Synthesis for heteroarylamine compounds

Details Synthesis for heteroarylamine compounds Synthesis for heteroarylamine compounds

2001-07-11

2003-08-05

Ford, John M. (Department: 1624)

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

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C546S256000

Reexamination Certificate

active

06603000

ABSTRACT:

FIELD OF INVENTION
This invention relates to the synthesis of heteroarylamine compounds which are useful in the production of heteroaryl ureas a key component in pharmaceutically active compounds possessing a heteroaryl urea group.
BACKGROUND OF THE INVENTION
Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production. These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory and autoimmune diseases. Examples of such compounds are reported in WO 99/23091 and in WO 98/52558.
A key step in the synthesis of these compounds is the formation of the urea bond. Various methods have been reported to accomplish this. For example, as reported in the above references, an aromatic or heteroaromatic amine, Ar
1
NH
2
, may be reacted with an aromatic or heteroaromatic isocyanate, Ar
2
NCO, to generate the urea Ar
1
HC(O)NHAr
2
.
If not commercially available, one may prepare the isocyanate by reaction of an aryl or heteroaryl amine Ar
2
—NH
2
with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937) or trichloromethyl chloroformate (diphosgene) (K. Kurita, T. Matsumura and Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanate Ar
2
—NCO, followed by reaction with Ar
1
NH
2
to provide the urea. Other approaches to forming the urea reported in the chemical literature include reaction of a carbamate with an aryl or heteroaryl amine, (see for example B. Thavonekham, Synthesis, 1997, 1189 and T. Patonay et al., Synthetic Communications, 1996, 26, 4253) as shown in Scheme II. U.S. Provisional Application No. 60/143,094 also discloses a process of making heteroaryl ureas by reacting particular carbamate intermediates with the desired arylamine.
U.S. application Ser. No. 09/505,582 and PCT/US00/03865 describe cytokine inhibiting ureas of the following formula:
An intermediate required to prepare preferred compounds described therein has a 1,4-disubstituted naphthalene as Ar
2
and is illustrated in the formula below.
The preparation of these intermediates require the coupling of the naphthyl ring with X. Preferred X include aryl and heteroaryl groups. Previously described methods, including U.S. application Ser. No. 09/505,582 and PCT/US00/03865 achieve the coupling of these aromatic residues by using a coupling reaction catalyzed by a transition metal, such as palladium, in the presence of a ligand, such as triphenyl phosphine. Coupling methods include Stille coupling, requiring the preparation of a tributylstannyl intermediate, or a Suzuki coupling, requiring the preparation of a boronic acid intermediate (Scheme III).
Some steps in these methods require cooling to extreme temperatures (−78° C.). Others require reaction under high pressure, require chromatography to purify the product, or use expensive reagents. For these reasons, these methods are not suitable for large-scale or industrial-scale production.
SUMMARY OF THE INVENTION
It is an object of the invention to provide a novel method of producing heteroaryl amines of the formula(I):
wherein X, Y and Z are described below, the heteroarylamines are useful in the production of heteroaryl ureas as mentioned above.
DETAILED DESCRIPTION OF THE INVENTION
Disclosed herein is a novel process for preparing preferred heteroarylamine intermediates including those heteroarylamine intermediates described in U.S. application Ser. No. 09/505,582, and PCT/US00/03865. The processes described herein have several advantages. They use inexpensive starting materials and reagents, the reactions are run at moderate temperatures, there are no high-pressure reactions and chromatography is not required.
The novel feature of the invention is the construction of naphthalene ring, as exemplified in Scheme I below, from the appropriately substituted carboxylic acid 5, which in turn was synthesized beginning from a novel ester of the formula (II) and a diester such as diethyl succinate. Any of the compounds of the formula (II) as described herein can be synthesized from readily available and cost efficient starting materials such as example 1 below.
This invention provides a novel strategy for the synthesis of heteroarylamine compounds of the formula (I):
wherein:
the naphthyl ring is further optionally substituted by one or more R
1
or R
2
;
X is chosen from
a C
5-8
cycloalkyl and cycloalkenyl optionally substituted with one to two oxo groups or one to three C
1-4
alkyl, C
1-4
alkoxy or C
1-4
alkylamino chains each being branched or unbranched;
aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl and pyrazinyl; each being optionally independently substituted with one to three C
1-4
alkyl, C
1-4
alkoxy, hydroxy, nitro, nitrile, amino, mono- or di-(C
1-3
alkyl)amino, mono- or di-(C
1-3
alkylamino)carbonyl, NH
2
C(O), C
1-6
alkyl-S(O)
m
or halogen;
Y is chosen from
a bond and a C
1-4
saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O)
m
and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C
1-4
alkyl optionally substituted by one or more halogen atoms;
Z is chosen from
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl, each being optionally substituted with one to three halogen, C
1-6
alkyl, C
1-6
alkoxy, hydroxy, amino, mono- or di-(C
1-3
alkyl)amino, C
1-6
alkyl-S(O)
m
, CN, CONH
2
, COOH or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C
1-6
alkyl or C
1-6
alkoxy;
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, thiomorpholinyl sulfonyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylene sulfonyl each being optionally substituted with one to three nitrile, C
1-6
alkyl, C
1-6
alkoxy, hydroxy, amino, mono- or di-(C
1-3
alkyl)amino-C
1-3
alkyl, CONH
2
, phenylamino-C
1-3
alkyl or C
1-3
alkoxy-C
1-3
alkyl;
halogen, C
1-4
alkyl, nitrile, amino, hydroxy, C
1-6
alkoxy, NH
2
C(O), mono- or di(C
1-3
alkyl) aminocarbonyl, mono- or di(C
1-3
alkyl)amino, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C
1-3
alkyl or C
1-5
alkoxyalkyl, pyridinyl-C
1-3
alkyl, imidazolyl-C
1-3
alkyl, tetrahydrofuranyl-C
1-3
alkyl, nitrile-C
1-3
alkyl, carboxamide-C
1-3
alkyl, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen, C
1-6
alkoxy, hydroxy or mono- or di-(C
1-3
alkyl)amino, C
1-6
alkyl-S(O)
m
, or phenyl-S(O)
m
, wherein the phenyl ring is optionally substituted with one to two halogen, C
1-6
alkoxy, hydroxy, halogen or mono- or di-(C
1-3
alkyl)amino;
C
1-6
alkyl-S(O)
m
, and phenyl-S(O)
m
, wherein the phenyl ring is optionally substituted with one to two halogen, C
1-6
alkoxy, hydroxy or mono- or di-(C
1-3
alkyl)amino;
R
1
and R
2
are independently chosen from:
a C
1-6
branched or unbranched alkyl optionally partially or fully halogenated, C
1-4
branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, C
1-3
alkyl-S(O)
m
optionally partially or fully halogenated and phenylsulfonyl;
and
m is 0, 1 or 2.
The process of the invention in its broadest generic aspect is provided below and exemplified in a non-limiting embodiment shown in Scheme 1:
said process comprising:
a) reacting a Z—Y—X—COO—R
x
ester (II) wherein R
x
is C
1-5
alkyl or aryl with a di-alkyl or diaryl ester (III) in a suitable

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