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Method for preparing ROMK inhibitor intermediate

A technology of intermediates and synthetic methods, applied in the field of organic chemical synthesis, can solve problems such as being unsuitable for industrial production, affecting the scope of application, and long reaction steps.

Active Publication Date: 2017-02-22
CHANGZHI MEDICAL COLLEGE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Patent WO2013039802 introduces the synthesis method of compound I. Since the second step of this method is prone to bromination reaction at the benzylic position, the other positions of the benzene ring cannot have alkyl groups, which greatly affects the scope of application of this method. In addition, Some reaction steps of this method are too long to be suitable for industrial production

Method used

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  • Method for preparing ROMK inhibitor intermediate
  • Method for preparing ROMK inhibitor intermediate
  • Method for preparing ROMK inhibitor intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] The first step: the preparation of 2-methyl-3-bromobenzoic acid methyl ester

[0070]

[0071] Add 2-methyl-3-bromobenzoic acid (10 g, 46.7 mmol) into 150 mL of methanol, stir, add 0.5 mL of concentrated sulfuric acid dropwise at room temperature, and heat to reflux overnight. TLC showed that the reaction was complete, cooled, adjusted the pH of the reaction solution to neutral, concentrated under reduced pressure to remove methanol, added 100 mL of ethyl acetate to the residue, washed with water, concentrated the organic phase under reduced pressure, and dried to obtain 2-methyl-3-bromo Methyl benzoate 10.2g (yield: 96%);

[0072] 1 H-NMR (400 MHz, CDCl 3 ): δ 7.76-7.69 (m, 2H), 7.11 (t, J = 8.0 Hz, 1H), 3.92 (s, 3H), 2.62 (s, 3H); LC / MS (M + 1) + = 229.1, 231.1.

[0073] The second step: the preparation of 2-methyl-3-bromobenzyl alcohol

[0074]

[0075] In an ice-water bath, dissolve methyl 2-methyl-3-bromobenzoate (10 g, 43.6 mmol) in 100 mL of abso...

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Abstract

The invention relates to a method for preparing a chiral glycidyl substituted benzoheterocycle compound as shown in the formula (I). The compound represented by the formula (I) can serve as a key chiral intermediate of a renal outer medullary potassium channel (ROMK) inhibitor. Please see the formula (I) in the description, wherein n is 1 or 2 or 3, and R1, R2 and R3 are selected from hydrogen, C1-C6 straight-chain or branched alkyl, C2-C8 straight-chain or branched alkynyl and 3-8-membered alicyclic groups.

Description

technical field [0001] The invention relates to the field of organic chemical synthesis, in particular to a synthesis method of a chiral glycidyl-substituted benzoheterocyclic compound, a key intermediate of an extrarenal medullary potassium ion (ROMK) channel inhibitor. Background technique [0002] Extrarenal medullary potassium (ROMK) channels are inwardly rectifying potassium channels that are predominantly expressed in two regions of the kidney [the thick ascending loop of Henle (TALH) and the cortical collecting duct (CCD)] (Ho, K., et al., Nature , 1993, 362(6415), 31-38). In the TALH region, ROMK is involved in the recycling of potassium across the luminal membrane, which is important for Na + / K + / 2Cl - Cotransporters are very important as a determining step in the rate of salt reabsorption in the kidney. At the CCD, ROMK provides a potassium secretion pathway that is tightly coupled to sodium uptake through the sodium channel of amiloride (Hebert, S. C. Phy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/04
CPCC07D407/04
Inventor 闫革新张辉周立宏
Owner CHANGZHI MEDICAL COLLEGE