Nahlsgen optical resolution method

A method for producing a diastereomeric mixture of a D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative and a D-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative, the method comprising

• esterifying the phosphoric acid moiety of D-2-amino-4-phosphonobutanoic acid represented by Formula (2) to give a diastereomeric mixture, represented by Formula (2-1), of a D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative and a D-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative,
• Formulae (2) and (2-1) expressed as follows:
• wherein the atom marked with an asterisk (*) indicates an asymmetric atom,
• wherein R1 is, identically or differently in each occurrence, selected from hydrogen and a carboxy-protecting group;
• R2 is selected from benzyloxycarbonyl, phenylmethylidene, and diphenylmethylidene, each being optionally substituted;
• k represents 0 or 1, where when R2 is optionally substituted benzyloxycarbonyl, k is 1 and the bond between the specified nitrogen atom and R2 is a single bond, and when R2 is optionally substituted phenylmethylidene or optionally substituted diphenylmethylidene, k is 0 and the bond between the specified nitrogen atom and R2 is a double bond;
• and * is as defined above.

A diastereomeric mixture of a D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative and a D-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative, the diastereomeric mixture being represented by Formula (2-1):

• wherein R1 is, identically or differently in each occurrence, selected from hydrogen and a carboxy-protecting group;
• R2 is selected from benzyloxycarbonyl, phenylmethylidene, and diphenylmethylidene, each being optionally substituted;
• k represents 0 or 1, where when R2 is optionally substituted benzyloxycarbonyl, k is 1 and the bond between the specified nitrogen atom and R2 is a single bond, and when R2 is optionally substituted phenylmethylidene or optionally substituted diphenylmethylidene, k is 0 and the bond between the specified nitrogen atom and R2 is a double bond;
• and the atoms marked with an asterisk (*) indicate asymmetric atoms.

A method for optically resolving a diastereomeric mixture of a D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative and a D-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative, the method comprising

• subjecting a diastereomeric mixture, represented by Formula (2-1), of a D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative and a D-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative to fractional crystallization, to give one of optical isomers represented by Formulae (1-1) and (1-2), Formulae (2-1), (1-1), and (1-2) expressed as follows:
• wherein R1 is, identically or differently in each occurrence, selected from hydrogen and a carboxy-protecting group;
• R2 is selected from benzyloxycarbonyl, phenylmethylidene, and diphenylmethylidene, each being optionally substituted;
• k represents 0 or 1, where when R2 is optionally substituted benzyloxycarbonyl, k is 1 and the bond between the specified nitrogen atom and R2 is a single bond, and when R2 is optionally substituted phenylmethylidene or optionally substituted diphenylmethylidene, k is 0 and the bond between the specified nitrogen atom and R2 is a double bond;
• and the atoms marked with an asterisk (*) indicate asymmetric atoms,
• wherein R1, R2, k, and * are as defined above.

A method for producing a D-2-amino-4-[(p)-(3 carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid hydrate, the method comprising:

• subjecting a D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative represented by Formulae (1-1) to deprotection treatment to give a D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid represented by Formula (1-1′);
• and
• subjecting the resulting D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid to crystallization from water or from a solvent mixture of water and a water-soluble organic solvent, to give a D-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid hydrate represented by Formula (1-1′-1), Formulae (1-1), (1-1′), and (1-1′-1) expressed as follows:
• wherein R1 is, identically or differently in each occurrence, selected from hydrogen and a carboxy-protecting group;
• R2 is selected from benzyloxycarbonyl, phenylmethylidene, and diphenylmethylidene, each being optionally substituted;
• k represents 0 or 1, where when R2 is optionally substituted benzyloxycarbonyl, k is 1 and the bond between the specified nitrogen atom and R2 is a single bond, and when R2 is optionally substituted phenylmethylidene or optionally substituted diphenylmethylidene, k is 0 and the bond between the specified nitrogen atom and R2 is a double bond;
• and the atoms marked with an asterisk (*) indicate asymmetric atoms,
• wherein * is as defined above,
• wherein the atoms marked with an asterisk (*) indicate asymmetric atoms;
• and t represents a number greater than 0.

A method for producing a diastereomeric mixture of an L-2-amino-4-[(Rp)-(3)-carboxymethylphenoxy) (methoxy)phosphoryl]butanoic acid derivative and an L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative, the method comprising

• esterifying the phosphonic acid moiety of L-2-amino-4-phosphonobutanoic acid represented by Formula (3) to give a diastereomeric mixture, represented by Formula (3-1), of an L-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative and an L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative
• Formulae (3) and (3-1) expressed as follows:
• wherein the atom marked with an asterisk (*) indicates an asymmetric atom,
• wherein R1 is, identically or differently in each occurrence, selected from hydrogen and a carboxy-protecting group;
• R2 is selected from benzyloxycarbonyl, phenylmethylidene, and diphenylmethylidene, each being optionally substituted;
• k represents 0 or 1, where when R2 is optionally substituted benzyloxycarbonyl, k is 1 and the bond between the specified nitrogen atom and R is a single bond, and when R2 is optionally substituted phenylmethylidene or optionally substituted diphenylmethylidene, k is 0 and the bond between the specified nitrogen atom and R2 is a double bond;
• and * is as defined above.

A diastereomeric mixture of an L-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative and an L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative, the diastereomeric mixture being represented by Formula (3-1):

• wherein R1 is, identically or differently in each occurrence, selected from hydrogen and a carboxy-protecting group;
• R2 is selected from benzyloxycarbonyl, phenylmethylidene, and diphenylmethylidene, each being optionally substituted;
• k represents 0 or 1, where when R2 is optionally substituted benzyloxycarbonyl, k is 1 and the bond between the specified nitrogen atom and R2 is a single bond, and when R2 is optionally substituted phenylmethylidene or optionally substituted diphenylmethylidene, k is 0 and the bond between the specified nitrogen atom and R2 is a double bond;
• and the atoms marked with an asterisk (*) indicate asymmetric atoms.

A method for optically resolving a diastereomeric mixture of an L-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative and an L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative, the method comprising

• subjecting a diastereomeric mixture, represented by Formula (3-1), of an L-2-amino-4-[(Rp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative and an L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative to fractional crystallization, to give one of optical isomers represented by Formulae (1-3) and (1-4), Formulae (3-1), (1-3), and (1-4) expressed as follows:
• wherein R1 is, identically or differently is each occurrence, selected from hydrogen and a carboxy-protecting group;
• R2 is selected from benzyloxycarbonyl, phenylmethylidene, and diphenylmethylidene, each being optionally substituted;
• k represents 0 or 1, where when R2 is optionally substituted benzyloxycarbonyl, k is 1 and the bond between the specified nitrogen atom and R2 is a single bond, and when R2 is optionally substituted phenylmethylidene or optionally substituted diphenylmethylidene, k is 0 and the bond between the specified nitrogen atom and R2 is a double bond;
• and the atoms marked with an asterisk (*) indicate asymmetric atoms,
• wherein R1, R2, k, and * are as defined above.

A method for producing an L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid hydrate, the method comprising:

• subjecting an L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid derivative represented by Formula (1-4) to deprotection treatment to give L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid represented by Formula (1-4′);
• and
• subjecting the resulting L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid to crystallization from water or from a solvent mixture of water and a water-soluble organic solvent, to give an L-2-amino-4-[(Sp)-(3-carboxymethylphenoxy)(methoxy)phosphoryl]butanoic acid hydrate represented by Formula (1-4′-1), Formulae (1-4), (1-4′), and (1-4′-1) expressed as follows:
• wherein R1 is, identically or differently in each occurrence, selected from hydrogen and a carboxy-protecting group;
• R2 is selected from benzyloxycarbonyl, phenylmethylidene, and diphenylmethylidene, each being optionally substituted;
• k represents 0 or 1, where when R2 is optionally substituted benzyloxycarbonyl, k is 1 and the bond between the specified nitrogen atom and R2 is a single bond, and when R2 is optionally substituted phenylmethylidene or optionally substituted diphenylmethylidene, k is 0 and the bond between the specified nitrogen atom and R2 is a double bond;
• and the atoms marked with an asterisk (*) indicate asymmetric atoms,
• wherein * is as defined above,
• wherein the atoms marked with an asterisk (*) indicate asymmetric atoms;
• and t represents a number greater than 0.