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Preparation method of eliglustat

A technology of ebrustat and preparation steps, which is applied in the field of preparation of ebrustat, a drug for treating type I Gaucher disease, can solve problems such as expensive reduction catalysts, difficulty in obtaining raw materials, and numerous reaction steps, so as to promote development and facilitate the development of raw materials. The effect of gain, process, environmental protection and economy

Active Publication Date: 2015-04-29
上海御略医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Examining the above synthetic route, although there are innovations in the use of starting materials, the method of chiral formation and the selection of unit reactions, and the target product can be successfully obtained, there are still difficulties in obtaining raw materials, numerous reaction steps, reduction Catalyst is expensive and other shortcomings, so it is difficult to realize its industrialization smoothly

Method used

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  • Preparation method of eliglustat
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  • Preparation method of eliglustat

Examples

Experimental program
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Effect test

Embodiment 1

[0041] 0-5°C under a nitrogen atmosphere, add pyrrolidine (7.1g, 0.1mol), cuprous bromide (0.72g, 5mmol), triethylamine (2.0g, 0.2mmol) and 50mL of tetrahydrofuran into a reaction flask, stir 1-Bromo-2-nitroethane (18.5 g, 0.12 mmol) was added dropwise. After the drop was completed, the temperature was slowly raised to 30-35° C., stirred for 36 hours, and the reaction was detected by TLC. Cool to room temperature, remove insoluble matter by filtration, recover the solvent under normal pressure, and distill under reduced pressure to obtain 11.8 g of light yellow liquid 2-(pyrrolidin-1-yl)-1-nitroethane (III), with a yield of 81.9%;1 H NMR (CDCl 3 )δ1.72(m, 4H), 2.47(m, 4H), 2.78(t, 2H), 4.70(t, 2H); EI-MS m / z: 145[M+H] + .

Embodiment 2

[0043] Under a nitrogen atmosphere and at -5-0°C, add 2-nitro-1-(1-pyrrolidinyl)ethanone (7.9g, 0.05mol) and 50mL of tetrahydrofuran into the reaction flask, and add lithium aluminum hydride (2.7g , 0.15mol), the addition was completed, the temperature was raised to 35-45° C., and the reaction was stirred for 6 hours, and the reaction was detected by TLC. Add 5 mL of water dropwise to quench the reaction, add 25 mL of 15% sodium hydroxide solution, stir for 15 minutes, and filter to remove insoluble matter. It was extracted three times with dichloromethane, and the organic phases were combined and concentrated to obtain a brown-yellow oil. Distilled under reduced pressure to obtain 6.2 g of light yellow liquid 2-(pyrrolidin-1-yl)-1-nitroethane (III), yield 86.1%; 1 H NMR (CDCl 3 )δ1.72(m, 4H), 2.47(m, 4H), 2.76(t, 2H), 4.70(t, 2H); EI-MS m / z: 145[M+H] + .

Embodiment 3

[0045] At room temperature and under a nitrogen atmosphere, copper acetate monohydrate (0.20 g, 1 mmol), (1S, 3R, 7R)-1-phenyl-3-(1-benzotriazolyl)-1H was added to the reaction flask, 6H-Naphtho[1,2-e]piperidino[2,1-b][1,3]oxazine (VI) (0.43g, 1mmol) and 15mL tetrahydrofuran, heated to 50-60°C, stirred React for 3 hours until the solution is clear. Cool down to room temperature, add 2,3-dihydro-1,4-benzodioxanyl-6-aldehyde (II) (1.64g, 10mmol), stir for 30 minutes, cool down to -20°C, and slowly add 2-(Pyrrolidin-1-yl)-1-nitroethane (III) (2.12g, 15mmol) in THF (15mL) and 1,4-diazabicyclo[2.2.2]octane Tetrahydrofuran (15 mL) solution was kept at -20°C and stirred for 24-28 hours, and the reaction was detected by TLC. The reaction was quenched with 5 mL of saturated ammonium chloride at low temperature, raised to room temperature, extracted three times with dichloromethane, and the organic phases were combined and dried over anhydrous magnesium sulfate. Concentrate to give l...

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Abstract

The invention discloses a preparation method of eliglustat serving as a medicament for an I type Gaucher disease. The preparation method comprises the following steps: carrying out Henry reaction on 2, 3-dihydro-1, 4-benzodioxane-6-aldehyde and 2-(pyrrolidine-1-yl)-1-nitroethane in the presence of a chiral catalyst, and then carrying out nitro reduction and amidation reaction on the product to prepare the eliglustat (I). The preparation method is easy in raw material acquisition and simple and concise in process, is economical and environmentally friendly and is suitable for industrial production. Meanwhile, the invention also discloses 2-(pyrrolidine-1-yl)-1-nitroethane (III) serving as a raw material for preparing the eliglustat and a preparation method of the eliglustat.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of Eliglustat, a medicine for treating type I Gaucher disease. Background technique [0002] Eliglustat is a glucosylceramide synthetase inhibitor developed by Genzyme, a subsidiary of Sanofi. The U.S. Food and Drug Administration (FDA) granted the drug orphan drug status on September 17, 2008, and officially approved its marketing (trade name Cerdelga) on August 19, 2014, for specific type 1 Gaucher disease ( The only first-line oral therapy for adult patients with Gaucher disease. Gaucher disease is a glucocerebrosidosis caused by autosomal recessive inheritance. It is mainly due to the mutation of the structural gene encoding glucocerebrosidase (GIucocerebrosidase), which leads to the lack of the enzyme, resulting in the Glucocerebroside cannot be further hydrolyzed and ...

Claims

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Application Information

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IPC IPC(8): C07D319/18C07D295/067
CPCC07D295/067C07D319/18
Inventor 许学农
Owner 上海御略医药科技有限公司
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