Process for producing erythromycin derivative

A method for preparing a fumarate salt of a compound represented by Formula (II):

• 50
• (wherein R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a lower alkyl group), which comprises:
• carbamating a compound represented by Formula (I):
• 51
• (wherein R1 represents a hydrogen atom or a lower alkyl group) to give a compound represented by Formula (III):
• 52
• (wherein R1 represents a hydrogen atom or a lower alkyl group, R3 represents a carbamate group, and R4 represents a hydrogen atom or a carbamate group);
• removing all carbamate groups from the compound represented by Formula (III) to give a compound represented by Formula (IV):
• 53
• (wherein R1 represents a hydrogen atom or a lower alkyl group);
• alkylating the nitrogen atom at the 3′-position of the desosamine ring in the compound represented by Formula (IV) to give the compound represented by Formula (II);
• and
• converting the compound represented by Formula (II) into a fumarate salt;
• wherein the carbamate groups of the compound represented by Formula (III) are removed in the presence of sodium bicarbonate to give the compound represented by Formula (IV).

A method for preparing a crystal of a fumarate salt of a compound represented by Formula (II):

• 54
• (wherein R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a lower alkyl group), which comprises:
• carbamating a compound represented by Formula (I):
• 55
• (wherein R1 represents a hydrogen atom or a lower alkyl group) to give a compound represented by Formula (III):
• 56
• (wherein R1 represents a hydrogen atom or a lower alkyl group, R3 represents a carbamate group, and R4 represents a hydrogen atom or a carbamate group);
• removing all carbamate groups from the compound represented by Formula (III) to give a compound represented by Formula (IV):
• 57
• (wherein R1 represents a hydrogen atom or a lower alkyl group);
• alkylating the nitrogen atom at the 3′-position of the desosamine ring in the compound represented by Formula (IV) to give the compound represented by Formula (II);
• converting the compound represented by Formula (II) into a fumarate salt to give a fumarate salt of the compound;
• and
• crystallizing the fumarate salt from an alcohol-containing solvent;
• wherein the crystal is obtained by crystallization from isopropanol.

A method for preparing a crystal of a fumarate salt of a compound represented by Formula (II):

• 58
• (wherein R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a lower alkyl group), which comprises:
• carbamating a compound represented by Formula (I):
• 59
• (wherein R1 represents a hydrogen atom or a lower alkyl group) to give a compound represented by Formula (III):
• 60
• (wherein R1 represents a hydrogen atom or a lower alkyl group, R3 represents a carbamate group, and R4 represents a hydrogen atom or a carbamate group);
• removing all carbamate groups from the compound represented by Formula (III) to give a compound represented by Formula (IV):
• 61
• (wherein R1 represents a hydrogen atom or a lower alkyl group);
• alkylating the nitrogen atom at the 3′-position of the desosamine ring in the compound represented by Formula (IV) to give the compound represented by Formula (II);
• converting the compound represented by Formula (II) into a fumarate salt to give a fumarate salt of the compound;
• crystallizing the fumarate salt from an alcohol-containing solvent to give a crystal;
• and
• recrystallizing the crystal from an alcohol-containing solvent;
• wherein the crystal is recrystallized from isopropanol.

A method for preparing a crystal of a fumarate salt of a compound represented by Formula (II):

• 62
• (wherein R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a lower alkyl group), which comprises:
• carbamating a compound represented by Formula (I):
• 63
• (wherein R1 represents a hydrogen atom or a lower alkyl group) to give a compound represented by Formula (III):
• 64
• (wherein R1 represents a hydrogen atom or a lower alkyl group, R3 represents a carbamate group, and R4 represents a hydrogen atom or a carbamate group);
• removing all carbamate groups from the compound represented by Formula (III) to give a compound represented by Formula (IV):
• 65
• (wherein R1 represents a hydrogen atom or a lower alkyl group);
• alkylating the nitrogen atom at the 3′-position of the desosamine ring in the compound represented by Formula (IV) to give the compound represented by Formula (II);
• converting the compound represented by Formula (II) into a fumarate salt to give a fumarate salt of the compound;
• crystallizing the fumarate salt from an alcohol-containing solvent to give a crystal;
• and
• recrystallizing the crystal from an alcohol-containing solvent;
• wherein the crystal is recrystallized from isopropanol and then from a mixed methanol/isopropanol solvent.

A method for preparing a crystal of a fumarate salt of a compound represented by Formula (II):

• 66
• (wherein R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a lower alkyl group), which comprises:
• carbamating a compound represented by Formula (I):
• 67
• (wherein R1 represents a hydrogen atom or a lower alkyl group) in the presence of a cyclic ether or a carboxylic ester to give a compound represented by Formula (III):
• 68
• (wherein R1 represents a hydrogen atom or a lower alkyl group, R3 represents a carbamate group, and R4 represents a hydrogen atom or a carbamate group);
• removing all carbamate groups from the compound represented by Formula (III):
• 69
• (wherein R1 represents a hydrogen atom or a lower alkyl group, R3 represents a carbamate group, and R4 represents a hydrogen atom or a carbamate group) in the presence of sodium bicarbonate to give a compound represented by Formula (IV):
• 70
• (wherein R1 represents a hydrogen atom or a lower alkyl group);
• crystallizing a fumarate salt of the compound represented by Formula (II) from isopropanol to give a crystal of the fumarate salt of the compound;
• and
• recrystallizing the crystal from isopropanol and then from a mixed methanol/isopropanol solvent.

A method for preparing a compound represented by Formula (III):

• 71
• (wherein R1 represents a hydrogen atom or a lower alkyl group, R3 represents a carbamate group, and R4 represents a hydrogen atom or a carbamate group), which comprises carbamating a compound represented by Formula (I):
• 72
• (wherein R1 represents a hydrogen atom or a lower alkyl group) in the presence of a cyclic ether or a carboxylic ester.

A method for preparing a compound represented by Formula (IV):

• 73
• (wherein R1 represents a hydrogen atom or a lower alkyl group), which comprises removing all carbamate groups from a compound represented by Formula (III):
• 74
• (wherein R1 represents a hydrogen atom or a lower alkyl group, R3 represents a carbamate group, and R4 represents a hydrogen atom or a carbamate group) in the presence of sodium bicarbonate.