Compounds and processes for preparing substituted aminomethyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-ones
View Patent ↗Processes and intermediates are provided for the preparation of substituted aminomethyl 2,3,8,9-tetrahydiO-7H-1,4-dioxino[2.3-e]indo]-8-ones of the Formula (A) wherein the variables n, R and R 3 are as described herein. Such compounds are useful, for example, as dopamine receptor agonists.
1. A compound of Formula 4 or a salt or hydrate thereof:
wherein:
n is the integer 0 or 1;
PG is an optionally substituted benzyl; and
R 3 is a ring substituent chosen from hydroxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyloxy, amino, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl and C 1 -C 6 alkylaminosulfonyl.
2. A compound or salt or hydrate thereof according to claim 1 , wherein the compound is (R)-2-((2-(benzyloxy)-4-nitrophenoxy)methyl)oxirane.
3. A process for preparing a compound of Formula 5 or a salt or hydrate thereof:
wherein:
n is the integer 0 or 1; and
R 3 is a ring substituent chosen from hydroxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyloxy, amino, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl and C 1 -C 6 alkylaminosulfonyl;
comprising cyclizing a compound of Formula 4 or a salt or hydrate thereof:
wherein PG is an optionally substituted benzyl;
for a time and under conditions effective to provide the compound of Formula 5 or a salt or hydrate thereof.
4. A process according to claim 3 , further comprising the step of alkylating a compound of Formula 3 or a salt or hydrate thereof:
with an alkylating agent of Formula:
wherein L is a leaving group;
for a time and under conditions effective to provide the compound of Formula 4 or salt or hydrate thereof.
5. A process according to claim 4 , wherein the compound of Formula 4 is (R)-2-((2-(benzyloxy)-4-nitrophenoxy)methyl)oxirane, and the compound of Formula 5 is (S)-(7-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol.
6. A compound of Formula 7 or Formula 8 or a salt or hydrate of Formula 7 or Formula 8:
wherein:
n is the integer 0 or 1;
D is COOH or —COOR w ;
R w is C 1 -C 8 alkyl; and
R 3 is a ring substituent chosen from hydroxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyloxy, amino, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl and C 1 -C 6 alkylaminosulfonyl.
7. A process for preparing a compound of Formula 7 or a salt or hydrate thereof:
wherein:
n is the integer 0 or 1;
D is COOH or —COOR w ;
R w is C 1 -C 8 alkyl; and
R 3 is a ring substituent chosen from hydroxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyloxy, amino, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl and C 1 -C 6 alkylaminosulfonyl;
comprising contacting a compound of Formula 6 or a salt or hydrate thereof:
wherein:
W is CN or —COOR w ;
with water or a C 1 -C 8 alkanol for a time and under conditions effective to provide the compound of Formula 7 or a salt or hydrate thereof.
8. A process for preparing a compound of Formula 8 or a salt or hydrate thereof:
wherein:
n is the integer 0 or 1; and
R 3 is a ring substituent chosen from hydroxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyloxy, amino, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)amino carbonyl and C 1 -C 6 alkylaminosulfonyl;
comprising reducing and cyclizing a compound of Formula 7 or a salt or hydrate thereof:
wherein:
D is COOH or —COOR w ; and
R w is C 1 -C 8 alkyl;
for a time and under conditions effective to provide the compound of Formula 8 or a salt or hydrate thereof.
9. A process for preparing a compound of Formula 9 or a salt or hydrate thereof:
wherein:
n is the integer 0 or 1; and
R 3 is a ring substituent chosen from hydroxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyloxy, amino, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl and C 1 -C 6 alkylaminosulfonyl;
comprising:
contacting a compound of Formula 8 or a salt or hydrate thereof:
with toluenesulfonyl chloride for a time and under conditions effective to provide the compound of Formula 9 or a salt or hydrate thereof.
10. A process for preparing a compound of Formula A or a pharmaceutically acceptable salt or hydrate thereof:
wherein:
n is the integer 0 or 1;
R is optionally substituted phenylC 1 -C 2 alkyl; and
R 3 is a ring substituent chosen from hydroxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyloxy, amino, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl and C 1 -C 6 alkylaminosulfonyl;
comprising:
contacting a compound of Formula 8 or a salt or hydrate thereof:
with toluenesulfonyl chloride for a time and under conditions effective to provide a compound of Formula 9 or a salt or hydrate thereof:
and
contacting the compound of Formula 9 or salt or hydrate thereof with RNH 2 for a time and under conditions effective to provide the compound of Formula A or a pharmaceutically acceptable salt or hydrate thereof.
11. A process according to claim 10 , wherein the compound of Formula A is:
12. A compound of Formula 12 or a salt or hydrate thereof:
wherein:
n is the integer 0 or 1;
R is optionally substituted benzyl; and
R 3 is a ring substituent chosen from hydroxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyloxy, amino, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl and C 1 -C 6 alkylaminosulfonyl.
13. A process comprising:
contacting a compound of Formula 12 or a salt or hydrate thereof:
n is the integer 0 or 1:
R 3 is a ring substituent chosen from hydroxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyloxy, amino, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl and C 1 -C 6 alkylaminosulfonyl; and
R is optionally substituted benzyl;
with
wherein R w is C 1 -C 8 alkyl and X is a leaving group;
for a time and under conditions effective to provide the compound of Formula 13 or a salt or hydrate thereof and thereby forming a compound of Formula 13
wherein W is CN or COOR w .
14. A process according to claim 13 , further comprising the step of contacting a compound of Formula 11 or a salt or hydrate thereof:
with RNH 2 for a time and under conditions effective to provide the compound of Formula 12 or a salt or hydrate thereof.
15. A process of claim 13 additionally comprising contacting the compound of Formula 13 or a salt or hydrate thereof:
wherein:
W is CN or —COOR w ; and
R w is C 1 -C 8 alkyl;
with water or a C 1 -C 8 alkanol for a time and under conditions effective to provide the compound of Formula 14 or a salt or hydrate thereof
wherein R x is hydrogen or C 1 -C 8 alkyl.
16. A process according to claim 15 , further comprising the step of contacting a compound of Formula 12 or a salt or hydrate thereof:
wherein X is a leaving group;
for a time and under conditions effective to provide the compound of Formula 13 or a salt or hydrate thereof.
17. A process according to claim 10 , further comprising the step of reducing and cyclizing a compound of Formula 7 or a salt or hydrate thereof:
wherein:
D is COOH or —COOR w ; and
R w is C 1 -C 8 alkyl;
for a time and under conditions effective to provide the compound of Formula 8 or a salt or hydrate thereof.
18. A process according to claim 17 , further comprising the step of contacting a compound of Formula 6 or a salt or hydrate thereof:
wherein W is CN or —COOR w ;
with water or a C 1 -C 8 alkanol for a time and under conditions effective to provide the compound of Formula 7 or a salt or hydrate thereof.