Process for the preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one

A technology of oxabicyclo and octane, applied in the field of preparation formula -4-bromo-6-oxabicyclo[3.2.1]octane-7-one, which can solve the problems of low yield and so on

Inactive Publication Date: 2015-07-15
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method produced a low yield of about 55%

Method used

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  • Process for the preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one
  • Process for the preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one
  • Process for the preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (I)

[0092] Controlled addition of (1S)-cyclohex-3-ene-1-carboxylic acid to mixtures of N-bromosuccinimide and calcium oxide

[0093] Solution A: Suspension in dichloromethane (150 mL), water (90 mL), (1S)-cyclohex-3-ene-1-carboxylic acid-(R)-phenylethylamine salt (30 g) Concentrated hydrochloric acid (35%, 13.9 mL) was added to the solution. The reaction mass was stirred for 15 minutes and the layers were separated. The aqueous layer was extracted with dichloromethane (90 mL). The combined organic layers were washed with water (90 mL) and recovered under vacuum at 35 °C to give an oil. Dichloromethane (75 mL) was added to the above oil to obtain solution A.

[0094] Solution B: N-bromosuccinimide (22.22 g) and calcium oxide (0.6 g) were dissolved in dichloromethane (30 mL) to obtain Solution B.

[0095] Solution A of (1S)-cyclohex-3-ene-1-carboxylic acid (II) in dichloromethane (75 mL) was added dro...

Embodiment 2

[0099] Preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (I)

[0100] Batch Addition of N-Bromosuccinimide and Calcium Oxide to (1S)-Cyclohex-3-ene-1-carboxylic Acid

[0101] (1S)-Cyclohex-3-ene-1-carboxylic acid (II) (5 g) was dissolved in dichloromethane (25 mL). To this solution was added N-bromosuccinimide (1.1 mol) at room temperature. Calcium oxide (0.25 mol) was added to the suspension in 2 portions. The reaction mixture was stirred at 20-25°C for 1 hour and filtered. The bed was washed with dichloromethane (10 mL). The washings were combined with the filtrate and the solvent was recovered under vacuum at 35-40°C. Deionized water (50 mL) was added to the solid, heated to 50 °C, stirred for 10 minutes and filtered. The bed was washed with deionized water (10 mL) and suction dried. The solid was dried under vacuum at 45-50°C to afford the title compound (I).

[0102] Yield: 61%

[0103] Chromatographic purity: 96.98%.

Embodiment 3

[0105] Preparation of (1s,4s,5s)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (I)

[0106] (1S)-Cyclohex-3-ene-1-carboxylic acid (II) (20.4 g) was dissolved in dichloromethane (100 mL). This solution was added to a solution of N-bromosuccinimide (30.22 g) and calcium oxide (0.906 g) dissolved in dichloromethane (40 mL) at room temperature over 30 minutes. The reaction mass was stirred for 30 minutes and filtered. The filtrate was concentrated to give a solid. Deionized water (100 mL) was added to the solid and heated to 50 °C and stirred for 15 minutes. The solids were filtered and recharged to the reaction flask. Deionized water (100 mL) was added to the solid, heated to 50 °C and stirred for 15 minutes. The solid was filtered and dried under vacuum to afford the title compound (I).

[0107] Yield: 77.7%

[0108] Chromatographic purity: 96.11%

[0109] Moisture content: 0.02%w / w.

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Abstract

The present invention relates to an improved and industrially advantageous process for the preparation of (1S, 4S, 5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one represented by the following formula (I) which is a key intermediate in the synthesis of edoxaban, a compound that exhibits an inhibitory effect on activated blood coagulation factor X (also referred to as activated factor X or FXa), and is useful as a preventive and / or therapeutic drug for thrombotic diseases. The process includes reacting (1S)-cyclohex-3-ene-1-carboxylic acid of formula (II) with a brominating agent selected from the group consisting of N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin in the presence of a base selected from calcium oxide or calcium hydroxide in a solvent selected from the group comprising of dichloromethane, toluene, tetrahydrofuran, ethy1 acetate, hexanes, cyclopentyl methyl ether (CPME) or a mixture thereof to get (1S, 4S, 5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one of formula (I).

Description

technical field [0001] The present invention relates to an improved and industrially advantageous process for the preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-ones of formula (I) Methods: [0002] [0003] It is a key intermediate in the synthesis of edoxaban, which exhibits inhibition of activated coagulation factor X (also known as activated factor X or FXa) compound, and can be used as a preventive and / or therapeutic drug for thrombotic diseases. Background technique [0004] Chemically, edoxaban is N represented by the following formula (A): 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c ]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide: [0005] [0006] The p-toluenesulfonic acid monohydrate salt of compound A is represented by the following formula (B): [0007] [0008] Edoxaban is known as a compound exhibiting an inhibitory effect on activated blood coagulation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/94C07D513/04
CPCC07D307/94C07D513/04C07D307/00A61P7/02C07C269/00
Inventor 中村嘉孝K.M.穆科斯M.I.伊纳姆达
Owner DAIICHI SANKYO CO LTD
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