USRE38073EExpiredUtility
Products for peptide coupling
Est. expirySep 28, 2012(expired)· nominal 20-yr term from priority
Inventors:Louis A. Carpino
Y02P20/55C07K 1/082C07K 1/084C07K 1/10C07F 9/6561C07D 513/04C07D 495/04C07D 491/04C07D 471/04
32
PatentIndex Score
2
Cited by
34
References
213
Claims
Abstract
This invention relates to a process for forming an amide or an ester from a reaction between an amine or an alcohol, respectively and an acylating derivative of a carboxylic acid, in the presence of an effective amount of a compound having the formula: and N-oxides thereof and salts thereof.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1. A process for preparing a peptide bond comprising reacting an amino compound with a carboxylic acid in the presence of an effective amount of a compound having the formula:
or N-oxides thereof a salts thereof;
wherein said amino compound is an amino acid or peptide and said carboxylic acid is a N-terminal amino protected amino acid or a N-terminal amino protected peptide;
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only one of A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl;
R 3 is SO 2 R 14 or a positively charged electron-withdrawing group, of the formula P ⊕ (NR 12 R 13 ) 3 ;
each R 12 and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl or R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 5 - or 6 - membered heterocylic ring containing up to a total of 5 ring carbon atoms; and
R 14 is lower alkyl, aryl or aryl loweralkyl.
2. A process for preparing a peptide bond comprising reacting an amino compound and a carboxylic acid in the presence of a dehydrating reagent and an effective amount of a compound, said compound having the formula:
or N-oxides thereof or salts thereof;
wherein said amino compound is an amino acid or peptide and said carboxylic acid is a N-terminal amino protected amino acid or a N-terminal amino protected peptide;
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only one of A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl;
and R 3 is hydrogen.
3. A process for preparing a peptide bond comprising reacting an amino compound and an acylating derivative of a carboxylic acid in the presence of an effective amount of a compound, said compound having the formula:
or N-oxides thereof or salts thereof;
wherein said amino compound is an amino acid or peptide and
said carboxylic acid is a N-terminal amino protected amino acid or a N-terminal amino protected peptide;
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only one of A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 8 R 5 are independently hydrogen or lower alkyl;
and R 3 is hydrogen.
4. A process for preparing a peptide bond comprising reacting an amino compound selected from the group consisting of an amino acid and a peptide with an effective amount of a compound having the formula:
wherein
or N-oxides thereof or salts thereof;
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only one of A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl;
R 3 is BLK 1 -AA 1 ;
BLK 1 is an amino acid protecting group; and
AA 1 is an amino acid or peptide less a hydrogen on the N-terminus and an OH on the C-terminus.
5. The process according to any of claim 1 - 4 wherein A or G is N.
6. The process according to any one of claims 1 - 4 wherein Y is CH or N and X is CH or N.
7. The process according to any one of claim 1 - 4 wherein the electron-donating group is amino, lower alkylamino, diloweralkylamino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
8. The process according to claim 7 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
9. The process according to claim 8 wherein the electron-donating group is OMe or Me 2 N.
10. The process according to claim 2 wherein the dehydrating agent is DCC or EDC.
11. The process according to claim 3 in which the acylating derivative of the carboxylic acid is
BLK-AA-M
wherein BLK is an amino protecting group;
AA is an amino acid;
M is halo or phenoxy ester wherein the phenyl group is of the formula:
wherein
R 20 is independently halo or an electron-withdrawing group and m is 1-5.
12. The process according to claim 11 wherein BLK is FMOC, BOC, TEOC, Aoc, Adoc, Bpoc, Azoc, Ddz, Proc, Foc, Moz, Nps, Dts, Cbz, Bspoc, Bsmoc, Nps, formyl, acetyl, trifluoroacetyl, CLIMOC or BIMOC.
13. The process according to claim 12 wherein BLK is Cbz, Bspoc, Bsmoc, BOC or FMOC.
14. The process according to claim 11 wherein the electron-withdrawing group is nitro or cyano.
15. The process according to claim 1 wherein the positively charged electron-withdrawing group is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl, lower alkoxy lower alkyl or R 10 and R 11 taken together with the atoms to which they are attached form a ring containing up to 6 ring atoms and up to a total of 5 carbon ring atoms or R 12 and R 13 taken together with the nitrogen atoms to which they are attached from a 5 or 6 membered nitrogen-containing heterocyclic ring containing up to a total of 5 carbon ring atoms.
16. The process according to claim 15 1 wherein R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
17. The process according to claim 16 wherein R 10 , R 11 , R 12 and R 13 are independently lower alkyl.
18. The process according to claim 17 wherein R 10 , R 11 , R 12 and R 13 are methyl.
19. The process according to claim 15 wherein the positively charged electron-withdrawing group is
wherein
R 10 , R 11 , R 12 are independently hydrogen, lower alkyl or loweralkoxy lower alkyl and m is 0 or 1.
20. The process according to claim 19 1 wherein R 11 and R 12 are the same and R 10 and R 11 R 12 and R 13 are the same.
21. The process according to claim 1 wherein R 3 is
wherein
R 10 , R 11 and R 12 and R 13 each are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or CH 2 CH 2 OCH 2 CH 3 .
22. The process according to claim 21 wherein R 10 , R 11 and R 12 R 12 and R 13 are the same.
23. The process according to claim 1 wherein R 3 is
wherein
U is N-ALK, CH 2 or O; and
ALK is lower alklyl or hydrogen.
24. The process according to claim 23 wherein U is CH 2 .
25. The process according to claim 1 wherein the compound has the formula:
26. The process according to claim 2 or claim 3 wherein the compound has the formula:
27. The process according to claim 4 wherein the compound has the formula:
28. The process according to claim 27 wherein R 3 is BLK 1 -AA 1 wherein BLK 1 is FMOC, BOC, TEOC, Aoc, Adoc, Bpoc, Azoc, Ddz, Poc, Foc, Moz, Nps, Nts, Cbz, Bspoc, Bsmoc, Nps, formyl, acetyl, trifluoroacetyl, CLI-MOC or BIMOC.
29. The process according to claim 28 wherein R 3 is BLK 1 -AA 1 , wherein BLK 1 is Cbz, Bspoc, Bsmoc, BOC or FMOC.
30. The process according to claim 25 wherein R 3 is a positively charged electron-withdrawing group.
31. The process according to claim 30 wherein R 3 is
wherein
R 10 , R 11 , and R 12 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
32. The process according to claim 31 wherein R 10 , R 11 , and R 12 are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or CH 2 CH 2 OCH 2 CH 3 .
33. The process according to claim 31 or 32 wherein R 10 , R 11 and R 12 are the same.
34. The process according to claim 25 wherein R 3 is
wherein
U is N-ALK, CH 2 or O, and ALK is lower alkyl or hydrogen.
35. The process according to claim 34 23 wherein U is CH 2 or NH.
36. The process for preparing a peptide bond comprising reacting an amino compound with a carboxylic acid in the presence of an effective amount of a compound having the formula:
or N-oxides thereof or salts thereof wherein
said amino compound is an amino acid or peptide and said carboxylic acid is a N-terminal amino protected amino acid or a N-terminal amino protected peptide;
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 15 CR 18 or N;
and one or two of A, D, E, G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
R 3 is SO 2 R 14 or a positively charged electron-withdrawing group having the formula P ⊕ (NR 12 R 13 ) 3 ;
each R 12 and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl or R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 5 - or 6 - membered heterocyclic ring containing up to a total of 5 ring carbon atoms ;
and R 14 is lower alkyl, aryl, or aryl lower alkyl.
37. A process for preparing a peptide bond comprising reacting an amino compound with a carboxylic acid in the presence of a dehydrating reagent and an effective amount of a compound having the formula
or N-oxides thereof or salts thereof; wherein
said amino compound is an amino acid or peptide and said carboxylic acid is a N-terminal amino protected amino acid or a N-terminal amino protected peptide,
D is CR 16 or N;
E is CR 17 or N;
A is CR 18 CR 15 or N;
G is CR 18 or N;
and one or two of A, D, E, G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
and R 3 is hydrogen.
38. A process for preparing a peptide bond comprising reacting an amino compound with an acrylating derivative of a carboxylic acid in the presence of an effective amount of a compound having the formula:
or N-oxides thereof or salts thereof; wherein
said amino compound is an amino acid or peptide and said carboxylic acid is a N-terminal amino protected amino acid or a N-terminal amino protected peptide;
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
and one or two of A, D, E, G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
and R 3 is hydrogen.
39. A process for preparing a peptide bond comprising reacting an amino compound selected from the group consisting of an amino acid and a peptide with an effective amount of a compound having the formula:
or N-oxides thereof or salts thereof wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
and one or two of A, D, E, G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
R 3 is BLK 1 -AA 1 ;
BLK 1 is an amino acid protecting group; and
AA 1 is an amino acid or peptide less a hydrogen on the N-terminus and OH on the C-terminus.
40. The process according to any of claims 36 - 39 wherein two of A, D, E and G are N.
41. The process according to any one of claims 36 - 39 wherein the electron-donating group is amino, lower alkylamino, diloweralkylamino, hydroxy, lower alkoxy, lower alkoxy, halo, aryl, mercapto or lower alkylthio.
42. The process according to claim 41 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
43. The process according to claim 36 wherein R 3 is a positively charged electron-withdrawing group.
44. The process according to claim 43 wherein R 3 is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl, lower alkoxy lower alkyl or R 10 and R 11 taken together with the atoms to which they are attached form a ring containing up to 6 ring atoms and up to a total of 5 carbon ring atoms or R 12 and R 3 taken together with the nitrogen atoms to which they are attached form a 5 or 6 membered nitrogen-containing heterocyclic ring containing up to a total of 5 carbon ring atoms.
45. The process according to claim 36 wherein R 3 is
wherein R 10 , R 11 , R 12 R 12 and R 13 each are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
46. The process according to claim 44 or 45 wherein R 10 , R 11 , and R 12 R 12 and R 13 each are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or CH 2 CH 2 OCH 2 CH 3 .
47. The process according to claim 46 45 wherein R 10 , R 11 and R 12 R 12 and R 13 are the same.
48. The process according to claim 36 wherein R 3 is
wherein
U is N-ALK, CH 2 or O and ALK is lower alkyl or hydrogen.
49. The process according to claim 48 wherein U is CH 2 or NH.
50. The process according to claim 1 wherein the compound has the formula
wherein
one of R 16 , R 17 and R 18 is hydrogen, lower alkyl or an electron-donating group and the others are hydrogen.
R 3 is a the positively charged electron-withdrawing group or SO 2 R 14 ; and
R 14 is lower alkyl, aryl or lower arylakyl.
51. The process according to claim 2 , wherein the compound has the formula:
wherein
one of R 16 , R 17 and R 18 is hydrogen, lower alkyl or an electron-donating group and the others are hydrogen, and
R 3 is H.
52. The process according to claim 3 , wherein the compound has the formula:
wherein
one of R 16 , R 17 and R 18 is hydrogen, lower alkyl or an electron donating group and the others are hydrogen and R 3 is H.
53. The processing according to claim 4 wherein the compound has the formula:
wherein
one of R 16 , R 17 and R 18 is hydrogen, lower alkyl or an electron-donating group and the others are hydrogen, and
R 3 is BLK 1 -AA 1 .
54. The process according to any of claims 50 - 53 wherein R 16 is an electron-donating group.
55. The process according to claim 54 wherein R 16 is lower alkylamino, diloweralkylamino, amino, hydroxy, lower alkoxy, loweraralkoxy, aryloxy, aryl, lower aralkyl, mercapto or loweralkylthio.
56. The process according to claim 55 wherein R 16 is diloweralkylamino or lower alkoxy.
57. The process according to claim 56 wherein R 16 is OCH 3 or Me 2 N.
58. The process according to any one of claims 50 - 53 wherein the compound has the formula:
59. The process according to any one of claims 50 - 53 wherein the compound has the formula:
60. The process according to claim 50 wherein R 3 is
wherein
R 10 , R 11 , R 12 R 12 and R 13 each are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
61. The process according to claim 60 wherein R 10 , R 11 , and R 12 R 12 and R 13 each are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or CH 2 CH 2 OCH 2 CH 3 .
62. The process according to claim 60 or 61 wherein R 10 , R 11 and R 12 R 12 and R 13 are the same.
63. The process according to claim 50 wherein R 3 is
wherein
U is N-ALK, CH 2 , or O, and ALK is lower alkyl or hydrogen.
64. The process according to claim 2 or claim 3 wherein the compound has the formula:
65. The process according to claim 1 wherein the compound is a salt and the cation has the formula:
66. The process according to claim 2 or claim 3 wherein the compound has the formula:
67. The process according to claim 1 wherein the compound has the formula:
68. The process according to claim 1 2 or 3 wherein the compound has the formula:
69. The process according to claim 1 or 3 where the compound is of the formula:
wherein
U is CH 2 , O or N-ALK and ALK is H or lower alkyl.
70. The process according to claim 69 wherein U is CH 2 .
71. The process for forming an amide comprising reacting an organic amine and a carboxylic acid in the presence of an effective amount of a compound having the formula:
or N-oxides thereof or salts thereof;
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only one of A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently or lower alkyl;
R 3 is SO 2 R 14 or a positively charged electron-withdrawing group of the formula P ⊕ (NR 12 R 13 ) 3 ;
each R 12 and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl or R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 5 - or 6 - membered heterocyclic ring containing up to a total of 5 ring carbon atoms ; and
and R 14 is lower alkyl, aryl or aryl loweralkyl.
72. A process for forming an amide comprising reacting an organic amine with a carboxylic acid in the presence of a dehydrating reagent with an effective amount of a compound having the formula:
or N-oxides thereof or salts thereof;
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only one of A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently, hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl; and R 3 is hydrogen.
73. The process according to claim 71 or 72 wherein A or G is N.
74. The process according to claim 71 or 72 wherein Y is CH or N and X is CH or N.
75. The process according to claim 71 or 72 wherein the electron-donating group is amino, lower alkylamino, dilower-alkylamino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
76. The process according to claim 71 or 72 wherein the electron-donating group is lower dialkyamino or lower alkoxy.
77. The process according to claim 76 wherein the electron-donating group is OMe or Me 2 N.
78. The process according to claim 71 wherein the positively charged electron-withdrawing group is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl, lower alkoxy lower alkyl or R 10 and R 11 taken together with the atoms to which they are attached form a ring containing up to 6 ring atoms and up to a total of 5 carbon ring atoms or R 12 and R 13 taken together with the nitrogen atoms to which they are attached from a 5 or 6 membered nitrogen-containing heterocyclic ring containing up to a total of 5 carbon ring atoms.
79. The process according to claim 78 71 wherein R 10 , R 11 , R 12 and R 13 are each independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
80. The process according to claim 79 wherein R 10 , R 11 , R 12 and R 13 are independently lower alkyl.
81. The process according to claim 78 80 wherein R 10 , R 11 , R 12 and R 13 are methyl.
82. The process according to claim 71 wherein the positively charged electron-withdrawing group is
wherein R 10 , R 11 , R 12 and R 13 each are independently hydrogen, or lower alkyl or loweralkoxy lower alkyl and m is 0 or 1 .
83. The process according to claim 82 wherein R 11 and R 12 are the same R 10 and R 11 R 12 and R 13 are the same.
84. The process according to claim 71 wherein R 3 is
wherein
R 10 , R 11 and R 12
R 12 and R 13 each are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or CH 2 CH 2 OCH 2 CH 3 .
85. The process according to claim 84 wherein R 10 , R 11 and R 12 R 12 and R 13 are the same.
86. The process according to claim 71 wherein R 3 is
wherein
U is N-ALK, CH 2 or O and
ALK is lower alkyl or hydrogen.
87. The process according to claim 86 wherein U is CH 2 .
88. The process according to claim 71 wherein the compound has the formula:
89. The process according to claim 72 wherein the compound has the formula:
90. The process according to claim 71 wherein R 3 is SO 2 R 14 .
91. The process according to claim 88 wherein R 3 is a the positively charged electron-withdrawing group.
92. The process according to claim 91 wherein the positively charged electron-withdrawing group is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl, lower alkoxy lower alkyl or R 10 and R 11 taken together with the atoms to which they are attached form a ring containing up to 6 ring atoms and up to a total of 5 carbon rings atoms or R 12 and R 13 taken together with the nitrogen atoms to which they are attached form a 5 or 6 membered nitrogen containing heterocyclic ring containing up to a total of 5 carbon ring atoms.
93. The process according to claim 92 91 wherein R 10 , R 11 , and R 12 R 12 and R 13 are each are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or CH 2 CH 2 OCH 2 CH 3 .
94. The process according to claim 88 wherein R 3 is
wherein
R 10 , R 11 , R 12 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
95. The process according to claim 88 wherein R 3 is
wherein
U is N-ALK, CH 2 or O, and ALK is lower alkyl or hydrogen.
96. The process according to claim 95 wherein U is CH 2 or NH.
97. The process for forming an amide comprising reacting an organic amine with a carboxylic acid in the presence of an effective amount of a compound having the formula:
or N-oxides thereof or salts thereof
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
and one or two of A, D, E, G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
R 3 SO 2 R 14 , or a positively charged electron-withdrawing group of the formula P ⊕ (NR 12 R 13 ) 3 ;
each R 12 and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl or R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 5 - or 6 - membered heterocyclic ring containing up to a total of 5 ring carbon atoms ; and
R 14 is lower alkyl, aryl, or aryl lower alkyl.
98. A process for forming an amide comprising reacting an organic amine with a carboxylic acid in the presence of a dehydrating reagent and an effective amount of a compound, said compound having the formula:
or N-oxides thereof or salts thereof,
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
and one two of A, D, E, G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group; and
R 3 is hydrogen.
99. The process according to claim 97 or 98 wherein two of A, D, E and G are N.
100. The process according to claim 97 or 98 wherein the electron-donating group is amino, lower alkyl amino, diloweralkyl amino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
101. The process according to claim 100 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
102. The process according to claim 97 wherein R 3 is an the electron withdrawing group.
103. The process according to claim 97 wherein R 3 is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl, lower alkoxy lower alkyl or R 10 and R 11 taken together with the atoms to which they are attached form a ring containing up to 6 ring atoms and up to a total of 5 carbon ring atoms or R 12 and R 13 taken together with the nitrogen atoms to which they are attached form a 5 or 6 membered nitrogen-containing heterocyclic ring containing up to a total of 5 carbon ring atoms.
104. The process according to claim 97 wherein R 3 is
wherein
R 10 , R 11 , R 12 R 12 and R 13 each are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
105. The process according to claim 97 wherein R 3 is
wherein
OU is N-ALK, CH 2 or U O and ALK is lower alkyl or hydrogen.
106. The process according to claim 105 wherein U is CH 2 or NH.
107. In the synthesis of a peptide wherein a first Nα-amino protected amino acid is covalently coupled to a solid phase peptide synthesis resin, the N-α-amino protecting group is cleaved off and the resulting free amino group is coupled via a peptide linkage to the carboxyl group of a second Nα-amino protected amino acid, and the cycle is repeated until the desired peptide has been obtained and then the peptide is cleaved from said resin, the improvement comprising adding to the coupling reaction an effective amount of a compound having the formula:
or N-oxides thereof or salts thereof;
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only are A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl;
R 3 is SO 2 R 14 or a positively charged electron-withdrawing group of the formula P ⊕ (NR 12 R 13 ) 3 ; and
each R 12 and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl or R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 5 - or 6 - membered heterocyclic ring containing up to a total of 5 ring carbon atoms;
R 14 is lower alkyl, aryl or aryl loweralkyl.
108. In the synthesis of a peptide wherein a first N-α-amino protected amino acid is covalently coupled to a solid phase peptide synthesis resin, the N-α-amino protecting group is cleaved off and the resulting free amino group is coupled via a peptide linkage to the carboxyl group of a second Nα-amino protected amino acid, and cycle is repeated until the desired peptide has been obtained and then the peptide is cleaved from said resin, the improvement comprising adding to the coupling reaction in effective amount of a compound having the formula:
or N-oxides thereof or salts thereof;
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only one of A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl; and
R 3 is hydrogen.
109. The process according to claim 4 wherein AA 1 is an α-amino acid.
110. The process according to claim 109 wherein AA 1 is a naturally occurring amino acid.
111. The process according to any one of claims 1 - 4 wherein the group protecting the N-terminal amino acid or peptide is FMOC, BOC, TEOC, Aoc, Adoc, Bpoc, Azoc, Ddz, Poc, Foc, Moz, Nps, Dts, Cbz, Bspoc, Bsmoc, Nps, formyl, acetyl or trifluoroacetyl.
112. The process according to claim 111 wherein the group protecting the N-terminal amino acid or peptide is FMOC, BOC, Cbz, Bspoc or Bsmoc.
113. The process according to any of claims 1 - 3 wherein the amino compound and the carboxylic acid are independently naturally occurring amino acids.
114. A process for forming an amide containing the moiety
H,
NR 3
comprising reacting an organic amine under amide forming conditions with an effective amount of a compound of the formula
or N-oxides thereof or salt thereof;
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
wherein one and only one of A, E, D or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl; and
R 3 is lower alkyl carbonyl, aryl carbonyl, or aryl lower alkyl carbonyl.
115. The process according to claim 114 wherein A or G N.
116. The process according to claim 114 wherein Y is CH or N and X is CH or N.
117. The process according to claim 114 wherein the electron-donating group is amino, lower alkylamino, dilower alkylamino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
118. The process according to claim 117 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
119. The process according to claim 118 wherein the electron-donating group is OMe or Me 2 N.
120. A process for forming an amide containing the moiety
H
NR 3
comprising reacting an organic amine under amide-forming conditions with an effective amount of a compound having the formula
or N-oxides thereof or salts thereof;
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
wherein one and only one or two of A, E, D or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group,
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl; and
R 3 is lower alkyl carbonyl, aryl carbonyl, or aryl lower alkyl carbonyl.
121. The process according to claim 120 wherein two one and only one of A, D, E and G are is N.
122. The process according to claim 120 wherein the electron-donating group is amino, lower alkyl amino, diloweralkyl amino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
123. The process according to claim 122 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
124. The process according to claim 114 wherein the compound is
125. A process for preparing a peptide bond comprising reacting an amino compound with a carboxylic acid in the presence of an effective amount of a compound, wherein said compound is prepared from the reaction of R 3 L with
or N-oxides thereof or salts thereof under substitution reaction conditions;
wherein said amino compound is an amino acid or peptide and said carboxylic acid is a N-terminal amino protected amino acid or a N-terminal amino protected peptide;
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only one of A, E, D, or G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl;
L is a leaving group;
R 3 is SO 2 R 14 or a positively charged electron withdrawing group; and
R 14 is loweralkyl, aryl or aryl lower alkyl.
126. A process for preparing a peptide bond comprising reacting an amino compound selected from the group consisting of an amino acid and a peptide with an effective amount of compound, wherein said compound is prepared from the reaction of R 3 L with
or N-oxides thereof or salts thereof;
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only one of A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
L is a leaving group;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl;
R 3 is BLK 1 -AA 1 ;
BLK 1 is an amino acid protecting group; and
AA 1 is an amino acid or peptide less a hydrogen on the N-terminus and an OH on the C-terminus.
127. The process according to claims 125 or 126 wherein A or G is N.
128. The process according to claims 125 or 126 wherein Y is CH or N and X is CH or N.
129. The process according to claims 125 or 126 wherein the electron-donating group is amino, lower alkylamino, diloweralkylamino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
130. The process according to claim 129 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
131. The process according to claim 130 wherein the electron-donating group is OMe or Me 2 N.
132. The process according to claim 125 wherein R 3 is a positively charged electron withdrawing group.
133. The process according to claim 132 wherein the positively charged electron-withdrawing group is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl, lower alkoxy lower alkyl or R 10 and R 11 taken together with the atoms to which they are attached form a ring containing up to 6 ring atoms and up to a total of 5 carbon ring atoms or R 12 and R 13 taken together with the nitrogen atoms to which they are attached form a 5 or 6 membered nitrogen-containing heterocyclic ring containing up to a total of 5 carbon ring atoms.
134. The process according to claim 133 wherein R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
135. The process according to claim 134 wherein R 10 , R 11 , R 12 and R 13 are independently lower alkyl.
136. The process according to claim 135 wherein R 10 , R 11 , R 12 and R 13 are methyl.
137. The process according to claim 132 wherein the positively charged electron-withdrawing group is
wherein
R 10 , R 11 , R 12 are independently hydrogen, lower alkyl or loweralkoxy lower alkyl and m is 0 or 1 .
138. The process according to claim 137 wherein R 11 and R 12 are the same or R 12 and R 13 are the same.
139. The process according to claim 125 wherein R 3 is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or CH 2 CH 2 OCH 2 CH 3 .
140. The process according to claim 139 wherein
(a) R 3 is
and R 10 , R 11 and R 12 are the same or
(b) R 3 is
and R 11 and R 12 are the same.
141. The process according to claim 132 wherein R 3 is
wherein
U is N-ALK, CH 2 or O; and
ALK is lower alkyl or hydrogen.
142. The process according to claim 141 wherein U is CH 2 or NH.
143. The process according to claim 126 wherein BLK 1 is FMOC, BOC, TEOC, Aoc, Adoc, Bpoc, Azoc, Ddz, Poc, Roc, Moz, Nps, Dts, Cbz, Bspoc, Bsmoc, formyl, acetyl, trifluoroacetyl, CLIMOC or BIMOC.
144. The process according to claim 143 wherein BLK 1 is Cbz, Bspoc, Bsmoc, BOC or FMOC.
145. A process for preparing a peptide bond comprising reacting an amine with a carboxylic acid in the presence of an effective amount of a compound, wherein said compound is prepared from the reaction of R 3 L with
or N-oxides thereof or salts thereof under substitution reaction conditions wherein
said amine is an amino acid or peptide and said carboxylic acid is a N-terminal amino protected amino acid or a N-terminal amino protected peptide;
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
and one or two of A, D, E, G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
L is a leaving group;
R 3 is SO 2 R 14 or a positively charged electron-withdrawing group; and R 14 is a lower alkyl, aryl or lower alkyl.
146. A process for preparing a peptide bond comprising reacting an amino compound selected from the group consisting of an amino acid and a peptide with an effective amount of a compound, wherein said compound is prepared from the reaction of R 3 L with
or N-oxides thereof or salts thereof wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
and one or two of A, D, E, G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
L is a leaving group;
R 3 is BLK 1 -AA 1 ;
BLK 1 is an amino acid protecting group; and
AA 1 is an amino acid or peptide less a hydrogen on the N-terminus and OH on the C-terminus.
147. The process according to claim 145 or 146 wherein one of A, D, E and G is N.
148. The process according to claim 145 or 146 wherein the electron-donating group is amino, lower alkylamino, diloweralkylamino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
149. The process according to claim 148 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
150. The process according to claim 145 wherein R 3 is a positively charged electron withdrawing group.
151. The process according to claim 150 wherein R 3 is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl, lower alkoxy lower alkyl or R 10 and R 11 taken together with the atoms to which they are attached form a ring containing up to 6 ring atoms and up to a total of 5 carbon ring atoms or R 12 and R 13 taken together with the nitrogen atoms to which they are attached form a 5 or 6 membered nitrogen-containing heterocyclic ring containing up to a total of 5 carbon ring atoms.
152. The process according to claim 150 wherein R 5
wherein
R 10 , R 11 , and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
153. The process according to claim 151 or 152 wherein R 10 , R 11 , R 12 , and R 13 are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or CH 2 CH 2 OCH 2 CH 3 .
154. The process according to claim 153 wherein (a) R 3 is
and R 10 , R 11 and R 12 are the same or
(b) R 3 is
and R 11 and R 12 are the same.
155. The process according to claim 150 wherein R 3 is
wherein
U is N-ALK, CH 2 or O and ALK is lower alkyl or CH 2 or NH.
156. The process according to claim 155 wherein U is CH 2 or NH.
157. The process according to claim 125 wherein R 3 L is reacted with
wherein
one of R 15 , R 16 and R 17 is hydrogen, lower alkyl or an electron donating group and the others are hydrogen.
158. The process according to claim 126 wherein R 3 L is reacted with
wherein one of R 15 , R 16 and R 17 is hydrogen, lower alkyl or an electron donating group and the others are hydrogen.
159. The process according to claim 157 wherein R 3 is
wherein
R 10 , R 11 , and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
160. The process according to claim 159 where R 10 , R 11 , R 12 and R 13 are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or CH 2 CH 2 OCH 2 CH 3 .
161 . The process according to claim 159 or 160
wherein
(a) R 3 is
and R 10 , R 11 and R 12 are the same or
(b) R 3 is
and R 11 and R 12 are the same.
162. The process according to claim 157 wherein R 3 is
wherein
U is N-ALK, CH 2 or O, and ALK is lower alkyl or hydrogen.
163. The process according to claim 146 or claim 147 wherein R 3 L is reacted with
164. The process according to claim 145 where R 3 L is reacted with
wherein
R 3 is
wherein
U is CH 2 , O or N-ALK and ALK is H or lower alkyl.
165. The process according to claim 164 wherein U is CH 2 .
166. A process for forming an amide comprising reacting an organic amine and a carboxylic acid in the presence of an effective amount of a compound, wherein said compound is prepared from the reaction of R 3 L with a compound of the formula:
or N-oxides thereof or salts thereof under substitution reaction conditions,
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one or two of A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl;
R 3 is a positively charged electron-withdrawing group; and
L is a leaving group.
167. The process according to claim 166 wherein A or G is N.
168. The process according to claim 166 wherein Y is CH or N and X is CH or N.
169. The process according to claim 166 wherein the electron-donating group is amino, lower alkylaminodilower-alkylamino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
170. The process according to claim 169 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
171. The process according to claim 170 wherein the electron-donating group is OMe or Me 2 N.
172. The process according to claim 166 wherein R 3 is a positively charged electron-withdrawing group.
173. The process according to claim 172 wherein the positively charged electron-withdrawing group is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl, lower alkoxy lower alkyl or R 10 and R 11 taken together with the atoms to which they are attached form a ring containing up to 6 ring atoms and up to a total of 5 carbon ring atoms or R 12 and R 13 taken together with the nitrogen atoms to which they are attached form a 5 or 6 membered nitrogen-containing heterocyclic ring containing up to a total of 5 carbon ring atoms.
174. The process according to claim 173 wherein R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
175. The process according to 173 wherein R 10 , R 11 , R 12 and R 13 are independently lower alkyl.
176. The process according to claim 175 wherein R 10 , R 11 , R 12 and R 13 are methyl.
177. The process according to claim 172 wherein the positively charged electron-withdrawing group is
wherein
R 11 , R 12 and R 13 are independently hydrogen, or lower alkyl or loweralkoxy lower alkyl and m is 0 or 1 .
178. The process according to claim 177 wherein R 11 and R 12 are the same or R 12 and R 13 are the same.
179. The process according to claim 172 wherein R 3 is
wherein
R 11 , R 12 and R 13 are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or CH 2 CH 2 OCH 2 CH 3 .
180. The process according to claim 179 wherein (a) R 3 is
and R 10 , R 11 and R 12 are the same or
(b) R 3 is
and R 11 and R 12 are the same.
181. The process according to claim 172 wherein R 3 is
wherein
U is N-ALK, CH 2 or O and
ALK is lower alkyl or hydrogen.
182. The process according to claim 181 wherein U is CH 2 .
183. The process according to claim 165 or 166 wherein R 3 L is reacted with
184. The process according to claim 183 wherein R 3 is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl, lower alkoxy lower alkyl or R 10 and R 11 taken together with the atoms to which they are attached form a ring containing up to 6 ring atoms and up to a total of 5 carbon ring atoms or R 12 and R 13 taken together with the nitrogen atoms to which they are attached form a 5 or 6 membered nitrogen containing heterocyclic ring containing up to a total of 5 carbon ring atoms.
185. The process according to claim 184 wherein R 10 , R 11 , R 12 and R 13 are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or CH 2 CH 2 OCH 2 CH 3 .
186. The process according to claim 183 wherein R 3 is
wherein
R 10 , R 11 , R 12 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
187. The process according to claim 183 wherein R 3 is
wherein
U is N-ALK, CH 2 or O, and ALK is lower alkyl or hydrogen.
188. The process according to claim 187 wherein U is CH 2 or NH.
189. A process for forming an amide comprising reacting an organic amine with a carboxylic acid in the presence of an effective amount of a compound, wherein said compound is prepared from the reaction of R 3 L with
or N-oxides thereof or salts thereof under substitution reaction conditions
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
an one or two of A, D, E, G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
R 3 is SO 2 R 14 or a positively charged electron-withdrawing group;
L is a leaving group; and
R 14 is loweralkyl, aryl or lower arylalkyl.
190. The process according to claim 189 for forming an amide comprising reacting an organic amine with a carboxylic acid in the presence of a dehydrating reagent and an effective amount of a compound, said compound prepared from the reaction of R 3 L with
or N-oxides thereof or salts thereof, under substitution reaction conditions.
191. The process according to claim 189 or 190 wherein one of A, D, E and G is N.
192. The process according to claim 189 or 190 wherein the electron-donating group is amino, lower alkyl amino, diloweralkyl amino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
193. The process according to claim 192 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
194. The process according to claim 189 or 190 wherein R 3 is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl, lower alkoxy lower alkyl or R 10 and R 11 taken together with the atoms to which they are attached form a ring containing up to 6 ring atoms and up to a total of 5 carbon ring atoms or R 12 and R 13 taken together with the nitrogen atoms to which they are attached form a 5 or 6 membered nitrogen-containing heterocyclic ring containing up to a total of 5 carbon ring atoms.
195. The process according to claim 189 or 190 wherein R 3 is
wherein
R 10 , R 11 , R 12 and R 13 are independently hydrogen, lower alkyl or lower alkoxy lower alkyl.
196. The process according to claim 189 or 190 wherein R 3 is
wherein
O is N-ALK, CH 2 or U and ALK is lower alkyl or hydrogen.
197. The process according to claim 196 wherein U is CH 2 or NH.
198. In the synthesis of a peptide wherein a first N-α-amino protected amino acid is covalently coupled to a solid phase peptide synthesis resin, the N-α-amino protecting group is cleaved off and the resulting free amino group is coupled via a peptide linkage to the carboxylic group of a second N-α-amino protected amino acid, and the cycle is repeated until the desired peptide has been obtained and then the peptide is cleaved from said resin, the improvement comprising adding to the coupling reaction an effective amount of a compound formed from the reaction of R 3 L with a compound of the formula:
or N-oxides thereof or salts thereof under substitution reaction conditions;
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
whereby one and only one of A, E, D, or G is N;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl;
R 3 is SO 2 R 14 or a positively charged electron-withdrawing group;
L is a leaving group; and
R 14 is lower alkyl, aryl, or aryl loweralkyl.
199. The process according to claim 126 wherein AA 1 is an α-amino acid.
200. The process according to 199 wherein AA 1 is a naturally occurring amino acid.
201. The process according to claim 125 or 126 wherein the amino compound and the carboxylic acid are independently naturally occurring amino acids.
202. A process for forming an amide containing the moiety
H
NR 3
comprising reacting an organic amine under amide forming conditions with an effective amount of a compound prepared by reacting R 3 L with
or N-oxides thereof or salts thereof;
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
wherein
one and only one of A, E, D or G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
R 7 and R 5 are independently hydrogen or lower alkyl; and
R 3 is lower alkyl carbonyl, aryl carbonyl, or aryl lower alkyl carbonyl; and
L is a leaving group.
203. The process according to claim 202 wherein A or G is N.
204. The process according to claim 202 wherein Y is CH or N and X is CH or N.
205. The process according to claim 202 wherein the electron-donating group is amino, lower alkylamino, diloweralkylamino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
206. The process according to claim 205 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
207. The process according to claim 206 wherein the electron-donating group is Me 2 N or OMe.
208. The process for forming an amide containing the moiety
H
NR 3
comprising reacting an organic amine under amide-forming conditions with an effective amount of a compound prepared by reacting R 3 L with
or N-oxides thereof or salts thereof;
wherein
D is CR 16 or N;
E is CR 17 or N;
A is CR 15 or N;
G is CR 18 or N;
wherein
one or two of A, E, D or G is N;
R 15 , R 16 , R 17 and R 18 are independently hydrogen, lower alkyl or an electron-donating group;
X is CR 7 or N;
Y is N or CR 5 ;
L is a leaving group;
R 7 and R 5 are independently hydrogen or lower alkyl; and
R 3 is lower alkyl carbonyl, aryl carbonyl, or aryl lower alkyl carbonyl.
209. The process according to claim 208 wherein one of A, D, E and G is N.
210. The process according to claim 200 wherein the electron-donating group is amino, lower alkyl amino, diloweralkyl amino, hydroxy, lower alkoxy, lower aralkoxy, halo, aryl, mercapto or lower alkylthio.
211. The process according to claim 210 wherein the electron-donating group is lower dialkylamino or lower alkoxy.
212. The process according to claim 145 or 166 wherein the compound is formed by reacting 1 -hydroxy- 7 -axa-benzotriazole with R 3 L, wherein R 3 is 1 , 1 , 3 , 3 -tetramethyluronium salt and L is a leaving group.
213. The process according to claim 212 wherein the leaving group is a halide.Cited by (0)
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