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A compound and organic solvent technology, applied in the field of medicinal chemical synthesis, can solve the problems of low purity and difficult removal of the final product
Inactive Publication Date: 2016-06-08
北京启慧生物医药有限公司
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Problems solved by technology
Since the structure and physical and chemical properties of the by-product and the target compound are very similar, it is difficult to remove by recrystallization, resulting in a very low purity of the final product
Method used
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Embodiment 1
[0047] The preparation of embodiment 1 formula (III) compound
[0048] In a 5L round-bottomed three-neck flask equipped with a drying tube, add the compound of formula (II) (278g, 1mol) and acetonitrile (2.8L), add potassium carbonate (276g, 2mol) under stirring, and add Boc anhydride dropwise in an external bath at 10°C (327g, 1.5mol) in acetonitrile (300mL) solution, continue to react for 3h after addition, then add water (3L), extract three times with ethyl acetate (800mL×3), combine organic phases, wash with saturated brine (800mL) washed, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 368 g of light yellow oil, with a yield of 97.6%.
Embodiment 2
[0049] The preparation of embodiment 2 formula (IV) compound
[0050]In a 5L round-bottomed three-neck flask equipped with a drying tube, add the compound of formula (III) (302g, 0.8mol) and DMF (3.6L), after stirring and dissolving, add potassium carbonate (276g, 2mol) and benzyl bromide (205g , 1.2mol), continued to react for 7h in an external bath at 160°C, cooled, poured into water (20L), extracted three times with ethyl acetate (2L×3), combined the organic phases, followed by water (2L×5), saturated brine (2L), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 318 g of a yellow oil with a yield of 85.1%.
Embodiment 3
[0051] The preparation of embodiment 3 formula (V) compound
[0052] Add the compound of formula (IV) (280g, 0.6mol) and tetrahydrofuran (2.2L) into a 3L round-bottomed three-necked flask equipped with a drying tube. After stirring to dissolve, add 4N hydrochloric acid aqueous solution (300mL, 1.2mol), and continue the reaction at room temperature 2h, add 2L of water, concentrate under reduced pressure and distill THF off, extract three times with ethyl acetate (500mL×3), combine the organic phases, wash with water (500mL) and saturated brine (500mL) successively, dry over anhydrous sodium sulfate, filter , and concentrated to obtain 208 g of a yellow oil, with a yield of 94.2%.
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Abstract
The invention discloses a preparation method of eliglustat. Eliglustat is the first micromolecular oral drug for treating gaucher disease, and is applied to a first-line oral administration treatment of adult patients of I type gaucher disease. The invention provides a synthesis method of eliglustat. The synthesis method comprises the following steps: taking a compound represented by the formula (II) as the primary material, carrying out reactions between the compound (II) and Boc anhydride in an organic solvent in the presence of weak alkali so as to obtain a compound represented by the formula (III); reacting the compound (III) with benzyl bromide to obtain a compound represented by the formula (IV), subjecting the compound (IV) to deprotection in an organic solvent to obtain a compound represented by the formula (V); reacting the compound (V) with caprylyl chloride in an organic solvent (dichloromethane, etc.) to generate a compound represented by the formula (VI), and finally hydrogenating the compound (VI) to obtain the target compound represented by the formula (I). The synthesis method has the advantages that the operation is convenient, the process can be controlled convenient, the product purity is high, and the method can be easily applied to industrial production.
Description
technical field [0001] The invention relates to the field of chemical synthesis of medicines, and more particularly relates to a synthesis method of a specific ceramide analog inhibitor acting on glucosylceramide synthetase (GCS). Background technique [0002] Eliglustat, the chemical name is N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxan-6-yl)-2-hydroxyl-1-( 1-pyrrolidinylmethyl) ethyl] octanamide, is a kind of first small molecule compound that is used for the treatment of specific type I Gaucher disease, and its structural formula is as shown in formula (I): [0003] [0004] There are 7,000 types of rare diseases known in the world, accounting for 10% of human diseases. China has discovered 5,781 types of rare diseases, with more than 10 million patients. Gaucher's disease is the most common genetic rare disease of lysosomal storage disease. It is caused by the reduction or deficiency of β-glucocerebrosidase, which makes glucocerebroside in monocytes and macrophages. A l...
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