930117-83-2

Upstream product

• 14720-70-8 1,4-bis(hydroxymethyl)benzene diacetate 
• 54549-74-5 4-(acetoxymethyl)benzaldehyde 
• 543-24-8 N-acetylglycine 
• 623-27-8 terephthalaldehyde, 
• 52010-97-6 4-(hydroxylmethyl)benzaldehyde 

Downstream Products

• 1332232-67-3 methyl (Z)-2-(acetylamino)-3-[4-(acetoxymethyl)phenyl]propenoate 
• 1332232-70-8 (Z)-2-(acetylamino)-3-[4-(hydroxymethyl)phenyl]propenoic acid 
• 1332232-74-2 methyl (2R)-2-(acetylamino)-3-[4-(acetoxymethyl)phenyl]propanoate 
• 1332232-58-2 methyl (2S)-2-(acetylamino)-3-[4-(acetoxymethyl)phenyl]propanoate 
• 930117-87-6 methyl (2R)-2-acetylamino-3-(4-{[(2R,6S)-2,6-dimethylpiperidin-1-yl]methyl}phenyl)propanoate 
• 930117-88-7 methyl 2(R)-acetyl-(tert-butoxycarbonyl)amino-3-(4-{[(2R,6S)-2,6-dimethylpiperidin-1-yl]methyl}phenyl)propanoate 
• 464931-30-4 (2R)-(tert-butoxycarbonylamino)-3-(4-((2R,6S)-2,6-dimethylpiperidine-1-yl)methylphenyl)propionic acid 
• 930117-84-3 methyl (Z)-2-(acetylamino)-3-[4-(hydroxymethyl)phenyl]propenoate 

Relevant academic research and scientific papers

Large-scale synthesis of a substituted d -phenylalanine using asymmetric hydrogenation

A synthetic route to an N-BOC d-phenylalanine pharmaceutical intermediate suitable for rapid scale-up to 150-kg scale was required. A seven-step route based on asymmetric hydrogenation of an N-acetyl dehydroamino-acid was developed. Starting with terephthalic dialdehyde, monoreduction of one aldehyde group, Erlenmeyer condensation, and ring-opening/O-deacetylation with methanol provided the 4-(hydroxymethyl)-substituted dehydrophenylalanine hydrogenation substrate. Asymmetric hydrogenation of this enamide using [((R,R)-Ethyl-DuPhos) Rh(COD)BF4 proceeded in high enantiomeric excess. Subsequently, the cis-2,6-piperidyl group was introduced by mesylation/displacement, the BOC group was introduced, and acetyl and methyl ester groups were removed by basic hydrolysis. This route was used to manufacture 150 kg of the BOC amino acid 1.

PROCESS TO PREPARE AMINO ACID DERIVATIVES

The present invention comprises a novel multi-step process to a specific amino acid derivative (1) from (4-hydroxymethyl)benzaldehyde including the key steps of: (i) asymmetric hydrogenation, thereby avoiding yield losses associated with the resolution approach and (ii) introduction of the cis-2,6-dimethylpiperidine sub-unit by JV-alkylation, thereby avoiding a problematic reductive animation step that is prone to side reactions. In one aspect, the present invention comprises a synthetic route in which step (i) precedes step (ii). In another aspect of the invention, step (ii) precedes step (i) (I).