Processes for producing diazabicyclooctane compounds

1. A process for producing a compound represented by Formula (VII), the process comprising reacting a compound represented by the following Formula (III):

with a compound R 3 ONH 2 to obtain a compound represented by the following Formula (IV):

treating the compound of Formula (IV) with a palladium carbon catalyst under a hydrogen atmosphere, simultaneously or consecutively subjecting the resultant compound to a sulfation reaction with a sulfur trioxide-trimethylamine complex in the presence of a catalytic amount of base in a hydrous solvent and treating the resultant compound with tetrabutylammonium hydrogensulfate to obtain a compound represented by the following Formula (VI):

followed by, in a case where the R 3 ONHC(═O)— side chain has a protecting group, removing the protecting group with an acid, and precipitating a crude product by adding a poor solvent to the resultant reaction solution to obtain a crude compound represented by the following Formula (VII-CR):

followed by alternately adding the crude compound represented by Formula (VII-CR) and an ice-cold buffer to obtain a solution having a pH of 4 to 5.5, optionally carrying out desalting with a synthetic adsorbent to produce a compound represented by the following Formula (VII):

wherein in the above formulas, OBn is benzyloxy; R 1 is 2,5-dioxopyrrolidin-1-yl, 1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-yl, 1,3-dioxohexahydro-1H-isoindol-2(3H)-yl, or 3,5-dioxo-4-azatricyclo[5.2.1.0 2.6 ]dec-8-en-4-yl; and R 3 is a C 1-6 alkyl or a heterocyclyl, wherein R 3 is optionally substituted with 1 to 5 R 4 groups, wherein R 4 is selected from the group consisting of a C 1-6 alkyl, a heterocyclyl, R 5 (R 6 )N- and a protecting group, wherein R 4 is optionally substituted with one or more groups selected from the group consisting of a C 1-6 alkyl, a heterocyclyl, R 5 (R 6 )N- and a protecting group, wherein R 5 and R 6 each independently is hydrogen or a C 1-6 alkyl or together form a heterocyclyl, wherein R 3 , R 5 and R 6 can together undergo ring closure.

2. A process for producing a compound represented by a Formula (IV), the process comprising reacting a compound represented by the following Formula (III):

with a compound: R 3 ONH 2 to produce a compound represented by the following Formula (IV):

wherein in the above formulas, same as OBn is benzyloxy; R 1 is 2,5-dioxopyrrolidin-1-yl, 1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-yl, 1,3-dioxohexahydro-1H-isoindol-2(3H)-yl, or 3,5-dioxo-4-azatricyclo[5.2.1.0 2.6 ]dec-8-en-4-yl; and R 3 is a C 1-6 alkyl or a heterocyclyl, wherein R 3 is optionally substituted with 1 to 5 R 4 groups, wherein R 4 is selected from the group consisting of a C 1-6 alkyl, a heterocyclyl, R 5 (R 6 )N- and a protecting group, wherein R 4 is optionally substituted with one or more groups selected from the group consisting of a C 1-6 alkyl, a heterocyclyl, R 5 (R 6 )N- and a protecting group, wherein R 5 and R 6 each independently is hydrogen or a C 1-6 alkyl or together form a heterocyclyl, wherein R 3 , R 5 and R 6 can together undergo ring closure.

3. A process for producing a compound represented by a Formula (VI), the process comprising treating a compound represented by the following Formula (IV):

with a palladium carbon catalyst under a hydrogen atmosphere, simultaneously or consecutively subjecting the compound of Formula IV to a sulfation reaction with a sulfur trioxide-trimethylamine complex in the presence of a catalytic amount of base in a hydrous solvent, and treating the resultant compound with tetrabutylammonium hydrogensulfate to produce a compound represented by the following Formula (VI):

wherein in the above formulas, OBn is benzyloxy and R 3 is a C 1-6 alkyl or a heterocyclyl, wherein R 3 is optionally substituted with 1 to 5 R 4 groups, wherein R 4 is selected from the group consisting of a C 1-6 alkyl, a heterocyclyl, R 5 (R 6 )N- and a protecting group, wherein R 4 is optionally substituted with one or more groups selected from the group consisting of a C 1-6 alkyl, a heterocyclyl, R 5 (R 6 )N- and a protecting group, wherein R 5 and R 6 each independently is hydrogen or a C 1-6 alkyl or together form a heterocyclyl, wherein R 3 , R 5 and R 6 can together undergo ring closure.

4. A process for producing a compound represented by Formula (VII), the process comprising alternately adding a crude compound represented by the following Formula (VII-CR):

and an ice-cold buffer to obtain a solution having a pH of 4 to 5.5, optionally carrying out desalting with a synthetic adsorbent to produce the compound represented by the following Formula (VII):

wherein each of the Formulas VII-CR and VII, R 3 is is a C 1-6 alkyl or a heterocyclyl, wherein R 3 is optionally substituted with 1 to 5 R 4 groups, wherein R 4 is selected from the group consisting of a C 1-6 alkyl, a heterocyclyl, R 5 (R 6 )N- and a protecting group, wherein R 4 is optionally substituted with one or more groups selected from the group consisting of a C 1-6 alkyl, a heterocyclyl, R 5 (R 6 )N- and a protecting group, wherein R 5 and R 6 each independently is hydrogen or a C 1-6 alkyl or together form a heterocyclyl, wherein R 3 , R 5 and R 6 can together undergo ring closure.

5. The process according to any of claim 1 , 2 , 3 or 4 , wherein R 3 in Formulas (IV), (VI), (VII-CR) and (VII) is selected from the group consisting of:

2-(tert-butoxycarbonylamino)ethyl;

2-aminoethyl;

2-((tert-butoxycarbonyl)(methyl)amino)ethyl;

2-(methylamino)ethyl;

2-((tert-butoxycarbonyl)(isopropyl)amino)ethyl;

2-(isopropylamino)ethyl;

2-(dimethylamino)ethyl;

(2S)-2-((tert-butoxycarbonyl)amino)propyl;

(2S)-2-(amino)propyl;

(2R)-2-((tert-butoxycarbonyl)amino)propyl;

(2R)-2-(amino)propyl;

3-((tert-butoxycarbonyl)amino)propyl;

3-(amino)propyl;

(2S)-tert-butoxycarbonylazetidin-2-ylmethyl;

(2S)-azetidin-2-ylmethyl;

(2R)-tert-butoxycarbonylpyrrolidin-2-ylmethyl;

(2R)-pyrrolidin-2-ylmethyl;

(3R)-tert-butoxycarbonylpiperidin-3-ylmethyl;

(3R)-piperidin-3-ylmethyl;

(3S)-tert-butoxycarbonylpyrrolidin-3-yl;

(3S)-pyrrolidin-3-yl;

1-(tert-butoxycarbonyl)azetidin-3-yl; and

azetidin-3-yl.

6. A process for producing a compound represented by Formula (VII-1), the process comprising reacting a compound represented by the following Formula (III):

with tert-butyl 2-(aminooxy)ethylcarbamate in the presence of a base to obtain a compound represented by the following Formula (IV-1):

followed by treating the compound of Formula IV-1 with a palladium carbon catalyst under a hydrogen atmosphere, simultaneously or consecutively subjecting the resultant compound to a sulfation reaction with a sulfur trioxide-trimethylamine complex in the presence of a catalytic amount of base in a hydrous solvent, and treating the resultant compound with tetrabutylammonium hydrogensulfate to obtain a compound represented by the following Formula (VI-1):

followed by removing the tert-butoxycarbonyl group with trifluoroacetic acid and dropping ethyl acetate into the resultant reaction solution to precipitate a crude product and obtain a crude compound represented by the following Formula (VII-1-CR):

followed by alternately adding the crude compound represented by Formula (VII-1-CR) and an ice-cold phosphate buffer to obtain a solution having a pH of 4 to 5.5, optionally carrying out desalting with a synthetic adsorbent to produce a compound represented by the following Formula (VII-1):

wherein in the above formulas, OBn is benzyloxy and R 1 is 2,5-dioxopyrrolidin-1-yl, 1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-yl, 1,3-dioxohexahydro-1H-isoindol-2(3H)-yl, or 3,5-dioxo-4-azatricyclo[5.2.1.0 2.6 ]dec-8-en-4-yl.

7. A process for producing a compound represented by Formula (IV-1), the process comprising reacting a compound represented by the following Formula (III):

with tert-butyl 2-(aminooxy)ethylcarbamate in the presence of a base to produce the compound represented by the following Formula (IV-1):

wherein Boc is a tert-butoxycarbonyl group and in the above formulas, OBn is benzyloxy and R 1 is 2,5-dioxopyrrolidin-1-yl, 1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-yl, 1,3-dioxohexahydro-1H-isoindol-2(3H)-yl, or 3,5-dioxo-4-azatricyclo[5.2.1.0 2.6 ]dec-8-en-4-yl.

8. A process for producing a compound represented by Formula (VI-1), the process comprising treating a compound represented by the following Formula (IV-1):

with a palladium carbon catalyst under a hydrogen atmosphere, simultaneously or consecutively subjecting to a sulfation reaction using sulfur trioxide-trimethylamine complex in the presence of a catalytic amount of a base in a hydrous solvent, and carrying out treating with tetrabutylammonium hydrogensulfate to produce the compound represented by the following Formula (VI-1):

wherein Boc is a tert-butoxycarbonyl group and in the above formulas, and OBn is benzyloxy.

9. A process for producing a compound represented by Formula (VII-1), the process comprising alternately adding a crude compound represented by the following Formula (VII-1-CR):

and an ice-cold phosphate buffer to obtain a solution having a pH of 4 to 5.5, optionally carrying out desalting with a synthetic adsorbent to produce the compound represented by the following Formula (VII-1):

10. The process according to claim 1 , wherein in the formula (III), R 1 is selected from the group consisting of 1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-yl, 1,3-dioxohexahydro-1H-isoindol-2 (3H)-yl and 3,5-dioxo-4-azatricyclo[5.2.1.0 2.6 ]dec-8-en-4-yl.

11. The process according to claim 2 , wherein in the formula (III), R 1 is selected from the group consisting of 1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-yl, 1,3-dioxohexahydro-1H-isoindol-2 (3H)-yl and 3,5-dioxo-4-azatricyclo[5.2.1.0 2.6 ]dec-8-en-4-yl.

12. The process according to claim 6 , wherein in the formula (III), R 1 is selected from the group consisting of 1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-yl, 1,3-dioxohexahydro-1H-isoindol-2 (3H)-yl and 3,5-dioxo-4-azatricyclo[5.2.1.0 2.6 ]dec-8-en-4-yl.

13. The process according to claim 7 , wherein in the formula (III), R 1 is selected from the group consisting of 1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-yl, 1,3-dioxohexahydro-1H-isoindol-2 (3H)-yl and 3,5-dioxo-4-azatricyclo[5.2.1.0 2.6 ]dec-8-en-4-yl.

14. The process according to claim 1 , wherein the hydrous solvent is a mixture of water and an alcohol selected from the group consisting of methanol, ethanol and isopropanol.

15. The process according to claim 3 , wherein the hydrous solvent is a mixture of water and an alcohol selected from the group consisting of methanol, ethanol and isopropanol.

16. The process according to claim 6 , wherein the hydrous solvent is a mixture of water and an alcohol selected from the group consisting of methanol, ethanol and isopropanol.

17. The process according to claim 8 , wherein the hydrous solvent is a mixture of water and an alcohol selected from the group consisting of methanol, ethanol and isopropanol.