METHOD OF UTILIZING RECYCLED DEUTERIUM OXIDE IN THE SYNTHESIS OF DEUTERATED COMPOUNDS

1 . A method of deuterating multiple batches of a compound of formula I:

or a salt thereof, wherein:

R 1 is CH(R 3 )(R 3 );

R 2 is CH(R 3 )(R 3 ); and

each R 3 is independently H; or C 1 -C 6 alkyl (i) optionally substituted with one or more cyclic groups independently selected from C 6 -C 10 aryl, 5-10-membered heteroaryl, C 3 -C 8 cycloalkyl, and 3-8-membered heterocyclyl, wherein each cyclic group is optionally further substituted with one or more independently groups selected from C 1 -C 2 alkyl, deutero-substituted C 1 -C 2 alkyl and —OH; (ii) optionally substituted with one or more tautomers of the cyclic groups; and (iii) optionally substituted with deuterium, the method comprising the steps of:

(a) Combining:

i. a first batch of a compound of Formula I that has previously been subjected to first cycle of deuteration in the presence of D 2 O; with

ii. D 2 O and an organic solvent thereby subjecting any undeuterated or partially deuterated molecules of the compound of Formula I in the first batch to deuteration;

(b) Separating the combination from step (a) into a first organic phase and a first aqueous phase;

(c) Combining a second batch of a compound of Formula I with an organic solvent and the first aqueous phase thereby subjecting the compound of Formula Ito deuteration; and

(d) Separating the combination in step (c) into a third organic phase and a third aqueous phase.

2 . The method of claim 1 , wherein the D 2 O in step (a)(ii) has at least 99% isotopic purity.

3 . The method of claim 1 , further comprising the step of

(e) combining the first organic phase with D 2 O thereby subjecting any undeuterated or partially deuterated molecules of a compound of Formula I present in the first organic phase to deuteration; and

(f) separating the combination in step (e) into a second organic phase and a second aqueous phase.

4 . The method of claim 3 , wherein the D 2 O in step (e) has at least 99% isotopic purity.

5 . The method of claim 1 , further comprising the step of combining the third organic phase with D 2 O thereby subjecting any undeuterated or partially deuterated molecules of a compound of Formula I present in the third organic phase to deuteration.

6 . The method of claim 5 , wherein the D 2 O that is combined with the third organic phase has at least 99% isotopic purity.

7 . The method of claim 1 , further comprising the steps of:

(g) Combining the third organic phase with the second aqueous phase thereby subjecting any undeuterated or partially deuterated molecules of a compound of Formula I present in the third organic phase to deuteration;

(h) separating the combination from step (g) into a fourth organic phase and a fourth aqueous phase;

(i) combining the fourth organic phase with D 2 O thereby subjecting any undeuterated or partially deuterated molecules of a compound of Formula I present in the fourth organic phase to deuteration; and

(j) separating the combination from step (i) into a fifth organic phase and a fifth aqueous phase.

8 . The method of claim 7 , wherein the D 2 O in step (i) has at least 99% isotopic purity.

9 . The method of claim 1 , further comprising the steps of:

(k) Combining a third batch of a compound of Formula I with the fourth aqueous phase and an organic solvent thereby subjecting the compound of Formula Ito deuteration;

(l) separating the combination from step (k) into a sixth organic phase and a sixth aqueous phase; and

(m) combining the sixth organic phase with D 2 O thereby subjecting any undeuterated or partially deuterated molecules of a compound of Formula I present in the sixth organic phase to deuteration.

10 . The method of claim 9 , wherein the D 2 O in step (m) has at least 99% isotopic purity.

11 . The method of claim 1 , further comprising the steps of:

(k) Combining a third batch of a compound of Formula I with the fourth aqueous phase and an organic solvent thereby subjecting the compound of Formula Ito deuteration;

(l) separating the combination from step (k) into a sixth organic phase and a sixth aqueous phase;

(m) combining the sixth organic phase with the fifth aqueous phase thereby subjecting any undeuterated or partially deuterated molecules of a compound of Formula I present in the sixth organic phase to deuteration;

(n) separating the combination from step (m) into a seventh organic phase and a seventh aqueous phase; and

(o) combining the seventh organic phase with D 2 O thereby subjecting any undeuterated or partially deuterated molecules of a compound of Formula I present in the seventh organic phase to deuteration.

12 . The method of claim 11 , wherein the D 2 O in step (o) has at least 99% isotopic purity.

13 . The method of claim 1 , wherein in the compound of Formula I:

R 1 is CH 2 R 3 ; and

R 2 is CH 2 R 3 .

14 . The method of claim 13 , wherein R 1 is CH 3 .

15 . The method of claim 14 , wherein R 2 is —CH 2 —(C 1 -C 5 alkyl), wherein the C 1 -C 5 alkyl is (i) optionally substituted with one or more cyclic groups independently selected from C 6 -C 10 aryl, 5-10-membered heteroaryl, C 3 -C 8 cycloalkyl, and 3-8-membered saturated heterocyclyl, wherein each cyclic group is optionally further substituted with one or more groups independently selected from C 1 -C 2 alkyl, deutero-substituted C 1 -C 2 alkyl and —OH; (ii) optionally substituted with one or more tautomers of the cyclic groups; and (iii) optionally substituted with deuterium.

16 . The method of claim 15 , wherein:

R 2 is:

wherein R 4 and R 6 are independently selected from —CH 3 and —CD 3 ; and R 5 is selected from H and D.

17 . The method of claim 16 , wherein the compound of Formula I is pentoxifylline: