Synthesis of 3-amino-3-aryl propanoates

Details Synthesis of 3-amino-3-aryl propanoates Synthesis of 3-amino-3-aryl propanoates

2000-03-21

2001-07-10

Davis, Zinna Northington (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C564S442000, C560S037000

Reexamination Certificate

active

06258956

ABSTRACT:

FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION
The invention relates to a process of preparing a compound of the formula
wherein R
1
is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R
2
is hydrogen, alkyl or aralkyl, or salt thereof.
Compounds of Formula I are useful as intermediates in the synthesis of, inter alia, compounds described in WO 97/41102. 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 (R)-N-(trimethylsilyl)-(1)-phenethylamide to ethyl 3-pyridyl acrylate to give the ethyl &bgr;-aminoester disclosed in U.S. Pat. No. 5,254,573. This process results in inefficient formation of lithium amide and difficult removal of N-(-methylbenzyl) group.
J. Org. Chem. vol. 61, p. 2222 (1996) discloses a process wherein the lithium enolate of ethyl acetate is added to an enantiomoric 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 chromatographic purification makes this process unattractive for large-scale production.
WO 98/02410 discloses a process of stereoselective addition of the Reformatsky reagent prepared from t-butylbromoacetate to the enantiomeric 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.
BRIEF SUMMARY OF THE INVENTION
The invention relates to a process for preparing a compound of the formula
wherein R1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R
2
is hydrogen, alkyl or aralkyl, or salt thereof,
comprising reacting a compound of the formula II
wherein R
1
is as described above and R
2
′ is alkyl or aralkyl, with a compound of the formula III
wherein R
5
is hydrogen or alkoxy, under conditions of reduced pressure, such that the reaction solution boils at temperatures of between about 400 and about 65° C., in an inert solvent, which solvent under reduced pressure is capable of azeotropic removal of water, to form the compound of formula IV,
reacting the compound of formula IV with hydrogen gas in the presence of a palladium catalyst to form the compound of formula V
and reacting the compound of formula V to form the compound of formula Ia or a salt thereof
wherein R
2
′ is alkyl or aralkyl.
If desired, compound Ia can further be converted to a compound of formula Ib or a salt thereof,
wherein R
2
″ is hydrogen via saponification of the ester.
The process of this invention, as described herein, is advantageous over previously disclosed methods in that it is volume efficient, making it suitable for large scale production.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, unless otherwise noted, alkyl whether used alone or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl and the like. Unless otherwise noted, “lower” when used with alkyl means a carbon-chain composition of 1-4 carbon atoms.
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 alone or as part of a substituent group, unless otherwise noted, “aryl” shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like. The aryl group may be substituted with at least one substituent. Suitable substituents on the aryl group are selected independently from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, lower aralkyl, —NR
3
2
, wherein R
3
is a lower alkyl; R
4
CONH, wherein R
4
is phenyl or a lower alkyl; and —OC(O)R
6
wherein R6 is hydrogen, alkyl or aralkyl.
As used herein, unless otherwise noted, “heteroaryl” shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from O, N and S or a bicyclic system wherein the monocyclic heteroaryl is fused to an aryl or monocyclic heteroaryl. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridazinyl, furanyl, pyranyl, imidazolyl, thienyl, oxazolyl, isothiazolyl, isoxazolyl, furazanyl, benzothienyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, isoquinolyl, quinolyl, isothiazolyl, and the like. The heteroaryl may be substituted with at least one substituent. Suitable substituents on the heteroaryl group are selected independently from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, lower aralkyl, —NR
3
2
, wherein R
3
is a lower alkyl; R
4
CONH, wherein R
4
is phenyl or a lower alkyl, and
—OC(O)R
6
wherein R
6
is hydrogen, alkyl or aralkyl;
preferably halogen or lower alkyl. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Preferably, the heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, furanyl and thienyl.
As used herein, unless otherwise noted, “aralkyl” shall mean any lower alkyl group substituted with an aryl group such as phenyl, naphthyl and the like.
As used herein, “halogen” shall mean chlorine, bromine, fluorine and iodine.
As used herein, the notation “*” shall denote the presence of a stereogenic center.
Compound of formula IV, because of the presence of a double bond, can exist in either the cis or the trans configuration or as a mixture of the two configurations.
Compound of formula V, because of the presence of two stereogenic centers can exist as any of four diastereomers, or mixture thereof.
As used herein, with respect to reagents and reaction products, the term “enantiomeric excess or ee” shall mean the excess amount of one enantiomer over another enantiomer. The enantiomeric excess (expressed as a percentage) is calculated as:
[(Amount Enantiomer
(1)
−Amount Enantiomer
(2)
)/(Total Amount Both Enantiomers)]*100%
Application of the present invention to a mixture of enantiomers of formula III, substantially free of the R enantiomer, will result in the production of a mixture of enantiomers of formula I, substantially free of the R enantiomer. Similarly, application of the present invention to a mixture of enantiomers of formula III, substantially free of the S enantiomer, will result in the production of a mixture of enantiomers of formula I, substantially free of the S enantiomer. Preferably, the enantiomeric excess of the desired enantiomer of formula III is at least 90 percent ee, more preferably at least 98 percent ee, most preferably 99 percent ee.
In a preferred embodiment of the invention, in the compound of formula I, R
1
is phenyl, pyrimidyl, unsubstituted or substituted pyridyl, napthyl or 3,5-dichlorophenyl, more preferably 2-pyridyl, 3-pyridyl or 4-pyridyl, most preferably 3-pyridyl. R
2
is preferably lower alkyl, more preferably methyl or ethyl.
The invention relates to a pro

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