Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-07
2002-06-18
Huang, Evelyn Mei (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S300000, C546S301000, C544S238000, C544S264000, C544S333000, C544S405000
Reexamination Certificate
active
06407241
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention provides an improved process for the preparation of imidazolidinone &agr;v&bgr;3/&agr;v&bgr;5 integrin antagonists of general structural formula (I).
The present invention also provides intermediates useful in the disclosed process.
The compounds of structural formula (I), along with their use as &agr;v&bgr;3/&agr;v&bgr;5 integrin antagonists for inhibiting bone resorption and treating and/or preventing osteoporosis, were disclosed in U.S. Pat. No. 6,017,926 (Jan. 25, 2000), which is incorporated by reference herein in its entirety, and in WO 99/31099 (published Jun. 24, 1999). The compounds disclosed therein are also useful in inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.
U.S. Pat. No. 6,017,926 also described a process for preparing the compounds of formula (I). However, a large number of synthetic transformations was required (the longest linear sequence being about 14 steps) with an overall yield of less than 5%. Silica gel column chromatography was required after most of the steps, and final products were obtained with an enantiomeric purity of less than 90%.
With the present invention there are produced more efficiently compounds of structural formula (I) with an enantiomeric purity in excess of 99% in considerably fewer chemical steps (the longest linear sequence being 10 steps) with an overall yield of about 30%. Moreover, a smaller number of chromatographic purification steps is necessary throughout the synthetic sequence.
SUMMARY OF THE INVENTION
This invention is concerned with a process for preparing compounds of structural formula (I) and certain useful intermediates obtained during that process.
The novel process and novel intermediates can be exemplified in the following embodiment, which illustrates the preparation of 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]imidazolidin-1-yl}-3(S)-(6-methoxypyridin-3-yl)-propionic acid (3-4). The overall process converges two Series A and B of reaction steps, each producing a key intermediate, into a third Series C of steps in which the two intermediates are combined to ultimately produce the desired products of structural formula (I). Series A affords intermediates exemplified by 2-6, and Series B yields intermediates exemplified by 1-8.
Also provided are intermediate compounds which are useful for the preparation of compounds of structural formula (I).
Another aspect of the present invention provides compound 3-4 in the form of a hemihydrate as well as a method for the preparation of the hemihydrate.
The products of the present process are antagonists of &agr;v&bgr;3/&agr;v&bgr;5 integrin receptors and therefore useful for inhibiting bone resorption and treating and/or preventing osteoporosis. They are also useful in inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammnatory arthritis, cancer, and metastatic tumor growth.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an efficient process for the preparation of compounds of structural formula (I):
wherein
Ar is mono- or di-substituted phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazolyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, isoindolyl, purinyl, or carbazolyl, wherein the substituent is independently selected from the group consisting of hydrogen, C
1-6
alkyl, halogen, C
3-6
cycloalkyl, C
1-3
acylamino, C
1-4
alkoxy, C
1-5
alkoxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C
1-4
alkylamino, di-C
1-4
alkylamino, and C
1-5
alkylcarbonyloxy; and
R
1
is selected from the group consisting of hydrogen, halogen, C
1-10
alkyl, C
3-6
cycloalkyl, and C
1-3
alkoxy;
which comprises the steps of:
(a) producing a compound of structural formula (III):
wherein R
2
is C
1-4
alkyl and R
3
is C
1-4
alkyl, phenyl-C
1-3
alkyl, diphenylmethyl, or triphenylmethyl;
by treating a compound of structural formula (V):
with glyoxal-1,1-di-C
1-4
alkyl acetal in the presence of a reducing agent and isolating the resulting product;
(b) preparing a compound of structural formula (II):
by treating an amine of structural formula (III):
wherein R
2
is C
1-4
alkyl and R
3
is C
1-4
alkyl, phenyl-C
1-3
alkyl, diphenylmethyl, or triphenylmethyl;
with an amine of structural formula (IV),
wherein R
1
is as defined above, in the presence of phosgene or a phosgene equivalent and base to produce a compound of structural formula (VI):
followed by treatment with aqueous acid;
(c) cleaving the R
3
protecting group in a compound of structural formula (II) to afford a compound of structural formula (VII),
(d) reducing the imidazolin-2-one double bond in a compound of structural formula (VII), and
(e) isolating the resulting product.
The order in which the last two steps of the process of the present invention are carried out may be reversed such that the imidazolin-2-one double bond in a compound of structural formula (II):
is first reduced to afford a compound of structural formula (VIII):
and the R
3
protecting group in a compound of structural formula (VIII) is then cleaved to afford a compound of structural formula (I).
In one embodiment of the present invention, there is provided a process for preparing a compound of structural formula (I):
wherein
Ar is mono-or di-substituted phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazolyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, isoindolyl, purinyl, or carbazolyl, wherein the substituent is independently selected from the group consisting of hydrogen, C
1-6
alkyl, halogen, C
3-6
cycloalkyl, C
1-3
acylamino, C
1-4
alkoxy, C
1-5
alkoxycarbonyl, cyano, trifluoromethyl, hydroxy, trifluoromethoxy, amino, C
1-4
alkylamino, di-C
1-4
alkylamnino, and C
1-5
alkylcarbonyloxy; and
R
1
is selected from the group consisting of hydrogen, halogen, C
1-10
alkyl, C
3-6
cycloalkyl, and C
1-3
alkoxy;
which comprises the steps of:
(a) cleaving the R
3
protecting group in a compound of structural formula (II):
wherein R
3
is C
1-4
alkyl, phenyl-C
1-3
alkyl, diphenylmethyl, or triphenylmethyl, to afford a compound of structural formula (VII);
(b) reducing the imidazolin-2-one double bond in a compound of structural formula (VII); and
(c) isolating the resulting product.
In another embodiment of the present invention, the imidazolin-2-one double bond in a compound of structural formula (II) is first reduced to afford a compound of structural formula (VIII) followed by cleavage of the R
3
protecting group to afford a compound of structural formula (I).
In a class of these two embodiments, R
3
is tert-butyl.
In a second class class of these two embodiments, R
1
is hydrogen and Ar is 6-methoxy-pyridin-3-yl. In a subclass of this class of these two embodiments, Ar is (S)-6-methoxy-pyridin-3-yl.
In a third class of these two embodiments, the imidazolin-2-one double bond is reduced by catalytic hydrogenation.
In a third embodiment of the present invention, there is provided a process for preparing a compound of structural formula (II):
which comprises treating an amine of structural formula (III):
wherein R
2
is C
1-4
alkyl and R
3
is C
1-4
alkyl, phenyl-C
1-3
alkyl, diphenylmethyl, or triphenylmethyl;
with an amine of structural formula (IV):
wherein R
1
is as defined above, in the presence of phosgene or a phosgene equivalent and base to produce a compound of structural formula (VI):
followed by treatment with aqueous acid, and isolating the resulting product.
In a class of this embodiment, the phosgene equivalent is chlorocarbonic acid tri
Jensen Mark S
Palucki Michael
Rivera Nelo R.
Wang Yaling
Wells Kenneth M.
Durette Philippe L.
Huang Evelyn Mei
Merck & Co. , Inc.
Winokur Melvin
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