CN1688568A - Process for the production of gamma-keto acetals - Google Patents
Process for the production of gamma-keto acetals Download PDFInfo
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- CN1688568A CN1688568A CN 03824449 CN03824449A CN1688568A CN 1688568 A CN1688568 A CN 1688568A CN 03824449 CN03824449 CN 03824449 CN 03824449 A CN03824449 A CN 03824449A CN 1688568 A CN1688568 A CN 1688568A
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Abstract
The present invention provides a method which utilizes a simple operation to produce Gamma-ketone acetal compound with a higt yield rate. The method of the present invention carries out a reaction according to the right graphic in which Ar represents aryl, X represents halogen atoms, R<a> and R<b> are alkyl, etc., and W represents alkylidene.
Description
Technical field
The present invention relates to the manufacture method of gamma-keto acetals.
Background technology
Known γ-ketone acetal (below have general formula (A) compound) is the 4-methyl isophthalic acid, the intermediate of 2-diaryl pyrrole derivant (spy opens 2000-80078 number), 4-methyl isophthalic acid, the 2-diaryl pyrrole derivant is as analgesic agent (No. 5908858 specification sheets of United States Patent (USP)).
(in the following formula, Ar
1Expression can substituted aryl, R
1And R
2Represent low alkyl group respectively, perhaps R
1And R
2Represent trimethylene etc. together.)
The known use Nitromethane 99Min. of the manufacture method of this gamma-keto acetals (CH
3NO
2) and the method (spy opens 2000-80078 number) of alkali still, Nitromethane 99Min. is the compound of blast easily, so want exactissima diligentia during operation, for this reason, when utilizing this manufacture method manufacturing gamma-keto acetals, when particularly making in a large number, has the problem of complicated operation.
Summary of the invention
The present inventor furthers investigate the manufacture method of gamma-keto acetals, found that by using enamine derivates, does not use Nitromethane 99Min., utilizes simple operation can obtain highly purified gamma-keto acetals with high yield, until finishing the present invention.
The present invention relates to
(1) a kind of have a general formula (1),
(in the formula, Ar has identical meaning with W with aftermentioned.) manufacture method of compound, it is characterized in that, in inert solvent, make to have general formula (2)
(in the formula, Ar represents C
6-C
10Aryl or the C that replaces with the group that is selected from substituting group group α
6-C
14Aryl, substituting group group α represents by halogen atom, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, sulfydryl, C
1-C
6The group that alkyl sulphonyl and sulfamyl constitute, X represents halogen atom.) compound and have a general formula (3)
(in the formula, R
aAnd R
bCan be identical or different, represent C respectively
1-C
6Alkyl, C
1-C
6The C that alkoxyl group replaces
1-C
6Alkyl or C
3-C
6Cycloalkyl, perhaps, R
aAnd R
bCan represent C together
4-C
8Alkylidene group.) compound reaction, under sour condition, be hydrolyzed, make and have general formula (4)
(in the formula, Ar has an identical meaning with aforementioned.) compound, then, in the presence of acid, make the have general formula compound and the general formula (5) of (4)
HO-W-OH (5)
(in the formula, W represents C
1-C
6Alkylidene group.) compound reaction.
Preferable methods is in above-mentioned
(2) Ar is a phenyl or with the method that is selected from the phenyl that group among the substituting group group α replaces,
(3) Ar is the method for phenyl or the phenyl that replaces with the group in methyl, methoxyl group, oxyethyl group and the methylthio group,
(4) Ar is 4-aminomethyl phenyl, 3-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-ethoxyl phenenyl, 4-methylthio group phenyl, 3,4-3,5-dimethylphenyl or 3, and the method for 4-Dimethoxyphenyl,
(5) X is the method for bromine atoms or iodine atom,
(6) X is the method for bromine atoms,
(7) R
aAnd R
bCan be identical or different, be respectively C
2-C
5Alkyl, C
1-C
4The C that alkoxyl group replaces
2-C
5Alkyl or C
4-C
6The method of cycloalkyl,
(8) R
aAnd R
bCan be identical or different, be respectively the method for sec.-propyl, isobutyl-, isopentyl, 2-methoxy ethyl, 3-methoxy-propyl, 2-ethoxyethyl group, cyclopentyl or cyclohexyl,
(9) R
aAnd R
bThe method of representing isobutyl-respectively,
(10) W is C
3-C
5The method of straight or branched alkylidene group,
(11) W is C
3-C
5The method of straight-chain alkyl-sub-, and
(12) W is 2-methyl trimethylene or 2, the method for 2-dimethyl trimethylene.
In addition, the invention provides following manufacture method,
(13) a kind of have a general formula (7)
[in the formula, Ar represents C
6-C
10Aryl or the C that replaces with the group that is selected from substituting group group α
6-C
14Aryl, substituting group group α represents by halogen atom, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, sulfydryl, C
1-C
6The group that alkyl sulphonyl and sulfamyl constitute, Y represents methyl or amino (Y is preferably amino).] the manufacture method of compound, it is characterized in that, comprise following operation, that is, make to have general formula (2)
(in the formula, Ar represents C
6-C
10Aryl or the C that replaces with the group that is selected from substituting group group α
6-C
14Aryl, substituting group group α represents by halogen atom, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, sulfydryl, C
1-C
6The group that alkyl sulphonyl and sulfamyl constitute, X represents halogen atom.) compound and have a general formula (3)
(in the formula, R
aAnd R
bCan be identical or different, represent C respectively
1-C
6Alkyl, C
1-C
6The C that alkoxyl group replaces
1-C
6Alkyl or C
3-C
6Cycloalkyl, perhaps, R
aAnd R
bCan represent C together
4-C
8Alkylidene group.) compound in inert solvent, react, be hydrolyzed with acid, make and to have general formula (4)
(in the formula, Ar has an identical meaning with aforementioned.) the operation of compound; And in the presence of acid, make have general formula (4) compound and have a general formula (5)
HO-W-OH (5)
(in the formula, W represents C
1-C
6Alkylidene group.) compound react, make general formula (1)
(in the formula, Ar has identical meaning with W with aftermentioned.) operation and
(14) a kind of have a general formula (7)
[in the formula, Ar represents C
6-C
10Aryl or the C that replaces with the group that is selected from substituting group group α
6-C
14Aryl, substituting group group α represents by halogen atom, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, sulfydryl, C
1-C
6The group that alkyl sulphonyl and sulfamyl constitute, Y represents methyl or amino (Y is preferably amino).] the manufacture method of compound, it makes has general formula (2)
(in the formula, Ar represents C
6-C
10Aryl or the C that replaces with the group that is selected from substituting group group α
6-C
14Aryl, substituting group group α represents by halogen atom, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, sulfydryl, C
1-C
6The group that alkyl sulphonyl and sulfamyl constitute, X represents halogen atom.) compound and have a general formula (3)
(in the formula, R
aAnd R
bCan be identical or different, represent C respectively
1-C
6Alkyl, C
1-C
6The C that alkoxyl group replaces
1-C
6Alkyl or C
3-C
6Cycloalkyl, perhaps, R
aAnd R
bCan represent C together
4-C
8Alkylidene group.) compound in inert solvent, react, add water decomposition with acid, make and to have general formula (4)
(in the formula, Ar has an identical meaning with aforementioned.) compound, then, in the presence of acid, make have general formula (4) compound and have a general formula (5)
HO-W-OH (5)
(in the formula, W represents C
1-C
6Alkylidene group.) compound react, make general formula (1)
(in the formula, Ar and W have an identical meaning with aforementioned.), make compound again and have general formula (6) with general formula (1)
[in the formula, Y represents methyl or amino (Y is preferably amino).] compound reaction, make compound with general formula (7).
In order to stipulate " C of the present invention
1-C
6Aryl ", " halogen atom ", " C
1-C
6Alkyl ", " halo C
1-C
6Alkyl ", " C
1-C
6Alkoxyl group ", " C
1-C
6Alkylthio ", " C
1-C
6Alkyl sulphonyl ", " C
3-C
6Cycloalkyl ", " C
4-C
8Alkylidene group " and " C
1-C
6Alkylidene group ", define by following respectively.
In the definition of Ar, " C
1-C
6Aryl " and " with the C of the group replacement that is selected from substituting group group α
1-C
6Aryl " " C
1-C
6Aryl " can be phenyl or naphthyl partly, preferred phenyl.
In addition, above-mentioned C
1-C
6Aryl can cyclization be C
3-C
10Cycloalkyl (preferred C
5-C
6Cycloalkyl), for example can be the 5-indanyl.
In the definition of Ar, " with the C of the group replacement that is selected from substituting group group α
6-C
10Aryl " C that preferably replaces with 1 to 4 group that is selected from substituting group group α
6-C
10Aryl, the further preferred C that replaces with 1 to 3 group that is selected from substituting group group α
6-C
10Aryl, the more preferably C that replaces with 1 or 2 group that is selected from substituting group group α
6-C
10Aryl.
A halogen atom in the definition of substituting group group α and X " be fluorine atom, chlorine atom, bromine atoms or iodine atom.The preferred fluorine atom of substituting group group α, chlorine atom or bromine atoms, more preferably fluorine atom or chlorine atom.Preferred bromine atoms of X or iodine atom, preferred especially bromine atoms.
Substituting group group α, R
aAnd R
bDefinition in " C
1-C
6Alkyl ", and R
aAnd R
bDefinition in " C
1-C
6The C that alkoxyl group replaces
1-C
6Alkyl " moieties can be: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, hexyl, isohexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1; 2-dimethylbutyl, 1; 3-dimethylbutyl, 2, the straight or branched alkyl of 3-dimethylbutyl or 2-ethyl-butyl and so on, the preferred C of substituting group group α
1-C
4The straight or branched alkyl, more preferably methyl, ethyl, propyl group, sec.-propyl or butyl, special preferable methyl, ethyl or propyl group, most preferable.R
aAnd R
bPreferred C
2-C
5Straight or branched alkyl, more preferably ethyl, propyl group, sec.-propyl, butyl, isobutyl-or isopentyl, especially preferably sec.-propyl, isobutyl-or isopentyl, most preferably isobutyl-.
In the definition of substituting group group α, " halo C
1-C
6Alkyl " be aforementioned " C
1-C
6Alkyl " the group that replaces with aforementioned " halogen atom " of one or more hydrogen atom, preferred halo C
1-C
4Alkyl, more preferably trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, two brooethyls, fluoro methyl, 2,2,2-three chloroethyls, 2,2,2-trifluoroethyl, 2-bromotrifluoromethane, 2-chloroethyl, 2-fluoro ethyl or 2,2-two bromotrifluoromethanes, more preferably trifluoromethyl, trichloromethyl, difluoromethyl or fluoro methyl, most preferably trifluoromethyl.
In the definition of substituting group group α, " C
1-C
6Alkoxyl group " and, R
aAnd R
bDefinition in " C
1-C
6The C that alkoxyl group replaces
1-C
6Alkyl " alkoxyl group partly be at above-mentioned " C
1-C
6Alkyl " go up the group that bonding has Sauerstoffatom, preferred C
1-C
4Straight or branched alkoxyl group, more preferably methoxyl group, oxyethyl group, propoxy-, isopropoxy or butoxy, especially preferably methoxyl group, oxyethyl group or propoxy-.Substituting group group α is oxyethyl group most preferably.
In the definition of substituting group group α, " C
1-C
6Alkylthio " be at above-mentioned " C
1-C
6Alkyl " go up the group that bonding has sulphur atom, preferred C
1-C
4Straight or branched alkylthio, more preferably methylthio group, ethylmercapto group, rosickyite base, iprotiazem base or butylthio, especially preferably methylthio group, ethylmercapto group or rosickyite base.
In the definition of substituting group group α, " C
1-C
6Alkyl sulphonyl " be at above-mentioned " C
1-C
6Alkyl " go up bonding alkylsulfonyl (SO is arranged
2-) group, preferred C
1-C
4Straight or branched alkane alkylsulfonyl, more preferably methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, different third alkylsulfonyl or fourth alkylsulfonyl, especially preferably methylsulfonyl, ethylsulfonyl or third alkylsulfonyl, most preferably methylsulfonyl.
R
aAnd R
bDefinition in, " C
3-C
6Cycloalkyl " can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferred C
4-C
6Cycloalkyl, more preferably cyclopentyl or cyclohexyl.
R
aAnd R
bBiao Shi " C together
4-C
8Alkylidene group " can be tetramethylene, 1-methyl trimethylene, 2-methyl trimethylene, 1; 1-dimethyl ethylidene, pentamethylene, 1; 1-dimethyl trimethylene, 2; 2-dimethyl trimethylene, 1; 2-dimethyl trimethylene, hexa-methylene, 2-methyl pentamethylene, heptamethylene or 2; 4-dimethyl pentamethylene, preferred C
4-C
6Ring straight or branched alkylene group, more preferably tetramethylene or pentamethylene, especially preferably tetramethylene.
C in the definition of W
1-C
6Alkylidene group can be methylene radical, ethylidene, trimethylene, 1,2-propylidene, tetramethylene, 1-methyl trimethylene, 2-methyl trimethylene, 1,1-dimethyl ethylidene, pentamethylene, 1,1-dimethyl trimethylene, 2,2-dimethyl trimethylene, 1, the straight or branched alkylene group of 2-dimethyl trimethylene or hexa-methylene and so on, preferred C
3-C
5The straight or branched alkylene group, more preferably trimethylene, 2-methyl trimethylene or 2,2-dimethyl trimethylene, preferred especially trimethylene or 2,2-dimethyl trimethylene, preferred especially 2,2-dimethyl trimethylene.
Ar, X, W and substituting group group α represent the group of aforementioned definitions respectively, and wherein, preferred group is as described below.
The phenyl that Ar preferably uses phenyl or replaces with the group that is selected from substituting group group α, more preferably phenyl, or the phenyl that replaces with the group that is selected from methyl, methoxyl group, oxyethyl group and methylthio group, more preferably use the phenyl of the group replacement that is selected from methyl, methoxyl group, oxyethyl group and methylthio group, preferred especially 4-aminomethyl phenyl, 3-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-ethoxyl phenenyl, 4-first thio-phenyl, 3,4-3,5-dimethylphenyl or 3, the 4-Dimethoxyphenyl, 4-ethoxyl phenenyl or 3 most preferably, the 4-3,5-dimethylphenyl.
X preferably uses the bromine or iodine atom, preferred especially bromine atoms.
W is C most preferably
3-C
5Straight or branched alkylene group, more preferably C
3-C
5Straight-chain alkyl-sub-group, preferred especially trimethylene, 2-methyl trimethylene or 2,2-dimethyl trimethylene, preferred especially trimethylene or 2,2-dimethyl trimethylene, most preferably 2,2-dimethyl trimethylene.
Substituting group group α is preferably by C
1-C
4Alkyl, C
1-C
4Alkoxyl group and C
1-C
4Alkylthio constitutes, and most preferably is made of methyl, methoxyl group, oxyethyl group and methylthio group, especially preferably is made of methyl and oxyethyl group.
The invention embodiment
The manufacture method of gamma-keto acetals of the present invention is by following enforcement.
(in the above-mentioned formula, Ar, R
a, R
b, X has and aforementioned identical meaning with W)
Operation 1a is in inert solvent, in the alkali existence or not phenacyl halogenide (2) and enamine compound (3) is reacted, and adds acid then and be hydrolyzed in mixture, makes dioxo compound (4).
The inert solvent that uses for example has: the aliphatic hydrocarbon of pentane, hexane or heptane and so on; Benzene, toluene or dimethylbenzene and so on aromatic hydrocarbon based; Halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin or ethylene dichloride; The ethers of diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF) Huo diox and so on; The alcohols of methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, sec-butyl alcohol, isopropylcarbinol or trimethyl carbinol and so on; N, the non-proton property polar solvent of dinethylformamide, N,N-dimethylacetamide or methyl-sulphoxide and so on; The nitrile of acetonitrile and so on; Perhaps, the ester class of methyl acetate or ethyl acetate and so on, preferred non-proton property polar solvent or nitrile, preferred especially N,N-dimethylacetamide or acetonitrile.
The alkali that uses for example has the organic amine of pyridine, picoline, 4-(N, N-dimethylamino) pyridine, triethylamine, tributylamine, diisopropyl ethyl amine, N-methyl piperidine and so on, preferred triethylamine, tributylamine or diisopropyl ethyl amine.
Temperature of reaction is-30 ℃ to 200 ℃ (preferred 0 ℃ to 100 ℃), and the reaction times is generally 30 minutes to 30 hours (preferred 1 hour to 20 hours) according to temperature of reaction etc. and different.
After the addition reaction of phenacyl halogenide (2) and enamine compound (3) finishes, dioxo compound (4) is generated by in the reaction mixture thing, adding acid.The acid of using for example has the mineral acid of hydrochloric acid, Hydrogen bromide, sulfuric acid, perchloric acid or phosphoric acid and so on; Perhaps the organic acid of acetate, formic acid, oxalic acid, methylsulphonic acid, tosic acid, trifluoroacetic acid or trifluoromethane sulfonic acid and so on preferably uses sulfuric acid, hydrochloric acid or tosic acid.
After reaction finished, the purpose compound was isolated from reaction mixture according to usual method.
For example, make the reaction mixture cooling, crystallization is separated out, and perhaps, carries out suitable neutralization, under having the situation of insolubles by after removing by filter, add water, with unmixed organic solvent extraction of toluene and so on, washings such as water,, remove solvent by distillation and obtain after the dryings such as extraction liquid with anhydrous magnesium sulfate etc.
The compound that obtains can use usual method as required, for example uses silica gel column chromatography method to separate, and is refining.
In addition, the dioxo compound of making in this operation (4) also can be used in the subsequent processing (operation 1b) not refiningly.
Operation 1b is in the presence of inert solvent (using and the described same solvent of operation 1a), in the presence of acid (using and the described identical acid of operation 1a), makes the reaction of dioxo compound (4) and diol compound, makes compound (1).
Temperature of reaction is generally-70 ℃ to 100 ℃, preferred-30 ℃ to 60 ℃.Normally 10 minutes to 20 hours reaction times, preferred 30 minutes to 2 hours.
After reaction finished, the purpose compound was isolated from reaction mixture according to usual method.
For example, make the reaction mixture cooling, crystallization is separated out, and perhaps, carries out suitable neutralization, under having the situation of insolubles by after removing by filter, add water, with unmixed organic solvent extraction of toluene and so on, washings such as water,, remove solvent by distillation and obtain after the dryings such as extraction liquid with anhydrous magnesium sulfate etc.
The compound that obtains can use usual method as required, for example uses silica gel column chromatography method to separate, and is refining.
The compound of the starting raw material in the inventive method (2), compound (3) and compound (5) are known compound, and compound (2) and compound (3) for example are disclosed among the US5908858.
Use the compound of making as mentioned above (1), by following reaction, can make the 4-methyl isophthalic acid, 2-diaryl pyrrole derivant (7).
(in the formula, Ar represents and aforementioned identical meaning that with W Y represents methyl or amino.)
The 2nd operationBe in inert solvent, make compound (1) and aniline compound (6) carry out dehydrating condensation, make its cyclization, make 1,2-diaryl pyrrole compound (7) in the acid existence or not.
The solvent that uses only otherwise the influence reaction, it is just passable to dissolve initial substance to a certain degree, be not particularly limited, for example can be the aliphatic hydrocarbon of hexane, heptane or sherwood oil and so on; Benzene, toluene or dimethylbenzene and so on aromatic hydrocarbon based; The halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin or ethylene dichloride and so on; Ethers such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF) Huo diox; The alcohols of methyl alcohol, ethanol, propyl alcohol, Virahol or butanols and so on; The nitrile of acetonitrile and so on; The organic acid of formic acid, acetate or propionic acid and so on; Perhaps water, these can use separately, or mix multiple use.Preferred alcohol-water system mixed solvent, the more preferably mixed solvent of propyl alcohol and water of using.
The acid of using for example has the inorganic acids of hydrochloric acid or sulfuric acid and so on; Perhaps organic acids such as acetate, trifluoroacetic acid, methylsulfonic acid, tosic acid or trifluoromethanesulfonic acid, preferred especially organic acid.More preferably acetate or tosic acid, preferred especially tosic acid.The acid amount of using is 0.01 equivalent to 50 equivalent, preferred 0.05 equivalent to 20 equivalent, more preferably 0.1 equivalent to 10 equivalent.
The amount of the aniline compound (6) that relative 1 normal compound (1) uses is 1 equivalent to 10 equivalent, preferred 1 equivalent to 3 equivalent.
Temperature of reaction is according to the solvent that uses and difference is generally 0 ℃ to 200 ℃, preferably room temperature to 150 ℃.Reaction times is also because of differences such as temperature of reaction.Be generally 10 minutes to 48 hours, preferred 30 minutes to 15 hours.
In addition, also can react except that the waterside that generates in the dereaction on the limit, also can not react fully but do not carry out aforesaid operations usually.
After above-mentioned each reaction finishes, utilize usual method from reaction mixture, to collect the purpose compound.
For example, make reaction mixture carry out suitable neutralization, perhaps under having the situation of insolubles by after removing by filter, add water, unmixed organic solvent extraction with ethyl acetate and so on, washings such as water, are removed solvent by distillation and are obtained after the extraction liquid drying with anhydrous magnesium sulfate etc.
The purpose compound that obtains can use usual method as required, and for example recrystallization, redeposition or use silica gel column chromatography separate, and be refining.
Utilize manufacture method of the present invention, can not use Nitromethane 99Min., utilize simple operation, obtain highly purified gamma-keto acetals with high yield.
Embodiment
Below utilize embodiment that the present invention is carried out specific description more, the invention is not restricted to this.
Embodiment
Embodiment 1
3-(5,5-dimethyl-1,3-diox-2-yl)-1-(4-ethoxyl phenenyl) butane-1-ketone
Under nitrogen gas stream, in acetonitrile 20L, add 2-bromo-1-(4-ethoxyl phenenyl)-ethane-1-ketone 5.0kg and N, two (2-the methyl-propyl)-1-propenyl amine 5.1kg of N-stirred 1.5 hours down at about 50 ℃.In reaction mixture, add entry 20L, vitriol oil 5.0kg, neopentyl glycol 3.2kg and tosic acid 0.5kg successively, stirred 1.5 hours down at about 50 ℃.After being cooled to room temperature, filter the crystallization of separating out, obtain the white crystals 4.3kg (yield 71%) of purpose compound.
1H-nuclear magnetic resonance spectrum (400MHz, CDCl
3) δ ppm:0.71 (s, 3H), 1.03 (d, J=6.8Hz, 3H), 1.18 (s, 3H), 1.44 (t, J=7.0Hz, 3H), 2.42-2.52 (m, 1H), 2.78 (dd, J=16.6Hz, J=8.5Hz, 1H), 3.25 (dd, J=16.6Hz, J=4.6Hz, 1H), 3.41 (dd, J=11.0Hz, J=3.7Hz, 2H), 3.57-3.63 (m, 2H), 4.10 (q, J=7.0Hz, 2H), 4.38 (d, J=3.7Hz, 1H), 6.91 (d, J=8.7Hz, 2H), 7.96 (d, J=8.7Hz, 2H).
Embodiment 2
3-(5,5-dimethyl-1,3-diox-2-yl)-1-(4-ethoxyl phenenyl) butane-1-ketone
Under nitrogen gas stream, in N,N-DIMETHYLACETAMIDE 16mL, add 2-bromo-1-(4-ethoxyl phenenyl)-ethane-1-ketone 4.0g and N, two (2-the methyl-propyl)-1-propenyl amine 4.0g of N-stirred 2 hours down at 50-55 ℃.In reaction mixture, add tosic acid 1.6g and neopentyl glycol 2.1g successively, under 50-60 ℃, make its reaction 3 hours.Add entry 8mL postcooling to room temperature, filter the crystallization of separating out, obtain the white crystals 3.7g (yield 74%) of purpose compound.
1The H-nuclear magnetic resonance spectrum is in fact with embodiment's 1
1The H-nuclear magnetic resonance spectrum is identical.
Embodiment 3
3-(5,5-dimethyl-1,3-diox-2-yl)-1-(4-ethoxyl phenenyl) butane-1-ketone
Under nitrogen gas stream, in dimethyl formamide 16mL, add 2-bromo-1-(4-ethoxyl phenenyl)-ethane-1-ketone 4.0g and N, two (2-the methyl-propyl)-1-propenyl amine 4.0g of N-stirred 2 hours down at 50-55 ℃.In reaction mixture, add tosic acid 1.6g and neopentyl glycol 2.1g successively, stirred 3 hours down at 50-60 ℃.Add entry 8mL postcooling to room temperature, filter the crystallization of separating out, obtain the white crystals 3.7g (yield 72%) of purpose compound.
1The H-nuclear magnetic resonance spectrum is in fact with embodiment's 1
1The H-nuclear magnetic resonance spectrum is identical.
Embodiment 4
3-(5,5-dimethyl-1,3-diox-2-yl)-1-(3, the 4-3,5-dimethylphenyl) butane-1-ketone
Under nitrogen gas stream, in dimethyl formamide 990mL, add 2-bromo-1-(3, the 4-3,5-dimethylphenyl)-ethane-1-ketone 220g and N, two (2-the methyl-propyl)-1-propenyl amine 249g of N-stirred 2 hours down at about 50 ℃.After being cooled to about 10 ℃, add entry 990mL, neopentyl glycol 170g and vitriol oil 173g successively, stirred 2 hours down at about 60 ℃.After being cooled to room temperature, filter the crystallization of separating out, obtain the white crystals 262g (yield 83%) of purpose compound.
1H-nuclear magnetic resonance spectrum (400MHz, CDCl
3) δ ppm:0.71 (s, 3H), 1.03 (d, J=6.8Hz, 3H), 1.18 (s, 3H), 2.31 (s, 6H), 2.43-2.53 (m, 1H), 2.81 (dd, J=16.8Hz, J=8.5Hz, 1H), 3.26 (dd, J=16.7Hz, J=4.8Hz, 1H), 3.41 (dd, J=11.1Hz, J=4.3Hz, 2H), 3.58-3.63 (m, 2H), 4.39 (d, J=3.4Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.72 (d, J=7.6Hz, 1H), 7.76 (s, 1H).
Embodiment 5
3-(5,5-dimethyl-1,3-diox-2-yl)-1-(3, the 4-3,5-dimethylphenyl) butane-1-ketone
Under nitrogen gas stream, in acetonitrile 25mL, add 2-bromo-1-(3, the 4-3,5-dimethylphenyl)-ethane-1-ketone 6.2g and N, two (2-the methyl-propyl)-1-propenyl amine 6.8g of N-stirred 4 hours down at about 50 ℃.Be cooled to after about 10 ℃, add entry 25mL, neopentyl glycol 4.3g, vitriol oil 6.2g and tosic acid 0.62g, stirred 1 hour down at about 60 ℃, be cooled to room temperature after, the crystallization that filtration is separated out obtains the white crystals 6.6g (yield 84%) of purpose compound.
1The H-nuclear magnetic resonance spectrum is in fact with embodiment's 4
1The H-nuclear magnetic resonance spectrum is identical.
Industrial applicibility
Utilize manufacture method of the present invention not use nitromethane, utilize shirtsleeve operation, Obtain with high yield highly purified gamma-keto acetals.
Claims (14)
1. one kind has general formula (1)
(in the formula, Ar has identical meaning with W with aftermentioned.) the manufacture method of compound, it is characterized in that, in inert solvent, make to have general formula (2)
(in the formula, Ar represents C
6-C
10Aryl or the C that replaces with the group that is selected from substituting group group α
6-C
14Aryl, substituting group group α represents by halogen atom, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, sulfydryl, C
1-C
6The group that alkyl sulphonyl and sulfamyl constitute, X represents halogen atom.) compound and have a general formula (3)
(in the formula, R
aAnd R
bCan be identical or different, represent C respectively
1-C
6Alkyl, C
1-C
6The C that alkoxyl group replaces
1-C
6Alkyl or C
3-C
6Cycloalkyl, perhaps, R
aAnd R
bCan together represent C
4-C
8Alkylidene group.) compound reaction, be hydrolyzed with acid, make and have general formula (4)
(in the formula, Ar has an identical meaning with aforementioned.) compound, then, in the presence of acid, make have general formula (4) compound and have a general formula (5)
HO-W-OH (5)
(in the formula, W represents C
1-C
6Alkylidene group.) compound reaction.
2. the method for claim 1, wherein Ar is phenyl or the phenyl that replaces with the group that is selected from substituting group group α.
3. the method for claim 1, wherein Ar is phenyl or the phenyl that replaces with the group that is selected from methyl, methoxyl group, oxyethyl group and methylthio group.
4. the method for claim 1, wherein Ar is 4-aminomethyl phenyl, 3-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-ethoxyl phenenyl, 4-methylthio group phenyl, 3,4-3,5-dimethylphenyl or 3,4-Dimethoxyphenyl.
5. as any one described method in the claim 1 to 4, wherein, X is bromine atoms or iodine atom.
6. as any one described method in the claim 1 to 4, wherein, X is a bromine atoms.
7. as any one described method in the claim 1 to 6, wherein, R
aAnd R
bCan be identical or different, be respectively C
2-C
5Alkyl, C
1-C
4The C that alkoxyl group replaces
2-C
5Alkyl or C
4-C
6Cycloalkyl.
8. as any one described method in the claim 1 to 6, wherein, R
aAnd R
bCan be identical or different, be respectively sec.-propyl, isobutyl-, isopentyl, 2-methoxy ethyl, 3-methoxy-propyl, 2-ethoxyethyl group, cyclopentyl or cyclohexyl.
9. as any one described method in the claim 1 to 6, wherein, R
aAnd R
bBe respectively isobutyl-.
10. as any one described method in the claim 1 to 9, wherein, W is C
3-C
5Straight or branched.
11. as any one described method in the claim 1 to 9, wherein, W is C
3-C
5Straight-chain alkyl-sub-.
12. as any one described method in the claim 1 to 9, wherein, W is 2-methyl trimethylene or 2,2-dimethyl trimethylene.
13. one kind has general formula (7)
[in the formula, Ar represents C
6-C
10Aryl or the C that replaces with the group that is selected from substituting group group α
6-C
14Aryl, substituting group group α represents by halogen atom, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, sulfydryl, C
1-C
6The group that alkyl sulphonyl and sulfamyl constitute, Y represents methyl or amino (Y is preferably amino).] the manufacture method of compound, it is characterized in that, comprise following operation, that is, make to have general formula (2)
(in the formula, Ar represents C
6-C
10Aryl or the C that replaces with the group that is selected from substituting group group α
6-C
14Aryl, substituting group group α represents by halogen atom, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, sulfydryl, C
1-C
6The group that alkyl sulphonyl and sulfamyl constitute, X represents halogen atom.) compound and have a general formula (3)
(in the formula, R
aAnd R
bCan be identical or different, represent C respectively
1-C
6Alkyl, C
1-C
6The C that alkoxyl group replaces
1-C
6Alkyl or C
3-C
6Cycloalkyl, perhaps, R
aAnd R
bCan together represent C
4-C
8Alkylidene group.) compound, in inert solvent, react, be hydrolyzed with acid, make and to have general formula (4)
(in the formula, Ar represents and aforementioned identical meaning.) the operation of compound; And
In the presence of acid, make have general formula (4) compound and have a general formula (5)
HO-W-OH (5)
(in the formula, W represents C
1-C
6Alkylidene group.) compound react, make general formula (1)
(in the formula, Ar has and aforementioned identical meaning with W.) operation.
14. one kind has general formula (7)
[in the formula, Ar represents C
6-C
10Aryl or the C that replaces with the group that is selected from substituting group group α
6-C
14Aryl, substituting group group α represents by halogen atom, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, sulfydryl, C
1-C
6The group that alkyl sulphonyl and sulfamyl constitute, Y represents methyl or amino (Y is preferably amino).] the manufacture method of compound, it makes has general formula (2)
(in the formula, Ar represents C
6-C
10Aryl or the C that replaces with the group that is selected from substituting group group α
6-C
14Aryl, substituting group group α represents by halogen atom, C
1-C
6Alkyl, halo C
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, sulfydryl, C
1-C
6The group that alkyl sulphonyl and sulfamyl constitute, X represents halogen atom.) compound and have a general formula (3)
(in the formula, R
aAnd R
bCan be identical or different, represent C respectively
1-C
6Alkyl, C
1-C
6The C that alkoxyl group replaces
1-C
6Alkyl or C
3-C
6Cycloalkyl, perhaps, R
aAnd R
bCan together represent C
4-C
8Alkylidene group.) compound, in inert solvent, react, be hydrolyzed with acid, make and to have general formula (4)
(in the formula, Ar has and aforementioned identical meaning.) compound, then, in the presence of acid, make have general formula (4) compound and have a general formula (5)
HO-W-OH (5)
(in the formula, W represents C
1-C
6Alkylidene group.) compound react, make general formula (1)
(in the formula, Ar has and aforementioned identical meaning with W.), make compound again and have general formula (6) with general formula (1)
[in the formula, Y represents methyl or amino (Y is preferably amino).] compound reaction, make compound with general formula (7).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP238786/2002 | 2002-08-20 | ||
| JP2002238786 | 2002-08-20 | ||
| JP131270/2003 | 2003-05-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1688568A true CN1688568A (en) | 2005-10-26 |
Family
ID=35306301
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108863734A (en) * | 2018-07-11 | 2018-11-23 | 华南理工大学 | A kind of two bornyl acetal derivant of benzaldehyde and preparation method thereof and purposes |
-
2003
- 2003-08-19 CN CN 03824449 patent/CN1688568A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108863734A (en) * | 2018-07-11 | 2018-11-23 | 华南理工大学 | A kind of two bornyl acetal derivant of benzaldehyde and preparation method thereof and purposes |
| CN108863734B (en) * | 2018-07-11 | 2021-02-19 | 华南理工大学 | Benzaldehyde di-bornyl acetal derivative and preparation method and application thereof |
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