Process for preparing cis- aminochromanols

Details Process for preparing cis- aminochromanols Process for preparing cis- aminochromanols

2001-05-11

2002-05-07

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06384244

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the preparation of cis-aminochromanols by reduction of the corresponding &agr;-hydroxyoximes. 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 US '999, the third entry in cols. 33-34.
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 US '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 a process for preparing cis-4-aminochroman-3-ols via oxime hydrogenation. The process of the present invention has unexpectedly been found to afford cis-aminochromanol in high yields and with a relatively high selectivity relative to the trans isomer. More particularly, the present invention is a process for preparing a cis-aminochromanol of Formula (I):
which comprises:
(A) hydrogenating in the presence of a catalyst a mixture comprising an oxime of Formula (II):
 solvent, and an acid selected from the group consisting of (i) HBr, (ii) HCl, and (iii) organic sulfonic acids; wherein
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
b
—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
(1) hydrogen;
(2) C
1
-C
6
alkyl;
(3) C
1
-C
6
alkyl substituted with one or more substituents, each of which is independently halo, cyano, C
1
-C
4
alkoxy, C
1
-C
4
haloalkoxy, C
3
-C
8
cycloalkyl, or phenyl;
(4) C
3
-C
8
cycloalkyl;
(5) C
3
-C
8
cycloalkyl substituted with one or more substituents, each of which is independently halo, cyano, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy, C
1
-C
4
haloalkoxy, or phenyl;
(6) phenyl; or
(7) phenyl substituted with one or more substituents, each of which is independently C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy, C
1
-C
4
haloalkoxy, cyano, or 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.
In one embodiment, the present invention further comprises:
(B) treating the hydrogenated mixture with base to provide free amine.
The process of the present invention has distinct advantages over known methods for producing aminochromanols. For example, the PtO
2
-catalyzed hydrogenation disclosed in Bognar et al. (cited above) employs acetic acid, which has poor selectivity for the cis product over the trans. The preparation of aminothiochromanol disclosed in Ghosh et al. (cited above) requires reduction of a benzyloxime reactant with borane, which is a relatively expensive reducing agent, and has a relatively poor yield and poor cis/trans selectivity. On the other hand, the hydrogenation process of the present invention can achieve relatively high yields and high cis over trans selectivity using inexpensive reagents (i.e., H
2
and HBr, HCl, or an organic sulfonic acid) and a reusable catalyst (e.g., palladium).
The process of the invention is distinct from the hydrogenation chemistry disclosed in U.S. Pat. No. 6,057,479, which is limited to the preparation of cis-1-amino-2-indanol. Furthermore, the C6:C5O chromanyl ring system is much more flexible than the relatively rigid C6:C5 indanyl system, and thus has access to a number of low energy conformations that would not be available to the indanyl. Accordingly, the relative high cis/trans selectivity for the aminoindanol product disclosed in US '479 is not predictive of the selectivity that can be achieved for an aminochromanol product prepared using the analogous chemistry. Further evidence of the distinctiveness of the process of the invention with respect to US '479 is that US '479 discloses essentially the same cis/trans selectivity for both HCl and HBr, whereas the process of the invention can achieve much higher cis-trans selectivity for HBr, than for HCl (see Examples 3 and 5 below).
Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes a process for preparing cis-amino-chromanols by catalytically hydrogenating the corresponding &agr;-hydroxyoxime in the presence of an acid. This process is set forth in the Summary of the Invention as Step A.
In this process, each group R
1
in the definition of Compounds I and II 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
b
—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
. In one embodiment, each R
1
is independently halo, C
1
-C
6
alkyl, halogenated C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or halogenated C
1
-C
6
alkoxy. In another embodiment, each R
1
is independently halo, C
1
-C
4
alkyl, halogenated C
1
-C
4
alkyl, C
1
-C
4
alkoxy, or halogenated C
1
-C
4
alkoxy. In still another embodiment, each R
1
is independently chloro, fluoro, C
1
-C
4
alkyl, fluorinated C
1
-C
4
alkyl, C
1
-C
4
alkoxy, or fluorinated C
1
-C
4
alkoxy. In still another embodiment, each R
1
is fluoro, C
1
-

Affiliated with

Also associated with

Rating

Process for preparing cis- aminochromanols 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 for preparing cis- aminochromanols, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing cis- aminochromanols will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2878772