Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-24
2003-03-11
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S401000
Reexamination Certificate
active
06531617
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the preparation of enantiomerically enriched hydroxychromanones by the AlCl
3
-catalyzed intramolecular Friedel-Crafts acylation of the corresponding 3-phenoxy-2-alkylcarbonyloxy-propionic acid followed by cleavage of the carboxylate in the presence of an alkali metal peroxide or hydroperoxide. The present invention further relates to the preparation of enantiomerically enriched cis-aminochromanols by the diastereomeric reduction of oximes derived from the hydroxychromanones. The cis-aminochromanols are useful as intermediates in the preparation of HIV protease inhibitors.
References are made throughout this application to various published documents in order to more fully describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
cis-Aminochromanols are useful as intermediates in the preparation of HIV protease inhibitor compounds, which can be used to treat HIV infection, AIDS and ARC. EP 434,365 discloses, inter alia, a series of N-substituted 2(R)-((morpholinyl-ethoxy)phenylmethyl)-5(S)-((dimethylethoxycarbonyl)amino)-4(S)-hydroxy-6-phenyl-hexanamide derivatives which are useful as HIV protease inhibitors, including inhibitors prepared using cis-aminochromanol. In particular, reference is made to Example 21 of EP '365. U.S. Pat. No. 5,413,999 discloses certain N-substituted 2(R)-phenylmethyl-4(S)-hydroxy-pentaneamide derivatives which are useful as HIV protease inhibitors, including inhibitors which can be prepared from cis-aminochromanol. Reference is made, for example, to Table 1 of U.S. '999, the third entry in cols. 33-34.
The HIV protease inhibitor compounds typically have asymmetric centers, and the active form is often a particular enantiomer or diastereomer of the compound. In order to avoid a potentially complex and time-consuming resolution of the desired enantiomer or diastereomer from a mixture of optical isomers, it is desirable to prepare a relatively pure form of the active isomer directly using the appropriate optically active intermediates. Accordingly, it is also desirable to have an efficient, practical route for preparing optically enriched forms of cis-aminochromanols and also for preparing optically enriched forms of any intermediates and precursors thereof having chiral centers.
The present invention is directed to an efficient route for preparing optically enriched hydroxychromanones, the subsequent use of the hydroxychromanones for preparing optically enriched hydroxychromanone oximes, and the use of the oximes for preparing optically enriched cis-aminochromanols.
The following references are of interest as background:
Sethna, “Cycliacylation”, Chapter XXXV in
Friedel
-
Crafts and Related Reactions,
Vol. III, part 2, Interscience, 1964, pages 911-1002, describes the formation of cyclic compounds via intramolecular Friedel-Crafts acylations, such as the formation of cyclic ketones from arylaliphatic acids.
Kajiro et al.,
Bull. Chem. Soc. Jap.
1999, 72: 1093-1100, discloses the preparation of (R)-2-hydroxy-1-indanone by the intramolecular Friedel-Crafts acylation of (R)-2-acetoxy-3-phenylpropanoic acid. Kajiro et al. further discloses the preparation of the corresponding hydroxyindanone oxime from (R)-2-hydroxy-1-indanone, and then hydrogenating the oxime in the presence of HBr and Pd black to obtain (1S,2R)-1-amino-2-indanol.
Bognar et al.,
Tetrahedron
1963, 19: 391-394, discloses the preparation of 4-amino-3-hydroxyflavan by the hydrogenation of the corresponding oxime in the presence of PtO
2
at atmospheric pressure in warm aqueous (80%) acetic acid. Bognar et al.,
Tet. Letters
1959, No. 19: 4-8, has a similar disclosure.
Julian et al.,
J. Het. Chem.
1975, 12: 1179-1182, discloses the preparation of cis-4-aminochroman-3-ol by reaction of 2-oxo-1,3a,4,9b-tetrahydro-2H[1]benzo-pyrano[4,3-d]oxazole with methanolic potassium hydroxide. EP 434,365 discloses substantially the same preparation in Example 21, Steps A and B.
Ghosh et al.,
Tet. Letters
1991, 32: 711-714, discloses the preparation of 4-aminothiochroman-3-ol by the reduction of the corresponding &agr;-hydroxy benzyloxime with borane in tetrahydrofuran. It is further disclosed that borane reduction of an equilibrium mixture (3:2) of the anti and syn oximes afforded a 90/10 mixture of the cis/trans 4-aminothiochroman-3-ols.
U.S. Pat. No. 6,057,479 (Mitamura et al.) discloses the preparation of cis-1-amino-2-indanol by the catalytic hydrogenation of 2-hydroxy-1-indanone oxime in methanol. Example 21 of U.S. '479 discloses the hydrogenation in the presence of Pd black and HCl to give an aminoindanol product having a cis/trans selectivity of 95.5:4.5. Examples 22-23 report similar results for analogous hydrogenations using Pd/C and Pd/alumina. Example 24 discloses an analogous hydrogenation using Pd black and aqueous HBr to provide 1-amino-2-indanol product with a cis/trans ratio of 95.6:4.4. Results substantially the same as in Example 24 are also reported in Kajiro et al.,
SYNLETT
1998, p. 51.
SUMMARY OF THE INVENTION
The present invention is directed to an efficient process for preparing enantiomerically enriched 3-hydroxychroman-4-ones via the intramolecular Friedel-Crafts acylation of the corresponding 3-phenoxy-2-alkylcarbonyloxy-propionic acid followed by cleavage of the carboxylate group in the presence of an alkali metal peroxide or hydroperoxide. More particularly, the present invention is a process for preparing a hydroxychromanone of Formula (I):
which comprises:
(C) adding an acid halide of Formula (II-C):
to a solution of AlCl
3
in a first organic solvent at a temperature of less than about 0° C. to form an alkylcarbonyloxy chromanone of Formula (III):
and
(D) reacting Compound III with an alkali metal peroxide or hydroperoxide in a second organic solvent at a temperature of less than about 0° C. to form Compound I;
wherein:
stereocenter &agr; is in the R configuration or the S configuration;
each R
1
is independently halo, C
1
-C
6
alkyl, halogenated C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogenated C
1
-C
6
alkoxy, —CO
2
R
a
, —COR
a
, —NR
a
R
b
, —NR
a
—COR
b
, —NR
a
—CO
2
R
b
, —CO—NR
a
R
b
, —OCO—NR
a
R
b
, —NR
a
CO—NR
a
R
b
, —S(O)
p
—R
a
, wherein p is an integer from 0 to 2, —S(O)
2
—NR
a
R
b
, —NR
a
S(O)
2
—R
b
, or —NR
a
S(O)
2
—NR
a
R
b
;
R
2
is C
1
-C
6
alkyl;
X is halo;
each R
a
and R
b
is independently hydrogen, C
1
-C
4
alkyl, or (CH
2
)
0-3
CF
3
; and
m is an integer from 0 to 4.
The process of the invention can be conducted with the occurrence of little or no racemization. It has unexpectedly been found that the order of addition of the reactants and the reaction temperature in Step C of the process of the invention are key factors for minimizing racemization. More particularly, processes essentially the same as the process of the invention except that (i) AlCl
3
is added to a solution of the acid halide (versus addition of acid halide to an AlCl
3
solution) and/or (ii) the acylation is conducted at a temperature above 0° C. (versus temperatures below 0° C.) will typically afford a hydroxychromanone product having a comparatively much higher degree of racemization and a greater loss of enantiomeric excess. It has also unexpectedly been found that the use of an alkali metal peroxide or hydroperoxide (e.g., LiOOH) and low temperatures in the Step D carboxylate cleavage (e.g., deacetylation) is important for minimizing product racemization; i.e., processes which are the same as the process of the invention except for the use of reagents other than akali metal (hydro)peroxides for the cleavage of the carboxylate (e.g., strong acids such as sulfuric acid and hydrochloric acid) and/or a higher reaction temperature will typically result in a hydroxychromanone product having much greater racemization.
The present invention also includes a process for preparing an aminochromanol of Formula (VII):
in which the stereocenters
Devine Paul
Hansen Karl
Rabbat Philippe M.
Camara Valerie J.
Merck & Co. , Inc.
Trinh Ba K.
Walton Kenneth R.
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