Ketosulfone derivatives and process for producing the same

Details Ketosulfone derivatives and process for producing the same Ketosulfone derivatives and process for producing the same

2000-08-22

2001-10-02

Vollano, Jean F. (Department: 1621)

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

Organic compounds

Sulfur containing

C568S031000, C568S032000, C568S033000

Reexamination Certificate

active

06297402

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to sulfone derivatives useful in the fields of pharmaceuticals, food and feed additives, and to a process for producing the same.
2. Description of the Related Art
Heretofore, as processes for producing canthaxanthin derivatives and astaxanthin derivatives, a method is known in which a key intermediate, a specific C13 ketone (&bgr;-ionone), is subjected to a carbon-increment reaction at its side chain to produce the target ccmpounds via Vitamin A and further &bgr;-carotene (Pure Appl. Chem. (1991), 63(1), 35-44). However, &bgr;-ionone, which is synthesized via multiple steps, is commercially rather expensive.
SUMMARY OF THE INVENTION
An object of the invention is to provide a process for industrially advantageously producing sulfone derivatives, which are key intermediates for producing canthaxanthin derivatives and astaxanthin derivatives, by oxidizing sulfone compounds derived from inexpensive C10 compounds.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides:
1. A ketosulfone derivative represented by the formula (I):
wherein Ar represents an aryl group which may be substituted, and R
1
′ and R
2
′ represent a hydrogen atom or a protective group of a hydroxyl group;
2. A process for producing the ketosulfone derivative represented by the formula (I), which comprises reacting a sulfone compound represented by the formula (II):
wherein Ar has the same meaning as defined above with a halohydrin derivative represented by the formula (III):
wherein X represents a halogen atom and R
1
and R
2
represent a protective group of a hydroxyl group, in the presence of a base, optionally followed by removal of the protective group;
3. A process for producing the ketosulfone derivative represented by the formula (I), which comprises reacting a sulfone compound represented by the formula (IV):
wherein Ar represents an aryl group which may be substituted, and R
1
and R
2
represent a protective group of a hydroxyl group with an oxidizing agent;
4. A sulfone derivative represented by the formula (V):
wherein Ar represents an aryl group which may be substituted, Z represents an oxo group (═O) or a hydroxyl group and Y represents a hydrogen atom, a halogen atom or a hydroxyl group; and a process for producing the same.
First, the ketosulfone derivative of the formula (I) will be explained.
R
1
′ and R
2
′ in the ketosulfone derivative of the formula (I) represent a hydrogen atom or a protective group of a hydroxyl group. Specific examples of the protective group of the hydroxyl group include acyl groups such as an acetyl group, a pivaloyl group, a benzoyl group and a p-nitrobenzoyl group, silyl groups such as a trimethylsilyl group, a t-butyldimethylsilyl group and a t-butyldiphenylsilyl group, a tetrahydropyranyl group, alkoxymethyl groups such as methoxyethoxymethyl group and a 1-ethoxymethyl group, a benzyl group, a p-methoxybenzyl group, a t-butyl group, a trityl group, a 2,2,2-trichloroethoxycarbonyl group, an allyloxycarbonyl group and so on.
“Ar” in the ketosulfone derivative of the formula (I) represents an optionally substituted aryl group. The aryl group includes a phenyl group, a naphthyl group and the like. Suitable substituents for the aryl groups include C1-C5 alkyl groups such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group and a n-pentyl group, C1-C5 alkoxy groups such as a methoxy group, an ethoxy group, a n-propoxy group, a butoxy group and a pentyloxy group, halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a nitro group, etc.
Specific examples of the optionally substituted aryl group include a phenyl group, a naphthyl group, an o-tolyl group, a m-tolyl group, a p-tolyl group, an o-methoxyphenyl group, a m-methoxyphenyl group, a p-methoxyphenyl group, an o-chlorophenyl group, a m-chlorophenyl group, a p-chlorophenyl group, an o-bromophenyl group, a m-bromophenyl group, a p-bromophenyl group, an o-iodophenyl group, a m-iodophenyl group, a p-iodophenyl group, an o-fluorophenyl group, a m-fluorophenyl group, a p-fluorophenyl group, an o-nitrophenyl group, a m-nitrophenyl group, a p-nitrophenyl group, and the like.
Some ketosulfone derivatives represented by the formula (I) are given in the following Table 1.
TABLE 1
Ketosulfone derivatives of the formula (I)
No.
Ar
R
1
′
R
2
′
1
phenyl
Acetyl
Acetyl
2
naphthyl
Acetyl
Acetyl
3
o-tolyl
Acetyl
Acetyl
4
m-tolyl
Acetyl
Acetyl
5
p-tolyl
Acetyl
Acetyl
6
o-methoxyphenyl
Acetyl
Acetyl
7
m-methoxyphenyl
Acetyl
Acetyl
8
p-methoxyphenyl
Acetyl
Acetyl
9
o-chlorophenyl
Acetyl
Acetyl
10
m-chlorophenyl
Acetyl
Acetyl
11.
p-chlorophenyl
Acetyl
Acetyl
12.
o-bromophenyl
Acetyl
Acetyl
13
m-bromophenyl
Acetyl
Acetyl
14
p-bromophenyl
Acetyl
Acetyl
15
o-iodophenyl
Acetyl
Acetyl
16
m-iodophenyl
Acetyl
Acetyl
17
p-iodophenyl
Acetyl
Acetyl
18
o-fluorophenyl
Acetyl
Acetyl
19
m-fluorophenyl
Acetyl
Acetyl
20
p-fluorophenyl
Acetyl
Acetyl
21
o-nitrophenyl
Acetyl
Acetyl
22
m-nitrophenyl
Acetyl
Acetyl
23
p-nitrophenyl
Acetyl
Acetyl
Further specific examples of ketosulfone derivatives represented by the formula (I) include those compounds having a pivaloyl group, a benzoyl group, a p-nitrobenzoyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a tetrahydropyranyl group, a methoxymethyl group, a methoxyethoxymethyl group and a 1-ethoxyethyl group, a benzyl group, a p-methoxybenzyl group, a t-butyl group, a trityl group, a 2,2,2-trichloroethoxycarbonyl group or an allyloxycarbonyl group in place of the acetyl group for R
1
′ and R
2
′ in the compound as listed in Table 1. Also those compounds having a hydrogen atom for R
1
′ and/or R
2
′ are included in ketosulfone derivative of the formula (I).
The ketosulfone derivative of the formula (I) can be obtained by reacting the sulfone compound of the formula (II) with the halohydrin derivative of the formula (III) wherein R
1
and R
2
represent a protective group of a hydroxyl group in the presence of a base, and optionally followed by removal of the protective group(s). The removal of the protective group can be carried out in a conventional manner according to “Protective Groups in Organic Synthesis, Greene and Wuts, 2nd Edition (1992), John Wiley & Sons, Inc, the whole disclosure of which is incorporated herein by reference.
X of the halohydrin derivative of the formula (III) may be a halogen atom such as a chlorine atom, a bromine atom and an iodine atom.
Examples of R
1
and R
2
of the halohydrin derivative (III) include protective groups of a hydroxyl group mentioned in the explanation of R
1
′ and R
2
′ of the ketosulfone derivative of the formula (I).
Some halohydrin derivatives represented by the formula (III) are given in the following Table 2.
TABLE 2
Halohydrin derivatives of the formula (III)
No.
X
R
1
R
2
1
Br
Acetyl
Acetyl
2
Cl
Acetyl
Acetyl
3
I
Acetyl
Acetyl
Further specific examples of halohydrin derivatives represented by the formula (III) include those compounds having a pivaloyl group, a benzoyl group, a p-nitrobenzoyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a tetrahydropyranyl group, a methoxymethyl group, a methoxyethoxymethyl group and a 1-ethoxyethyl group, a benzyl group, a p-methoxybenzyl group, a t-butyl group, a trityl group, a 2,2,2-trichloroethoxycarbonyl group or an allyloxycarbonyl group in place of the acetyl group for R
1
and/or R
2
in the compound as listed in Table 2.
Examples of the base used in the reaction include alkyllithiums, Grignard reagents, hydroxides of alkaline metals, hydroxides of alkaline earth metals, hydrides of alkali metals, hydrides of alkaline earth metals, alkoxides of alkali metals, alkoxides of alkaline earth metals, etc. Specific examples of the base include n-butyllithium, s-butyllithium, t-butyllithium, ethylmagnesium bromide, ethylmagnesium chloride, sodium hydroxide, potassium hydroxide, s

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