Process for asymmetric hydrogenation

Details Process for asymmetric hydrogenation Process for asymmetric hydrogenation

2000-03-14

2001-04-03

Trinh, Ba K. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S294000

Reexamination Certificate

active

06211386

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is an improved process for the asymmetric hydrogenation of a double bond.
2. Description of the Related Art
[R-(R*,R*)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide is a protease inhibitor useful in treating humans infected with the HIV virus (AIDS) and is known as tipranavir.
J. Am. Chem. Soc.,
119, 3627 (1997) and the
J. Org. Chem.,
63, 7348 (1998) both disclose processes to produce tipranavir.
U.S. patent application Ser. No. 09/213,887 discloses a process to convert the ketone (I) to the cyclic ester (VI) as set forth in CHART A and EXAMPLES 1 thru 4 of U.S. patent application Ser. No. 09/213,887. CHART F of U.S. patent application Ser. No. 09/213,887 then discloses the transformation of the cyclic ester (VI) to the corresponding 6(R)- and 6(S)-olefin (XXV) by the process of EXAMPLE 16 which is then hydrogenated by the process of EXAMPLE 17 to produce the nitro-&agr;,&bgr;-unsaturated ester (XVII). The nitro-&agr;,&bgr;-unsaturated ester (XVII) is then transformed into tipranavir (XIX) by the process of EXAMPLES 14 and 15.
Hydrogenation reactions are very well known to those skilled in the art. In some hydrogenation reactions the product produced has an asymmetric carbon atom as in EXAMPLE 17 of U.S. patent application Ser. No. 09/213,887. It is known to those skilled in the art that the enantioselectivity of the hydrogenation can be influenced by the catalyst used. U.S. Pat. Nos. 5,171,892, 5,532,395 and 5,559,267 disclose enantioselective rhodium catalysts known as “DuPHOS” catalysts which can provide enantioselective hydrogenations in the 70 to 89% range.
U.S. Pat. No. 5,686,631 and
Tetrahedron Lett.
37, 8321 (1996) disclose an asymmetric hydrogenation of warfarin, a 2-pyranone derivative, with 89% enantioselectivity with a DuPHOS catalyst. However, warfarin has a phenyl ring attached to the 5,6-position of the compounds of the present invention which would change the three dimensional nature of the compound.
Chem. Rev.
93, 1307 (1993) and
Chem. Int. Ed. Engl.
26, 190 (1987) disclose that an important feature in some stereoselective hydrogenation reactions is a secondary coordination of functional groups.
Catalytic Asymmetric Synthesis; VCH, New York, 1993, Chapter 1 and Asymmetric Catalysis in Organic Synthesis, Wiley & Sons, New York, 1993, Chapter 2 disclose an important feature of stereoselective hydrogenation of olefin substrates is the geometry (E or Z) of the double bond. It is known that one isomer of an olefin would be a preferred substrate to obtain higher enantioselectivity of a particular enantiomeric product.
SUMMARY OF INVENTION
Disclosed is a process for the preparation of a compound of the formula:
where R
3
is selected from the group consisting of:
—NO
2
,
—NH
2
,
—NH—SO
2
-[4-trifluoromethylpyridin-2-yl],
—N(—CH
2
-&phgr;)
2
,
—N(R
3-1
)(R
3-2
) where R
3-1
and R
3-2
are the same or different and are:
—H,
—CO—O—(t-butyl),
—CO—O—CH
2
-&phgr;,
—CO—CH
3
,
—CO-&phgr;,
—Cl,
—Br,
—I,
—OH,
—O—SO
2
—CF
3
,
where n is 0 or 1 with the provisos, (1) that when n is 0 the R
3
group must be in the meta position and (2) that when n is 1, one of R
3
must be —Cl, —Br, —I, —OH or —O—SO
2
—CF
3
, where R
4
is selected from the group consisting of —H and —Si(CH
3
)
3
, which comprises hydrogenating a compound of the formula:
 the E-geometrical isomer thereof or a mixture of the Z- and E-isomers, where R
3
and R
4
are as defined above, in the presence of catalyst containing Rh, a chiral ligand with at least one phosphorous atom where the hydrogenation is conducted in the presence of a base.
Also disclosed is a process for the preparation of a compound of the formula:
where R
3
and n are as defined above, where R
4
is selected from the group consisting of Na
+
, K
+
, Li
+
, Cs
+
and (R
4-1
)
4
N
+
where R
4-1
are the same or different and are CH
3
—, C
2
H
5
—, C
4
H
9
—, &phgr;-CH
2
— and C
8
H
17
— which comprises hydrogenating a compound of the formula:
 the E-geometrical isomer thereof or a mixture of the Z- and E-isomers in the presence of catalyst containing Rh, a chiral ligand with at least one phosphorous atom.
Additionally disclosed is a process for the preparation of a compound of the formula
where R
1
and R
2
are the same or different groups and are each —H or up to 30 carbon atoms;
where R
3
is C
1
-C
8
alkyl;
where R
4
is aryl optionally substituted by a functional group; and
where R
4
is —H or —Si(CH
3
)
3
which comprises asymmetric hydrogenation of a compound of the formula
 where R
1
, R
2
, R
3
, R
4
and R
4
is as defined above in the presence of as a catalyst a complex of a transition metal and a chiral phosphine ligand with the proviso that when one of R
1
or R
2
is propyl, the other of R
1
or R
2
is not 1-(2-phenyl)ethyl.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is an improved catalytic hydrogenation of the olefin (VII) to the corresponding chiral compound (VIII); the improvement is the addition of base or starting with the enolate. Another invention is the improved catalytic hydrogenation of the olefin where when one of R
1
or R
2
is propyl the other of R
1
or R
2
is not 1-(2-phenyl)ethyl.
It is preferred that the catalyst be the (2R,5R)-enantiomer of a catalyst of the formula:
X
1
—Rh
+
-cyclooctadiene X
2
−
where X
1
is selected from the group consisting of:
(1) BPE
 where X
1-1
is —CH
3
or —C
2
H
5
,
(2) DuPHOS
 where X
1-1
is as defined above;
where X
2
is selected from the group consisting of:
(1) BF
4
−
and
(2) CF
3
—CO—O
−
.
It is preferred that the olefin used be a mixture of E/Z-isomers of (VII). It is preferred that n be 0. For the olefin (VII), R
3
is selected from the group consisting of:
—NO
2
,
—NH
2
,
—NH—SO
2
-[4-trifluoromethylpyridin-2-yl],
—N(—CH
2
-&phgr;)
2
,
—N(R
3-1
)(R
3-2
) where R
3-1
and R
3-2
are the same or different and are:
—H,
—CO—O—(t-butyl),
—CO—O—CH
2
-&phgr;,
—CO—CH
3
,
—CO-&phgr;,
—Cl,
—Br,
—I
—OH,
—O—SO
2
—CF
3
; it is preferred that R
3
is —NO
2
, —NH
2
and —N(R
3-1
)(R
3-2
) where one of R
3-1
and R
3-2
is —H and the other is —CO—O—(t-butyl); it is more preferred that R
3
is —NO
2
. n is 0 or 1 with the provisos, (1) that when n is 0 the R
3
group must be in the meta position and (2) that when n is 1, one of R
3
must be —Cl, —Br, —I, —OH or —O—SO
2
—CF
3
. When n is 0, the chiral compound (VIII) is represented with one R
3
group as (VIII-A) and when n is 1, the chiral compound (VIII) is represented with two R
3
groups as (VIII-B). R
4
is selected from the group consisting of —H, —Si(CH
3
)
3
, Na
+
, K
+
, Li
+
, Cs
+
and (R
4-1
)
4
N
+
where R
4-1
are the same or different and are CH
3
—, C
2
H
5
—, C
4
H
9
—, &phgr;-CH
2
— and C
8
H
17
—. It is preferred that the compound (VIII) is [3&agr;(R),6(R)]5,6-dihydro-4-hydroxy-3-[1-(3-nitrophenyl)propyl]-6-[1-(2-phenyl)ethyl]-6-propyl-2H-pyran-2-one.
The process of the present invention has two very similar forms. In the first form of the process, the olefin (VII) has at the 4-position the hydroxy functionality or a silylated ether derivative; R
4
is either —H or —Si(CH
3
)
3
. The alternative form starts with the enolate at C-4, where R
4
is a cation, Na
+
, K
+
, Li
+
, Cs
+
, (R
4-1
)
4
N
+
where the R
4-1
are the same or different and are CH
3
—, C
2
H
5
—, C
4
H
9
—, &phgr;-CH
2
— and C
8
H
17
—.
When R
4
is either —H or —Si(CH
3
)
3
the reaction requires a base. The operable bases are those where the base has a pK
a
>5; it is preferred that the base be selected from the group consisting of hydroxide, alkoxide where the alkyl group is from C
1
-C
5
, bicarbonate, carbonate, di- and tri-basic phosphate, borate, fluoride and R
a
R
b
R
c
N where R
a
, R
b
and R
c
are the same or different and are:

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