Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-17
2003-11-11
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S300000, C514S351000
Reexamination Certificate
active
06646130
ABSTRACT:
BACKGROUND OF THE INVENTION
U.S. Pat. No. 6,017,926 (issued Jan. 25, 2000) discloses compounds of the structural formula:
which include the two enantiomeric forms at the C-3 position (marked with an *) of the right-hand propionic acid side-chain.
These compounds are antagonists of the integrin receptor &agr;v&bgr;3 and are therefore useful for inhibiting bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory arthritis, cancer, and metastatic tumor growth. They are particularly useful for inhibiting bone resorption and for the treatment and prevention of osteoporosis.
Processes for the preparation of the enantiomerically enriched (R) and (S) forms of the above compound are disclosed in U.S. Pat. No. 6,017,926 and WO 01/34602. A key intermediate in these published processes is enantiomerically enriched 3(S)- or 3(R)-(6-methoxy-pyridin-3-yl)-&bgr;-alanine methyl, ethyl or tert-butyl ester of structural formulae (1) and (2), respectively.
The published chemical routes to the above chiral &bgr;-amino acids involve a diastereoselective Michael addition of the lithium amide derived from N-benzyl-(S)- or (R)-2-methylbenzylamine using conditions described by Davies et al., in
Tetrahedron: Asymmetry,
Vol. 2, pp. 183-186, 1991. However, this methodology suffers from economic disadvantages associated with the high costs of reagents in the Davies chemistry and from operational limitations in the diastereoselective Michael addition reaction. The present invention is concerned with a short and efficient route to enantiomerically enriched mixtures of alkyl esters of 3-(6-methoxy-pyridin-3-yl)-&bgr;-alanine which employs a chiral resolution by crystallization.
SUMMARY OF THE INVENTION
The present invention encompasses a process for the preparation of enantiomerically enriched mixtures of alkyl esters of 3-(6-methoxy-pyridin-3-yl)-&bgr;-alanine which are useful in the synthesis of integrin &agr;v&bgr;3 antagonists. Another aspect of the present invention is concerned with novel salts of 3-(6-methoxy-pyridin-3-yl)-&bgr;-alanine alkyl esters and a enantiomerically enriched N-protected-&agr;-amino acid.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention is concerned with a process for the preparation of enantiomerically enriched mixtures of compounds of structural I:
wherein
R
1
is C
1-4
alkyl;
comprising the steps of:
(a) mixing a compound of structural formula I with an (R)- or (S)-amino acid of structural formula II:
wherein R
2
is selected from the group consisting of phenyl, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-imidazolylmethyl, and 4-hydroxybenzyl; and and R
3
is tert-butyl, benzyl or 9-fluorenylmethyl; in an alcohol solvent system;
(b) heating the mixture from about 10° C. to about 100° C.;
(c) allowing the mixture to cool so that a crystalline (R)- or (S)-amino acid salt of said compound of formula I is formed;
(d) filtering the mixture to separate the crystalline salt from the supernatant; and
(e) liberating said compound of formula I from the crystalline salt by treating the salt with a base.
In one embodiment of this aspect of the present invention, R
1
is methyl, ethyl, or tert-butyl. In a second embodiment, R
2
is benzyl. In a third embodiment, R
3
is benzyl. In a class of the first embodiment, both R
2
and R
3
represent benzyl.
In a further embodiment, the amino acid used in Step (a) is N-(benzyloxycarbonyl)-(S)-phenylalanine.
In yet a further embodiment the alcohol solvent system is about 0% to about 50% water in an alcohol selected from the group consisting of methanol, ethanol, and isopropanol. In a class of this embodiment the alcohol solvent system is aquous ethanol or aqueous methanol.
The racemic amino ester for the chiral resolution step can be prepared as described in Scheme 1.
A partially enantiomerically enriched amino ester for further chiral resolution can be prepared as described in Scheme 2. This route is based on a published method for methyl 3-amino-3-(3-pyridyl)-propanoate [H. M. Zhong, et al.,
Tetrahedron Lett.,
40: 7721-7725 (1999)].
Another aspect of the process of the present invention is concerned with a crystalline salt of the structural formula:
wherein
R
1
is C
1-4
alkyl;
or the corresponding enantiomeric salt.
In one embodiment of this aspect, R
1
is methyl.
The term “enantiomerically enriched” is intended to include compounds that are enantiomerically pure.
The term “% enantiomeric excess” (abbreviated “ee”) shall mean the % major enantiomer less the % minor enantiomer. Thus, an 80% enantiomeric excess corresponds to formation of 90% of one enantiomer and 10% of the other. The term “enantiomeric excess” is synonymous with the term “optical purity.”
The term “Cbz” represents “benzyloxycarbonyl.”
Representative experimental procedures utilizing the novel process of the present invention are detailed below. For purposes of illustration, the following Examples are directed to the preparation of enantiomerically enriched mixtures of 3(S)-(6-methoxy-pyridin-3-yl)-&bgr;-alanine methyl ester, but doing so is not intended to limit the present invention to a process for making those specific mixtures.
The differential scanning calorimeter (DSC) curve was taken on a TA 2910 Differential Scanning Calorimeter with a heating rate of 10° C./minute under nitrogen.
X-ray powder diffraction patterns were generated on a Philip Analytical X-ray diffractometer using Cu K&agr; radiation. The experiments were run at ambient condition.
REFERENCES:
patent: 6017926 (2000-01-01), Askew et al.
patent: WO 01/34602 (2001-05-01), None
S.G. Davies et al., Tetrahedron: Asymmetry, vol. 2, No. 3, pp. 183-186 (1991).*
S. G. Davies et al., Tetrahedron: Asymmetry vol. 2, No.3, pp.183-186 (1991).
H. Marlon Zhong et al., Tetrahedron Letters 40 pp. 7721-7725 (1999).
Rivera Nelo R.
Welch Christopher J.
Xiao Yi
Yasuda Nobuyoshi
Coppins Janet L
Daniel Mark R.
Merck & Co. , Inc.
Rotman Alan L.
Shatynski Patricia A.
LandOfFree
Process to chiral integrin antagonist beta-amino acid... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process to chiral integrin antagonist beta-amino acid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process to chiral integrin antagonist beta-amino acid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3126240