Process for the Synthesis of Substituted Morphinans

1 . 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)