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3-aminopyrrolidine compounds, and synthetic method and uses thereof

A technology of aminopyrrolidine and compounds, applied in the field of biomedicine, can solve the problems of high process cost, unfriendly environment, expensive reducing agent, etc., and achieve the effect of short process flow, huge market application value and low cost

Active Publication Date: 2015-01-07
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] No matter adopt resolution method or asymmetric synthesis method to prepare formula (I) compound, prior art all has the problem of using high-pressure hydrogenation technology and expensive reducing agent; All there is process cost height, unfriendly shortcoming to environment equally

Method used

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  • 3-aminopyrrolidine compounds, and synthetic method and uses thereof
  • 3-aminopyrrolidine compounds, and synthetic method and uses thereof
  • 3-aminopyrrolidine compounds, and synthetic method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 Preparation of (3S)-1-benzyl-3-amino-4-(3-ethoxycarbonylpropyl)-pyrrolidine

[0051]

[0052]Dissolve 100 g of isopropylamine in 100 ml of water, adjust the pH value to 8.0 with hydrochloric acid aqueous solution under ice-water bath cooling, and add 20 ml of tetrahydrofuran, then dilute to 700 ml with 0.1 M Tris-HCl buffer solution and preheat to 30 ° C, then Add 200ml of tetrahydrofuran solution containing 50g of 1-benzyl-4-(3-ethoxycarbonylpropyl)-3-pyrrolidone (3-1), and finally add 1g of ω-transaminase freeze-dried powder and 0.8g of PLP (pyridoxal phosphate) , the reaction is controlled by 20% isopropylamine aqueous solution to pH = 7-10, the temperature is converted at 10-50° C. for more than 24 hours, and the reaction is completed by TLC monitoring. The solid was removed by filtration, the mother liquor was extracted three times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, and concentrated to obtain 45 g ...

Embodiment 2

[0053] Example 2 Preparation of (1S,6S)-8-benzyl-2,8-diazabicyclo[4,3,0]nonane

[0054]

[0055] (3S)-1-benzyl-3-amino-4-(3-ethoxycarbonylpropyl)-pyrrolidine (compound 2-1 in Example 1, 27.4g, 100mmol), 270ml toluene, 35ml acetic acid, The temperature was raised to 70°C for 16h. After the reaction was carried out completely, it was washed with aqueous sodium bicarbonate to a pH of about 8, the combined water phase was extracted with 100ml toluene, the combined toluene phase was washed with water, the toluene phase was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain an oily product (1 -2) (21.2 g, yield 92%). 1 H-NMR (400MHz, CDCl 3 ):δ7.14(2H),7.07(1H),7.06(2H),3.68(1H),3.62(2H),2.60(2H),2.34(2H),2.23(2H),2.20(1H),1.65 (2H). MS-ESI: m / z: 229 (M + +1).

[0056] Add 35.0 g of lithium aluminum hydride into 50 ml of anhydrous tetrahydrofuran, and slowly add a solution of the product (compound 1-2, 21.2 g, 92 mmol) dis...

Embodiment 3

[0057] Example 3 Preparation of (S, S)-2,8-diazabicyclo[4,3,0]nonane

[0058]

[0059] The product from the previous step (compound 1-1, 10.8g, 50mmol) was dissolved in 250ml of methanol, 0.5g of 10% palladium carbon was added to the autoclave, and hydrogenation reaction was carried out at room temperature under a pressure of 1.0MPa for 24 hours. After the reaction was complete, the palladium carbon was removed by filtration , the filtrate was adjusted to PH=10.0 with sodium methoxide / methanol solution, filtered, the filtrate was concentrated to dryness and then distilled under reduced pressure to obtain 5.3 g of the product (S,S)-2,8-diazabicyclo[4,3,0]nonane, The yield is about 84%, and the ee value is 98.1%.

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Abstract

The invention relates to 3-aminopyrrolidine compounds, and a synthetic method and uses thereof. 3-pyrrolidone compounds (compounds IIIa or IIIb) are adopted as substrates and subjected to transaminase reactions under the actions of transaminase and an amino donator to obtain the (S)-3-aminopyrrolidine compounds (compounds II). Then intramolecular cyclization and removal of amino protective groups are performed to obtain (S,S)-2,8-diazabicyclo[4,3,0] nonane (a compound I). According to the 3-aminopyrrolidine compounds, the synthetic method and the uses, a synthetic technology that is low in cost, short in process steps and environmental friendly is provided for a moxifloxacin intermediate, and the synthetic technology will have great market application value and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of biomedicine and relates to the technical field of preparation of 3-aminopyrrolidine compounds, in particular to a 3-aminopyrrolidine compound and its synthesis method and application. Background technique [0002] The 3-aminopyrrolidine compound is mainly used to prepare the chiral intermediate (S, S)-2,8-diazabicyclo[4,3,0]nonane of the quinolone antibacterial drug moxifloxacin. [0003] Moxifloxacin (Moxifloxacin) is a new generation of fluoroquinolone antibacterial drugs, which was first successfully developed by Bayer Company of Germany. It was first listed in Germany in September 1999 under the trade name Avelox. In December of the same year, moxifloxacin was approved by the FDA to be launched in the United States, and later it was launched in many countries and regions around the world. It is widely used clinically in the treatment of respiratory infections such as acquired pneumonia, chronic bronc...

Claims

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Application Information

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IPC IPC(8): C07D207/14C07D471/04C12P17/18C12P17/10
CPCY02P20/55C07D207/14C07D471/04C12P17/10C12P17/182
Inventor 林义洪华斌颜剑波王志华
Owner ZHEJIANG LEPU PHARMA CO LTD
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