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Optically pure itraconazole key intermediate, synthetic method thereof, and method for synthesizing optically pure itraconazole from the intermediate

A technology for itraconazole and intermediates, applied in the field of synthesis of optically pure itraconazole, which can solve the problems of high production cost, difficulty in industrialization, and complex components of glycerol tosylate, so as to reduce prices and production costs Effect

Active Publication Date: 2015-07-15
广州力鑫生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is relatively simple, but the key raw material compound Ⅲ p-toluenesulfonate glycerol esterification composition is complicated, and p-toluenesulfonate glycerol that meets the requirements of purity and optical purity often needs to be customized, the production cost is high, and it is not easy to industrialize

Method used

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  • Optically pure itraconazole key intermediate, synthetic method thereof, and method for synthesizing optically pure itraconazole from the intermediate
  • Optically pure itraconazole key intermediate, synthetic method thereof, and method for synthesizing optically pure itraconazole from the intermediate
  • Optically pure itraconazole key intermediate, synthetic method thereof, and method for synthesizing optically pure itraconazole from the intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of Compound Ⅶ-a

[0037]

[0038]In a 200ml three-necked flask, add compound I (9.50g, 37mmol, 1.0eq), S-3-chloro-1,2-propanediol (8.20g, 74mmol, 2.0eq) and 80mL of toluene, and add three Fluoromethanesulfonic acid (22g, 5.0mmol, 4.0eq), after the dropwise addition, heat to 80°C, stir and react for 6h, add 100ml of saturated sodium bicarbonate solution to the reaction solution, stir for 30min, separate the liquids, and collect the organic phase , and concentrated under reduced pressure to obtain 15 g of optically pure compound VII-a (yellow oil, S, S-configuration), with a purity of 86% and a yield of 99.7%.

[0039] 1 HNMR (400MHz, CDCl 3 ,):

[0040] 8.13(s,1H),7.77(s,1H),7.42~7.44(d,H,J=8.0),7.35(s,1H),7.14~7.16(d,1H,J=8.0),4.63~4.75 (m,2H,J=16.0),4.16(m,1H),3.69~3.78(m,2H),2.88~2.93,3.23~3.26(m,2H)

[0041] ESI-MS: 348.0 (M+H + ).

Embodiment 2

[0043] Synthesis of Compound Ⅶ-a

[0044]

[0045] In a 500ml three-necked flask, add compound I (9.50g, 37mmol, 1.0eq), S-3-chloro-1,2-propanediol (16g, 148mmol, 4eq) and toluene 90mL, and add p-toluenesulfonic acid while stirring (14g, 74mmol, 2eq), after the dropwise addition, heated to 100°C, stirred and reacted for 12h, added 150ml of saturated sodium bicarbonate solution to the reaction solution, stirred for 30min, separated, collected the organic phase, and concentrated under reduced pressure to obtain 12g of optically pure compound VII (yellow oil, S,S-configuration), purity 84%, yield 78.1%.

Embodiment 3

[0047] Synthesis of Compound Ⅶ-b

[0048]

[0049] In a 500ml three-necked flask, add compound I (9.50g, 37mmol, 1.0eq), R-3-chloro-1,2-propanediol (20.5g, 185mmol, 5eq) and 90mL of toluene, and add methanesulfonate dropwise while stirring Acid (28g, 296mmol, 8eq), after the dropwise addition, heated to 40°C, stirred and reacted for 4h, added 200ml of saturated sodium bicarbonate solution to the reaction solution, stirred for 30min, separated, collected the organic phase, concentrated under reduced pressure, 14 g of optically pure compound VII (yellow oil, S,S-configuration) was obtained with a purity of 83% and a yield of 90%.

[0050] 1 HNMR (400MHz, CDCl 3 ,):

[0051] 7.98(s,1H),7.58(s,1H),7.25~7.28(d,H,J=12.0),7.17(s,1H),6.97~6.99(d,1H,J=8.0),4.47~4.63 (m,2H,J=16.0),3.98(m,1H),3.51~3.60(m,2H),2.73~2.78,3.06~3.08(m,2H)

[0052] ESI-MS: 348.1 (M+H + ).

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PUM

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Abstract

The invention disclsoes an optically pure itraconazole key intermediate and synthetic method thereof, and a method for synthesizing the optically pure itraconazole from the intermediate. The method of the invention uses 1-(2,4-dichlorobenzene)-2-(1-methylene-1,2,4-triazole)-1-ketone for preparing the optically pure itraconazole key intermediate, and the optically pure itraconazole key intermediate is used for the preparation of optically pure itraconazole. The method uses easily available raw materials, not only reduces the production cost, but also obtains the product with high purity; through the control of the optical purity of the key intermediate compound VII, the optical purity of the target product itraconazole can be effectively controlled; therefore, the invention has with industrial value.

Description

technical field [0001] The present invention relates to the technical field of synthesizing optically pure itraconazole, in particular to a key intermediate of optically pure itraconazole and a synthesis method as well as a method for synthesizing optically pure itraconazole from the intermediate. Background technique [0002] Itraconazole is a triazole broad-spectrum antifungal drug, its English name is Itraconazole, its Chinese chemical name is cis-4-[4-[4-[4-[[-2-(2,4-dichloro Phenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine-1- base]phenyl]-2-[(2'S)-1-methylpropyl]-1,2,4-triazol-3-one. Itraconazole has 3 chiral carbon atoms, and there are 8 optical isomers in total. The antifungal clinical use is a mixture of 4 cis isomers on dioxolane in its structure, corresponding to 2S, 4R ,2'S-Itraconazole, 2S, 4R, 2'R-Itraconazole, 2R, 4S, 2'S-Itraconazole and 2R, 4S, 2'R-Itraconazole. Studies have found that there are large differences in the b...

Claims

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Application Information

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IPC IPC(8): C07D405/06C07D405/14
CPCC07B53/00C07D405/06C07D405/14
Inventor 沈小宁孙建华刘贞兴陈鹿鹿
Owner 广州力鑫生物科技有限公司
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