Asymmetric synthesis of amino-pyrrolidinones

Details Asymmetric synthesis of amino-pyrrolidinones Asymmetric synthesis of amino-pyrrolidinones

2003-03-14

2004-08-03

Chang, Ceila (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S551000, C502S333000, C546S248000

Reexamination Certificate

active

06770763

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to processes for the asymmetric synthesis of amino-pyrrolidinones, such pyrrolidinones being useful as intermediates for MMP and TACE inhibitors.
BACKGROUND OF THE INVENTION
Amino-pyrrolidinones of the type shown below are currently being studied as MMP and TACE inhibitors in clinical settings. As one of ordinary skill in the art understands, clinical trials and NDA submissions require practical, large-scale synthesis of the active drug.
Consequently, it is desirable to find new synthetic procedures for making amino-pyrrolidinones.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a novel intermediate for making an amino-pyrrolidinone.
The present invention provides a novel amino-pyrrolidinone.
The present invention provides a novel process for making amino-pyrrolidinones.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that novel compounds of formula II can be formed from novel compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
Thus, in an embodiment, the present invention provides a novel process of forming a compound of formula II, comprising:
(a) contacting a compound of formula I with a strong base in the presence of a first solvent, wherein the first solvent is an aprotic solvent;
(b) contacting the resulting solution from (a) with an aminating reagent, wherein the aminating reagent is an electrophilic nitrogen source; and,
(c) if necessary, treating the amination product of (b) by reducing, hydrolyzing, or a combination thereof to form a compound of formula II;
wherein:
R
f
is absent;
R
y
is selected from H, OH, C
1-6
alkyl, and C
3-12
cycloalkyl;
R
z
is selected from H, C
1-6
alkyl, and C
3-12
cycloalkyl;
alternatively, R
f
is O, R
z
is absent, and R
y
forms a C
3-12
cycloalkyl group double bonded to the nitrone nitrogen or is a carbon atom double bonded to the nitrone nitrogen and substituted with R
6
and R
7
;
R
6
is C
1-6
alkyl or C
3-12
cycloalkyl;
R
7
is C
1-6
alkyl or C
3-12
cycloalkyl;
R
1
is Z—U
a
—X
a
—Y
a
—Z
a
;
Z is phenyl or pyridyl substituted with 1-5 R
b
;
U
a
is absent or is selected from O and NR
a
;
X
a
is absent or is selected from C
1-10
alkylene, C
2-10
alkenylene, and C
2-10
alkynylene;
Y
a
is absent or is selected from O and NR
a
;
Z
a
is selected from H, C
3-13
carbocyclic residue substituted with 0-5 R
c
, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0-5 R
c
;
R
2
is H;
R
3
is selected from H, Q, C
1-10
alkylene-Q, C
2-10
alkenylene-Q, C
2-10
alkynylene-Q, (CRR
x
)
r1
O(CRR
x
)
r
—Q, and (CRR
x
)
r1
NR
a
(CRR
x
)
r
—Q;
Q is selected from H and a C
3-13
carbocyclic residue substituted with 0-5 R
d
;
R, at each occurrence, is independently selected from H, CH
3
, CH
2
CH
3
, CH═CH
2
, CH═CHCH
3
, and CH
2
CH═CH
2
;
R
x
, at each occurrence, is independently selected from H, CH
3
, CH
2
CH
3
, and CH(CH
3
)
2
;
R
4
is selected from H, C
1-10
alkylene-H, C
2-10
alkenylene-H, C
2-10
alkynylene-H, (CRR
x
)
r1
O(CRR
x
)
r
—H, and (CRR
x
)
r1
NR
a
(CRR
x
)
r
—H;
alternatively, R
3
and R
4
combine to form a C
3-13
carbocyclic residue substituted with R
4a
and 0-3 R
b
;
R
4a
is U
a
—X
a
—Y
a
—Z
a
;
R
5
is selected from H, C
1-6
alkyl, phenyl, and benzyl;
R
a
, at each occurrence, is independently selected from H, C
1-4
alkyl, phenyl, and benzyl;
R
a1
, at each occurrence, is independently selected from H, C
1-4
alkyl, phenyl, and benzyl;
R
a2
, at each occurrence, is independently selected from H, C
1-4
alkyl, benzyl, C
3-7
carbocyclic residue, and a 5 to 6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, R
a
and R
a1
taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R
b
, at each occurrence, is independently selected from C
1-6
alkyl, OR
a
, Cl, F, Br, I, CN, NR
a
R
a1
, S(O)
2
NR
a
R
a1
, CF
3
, and CF
2
CF
3
;
R
c
, at each occurrence, is independently selected from C
1-6
alkyl, OR
a
, F, NR
a
R
a1
, CF
3
, and CF
2
CF
3
;
R
d
, at each occurrence, is independently selected from C
1-6
alkyl, OR
a
, F, NR
a
R
a1
, S(O)
2
NR
a
R
a1
, CF
3
, and CF
2
CF
3
;
n is selected from 0, 1, 2, and 3;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5; and,
rl, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5.
In a preferred embodiment, the present invention provides a novel process, wherein (c) is performed by reducing the amination product from (b) to form a compound of formula II, wherein:
R
y
is selected from H, C
1-6
alkyl, and C
3-12
cycloalkyl; and,
R
z
is selected from H, C
1-6
alkyl, and C
3-12
cycloalkyl.
In another preferred embodiment, the present invention provides a novel process, wherein (a) is performed in the presence of an inorganic salt selected from a lithium salt, a potassium salt, and a sodium salt; and (c) is performed by contacting the amination product from (b) with a reducing agent and an acid;
the compound of formula I is the compound of formula Ia:
the compound of formula II is a compound of formula IIa:
the strong base is selected from an alkyl lithium, lithium amide, hydride base, and an organometallic base;
the first solvent is selected from an ethereal solvent, a hydrocarbon solvent, and an aromatic hydrocarbon solvent;
the aminating reagent is selected from a chloro-nitroso compound, a sulfonyl azide, a nitroso compound, an azodicarboxylate, a sulfonamide, and an oxaziridine compound;
the reducing agent is selected from zinc and iron;
the acid is selected from formic acid, acetic acid, and methanesulfonic acid;
wherein:
R
y
is H;
R
z
is H;
U
a
is absent or is O;
X
a
is absent or is C
1-4
alkylene;
Y
a
is absent;
Z
a
is selected from H, C
5-6
carbocyclic residue substituted with 0-2 R
c
, and a 5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S, and substituted with 0-2 R
c
; and,
R
b
, at each occurrence, is independently selected from C
1-4
alkyl, OR
a
, Cl, F, NR
a
R
a1
, and CF
3
;
R
c
, at each occurrence, is independently selected from C
1-4
alkyl, OR
a
, F, NR
a
R
a1
, and CF
3
; and,
R
5
is H or C
1-6
alkyl.
In another preferred embodiment, the present invention provides a novel process, wherein (b) is performed in the presence of a second solvent and the second solvent is an aprotic solvent;
the inorganic salt is selected from lithium chloride, lithium perchlorate, lithium bromide, lithium iodide, potassium chloride, potassium bromide, potassium iodide, sodium chloride, sodium bromide, and sodium iodide;
the strong base is selected from methyl lithium, ethyl lithium, n-propyl lithium, i-propyl lithium, n-butyl lithium, i-butyl lithium, s-butyl lithium, t-butyl lithium, hexyl lithium, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, potassium bis(trimethylsilyl)amide, potassium hydride, and sodium hydride;
the first solvent is selected from tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether, and dimethoxymethane;
the second solvent is selected from tetrahydrofuran, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether, dimethoxymethane, and toluene;
the aminating reagent is selected from 1-chloro-1-nitrosocyclopentane, 1-chloro-1-nitrosocyclohexane, and 2-chloro-2-nitrosopropane;
the reducing agent is zinc;
wherein:
U
a
is O;
X
a
is absent or is CH
2
;
Z
a
is H or phenyl; and,
R
5
is H or CH
3
.
In another preferred embodiment, the present invention provides a novel process, wherein:
the inorganic salt is selected from lithium chloride and lithium perchlorate;
the strong base is selected from n-butyl lithium and hexyl lithium;
the first solvent is selected from tetrahydrofuran and

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