A method for the quantification of solid-phase reactions using fluorine NMR, and a fluorine-containing solid-phase reaction component

摘要

1. A method of quantitating a solid-phase reaction comprising: (a) reacting a solid-phase reaction component or a fluorine-containing solid-phase reaction component with a reactant or fluorine-containing reactant to form a fluorine-containing solid-phase reaction product; (b) obtaining a 19F NMR spectrum of the fluorine-containing solid-phase reaction product; and (c) comparing the integral corresponding to the fluorine-containing solid-phase reaction product 19F resonance to the integral corresponding to a standard 19F resonance. 2. The method according to Claim 1 wherein the 19F NMR spectra are obtained using magic angle spinning. 3. The method according to Claim 1 wherein the internal standard is a fluorine-containing solid-phase reaction component of the formula wherein is a solid support optionally containing one or more fluorine atoms; L is absent or a linking group optionally containing one or more fluorine atoms, provided that at least one of the components selected from solid support and the linking group contains at least one fluorine atom; and B is a functional group suitable for reaction with a reactant to form a fluorine-containing solid-phase reaction product. 4. The method according to Claim 3 wherein the solid support contains one or more fluorine atoms. 5. The method according to Claim 3 wherein is a solid support; L is a group of formula A is absent or is selected from -C(O)-, -YC(O)-, -SO2-, -NR7SO2-, -CHR7-, -CHR7Y- and -CHR7YC(O)(CH2)m-; or when B is halogen, NHP, OW or SO2Z; D is CH or N; P is H or an amine protecting group; W is H, NHP, NPR9, NC(O)Cl, C(O)R9, C(O)NR10R11, C(O)OR9, SO2R9 or C(O)-imidazol-1-yl; Y is -O- or-NR8-; Z is Cl, OH, ORa or NR9R12; R1 is F, or when one of R16, R17, R18 and R19 is F, R1 is H, alkyl, alkoxy, halogen, CN or NO2; R2, R3 and R4 are independently H, alkyl, alkoxy, halogen, CN or NO2, or one of R2, R and R4, taken together with one of R5 and R6 and the carbon atoms to which they are attached, define a group of formula R5 and R6 are independently -H, alkyl, phenyl or phenyl substituted with one or more substituents selected from alkyl, alkoxy, halogen, nitrile and -NO2; R7 and R8 are independently H or alkyl comprising 1 to 4 carbon atoms; R9 and R13 are independently aliphatic or aromatic; R10 and R11 are independently H, aliphatic or aromatic; R12 is -CH2R13; R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 are independently selected from H, alkyl, alkoxy, halogen, -CN and -NO2; m is 0 or 1; n is 1-6; and p is 0, 1 or 2. 6. The method according to Claim 5 wherein R1, R2, R3 and R4 are F; and one of R5 and R6 is H and the other of R5 and R6 is H or 2,4-dimethoxyphenyl. 7. The method according to Claim 6 wherein B is F, OW or SO2Z. 8. The method according to Claim 7 wherein A is phenylene, -C(O)-, -YC(O)-, -SO2-, -NR7SO2- or -CHR7O-. 9. The method according to Claim 5 wherein the fluorine-containing solid-phase reaction component is selected from 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%-divinylbenzene) resin, 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl-polystyrene resin, 2,3,5,6-tetrafluorobenzamidomethyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorobenzamidomethyl-4-sulfonylchloride-polystyrene resin, 4-hydroxy-2,3,5,6-tetrafluorobenzoyloxymethyl-polystyrene resin, 2,3,5,6-tetrafluorobenzoyloxymethyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorobenzoyloxymethyl-4-sulfonylchloride-polystyrene resin, 4-hydroxy-2,3,5,6-pentafluorobenzoyl-polystyrene resin, 2,3,5,6-tetrafluorobenzoyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorobenzoyl-4-sulfonylchloride-polystyrene resin, 4-hydroxy-2,3,5,6-tetrafluorophenylsulfonamidomethyl-polystyrene resin, 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonylchloride-polystyrene resin, N-(4-hydroxy-2,3,5,6-tetrafluorobenzoyl)-piperidinomethyl-polystyrene resin, N-(2,3,5,6-tetrafluorobenzoyl-4-sulfonic acid)-piperidinomethyl-polystyrene resin, N-(2,3,5,6-tetrafluorobenzoyl-4-sulfonyl chloride)-piperidinomethyl-4-polystyrene resin, N-(4-hydroxy-2,3 ,5 ,6-tetrafluorophenylsulfonyl)-piperidinomethyl-polystyrene resin, N-((2,3,5,6-tetrafluorophenyl-4-sulfonic acid)sulfonyl)-piperidinomethyl-polystyrene resin, N-((2,3,5,6-tetrafluorophenyl-4-sulfonylchloride)sulfonyl)-piperidinomethyl-polystyrene resin, 4-hydroxy-2,3,5,6-tetrafluorophenyl-polystyrene resin, 2,3,5,6-tetrafluorophenyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorophenyl-4-sulfonylchloride polystyrene resin, 4-hydroxy-2,3,5,6-tetrafluorophenylsulfonyl-polystyrene resin, 2,3,5,6-tetrafluorophenylsulfonyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorophenylsulfonyl-4-sulfonylchloride-polystyrene resin. 10. The method according to Claim 5 wherein the fluorine-containing solid-phase reaction component is selected from 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetra-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl-polystyrene resin, 2,3,5,6-tetrafluorobenzamidomethyl-4-sulfonic acid-polystyrene resin, 2,3,5,6-tetrafluorobenzamidomethyl-4-sulfonylchloride-polystyrene resin, 4-hydroxy-2,3,5,6-pentafluorobenzoyl-polystyrene resin, 2,3,5,6-tetrafluorobenzoyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorobenzoyl-4-sulfonylchloride-polystyrene resin, 4-hydroxy-2,3,5,6-tetrafluorophenylsulfonamidomethyl-polystyrene resin, 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-(sulfonic acid)-polystyrene resin and 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonylchloride-polystyrene resin. 11. The method according to Claim 5 wherein the fluorine-containing solid-phase reaction component is 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl-polystyrene resin. 12. The method according to Claim 1 wherein the solid-phase reaction component is chloromethylated polystyrene resin and the fluorine-containing reactant is 4-fluorophenol. 13. A fluorine-containing solid-phase reaction component of formula wherein is a solid support containing one or more fluorine atoms; LG is absent or a linking group wherein LG is optionally substituted by one or more fluorine atoms; and B is a functional group suitable for reaction with a reactant to form a fluorine-containing solid-phase reaction product. 14. The fluorine-containing solid-phase reaction component according to Claim 13 which is prepared by polymerizing a mixture comprising at least one fluorine-containing monomer. 15. The fluorine-containing solid-phase reaction component according to Claim 14 wherein the fluorine-containing monomer is 4-fluorostyrene. 16. The fluorine-containing solid-phase reaction component according to Claim 14 which is prepared by polymerizing a mixture of 4-fluorostyrene, 1,4-divinylbenzene and 4-vinylbenzylchloride.