Synthesis of alpha--amino-alpha, alpha'- dihaloketones and process for the preparation of beta--amino acid derivatives by the use of the same

A process for producing a β-amino acid ester derivative of the following formula (4):

• 6
• wherein R1 represents a substituted or unsubstituted alkyl group containing 1 to 18 carbon atoms, an aralkyl group containing 7 to 18 carbon atoms or an aryl group containing 6 to 18 carbon atoms, R3 represents an alkyl group containing 1 to 5 carbon atoms, and P1 and P2 each independently represents a hydrogen atom or an amino-protecting group or P1 and P2 taken together represents a phthaloyl group, excluding the case in which both P1 and P2 are hydrogen atoms,
• which comprises reacting an α-amino acid ester derivative of the following formula (1):
• 7
• wherein R1, P1 and P2 are as respectively defined above,
• with a base and a dihalomethane of the following formula (2):
• CH2X1X2 (2)
• wherein X1 and X2 each independently represents a halogen atom, to synthesize an α-amino-α′,α′-dihaloketone derivative of the following formula (3):
• 8
• wherein R1, P1, P2, X1 and X2 are as respectively defined above,
• reacting this derivative with a lithium amide and an alkyllithium in succession,
• and treating the reaction product with an acid in an alcohol.

A process for producing a β-amino acid ester derivative of the following formula (4):

• 9
• wherein R1 represents a substituted or unsubstituted alkyl group containing 1 to 18 carbon atoms, an aralkyl group containing 7 to 18 carbon atoms or an aryl group containing 6 to 18 carbon atoms, R3 represents an alkyl group containing 1 to 5 carbon atoms, and P1 and P2 each independently represents a hydrogen atom or an amino-protecting group or P1 and P2 taken together represents a phthaloyl group, excluding the case in which both P1 and P2 are hydrogen atoms,
• which comprises reacting an α-amino-α′,α′-dihaloketone derivative of the following formula (3):
• 10
• wherein R1, P1 and P2 are as respectively defined above, and X1 and X2 each independently represents a halogen atom, with a lithium amide and an alkyllithium in succession,
• and treating the reaction product with an acid in an alcohol.

An α-amino-α′,α′-dihaloketone derivative of the following general formula (3):

• 11
• wherein P1 and P2 each independently represents a hydrogen atom or an amino-protecting group or P1 and P2 taken together represents a phthaloyl group, exclusive of the case in which both P1 and P2 are hydrogen atoms,
• R1 represents a benzyl group,
• X1 represents a bromine atom, and
• X2 represents a chlorine atom or a bromine atom.