Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-21
2002-12-17
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06495689
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention provides an improved process for preparing intermediates useful in the preparation of tricyclic compounds known as antihistamines and as inhibitors of farnesyl protein transferase (FPT). In particular, the compounds of this invention are useful in the preparation of antihistamines such as those disclosed in U.S. Pat. Nos. 4,282,233 and 5,151,423, and of FPT inhibitors disclosed in PCT Publication No. WO97/23478, published Jul. 3, 1997.
SUMMARY OF THE INVENTION
This invention provides a process for preparing a compound having the formula:
wherein R, R
1
, R
2
, R
3
, and R
4
are independently selected from the group consisting of H, Br, Cl, F, alkyl, or alkoxy, said process comprising:
(A) reacting a compound having the formula
wherein R
A
, R
B
, R
C
, R
D
, and R
E
are independently selected from the group consisting of H, halo, alkyl, or alkoxy, and R
5
is aryl or heteroaryl, with a dehydrating agent to produce an imine having the formula:
(B) hydrolyzing the imine produced in step (A) to produce the compound having formula (I).
This invention also provides novel intermediates having the formula
wherein R
A
, R
B
, R
C
, R
D
, and R
E
are independently selected from the group consisting of H, halo, alkyl, or alkoxy, and R
5
is aryl or heteroaryl.
This invention further provides a process for preparing a compound having the formula:
comprising:
reacting a compound having the formula:
with NH
2
R
5
in the presence of a palladium catalyst, carbon monoxide, a base, and an ether selected from the group consisting of: ethylene glycol dimethyl ether (i.e., CH
3
OCH
2
CH
2
OCH
3
); 2-methoxyethyl ether (i.e, CH
3
OCH
2
CH
2
OCH
2
CH
2
OCH
3
); and triethylene glycol dimethyl ether (i.e, CH
3
OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
OCH
3
), wherein X is H, Br, Cl, or F, and R
5
is aryl or heteroaryl. The compounds of formula III can be reacted with compounds having the formula
wherein U is Br or Cl and R
B
, R
C
, R
D
, and R
E
are as defined above, in the presence of a strong base to provide compounds having the formula II, wherein R
A
is Br, Cl or F.
DETAILED DESCRIPTION
As used herein, the term “alkyl” means straight or branched hydrocarbon chains of 1 t o 6 carbon atoms.
“Halo” refers to fluorine, chlorine, bromine or iodine radicals.
“Aryl” means phenyl; benzyl; or a polyaromatic ring (e.g., napthyl), each of the foregoing being optionally substituted by 1 to 3 substituents independently selected from the group consisting of C
1
to C
6
alkyl, C
1
to C
6
alkoxy, and halo.
“Heteroaryl” means a 5- or 6-membered aromatic ring having one or two nitrogen atoms, e.g., pyridyl, pyrimidyl, imidazolyl or pyrrolyl.
“Ac” refers to acetyl.
“Et” refers to —C
2
H
5
.
“Ph” refers to phenyl.
The present process is a significant improvement over prior art processes for preparing the tricyclic ketone of formula (I). For example, U.S. Pat. No. 4,731,447 discloses the following process:
In contrast to this process, in which the product from the hydrolysis step must be isolated and purified prior to the next step (the Friedel-Crafts cyclization), the present process for preparing compounds of formula (I) offers a more simplified synthesis that can be carried out in one pot.
PCT Publication WO96/31478, published Oct. 10, 1996, discloses the following process:
In this process, a tert-butyl substituted compound is reacted with POCl
3
in toluene at reflux to form the nitrile, the nitrile is reacted with CF
3
SO
3
H to form an imine, and the imine is hydrolyzed to form the ketone. Again, in contrast to this process, which is a two-pot process, because the nitrile must be isolated and purified prior to reaction with CF
3
SO
3
H, the present process can be carried out in one pot.
The compounds prepared by the present process are useful as intermediates in the procedures described in PCT Publication No. WO97/23478 and U.S. Pat. No. 5,151,423 to obtain the desired compounds wherein the piperidinyl ring is N-substituted. Using those procedures, the compounds of the present invention are reacted with a substituted piperidine of the formula
wherein L
1
is a leaving group selected from the group consisting of Cl and Br, to obtain a compound of the formula
This compound is converted to the corresponding piperidylidene, the nitrogen is deprotected, and the compound is reduced to the piperidyl form. The piperidinyl nitrogen can then be reacted with a variety of compounds, e.g., an acyl compound such as an ester or acyl chloride to form the desired amide.
Alternatively, when chiral FPT inhibitors, such as those described in PCT Publication No. WO97/23478 are desired, the compounds made by the present process may be reduced by treating with Zn and 2 equivalents of trifluoroacetic acid in acetic anhydride to remove the carbonyl oxygen. The reduced compound can then be reacted with about 3.5 equivalents of lithium dilsopropylamide, about 1.3 equivalents of quinine or a compound of the formula
about 1.2 equivalents of 4-mesyl-N-Boc-piperidine, and about 1.1 equivalents of water in toluene to form the following chiral compound:
This chiral compound can then be deprotected by treatment with acid (e.g., H
2
SO
4
), reacted with a suitable acid (e.g., N-acetyl-L-phenylalanine) to form a stable salt, and the stable salt can then be acylated with the desired acyl group.
Compounds of formula (I) can be converted to other compounds of formula (I) by methods known in the art, i.e., compounds wherein R, R
1
, R
2
, R
3
or R
4
is hydrogen can be converted to the corresponding compounds wherein R, R
1
, R
2
, R
3
or R
4
is halogen. Such procedures are shown in WO97/23478, wherein, for example, a compound wherein R
2
is Cl, R
1
, R
3
and R
4
are hydrogen and the piperidinyl nitrogen is protected by a —COOCH
2
CH
3
group is reacted with KNO
3
, the resulting nitro-substituted compound is reduced to the amine, the resulting compound is reacted with Br
2
and the amino group is removed to obtain a compound wherein R
2
is Cl, R
4
is Br and R
1
and R
3
are hydrogen.
Preferred compounds of formula (I) are those in which R
2
is Cl, Br or F, more preferably Cl or Br, most preferably, Cl. Another group of preferred compounds are those in which R, R
1
, R
3
and R
4
are each hydrogen, and R
2
is Cl, Br or F, more preferably Cl or Br, most preferably, Cl. Still another group of preferred compounds are those in which R
1
, R
3
, and R
4
are each hydrogen and R and R
2
are independently selected from Cl, Br and F, more preferably from Cl and Br, and most preferably, in which R is Br and R
2
is Cl. Yet another group of preferred compounds are those in which R
1
and R
3
are each hydrogen, and R, R
2
and R
4
are independently selected from Cl, Br and F, more preferably from Cl and Br, and most preferably, in which R is Br, R
2
is Cl and R
4
is Br. These preferred compounds may be made from compounds of formula (II) having correspondingly positioned halo substituents. It will be appreciated by those skilled in the art that when the compounds of formula (II) have iodo substituents, those iodo substituents are displaced by H when the present process is carried out.
R
5
is preferably aryl, most preferably, phenyl, 4-methoxyphenyl, 4-chlorophenyl, or 3-chlorophenyl.
The dehydrating agent is preferably selected from the group consisting of P
2
O
5
, P
2
O
3
, P
2
O
3
Cl
4
, POCl
3
, PCl
3
, PCl
5
, C
6
H
6
P(O)Cl
2
(phenyl phosphonic dichloride), PBr
3
, PBr
5
, SOCl
2
, SOBr
2
, COCl
2
, H
2
SO
4
, super acids, and anhydrides of super acids. More preferably, the dehydrating agent is selected from P
2
O
5
, P
2
O
3
Cl
4
, PBr
3
, PCl
5
, POCl
3
, C
6
H
6
P(O)Cl
2
, (CF
3
SO
2
)
2
O, and (CF
3
CF
3
SO
2
)
2
O.
Preferably, step (A) of our process is carried out by contacting the reaction mixture of the compound of formula (II) and the dehydrating agent with an additional agent selected from the group consisting of a Lewis acid or a super acid. Non-limitative examples of Lewis acids include AlCl
3
, FeCl
3
, ZnCl
2
, AlBr
3
, ZnBr
2
, TiCl
4
, and SnCl
4
. Of the
Bernard Charles F.
Casey Michael
Chen Frank Xing
Grogan Denise C.
Poirier Marc
Lee William Y.
Mann Arthur
Morris Patricia L.
Schering Corporation
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