Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-05-14
2001-05-01
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S513000, C540S593000
Reexamination Certificate
active
06225465
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to processes and intermediates for preparing pharmaceutically active compounds. More, particularly, this invention relate to the aminocarbonylation of benzazepines and benzodiazepines.
BACKGROUND OF THE INVENTION
Tetraydro-1-benzazepines and tetrahydro-1,4-benzodiazepines form the core structure of a variety of pharmaceutically useful compounds. In particular, WO 93/00095 (PCT/US92/05463) and WO 94/14776 (PCT/US93/12436) disclose 7-aminocarbonyl tetrahydro-1-benzazepines and tetrahydro-1,4-benzodiazepines which are reported, to be inhibitors of the fibrinogen and vitronectin receptors and useful as inhibitors of platelet aggregation, osteoporosis, angiogenesis and cancer metastasis.
Methods to prepare such compounds typically employ a trisubstituted phenyl derivative as a starting material. The trisubstituted phenyl derivative incorporates two substituents to form the azepine ring, and a third substituent to introduce the 7-carbonyl substituent. Such starting materials may be difficult and costly to obtain, and may limit the chemistry which may be employed to form the azepine ring,. Prior processes generally introduce the aminocarbonyl group into the molecule via a 7-carboxyl group which is coupled to an amino group by conventional methods for forming amide bonds. Methods disclosed in WO 93/00095 and WO 94/14776 are exemplary.
We have now discovered new useful intermediates and a new process for preparing certain substituted 7-aminocarbonyl benzazepines and benzodiazepines. The new process uses a simple disubstituted benzene as a starting material, and also introduces the aminocarbonyl function in a single palladium catalyzed aminocarbonylation step. This process is more efficient than prior processes for preparing such compounds and adaptable to large scale synthesis.
Various types of palladium catalyzed reactions with aryl and vinyl halides are known to the art, and the problems attendant to their use with electron rich systems have been studied. For instance, Ziegler et al.,
J. Org. Chem.
1978, 43, 2941, report that highly activated aryl bromides, such as bromo-anilines, reacted very poorly in palladium catalyzed vinylic substitution reactions, but observed that some improvement was noted when aryl iodides were used, and when the palladium ligand was an tri-o-tolyl phosphine rather than a triphenylphosphine. Cortese et al.,
J. Org. Chem.
1978 43, 2952, report a palladium catalyzed vinylic substitution reaction on an o-iodo aniline.
Valentine et al.,
J. Org. Chem.
1981, 4614, suggest that the unreactivity of o-bromo-anilines toward carbonylation may be overcome by acetylation of the anilino amine group. Kraus et al.,
Tet. Lett.
1994 49, 9189 disclose an alkoxycarbonylation of a 7-triflic-tetrahydro-1,4benzodiazpine.
Heck et al.,
J. Org. Chem.
1974, 39, 3327, report typical conditions for aminocarbonylation reactions on aromatic systems; however, they do not report conditions for aminocarbonylation of electron-rich systems such as halo-anilines. Certain o-bromoanilines have been reported to undergo aminocarbonylation in low yield by Mori et al.,
Heterocycles
1981, 16 1491, and Perry,
Chemtech
Feb. 18, 1994 reports the use of iodo-aryl and amino-aryl monomers in a palladium catalyzed carbonylation reaction to prepare aramide polymers.
SUMMARY OF THE INVENTION
It is an object of is invention to provide a new and efficient process for the preparation of 7-aminocarbontyl benzazepines and benzodiazepines of formula (I):
as hereinafter defined.
One aspect of this invention is an intermediate compound of formula (II):
as hereinafter defined, wherein R
10
is Br or I.
Another aspect of this invention are processes for preparing a compound of formula (II), wherein R
10
is I or Br, from a compound of formula (IV):
wherein R
2
and A
1
are as defined for formula (I).
DETAILED DESCRIPTION
This invention comprises a process for preparing compounds of formula (I):
wherein
A
1
is NR
1
or CHR
1
;
R
1
is H, T—C
1-6
alyl, T—C
1-6
oxoalkyl, T—C
2-6
alkenyl, T—C
3-4
oxoalkenyl, T—C
3-4
oxoalkynyl, T—C
3-4
alkynyl, C
3-6
cycloalkyl, Ar or Het, optionally substituted by one or more of halo, —OR′, —CN, —NR′
2
, —NO
2
, —CF
3
, —CO
2
R′, —CONR′
2
, Ar—C
0-6
alkyl or Het-C
0-6
alkyl, wherein T is H, C
3-6
cycloalkyl, Het or Ar.
R
2
is CH
2
CO
2
R
3
;
R
3
is H, C
1-6
alkyl, C
3-7
cycloalkyl-C
0-4
alkyl or Ar—C
0-4
alkyl;
R
5
is W—(CR′
2
)
q
—Z—(CHR′)
m
, and
R
6
is H, C
1-6
alkyl, Ar—C
0-6
alkyl, Het-C
0-6
alkyl, or C
3-6
cycloalkyl-C
0-6
alkyl, or
R
5
and R
6
together form a five- or six-membered Het ring which is substituted by W;
W is R
9
R″N—, R′R″NR′N—, R′R″NR′NCO—, R′
2
NR′NC(═NR′)—, R′ONR′C(═NR′)—,
R′ is H, C
1-6
alkyl, C
3-7
cycloalkyl-C
0-4
alkyl or Ar—C
0-4
alkyl;
R″ is R′, —C(O)R′ or —C(O)OR″′;
R″′ is H, C
1-6
alkyl or Ar—C
0-4
alkyl;
R
7
is R′, —CF
3
, —SR′, or —OR′;
R
8
is R′, C(O)R′, CN, NO
2
, SO
2
R′ or C(O)OR
15
;
R
9
is H, C
1-6
alkyl, C
3-7
cycloalkyl-C
0-4
alkyl, Het-C
0-4
alkl or Ar—C
0-4
alkyl;
X is N═CR′, C(O) or O;
Y is absent, S or O;
Z is (CH
2
)
t
, Het, Ar or C
3-7
cycloalkyl;
q is 0 to 3;
m is 0 to 2; and
t is 0 to 2;
which process comprises:
reacting a compound of formula (II):
wherein
A
1
and R
2
are as defined above for formula (I); and
R
10
is Cl, Br, I, FSO
3
—, ClSO
3
— or CF
3
SO
3
—;
with a Pd catalyst, carbon monoxide and an amine of the formula (III)
wherein R
5
and R
6
are defined as above in formula (I) except that any basic nitrogen group in R
5
or R
6
is protected, and thereafter removing any protecting groups.
Suitably R
1
is H, C
1-6
alkyl or Ar—C
1-4
alkyl. Preferably R
1
is H. methyl, ethyl, i-propyl, benzyl or phenylethyl. Most preferably R
1
is methyl.
Suitably R
3
is C
1-6
alkyl, Ar or Ar—C
1-4
alkyl. Preferably R
3
is methyl, t-butyl or benzyl.
Preferably, R
10
is Br or I.
Typically the process is carried out by combining the compound of formula (II) with the palladium catalyst, the amine of formula (III) and a base in a suitable solvent and heating the reactants under an Atmosphere of carbon monoxide.
Any stable palladium(0) or palladium(II) source is a suitable catalyst for the aminocarbonylation. (Ph
3
P)
4
Pd, bis(dibenzylideneacetone)Pd(0), bis(di-(1,2-diphenylphosphino)ethane)Pd(O), PdCl
2
, Pd(OAc)
2
, (Ph
3
P)
2
PdCl
2
or (Ph
3
P)
2
Pd(OAc)
2
are typical.
However, tetrahydro-benzazepine/benzodiazepines in which a bromide is para to an azepine —NH— are electron rich and, like p-bromo anilines, react poorly in aminocarbonylation reactions under the normal conditions reported for such reactions. It has now been discovered that catalyst loading and the addition of a suitable ligand for the palladium are important parameters in such reactions. For instance, at a catalyst loading of about 20 mole % of (Ph
3
P)
4
Pd and 25 mole % of triphenyl phosphine, the aminocarbonylation reaction is complete after 5-6 h; whereas, at a catalyst loading of 5 mole % the reaction does not proceed at all. A loading of about 15-100 mole % is suitable, typically about 20-25 mole % produces optimal results. Triphenyl phosphine is a preferred ligand for use in the reaction, as it stabilizes and solubilizes the palladium(0) and provides an active complex. Other ligands may be used, but they generally provide either too much stabilization so that the complex is inert, or do not provide enough stabilization so that the metal precipitates.
In spite of the advances realized by the combined use of high catalyst loadings and added Pd ligand, the cost of the palladium required for the high loading is a serious drawback to the use of such conditions for an industrial process. Thus, in another aspect, this invention is also an improvement which comprises conducting the reaction in the presence of a small amount of a reducing agent. Thus, if the reaction is run in the pre
Etridge Stephen K.
Hayes Jerome
Walsgrove Timothy Charles
Wells Andrew S.
Han William T.
Kifle Bruck
King William T.
Kinzig Charles M.
SmithKline Beecham Plc
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