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Chiral (-)-5-azaspiro [2.4] heptane-7-alcohol as well as preparation method and application thereof

An azaspiro and heptane technology, applied in the field of chiral compound synthesis, can solve the problems of no splitting, few industrial examples, limited biological fermentation varieties, etc.

Active Publication Date: 2021-07-06
常州佳德医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Optical chiral compounds can be obtained by a variety of methods, including natural purification, biological fermentation, synthesis from chiral precursors, chemical resolution and asymmetric chemical synthesis, but these methods have certain limitations: natural extraction is limited by resource sources; The variety of biological fermentation is limited; asymmetric chemical synthesis is still in the development stage, and there are not many industrial examples
However, there are no examples of the resolution of the compound 5-azaspiro[2.4]heptan-7-ol racemate at home and abroad, and its chiral compound is a brand new chemical structure

Method used

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  • Chiral (-)-5-azaspiro [2.4] heptane-7-alcohol as well as preparation method and application thereof
  • Chiral (-)-5-azaspiro [2.4] heptane-7-alcohol as well as preparation method and application thereof
  • Chiral (-)-5-azaspiro [2.4] heptane-7-alcohol as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] A kind of chiral (-)-5-azaspiro[2.4]heptan-7-ol is prepared by the method of the present invention, comprising the steps of:

[0035] S1: Put (2g, 0.0098mol) 5-azaspiro[2.4]heptan-7-ol, (1.48g, 0.01mol) phthalic anhydride, (0.79g, 0.01mol) pyridine into a three-necked flask, stir and heat Raise the temperature to 100°C, keep it warm for 1 hour, and cool down to normal temperature after the reaction; add 10% hydrochloric acid dropwise to the reaction product mixture until pH = 2-3, stir for 1 hour, and extract the reaction solution with dichloromethane , and the organic layer was concentrated to dryness under reduced pressure to obtain 2.82 g of benzoic acid ester.

[0036]HPLC detects that the purity of benzoic acid ester is 98.76%, and the molar yield is 80.5%, and melting point (m.p.) is 88-90 ℃, (HPLC peak area normalization method: chromatographic column Inertsustain C18 column (4.6mm * 150mm, 5 μ m ); the mobile phase volume ratio is acetonitrile:0.01% ammonium ac...

Embodiment 2

[0057] A kind of chiral (-)-5-azaspiro[2.4]heptan-7-ol is prepared by the method of the present invention, comprising the steps of:

[0058] S1: Put (2g, 0.0098mol) 5-azaspiro[2.4]heptan-7-ol, (2.176g, 0.0147mol) phthalic anhydride, (1.16g, 0.0147mol) pyridine into a three-necked flask, stir and heat Raise the temperature to 50°C, keep it warm for 6 hours, and cool down to normal temperature after the reaction; add 10% hydrochloric acid dropwise to the reaction product mixture until pH=2-3, stir for 1 hour, and extract the reaction solution with dichloromethane , and the organic layer was concentrated to dryness under pressure to obtain 2.65 g of benzoic acid ester.

[0059] HPLC detects that the purity of benzoic acid ester is 96.5%, and the molar yield is 74.5%, and melting point (m.p.) is 84-92 ℃, (HPLC peak area normalization method: chromatographic column Inertsustain C18 column (4.6mm * 150mm, 5 μ m ); the mobile phase volume ratio is acetonitrile:0.01% ammonium acetate...

Embodiment 3

[0070] A kind of chiral (-)-5-azaspiro[2.4]heptan-7-ol is prepared by the method of the present invention, comprising the steps of:

[0071] S1: Put (2g, 0.0098mol) 5-azaspiro[2.4]heptan-7-ol, (2.96g, 0.02mol) phthalic anhydride, (1.58g, 0.02mol) pyridine into a three-necked flask, stir and heat Raise the temperature to 120°C, keep it warm for 1 hour, and cool down to room temperature after the reaction; add 10% hydrochloric acid dropwise to the reaction product mixture to pH=2-3, stir for 1 hour, and extract the reaction solution with dichloromethane , and the organic layer was concentrated to dryness under pressure to obtain 2.88 g of benzoic acid ester.

[0072] HPLC detects that the purity of benzoate is 86.8%, and the molar yield is 72.6%, and melting point (m.p.) is 76-84 ℃, (HPLC peak area normalization method: chromatographic column Inertsustain C18 column (4.6mm * 150mm, 5 μ m ); the mobile phase volume ratio is acetonitrile:0.01% ammonium acetate aqueous solution=40...

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Abstract

The invention discloses chiral (-)-5-azaspiro [2.4] heptane-7-alcohol as well as a preparation method and application thereof. The chiral (-)-5-azaspiro [2.4] heptane-7-alcohol is an important intermediate for producing a single isomer drug (-) AL8326, so that the drug AL8326 is expected to be separated into a compound with a single configuration, and the research progress of the chiral drug (-) AL8326 is greatly promoted through synthesis of the chiral (-)-5-azaspiro [2.4] heptane-7-alcohol; according to the preparation method disclosed by the invention, chemical resolution is carried out by utilizing hydroxyl on chiral carbon, and separation is carried out according to completely different solubility of phenylethylamine salts with two configurations in an aqueous solution, so that a product with relatively high chemical purity and optical purity is obtained; compared with traditional biological enzyme reduction method resolution and chiral preparative column resolution, the method has the advantages that consumed time is shorter, raw materials are low in price and convenient in source, operation steps are simple, the method is suitable for industrial large-scale production, and a foundation is laid for industrial production of the single isomer drug (-) AL8326.

Description

technical field [0001] The invention belongs to the technical field of chiral compound synthesis, and specifically relates to a chiral (-)-5-azaspiro[2.4]heptan-7-ol, a preparation method and an application. Background technique [0002] AL8326 is a new type of multi-target small molecule tyrosine kinase inhibitor. It has a new structure, clear anti-tumor effect and low toxicity. The potential of new multi-target anti-tumor drugs is currently in preclinical research and has a good prospect for clinical application. AL8326 not only has very good in vitro inhibitory activity against ovarian cancer, leukemia, liver cancer, breast cancer, lymphoma, lung cancer, gastric cancer, kidney cancer, colon cancer, cervical cancer and other cells, but also has better performance than sunitinib in vivo (Sunitinib) inhibits tumor growth activity. [0003] AL8326 currently used in preclinical research is a mixed-rotational compound, which has two structures, left-handed and right-handed. A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/54
CPCC07D209/54C07B2200/07Y02P20/584
Inventor 邵翀吕列超朱小华刘巧云张文超刘咏琪程舒扬秦东
Owner 常州佳德医药科技有限公司
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