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Method for preparing an N-[(aliphatic or aromatic) carbonyl]-2-aminoacetamide compound and a cyclyzed compound

A kind of compound, the technology of alkylamino, which is applied in the field of preparing N-[carbonyl]-2-aminoacetamide compound and its cyclization compound

Inactive Publication Date: 2004-11-03
AVENTIS PHARMA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite such enormous synthetic capacity, the Ugi reaction is limited by the production of products that are soft, peptide-like and generally classified as "non-drug" and face bioavailability issues

Method used

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  • Method for preparing an N-[(aliphatic or aromatic) carbonyl]-2-aminoacetamide compound and a cyclyzed compound
  • Method for preparing an N-[(aliphatic or aromatic) carbonyl]-2-aminoacetamide compound and a cyclyzed compound
  • Method for preparing an N-[(aliphatic or aromatic) carbonyl]-2-aminoacetamide compound and a cyclyzed compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0537] Solutions of compounds of formula (I) by the '3-step-one-pot' method using the Ugi multi-component reaction Composite

[0538] Using an equivalent (0.1 ml) 0.1 M solution of the four appropriate components of the compounds of formula (XIV), (XV), (XVI) and (IXb), due to 100% conversion, 10 μmol of the final product is theoretically generated 1,4 - Benzodiazepine-2,5-dione (I). This 4-component condensation was carried out in methanol at room temperature and the solvent was evaporated at 65 °C (using SAVANT _ evaporator for 2 hours). The deprotection / cyclization step was performed with acetyl chloride in 10% methanol or trifluoroacetic acid in 10% dichloroethane. The solvent is then evaporated at 65°C to give the cyclization product compound of formula (I). Use 10%-100% H with 0.1% TFA 2 O / CH 3 C18 Hypersil BDS 3m 4.6×50mm column (UV220nm) with CN mobile phase, 15min Lc / ms analysis (liquid chromatography / mass spectrometry) at a speed of 1ml / min. The desired pro...

Embodiment 2

[0552] General Solid-Phase Synthesis of Compounds of Formula (I) Using Ugi Reaction and Resin (IXa)

[0553] 60 mg of resin (IXa) were preswelled with THF. 0.5M THF:MeOH (1:1) solution containing aldehyde (XV) (10 equivalents), amine (XVI) (10 equivalents) and carboxylic acid (XIV) (10 equivalents) was sequentially added to resin (IXa), The reaction was stirred at room temperature for 3 days. use CH 2 Cl 2 , THF, DMF, THF and MeOH were washed sequentially and the resin was dried in high vacuum to obtain the resin-bound Ugi product (IXa). use BOC 2 O (10 equivalents), Et 3 N (10 equiv) and CH of DMAP 2 Cl 2 Solution work-up (15 hours) gave the active resin (XX) for cleavage. A THF:MeOH 1:1 solution of sodium methoxide (5 mg) was added to the resin and shaken for 20 hours. Evaporation of the solvent in vacuo gave the desired methyl ester (XXI). The deprotection / cyclization step was performed with acetyl chloride in 10% methanol or trifluoroacetic acid in 10% dichloro...

Embodiment 3

[0558] Solutions of compounds of formula (II) by the '3-step-one-pot' method using the Ugi multi-component reaction Composite

[0559] Using equal amounts (0.1 ml) of 0.1 M solutions of the four appropriate constituent compounds of formulas (XXII), (XV), (XVI) and (IXb), due to 100% conversion, 10 μmol of the final product diketopiperazine is theoretically generated (II). This 4-component condensation was carried out in methanol at room temperature and the solvent was evaporated at 65 °C (using SAVANT _ evaporator for 2 hours). Deprotection / cyclization step with acetyl chloride in 10% methanol or trifluoroacetic acid in 10% dichloroethane, and diethylamine in 5% dichloroethane [Note: 10-15 mg N,N- (Diisopropyl)amino-methylpolystyrene (PS-DIEA) is an excellent binding resin to replace diethylamine]. The solvent is then evaporated at 65°C to give the cyclized product of formula (II).

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Abstract

The present invention relates to a method for preparing an N-[(aliphatic or aromatic)carbonyl]-2-aminoacetamide compound of formula (I) wherein Ra is (II); Raa is hydrogen, optionally substituted aliphatic or optionally substituted aromatic; Rb is hydrogen, optionally substituted aliphatic or optionally substituted aromatic; Rca and Rcb are independently hydrogen, optionally substituted aliphatic or optionally substituted aromatic; Rd is (III); and Rda is optionally substituted aliphatic or optionally substituted aromatic; and Raa is substituted with a primary or secondary protected amine that upon deprotection can react with the *ab or *db carbon, or at least one of Rb, Rca or Rcb where each is at least substituted with an activated carboxylic acid to form a 5-7 membered cyclic ring; or Rb is substituted with a primary or secondary protected amine that upon deprotection can react with the *ab or *db carbon, or at least one of Raa, Rca or Rcb where each is at least substituted with an activated carboxylic acid to form a 5-7 membered cyclic ring; or Rca and Rcb are independently substituted with a primary or secondary protected amine that upon deprotection can react with the *ab or *db carbon, or at least one of Raa, Rb, Rca, Rcb or Rda where each is at least substituted with an activated carboxylic acid to form a 5-7 membered cyclic ring; or Rda is substituted with a primary or secondary protected amine that upon deprotection can react with at least one of Rca or Rcb where each is at least substituted with an activated carboxylic acid to form a 5-7 membered cyclic ring, provided that when Raa is substituted with a primary or secondary protected amine that upon deprotection can react with Rb at least substituted with an activated carboxylic acid, then Raa is other than substituted aliphatic, comprising reacting the following four compounds.

Description

[0001] The present invention relates to processes for the preparation of N-[(aliphatic or aromatic)carbonyl]-2-aminoacetamide compounds and cyclized compounds thereof, and to these compounds. Background of the invention [0002] 1,4-Benzodiazepine-2,5-dione is an important class of bioactive compounds. This class of compounds has been identified to have platelet aggregation inhibitory activity, anticonvulsant activity, anxiolytic activity, and can also be used as an antitumor agent (Mc Dowell, R.S. et al. "Journal of the American Chemical Society" 1994, 116, 5077; Cho, N.S. et al. Journal of Heterocyclic Chemistry" 1989, 26, 1807; Wright, W.B. et al. "Journal of Medicinal Chemistry" 1978, 21, 1087; Jones, G.B. et al. "Review of Anticancer Drugs" 1990, 5, 249). [0003] Diketopiperazines are known ligands for neurokinin-2 and neurokinin-3 receptors (Gordon, D.W.; Steele, Journal of Bioorganic and Medicinal Chemistry Letters 1995, 5, 47. (b) Terrett , N.K.; Gardner, M.; Gordon,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D243/14C07B61/00C07C231/14C07C237/22C07C269/04C07C269/06C07C271/22C07C271/28C07D207/14C07D207/26C07D207/273C07D233/28C07D233/54C07D233/64C07D233/90C07D241/08C07D241/18C07D241/36C07D241/44C07D243/24C07D295/12C07D401/04C07D401/12C07D403/04C07D403/06C07D403/12C07D405/06C07D405/12C07D409/06C07D521/00C07F9/645
CPCC07D403/04C07D403/12C07D405/12C07C231/14C07C2101/02C07D207/273C07D243/24C07D409/06C07C2101/16C07D405/06C07D233/28C07D231/12C07F9/645C07D249/08C40B40/00C07D233/64C07D241/18C07D233/56C07C269/06C07D241/44C07D403/06C07D401/04Y02P20/55C07C2601/02C07C2601/16C07C237/22C07C271/28
Inventor C·哈尔姆G·C·莫顿J·M·萨尔威诺R·F·拉保迪尼勒H·J·梅森M·M·莫里斯特马良M-P·彻里尔
Owner AVENTIS PHARMA SA