Process for the preparation of (1S, 3S, 5S)-2-[2(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile
Inventors
Divi, Murali Krishna Prasad • Padakandla, Gundu Rao • Bolneni, Nageswara Rao • Bodala, Gopinarayana
Assignees
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Publication Number
US-8664443-B2
Publication Date
2014-03-04
Expiration Date
Abstract
The present invention relates to an improved process for the preparation of (1S,3S,5S)-2-[2(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and its intermediates.
Core Innovation
The document describes saxagliptin of Formula-I and related prior-art routes to the free base from saxagliptin hydrochloride by employing alkaline conditions, while noting drawbacks in forming impurities under basic pH and sensitivity to acidic conditions for BOC-protected intermediates. In particular, the document highlights the formation of a cyclic amidine impurity under basic pH and presents cyclic amidine contents as a key impurity outcome.
The invention uses CBZ-protected saxagliptin, benzyl carbamate of Formula-XI, to enable debenzylation by mild hydrogenolysis. In the disclosed process, Formula-XI is dissolved in a suitable solvent and reacted with a hydrogen source in the presence of a metal catalyst to directly furnish saxagliptin of Formula-I (free base), while minimizing cyclic amidine impurity.
The document also outlines how CBZ-protected intermediates are prepared and connected to the debenzylation step, including coupling to form (2S)-2-{[(benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of Formula-XIV, transformation through the related cyano/carbamide intermediates, and hydrogenation/deprotection of the CBZ benzyl carbamate. Downstream, saxagliptin of Formula-I is further converted into saxagliptin monohydrate (Formula-XII) and saxagliptin hydrochloride salts/hydrates, with reported impurity levels in examples.
Claims Coverage
The document contains one independent claim defining the core process, with dependent claims refining the inventive features by specifying catalyst, hydrogen source, solvent selection, and reaction temperature ranges. Across the claim set, the process is centered on debenzylation of a benzyl carbamate intermediate by hydrogenolysis to obtain saxagliptin free base of Formula-I.
Hydrogenolysis debenzylation of benzyl carbamate intermediate
A process for the preparation of saxagliptin of Formula-I by dissolving the benzyl carbamate of Formula-XI and reacting it with a hydrogen source in the presence of a metal catalyst to effect debenzylation.
Pd/C metal catalyst with enumerated hydrogen sources
The process where the metal catalyst is palladium on carbon (Pd/C) and the hydrogen source is selected from hydrogen gas, ammonium formate, ammonium acetate, ammonium chloride, or formic acid.
Selected solvent set
The process where the suitable solvent is selected from acetonitrile, methanol, ethanol, and 2-propanol.
Broad reaction temperature range
The process is carried out with a reaction temperature in the range of about 0°C to 50°C.
Narrower reaction temperature sub-range
The process is performed at a reaction temperature of about 15–30°C.
Overall, the claim coverage defines a debenzylation/hydrogenolysis process of the CBZ-protected benzyl carbamate intermediate (Formula-XI) to produce saxagliptin free base (Formula-I), further specifying Pd/C and particular hydrogen sources, defined solvents, and reaction temperature constraints.
Stated Advantages
Minimizes formation of cyclic amidine impurity.
Enables mild hydrogenolysis using CBZ-protected saxagliptin to directly furnish the saxagliptin free base (Formula-I).
Supports industrial-scale applicability, as stated in the document.
Documented Applications
Preparation of saxagliptin of Formula-I (free base) from the benzyl carbamate intermediate (Formula-XI) through debenzylation by hydrogen-source and metal-catalyst hydrogenolysis.
Preparation of saxagliptin monohydrate (Formula-XII) and saxagliptin hydrochloride salts/hydrates as downstream forms.
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