Synthesis of functionalized esters

Details Synthesis of functionalized esters Synthesis of functionalized esters

1999-03-03

2001-01-16

Killos, Paul J. (Department: 1623)

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

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S225000, C560S179000, C560S226000, C562S579000, C562S602000

Reexamination Certificate

active

06175024

ABSTRACT:

FIELD OF INVENTION
The present invention relates to the synthesis of functionalized esters. More specifically, this invention relates to the synthesis of ethyl 10-bromodecanoate.
BACKGROUND OF THE INVENTION
Functionalized esters, such as ethyl 10-bromodecanoate, are used commonly in the synthesis of fine organic chemicals which, in turn, are used in pharmaceutical, flavor and fragrance, and agricultural products just to name a few. These compounds are especially useful as intermediates since the relatively-high reactivity of their functional group facilitates the compound's combination with other compounds to form complex esters. For example, ethyl 10-bromodecanoate is used as an intermediate in the production of drug carriers in the pharmaceutical field.
The traditional preparation of such functionalized esters, however, involves the consumption of expensive raw materials in reactions which are complex and difficult to control. Additionally, these reactions tend to have low yields and to result in the generation of unwanted by-products. For example, the conventional synthesis of ethyl 10-bromodecanoate involves a three-step process which is complex, costly and inefficient.
In the first step, 1,8-dibromooctane is alkylated using diethylmalonate, sodium ethoxide and ethanol to form 8-bromo octylmalonic acid diethylester. Besides being a relatively expensive, synthesized material, 1,8-dibromo octane is terminated in similar bromine functionality, which are equally as likely to react. Consequently, reactions involving just one of the bromine groups, like the alkylation reaction described above, tend to be difficult to control and result in poor selectivities. To some extent, the reaction of both bromo groups is unavoidable and the resulting compound, octanebismalonic acid tetraethylester, is similar enough to 8-bromo octylmalonic acid diethylester that separation between the two is difficult, thereby resulting in poor yields. Furthermore, the difficult separation of these compounds is particularly problematic since pharmaceutical applications mandate extremely high purity levels.
In the second step, 10-bromodecanoic acid is produced through the decarboxylation of the distilled 8-bromo octylmalonic acid diethylester produced in the first step. The timing of the termination of the decarboxylation is very critical, otherwise over-decarboxylation will occur to give low yields and impurities. Additionally, this step produces hazardous ethyl bromide as a byproduct which necessitates special handling.
In the third step, the desired product, ethyl 10-bromodecanoate, is produced through the esterification of 10-bromodecanoic acid in ethanol. The overall yield of this process is about 47%. In general, this process is costly, complex, inefficient, and produces hazardous waste.
Accordingly, there is a need for a process for preparing functionalized esters that uses relatively inexpensive starting materials and that involves reactions which are controlled readily to produce the desired product at high yields with minimal formation of hazardous byproducts. The present invention fulfills this need among others.
DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
The present invention overcomes the problems encountered in the conventional preparation of functionalized esters by using a commercially-available or readily-synthesized starting material having a vinyl group and a carboxyl group. The vinyl group facilitates convenient functionalization of the compound while the carboxyl group is readily esterified. Since the vinyl and carboxyl moiety of the starting material are significantly different and can be reacted selectively, high yields of the functionalized esters can be achieved with a minimal production of by-products including hazardous materials. Additionally, by starting with a material having a carbon backbone longer than that of the desired product, low-selectivity alkylation reactions for increasing molecule length can be avoided.
One aspect of the invention is a method of preparing a functionalized ester using a starting material having a vinyl group and a carboxyl group. In a preferred embodiment, the process comprises: (a) providing a carboxylic acid having a vinyl group; and (b) functionalizing the vinyl carbon closest to the carboxyl group with a moiety selected from the group consisting of halides, sulfonates, ethers, hydroxyl, amines, and aldehydes and their derivatives, wherein the step of functionalizing comprises cleaving the vinyl group.
As mentioned above, the vinyl and carboxyl groups of the starting material facilitate its functionalization and esterification respectively. During functionalization, the double bond of the vinyl group is cleaved and the functionality is introduced. It is well known that the vinyl group may be cleaved with high selectivity since double bonds tend to be reactive sites in a molecule. Approaches to cleaving a vinyl group are known in the art, and include, for example, ozonization, oxidation using osmium oxide, and oxidation using potassium permanganate. Furthermore, it is well known that the step of cleaving the vinyl group can be performed in a single step or a number of discrete steps.
Preferably, cleaving comprises ozonolysis of the vinyl group to form an ozonide and then reduction of the ozonide in such a way as to avoid or minimize formation of an acid. In the preferred embodiment, the work up of the ozonolysis is such that the ozonide is reduced to a hydroxylated compound. For example, the ozonization and reduction of 10-undecylenic acid may be conducted according to the following reaction:
CH
2
=CH(CH
2
)
8
COOH+O
3
—>HOCH
2
(CH
2
)
8
COOH
Reduction can be effected, for example, using a basic solution of sodium borohydride (NaBH
4
). It should be noted, however, that other conventional techniques for reducing the ozonide are known. For example, the ozonide may be reduced to an aldehyde (OCH
3
(CH
2
)
8
COOH) and then to NH
2
CH
2
(CH
2
)
8
COOH through reduction amination. It is difficult, however, to avoid the production of acids in this latter process. Ozonolysis and reduction may be performed in two or more separate reactions, although, preferably, the ozonide is reduced immediately without removal from the reaction mixture since it tends to be explosive.
After cleaving, it may be desirable to introduce particular functionality into the compound by converting the terminal group which may be, for example, a hydroxyl or an amine group. Conversion reactions are well known and depend upon the terminal group of the cleaved intermediate and the desired functionality. For example, in the conversion of the hydroxyl group to bromine, it is known to react the hydroxylated compound with PBr
3
in acetic acid. In this case, however, it has been found that these complex reagents are not necessary and the conversion can be effected through contact with a hydrogen bromide solution. For example, the conversion of 10-hydroxydecanoic acid may be conducted according to the following reaction:
HOCH
2
(CH
2
)
8
COOH+HBr—>BrCH
2
(CH
2
)
8
COOH+H
2
O
In esterifying the carboxyl group, an alcohol, ROH, reacts with the carboxyl group to form water and an ester of the alkyl group of the alcohol. The particular choice of alcohol depends upon the desired alkyl group to be esterified to the compound. Esterification is a well known process and those skilled in the art can determine readily the conditions under which to conduct the reaction. For example, 10-bromodecanoic acid may be esterified according to the following reaction:
BrCH
2
(CH
2
)
8
COOH+CH
3
CH
2
OH—>BrCH
2
(CH
2
)C(O)OCH
3
CH
2
+H
2
O.
The order of functionalization and esterification is not critical. For example, rather than performing an ozonolysis of the starting material, for example, 10-undecylenic acid, as described above, the starting material first may be esterified with ethanol or other alcohol to form an ester, for example, ethyl 10-undecylenate. Next, the ester can undergo functionalization by first ozonating the ester and then reduci

Affiliated with

Also associated with

Rating

Synthesis of functionalized esters 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 functionalized esters, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Synthesis of functionalized esters will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2542444