U.S. patent application number 14/705457 was filed with the patent office on 2015-08-20 for process for the preparation of c-fms kinase inhibitors.
The applicant listed for this patent is Janssen Pharmaceutica NV. Invention is credited to Koen Johan HERMAN, Krzysztof KOLODZIEJCZYK, Alfred Elisabeth STAPPERS, Christopher A. TELEHA.
Application Number | 20150232439 14/705457 |
Document ID | / |
Family ID | 48980367 |
Filed Date | 2015-08-20 |
United States Patent
Application |
20150232439 |
Kind Code |
A1 |
KOLODZIEJCZYK; Krzysztof ;
et al. |
August 20, 2015 |
PROCESS FOR THE PREPARATION OF C-FMS KINASE INHIBITORS
Abstract
The present invention is directed to a process for the
preparation of heterocyclic derivatives of formula I ##STR00001##
wherein J, X, Z, and R.sup.2 are as defined herein. Such compounds
are useful as protein tyrosine kinase inhibitors, more particularly
inhibitors of c-fms kinase.
Inventors: |
KOLODZIEJCZYK; Krzysztof;
(Reading, GB) ; STAPPERS; Alfred Elisabeth;
(Oud-Turnhout, BE) ; TELEHA; Christopher A.; (Fort
Washington, PA) ; HERMAN; Koen Johan; (Vosselaar,
BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutica NV |
Beerse |
|
BE |
|
|
Family ID: |
48980367 |
Appl. No.: |
14/705457 |
Filed: |
May 6, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13959158 |
Aug 5, 2013 |
9029352 |
|
|
14705457 |
|
|
|
|
61680446 |
Aug 7, 2012 |
|
|
|
Current U.S.
Class: |
549/423 |
Current CPC
Class: |
A61P 25/18 20180101;
A61P 11/00 20180101; A61P 35/00 20180101; C07D 309/30 20130101;
A61P 31/00 20180101; A61P 35/04 20180101; A61P 11/06 20180101; A61P
13/08 20180101; A61P 9/10 20180101; A61P 25/28 20180101; A61P 27/02
20180101; A61P 19/02 20180101; A61P 17/06 20180101; C07F 7/10
20130101; A61P 25/04 20180101; A61P 43/00 20180101; A61P 19/00
20180101; A61P 1/18 20180101; A61P 1/04 20180101; C07D 405/14
20130101; A61P 3/10 20180101; A61P 13/12 20180101; A61P 35/02
20180101; A61P 25/00 20180101; A61P 31/18 20180101; A61P 37/06
20180101; A61P 19/10 20180101; A61P 29/00 20180101; A61P 3/00
20180101; A61P 15/00 20180101 |
International
Class: |
C07D 309/30 20060101
C07D309/30 |
Claims
1-75. (canceled)
76. A process for the preparation of a compound of formula (XX)
##STR00091## comprising ##STR00092## reacting a compound of formula
(XXII) is reacted with NfsulphF, in the presence of DBU; in an
organic solvent; at a temperature of from about 0.degree. C. to
about room temperature; to yield the corresponding compound of
formula (XX).
77. A process according to claim 76, wherein the NfsulphF is
present in an amount of form about 1.0 molar equivalents to about
1.5 molar equivalents.
78. A process according to claim 77, wherein the NfsulphF is
present in an amount of form about 1.1 molar equivalents to about
1.3 molar equivalents.
79. A process according to claim 78, wherein the NfsulphF is
present in an amount of about 1.2 molar equivalents.
80. A process according to claim 76, wherein the DBU is present in
an amount in the range of from about 1.1 molar equivalents to about
4.0 molar equivalents.
81. A process according to claim 80, wherein the DBU is present in
an amount of from about 1.5 molar equivalents to about 2.5 molar
equivalents.
82. A process according to claim 81, wherein the DBU is present in
an amount of about 2.0 molar equivalents.
83. A process according to claim 76, wherein the organic solvent is
selected from the group consisting of 2-methyl-THF, THF and
toluene.
84. A process according to claim 83, wherein the organic solvent is
2-methyl-THF.
85. A process according to claim 76, wherein the compound of
formula (XXII) is reacted with NfsulphF at a temperature of from
about 0.degree. C. to about room temperature.
86. A process according to claim 85, wherein the compound of
formula (XXII) is reacted with NfsulphF at about room temperature.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 61/680,446, filed Aug. 7, 2012, which is
hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to a process for the
preparation of heterocyclic derivatives useful as protein tyrosine
kinase inhibitors, more particularly inhibitors of c-fms
kinase.
BACKGROUND OF THE INVENTION
[0003] Protein kinases are enzymes that serve as key components of
signal transduction pathways by catalyzing the transfer of the
terminal phosphate from adenosine 5'-triphosphate (ATP) to the
hydroxy group of tyrosine, serine and threonine residues of
proteins. As a consequence, protein kinase inhibitors and
substrates are valuable tools for assessing the physiological
consequences of protein kinase activation. The over-expression or
inappropriate expression of normal or mutant protein kinases in
mammals has been demonstrated to play significant roles in the
development of many diseases, including cancer and diabetes.
[0004] Protein kinases can be divided into two classes: those which
preferentially phosphorylate tyrosine residues (protein tyrosine
kinases) and those which preferentially phosphorylate serine and/or
threonine residues (protein serine/threonine kinases). Protein
tyrosine kinases perform diverse functions ranging from stimulation
of cell growth and differentiation to arrest of cell proliferation.
They can be classified as either receptor protein tyrosine kinases
or intracellular protein tyrosine kinases. The receptor protein
tyrosine kinases, which possess an extracellular ligand binding
domain and an intracellular catalytic domain with intrinsic
tyrosine kinase activity, are distributed among 20 subfamilies.
[0005] Receptor tyrosine kinases of the epidermal growth factor
("EGF") family, which includes HER-1, HER-2/neu and HER-3
receptors, contain an extracellular binding domain, a transmembrane
domain and an intracellular cytoplasmic catalytic domain. Receptor
binding leads to the initiation of multiple intracellular tyrosine
kinase dependent phosphorylation processes, which ultimately
results in oncogene transcription. Breast, colorectal and prostate
cancers have been linked to this family of receptors.
[0006] Insulin receptor ("IR") and insulin-like growth factor I
receptor ("IGF-1R") are structurally and functionally related but
exert distinct biological effects. IGF-1R over-expression has been
associated with breast cancer.
[0007] Platelet derived growth factor ("PDGF") receptors mediate
cellular responses that include proliferation, migration and
survival and include PDGFR, the stem cell factor receptor (c-kit)
and c-fms. These receptors have been linked to diseases such as
atherosclerosis, fibrosis and proliferative vitreoretinopathy.
[0008] Fibroblast growth factor ("FGR") receptors consist of four
receptors which are responsible for the production of blood
vessels, for limb outgrowth, and for the growth and differentiation
of numerous cell types.
[0009] Vascular endothelial growth factor ("VEGF"), a potent
mitogen of endothelial cells, is produced in elevated amounts by
many tumors, including ovarian carcinomas. The known receptors for
VEGF are designated as VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3
(Flt-4). A related group of receptors, tie-1 and tie-2 kinases,
have been identified in vascular endothelium and hematopoietic
cells. VEGF receptors have been linked to vasculogenesis and
angiogenesis.
[0010] Intracellular protein tyrosine kinases are also known as
non-receptor protein tyrosine kinases. Over 24 such kinases have
been identified and have been classified into 11 subfamilies. The
serine/threonine protein kinases, like the cellular protein
tyrosine kinases, are predominantly intracellular.
[0011] Diabetes, angiogenesis, psoriasis, restenosis, ocular
diseases, schizophrenia, rheumatoid arthritis, cardiovascular
disease and cancer are exemplary of pathogenic conditions that have
been linked with abnormal protein tyrosine kinase activity. Thus, a
need exists for selective and potent small-molecule protein
tyrosine kinase inhibitors.
[0012] Illig, C., et al., in US Patent Publication US2009/0105296
A1, published Apr. 23, 2009 discloses c-fms kinase inhibitors of
the following structural formula
##STR00002##
and pharmaceutically acceptable salts thereof; and a process for
their preparation. Illig, C., et al., in Scheme 1, teach
preparation of the derivatives of the above structural formula
comprising reacting a compound of formula 1-5
##STR00003##
with a heterocyclic acid P.sup.1--WCOOH (or a corresponding salt
thereof P.sup.1--WCOOM.sup.2, where M.sup.2 is Li, Na or K) where
P.sup.1 is an optional protecting group (for example
2-(trimethylsilyl)ethoxymethyl (SEM) such as when W is imidazole,
triazole, pyrrole, or benzimidazole). The coupling can be carried
out according to standard procedures for amide bond formation or by
reaction with acid chlorides P.sup.1--WCOCI or activated esters
P.sup.1--WCO.sub.2R.sup.q (where R.sup.q is a leaving group such as
pentafluorophenyl or N-succinimide).
[0013] There remains a need for a process for the preparation of
compounds of formula (I), wherein the said process is suitable for
large scale manufacture.
SUMMARY OF THE INVENTION
[0014] The present invention is directed to a process for the
preparation of compounds of formula (XII)
##STR00004##
wherein
##STR00005##
is selected from the group consisting of
##STR00006##
each R.sup.4 is independently selected from the group consisting of
hydrogen, F, Cl, Br, I, --OH, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--SC.sub.(1-4)alkyl, --SOC.sub.(1-4)alkyl,
--SO.sub.2C.sub.(1-4)alkyl, --C.sub.(1-3)alkyl, --CO.sub.2R.sup.d,
--CONR.sup.eR.sup.f, --CCR.sup.g and --CN;
[0015] wherein R.sup.d is selected from the group consisting of H
and --C.sub.(1-3)alkyl; R.sup.e is selected from the group
consisting of H and --C.sub.(1-3)alkyl; R.sup.f is selected from
the group consisting of H and --C.sub.(1-3)alkyl; and R.sup.g is
selected from the group consisting of hydrogen, --CH.sub.2OH and
--CH.sub.2CH.sub.2OH;
[0016] J is selected from the group consisting of CH and N;
[0017] R.sup.2 is selected from the group consisting of cycloalkyl,
spiro-substituted cycloalkenyl, thiophenyl, dihydrosulfonopyranyl,
phenyl, furanyl, tetrahydropyridyl and dihydropyranyl; any of which
may be independently substituted with one or two of each of the
following: chloro, fluoro, hydroxy, and C.sub.(1-4)alkyl;
[0018] Z is selected from the group consisting of hydrogen, F, Cl
and CH.sub.3;
[0019] X is selected from the group consisting of
##STR00007## ##STR00008## ##STR00009##
[0020] wherein R.sup.w is selected from the group consisting of
hydrogen, --C.sub.(1-4)alkyl, --CO.sub.2C.sub.(1-4)alkyl,
--CONH.sub.2, --CONHC.sub.(1-4)alkyl, --CON(C.sub.(1-4)alkyl).sub.2
and COC.sub.(1-4)alkyl.
[0021] or a tautomer or pharmaceutically acceptable salt thereof;
comprising
##STR00010##
reacting a compound of formula (X) with a compound of formula (XI)
or mixture of SEM protected regioisomers thereof; in the presence
of carbon monoxide gas or a source of carbon monoxide; in the
presence of an organic or inorganic base; in the presence of a
suitably selected coupling system comprising a palladium compound
and a ligand; in an organic solvent; at a temperature in the range
of from about 60.degree. C. to about 120.degree. C. to yield the
corresponding compound of formula (XII).
[0022] The present invention is further directed to a process for
the preparation of compounds of formula (I)
##STR00011##
[0023] wherein
[0024] W is selected from the group consisting of
##STR00012##
[0025] each R.sup.4 is independently selected from the group
consisting of hydrogen, F, Cl, Br, I, --OH, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --SC.sub.(1-4)alkyl, --SOC.sub.(1-4)alkyl,
--SO.sub.2C.sub.(1-4)alkyl, --C.sub.(1-3)alkyl, --CO.sub.2R.sup.d,
--CONR.sup.eR.sup.f, --CCR.sup.g and --CN;
[0026] wherein R.sup.d is selected from the group consisting of H
and --C.sub.(1-3)alkyl; R.sup.e is selected from the group
consisting of H and --C.sub.(1-3)alkyl; R.sup.f is selected from
the group consisting of H and --C.sub.(1-3)alkyl; and R.sup.g is
selected from the group consisting of hydrogen, --CH.sub.2OH and
--CH.sub.2CH.sub.2OH;
[0027] J is selected from the group consisting of CH and N;
[0028] R.sup.2 is selected from the group consisting of cycloalkyl,
spiro-substituted cycloalkenyl, thiophenyl, dihydrosulfonopyranyl,
phenyl, furanyl, tetrahydropyridyl and dihydropyranyl; any of which
may be independently substituted with one or two of each of the
following: chloro, fluoro, hydroxy, and C.sub.(1-4)alkyl;
[0029] Z is selected from the group consisting of hydrogen, F, Cl
and CH.sub.3;
[0030] X is selected from the group consisting of
##STR00013## ##STR00014## ##STR00015##
wherein R.sup.w is selected from the group consisting of hydrogen,
--C.sub.(1-4)alkyl, --CO.sub.2C.sub.(1-4)alkyl, --CONH.sub.2,
--CONHC.sub.(1-4)alkyl, --CON(C.sub.(1-4)alkyl).sub.2 and
--COC.sub.(1-4)alkyl.
[0031] or a tautomer or pharmaceutically acceptable salt thereof;
comprising
##STR00016##
reacting a compound of formula (X) with a compound of formula (XI)
or mixture of SEM protected regioisomers thereof; wherein
##STR00017##
is selected from the group consisting of
##STR00018##
in the presence of carbon monoxide gas or a source of carbon
monoxide; in the presence of an organic or inorganic base; in the
presence of a suitably selected coupling system comprising a
palladium compound and a ligand; in an organic solvent; at a
temperature in the range of from about 60.degree. C. to about
120.degree. C. to yield the corresponding compound of formula
(XII);
##STR00019##
[0032] de-protecting the compound of formula (XII), to yield the
corresponding compound of formula (I).
[0033] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (XII-S)
##STR00020##
[0034] or a tautomer or pharmaceutically acceptable salt thereof;
comprising
##STR00021##
reacting a compound of formula (X-S) with a compound of formula
(XI-S); in the presence of carbon monoxide gas or a source of
carbon monoxide; in the presence of an organic or inorganic base;
in the presence of a suitably selected coupling system comprising a
palladium compound and a ligand; in an organic solvent; at a
temperature in the range of from about 60.degree. C. to about
120.degree. C. to yield the corresponding compound of formula
(XII-S).
[0035] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-S)
##STR00022##
[0036] (also known
4-cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetra-
hydro-2H-pyran-4-yl)pyridin-3-yl)-1H-imidazole-2-carboxamide) or a
tautomer or pharmaceutically acceptable salt thereof;
comprising
##STR00023##
reacting a compound of formula (X-S) with a compound of formula
(XI-S); in the presence of carbon monoxide gas or a source of
carbon monoxide; in the presence of an organic or inorganic base;
in the presence of a suitably selected coupling system comprising a
palladium compound and a ligand; in an organic solvent; at a
temperature in the range of from about 60.degree. C. to about
120.degree. C. to yield the corresponding compound of formula
(XII-S)
##STR00024##
[0037] de-protecting the compound of formula (XII-S), to yield the
corresponding compound of formula (I-S).
[0038] The present invention is further directed to a process for
the preparation of a compound of formula (XX)
##STR00025##
also known as 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate; comprising
##STR00026##
reacting the compound of formula (XXII) with nonafluorosulfonyl
fluoride (NfsulphF); in the presence of DBU; in an organic solvent;
at a temperature in the range of from about 0.degree. C. to about
room temperature; to yield the corresponding compound of formula
(XX).
[0039] The present invention is further directed to a product
prepared according to any of the processes described herein.
[0040] Illustrative of the invention is a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and a
product prepared according to any of the processes described
herein. An illustration of the invention is a pharmaceutical
composition made by mixing a product prepared according to any of
the processes described herein and a pharmaceutically acceptable
carrier. Illustrating the invention is a process for making a
pharmaceutical composition comprising mixing a product prepared
according to any of the processed described herein and a
pharmaceutically acceptable carrier.
[0041] Exemplifying the invention are methods of treating a
disorder mediated by c-fms kinase (selected from the group
consisting of osteoporosis, Paget's disease, rheumatoid arthritis
other forms of inflammatory arthritis, osteoarthritis, prosthesis
failure, osteolytic sarcoma, myeloma, tumor metastasis to bone,
ovarian cancer, uterine cancer, breast cancer, prostate cancer,
lung cancer, colon cancer, stomach cancer, hairy cell leukemia;
metastasis from ovarian cancer, uterine cancer, breast cancer,
prostate cancer, lung cancer, colon cancer, stomach cancer, or
hairy cell leukemia; glomerulonephritis, inflammatory bowel
disease, sarcoidosis, congestive obstructive pulmonary disease,
idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection,
psoriasis, diabetes, tumor related angiogenesis, age-related
macular degeneration, diabetic retinopathy, restenosis,
schizophrenia, Alzheimer's dementia; pain, skeletal pain caused by
tumor metastasis or osteoarthritis, visceral pain, inflammatory
pain, neurogenic pain; an autoimmune disease, systemic lupus
erythematosus, rheumatoid arthritis, other forms of inflammatory
arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis and
uveitis; preferably rhematoid arthritis) comprising administering
to a subject in need thereof a therapeutically effective amount of
a compound prepared according to any of the processes described
herein, or a pharmaceutical composition comprising a compound
prepared according to any of the processes described herein, as
described above.
[0042] In another embodiment, the present invention is directed to
a product prepared according to any of the processes described
herein, for use in the treatment of a disorder selected from the
group consisting of osteoporosis, Paget's disease, rheumatoid
arthritis other forms of inflammatory arthritis, osteoarthritis,
prosthesis failure, osteolytic sarcoma, myeloma, tumor metastasis
to bone, ovarian cancer, uterine cancer, breast cancer, prostate
cancer, lung cancer, colon cancer, stomach cancer, hairy cell
leukemia; metastasis from ovarian cancer, uterine cancer, breast
cancer, prostate cancer, lung cancer, colon cancer, stomach cancer,
or hairy cell leukemia; glomerulonephritis, inflammatory bowel
disease, sarcoidosis, congestive obstructive pulmonary disease,
idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection,
psoriasis, diabetes, tumor related angiogenesis, age-related
macular degeneration, diabetic retinopathy, restenosis,
schizophrenia, Alzheimer's dementia; pain, skeletal pain caused by
tumor metastasis or osteoarthritis, visceral pain, inflammatory
pain, neurogenic pain; an autoimmune disease, systemic lupus
erythematosus, rheumatoid arthritis, other forms of inflammatory
arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis and
uveitis. Preferably, the disorder mediated by c-fms kinase is
rhematoid arthritis.
[0043] In an embodiment, the present invention is directed to a
product prepared according to any of the processes described
herein, for use as a medicament; preferably for use as a medicament
for the treatment of rheumatoid arthritis.
[0044] Another example of the invention is the use of a product
prepared according to any of the processes described herein, in the
preparation of a medicament for treating: (a) osteoporosis, (b)
Paget's disease, (c) rheumatoid arthritis, (d) other forms of
inflammatory arthritis, (e) osteoarthritis, (f) prosthesis failure,
(g) osteolytic sarcoma, (h) myeloma, (i) tumor metastasis to bone,
(j) ovarian cancer, (k) uterine cancer, (l) breast cancer, (m)
prostate cancer, (n) lung cancer, (o) colon cancer, (p) stomach
cancer, (q) hairy cell leukemia; (r) metastasis from ovarian
cancer, uterine cancer, breast cancer, prostate cancer, lung
cancer, colon cancer, stomach cancer, or hairy cell leukemia; (s)
glomerulonephritis, (t) inflammatory bowel disease, (u)
sarcoidosis, (v) congestive obstructive pulmonary disease, (w)
idiopathic pulmonary fibrosis, (x) asthma, (y) pancreatitis, (z)
HIV infection, (aa) psoriasis, (ab) diabetes, (ac) tumor related
angiogenesis, (ad) age-related macular degeneration, (ae) diabetic
retinopathy, (af) restenosis, (ag) schizophrenia, (ah) Alzheimer's
dementia; (ai) pain, (aj) skeletal pain caused by tumor metastasis
or osteoarthritis, or (ak) visceral pain, (al) inflammatory pain,
(am) neurogenic pain; (an) an autoimmune disease, (ao) systemic
lupus erythematosus, (ap) rheumatoid arthritis, (aq) other forms of
inflammatory arthritis, (ar) psoriasis, (as) Sjogren's syndrome,
(at) multiple sclerosis and (au) uveitis, in a subject in need
thereof.
[0045] In another example, the present invention is directed to a
product prepared according to any of the processes described
herein, for use in a methods for treating a disorder mediated by
c-fms kinase (selected from the group consisting of osteoporosis,
Paget's disease, rheumatoid arthritis other forms of inflammatory
arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma,
myeloma, tumor metastasis to bone, ovarian cancer, uterine cancer,
breast cancer, prostate cancer, lung cancer, colon cancer, stomach
cancer, hairy cell leukemia; metastasis from ovarian cancer,
uterine cancer, breast cancer, prostate cancer, lung cancer, colon
cancer, stomach cancer, or hairy cell leukemia; glomerulonephritis,
inflammatory bowel disease, sarcoidosis, congestive obstructive
pulmonary disease, idiopathic pulmonary fibrosis, asthma,
pancreatitis, HIV infection, psoriasis, diabetes, tumor related
angiogenesis, age-related macular degeneration, diabetic
retinopathy, restenosis, schizophrenia, Alzheimer's dementia; pain,
skeletal pain caused by tumor metastasis or osteoarthritis,
visceral pain, inflammatory pain, neurogenic pain; an autoimmune
disease, systemic lupus erythematosus, rheumatoid arthritis, other
forms of inflammatory arthritis, psoriasis, Sjogren's syndrome,
multiple sclerosis and uveitis), in a subject in need thereof.
[0046] In another embodiment, the present invention is directed to
a product prepared according to any of the processes described
herein, for the treatment of a disorder mediated by c-fms kinase
(selected from the group consisting of osteoporosis, Paget's
disease, rheumatoid arthritis other forms of inflammatory
arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma,
myeloma, tumor metastasis to bone, ovarian cancer, uterine cancer,
breast cancer, prostate cancer, lung cancer, colon cancer, stomach
cancer, hairy cell leukemia; metastasis from ovarian cancer,
uterine cancer, breast cancer, prostate cancer, lung cancer, colon
cancer, stomach cancer, or hairy cell leukemia; glomerulonephritis,
inflammatory bowel disease, sarcoidosis, congestive obstructive
pulmonary disease, idiopathic pulmonary fibrosis, asthma,
pancreatitis, HIV infection, psoriasis, diabetes, tumor related
angiogenesis, age-related macular degeneration, diabetic
retinopathy, restenosis, schizophrenia, Alzheimer's dementia; pain,
skeletal pain caused by tumor metastasis or osteoarthritis,
visceral pain, inflammatory pain, neurogenic pain; an autoimmune
disease, systemic lupus erythematosus, rheumatoid arthritis, other
forms of inflammatory arthritis, psoriasis, Sjogren's syndrome,
multiple sclerosis and uveitis; preferably rhematoid
arthritis).
DETAILED DESCRIPTION OF THE INVENTION
[0047] The present invention is directed to a process for the
preparation of compounds of formula (XII)
##STR00027##
[0048] wherein
##STR00028##
J, X, Z and R.sup.2 are as herein defined. The compounds of formula
(XII) are useful as intermediates in the synthesis of c-fms kinase
inhibitors of formula (I). The present invention is further
directed to a process for the preparation of compounds of formula
(I)
##STR00029##
[0049] wherein W, J, X, Z and R.sup.2 are as herein defined. More
particularly, the process of the present invention is particularly
preferred for large scale manufacture, providing cleaner reaction
mixture profiles (improved product/impurity profiles) which in turn
result in the elimination of additional purification step(s),
increased cycle times (shorter reaction times) and reduced
costs.
[0050] The compounds of formula (I) are useful as protein tyrosine
kinase inhibitors, more particularly inhibitors of c-fms kinase.
More particularly, as disclosed in Illig, C., et al., US Patent
Publication US2009/0105296 A1, the c-fms kinase inhibitors of
formula (I) are useful for the treatment of diseases including, but
not limited to: osteoporosis, Paget's disease, rheumatoid
arthritis, other forms of inflammatory arthritis, osteoarthritis,
prosthesis failure, osteolytic sarcoma, myeloma, tumor metastasis
to bone, ovarian cancer, uterine cancer, breast cancer, prostate
cancer, lung cancer, colon cancer, stomach cancer, hairy cell
leukemia; metastasis from ovarian cancer, uterine cancer, breast
cancer, prostate cancer, lung cancer, colon cancer, stomach cancer,
or hairy cell leukemia; glomerulonephritis, inflammatory bowel
disease, sarcoidosis, congestive obstructive pulmonary disease,
idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection,
psoriasis, diabetes, tumor related angiogenesis, age-related
macular degeneration, diabetic retinopathy, restenosis,
schizophrenia, Alzheimer's dementia; pain, skeletal pain caused by
tumor metastasis or osteoarthritis, visceral pain, inflammatory
pain, neurogenic pain; an autoimmune disease, systemic lupus
erythematosus, rheumatoid arthritis, other forms of inflammatory
arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis and
uveitis.
[0051] The present invention is further directed to a process for
the preparation of a compound of formula (XX)
##STR00030##
[0052] The compound of formula (XX) is useful as an intermediate in
the synthesis of compounds of formula (I), as disclosed in Illig,
C., et al., U.S. Patent Publication 2009/0105296 A1.
[0053] In an embodiment, the present invention is directed to a
process for the preparation of compounds of formula (I) wherein
[0054] W is selected from the group consisting of
##STR00031##
[0055] J is selected from the group consisting of CH and N;
[0056] R.sup.2 is selected from the group consisting of
##STR00032##
[0057] Z is H;
[0058] X is selected from the group consisting of
##STR00033## ##STR00034##
[0059] and tautomers and pharmaceutically acceptable salts
thereof.
[0060] In another embodiment, the present invention is directed to
a process for the preparation of compounds of formula (I)
wherein
[0061] W is selected from the group consisting of
##STR00035##
[0062] J is selected from the group consisting of CH and N;
[0063] R.sup.2 is selected from the group consisting of
##STR00036##
[0064] Z is H;
[0065] X is selected from the group consisting of
##STR00037## ##STR00038##
[0066] and tautomers and pharmaceutically acceptable salts
thereof.
[0067] In another embodiment, the present invention is directed to
a process for the preparation of compounds of formula (I)
wherein
[0068] W is selected from the group consisting of
##STR00039##
[0069] J is selected from the group consisting of CH and N;
[0070] R.sup.2 is selected from the group consisting of
##STR00040##
[0071] Z is H;
[0072] X is selected from the group consisting of
##STR00041## ##STR00042## ##STR00043##
[0073] and tautomers and pharmaceutically acceptable salts
thereof.
[0074] In another embodiment, the present invention is directed to
a process for the preparation of compounds of formula (I)
wherein
[0075] W is
##STR00044##
[0076] J is selected from the group consisting of CH and N;
[0077] R.sup.2 is selected from the group consisting of
##STR00045##
[0078] Z is H;
[0079] X is selected from the group consisting of
##STR00046## ##STR00047## ##STR00048##
[0080] and tautomers and pharmaceutically acceptable salts
thereof.
[0081] In another embodiment, the present invention is directed to
a process for the preparation of compounds of formula (Ia)
wherein
##STR00049##
[0082] wherein
[0083] J is selected from the group consisting of CH and N;
[0084] R.sup.2 is selected from the group consisting of
##STR00050##
[0085] X is selected from the group consisting of
##STR00051## ##STR00052##
[0086] wherein R.sup.w is selected from the group consisting of
hydrogen, --C.sub.(1-4)alkyl, --CO.sub.2C.sub.(1-4)alkyl,
--CONH.sub.2, --CONHC.sub.(1-4)alkyl,
--CON(C.sub.(1-4)alkyl).sub.2, or --COC.sub.(1-4)alkyl;
[0087] and tautomers and pharmaceutically acceptable salts
thereof.
[0088] In another embodiment, the present invention is directed to
a process for the preparation of compounds of formula (Ia)
wherein
[0089] J is selected from the group consisting of CH and N;
[0090] R.sup.2 is selected from the group consisting of
##STR00053##
[0091] X is selected from the group consisting of
##STR00054## ##STR00055##
[0092] and tautomers and pharmaceutically acceptable salts
thereof.
[0093] In another embodiment, the present invention is directed to
a process for the preparation of compounds of formula (I) selected
from the group consisting of
##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060##
##STR00061## ##STR00062## ##STR00063##
[0094] and tautomers, and pharmaceutically acceptable salts
thereof.
[0095] In another embodiment, the present invention is directed to
a process for the preparation of compounds of formula (I) selected
from the group consisting of [0096]
4-cyano-1H-imidazole-2-carboxylic acid
[2-cyclohex-1-enyl-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin--
3-yl]-amide; [0097] 4-cyano-1H-imidazole-2-carboxylic acid
[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-
-4-yl)-pyridin-3-yl]-amide hydrochloride salt;
4-cyano-1H-imidazole-2-carboxylic acid
[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-
-4-yl)-pyridin-3-yl]-amide methanesulfonic acid salt; and [0098]
4-cyano-1H-imidazole-2-carboxylic acid
[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-
-4-yl)-pyridin-3-yl]-amide (1 S)-(+)-10-camphorsulfonic acid salt.
Most preferably, the compound is 4-cyano-1H-imidazole-2-carboxylic
acid
[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-
-4-yl)-pyridin-3-yl]-amide hydrochloride salt.
[0099] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-S)
##STR00064##
[0100] and tautomers, and pharmaceutically acceptable salts thereof
(for example, the HCl salt thereof).
[0101] Additional embodiments of the present invention, include
those wherein the substituents selected for one or more of the
variables defined herein (i.e. W, J, X, Z, R.sup.2, etc.) are
independently selected to be any individual substituent or any
subset of substituents selected from the complete list as defined
herein.
[0102] As used herein, the term "alkyl" refers to both linear and
branched chain radicals of up to 12 carbon atoms, preferably up to
6 carbon atoms, unless otherwise indicated, and includes, but is
not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl,
octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and
dodecyl.
[0103] As used herein, the term "cycloalkyl" refers to a saturated
or partially unsaturated ring composed of from 3 to 8 carbon atoms.
Up to four alkyl substituents may optionally be present on the
ring. Examples include cyclopropyl, 1,1-dimethyl cyclobutyl,
1,2,3-trimethylcyclopentyl, cyclohexyl, cyclopentenyl,
cyclohexenyl, and 4,4-dimethyl cyclohexenyl.
[0104] As used herein, the term "alkylamino" refers to an amino
with one alkyl substituent, wherein the amino group is the point of
attachment to the rest of the molecule.
[0105] As used herein, the term "heteroaryl" refers to 5- to
7-membered mono- or 8- to 10-membered bicyclic aromatic ring
systems, any ring of which may contain from one to four heteroatoms
selected from N, O and S where the nitrogen and sulfur atoms can
exist in any allowed oxidation state. Examples include
benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl,
imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl
and thienyl.
[0106] As used herein, the term "heteroatom" refers to a nitrogen
atom, an oxygen atom or a sulfur atom wherein the nitrogen and
sulfur atoms can exist in any allowed oxidation states.
[0107] As used herein, the term "alkoxy" refers to straight or
branched chain radicals of up to 12 carbon atoms, unless otherwise
indicated, bonded to an oxygen atom. Examples include methoxy,
ethoxy, propoxy, isopropoxy and butoxy.
[0108] As used herein, the term "spiro-substituted cycloalkenyl"
refers to a pair of cycloalkyl rings that share a single carbon
atom and wherein at least one of the rings is partially
unsaturated, for example:
##STR00065##
[0109] The pharmaceutically-acceptable salts of the compounds of
formula (I) include the conventional non-toxic salts or the
quaternary ammonium salts which are formed from inorganic or
organic acids or bases. Examples of such acid addition salts
include acetate, adipate, benzoate, benzenesulfonate, citrate,
camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate,
maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate,
succinate, sulfate and tartrate. Base salts include ammonium salts,
alkali metal salts such as sodium and potassium salts, alkaline
earth metal salts such as calcium and magnesium salts, salts with
organic bases such as dicyclohexylamino salts and salts with amino
acids such as arginine. Also, the basic nitrogen-containing groups
may be quaternized with, for example, alkyl halides.
[0110] As used herein, the notation "*" shall denote the presence
of a stereogenic center.
[0111] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Preferably, wherein the compound is
present as an enantiomer, the enantiomer is present at an
enantiomeric excess of greater than or equal to about 80%, more
preferably, at an enantiomeric excess of greater than or equal to
about 90%, more preferably still, at an enantiomeric excess of
greater than or equal to about 95%, more preferably still, at an
enantiomeric excess of greater than or equal to about 98%, most
preferably, at an enantiomeric excess of greater than or equal to
about 99%. Similarly, wherein the compound is present as a
diastereomer, the diastereomer is present at an diastereomeric
excess of greater than or equal to about 80%, more preferably, at
an diastereomeric excess of greater than or equal to about 90%,
more preferably still, at an diastereomeric excess of greater than
or equal to about 95%, more preferably still, at an diastereomeric
excess of greater than or equal to about 98%, most preferably, at
an diastereomeric excess of greater than or equal to about 99%.
[0112] Furthermore, some of the crystalline forms for the compounds
of the present invention may exist as polymorphs and as such are
intended to be included in the present invention. In addition, some
of the compounds of the present invention may form solvates with
water (i.e., hydrates) or common organic solvents, and such
solvates are also intended to be encompassed within the scope of
this invention.
[0113] Under standard nomenclature used throughout this disclosure,
the terminal portion of the designated side chain is described
first, followed by the adjacent functionality toward the point of
attachment. Thus, for example, a
"phenylC.sub.1-C.sub.6alkylaminocarbonylC.sub.1-C.sub.6alkyl"
substituent refers to a group of the formula
##STR00066##
[0114] Abbreviations used in the specification, particularly the
Schemes and Examples, are as follows: [0115]
BINAP=2,2'-Bis-(diphenylphosphino)-1,1'-binaphthyl [0116]
DBU=1,8-Diazabicycloundec-7-ene [0117] DME=1,2-Dimethoxyethane
[0118] DMSO=Dimethylsulfoxide [0119]
dppf=1,1'-Bis(diphenylphosphino)ferrocene [0120] HPLC=High
Performance Liquid Chromatography [0121] IPA=Isopropyl Alcohol
[0122] KOAc=Potassium Acetate [0123] LC=Liquid Chromatography
[0124] LDA=Lithium Diisopropylamide [0125] Me=Methyl (i.e.
--CH.sub.3) [0126] 2-methyl-THF=2-Methyl-tetrahydrofuran or
2-Me-THF [0127] MOM=Methoxymethyl ether [0128] NORIT
A-SUPRA=Powdered activated carbon available from NORIT America Inc.
[0129] NsulphF=1,1,1,2,2,3,3,4,4-nonafluoro-1-butanesulfonyl
fluoride [0130] Pd.sub.2(OAc).sub.2=Palladium(II)acetate [0131]
Pd.sub.2(dba).sub.3=Tris(dibenzylidene acetone)dipalladium(0)
[0132] Pd(dppf)Cl.sub.2=[1,1'-Bis(diphenylphosphino)ferrocene]
palladium(II) dichloride [0133] PPh.sub.3=Triphenylphosphine [0134]
SEM=2-(Trimethylsilyl)ethoxymethyl [0135] TEA=Triethylamine [0136]
THF=Tetrahydrofuran [0137] THP=Tetrahydropyranyl [0138]
XantPhos=4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
[0139] As used herein, unless otherwise noted, the term "isolated
form" shall mean that the compound is present in a form which is
separate from any solid mixture with another compound(s), solvent
system or biological environment. In an embodiment, the present
invention is directed to a process for the prepared of the compound
of formula (I), preferably the compound of formula (I-S) in an
isolated form. In another embodiment, the present invention is
directed to a product prepared according to any of the processes as
described herein, wherein the product is prepared in an isolated
form.
[0140] As used herein, unless otherwise noted, the term
"substantially pure form" shall mean that the mole percent of
impurities in the isolated compound is less than about 5.0 mole
percent, preferably less than about 2.0 mole percent, more
preferably, less than about 0.5 mole percent, most preferably, less
than about 0.1 mole percent. In an embodiment, the present
invention is directed to a process for the prepared of the compound
of formula (I), preferably the compound of formula (I-S) as a
substantially pure form. In another embodiment, the present
invention is directed to a product prepared according to any of the
processes as described herein, wherein the product is prepared as a
substantially pure form.
[0141] As used herein, unless otherwise noted, the term
"substantially free of a corresponding salt form(s)" when used to
described the compound of formula (I) shall mean that mole percent
of the corresponding salt form(s) in the isolated base of formula
(I) is less than about 5.0 mole percent, preferably less than about
2.0 mole percent, more preferably, less than about 0.5 mole
percent, most preferably less than about 0.1 mole percent. In an
embodiment, the present invention is directed to a process for the
prepared of the compound of formula (I), preferably the compound of
formula (I-S) substantially free of corresponding salt form(s). In
another embodiment, the present invention is directed to a product
prepared according to any of the processes as described herein,
wherein the product is prepared in a form which is substantially
free of corresponding salt form(s).
[0142] As used herein, unless otherwise noted, the terms
"treating", "treatment" and the like, shall include the management
and care of a subject or patient (preferably mammal, more
preferably human) for the purpose of combating a disease,
condition, or disorder and includes the administration of a
compound of the present invention to prevent the onset of the
symptoms or complications, alleviate the symptoms or complications,
or eliminate the disease, condition, or disorder.
[0143] As used herein, unless otherwise noted, the term
"prevention" shall include (a) reduction in the frequency of one or
more symptoms; (b) reduction in the severity of one or more
symptoms; (c) the delay or avoidance of the development of
additional symptoms; and/or (d) delay or avoidance of the
development of the disorder or condition.
[0144] One skilled in the art will recognize that wherein the
present invention is directed to methods of prevention, a subject
in need of thereof (i.e. a subject in need of prevention) shall
include any subject or patient (preferably a mammal, more
preferably a human) who has experienced or exhibited at least one
symptom of the disorder, disease or condition to be prevented.
Further, a subject in need thereof may additionally be a subject
(preferably a mammal, more preferably a human) who has not
exhibited any symptoms of the disorder, disease or condition to be
prevented, but who has been deemed by a physician, clinician or
other medical profession to be at risk of developing said disorder,
disease or condition. For example, the subject may be deemed at
risk of developing a disorder, disease or condition (and therefore
in need of prevention or preventive treatment) as a consequence of
the subject's medical history, including, but not limited to,
family history, pre-disposition, co-existing (comorbid) disorders
or conditions, genetic testing, and the like.
[0145] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment. Preferably, the
subject has experienced and/or exhibited at least one symptom of
the disease or disorder to be treated and/or prevented.
[0146] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation,
prevention, treatment, or the delay of the onset or progression of
the symptoms of the disease or disorder being treated.
[0147] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0148] As more extensively provided in this written description,
terms such as "reacting" and "reacted" are used herein in reference
to a chemical entity that is any one of: (a) the actually recited
form of such chemical entity, and (b) any of the forms of such
chemical entity in the medium in which the compound is being
considered when named.
[0149] One skilled in the art will recognize that, where not
otherwise specified, the reaction step(s) is performed under
suitable conditions, according to known methods, to provide the
desired product. One skilled in the art will further recognize
that, in the specification and claims as presented herein, wherein
a reagent or reagent class/type (e.g. base, solvent, etc.) is
recited in more than one step of a process, the individual reagents
are independently selected for each reaction step and may be the
same of different from each other. For example wherein two steps of
a process recite an organic or inorganic base as a reagent, the
organic or inorganic base selected for the first step may be the
same or different than the organic or inorganic base of the second
step. Further, one skilled in the art will recognize that wherein a
reaction step of the present invention may be carried out in a
variety of solvents or solvent systems, said reaction step may also
be carried out in a mixture of the suitable solvents or solvent
systems. One skilled in the art will further recognize that wherein
two consecutive reaction or process steps are run without isolation
of the intermediate product (i.e. the product of the first of the
two consecutive reaction or process steps), then the first and
second reaction or process steps may be run in the same solvent or
solvent system; or alternatively may be run in different solvents
or solvent systems following solvent exchange, which may be
completed according to known methods.
[0150] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including, but not
limited to, approximations due to the experimental and/or
measurement conditions for such given value.
[0151] To provide a more concise description, some of the
quantitative expressions herein are recited as a range from about
amount X to about amount Y. It is understood that wherein a range
is recited, the range is not limited to the recited upper and lower
bounds, but rather includes the full range from about amount X
through about amount Y, or any amount or range therein.
[0152] Examples of suitable solvents, bases, reaction temperatures,
and other reaction parameters and components are provided in the
detailed descriptions which follow herein. One skilled in the art
will recognize that the listing of said examples is not intended,
and should not be construed, as limiting in any way the invention
set forth in the claims which follow thereafter. One skilled in the
art will further recognize that wherein a reaction step of the
present invention may be carried out in a variety of solvents or
solvent systems, said reaction step may also be carried out in a
mixture of the suitable solvents or solvent systems.
[0153] As used herein, unless otherwise noted, the term "leaving
group" shall mean a charged or uncharged atom or group which
departs during a substitution or displacement reaction. Suitable
examples include, but are not limited to, Br, Cl, I, mesylate,
tosylate, and the like.
[0154] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known from the
art.
[0155] As used herein, unless otherwise noted, the term "nitrogen
protecting group" shall mean a group which may be attached to a
nitrogen atom to protect said nitrogen atom from participating in a
reaction and which may be readily removed following the reaction.
Suitable nitrogen protecting groups include, but are not limited to
carbamates--groups of the formula --C(O)O--R wherein R is for
example methyl, ethyl, t-butyl, benzyl, phenylethyl,
CH.sub.2.dbd.CH--CH.sub.2--, and the like; amides--groups of the
formula --C(O)--R' wherein R' is for example methyl, phenyl,
trifluoromethyl, and the like; N-sulfonyl derivatives--groups of
the formula --SO.sub.2--R'' wherein R'' is for example tolyl,
phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,
2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable
nitrogen protecting groups may be found in texts such as T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991.
[0156] As used herein, unless otherwise noted, the term "oxygen
protecting group" shall mean a group which may be attached to an
oxygen atom to protect said oxygen atom from participating in a
reaction and which may be readily removed following the reaction.
Suitable oxygen protecting groups include, but are not limited to,
acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM,
THP, and the like. Other suitable oxygen protecting groups may be
found in texts such as T. W. Greene & P. G. M. Wuts, Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991.
[0157] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.
[0158] Additionally, chiral HPLC against a standard may be used to
determine percent enantiomeric excess (% ee). The enantiomeric
excess may be calculated as follows:
[(Rmoles-Smoles)/(Rmoles+Smoles)].times.100%
[0159] where Rmoles and Smoles are the R and S mole fractions in
the mixture such that Rmoles+Smoles=1. The enantiomeric excess may
alternatively be calculated from the specific rotations of the
desired enantiomer and the prepared mixture as follows:
ee=([.alpha.-obs]/[.alpha.-max]).times.100.
PROCESSES OF THE PRESENT INVENTION
[0160] The present invention is directed to a process for the
preparation of a compound of formula (I), as outlined in Scheme 1,
below.
##STR00067##
[0161] Accordingly, a suitably substituted compound of formula (X),
a known compound or compound prepared by known methods, is reacted
with a suitably substituted compound of formula (XI) or mixture of
SEM protected region-isomers thereof, wherein
##STR00068##
is selected from the group consisting of
##STR00069##
a known compound or compound prepared by known methods;
[0162] in the presence of carbon monoxide gas or a source of carbon
monoxide, wherein the source of carbon monoxide is for example, a
metal carbonyl such as tungsten hexacarbonyl, molibdinum
hexacarbonyl, and the like; preferably in the presence of carbon
monoxide gas; wherein the carbon monoxide gas is preferably present
at a pressure in the range of from about 3.0 bar to about 5.0 bar,
more preferably at a pressure in the range of from about 3.0 bar to
about 4.0 bar, more preferably at a pressure of about 4.0 bar;
(preferably the compound of formula (X) is reacted with the
compound of formula (XI) under a carbon monoxide atmosphere);
[0163] in the presence of a suitably selected organic or inorganic
base such as K.sub.3PO.sub.4, K.sub.2CO.sub.3, DBU, TEA, pyridine,
and the like, preferably an inorganic base such as K.sub.3PO.sub.4,
K.sub.2CO.sub.3, and the like, more preferably, K.sub.3PO.sub.4;
wherein the base is preferably present in an amount in the range of
from about 1.0 to about 2.0 molar equivalents (relative to the
moles of the compound of formula (X)), more preferably in an amount
in the range of from about 1.5 to about 4.0 molar equivalents, more
preferably in an amount in the range of from about 2.0 to about 3.0
molar equivalents;
[0164] in the presence of a suitably selected coupling system
comprising a suitably selected palladium compound as such as
Pd(OAc).sub.2, Pd.sub.2(dba).sub.3, and the like, preferably
Pd(OAc).sub.2, and a suitably selected ligand such as XantPhos,
BINAP, and the like, preferably XantPhos; more preferably, a
mixture of Pd(OAc).sub.2 and XantPhos, more preferably a 1:1
(molar) mixture of Pd(OAc).sub.2 and XantPhos;
[0165] wherein the palladium compound is preferably present in an
amount of in the range of from about 1.0 mol % (i.e. 0.01 molar
equivalents relative to the moles of the compound of formula (X))
to about 4.0 mol %, more preferably in an amount in the range of
from about 2.0 mol % to about 3.0 mol %; and wherein the ligand is
preferably present in an amount of in the range of from about 1.0
mol % (i.e. 0.01 molar equivalents relative to the moles of the
compound of formula (X)) to about 4.0 mol %, more preferably in an
amount in the range of from about 2.0 mol % to about 3.0 mol %;
[0166] in a suitably selected organic solvent such as toluene,
xylene, and the like, preferably toluene; at a temperature in the
range of from about 60.degree. C. to about 120.degree. C., more
preferably at a temperature in the range of form about 75.degree.
C. to about 100.degree. C., more preferably at a temperature of
about 90.degree. C.; to yield the corresponding compound of formula
(XII).
[0167] The compound of formula (XII) is de-protected according to
known methods, to yield the corresponding compound of formula (I).
For example, the compound of formula (XII) may be de-protected by
reacting with a suitably selected acid such as HCl,
H.sub.2SO.sub.4, and the like, in a suitably selected organic
solvent such as isopropanol, ethanol, water, and the like, to yield
the corresponding compound of formula (I) or pharmaceutically
acceptable salt thereof.
[0168] One skilled in the art will readily recognize that when
##STR00070##
is other than
##STR00071##
then the compound of formula (XI) may exist as a mixture of its
corresponding SEM-protected regioisomers. More particularly,
when
##STR00072##
then the mixture of SEM-protected regioisomers of the compound of
formula (XI) is a mixture of a compound of formula (XI-R2) and a
compound of formula (XI-R3)
##STR00073##
[0169] when
##STR00074##
then the mixture of SEM-protected regioisomers of the compound of
formula (XI) is a mixture of a compound of formula (XI-R4) and a
compound of formula (XI-R5)
##STR00075##
[0170] when
##STR00076##
then the mixture of SEM-protected regioisomers of the compound of
formula (XI) is a mixture of the following compounds of formula
(XI-R6) and a compound of formula (XI-R7)
##STR00077##
[0171] and when
##STR00078##
then the mixture of SEM-protected regioisomers of the compound of
formula (XI) is a mixture of two or three of a compound of formula
(XI-R8), a compound of formula (XI-R9) and/or a compound of formula
(XI-R10)
##STR00079##
[0172] One skilled in the art will further readily recognize that
the compound of formula (X) may be reacted with a mixture of
SEM-protected regioisomers of the compounds of formula (XI) as
described above, according to the process as described in Scheme 1,
to yield the corresponding compound of formula (XIII).
[0173] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I-S), as
outlined in Scheme 2, below.
##STR00080##
[0174] Accordingly, a suitably substituted compound of formula
(X-S), a known compound or compound prepared by known methods, is
reacted with a suitably substituted compound of formula (XI-S), a
known compound or compound prepared by known methods;
[0175] in the presence of carbon monoxide gas or a source of carbon
monoxide, wherein the source of carbon monoxide is for example, a
metal carbonyl such as tungsten hexacarbonyl, molibdinum
hexacarbonyl, and the like; preferably in the presence of carbon
monoxide gas; wherein the carbon monoxide gas, preferably at a
pressure in the range of from about 3.0 bar to about 5.0 bar, more
preferably at a pressure in the range of from about 3.0 bar to
about 4.0 bar, more preferably at a pressure of about 4.0 bar;
(preferably the compound of formula (X) is reacted with the
compound of formula (XI) under a carbon monoxide atmosphere);
[0176] in the presence of a suitably selected organic or inorganic
base such as K.sub.3PO.sub.4, K.sub.2CO.sub.3, DBU, TEA, pyridine,
and the like, preferably an inorganic base such as K.sub.3PO.sub.4,
K.sub.2CO.sub.3, and the like, more preferably, K.sub.3PO.sub.4;
wherein the base is preferably present in an amount in the range of
from about 1.0 to about 2.0 molar equivalents (relative to the
moles of the compound of formula (X-S)), more preferably in an
amount in the range of from about 1.5 to about 4.0 molar
equivalents, more preferably in an amount in the range of from
about 2.0 to about 3.0 molar equivalents;
[0177] in the presence of a suitably selected coupling system
comprising a suitably selected palladium compound as such as
Pd(OAc).sub.2, Pd.sub.2(dba).sub.3, and the like, preferably
Pd(OAc).sub.2, and a suitably selected ligand such as XantPhos,
BINAP, and the like, preferably XantPhos; more preferably, a
mixture of Pd(OAc).sub.2 and XantPhos, more preferably a 1:1
(molar) mixture of Pd(OAc).sub.2 and XantPhos;
[0178] wherein the palladium compound is preferably present in an
amount of in the range of from about 1.0 mol % (i.e. 0.01 molar
equivalents relative to the moles of the compound of formula (X-S))
to about 4.0 mol %, more preferably in an amount in the range of
from about 2.0 mol % to about 3.0 mol %; and wherein the ligand is
preferably present in an amount of in the range of from about 1.0
mol % (i.e. 0.01 molar equivalents relative to the moles of the
compound of formula (X-S)) to about 4.0 mol %, more preferably in
an amount in the range of from about 2.0 mol % to about 3.0 mol
%;
[0179] in a suitably selected organic solvent such as toluene,
xylene, and the like, preferably toluene; at a temperature in the
range of from about 60.degree. C. to about 120.degree. C., more
preferably at a temperature in the range of form about 75.degree.
C. to about 100.degree. C., more preferably at a temperature of
about 90.degree. C.; to yield the corresponding compound of formula
(XII-S).
[0180] The compound of formula (XII-S) is de-protected according to
known methods, to yield the corresponding compound of formula
(I-S). For example, the compound of formula (XII-S) may be
de-protected by reacting with a suitably selected acid such as HCl,
H.sub.2SO.sub.4, and the like, in a suitably selected organic
solvent such as isopropanol, ethanol, water, and the like, to yield
the corresponding compound of formula (I-S) or pharmaceutically
acceptable salt thereof.
[0181] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I-S), wherein
the compound of formula (X-S) is reacted, according to the process
described in Scheme 2 above, with a mixture of a compound of
formula (XIII-S) and compound of formula (XIV-S)
##STR00081##
[0182] to yield the corresponding compound of formula (I-S).
[0183] In another embodiment, the compound of formula (X-S) is
reacted with a mixture of a compound of formula (XIII-S) and a
compound of formula (XIV-S);
[0184] in the presence of carbon monoxide gas or a source of carbon
monoxide, wherein the source of carbon monoxide is for example, a
metal carbonyl such as tungsten hexacarbonyl, molibdinum
hexacarbonyl, and the like; preferably in the presence of carbon
monoxide gas; wherein the carbon monoxide gas, preferably at a
pressure in the range of from about 3.0 bar to about 5.0 bar, more
preferably at a pressure in the range of from about 3.0 bar to
about 4.0 bar, more preferably at a pressure of about 4.0 bar;
(preferably the compound of formula (X) is reacted with the
compound of formula (XI) under a carbon monoxide atmosphere);
[0185] in the presence of a suitably selected organic or inorganic
base such as K.sub.3PO.sub.4, K.sub.2CO.sub.3, DBU, TEA, pyridine,
and the like, preferably an inorganic base such as K.sub.3PO.sub.4,
K.sub.2CO.sub.3, and the like, more preferably, K.sub.3PO.sub.4;
wherein the base is preferably present in an amount in the range of
from about 1.0 to about 2.0 molar equivalents (relative to the
moles of the compound of formula (X-S)), more preferably in an
amount in the range of from about 1.5 to about 4.0 molar
equivalents, more preferably in an amount in the range of from
about 2.0 to about 3.0 molar equivalents;
[0186] in the presence of a suitably selected coupling system
comprising a suitably selected palladium compound as such as
Pd(OAc).sub.2, Pd.sub.2(dba).sub.3, and the like, preferably
Pd(OAc).sub.2, and a suitably selected ligand such as XantPhos,
BINAP, and the like, preferably XantPhos; more preferably, a
mixture of Pd(OAc).sub.2 and XantPhos, more preferably a 1:1
(molar) mixture of Pd(OAc).sub.2 and XantPhos;
[0187] wherein the palladium compound is preferably present in an
amount of in the range of from about 1.0 mol % (i.e. 0.01 molar
equivalents relative to the moles of the compound of formula (X-S))
to about 4.0 mol %, more preferably in an amount in the range of
from about 2.0 mol % to about 3.0 mol %; and wherein the ligand is
preferably present in an amount of in the range of from about 1.0
mol % (i.e. 0.01 molar equivalents relative to the moles of the
compound of formula (X-S)) to about 4.0 mol %, more preferably in
an amount in the range of from about 2.0 mol % to about 3.0 mol
%;
[0188] in a suitably selected organic solvent such as toluene,
xylene, and the like, preferably toluene; at a temperature in the
range of from about 60.degree. C. to about 120.degree. C., more
preferably at a temperature in the range of form about 75.degree.
C. to about 100.degree. C., more preferably at a temperature of
about 90.degree. C.; to yield the corresponding compound of formula
(XII-S).
[0189] The compound of formula (XII-S) is de-protected according to
known methods, preferably be reacting with a suitably selected acid
such as HCl, H.sub.2SO.sub.4, and the like, in a suitably selected
organic solvent such as isopropanol, ethanol, water, and the like,
to yield the corresponding compound of formula (I-S) or
pharmaceutically acceptable salt thereof.
[0190] The present invention is further directed to an improved
process for the preparation of a compound of formula (XX) (useful
as an intermediate in the synthesis of pharmaceutical agents), as
described in Scheme 3, below.
##STR00082##
[0191] Accordingly, a compound of formula (XXI), a known compound
also known as 2,6-dimethylhepta-2,5-dien-4-one, is reacted with a
suitably selected acid such as HCl, H.sub.2SO.sub.4, HBr and the
like, preferably HCl, more preferably 3N HCl; wherein the acid is
preferably present in an amount in the range of form about 1.0 to
about 5.0 molar equivalents (relative to the moles of the compound
of formula (XXI)), more preferably in an amount in the range of
about 2.0 to about 4.0 molar equivalents, more preferably in an
amount of about 3.0 to about 3.25 molar equivalents; in a suitably
selected organic solvent such as methanol, ethanol, isopropanol,
and the like, preferably methanol; at a temperature in the range of
form about room temperature to about 45.degree. C., more preferably
at about 30.degree. C.; to yield the corresponding compound of
formula (XXII), also known as
2,2,6,6-tetramethyldihydro-2H-pyran-4(3H)-one.
[0192] The compound of formula (XXII) is reacted with NfsulphF, a
known compound (also known as
1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl fluoride); wherein
the NfsulphF is preferably present in an amount in the range of
from about 1.0 to about 1.5 molar equivalents (relative to the
moles of the compound of formula (XXII)), more preferably in an
amount in the range of form about 1.1 to about 1.3 molar
equivalents, more preferably in an amount of about 1.2 molar
equivalents;
[0193] in the presence of DBU; wherein the DBU is preferably
present in an amount in the range of from about 1.1 to about 4.0
molar equivalents (relative to the moles of the compound of formula
(XXII)), more preferably in an amount in the range of form about
1.5 to about 2.5 molar equivalents, more preferably in an amount of
about 2.0 molar equivalents;
[0194] in a suitably selected organic solvent such as 2-methyl-THF,
THF, toluene, and the like, preferably 2-methyl-THF; at a
temperature in the range of from about 0.degree. C. to about room
temperature, preferably at about room temperature; to yield the
corresponding compound of formula (XX), also known as
2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate.
[0195] The process of the present invention for the preparation of
a compound of formula (XX) (more particularly the reaction of a
compound of formula (XXII) to yield the corresponding compound of
formula (XX) as described above) is improved over previously
disclosed processes. In the process of the present invention, the
use of DBU rather than LDA was unexpectedly found to allow the
reaction to proceed at a temperature in the range of from about
0.degree. C. to about room temperature (versus about -78.degree. C.
for LDA), which lower temperature is advantageous and/or preferred
for large scale manufacture and/or for safety. The process of the
present invention for the preparation of the compound of formula
(XX) as described above further eliminates the use of methanol (or
similarly alcohol), and increases product yield.
[0196] The compound of formula (XX) may be further, optionally
reacted with diboron pinacol ester (also known as pinacol
diborane), a known compound; wherein the diboron pinacol ester is
preferably present in an amount in the range of from about 1.0 to
about 3.0 molar equivalents (relative to the moles of the compound
of formula (XX)), more preferably in an amount in the range of from
about 1.05 to about 1.5 molar equivalents, more preferably in an
amount of about 1.1 molar equivalents;
[0197] in the presence of a suitably selected coupling system
comprising a palladium compound and ligand, such as
Pd(dppf)Cl.sub.2 in a mixture with dppf, Pd(OAc).sub.2 in a mixture
with PPh.sub.3, and the like; wherein the palladium compound
(preferably Pd(dppf)Cl.sub.2) is preferably present in an amount in
the range of from about 0.01 to about 0.05 molar equivalents (i.e.
in an amount in the range of from about 1.0 mol % to about 5.0 mol
%), more preferably in an amount in the range of from about 0.02 to
about 0.03 molar equivalents (i.e. in an amount in the range of
from about 2.0 mol % to about 3.0 mol %), more preferably in an
amount of about 0.027 molar equivalents (i.e. in an amount of about
2.7 mol %); and wherein the ligand (preferably, dppf) is preferably
present in an amount in the range of from about 0.01 to about 0.05
molar equivalents (i.e. in an amount in the range of from about 1.0
mol % to about 5.0 mol %), more preferably in an amount in the
range of from about 0.02 to about 0.03 molar equivalents (i.e. in
an amount in the range of from about 2.0 mol % to about 3.0 mole
percent), more preferably in an amount of about 0.029 molar
equivalents (i.e. in an amount of about 2.9 mol %);
[0198] in the presence of a inorganic base such as KOAc,
Cs.sub.2CO.sub.3, and the like; wherein the inorganic base is
preferably present in an amount in the range of from about 1.0 to
about 5.0 molar equivalents (relative to the moles of the compound
of formula (XX)), more preferably in an amount in the range of from
about 2.0 to about 4.0 molar equivalents, more preferably in an
amount of about 3.0 molar equivalents;
[0199] in a suitably selected organic solvent such as DME, toluene,
and the like, preferably DME; at a temperature in the range of from
about 60.degree. C. to about 100.degree. C., preferably at a
temperature of about 80.degree. C.; to yield the corresponding
compound of formula (XXIII), also known as
4,4,5,5-tetramethyl-2-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1,3,2-
-dioxaborolane.
[0200] One skilled in the art will recognize that the compound of
formula (XXIII) is a reactive species, useful as an intermediate in
the synthesis of pharmaceutical compounds, for example, as
described in Illig, C., et al., US Patent Publication US
2009/0105296 A1.
[0201] The present invention further comprises pharmaceutical
compositions containing one or more compounds of formula (I),
prepared as described herein, with a pharmaceutically acceptable
carrier. Pharmaceutical compositions containing one or more of the
compounds of the invention described herein as the active
ingredient can be prepared by intimately mixing the compound or
compounds with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier may take a wide
variety of forms depending upon the desired route of administration
(e.g., oral, parenteral). Thus for liquid oral preparations such as
suspensions, elixirs and solutions, suitable carriers and additives
include water, glycols, oils, alcohols, flavoring agents,
preservatives, stabilizers, coloring agents and the like; for solid
oral preparations, such as powders, capsules and tablets, suitable
carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like. Solid oral preparations may also be coated with
substances such as sugars or be enteric-coated so as to modulate
major site of absorption. For parenteral administration, the
carrier will usually consist of sterile water and other ingredients
may be added to increase solubility or preservation. Injectable
suspensions or solutions may also be prepared utilizing aqueous
carriers along with appropriate additives.
[0202] To prepare the pharmaceutical compositions of this
invention, one or more compounds of the present invention as the
active ingredient is intimately admixed with a pharmaceutical
carrier according to conventional pharmaceutical compounding
techniques, which carrier may take a wide variety of forms
depending of the form of preparation desired for administration,
e.g., oral or parenteral such as intramuscular. In preparing the
compositions in oral dosage form, any of the usual pharmaceutical
media may be employed. Thus, for liquid oral preparations, such as
for example, suspensions, elixirs and solutions, suitable carriers
and additives include water, glycols, oils, alcohols, flavoring
agents, preservatives, coloring agents and the like; for solid oral
preparations such as, for example, powders, capsules, caplets,
gelcaps and tablets, suitable carriers and additives include
starches, sugars, diluents, granulating agents, lubricants,
binders, disintegrating agents and the like. Because of their ease
in administration, tablets and capsules represent the most
advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are obviously employed. If desired, tablets
may be sugar coated or enteric coated by standard techniques. For
parenterals, the carrier will usually comprise sterile water,
through other ingredients, for example, for purposes such as aiding
solubility or for preservation, may be included. Injectable
suspensions may also be prepared, in which case appropriate liquid
carriers, suspending agents and the like may be employed. The
pharmaceutical compositions herein will contain, per dosage unit,
e.g., tablet, capsule, powder, injection, teaspoonful and the like,
an amount of the active ingredient necessary to deliver an
effective dose as described above. The pharmaceutical compositions
herein will contain, per unit dosage unit, e.g., tablet, capsule,
powder, injection, suppository, teaspoonful and the like, of from
about 0.01 mg to about 1000 mg or any amount or range therein, and
may be given at a dosage of from about 0.01 mg/kg/day to about 300
mg/kg/day, or any amount or range therein, preferably from about
0.1 mg/kg/day to about 50 mg/kg/day, or any amount or range
therein, preferably from about 0.05 mg/kg/day to about 15.0
mg/kg/day, or any amount or range therein, preferably from about
0.1 mg/kg/day to about 10.0 mg/kg/day, or any amount or range
therein. The dosages, however, may be varied depending upon the
requirement of the patients, the severity of the condition being
treated and the compound being employed. The use of either daily
administration or post-periodic dosing may be employed.
[0203] Preferably these compositions are in unit dosage forms from
such as tablets, pills, capsules, powders, granules, sterile
parenteral solutions or suspensions, metered aerosol or liquid
sprays, drops, ampoules, autoinjector devices or suppositories; for
oral parenteral, intranasal, sublingual or rectal administration,
or for administration by inhalation or insufflation. Alternatively,
the composition may be presented in a form suitable for once-weekly
or once-monthly administration; for example, an insoluble salt of
the active compound, such as the decanoate salt, may be adapted to
provide a depot preparation for intramuscular injection. For
preparing solid compositions such as tablets, the principal active
ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose,
sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums, and other pharmaceutical diluents,
e.g. water, to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention, or a
pharmaceutically acceptable salt thereof. When referring to these
preformulation compositions as homogeneous, it is meant that the
active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally
effective dosage forms such as tablets, pills and capsules. This
solid preformulation composition is then subdivided into unit
dosage forms of the type described above containing from about 0.01
mg to about 1,000 mg, or any amount or range therein, of the active
ingredient of the present invention. The tablets or pills of the
novel composition can be coated or otherwise compounded to provide
a dosage form affording the advantage of prolonged action. For
example, the tablet or pill can comprise an inner dosage and an
outer dosage component, the latter being in the form of an envelope
over the former. The two components can be separated by an enteric
layer which serves to resist disintegration in the stomach and
permits the inner component to pass intact into the duodenum or to
be delayed in release. A variety of material can be used for such
enteric layers or coatings, such materials including a number of
polymeric acids with such materials as shellac, cetyl alcohol and
cellulose acetate.
[0204] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include, aqueous solutions, suitably flavoured syrups,
aqueous or oil suspensions, and flavoured emulsions with edible
oils such as cottonseed oil, sesame oil, coconut oil or peanut oil,
as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions, include
synthetic and natural gums such as tragacanth, acacia, alginate,
dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinyl-pyrrolidone or gelatin.
[0205] The method of treating c-FMS kinase mediated disorders
described in the present invention may also be carried out using a
pharmaceutical composition comprising any of the compounds as
defined herein and a pharmaceutically acceptable carrier. The
pharmaceutical composition may contain between about 0.01 mg and
about 1000 mg of the compound, or any amount or range therein;
preferably from about 1.0 mg to about 500 mg of the compound, or
any amount or range therein, and may be constituted into any form
suitable for the mode of administration selected. Carriers include
necessary and inert pharmaceutical excipients, including, but not
limited to, binders, suspending agents, lubricants, flavorants,
sweeteners, preservatives, dyes, and coatings. Compositions
suitable for oral administration include solid forms, such as
pills, tablets, caplets, capsules (each including immediate
release, timed release and sustained release formulations),
granules, and powders, and liquid forms, such as solutions, syrups,
elixers, emulsions, and suspensions. Forms useful for parenteral
administration include sterile solutions, emulsions and
suspensions.
[0206] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those of ordinary skill in that art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
[0207] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders; lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable
binders include, without limitation, starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
[0208] The liquid forms in suitably flavored suspending or
dispersing agents such as the synthetic and natural gums, for
example, tragacanth, acacia, methylcellulose and the like. For
parenteral administration, sterile suspensions and solutions are
desired. Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is
desired.
[0209] To prepare a pharmaceutical composition of the present
invention, a compound of formula (I) as the active ingredient is
intimately admixed with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques, which carrier
may take a wide variety of forms depending of the form of
preparation desired for administration (e.g. oral or parenteral).
Suitable pharmaceutically acceptable carriers are well known in the
art. Descriptions of some of these pharmaceutically acceptable
carriers may be found in The Handbook of Pharmaceutical Excipients,
published by the American Pharmaceutical Association and the
Pharmaceutical Society of Great Britain.
[0210] Methods of formulating pharmaceutical compositions have been
described in numerous publications such as Pharmaceutical Dosage
Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3,
edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral
Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical
Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et
al; published by Marcel Dekker, Inc.
[0211] Compounds of this invention may be administered in any of
the foregoing compositions and according to dosage regimens
established in the art whenever treatment of disorders mediated by
c-FMS kinase is required.
[0212] The daily dosage of the products may be varied over a wide
range from about 0.01 mg to about 1,000 mg per adult human per day,
or any amount or range therein. For oral administration, the
compositions are preferably provided in the form of tablets
containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0,
50.0, 100, 150, 200, 250 and 500 milligrams of the active
ingredient for the symptomatic adjustment of the dosage to the
patient to be treated. An effective amount of the drug is
ordinarily supplied at a dosage level of from about 0.01 mg/kg to
about 500 mg/kg of body weight per day, or any amount or range
therein. Preferably, the range is from about 0.1 to about 50.0
mg/kg of body weight per day, or any amount or range therein. More
preferably, from about 0.5 to about 15.0 mg/kg of body weight per
day, or any amount or range therein. More preferably, from about
1.0 to about 7.5 mg/kg of body weight per day, or any amount or
range therein. The compounds may be administered on a regimen of 1
to 4 times per day.
[0213] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mode of administration, the strength of the
preparation, the mode of administration, and the advancement of the
disease condition. In addition, factors associated with the
particular patient being treated, including patient age, weight,
diet and time of administration, will result in the need to adjust
dosages.
[0214] One skilled in the art will recognize that, both in vivo and
in vitro trials using suitable, known and generally accepted cell
and/or animal models are predictive of the ability of a test
compound to treat or prevent a given disorder.
[0215] One skilled in the art will further recognize that human
clinical trials including first-in-human, dose ranging and efficacy
trials, in healthy patients and/or those suffering from a given
disorder, may be completed according to methods well known in the
clinical and medical arts.
Synthesis Examples
[0216] The following Examples are set forth to aid in the
understanding of the invention, and are not intended and should not
be construed to limit in any way the invention set forth in the
claims which follow thereafter.
[0217] In the Examples which follow, some synthesis products are
listed as having been isolated as a residue. It will be understood
by one of ordinary skill in the art that the term "residue" does
not limit the physical state in which the product was isolated and
may include, for example, a solid, an oil, a foam, a gum, a syrup,
and the like. One skilled in the art will further recognize that in
the Examples which follow, the term "rag-layer" refers to the
emulsion which may form between the organic and aqueous layers
during separation work-up.
Example 1
4-cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrah-
ydro-2H-pyran-4-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-i-
midazole-2-carboxamide
##STR00083##
[0219] A 60 mL stainless steel MULTIMAX reactor was charged with
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile
(3.26 g, 10.79 mmol, 1.20 equiv),
2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-py-
ran-4-yl)pyridin-3-amine (3.08 g, 8.99 mmol, 1.0 equiv), toluene
(28 mL, 24.39 g), DBU (4.10 mL, 4.15 g, 27.28 mmol), XantPhos
(155.0 mg, 0.27 mmol) and Pd(OAc).sub.2 (60.0 mg, 0.27 mmol). The
reactor was closed, flushed three times with carbon monoxide, and
then heated to 90.degree. C. with 2 bar CO present. Carbon monoxide
was introduced into the reactor at a pressure of 3 bar and then
increased to 4 bar, with the reaction mixture stirring at 750 rpm.
The reaction was allowed to proceed with GC monitoring. After 24
hours at 70.degree. C., the reaction mixture was cooled to room
temperature.
LC Purity (Area % product/Area % starting
material+product+aniline)=90%
[0220] Water (20 mL) was added, resulting in some gas formation.
The reaction mixture was transferred to an Erlemeyer flask and
stirred for 20 minutes. The resulting layers were separated. The
organic layer was washed three times with water, filtered and
evaporated at 50.degree. C. on a rotovap to yield a dark brown
residue. Methanol (18 mL) was added to the residue and the
resulting mixture heated to 55.degree. C. Water (1.6 mL) was added
and the turbid mixture seeded, resulting in the start of
precipitation. The resulting mixture was stirred for 30 min, cooled
to room temperature, then placed in a 5.degree. C. ice-water bath,
with stirring, for 15 minutes. The resulting mixture was filtered,
the solids washed with 5:1 methanol: water mixture, then dried
overnight in a vacuum oven at 50.degree. C., to yield the title
compound (3.15 g, 5.32 mmol).
[0221] Yield: 59.2% (H PLC purity: 97%)
Example 2
4-cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrah-
ydro-2H-pyran-4-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-i-
midazole-2-carboxamide
##STR00084##
[0223] A 60 mL stainless steel MULTIMAX reactor was charged with
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile
(2.97 g, 9.83 mmol, 1.08 equiv),
2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-py-
ran-4-yl)pyridin-3-amine (3.11 g, 9.08 mmol, 1.0 equiv), toluene
(27 mL, 23.52 g), potassium phosphate, tribasic, N-hydrate (5.88 g,
26.29 mmol), XantPhos (142.0 mg, 0.25 mmol) and Pd(OAc).sub.2 (54.0
mg, 0.24 mmol). The reactor was closed, flushed three times with
nitrogen, and then heated to 90.degree. C. Carbon monoxide was
introduced into the reactor at a pressure of 4 bar, with the
reaction mixture stirring at 750 rpm. The reaction was allowed to
proceed with LC monitoring. The reaction mixture was stirred for a
total of 22.5 hours, then cooled to 25.degree. C.
LC Purity (Area % product/Area % starting
material+product+aniline)=86%
[0224] Water (15 mL) was added, resulting in a temperature increase
and formation of foam. The resulting biphasic mixture was stirred
for 30 minutes, then the resulting layers were separated. The
organic layer was washed three times with water (15 mL), with the
pH of the last aqueous layer measured at between pH7 and pH8. The
rag-layer was discarded, the organic layer was filtered, then
evaporated to yield a residue. Methanol (18 mL) was added to the
residue and the resulting mixture heated to 55.degree. C. Water
(2.6 mL) was added and the turbid mixture seeded, resulting in the
start of crystallization. After a few moments, additional water (1
mL) was added, the resulting mixture cooled to room temperature,
then to 2.degree. C. The resulting mixture was filtered, the solids
washed with 1:1 methanol: water mixture, then dried overnight to
yield the title compound (3.59 g, 6.07 mmol).
[0225] Yield: 66.8% (HPLC purity: 96%)
Example 3
4-cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrah-
ydro-2H-pyran-4-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-i-
midazole-2-carboxamide
##STR00085##
[0227] A 60 mL stainless steel MULTIMAX reactor was charged with
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile
(3.80 g, 12.57 mmol, 1.39 equiv),
2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-py-
ran-4-yl)pyridin-3-amine (3.09 g, 9.02 mmol, 1.0 equiv), toluene
(27 mL, 23.52 g), potassium phosphate, tribasic, N-hydrate (5.74 g,
27.04 mmol), XantPhos (0.13 g, 0.22 mmol) and Pd(OAc).sub.2 (0.05
g, 0.23 mmol). The reactor was closed, flushed three times with
nitrogen, and then heated to 90.degree. C. Carbon monoxide was
introduced into the reactor at a pressure of 4 bar, with the
reaction mixture stirring at 750 rpm. The reaction was allowed to
proceed with LC monitoring. The reaction mixture was stirred
overnight (23 hours), then cooled to 25.degree. C.
LC Purity (Area % product/Area % product+aniline)=96%
[0228] Water (15 mL) was added, resulting in the observed formation
of some gas. The resulting biphasic mixture was transferred to an
Erlemeyer flask with magnetic stirred and stirred for 20 minutes.
The resulting mixture was filtered, the filter washed with toluene,
and the resulting layers were separated. The organic layer was
washed three times with water (15 mL). The organic layer was then
evaporated to yield a dark brown solid residue. Methanol (18 mL)
was added to the residue and the resulting mixture heated to
55.degree. C. Water (1.8 mL) was added, the resulting mixture
seeded and allowed to cool to room temperature. The resulting
mixture was then cooled 2.degree. C. and stirred for an addition 30
min. The resulting mixture was filtered, the solids washed with 5:1
methanol: water mixture, then dried overnight in a vacuum oven at
50.degree. C. to yield the title compound (4.07 g, 6.88 mmol).
[0229] Yield: 76.2% (HPLC purity: 95%)
Example 4
4-cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrah-
ydro-2H-pyran-4-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-i-
midazole-2-carboxamide
##STR00086##
[0231] A 60 mL stainless steel MULTIMAX reactor was charged with
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile
(3.26 g, 10.79 mmol, 1.20 equiv),
2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-py-
ran-4-yl)pyridin-3-amine (3.08 g, 8.99 mmol, 1.0 equiv), toluene
(27 mL, 23.52 g), potassium phosphate, tribasic, N-hydrate (5.71 g,
26.90 mmol), XantPhos (0.15 g, 0.26 mmol) and Pd(OAc).sub.2 (0.06
g, 0.27 mmol). The reactor was closed, flushed three times with
carbon monoxide, and then heated to 90.degree. C. with 2 bar CO
present. Carbon monoxide was introduced into the reactor at a
pressure of 4 bar, with the reaction mixture stirring at 750 rpm.
The reaction was allowed to proceed with LC monitoring. The
reaction was allowed to proceed overnight, then cooled to room
temperature.
LC Purity (Area % product/Area % product+aniline)=95%
[0232] Water (20 mL) was added, resulting in some gas formation.
The reaction mixture was transferred to an Erlemeyer flask and
stirred for 20 minutes. The resulting layers were filtered, then
washed with toluene, resulting in good separation of the layers.
The layers were separated, with almost no rag-layer. The organic
layer was filtered and the solvent evaporated on a rotovap at
50.degree. C., to yield a dark brown residue. Methanol (18 mL) was
added to the residue and the resulting mixture heated to 50.degree.
C. Water (1.6 mL) was added and the resulting mixture seeded,
resulting in the start of precipitation. The resulting mixture was
stirred while cooling to room temperature, then placed in an
ice-water bath, with stirring, for 15 minutes. The resulting
mixture was filtered, the solids washed with 5:1 methanol:water
mixture, then dried overnight in a vacuum oven at 50.degree. C., to
yield the title compound (3.75 g, 6.34 mmol).
[0233] Yield: 70.5% (H PLC purity: 95%)
Example 5
4-cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrah-
ydro-2H-pyran-4-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-i-
midazole-2-carboxamide
##STR00087##
[0235] A 60 mL stainless steel MULTIMAX reactor was charged with
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile
(23.58 g, 78.02 mmol, 1.30 equiv),
2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-py-
ran-4-yl)pyridin-3-amine (20.56 g, 60.02 mmol, 1.0 equiv), toluene
(242 mL, 210.83 g), potassium phosphate, tribasic, N-hydrate (25.50
g, 120.13 mmol), XantPhos (0.87 g, 1.50 mmol) and Pd(OAc).sub.2
(0.34 g, 1.51 mmol). The reactor was closed, flushed two times with
nitrogen, flushed two times with carbon monoxide, and then heated
to 90.degree. C. with 2 bar CO present. Carbon monoxide was
introduced into the reactor at a pressure of 4 bar, with the
reaction mixture stirring at 750 rpm. The reaction was allowed to
proceed with LC monitoring. The reaction was allowed to proceed for
40 hours, then stirred at 4 bar pressure, but without additional CO
supply for an additional 44 hrs, then cooled to 20.degree. C.
LC Purity (Area % product/Area % product+bromide)=98%
[0236] Water (120 mL) was added, resulting in some gas formation.
The reaction mixture was then stirred vigorously for 30 min. The
resulting biphasic mixture was filtered and the solids washed with
toluene. The layers were separated--the colorless aqueous layer had
a pH+10, and the dark brown organic layer retained. The organic
layer was washed with water (120 mL), the layers separated--the
colorless aqueous layer had a pH of .about.8, with very little
rag-layer. The organic layer was washed a second time with water
(120 mL), and the layers separated--the colorless layer had a
neutral pH. The retained organic layer was transferred to an 500 mL
round bottom flask (RBF) equipped with a Dean-Stark trap and the
resulting mixture azeotropically dried at 110.degree. C., removing
about 50 mL. The resulting mixture was cooled to 80.degree. C.,
NORIT A-SUPRA (3.59 g) was added and the resulting mixture heated
to 100.degree. C., then stirred for 4 hours. The resulting mixture
was then cooled to 60.degree. C., filtered and the solids washed
with toluene. The resulting mixture was then transferred to a new
RBF, silica gel thiol (9 g) added, the mixture stirred overnight at
90.degree. C., then cooled to room temperature. The resulting dark
brown mixture was filtered, and the solids washed with toluene. The
resulting mixture was again transferred to a new RBF, silica gel
thiol (9 g) added, the mixture stirred overnight at 90.degree. C.,
then cooled to room temperature. The resulting mixture was
filtered, the solids washed with toluene and the solvent evaporated
by rotovap to yield a residue. The flask containing the residue was
flushed two times with methanol (60 mL). Methanol (150 mL) was
added to the residue and the resulting mixture heated to reflux.
The resulting mixture was allowed to cool to room temperature, with
spontaneous precipitation observed at about 40.degree. C. The
resulting mixture was then stirred for 2 hrs at room temperature,
filtered, the solids washed twice with methanol (30 mL) and the
resulting solids dried in vacuo overnight at 50.degree. C., to
yield the title compound (21.05 g, 35.57 mmol).
[0237] Yield: 59.2%
Example 6
4-cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrah-
ydro-2H-pyran-4-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-i-
midazole-2-carboxamide
##STR00088##
[0239] A 60 mL stainless steel MULTIMAX reactor was charged with
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile
(3.28 g, 10.85 mmol, 1.21 equiv),
2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-py-
ran-4-yl)pyridin-3-amine (3.07 g, 8.96 mmol, 1.0 equiv), toluene
(27 mL, 23.52 g), potassium carbonate (1.88 g, 13.60 mmol),
XantPhos (0.16 g, 0.27 mmol) and Pd(OAc).sub.2 (0.06 g, 0.26 mmol).
The reactor was closed, flushed three times with carbon monoxide,
and then heated to 90.degree. C., while maintaining carbon monoxide
at a pressure of 2.5 bar. Carbon monoxide was introduced into the
reactor at a pressure of 4 bar, with the reaction mixture stirring
at 750 rpm. The reaction was allowed to proceed with LC monitoring.
The reaction mixture was stirred overnight. To the reaction mixture
was then added a solution of
2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile
(0.65 g) in toluene. The resulting mixture was stirred for an
additional 2 hours, sampled and then stirred further, overnight at
90.degree. C. The resulting mixture was then cooled to 25.degree.
C. and allowed to stand at room temperature.
LC Purity (Area % product/Area % product+aniline)=96%
[0240] Water (20 mL) was added, and the resulting mixture was then
transferred to an Erlemeyer flask stirred for 30 minutes. The
resulting mixture was filtered, and the resulting layers were
separated. The organic layer was washed three times with water (20
mL). The rag-layer was filtered off. Toluene (50 mL) was added to
the organic layer, the resulting mixture transferred to a 250 mL
RBF and azeotropically distilled by removing about 50 mL. NORIT
A-SUPRA (0.53 g) was added and the resulting mixture stirred at
100.degree. C. for 1.5 hrs. The resulting mixture was filtered, the
filter washed with toluene, then transferred to a clean RBF and
stirred at for 3 hrs, at 100.degree. C., in the presence of Silica
gel thiol (1.04 g). The resulting mixture was cooled to room
temperature, then filtered. The reaction mixture was returned to
the RBF, then stirred overnight at 90.degree. C. in the presence of
Silica gel thiol (1.0 g). The resulting mixture was cooled to room
temperature, filtered and the solids washed with toluene. The
solvent was evaporated on a rotovap to yield a residue. Methanol
(18 mL) was added to the residue and the resulting mixture heated
to 55.degree. C. Water (1.8 mL) was added at 50.degree. C., the
resulting mixture seeded and then allowed to cool to room
temperature, resulting in precipitation of a solid. The resulting
mixture was stirred for an additional 2 hrs at room temperature,
then filtered. The resulting solids were washed with 5:1
methanol:water mixture, then dried overnight in a vacuum oven at
50.degree. C. to yield the title compound (4.09 g, 6.91 mmol).
[0241] Yield: 77.1% (relative HPLC purity 97%)
Example 7
4-cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrah-
ydro-2H-pyran-4-yl)pyridin-3-yl)-1H-imidazole-2-carboxamide HCl
salt
##STR00089##
[0243] To a 1 L 3-neck round bottom flask equipped with an overhead
stirrer, 250 mL addition funnel, argon inlet and heating mantle was
added 4-cyano-N-(2-(4,4-di
methylcyclohex-1-enyl)-6-(2,2,6,6-tetramethyltetrahydro-1H-pyran-4-yl)pyr-
idine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1-imidazole-2-carboxamide
(60.5 g, 0.102 mol) followed by 3% aqueous IPA (265 mL). The
temperature was set at 65.degree. C., HCl in IPA (.about.5.5 N, 185
mL) was added dropwise to the mixture at room temperature. After 7
min, an additional portion of HCl-IPA (90 mL) was added, and the
internal temperature was 50.degree. C. Addition was complete after
18 min, with the internal temperature at 65.degree. C. The
temperature was then increased to 70.degree. C. The de-protection
was monitored by HPLC. After 1.5 hours, the heating mantle was
removed and the mixture immersed in a dry ice/acetone bath, cooling
the reaction to -18.degree. C. After standing in the bath at
-10.degree. C. and -18.degree. C. for 30 minutes, the resulting
solid precipitate was isolated by filtration. The solids were
washed with cold IPA (60 mL) and dried to yield the title compound
as a solid (29 g). The mother liquor was diluted with diethyl ether
(20 mL) and set in a refrigerator overnight. The resulting mixture
was then concentrated to 1/2 volume, diethyl ether (6 mL) was added
and the resulting mixture cooled on dry ice for 30 min. The
resulting mixture was filtered to yield the title compound as a
solid (7.1 g). The combined solids were dried at 140.degree. C. for
1.5 days in a vacuum oven to yield the title compound. Yield: 36.1
g, 73%
Example 8
2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate
##STR00090##
[0245] A 2 L RBF under light nitrogen flow was charged with
2,2,6,6-tetramethyldihydro-2H-pyran-4(3H)-one (1.00 equiv; 49.10
mL; 43.45 g), (a known compound which may be prepared as described
in, for example, MAGNUS, P., et al., "Synthesis of the ABCD-rings
of the insecticidal indole alkaloid nodulisporic acid", Tet. Lett.,
1999, pp 6909-6912, Vol. 40) 2-methyl-THF (375.00 mL; 322.05 g) and
DBU (76.67 mL; 77.67 g). The resulting mixture was stirred and
cooled to about 2.degree. C. with a water-ice bath. NfsulphF (1.20
equiv; 56.07 mL; 94.20 g) was introduced into a dropping funnel and
the NfsulphF was then added to the reaction mixture over 20
minutes, with a light exotherm is observed. After complete
addition, the water-ice bath was taken away and the temperature
allowed to rise to room temperature. Precipitation was observed to
start forming, resulting in a yellow suspension. The yellow
suspension was stirred overnight at room temperature and yielded
yield a brown suspension.
[0246] To the brown suspension was slowly added water (1.12 L; 1.12
kg), with an observed exotherm. The resulting mixture was warmed
44.degree. C., resulting in a multi-phase mixture with good
separation (the organic layer was the top layer). The mixture was
stirred for 20 minutes and the phases warm separated at about
44.degree. C. The aqueous (orange colored) layer was returned to
the RBF, and then extracted with 2-methyl-THF (185.00 mL; 158.88 g)
by stirring 20 minutes at 44.degree. C., then warm separating the
resulting layers. The organic layers were then combined. Water
(190.00 mL; 190.00 g) was added and the resulting mixture stir for
20 minutes, and the resulting layers warm separated at 44.degree.
C. The organic layer was then washed second time with water (190.00
mL; 190.00 g), with some white fluffy precipitation observed in the
water layer. The organic layer was then evaporated on a rotavap at
45.degree. C. The resulting biphasic residue included a thick brown
bottom layer (129.17 g) and light colored material on top. To the
residue was added HEPTANE 50% (a mixture of 50% n-heptane, 20%
other heptane isomers and 30% methyl cyclohexane; 250.00 mL; 176.75
g), then acetonitrile (19.00 mL; 14.88 g). The resulting mixture
was stirred firmly, the acetonitrile was observed to take up the
oily layer, resulting in a biphasic system. The mixture was then
stirred for 1 hour, the layers separated. The heptane layer was
evaporated on a rotovap at 42.degree. C. to yield the title
compound as a residue (102.60 g)
TABLE-US-00001 Actual Yield: 93.52% 102.60 g, 234.08 mmol
Theoretical Yield: 100% 109.58 g, 250.00 mmol
[0247] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *