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New compound 1-(diphenyl methylene) amino-2-amino-2-methylmethane, preparation method and application thereof in Anagliptin synthesis

A technology of diphenylmethyleneaminoacetonitrile and diphenylmethylene, which is applied in the application field of the synthesis of new compounds 1-amino-2-amino-2-methylpropane and anagliptin

Active Publication Date: 2015-06-10
SHANDONG BESTCOMM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compound is a new compound, no journals, magazines, patent reports
[0006] In addition, regarding the synthetic method of Anagliptin (Anagliptin), there is no complete synthetic route, only on the 18th and 47th pages of the patent CN102791712A There is a brief report in Bioorganic & Medicinal Chemistry 19 (2011) 7221-7227, the intermediate 1,2-diamino-2-methylpropane reported in the patent is relatively difficult to synthesize, and the intermediate It is a small molecular compound with poor stability and low boiling point, which is not conducive to preservation. When the two terminal amino groups participate in the chemical reaction, the regioselectivity is low, there are many side reactions in the reaction, and the product is not easy to purify, which brings more problems to the post-treatment operation. great difficulty

Method used

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  • New compound 1-(diphenyl methylene) amino-2-amino-2-methylmethane, preparation method and application thereof in Anagliptin synthesis
  • New compound 1-(diphenyl methylene) amino-2-amino-2-methylmethane, preparation method and application thereof in Anagliptin synthesis
  • New compound 1-(diphenyl methylene) amino-2-amino-2-methylmethane, preparation method and application thereof in Anagliptin synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: Compound of formula (II): 2-(diphenylmethylene)amino-2-methylpropionitrile Preparation method 1

[0062]

[0063] At room temperature, dissolve 200 g (907.9 mmol) of dibenzylidene aminoacetonitrile (ie, the compound of formula (Ⅲ)) in 4 L of N,N-dimethylformamide (DMF), cool down to 0°C, and add 109 g (2.724 mol) NaOH, add 387g (2.724mol) methyl iodide liquid dropwise at 0°C for 1 hour, after the dropwise addition, keep the reaction at 0°C for 24 hours, TLC monitors until the compound of formula (Ⅲ) completely disappears; Drop it down to 10°C, and add 4L of water dropwise at this temperature. After the dropwise addition, keep stirring for 0.5h, then filter, wash the filter cake with 200mL of water, and dry at 50°C to obtain a light yellow crystalline solid, which is the formula ( Ⅱ) Compound 176.6g, yield 78%.

[0064] MS: 249 [M+H]

[0065] 1 H NMR (400MHz, DMSO-d 6 ), ppm: 7.37-7.29(m, 6H), 7.25-7.22(m, 2H), 7.16-7.14(dd, J=1.6, J=2.4, 2H), 1.51(s, ...

Embodiment 2

[0066] Example 2: Compound of formula (II): 2-(diphenylmethylene)amino-2-methylpropionitrile Preparation method 2

[0067]

[0068] At room temperature, dissolve 200 g (907.9 mmol) of dibenzylidene aminoacetonitrile (ie, the compound of formula (Ⅲ)) in 4 L of N,N-dimethylformamide (DMF), cool down to 0°C, and add 109 g (2.724 mol) NaOH, add 387g (2.724mol) iodomethane liquid dropwise at 0°C, add dropwise for 1h, after the dropwise addition, keep it warm at 0°C for 0.5h, then rise to 50°C for 6h, TLC monitoring to the raw material formula (Ⅲ) The compound disappears completely; lower the system to 10°C, and add 4L of water dropwise at this temperature. After the dropwise addition, keep stirring for 0.5h, then filter, wash the filter cake with 200mL of water, and dry it at 50°C. A light yellow crystalline solid was obtained, namely 181 g of the compound of formula (II), with a yield of 80%.

Embodiment 3

[0069] Example 3: Compound of formula (II): 2-(diphenylmethylene)amino-2-methylpropionitrile Preparation method 3

[0070]

[0071] At room temperature, dissolve 200 g (907.9 mmol) of dibenzylidene aminoacetonitrile (ie, the compound of formula (Ⅲ)) in 4 L of N,N-dimethylformamide (DMF), cool down to 0°C, and add 109 g (2.724 mol) NaOH, add 387g (2.724mol) methyl iodide liquid dropwise at 0°C, add dropwise for 1h, after the dropwise addition, keep it warm at 0°C for 0.5h, then rise to room temperature for 15h, TLC monitors to the raw material formula ( Ⅲ) The compound disappeared completely; the system was lowered to 10°C, and 4L of water was added dropwise at this temperature. After the dropwise addition, it was kept and stirred for 0.5h, then filtered, and the filter cake was washed with 200mL of water and dried at 50°C to obtain Light yellow crystalline solid, that is, compound of formula (II) 185.7g, yield 82%.

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Abstract

The invention relates to a new compound 1-(diphenyl methylene) amino-2-amino-2-methylmethane, a preparation method and application thereof in Anagliptin synthesis. 1-(diphenyl methylene) amino-2-amino-2-methylmethane is a (I) compound; the Formula is a key intermediate in the Anagliptin synthesis; the intermediate is stable and easy to get, plays a vital role in synthesizing the final target compound; moreover, the method is simple in technical flow process, higher in yielding and applicable to large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a new compound 1-(diphenylmethylene)amino-2-amino-2-methylpropane. Application in the synthesis of Anagliptin. Background technique [0002] Dipeptidyl Peptidase-4 (Dipeptidyl Peptidase4, DPP-4) is one of the hottest targets since the 21st century for the treatment of type 2 diabetes. Selectively inhibit DPP-4, inhibit the inactivation of endogenous incretin hormones (glucagon-like peptide-1 and glucose-dependent insulinotropic), and promote the role of incretin hormones, thereby improving hyperglycemia control. The listing of DPP-4 inhibitor drugs provides a new choice for diabetic patients, and has achieved great success, and will rise to become the leading role in the anti-diabetic drug market in the future. [0003] Anagliptin is a new generation of DPP-4 inhibitor developed by Sanwa Chemical Research Institute in Japan for the treatment of type 2 diabetes. On December 22, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C251/24C07C249/02C07D487/04
Inventor 甄宜战张志强高常松柴迪坤李娜娜
Owner SHANDONG BESTCOMM PHARMA CO LTD