Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-12-20
2003-07-29
Trinh, Ba K (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S024000, C560S164000, C568S857000, C568S875000
Reexamination Certificate
active
06600062
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method of stereoselectively producing 6,7-dihydroxy geranyloxy compounds.
BACKGROUND OF THE INVENTION
Dihydroxy geranyloxy moieties are present in a variety of pharmaceutically active compounds, including, but not limited to, 6,7-dihydroxybergamottin, and compounds such as those disclosed in U.S. Pat. Nos. 5,990,154; 6,054,477; 6,063,809; 6,124,477; 6,162,479; and 6,248,776. In particular, 6,7-dihydroxy geranyloxy moiety is present in many of these pharmaceutically active compounds.
6,7-Dihydroxy geranyloxy moiety comprises a chiral center, and it is well known that the stereochemistry of a molecule is important in many of the properties of the molecule. For example, physiological properties of pharmaceutically active compounds having one or more chiral centers, i.e., stereochemical centers, can depend on the stereochemistry of the compound's chiral center.
Therefore, there is a need for a method of stereoselectively producing 6,7-dihydroxy geranyloxy moiety.
SUMMARY OF THE INVENTION
One aspect of the present invention provides a method for enantioselectively producing a nonracemic dihydroxy geranyloxy compound from a geranyloxy compound. In particular, methods of the present invention utilize an asymmetric epoxidation reaction to selectively epoxidize the olefin moiety in the 6,7-position of the geranyloxy moiety. The resulting nonracemic epoxide is then hydrolyzed to produce a nonracemic 6,7-dihydroxy geranyloxy compound.
The enantiomeric excess of the nonracemic 6,7-dihydroxy geranyloxy compound can be further increased (i.e., enriched) by increasing the enantiomeric excess of the nonracemic 6,7-epoxy geranyloxy compound prior to hydrolyzing the epoxide moiety. When the 6,7-epoxy geranyloxy compound is a solid, enantiomeric excess enrichment can be achieved by crystallization, and optionally by recrystallization. The enantiomeric excess of the nonracemic 6,7-dihydroxy geranyloxy compound can be further increased after it is produced by the epoxide hydrolysis reaction step. When the 6,7-dihydroxy geranyloxy compound is a solid, enantiomeric excess enrichment can be achieved by crystallization, and optionally by recrystallization.
DEFINITIONS
“Geranyloxy compound” refers to any compound which comprises a geranyloxy moiety of the formula:
Geranyloxy compounds include, but are not limited to, geraniol, geranyl ethers, geranyl esters of organic and inorganic acids, geranyl carbonates, and geranyl carbamates, as defined herein.
“Epoxy geranyloxy compound” refers to any compound which comprises a geranyloxy moiety, as defined herein, in which one or both, preferably one, of the olefins in the geranyloxy moiety have been epoxidized.
“6,7-dihydroxy geranyloxy compound” refers to a geranyloxy compound as defined herein in which the 6,7-position of the geranyloxy moiety comprises hydroxyl groups, i.e., compound comprising a moiety of the formula:
“Hydrolyzing” refers to opening the epoxide ring moiety by the addition of a molecule of water to provide a vic-diol. For example, hydrolyzing a 6,7-epoxide geranyloxy compound to produce a 6,7-dihydroxy geranyloxy compound.
“Peracid” has the usual meaning in the art and refers to any oxyacid compound wherein the —OH group is replaced with the —OOH group. Peracids include percarboxylic acids (e.g., meta-chloroperbenzoic acid), persulfuric acid (H
2
SO
5
), and imidoperacids (e.g., CH
3
—C(═NH)—OOH). As used herein, the term “peracid” includes salts of peracids (e.g., potassium bipersulfate, KHSO
5
).
“Peroxyimidate” (also known as imidoperacid) refers to an oxidizing agent which is produced from a mixture of an oxidizing agent, preferably hydrogen peroxide, and a nitrile compound. Without being bound by any theory, it is believed that the mixture of hydrogen peroxide and a nitrile compound (e.g., R—CN) result in a peroxyimidate of the formula R—C(═NH)—OOH.
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.
“Side-reaction” is a reaction that does not ultimately lead to a production of a desired product. For example, a desired product of the reaction comprising an oxidizing agent, a ketone and an olefin is an epoxide.
“Chiral center”, i.e., stereochemical center or stereogenic center, is, of course, an atom to which four different groups are attached. However, the ultimate criterion of a chiral center is nonsuperimposability on the mirror image.
“Facially selective,” “stereoselective,” “enantioselective” or “asymmetric” synthetic reactions are those in which one of a set of stereoisomers is formed exclusively or predominantly.
“Crystallization” refers to a purification process of isolating a solid from the reaction mixture or an extraction solution.
“Recrystallization” refers to a further purification process of an isolated solid, whereby the solid is dissolved in a crystallizing solution and is recrystallized to provide a solid of higher purity.
DETAILED DESCRIPTION
One aspect of the present invention provides a method for enantioselectively producing a dihydroxy geranyloxy compound from a geranyloxy compound utilizing an asymmetric epoxidation reaction and hydrolyzing the resulting nonracemic epoxy geranyloxy compound to produce a nonracemic dihydroxy geranyloxy compound. In particular, the present invention is directed to enantioselectively producing a nonracemic 6,7-dihydroxy geranyloxy compound.
Methods of the present invention comprise:
(a) contacting a reaction mixture comprising the geranyloxy compound with an oxidizing agent in the presence of a nonracemic chiral ketone under conditions sufficient to enantioselectively produce a nonracemic 6,7-epoxy geranyloxy compound; and
(b) hydrolyzing the epoxide moiety of the nonracemic 6,7-epoxy geranyloxy compound under conditions sufficient to produce the nonracemic 6,7-dihydroxy geranyloxy compound.
Epoxidation of an olefin is a useful synthetic reaction in the field of organic chemistry. Such reaction has been used frequently in the preparation of an intermediate and/or the final product of many pharmaceutically active compounds. Many epoxidation reactions have been developed over the years including asymmetric epoxidations. Some of these epoxidation reactions require the use of transition metals or other heavy metals which are potentially harmful even in trace amounts. Still others methods require expensive reagents which significantly increase the overall cost of epoxidation reaction. Methods of the present invention avoid these problems by using an asymmetric epoxidation reaction that is based on a combination of an oxidizing agent and a chiral ketone compound.
Without being bound by any theory, it is believed that a reaction between the oxidizing agent and a ketone generates a dioxirane, which is believed to be the reactive species that epoxidizes the geranyloxy compound. By using a nonracemic chiral ketone, one can affect an asymmetric epoxidation of the geranyloxy compound, thereby producing a nonracemic epoxy geranyloxy compound.
It is also believed that the reaction between the geranyloxy compound and the dioxirane provides a nonracemic epoxy geranyloxy compound and regenerates the nonracemic chiral ketone; therefore, the nonracemic chiral ketone can be used in a catalytic amount. Thus, in one particular embodiment of the present invention, less than one equivalent of the nonracemic chiral ketone relative to the amount of the geranyloxy compound is used in the present invention. Preferably, methods of the present invention use about 1 equivalent or less of the nonracemic chiral ketone, more preferably about 0.3 equival
Seemayer Robert
Shi Yian
DSM Catalytica Pharmaceuticals, Inc.
Trinh Ba K
LandOfFree
Preparation of chiral 6,7-dihydroxy geranyloxy compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Preparation of chiral 6,7-dihydroxy geranyloxy compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of chiral 6,7-dihydroxy geranyloxy compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3089639