Methods of manufacture and synthesis of fluorescent dye compounds and uses thereof
The present disclosure relates to synthesizing and utilizing fluorescent dye compounds or pharmaceutically acceptable salts thereof. Conjugation of amino acid groups to the fluorescent dyes increase specificity and detection of the compound. Methods of manufacture and synthesis of the compounds for use thereof in diagnostic imaging are contemplated.
1. A method for synthesizing a compound of formula (I)
wherein:
R 1 is (CH 2 ) n and n is 1 or 3,
R 2 is Br, I, or X—R 3 , wherein X is (CH 2 ) m , NH, O, S, or Se,
m is 0, 1, 2, or 3,
R 3 is (CH 2 ) p CH(R 4 )COOH or C 6 H 4 —(CH 2 ) p CH(R 4 )COOH or (CH 2 ) p COOH or (CH 2 ) p NH 2 and p is 0, 1, 2, or 3,
R 4 is H or NHR 5 ,
R 5 is H or alkyl group,
R 8 is (CH 2 ) q SO 3 H and q is 0, 1, 2, or 3, and
A is sodium, calcium, magnesium, lithium, cholinate, lysinium, ammonium, or hydrogen comprising the steps of
(a) reacting a compound of a formula
with a compound of a formula
in the presence of an acetate salt to generate a compound of the formula
(b) reacting the resulting compound with a compound of the formula
in the presence of 1,2-dichlorobenzene to generate a compound of the formula
(c) reacting a compound of the formula
in the presence of an acetate salt, sultone, and 1,2-dichlorobenzene to generate a compound of the formula
(d) reacting the compound of the formula
with a compound of the formula
in the presence of an acetate salt to generate a compound of the formula
wherein the resulting compound is selected from the group consisting of:
2. The method of claim 1 , further comprising step (e) wherein the compound of the formula
is reacted with X—R in water, methanol, or DMSO, wherein X=OH, NH2, SH, or SeH to generate a compound of the formula
3. The method of claim 2 , further comprising reacting the resulting compound of step (e) with a base and a compound of the formula Ligand-Linker-Z, wherein the Ligand-Linker comprises Pteroyl-Tyr-, Pteroyl-Lys-, —NH-Phenyl-CH 2 —CH 2 —, NH—CH 2 —CH 2 —, O-Phenyl-CH 2 —CH 2 , —O-Phenyl, S—CH 2 —CH 2 —, or chloro-dyes, and wherein Z is COOH, NH 2 , OH, or SH.
4. The method of claim 1 , wherein the resulting compound is precipitated in the presence of 1,2-dichlorobenzene or purified by chromatographic methods or crystallization method.
5. The method of claim 1 , wherein the yield of the resulting compound in is at least 60%.
6. The method of claim 2 , wherein the purity of the resulting compound in step (e) is at least 90%.