Process for the preparation of radioiodinated 3-fluoropropyl-nor-β-CIT
View Patent ↗The invention generally provides processes for the preparation of radioiodinated 3-fluoropropyl-nor-β-CIT. In particular, the process uses an arylsilane intermediate, thus avoiding the use of hexamethylditin, and reducing the number of steps previously required for the preparation of radioiodinated 3-fluoropropyl-nor-β-CIT from anhydroecgonine methyl ester. The invention also relates to the alkylation of a nortropane to the corresponding N-(3-fluoropropyl) analog using 3-fluoropropanal.
1. A process for the preparation of compound (I) comprising the following reaction scheme:
wherein:
X is a halogen, and
Me is methyl; and
wherein the alkylating agent is 3-fluoropropanol.
2. The process of claim 1 , wherein X is Br or I.
3. The process of claim 1 , wherein Step A comprises contacting a halogen-substituted phenyltrimethyl silane of formula:
with magnesium to form a Grignard reagent.
4. The process of claim 3 , further comprising contacting the Grignard reagent with compound 1-1 to form compound 2-1.
5. The process of claim 4 , wherein the Grignard reagent is contacted with compound 1-1 at a temperature of from about −40° C. to about −90° C.
6. The process of claim 5 , further comprising quenching the Step A reaction with trifluoroacetic acid.
7. The process of claim 1 , wherein the demethylation reagent is selected from the group consisting of 1-chloroethylchloroformate, vinyl chloroformate, and 2,2,2-trichloroethylchloroformate.
8. The process of claim 1 , wherein the reducing agent is selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride, and formic acid.
9. The process of claim 8 , wherein the reducing agent is present in the reaction mixture in an amount of from about 2 equivalents to about 15 equivalents, relative to compound 3-1.
10. The process of claim 1 , wherein the reaction mixture of Step D comprises an oxidizing agent selected from the group consisting of Chloramine-T, tert-butyl hypochlorite, peracetic acid, and combinations thereof.
11. The process of claim 1 , wherein the reaction mixture of Step D comprises iodinemonochloride and silver tetrafluoroborate.
12. A process for the preparation of a N-(3-fluoropropyl) compound (III), the process comprising contacting a nortropane compound (II) with 3-fluoropropanol in the presence of a reducing agent to form compound (III):
wherein R 1 is selected from the group consisting of halogen, Si(CH 3 ) 3 , and Sn(CH 3 ) 3 .
13. The process of claim 12 , wherein the halogen is I.
14. The process of claim 12 , wherein R 1 is Si(CH 3 ) 3 .
15. The process of claim 12 , wherein the reducing agent is selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride, and formic acid.
16. The process of claim 12 , wherein the reducing agent is present in the reaction mixture in an amount of from about 2 equivalents to about 15 equivalents, relative to compound (II).