Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-02-28
2001-07-24
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C562S451000
Reexamination Certificate
active
06265604
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is a novel process and novel intermediates to prepare [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 (XIX) which is a protease inhibitor useful in treating humans infected with the HIV virus.
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 (XIX) can be produced by the process set forth in International Publications WO95/30670 and WO94/11361.
J. Med. Chem.,
39(22), 4349 (1996) discloses the cyclic ester (VI) but in the racemic form. This document also discloses the transformation of the cyclic ester (VI) to the protease inhibitor (XIX) but by a different synthetic pathway.
J. Am. Chem. Soc.,
111, 3627 (1997) discloses the amino compound (XVIII).
Tetrahedron Letters,
34(2), 277-280 (1993) discloses a method for the conversion of a &bgr;-hydroxycarbonyl compound to a ring similar to that of formulas (VI) and (CVI). The &bgr;-hydroxycarbonyl compound in the prior art is a secondary alcohol and that in the present invention is a tertiary alcohol. In addition, the processes are completely different with the process of
Tetrahedron Letters
not being operable on the tertiary alcohols (IV) and (CIV) of the present invention.
J. Med Chem.,
39(23), 4630-4642 (1996) discloses a method to make compounds similar to that of formulas (VI) and (CVI) but in racemic form from starting materials different from the present invention by an unrelated method.
International Publication WO95/14012 claims a cyclic compound similar to the cyclic compounds (VI), (XVII) and (XXV) of the present invention but in racemic form. The process of the present invention produces these compounds in optically pure form.
International Publication WO94/11361 discloses the cyclic ester (VI) but in racemic form.
Acta Chemica Scandinavica,
B31, 671-678 (1977) discloses a number of 5,6-dihydro-2-pyranones including the 6-(2-phenylethyl) compound of formula 3a in Table 1.
SUMMARY OF THE INVENTION
Disclosed is (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid (IV) and pharmaceutically acceptable salts thereof.
Also disclosed is (6R)-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]-6-propyl-2H-pyran-2-one.
Further disclosed 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 (XVII).
Additionally disclosed is (S)-methyl 3-(3-nitrophenyl)pentanoate.
Also disclosed is (3&agr;(R),6(R)]5,6dihydro-4-hydroxy-3-[(Z)-1-(3-nitrophenyl)propenyl]-6-[1-(2-phenyl)ethyl]-6-propyl-2H-pyran-2-one.
Also disclosed is a process for the production of the hydroxy lactone of formula (CVI)
where R
1
is:
C
1
-C
6
alkyl,
cyclohexyl,
phenyl,
—CH
2
—CH
2
—&phgr;R
1-1
where R
1-1
is
—OH (and protected froms thereof),
—NH
2
(and protected forms thereof),
—H,
—NH—CO—CH
3
,
—N(—CO—CH
3
)
2
;
where R
2
is:
C
1
-C
6
alkyl,
cyclohexyl,
phenyl,
—CH
2
—CH
2
—&phgr;R
2-1
where R
2-1
is
—OH (and protected froms thereof),
—NH
2
(and protected forms thereof),
—H,
—NH—CO—CH
3
,
—N(—CO—CH
3
)
2
;
which comprises:
(1) contacting a salt of the formula (CIV)
with an acid to produce a free acid,
(2) extracting the free acid from the reaction mixture,
(3) contacting the free acid with an activating agent,
(4) contacting the reaction mixture of free acid/activating agent with malonate monoester and a divalent metal,
(5) contacting the reaction mixture of step (4) with an acid,
(6) contacting the reaction mixture of step (5) with a base in the presence of a C
1
-C
4
alcohol, THF or DMF.
Further disclosed is a process for the production of the hydroxy lactone of formula (CVI)
where R
1
is:
C
1
-C
6
alkyl,
cyclohexyl,
phenyl,
—CH
2
—CH
2
—&phgr;R
1-1
where R
1-1
is
—OH (and protected froms thereof),
—NH
2
(and protected forms thereof),
—H,
—NH—CO—CH
3
,
—N(—CO—CH
3
)
2
;
where R
2
is:
C
1
-C
6
alkyl,
cyclohexyl,
phenyl,
—CH
2
—CH
2
—&phgr;R
2-1
where R
2-1
is
—OH (and protected froms thereof),
—NH
2
(and protected forms thereof),
—H,
—NH—CO—CH
3
,
—N(—CO—CH
3
)
2
;
which comprises:
(1) contacting the anion of the formula (CIV)
or the free acid form thereof with an activating agent,
(2) contacting the reaction mixture of free acid/activating agent with malonate monoester and a divalent metal,
(3) contacting the reaction mire of step (4) with an acid,
(4) contacting the reaction mixture of step (5) with a base in the presence of a C
1
-C
4
alcohol, THF or DMF.
REFERENCES:
patent: 1355 668 (1971-07-01), None
patent: 1355 667 (1971-07-01), None
patent: WO 94/11361 (1994-05-01), None
patent: WO 95/14012 (1995-05-01), None
patent: WO 95/30670 (1995-11-01), None
S. Thaisrivongs, et al.: Journal of Medicinal Chemistry, vol. 39, No. 23, 1996, pp. 4630-4642, XP002088571, “Structure-Based Design of HIV Protease Inhibitors: 5,6-Dihydro-4-hydroxy-2-pyrones as Effective, Nonpeptidic Inhibitors”.
Hanno Wild, Bayer AG, Chemistry Science Laboratories Pharma,—Tetrahedron Letters, vol. 34, No. 2, pp. 285-288 (1993)—Are 6-Acylamino Oxapenems Stable Compounds?
TM Judge, et al.—“Asymmetric Syntheses and Absolute Stereochemistry of 5,6-Dihydro-a-pyrones, A New Class of Potent HIV Protease Inhibitors”—J. Am. Chem. Soc. 1997, vol. 119, No. 15, 3627-3628.
S. Thaisrivongs, et al.: “Structure-Based Design of HIV Protease Inhibitors: Sulfonamide-Containing 5,6-Dihydro-4-hydroxy-2-pyrones as Non-Peptidic Inhibitors”—Journal of Medicinal Chemistry, vol. 39, No. 22, Oct. 25, 1996.
Gage James R.
Hewitt Bradley D.
Kelly Robert Charles
Owens Amelia
Pharmacia & Upjohn Company
Stein Bruce
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