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Tolvaptan intermediate and preparation method thereof

A compound, benzyl technology, applied in the field of tolvaptan intermediates and its preparation, can solve the problems of large-scale production material transfer and difficult reaction operation, high viscosity of polyphosphoric acid, low reaction yield, etc., to achieve simple operation, Environmental friendliness and the effect of improving the reaction yield

Active Publication Date: 2013-07-17
JIANGSU KANION PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patented process involves reacting certain chemicals with strong acids like hydrochloric acid (HCl), sulfur trioxide gas (SO2), nitric oxidant (NOx). These chemistry makes some molecules lose their ability to bind other substances during synthesis processes that require these chemicals. By doing this, they become less effective when combined together into larger structures called polymers.

Problems solved by technology

Technological Problem addressed in this patents relates to improving methods for producing tegaserodium that does not involve harmful substances such as HCl gas when administered into patients who suffer from excessive loss of fluid due to edema caused by heart failure.

Method used

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  • Tolvaptan intermediate and preparation method thereof
  • Tolvaptan intermediate and preparation method thereof
  • Tolvaptan intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylic acid methyl ester

[0050] In a 500mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H-1-benzene 8.1 g of methyl azepine-4-carboxylate, 2.0 g of concentrated sulfuric acid. React at 40°C for 2 hours, TLC shows that the reaction is complete, then cool with an ice-salt bath, slowly add saturated sodium bicarbonate solution dropwise, adjust the pH to 7-8, extract with 100mL ethyl acetate, wash the organic phase with brine after liquid separation, anhydrous magnesium sulfate After drying, filtering and evaporating the solvent, silica gel column chromatography obtained 4.4 g of the compound represented by formula I as a light yellow oily liquid with a yield of 87.6%.

[0051] ESI-MS(m / z): 254(M+H), 277(M+Na), 293(M+K)

[0052] 1 HNMR: (400MHz, CDCl 3 )2.10(2H, m), 3.16(2H, m), 3.77(1H, t), 3...

Embodiment 2

[0053] Example 2: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylic acid ethyl ester

[0054]In a 500mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H-1-benzene 8.4 g of ethyl azepine-4-carboxylate, 122.5 g of 80% phosphoric acid. React at 100°C for 2 hours, TLC shows that the reaction is complete, cool with ice-salt bath, slowly add saturated sodium bicarbonate solution dropwise, adjust the pH to 7-8, extract with 100mL ethyl acetate, wash the organic phase with brine after liquid separation, and anhydrous magnesium sulfate After drying, filtering and evaporating the solvent, silica gel column chromatography obtained 4.8 g of the compound represented by formula I as a pale yellow oily liquid with a yield of 89.1%.

[0055] ESI-MS(m / z): 268(M+H), 290(M+Na), 306(M+K)

[0056] 1 HNMR: (400MHz, CDCl 3 )1.30(3H, t), 2.15(2H, m), 3.11(2H, m), 3.85(1H, t), ...

Embodiment 3

[0057] Example 3: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate

[0058] In a 500mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H-1-benzene 8.1 g of methyl azepine-4-carboxylate, 20.0 g of concentrated sulfuric acid, and 33.8 g of polyphosphoric acid. React at 70°C for 2 hours, TLC shows that the reaction is complete, then cool with an ice-salt bath, slowly add saturated sodium bicarbonate solution dropwise, adjust the pH to 7-8, extract with 100mL ethyl acetate, wash the organic phase with brine after liquid separation, anhydrous magnesium sulfate After drying, filtering and evaporating the solvent, silica gel column chromatography obtained 4.2 g of the compound represented by formula I as a light yellow oily liquid with a yield of 83.6%.

[0059] ESI-MS(m / z): 254(M+H), 277(M+Na), 293(M+K)

[0060] 1 HNMR: (400MHz, CDCl 3 )2.10(2H, m), 3.16(2H,...

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Abstract

The invention discloses a 7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-1H-1-benzoazepine carboxylic ester compound, its preparation method, and a method of utilizing the compound to prepare another tolvaptan intermediate 7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-1H-1-benzoazepine. The 7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-1H-1-benzoazepine prepared by the method provided in the invention has a high yield, and can be prepared by a one-pot process, thus greatly simplifying the reaction operation. Also, the used materials and reagents are cheap and commercially available, the reaction is mild and environment-friendly, so that the method is suitable for large-scale production.

Description

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Claims

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Application Information

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Owner JIANGSU KANION PHARMA CO LTD
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