Preparation method of choline receptor antagonist

A choline receptor and antagonist technology, applied in the field of drug synthesis, can solve the problems of high cost, low yield, unsuitable for industrial production, etc., and achieves high reaction yield and product purity, simple operation, and remarkable economic benefits. Effect

Active Publication Date: 2022-01-18
SHANGHAI FANGYU HEALTH PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, when using the above method to synthesize ipratropium bromide, the hydrolysis reaction of the second step easily causes the hydrolysis of the ester group of the target compound, the yield is lower, and the cost is higher, so it is not suitable for industrialized production

Method used

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  • Preparation method of choline receptor antagonist
  • Preparation method of choline receptor antagonist
  • Preparation method of choline receptor antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Step 1): Preparation of 2-formylphenylacetic acid-(1R,3r,5S)-8-isopropyl-8-nitrobicyclo[3.2.1]octane-3-yl ester (compound II)

[0047] Under nitrogen protection, 164.27g of α-formylphenylacetic acid (1.0mol) and 1L of tetrahydrofuran were added to the reaction flask, the temperature was lowered to 0-5°C, and 243.23g (1.5mol) of N,N'-carbonyldiimidazole was added. Keep stirring at 0-5° C. for 1 hour, and then add 186.20 g (1.1 mol) of isopropyltropine alcohol. After the addition is complete, keep the reaction at 20-30°C for 8 hours. Then lower the temperature to 0-5°C, add 1L water in drops while keeping warm, keep stirring at 0-5°C for 2 hours after dropping the water, filter, and vacuum-dry the filter cake at 60°C until constant weight to obtain 299.64g off-white solid. Yield 95%, purity HPLC: 99.8%;

[0048]1HNMR (DMSO-d6): δppm 1.05-1.08 (d, 6H), 1.54-1.58 (d, 2H), 1.72-1.74 (d, 4H), 2.05-2.09 (m, 2H), 2.77-2.80 (m, 1H), 3.36-3.58(m, 3H), 4.96-4.98(t, 1H), 7.09-7....

Embodiment 2

[0062] Step 1): Preparation of 2-formylphenylacetic acid-(1R,3r,5S)-8-isopropyl-8-nitrobicyclo[3.2.1]octane-3-yl ester (compound II)

[0063] Under nitrogen protection, 164.27g of α-formylphenylacetic acid (1.0mol) and 1L of tetrahydrofuran were added to the reaction flask, the temperature was lowered to 0-5°C, and 162.15g (1.0mol) of N,N'-carbonyldiimidazole was added. Keep stirring at 0-5° C. for 1 hour, and then add 186.20 g (1.1 mol) of isopropyltropine alcohol. After the addition is complete, keep the reaction at 20-30°C for 8 hours. Then lower the temperature to 0-5°C, drop 1L of water into it while keeping it warm, keep stirring at 0-5°C for 2 hours after dropping the water, filter, and vacuum-dry the filter cake at 60°C until constant weight to obtain 293.33g of off-white solid. Yield 93%, purity HPLC: 99.6%. NMR results are the same as in Example 1.

[0064] Steps 2), 3), and 4) are consistent with Example 1.

Embodiment 3

[0066] Step 1): Preparation of 2-formylphenylacetic acid-(1R,3r,5S)-8-isopropyl-8-nitrobicyclo[3.2.1]octane-3-yl ester (compound II)

[0067] Under nitrogen protection, 164.27g of α-formylphenylacetic acid (1.0mol) and 1L of tetrahydrofuran were added to the reaction flask, the temperature was lowered to 0-5°C, and 486.45g (3.0mol) of N,N'-carbonyldiimidazole was added. Keep stirring at 0-5° C. for 1 hour, and then add 186.20 g (1.1 mol) of isopropyltropine alcohol. After the addition is complete, keep the reaction at 20-30°C for 8 hours. Then lower the temperature to 0-5°C, drop 1L of water into it while keeping it warm, keep stirring at 0-5°C for 2 hours after dropping the water, filter, and vacuum-dry the filter cake at 60°C to constant weight to obtain 290.18g of off-white solid. Yield 92%, purity HPLC: 99.7%. NMR results are the same as in Example 1.

[0068] Steps 2), 3), and 4) are consistent with Example 1.

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Abstract

The invention provides a preparation method of a choline receptor antagonist. The choline receptor antagonist is ipratropium bromide. According to the method provided by the invention, alpha-formyl phenylacetic acid is taken as an initial raw material and reacts with isopropyl tropine alcohol to generate a compound II, the compound II is subjected to a reduction reaction to generate a compound III, and the compound III reacts with bromomethane to generate ipratropium bromide. Compared with the prior art, the method is easy to operate, high in safety, low in cost, high in yield and product purity and more suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of a choline receptor antagonist. More specifically, the present invention relates to a kind of new preparation technique of different third detropammonium bromide and monohydrate thereof. Background technique [0002] Ipratropium bromide monohydrate is white or off-white crystalline powder, soluble in water, easily soluble in methanol, slightly soluble in ethanol. The common English name of Ipratropium bromide is Ipratropium Bromide, and the structural formula of its monohydrate is as follows: [0003] [0004] Ipratropium bromide is usually used clinically as a bronchodilator for the maintenance treatment of bronchospasm caused by chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. With different third detropammonium bromide as the pharmaceutical dosage form of active ingredient has inhalation aerosol, inhalation s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/10
CPCC07D451/10
Inventor 俞雄张袁伟郭辉辉
Owner SHANGHAI FANGYU HEALTH PHARMA TECH CO LTD
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