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1,8-dicarbonyl-4,5-epoxy compound and preparation method thereof

An epoxy compound and dicarbonyl technology, applied in the field of aliskiren intermediate 1,8-dicarbonyl-4,5-epoxy compound and its preparation, can solve the problem of poor selectivity, poor chiral selectivity and poor yield. higher question

Active Publication Date: 2013-04-24
SHANGHAI HISOAR PHARMA TECH & DEV CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The halide lactonization reaction reported in the above-mentioned patent literature generally has a low yield (50~65%), and the chiral selectivity is poor (the ee value has not been reported, but the inventor repeated the literature operation to obtain an ee value<60%) In addition, the selectivity of the subsequent azide substitution reaction is also relatively poor, and a high proportion of the elimination product is produced (greater than 20%) in the reaction process, so that the yield of this step reaction is not high, and the purification of the product is also more difficult

Method used

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  • 1,8-dicarbonyl-4,5-epoxy compound and preparation method thereof
  • 1,8-dicarbonyl-4,5-epoxy compound and preparation method thereof
  • 1,8-dicarbonyl-4,5-epoxy compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073]

[0074] N 2 Under protection, in a 500mL three-necked flask, dissolve compound 4 (26.83g, 102.7mmol) in 80mL of anhydrous THF, and add 1.0M LiHMDS (110mL, 110mmol) dropwise at low temperature (-50°C). After the addition is complete, - Stir at 50°C for 1 hour, then add 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU) (28.95g, 225.8mmol) dropwise. Stir at 50°C for 0.5h, then add cis-1,4-dibromo-2-butene 5 (8.78g, 41.0mmol) in 18mL of anhydrous THF solution, stir at -50°C for 1h, then naturally warm to 0°C, Keep it at 0°C for 1h, then raise it to 5-10°C for 1.5h, and track it with TLC until the end of the reaction. Saturated with 50 mL of NH 4 Quench the reaction with Cl solution, remove THF by rotary evaporation, extract the aqueous phase with (30mL×3) ethyl acetate, combine the EA phases, wash the EA phase with 1M (50mL×4) dilute HCl for about 3 times, wash the EA phase with anhydrous MgSO 4 Dry, spin dry, drain the solvent, and recrystallize the obtained cru...

Embodiment 2

[0077]

[0078] Add compound 2.3 (287.15g, 0.5mol), tetrahydrofuran (300mL), water (100mL), lithium hydroxide monohydrate (33.56g, 0.8mol) in sequence in a 1L three-necked flask, and add 30% hydrogen peroxide dropwise at 0-5°C (247.2mL, 2.4mol), after reacting at room temperature for 3 hours, at 0°C, dropwise add a saturated aqueous solution of sodium bisulfite (250.00g, 2.4mol) to quench the reaction, adjust the pH of the system to 10 with 6M aqueous sodium hydroxide solution, and spin The tetrahydrofuran was evaporated, the aqueous phase was washed with ethyl acetate (3×100 mL), the pH of the system was adjusted to 2 with 6M hydrochloric acid at 0° C., the aqueous phase was extracted with ethyl acetate (3×100 mL), the organic phases were combined, and dried over anhydrous magnesium sulfate. After filtration, the organic phase was removed by rotary evaporation to obtain 117.76 g of light yellow viscous liquid, which was the target compound 6, with a yield of 92%.

[0079] ...

Embodiment 3

[0081]

[0082] In a 250mL one-mouth bottle, add 60mL of methanol and compound 6 (11.70g, 45.66mmol) in sequence, add thionyl chloride (16.31g, 136.98mmol) dropwise at 0°C, and reflux for 4 hours after dropping, and cool to room temperature. Remove the organic phase by rotary evaporation, add ethyl acetate (100 mL), wash the organic phase with saturated aqueous sodium bicarbonate (20 mL), saturated brine (20 mL), and water (20 mL) successively, dry the organic phase with anhydrous magnesium sulfate, filter, Rotary evaporation gave 11.52 grams of light brown liquid, which was the target compound 2.1,

[0083] Yield 89%.

[0084] 1 H NMR (500MHz, CDCl 3 )δ5.42(d,J=3.7Hz,2H),3.71(s,6H),2.23(m,4H),1.88(dd,J=13.6,6.8Hz,2H),0.96(dd,J=18.4 ,6.7Hz,12H). MS-ESI: m / z(%)=285.2(100)[M+H] + . [α]D=-9.1°(c=1.0,CH 2 Cl 2 ).

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Abstract

The invention relates to 1,8-dicarbonyl-4,5-epoxy compound and a preparation method thereof. The structure formula of the 1,8-dicarbonyl-4,5-epoxy compound is shown in the formula I, and the compound I is further opened and closed by azide substitution. A critical midbody azide lactone compound of aliskiren can be obtained at high selectivity and high yield.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an Alikren intermediate 1,8-dicarbonyl-4,5-epoxy compound and a preparation method thereof. Background technique [0002] Aliskiren Hemifumarate (Aliskiren Hemifumarate, structural formula shown below) is a new, safe and effective non-peptide direct oral renin inhibitor developed by Novartis, mainly used for the treatment of hypertension. In 2007, the U.S. Food and Drug Administration approved it for marketing. It is used alone or in combination with angiotensin-converting enzyme (ACE) inhibitors (such as ramipril), angiotensin II (ANG II) receptor inhibitors (such as valerian Sartan) and thiazide diuretics have good antihypertensive effect, good patient tolerance, long half-life, renal protection and reduction of left ventricular hypertrophy, and have potential benefits for long-term blood pressure control and improvement of cardiovascular and cerebrovascular disea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D303/40C07D303/46C07D301/19C07D301/14C07D301/12C07D301/03C07D413/06C07D307/33C07C237/20C07C231/12C07C231/02
Inventor 潘仙华刘烽李洪明黄瑞李一鸣张群辉邓飞陈文斌
Owner SHANGHAI HISOAR PHARMA TECH & DEV CO LTD
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