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An Improved Preparation of (R)-3-Aminobutanol, a Key Intermediate for the Synthesis of Dolutegravir Sodium

[ Vol. 14 , Issue. 12 ]

Author(s):

Y. Srinivasa Rao, B. Hari Babu*, I. Aminual, D. Nageshwar and P.V.V. Satyanarayana   Pages 1371 - 1375 ( 5 )

Abstract:


Background: Dolutegravir sodium is a HIV-1 integrase strand transfer inhibitor (INSTI) and in combination with other anti-retroviral agents, is recommended for the treatment of HIV-1 infection. Moreover, it is a second generation HIV integrase inhibitor designed to deliver potent antiviral activity. Originally, collaboration between Shionogi and Glaxo Smith Kline (GSK) led to dolutegravir sodium which is marketed under the trade name Tivicay®. Its synthesis involves the reaction of (R)-3-aminobutanol (1) with 3-benzyloxy-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine- 2,5-dicarboxylic acid 2-methyl ester. Later, the (R)-3-aminobutanol became a key intermediate for the synthesis of Dolutegravir sodium.

Methods: In our method the (R)-3-aminobutanol is synthesized in a three/four-step synthetic protocol using 4-Hydroxy 2-butanone as starting material, initial formation of oxime with hydroxyl amine, followed by replacement of developed lithium aluminum hydride (LAH) for reduction of oxime using Raney ‘Ni’, which provided the enantiomeric mixture of 3-aminobutanol in about 85-90 % yield, which is more significant compared to earlier approach (yield: 70 %). Further the mixture was resolved with D-(-)-tartaic acid to obtain the R-isomer as an ester. The ester is then hydrolyzed with potassium carbonate in methanol to give pure (R)-3-amino butanol in 90 % yield and chiral purity was found to be 99.89 % by HPLC.

Results: The present method is highly economical and eliminates the use of expensive catalysts. Moreover, the reaction conditions adopted in this process are mild and suitable for industrial applications and is further supported by our study with a large scale (up to 30 Kg) and the yields obtained are quite good. It is our claim that the present methodology is extremely useful for preparation of (R)-3-aminobutanol on commercial scale.

Conclusion: We have developed a simple and efficient method for the synthesis of (R)-3- aminobutanol in industrial scale from 4-hydroxy-2-butanone. The process also involves the use of Raney Ni as an eco friendly reagent for the conversion of oxime to amine which is superior to reported LAH approach. Further, the process also uses an inexpensive D-(-)-tartaric acid as a chiral reagent. The developed method involves very cheap reagents, experimental procedures are highly convenient and the yields are impressive.

Keywords:

Dolutegravir sodium, (R)-3-aminobutanol, D-tartaric acid, resolution, Raney ‘Ni’, 4-hydroxy-2-butanone, chiral reagent.

Affiliation:

Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, AP, Department of Chemistry, Faculty of sciences, Acharya Nagarjuna University, P.O. Box: 522510, Guntur, Chemical Research and Development, Aurobindo Pharma Ltd., Sangareddy (M), Medak District 502329, Telangana, Chemical Research and Development, Aurobindo Pharma Ltd., Sangareddy (M), Medak District 502329, Telangana, Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, AP

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