A kind of preparation method of edoxaban intermediate

Abstract

The invention relates to the technical field of medicine, and specifically discloses a preparation method of an edoxaban intermediate. The preparation method comprises the following steps: compound II thiophene derivatives and acrylic acid are synthesized into diene, and undergo chiral resolution to obtain compound IV; carry out amidation reaction with dimethylamine hydrochloride to obtain compound V; Di-tert-butyl carbonate was reacted under a hydrogen atmosphere to obtain compound VI and compound VI'; after deprotection of the amino group and chiral resolution, compound I, the intermediate of edoxaban, was obtained. The preparation method provided by the invention has simple operation steps and high diastereomer selectivity, which is beneficial to increase product yield and reduce production cost, and does not use dangerous reagent sodium azide, and does not involve low-temperature reaction, which reduces production Risk, to ensure the safety and 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...

Examples

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...

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...

Examples

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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