Selective solvent free phosphorylation

A method of making a compound of formula (II), or a salt thereof:

• wherein Y1 and Y2 are independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, and substituted or unsubstituted amino;
• or alternatively, Y1 and Y2 taken together are selected from the group consisting of sodium, potassium, lithium, magnesium, calcium, strontium, and barium;
• Z1 and Z2 are independently NH or oxygen;
• n is 0 or 1;
• R1 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, and —C*H—(RA)—CO2RB;
• wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halogen, —CN, —NO2, —C(O)RC, —C(O)ORC, —C(O)NRC2, —C(═NRC)NRC2, —ORC, —OC(O)(C1-C6)alkyl, —OC(O)O(C1-C6)alkyl, —OC(O)NRC2, —(C1-C6)alkylene-NRC2, —NRC2, —NRCC(O)RC, —NRCC(O)O(C1-C6)alkyl, —NRCC(O)NRC2, —NRCSO2NRC, —SRC, —S(O)RC, —SO2RC, —OSO2(C1-C6)alkyl, —SO2NRC2, —(C1-C6)perfluoroalkyl, and —(C1-C6)alkylene-ORC;
• RA is selected from the group consisting of —H, —(C1-C6)alkyl, —(CH2)3—NH—C(NH2)(═NH), —CH2C(═O)NH2, —CH2COOH, —CH2SH, —(CH2)2C(═O)—NH2, —(CH2)2COOH, —CH2-(2-imidazolyl), —CH(CH3)—CH2—CH3, —CH2CH(CH3)2, —(CH2)4—NH2, —(CH2)2—S—CH3, phenyl, —CH2-phenyl, —CH2—OH, —CH(OH)—CH3, —CH2-(3-indolyl), —CH2-(4-hydroxyphenyl), —CH(CH3)2, and —CH2—CH3;
• RB is hydrogen or —(C1-C8)alkyl;
• each RC is independently selected from the group consisting of hydrogen and —(C1-C8)alkyl;
• and
• R2, R3, R4, and R5 are each independently selected from the group consisting of —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halogen, —CN, —NO2, —C(O)RC, —C(O)ORC, —C(O)NRC2, —C(═NRC)NRC2, —ORC, —OC(O)(C1-C6)alkyl, —OC(O)O(C1-C6)alkyl, —OC(O)NRC2, —(C1-C6)alkylene-NRC2, —NRC2, —NRCC(O)RC, —NRCC(O)O(C1-C6)alkyl, —NRCC(O)NRC2, —NRCSO2NRC, —SRC, —S(O)RC, —SO2RC, —OSO2(C1-C6)alkyl, —SO2NRC2, —(C1-C6)perfluoroalkyl, and —(C1-C6)alkylene-ORC;
• R6 and R7 are independently selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl;
• wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halogen, —CN, —NO2, —C(O)RC, —C(O)ORC, —C(O)NRC2, —C(═NRC)NRC2, —ORC, —OC(O)(C1-C6)alkyl, —OC(O)O(C1-C6)alkyl, —OC(O)NRC2, —(C1-C6)alkylene-NRC2, —NRC2, —NRCC(O)RC, —NRCC(O)O(C1-C6)alkyl, —NRCC(O)NRC2, —NRCSO2NRC, —SRC, —S(O)RC, —SO2RC, —OSO2(C1-C6)alkyl, —SO2NRC2, —(C1-C6)perfluoroalkyl, and —(C1-C6)alkylene-ORC;
• R′ is selected from the group consisting of hydrogen, —(C1-C8)alkyl, —(C1-C8)cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C1-C4)alkyl, and heterocycle(C1-C4)alkyl;
• R″ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, and —C*H—(RA)—CO2RB;
• wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halogen, —CN, —NO2, —C(O)RC, —C(O)ORC, —C(O)NRC2, —C(═NRC)NRC2, —ORC, —OC(O)(C1-C6)alkyl, —OC(O)O(C1-C6)alkyl, —OC(O)NRC2, —(C1-C6)alkylene-NRC2, —NRC2, —NRCC(O)RC, —NRCC(O)O(C1-C6)alkyl, —NRCC(O)NRC2, —NRCSO2NRC, —SRC, —S(O)RC, —SO2RC, —OSO2(C1-C6)alkyl, —SO2NRC2, —(C1-C6)perfluoroalkyl, and —(C1-C6)alkylene-ORC;
• provided that when Z2 is NH, the absolute configuration of C* is D or L, or a mixture of D and L;
• comprising the steps of:
• (a) providing a compound or derivative having formula (2), or a salt thereof:
• wherein Z1 and Z2 are independently NH or oxygen;
• n is 0 or 1;
• R1 is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, and —C*H—(RA)—CO2RB;
• wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halogen, —CN, —NO2, —C(O)RC, —C(O)ORC, —C(O)NRC2, —C(═NRC)NRC2, —ORC, —OC(O)(C1-C6)alkyl, —OC(O)O(C1-C6)alkyl, —OC(O)NRC2, —(C1-C6)alkylene-NRC2, —NRC2, —NRCC(O)RC, —NRCC(O)O(C1-C6)alkyl, —NRCC(O)NRC2, —NRCSO2NRC, —SRC, —S(O)RC, —SO2RC, —OSO2(C1-C6)alkyl, —SO2NRC2, —(C1-C6)perfluoroalkyl, and —(C1-C6)alkylene-ORC;
• RA is selected from the group consisting of —H, —(C1-C6)alkyl, —(CH2)3-NH—C(NH2)(═NH), —CH2C(═O)NH2, —CH2COOH, —CH2SH, —(CH2)2C(═O)—NH2, —(CH2)2COOH, —CH2-(2-imidazolyl), —CH(CH3)—CH2—CH3, —CH2CH(CH3)2, —(CH2)4—NH2, —(CH2)2—S—CH3, phenyl, —CH2-phenyl, —CH2—OH, —CH(OH)—CH3, —CH2-(3-indolyl), —CH2-(4-hydroxyphenyl), —CH(CH3)2, and —CH2—CH3;
• RB is hydrogen or —(C1-C8)alkyl;
• each RC is independently selected from the group consisting of hydrogen and —(C1-C8)alkyl;
• and
• R2, R3, R4, and R5 are each independently selected from the group consisting of —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halogen, —CN, —NO2, —C(O)RC, —C(O)ORC, —C(O)NRC2, —C(═NRC)NRC2, —OC(O)(C1-C6)alkyl, —OC(O)O(C1-C6)alkyl, —OC(O)NRC2, —(C1-C6)alkylene-NRC2, —NRC2, —NRCC(O)RC, —NRCC(O)O(C1-C6)alkyl, —NRCC(O)NRC2, —NRCSO2NRC, —SRC, —S(O)RC, —SO2RC, —OSO2(C1-C6)alkyl, —SO2NRC2, —(C1-C6)perfluoroalkyl, and —(C1-C6)alkylene-ORC;
• R6 and R7 are independently selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl;
• wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halogen, —CN, —NO2, —C(O)RC, —C(O)ORC, —C(O)NRC2, —C(═NRC)NRC2, —ORC, —OC(O)(C1-C6)alkyl, —OC(O)O(C1-C6)alkyl, —OC(O)NRC2, —(C1-C6)alkylene-NRC2, —NRC2, —NRCC(O)RC, —NRCC(O)O(C1-C6)alkyl, —NRCC(O)NRC2, —NRCSO2NRC, —SRC, —S(O)RC, —SO2RC, —OSO2(C1-C6)alkyl, —SO2NRC2, —(C1-C6)perfluoroalkyl, and —(C1-C6)alkylene-ORC;
• R′ is selected from the group consisting of hydrogen, —(C1-C8)alkyl, —(C1-C8)cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C1-C4)alkyl, and heterocycle(C1-C4)alkyl;
• R″ is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, and —C*H—(RA)—CO2RB;
• wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted with one to five substituents independently selected from the group consisting of —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, halogen, —CN, —NO2, —C(O)RC, —C(O)ORC, —C(O)NRC, —C(═NRC)NRC2, —ORC, —OC(O)(C1-C6)alkyl, —OC(O)O(C1-C6)alkyl, —OC(O)NRC2, —(C1-C6)alkylene-NRC2, —NRC2, —NRCC(O)RC, —NRCC(O)O(C1-C6)alkyl, —NRCC(O)NRC2, —NRCSO2NRC, —SRC, —S(O)RC, —SO2RC, —OSO2(C1-C6)alkyl, —SO2NRC2, —(C1-C6)perfluoroalkyl, and —(C1-C6)alkylene-ORC;
• provided that when Z2 is NH, the absolute configuration of C* is D or L, or a mixture of D and L;
• (b) treating the compound of formula (2) with a base;
• (c) mechanically processing the components in the presence of phosphorus oxychloride;
• (d) adding water to the mixture;
• (e) filtering;
• (f) adjusting the pH with an aqueous base;
• and
• (g) precipitating the compound of formula (II).

A method of making thiaminyl monophosphate, or a salt thereof, comprising the steps of:

• (a) providing thiamine or a salt thereof;
• (b) treating the thiamine or salt thereof with phosphorus oxychloride;
• (c) mechanically processing the components;
• (d) adding water to the mixture;
• (e) adjusting the pH with an aqueous base;
• and
• precipitating the thiaminyl monophosphate.

A method of making pyridoxyl monophosphate, or a salt thereof, comprising the steps of:

• (a) providing pyridoxine or a salt thereof;
• (b) treating the pyridoxine or salt thereof with phosphorus oxychloride;
• (c) mechanically processing the components;
• (d) adding water to the mixture;
• (e) adjusting the pH with an aqueous base;
• and
• (f) precipitating the pyridoxyl monophosphate.

A method of making adenosyl monophosphate, or a salt thereof, comprising the steps of:

• (a) providing adenosine or a salt thereof;
• (b) treating the adenosine or salt thereof with phosphorus oxychloride;
• (c) mechanically processing the components;
• (d) adding water to the mixture;
• (e) adjusting the pH with an aqueous base;
• and
• precipitating the adenosyl monophosphate.