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Preparation method of posaconazole intermediate

A technology for posaconazole and intermediates, which is applied in the field of medicinal chemistry synthesis, can solve the problems of expensive enzyme catalysts, complicated process operation, unfavorable production amplification, etc., and achieves the effects of reducing cost, simple operation process and improving catalytic efficiency.

Inactive Publication Date: 2016-02-03
成都培隆生物医药科技有限责任公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This method is catalyzed by Novozymes lipase 435 to make compound (II) construct compound (V) through a series of reactions, so that compound (V) has two chiral carbon atoms; the synthesis route of this method has short steps and ingenious design, but Enzyme catalysts are relatively expensive, the production cost is high, and the process operation is complicated, which is not conducive to production scale-up

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  • Preparation method of posaconazole intermediate
  • Preparation method of posaconazole intermediate
  • Preparation method of posaconazole intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Put 5.7 g of compound (II) into a conical flask, add 60 ml of phosphate buffer solution with pH=5.5, add 2.4 g of isobutyric anhydride, add 0.6 ml of Tween 80 liquid, stir well, add diatomaceous earth to immobilize lipase 100unit / mol, put the Erlenmeyer flask on a shaker, 37°C, 200r / min, and react for 24h. Filtration of immobilized lipase is treated and reused, and the filtrate is organically extracted and concentrated to obtain a mixture of posaconazole intermediates (II) and (III), separated by flash column chromatography to obtain posaconazole intermediate (III) 3.5g, the yield is about 47%, and the determined ee value is 99.1%. The NMR results are as follows:

[0028] 1H-NMR (400MHZ, CDCl3):

[0029] 7.53-7.46(m, 1H), 6.89-6.86(m, 1H), 6.83-6.78(m, 1H), 4.16-4.12(dd, 1H), 4.09-4.04(m, 2H), 3.87-3.84(dd , 1H), 3.69(s, 2H), 2.59-2.53(m, 3H), 2.19-2.12(dd, 1H), 1.18(s, 3H), 1.15(S, 3H).

[0030] MS=271M+

[0031] The reaction is shown in the following formula:

...

Embodiment 2

[0034] Put 5.7 g of compound (II) into a conical flask, add 60 ml of phosphate buffer solution with pH=6.5, add 2.4 g of isobutyric anhydride, add 1.2 ml of Tween 80 liquid, stir well, add diatomaceous earth to immobilize lipase 100unit / mol, the Erlenmeyer flask was placed on a shaker, 37°C, 200r / min, and reacted for 20h. Filtration of immobilized lipase is treated and reused, and the filtrate is organically extracted and concentrated to obtain a mixture of posaconazole intermediates (II) and (III), separated by flash column chromatography to obtain posaconazole intermediate (III) 3.2g, the yield is about 42.9%, and the determined ee value is 99.2%.

Embodiment 3

[0036] Put 5.7 g of compound (II) into a conical flask, add 60 ml of phosphate buffer solution with pH=7.0, add 2.4 g of isobutyric anhydride, add 1.8 ml of Tween 80 liquid, stir well, add diatomaceous earth to immobilize lipase 50unit / mol, put the Erlenmeyer flask on a shaker, 35°C, 200r / min, and react for 24h. Filtration of immobilized lipase is treated and reused, and the filtrate is organically extracted and concentrated to obtain a mixture of posaconazole intermediates (II) and (III), separated by flash column chromatography to obtain posaconazole intermediate (III) 3.7g, the yield is about 49.6%, and the determined ee value is 99.0%.

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Abstract

The invention discloses a preparation method of a posaconazole intermediate (III). The preparation method comprises the following steps of adopting an immobilized enzyme technology, and esterfying a compound (II) with isobutyric anhydride at the temperature of 35 to 40 DEG C in a weak acidic buffer under the catalysis of candida rugosa lipase, so as to obtain a mixture of posaconazole intermediates (II) and (III), and obtain the posaconazole intermediate (III) through quick column chromatography separation. By compared with a known invention of enzymic catalytic reaction, the method provided by the invention adopts the immobilized enzyme technology, the lipase can be recycled, the operation process is simple, and the cost is low. The posaconazole intermediate (III) obtained by the method provided by the invention can be used for the synthesis of posaconazole, and the ee value is larger than 99 percent.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis and relates to the preparation of a posaconazole intermediate. Background technique [0002] Posaconazole (4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazole-1 -ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypent-3-yl] -1,2,4-triazol-3-one, posaconazole), the structural formula is: [0003] [0004] Posaconazole, a second-generation triazole antifungal drug approved by the US FDA in 2006, has a broad antibacterial spectrum, good safety and tolerance, and provides a new option for the prevention and treatment of deep fungal infections. The drug is effective against Candida spp., Histoplasma capsulatus, Seidospora, Bipolar zygomycetes, Fusarium, yeasts, including fluconazole-resistant non-albicans strains, Cryptococcus neoformans, and Aspergillus Strong inhibitory activity; especially effective against relatively rare but lif...

Claims

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Application Information

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IPC IPC(8): C12P7/62
Inventor 王俊贤张法王建昌阎隽阎家麒
Owner 成都培隆生物医药科技有限责任公司
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