Asymmetric synthesis method, relevant raw materials and preparation method of (S,S)-2,8-diazabicyclo[4,3,0] nonane

一种二氮杂双环、合成方法的技术，应用在散装化学品生产、有机化学等方向，能够解决工艺成本高、工艺流程短、工艺流程复杂等问题

Active Publication Date: 2013-04-17
ABA CHEM SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Regardless of adopting the resolution method or the asymmetric synthesis method to prepare the compound of formula (I), the existing synthetic technology has the disadvantages of high process cost and complicated process flow. Since this compound is the main intermediate for preparing moxifloxacin, it is necessary to develop a A synthesis technology with low cost and short process flow will have huge market application value

Method used

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  • Asymmetric synthesis method, relevant raw materials and preparation method of (S,S)-2,8-diazabicyclo[4,3,0] nonane
  • Asymmetric synthesis method, relevant raw materials and preparation method of (S,S)-2,8-diazabicyclo[4,3,0] nonane
  • Asymmetric synthesis method, relevant raw materials and preparation method of (S,S)-2,8-diazabicyclo[4,3,0] nonane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1 Preparation of 1-benzyl-4-(3-ethoxycarbonylpropyl)-3-pyrrolidone

[0080]

[0081] 1-benzyl-4-ethoxycarbonyl-3-pyrrolidone (5.0g, 20.2mmol), ethyl acrylate (6.0g, 60.0mmol), triphenylphosphine (0.45g, 1.7mmol), and 25ml of acetonitrile were heated to Reflux reaction for 20 hours, after the reaction was completed, the dry solvent was concentrated under reduced pressure to obtain an oily liquid, which was separated by column chromatography to obtain oily substance (1-1) (3.7 g, yield 53%). 1 HNMR (500MHZ, CDCl 3 )δ7.38-7.26 (m, 5H), 4.22-4.09 (m, 4H), 3.76-3.70 (m, 2H), 3.37 (d, J=9.65Hz, 1H), 3.10 (dd, J=77.5Hz17 .3Hz, 2H), 2.76 (d, J = 9.65Hz, 1H), 2.51-2.10 (m, 4H), 1.30-1.22 (m, 6H). MS-ESI: m / z: 348 (M + +1).

[0082] The product (1-1) (3.0 g, 8.6 mmol) and 30 g of 6N hydrochloric acid were heated to reflux for 10 hours. After the reaction was complete, the water was concentrated to dryness under reduced pressure, and 15 ml of isopropanol was added,...

Embodiment 2

[0083] Example 2 Preparation of 1-benzyl-4-(3-chloropropyl)-3-pyrrolidone

[0084]

[0085] Dissolve 1-benzyl-4-ethoxycarbonyl-3-pyrrolidone (2.5g, 10.1mmol) in 25ml of tetrahydrofuran, cool in an ice-water bath, add triethylamine (2g, 20.2mmol) and stir for 30 minutes, add dropwise 1-chloro - 3-Iodopropane (4.12g, 20.2mmol), the dropwise addition was completed in 30 minutes, then warmed to room temperature, and the reaction was continued for 18 hours. After the reaction was completed, it was extracted with dichloromethane (10ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and the dry solvent was concentrated under reduced pressure to obtain an oil, which was purified by column chromatography to obtain an oil (2-1) (2.12g, 6.57 mmol, yield: 65%). 1 H NMR (500MHz, CDCl 3 )δ7.34-7.27(m, 5H), 4, 17(q, J=7.1Hz, 2H), 3.71(s, 2H), 3.48-3.51(m, 2H), 3.40(d, J=9.6Hz , 1H), 3.19(d, J=17.2Hz, 1H), 2.99(d, J=17.2Hz, 1H), 2.73(d, J=9.6Hz, 1H), 2.0...

Embodiment 3

[0087] Example 3 Preparation of (3S, 4S)-1-benzyl-3-[(1R)-phenethylamino]-4-(3-ethoxycarbonylpropyl)-pyrrolidine

[0088]

[0089] 1-benzyl-4-(3-ethoxycarbonylpropyl)-3-pyrrolidone (compound 1-2 in Example 1, 17.0g, 62mmol), (R)-1-phenylethylamine (7.87g, 65mmol), benzene 150ml, reflux and water separation reaction under nitrogen protection for 6h. After the reaction was completed, the solvent was concentrated under reduced pressure, and the obtained oily product was dissolved in 100 ml of absolute ethanol, added to an autoclave, 10 g of Raney nickel was added, and hydrogenation reaction was carried out at room temperature under a pressure of 1.0 MPa for 72 hours. After the reaction was complete, suction filtration was performed, and the filtrate was concentrated to dryness under reduced pressure to obtain 20 g of an oily product, which was separated by column chromatography to obtain an oily product (3-1) (13.5 g, yield 57%). 1 H NMR (500MHZ, CDCl 3 )δ7.34-7.23 (m, 10H),...

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Abstract

The invention relates to an asymmetric synthesis method of (S,S)-2,8-diazabicyclo[4,3,0] nonane (I) as a chiral intermediate of moxifloxacin. The asymmetric synthesis method comprises the steps of: firstly, carrying out a dewatering reaction on a 3-pyrrolidone compound (shown as formula III or IV) and chiral amine, reducing a dewatered product to obtain enantiopure compounds shown as a formula (II) under different reducing conditions, and carrying out intramolecularly cyclization and removal of chiral prothetic groups on the compounds shown as the formula (II) to obtain (S,S)-2,8-diazabicyclo[4, 3, 0] nonane (I). The invention also relates to 3-pyrrolidone shown as a formula (III) or (IV) and a preparation method thereof, wherein R is an amino protection group; in the formula (II), * is a chiral center mark of the chiral prothetic groups, R1 and R2 are respectively C1-4 alkyl, C1-4 hydroxyl or carboxyl substituted C1-4 alkyl, aryl, carboxyl, C1-4 carbalkoxy or carbamoyl, when Z is H2, Y is chlorine, bromine, iodine or hydroxyl sulphonate, when Z is O, Y is hydrogen, hydroxyl or C1-4 alkoxy; in the formula (III), R3 is hydrogen or C1-4 alkyl; and in the formula (IV), Y is chlorine, bromine, iodine or hydroxyl sulphonate.

Description

technical field [0001] The present invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to the technical field of preparation of chiral intermediates of quinolone antibacterial drug moxifloxacin, specifically a chiral intermediate (S, S) of quinolone antibacterial drug moxifloxacin - an asymmetric synthesis method of 2,8-diazabicyclo[4,3,0]nonane, and also relates to a raw material 3-pyrrolidone compound used to prepare the intermediate and a preparation method. Background technique [0002] Moxifloxacin is a third-generation quinolone broad-spectrum antibacterial drug. It was launched in 1999 and has been widely used clinically to treat respiratory tract infections such as acquired pneumonia, acute exacerbation of chronic bronchitis, and acute bacterial sinusitis. [0003] [0004] (S, S)-2,8-diazabicyclo[4,3,0]nonane compound (I) is the key chiral intermediate of moxifloxacin, and its molecular structure has two skeleton...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D207/14C07D207/24
CPCC07D471/04C07D207/14C07D207/24C07D207/27Y02P20/55
Inventor 申屠晓波祁彦涛王博
Owner ABA CHEM SHANGHAI
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