A kind of synthetic method of efluconazole intermediate

A technology of efluconazole and a synthesis method, which is applied in the field of pharmaceutical intermediate synthesis, can solve the problems of numerous intermediates, complicated processes, and many synthesis steps, and achieves the effects of high yield, good product quality and low cost

Inactive Publication Date: 2018-08-10
南京迪缘医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the synthesis method of efluconazole intermediate in the prior art, Chinese patent CN104292214A discloses a synthesis method of efluconazole and its intermediate, the preparation of the intermediate includes substitution reaction, acylation reaction and addition reaction , chiral resolution and reduction reaction, etc., there are many intermediates, and the process is complicated; CN104557746A discloses a synthetic method of efluconazole intermediate, including asymmetric Benzoin condensation reaction, hydroxyl protection, reduction reaction and hydroxyl deprotection, Finally, the intermediate is obtained. Although there is only one intermediate, there are many synthetic steps and the process is complicated.

Method used

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  • A kind of synthetic method of efluconazole intermediate
  • A kind of synthetic method of efluconazole intermediate
  • A kind of synthetic method of efluconazole intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] At 25°C, add the reaction solvent to the reaction kettle, then add the ammonia source, adjust the pH to 8.0 with hydrochloric acid, then add PLP and transaminase H62T, stir slowly until all are dissolved, then add compound (2) and react for 16 hours, After the reaction, adjust the pH to 2.0 with hydrochloric acid, add isopropyl acetate for extraction, leave the aqueous phase, adjust the pH to 12.0 with aqueous sodium hydroxide solution, add isopropyl acetate for extraction, and concentrate the isopropyl acetate under reduced pressure to obtain the compound ( 1).

[0030] The reaction solvent is water and dimethylsulfoxide, and the volume ratio of the two is 1:1.

[0031] The ammonia source is isopropylamine and triethylamine, the concentration is 0.5M, and the molar ratio of the two is 1:1.

[0032] The mass concentration of the compound (2) is 100g / L.

[0033] The mass concentration ratio of the compound (2) and the directed mutant of transaminase ATA-117 is 35:1.

...

Embodiment 2

[0036] At 22°C, add the reaction solvent to the reaction kettle, then add the ammonia source, adjust the pH to 7.5 with hydrochloric acid, then add PLP and transaminase G69C, stir slowly until all are dissolved, then add compound (2) and react for 14 hours. After the reaction, adjust the pH to 2.0 with hydrochloric acid, add isopropyl acetate for extraction, leave the aqueous phase, adjust the pH to 12.0 with aqueous sodium hydroxide solution, add isopropyl acetate for extraction, and concentrate the isopropyl acetate under reduced pressure to obtain the compound ( 1).

[0037] The reaction solvent is selected from water / methanol.

[0038] The source of ammonia is isopropylamine with a concentration of 0.2M.

[0039] The mass concentration of the compound (2) is 2g / L.

[0040] The mass concentration ratio of the compound (2) and the directed mutant of transaminase ATA-117 is 1:1.

[0041] The obtained intermediate was detected according to the aforementioned method, and its...

Embodiment 3

[0043] At 45°C, add the reaction solvent to the reaction kettle, then add the ammonia source, adjust the pH to 8.5 with hydrochloric acid, then add PLP and transaminase A209L, stir slowly until all are dissolved, then add compound (2) and react for 18 hours, After the reaction, adjust the pH to 2.0 with hydrochloric acid, add isopropyl acetate for extraction, leave the aqueous phase, adjust the pH to 12.0 with aqueous sodium hydroxide solution, add isopropyl acetate for extraction, and concentrate the isopropyl acetate under reduced pressure to obtain the compound ( 1).

[0044] The reaction solvent is selected from water / dimethylsulfoxide / methanol, and the volume ratio of the three is 1:1:1.

[0045] The source of ammonia is butylamine at a concentration of 1M.

[0046] The mass concentration of the compound (2) is 200g / L.

[0047] The mass concentration ratio of the compound (2) and the directed mutant of transaminase ATA-117 is 70:1.

[0048] The obtained intermediate wa...

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Abstract

The invention provides a synthetic method of an efinaconazole intermediate. In a reactive solvent, a chemical compound (2) is subjected to asymmetric ammonolysis reaction under the catalysis of aminopherase to obtain a chemical compound (1), which is the efinaconazole intermediate, and the response equation is as shown in the description. Compared with the prior art that the synthetic procedures of the efinaconazole intermediate are multiple and the synthetic process is complex, the synthetic method of the efinaconazole intermediate, provided by the invention, has the advantages that the intermediate product can be synthesized through one step, the preparation method is simple and easy to operate, low in cost, high in yield, good in product quality, and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing an efluconazole intermediate, belonging to the technical field of synthesis of pharmaceutical intermediates. Background technique [0002] Efluconazole (common name: Efinaconazole, trade name Jublia), chemical name (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1 -yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol. The molecular weight of efluconazole: 762.75; CAS registration number: 164650-44-6; the structural formula is shown in Formula 1: [0003] [0004] Efluconazole was developed by Dow Pharmaceutical. The antifungal drug approved by the FDA on June 6, 2014 is effective for the treatment of fungal diseases in humans and animals, and a 10% solution is used clinically to treat onychomycosis. [0005] At present, the synthesis method of efluconazole intermediate in the prior art, Chinese patent CN104292214A discloses a synthesis method of efluconazole and its intermediate, the preparation of th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P17/10C12N9/10
Inventor 曲大辉黄燕鸽
Owner 南京迪缘医药科技有限公司
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