Process for the synthesis of progesterone receptor modulators
Processes for preparing oxindoles, which can be utilized in the preparation of a variety of useful compounds, and methods for minimizing or preventing N-alkylation of amide containing compounds, including oxindoles, are provided. Also provided is a compound of the following structure:
1. A process for producing an oxindole of the structure:
wherein
R 1 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, OR 6 , N(R 7 ) 2 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , and COOH; or
R 2 and R 3 ; R 3 and R 4 ; R 4 and R 5 ; or R 5 and R 1 are fused to form:
(i) a 3 to 9 membered carbon-based saturated or unsaturated ring; or
(ii) a 3 to 9 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
wherein rings (i)-(ii) are optionally substituted by 1 to 3 groups selected from the group consisting of C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, halogen, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, and N(R 8 ) 2 ;
R 6 is selected from the group consisting of C 1 to C 6 alkyl and C 1 to C 6 substituted alkyl;
each R 7 is independently selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, and CF 3 ; and
each R 8 is independently selected from the group consisting of C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 1 to C 6 alkoxy, and substituted C 1 to C 6 alkoxy;
said process comprising:
(a) reacting aqueous hydrazine and an isatin in ethylene glycol, wherein said isatin is of the following structure:
wherein:
R 1 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, OR 6 , N(R 7 ) 2 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , and COOH; or
R 2 and R 3 ; R 3 and R 4 ; R 4 and R 5 ; or R 5 and R 1 are fused to form:
(i) a 3 to 9 membered carbon-based saturated or unsaturated ring; or
(ii) a 3 to 9 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
wherein rings (i)-(ii) are optionally substituted by 1 to 3 groups selected from the group consisting of C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, halogen, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, and N(R 8 ) 2 ;
R 6 is selected from the group consisting of C 1 to C 6 alkyl and C 1 to C 6 substituted alkyl;
each R 7 is independently selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, and CF 3 ; and
each R 8 is independently selected from the group consisting of C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 1 to C 6 alkoxy, and substituted C 1 to C 6 alkoxy;
wherein the ratio of ethylene glycol:isatin is about 2 to about 10 mL ethylene glycol:about 1 g isatin and ratio of aqueous hydrazine:isatin is about 1.5: about 3; and
(b) isolating said oxindole.
2. The process according to claim 1 , wherein said isatin is 7-fluoroisatin.
3. The process according to claim 1 , wherein the ratio of ethylene glycol:isatin is about 2 mL ethylene glycol:about 1 g isatin.
4. The process according to claim 1 , wherein the ratio of aqueous hydrazine:isatin in step (b) is about 2: about 1.
5. The process according to claim 1 , wherein step (a) is performed at about 110 to about 140° C.
6. The process according to claim 5 , wherein step (a) is performed at about 120° C.
7. The process according to claim 1 , wherein step (a) is performed over about 4 to about 8 hours.
8. The process according to claim 1 , wherein an impurity of the following structure is formed in step (a):
wherein:
R 1 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, OR 6 , N(R 7 ) 2 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , and COOH; or
R 2 and R 3 ; R 3 and R 4 ; R 4 and R 5 ; or R 5 and R 1 are fused to form:
(i) a 3 to 9 membered carbon-based saturated or unsaturated ring; or
(ii) a 3 to 9 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
wherein rings (i)-(ii) are optionally substituted by 1 to 3 groups selected from the group consisting of C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, halogen, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, and N(R 8 ) 2 ;
R 6 is selected from the group consisting of C 1 to C 6 alkyl and C 1 to C 6 substituted alkyl;
each R 7 is independently selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, and CF 3 ; and
each R 8 is independently selected from the group consisting of C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 1 to C 6 alkoxy, and substituted C 1 to C 6 alkoxy.
9. The process according to claim 8 , wherein said impurity is converted to said oxindole using an inorganic acid.
10. The process according to claim 1 , wherein said oxindole is converted to an alkylated oxindole, comprising reacting said oxindole with an alkyl halide in the presence of a copper halide or a copper halide adduct.
11. The process according to claim 10 , wherein said alkylated oxindole is of the structure:
wherein:
R 1 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, OR 6 , N(R 7 ) 2 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , and COOH; or
R 2 and R 3 ; R 3 and R 4 ; R 4 and R 5 ; or R 5 and R 1 are fused to form:
(i) a 3 to 9 membered carbon-based saturated or unsaturated ring; or
(ii) a 3 to 9 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
wherein rings (i)-(ii) are optionally substituted by 1 to 3 groups selected from the group consisting of C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, halogen, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, and N(R 8 ) 2 ;
R 6 is selected from the group consisting of C 1 to C 6 alkyl and C 1 to C 6 substituted alkyl;
each R 7 is independently selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, and CF 3 ;
each R 8 is independently selected from the group consisting of C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 1 to C 6 alkoxy, and substituted C 1 to C 6 alkoxy;
R 9 is C 1 to C 6 alkyl or C 1 to C 6 substituted alkyl; and
R 10 is H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, or CF 3 .
12. The process according to claim 10 , wherein the copper halide adduct is CuBr.(CH 3 ) 2 S.
13. The process according to claim 10 , which is performed in the presence of a base.
14. The process according to claim 13 , where said base is potassium or sodium tert-butoxide.
15. The process according to claim 13 , which comprises about 3 to about 6 equivalents of said base.
16. The process according to claim 15 , which comprises about 5 equivalents of said base.
17. The process according to claim 10 , which is performed at a temperature of about 0 to about 15° C.
18. The process according to claim 17 , which is performed at a temperature of about 6 to about 12° C.
19. The process according to claim 10 , wherein said alkyl halide is methyl iodide.
20. The process according to claim 10 , wherein said alkylated oxindole is isolated by:
(i) quenching the alkylation with ammonium chloride;
(ii) extracting the alkylated oxindole with t-butyl methyl ether;
(iii) removing the t-butyl methyl ether by distillation; and
(iv) removing residual water from the product of step (iii) using acetic acid.
21. The process according to claim 10 , wherein said alkylated oxindole is brominated.
22. The process according to claim 21 , wherein said brominated oxindole is of the structure:
23. The process according to claim 21 , wherein said brominated oxindole is coupled with an aryl compound.
24. The process according to claim 23 , wherein said coupling is performed in the presence of a palladium catalyst.
25. The process according to claim 24 , wherein said palladium catalyst is dichloro bis(triphenylphosphine) palladium (II).
26. The process according to claim 24 , further comprising reducing the content of palladium and palladium compounds.
27. The process according to claim 26 , wherein said reducing step is performed using N-acetyl-L-cysteine.
28. The process according to claim 23 , wherein said coupling is performed using [1,3,6,2]dioxazaborcan-2-yl-1-methyl-1H-pyrrole-2-carbonitrile.
29. A process for preparing an oxindole, said process comprising:
(a) combining about 2 mL ethylene glycol:about 1 g of an isatin of the structure:
wherein:
R 1 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, OR 6 , N(R 7 ) 2 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , and COOH; or
R 2 and R 3 ; R 3 and R 4 ; R 4 and R 5 ; or R 5 and R 1 are fused to form:
(i) a 3 to 9 membered carbon-based saturated or unsaturated ring; or
(ii) a 3 to 9 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
wherein rings (i)-(ii) are optionally substituted by 1 to 3 groups selected from the group consisting of C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, halogen, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, and N(R 8 ) 2 ;
R 6 is selected from the group consisting of C 1 to C 6 alkyl and C 1 to C 6 substituted alkyl;
each R 7 is independently selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, and CF 3 ; and
each R 8 is independently selected from the group consisting of C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 1 to C 6 alkoxy, and substituted C 1 to C 6 alkoxy;
(b) reacting the solution of step (a) with about 2 equivalents of aqueous hydrazine; and
(c) isolating said oxindole of the structure:
30. A process for preparing an aryl substituted oxindole, said process comprising:
(a) combining about 2 mL ethylene glycol:about 1 g of an isatin of the structure:
wherein:
R 1 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, OR 6 , N(R 7 ) 2 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , and COOH; or
R 2 and R 3 ; R 3 and R 4 ; R 4 and R 5 ; or R 5 and R 1 are fused to form:
(i) a 3 to 9 membered carbon-based saturated or unsaturated ring; or
(ii) a 3 to 9 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
wherein rings (i)-(ii) are optionally substituted by 1 to 3 groups selected from the group consisting of C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, halogen, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, and N(R 8 ) 2 ;
R 6 is selected from the group consisting of C 1 to C 6 alkyl and C 1 to C 6 substituted alkyl;
each R 7 is independently selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, and CF 3 ; and
each R 8 is independently selected from the group consisting of C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 1 to C 6 alkoxy, and substituted C 1 to C 6 alkoxy;
(b) reacting the solution of step (a) with about 2 equivalents of aqueous hydrazine to form an oxindole of the structure:
(c) alkylating said oxindole with an alkyl halide in the presence of a copper halide or a copper halide adduct to form an alkylated oxindole of the structure:
wherein
R 9 is C 1 to C 6 alkyl or C 1 to C 6 substituted alkyl; and
R 10 is H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, or CF 3 ;
(d) brominating said alkylated oxindole;
(e) coupling said brominated oxindole with an aryl compound in the presence of a palladium catalyst; and
(f) reducing the content of palladium or palladium compounds in the product of step (e) using N-acetyl-L-cysteine.
31. A process for preparing an oxindole of the structure:
wherein:
R 1 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, OR 6 , N(R 7 ) 2 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , and COOH; or
R 2 and R 3 ; R 3 and R 4 ; R 4 and R 5 ; or R 5 and R 1 are fused to form:
(i) a 3 to 9 membered carbon-based saturated or unsaturated ring; or
(ii) a 3 to 9 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
wherein rings (i)-(ii) are optionally substituted by 1 to 3 groups selected from the group consisting of C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, halogen, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, and N(R 8 ) 2 ;
R 6 is selected from the group consisting of C 1 to C 6 alkyl and C 1 to C 6 substituted alkyl;
each R 7 is independently selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, and CF 3 ; and
each R 8 is independently selected from the group consisting of C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 1 to C 6 alkoxy, and substituted C 1 to C 6 alkoxy;
or a pharmaceutically acceptable salt or tautomer thereof;
said process comprising reacting an inorganic acid and a compound of the following structure:
or a pharmaceutically acceptable salt or tautomer thereof.
32. A compound of the structure:
or a pharmaceutically acceptable salt or tautomer thereof.
33. A process for preparing 7-fluoro-2-oxindole, comprising reacting the compound of claim 32 with an inorganic acid.
34. A process for producing an oxindole of the structure:
wherein
R 1 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, OR 6 , N(R 7 ) 2 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , and COOH; or
R 2 and R 3 ; R 3 and R 4 ; R 4 and R 5 ; or R 5 and R 1 are fused to form:
(i) a 3 to 9 membered carbon-based saturated or unsaturated ring; or
(ii) a 3 to 9 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
wherein rings (i)-(ii) are optionally substituted by 1 to 3 groups selected from the group consisting of C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, halogen, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, and N(R 8 ) 2 ;
R 6 is selected from the group consisting of C 1 to C 6 alkyl and C 1 to C 6 substituted alkyl;
each R 7 is independently selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, and CF 3 ; and
each R 8 is independently selected from the group consisting of C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 1 to C 6 alkoxy, and substituted C 1 to C 6 alkoxy;
said process comprising:
(a) reacting aqueous hydrazine and an isatin in ethylene glycol, wherein said isatin is of the following structure:
wherein:
R 1 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, OR 6 , N(R 7 ) 2 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , and COOH; or
R 2 and R 3 ; R 3 and R 4 ; R 4 and R 5 ; or R 5 and R 1 are fused to form:
(i) a 3 to 9 membered carbon-based saturated or unsaturated ring; or
(ii) a 3 to 9 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
wherein rings (i)-(ii) are optionally substituted by 1 to 3 groups selected from the group consisting of C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, halogen, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, and N(R 8 ) 2 ;
R 6 is selected from the group consisting of C 1 to C 6 alkyl and C 1 to C 6 substituted alkyl;
each R 7 is independently selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, and CF 3 ; and
each R 8 is independently selected from the group consisting of C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 1 to C 6 alkoxy, and substituted C 1 to C 6 alkoxy;
wherein the ratio of ethylene glycol:isatin is about 2 to about 10 mL ethylene glycol:about 1 g isatin and the ratio of aqueous hydrazine:isatin is about 1.5: about 3;
(b) cooling the product of step (a) to about room temperature;
(c) adding water to the product of step (b);
(d) adding an inorganic acid to the product of step (c);
(e) cooling the product of step (d); and
(f) collecting the product of step (e) using filtration.