Synthesis of functionalized esters

A method of preparing an ester of a carboxylic acid functionalized with a moiety selected from the group consisting of halides, sulfonates, ethers, hydroxyl, amines, and aldehydes, said method comprising: (a) providing either a carboxylic acid having a vinyl group or an ester thereof; (b) functionalizing the vinyl carbon closest to the carboxyl group with said moiety, wherein said functionalizing comprises cleaving said vinyl group.

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:
EQU CH.sub.2 =CH(CH.sub.2).sub.8 COOH+O.sub.3 --&gt;HOCH.sub.2 (CH.sub.2).sub.8
 COOH
 Reduction can be effected, for example, using a basic solution of sodium
 borohydride (NaBH.sub.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.sub.3 (CH.sub.2).sub.8
 COOH) and then to NH.sub.2 CH.sub.2 (CH.sub.2).sub.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.sub.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:
EQU HOCH.sub.2 (CH.sub.2).sub.8 COOH+HBr--&gt;BrCH.sub.2 (CH.sub.2).sub.8
 COOH+H.sub.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:
EQU BrCH.sub.2 (CH.sub.2).sub.8 COOH+CH.sub.3 CH.sub.2 OH--&gt;BrCH.sub.2
 (CH.sub.2)C(O)OCH.sub.3 CH.sub.2 +H.sub.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 reducing the
 ozonide using, for example, sodium borohydride to form a hydroxylated
 ester, for example, ethyl 10-hydroxydecanoate. The hydroxylated ester
 finally is converted to the desired functionalized ester using, for
 example, PBr.sub.3 to form ethyl 10-bromodecanoate.
 Although not critical, functionalization prior to esterification usually
 results in higher yields. Functionalization prior to esterification also
 is more convenient since highly-effective solutions for converting the
 hydroxyl group to a bromo group, such as aqueous HBr, will not work once
 the carboxylic acid is esterified since HBr will convert the ester back to
 an acid. Therefore, it is generally preferred that functionalization
 precede esterification.
 Once functionalized and esterified, the product may be recovered using
 known techniques such as distillation, filtration and/or reaction.
 The synthesis method of the present invention is particularly effective in
 preparing functionalized esters having the formula:
EQU XCH.sub.2 (CR.sub.1 R.sub.2).sub.n.circle-solid.COOR (1)
 from a starting material having the formula:
EQU R.sub.3 R.sub.4 C=CH(CR.sub.1 R.sub.2).sub.n.circle-solid.COOH (2)
 wherein:
 X is the moiety selected from the group consisting of halides, sulfonates,
 ethers, hydroxyl, amines, and aldehydes and their derivatives;
 each of R.sub.1, R.sub.2, R.sub.3, and R.sub.4 is independently selected
 from hydrogen, an unsubstituted or substituted aliphatic radical, or
 unsubstituted or substituted aromatic radical;
 R is selected from an unsubstituted or substituted aliphatic radical, or
 unsubstituted or substituted aromatic radical; and
 n is an integer from 2 to 20.
 In Formulas (1) and (2), each of R.sub.1, R.sub.2, R.sub.3, and R.sub.4
 preferably is selected from hydrogen, an unsubstituted or substituted
 C.sub.1 -C.sub.10 aliphatic radical, an unsubstituted or substituted
 C.sub.3 -C.sub.10 alicyclic radical, or an unsubstituted or substituted
 C.sub.6 -C.sub.15 aromatic radical. More preferably, each of R.sub.1,
 R.sub.2, R.sub.3, and R.sub.4 is independently selected from an
 unsubstituted or substituted C.sub.1 -C.sub.10 alkyl, an unsubstituted or
 substituted C.sub.3 -C.sub.8 cycloalkyl, an unsubstituted or substituted
 3-6 ring member heterocyclic radical, an unsubstituted or substituted
 C.sub.6 -C.sub.15 aryl, or an unsubstituted or substituted C.sub.7
 -C.sub.11 aralkyl. Examples of substitution groups include fluorine,
 C.sub.1 -C.sub.6 alkyls, C.sub.1 -C.sub.6 halogenated alkyls, C.sub.6
 -C.sub.15 aryls, C.sub.1 -C.sub.6 alkoxys, nitros, aminos (primary and
 secondary), amidos, and cyanos.
 As a C.sub.1 -C.sub.10 alkyl, each of R.sub.1, R.sub.2, R.sub.3, and
 R.sub.4 may be a straight chain or branched molecule, for example, methyl,
 ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl,
 neopentyl, n-hexyl, n-heptyl, n-octyl, or 2-ethylhexyl. Additionally, any
 of these groups may substituted with methoxy, ethoxy, n-propoxy,
 isopropoxy, n-butoxy, methanesulphonyl, cyano, bromine, chlorine or
 fluorine, among others, to form such substituted alkyl groups as
 methoxymethyl, 2-methoxyethyl, 2-ethoxymethyl, 2-n-butoxyethyl,
 3-methoxypropyl, 1-methoxybutyl, 2-methoxybutyl, methanesulphonylmethyl,
 2-methanesulphonylethyl, 2-cyanoethyl, 2-fluoroethyl,
 2,2,2-trifluoroethyl, trichloromethyl, 2-chloroethyl,
 2-(chloromethyl)ethyl, 2,2,2-trichloroethyl, 2-chloro-n-propyl or
 3-chloro-n-butyl. In a preferred class of alkyls, each of R.sub.1,
 R.sub.2, R.sub.3, and R.sub.4 is an C.sub.1 -C.sub.6 alkyl, which may be
 substituted by cyano, halogen or C.sub.1 -C.sub.4 alkoxy, especially
 methyl, ethyl, n-butyl, 2-cyanoethyl, 1-(chloromethyl) ethyl or
 2-methoxyethyl. In another preferred class of alkyls, each of R.sub.1,
 R.sub.2, R.sub.3, and R.sub.4 is branched alkyl, preferably a C.sub.2
 -C.sub.6 branched alkyl, especially isobutyl.
 As a C.sub.3 -C.sub.8 cycloalkyl, each of R.sub.1, R.sub.2, R.sub.3, and
 R.sub.4 may be, for example, cyclopropyl, cyclobutyl, cyclopentyl,
 methylcyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl,
 cycloheptyl or cyclooctyl, preferably cyclohexyl. Any of these groups may
 be substituted with, for example, methoxy, ethoxy, n-propoxy, isopropoxy,
 n-butoxy, cyano, chlorine or fluorine. In a preferred class of cycloalkyl,
 each of R.sub.1, R.sub.2, R.sub.3, and R.sub.4 is a C.sub.5 -C.sub.7
 cycloalkyl, and, more preferably, cyclohexyl.
 As a 3-6 member heterocyclic radical, each of R.sub.1, R.sub.2, R.sub.3,
 and R.sub.4 may include any known heterocylic atom such as N, O, and S.
 Suitable heterocycles include, for example, pyridine, pyran, thiophan,
 pyrrole, furan, and thiophen.
 As a C.sub.6 -C.sub.15 aryl, each of R.sub.1, R.sub.2, R.sub.3, and R.sub.4
 may be, for example, phenyl, o-tolyl, m-tolyl, p-tolyl, o-xylyl, m-xylyl,
 p-xylyl, alpha-naphthyl or beta-naphthyl. Any of these groups may be
 substituted with, for example, halogen, C.sub.1 -C.sub.4 alkoxy or nitro.
 In a preferred class of aryls, each of R.sub.1, R.sub.2, R.sub.3, and
 R.sub.4 is C.sub.6 -C.sub.8 aryl or C.sub.12 -C.sub.14 aryl, and, more
 preferably, phenyl or naphthyl.
 As C.sub.7 -C.sub.13 aralkyl, each of R.sub.1, R.sub.2, R.sub.3, and
 R.sub.4 may be, for example, benzyl, 4-methylbenzyl, o-methoxybenzyl,
 p-methoxybenzyl, diphenylmethyl, 2-phenylethyl, 2-phenylpropyl or
 3-phenylpropyl, preferably C.sub.7 -C.sub.9 aralkyl, especially benzyl.
 In an even more preferred embodiment, each of R.sub.1, R.sub.2, R.sub.3,
 and R.sub.4 is hydrogen, thereby simplifying Formulas (1) and (2) to
 formulas (3) and (4), respectively, below:
EQU XCH.sub.2 (CH.sub.2).sub.n.circle-solid.COOR (3)
EQU CH.sub.2 =CH(CH.sub.2).sub.n.circle-solid.COOH (4)
 In the preferred and more preferred embodiments, R is the same for R.sub.1,
 R.sub.2, R.sub.3, and R.sub.4 above except that R cannot be hydrogen. In
 an even more preferred embodiment, R is a C.sub.1 -C.sub.3 alkyl group,
 and, most preferably, it is an ethyl group.
 The moiety, X, preferably is a halide or an aromatic sulfonate prepared
 from a sulfonic acid, such as, for example, para-toluenesulfonic acid
 (tosylate), methanesulfonic acid and bromobenzenesulfonic acid. More
 preferably, it is a halide selected from chlorine, bromine, or iodine, or
 an aromatic sulfonate. Most preferably, it is bromine.
 The integer, n, preferably is from 4 to 12, and, more preferably, from 8 to
 10. Most preferably, n is 8. It is noteworthy to mention that if n is
 greater than 1, thereby resulting in a plurality of R.sub.1 and R.sub.2
 groups, each R.sub.1 and R.sub.2 is independently selected such that, for
 example, one R.sub.1 may differ from another within the same molecule.
 In the most preferred embodiment, the functionalized ester is ethyl
 10-bromodecanoate, wherein R.sub.1 and R.sub.2 are hydrogen, X is bromine,
 R is ethyl, and n is 8, and the starting material is 10-undecylenic acid,
 which is commercially available and readily derived from
 naturally-occurring oils such as castor oil.
 According to the present invention, a functionalized ester can be
 synthesized with high yields. For example, in the preparation of ethyl
 10-bromodecanoate, the yield is preferably no less than 50% and, more
 preferably, no less than about 60%.
 The following example is illustrative of the practice of the present
 invention.

EXAMPLE 1
 This example illustrates the synthesis of ethyl 10-bromodecanoate from
 10-undecylenic acid where the functionalization is performed prior to the
 esterification.
 The functionalization first involved the ozonization and reduction of the
 10-undecylenic acid according to the following reaction:
EQU CH.sub.2 =CH(CH.sub.2).sub.8 COOH+O.sub.3 --&gt;HOCH.sub.2 (CH.sub.2).sub.8
 COOH (Step I)
 The reactor used was a 2 L vessel equipped with a cooling jacket filled
 with ethylene glycol and water, a mechanical agitator, a thermocouple, a
 gas sparger, and a cooled condenser. The gas sparger was operatively
 connected to an ozone generator and a source of air and nitrogen.
 To the reactor was added 186.14 g (1 mol) of 99% pure 10-undecylenic acid
 (commercial source) in 475 g absolute ethanol. The mixture was cooled to
 -5.degree. C. The reaction mixture was sparged first with air to agitate
 it, and then with ozone at a rate of about 0.75 lb/day. After about four
 hours, the reaction mixture was checked periodically (every hour or so)
 for the presence of olefin. Once the olefin was consumed, the reaction
 mixture was sparged with nitrogen for half an hour to sparge the residual
 ozone while still cooling. The reaction mixture (670 g) containing the
 ozonide was drained into a stoppered flask and kept cool with dry ice.
 The reaction mixture containing the ozonide next was reduced by adding it
 dropwise to a 5 L reactor containing 112 g (1.4 mol) of 50% NaOH and 54.05
 g (1.4 mol) of 98% pure NaBH.sub.4 dissolved in 550 g absolute ethanol.
 The reaction mixture in the 5 L reactor was stirred mechanically and
 maintained at about 0-5.degree. C. with dry ice. After all the ozonide was
 reduced, the mixture was stirred for 8 h at room temperature such that the
 solvent was evaporated leaving 624 g of 10-hydroxydecanoic acid sodium
 salt (white solid).
 The 10-hydroxydecanoic acid sodium salt then was dissolved in 2200 g of
 water and placed in the 5 L reactor. The reactor was equipped with an
 addition funnel. Through the funnel, 1095 g (3.0 mol) of 10% HCl solution
 was added dropwise to the reactor while stirring and cooling to maintain
 the temperature below 25.degree. C. The reaction mixture was stirred for
 about 4-6 h. During this time, hydrogen was liberated and a white solid
 formed. The solids were washed repeatedly with water, filtered, and then
 dried under nitrogen. The residue was 92.24% pure 10-hydroxydecanoic acid.
 The yield was 90%.
 Functionalization next involved the introduction of bromine functionality
 into the 10-hydroxydecanoic acid according to the following reaction:
EQU HOCH.sub.2 (CH.sub.2).sub.8 COOH+HBr--&gt;BrCH.sub.2 (CH.sub.2).sub.8
 COOH+H.sub.2 O (Step II)
 Specifically, 153.05 g of 10-hydroxydecanoic acid was mixed with 758.53 g
 of 48% HBr and heated to 125-130.degree. C. for about 9 h with vigorous
 stirring. The reaction mixture phase separated at about 50.degree. C. The
 top organic phase was 180.5 g 10-bromodecanoic acid and a trace amount of
 HBr which acted as a catalyst for esterification in the next step. The
 bottom phase comprised HBr and could have been recycled.
 After functionalization, 10-bromodecanoic acid was then esterified
 according to the following reaction:
EQU BrCH.sub.2 (CH.sub.2).sub.8 COOH+CH.sub.3 CH.sub.2 OH--&gt;BrCH.sub.2
 (CH.sub.2)C(O)OCH.sub.3 CH.sub.2 +H.sub.2 O (Step III)
 To this end, the 180.5 g of 10-bromodecanoic acid from Step II was added to
 the 11 reactor (described above) along with 645 g of absolute ethanol. The
 mixture was heated and stirred for about 3.5 h. GC analysis confirmed that
 reaction was completed when 10-bromodecanoic acid could not be detected.
 Next, excess ethanol and residual water were removed through evaporation
 leaving 197.8 g of 94.9% pure ethyl 10-bromodecanoate residue. 150 g MTBE
 was added to the ethyl 10-bromodecanoate residue which then was washed
 repeatedly with 10% sodium carbonate solution followed by water. The
 mixture was phase separated to obtain 340.7 g of a mixture of ethyl
 10-bromodecanoate and MTBE. According to GC analysis the yield from Steps
 II and III was 89.7%.
 Finally, the ethyl 10-bromodecanoate was purified through distillation
 using a 15-tray Older Shaw column equipped with a cold water-cooled
 condenser, a thermocouple, a heating mantle, a stirrer and a 500 ml 3-neck
 round-bottomed flask vacuum system capable of pulling a vacuum of 5 mm Hg.
 The 340.7 g of the mixture of ethyl 10-bromodecanoate and MTBE mixture
 from Step III was placed in the 500 ml round-bottomed flask. A main cut
 was collected at a pot temperature of 180-275.degree. C., a head
 temperature of 121-123.degree. C., and a reflux ratio of 1/5. The main cut
 had a composition of 99% pure ethyl 10-bromodecanoate and the distillation
 yield was 69.2%.