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    • 专利摘要:
    Disclosed is a disulfone compound of Formula 1, a process for its preparation, an intermediate compound thereof and a process for preparing retinol via a disulfone compound: [Wherein Ar represents an aryl group which may have a substituent, R 1 represents a protecting group of a hydrogen atom or a hydroxyl group, and a broken line means that the disulfone compound is an E or Z geometric isomer or a mixture thereof].
    公开号:KR20020031297A
    申请号:KR1020010064207
    申请日:2001-10-18
    公开日:2002-05-01
    发明作者:다까하시도시야；세꼬신조；기무라가즈따까；도이노리유끼；곤야나오또
    申请人:고사이 아끼오；스미또모 가가꾸 고오교오 가부시끼가이샤；
    IPC主号:
    专利说明:

    PROCESS FOR PRODUCING RETINOL AND INTERMEDIATE COMPOUNDS FOR PRODUCING THE SAME}
    [1] The present invention relates to sulfone compounds which are intermediate compounds useful for the manufacture of medicaments, feed additives or food additives such as retinol, methods for their preparation, and methods for preparing retinol using the same.
    [2] A method of preparing a retinol is disclosed by reacting a sulfone of formula 6 shown below with a C10 aldehyde compound derived from linalool in a number of steps to obtain a C20 hydroxy sulfone compound and inducing it in a number of steps. (US 4,825,006). However, there is a need for further development of industrial manufacturing methods for retinol production.
    [3] In the present invention, retinol can be easily obtained by using a novel sulfone compound and a readily available C5 allyl halide compound.
    [4] The present invention provides:
    [5] 1. Disulfone compound of formula (1):
    [6] [Formula 1]
    [7]
    [8] [Wherein Ar represents a substituted or unsubstituted aryl group, R 1 represents a protecting group of a hydrogen atom or a hydroxyl group, and a dashed line means that the disulfone compound is an E or Z geometric isomer or a mixture thereof];
    [9] 2. In the presence of a base selected from alkyl lithium, alkali metal alkoxide, alkali metal amide, alkali metal hydride, or alkali metal hydroxide, allylsulfone of formula (2) is reacted with an allyl halide compound of formula (3), A process for the preparation of disulfone compounds of formula 1 as defined above comprising optionally deprotecting:
    [10]
    [11] [Wherein Ar and dashed line have the same meaning as defined in connection with Formula 1 above],
    [12]
    [13] [Wherein X represents a halogen atom, R represents a protecting group of a hydroxyl group and a broken line has the same meaning as defined above];
    [14] 3. A process for preparing retinol comprising reacting a disulfone compound of formula 1 with a base selected from alkali metal alkoxides, alkali metal amides, alkali metal hydrides, or alkali metal hydroxides and optionally deprotecting:
    [15] [Formula 1]
    [16]
    [17] Wherein Ar, R 1 and dashed line have the same meaning as defined above;
    [18] 4. Allylsulfone compound of the formula:
    [19] [Formula 2]
    [20]
    [21] Wherein Ar and dashed line have the same meaning as defined above;
    [22] 5. A process for preparing the allylsulfone compound of formula 2 as defined above comprising reacting a sulfone compound of formula 4 with an arylsulfinate of formula 5 in the presence of a palladium catalyst:
    [23]
    [24] [Wherein R, Ar and dashed lines have the same meaning as defined above],
    [25] ArSO 2 M
    [26] [Wherein Ar has the same meaning as defined above in connection with formula (1) and M represents an alkali metal]; And
    [27] 6. A chemical formula as defined above comprising reacting a sulfone of formula 6 with an alkyl halide compound of formula 3 in the presence of a base selected from alkyl lithium, alkali metal alkoxide, alkali metal amide, or alkali metal hydride 4, manufacturing method of sulfone:
    [28]
    [29] [Wherein Ar has the same meaning as defined above],
    [30] [Formula 3]
    [31]
    [32] Wherein X, R and dashed line have the same meaning as defined above.
    [33] The substituents will be described in more detail through Formulas 1-6.
    [34] Examples of the protecting group represented by R 1 or R herein include, for example, an acyl group, silyl group, tetrahydropyranyl group, alkoxymethyl group (eg methoxymethyl group, methoxyethoxymethyl group, etc.), 1-ethoxy Ethyl group, p-methoxybenzyl group, t-butyl group, trityl group, and alkoxy carbonyl group such as 2,2,2-trichloroethoxycarbonyl group, allyloxycarbonyl and the like.
    [35] Examples of the acyl group include, for example, a C1-C6 alkanoyl group which may be substituted with a halogen atom or an alkoxy group, and a benzoyl group that may be substituted with a halogen atom, a hydroxyl group, an alkoxy group, an acetoxy group, a nitro group, or the like. do.
    [36] Examples of halogen atoms include fluorine atoms, chlorine atoms, bromine atoms and iodine atoms.
    [37] Specific examples of C1-C6 alkanoyl groups which may be substituted with halogen atoms or alkoxy groups are, for example, 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, pivaloyl and the like Include.
    [38] Examples of the benzoyl group which may be substituted with a halogen atom, a hydroxy group, an alkoxy group, an acetoxy group, a nitro group, etc. are, for example, benzoyl, o-chlorobenzoyl, m-chlorobenzoyl, p-chlorobenzoyl, o-hydride Hydroxybenzoyl, m-hydroxybenzoyl, p-hydroxybenzoyl, o-acetoxybenzoyl, o-methoxybenzoyl, m-methoxybenzoyl, p-methoxybenzoyl and p-nitrobenzoyl groups.
    [39] Examples of the silyl group include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl group and the like.
    [40] Preferred protecting groups are acyl groups (eg acetyl groups).
    [41] Examples of the unsubstituted or substituted aryl group represented by "Ar" include, for example, a phenyl group and a naphthyl group, and a linear or branched C1-C5 alkyl group, a linear or branched C1-C5 alkoxy group, a halogen atom, a nitro group, and the like. It includes a phenyl or naphthyl group substituted with.
    [42] Examples of the C1-C5 alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, sec-butyl group, t-butyl group, isobutyl group, n-pentyl group, t-amyl group and the like. Include.
    [43] Examples of the C1-C5 alkoxy group include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, sec-butoxy group, t-butoxy group, isobutoxy group, n-pentoxy group, t -Amyloxy group, and the like.
    [44] Specific examples of the unsubstituted or substituted aryl group include, for example, phenyl, naphthyl, o-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-iodophenyl, p-iodophenyl , o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl, m-nitrophenyl and p-nitrophenyl and the like. Preferably, they are a phenyl group and a tolyl group.
    [45] The disulfone compound of formula (1) may be, for example, an allylsulfone compound of formula (2) in the presence of a base selected from alkaline lithium, alkali metal alkoxides, alkali metal amides, alkali metal hydrides or alkali metal hydroxides. Obtained by the reaction with an allyl halide compound.
    [46] Examples of the halogen atom represented by X in the formula (3) typically include a chlorine atom, bromine atom, and iodine atom.
    [47] Specific examples of the allyl halide compound of formula (3) include, for example, allyl halide compounds of formula (3) wherein X is a bromine atom and R is an acetyl group.
    [48] Examples of alkyl lithium include, for example, n-butyl lithium, sec-butyl lithium, t-butyl lithium and the like.
    [49] Examples of alkali metal alkoxides include, for example, C1-C5 alcoholates of alkali metals such as sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, potassium t-butoxide , Sodium t-butoxide, lithium t-butoxide, sodium t-amylate, potassium t-amylate and the like.
    [50] Examples of alkali metal amides include, for example, lithium amide, potassium amide, sodium amide, lithium diisopropylamide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, and the like. .
    [51] Examples of alkali metal hydrides include, for example, sodium hydride, potassium hydride, lithium hydride and the like.
    [52] Examples of alkali metal hydroxides include, for example, sodium hydroxide, potassium hydroxide and lithium hydroxide.
    [53] Any base selected from alkyl lithium, alkali metal alkoxides, alkali metal amides, alkali metal hydrides and alkali metal hydroxides can be used together. For example, sodium t-butoxide and sodium hydroxide can be used together. Moreover, sodium t-butoxide can be prepared by itself from a combination of sodium hydride and t-butanol in the reaction mixture, and lithium diisopropyl amide can be prepared from a combination of diisopropylamine and n-butyl lithium. .
    [54] The amount of base that can be used in the reaction is usually 0.5 to 3 moles per mole of allylsulfone compound of formula (2).
    [55] The reaction can usually be carried out in an organic solvent. Examples of organic solvents that can be used are, for example, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, hexamethylphosphoric triamide, sulfolane, 1,3-dimethyl-2-imide Ether solvents such as zolidinone, 1-methyl-2-pyrrolidinone and the like, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane and anisole, hydrocarbon (aliphatic or aromatic) solvents such as n- Hexane, cyclohexane, n-pentane, benzene, toluene and xylene. The solvent can be used alone or as a mixture thereof.
    [56] The reaction temperature can be set in the range of -78 ° C to the boiling point of the solvent used.
    [57] If desired, any suitable phase transfer catalyst may be used to promote the reaction.
    [58] Examples of phase transfer catalysts may mention, for example, quaternary ammonium salts, quaternary phosphonium salts, sulfonium salts, and the like. Preferably it is a quaternary ammonium salt.
    [59] Examples of quaternary ammonium salts are tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, tetrapentylammonium chloride, tetrahexylammonium chloride, tetraheptylammonium chloride, tetraoctylammonium chloride, tetrahexadecylammonium Chloride, tetraoctadecylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, 1-methylpyridinium chloride, 1-hexadecylpyridinium chloride, 1,4-dimethylpyridinium chloride, Tetramethyl-2-butylammonium chloride, trimethylcyclopropylammonium chloride, tetramethylammonium bromide, tetraethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide , Tetrapentylammonium bromide, tetrahexylammonium bromide, tetraheptylammonium bromide, tetraoctylammonium bromide, tetrahexadecylammonium bromide, tetraoctadecylammonium bromide, benzyltrimethylammonium bromide, benzyltriethylammonium bromide, benzyltributylammonium bromide, 1-methylpyridinium bromide, 1-hexadecylpyridinium bromide, 1,4-dimethylpyridinium bromide, tetramethyl-2-butylammonium bromide, trimethylcyclopropylammonium bromide, tetramethylammonium iodide, tetrabutylammonium Iodide, tetraoctylammonium iodide, t-butylethyldimethylammonium iodide, tetradecyltrimethylammonium iodide, hexadecyltrimethylammonium iodide, octadecyltrimethylammonium iodide, benzyltrimethylammonium iodide Id, benzyltriethylammonium iodide and tetraethylammonium including beads and benzyl tributyl ammonium iodide and the like.
    [60] Examples of quaternary phosphonium salts include tributylmethylphosphonium chloride, triethylmethylphosphonium chloride, methyltriphenoxyphosphonium chloride, butyltriphenylphosphonium chloride, tetrabutylphosphonium chloride, benzyltriphenylphosphonium chloride, hexa Decyltrimethylphosphonium chloride, hexadecyltributylphosphonium chloride, hexadecyldimethylethylphosphonium chloride, tetraphenylphosphonium chloride, tributylmethylphosphonium bromide, triethylmethylphosphonium bromide, methyltriphenoxyphosphonium bromide, Butyltriphenylphosphonium bromide, tetrabutylphosphonium bromide, benzyltriphenylphosphonium bromide, hexadecyltrimethylphosphonium bromide, hexadecyltributylphosphonium bromide, hexadecyldimethylethylphosphonium bromide, tetraphenylfo Sponium bromide, tributylmethylphosphonium iodide, triethylmethylphosphonium iodide, methyltriphenoxyphosphonium iodide, butyltriphenylphosphonium iodide, tetrabutylphosphonium iodide, benzyl Triphenylphosphonium iodide, hexadecyltrimethylphosphonium iodide and the like.
    [61] Examples of sulfonium salts include dibutylmethylsulfonium chloride, trimethylsulfonium chloride, triethylsulfonium chloride, dibutylmethylsulfonium bromide, trimethylsulfonium bromide, triethylsulfonium bromide, dibutylmethylsulfonium iodide, Trimethylsulfonium iodide, triethylsulfonium iodide and the like.
    [62] The amount of phase transfer catalyst that can be used is usually about 0.01 to about 0.2 moles, preferably about 0.02 to about 0.1 moles, per mole of allylsulfone compound 2.
    [63] The reaction is preferably carried out in the absence of oxygen, for example in an inert atmosphere of nitrogen gas or argon gas. The solvent which can be used is preferably degassed before use. Antioxidants such as 3,5-di-t-butyl-4-hydroxytoluene (BHT), 2- & 3-t-butyl-4-hydroxyanisole (BHA), vitamin E, ethoxyquin And the like can preferably be added to the reaction.
    [64] After completion of the reaction, the disulfone compound of formula 1 can be isolated by conventional work-up such as extraction, crystallization, various chromatography and the like. A disulfone compound of formula (1) wherein R 1 is a hydrogen atom can be prepared by reaction of an alkali hydroxide while protecting group R such as an acyl group during the reaction. Instead, if desired, the protecting group may optionally be deprotected by a suitable process described below for retinol preparation.
    [65] Reacting the disulfone compound of formula 1 with a base selected from alkali metal alkoxides, alkali metal amides, alkali metal hydrides, or alkali metal hydroxides, and optionally deprotecting Can be converted to retinol.
    [66] The same alkali metal alkoxides, alkali metal amides, alkali metal hydrides, and alkali metal hydroxides described above for the process for the preparation of the disulfone compounds of formula 1 can be used in this reaction.
    [67] The amount of base that can be used is usually 2 to 40 moles, preferably 5 to 30 moles per mole of disulfone compound of formula (1). Preferably alkali metal hydroxides are used. Preferably, poor alkali metal hydroxides are used.
    [68] Instead, the reaction of the disulfone compound of formula 1 with a base is preferably carried out in the presence of a lower alcohol or the phase transfer catalyst described above.
    [69] Preferred phase transfer catalysts are quaternary ammonium salts and the appropriate amount of phase transfer catalyst is from 0.01 to 0.2 moles per mole of disulfone compound of formula (1).
    [70] Examples of lower alcohols include, for example, methanol, ethanol, isopropanol, n-propanol, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, ethylene glycol, ethylene glycol monomethyl ether and the like.
    [71] The amount of lower alcohol that can be used is usually 0.1 to 3 moles per mole of disulfone compound of formula (1).
    [72] In the above-mentioned reactions, organic solvents that can be used in the process for preparing the disulfone compound of formula (1) can be used. Preferably the hydrocarbon solvent described above.
    [73] The reaction temperature is usually in the range of -30 ° C to the boiling point of the solvent used, preferably in the range of about 0 to about 50 ° C.
    [74] The reaction is preferably carried out in the absence of oxygen, for example in an inert atmosphere of nitrogen gas or argon, and blocked from light. Solvents that can be used are preferably degassed prior to use. Antioxidants such as 3,5-di-t-butyl-4-hydroxytoluene (BHT), 2- & 3-t-butyl-4-hydroxyanisole (BHA), vitamin E, ethoxyquine and the like are preferred. Preferably to the reaction.
    [75] After completion of the reaction, the retinol can be isolated by conventional post-treatment, or by performing any deprotection of the retinol with a protected hydroxy group.
    [76] For example, retinol can be obtained by reaction of a disulfone of formula (1) having an acyl group as R 1 with a base such as alkali metal hydroxide, alkali metal hydride, or the like.
    [77] Instead, for example, the retinol can be obtained by a suitable deprotection process for removing the protecting group R from the obtained retinol having a protected hydroxy group, which is treated with acid or base treatment, tetraalkylammonium fluorine to remove the silyl group. Ride treatment, or Protective Groups in Organic Synthesis, hereby incorporated by reference in its entirety [Greene, TW] Similar method disclosed in the third edition, Wiley.
    [78] If necessary, the retinol is typically purified in protected form by crystallization, various chromatography and the like. Protected retinol can be prepared by introducing any suitable protecting group such as an acetyl group or the like in a conventional manner (eg JP4-3391B, or references described above).
    [79] It will then be described a process for preparing allylsulfone compounds of formula (2), which can be used to prepare disulfone compounds of formula (1). The method for preparing the allylsulfone compound of Formula 2 includes reacting a sulfone compound of Formula 4 with an arylsulfinate of Formula 5 in the presence of a palladium catalyst.
    [80] In the arylsulfinate of the formula (5), examples of the alkali metal represented by M include, for example, lithium, sodium or potassium.
    [81] Recall the substituted or unsubstituted aryl group represented by Ar in the formula (5).
    [82] Examples of arylsulfinates include, for example, lithium, sodium, or potassium arylsulfinates, and specific examples thereof include, for example, sodium benzenesulfinate, sodium 1-naphthalenesulfinate, sodium 2-naphthalenesulphi Nate, sodium o-, m- or p-toluenesulfinate, sodium o-, m- or p-methoxybenzenesulfinate, sodium o-, m-, or p-chlorobenzenesulfinate, sodium o-, m Or p-bromobenzenesulfinate, sodium o-, m-, or p-iodobenzenesulfinate, sodium o-, m-, or p-fluorobenzenesulfinate, sodium o-, m-, Or p-nitrobenzenesulfinate, and sulfinate salts having lithium or potassium in the sodium sites of the sodium sulfinates described above.
    [83] Preferred are sodium benzenesulfinate, potassium benzenesulfinate, sodium p-toluenesulfinate, potassium p-toluenesulfinate and the like. Arylsulfinate salts containing crystalline water can be used in the reaction.
    [84] The amount of arylsulfinate of formula 5 is usually about 1 to about 3 moles per mole of sulfone 4.
    [85] Examples of palladium catalysts include, for example, tetrakis (triphenylphosphine) palladium, allyl chloride palladium dimer, palladium acetate, palladium oxide, palladium chloride, palladium hydroxide, palladium propionate, dichlorobis (tri Phenylphosphine) palladium, di-μ-chlorobis (η-allyl) palladium, dichloro (η-1,5-cyclooctadiene) palladium, dichloro (η-2,5-norbornadiene) palladium, dichlorobis (Acetonitrile) palladium, dichlorobis (benzonitrile) palladium, dichlorobis (N, N-dimethylformamide) palladium, bis (acetylacetonato) palladium, palladium charcoal and the like.
    [86] The amount of palladium catalyst is usually from 0.001 mol% to 20 mol% per mol of sulfone compound of formula (4).
    [87] Appropriate ligands can be used for the reaction. Examples of ligands include, for example, phosphorus ligands such as phosphine ligands, phosphite ligands and the like.
    [88] Examples of phosphine ligands include, for example, triarylphosphine, trialkylphosphine, tris (dialkylamino) phosphine, and the like, which may have substituents. Examples of phosphite ligands include, for example, trialkyl phosphites, triaryl phosphites, and the like.
    [89] Specific examples thereof include, for example, triphenylphosphine, tri-t-butylphosphine, tricyclohexylphosphine, dicyclohexylphenylphosphine, dicyclohexyl-o-tolylphosphine, dicyclohexyl-m -Tolylphosphine, dicyclohexyl-p-tolylphosphine, dicyclohexyl-o-anisylphosphine, dicyclohexyl-o-biphenylphosphine, diamantyl-n-butylphosphine, tri-o Tolylphosphine, tri-m-tolylphosphine, tri-p-tolylphosphine and tris (dimethylamino) phosphine, triphenylphosphite, tri-p-tolylphosphite, tri-m-tolylphosphite, Tri-o-tolyl phosphite, trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, tri-t-butyl phosphite, tris (tridecyl) phosphite, tris (2,4-di-t-butyl Phenyl) phosphite and the like. The phosphorus ligand may be separately added to the palladium catalyst containing no phosphorus ligand.
    [90] The amount of phosphorus ligand that can be used is usually in the range of 1 mol% to 20 mol% per mol of palladium metal.
    [91] In the present process, a base compound or an acid compound is preferably used as an adjuvant to facilitate the reaction more smoothly, thereby reducing the amount of expensive palladium.
    [92] Examples of amines include, for example, mono-, di-, or tri- (C2-C6) alkyl amines, secondary or tertiary cyclic amines, primary, secondary or tertiary aryl amines.
    [93] Specific examples thereof include, for example, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, t-butylamine, n-pentylamine, n-hexylamine, cyclohexylamine, Aniline, o-, m-, or p-anisidine, 4-n-butylaniline, diethylamine, diisopropylamine, di-n-butylamine, di-n-hexylamine, pyrrolidine, piperi Dine, morpholine, N-methylaniline, N-ethylaniline, Nn-butylaniline, N-methyl-p-anisidine, diphenylamine, triethylamine, tri-n-propylamine, triisopropylamine, N , N-diisopropylethylamine, tri-n-butylamine, triisobutylamine, tri-n-pentylamine, tri-n-hexylamine, N-methylpyrrolidine, N-methylpiperidine, N Ethylpiperidine, N-methylmorpholine, triphenylamine, and ethylenediamine, N, N, N ', N'-tetramethylethylenediamine.
    [94] Examples of acid compounds include carboxylic acids (eg C1-C3 carboxylic acids such as formic acid, acetic acid, propionic acid, oxalic acid, etc.), halo-substituted or nitro-substituted benzoic acids such as p-nitrobenzoic acid, p-chlorobenzoic acid, and the like. .
    [95] In the reaction, an organic solvent is usually used. Examples of the solvent used include, for example, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, anisole and the like, alcohol solvents such as methanol, ethanol, 2-propanol, t- Aprotic polar solvents such as butanol such as acetonitrile, N, N-dimethylformamide, hexamethylphosphoric triamide, sulfolane, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pi Rollidinone and the like, and hydrocarbon (aliphatic or aromatic) solvents such as n-hexane, cyclohexane, n-pentane, benzene, toluene, xylene and the like. The above may be used alone or as a mixture thereof.
    [96] The reaction temperature can optionally be selected in the range of -78 ° C to the boiling point of the solvent used, preferably in the range of about 20 to about 100 ° C. Allylsulfone derivative 2 can be prepared after the reaction by conventional post-treatment such as water washing, extraction, crystallization and various chromatography.
    [97] A sulfone compound of formula 4 is prepared by a method comprising reacting a sulfone compound of formula 6 with an allyl halide compound of formula 3 in the presence of a base selected from alkyl lithium, alkali metal alkoxide, alkali metal amide, or alkali metal hydride can do.
    [98] Alkyl lithium, alkali metal alkoxides, alkali metal amides, or alkali metal hydrides described for the process can be used in the reaction. Preferred bases are alkyl lithium (eg n-butyl lithium, s-butyl lithium, t-butyl lithium, etc.), alkali metal alkoxides (eg sodium methoxide, potassium methoxide, potassium t-butoxide, sodium t-butoxide) Seed and the like).
    [99] Alkali metal hydrides are preferably used, for example, alcohols such as n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, t-amyl alcohol and the like, amines such as aniline, diisopropylamine and the like, sulfones such as dimethyl sulfone And sulfoxides such as dimethyl sulfoxide and the like, and mixtures thereof. The amount of adjuvant is usually 0.1 to 3 moles per mole of sulfone 6. Adjuvants can be used as the solvent.
    [100] Furthermore, anionic activators such as crown ethers, tetramethylethylenediamine and the like can be added to the reaction, or allyl halide activators such as sodium iodide, tetrabutylammonium iodide and the like can be added.
    [101] The amount of base that can be used is usually about 0.5 to about 3 moles per mole of sulfone (6).
    [102] In the above-mentioned reactions, organic solvents are usually used. The solvents described above for the process for the preparation of disulfone compounds of formula (1) may be used in this reaction.
    [103] The reaction is preferably carried out in the absence of oxygen, for example in an inert atmosphere of nitrogen gas or argon. Solvents that can be used are preferably degassed prior to use. Antioxidants such as 3,5-di-t-butyl-4-hydroxytoluene (BHT), 2- & 3-t-butyl-4-hydroxyanisole (BHA), vitamin E, ethoxyquine and the like are preferred. May be added to the reaction.
    [104] After completion of the reaction, the sulfone compound of formula 4 can be isolated by conventional workup such as extraction, crystallization, chromatography and the like.
    [105] The sulfone of formula 6 was converted to Chem. Lett. 479 (1975) can be readily prepared and allyl halide compounds of formula (3) can be readily prepared by the methods described in US Pat. No. 4,175,204.
    [106] Example
    [107] Although the present invention will be described by way of examples, it should not be construed that the present invention is limited thereto.
    [108] Example 1
    [109]
    [110] After cooling a solution of 224 mg (2 mmol) of potassium t-butoxide in 6 ml of N, N-dimethylformamide (DMF) to −60 ° C., 585 mg (2 mmol) of sulfone (I) in DMF (4 ml) ) Was added dropwise over 20 seconds. A solution of 215 mg (1 mmol, purity 96%) of allyl halide (II) in DMF (4 ml) was then added dropwise over 5 minutes at the same temperature and stirred for 3 hours at the same temperature. After the reaction, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was then distilled off to yield a yellow oily crude product. Analysis by high performance liquid chromatography showed sulfone compounds (III) and (IV) in yields of 71.2% and 15.4%, respectively.
    [111] Sulfone (III)
    [112]
    [113] Sulfone (IV)
    [114]
    [115] Example 2
    [116] After cooling a solution of 224 mg (2 mmol) of potassium t-butoxide in 6 ml of DMF to −20 ° C., a solution of 585 mg (2 mmol) of sulfone (I) in DMF (4 ml) was added dropwise over 20 seconds. The mixture was then held for 5 minutes and then cooled to -60 ° C. A solution of 215 mg (1 mmol, purity 96%) of allyl halide (II) in DMF (3 ml) was then added dropwise over 5 minutes at the same temperature and stirred for 3 hours. After the reaction, the resultant was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was then distilled off to yield a yellow oil crude product.
    [117] As a result of measuring the amount of the crude product by HPLC, the yield of sulfone compound (III) was 99.5%.
    [118] Example 3
    [119] After cooling a solution of 116 mg (1.2 mmol) of sodium t-butoxide in 6 ml of DMF to 0 ° C., a solution of 876 mg (3 mmol) of sulfone (I) in DMF (4 ml) was added dropwise thereto over 20 seconds. The resulting mixture was kept at the same temperature for 5 minutes and cooled to -20 ° C. A solution of 215 mg (1 mmol, 96%) of allyl halide (II) in DMF (3 ml) was then added dropwise over 5 minutes at the same temperature and stirred for 3 hours. After the reaction, the reaction was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride brine, and dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off to obtain a yellow oil crude product. HPLC analysis showed the yield of sulfone (III) was 65.9%.
    [120] Example 4
    [121] To a solution of 585 mg of sulfone (I) in 6 ml of tetrahydrofuran cooled to −60 ° C., 1.16 ml (1.2 mmol) of a tetrahydrofuran solution of sodium hexamethyldisilazide at a concentration of 0.96 mol / L was added dropwise over 20 seconds. And held at the same temperature for 30 minutes. A solution of 215 mg (1 mmol, purity 96%) of allyl halide (II) in tetrahydrofuran (3 ml) was then added dropwise thereto over 5 minutes at the same temperature and stirred for 3 hours. After the reaction, the reaction solution was poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The filtrate was evaporated to yield a yellow oil product. HPLC analysis of the product showed the yield of sulfone compound (III) to 70.0%.
    [122] Example 5
    [123] HPLC analysis of the yellow oil product obtained in this experiment showed that Example 1.0 was used instead of a 0.96 mol / l THF solution of sodium hexamethyldisilazide, and a 1.0 mol / l THF solution of lithium diisopropyl amide. The experiment was carried out in a similar manner as in that the yield of sulfone derivative (III) was 59.4%.
    [124] Example 6
    [125] 80 mg (2 mmol) of sodium hydride (60% oil suspension) was added to DMF (5 ml), 88.9 mg (1.2 mmol) of sodium t-butoxide was added thereto and stirred at 50 ° C. for 2 hours. A solution of 585 mg (2 mmol) of sulfone (I) and 4 mg (0.02 mmol) of 3,5-dt-butyl-4-hydroxytoluene (BHT) in 3 ml of DMF was added thereto at the same temperature, followed by 3 minutes After stirring, it was cooled to -20 ° C, and a solution of 215 mg (1 mmol, purity 96%) of allyl halide (II) in DMF (2 ml) was added thereto for 1 minute, and kept at the same temperature for 2 hours. After the reaction, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer obtained was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the filtrate was evaporated to yield a yellow oil crude product. As a result of analyzing the obtained crude product by HPLC, the yield of sulfone compound (III) was 59.5%.
    [126] Example 7
    [127] 40 mg (1 mmol) of sodium hydride (60% oil suspension) were added to DMF (5 ml), 99.1 mg (1 mmol) of sodium t-butoxide was added thereto and stirred at 40 ° C. A solution of 585 mg (2 mmol) of sulfone (I) and 4 mg (0.02 mmol) of 3,5-dt-butyl-4-hydroxytoluene (BHT) in 3 ml of DMF was added thereto at the same temperature, followed by 20 minutes After stirring, cooled to -20 ° C, stirred for 30 minutes, a solution of 215 mg (1 mmol, purity 96%) of allyl halide (II) in DMF (2 ml) was added thereto for 1 minute and at the same temperature for 2 hours For a while. After the reaction, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer obtained was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the filtrate was evaporated to yield a yellow oil crude product. As a result of analyzing the obtained crude product by HPLC, the yield of sulfone compound (III) was 59.6%.
    [128] Example 8
    [129] 48 mg (1.2 mmol) of sodium hydride (60% oil suspension) were added to dimethyl sulfoxide (1 ml, DMSO) and stirred at room temperature for 3 hours. A solution of 585 mg (2 mmol) of sulfone (I) in DMSO (6 ml) was added dropwise thereto at the same temperature and stirred for 1 hour. A solution of 211 mg (1 mmol, purity 96%) of allyl halide (II) in DMSO (2 ml) was then added dropwise thereto for 1 minute, and kept at the same temperature for 5 minutes under stirring. After the reaction, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer obtained was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the filtrate was evaporated to yield a yellow oil crude product. As a result of analyzing the obtained crude product by HPLC, the yield of sulfone compound (III) was 37.6%.
    [130] Example 9
    [131] To a solution of 116 mg (1.2 mmol) of sodium t-butoxide dissolved in DMF (6 ml), cooled to 0 ° C., a solution of 585 mg (2 mmol) of sulfone (I) in DMF (4 ml) was added in 20 seconds. Dropped over, 22 mg (0.1 mmol) of 15-crown-5 was added thereto and maintained for 5 minutes. A solution of 215 mg (1 mmol, purity 96%) of allyl halide (II) in DMF (4 ml) was added thereto for 5 minutes and stirred at the same temperature for 3 hours. After the reaction, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer obtained was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the filtrate was evaporated to yield a yellow oil crude product. As a result of analyzing the obtained crude product by HPLC, the yield of sulfone compound (III) was 69.6%.
    [132] Example 10
    [133] The experiment was carried out in a similar manner as in Example 9 except that 38 mg of tetrabutyl ammonium iodide was used in place of 15-crown-5. As a result of analyzing the obtained crude product by HPLC, the yield of sulfone compound (III) was 65.2%.
    [134] Example 11
    [135]
    [136] To a solution of 116 mg (1.2 mmol) of sodium t-butoxide dissolved in DMF (5 ml), cooled to -20 ° C, a solution of 585 mg (2 mmol) of sulfone (I) in DMF (4 ml) was added dropwise, Stirred at the same temperature for 5 minutes. After cooling to −30 ° C., a solution of 269 mg (1 mmol) of allyl halide (V) in DMF (2 ml) was added dropwise thereto and stirred for 2.5 hours. After the reaction, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer obtained was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the filtrate was evaporated to yield a yellow oil crude product. The obtained crude product was purified by thin film silica gel chromatography to give the sulfone compound (VI) in a yield of 69.5%.
    [137] Sulfone (VI)
    [138]
    [139] Example 12
    [140]
    [141] 9 mg (0.05 mmol) of palladium chloride and 178 mg (1 mmol) of sodium p-toluenesulfinate were suspended in 2 ml of methanol under a nitrogen atmosphere. A solution of 211 mg (0.5 mmol, purity 98.3%) of sulfone (III) and 62 mg (0.2 mmol) of triphenylphosphite in tetrahydrofuran (2 ml) was added thereto, then stirred at room temperature for 1.5 hours, and the mixture Warmed to 60 ° C. and stirred for 5.5 h. After the reaction, water and saturated aqueous sodium chloride solution were poured into it, and extracted with ethyl acetate. The organic layer obtained was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield the crude product. HPLC analysis of the product showed a yield of allylsulfone compound (VII) of 89.1%.
    [142] Allyl sulfone derivative (VII)
    [143]
    [144] Example 13
    [145] 9 mg (0.05 mmol) of palladium chloride, 54 mg (O.2 mmol) of triphenylphosphine, 250 mg (1 mmol) of sodium p-toluenesulfinate tetrahydrate, and 211 mg (0.5 mmol, purity of sulfone compound (III) 98.3%) was suspended in 3 ml of methanol and 3 ml of toluene and stirred at 60 ° C. for 4 hours. After the reaction, water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer obtained was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield the crude product. HPLC analysis of the product showed the yield of allylsulfone compound (VII) was 78%.
    [146] Example 14
    [147] 9 mg (0.05 mmol) of palladium chloride and 254 mg (1 mmol) of sodium p-toluenesulfinate tetrahydrate were suspended in methanol (1 ml). A solution of 52 mg (0.2 mmol) of triphenylphosphine, 211 mg of sulfone compound (III) (0.5 mmol, 98.3% purity) and 60 mg (1 mmol) of acetic acid in toluene (3 ml) was added thereto and at 60 ° C. Stir for 3 hours. After the reaction, water and saturated aqueous sodium chloride solution were poured into the reaction mixture and extracted with ethyl acetate. The organic layer obtained was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield the crude product. HPLC analysis of the product showed the yield of allylsulfone compound (VII) was 76.9%.
    [148] Example 15
    [149] 2.6 mg (0.015 mmol) of palladium chloride, 156 mg (0.6 mmol) of triphenylphosphine, and 452 mg (1.8 mmol) of sodium p-toluenesulfinate tetrahydrate were suspended in methanol (1 ml) and triethylamine 46 mg (0.45 mmol) and 3 ml of toluene were added thereto and stirred at 60 ° C. for 10 hours. After the reaction, water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer obtained was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield the crude product. HPLC analysis of the product showed the yield of allylsulfone compound (VII) was 74%.
    [150] Example 16
    [151] 4.9 mg (0.028 mmol) of palladium chloride, 151.6 mg (0.61 mmol) of sodium p-toluenesulfinate tetrahydrate, 211.9 mg (99.6%, 0.5 mmol) of sulfone compound (III), 124.3 mg of tris (tridecyl) phosphite 0.2 mmol) and 16.2 mg (0.16 mmol) of triethylamine were dissolved in methanol (1 ml) and toluene (3 ml) and stirred at 60 ° C. for 6 hours. After the reaction, water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer obtained was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield the crude product. HPLC analysis of the product showed the yield of allylsulfone compound (VII) to 83%.
    [152] Example 17
    [153]
    [154] A solution of 47 mg (0.49 mmol) of sodium t-butoxide in DMF (6 ml) was cooled to 0 ° C. and a solution of 196 mg (0.38 mmol) of allyl sulfone compound (VII) in DMF (3 ml) was added thereto for 5 seconds. It was dripped and maintained for 2 minutes at the same temperature. The reaction mixture was then cooled to -60 ° C and 88 mg (0.41 mmol, purity 96%) of allyl halide (II) in DMF (3 ml) was added dropwise thereto for 20 seconds and stirred for 3 hours. After the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield a yellow crude product which was analyzed by HPLC and the yield of disulfone (VIII) was 92.8%.
    [155] Disulfone Compound (VIII)
    [156]
    [157] Example 18
    [158] 19 mg (0.48 mmol) of sodium hydride (60%, oil suspension) were dissolved in DMF (6 ml) and cooled to 0 ° C. A solution of 190 mg (0.37 mmol) of allyl sulfone compound (VII) in DMF (3 ml) was added dropwise thereto over 20 seconds and maintained for 20 minutes. A solution of 88 mg (0.41 mmol, purity 96%) of allyl halide (II) in DMF (3 ml) was then added dropwise thereto for 5 minutes and left at room temperature under stirring for 3 hours. After the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield a yellow crude product which was analyzed by HPLC and the yield of disulfone (VIII) was 94.8%.
    [159] Example 19
    [160] To a solution of 21 mg (0.53 mmol) of sodium hydride and 4.5 mg (0.02 mmol) of benzyltriethylammonium chloride in DMF (6 ml) at room temperature 211 mg (0.41 mmol) of allyl sulfone compound (VII) in DMF (3 ml) The solution of was added dropwise for 20 seconds, and kept at the same temperature for 20 minutes. A solution of 88 mg (0.41 mmol, purity 96%) of allyl halide (II) in DMF (3 ml) was then added dropwise over 20 seconds and stirred for 3 hours. After the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield a yellow crude product which was analyzed by HPLC and the yield of disulfone (VIII) was 60.8%.
    [161] Example 20
    [162] In a solution of 46 mg (0.82 mmol) of potassium hydroxide and 4.5 mg (0.02 mmol) of benzyltriethylammonium chloride in DMF (6 ml), cooled to 0 ° C., allyl sulfone compound (VII) 211 in DMF (3 ml) at room temperature. A solution of mg (0.41 mmol) was added for 20 seconds and kept at the same temperature for 20 minutes. 88 mg (0.41 mmol, purity 96%) of allyl halide (II) in DMF (3 ml) was then added dropwise over 20 seconds and stirred for 3 hours. After the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride solution and Extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield a yellow crude product which was analyzed by HPLC and the yield of disulfone (VIII) was 68.1%.
    [163] Example 21
    [164]
    [165] To a solution of 192 mg (0.3 mmol) of the disulfone compound (VIII) in toluene (2 ml, BHT content: 300 ppm) was added 500 mg (9 mmol) of 95% potassium hydroxide, 19 mg (0.6 mmol) of methanol, and 3 mg (0.015 mmol) of benzyltriethylammonium chloride were added thereto and stirred at 30 ° C. for 1 hour. After the reaction, saturated aqueous sodium chloride solution was poured into the reaction mixture and extracted with ethyl acetate. The obtained organic layer was washed successively with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was filtered and evaporated to yield crude retinol as a reddish oil. The crude retinol obtained was acetylated in a conventional manner and analyzed by HPLC, and the yield of retinol acetate (IX) was 63.3%.
    [166] Example 22
    [167] To a solution of 256 mg (0.4 mmol) of disulfone compound (VIII) in hexane (2 ml, BHT content: 300 ppm) 240 mg (4 mmol) of 95% potassium hydroxide, 7 mg (0.2 mmol) of methanol, and benzyltriethyl 4 mg (0.02 mmol) of ammonium chloride were added and stirred at 30 ° C. for 18 hours. After the reaction, saturated aqueous sodium chloride solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer obtained was washed in the order of water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was filtered and evaporated to yield crude retinol as a reddish oil. The crude retinol obtained was acetylated in a conventional manner and analyzed by HPLC, and the yield of retinol acetate (IX) was 91.3%.
    [168] Example 23
    [169] To a solution of 256 mg (0.4 mmol) of disulfone compound (VIII) in toluene (2 ml, BHT content: 300 ppm) was added 240 mg (4 mmol) of 95% potassium hydroxide and 27 mg (0.8 mmol) benzyltri methanol 4 mg (0.02 mmol) of ethylammonium chloride were added thereto and stirred at 40 ° C. for 11 hours. After the reaction, saturated aqueous sodium chloride solution was poured into the reaction mixture and extracted with ethyl acetate. The obtained organic layer was washed successively with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was filtered and evaporated to yield crude retinol as a reddish oil. The crude retinol obtained was acetylated in a conventional manner and analyzed by HPLC. The yield of retinol acetate (IX) was 89.3%.
    [170] Example 24
    [171] To a solution of 256 mg (0.4 mmol) of disulfone compound (VIII) in diisopropyl ether (2 ml, BHT content: 300 ppm) was added 240 mg (4 mmol) of 95% potassium hydroxide and 27 mg (0.8 mmol) of methanol ) And 4 mg (0.02 mmol) of benzyltriethylammonium chloride were added thereto and stirred at 30 ° C. for 16 hours. After the reaction, saturated aqueous sodium chloride solution was poured into the reaction mixture and extracted with ethyl acetate. The obtained organic layer was washed successively with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The dried solution was filtered and evaporated to yield crude retinol as a reddish oil. The crude retinol obtained was acetylated in a conventional manner and analyzed by HPLC, and the yield of retinol acetate (IX) was 94.7%.
    [172] The sulfone compounds of the present invention are intermediate compounds useful for the manufacture of medicaments, feed additives or food additives.
    权利要求:
    Claims (30)
    [1" claim-type="Currently amended] Disulfone Compounds of Formula 1:
    [Formula 1]
    [Wherein Ar represents a substituted or unsubstituted aryl group, R 1 represents a protecting group of a hydrogen atom or a hydroxyl group, and a broken line means that the disulfone compound is an E or Z geometric isomer or a mixture thereof].
    [2" claim-type="Currently amended] Reacting allylsulfone of formula (2) with an allyl halide compound of formula (3) in the presence of a base selected from alkyl lithium, alkali metal alkoxide, alkali metal amide, alkali metal hydride, or alkali metal hydroxide To prepare a disulfone compound of formula 1:
    [Formula 1]
    [Wherein Ar represents a substituted or unsubstituted aryl group, R 1 represents a protecting group of a hydrogen atom or a hydroxyl group and a dashed line means that the disulfone compound is an E or Z geometric isomer or a mixture thereof],
    [Formula 2]
    [Wherein Ar and dashed line have the same meaning as defined in connection with Formula 1 above],
    [Formula 3]
    [Wherein X represents a halogen atom, R represents a protecting group of a hydroxyl group and a dashed line has the same meaning as defined above].
    [3" claim-type="Currently amended] 3. The disulfone compound of formula 1 is reacted with a base selected from alkali metal hydrides, alkali metal alkoxides, alkali metal amides, or alkali metal hydroxides and optionally deprotected to provide retinol. Further comprising preparing.
    [4" claim-type="Currently amended] A process for preparing retinol comprising reacting a compound of Formula 1 with a base selected from alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, or alkali metal amides and optionally deprotecting:
    [Formula 1]
    [Wherein Ar represents an aryl group which may have a substituent, R 1 represents a protecting group of a hydrogen atom or a hydroxyl group, and a dashed line means that the disulfone compound is an E or Z geometric isomer or a mixture thereof].
    [5" claim-type="Currently amended] Allyl sulfone compound of the formula
    [Formula 2]
    [Wherein Ar represents a substituted or unsubstituted aryl group and a broken line means that the disulfone compound is an E or Z geometric isomer or a mixture thereof].
    [6" claim-type="Currently amended] A process for preparing an allylsulfone compound of formula 2, comprising reacting a sulfone compound of formula 4 with an arylsulfinate of formula 5 in the presence of a palladium catalyst:
    [Formula 2]
    [Wherein Ar represents a substituted or unsubstituted aryl group and a dashed line means that the disulfone compound is an E or Z geometric isomer or a mixture thereof],
    [Formula 4]
    [Wherein R represents a protecting group of a hydroxyl group, and Ar and a broken line have the same meaning as defined above],
    [Formula 5] ArSO 2 M
    [Wherein Ar has the same meaning as defined above and M represents an alkali metal].
    [7" claim-type="Currently amended] The method of claim 6 further comprising the following steps:
    (a) reacting an allyl sulfone compound of formula (2) with an allyl halide compound of formula (3) in the presence of a base selected from alkyl lithium, alkali metal alkoxides, alkali metal amides, alkali metal hydrides, or alkali metal hydroxides To prepare a disulfone compound of formula (I):
    [Formula 2]
    [Wherein Ar and dashed line have the same meaning defined in connection with formula (4)],
    [Formula 3]
    [Wherein X represents a halogen atom, R represents a protecting group of a hydroxyl group and a dashed line has the same meaning as defined above],
    [Formula 1]
    [Wherein Ar represents a substituted or unsubstituted aryl group, R 1 represents a protecting group of a hydrogen atom or a hydroxyl group and a broken line means that the disulfone compound (1) is an E or Z geometric isomer or a mixture thereof]; And
    (b) reacting the disulfone compound of formula 1 with a base selected from alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides or alkali metal amides, optionally deprotecting to produce retinol.
    [8" claim-type="Currently amended] Of a sulfone of formula (4) comprising reacting a sulfone of formula (6) with an allyl halide compound of formula (3) in the presence of a base selected from alkyl lithium, alkali metal alkoxide, alkali metal amide, or alkali metal hydride Manufacturing method:
    [Formula 4]
    [Wherein R represents a protecting group of a hydroxyl group, Ar represents a substituted or unsubstituted aryl group, R represents a protecting group of a hydroxyl group, and a dashed line means that the sulfone compound is an E or Z geometric isomer or a mixture thereof],
    [Formula 6]
    [Wherein Ar has the same meaning as defined above],
    [Formula 3]
    [Wherein X represents a halogen atom and R and a broken line have the same meaning as defined above].
    [9" claim-type="Currently amended] The method of claim 8 further comprising the following steps:
    (a) reacting a sulfone of formula (4) with an arylsulfinate of formula (5) in the presence of a palladium catalyst to prepare allylsulfone of formula (2):
    [Formula 5] ArSO 2 M
    [Wherein Ar has the same meaning as defined above and M represents an alkali metal],
    [Formula 2]
    Wherein Ar and dashed line have the same meaning as defined with respect to formula [4];
    (b) Allyl sulfone of formula (2) is reacted with an allyl halide compound of formula (3) in the presence of a base selected from alkyl lithium, alkali metal alkoxide, alkali metal amide, alkali metal hydride, or alkali metal hydroxide To prepare a disulfone compound of formula 1:
    [Formula 3]
    [Wherein X represents a halogen atom, R represents a protecting group of a hydroxyl group and a broken line has the same meaning as defined above],
    [Formula 1]
    [Wherein Ar represents a substituted or unsubstituted aryl group, R 1 represents a protecting group of a hydrogen atom or a hydroxyl group and a dashed line means that the disulfone compound is an E or Z geometric isomer or a mixture thereof]; And
    (c) reacting the disulfone compound of formula 1 with a base selected from alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides or alkali metal amides, optionally deprotecting to produce retinol.
    [10" claim-type="Currently amended] 10. The process according to any one of claims 3, 4, 7, and 9, wherein the disulfone compound of formula 1 is reacted with a base in the presence of a phase transfer catalyst and a lower alcohol.
    [11" claim-type="Currently amended] The process of claim 10 wherein the phase transfer catalyst is a quaternary ammonium salt.
    [12" claim-type="Currently amended] 12. The process of claim 11 wherein the quaternary ammonium salt is benzyltriethylammonium chloride.
    [13" claim-type="Currently amended] The process of claim 10 wherein the lower alcohol is methanol, ethanol, isopropanol or n-propanol.
    [14" claim-type="Currently amended] 10. The alkali metal alkoxide according to any one of claims 2, 3, 4, 7, 8, and 9, wherein the alkali metal alkoxide is sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium Ethoxide, lithium ethoxide, potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, sodium t-amylate, or potassium t-amylate.
    [15" claim-type="Currently amended] 10. The alkali metal amide according to any one of claims 2, 3, 4, 7, 8, and 9, wherein the alkali metal amide is lithium amide, potassium amide, sodium amide, lithium diisopropylamide, sodium hexa Methyldisilazide, potassium hexamethyldisilazide, or lithium hexamethyldisilazide.
    [16" claim-type="Currently amended] 10. The method of any one of claims 2, 3, 4, 7, 7, 8 and 9, wherein the alkali metal hydride is sodium hydride, potassium hydride, or lithium hydride.
    [17" claim-type="Currently amended] 10. The process according to any one of claims 2, 3, 4, 7, and 9, wherein the alkali metal hydroxide is lithium hydroxide, sodium hydroxide, or potassium hydroxide.
    [18" claim-type="Currently amended] 10. The process according to any one of claims 3, 7, and 9, wherein the alkali metal alkoxide is sodium t-butoxide or potassium t-butoxide.
    [19" claim-type="Currently amended] The method according to any one of claims 2, 3, 7, 8, and 9, wherein R of the allyl halide compound of formula 3 is an acyl group.
    [20" claim-type="Currently amended] 20. The method of claim 19, wherein R in the allyl halide compound of formula 3 is an acetyl group.
    [21" claim-type="Currently amended] 10. The process of any of claims 6, 7, and 9, wherein the arylsulfinate of formula 5 is reacted in the presence of a palladium catalyst and a phosphorus ligand.
    [22" claim-type="Currently amended] 22. The process of claim 21, wherein the reaction of the arylsulfinate of Formula 5 is carried out in the presence of a palladium catalyst, a phosphorus ligand and an amine compound.
    [23" claim-type="Currently amended] 22. The process of claim 21, wherein the reaction of the arylsulfinate of formula 5 is carried out in the presence of a palladium catalyst, a phosphorus ligand and an acid compound.
    [24" claim-type="Currently amended] The method of claim 22, wherein the amine compound is a mono-, di-, or tri- (C 2 -C 6) alkyl amine, secondary or tertiary cyclic amine, primary, secondary or tertiary aryl amine.
    [25" claim-type="Currently amended] 23. The compound of claim 22 wherein the amine compound is ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, t-butylamine, n-pentylamine, n-hexylamine, cyclohexylamine, Aniline, o-, m-, or p-anisidine, 4-n-butylaniline, diethylamine, diisopropylamine, di-n-butylamine, di-n-hexylamine, pyrrolidine, piperi Dine, morpholine, N-methylaniline, N-ethylaniline, Nn-butylaniline, N-methyl-p-anisidine, diphenylamine, triethylamine, tri-n-propylamine, triisopropylamine, N , N-diisopropylethylamine, tri-n-butylamine, triisobutylamine, tri-n-pentylamine, tri-n-hexylamine, N-methylpyrrolidine, N-methylpiperidine, N Ethylpiperidine, N-methylmorpholine, triphenylamine, or ethylenediamine, N, N, N ', N'-tetramethylethylenediamine.
    [26" claim-type="Currently amended] The method of claim 23, wherein the acid compound is a carboxylic acid.
    [27" claim-type="Currently amended] 27. The method of claim 26, wherein the carboxylic acid compound is formic acid, acetic acid, propionic acid, oxalic acid, benzoic acid, p-nitrobenzoic acid or p-chlorobenzoic acid.
    [28" claim-type="Currently amended] 24. The method of any of claims 21, 22 and 23, wherein the arylsulfinate is sodium phenylsulfinate, potassium phenylsulfinate, sodium p-toluenesulfinate or potassium p-toluenesulfinate.
    [29" claim-type="Currently amended] 10. The method of any one of claims 6, 7, 8, or 9, wherein R of the compound of formula 4 is an acyl group.
    [30" claim-type="Currently amended] 30. The method of claim 29, wherein the acyl group is an acetyl group.
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    同族专利:
    公开号 | 公开日
    US20020058844A1|2002-05-16|
    US20040082814A1|2004-04-29|
    EP1199303A1|2002-04-24|
    CN1356317A|2002-07-03|
    EP1199303B1|2004-09-22|
    CN1660799A|2005-08-31|
    US6660888B2|2003-12-09|
    DE60105729T2|2006-02-16|
    US6784321B2|2004-08-31|
    CN1208316C|2005-06-29|
    DE60105729D1|2004-10-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-10-18|Priority to JP2000317547
    2000-10-18|Priority to JPJP-P-2000-00317546
    2000-10-18|Priority to JPJP-P-2000-00317549
    2000-10-18|Priority to JPJP-P-2000-00317548
    2000-10-18|Priority to JP2000317549
    2000-10-18|Priority to JP2000317546
    2000-10-18|Priority to JPJP-P-2000-00317547
    2000-10-18|Priority to JP2000317548
    2001-10-18|Application filed by 고사이 아끼오, 스미또모 가가꾸 고오교오 가부시끼가이샤
    2002-05-01|Publication of KR20020031297A
    优先权:
    申请号 | 申请日 | 专利标题
    JPJP-P-2000-00317546|2000-10-18|
    JPJP-P-2000-00317549|2000-10-18|
    JPJP-P-2000-00317548|2000-10-18|
    JP2000317549|2000-10-18|
    JP2000317546|2000-10-18|
    JP2000317547|2000-10-18|
    JPJP-P-2000-00317547|2000-10-18|
    JP2000317548|2000-10-18|
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