Process for the synthesis of substituted chloromethyl dialkylphosphates
Disclosed are compounds including phosphate and N-oxide prodrugs of the NK1 antagonist netupitant, useful in the prevention and/or treatment of diseases including emesis induced by chemotherapy. Also disclosed are methods of making a di-tert-butyl (chloromethyl) phosphate useful in the manufacture of such prodrugs by reacting a dialkylphosphate salt with an acid to obtain the corresponding ester of phosphoric acid, reacting the ester with a quaternary ammonium hydroxide base to form a monobasic salt, and reacting the monobasic salt with chloroiodomethane to form the corresponding chloromethyl dialkyl phosphate.
1. A process for synthesizing a composition comprising a chloromethyl dialkylphosphate having the following formula:
wherein:
R 200 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more independently selected R 103 substituents;
R 300 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more independently selected R 103 substituents;
each R 103 is independently halogen, CN, NO 2 , C(O)R 104 , C(O)NR 104 R 105 , C(O)OR 104 , NR 104 R 105 , NR 104 C(O)R 105 , NR 104 S(O) 2 R 105 , O − , OR 104 , SR 104 , S(O) 2 R 104 , S(O) 2 NR 104 R 105 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 104 is independently H, halogen, CN, NO 2 , alkyl, alkyl(hydroxy), alkyl(Oalkyl), alkyl(heterocycloalkyl), alkyl(aryl), alkyl(heteroaryl), alkenyl, NH 2 , O − , OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and
each R 105 is independently H, halogen, CN, NO 2 , alkyl, alkyl(hydroxy), alkyl(Oalkyl), alkyl(heterocycloalkyl), alkyl(aryl), alkyl(heteroaryl), alkenyl, NH 2 , O − , OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
wherein the process comprises the following steps:
(a) contacting a solution comprising a first C 1 -C 6 alcohol solvent and a dialkylphosphate salt having the following formula:
wherein:
R 200 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more independently selected R 103 substituents;
R 300 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more independently selected R 103 substituents;
each R 103 is independently halogen, CN, NO 2 , C(O)R 104 , C(O)NR 104 R 105 , C(O)OR 104 , NR 104 R 105 , NR 104 C(O)R 105 , NR 104 S(O) 2 R 105 , O − , OR 104 , SR 104 , S(O) 2 R 104 , S(O) 2 NR 104 R 105 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 104 is independently H, halogen, CN, NO 2 , alkyl, alkyl(hydroxy), alkyl(Oalkyl), alkyl(heterocycloalkyl), alkyl(aryl), alkyl(heteroaryl), alkenyl, NH 2 , O −1 , OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 105 is independently H, halogen, CN, NO 2 , alkyl, alkyl(hydroxy), alkyl(Oalkyl), alkyl(heterocycloalkyl), alkyl(aryl), alkyl(heteroaryl), alkenyl, NH 2 , O −1 , OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and
M + is K + ;
with an inorganic acid selected from the group consisting of boric acid, fluoroboric acid, carbonic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, metaphosphoric acid, nitric acid, phosphoric acid, and sulfuric acid, to form a compound having the following formula, in situ:
wherein:
R 200 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more independently selected R 103 substituents;
R 300 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more independently selected R 103 substituents;
each R 103 is independently halogen, CN, NO 2 , C(O)R 104 , C(O)NR 104 R 105 , C(O)OR 104 , NR 104 R 105 , NR 104 C(O)R 105 , NR 104 S(O) 2 R 15 , O −1 , OR 104 , SR 104 , S(O) 2 R 104 , S(O) 2 NR 104 R 105 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 104 is independently H, halogen, CN, NO 2 , alkyl, alkyl(hydroxy), alkyl(Oalkyl), alkyl(heterocycloalkyl), alkyl(aryl), alkyl(heteroaryl), alkenyl, NH 2 , O −1 , OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and
each R 105 is independently H, halogen, CN, NO 2 , alkyl, alkyl(hydroxy), alkyl(Oalkyl), alkyl(heterocycloalkyl), alkyl(aryl), alkyl(heteroaryl), alkenyl, NH 2 , O −1 , OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
(b) contacting the compound formed in situ in step (a) above with a solution comprising a second C 1 -C 6 alcohol solvent and a compound having the following formula:
N(C 1-6 alkyl) 4 + OH − ,
to form a compound having the following formula:
wherein:
R 200 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more independently selected R 103 substituents;
R 300 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more independently selected R 103 substituents;
each R 103 is independently halogen, CN, NO 2 , C(O)R 104 , C(O)NR 104 R 105 , C(O)OR 104 , NR 104 R 105 , NR 104 C(O)R 105 , NR 104 S(O) 2 R 105 , O −1 , OR 104 , SR 104 , S(O) 2 R 104 , S(O) 2 NR 104 R 105 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 104 is independently H, halogen, CN, NO 2 , alkyl, alkyl(hydroxy), alkyl(Oalkyl), alkyl(heterocycloalkyl), alkyl(aryl), alkyl(heteroaryl), alkenyl, NH 2 , O −1 , OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and
each R 105 is independently H, halogen, CN, NO 2 , alkyl, alkyl(hydroxy), alkyl(Oalkyl), alkyl(heterocycloalkyl), alkyl(aryl), alkyl(heteroaryl), alkenyl, NH 2 , O −1 , OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
(c) contacting the compound formed in step (b) above with a solution comprising a C 1 -C 6 aldehyde solvent or a C 1 -C 6 ketone solvent and chloroiodomethane having the following formula:
(d) removing the remaining C 1 -C 6 aldehyde solvent or C 1 -C 6 ketone solvent and any excess of chloroiodomethane used in step (c) above via distillation, to form a reaction mass;
(e) suspending the reaction mass formed in step (d) above in tert-butyl methyl ether (TBME);
(f) filtering the reaction mass-containing suspension formed in step (e) above, to form a filtrate;
(g) washing the filtrate formed in step (f) above with a saturated solution of sodium bicarbonate and water, to form a washed filtrate; and
(h) placing the washed filtrate formed in step (g) above under reduced pressure, to substitute any remaining solvent with acetone and form a composition comprising a chloromethyl dialkylphosphate having the following formula:
wherein:
R 200 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more independently selected R 103 substituents;
R 300 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more independently selected R 103 substituents;
each R 103 is independently halogen, CN, NO 2 , C(O)R 104 , C(O)NR 104 R 105 , C(O)OR 104 , NR 104 R 105 , NR 104 C(O)R 105 , NR 104 S(O) 2 R 105 , O −1 , OR 104 , SR 104 , S(O) 2 R 104 , S(O) 2 NR 104 R 105 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 104 is independently H, halogen, CN, NO 2 , alkyl, alkyl(hydroxy), alkyl(Oalkyl), alkyl(heterocycloalkyl), alkyl(aryl), alkyl(heteroaryl), alkenyl, NH 2 , O −1 , OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and
each R 105 is independently H, halogen, CN, NO 2 , alkyl, alkyl(hydroxy), alkyl(Oalkyl), alkyl(heterocycloalkyl), alkyl(aryl), alkyl(heteroaryl), alkenyl, NH 2 , O −1 , OH, O(alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
2. The process of claim 1 , wherein, in step (a):
R 200 is C(CH 3 ) 3 ;
R 300 is C(CH 3 ) 3 ; and
the inorganic acid is hydrochloric acid.
3. The process of claim 1 , wherein:
(i) in step (a), the first C 1 -C 6 alcohol solvent is methanol;
(ii) in step (b), the second C 1 -C 6 alcohol solvent is methanol; and
(iii) in step (c), the C 1 -C 6 aldehyde solvent or C 1 -C 6 ketone solvent is acetone.