Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates

A process for producing p-nitrobenzyl(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3-carboxylate.oxalate (II-III), which comprises:

• reacting p-nitrobenzyl(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate-2-active compound (XIV) represented by the following formula:
• wherein PNB has the same meaning as described above;
• and L represents a leaving group, with (2S,4S)-2-{[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}-4-mercaptopyrrolidine.dihydrochloride (XV) represented by the following formula:
• then converting the resultant into an oxalate.

A process for producing (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3-carboxylic acid.hydrochloride (VIII) represented by the following formula:

• said method comprising:
• subjecting a basic antibiotic protector-oxalate of p-nitrobenzyl(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3-carboxylate.oxalate (VII) represented by the following formula:
• wherein PNB represents p-nitrobenzyl group, to deprotection reaction;
• then subjecting to salt-exchange with calcium chloride;
• then crystallizing the resultant after said salt-exchange by adding methanol and/or isopropanol;
• and
• to producing said basic (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3-carboxylic acid.hydrochloride (VIII).

A process for producing a basic antibiotic.inorganic acid salt (I), said method comprising:

• subjecting a basic antibiotic.oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid:
• wherein the ring A represents the basic antibiotic;
• R10 represents a protected functional group;
• Ak—E represents the alkali earth metal;
• and B represents the inorganic acid;
• and
• producing said basic antibiotic.inorganic acid salt (I);
• wherein said basic antibiotic.oxalate (II) is an oxalate (II-I) of a carbapenem compound, represented by the following formula:
• wherein the ring A means a 3- to 7-membered ring having at least one nitrogen atom;
• R1 represents hydrogen or methyl group;
• R2 and R5 are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group;
• R3 represents a carboxyl-protecting group;
• R4 represents hydrogen, a lower alkyl group or an amino-protecting group;
• and
• R6 represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula:
• wherein R7 and R8 are the same as or different from each other and each represents hydrogen, a lower alkyl groups or an amino-protecting group, or (3) an amino-protecting group or an imino-protecting group;
• and
• m is 0 or 1.

An oxalate (II-I) of a carbapenem compound, represented by the following formula:

• wherein the ring A represents a 3- to 7-membered ring having at least one nitrogen atom, and the ring A is optionally substituted with a substituent other than R6;
• R1 represents hydrogen or methyl group;
• R2 and R5 are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group;
• R3 represents a carboxyl-protecting group;
• R4 represents hydrogen, a lower alkyl group or an amino-protecting group;
• R6 represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula:
• wherein R7 and R8 are the same as or different from each other and each represents hydrogen, a lower alkyl groups or an amino-protecting group, or (3) an amino-protecting group or an imino-protecting group;
• and
• m is 0 or 1.