Preparation method of (S, S)-8H-6H-pyrrolo [3, 4-b] pyridine

A technology of 4-b and pyridine, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of low total yield and achieve the effect of simple method and low cost

Active Publication Date: 2013-04-10
CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Looking at the three types of methods, the main difference is that the methods for constructing the two heterocycles are different, but they all use the resolution method to prepare the final product, so the overall yield is low

Method used

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  • Preparation method of (S, S)-8H-6H-pyrrolo [3, 4-b] pyridine
  • Preparation method of (S, S)-8H-6H-pyrrolo [3, 4-b] pyridine
  • Preparation method of (S, S)-8H-6H-pyrrolo [3, 4-b] pyridine

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Embodiment 1

[0031] Embodiment 1: the preparation of intermediate 2

[0032] Dissolve 13.7g (R)-2-phenylglycinol in 50ml of methanol, add 14.2g of dimethyl butynedicarboxylate in 150ml of methanol dropwise, add dropwise for about 1 hour, then stir at room temperature 6 hours. After the reaction was completed, the methanol was concentrated under reduced pressure, and the product was crystallized in a refrigerator at 0°C, and then recrystallized with diethyl ether / oil ether to obtain colorless needle-like crystals (intermediate 2). The yield is 85%, M.P 67-68℃, (c=0.59, CHCl 3 );

Embodiment 2

[0033] Embodiment 2: the preparation of intermediate 3

[0034] Weigh 16g of intermediate 2 into a 500ml round bottom flask, add 300ml of THF to dissolve, slowly add 7.5g of acryloyl chloride dropwise at room temperature, after the dropwise addition is completed, raise the reaction temperature to 70°C and reflux for 3 hours, then place The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution was added to adjust the pH to neutral, then extracted with dichloromethane, concentrated under reduced pressure, and recrystallized from anhydrous ether to obtain 17.6 g of the product (intermediate 3). The yield is 90%. M.P 128℃, (C=0.5, CHCl 3 );

Embodiment 3

[0035] Embodiment 3: the preparation of intermediate 4

[0036] Weigh 1.5g of intermediate 3 and place it in a 50ml round bottom flask, add 150mg of 10% palladium carbon, 20ml of methanol, and react with hydrogen at room temperature for 12 hours, filter with diatomaceous earth to obtain the filtrate, and concentrate under reduced pressure The resulting product (intermediate 4) was directly used in the next reaction. M.P 108℃, (C=1.05, CHCl 3 );

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Abstract

The invention discloses a method for enantioselectively synthetizing (S, S)-8H-6H-pyrrolo [3,4-b] pyridine by using (R)-2-phenylglycinol as a chiral inducing reagent. The method comprises the following steps: by taking (R)-2-phenylglycinol as a raw material, carrying out one-step Michael addition reaction and ester exchange reaction to synthetize a intermediate 2; carrying out condensation on the intermediate 2 and acryloyl chloride to obtain a double-ring intermediate 3; carrying out hydrogenation reduction to obtain an intermediate 4 in high stereoselectivity; reacting the intermediate 4 with benzylamine through one-step amine-ester exchange to obtain an intermediate 5; hydrolyzing the intermediate 5 to obtain an intermediate 6; and carrying out ring closing reaction, reducing, removing protecting group on nitrogen to obtain a final product II. The method has the characteristics of favorable stereoselectivity and high yield, and is simple to operate; compared with the traditional method, for no need of hydrogenating and reducing pyridine ring under high pressure, no need of resolution and the like, the preparation method disclosed by the invention is low in cost, safe and reliable, the yield can achieve 20%-30%; and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of side chain (S, S)-octahydro-6H-pyrrolo[3,4-b]pyridine of moxifloxacin. Background technique [0002] Moxifloxacin (moxifloxacin, formula I), the chemical name is 1-cyclopropyl-6 fluoro-1,4-dihydro-7-[(4as,7as)-octahydro-6H-pyrrolo[3,5- b] pyridin-6-yl]-4-oxo-3-quinoline carboxylic acid is a fluoronolone antibacterial drug developed by Bayer Company of Germany, and its hydrochloride is used clinically. This product is characterized as one of the better drugs for the treatment of respiratory tract infections. Formula II is the side chain of moxifloxacin, which is the key intermediate for the synthesis of moxifloxacin. [0003] [0004] So far, the preparation of moxifloxacin side chain intermediate II is still a hot topic of research in various countries. There are three main categories of existing synthetic methods (see Scheme 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCY02P20/55
Inventor 唐卓李光勋
Owner CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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