Drug Metabolism in Drug Design and Development Basic Concepts and Practice

TABLE 12.11 (

Continued

)

Metabolicreaction

Metabolite identification examples

NMR indications

Confirmation method

and comments

5.

N

-oxidation

(Jairaj et al.,2002)

O

N

O

N

O

HO

O

N

O

N

O

HO

O

9

16

17

Pholcodine-N-Oxide

Pholcodine

The large downfield carbon

(D

d

>

12 ppm) and proton

(D

d

>

0.6 ppm) shifts for

C16, C17, and C9 wereindicative of N–oxideformation at the

N

15

nitrogen (chemical shiftschanges are listed in theTable 12.12)

The N-oxidation position

could be confirmed by

15

N

HMBC experiment. Thedownfield 10–30 ppmnitrogen shift is indicativeof the

N

-oxide.

However, this experimentrequires

>

100

m

g of sample

6.

S-Oxidationand

S-reduction

N

S

N

S

HN

NONH

2

N

S

N

S

HN

NO NH

2

O

Nizatidine

Nizatidin Sulfoxide

The methylene carbons

that connected to thesulfur group shiftedfrom



35 to



52 ppm

There is no direct NMR

method to confirm theexistence of the sulfoxidegroup as sulfur is not anNMR active nucleus

The

a

-methylene protons shifted

from



2.3 to



3.0 ppm

7. Alkene

reduction

OH

O

OH

O

Cinnamic acid

Phenylpropionic acid

The olefinic protons shifted

from 6.36 and 7.73 to 2.59and 2.89 ppm, respectively

The alkene reduction can be

further confirmed byobserving the changes in thecarbon shifts from110–140 ppm to about30 ppm by performing an 1 H



13

C

HMQC experiment

The coupling pattern changed

from large doublet (14.8 Hz)to the smaller multiplets

The integration of the

corresponded signals increasedfrom one proton to two protons

400