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Method for synthesizing (S,S)-2,8-diazabicyclo[4.3.0]nonane

A technology of nonane and alkyl, applied in the field of drug synthesis, can solve the problems of high production cost and high process cost

Active Publication Date: 2018-03-13
SHANGYU JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the process of this route is as long as 11 steps, and the Sharpless method and format reaction with high process cost are adopted, the production cost is high

Method used

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  • Method for synthesizing (S,S)-2,8-diazabicyclo[4.3.0]nonane
  • Method for synthesizing (S,S)-2,8-diazabicyclo[4.3.0]nonane
  • Method for synthesizing (S,S)-2,8-diazabicyclo[4.3.0]nonane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Example 1 Synthesis of 1-benzyl-3-methoxycarbonyl-4-pyrrolidone

[0118]

[0119] Put benzylamine (174mL, 1.6mol) into the reaction flask, control the temperature at 9-12°C, add methyl acrylate (1.6mol) dropwise, and complete the dropwise addition in 3 to 5 hours. Keep the temperature for 4 hours, distill under reduced pressure, and collect the positive fraction to obtain 150 g of the addition product with a molar yield of 78%.

[0120] Put the distilled addition product (77g, 0.4mol) into the reaction flask, control the temperature at 20-25°C, and add potassium iodide (1.0g, 0.006mol), methyl chloroacetate (65g, 0.6mol), potassium carbonate (60.7 g, 0.44 mol), kept stirring for 24 hours, filtered, the mother liquor was distilled under reduced pressure, and the positive fraction was collected to obtain 85 g of the product with a yield of 81%.

[0121] Sodium methoxide (19.2g, 0.35mol) was suspended in 40mL of toluene, the temperature was raised to 60-80°C, and the toluene sol...

Embodiment 2-1

[0123] Example 2-1 Synthesis of (R)-N-(1-phenyl-1-ethyl)-3-chloropropylamine

[0124]

[0125] Put (R)-methylbenzylamine (121g, 1mol) into the reaction flask, add 1-chloro-3-iodopropane (203g, 1mol) dropwise, and stir at room temperature for 16 hours. GC detects the reaction solution and the reaction is complete. The reaction liquid was distilled under reduced pressure, and the positive fraction was collected to obtain 142 g of fraction with a purity greater than 97%, with a yield of 72%.

[0126] ESI-MS: 198.1(M+1)

Embodiment 2-2

[0127] Example 2-2 Synthesis of (R)-N-(1-phenyl-1-ethyl)-acrylamide

[0128]

[0129] Dissolve (R)-methylbenzylamine (121g, 1mol) in dichloromethane (200mL), add triethylamine (111g, 1.1mol), add chloropropionyl chloride (130g, 1.02mol) dropwise, control the temperature No more than 10°C, after dropping, warm up to room temperature and stir for 0.5 hours. The reaction solution is washed with saturated brine, and the organic phase is concentrated to dryness to obtain (R)-N-(1-phenyl-1-ethyl)-chloride Crude propionamide (100% yield). Potassium tert-butoxide (112 g, 1 mol) was suspended in 300 mL anhydrous tetrahydrofuran, the temperature was raised to reflux, and the solution of the above amide intermediate in 100 mL tetrahydrofuran was added dropwise, and the reflux was maintained. The addition is completed in about 2 hours. Reflux for half an hour. The dry solvent was concentrated, the residue was dispersed with dichloromethane, washed with water, dried, and distilled under re...

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Abstract

The invention discloses a method for synthesizing (S,S)-2,8-diazabicyclo[4.3.0]nonane. The method comprises the following steps of: (a) adopting a compound which is shown in a formula V and comprisesa chiral auxiliary group and an amino protecting group as a raw material, and performing an intramolecular cyclization reaction to obtain a compound shown in a formula VI; (b) removing the chiral auxiliary group and amino protecting group from the compound shown in the formula V so as to obtain a compound shown in a formula VII, wherein when X is a hydrogen atom, the compound shown in the formulaVII is (S,S)-2,8-diazabicyclo[4.3.0]nonane; and (c) when X is an oxygen atom, performing a reduction reaction on the compound shown in the formula VII by using amide so as to obtain (S,S)-2 ,8-diazabicyclo[4.3.0]nonane.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a method for preparing a key chiral intermediate (S,S)-2,8-diazabicyclo[4.3.0]nonane of the quinolone drug moxifloxacin. Background technique [0002] Moxifloxacin is a fourth-generation quinolone broad-spectrum antibacterial drug. It has the advantages of strong antibacterial activity, broad antibacterial spectrum, resistance to resistance, and effectiveness for common drug-resistant bacteria, long half-life, and fewer adverse reactions. Its chemical name is 1-cyclopropyl-7-{(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl}-6-fluoro-8-methoxy-4- Oxygen-1,4-dihydro-3-quinolinecarboxylic acid, CAS registration number is 151096-09-2, the structural formula is as follows: [0003] [0004] The traditional synthesis process of moxifloxacin includes a multi-step condensation reaction, see the following reaction route: [0005] [0006] Although the route has been improved and optimized in recen...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D207/277C07D207/267
CPCY02P20/55C07D471/04C07D207/267C07D207/277
Inventor 罗光顺丁二伟苏琦
Owner SHANGYU JINGXIN PHARMA
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