Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2000-01-26
2002-08-13
Killos, Paul J. (Department: 1609)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C560S037000, C560S038000, C560S155000
Reexamination Certificate
active
06433209
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to a method for stereoselective &agr;-substitution of unprotected &bgr;-amino ester compounds under mild conditions. The resultant &agr;-substituted unprotected &bgr;-amino ester compounds are useful in preparing a plethora of biologically active compounds, for example, Factor Xa inhibitors that are useful for treating physiological conditions in a patient that can be ameliorated by administering the inhibitor of Factor Xa.
RECENT DEVELOPMENTS
Current methods for &agr;-substitution of &bgr;-amino ester or acid compounds require the amine to be protected/functionalized before the substitution. In addition, current methods also necessitate the eventual removal of the amine protecting/functionalization group.
Juaristi et al., J. Org. Chem., 58, 2282-5 (1993) disclose the &agr;-substitution of &bgr;-amino acid compounds as follows in Scheme I: (1) converting the &bgr;-amino acid compounds
Scheme I
to corresponding perhydropyrimidine-4-one compounds; (2) alkylating the perhydropyrimidine-4-one compounds; and (3) ring opening the resultant alkylated perhydropyrimidine-4-one compounds to yield the corresponding &agr;-alkylated &bgr;-amino acid compounds. See Jurasti, Enantio-selective Synthesis of &bgr;-amino Acids (Wiley-VCH, New York, 1997) 263-70. Juaristi et al. do not disclose the &agr;-substitution of unprotected or unfunctionalized &bgr;-amino acid compounds.
Seebach et al., Tetrahedron Lett., 28(7), 3103-6 (1987) disclose the &agr;-substitution of &bgr;-amino ester compounds as follows in Scheme II: (1) protecting the amine group of the &bgr;-amino ester compounds; (2) alkylating the N-protected &bgr;-amino ester compounds; and (3) deprotecting the &agr;-alkylated N-protected &bgr;-amino acid com-pounds. See also Estermann et al., Helv. Chim. Acta, 71, 1824-39 (1988). Neither Seebach or Estermann disclose &agr;-substitution of unprotected or unfunctionalized &bgr;-amino acid compounds.
Scheme II
In view of the aforesaid, it would be worthwhile to have synthetic procedures for preparing &agr;-substituted &bgr;-amino ester compounds that require fewer reactants and/or steps, i.e., simplified and less costly synthetic procedures.
SUMMARY OF THE INVENTION
The present invention is directed to a method for stereoselective substitution in which a (mono or un)-&agr;-substituted unprotected &bgr;-amino ester compound or salt thereof is reacted with an aliphatic electrophile in the presence of a base selected from alkyl lithium compounds, lithium hydride, lithium amide, lithium dialkyl amides and alkali hexamethyldisilylamines.
DETAILED DESCRIPTION OF THE INVENTION
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
Definitions
“Patient” includes both human and other mammals.
“Acid protecting group” means an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and preferably to be selectively removable. The use of acid protecting groups is well known in the art for protecting against undesirable reactions during a synthetic procedure and many such protecting groups are known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields. (See U.S. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are incorporated herein by reference, and T. W. Green and P. G. M. Wuts, “Protective Groups in Organic Chemistry” John Wiley & Sons, 1991.) Examples of carboxylic acid protecting groups include esters such as methoxymethyl, methylthiomethyl, tetrahydropyranyl, substituted and unsubstituted phenacyl, 2,2,2-trichloroethyl, tert-butyl, cinnamyl, dialkylaminoalkyl (e.g., dimethylaminoethyl and the like), trimethylsilyl, and the like, and amides and hydrazides including N,N-dimethyl, 7-nitroindolyl, hydrazide, N-pbenyl-bydrazide, C
1
to C
8
loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; alkanoyloxy-alkyl groups such as pivaloyloxymethyl or propionyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxy-carbonylmethyl and the like; alkoxycarbonyloxyalkyl, such as t-butyloxycarbon-yloxymethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxy-alkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylamino-carbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl) alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.
“Amine protecting group” means an easily removable group known in the art to protect an amino group against undesirable reaction during synthetic procedures and preferably selectively removable. The use of amine protecting groups is well known in the art for protecting against undesirable reactions during a synthetic procedure and many such protecting groups are known (see, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2
nd
edition, John Wiley & Sons, New York (1991)). Preferred protecting groups are acyl, including formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, benz-oyl, aminocaproyl, and the like, and acyloxy including methoxy-carbonyl, 9-fluorenylmethoxy-carbonyl, 2,2,2-tri-fluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl (BOC), 1,1-di-methylpropynyloxycarbonyl, benzyloxy-carbonyl (CBZ), p-nitrobenzyloxycarbony, 2,4-di-chlorobenzyloxy-carbonyl, and the like.
“Acid labile amine protecting group” means an amine protecting group as defined above which is readily removed by treatment with acid while remaining relatively stable to other reagents. A preferred acid labile amine protecting group is tert-butoxycarbonyl (BOC).
“Hydrogenation labile amine protecting group” means an amine protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile protecting group is benzyloxycarbonyl (CBZ).
“Hydrogenation labile acid protecting group” means an acid protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile acid protecting group is benzyl.
“Thiol protecting group” means a protecting group that is readily removed by some reagents while being relatively stable to other reagents. The use of thiol protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2
nd
edition, John Wiley & Sons, New York (1991), incorporated herein by reference. Exemplary thiol protecting groups are trityl (Trt), acetamidomethyl (Acm), and the like.
“Hydroxy protecting group” means a protecting group that is readily removed by some reagents while being relatively stable to other reagents. The use of hydroxy protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2
nd
edition, John Wiley & Sons, New York (1991), incorporated herein by reference. Exemplary hydroxy protecting groups are t-butyl, benzyl
Chandramouli Sithamalli V.
O'Brien Michael K.
Powner Tory H.
Aventis Pharmaceuticals Inc.
Butch, III Peter J.
Killos Paul J.
Wang George G.
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