Methods for Preparing Oltipraz
The invention provides improved methods of synthesizing oltipraz, which result in higher overall yield and better purity of the desired product.
1 . A method comprising the steps of:
a) combining in a first container a first solvent and a first base;
b) stirring the contents of the first container at a temperature of about 0° C. for about 5 minutes;
c) adding to the first container, over a period of time of about 15 minutes, methyl propionate;
d) stirring the contents of the first container at about 0° C. for about 15 minutes;
e) adding to the first container a solution of
in a second solvent, wherein the solution is added over a period of time of about 30 minutes while warming the first container to a temperature of about 22° C.; and the second solvent is a mixture of tetrahydrofuran and 1,4-dioxane; and
f) stirring the contents of the first container at about 22° C. for a first period of time.
2 . The method of claim 1 , wherein the first solvent is tetrahydrofuran.
3 . The method of claim 1 , wherein the first solvent is a mixture of tetrahydrofuran and 1,4-dioxane.
4 . The method of claim 1 , wherein the first solvent is about a 5:1, about a 4:1, or about a 3:1 mixture by volume of tetrahydrofuran and 1,4-dioxane.
5 . The method of claim 1 , wherein the first base is sodium pentanoate or potassium t-butoxide.
6 . The method of claim 1 , wherein the concentration of the first base in the first solvent is about 1.0 M, about 1.2 M, about 1.4 M, about 1.6 M, or about 1.8 M.
7 . The method of claim 1 , wherein the mole ratio of first base to methyl propionate is about 3:1, about 2:1, or about 1:1.
8 . The method of claim 1 , wherein the concentration of
in the second solvent is about 1.6 M, about 1.8 M, or about 2.0 M.
9 . The method of claim 1 , wherein the mole ratio of methyl propionate to
is about 2:1, about 1.8:1, or about 1.6:1.
10 . The method of claim 1 , wherein the second solvent is about a 1.2:1, about a 1:1, or about a 0.8:1 mixture by volume of tetrahydrofuran and 1,4-dioxane.
11 . The method of claim 1 , wherein the method is a method of synthesizing
in a yield greater than 80%, greater than 81%, greater than 82%, greater than 83%, greater than 84%, greater than 85%, greater than 86%, greater than 87%, greater than 88%, greater than 89%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.
12 . The method of claim 1 , wherein the method is a method of synthesizing
in a yield greater than 80%, greater than 81%, greater than 82%, greater than 83%, greater than 84%, greater than 85%, greater than 86%, greater than 87%, greater than 88%, greater than 89%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99% without purification other than isolation.
13 . A method comprising the steps of:
i) combining in a second container P 2 S 5 and a first quantity of toluene;
ii) heating the second container at a temperature of about 100° C.;
iii) adding to the second container a solution of
in a second quantity of toluene; and
iv) heating the contents of the second container to reflux for a second period of time, wherein no xylene is added or included at any step; and
further comprising synthesizing
according to steps a-f:
a) combining in a first container a first solvent and a first base;
b) stirring the contents of the first container at a temperature of about 0° C. for about 5 minutes;
c) adding to the first container, over a period of time of about 15 minutes, methyl propionate;
d) stirring the contents of the first container at about 0° C. for about 15 minutes;
e) adding to the first container a solution of
in a second solvent, wherein the solution is added over a period of time of about 30 minutes while warming the first container to a temperature of about 22° C.; and the second solvent is a mixture of tetrahydrofuran and 1,4-dioxane; and
f) stirring the contents of the first container at about 22° C. for a first period of time.
14 . The method of claim 13 , wherein the concentration of P 2 S 5 in the first quantity of toluene is about 0.2 M, about 0.25 M, about 0.3 M, about 0.35 M, about 0.4 M, about 0.45 M, or about 0.5 M.
15 . The method of claim 13 , wherein P 2 S 5 and the first quantity of toluene are combined in the second container under an inert atmosphere.
16 . The method of claim 13 , wherein the method is a method of synthesizing oltipraz; and the purity of the oltipraz produced by the claimed method is greater than 97%, greater than 98%, or greater than 99%, as determined by gas chromatography.
17 . (canceled)
18 . The method of claim 13 , wherein the mole ratio of
to P 2 S 5 is about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, or about 1.8:1.
19 . The method of claim 13 , wherein the method is a method of synthesizing oltipraz; and the overall yield of oltipraz from
is greater than 21%, greater than 22%, greater than 23%, greater than 24%, greater than 25%, greater than 26%, greater than 27%, greater than 28%, greater than 29%, or greater than 30%.
20 . The method of claim 13 , wherein the method is a method of synthesizing oltipraz; and the overall yield of oltipraz from
is greater than 21%, and the purity of the resulting oltipraz is greater than 97%, as determined by gas chromatography.