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A kind of preparation method of 5-azaspiro[2.4]heptane and salt thereof

An azaspiro and heptane technology, which is applied in the field of preparation of 5-azaspiro[2.4]heptane and its salts, can solve the problems of being unsuitable for large-scale production, complicated production process and high cost of raw materials, and achieves low toxicity , the reaction operation is simple, the effect of less synthesis process steps

Active Publication Date: 2022-07-01
南京合巨药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] Therefore, the technical problem to be solved in the present invention is to overcome the defects of complex production process of 5-azaspiro[2.4]heptane and its salts in the prior art, high cost of raw materials, use of high-risk reagents, and unsuitability for large-scale production. Thereby providing a kind of preparation method of 5-azaspiro[2.4]heptane and its salt, the raw material used in this method is cheap and easy to get, the reaction operation is simple and convenient, the yield is high, suitable for large-scale production

Method used

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  • A kind of preparation method of 5-azaspiro[2.4]heptane and salt thereof
  • A kind of preparation method of 5-azaspiro[2.4]heptane and salt thereof
  • A kind of preparation method of 5-azaspiro[2.4]heptane and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Synthesis of Compound III:

[0051]

[0052] Under nitrogen protection, n-BuLi (2.5M dissolved in n-hexane, 390mL, 0.975mol, 1.3equiv.) was added dropwise to diisopropylamine (101.8g, 1.01mol, 1.36equiv.) in ether (1.5L) at -78°C. In the solution, react for half an hour to obtain an LDA solution, then slowly dropwise cyclopropyl nitrile (II) (50.0 g, 0.745 mol, 1.0 equiv.), and react at -78° C. for 1 hour. Slowly add ethylene oxide (98.45 g, 2.235 mol, 3.0 equiv.) dropwise, react at -78° C. for 3 hours, and then naturally warm to room temperature and react overnight. TLC showed that the reaction of the raw materials was complete, 600 mL of 2N hydrochloric acid was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (200 mL*4), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 69.78 g of a red oil, yield:...

Embodiment 2

[0067] The synthesis of compounds III, IV and V-1 is the same as that of Example 1.

[0068] Synthesis of compound I-1:

[0069]

[0070] 5-(2-Nitrobenzenesulfonyl)-5-aza-spiro[2.4]heptane (V-1) (15.00 g, 0.053 mol, 1.0 equiv.) was dissolved in 80 ml of EtOAc, cooled in an ice bath, 4-tert-butylthiophenol (26.40g, 0.159mol, 3.0equiv.), DBU (24.20g, 0.159mol, 3.0equiv.) were added, and the mixture was stirred at room temperature for 3h. TLC showed that the reaction of the raw materials was complete. 1N HCl was added, the pH was adjusted to 3, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate 50 mL*2. The aqueous phase was adjusted to pH 10 with 1N NaOH water, extracted with ethyl acetate 60 mL*3, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, added with 1N HCl / ethyl acetate 70 mL, fully stirred and concentrated under reduced pressure to obtain pro...

Embodiment 3

[0073] Synthesis of Compound III:

[0074]

[0075] Cyclopropyl nitrile (II) (20.0 g, 0.298 mol, 1.0 equiv.) was dissolved in anhydrous THF (100 mL) solution, under nitrogen protection, cooled to -78 ° C, slowly added dropwise KHMDS (1.0 M dissolved in tetrahydrofuran, 0.358L, 0.358mol, 1.2equiv.), react for one hour, slowly add ethylene oxide (19.70g, 0.447mol, 1.5equiv.) dropwise, react at -78°C for 5 hours, and then naturally rise to room temperature. 200 mL of 2N hydrochloric acid was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (80 mL*4), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 17.95 g of red oil (III) with a yield of 54.3%.

[0076] Synthesis of Compound IV:

[0077]

[0078] 1-(2-Hydroxy-ethyl)-cyclopropanecarbonitrile (III) (8.00 g, 0.072 mol, 1.0 equiv.) was dissolved in 50 mL of e...

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Abstract

The invention discloses a preparation method of 5-azaspiro[2.4]heptane and salts thereof, comprising: reacting cyclopropyl nitrile and ethylene oxide under strong basic conditions to obtain 1-(2-hydroxy-ethyl base)-cyclopropanecarbonitrile; 1-(2-hydroxy-ethyl)-cyclopropanecarbonitrile obtains 2-(1-aminomethyl-cyclopropyl)-ethanol through reduction; 2-(1-aminomethyl -Cyclopropyl)-ethanol obtains protected 5-(R-)azaspiro[2.4]heptane through ring-closure reaction; protected 5-(R-)azaspiro[2.4]heptane is obtained through deprotection to obtain 5 - Azaspiro[2.4]heptane or a salt thereof. The raw materials used in the invention are cheap and easy to obtain, low in toxicity, and at the same time, the synthesis process steps are few, the reaction operation is simple and the yield is high, and the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of 5-azaspiro[2.4]heptane and salts thereof. Background technique [0002] 5-Azaspiro[2.4]heptane (I), as a homologue of tetrahydropyrrole, has a wide range of applications in drug development. For example, patent US2007167470A1 reported that (I) can be used to synthesize a class of spirocyclic tyrosine kinase inhibitors, in cancers related to protein tyrosine kinases, especially epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) ) has important applications in cancer treatment. Patent WO2014170197A1 reports that (I) can be used to synthesize a class of ACC inhibitors for the treatment of metabolic diseases, such as obesity or diabetes. Therefore, (I) the market prospect is very broad. [0003] The existing synthesis technique of 5-azaspiro[2.4]heptane (I) is as follows: [0004] Patent US20071674...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/54
CPCC07D209/54
Inventor 潘国骏陈书林郏如雪
Owner 南京合巨药业有限公司
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