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Sodium salt, crystal form and preparation method of pyrrolidine carboxylic acid compound

A compound and sodium salt technology, applied in the field of medicinal chemistry, can solve the problems of easy degradation and discoloration, poor stability, aggravated degradation and racemization, etc., and achieve good curative effect.

Active Publication Date: 2020-07-28
NANJING HERON PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The first object of the present invention is to provide a sodium salt of a compound of formula I (S)-5-benzoyl-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid, to overcome formula I in the prior art The compound has poor stability and is easy to degrade and change color when left at room temperature
In aqueous solution, especially under alkaline conditions, its degradation and racemization will be aggravated, and it will be difficult to operate in the preparation process.

Method used

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  • Sodium salt, crystal form and preparation method of pyrrolidine carboxylic acid compound
  • Sodium salt, crystal form and preparation method of pyrrolidine carboxylic acid compound
  • Sodium salt, crystal form and preparation method of pyrrolidine carboxylic acid compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The preparation of embodiment 1 formula II compound

[0055] The structure of the compound of formula II is shown below:

[0056]

[0057] Formula II compound is the preparation method of the sodium salt of formula I compound, comprises the following steps:

[0058] Step 1: Add 100 g of ketorolac, 550 mL of 95% ethanol, and 115 g of octylglucamine into the reaction flask, heat up to an internal temperature of 75° C. under stirring, and keep the reaction for 0.5 h. Slowly cool down to 35°C within 2h, keep stirring for 2h, then cool down to -10°C, keep stirring for 12h, filter, wash the filter cake with 95% ethanol at 0°C, and dry it under reduced pressure at 50°C for 7h to obtain off-white 129 g of the solid was compound 3, and the yield was 60%.

[0059] Step 2, add 129g of compound 3 to 1400mL of purified water and 1000mL of ethyl acetate, adjust the pH value of the system to 6-7 with 4N dilute hydrochloric acid, continue stirring at room temperature for 0.5h, let...

Embodiment 2

[0064] The preparation of embodiment 2 formula II compound

[0065] The structure of the compound of formula II is shown below:

[0066]

[0067] Formula II compound is the preparation method of the sodium salt of formula I compound, comprises the following steps:

[0068] Step 1: Add 100 g of ketorolac, 550 mL of 95% ethanol, and 100 g of octylglucamine into the reaction flask, heat up to 70° C. under stirring, and keep the reaction for 0.5 h. Slowly cool down to 30°C within 2h, keep stirring for 1h, then cool down to -5°C, keep stirring for 12h, filter, wash the filter cake with 95% ethanol at 5°C, and dry under reduced pressure at 45°C for 5h to obtain off-white 125 g of the solid was compound 3, and the yield was 56%.

[0069] Step 2, add 125g of compound 3 to 1400mL of purified water and 1000mL of ethyl acetate, adjust the pH value of the system to 6-7 with 4N dilute hydrochloric acid, continue to stir at room temperature for 0.5h, let stand to separate the liquid, c...

Embodiment 3

[0073] The preparation of embodiment 3 formula II compound

[0074] The structure of the compound of formula II is shown below:

[0075]

[0076] Formula II compound is the preparation method of the sodium salt of formula I compound, comprises the following steps:

[0077] Step 1: Add 100 g of ketorolac, 550 mL of 95% ethanol, and 150 g of octylglucamine into the reaction flask, raise the temperature to 70° C. under stirring, and keep the reaction for 0.5 h. Slowly cool down to 30-35°C within 2h, keep stirring for 1-2h, then cool down to -8°C, keep stirring for 12-15h, filter, wash the filter cake with 95% ethanol at 0°C, and depressurize at 45°C After drying for 5-7 hours, 130 g of compound 3 was obtained as an off-white solid with a yield of 60%.

[0078]Step 2, add 130g of compound 3 to 1500mL of purified water and 1000mL of ethyl acetate, adjust the pH value of the system to 6-7 with 4N dilute hydrochloric acid, continue to stir at room temperature for 0.5h, let stand...

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Abstract

The invention provides a sodium salt, crystal form and preparation method of a pyrrolidine carboxylic acid compound, and a pharmaceutical composition containing the sodium salt, a preparation form anda pharmaceutical application. The compound shown in the formula I is a pharmaceutically active substance belonging to pyrrolidine carboxylic acid compounds. The sodium salt or the crystal form of thecompound shown in the formula I is high in water solubility and physicochemical stability, has the advantages of being small in administration dosage, quick in drug effect exertion and small in toxicand side effect, and the pharmaceutical composition containing the alkali addition sodium salt of the compound shown in the formula I can be widely applied to preparation of analgesic, antipyretic and anti-inflammatory drugs.

Description

technical field [0001] The present invention relates to a sodium salt, crystalline form and preparation method of pyrrolidine carboxylic acid compounds, in particular to compound (S)-5-benzoyl-2, 3-dihydro-1H-pyrrolazine-1 of formula I - Sodium salt of carboxylic acid, crystal form of salt and preparation method, belonging to the field of medicinal chemistry. Background technique [0002] Ketorolac tromethamine is a non-steroidal anti-inflammatory analgesic drug, which mainly works by blocking the cyclooxygenase enzyme in the metabolism of arachidonic acid, thereby reducing the production of prostaglandins. The reduction of prostaglandins can reduce the sensitivity of nerve fibers to noxious stimuli, thereby playing analgesic, anti-inflammatory and antipyretic effects. The ketorolac trometamol is converted into ketorolac in the human body to exert curative effects. The ketorolac has analgesic, anti-inflammatory, antipyretic and platelet aggregation inhibiting effects, but h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/407A61P29/00
CPCC07D487/04A61P29/00C07B2200/13
Inventor 陆晨光王芳徐丽
Owner NANJING HERON PHARMA SCI & TECH CO LTD
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