Process Development toward a Pro-Drug of R-Baclofen
This paper describes the process development conducted toward the multi-kilogram synthesis of a novel transported pro-drug of R-baclofen. The key steps in the synthesis were the enzyme-catalyzed kinetic resolution of isopropyl(methylthiocarbonyloxy)methyl-2-methylpropionate using Candida antarctica lipase A to provide the desired (S)-enantiomer. This was followed by the reaction with sulfuryl chloride and N-hydroxysuccinimide to produce (S) 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanate. The synthesis of (S) 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanate enabled the efficient use of R-baclofen in the final coupling stage of the synthesis. The new route reported here is more efficient and sustainable than those reported previously and had the potential to become the commercial route of manufacture.
Allsop, Glyn L.,Carey, John S.,Joshi, Sudhir,Leong, Paul,Mirata, Marco A.
p. 136 - 147
(2021/01/09)
ANHYDROUS AND HEMIHYDRATE CRYSTALLINE FORMS OF AN (R)-BACLOFEN PRODRUG, METHODS OF SYNTHESIS AND METHODS OF USE
Crystalline (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid anhydrate and crystalline (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid hemihydrate, pharmaceutical compositions comprising such compounds, methods of making and methods of using the same are disclosed.
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Paragraph 0225; 0226
(2013/03/26)
METHODS OF TREATING FRAGILE X SYNDROME, DOWN?S SYNDROME, AUTISM AND RELATED DISORDERS
Disclosed herein are methods of treating fragile X syndrome, fragile X-associated tremor/ataxia syndrome, Down?s syndrome and other forms of mental retardation, and/or autism comprising administering a GABA B agonist prodlug to a subject suffering therefrom. The GABAB agonist prodrugs can be compounds of Formula (I), (II) or (III) as disclosed herein
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(2012/02/01)
USE OF (3R)-4--3-(4-CHLOROPHENYL) BUTANOIC ACID FOR TREATING URINARY INCONTINENCE
Use of (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl) butanoic acid for treating urinary incontinence is disclosed.
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(2011/09/20)
SYNTHESIS OF ACYLOXYALKYL CARBAMATE PRODRUGS AND INTERMEDIATES THEREOF
Methods for synthesis of 1-(acyloxy)-alkyl carbamates, particularly, the synthesis of 1-(acyloxy)-alkyl carbamate prodrugs of primary or secondary amine containing drugs are described. Also described are methods for synthesis of 1-(acyloxy)-alkyl N-hydroxysuccinimidyl carbonates which are useful intermediates in the synthesis of 1-(acyloxy)-alkyl carbamates are also described.
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Page/Page column 58
(2008/06/13)
ACYLOXYALKYL CARBAMATE PRODRUGS, METHODS OF SYNTHESIS AND USE
The disclosures herein relate generally to acyloxyalkyl carbamate prodrugs of (±) 4 amino 3 (4 chlorophenyl)butanoic acid and analogs thereof, pharmaceutical compositions thereof , methods of making prodrugs of (±) 4 amino 3 (4 chlorophenyl)butanoic acid and analogs thereof, methods of using prodrugs of (±) 4 amino 3 (4 chlorophenyl)butanoic acid and analogs thereof, and pharmaceutical compositions thereof for treating or preventing common diseases and/or disorders such as spasticity and/or acid reflux disease. The disclosures herein also relate to acyloxyalkyl carbamate prodrugs of (±) 4 amino 3 (4 chlorophenyl)butanoic acid and analogs thereof which are suitable for oral administration and to sustained release oral dosage forms thereof.
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Page/Page column 100-101; 106
(2008/06/13)
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