Synthesis of N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester and its regioselective radiofluorodestannylation to 6-[.sup.18 F]fluoro-L-dopa
OwnerNagichettiar Satyamurthy, Jorge R. Barrio +2inventors
InventorsNagichettiar Satyamurthy, Jorge R. Barrio, Allyson J. Bishop, Mohammad Namavari
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Abstract
A protected 6-trimethylstannyl dopa derivative has been synthesized for the as a precursor for the preparation of 6-[.sup.18 F]fluoro-L-dopa. The tin derivative readily reacts with electrophilic radiofluorinating agents such as [.sup.18 F]F.sub.2, [.sup.18 F]OF.sub.2 and [.sup.18 F]AcOF. The [.sup.18 F]fluoro intermediate was easily hydrolyzed with HBr and the product 6-[.sup.18 F]fluoro-L-dopa was isolated after HPLC purification in a maximum radiochemical yield of 23%, ready for human use.
Claims12
N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester.
The process for producing N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester comprising:
- (a) forming N-formyl-3,4-dimethoxy-L-phenylalanine ethyl ester by reacting 3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride with sodium formate,
- (b) reacting the product of step a) above with iodine and silver trifluoroacetate to form N-formyl-3,4-dimethoxy-6-iodo-L-phenylalanine ethyl ester,
- (c) exposing the product of step b) above to BBr.sub.3 to form N-formyl-3,4-dihydroxy-6-iodo-L-phenylalanine ethyl ester,
- (d) reacting the product of step c) above with di-t-butyl dicarbonate to produce N-formyl-3,4-di-t-butoxycarbonyloxy-6-iodo-L-phenylalanine ethyl ester, and
- (e) reacting the product of step d) above with hexamethylditin to produce N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester.
The process of forming unlabelled 6-fluoro-L-dopa and 6-[.sup.18 F]fluoro-L-dopa comprising:
- (a) bubbling an unlabelled or radiolabeled fluorine compound selected from the group consisting of [.sup.18 F]CH.sub.3 COOF, [.sup.18 F]F.sub.2, and [.sup.18 F]OF.sub.2 and combinations thereof through N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester,
- (b) treating the product of step a) above with hydrobromic acid, and
- (c) raising the pH of the product of step b) above to a value .ltoreq.7 by the addition of NaOH.
The process of forming unlabelled 6-fluoro-L-dopa and 6-[.sup.18 F]fluoro-L-dopa comprising:
- (a) forming N-formyl-3,4-dimethoxy-L-phenylalanine ethyl ester by reacting 3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride with sodium formate,
- (b) reacting the product of step a) above with iodine and silver trifluoroacetate to form N-formyl-3,4-dimethoxy-6-iodo-L-phenylalanine ethyl ester,
- (c) exposing the product of step b) above to BBr.sub.3 to form N-formyl-3,4-dihydroxy-6-iodo-L-phenylalanine ethyl ester,
- (d) reacting the product of step c) above with di-t-butyl dicarbonate to produce N-formyl-3,4-di-t-butoxycarbonyloxy-6-iodo-L-phenylalanine ethyl ester, and
- (e) reacting the product of step d) above with hexamethylditin to produce N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester,
- (f) bubbling an unlabelled or radiolabeled fluorine compound selected from the group consisting of [.sup.18 F]CH.sub.3 COOF, [.sup.18 F]F.sub.2, and [.sup.18 F]OF.sub.2 and combinations thereof through the product of step e) above,
- (g) treating the product of step f) above with hydrobromic acid, and
- (h) raising the pH of the product of step c) above to a value .ltoreq.7 by the addition of NaOH.
The process for producing an aryltin precursor to be used in the formation of a fluorine labeled L-dopa compound comprising:
- (a) reacting 3,4-dialkoxy-L-phenylalanine alkyl ester-hydrochloride with a salt of an organic acid,
- (b) reacting the product of step a) above with an acyl hypoiodite,
- (c) exposing the product of step b) above to trihalogen boride,
- (d) reacting the product of step c) above with di-t-alkyl dicarbonate, and
- (e) reacting the product of step d) above with hexaalkylditin.
The process of forming unlabelled as well as 6-[.sup.18 F]fluoro-L-dopa comprising:
- (a) reacting 3,4-dialkoxy-L-phenylalanine alkyl ester-hydrochloride with a salt of an organic acid,
- (b) reacting the product of step a) above with a halogen,
- (c) exposing the product of step b) above to trihalogen boride,
- (d) reacting the product of step c) above with di-t-alkyl dicarbonate,
- (e) reacting the product of step d) above with hexaalkylditin,
- (f) bubbling an unlabelled or radiolabeled fluorine compound selected from the group consisting of [.sup.18 F]CH.sub.3 COOF, [.sup.18 F]F.sub.2, and [.sup.18 F]OF.sub.2 and combinations thereof through the product of step e) above,
- (g) treating the product of step f) above with a halogen acid, and
- (h) raising the pH of the product of step g) above to a value .ltoreq.7 by the addition of a base.
A compound having the formula:
- ##STR1## Wherein:
- R.sub.1 and R.sub.2 are electron withdrawing groups,
- R.sub.3 is an amino acid, and
- R.sub.4, R.sub.5 and R.sub.6 are alkyl groups.
Dependencies are inferred from the claim text.