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A class of carboxylic acid derivatives and their use in the preparation of prodrugs

A technology of carboxylic acid derivatives and alkyl groups, applied in the field of medicine, can solve problems such as patient injury

Active Publication Date: 2018-12-28
李勤耕
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although fospropofol solves the problem that propofol is insoluble in water, it can be seen from the above formula that fospropofol will metabolize formaldehyde with high toxicity in the body, which is destined to cause unnecessary harm to patients. harm; and from published data (as shown below), the dosage of fospropofol is much higher than that of propofol, and the incubation period and duration are much longer than propofol

Method used

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  • A class of carboxylic acid derivatives and their use in the preparation of prodrugs
  • A class of carboxylic acid derivatives and their use in the preparation of prodrugs
  • A class of carboxylic acid derivatives and their use in the preparation of prodrugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0140] Preparation of 4-N,N-dimethylamino-2(R)-fluorobutyrate hydrochloride

[0141] Add 4-amino-2(R)-fluorobutyrate hydrochloride (1.1g, 7.0mmol) in a round bottom flask, wash with saturated Na 2 CO 3 Adjust the pH value of the aqueous solution to 8, then add 88% formic acid (6ml) and 35% formaldehyde aqueous solution (5ml), slowly warm up to 80 ° C, react for 15 hours, cool to room temperature, add 2ml of 6N hydrochloric acid, and then concentrate under reduced pressure, A pale yellow solid was obtained. Add 10ml of methanol to dissolve it, place it in an ice bath and stir for 30min, filter, concentrate the filtrate, reflux the residue with 6N hydrochloric acid (100ml) for 4 hours, remove the liquid by rotary evaporation, and treat the obtained solid with acetonitrile to obtain white Solid 1.1g, yield 85%.

[0142] m.p.: 136-138°C;

[0143] 1 H-NMR (400MHz,D 2 O): δ4.72(ddd,1H),2.90(dtd,2H),2.43(s,6H),1.93(m,2H);

[0144] 13 C-NMR (600MHz,D 2 O): δ173.13, 86.90, 53....

Embodiment 2

[0147] Preparation of 4-N-isopropylamino-2(R,S)-fluorobutyrate hydrochloride

[0148] Add 4-amino-2(R,S)-fluorobutyrate hydrochloride (1.1g, 7.0mmol) in a 50ml round bottom flask, wash with saturated Na 2 CO 3 Adjust the pH value of the aqueous solution to 8, add acetone (15ml) and 5% Pd-C (100mg), replace the air with nitrogen and then replace the nitrogen with hydrogen, react at room temperature for 6 hours, filter to remove Pd-C, adjust with 6N hydrochloric acid The pH of the solution was acidic, and concentrated under reduced pressure to obtain a light yellow solid. Add 10ml of methanol to dissolve it, place it in an ice bath and stir for 30min, filter, concentrate the filtrate, reflux the residue with 6N hydrochloric acid (100ml) for 4 hours, remove the solvent by rotary evaporation, and treat the resulting solid with acetonitrile to obtain a white Solid 1.05g, yield 75%.

[0149] ESI-MS m / z[M+H] + 164.12.

Embodiment 3

[0151] Preparation of 4-N,N-diethylamino-2(R,S)-trifluoromethylbutyrate hydrochloride

[0152] Add 4-amino-2-trifluoromethylbutyrate hydrochloride (2.07g, 10mmol) in 50ml round bottom flask, wash with 1NNaHCO 3 Adjust the pH value of the aqueous solution to 8, add acetonitrile 50ml, add dropwise a mixed solution (10ml) of bromoethane (2.18g, 20mmol) and acetonitrile, and maintain the pH of the reaction solution at 7-8 with sodium bicarbonate solution. After the reaction, add Adjust the pH to below 5 with hydrochloric acid, and concentrate under reduced pressure to obtain a light yellow solid. 10ml of methanol was added, stirred for 30min, filtered, the filtrate was concentrated, the residue was refluxed with 6N hydrochloric acid (100ml) for 4 hours, and the solvent was removed by rotary evaporation to obtain a white solid with a yield of 13%.

[0153] ESI-MS m / z[M+H] + 228.16.

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PUM

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Abstract

The present invention discloses a class of carboxylic acid derivatives and use thereof in preparation of prodrugs. The carboxylic acid derivatives have the general formula (I), wherein R 1 is H or alkyl; X is H or F; Y is F or fluoroalkyl; n is 0, 1, 2, 3, 4, 5, or 6; W is W 1 or W 2 ; W 1 is NR 2 R 3 NR 2 R 3 ·A, R 2 and R 3 are each independently H, alkyl, cycloalkyl, or a protecting group for amino; m is 0, 1, 2, or 3; A is an acid; W 2 is COOR 4 , OPO(OR 4 ) 2 , or PO(OR 4 ) 2 ; R 4 is H, or a protecting group for carboxyl or hydroxyl in phosphoric acid.

Description

[0001] Cross References to Related Applications [0002] This application claims the priority of Chinese patent application 201410053129.9 filed on February 17, 2014 and Chinese patent application 201410154956.7 filed on April 17, 2014, the disclosures of which are incorporated herein by reference. technical field [0003] The invention relates to the field of medicine, in particular to a class of carboxylic acid derivatives and their use in the preparation of prodrugs. Background technique [0004] Prodrugs are prodrugs, also known as drug precursors, prodrugs, etc., which refer to compounds that have pharmacological effects after in vivo transformation. The prodrug itself has no biological activity or very low activity, and releases active substances after metabolism in the body. The purpose of researching and preparing prodrugs is to increase the bioavailability of the original drug, change the solubility of the original drug, enhance targeting or reduce the toxicity and...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/20C07C227/04C07C227/18C07D203/08C07D203/02C07D295/15C07C229/22C07D305/14C07C69/63C07C67/30C07F9/09
CPCA61P23/00C07C229/20C07C229/22C07D203/02C07D203/08C07D207/06C07D295/15C07D305/14C07D405/12C07F9/091C07F9/3808Y02P20/55C07C227/04C07C227/18
Inventor 李勤耕王涛陈刚王元忠毛伟吴酮曾令国
Owner 李勤耕
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