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Preparation method for 5-benzyl-7(S)-t-butyloxycarborylamino-5-aza-spiro[2,4]heptanes

A technology of tert-butoxycarbonylamino and azaspiro, which is applied in the field of compound preparation, can solve problems such as unfavorable industrial production, and achieve the effects of low cost, easy reaction operation, and easy price

Active Publication Date: 2013-12-04
苏州楚凯药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The object of the present invention is to provide a preparation method of 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane, aiming at overcoming the unfavorable industrialization of existing synthetic methods The shortcomings of production provide a method with cheap and easy-to-get raw materials and simple process routes

Method used

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  • Preparation method for 5-benzyl-7(S)-t-butyloxycarborylamino-5-aza-spiro[2,4]heptanes
  • Preparation method for 5-benzyl-7(S)-t-butyloxycarborylamino-5-aza-spiro[2,4]heptanes
  • Preparation method for 5-benzyl-7(S)-t-butyloxycarborylamino-5-aza-spiro[2,4]heptanes

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Embodiment 1

[0041] 3-Cyclopropylacetoacetate benzamide III

[0042] Take benzylamide II (3.76kg, 19.7mol) of acetoacetate in a 50L reaction kettle, add 1,2-dichloroethane (2.16kg, 21.8mol), 18L of anhydrous dimethylformamide, anhydrous carbonic acid Potassium (9.38kg, 68mol) controlled the reaction temperature and stirred at room temperature 20-35°C for 24h. After the reaction, add 10L of ice water, extract with ether (20L×3), wash with saturated brine until neutral, and anhydrous sulfuric acid The sodium was dried, the solvent was evaporated to dryness and a little diethyl ether was added to precipitate crystals, and 3-cyclopropylacetoacetate benzylamide III was obtained by filtration, which was 3.2 kg. The separated mother liquor was evaporated to dryness with an oil pump, and a small amount of ethyl acetate was added to recrystallize to obtain 0.4kg of III. The total yield is 84%, mp66~67℃.

[0043] 1-Bromo-3-cyclopropylacetoacetate benzamide IV

[0044] Take 3-cyclopropylacetoaceta...

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Abstract

The invention discloses a preparation method for 5-benzyl-7(S)-t-butyloxycarborylamino-5-aza-spiro[2,4]heptane. The method comprises the following steps: reacting benzoylamide acetoacetate as a raw material with 1,2-dichloroethane to obtain 3-cyclopropyl benzoylamide acetoacetate, brominating 3-cyclopropyl benzoylamide acetoacetate by NBS (n-bromosuccinimide) to obtain 1-bromo-3-cyclopropyl benzoylamide acetoacetate, cyclizing under alkaline conditions to obtain 5-benzyl-5-aza-spiro[2,4]heptane-4,7-diketone, further reacting with hydroxylamine hydrochloride to form an oxime compound-4-oxo-5-benzyl-7-oximido-5-aza-spiro[2,4]heptane, reducing by NaBH4 and boron trifluoride diethyl etherate to obtain 5-benzyl-7-amino-5-aza-spiro[2,4]heptane, performing chiral resolution by a resolving agent-L-camphorsulfonic acid to obtain 5-benzyl-7(S)-amino-5-aza-spiro[2,4]heptane, and reacting with di-tert-butyl dicarbonate ester to obtain 5-benzyl-7(S)-t-butyloxycarborylamino-5-aza-spiro[2,4]heptane. According to the method, an intermediate body-carbonyl does not need protection, raw materials are easy to get, a process route is simple, and the method is suitable for industrial production.

Description

technical field [0001] The present invention relates to a preparation method of a compound, more specifically relates to the intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2, 4] Preparation method of heptane. Background technique [0002] Sitafloxacin is a broad-spectrum quinolone antibacterial drug, its chemical name is 7-[(7S)-7-amino-5-azaspiro[2,4]hept-5-yl]-8-chloro- 6-Fluoro-1-[(1R,2S)-cis-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (structure shown below). Because the product 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. [0003] [0004] 7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane (I) is an important intermediate for the synthesis of sitafloxacin. But because of its instability, the preservation of this intermediate has been greatly hindered....

Claims

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Application Information

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IPC IPC(8): C07D209/54
Inventor 刘现军张中剑余飞飞黄文飞
Owner 苏州楚凯药业有限公司
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