Methods for the synthesis of 13C labeled iodotridecane and use as a reference standard

1. A process for preparing a 13 C labeled haloalkane as represented by Formula (i):

wherein R is a C 1 -C 28 carbon chain, X is a halogen, and the compound of Formula (i) is 13 C labeled at one or more of the carbon atoms labeled with an asterisk, the process comprising:

(a) protecting the primary alcohol present in 13 C labeled propargyl alcohol by ether bond formation to obtain a compound of Formula (ii):

wherein the 13 C labeled propargyl alcohol is labeled at C 1 , C 2 or C 3 thereof, or a combination thereof, and the compound of Formula (ii) is 13 C labeled at one or more of the carbon atoms labeled with an asterisk;

(b) alkylating the compound of Formula (ii) with X—R, wherein R is as defined above, and X is a halogen, to obtain a compound as represented by Formula (iii):

wherein the compound of Formula (iii) is 13 C labeled at one or more of the carbon atoms labeled with an asterisk;

(c) hydrogenating the compound of Formula (iii) to obtain a compound as represented by Formula (iv):

wherein the compound of Formula (iv) is 13 C labeled at one or more of the carbon atoms labeled with an asterisk;

(d) removing the protecting group in the compound of Formula (iv) to obtain the compound of Formula (v):

wherein the compound of Formula (v) is 13 C labeled at one or more of the carbon atoms labeled with an asterisk; and

(e) halogenating the primary alcohol present in the compound represented by Formula (v) to obtain the compound of Formula (i).

2. The process of claim 1 , wherein R is a C 5 -C 20 carbon chain.

3. The process of claim 1 , wherein R is a C 10 alkyl chain.

4. The process of claim 1 , wherein X is F, Cl, Br or I.

5. The process of claim 1 , wherein X is I.

6. The process of claim 1 , wherein the protecting group is a tetrahydropyran (THP) group.

7. The process of claim 1 , wherein the compound of Formula (ii) is alkylated with a halodecane to obtain a compound as represented by Formula 3:

8. The process of claim 1 , wherein two or three of the carbon atoms labeled with an asterisk are 13 C labeled.

9. The process of claim 6 , wherein the 13 C labeled propargyl alcohol is reacted in step (a) with dihydropyran (DHP) and p-toluenesulfonic acid (PTSA) to produce a compound represented by Formula 2:

10. The process of claim 1 , wherein the primary alcohol present in the compound represented by Formula (v) is halogenated by iodination.

11. A process for preparing a compound represented by Formula A:

the process comprising the steps of:

(a) protecting the primary alcohol of a 13 C labeled propargyl alcohol of Formula 1:

wherein the 13 C labeled propargyl alcohol of Formula 1 is labeled at one or more carbon atoms marked with an asterisk,

using a protecting agent to obtain a compound represented by Formula 2:

(b) alkylating the compound represented by Formula 2 with iododecane to yield a compound represented by Formula 3:

(c) hydrogenating the alkyne present in the compound represented by Formula 3 to yield a compound represented by Formula 4:

(d) removing the tetrahydropyran (THP) present in the compound represented by Formula 4 to yield a compound represented by Formula 5

(e) iodinizing the primary alcohol present in the compound represented by Formula 5 to yield the compound represented by Formula A.

12. The process as claimed in claim 11 , wherein step (a) is carried out in the presence of dichloromethane, dihydropyran (DHP) and p-toluenesulfonic acid (PTSA).

13. The process as claimed in claim 12 , wherein the step (a) is carried out at about room temperature.

14. The process as claimed in claim 11 , wherein the alkylation reaction of step (b) is carried out in the presence of tetrahydrofuran (THF), hexamethylphosphoramide (HPMA) and n-BuLi.

15. The process as claimed in claim 14 , wherein the step (b) is carried out at a temperature of between about −78° C. to about room temperature.

16. The process as claimed in claim 11 , wherein the hydrogenation reaction of step (c) is carried out in a hydrogen atmosphere in the presence of ethyl acetate and palladium on carbon (Pd/C).

17. The process as clamed in claim 11 , wherein the reaction of step (d) is carried out in the presence of methanol and p-toluenesulfonic acid (PTSA).

18. The process as claimed in claim 17 , wherein the reaction of step (d) is carried out at about room temperature.

19. The process as claimed in claim 11 , wherein the iodinization reaction of step (e) is carried out in presence of dichloromethane, triphenyl phosphine and imidazole.

20. The process as claimed in claim 19 , wherein the iodonization reaction of step (d) is carried out at a temperature of between about 0° C. to about room temperature.