Synthesis of Raltegravir
Inventors
Gurjar, Mukund Keshav • Sonawane, Swapnil Panditrao • Maikap, Golakchandra Sudarshan • Patil, Gulabrao Dagadu • Shinde, Shivnath Bhaupatil • Shalikrao, Pankaj • Mehta, Samit Satish
Assignees
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Publication Number
US-9475799-B1
Publication Date
2016-10-25
Expiration Date
Abstract
The present invention relates to a novel synthetic route for the preparation of raltegravir and pharmaceutically acceptable salts, starting from 2-amino-2-methylpropanenitrile and oxadiazole carbonyl chloride, through the formation of a pyrimidinone intermediate of formula (V).
Core Innovation
The background and summary describe problems in prior art routes to raltegravir, including formation of impurities such as an O-methyl impurity and the formation of an E/Z isomer mixture. The disclosed work states a need for a cost-effective synthetic route that controls impurity formation and avoids those prior-art problems.
The invention describes a synthetic sequence that starts from 2-amino-2-methylpropanenitrile and oxadiazole carbonyl chloride to form an amino-protected oxadiazole carboxamide intermediate. The sequence converts the intermediate to amidoxime/imine intermediates using hydroxylamine or N-methyl hydroxylamine, cyclizes with dialkyl acetylene dicarboxylate to give a pyrimidinone ester intermediate, and amidates with p-fluorobenzylamine to give an intermediate.
The synthesis further includes regioselective N-methylation to yield raltegravir while avoiding oxygen methylation. The disclosed approach is presented as producing increased intermediate yields and high final purity, with an overall yield reported as 55–58% and a final purity reported as greater than 99.5%.
Claims Coverage
The claims provided define one compound-based independent claim with associated dependent refinements, covering a chemical formula with explicit substituent constraints. In total, the inventive coverage centers on the formula definition and three stated substituent conditions.
Compound defined by specified chemical formula with substituent constraints
A compound according to a formula wherein R is CN, R' is H or CH3, R2 is H, and R3 is a C1-4 alkyl group.
Optional R' restriction to H or CH3
The compound is defined by the formula wherein R' is H or CH3.
Fixed R2 and range-limited R3 substituents
The compound is defined by the formula where R2 is H and R3 is a C1-4 alkyl group.
Coverage is limited to compounds defined by the stated chemical formula and the explicit substituent constraints on R, R', R2, and R3; the key features are the CN substituent for R, the H/CH3 option for R', fixed H for R2, and the C1-4 alkyl range for R3.
Stated Advantages
Cost-effective synthetic route to raltegravir designed to control impurity formation and avoid prior-art problems.
Avoidance of oxygen methylation and reduction of O-methyl impurity formation relative to prior art.
Avoidance of an E/Z isomer mixture problem described for prior art.
Regioselective N-methylation with reported greater than 99% versus oxygen methylation.
Reduced number of steps and avoidance of amine protection/deprotection as stated in the summary.
Increased intermediate yield and high final purity, with final purity reported as greater than 99.5% and overall yield reported as 55-58%.
Documented Applications
Synthetic route for making raltegravir and salts, including raltegravir potassium (Isentress/1a).
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