U.S. patent application number 09/965059 was filed with the patent office on 2002-02-28 for process for preparing 2,7-dimethyl-2,4,6-octatriene-1,8-dial.
This patent application is currently assigned to Sangho Koo. Invention is credited to Choi, Hojin, Ji, Minkoo, Koo, Sangho, Park, Minsoo.
Application Number | 20020026082 09/965059 |
Document ID | / |
Family ID | 19557410 |
Filed Date | 2002-02-28 |
United States Patent
Application |
20020026082 |
Kind Code |
A1 |
Koo, Sangho ; et
al. |
February 28, 2002 |
Process for preparing 2,7-dimethyl-2,4,6-octatriene-1,8-dial
Abstract
Intermediates useful in the synthesis of a compound having
polyene chain structure, processes for preparing the same, and a
process for preparing .beta.-carotene utilizing the same are
disclosed. Also disclosed is a novel compound, retinyl sulfide,
which was synthesized by the coupling of a diallylic sulfide of the
present invention with the corresponding Wittig salt.
Inventors: |
Koo, Sangho; (Seoul, KR)
; Choi, Hojin; (Kyunggi-do, KR) ; Park,
Minsoo; (Seoul, KR) ; Ji, Minkoo; (Seoul,
KR) |
Correspondence
Address: |
Candice J. Clement, Esq.
Heslin Rothenberg Farley & Mesiti P.C.
5 Columbia Circle
Albany
NY
12203-5160
US
|
Assignee: |
Sangho Koo
Seoul
KR
|
Family ID: |
19557410 |
Appl. No.: |
09/965059 |
Filed: |
September 27, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09965059 |
Sep 27, 2001 |
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09873672 |
Jun 4, 2001 |
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09873672 |
Jun 4, 2001 |
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09435336 |
Nov 5, 1999 |
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6297416 |
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Current U.S.
Class: |
568/38 ; 558/51;
568/39; 568/41 |
Current CPC
Class: |
C07C 323/22 20130101;
C07C 323/14 20130101; C07C 319/20 20130101; C07C 2601/16 20170501;
C07C 403/24 20130101; C07C 323/05 20130101; C07C 45/60 20130101;
C07C 315/02 20130101; C07C 45/60 20130101; C07C 47/21 20130101;
C07C 315/02 20130101; C07C 317/14 20130101; C07C 319/20 20130101;
C07C 323/65 20130101 |
Class at
Publication: |
568/38 ; 558/51;
568/39; 568/41 |
International
Class: |
C07C 321/08; C07C
323/10; C07C 323/22 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 6, 1998 |
KR |
98-47549 |
Claims
We claim:
1. A diallylic sulfide compound represented by Formula 1 14wherein:
R.sub.1 and R.sub.2 are independently chosen from the group
consisting of --CHO, --CH.sub.2Cl, --CH.sub.2Br, --CH.sub.2I,
--CH.sub.2OH, CH.sub.2OSO.sub.2CF.sub.3, --CH.sub.2OSO.sub.2Ph,
--CH.sub.2OSO.sub.2C.su- b.6H.sub.4CH.sub.3 and
--CH.sub.2OSO.sub.2CH.sub.3.
2. A process for preparing a diallylic sulfide compound according
to claim 1, wherein R.sub.1 and R.sub.2 are each --CHO, which
comprises the steps of: (a) providing an allylic halide of Formula
(A) 15wherein X is chosen from Br, Cl and I; (b) adding a catalytic
amount of acid to the allylic halide of step (a) in the presence of
an alcoholic solvent to obtain an acetal; (c) reacting the acetal
of step (b) with sodium sulfide; and (d) concentrating the solvent
and hydrolyzing the product of step (c) to obtain a diallylic
sulfide compound according to claim 1, wherein R.sub.1 and R.sub.2
are each --CHO.
3. A process for preparing a diallylic sulfide compound according
to claim 1, wherein R.sub.1 and R.sub.2 are chosen from
--CH.sub.2Cl, --CH.sub.2Br and --CH.sub.2I, which comprises the
steps of: (a) providing an allylic halide of Formula (A) 16wherein
X is chosen from Br, Cl and I; (b) adding a catalytic amount of
acid to the allylic halide of step (a) in the presence of an
alcoholic solvent to obtain an acetal; (c) reacting the acetal of
step (b) with sodium sulfide; (d) concentrating the solvent and
hydrolyzing the product of step (c); and (e) reducing and
halogenating the product of step (d) to obtain a diallylic sulfide
compound according to claim 1, wherein R.sub.1 and R.sub.2 are
chosen from --CH.sub.2Cl, --CH.sub.2Br and --CH.sub.2I.
4. A process for preparing 2,7-dimethyl-2,4,6-octatriene-1,8-dial,
represented by Formula 2 17which comprises the steps of: (a)
providing an allylic halide of Formula (A) 18wherein X is chosen
from Br, Cl and I; (b) protecting the aldehyde of the allylic
halide to obtain an acetal of Formula G 19wherein R.sub.3 and
R.sub.4 are independently chosen from --H and --CH.sub.3; (c)
reacting the acetal of step (b) with sodium sulfide to obtain
di(3-formyl-3-methyl-2-propenyl)sulfide, dialkyl diacetal of
Formula H; 20(d) oxidizing the product of step (c) to obtain an
allylic sulfone of Formula I; 21(e) subjecting the allylic sulfone
of step (d) to a Ramberg-Bcklund reaction to obtain a triene of
Formula J; 22(f) hydrolyzing the triene of step (e) to obtain a
compound of Formula 2.
5. The process according to claim 4, wherein step (d) comprises
adding a mixture of urea-hydrogen peroxide and phthalic anhydride
to the product of step (c).
6. A process for preparing .beta.-carotene, represented by Formula
3 23which comprises the steps of: (a) providing a sulfone compound
of Formula B 24(b) deprotonating the sulfone compound of Formula B
and reacting not more than 1/2 equivalent, based upon the sulfone
compound, of an allylic sulfide, represented by Formula C 25wherein
X is a halogen, to provide a sulfide compound of Formula D 26(c)
oxidizing the sulfide compound of step (b) to provide a sulfone
compound of Formula E 27(d) subjecting the sulfone compound of step
(c) to a Ramberg-Bcklund reaction to provide
11,20-dibenzenesulfonyl)-11,12,19,20 tetrahydro-.beta.-carotene of
Formula F 28(e) reacting the product of step (d) with a base to
obtain .beta.-carotene of Formula 3.
7. The process according to claim 6, wherein X is Cl and step (b)
further comprises adding a stoichiometric amount of sodium iodide
to the reaction mixture.
8. The process according to claim 6, step (c) comprises adding a
mixture of urea-hydrogen peroxide and phthalic anhydride to the
sulfide compound of step (b).
9. The process according to claim 6, wherein step (e) comprises
reacting the product of step (d) with a metal alkoxide.
10. A compound represented by Formula 4 29
11. A process for preparing a compound according to claim 10 which
comprises a Wittig reaction of a diallylic sulfide of Formula C-1
30with a Wittig salt, represented by Formula K. 31
Description
CLAIM FOR FOREIGN PRIORITY
[0001] This application claims priority of KR 98-47549, filed Nov.
6, 1998.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds having a polyene
chain structure, and processes for preparing the same. More
specifically, it relates to intermediate compounds, which can be
effectively used in the synthesis of .beta.-carotene, processes for
preparing the same, processes for preparing .beta.-carotene by
using the intermediate compounds, and "retinyl sulfide," named by
the present inventors, and a process for preparing the same.
BACKGROUND OF THE INVENTION
[0003] Carotenoid compounds have a polyene chain structure, and
specific examples of such include .beta.-carotene, lycopene,
astaxanthin and the like. .beta.-carotene is known as pro-vitamin
A, which decomposes to vitamin A according to the needs of a living
body.
[0004] Carotenoid compounds are generally used as natural pigments
for foodstuffs, and are apt to selectively react with carcinogens
such as singlet oxygen radical and the like, and as such, they are
expected to have use as a prophylactic agent for cancers. In light
of this expectation, there is an increasing need to develope a
process that can effectively and efficiently synthesize the polyene
chain structure.
[0005] .beta.-carotene has been manufactured by Hoffman-La Roche
since 1954, and by BASF since 1972 [Paust, J., Pure Appl. Chem.,
63:45-58 (1991)].
[0006] According to the Roche process, two C.sub.19 molecular units
are connected by using bis(magnesium halide) acetylide, and the
resulting product is subjected to partial hydrogenation of the
triple bond and dehydration in the presence of acid catalyst, to
provide .beta.-carotene, as shown in Scheme 1 below: 1
[0007] As can be seen from Scheme 1, however, the synthesis of the
C.sub.19 compound from the C.sub.14 compound is not a convergent
process, and requires two consecutive enol ether condensations,
thereby providing the process with a low effectiveness.
[0008] With regard to the BASF process, .beta.-carotene is
synthesized via a Wittig reaction of C.sub.15 phosphonium salt and
C.sub.10 dialdehyde, as is shown in Scheme 2 below. According to
this process, a double bond can be effectively formed by the Wittig
reaction, but the process has a further problem in that phosphine
oxide (Ph.sub.3P.dbd.O), produced as a by-product, cannot be easily
separated or removed. 2
SUMMARY OF THE INVENTION
[0009] The present invention provides intermediate compounds useful
for the efficient synthesis of the polyene chain structure, taking
fill advantage of its symmetry and which solve the problem of
by-products such as phosphine oxide by the employment of the
Julia-type sulfone olefination strategy; processes for preparing
the same; and processes for preparing .beta.-carotene using the
same.
[0010] The present invention also provides a novel compound having
a polyene chain structure which is synthesized via the
aforementioned intermediate compound, and a process for preparing
the same.
[0011] The present invention further provides an improved process
for preparing 2,7-dimethyl-2,4,6-octatriene-1,8-dial, a compound
used in the BASF process for preparing .beta.-carotene, which
requires fewer synthetic steps than the conventional process.
[0012] Accordingly, one embodiment of the invention is a diallylic
sulfide, represented by Chemical Formula 1: 3
[0013] wherein, R.sub.1 and R.sub.2 are independently chosen from
the group consisting of --CHO, --CH.sub.2Cl, --CH.sub.2Br,
--CH.sub.2I, --CH.sub.2OH, --CH.sub.2OSO.sub.2CF.sub.3,
--CH.sub.2OSO.sub.2Ph, --CH.sub.2OSO.sub.2C.sub.6HCH.sub.3 and
--CH.sub.2OSO.sub.2CH.sub.3. Preferably, R.sub.1 and R.sub.2 are
both --CHO or --CH.sub.2Cl.
[0014] Another embodiment of the present invention is a process for
preparing a diallylic sulfide represented by Chemical Formula 1,
which comprises the steps of:
[0015] (a) oxidizing isoprene to give isoprene monoxide;
[0016] (b) reacting the isoprene monoxide with cupric halide
(CuX.sub.2)/lithium halide (LiX) to provide an allylic halide (A);
and
[0017] (c) reacting the allylic halide (A) with sodium sulfide
(Na.sub.2S) to produce a compound represented by Chemical Formula
1.
[0018] The process may be represented by: 4
[0019] wherein R.sub.1 and R.sub.2 are independently chosen from
the group consisting of --CHO, --CH.sub.2Cl, --CH.sub.2Br,
--CH.sub.2I, --CH.sub.2OH, --CH.sub.2OSO.sub.2CF.sub.3,
--CH.sub.2OSO.sub.2Ph, --CH.sub.2OSO.sub.2C.sub.6H.sub.4CH.sub.3
and --CH.sub.2OSO.sub.2CH.sub.3- , and X is chosen from Cl, Br and
I.
[0020] For the diallylic sulfides represented by Chemical Formula
1, wherein R.sub.1 and R.sub.2 are --CH.sub.2Cl, --CH.sub.2Br or
--CH.sub.2I, the synthesis comprises the further step of reducing
and halogenating the resultant product from step (c).
[0021] Step (c) is preferably performed via the sequence of (1)
adding a catalytic amount of acid to the allylic halide (A) in
alcoholic solvent to form an acetal in situ; (2) reacting said
acetal with sodium sulfide for a predetermined period; and (3)
evaporating the solvent and hydrolyzing the residue.
[0022] Another embodiment of the present invention provides a
process for preparing 2,7-dimethyl-2,4,6-octatriene-1,8-dial
represented by Chemical Formula 2, which comprises the steps
of:
[0023] (a) protecting the aldehyde group of allylic halide (A) to
provide the corresponding acetal compound (G);
[0024] (b) reacting the acetal compound (G) with Na.sub.2S to
provide di(3-formyl-3-methyl-2-propenyl)sulfide, dialkyl diacetal
A);
[0025] (c) selectively oxidizing the
di(3-formyl-3-methyl-2-propenyl) sulfide, dialkyl diacetal (H) to
provide the corresponding allylic sulfone compound (I);
[0026] (d) applying a Ramberg-Bcklund reaction to the allylic
sulfone compound (I) to provide the corresponding triene compound
(J); and
[0027] (e) hydrolyzing the triene compound (J) to provide
2,7-dimethyl-2,4,6-octatriene-1,8-dial, represented by Chemical
Formula 2. 5
[0028] Here, X represents a halogen atom and R.sub.3 and R.sub.4
independently represent hydrogen or a methyl group.
[0029] In this embodiment, the selective oxidation reaction of step
(c) is preferably performed by adding a mixture of urea-hydrogen
peroxide (hereinafter, referred to as "UHP")and phthalic anhydride
dropwise to a solution containing di(3-formyl-3-methyl-2-propenyl)
sulfide, dialkyl diacetal at low temperature.
[0030] Yet another embodiment of the invention provides a process
for preparing .beta.-carotene represented by Chemical Formula 3,
which comprises the steps of
[0031] (a) deprotonating the sulfone compound (B), and reacting not
more than 1/2 equivalent (based on the sulfone compound) of allylic
sulfide (C) represented by Chemical Formula 1 (R.sub.1,
R.sub.2.dbd.CH.sub.2X, X.dbd.halogen atom) thereto, to provide
sulfide compound (D);
[0032] (b) selectively oxidizing the sulfide compound (D) to
prepare the sulfone compound (E);
[0033] (c) subjecting the sulfone compound (E) to a Ramberg-Bcklund
reaction to prepare
11,20-di(benzenesulfonyl)-11,12,19,20-tetrahydro-.bet- a.-carotene
(F); and
[0034] (d) reacting
11,20-di(benzenesulfonyl)-11,12,19,20-tetrahydro-.beta- .-carotene
(F) with a base to provide-.beta.-carotene, represented by Chemical
Formula 3. 6
[0035] In this embodiment, when X is Cl, step (a) is preferably
performed by adding a stoichiometric amount of sodium iodide (NaI)
in terms of reactivity. The selective oxidation of step (b) is
preferably carried out by adding a mixture of UHP and phthalic
anhydride dropwise to a solution containing the sulfide compound
(D) at low temperature.
[0036] The base used in step (d) is not specifically restricted.
Appropriate bases include, but are not limited to, for example,
NaNH.sub.2/NH.sub.3, metal alkoxides such as CH.sub.3OK/CH.sub.3OH,
CH.sub.3CH.sub.2OK/CH.sub.3CH.sub.2OH and
CH.sub.3CH.sub.2ONa/CH.sub.3CH.- sub.2OH, and t-BuOK/t-BuOH. Among
these example, metal alkoxides are more preferable.
[0037] Yet another embodiment of the present invention provides a
novel compound, retinyl sulfide, represented by Chemical Formula 4:
7
[0038] Still another embodiment of the present invention provides a
process for preparing retinyl sulfide represented by the Chemical
Formula 4, which comprises a Wittig reaction of diallylic sulfide
(C-1) represented by Chemical Formula 1 (R.sub.1 and R.sub.2 are
each --CHO) and the Wittig salt (K). 8
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] FIG. 1a is the .sup.1H NMR spectrum of trans-.beta.-carotene
as the authentic sample;
[0040] FIG. 1b is the .sup.1H NMR spectrum of trans-.beta.-carotene
prepared according to Synthetic Example 6 of the present invention;
and
[0041] FIG. 2 is the .sup.1H NMR spectrum of retinyl sulfide
(Chemical Formula 4) prepared according to Synthetic Example 9 of
the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0042] The diallylic sulfide represented by Chemical Formula 1,
which is used as a basic material in the synthesis of compounds
having polyene chain structure, may be synthesized according to the
following procedure, illustrated in Scheme 3, below.
[0043] First, isoprene is oxidized to obtain isoprene monoxide. The
oxidation may be carried out under the condition of using an
oxidant such as m-chloroperoxybenzoic acid (MCPBA), or the
condition of forming a corresponding halohydrin, which is then
reacted with a base [J. Am. Chem. Soc, 72:4608 (1950)], or the
like. Among these, the latter process is more preferable, when
considering the regio-selectivity on two double bonds of
isoprene.
[0044] Then, said isoprene monoxide is subjected to ring opening
reaction by reacting with cupric halide (CuX.sub.2.2H.sub.2O)/
lithium halide (LiX), to obtain allylic halide (A). For the ring
opening reaction, the reaction condition disclosed in literature
[J. Org. Chem., 41:1648 (1976)] is referred, and the reaction
condition of cupric chloride (CuCl.sub.2.2H.sub.2O)/ lithium
chloride (LiCl) is preferably employed.
[0045] Then, from the allylic halide (A), diallylic sulfide
represented by Chemical Formula 1 is obtained. 9
[0046] In this process, when R.sub.1 and R2 are each aldehyde
groups, allylic halide (A) is allylated to obtain diallylic sulfide
(Chemical Formula 1) which has aldehyde functional groups at both
ends. The allylation is preferably carried out by adding a
catalytic amount of acid such as p-toluenesulfonic acid (p-TsOH) in
alcoholic solvent to form an acetal, which is then reacted with
sodium sulfide and hydrolyzed. In such a reaction condition,
allylation can be proceeded without side reactions. The acid such
as p-TsOH serves as a catalyst that promotes the formation of
acetal.
[0047] As seen in Scheme 4, below, when R.sub.1 and R.sub.2 are
each --CH.sub.2X (wherein, X is a halogen atom), the allylic
sulfide is first reduced to give the corresponding diol compound
(C-1), which is then halogenated to obtain diallylic sulfide (C) in
which halogen atoms have been introduced at both ends. The
halogenation of diol compounds may be carried out under various
reaction conditions. For example, halogenation is performed by
using a reaction condition of CH.sub.3SO.sub.2Cl/LiCl, HCl, HBr,
PPh.sub.3/CCl.sub.4, or the like. 10
[0048] As previously discussed,
2,7-dimethyl-2,4,6-octatriene-1,8-dial represented by Chemical
Formula 2 is an important compound used in the synthesis of
.beta.-carotene of Chemical Formula 3, by reacting with Wittig salt
(K) according to the BASF process. Here-in-after, the process for
preparing 2,7-dimethyl-2,4,6-octatriene-1,8-dial of Chemical
Formula 2 is described with reference to Scheme 5 below.
[0049] First, the aldehyde group of the allylic halide (A) must be
protected. The protection of aldehyde group is performed by
converting the compound to the corresponding cyclic acetal compound
(G) by using glycol compounds such as neopentyl glycol, propylene
glycol, ethylene glycol, or the like.
[0050] The cyclic acetal compound (G) is then reacted with
Na.sub.2S to obtain the corresponding allylic sulfide, dialkyl
diacetal (H). The compound (H) may be used as a basic material for
the synthesis of compounds having polyene chain structure.
[0051] The sulfur of the compound (H) is then selectively oxidized
to obtain the corresponding allylic sulfone compound (I). The
selective oxidation is performed under a condition of slowly adding
an oxidant to the allylic sulfide compound (H) at low temperature.
As the oxidant, peroxyphthalic acid, which is the resulting
product. of reaction of UHP and phthalic anhydride, is preferably
used.
[0052] Through a Ramberg-Bccklund reaction, the corresponding
triene compound (J) is obtained from the allylic sulfone compound
(I). Deprotection by hydrolysis of acetal groups of the triene
compound (J) gives 2,7-dimethyl-2,4,6-octatriene-1,8-dial
represented by Chemical Formula 2. 11
[0053] The process for preparing
2,7-dimethyl-2,4,6-octatriene-1,8-dial described herein requires
fewer steps than the conventional process, making the process
simpler in terms of manufacturing.
[0054] Referring now to Scheme 6, the process for preparing
.beta.-carotene of Chemical Formula 3, according to the present
invention, is described. The process is characterized in that a
Ramberg-Bcklund reaction is performed on diallylic sulfone which
was obtained by the oxidation of diallylic sulfide, as previously
described herein.
[0055] According to the process, allylic sulfide (C) and 2
equivalents or more of sulfone compound (B) based on the amount of
the allylic sulfide are first coupled according to the Julia
process (Bull Soc. Chim. Fr., 1973). As a result of the coupling,
the allylic sulfide (D) is obtained, which contains all the carbons
required for the synthesis of .beta.-carotene. The coupling
reaction of allylic sulfide (C) with sulfone compound (B) may be
carried out under various reaction conditions. If X is Cl, it is
preferable to quantitatively add sodium iodide (NaI). Under such a
reaction condition, the halogen atoms at both end of allylic
sulfide (C) are substituted by iodine, and then allylation of the
sulfone compound actively occurs.
[0056] Then, the sulfur atom only of allylic sulfide (D) is
selectively oxidized to obtain the corresponding sulfone compound
(E). The selective oxidation is preferably carried out under the
reaction condition of adding an oxidant to the allylic sulfide
compound at low temperature. Under such a reaction condition, the
double bond of allylic sulfide (D) is not oxidized, but only the
sulfur is selectively oxidized.
[0057] Subsequently, SO.sub.2 of the central part of the structure
of sulfone compound (E) is removed by forming a double bond, to
give compound (F). Preferably, the reaction is carried out by
applying a Ramberg-Bcklund reaction to sulfone compound (E).
[0058] Compound (F) is then heated in the presence of alcoholic
solvent and alkoxide base such as sodium alkoxide to remove two
benzenesulfonyl groups, thereby obtaining .beta.-carotene of
Chemical Formula 3. 12
[0059] In accordance with the present invention, retinyl sulfide of
Chemical Formula 4 may be obtained by a Wittig reaction wherein the
allylic sulfide having aldehyde groups at both ends is reacted with
Wittig salt (K), as illustrated in Scheme 7 below. 13
[0060] As retinyl sulfide of Chemical Formula 4 has a structure
wherein the units of vitamin A are linked by a sulfur atom, the
compound is expected to exhibit the activity of vitamin A.
EXAMPLES
[0061] The principles of the present invention are herein described
in detail with reference to the following Examples. It should be
noted, however, that these examples are provided by way of
illustration only, and are not intended to limit or restrict the
scope of this invention in any way.
Synthetic Example 1: Di(3-formyl-3methyl-2-propenyl) Sulfide
[0062] To a solution of 4-chloro-2-methyl-2-buten-1-al (10.48 g,
88.2 mmol) in MeOH (80 mL) was added p-TsOH (48 mg, 0.25 mmol). The
mixture was stirred for 1 h, and then Na.sub.2S.9H.sub.2O (10.59 g,
44.1 mmol) was added. The resulting mixture was then stirred at
room temperature for 10 h.
[0063] When the reaction was completed, most of solvent was removed
by evaporating the reaction mixture under reduced pressure. After
adding 1 M HCl (50 mL) thereto, the resultant mixture was stirred
for 1 h, and extracted with methylene chloride (50 mL.times.3). The
combined methylene chloride layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
over silica gel to give di-(3-formyl-3-methyl-2-prop- enyl) sulfide
(7.43 g, 37.5 mmol) in 85% yield.
[0064] .sup.1H NMR .delta.1.78 (6H, s), 3.44 (4H d, J=7.7 Hz), 6.53
(2H t, J=7.7 Ez), 9.49 (2H, s)
[0065] .sup.13C NMR .delta.9.3, 29.1, 140.9, 147.5, 194.4
Synthetic Example 2: Di(4-chloro-3methyl-2-butenyl) Sulfide
[0066] To a stirred solution of di(3-formyl-3-methyl-2-propenyl)
sulfide (10.5 g 53.0 mmol) in TBF (80 mL) was added LiAlH.sub.4
(1.33 g, 35.0 mmol). The mixture was starred for 1 h, and then
quenched with 1 M HCl (30 mL). The mixture was extracted with EtOAc
(50 mL.times.3). The combined organic layer was dried over
anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure.
[0067] The above residue was dissolved in CH.sub.3CN (50 mL), and
then PPh.sub.3 (30.43 g, 0.116 mol) and CCl.sub.4 (20 mL) were
added thereto. The resulting mixture was stirred for about 5 h,
diluted with ether (100 ml), and subsequently washed with 1 M HCl
(20 mL.times.2) and H.sub.2O (30 mL).
[0068] The organic phase was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The crude product
was purified by flash chromatography over silica gel to produce
di(4-chloro-3-methyl-2-butenyl) sulfide (9.26 g, 38.7 mmol) in 73%
yield.
[0069] .sup.1H .delta.1.78 (6H, s), 3.14 (4H, d, J=7.7 Hz), 4.03
(4H, s), 5.62 (2H t, J=7.7 H)
[0070] MS (EI, 70 eV): 240 [(M+2).sup.+], 239 [(M+1).sup.+], 238
(M.sup.+), 203, 135, 102, 67
Synthetic Example 3: Di(11-benzenesulfonyl-11,12-dihydroretinyl)
Sulfide
[0071] To a stirred solution of sulfone compound (B) (14.4 g, 41.8
mmol) in THF (80 mL), was added NaH (1.20 g, 50.1 mmol). The
mixture was stirred for 15 min, and then
di(4-chloro-3-methyl-2-butenyl) sulfide (5.0 g, 20.9 mmol) and Nal
(7.5 g, 50.1 mmol) were added consecutively The resulting mixture
was stirred at room temperature for 15 h and diluted with ether.
The dilute mixture was subsequently washed with 1 M HCl (20
mL.times.2) and distilled water (30 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
over silica gel to give di(11-benzenesulfonyl-11,12-dihydroretinyl)
sulfide (D) (15.7 g, 17.8 mmol) in 85% yield.
[0072] .sup.1H NMR .delta.0.93 (6H, s), 0.96 (6H, s), 1.21 (6H, s),
1.45-1.65 (8H, m), 1.63 (12H, s), 2.00 (4H t, J=6.0 Hz), 2.39 (2H,
dd, J=13.2, 11.5 Hz), 2.90 (4H, d, J=6.8 Hz), 2.90-3.10 (2H, m),
4.02 (2H, dt, J.sub.d=3.1, J.sub.t=11.0 Hz), 5.07 (2H, d, J=10.3
Hz), 5.21 (2H, J=7.0 Hz), 5.93 (4H, s), 7.45-7.53 (4H, m),
7.58-7.65 (2H, m), 7.78-7.84 (4H, m)
[0073] .sup.13C NMR .delta.12.3, 16.0, 16.0, 19.2, 21.6, 28.9,
28.9, 33.0, 34.2, 37.4, 39.5, 64.1, 122.3, 125.8, 129.2, 129.6,
130.2, 130.4, 134.0, 134.4, 136.8, 138.1, 138.5, 143.2
Synthetic Example 4: Di(11-benzenesulfonyl-11,12-dihydroretinyl)
Sulfone
[0074] The mixture of UHP (6.88 g, 73.1 mmol) and phthalic
anhydride (5.41 g, 36.5 mmol) in CH.sub.3CN (70 mL) was stirred
vigorously at room temperature for 2 h to give a clear solution.
This solution was charged in a dropping funnel, and slowly added
over three hour period to a solution of
di(11-benzenesulfonyl-11,12-dihydroretinyl) sulfide (D) (10.8 g,
12.2 mmol) in CH.sub.3CN (30 mL). The temperature of the reaction
mixture was adjusted to be maintained at 0.degree. C.
[0075] When the dropping was complete, the reaction mixture was
stirred at 0.degree. C. for 1 h. After adding 1 M aqueous HCl (30
mL) thereto, the reaction mixture was extracted with ether (50
mL.times.2). The combined ether layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure
to give a white solid. The crude solid was dissolved in CHCl.sub.3,
and insoluble solid was filtered off. The filtrate was
concentrated, and the residue was purified by flash chromatography
over silica gel to give di(11-benzenesulfonyl-11,12-dihydr-
oretinyl) sulfone (8.06 g, 8.77 mmol) in 72% yield. Two stereo
isomers of the obtained allylic sulfone compound were found, and
one of which was isolated in pure state through silica gel column
chromatography.
[0076] .sup.1H NMR .delta.0.91 (6H, s), 0.96 (6H, s), 1.22 (6H, s),
1.37-1.49 (4H, m), 1.55-1.67 (4H, m), 1.62 (6H, s), 1.65 (6H, s),
1.99 (4H, t, J=5.9 Hz), 2.47 (2H, dd, J=13.0, 11.3 Hz), 3.05 (2H,
d, J=13.0 Hz), 3.47 (4H, d, J=4.5 Hz), 4.06 (2H, dt, J.sub.d=3.1,
J.sub.t=10.8 Hz), 5.07 (2H, d, J=10.5 Hz), 5.24 (2H, t, J=7.4 Hz),
5.92 (2H, A of ABq, J=16.4 Hz), 5.97 (2H, of ABq, J=16.4 Hz),
7.40-7.55 (4H, m), 7.55-7.70 (2H, m), 7.75-7.90 (4H, m)
[0077] .sup.13C NMR .delta.12.3, 17.0, 19.1, 21.5, 28.7, 28.8,
32.8, 34.0, 37.3, 39.3, 51.0, 63.4, 114.1, 121.0, 128.8, 129.0,
129.3, 129.7, 133.7, 135.5, 137.1, 137.2, 140.8, 142.8
Synthetic Example 5:
11,20-Dibenzenesulfonyl-11,12,19,20-tetrahydro-.beta.-
-carotene
[0078] To a stirred solution of
di(11-benzenesulfonyl-11,12-dihydroretinyl- ) sulfone (E) (1.51 g,
1.64 mmol) in t-BuOH (20 mL) and CCl.sub.4 (20 mL), was added KOH
(1.85 g, 32.9 mmol) under argon atmosphere. The mixture was stirred
vigorously for 5 h.
[0079] When the reaction was completed, most of solvent was removed
from the reaction mixture under reduced pressure. The crude product
was dissolved in CH.sub.2Cl.sub.2 (60 mL) and washed with 1 M HCl
(20 mL). The combined methylene chloride layer was dried over
anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The crude
product was purified by flash chromatography over silica gel to
give 11,20-dibenzenesulfonyl-11,12,19,20-tetrahydro-.beta.-carotene
(F) (932 mg, 1.13 mmol) in 69% yield.
[0080] .sup.1H NMR .delta.0.93 (6H, s), 0.96 (6H, s), 1.20 (6H, s),
1.37-1.50 (4H, m), 1.53-1.65 (4H, m), 1.63 (6H, s), 1.68 (6H, s),
1.98 (4H, br s), 2.45 (2H, dd, J=13.0, 11.6 Hz), 3.04 (2H, d,
J=14.2 Hz), 4.05 (2H, dt, J.sub.d=3.0, J.sub.t=10.9 Hz), 5.82-5.98
(2H, m), 5.92 (4H, s), 6.15-6.28 (2H, m), 7.40-7.54 (4H, m),
7.56-7.67 (2H, m), 7.76-7.90 (4H, m)
[0081] .sup.13C NMR .delta.12.3, 12.3, 16.7, 16.8, 19.1, 21.5,
28.8, 32.8, 34.1, 39.4, 64.2, 121.4, 127.8, 128.1, 128.7, 129.0,
129.3, 129.5, 132.9, 133.5, 136.0, 137.2, 137.6, 142.1
Synthetic Example 6: .beta.-Carotene
[0082] Sodium (674 mg, 29.3 mmol) was added to a stirred solution
of 11,20-di(benzenesulfonyl)-11,12,19,20-tetrahydro-.beta.-carotene
(F) (602 mg, 0.73 mmol) in EtOH (20 mL) under argon atmosphere. The
reaction mixture was heated under reflux for 10 h with vigorous
stirring.
[0083] When the reaction was completed, the reaction mixture was
concentrated under reduced pressure to remove most of the solvent.
Toluene (50 mL) was added thereto to dissolve the residue, and the
resultant mixture was washed with 1 M HCl, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
over silica gel to give exclusively trus-.beta.-carotene of
Chemical Formula 3 (295 mg, 0.55 mmol) in 75% yield.
[0084] NMR spectrum (JEOL, 300 MHz) data of trans-.beta.-carotene
is shown in FIG. 1b. The NMR data of the synthetic sample was
identical to that of the authentic sample, shown in FIG. 1a.
Synthetic Example 7: Di(3-formyl-3methyl-2-propenyl) Sulfide,
Dineopentyl Diacetal
[0085] To a solution of 4-chloro-2-methyl-2-buten-1-al (15.8 g,
0.134 mol) in toluene (100 mL) were added neopentyl glycol (16.7 g,
0.161 mol) and p-TsOH (190.2 mg, 6.7 mol). The mixture was heated
under reflux for 3 h and cooled to room temperature. The mixture
was diluted with ether (100 mL) and washed with distilled water (20
mL.times.3). The organic phase was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude product was purified by flash chromatography over silica
gel to give acetal (G) (R.sub.3, R.sub.4.dbd.CH.sub.3) (20.6 g,
0.100 mol) in 75% yield.
[0086] .sup.1H NMR .delta.0.73 (3H, s), 1.20 (3H, s), 1.79 (3H, s),
3.47 (2H, A of ABq, J=11.0 Hz), 3.62 (2H, B of ABq, J=11.0 Hz),
4.09 (2H, d, J=7.9 Hz), 4.72 (1H, s), 5.85 (1H, t, J=7.2 Hz)
[0087] .sup.13C NMR .delta.11.3, 21.7, 22.8, 30.1, 39.4, 77.1,
103.4, 124.2, 138.1
[0088] MS (EI, 70eV): 205 [(M+2).sup.+], 203 (M.sup.+), 169, 119,
83, 69; 55.
[0089] The above acetal (G) (20.6 g, 0.100 mmol) was dissolved in
MeOH (100 mL) and Na.sub.2S.9H.sub.2O (12.0 g, 50 mmol) was added
thereto. The resulting mixture was stirred at room temperature for
10 h.
[0090] When the reaction was completed, most of solvent was removed
by evaporating under reduced pressure. The crude oil was dissolved
in ether (100 mL) and washed with distilled water (30 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The crude product was purified by flash
chromatography over silica gel to give
di(3-formyl-3-methyl-2-propenyl) sulfide, dineopentyl diacetal
(17.6 g, 47.5 mmol) in 95% yield.
[0091] .sup.1H NMR .delta.0.68 (6H, s), 1.15 (6H, s), 1.68 (6H s),
3.09 (4H, d, J=7.5 Hz), 3.43 (4H, A of ABq, J=11.1 Hz), 3.58 (4H, B
of ABq, J=11.1 Hz), 4.66 (2H, s), 5.63 (2H, t, J=7.5 Hz)
[0092] .sup.13C NMR .delta.11.2, 21.8, 22.9, 28.0, 30.1, 77.1,
104.4, 125.4, 135.8
Synthetic Example 8: 2,7-Dimethyl-2,4,6-octatriene1,8-dial of
Chemical Formula 2
[0093] The mixture of UHP (5.17 g, 54.9 mmol) and phthalic
anhydride (4.07 g, 27.5 mmol) in CH.sub.3CN (30 mL) was stirred
vigorously at room temperature for 2 h to give a clear solution.
This solution was charged in a dropping funnel, and slowly added
over three hour period to a solution of
di(3-formyl-3-methyl-2-propenyl)sulfide dineopentyl diacetal (3.39
g, 9.15 mmol) in CH.sub.3CN (20 mL). The temperature of the
reaction mixture was adjusted to be maintained at 0.degree. C.
[0094] When the dropping was completed, the reaction mixture was
stirred at 0.degree. C. for 1 h. After adding 30 mL of distilled
water thereto, the reaction mixture was extracted with ether (100
mL). The combined ether layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure
to give a white solid. The crude solid was dissolved in CHCl.sub.3,
and insoluble solid was filtered off. The filtrate was concentrated
under reduced pressure, and the residue was purified by flash
chromatography over silica gel to give allylic sulfone compound (I)
(R.sub.3, R.sub.4.dbd.CH.sub.3) (2.94 g, 7.3 mmol) in 80%
yield.
[0095] .sup.1H NMR .delta.0.75 (6H, s), 1.20 (6H, s), 1.79 (6H, s),
3.50 (4H, A of ABq, J=10.9 Hz), 3.66 (4H, B of ABq, J=10.9 Hz),
3.72 (4H, d, J=7.7 Hz), 4.76 (s, 2H), 5.79 (2H, t, J=7.7Hz).
[0096] The allylic sulfone compound (I) (R.sub.3,
R.sub.4.dbd.CH.sub.3) (3.00 g, 7.45 mmol) was dissolved in a mixed
solvent of t-butanol (30 mL) and carbon tetrachloride (30 mL), and
KOH (4.18 g, 74.5 mmol) was added thereto under argon atmosphere.
The reaction mixture was stirred vigorously for 6 h.
[0097] When the reaction was completed, most of solvent was removed
from the reaction mixture under reduced pressure. The crude product
was dissolved in ether (70 mL), and washed with distilled water (20
mL.times.2). The organic layer was filtered and concentrated. The
crude product was purified by flash chromatography over silica gel
to give triene compound (J) (R.sub.3, R.sub.4.dbd.CH.sub.3) (2.04
g, 6.07 mmol) in 82% yield.
[0098] .sup.1H NMR .delta.0.73 (6H, s), 1.22 (6H, s), 1.85 (6H, s),
3.51 (4H, A of ABq, J=9.8 Hz), 3.66 (4H, B of ABq, J=9.8 Hz), 4.75
(2H, s), 6.30 (2H, d, J=8.1 Hz), 6.50 (2H, dd, J=7.7, 2.8 Hz)
[0099] .sup.13C NMR .delta.11.7, 21.4, 22.6, 29.8, 76.8, 103.9,
127.6, 129.1, 134.2
[0100] The triene compound (J) (R.sub.3, R.sub.4.dbd.CH.sub.3) (66
mg, 1.97 mmol) was dissolved in THF (30 mL), and 1 M HCl (30 mL)
was added thereto. The reaction mixture was stirred at room
temperature for 3 h. Then the reaction ire was extracted with ether
(50 mL.times.2). The organic layer was filtered and concentrated.
The crude product was purified by flash chromatography over silica
gel to give 2,7-dimethyl-2,4,6-octatriene-1,8-dial (226 mg, 1.38
mmol) in 70% yield.
[0101] .sup.1H NMR .delta.1.96 (6H, s), 7.00-7.15 (4H, m), 9.56
(2H, s)
[0102] .sup.13C NMR .delta.9.7, 134.3, 140.8, 146.1, 194.4
Synthetic Example 9: Retinyl Sulfide of Chemical Formula 4
[0103] Wittig salt compound K) (7.75 g, 14.2 mmol) and
di(3-formyl-3-methyl-2-propenyl)sulfide (1.41 g, 7.1 mmol) of
Chemical Formula 1 were dissolved in DMF (50 mL). The reaction
mixture was sufficiently stirred at -20.degree. C.
[0104] To the reaction mixture, sodium methoxide (8.1 g, 0.15 mmol)
was added, and the resultant mixture was stirred for 30 minutes.
After raising the temperature to room temperature, the reaction
mixture was further stirred for 3 h.
[0105] The reaction mixture was diluted with toluene (100 ml), and
washed with 1M HCl (30 mL.times.2). The organic layer was dried
over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The
crude product was purified by flash chromatography over silica gel
to give retinyl sulfide (2.75 g, 4.82 mmol) comprising three stereo
isomers in 68% yield.
[0106] .sup.1H NMR for the major isomer .delta.0.97 (6 s),
1.38.about.1.47 (2H, m), 1.54 (3H, s), 1.55.about.1.65 (2H, m),
1.59 (3H, s), 1.77 (3H, s), 1.92 (2H, t, J=6.3 Hz), 2.88 (2H, d,
J=6.4 Hz), 4.96 (1H, m), 5.24 (3H, m), 5.54 (1H, t, J=6.8 Hz), 6.05
(1H, d, J=15.6 Hz). Characteristic peaks for the minor isomers:
.delta.1.55 (3H, s), 1.58 (3H, s), 2.69 (2H, d, J=7.1 Hz), 2.69
(2H, d, J=6.8 Hz), 5.49 (1H, t, J=6.4 Hz), 6.01 (1H, d, J=7.5
Hz).
[0107] As described above, when .beta.-carotene is prepared
according to Synthetic Examples 1 to 6, the process becomes simpler
as compared to the conventional processes, and the problem involved
with the by-products such as phosphine oxide can be avoided.
According to Synthetic Example
8,2,7-dimethyl-2,4,6-octatriene-1,8-dial of Chemical Formula 2 can
be prepared through synthetic steps having two stages reduced as
compared with the conventional process.
[0108] In addition, the yield of retinyl sulfide of Chemical
Formula 4 prepared according to Synthetic Example 9 was 68%.
Retinyl sulfide is expected to have an activity of vitamin A.
Industrial Applicability
[0109] The allylic sulfide compounds of Chemical Formula 1
according to the present invention may be effectively used as
intermediates for the synthesis of compounds having polyene chain
structure such as .beta.-carotene. The compound represented by
Chemical Formula 2,2,7-dimethyl-2,4,6-octatriene-1,8-dial, is also
an important intermediate used for the synthesis of
.beta.-carotene. According to the present invention, the process
for 2,7-dimethyl-2,4,6-octatriene-1,8-dial can be shortened by two
stages as compared to the process according to BASF, so that the
time required for the production and production cost may be
reduced.
[0110] According to the present invention, allylic sulfide compound
(D) is oxidized to provide the corresponding diallylic sulfone
compound, to which a Ramberg-Bcklund reaction is applied to provide
the carotene compound of Chemical Formula 3, having the polyene
chain structure. When .beta.-carotene is prepared according to the
principles of the present invention, the process can be easily
performed as compared to the conventional process according to BASF
or Roche, and problems involved with by-products are avoided.
[0111] Retinyl sulfide of chemical formula 4 is expected to have
the activity of vitamin A.
* * * * *