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Isomerically pure 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-oxypiperidin-1-yl]ethyl]-7-hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one and processes for preparation thereof

IP.com Disclosure Number: IPCOM000178796D
Publication Date: 2009-Jan-25
Document File: 3 page(s) / 37K

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The IP.com Prior Art Database

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Page 1 of 3

    Isomerically pure 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-oxypiperidin- 1-yl]ethyl]-7-hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one and processes for preparation thereof

    3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-7-hydroxy-4- methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one is depicted in the following chemical structure

N

N

O

H

N

N O

O

F

P

a

l

i

p

e

r

i

d

o

n

e

    3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-oxypiperidin-1-yl]ethyl]-7- hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one is an impurity of 3-[2- [4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-7-hydroxy-4-methyl-1,5- diazabicyclo[4.4.0]deca-3,5-dien-2-one which remains in small quantities in the final product.

    The processes known in the art result in the formation of both the cis and trans isomers of 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-oxypiperidin-1-yl]ethyl]-7- hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one.

N

N

H

R1

R2 O

N

N

OH

trans PLP-NO

N

N O

O O

PLP-NO

H

R1

F

O

R2

3-[2-[4-(6-fluorobenzo[d]isoxazol-3-

yl)-1-oxypiperidin-1-yl]ethyl]-7-

hydroxy-4-methyl-1,5-

diazabicyclo[4.4.0]deca-3,5-dien-2-one

C

i

s

P

L

P

-

N

O

Page 2 of 3

    cis 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-oxypiperidin-1-yl]ethyl]-7- hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one can be prepared by slurrying 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-oxypiperidin-1-yl]ethyl]-7- hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one in a solvent or mixture of solvents such as C1-4 alkyl alcohols, C4-C8 ethers and C4-C10 alkanes to form a mixture, filtering the mixture to obtain a liquid and removing the solvent from the liquid to precipitate cis 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-oxypiperidin-1- yl]ethyl]-7-hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one. The precipitated cis 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-oxypiperidin-1-yl]ethyl]-7- hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one may be isolated.

    cis 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-oxypiperidin-1-yl]ethyl]-7- hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one was prepared according to the following process: 30g of 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1- piperidyl]ethyl]-7-hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one, 150 ml of hydrogen peroxide 30% and 60 ml methanol were stirred at room temperature for 4 hours, self heated to reflux and cooled in a water bath. The mixture was then filtrated, and the methanol filtrat...