Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-01-26
2002-05-14
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S128000, C560S129000, C560S205000, C568S028000, C568S032000, C568S850000, C568S824000, C568S841000
Reexamination Certificate
active
06388124
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a dihalo-compound which useful as an intermediate producing for retinol and the like, and a process for producing the same.
BACKGROUND OF THE INVENTION
There have been known a method for producing vitamin A by a carbon-increment reaction at the side chain of &bgr;-ionone (C13) (Pure & Appl. Chem. 66, 1509, (1994)) and a process of coupling C10 sulfones with C10 aldehydes, and eliminating a sulfone group (JP-B 4-3388, JP-B 5-61265 and the like). However, &bgr;-ionone (C13) is very expensive and an expensive acetaldehyde derivative is required as an oxidizing agent in a step of preparing said C10 aldehyde.
SUMMARY OF THE INVENTION
According to the present invention, vitamin A can be industrially advantageously produced in a good yield using a dihalo-compound, which can be readily derived from economically available linalool or geraniol, and
The present invention provides:
1. a dihalo-compound of formula (1):
wherein
X
1
and X
2
represent different halogen atoms,
R represents a hydrogen atom or a protective group for a hydroxyl group, and the wavy line denoted by “
” means that the stereochemistry relating to the double bond to which said wavy line is bonded is E, Z or a mixture thereof,
2. a method for producing a dihalo-compound of formula (1) as defined above, which comprises
reacting at least one compound selected from an alcohol compound of formula (2):
an alcohol compound of formula (3):
with a halogenating agent having a halogen atom represented by X
2
as defined in connection with formula (1) above,
wherein in formulae (2) and (3) X
1
represents a halogen atom, R represents a protective group for a hydroxy group, and the wavy line denoted by “
” means that the stereochemistry relating to the double bond to which said wavy line is bonded is E, Z or a mixture thereof, and
3. a method for producing a sulfone derivative of formula (5):
wherein
Ar represents an optionally substituted aryl group,
R represents a hydrogen atom or a protective group for a hydroxy group, and the wavy line denoted by “
” means that the stereochemistry relating to the double bond to which said wavy line is bonded is E, Z or a mixture thereof,
which comprises
reacting a sulfone compound of formula (6):
wherein Ar is the same as defined above, with a dihalo-compound of formula (1):
wherein X
1
and X
2
represent different halogen atoms and the wavy line denoted by “
” means that the stereochemistry relating to the double bond to which said wavy line is bonded is E, Z or a mixture thereof, in the presence of a base.
DETAILED DESCRIPTION
The present invention will be explained in detail below.
X
1
and X
2
represent different halogen atoms. Examples of a halogen atom represented by X
1
or X
2
in the formulae of the present invention include a chlorine atom, a bromine atom, and an iodine atom. X
1
preferably represents a bromine atom, and X
2
preferably represents a chlorine atom.
Examples of the protecting group for a hydroxy group represented by R include
an acyl group such as formyl, acetyl, ethoxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl, tribromoacetyl, propionyl, 2-chloropropionyl, 3-chloropropionyl, butyryl, 2-chlorobutyryl,3-chlorobutyryl,4-chlorobutyryl, 2-methylbutyryl, 2-ethylbutyryl, valeryl, 2-methylvaleryl, 4-methylvaleryl, hexanoyl, isobutyryl, isovaleryl, or pivaloyl group,
a benzoyl, o-chlorobenzoyl, m-chlorobenzoyl, p-chlorobenzoyl, o-hydroxybenzoyl, m-hydroxybenzoyl, p-hydroxybenzoyl, o-acetoxybenzoyl, o-methoxybenzoyl, m-ethoxybenzoyl, p-methoxybenzoyl, p-nitrobenzoyl group or the like,
a silyl group such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or the like,
an alkoxyalkyl group such as methoxymethyl, methoxyethoxymethyl, 1-ethoxyethyl or the like,
a tetrahydropyranyl group and the like, a benzyl group, a p-methoxybenzyl group, a t-butyl group, a trityl group, a 2,2,2-trichloroethoxycarbonyl group, allyloxycarbonyl group and the like.
Examples of the halogenating agent having a halogen atom represented by X
2
as defined in connection with formula (1) above include
a halide of a transition metal of Group 4, a halide of sulfur and a halide of phosphorus.
Said halide of a transition metal of Group 4 include
a halide of formula (4):
M(X
2
)
a
(OR′)
4−a
(4)
wherein M is a transition metal of Group 4, “a” is an integer of 1 to 4 and R′ is a straight or branched chain alkyl group having 1 to 5 carbon atoms.
Examples of the metal atom “M” in the halide (4) of a transition metal of Group 4 include titanium, zirconium and hafnium. In particular, a titanium is preferred among them.
Examples of the linear or branched alkyl group having a carbon number of 1 to 5 represented by R′ in formula (4) include a methyl, ethyl, n-propyl, iso-propyl, n-butyl, s-butyl, t-butyl and n-pentyl group. Specific examples of the halide of a transition metal of Group 4 represented by formula (4) include titanium tetrachloride, titanium tetrabromide, dichlorotitanium diisopropoxide, zirconium tetrachloride, hafnium tetrachloride and the like.
Examples of the halide of sulfur is thionyl chloride and examples of the halide of phosphorus include phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride.
An amount of the halogenating agent to be used is usually around 0.25 to 2 moles, preferably around 0.5 to 1.1 moles per mol of the total amount of the alcohols (2) and (3).
The halide of sulfur or phosphorus is preferably used in the presence of a base. The base is not particularly limited and includes an organic amine base and inorganic bases.
Specific examples thereof include pyridine, 4-dimethylaminopyridine, 3-ethyl-4-methylpyridine, 5-ethyl-2-methylpyridine, imidazole, 2-methylimidazole, 3-methylimidazole, 2-ethyl-4-methylimidazole, DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), trimethylamine, triethylamine, dimethylethylamine, methyldiethylamine, t-butyldimethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. An amount of the base to be used is usually around 1 to 2 moles per mol of the alcohols (2) or (3).
The reaction is usually conducted in an organic solvent and examples of the solvent include
an ether solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, anisole and the like,
a hydrocarbon solvent such as n-hexane, cyclohexane, n-pentane, benzene, toluene, xylene and the like,
a halogenated solvent such as chloroform, dichloromethane, 1,2-dichloroethane, monochlorobenzene, o-dichlorobenzene and the like, and
an aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, hexamethylphosphoric triamide and the like.
The halide of a transition metal of Group 4 is preferably used, together with an ether solvent, and dimethoxyethane is more preferable. These may be used alone or as a mixed solvent thereof. A reaction temperature can be optionally set at a range of −78° C. to a boiling point of a solvent, preferably a range of around −20 to 60° C.
A dihalo-compound of formula (1), wherein X
1
is a bromine atom and X
2
is a chlorine atom is preferred.
After completion of the reaction, the dihalo-compound (1) can be obtained by conventional post-treatment procedures. It may be purified by extraction, washing, various chromatographies or the like, if necessary.
Next, a description will be made to the method for producing a sulfone derivative of formula (5) as defined above which method comprises reacting a sulfone compound of formula (6) as defined above, with a dihalo-compound of formula (1) in the presence of a base.
Examples of the base to be used include an alkali metal alkoxide, an alkali metal hexamethyldisilazane, a hydride of an alkali metal, an alkyl lithium, a Grignard reagent. Specific examples thereof include
sodium methoxide, potassium methoxide, sodium ethoxide,
Seko Shinzo
Takahashi Toshiya
Price Elvis O.
Richter Johann
Sumitomo Chemical Company Limited
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