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1-(2-methoxypheny1)-4-[3-(naphthalene-1-oxy)-2-hydroxypropyl] piperazine optical isomer and salt thereof, preparation method and application

A technology of methoxyphenyl and methoxyphenyl, applied in salts of optical isomers, optical isomers of 1--4-[3--2-hydroxypropyl]piperazine, and applications in medicine field, can solve the problems of no receptor subtype selectivity, reflex tachycardia, etc., and achieve the effect of high selectivity and small side effects

Inactive Publication Date: 2010-01-20
广州医学院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the currently used α 1 - Receptor antagonists are also not receptor subtype selective, so they can also cause side effects such as orthostatic hypotension and reflex tachycardia

Method used

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  • 1-(2-methoxypheny1)-4-[3-(naphthalene-1-oxy)-2-hydroxypropyl] piperazine optical isomer and salt thereof, preparation method and application
  • 1-(2-methoxypheny1)-4-[3-(naphthalene-1-oxy)-2-hydroxypropyl] piperazine optical isomer and salt thereof, preparation method and application
  • 1-(2-methoxypheny1)-4-[3-(naphthalene-1-oxy)-2-hydroxypropyl] piperazine optical isomer and salt thereof, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Dissolve 0.97g (0.04mol) of sodium hydride in 60ml of DMF (thionyl chloride), and add dropwise 20mL of a DMF solution containing 4.32g (0.03mol) of 1-naphthol, and (2R)- Tosylglycidyl 6.84g (0.03mol, 91% ee) DMF solution 20mL, room temperature reaction for 6 hours, add water 80mL to stop the reaction, extract 3 times, each time with ethyl acetate 100mL, wash the organic layer 3 times , with saturated saline 100mL each time, anhydrous Na 2 SO 4 After drying, the solvent was recovered to obtain 13.45 g of a brown oily crude product. The crude product was purified by silica gel column chromatography using petroleum ether-ethyl acetate at a volume ratio of 30:1 as the eluent to obtain 4.98 g of the product with a yield of 83% and 92% ee. Detected MSm / z(M+H + ) 201, bp118~122°C (0.25mm), it was confirmed by HPLC and standard comparison that it was (2R)-(1-naphthyloxy)-methyloxirane represented by the above formula (1).

[0039] Dissolve 26.5g (0.25mol) of diethanolamine ...

Embodiment 2

[0043] Replace (2R)-p-toluenesulfonyl glycidyl ester with (2S)-p-toluenesulfonyl glycidyl ester, and the rest of the operations are the same as in Example 1 to prepare (2S)-(1-naphthyloxy)-methyloxirane alkyl. Replace (2R)-(1-naphthyloxy)-methyl oxirane with (2S)-(1-naphthyloxy)-methyl oxirane, and the rest of the operations are the same as in Example 1 to prepare (2S) -1-(2-methoxyphenyl)-4-[3-(naphthalene-1-oxyl)-2-hydroxypropyl]piperazine, MSm / z (M+H + )393, mp.124~126°C, through HPLC and (2R)-1-(2-methoxyphenyl)-4-[3-(naphthalene-1-oxyl)-2-hydroxypropyl]piper The azine was comparatively identified as (2S)-1-(2-methoxyphenyl)-4-[3-(naphthalene-1-oxyl)-2-hydroxypropyl]piperazine.

Embodiment 3

[0045] Dissolve 50 g (0.348 mol) of 1-naphthol in 350 mL of absolute ethanol, add 15.2 g (0.38 mol) of sodium hydroxide under stirring, slowly add 96.4 g (1.044 mol) of racemic epichlorohydrin dropwise, and react at room temperature for 10 After 1 hour, the ethanol was distilled off under reduced pressure, and the residue was added with 150 mL of water, and extracted 3 times, each time using CHCl 3 50mL, combined the extracts, washed the organic phase with 5% sodium hydroxide solution, dried over anhydrous sodium sulfate, recovered the solvent, distilled the crude product under reduced pressure, collected fractions at 160~165℃ / 266Pa, and obtained 60g of viscous colorless oily liquid , yield 86.2%. Detected MSm / z(M+H + ) 201, bp 118-122°C (0.25mm), it was confirmed that the above formula (2) represented (1-naphthyloxy)-methyloxirane.

[0046] The method of Example 1 was used to obtain 9.6 g of 1-(2-methoxyphenyl)piperazine.

[0047] Dissolve 53 mg (0.88 mmol) of (S, S)-salen...

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Abstract

The invention relates to an optical isomer R or S of 1-(2-methoxypheny1)-4-[3-(naphthalene-1-oxy)-2-hydroxypropyl] piperazine expressed by the following formula (1) or formula (2), and also relates to a preparation method thereof. The optical isomer is characterized in that the optical isomer is obtained by the reaction of 1-(2-methoxypheny1) piperazine and intermediate which is generated by the reaction of R- or S-p-toluenesulfonyl glycidyl ester and 1-naphthol, or obtained by the reaction of 1-(2-methoxypheny1) piperazine and intermediate which is generated by the reaction of racemic epoxy chloropropane and 1-naphthol. In addition, the invention also relates to application of the optical isomer R or S and physiologically acceptable inorganic salt or organic salt thereof. Because the optical isomer R and S are selective alpha1 epinephrine receptor antagonists which have obvious inhibiting effects on benign prostatic hyperplasia and hypertension and have higher selectivity and less toxic and side effects compared with the prior alpha1 receptor antagonists used in clinic, the optical isomer R and S can be used for preparing medicaments for treating the benign prostatic hyperplasia and the hypertension.

Description

technical field [0001] The present invention relates to optical isomers of piperazine, in particular to 1-(2-methoxyphenyl)-4-[3-(naphthalene-1-oxyl)-2-hydroxypropyl]piperazine The optical isomers also relate to salts of these optical isomers, preparation methods and applications in the preparation of medicines for treating hypertension and benign prostatic hyperplasia. Background technique [0002] Chirality is a basic feature of biological systems. Many endogenous macromolecular substances, such as enzymes, carriers, receptors, plasma proteins and polysaccharides, contain chiral enantiomers. Chiral enantiomer drugs can produce different distribution, absorption, metabolism and excretion processes through different stereocombinations with macromolecules in the body, resulting in changes in pharmacokinetic parameters. Since the two enantiomers of a chiral drug have different in vivo processes, they may have different pharmacological effects, or even antagonize the pharmacol...

Claims

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Application Information

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IPC IPC(8): C07D295/096A61K31/495A61P9/12A61P13/12
Inventor 袁牧陈敏生刘宇平朱柳季红黄碧云余清声白宝清
Owner 广州医学院
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