US2014200354A1PendingUtilityA1
Process for the Manufacture of Non-Steroidal Anti-Inflammatory Agents and Intermediates Thereof
Est. expiryApr 18, 2027(~0.8 yrs left)· nominal 20-yr term from priority
Inventors:Steffen Schweizer
C07D 333/72C07D 307/79C07D 209/44A61P 29/00C07D 333/54C07D 317/06C07D 209/08C07D 405/12C07D 307/78C07D 307/87C07D 405/08
50
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Claims
Abstract
The current invention describes novel chiral synthetic routes and intermediates for the manufacture of chiral anti-inflammatory agents of general formula VIII in which at least one of the groups X 1 , X 2 , X 3 is selected from fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl, amino whereas the other groups X 1 , X 2 , X 3 have the meaning of a hydrogen atom, in which at least one of the groups Z 1 , Z 2 , Z 3 is selected from —O—, —S—, —N(—CH 3 )—, whereas the other groups Z 1 , Z 2 , Z 3 have the meaning of a —CH 2 — group, and in which Ar is an aromatic group.
Claims
exact text as granted — not AI-modified1 .- 18 . (canceled)
19 . A process for producing a compound according to formula VIII
in which at least one of the groups X 1 , X 2 , X 3 is fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl or amino
and the other groups X 1 , X 2 , X 3 are hydrogen,
and in which at least one of the groups Z 1 , Z 2 , Z 3 is —O—, —S—, —NH—, or —N(—CH 3 )—, and the other groups Z 1 , Z 2 , Z 3 are —CH 2 — groups
and in which Ar stands for an aromatic group comprising reducing an enantiomerically pure imine of formula VII
in which
at least one of the groups X 1 , X 2 , X 3 is fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl or amino and the other groups X 1 , X 2 , X 3 are hydrogen,
and in which at least one of the groups Z 1 , Z 2 , Z 3 is —O—, —S—, —NH— or —N(—CH 3 )—, and the other groups Z 1 , Z 2 , Z 3 are —CH 2 — groups
and in which Ar stands for an aromatic group.
20 . The process of claim 19 , wherein said compound of formula VII is obtained by reacting a compound according VI
H 2 N—Ar (VI)
in which Ar is an aromatic group
with an enantiomerically pure aldehyde of formula V
in which X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 have the above described meaning.
21 . The process according to claim 20 , wherein said compound of formula V is obtained by oxidizing an enantiomerically pure compound according to formula I
in which at least one of the groups X 1 , X 2 , X 3 is fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, trifluoromethyl or amino and the other groups X 1 , X 2 , X 3 are hydrogen, and in which at least one of the groups Z 1 , Z 2 , Z 3 is —O—, —S—, —NH—, or —N(—CH 3 )—, and the other groups Z 1 , Z 2 , Z 3 are —CH 2 —.
22 . A process according to claim 21 , wherein the compound of formula I is reacted with SO 3 /pyridine complex to form the aldehyde of formula V.
23 . A process according to claim 20 , wherein, in producing the compound of formula VII the compound of formula V is dissolved in acetic acid, the amine of formula VI is added at room temperature, toluene is added and the mixture is refluxed for 5-50 h to yield the imine of formula VII.
24 . A process according to claim 20 , wherein the amine of formula VI is:
1-amino-2-methyl-benzene 1-amino-4-methyl-benzene 2-amino-4-methylpyridine 2-amino-pyridine 2-amino-pyrimidine 3-amino-quinoline 4-amino-pyridine 4-amino-pyrimidine 5-amino-isoquinoline 5-amino-1-methyl-isoquinoline 5-amino-2,6-di-methylquinoline 5-amino-2-methyl-indole 5-amino-2-methyl-isoquinol-1(2H)-one 5-amino-2-methylquinoline 5-amino-6-chloro-2-methylquinoline 5-amino-6-fluoro-2-methylquinoline 5-amino-isoquinol-2(1H)-one 5-amino-quinoline amino-benzene or N-(4-aminophenyl)-piperidine
25 . A process according to claim 24 , wherein the amine of formula VI is 5-amino-2-methylquinoline.
26 . A process according to claim 19 , wherein the imine of formula VII is reacted with sodium borohydride in alcoholic solution to yield the compound according to formula VIII.
27 . A process according to claim 19 , wherein the compound of formula VIII is:
1,1,1 trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[(2-methyl-5-quinoline-5-ylimino]methyl}pentane-2-ol).
28 . A process according to claim 19 , wherein the compound of formula VIII is:
1,1,1 trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[(2-methyl-5-quinolinyl]methyl}pentane-2-ol).
29 . A process according to claim 21 , wherein the enantiomerically pure compound of formula I is:
Z 1
Z 2
Z 3
X 1
X 2
X 3
enantiomer
a)
O
F
R
b)
O
F
R
c)
O
F
R
d)
NH
F
R
e)
O
F
R
f)
S
F
R
g)
NH
Cl
R
h)
NH
Cl
R
i)
S
Cl
R
j)
S
CF 3
R
k)
S
CF 3
R
l)
O
CF 3
R
m)
O
O—CH 3
R
n)
O
O—CH 3
R
o)
O
O
O—CH 3
R
p)
O
F
R
q)
NH
F
R
r)
NH
NH 2
R
s)
NH
NH 2
R
t)
O
Br
R
u)
O
F
S
v)
O
F
S
w)
O
F
S
x)
NH
F
S
y)
O
F
S
z)
S
F
S
aa)
NH
Cl
S
bb)
NH
Cl
S
cc)
S
Cl
S
dd)
S
CF 3
S
ee)
S
CF 3
S
ff)
O
CF 3
S
gg)
O
O—CH 3
S
hh)
O
O—CH 3
S
ii)
O
O
O—CH 3
S
jj)
O
F
S
kk)
NH
F
S
ll)
NH
NH 2
S
mm)
NH
NH 2
S
nn)
O
Br
S.
30 . A process according to claim 19 , wherein one of the groups X 1 , X 2 , X 3 is fluoro and the other groups X 1 , X 2 , X 3 are hydrogen.
31 . A process according to claim 19 , wherein one of the groups Z 1 , Z 2 , Z 3 is —O— and the others are —CH 2 — groups.
32 . A process according to claim 19 , wherein Ar is 5-amino 2-methylquinoline.
33 . A process according to claim 19 , wherein X 1 is H, X 2 is fluoro, X 3 is H, Z 1 is CH 2 , Z 2 is CH 2 , and Z 3 is O.
34 . A process according to claim 19 , wherein said compound according to formula VIII is:
35 . A process according to claim 29 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>80%.
36 . A process according to claim 35 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>90%.
37 . A process according to claim 36 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>95%.
38 . A process according to claim 37 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>97%.
39 . An enantiomerically pure compound of formula I
wherein:
Z 1
Z 2
Z 3
X 1
X 2
X 3
enantiomer
a)
O
F
R
b)
O
F
R
c)
O
F
R
d)
NH
F
R
e)
S
F
R
f)
NH
Cl
R
g)
NH
Cl
R
h)
S
Cl
R
i)
S
CF 3
R
j)
S
CF 3
R
k)
O
CF 3
R
l)
O
O—CH 3
R
m)
O
O—CH 3
R
n)
O
O
O—CH 3
R
o)
O
F
R
p)
NH
F
R
q)
NH
NH 2
R
r)
NH
NH 2
R
s)
O
Br
R
t)
O
F
S
u)
O
F
S
v)
O
F
S
w)
NH
F
S
x)
S
F
S
y)
NH
Cl
S
z)
NH
Cl
S
aa)
S
Cl
S
bb)
S
CF 3
S
cc)
S
CF 3
S
dd)
O
CF 3
S
ee)
O
O—CH 3
S
ff)
O
O—CH 3
S
gg)
O
O
O—CH 3
S
hh)
O
F
S
ii)
NH
F
S
jj)
NH
NH 2
S
kk)
NH
NH 2
S
ll)
O
Br
S.
40 . A compound according to claim 39 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>80%.
41 . A compound according to claim 39 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>90%.
42 . A compound according to claim 39 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>95%.
43 . A compound according to claim 39 , wherein said enantiomerically pure compound of formula I has an enantiomeric excess (ee)>97%.
44 . A process according to claim 29 , wherein
one of the groups X 1 , X 2 , X 3 is F, Cl, CF 3 , OCH 3 , NH 2 or Br and the other groups X 1 , X 2 , X 3 are each H;
and
one of the groups Z 1 , Z 2 , Z 3 is O, S or NH and the other groups Z 1 , Z 2 , Z 3 are each —CH 2 —.Cited by (0)
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