Synthesis of a substituted indene derivative
Inventors
Harwig, Curtis • Seenisamy, Jeyaprakashnarayanan • Keregadde, Mahesh Narayan • Chetia, Lakshindra
Assignees
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Publication Number
US-10053415-B2
Publication Date
2018-08-21
Expiration Date
Abstract
This invention is directed to methods of preparing AQX-1125 having the formula:This invention is also directed to intermediates utilized in the methods of preparing AQX-1125.
Core Innovation
The patent describes methods of preparing AQX-1125 by converting defined intermediates through sequential functional-group transformations and intermediate conversions, culminating in acetate salt formation to AQX-1125. The routes use carbonyl protection, hydroxyl protection, allylic oxidation, carbonyl reduction and hydroboration-oxidation, carbonyl deprotection, olefination or Wittig reaction, oxidative 1,2-diol carbon-carbon bond cleavage, oxime or oxime O-ether formation, and lactone and oxime O-ether reduction.
A central sequence converts an oxime or oxime O-ether precursor under suitable lactone and oxime O-ether reduction conditions in a polar aprotic solvent with a reducing agent to provide Compound 16, followed by conversion of Compound 16 to AQX-1125 under acetate salt formation conditions. The acetate salt formation conditions comprise treating Compound 16 in a polar protic solvent with glacial acetic acid, followed by treatment with a less polar organic solvent.
Alternative routes begin from Compound 1 and proceed through compound intermediates including Compound 2A, 3A, 23A, 17A, 19A, 18A, 66A, 67A, 53A, 16, and related protected intermediates. These routes specify carbonyl protection, hydroxyl protection, allylic oxidation, oxidation, enol ether formation, oxidative carbon-carbon bond cleavage, oxime or oxime O-ether formation, carbonyl deprotection, Wittig reaction or olefination, lactone and oxime O-ether reduction, and final acetate salt formation.
Claims Coverage
The consolidated content identifies three independent claims. Across the claims, the inventive coverage centers on multi-step methods for preparing AQX-1125 through defined intermediate sequences, with the final conversion of Compound 16 to the AQX-1125 acetate salt and upstream route variants that differ in protecting-group and functional-group transformations.
Lactone and oxime O-ether reduction to compound 16 followed by acetate salt formation
Treating Compound 53A under suitable lactone and oxime O-ether reduction conditions in a polar aprotic solvent with a reducing agent to provide Compound 16, then treating Compound 16 under suitable acetate salt formation conditions in a polar protic solvent with glacial acetic acid followed by treatment with a less polar organic solvent to provide AQX-1125.
Multi-step synthesis from Compound 1 via protection, allylic oxidation, deprotection, Wittig reaction, oxidative cleavage, oxime formation, and acetate salt formation
Treating Compound 1 under suitable carbonyl protection conditions to provide Compound 69A, treating Compound 69A under suitable hydroxyl protection conditions to provide Compound 70A, treating Compound 70A under suitable allylic oxidation conditions to provide Compound 71A, treating Compound 71A under suitable carbonyl reduction and hydroboration-oxidation conditions to provide Compound 72A, treating Compound 72A under suitable carbonyl deprotection conditions to provide Compound 6, treating Compound 6 under suitable olefination or Wittig reaction conditions to provide Compound 54, treating Compound 54 under suitable 1,2-diol oxidative carbon-carbon bond cleavage conditions to provide Compound 51, treating Compound 51 under suitable oxidation conditions to provide Compound 52, treating Compound 52 under suitable oxime or oxime O-ether formation conditions to provide Compound 53A, treating Compound 53A under suitable lactone and oxime O-ether reduction conditions to provide Compound 16, and treating Compound 16 under suitable acetate salt formation conditions to provide AQX-1125.
Alternative synthesis from Compound 1 via carbonyl and hydroxyl protection, hydroboration-oxidation, oxidation, enol ether formation, oxidative cleavage, oxime formation, and acetate salt formation
Treating Compound 1 under suitable carbonyl protection conditions to provide Compound 2A, treating Compound 2A under suitable hydroxyl protection conditions to provide Compound 3A, treating Compound 3A under suitable hydroboration-oxidation conditions to provide Compound 23A, treating Compound 23A under suitable oxidation conditions to provide Compound 17A, treating Compound 17A under suitable enol ether formation conditions to provide Compound 19A, treating Compound 19A under suitable oxidative carbon-carbon bond cleavage conditions to provide Compound 18A, treating Compound 18A under suitable oxime or oxime O-ether formation conditions to provide Compound 66A, treating Compound 66A under suitable carbonyl deprotection conditions to provide Compound 67A, treating Compound 67A under suitable Wittig reaction or olefination conditions to provide Compound 53A, treating Compound 53A under suitable lactone and oxime O-ether reduction conditions to provide Compound 16, and treating Compound 16 under suitable acetate salt formation conditions to provide AQX-1125.
Across the independent claims, the coverage centers on producing AQX-1125 by transforming defined intermediates through lactone and oxime O-ether reduction to Compound 16 and then converting Compound 16 to AQX-1125 via acetate salt formation using glacial acetic acid followed by a less polar organic solvent. The longer claims further define ordered protecting-group and functional-group transformation sequences leading to Compound 53A.
Stated Advantages
Aim to improve yield and reduce steps versus prior methods.
Documented Applications
No documented applications found
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