of [(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate tert-butyl mainly include: cyclohexylamino alcohol is mesylated , Sodium azide substitution, hydrolysis, amidati...

Claims

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Application Information

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IPC IPC(8): C07C269/00C07C269/06C07C271/24C07D495/08
CPCC07C269/00C07C269/06C07D495/08C07C2601/14C07B2200/07C07C271/24
Inventor 李培申张少平王林玉漆定超
Owner CANGZHOU SENARY CHEM SCI TEC
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