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Tolvaptan impurity and preparation method thereof

A technology of tolvaptan and impurities, applied in the field of medicinal chemistry, can solve the problems of searching for structural information, etc., and achieve the effects of high yield and purity, mild reaction conditions, and simple post-treatment

Active Publication Date: 2021-08-20
NANJING HEALTHNICE MEDICAL TECH +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] A new impurity was found in the synthesis process of tolvaptan, but it was not described in the report on the impurity research of the tolvaptan process, and its structural information has not yet been searched in SCIFINDER

Method used

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  • Tolvaptan impurity and preparation method thereof
  • Tolvaptan impurity and preparation method thereof
  • Tolvaptan impurity and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0045] Example 1: N 1 , N 2 -bis(4-((7-chloro-2,3,4,5-tetrahydro-5-carbonyl-1H-1-benzazepin-1-yl)carbonyl)-3-methylphenyl) Preparation of oxamide (impurity shown in formula III)

[0046] Add 140ml dichloromethane, 5g N-methylmorpholine and 7g tolvaptan intermediate (compound shown in formula IV) in 250ml reaction bottle, stir and be warmed up to 30 ℃ after, then, in the process of stirring Slowly add 5ml of oxalyl chloride methylene chloride solution (containing 3.6ml of oxalyl chloride) dropwise at a uniform speed, keep the temperature not higher than 35°C during the dropping process, and control the dropping time within 1-2 hours. After the dropping is completed, keep warm and continue stirring React for 12 hours. After the reaction is completed, quench the reaction with 10ml of 2N hydrochloric acid, stir for 0.5h, stop stirring, and then let stand for 5-10min, remove the water phase; add 12ml of water to the organic phase, stir for 5-10min, and let stand for 5-10min, Re...

Embodiment 2

[0050] Example 2: N 1 , N 2 -bis(4-((7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl)-3-methylphenyl) Preparation of oxamide (impurity shown in formula II)

[0051] Add 40.3g N to a 1L three-necked reaction flask 1 , N 2 -bis(4-((7-chloro-2,3,4,5-tetrahydro-5-carbonyl-1H-1-benzazepin-1-yl)carbonyl)-3-methylphenyl) Oxamide (the impurity shown in formula III) and 500ml of absolute ethanol and dichloromethane (volume ratio 2:1) mixed solvent, after stirring evenly, the temperature of the water bath is controlled to 15-25°C, and 3.2g of KBH is slowly and uniformly added dropwise 4 , the dropping time is controlled at 10 minutes, after the dropping is completed, an off-white suspension is obtained, continue to stir for half an hour, and then slowly and uniformly drop the remaining 5.5g KBH 4 , After the dropwise addition was completed, the temperature was slowly raised to 25-35°C, and the reaction was stirred overnight. After the reaction is completed, coo...

Embodiment 3

[0055] Embodiment 3: the detection of tolvaptan intermediate 3 and finished product

[0056] 1. Intermediate 3 (an intermediate in the synthesis of tolvaptan)

[0057]

[0058] Take an appropriate amount of intermediate 3, accurately weighed, dissolve and dilute with a diluent [acetonitrile-0.1% phosphoric acid solution (60:40)] to make a solution containing about 1.0 mg per 1 ml, as the test solution. Refer to the high-performance liquid chromatography (Chinese Pharmacopoeia 2015 edition four general rules 0512) test, use pentafluorophenyl bond and silica gel as filler (250×4.6mm, 5μm); use 0.1% phosphoric acid solution as mobile phase A, acetonitrile as mobile phase For phase B, carry out gradient elution according to the table below; the detection wavelength is 254nm. Precisely measure 20 μl of the test solution, inject it into the liquid mass spectrometry detector, and record the spectrum.

[0059] time (min) Mobile phase A(%) Mobile phase B(%) 0 60...

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Abstract

The invention relates to a tolvaptan impurity and a preparation method thereof. The tolvaptan impurity as shown in a formula II and a formula III has a structural formula as shown in the specification. The invention also provides a preparation method of the tolvaptan impurity as shown in the formula II, which comprises the following steps of (1) in the presence of an acid-binding agent, carrying out acylation reaction on a compound IV, oxalyl chloride and a solvent I at -20 to 100 DEG C to prepare an impurity as shown in a formula III, and (2) mixing the impurity shown in the formula III obtained in the step (1) with a solvent II, and carrying out a reduction reaction at -20 to 100 DEG C in the presence of a reducing agent to prepare the impurity shown in the formula II, and the specific synthesis route is as follows. The tolvaptan impurity provided by the invention provides a new reference substance for impurity detection in the tolvaptan raw material medicine, can be used for calibrating the content of the tolvaptan impurity in the tolvaptan raw material medicine, and is more beneficial to development of a method for detecting related substances in the tolvaptan raw material medicine, so that the product quality is controlled.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a new impurity of tolvaptan and a preparation method thereof. Background technique [0002] Tolvaptan (tolvaptan), trade name Samsca, is a selective non-peptide novel arginine vasopressin (AVP) V that can be taken orally developed by Otsuka Pharm in Japan. 2 Receptor antagonists that prevent AVP from interacting with V in distal nephrons 2 Receptor binding increases water excretion in urine, reduces urine osmotic pressure, increases blood sodium value, but does not change urine sodium and potassium secretion and blood potassium value. FDA approved it in May 2009 for the treatment of hypervolemic or isometric hyponatremia caused by congestive heart failure (CHF), liver cirrhosis, and syndrome of insufficient secretion of antidiuretic hormone (SIADH), in 2011 Tolvaptan was formally approved by the State Food and Drug Administration and started to be produc...

Claims

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Application Information

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IPC IPC(8): C07D223/16G01N30/06
CPCC07D223/16G01N30/06Y02P20/55
Inventor 陈圣志薛亚军王华娟
Owner NANJING HEALTHNICE MEDICAL TECH
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