Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-12-09
2001-08-21
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S129000, C568S877000
Reexamination Certificate
active
06278016
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods for preparing prenyl alcohol (3-methyl-2-buten-1-ol) (2) and ester derivatives of prenyl alcohol (2) from isoprene. Prenyl alcohol (2) is an intermediate in the manufacture of citral (5), a specialty chemical used in the flavor and fragrance industries, as well as in the manufacture of vitamins A and E, the anti-acne drugs tretinoin (sold by Ortho Pharmaceutical Corp. under the mark RETIN-A) and isotretinoin (sold by Hoffmann-La Roche Inc. under the name ACCUTANE), and several widely-used carotenoids, including beta-carotene.
2. Brief Description of Related Technology
One of the most expedient routes to citral (5) involves a thermal rearrangement of 3-methyl-1-(3-methyl-2-buten-1-oxy)-1,3-butadiene (4), which is readily obtained when acetal (3) [prepared from prenyl alcohol (2) and 3-methyl-2-butenal (prenal, (1))] is heated in the presence of a weak acid catalyst (e.g., acetic acid or 2,4-nitrophenol) at temperatures in the range of 125° C. to 150° C. The pathway by which unsaturated ether (4) is converted to citral (5) involves a Claisen rearrangement, followed by a subsequent Cope rearrangement in the same reaction vessel:
The approach to citral (5) described above has been known for more than 25 years and has continued to be developed to the stage where one is able to effect the conversion of prenal (1) and prenyl alcohol (2) to citral (5) in a “one-pot” process. See, European patent application EP 344,043 (Nov. 29, 1989) filed by Rhône-Poulenc [
Chem. Abstracts
1990, 112, 179516d] and PCT Int. Appl. WO 91 09,830 (Jul. 11, 1991) [
Chem. Abstracts
1991, 115, 114815t]. Previous patents have verified that unsaturated ether (4), obtained directly from acetal (3), can be converted to citral (5) in high yield (90-100%), e.g.:
(a) German patent 2,411,530 (Sep. 26, 1974 to Hoffinann-LaRoche):
Chem. Abstracts
1975, 82, 4434k.
(b) U.S. Pat. No. 4,016,212 (Apr. 5, 1977 to Hoffinann-LaRoche):
Chem. Abstracts
1977, 87, 136042u.
(c) German patent 2,423,409 (Nov. 28, 1974 to Teijin Ltd. of Japan):
Chem. Abstracts
1979, 91, 123406y.
(d) German patent 2,625,074 (Dec. 8, 1977 to BASF):
Chem. Abstracts
1978,88, 89114c.
(e) European patent application 21,074 (Jan. 7, 1981, filed by BASF):
Chem. Abstracts
1981, 95, 7513q.
(f) Japanese patent 61 22,038 issued to Kuraray Co., Ltd.:
Chem. Abstracts
1986, 10, 134188n.
The principal difficulty with the above process is the high cost of prenyl alcohol (2)—which is almost as costly as citral (5). Once prenyl alcohol (2) is obtained, however, it can be oxidized conveniently with air in the presence of various metallic or metallic salt catalysts to yield the corresponding aldehyde [prenal (1)]. Refer to: M. Matsumoto et al.,
J. Org. Chem
. 1984, 49, 3435; Japanese patent 60 239,443 issued to Kuraray Co., Ltd. [
Chem. Abstracts
1986, 104, 148312q]; and K. Kaneda etal.,
J. Org. Chem
. 1996, 61, 4502.
Isoprene [2-methyl-1,3-butadiene, CH
2
═C(CH
3
)CH═CH
2
] would seem to be a useful and potentially low-cost precursor to prenyl alcohol (2). Isoprene, which is used to make “synthetic natural rubber,” can be obtained by “cracking” petroleum or—more conveniently—by a Prins reaction involving isobutylene and formaldehyde.
See, Japanese patent 71 14,107, issued to Sumitomo Chemical Co., Ltd. [
Chem. Abstracts
1972, 77, 153520j].
Unfortunately, acid-catalyzed addition of water to isoprene yields only a minor amount of prenyl alcohol (2) and a substantial amount of the isomeric tertiary alcohol shown below.
In addition to the above two alcohols, various other products are obtained in this reaction. See,
Chem. Abstracts
1973, 78, 84547e.
Another approach to the formation of prenyl alcohol (2) from isoprene involves prenyl halide (6) [(CH
3
)
2
C═CHCH
2
X, X═Br or Cl] intermediates. If one has prenyl halides (6) available, the following route to prenyl alcohol has been developed:
Refer to: Japanese patent 77 10,207 issued to Kuraray Co., Ltd. [
Chem. Abstracts
1977, 87, 38852p] and German patent 3,021,414 (Dec. 11, 1980, issued to Montedison;
Chem. Abstracts
1981, 94, 17431 1h).
Prenyl halides (6) can be formed by the addition of hydrohalic acids (FIX: HCl or HBr) to isoprene. Although this reaction does yield prenyl halides (6), yields are only moderate and the reaction is complicated by the fact that HX also adds to the double bond in the initially formed prenyl halide (6) to give a dihalide: (CH
3
)
2
C(X)CH
2
CH
2
X.
Furthermore, prenyl bromide (or chloride) is highly toxic, rather volatile, and decomposes if one attempts to distill it at atmospheric pressure.
Other methods for the conversion of isoprene to prenyl alcohol (2,) were reported by J. H. Babler in U.S. Pat. No. 5,872,277 (Feb. 16, 1999) (the '277 patent). In one particular method of the '277 patent, slow, preferably dropwise, addition of isoprene to a carboxylic acid (8) whose acid ionization constant, K
a
, (relative to water) is greater than 10
−4
yields the corresponding prenyl ester (7):
This reaction fails for acetic acid (K
a
=1.75×10
−5
), propionic acid (K
a
=1.34×10
−5
), et al., and is even quite slow when one uses formic acid (K
a
=1.77×10
−4
). In contrast, the use of dichloroacetic acid (K
a
=5.53×10
−2
) in molar excess in the above reaction results in a moderate yield of the corresponding prenyl ester (7), prenyl dichloroacetate. Once the ester (7) is obtained, it can be readily saponified using sodium carbonate, sodium hydroxide, potassium carbonate et al., in aqueous alcohol at room temperature to yield prenyl alcohol (2).
Although the addition of dichloroacetic acid to isoprene is useful for synthesis of small quantities of prenyl alcohol (2), the high cost of dichloroacetic acid requires that it be recovered after the saponification of prenyl dichloroacetate and subsequently recycled—a process that proved to be difficult to accomplish on a large scale.
SUMMARY OF THE INVENTION
Methods for converting isoprene to certain prenyl esters (7) in good yield have been developed.
A preferred process involves addition of isoprene (bp: 34° C.) to a mixture including an alkanoic acid (8), RCO
2
H, wherein R is a C
1
-C
4
alkyl group, and an inorganic acid catalyst.
In another method of the invention, an inorganic acid catalyst is added to a mixture including an alkanoic acid (8), RCO
2
H, wherein R is a C
1
-C
4
alkyl group, and isoprene. Because the prenyl esters (7) will be subsequently hydrolyzed to prenyl alcohol (2) and the corresponding alkanoic acid (8), RCO
2
H, mixtures of carboxylic acids, RCO
2
H, can also be employed.
The above reaction will not occur unless the inorganic acid catalyst has a K
a
(relative to water) that is about 10
−3
to about 10
−6
, preferably about 10
−3
to about 10
−2
. Phosphoric acid [K
a
=7.1×10
−3
; see: “The Merck Index,” Ninth Edition, page 956] is a preferred catalyst for effecting the desired transformation [i.e., isoprene→prenyl ester (7)].
In contrast, organic acids such as dichloroacetic acid (K
a
=5.5×10
−2
) or oxalic acid (K
a
=5.4×10
−2
)[see:
Organic Chemistry
, Third Edition, page 600, by Morrison and Boyd] that are stronger than phosphoric acid failed to catalyze the process under reaction conditions for which phosphoric acid gave a high yield of prenyl ester (7)—e.g., no reaction occurred using dichloroacetic acid as the catalyst.
Although the addition of acetic acid to isoprene in the presence of a catalytic amount of phosphoric acid will occur slowly at room temperature to yield prenyl acetate (systematically named as 3-methyl-2-buten-1-yl acetate), gentle heating of the reaction mixture in a pressure vessel at temperatures of approximately 40° C. to 100° C. is preferred if one wishes to conduct t
Deemie Robert W.
Killos Paul J.
Loyola University of Chicago
Marshall O'Toole Gerstein Murray & Borun
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