Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-10-29
2004-01-06
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C546S334000, C546S335000
Reexamination Certificate
active
06673926
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a process for preparing 3S-3-amino-3-aryl propionic acid and derivatives thereof.
BACKGROUND OF THE INVENTION
3S-3-amino-3-aryl propionic acid derivatives of the formula I
wherein
R
1
is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R
2
is hydrogen, alkyl or aralkyl, or acid addition salts thereof, are useful as intermediates in the synthesis of compounds described in WO 97/41102, which is incorporated by reference herein. Compounds described in WO 97/41102 are antagonists of the platelet fibrinogen receptor (gp IIb/IIIa antagonist) and thus are useful for treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, reocclusion following thrombolytic therapy and angioplasty, inflammation, unstable angina and vaso-occlusive disorders.
Known methods for preparing compounds of Formula I include an asymmetric Michael addition of lithium N-(trimethylsilyl)-(R)-phenethylamide to ethyl 3-pyridyl acrylate to give the ethyl &bgr;-aminoester [Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P. R.
J. Org. Chem.
1993, 58, 7948]. This process results in inefficient formation of lithium amide and difficult removal of N-&agr;-methylbenzyl group.
J. Org. Chem. vol. 61, p. 2222 (1996) discloses a process wherein the lithium enolate of ethyl acetate is added to an enantiomerically pure sulfinimine, the product of which is purified by chromatography and deprotected under acidic conditions to afford the &bgr;-amino ester in greater than 90% ee. The need for chromatography makes this process unattractive for large-scale production. Similarly, J. Org. Chem., vol 64, p. 12 (1999) discloses a process wherein a titanium enolate of methyl acetate is added to an enantiomerically pure t-butylsulfinimine to afford the &bgr;-amino ester in about 90% ee.
WO 98/02410 discloses a process of stereoselective addition of the Reformatsky reagent prepared from t-butylbromoacetate to the enantiomerically pure imine prepared from 3-pyridine carboxaldehyde and (R)-2-phenylglycinol. Oxidative cleavage of the N-(1-phenyl-2-hydroxy ethyl) group with NaIO
4
in ethanol followed by acid hydrolysis affords the enantiomerically pure t-butyl &bgr;-amino ester. Use of oxidizing agents makes this process unattractive for large-scale production.
WO 97/41102 discloses enzymatic resolution of the (±)&bgr;-phenylacetamido acid using penicillin amidase to afford the S-acid. This process, which utilizes enzymes, is inefficient and impractical for large scale production.
Thus there exists a need for a process which is compatible with large scale production needs and which achieves acceptable levels of purity and yield.
SUMMARY OF THE INVENTION
The invention is directed to a process of making a compound of formula I, as described above, comprising reacting a compound of formula II,
wherein R
1
is aryl, heteroaryl, substituted aryl or substituted heteroaryl, at a pH range of between about 7 and about 11, to form a compound of formula III
wherein R
5
is N-t-butoxycarbonyl,
reacting a compound of formula III with at least 0.5 equivalents of (1R,2S)-(−)ephedrine, in an alkyl acetate solvent, to form a salt of formula IV
wherein Ph is phenyl, reacting the salt of formula IV with an inorganic base in water to form a carboxylate salt of the compound of formula V, acidifying the carboxylate salt of the compound of formula V with an acid of pKa less than or equal to three, to a pH of between about 3.5 and about 6.5, to form the compound of formula V
reacting the compound of formula V, at a temperature less than about 25° C., to form the compound of formula I.
In another aspect, the invention is directed to a novel crystal form of (3S)-3-[(tert-butoxy)carbonyl]amino-3-[3′-pyridyl]propionic acid, the intermediate of formula Va
wherein Boc is (tert-butoxy)carbonyl designated Form 2 and characterized by its x-ray powder diffraction patterns.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, unless otherwise noted, “alkyl” whether used alone or as part of a substituent group, shall include straight and branched chains containing 1 to 10 carbon atoms. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl and the like.
As used herein, unless otherwise noted, “alkoxy” shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein, unless otherwise noted, “aryl” shall refer to unsubstituted aromatic groups such as phenyl, napthyl, and the like. The aryl group may be substituted with one or two substituents. Suitable substituents on the aryl group are selected independently from the group consisting of halogen, alkyl, alkoxy, aralkyl, —NR
3
2
, wherein R
3
is alkyl; and R
4
CONH, wherein R
4
is phenyl or alkyl.
As used herein, unless otherwise noted, “heteroaryl” shall denote any five or six membered monocyclic ring structure containing at least one heteroatom selected from O, N and S or a bicyclic ring system wherein the heteroaryl is fused to an aryl group. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridazinyl, furanyl, pyranyl, imidazolyl, thiophenyl, oxazolyl, isothiazolyl, isoxazolyl, furazanyl, benzothienyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, isoquinolyl, quinolyl, isothiazolyl, and the like. The heteroaryl may be substituted with one or two substituents. Suitable substituents on the heteroaryl group are selected independently from the group consisting of halogen, alkyl, alkoxy, aralkyl, —NR
3
2
, wherein R
3
is alkyl; and R
4
CONH, wherein R
4
is phenyl or alkyl. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure, except when the heteroaryl contains only one heteroatom, then the heteroaryl must be attached at a carbon atom.
Preferably, the heteroaryl is pyridyl. The preferred heteroaryl may be substituted with one or two substituents as described above. Most preferably, the pyridyl is unsubstituted.
As used herein, unless otherwise noted, “aralkyl” shall mean any alkyl group substituted with an aryl group such as phenyl, napthyl and the like.
As used herein, unless otherwise noted, “halogen” shall mean chlorine, bromine, fluorine and iodine.
As used herein, unless otherwise noted, “an acid of pKa less than or equal to three” includes monochloroacetic, dichloroacetic, trichloroacetic, hydrochloric, hydrobromic, hydroiodic, perchloric, picric, nitric, sulfuric, phosphoric, methanesulfonic, tosic, trifluoromethanesulfonic, trifluoracetic, potassium bisulfate, sodium bisulfate, citric and the like.
As used herein, unless otherwise noted, “inorganic base” shall mean a base having a monovalent cation component, such as lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetrabutyl ammonium hydroxide, trimethylbenzyl ammonium hydroxide and the like.
As used herein, unless otherwise noted, “alkyl alcohol” shall denote a hydroxy derivative of the above described straight or branched chain alkyl groups. For example, methanol, ethanol, N-propanol, isopropanol, isobutanol, t-butanol and the like.
As used herein, the notation “S” and “R” shall denote the presence of a stereogenic center having the S or R configuration.
In a preferred embodiment of the invention, in the compound of formula I, R
1
is unsubstituted phenyl, substituted phenyl, unsubstituted pyrimidyl, substituted pyrimidyl, unsubstituted pyridyl, substituted pyridyl, unsubstituted napthyl or substituted naphthyl. Suitable substituents are selected independently from the group consisting of halogen, alkyl, alkoxy, aralkyl, —NR
3
2
, wherein R
3
is alkyl, and R
4
CONH, wherein R
4
is phenyl or alkyl. More preferably, R
1
is
Scott Lorraine
Villani, Jr. Frank John
Walker Donald G.
Ortho-McNeil Pharmaceutical , Inc.
Seaman D. Margaret
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