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Preparation method of quininone derivative

A derivative, quinidone technology, applied in organic chemistry and other directions, can solve the problem of low reaction yield

Active Publication Date: 2020-03-27
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Wherein the third step condensation reaction needs to use strong base: potassium, sodium, potassium tert-butoxide, sodium ethylate, potassium ethylate, etc., and the reaction needs to be at a higher temperature (≥100 degrees), and the reaction process is prone to intermolecular condensation. The yield is low (≈50%)

Method used

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  • Preparation method of quininone derivative
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  • Preparation method of quininone derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The preparation of embodiment 1 formula II compound (X is methylsulfonyl)

[0042] Add compound formula I (10.00g), dichloromethane (100mL), and triethylamine (10.14g) into the reaction flask, stir at 0°C, then add methanesulfonyl chloride (10.45g) dropwise, after the addition is complete, the Stir at ℃, filter after the reaction is complete, and evaporate the filtrate to dryness under reduced pressure to obtain the compound of formula II. Yield 100%.

[0043] GC-MS: [M]=375.10

Embodiment 2

[0044] The preparation of embodiment 2 formula III compound

[0045] Add compound diethyl malonate (6.41g), tetrahydrofuran (100ml) to the reaction flask at room temperature, and sodium hydrogen (3.20g) is warmed up to 65°C, and a tetrahydrofuran solution (50ml) of the compound of formula II (15.02) is added to complete Stirring was continued, and the reaction was complete. Dichloromethane (150ml) and water (50mL) were added, and the organic phase was concentrated to dryness under reduced pressure at 30°C to obtain the compound of formula III (10.35g), with a yield of 75.0%.

[0046] GC-MS: [M]=343.20

Embodiment 3

[0047] The preparation of embodiment 3 formula IV compound

[0048] Add toluene (100ml) and potassium tert-butoxide (4.25g) to the reaction flask at room temperature, raise the temperature to 100°C, add the toluene solution (40ml) of the compound of formula III (10.00g) dropwise, continue stirring after the dropwise addition, and the reaction is complete , the reaction solution was cooled to 20°C, water (30ml) and chloroform (150ml) were added, and the organic phase was concentrated to dryness under reduced pressure at 40°C to obtain the compound of formula IV (4.71g), with a yield of 82.0%.

[0049] GC-MS: [M]=197.23

[0050] 1H NMR (400MHz, DMSO) δ4.30(s, 1H), 4.18(q, J=7.1Hz, 2H), 2.56–2.30(m, 5H), 1.95–1.80(m, 2H), 1.75–1.62( m,2H),1.29(t,J=7.1Hz,3H).

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Abstract

The invention provides a preparation method of a quininone derivative, and belongs to the field of pharmaceutical chemical industry. According to the method disclosed by the invention, the 3-quininonederivative is obtained by taking a diethanolamine derivative as a starting material through chlorination or methanesulfonic acid and diethyl malonate cyclization and Dieckmann Condensation. The product produced by the method has the characteristics of high purity, high yield, low cost, simple operation and stable process.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation method of quinine derivatives. Background technique [0002] The chemical name of 3-quinine hydrochloride is 1-azacyclo[2.2.2]oct-3-one hydrochloride, which is synthesized from azasetron, palonosetron, solifenacin, maro It is an important raw material for Pitan and other medicines; at the same time, as a precursor of chiral catalysts, it is widely used in reactions such as asymmetric dihydroxylation. [0003] At present, the method for synthesizing 3-quinuclidone hydrochloride is shown in the above synthetic route. The starting material is 4-piperidinecarboxylic acid, and 3-quinuclidine is obtained through esterification, alkylation of N, Dieckmann Condensation, and decarboxylation. Ketone hydrochloride. The price of the starting material 4-piperidinecarboxylic acid is 400 yuan / kg, the yield of the four-step reaction is about 50%, and the total cost i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 林碧悦孙国栋寇景平梁桂挺王文迪胡吉安王仲清罗忠华黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD
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