US2012010412A1PendingUtilityA1
Process for the Synthesis of Substituted Morphinans
Est. expiryJul 8, 2030(~4 yrs left)· nominal 20-yr term from priority
Inventors:Scott Duncan
C07D 491/20C07D 489/08A61P 25/36
53
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Claims
Abstract
The present invention relates to a process for the synthesis of a compound of formula I:
Claims
exact text as granted — not AI-modified1 . A compound of Formula IB:
or a pharmaceutically acceptable salt or ester thereof:
wherein, R 1 is chosen from hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 2 is —CON(R 20 )(R 21 ) or —CSN(R 20 )(R 21 ), wherein each R 20 and R 21 is independently hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 3 and R 4 are independently H, —OH, —SH, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl; or together R 3 and R 4 form an —O— or —S— group;
Each R 5 , R 6 , R 7 , and R 8 is independently hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl;
Each R 11 is independently, hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino or optionally substituted C 1 -C 8 aryl; and
Each m and n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.
2 . A compound of claim 1 , selected from Table 1:
TABLE 1
3 . A compound of Formula IC:
or a pharmaceutically acceptable salt or ester thereof:
wherein, R 1 is chosen from hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 2 is —CON(R 20 )(R 21 ) or —CSN(R 20 )(R 21 ), wherein each R 20 and R 21 is independently hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 3 and R 4 are independently H, —OH, —SH, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl; or together R 3 and R 4 form an —O— or —S— group;
Each R 5 R 6 , R 7 , and R 8 is independently hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl;
Each R 11 is independently, hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino or optionally substituted C 1 -C 8 aryl;
y is 0, 1 or 2; and
Each m and n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.
4 . A compound of claim 3 , selected from Table 2:
TABLE 2
5 . A compound of formula ID:
or a pharmaceutically acceptable salt or ester thereof:
wherein, R 1 is chosen from hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 2 is —CON(R 20 )(R 21 ) or —CSN(R 20 )(R 21 ), wherein each R 20 and R 21 is independently hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 3 and R 4 are independently H, —OH, —SH, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl; or together R 3 and R 4 form an —O— or —S— group;
Each R 5 R 6 , R 7 , and R 8 is independently hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl;
Each R 11 is independently, hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino or optionally substituted C 1 -C 8 aryl;
y is 0, 1 or 2; and
Each m and n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.
6 . A compound of claim 5 , selected from Table 3:
TABLE 3
7 . A compound of formula IE:
or a pharmaceutically acceptable salt or ester thereof:
Wherein, R 1 is chosen from hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 2 is —CON(R 20 )(R 21 ) or —CSN(R 20 )(R 21 ), wherein each R 20 and R 21 is independently hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 3 and R 4 are independently H, —OH, —SH, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl; or together R 3 and R 4 form an —O— or —S— group;
Each R 5 R 6 , R 7 , and R 8 is independently hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl;
Each R 11 is independently, hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino or optionally substituted C 1 -C 8 aryl;
y is 0, 1 or 2; and
Each m and n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.
8 . A compound of claim 7 , selected from Table 4:
TABLE 4
9 . A process for the synthesis of a compound of Formula I:
or a pharmaceutically acceptable salt or ester thereof wherein;
R 1 is chosen from hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 2 is —CON(R 20 )(R 21 ) or —CSN(R 20 )(R 21 ), wherein each R 20 and R 21 is independently hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 3 and R 4 are independently H, —OH, —SH, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl; or together R 3 and R 4 form an —O— or —S— group;
Each R 5 R 6 , R 7 , and R 8 is independently hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl; and
y is 0, 1 or 2;
comprising the steps of:
Step 1: Reacting a compound of Formula IA:
with a diol of the formula,
to produce a compound of Formula IB:
wherein each R 11 is independently, hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino or optionally substituted C 1 -C 8 aryl; and
Each m and n is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
Step 2: Reacting the compound of formula IB with a triflating agent to produce a compound of Formula IC:
Step 3: Reacting the compound of formula IC with cyanide to produce a compound of Formula ID:
and, optionally,
Step 4: Hydrolyzing the compound of formula ID to produce a compound of Formula IE;
and, optionally,
Step 5: Reacting the compound of Formula IE with a Lewis acid or a Bronsted acid to produce the compound of Formula I.
10 - 27 . (canceled)
28 . A process for the synthesis of a compound of Formula IIB or a pharmaceutically acceptable salt or ester thereof:
Wherein, R 1 is chosen from hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 3 and R 4 are independently H, —OH, —SH, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl; or together R 3 and R 4 form an —O— or —S— group;
Each R 5 R 6 , R 7 , and R 8 is independently hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl;
R 30 is selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 2 OR 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; Each R 11 is independently, hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino or optionally substituted C 1 -C 8 aryl;
Each m and n is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; and,
y is 0, 1 or 2;
comprising the step of reacting a compound of Formula IIA:
with a diol of the formula,
29 - 32 . (canceled)
33 . The method according to claim 28 , wherein said compound of Formula IIB is selected from Table 5:
TABLE 5
34 . The method according to claim 28 , wherein said compound of Formula IIB is selected from Table 1.
35 . The method according to claim 28 , wherein said compound of Formula IIA is selected from Table 6:
TABLE 6
36 . The method according to claim 28 , wherein —R 30 is —OMe.
37 . The method according to claim 28 , wherein said —R 30 group is converted to —OH to give a compound of Formula IB.
38 . The method according to claim 37 , further comprising the step of reacting the compound of formula IB with a triflating agent to produce a compound of Formula IC:
39 . The method according to claim 38 , further comprising the step of reacting the compound of Formula IC with cyanide to produce a compound of Formula ID:
40 . The method according to claim 39 , further comprising the step of hydrolyzing the compound of formula ID to produce a compound of Formula IE;
41 . The method according to claim 40 , further comprising the step of reacting the compound of Formula IE with a Lewis acid or a Bronsted acid to produce the compound of Formula I.
42 - 55 . (canceled)
56 . The method of claim 39 , wherein said compound of Formula ID or Formula IE is hydrolyzed to give a compound of Formula I.
57 . A compound of Formula IIB or a pharmaceutically acceptable salt or ester thereof:
Wherein, R 1 is chosen from hydrogen, halogen, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 3 and R 4 are independently H, —OH, —SH, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl; or together R 3 and R 4 form an —O— or —S— group;
Each R 5 R 6 , R 7 , and R 8 is independently hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino and optionally substituted C 1 -C 8 aryl;
R 30 is selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; Each R 11 is independently, hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino or optionally substituted C 1 -C 8 aryl;
Each m and n is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; and,
y is 0, 1 or 2.
58 . The compound according to claim 57 , wherein R 30 is —OMe.
59 . The compound according to claim 57 , wherein R 1 is selected from —CH 3 , —CH 2 -c-C 3 H 5 , —CH 2 -c-C 4 H 7 , —CH 2 —CH═CH 2 , —CH 2 —CH═C(CH 3 ) 2 .
60 . A process for the synthesis of a compound of Formula IIIA:
Comprising the step of reacting a compound of Formula IIIB with an acid, preferably an organic acid;
Wherein R 21 is an alkyl, substituted alkyl, aryl, or substituted aryl.
61 - 62 . (canceled)
63 . The method according to claim 60 , wherein said compound of formula IIIB is thebaine, and said compound of Formula IIIA is 14-hydroxycodeinone.
64 . The method according to claim 60 , further comprising the step of hydrogenating a compound of Formula IIIA to give a compound of Formula IIIC:
65 . The method according to claim 64 , wherein said hydrogenation is in the presence of Pd/C.
66 . The method according to claim 65 , wherein said compound of Formula IIIA is 14-hydroxycodeinone, and said compound of Formula IIIC is oxycodone.
67 . A process for the synthesis of a compound of Formula IVB, comprising the step of reacting a compound of Formula IVA:
with a trifilating agent to give a compound of Formula IVB:
68 . A method according to claim 67 , further comprising the step of reacting a compound of Formula IVB with a cyanide to produce a compound of Formula IVC:
69 . The method according to claim 68 , further comprising the step of reacting a compound of Formula IVC with an acid to give a compound of Formula IVD:
70 . The method according to claim 69 , further comprising the step of hydrogenation to give a compound of Formula IVE:
71 . The method according to claim 70 , further comprising the step of reacting a compound of Formula IVE with a compound of formula:
to give a compound of Formula ID.
72 . The method according to claim 67 , wherein said compound of Formula IVA is oripavine.
73 - 74 . (canceled)Join the waitlist — get patent alerts
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