Process for the preparation of advantame
Inventors
Divi, Murali Krishna Prasad • Rao, Mysore Aswatha Narayana • Nowshuddin, Shaik
Assignees
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Publication Number
US-9512063-B2
Publication Date
2016-12-06
Expiration Date
Abstract
A novelprocess for the preparation of N—[N-[3-(3-hydroxy-4-methoxyphenyl)-propyl]-L-α-aspartyl]-L-phenylalanine-1-methyl ester is described. It comprises, reacting isovanillin or its derivative with vinyl acetate followed by reductive condensation with L-[α-aspartyl]-L-phenylalanine-1-methyl ester.
Core Innovation
The disclosed invention relates to an improved process for the preparation of N—[N-[3-(3-hydroxy-4-methoxyphenyl)-propyl]-α-aspartyl]-L-phenylalanine-1-methyl ester (Advantame). The process comprises condensing isovanillin or O-benzylisovanillin with vinyl acetate in an aqueous alkaline medium to obtain (3-hydroxy-4-methoxy) cinnamaldehyde (II) or its derivative (IIa).
The intermediate (3-hydroxy-4-methoxy) cinnamaldehyde (II) or its derivative (IIa) is then condensed with Aspartame through reductive amination to obtain a phenylpropenyl derivative of Aspartame (V or Vb). This sequence connects the cinnamaldehyde intermediate to the phenylpropenyl Aspartame derivative before final conversion.
Finally, (V) or (Vb) is subjected to catalytic hydrogenation to yield Advantame. The disclosure presents this as a vinyl acetate-based aldol approach and contrasts it with prior routes involving aldehyde/cinnamic acid intermediates and/or benzyl protecting group steps, which are described as having drawbacks such as extra steps, poor yields/purity, and slow aldol addition.
Claims Coverage
The document contains two independent claims that cover a full multi-step process to prepare Advantame and a condensation step used to prepare the key (3-hydroxy-4-methoxy) cinnamaldehyde intermediate (II)/(IIa). The inventive subject matter is organized into four inventive features.
Vinyl acetate condensation in aqueous alkaline medium to form cinnamaldehyde (II)/(IIa)
Condensing isovanillin or O-benzylisovanillin with vinyl acetate in aqueous alkaline medium to obtain (3-hydroxy-4-methoxy) cinnamaldehyde (II) or its derivative (IIa).
Reductive amination of (II)/(IIa) with Aspartame to form phenylpropenyl Aspartame derivative (V/Vb)
Condensing (3-hydroxy-4-methoxy) cinnamaldehyde (II) or its derivative (IIa) with Aspartame through reductive amination to obtain a phenylpropenyl derivative of Aspartame (V or Vb).
Catalytic hydrogenation of (V)/(Vb)
Subjecting (V) or (Vb) to catalytic hydrogenation.
Condensation step to prepare (3-hydroxy-4-methoxy) cinnamaldehyde (II)/(IIa)
A process for the preparation of (3-hydroxy-4-methoxy) cinnamaldehyde (II) or its derivative (IIa) by condensing isovanillin or O-benzylisovanillin with vinyl acetate in aqueous alkaline medium.
The independent claims collectively cover the sequence from forming (3-hydroxy-4-methoxy) cinnamaldehyde (II)/(IIa) by condensing isovanillin or O-benzylisovanillin with vinyl acetate in aqueous alkaline medium, through reductive amination with Aspartame to obtain a phenylpropenyl Aspartame derivative (V/Vb), and then catalytic hydrogenation to obtain Advantame; a second independent claim separately covers the condensation step for preparing the (II)/(IIa) intermediate.
Stated Advantages
Improved process described as addressing drawbacks of prior routes, including extra steps, poor yields/purity, and slow aldol addition.
Documented Applications
No documented applications found
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