Novel preparation method for sitafloxacin intermediate

A sitafloxacin and intermediate technology, applied in the new preparation field, can solve the problems of high cost, high equipment requirements, harsh reaction conditions, etc., and achieves mild reaction conditions, reduced splitting costs, and low equipment requirements. Effect

Inactive Publication Date: 2010-06-30
PEKING UNIV FOUNDER GRP CO LTD +2
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The shortcoming of this splitting method is: splitting yield is lower (<50%), and operation step is complicated, and cost is high, requires high to instrument and equipment, and output is small, is more suitable for laboratory operation, and is not suitable for industrialized large-scale production. Requirements, the industrialization prospect of this split method is poor
[0021] The shortcoming of this preparation method is: the Phaeocrepsis sp.JCM1880 involved in the microbial asymmetric reduction method in this operation process is not easy to get and complicated to operate, and reaction condition is harsh, post-processing is loaded down with trivial details, and cost is higher; Reagent DPPA and Lithium aluminum hydride is active and has certain dangers, so it is not suitable for industrial operation

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  • Novel preparation method for sitafloxacin intermediate
  • Novel preparation method for sitafloxacin intermediate
  • Novel preparation method for sitafloxacin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: (7S)-amino-5-[1(R)-5-phenylethyl]4-oxo-5-azaspiro[2.4]-heptane pyroglutamate (formula III) preparation

[0047] The racemate (7R, 7S)-amino-5-[1(R)-5-phenethyl]4-oxo-5-azaspiro[2.4]-heptane (Formula II) 23.0g (100mmol ) into a 2000ml reaction flask, 1000ml of 80% isopropanol solution was added, the temperature was raised to 50°C, 10.3g (80mmol, 0.8 equivalent) of pyroglutamic acid was added, and the temperature was controlled at 60°C for 5 hours. After 5 hours, 0.95 g (5 mmol, 5%) of 3,4-dichlorosalicylaldehyde was added, and the temperature was controlled at 80° C. for 15 hours. After cooling down to room temperature, let stand for 12 hours, filter, and dry under reduced pressure at 60°C to obtain 28.9 g of the compound of formula III with a yield of 81%.

Embodiment 2

[0048] Example 2: Preparation of (7S)-amino-5-[1(R)-5-phenylethyl]4-oxo-5-azaspiro[2.4]-heptane (Formula I)

[0049] (7S)-amino-5-[1(R)-5-phenylethyl]4-oxo-5-azaspiro[2.4]-heptane pyroglutamate (Formula III) 28.6g (80mmol ) was dissolved in 500ml of water, and the pH was adjusted to about 12 with 1mol / L sodium hydroxide solution, and the solid was precipitated, filtered, and dried to obtain (7S)-amino-5-[1(R)-5-phenylethyl]4- Oxo-5-azaspiro[2.4]-heptane (Formula I) 18.1g, yield 97%,

[0050] 1 HNMR (400mz, CDCl3) δ 0.8-1.42 (m, 4H), 1.53 (d, 1H, J=7Hz), 2.88 (dd, 1H, J=10.2Hz). 3.3-3.9(m, 2H), 4.28(brs, 1H), 5.24(q, 1H, J-7Hz), 7.29(m, 5H)

[0051] Purity determination: CHIRALPAK MA (+) chiral analysis column, n-hexane: isopropanol: methanol = 60:30:10 (0.1% ethylenediamine), 0.6mL / min, UV254nm, purity > 97%, ee > 95 %.

Embodiment 3

[0052] Example 3: (7S)-amino-5-[1(R)-5-phenylethyl]4-oxo-5-azaspiro[2.4]-heptane pyroglutamate (formula III) preparation

[0053] The racemate (7R, 7S)-amino-5-[1(R)-5-phenethyl]4-oxo-5-azaspiro[2.4]-heptane (Formula II) 23.0g (100mmol ) into a 2000ml reaction flask, 1000ml of 80% propanol solution was added, the temperature was raised to 50°C, 10.3g (80mmol, 0.8 equivalent) of pyroglutamic acid was added, and the temperature was controlled at 60°C for 5 hours. After 5 hours, 0.83 g (5 mmol, 5%) of 5-nitrosalicylaldehyde was added, and the temperature was controlled at 80° C. for 10 hours. After cooling down to room temperature, let it stand for 15 hours, filter, and dry under reduced pressure at 60°C to obtain 28.1 g of the compound of formula III with a yield of 78.2%.

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Abstract

The invention provides a novel preparation method for sitafloxacin intermediate (7S)-amino-5-[1(R)-5-phenethyl] 4-oxo-5-azaspiro [2.4]-heptane. The method comprises the following steps: adopting raceme (7R, 7S)-amino-5-[1(R)-5-phenethyl] 4-oxo-5-azaspiro [2.4]-heptane as the raw material, and obtaining (7S)-amino-5-[1(R)-5-phenethyl] 4-oxo-5-azaspiro [2.4]-heptane after optical resolution. The method has the advantages that the cost is low, the operation is simple, the reaction is mild, toxic and harmful substances are not used and generated, the yield is high, and the optical purity of the product is high, thereby being suitable for large-scale industrialized production.

Description

technical field [0001] The invention relates to a new preparation method of a sitafloxacin intermediate, which belongs to the field of new technology for preparing chemical medicines. Background technique [0002] Sitafloxacin hydrate is a broad-spectrum quinolone antibacterial drug newly developed by Daiichi Sankyo, which is used to treat severe refractory infectious diseases and bacterial infections caused by drug-resistant bacteria. [0003] Because sitafloxacin contains a cis-fluorocyclopropylamine group in its structure, it has good pharmacokinetic properties and can reduce adverse reactions. Its antibacterial activity in vitro is significantly stronger than most similar drugs. Sitafloxacin not only significantly enhanced the antibacterial activity against Gram-positive bacteria, but also had antibacterial activity against many fluoroquinolone-resistant strains isolated clinically. Studies on the antibacterial activity of sitafloxacin in vitro have proved that sitaflox...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/54C07B57/00
CPCY02P20/582
Inventor 邱传亮黄少林罗雪磊易崇勤谢小飞
Owner PEKING UNIV FOUNDER GRP CO LTD
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