Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

A kind of preparation method of high-efficiency and low-toxicity vasopressin antagonist drug

A halogen and compound technology, which is applied in the field of preparation of tolvaptan, a selective non-peptidin arginine vasopressin V2 receptor antagonist, can solve problems such as difficulties in the preparation of analogues

Active Publication Date: 2020-01-17
上海天慈中商药业有限公司
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] Route five is the synthetic method reported by Alejandro Cordero-Vargas et al. in Bioorg.Med.Chem., 2006,14(18):6165-6173, wherein, 7-chloro-5-oxo-2,3,4,5 -Tetrahydro-1H-1-benzazepine The preparation of analogues is more difficult

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of preparation method of high-efficiency and low-toxicity vasopressin antagonist drug
  • A kind of preparation method of high-efficiency and low-toxicity vasopressin antagonist drug
  • A kind of preparation method of high-efficiency and low-toxicity vasopressin antagonist drug

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0136] Specifically, the preparation method of the compound of the formula (VIII) comprises the steps:

[0137] (4) in an inert solvent, react with the compound of formula (VII) to obtain the compound of formula (VIII);

[0138]

[0139] Preferably, described step (4) comprises the following sub-steps:

[0140] (4.1) in an inert solvent, the compound of formula (VII) is reacted with a chlorinating reagent to obtain a compound of formula B;

[0141]

[0142] (4.2) in an inert solvent, in the presence of a catalyst, perform cyclization with a compound of formula B to obtain a compound of formula (VIII);

[0143]

[0144] The reaction conditions are not particularly limited. In another preferred example, in the step (4.1), the chlorinating reagent is selected from the following group: chlorine, NCS, thionyl chloride, trichloride phosphorus oxychloride, phosphorus oxychloride, phosphorus pentachloride, trichloroisocyanuric acid, or a combination thereof.

[0145] In an...

Embodiment 1

[0207] (1) Synthesis of compound (IV)

[0208] p-Chloroaniline (20.0 g, 156.78 mmol) and ethyl 4-bromobutyrate (III) (30.58 g, 156.78 mmol) were dissolved in acetonitrile (500 mL), sodium carbonate (32.23 g, 313.55 mmol) was added, followed by stirring It was heated to 80° C., reacted for 4 h, detected by TLC, and the reaction was completed. Cool to room temperature, pour the reaction solution into water (300 mL), take the organic phase, extract the aqueous phase twice with ethyl acetate (200 mL x 2), combine the organic phases, and wash twice with water (200 mL x 2), anhydrous It was dried with sodium sulfate, and the solvent was spun off to obtain 32.21 g of compound (IV) with a yield of 85.0%.

[0209] (2) Synthesis of compound (VI)

[0210] Compound (IV) (32.0 g, 132.39 mmol) was dissolved in dichloromethane (600 mL), triethylamine (36.9 mL, 264.78 mmol) was added under stirring, and 2-methyl-4-nitrogen was slowly added at room temperature benzoyl chloride (V) (31.71 g,...

Embodiment 2

[0224] (1) Synthesis of Compound (Ⅳ)

[0225] Dissolve p-chloroaniline (20.0g, 156.78mmol) and ethyl 4-bromobutyrate (Ⅲ) (30.58g, 156.78mmol) in acetonitrile (500mL), add potassium carbonate (43.34g, 313.55mmol), and stir Heated to 80°C, reacted for 4h, and detected by TLC, the reaction was complete. Cool to room temperature, pour the reaction solution into water (300mL), take the organic phase, extract the aqueous phase with ethyl acetate twice (200mL x 2), combine the organic phases, and wash twice with water (200mL x 2), anhydrous After drying over sodium sulfate, the solvent was spun off to obtain 32.97 g of compound (IV), with a yield of 87.0%.

[0226] (2) Synthesis of compound (Ⅵ)

[0227] Compound (Ⅳ) (32.0g, 132.39mmol) was dissolved in dichloromethane (600mL), diisopropylethylamine (34.22g, 264.78mmol) was added under stirring, and 2-methyl- 4-Nitrobenzoyl chloride (Ⅴ) (31.71g, 158.87mmol), reacted for 3h, and TLC detected that the reaction was complete. The reac...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides a preparation method of a high-efficiency low-toxicity pitressin antagonist. Specifically, the invention provides a compound having the formula A shown in the description, and a method for preparing tolvaptan through the compound having the formula A. All groups in the formula are defined in the description. The method has advantages of environmental protection, available raw materials, and high overall yield, and is suitable for industrial preparation of tolvaptan.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and relates to a selective non-peptide arginine vasopressin (AVP) V 2 Method for preparing tolvaptan for receptor antagonists. Background technique [0002] Tolvaptan English name Tolvaptan, trade name: Samsca. The drug is a selective vasopressin V 2 Receptor antagonists that prevent AVP from interacting with V at the distal end of the nephron 2 Receptor binding increases water excretion in urine, but does not change urine sodium and potassium secretion and blood potassium value, reduces urine osmotic pressure, and increases blood sodium value, so it is clinically used for the treatment of liver cirrhosis, heart failure, Hypervolemic and isovolemic hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH). The drug is well tolerated, does not disrupt electrolyte balance, and has mild adverse reactions. Tolvaptan was approved by the FDA in 2009 as an oral ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/83C07C231/02C07C231/12C07D223/16
Inventor 李新涓子李健之马西来池王胄刘海胡旭华郑肖利翟志军李建勋
Owner 上海天慈中商药业有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com