Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one

Details Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one

2000-09-22

2003-04-22

Chang, Celia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C556S435000, C556S436000

Reexamination Certificate

active

06552204

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 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, 5,6-dihydro-3-hexyl-4-hydroxy-6-undecyl-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.
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(s). 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 &dgr;-lactone and &bgr;-hydroxy ester used 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 the preparation of a racemic mixture which is then resolved at a later step to isolate the desired isomer. Other methods are directed to an asymmetric synthesis of &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 reaction conditions, 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. And there is a need for enantioselectively reducing &bgr;-ketoesters under conditions which do not require extremely pure reaction conditions 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:
(a) treating an acyl halide of the formula:
 with a ketene acetal of the formula:
 under conditions sufficient to produce a coupled intermediate product; and
(b) providing conditions sufficient to produce the &dgr;-lactone I from the coupled intermediate product, where R
1
is C
1
-C
20
alkyl; R
2
is H or C
1
-C
10
alkyl; R
3
is a hydroxy protecting group; each of R
4
and R
5
is independently C
1
-C
6
alkyl, C
5
-C
20
aryl, C
6
-C
20
arylalkyl or —SiR
8
R
9
R
10
; each of R
8
, R
9
, R
10
is independently C
1
-C
6
alkyl or phenyl; and X is,a halide.
The coupled product can be “trapped” (i.e., reacted) with a protecting group to produce an enol ether compound. Without being bound by any theory, it is believed that the coupled product or the enol ether compound is &dgr;-hydroxy-&bgr;-enol ether ester or &dgr;-hydroxy-protected-&bgr;-enol ether ester of the formula:
where R
6
is H or R
4
, and R
1
, R
2
, R
3
, R
4
, and R
5
are those defined above. It should be appreciated that while Compound IV is depicted with the double bond in the &bgr;,&ggr;-position, it can also exist with the double bond in the &agr;,&bgr;-position. Moreover, the double bond can be either E- or Z-configuration. Thus, when referring to Compound IV, it is intended that these isomers, or mixtures thereof are also within the scope of the present invention.
Where R
6
of the coupled intermediate product (i.e., Compound IV) is not hydrogen (i.e., R
6
is a hydroxy protecting group), the step (b) above can include the steps of removing (i.e., deprotecting) R
6
or R
3
and R
6
to produce a deprotected intermediate, and contacting the deprotected intermediate with an acid under conditions sufficient to produce the &dgr;-lactone I.
Another embodiment of the present invention provides a process for the preparation of the &dgr;-lactone I comprising the steps of:
(a) treating an acyl halide of the formula:
 with a malonate half acid of the formula:
 under conditions sufficient to produce a &dgr;-hydroxy-&bgr;-ketoester of the formula:
 and
(b) contacting the &dgr;-hydroxy-protected-&bgr;-enol ether ester VI with an acid under conditions sufficient to produce the &dgr;-lactone I, where R
1
, R
2
, R
3
, R
5
, and X are those described above, and R
7
is H or R
3
.
Because Compound VII contains acidic group, it may exist in its enol (i.e., tautomeric) form under certain conditions. Thus, any reference to the Compound VII implicitly includes its tautomeric form.
Preferably, methods of the present invention provide an enantioselective synthesis of the &dgr;-lactone I.
Another embodiment of the present invention provides a process for enantioselective preparation of a &bgr;-hydroxy ester of the formula:
comprising hydrogenating a &bgr;-ketoester of the formula:
in the presence of about 40 bar of pressure or less of hydrogen gas and a ruthenium hydrogenation catalyst comprising a halide and a chiral substituted biphenyl phosphorous ligand, where R
1
is that described above, and R
18
is C
1
-C
6
alkyl, C
5
-C
20
aryl or C
6
-C
20
arylalkyl.
Still another embodiment of the present invention provides compound selected from the group consisting of &bgr;-siloxy acyl halides of the formula:
&dgr;-siloxy-&bgr;-silyl enol ether esters of the formula:
and &dgr;-siloxy-&bgr;-ketoesters of the formula:
where R
1
, R
2
, R
5
, R
8
, R
9
, R
10
, and X are those described above, and each of R
11
, R
12
and R
13
is independently C
1
-C
6
alkyl or phenyl.
Similar to Compound IV, Compound XI can also exist in different olefin geometry (i.e., E- or Z- isomers) and/or different double bond location (i.e., in the &agr;,&bgr;-position instead of in the &bgr;,&ggr;-position as depicted). Thus, while Compound XI is depicted as that shown above, it is intended that the scope of the present invention includes these isomers of Compound XI.
DETAILED DESCRIPTION
As used herein, the term “treating”, “contacting” or “reacting” refers to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
The term “alkyl” refers to aliphatic hydrocarbons which can be straight or branched chain groups. Alkyl groups optionally can be substituted with one or more substituents, such as a halogen, alkenyl, alkynyl, aryl, hydroxy, amino, thio, alkoxy, carboxy, oxo or cycloalkyl. There may be optionally inserted along the alkyl group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms. Exemplary alkyl groups include methyl, ethyl, i-propyl, n-butyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, trichloromethyl, pentyl,

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