Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-22
2003-04-08
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
06545165
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a process for producing 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one. In particular, the present invention is directed to an enantioselective process for producing the same.
BACKGROUND OF THE INVENTION
&dgr;-Lactones, including pyranones such as 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-ones are useful intermediates in the preparation of a variety of fine chemicals and pharmaceutically active compounds. For example, 3-hexyl-4-hydroxy-6-undecyl-5,6-dihydro-pyran-2-one is a well known precursor for the preparation of oxetanones such as tetrahydrolipstatin. See for example, U.S. Pat. Nos. 5,245,056 and 5,399,720, both issued to Karpf et al.; and U.S. Pat. Nos. 5,274,143 and 5,420,305, both issued to Ramig et al.
One method of preparing 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-ones such as 3-hexyl-4-hydroxy-6-undecyl-5,6-dihydro-pyran-2-one involves intramolecular cyclization of &agr;-haloesters, typically (&agr;-bromoesters, using a metal as a reducing agent. Broadly, this type of reaction is generally known as an intramolecular Reformatsky reaction. For example, the above mentioned U.S. Pat. Nos. 5,274,143 and 5,420,305, both issued to Ramig et al. disclose intramolecular Reformatsky using a “low valent metal” such as zinc, Li, Na, K and the like including amalgams of Zn such as Zn(Cu) and Zn(Ag).
While a variety of metals may be used in the Reformatsky reaction, it is generally believed and widely accepted that some metals such as magnesium cannot be generally used in the Reformatsky reaction. See for example,
Advanced Organic Chemistry
, 3
rd
ed
., March, J., John Wiley & Sons, New York, N.Y., 1985, pp. 822-824. However, the use of magnesium is more desirable than zinc in industrial processes, because the magnesium waste can be more easily disposed of and is less hazardous to the environment than the zinc waste. Moreover, many Reformatsky reactions, including those disclosed in U.S. Pat. Nos. 5,274,143 and 5,420,305, use ether as a solvent (see Examples 5, 10 and 12), which has a low boiling point, i.e., less than 40° C., which may result in a high concentration of solvent vapor within the production facility, thereby creating a potentially hazardous condition, especially in large scale production facilities.
Other methods of preparing tetrahydrolipstatin use a &bgr;-hydroxy ester, e.g., methyl 3-hydroxy tetradecanoate, as an intermediate. See for example, Pommier et al.,
Synthesis
, 1994, 1294-1300, Case-Green et al.,
Synlett
., 1991, 781-782, Schmid et al.,
Proceedings of the Chiral Europe
'94
Symposium
, Sep. 19-20, 1994, Nice, France, and the above mentioned U.S. Patents. Some methods of preparing oxetanones, such as those disclosed in the above mentioned U.S. Patents issued to Karpf et al., use a &bgr;-hydroxy ester as an intermediate to prepare the &dgr;-lactone which is then used in the synthesis of oxetanones.
The stereochemistry of a molecule is important in many of the properties of the molecule. For example, it is well known that physiological properties of drugs having one or more chiral centers, i.e., stereochemical centers, may depend on the stereochemistry of a drug's chiral center. Thus, it is advantageous to be able to control the stereochemistry of a chemical reaction.
Many oxetanones, e.g., tetrahydrolipstatin, contain one or more chiral centers. Intermediates such as &dgr;-lactones and &bgr;-hydroxy esters in the synthesis of tetrahydrolipstatin contain one chiral center. Some syntheses of these intermediates, such as those disclosed in the above mentioned U.S. Patents issued to Karpf et al., are directed to preparation of a racemic mixture which is then resolved at a later stage to isolate the desired isomer. Other methods are directed to an asymmetric synthesis of the &bgr;-hydroxy ester by enantioselectively reducing the corresponding &bgr;-ketoester.
Moreover, in order to achieve a high yield of the desired product, some current asymmetric hydrogenation processes for reducing methyl 3-oxo-tetradecanoate require extremely pure reactants, e.g., hydrogen gas purity of at least 99.99%, thus further increasing the cost of producing the corresponding &bgr;-hydroxy ester.
Therefore, there is a need for a process for producing &dgr;-lactones which does not require zinc based Reformatsky-type reactions. There is also a need for enantioselective reduction of &bgr;-ketoesters under conditions which do not require extremely pure reactants or high hydrogen gas pressure.
SUMMARY OF THE INVENTION
One embodiment of the present invention provides a process for the preparation of a &dgr;-lactone of the formula:
comprising contacting an &agr;-halo ester of the formula:
with a reactive species generating reagent selected from the group consisting of Grignard reagents, magnesium, magnesium-sodium mixtures, samarium, manganese, and mixtures thereof under conditions sufficient to produce said &dgr;-lactone, where R
1
is C
1
-C
20
alkyl; R
2
is H or C
1
-C
10
alkyl; Y is a halide; and Z is nitrile, ester, amide, hydroxyamino amide, acid halide, anhydride, carboxyl carbonate or carboxyl haloformate.
Another embodiment of the present invention provides a process for producing (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one comprising contacting an &agr;-bromo ester of the formula:
with a reactive species generating reagent described above under conditions sufficient to produce (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one, where Z is nitrile or a moiety of the formula —C(═O)W; W is C
1
-C
6
alkoxide, C
6
-C
20
aryloxide, C
7
-C
20
arylalkoxide, halide, C
1
-C
6
carboxylate or a moiety of the formula —NR
3
R
4
; and each of R
3
and R
4
is independently C
1
-C
6
alkyl, C
6
-C
20
aryl, C
7
-C
20
arylalkyl, C
1
-C
6
alkoxide, C
6
-C
20
C
7
-C
20
arylalkoxide or R
3
and R
4
together form a moiety of the formula —(CR
5
R
6
)
a
—Q—(CR
7
R
8
)
b
—; each of R
5
, R
6
, R
7
and R
8
is independently H or C
1
-C
6
alkyl, C
6
-C
20
aryl, C
7
-C
20
arylalkyl; Q is O, NR
9
or S; R
9
is H, an amine protecting group, C
1
-C
6
alkyl, C
6
-C
20
aryl or C
7
-C
20
arylalkyl; and each of a and b is independently an integer from 1 to 4.
Yet another embodiment of the present invention provides a compound of the formula:
or its corresponding enolate of the formula:
where R
1
is C
1
-C
20
alkyl; R
2
is H or C
1
-C
10
alkyl; X is a halide; and Z is nitrile, ester, amide, hydroxyamino amide, acid halide, anhydride, carboxyl carbonate or carboxyl haloformate. A particularly preferred compound of the present invention is of the formula:
or its corresponding enolate of the formula:
Preferably, Z is an ester. More preferably Z is a moiety of the formula —C(═O)OMe or —C(═Ot-Bu.
Still yet another embodiment of the present invention provides a process for producing &bgr;-ketoester of the formula:
comprising:
(a) contacting an alkyl acetoacetate of the formula CH
3
C(═O)CH
2
C(═O)OR
10
, with a magnesium alkoxide, preferably magnesium methoxide, under conditions sufficient to produce a magnesium salt of said alkyl acetoacetate and a first alcohol, preferably methanol, and removing at least a portion of said first alcohol;
(b) contacting said alkyl acetoacetate magnesium salt with an alkyl acyl halide of the formula R
1
C(═O)X, preferably lauroyl chloride, under conditions sufficient to produce a tricarbonyl compound of the formula R
1
C(═O)CH[C(═O)CH
3
]C(═O)OR
10
; and
(c) contacting said tricarbonyl compound with a second alcohol, preferably methanol, under conditions sufficient to produce said &bgr;-ketoester, wherein
X is a halide, preferably chloride;
R
1
is C
1
-C
20
alkyl, preferably undecyl; and
R
10
is C
1
-C
6
alkyl, C
6
-C
20
aryl or C
7
-C
20
arylalkyl, preferably methyl.
Preferably, the reaction is carried out in a non-polar organic solvent, more preferably a solvent that forms an azeotrope with the alcohol that is generated in the reaction mixture, and most preferably toluene.
The reaction temperature of t
Fleming Michael P.
Han Yeun-Kwei
Hodges Lewis M.
Johnston David A.
Micheli Roger P.
Roche Colorado Corporation
Townsend and Townsend / and Crew LLP
Trinh Ba K.
LandOfFree
Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3061790