Preparation of opiate analgesics by reductive alkylation
View Patent ↗A process for preparing a compound of formula (A), (B) or (C): wherein P is H, CH 3 or a hydroxyl protecting group; X is O, a protected ketone, OH, a protected hydroxyl group or H; Y is OH, a protected hydroxyl group or H; W is C(CH 3 ) 2 OH, C(CH 3 )(C(CH 3 ) 3 )OH or COCH 3 ; Z is C 2 -C 10 alkyl or C 2 -C 10 arylalkyl; and is a single bond or a double bond, is disclosed. The process is a reductive alkylation in the presence of hydrogen and a reductive alkylation catalyst.
1. A process for preparing a compound of formula (A), (B) or (C):
wherein R is independently H, CH 3 or a hydroxyl protecting group;
X is O, a protected ketone, OH, a protected hydroxyl group or H;
Y is OH, a protected hydroxyl group or H;
W is C(CH 3 ) 2 OH, C(CH 3 )(C(CH 3 ) 3 )OH or COCH 3 ;
Z is C 2 -C 10 alkyl; and
is a single bond or a double bond;
comprising reacting a compound of formula (D), (E) or (F):
wherein R, X, Y, W and are as defined above, with a compound of formula (G):
wherein Z is as defined above, in the presence of hydrogen and a reductive alkylation catalyst.
2. A process according to claim 1 , wherein R is independently H or CH 3 .
3. The process according to claim 1 , wherein X is O or OH.
4. The process according to claim 1 , wherein Y is OH.
5. The process according to claim 1 , wherein Z is cyclopropyl or cyclobutyl.
6. The process according to claim 1 , wherein a compound of formula (D) is reacted with a compound of formula (G) to provide a compound of formula (A), and wherein R is H, X is O, Y is OH, and Z is cyclopropyl.
7. The process according to claim 1 , wherein a compound of formula (D) is reacted with a compound of formula (G) to provide a compound of formula (A), and wherein R is H, X is OH, Y is OH and Z is cyclobutyl.
8. The process according to claim 1 , wherein a compound of formula (E) is reacted with a compound of formula (G) to provide a compound of formula (B), and wherein R is H, X is O, Y is OH or H and Z is cyclopropyl.
9. The process according to claim 1 , wherein a compound of formula (E) is reacted with a compound of formula (G) to provide a compound of formula (B), and wherein R is H, X is H, Y is OH and Z is cyclobutyl.
10. The process according to claim 1 , wherein a compound of formula (F) is reacted with a compound of formula (G) to provide a compound of formula (C), and wherein R at C3 is H, R at C6 is CH 3 ,W is C(CH 3 ) 2 OH and Z is cyclopropyl.
11. The process according to claim 1 , wherein a compound of formula (F) is reacted with a compound of formula (G) to provide a compound of formula (C), and wherein R at C3 is H, R at C6 is CH 3 ,W is C(CH 3 )(C(CH 3 ) 3 )OH and Z is cyclopropyl.
12. The process according to claim 1 , wherein the process is carried out in a solvent, and wherein the solvent comprises N-methylpyrrolidinone.
13. The process according to claim 12 , wherein the solvent is a mixture of N-methylpyrrolidinone and methanol.
14. The process according to claim 13 , wherein the solvent is a 30:70 mixture of N-methylpyrrolidinone and methanol.
15. The process according to claim 1 , wherein the reductive alkylation catalyst is selected from the group consisting of platinum group metal catalysts, nickel catalysts, and mixtures of these.
16. The process according to claim 1 , wherein the reductive alkylation catalyst comprises palladium on carbon.
17. The process according to claim 1 , wherein the reductive alkylation catalyst comprises platinum on carbon.
18. The process according to claim 1 , wherein the reductive alkylation catalyst comprises palladium and platinum on carbon.