Process and intermediates for growth hormone secretagogues

Details Process and intermediates for growth hormone secretagogues Process and intermediates for growth hormone secretagogues

2001-08-03

2002-10-15

Bernhardt, Emily (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06465651

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a process for preparing a compound of Formula I,
wherein R
1
, R
2
, and Pt are as defined below, which can be used to prepare certain growth hormone secretagogues of Formula II below. This invention also relates to processes for preparing said growth hormone secretagogues.
The compounds of Formula II wherein R
1
and R
2
are as defined below are potent growth hormone secretagogues. These compounds and their preparation have been disclosed in International patent publication WO98/58947.
SUMMARY OF THE INVENTION
This invention is directed to a compound of Formula VII,
wherein
Pt is an amine protecting group.
A preferred compound of Formula VII is the compound wherein Pt is Boc.
This invention is also directed to a process, designated Process A, for preparing a compound of Formula III,
wherein
Pt is an amine protecting group;
R
2
is hydrogen, (C
1
-C
8
)alkyl, —(C
0
-C
3
)alkyl-(C
3
-C
8
)cycloalkyl, —(C
1
-C
4
)alkyl-A
1
or A
1
;
A
1
for each occurrence is independently selected from the group consisting of (C
5
-C
7
)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A
1
for each occurrence is independently optionally substituted, on one or optionally both rings if A
1
is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF
3
, OCF
2
H, CF
3
, CH
3
, OCH
3
, —OX
6
, —C(O)N(X
6
)(X
6
), —C(O)OX
6
, oxo, (C
1
-C
6
)alkyl, nitro, cyano, benzyl, —S(O)
m
(C
1
-C
6
)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, —N (X
6
)(X
6
), —N(X
6
)C(O)(X
6
), —S(O)
2
N(X
6
)(X
6
), —N(X
6
)S(O)
2
-phenyl, —N(X
6
)S(O)
2
X
6
, —CONX
11
X
12
, —S(O)
2
NX
11
X
12
, —NX
6
S(O)
2
X
12
, —NX
6
CONX
11
X
12
, —NX
6
S(O)
2
NX
11
X
12
, —NX
6
C(O)X
12
, imidazolyl, thiazolyl and tetrazolyl, provided that if A
1
is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X
11
is hydrogen or optionally substituted (C
1
-C
6
)alkyl;
the optionally substituted (C
1
-C
6
)alkyl defined for X
11
is optionally independently substituted with phenyl, phenoxy, (C
1
-C
6
)alkoxycarbonyl, —S(O)
m
(C
1
-C
6
)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C
1
-C
10
)alkanoyloxy groups or 1 to 3 (C
1
-C
6
)alkoxy groups;
X
12
is hydrogen, (C
1
-C
6
)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X
12
is not hydrogen, the X
12
group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH
3
, OCH
3
, OCF
3
and CF
3
;
or X
11
and X
12
are taken together to form —(CH
2
)
r
-L
1
-(CH
2
)
r
—;
L
1
is C(X
2
)(X
2
), O, S(O)
m
or N(X
2
);
X
6
for each occurrence is independently hydrogen, optionally substituted (C
1
-C
6
)alkyl, (C
2
-C
6
)halogenated alkyl, optionally substituted (C
3
-C
7
)cycloalkyl, (C
3
-C
7
)-halogenated cycloalkyl, where optionally substituted (C
1
-C
6
)alkyl and optionally substituted (C
3
-C
7
)cycloalkyl in the definition of X
6
is optionally independently mono- or di-substituted with (C
1
-C
4
)alkyl, hydroxy, (C
1
-C
4
)alkoxy, carboxyl, CONH
2
, —S(O)
m
(C
1
-C
6
)alkyl, carboxylate (C
1
-C
4
)alkyl ester or 1 H-tetrazol-5-yl; or when there are two X
6
groups on one atom and both X
6
are independently (C
1
-C
6
)alkyl, the two (C
1
-C
6
)alkyl groups may be optionally joined and, together with the atom to which the two X
6
groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX
7
as a ring member;
r for each occurrence is independently 1, 2 or 3;
comprising reacting a compound of Formula IV,
wherein R
3
is (C
1
-C
4
)alkyl and Pt is as defined above,
with a preformed isocyanate or a carbonyl equivalent and R
2
NH
2
, wherein R
2
is as defined hereinabove, in a reaction inert solvent for about one hour to about 72 hours at a temperature of about 0° C. to about 80° C.
A preferred process within Process A, designated Process B, comprises the process wherein R
2
is hydrogen, (C
1
-C
8
)alkyl or —(C
0
-C
3
)alkyl-(C
3
-C
8
)cycloalkyl; where the alkyl groups and the cycloalkyl groups in the definition of R
2
are optionally substituted with 1, 2 or 3 fluorine and wherein Pt is tert-butyloxycarbonyl.
A preferred process within Process B, designated Process C, comprises the process wherein said compound of Formula IV is reacted with a carbonyl equivalent selected from carbonyldiimidazole, phosgene, triphosgene and diphosgene.
A preferred process within Process C, designated Process D, comprises the process wherein said carbonyl equivalent is carbonyldiimidazole and said reaction inert solvent is methylene chloride.
A preferred process within Process D, designated Process E, comprises the process wherein R
2
is methyl, ethyl or 2,2,2-trifluoroethyl.
An especially preferred process within Process E is the process wherein R
2
is methyl.
Another especially preferred process within Process E is the process wherein R
2
is ethyl.
Yet another especially preferred process within Process E is the process wherein R
2
is 2,2,2-trifluoroethyl.
This invention is also directed to a process, designated Process F, for preparing a compound of Formula I,
wherein
R
1
is —(CH
2
)
q
N(X
6
)C(O)X
6
, —(CH
2
)
q
N(X
6
)C(O)(CH
2
)
t
-A
1
, —(CH
2
)
q
N (X
6
)S(O)
2
(CH
2
)
t
-A
1
, —(CH
2
)
q
N(X
6
)S(O)
2
X
6
, —(CH
2
)
q
N (X
6
)C(O)N(X
6
)(CH
2
)
t
-A
1
, —(CH
2
)
q
N (X
6
)C(O)N(X
6
)(X
6
), —(CH
2
)
q
C(O)N(X
6
)(X
6
), —(CH
2
)
q
C(O)N(X
6
)(CH
2
)
t
-A
1
, —(CH
2
)
q
C(O)OX
6
, —(CH
2
)
q
C(O)O(CH
2
)
t
-A
1
, —(CH
2
)
q
OX
6
, —(CH
2
)
q
OC(O)X
6
, —(CH
2
)
q
OC(O)(CH
2
)
t
-A
1
, —(CH
2
)
q
OC(O)N (X
6
)(CH
2
)
t
-A
1
, —(CH
2
)
q
OC(O)N(X
6
)(X
6
), —(CH
2
)
q
C(O)X
6
, —(CH
2
)
q
C(O)(CH
2
)
t
-A
1
, —(CH
2
)
q
N(X
6
)C(O)OX
6
, —(CH
2
)
q
N(X
6
)S(O)
2
N(X
6
)(X
6
), —(CH
2
)
q
S(O)
m
X
6
, —(CH
2
)
q
S(O)
m
(CH
2
)
t
-A
1
, —(C
1
-C
10
)alkyl, —(CH
2
)
q
-A
1
, —(CH
2
)
q
—(C
3
-C
7
)cycloalkyl, —(CH
2
)
q
-Y
1
-(C
1
-C
6
)alkyl, —(CH
2
)
q
-Y
1
-(CH
2
)
t
-A
1
or —(CH
2
)
q
-Y
1
-(CH
2
)
t
—(C
3
-C
7
)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R
1
are optionally substituted with (C
1
-C
4
)alkyl, hydroxy, (C
1
-C
4
)alkoxy, carboxyl, —CONH
2
, —S(O)
m
(C
1
-C
6
)alkyl, —CO
2
(C
1
-C
4
)alkyl ester, 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
Y
1
is O, S(O)
m
, —C(O)NX
6
—, —CH═CH—, —C≡C—, —N(X
6
)C(O)—, —C(O)NX
6
—, —C(O)O—, —OC(O)N(X
6
)— or —OC(O)—;
q is 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH
2
)
q
group and (CH
2
)
t
group in the definition of R
1
are optionally independently substituted with hydroxy, (C
1
-C
4
)alkoxy, carboxyl, —CON H
2
, —S(O)
m
(
1
-C
6
)alkyl, —CO
2
(C
1
-C
4
)alkyl ester, 1 H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C
1
-C
4
)alkyl groups; and
R
2
is hydrogen, (C
1
-C
8
)alkyl, —(C
0
-C
3
)alkyl-(C
3
-C
8
)cycloalkyl, —(C
1
-C
4
)alkyl-A
1
or A
1
;
where the alkyl groups and the cycloalkyl groups in the definition of R
1
are optionally substituted with hydroxy, —C(O)OX
6
, —C(O)N(X
6
)(X
6
), —N (X
6
)(X
6
), —S(O)
m
(C
1
-C
6
)alkyl, —C(O)A
1
, —C(O)(X
6
), CF
3
, CN or 1, 2 or 3 independently selected halo groups;
A
1
for each occurrence is independently selected from the group consisting of (C
5
-C
7
)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally h

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