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A kind of method for preparing iligrusat

A technology for preparing steps and compounds, which is applied in the field of preparation of iligrusastat and glucosylceramide synthase inhibitors, and can solve problems such as low yield, difficult preparation of catalysts, and difficulty in preparation

Active Publication Date: 2021-01-12
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Although the synthetic routes of the above four documents are different in the application of starting materials and chiral control methods, there are some problems, such as (L)-phenylglycol in the international patent WO03008399 and WO201559679, where C is the raw material The preparation of the first step is difficult and the yield is low
In the preparation method of Chinese patent CN104557851, the catalyst is not easy to obtain
The method reported by the Overkleeft team using microwave reaction and high-temperature heating cannot be applied to large-scale industrial production

Method used

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  • A kind of method for preparing iligrusat
  • A kind of method for preparing iligrusat
  • A kind of method for preparing iligrusat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] The preparation of embodiment 1 formula (X) compound

[0051] Add formula (X) compound (4.47g, 25mmol), azidoacetic acid (3g, 30mmol), dicyclohexylcarbodiimide (5.7g, 27mmol) and 4-dimethylamino in a 250mL round bottom flask at 0°C Pyridine (370mg, 3.0mmol), dichloromethane 100mL, warmed to room temperature after 30min, reacted for 1h, filtered through silica gel, washed with cyclohexane: ethyl acetate = 7:3, concentrated the mother liquor to obtain the crude product, and then removed it with a short column. 6.3 g of the product was obtained with a yield of 97%.

[0052] [α]20D+165(c,1.0,CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ7.3-7.43 (m, 5H), 5.71 (dd, J = 3.2Hz, 8.4Hz, 1H), 4.81-4.94 (m, 3H), 4.54-4.57 (m, 1H); 13 C NMR (150MHz, CDCl 3 )δ184.8, 168.4, 137.8, 129.2, 126.2, 75.1, 62.2, 54.6.

Embodiment 2

[0053] The preparation of embodiment 2 formula (XII) compound

[0054] Add formula (XI) compound (4.8g, 25mmol), azidoacetic acid (3g, 30mmol), dicyclohexylcarbodiimide (5.7g, 27mmol), 4-dimethylamino in a 250mL round bottom flask at 0°C Pyridine (370 mg, 3.0 mmol), dichloromethane 100mL, rise to room temperature after 30min, react for 1h, filter on silica gel, wash with cyclohexane: ethyl acetate = 7:3, concentrate the crude product of the mother liquor, and then wash with dichloromethane / petroleum ether recrystallization to obtain 6.5g of product, yield 94.2%.

[0055] [α]20D+310(c,1.0,CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ7.25-7.42(m,5H),6.25(d,J=9.2Hz,1H),4.74-4.95(m,2H),4.04(dd,J=11.6Hz,8.4Hz,1H),3.17( dd,J=1.2Hz,11.2Hz,1H); 13 C NMR (150MHz, CDCl 3 )δ202.0, 168.7, 138.4, 129.1, 128.8, 125.4, 69.5, 55.3, 37.6.

Embodiment 3

[0056] The preparation of embodiment 3 formula (Ⅲ) compound

[0057] Formula (II) compound (5mmol) in 50mL dichloromethane, drop TiCl at -78°C 4 (0.575mL, 5.25mmol), reacted at this temperature for 15min, then added DIPEA (0.96mL, 5.5mmol) and stirred for 1h, then NMP (0.96mL, 10mmol), stirred for 15min and added 1,4-benzodiox alkane-6-carboxaldehyde, and stirred at this temperature for 40min, then warmed up to -30°C for 40min, after TLC showed that it was complete, the reaction was terminated with saturated ammonium chloride (20mL), extracted with 150mL ethyl acetate, washed with saturated sodium chloride, no Dry over sodium sulfate, filter, evaporate the solvent, recrystallize after desalting with a short column of silica gel to obtain 1.2 g of the oxazolidinone product, with a yield of 79%; 1.7 g of the thiazolidinone product, with a yield of 77%.

[0058] Oxazolidinone Products:

[0059] [α]20D+39(c,1.0,CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ7.27-7.42(m,5H),6.86-7.02(m,3...

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Abstract

The invention discloses a method for preparing Eliglustat. The Eliglustat is an effective specific glucosylceramide systhase inhibitor, which can be used for treating type-I Gaucher disease. The invention provides the synthetic method of Eliglustat, which comprises the following steps: 1,4-benzdioxan-6-formaldehyde and a chiral ligand are subjected to an adiastereoselectivity Aldol reaction, and then subjected to a reduction reaction, replacement and a Staudinger reaction, and an amidation reaction to obtain Eliglustat. The method has the advantages of easy acquisition of raw material, simpleoperation, high product yield and purity, and easy industrial large production.

Description

technical field [0001] The invention relates to a new method for preparing iligrusastat, which is an effective and specific inhibitor of glucosylceramide synthase and can be used for treating type I Gaucher disease. The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates. Background technique [0002] Iligrusat is a potent and specific glucosylceramide synthase inhibitor for the treatment of type I Gaucher disease. On August 19, 2014, the U.S. Food and Drug Administration (FDA) approved its marketing under the trade name Cerdelga for the long-term treatment of adult patients with type I Gaucher disease, a rare genetic disease. In 2015, the European Commission granted marketing rights to Cerdelga(R) for the long-term treatment of adult patients with CYP2D6 poor metabolizers, intermediate metabolizers or rapid metabolizers of Gaucher type I patients. Iligrusastat, a drug from Genzyme, is also on the ma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D319/18
CPCC07D319/18
Inventor 谢平刘晓宇焦晓臻李晓宇杨红光施翔杨飞龙
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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