CN100404479C - Method for producing aromatic unsaturated compound - Google Patents
Method for producing aromatic unsaturated compound Download PDFInfo
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- CN100404479C CN100404479C CNB2004800308854A CN200480030885A CN100404479C CN 100404479 C CN100404479 C CN 100404479C CN B2004800308854 A CNB2004800308854 A CN B2004800308854A CN 200480030885 A CN200480030885 A CN 200480030885A CN 100404479 C CN100404479 C CN 100404479C
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Abstract
A method for producing an aromatic unsaturated compound represented by the formula (4): (wherein Ar represents an aromatic group which may be substituted or a heteroaromatic group which may be substituted, and Y represents an electron-withdrawing group) is disclosed which includes a step for reacting (a) a compound represented by the formula (1): (wherein Ar is as defined above), with (b) a compound represented by the formula (2): (wherein Y is as defined above, and Z represents a lower alkoxy), or a compound represented by the formula (3): (wherein Y and Z are as defined above), in the presence of (c) an acid or a compound which produces a mineral acid through hydrolysis.
Description
Technical field
The present invention relates to the preparation method of aromatic unsaturated compound.
Background technology
Aromatic unsaturated compound shown in the formula (4) (below, abbreviate aromatic unsaturated compound (4) as) can be used as synthetic intermediate of medical agricultural chemicals for example etc.
(in the formula, Ar represents optional substituted aromatic group or optional substituted heteroaromatic base, and Y represents the electrophilic group.)
Compound shown in for example known following formula (7):
Be synthetic intermediate, for example described in the WO01/92223 as the effective fluvastatin of hyperlipidemia medicine.
Compound shown in following formula (8) and (9) is the compound that just is being developed as the arteriosclerosis curative described in Japanese kokai publication hei 9-202775 and Japanese kokai publication hei 7-206842 respectively.
Preparation method as described aromatic unsaturated compound (4), known have acrylic compounds such as for example making corresponding aromatic halide and vinylformic acid, the method that in the presence of palladium catalyst and alkali, reacts (for example WO01/92223), but this method not only needs to use to the big aromatic halide of environmental hazard as raw material, and reaction can produce by-product hydrogen halide when carrying out.And because this hydrogen halide need use alkali to neutralize, therefore from the raw material aspect, the high reaction of Atom economy of may not necessarily saying so.
On the other hand, as the higher method of Atom economy, have compound shown in the formula (1):
Ar-H (1)
(in the formula, Ar represents implication same as described above.)
As raw material, the method that itself and acrylic compound are reacted.For example, the someone proposes: (a) use ruthenium catalyst or palladium catalyst, the method for reacting in the presence of oxygen (J.Am.Chem.Soc. for example
125, 1476 (2003), J.Am.Chem.Soc.
123, 337 (2001)); (b) use the method (J.Org.Chem. for example of the above palladium complex of theoretical amount
46, 851 (1981); Heterocycles,
22, 1493 (1984)) etc.
But, the method for described (a), because use oxygen, thus require to be reflected under the reaction conditions that is lower than limits of explosion to carry out, all may not be favourable from operating aspect and the consideration of equipment aspect.And the method for described (b), although from the raw material angle high method of Atom economy of saying so, but owing to will use the above palladium complex of theoretical amount, consider it is disadvantageous from the cost aspect, and the aftertreatment of reaction back palladium complex is also complicated, and yield is also low, consider from the viewpoint that industry is made, and may not be advantageous method.
As the preparation method of the compound that contains indole ring, known have in the presence of palladium catalyst, makes the method that the nitrogen-atoms that constitutes indole ring reacts through benzenesulfonyl protection back and acrylic compound (for example Synthesis, 236 (1984)).But this method only limits to constitute the compound of the nitrogen-atoms of indole ring through the benzenesulfonyl protection, and in order to obtain target compound with good yield, require to use excessive prices such as silver acetate higher reoxidize agent.
Summary of the invention
Under such situation, the inventor is raw material for exploitation with compound shown in the above-mentioned formula (1), the preparation method of higher, the industrial more favourable above-mentioned aromatic unsaturated compound (4) of Atom economy has carried out deep research, found that: by making compound shown in compound shown in the above-mentioned formula (1) and the formula (2):
(in the formula, Y represents the electrophilic group, and Z represents lower alkoxy), perhaps compound shown in the formula (3):
(in the formula, Y and Z represent meaning same as described above), can generate by hydrolysis at acid such as hydrochloric acid or phosphoryl chloride etc. mineral acid compound in the presence of react, reached the application's purpose, thereby finished the present invention.
Promptly the present invention includes following invention:
＜1〉preparation method of aromatic unsaturated compound shown in the above-mentioned formula (4), this method comprises makes compound shown in (a) above-mentioned formula (1) and compound shown in (b) compound shown in the above-mentioned formula (2) or the above-mentioned formula (3), (c) acid or can generate through hydrolysis mineral acid compound in the presence of react.
＜2〉method of record＜1 〉, this method is implemented reaction under the coexistence of water.
＜3〉＜1〉or＜2 in the method for record, wherein (c) acid or be hydrogen halide through the compound that hydrolysis can generate mineral acid.
＜4〉＜1〉or＜2 in the method for record, wherein (c) acid or be phosphoryl halogen, Phosphorates phosphorus Halides, thionyl halide or sulfonic acid halide through the compound that hydrolysis can generate mineral acid.
＜5〉method of each record＜1 〉-＜4 〉, this method is being implemented reaction in acetate.
＜6〉method of each record＜1 〉-＜5 〉, the Ar in its Chinese style (1) and the formula (4) is selected from aromatic group or the heteroaromatic base that following group replaces for optional by at least 1: low alkyl group, lower alkoxy, hydroxyl ,-OR
x, amino ,-NHR
y,-NR
y 2, halogen and the optional phenyl that is replaced by halogen (R wherein
xThe protecting group of expression hydroxyl, R
yThe protecting group that expression is amino).
＜7〉method of each record＜1 〉-＜6 〉, the Ar in its Chinese style (1) and the formula (4) is optional substituted phenyl.
＜8〉method of each record＜1 〉-＜6 〉, the Ar in its Chinese style (1) and the formula (4) is optional substituted indyl.
＜9〉＜1 〉-＜6〉each or＜8 in the record method, compound shown in its Chinese style (1) is a compound shown in the formula (5):
(in the formula, R
1Optional phenyl, the hydrogen or alkyl that is replaced by halogen of expression, R
2Expression alkyl or the optional phenyl that is replaced by halogen); Aromatic unsaturated compound shown in the formula (4) is an aromatic unsaturated compound shown in the formula (6):
(in the formula, R
1And R
2Represent meaning same as described above).
The preferred forms of invention
Compound shown in the formula (1) (below abbreviate compound (1) as):
Ar-H (1)
Formula in, Ar represents optional substituted aromatic group or optional substituted heteroaromatic base.
The example of aromatic group has: phenyl, naphthyl, anthryl, phenanthryl, tetralyl, 9,10-dihydro anthryl, acenaphthenyl etc.The heteroaromatic base for example has the aromatic group as the aromatic ring constituting atom such as the heteroatoms that contains nitrogen-atoms, Sauerstoffatom, sulphur atom, object lesson has: indyl, benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, pyrryl, furyl, thienyl dibenzofuran group, dibenzothiophene base, 2,3-indolinyl or 2,3-dihydro benzo furyl etc.The preferred indyl of heteroaromatic base.
Described aromatic group or heteroaromatic base can be chosen wantonly and be substituted the base replacement, substituent example has: alkyl, normally carbonatomss such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl or n-hexyl are the alkyl of 1-6, and preferred carbonatoms is the low alkyl group of 1-4; Methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert.-butoxy etc. normally carbonatoms are the lower alkoxy of 1-4; Hydroxyl; Warp-OR
xShown in the hydroxyl of protecting group protection; Amino; Warp-NHR
yOr-NR
y 2Shown in the amino of protecting group protection; Halogens such as fluorine, chlorine, bromine and iodine; The optional phenyl that is replaced by halogen such as phenyl, 4-chloro-phenyl-or 4-fluorophenyl etc.R
xShown in the protecting group example of hydroxyl have: alkyloyls such as ethanoyl; Alkoxyalkyls such as methoxymethyl; Aralkyl such as benzyl; Alkylidene groups such as methylene radical, dimethylated methylene base etc.Through described-OR
xShown in the hydroxyl example of protecting group protection have: acetoxyl group, methoxymethoxy, benzyloxy, methylene-dioxy, dimethylated methylene dioxy base etc.R
yShown in amino protecting group example have: above-mentioned alkyloyl; Aralkyl such as benzyl; Sweet-smelling alkoxy alkyls such as benzyloxymethyl; Dialkoxy alkyl such as dimethoxy-methyl; Alkylsulfonyls such as benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl etc.Through described-NHR
yOr-NR
y 2Shown in the amino example of protecting group protection have: acetylamino, dibenzyl amino, benzyloxy methylamino, dimethoxy-methyl amino, benzenesulfonyl amino, p-toluenesulfonyl amino, methylsulfonyl amino etc.
The situation of the aromatic group that is replaced by described substituting group, unqualified to its substituent number, but consider from the angle of speed of response, preferably by the aromatic group more than 2, more preferably by the aromatic group more than 3 to the electron substituent group replacement to the electron substituent group replacement.The situation that is substituted the basic heteroaromatic base that replaces is also unqualified to its substituent number, but considers from the angle of speed of response, preferably by the heteroaromatic base to the electron substituent group replacement more than 1.Wherein saidly be meant the alkyl in the above-mentioned substituting group, lower alkoxy, hydroxyl, the warp-OR that carbonatoms is 1-4 to electron substituent group
xShown in hydroxyl, amino or the warp-NHR of protecting group protection
yOr-NR
y 2Shown in the amino of protecting group protection.
In the described compound (1), the heteroaromatic base is that the compound of indyl is important, because these compounds can be used as the synthesis material of benzazolyl compounds such as the effective fluvastatin of hyperlipidaemia medicine for example (for example Japanese kokai publication hei 2-46031 communique, international No. 01/92223 brochure etc. that disclose), the compound that described heteroaromatic base is an indyl for example has compound shown in the formula (5):
(in the formula, R
1Optional phenyl, the hydrogen or alkyl that is replaced by halogen of expression, R
2Expression alkyl or the optional phenyl that is replaced by halogen).
In the formula of above-mentioned formula (5), the optional phenyl that is replaced by halogen is with above-mentioned identical, and as alkyl, example has: carbonatomss such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-hexyl are the alkyl of 1-6.
The example of described compound (1) has: benzene, naphthalene, dimethoxy benzene, 1,3, the 5-trimethoxy-benzene, 1,2, the 3-trimethoxy-benzene, 2, the 6-syringol, the 2-anisidine, the 4-anisidine, the 2-methoxyacetanilide, the 4-methoxyacetanilide, the 2-acetoamidophenol, the 4-acetoamidophenol, catechol, Resorcinol, quinhydrones, the 4-tert-butyl catechol, capsicine, the 2-Methyl-1H-indole, 2-methyl isophthalic acid-Methyl-1H-indole, 2-methyl isophthalic acid-sec.-propyl-1H-indoles, 2-methyl isophthalic acid-phenyl-1H-indoles, 2-ethyl-1H-indoles, 2-ethyl-1-Methyl-1H-indole, 2-ethyl-1-phenyl-1H-indoles, 2-phenyl-1H-indoles, 2-phenyl-1-Methyl-1H-indole, 2-phenyl-1-phenyl-1H-indoles, the 3-Methyl-1H-indole, 3-methyl isophthalic acid-Methyl-1H-indole, 3-methyl isophthalic acid-sec.-propyl-1H-indoles, 3-methyl isophthalic acid-phenyl-1H-indoles, 3-ethyl-1H-indoles, 3-ethyl-1-Methyl-1H-indole, 3-ethyl-1-phenyl-1H-indoles, 3-phenyl-1H-indoles, 3-phenyl-1-Methyl-1H-indole, 3-phenyl-1-phenyl-1H-indoles, 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles etc.
Described compound (1) can use commercially available compound, also can use in accordance with known methods the compound of preparation, and for example aromatic group is that the compound of indyl can be according to as TetrahedronLetters,
26, known method preparations such as 2155 (1985).
Compound shown in the formula (2) (below abbreviate compound (2) as):
And compound shown in the formula (3) (below abbreviate compound (3) as):
Formula in, Y represents the electrophilic group, Z represents lower alkoxy.
The example of electrophilic group has: alkoxy carbonyl, aryloxycarbonyl, aromatic alkoxy carbonyl, acyl group or cyano group etc.The example of alkoxy carbonyl has: carbonatomss such as methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, isopropoxy carbonyl, n-butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl, positive hexyloxy carbonyl, n-octyloxy ketonic oxygen base are the alkoxy carbonyl of 2-9.The example of aryloxycarbonyl has: carbonatomss such as phenyloxycarbonyl are the aryloxycarbonyl of 7-13, and the example of aromatic alkoxy carbonyl has: carbonatomss such as benzyloxycarbonyl are the aromatic alkoxy carbonyl of 8-14.The example of acyl group has: carbonatomss such as ethanoyl, propionyl are the aliphatic acyl of 2-9; Carbonatomss such as benzoyl are the aromatic acyl group of 7-13 etc.The example of lower alkoxy has: carbonatomss such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy are the alkoxyl group of 1-6, and preferred carbonatoms is the alkoxyl group of 1-4.
The example of described compound (2) has: the 3-methoxy-methyl acrylate, 3-methoxy acrylic acid ethyl ester, 3-methoxy acrylic acid n-propyl, 3-methoxy acrylic acid isopropyl ester, the positive butyl ester of 3-methoxy acrylic acid, 3-methoxy acrylic acid isobutyl ester, the secondary butyl ester of 3-methoxy acrylic acid, the 3-methoxy acrylic acid tert-butyl ester, 3-methoxy acrylic acid phenyl ester, 3-methoxy acrylic acid benzyl ester, 3-ethoxy-c olefin(e) acid methyl esters, the 3-ethoxy ethyl acrylate, 3-ethoxy-c olefin(e) acid n-propyl, 3-ethoxy-c isopropyl gadoleate, the positive butyl ester of 3-ethoxy-c olefin(e) acid, 3-ethoxy-c olefin(e) acid isobutyl ester, the secondary butyl ester of 3-ethoxy-c olefin(e) acid, 3-ethoxy propylene tert-butyl acrylate, 3-ethoxy propylene acid phenenyl ester, 3-ethoxy-c olefin(e) acid benzyl ester, 3-isopropoxy methyl acrylate, 3-isopropoxy ethyl propenoate, 3-isopropoxy vinylformic acid n-propyl, 3-isopropoxy isopropyl acrylate, 3-isopropoxy n-butyl acrylate, 3-isopropoxy isobutyl acrylate, 3-isopropoxy sec-butyl acrylate, 3-isopropoxy tert-butyl acrylate, 3-isopropoxy phenyl acrylate, 3-isopropoxy vinylformic acid benzyl ester, 3-n-butoxy methyl acrylate, 3-n-butoxy ethyl propenoate, 3-n-butoxy vinylformic acid n-propyl, 3-n-butoxy isopropyl acrylate, 3-n-butoxy n-butyl acrylate, 3-n-butoxy isobutyl acrylate, 3-n-butoxy sec-butyl acrylate, 3-n-butoxy tert-butyl acrylate, 3-n-butoxy phenyl acrylate, 3-n-butoxy vinylformic acid benzyl ester, 3-tert.-butoxy methyl acrylate, 3-tert.-butoxy ethyl propenoate, 3-tert.-butoxy vinylformic acid n-propyl, 3-tert.-butoxy isopropyl acrylate, 3-tert.-butoxy n-butyl acrylate, 3-tert.-butoxy isobutyl acrylate, 3-tert.-butoxy sec-butyl acrylate, 3-tert.-butoxy tert-butyl acrylate, 3-tert.-butoxy phenyl acrylate, 3-tert.-butoxy vinylformic acid benzyl ester, the 3-methoxy acrylonitrile, 3-ethoxy propylene nitrile, 3-isopropoxy vinyl cyanide, 3-n-butoxy vinyl cyanide, 3-tert.-butoxy vinyl cyanide, 4-methoxyl group-3-butene-2-ketone, 4-oxyethyl group-3-butene-2-ketone, 3-methoxyl group-1-phenyl acrylketone etc.
Have trans-isomer(ide) and cis-isomeride in described compound (2), the present invention can use wherein any one, also can use both any mixture.
The example of compound (3) has: 3,3-dimethoxy methyl propionate, 3,3-dimethoxy ethyl propionate, 3,3-dimethoxy propionic acid n-propyl, 3,3-dimethoxy isopropyl propionate, 3,3-dimethoxy n-butyl propionate, 3,3-dimethoxy isobutyl propionate, 3,3-dimethoxy sec-butyl propionate, 3, the 3-dimethoxy propionic acid tert-butyl ester, 3,3-dimethoxy phenylpropionate, 3,3-dimethoxy propionic acid benzyl ester, 3,3-diethoxy methyl propionate, 3,3-diethoxy ethyl propionate, 3,3-diethoxy propionic acid n-propyl, 3,3-diethoxy isopropyl propionate, 3,3-diethoxy n-butyl propionate, 3,3-diethoxy isobutyl propionate, 3,3-diethoxy sec-butyl propionate, 3, the 3-diethoxy propionic acid tert-butyl ester, 3,3-diethoxy phenylpropionate, 3,3-diethoxy propionic acid benzyl ester, 3,3-diisopropoxy methyl propionate, 3,3-diisopropoxy ethyl propionate, 3,3-diisopropoxy propionic acid n-propyl, 3,3-diisopropoxy isopropyl propionate, 3,3-diisopropoxy n-butyl propionate, 3,3-diisopropoxy isobutyl propionate, 3,3-diisopropoxy sec-butyl propionate, 3, the 3-diisopropoxy propionic acid tert-butyl ester, 3,3-diisopropoxy phenylpropionate, 3,3-diisopropoxy propionic acid benzyl ester, 3,3-two (n-butoxy) methyl propionate, 3,3-two (n-butoxy) ethyl propionate, 3,3-two (n-butoxy) propionic acid n-propyl, 3,3-two (n-butoxy) isopropyl propionate, 3,3-two (n-butoxy) n-butyl propionate, 3,3-two (n-butoxy) isobutyl propionate, 3,3-two (n-butoxy) sec-butyl propionate, 3,3-two (n-butoxy) the propionic acid tert-butyl ester, 3,3-two (n-butoxy) phenylpropionate, 3,3-two (n-butoxy) propionic acid benzyl ester, 3,3-two (tert.-butoxy) methyl propionate, 3,3-two (tert.-butoxy) ethyl propionate, 3,3-two (tert.-butoxy) propionic acid n-propyl, 3,3-two (tert.-butoxy) isopropyl propionate, 3,3-two (tert.-butoxy) n-butyl propionate, 3,3-two (tert.-butoxy) isobutyl propionate, 3,3-two (tert.-butoxy) sec-butyl propionate, 3,3-two (tert.-butoxy) the propionic acid tert-butyl ester, 3,3-two (tert.-butoxy) phenylpropionate, 3,3-two (tert.-butoxy) propionic acid benzyl ester, 3,3-dimethoxy propionitrile, 3,3-diethoxy propionitrile, 3,3-diisopropoxy propionitrile, 3,3-two (n-butoxy) propionitrile, 3,3-two (tert.-butoxy) propionitrile, 1,1-dimethoxy-3-butanone, 1,1-diethoxy-3-butanone, 3,3-dimethoxy-1-phenyl third-1-ketone etc.
Commercially available compound can be used in described compound (2) or (3), also can use the compound according to known method preparation such as for example Japanese Patent Publication 61-45974 communique, Japanese kokai publication sho 58-26855 communique etc.
Compound (2) or (3) consumption amount to respect to compound (1) and are generally the 1-5 mole doubly, and preferred 1-3 mole doubly.
The example of acid has: sulfuric acid; Hydrogen halide such as hydrochloric acid, hydrogen bromide; Perhalogeno acid such as perchloric acid; Sulfonic acid such as methylsulfonic acid, Phenylsulfonic acid, tosic acid, trifluoromethanesulfonic acid; Perfluorocarboxylic acids such as trifluoroacetic acid; Aprotic acids such as boron trifluoride, aluminum chloride, aluminum bromide, zinc chloride, zinc bromide, tin chloride, titanium tetrachloride; Acidic ion exchange resin etc., preferred hydrogen halide.As aprotic acid, for example can use the complex compound of aprotic acids such as boron trifluoride tetrahydrofuran complex.In the method for the present invention, when employed acid was protonic acid, preferred pKa was the acid below 2.5, and more preferably pKa is the acid below 1.5.
The example that can generate the compound (below be called the MAGH compound) of mineral acid through hydrolysis has: phosphoryl halogens such as phosphoryl chloride, phosphoryl bromide; Phosphorates phosphorus Halides such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride; Thionyl halides such as thionyl chloride; Sulfonic acid halides such as SULPHURYL CHLORIDE etc., preferred phosphoryl halogen.
Compound (1) and compound (2) or compound (3) reaction be can in the presence of acid, make, compound (1) and compound (2) or compound (3) reaction perhaps can in the presence of the MAGH compound, be made.And, also can in the presence of acid and MAGH compound, make compound (1) and compound (2) or compound (3) reaction.
Order by merging to these compounds is not particularly limited, for example can in the mixture of compound (1) and compound (2) or compound (3), add acid or MAGH compound, also can in the mixture of compound (1) and acid or MAGH compound, add compound (2) or compound (3).
The consumption of acid or MAGH compound amounts to respect to compound (1) and is generally more than 0.001 mole times, preferred more than 0.01 mole times, its upper limit is not particularly limited, when under reaction conditions, being liquid, can use and excessively also play a role as solvent, but consider that from aftertreatment or economy angle practical amount is below 5 moles times, is preferably below 3 moles times.
Reaction is carried out in the presence of solvent usually, the example of solvent has: nitrile series solvents such as acetonitrile, propionitrile, carboxylic acid such as formic acid, acetate series solvent, halon series solvents such as methylene dichloride, chloroform, ether series solvents such as tetrahydrofuran (THF), ester series solvents such as ethyl acetate, pure series solvents such as methyl alcohol, ethanol, Virahol, the independent or mixed solvent of water etc., optimization acid's series solvent, nitrile series solvent, more preferably carboxylic acid series solvent, wherein preferred especially acetate.Usage quantity to described solvent is not particularly limited.As previously mentioned, under reaction conditions, when above-mentioned acid or MAGH compound were liquid, described acid or MAGH compound can be used as solvent and use.
By making compound (1) and compound (2) or compound (3), in the presence of acid or MAGH compound, react, can obtain target compound aromatic unsaturated compound (4).By under the coexistence of water, implementing described reaction, can obtain the reasonable aromatic unsaturated compound of yield (4).
When reacting under the coexistence of water, the usage quantity of water is generally more than 0.1 mole times with respect to compound (1), and its upper limit is not particularly limited, and practical amount is below 50 moles times, and is preferred below 10 moles times.
Temperature of reaction is generally-20 ℃ to 80 ℃.
After reaction finishes, can by for example with reaction solution with after water mixes, carry out filtration treatment, obtain target compound aromatic unsaturated compound (4).According to circumstances, aromatic unsaturated compound (4) is separated out in reaction solution as crystallization sometimes, under such situation, can obtain aromatic unsaturated compound (4) by direct filtration processing reaction liquid, also can carry out filtration treatment and obtain aromatic unsaturated compound (4) with reaction solution with after water mixes.In addition, also can in reaction solution, add entry and water-fast organic solvent such as toluene, ethyl acetate, methyl tert-butyl ether, methyl iso-butyl ketone (MIBK) etc., carry out extraction treatment by for example, the organic layer that obtains is carried out concentration, obtain aromatic unsaturated compound (4).The aromatic unsaturated compound (4) that obtains by common purification process such as for example recrystallization, column chromatography etc., can be further purified.
The example of the aromatic unsaturated compound that so obtains (4) has: 3-(2,4, the 6-trimethoxyphenyl) methyl acrylate, 3-(2,3, the 4-trimethoxyphenyl) methyl acrylate, 3-(3-hydroxyl-2, the 4-Dimethoxyphenyl) methyl acrylate, 3-(3, the 4-dihydroxy phenyl) methyl acrylate, 3-(2,4, the 6-trimethoxyphenyl) ethyl propenoate, 3-(2,3, the 4-trimethoxyphenyl) ethyl propenoate, 3-(3-hydroxyl-2, the 4-Dimethoxyphenyl) ethyl propenoate, 3-(3, the 4-dihydroxy phenyl) ethyl propenoate, 3-(2,4, the 6-trimethoxyphenyl) vinylformic acid n-propyl, 3-(2,3, the 4-trimethoxyphenyl) vinylformic acid n-propyl, 3-(3-hydroxyl-2, the 4-Dimethoxyphenyl) vinylformic acid n-propyl, 3-(3, the 4-dihydroxy phenyl) vinylformic acid n-propyl, 3-(2,4, the 6-trimethoxyphenyl) isopropyl acrylate, 3-(2,3, the 4-trimethoxyphenyl) isopropyl acrylate, 3-(3-hydroxyl-2, the 4-Dimethoxyphenyl) isopropyl acrylate, 3-(3, the 4-dihydroxy phenyl) isopropyl acrylate, 3-(2,4, the 6-trimethoxyphenyl) n-butyl acrylate, 3-(2,3, the 4-trimethoxyphenyl) n-butyl acrylate, 3-(3-hydroxyl-2, the 4-Dimethoxyphenyl) n-butyl acrylate, 3-(3, the 4-dihydroxy phenyl) n-butyl acrylate, 3-(2,4, the 6-trimethoxyphenyl) isobutyl acrylate, 3-(2,3, the 4-trimethoxyphenyl) isobutyl acrylate, 3-(3-hydroxyl-2, the 4-Dimethoxyphenyl) isobutyl acrylate, 3-(3, the 4-dihydroxy phenyl) isobutyl acrylate, 3-(2,4, the 6-trimethoxyphenyl) phenyl acrylate, 3-(2,3, the 4-trimethoxyphenyl) phenyl acrylate, 3-(3-hydroxyl-2,4-Dimethoxyphenyl) phenyl acrylate, 3-(3, the 4-dihydroxy phenyl) phenyl acrylate, 3-(2,4, the 6-trimethoxyphenyl) vinylformic acid benzyl ester, 3-(2,3, the 4-trimethoxyphenyl) vinylformic acid benzyl ester, 3-(3-hydroxyl-2, the 4-Dimethoxyphenyl) vinylformic acid benzyl ester, 3-(3, the 4-dihydroxy phenyl) vinylformic acid benzyl ester, 3-(2,4, the 6-trimethoxyphenyl) vinyl cyanide, 3-(2,3, the 4-trimethoxyphenyl) vinyl cyanide, 3-(3-hydroxyl-2,4-Dimethoxyphenyl) vinyl cyanide, 3-(3, the 4-dihydroxy phenyl) vinyl cyanide, 4-(2,4, the 6-trimethoxyphenyl)-3-butene-2-ketone, 4-(2,3, the 4-trimethoxyphenyl)-3-butene-2-ketone, 4-(3-hydroxyl-2, the 4-Dimethoxyphenyl)-3-butene-2-ketone, 4-(3, the 4-dihydroxy phenyl)-3-butene-2-ketone, 3-(2,3, the 4-trimethoxyphenyl)-1-phenyl acrylketone, 3-(3-hydroxyl-2, the 4-Dimethoxyphenyl)-1-phenyl acrylketone, 3-(3, the 4-dihydroxy phenyl)-1-phenyl acrylketone, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] methyl acrylate, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] ethyl propenoate, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] the vinylformic acid n-propyl, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] isopropyl acrylate, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] n-butyl acrylate, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] isobutyl acrylate, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] tert-butyl acrylate, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] phenyl acrylate, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] the vinylformic acid benzyl ester, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] vinyl cyanide, 3-(1-methyl-2-phenyl-1H-indol-3-yl) methyl acrylate, 3-(1-methyl-2-phenyl-1H-indol-3-yl) ethyl propenoate, 3-(1-methyl-2-phenyl-1H-indol-3-yl) vinylformic acid n-propyl, 3-(1-methyl-2-phenyl-1H-indol-3-yl) isopropyl acrylate, 3-(1-methyl-2-phenyl-1H-indol-3-yl) n-butyl acrylate, 3-(1-methyl-2-phenyl-1H-indol-3-yl) isobutyl acrylate, 3-(1-methyl-2-phenyl-1H-indol-3-yl) tert-butyl acrylate, 3-(1-methyl-2-phenyl-1H-indol-3-yl) phenyl acrylate, 3-(1-methyl-2-phenyl-1H-indol-3-yl) vinylformic acid benzyl ester, 3-(1-methyl-2-phenyl-1H-indol-3-yl) vinyl cyanide, 4-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl]-3-butene-2-ketone, 4-(1-methyl-2-phenyl-1H-indol-3-yl)-3-butene-2-ketone, 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl]-1-phenyl acrylketone, 3-(1-methyl-2-phenyl-1H-indol-3-yl)-1-phenyl acrylketone etc.
In this reaction, as compound (2), no matter use trans-isomer(ide) or cis-isomeride, all obtain the trans-isomer(ide) of aromatic unsaturated compound (4) usually or based on the trans cis mixtures of isomers of the aromatic unsaturated compound (4) of trans-isomer(ide).
In the described aromatic unsaturated compound (4), for example following formula (7):
Wait its intramolecularly to contain the compound of 3-(4-fluorophenyl) indyl, can convert to as the effective fluvastatin of hyperlipidemia medicine according to the method for for example WO01/92223.
Below, further describe the present invention by embodiment, but the present invention is not subjected to the qualification of these embodiment.
Embodiment 1
With 1.01g 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles, 0.92g 3, aqueous acetic acid of 3-dimethoxy methyl propionate, 0.72ml 90% weight (containing 4mmol water) and 6ml Glacial acetic acid mix, then under internal temperature is 25 ℃ condition, in this mixture, drip the 0.33g phosphoryl chloride, stirred 9 hours down synthermal, make it to react.After reaction finishes, in reaction solution, drip 16ml water, the crystallization that leaching is separated out.With the washing of the aqueous methanol of 20% volume, drying is handled then with this crystallization, obtain 1.25g trans-3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] methyl acrylate (yellow solid).Yield is 93%.
1H-NMR(δ/ppm，CDCl
3，400MHz)
1.70(6H，d，J＝7Hz)，3.76(3H，s)，4.95(1H，m)，5.96(1H，d，J＝16Hz)，7.50(1H，d，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.08-7.40(6H，m)，7.82(1H，d，J＝16Hz)
Embodiment 2
With 1.04g 1-methyl-2-phenyl-1H-indoles, 0.64g trans-3-methoxy-methyl acrylate, 94.5mg water and 6ml Glacial acetic acid mix, under 25 ℃ of internal temperatures, in this mixture, add the 124mg phosphoryl chloride, stirred 17 hours down, make it to react synthermal.After reaction finishes, in reaction solution, drip 30ml water, add the 50ml ethyl acetate then and extract, and the organic layer that obtains of concentration.The concentrated residue that obtains is carried out purification process by the flash chromatography method, obtain 1.11g trans-3-(1-methyl-2-phenyl-1H-indol-3-yl) methyl acrylate (yellow solid).Yield is 76%.
1H-NMR(δ/ppm，CDCl
3，400MHz)
3.64(3H，s)，3.74(3H，s)，6.46(1H，d，J＝16Hz)，7.29-7.55(9H，m)，7.72(1H，d，J＝16Hz)
Embodiment 3
With 1.68g 1,3,5-trimethoxy-benzene, 2.32g be trans-and 3-methoxy-methyl acrylate, 0.18g water and 6ml Glacial acetic acid mix, and under 25 ℃ of internal temperatures, adds the 164mg phosphoryl chloride in this mixture, stirred 3 hours down synthermal, make it to react.After reaction finishes, in reaction solution, drip 36ml water, the crystallization that leaching is separated out.With the washing of the aqueous methanol of 20% volume, drying is handled then with this crystallization, obtain 2.28g trans-3-(2,4, the 6-trimethoxyphenyl) methyl acrylate (white solid).Yield is 91%.
1H-NMR(δ/ppm，CDCl
3，400MHz)
3.79(3H，s)，3.85(3H，s)，3.87(6H，s)，6.12(2H，s)，6.76(1H，d，J＝16Hz)，8.08(1H，d，J＝16Hz)
Embodiment 4
With 1.7g 1,3,5-trimethoxy-benzene, 1.68g 3,3-dimethoxy methyl propionate and 12ml Glacial acetic acid mix, and under 25 ℃ of internal temperatures, add 313mg 35% weight hydrochloric acid in this mixture, stir 1 hour down synthermal, make it to react.After reaction finishes, in reaction solution, drip 36ml water, the crystallization that leaching is separated out.With the washing of the aqueous methanol of 20% volume, drying is handled then with this crystallization, obtain 2.46g trans-3-(2,4, the 6-trimethoxyphenyl) methyl acrylate (white solid).Yield is 98%.
Embodiment 5
With 1.68g 1,2,3-trimethoxy-benzene, 1.34g be trans-and 3-methoxy-methyl acrylate and 6ml Glacial acetic acid mix, and under 25 ℃ of internal temperatures, adds 313mg 35% weight hydrochloric acid in this mixture, stirred 16 hours down synthermal, make it to react.After reaction finished, adding 30ml water and 50ml ethyl acetate were carried out extraction treatment in reaction solution.Wash the organic layer that obtains with water, carry out concentration then, with the concentrated residue that obtains by silica gel column chromatography (developping solution: normal heptane/ethyl acetate=6/1-5/1) carry out purification process, obtain 0.63g trans-3-(2,3, the 4-trimethoxyphenyl) methyl acrylate (white solid).And, reclaimed 0.92g raw material 1,2, the 3-trimethoxy-benzene.With respect to 1,2 of conversion, the 3-trimethoxy-benzene, the yield of 3-(2,3, the 4-trimethoxyphenyl) methyl acrylate is 55%.
1H-NMR(δ/ppm，CDCl
3，400MHz)
3.80(3H，s)，3.88(3H，s)，3.89(3H，s)，3.92(3H，s)，6.42(1H，d，J＝16Hz)，6.69(1H，d，J＝9Hz)，7.26(1H，d，J＝9Hz)，7.88(1H，d，J＝16Hz)
Embodiment 6
Use 1.54g 2, the 6-syringol replaces 1.68g 1,2, and in addition the 3-trimethoxy-benzene reacts and aftertreatment similarly to Example 5, obtain 0.76g trans-3-(3-hydroxyl-2,4-Dimethoxyphenyl) methyl acrylate (white solid).Yield is 32%.
1H-NMR(δ/ppm，CDCl
3，400MHz)
3.80(3H，s)，3.91(3H，s)，3.93(3H，s)，5.58(1H，s)，6.45(1H，d，J＝16Hz)，6.67(1H，d，J＝9Hz)，7.07(1H，d，J＝9Hz)，7.87(1H，d，J＝16Hz)
Embodiment 7
0.63g 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles is dissolved in the 3ml methylene dichloride and makes solution, under internal temperature 0-10 ℃, in this solution, drip the 0.77g phosphoryl chloride, drip subsequently 0.92g trans-the 3-methoxy acrylonitrile.Then, this mixture is at room temperature stirred a night, make it to react, it was reacted 6 hours under reflux temperature.Reaction joins reaction solution in the aqueous carbonic acid hydrogen sodium of 100ml 5% weight after finishing, and handles 3 times with ethyl acetate extraction.The organic layer that obtains lumped together wash with water, use anhydrous magnesium sulfate to carry out drying treatment then.Remove by filter sal epsom, the filtrate that obtains carried out concentration, obtain containing 3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] concentrated residue of vinyl cyanide (based on the trans cis mixtures of isomers of trans-isomer(ide)).Utilize silica gel column chromatography (developping solution: normal heptane/ethyl acetate=10/1-5/1), the concentrated residue that obtains is carried out purification process, obtain 0.34g trans-3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] vinyl cyanide (yellow solid).Yield is 45%.
1H-NMR(δ/ppm，CDCl
3，400MHz)
1.70(6H，d，J＝7Hz)，4.85(1H，m)，5.35(1H，d，J＝16Hz)，7.09-7.46(7H，m)，7.55(1H，d，J＝8Hz)，7.48(1H，d，J＝16Hz)
Embodiment 8
With 0.62g 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles, 0.57g trans-3-methoxy-methyl acrylate, 46mg water and 6.4ml Glacial acetic acid mix, under 25 ℃ of internal temperatures, in this mixture, drip the 66mg phosphoryl chloride, stirred 21 hours down, make it to react synthermal.After reaction finishes, carry out aftertreatment similarly to Example 1, obtain 0.65g trans-3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] methyl acrylate (yellow solid).Yield is 79%.
Embodiment 9
The usage quantity of phosphoryl chloride is that 164mg, reaction times are 9 hours, in addition reacts similarly to Example 8 and aftertreatment, obtain 0.79g trans-3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] methyl acrylate (yellow solid).Yield is 96%.
Embodiment 10-13
Use the acid substitution phosphoryl chloride shown in the table 1, the usage quantity of Glacial acetic acid is the condition shown in 6ml and the employing table 1, in addition react similarly to Example 8 and aftertreatment, obtain trans-3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] methyl acrylate (yellow solid).The result is as shown in table 1.
Table 1
| Embodiment | Acid (mg) | Water | Reaction times | Yield |
| 10 | 99% weight percent sulfuric acid (156) | 46mg | 15 hours | 59％ |
| 11 | 35% weight hydrochloric acid (166) | 108mg (water in the hydrochloric acid) | 15 hours | 94％ |
| 12 | Tosic acid monohydrate (302) | 56mg (containing the 10mg crystal water) | 15 hours | 74％ |
| 13 | The aqueous hydrobromic acid of 47% weight (274) | 145mg (water in the aqueous hydrobromic acid) | 5 hours | 90％ |
Embodiment 14
With 0.31g 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles, 0.28g trans-after 3-methoxy-methyl acrylate, 36mg water and 6ml acetonitrile mix, under 25 ℃ of internal temperatures, in this mixture, drip the 164mg phosphoryl chloride, stirred 22 hours down, make it to react synthermal.After reaction finishes, carry out aftertreatment similarly to Example 1, obtain 0.21g trans-3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] methyl acrylate (yellow solid).Yield is 51%.
Embodiment 15
With 2.53g 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles, 2.32g trans-after 3-methoxy-methyl acrylate, 0.3g water and 15ml acetonitrile mix, under 25 ℃ of internal temperatures, in this mixture, drip the 2.51g phosphoryl chloride, stirred 19 hours down, make it to react synthermal.After reaction finishes, carry out aftertreatment similarly to Example 1, obtain 2.17g trans-3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] methyl acrylate (yellow solid).Yield is 65%.
Embodiment 16-18
The usage quantity of phosphoryl chloride and water is that the amount shown in the table 2, reaction times are 18 hours, in addition react similarly to Example 14 and aftertreatment, obtain trans-3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] methyl acrylate (yellow solid).The result is as shown in table 2.
Table 2
| Embodiment | Phosphoryl chloride usage quantity (mg) | Water usage quantity (mg) | Yield |
| 16 | 242 | 44 | 56％ |
| 17 | 398 | 44 | 75％ |
| 18 | 348 | 0 | 32％ |
Embodiment 19-20
Acid substitution phosphoryl chloride shown in the use table 3, reaction times are 19 hours, in addition react similarly to Example 14 and aftertreatment, obtain trans-3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] methyl acrylate (yellow solid).The result is as shown in table 3.
Table 3
| Embodiment | Acid (mg) | Yield |
| 19 | Boron trifluoride tetrahydrofuran complex (348) | 27％ |
| 20 | 99% weight percent sulfuric acid (119) | 39％ |
Embodiment 21
With 1.27g 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles, 1.16g trans-after 3-methoxy-methyl acrylate and 12ml Glacial acetic acid mix, under 25 ℃ of internal temperatures, in this mixture, drip 797mg 30% weight hydrogen bromide/acetic acid solution, stirred 5 hours down synthermal, make it to react.After reaction finishes, carry out aftertreatment similarly to Example 1, obtain 0.15g trans-3-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl] methyl acrylate (yellow solid).Yield is 8%.
Embodiment 22
With 1.27g 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles, 1.32g 1, after 1-dimethoxy-3-butanone and 6ml formic acid mix, at room temperature in this mixture, add 0.78g 30% weight hydrogen bromide/acetic acid solution,, make it to react synthermal stir about down 19 hours.After reaction finishes, add 50ml ethyl acetate and 20ml water, carry out extraction treatment, wash the organic layer that obtains with water, use anhydrous magnesium sulfate to carry out drying treatment then.After removing by filter sal epsom, the filtrate that obtains is carried out concentration, obtains containing trans-4-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl]-concentrated residue of 3-butene-2-ketone.Utilize silica gel chromatography (developping solution: normal heptane/ethyl acetate: 4/1), the concentrated residue that obtains is carried out purification process, obtain 0.72g trans-4-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl]-3-butene-2-ketone (yellow solid).Yield is 52%.And, reclaimed 0.18g raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles altogether.
1H-NMR(δ/ppm，CDCl
3，400MHz)
1.71(6H，d，J＝7Hz)，2.23(3H，s)，4.94(1H，m)，6.29(1H，d，J＝16Hz)，7.09-7.40(6H，m)，7.49(1H，J＝8Hz)，7.51(1H，J＝8Hz)，7.66(1H，d，J＝16Hz)
Embodiment 23
With 1.27g 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles, 1.32g 1, after 1-dimethoxy-3-butanone and 6ml acetate mix, at room temperature in this mixture, add 260mg 35% weight hydrochloric acid,, make it to react synthermal stir about down 18 hours.Reaction is got 2 reaction solutions as sample after finishing.Under reduced pressure, sample liquid is concentrated, the concentrated residue that obtains is dissolved in the deuterochloroform, measure
1The H-NMR wave spectrum, found that and contain trans-4-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl in the above-mentioned concentrated residue]-3-butene-2-ketone and raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles, it contains than (trans-4-[3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl]-3-butene-2-ketone/3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (integrated value according to NMR is calculated)) is 1/2.7.
Embodiment 24
With 2.07g 1-methyl-2-phenyl-1H-indoles, 1.32g 1, after 1-dimethoxy-3-butanone and 12ml acetate mix, at room temperature in this mixture, add 313mg 35% weight hydrochloric acid, synthermal stir about down 14 hours, make it to react.From stirring, when reaction begins through about 10 minutes, separating out blue solid, cause and stir the difficulty that becomes, therefore added 8ml acetate.After reaction finishes, drip 60ml water, the crystallization that leaching is separated out.This crystallization with 10% volumes methanol/water washing, is carried out drying treatment then, obtain 2.44g trans-4-[1-methyl-2-phenyl-1H-indol-3-yl]-3-butene-2-ketone (blue-greenish colour solid).Yield is 89%.
1H-NMR(δ/ppm，CDCl
3，400MHz)
2.24(3H，s)，3.65(3H，s)，6.83(1H，d，J＝16Hz)，7.30-7.43(5H，m)，7.52-7.59(4H，m)，8.02(1H，J＝8Hz)
Method of the present invention is the higher method of a kind of Atom economy, this method needn't be used the big aromatic halide of environmental hazard as raw material, also produce the hydrogen halide by product to carry out neutralizing treatment, can prepare the aromatic unsaturated compound that can change into medical agricultural chemicals etc.In addition, also use the transition metal of high price, aftertreatment complexity, therefore method of the present invention industrial also be advantageous method more.
Claims (8)
1. the preparation method of aromatic unsaturated compound shown in the formula (4):
In the formula, Ar represents optional substituted phenyl, naphthyl, anthryl, phenanthryl, the tetralyl, 9 of being selected from, the aryl of 10-dihydro anthryl and acenaphthenyl, perhaps be selected from indyl, benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, pyrryl, furyl, thienyl dibenzofuran group, dibenzothiophene base, 2,3-indolinyl, 2, the aryl of 3-dihydro benzo furyl
The substituting group of Ar is: carbonatoms is the alkyl of 1-6, lower alkoxy, hydroxyl, the warp-OR that carbonatoms is 1-4
XShown in hydroxyl, amino, the warp-NHR of protecting group protection
yOr-NR
y 2Shown in amino, phenyl, halogen or the optional phenyl that is replaced by halogen of protecting group protection,
Wherein, R
XExpression ethanoyl, methoxymethyl, benzyl, methylene radical, dimethylated methylene base,
R
yExpression ethanoyl, benzyl, benzyloxymethyl, dimethoxy-methyl, benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl,
Y represents that carbonatoms is the alkoxy carbonyl of 2-9, the aryloxycarbonyl that carbonatoms is 7-13, the aromatic alkoxy carbonyl that carbonatoms is 8-14, the aliphatic acyl that carbonatoms is 2-9, aromatic acyl group, the cyano group that carbonatoms is 7-13,
This method comprises to be made
(a) compound shown in the formula (1):
Ar-H (1)
In the formula, Ar represents meaning same as described above,
With compound shown in (b) formula (2):
In the formula, Y represents meaning same as described above,
Z represents that carbonatoms is the alkoxyl group of 1-6,
Or compound shown in the formula (3):
In the formula, Y and Z represent meaning same as described above,
(c) acid or through hydrolysis can generate mineral acid compound in the presence of react.
2. the method for claim 1, this method are implemented reaction under the coexistence of water.
3. the process of claim 1 wherein described (c) acid or be hydrogen halide through the compound that hydrolysis can generate mineral acid.
4. the process of claim 1 wherein described (c) acid or be phosphoryl halogen, Phosphorates phosphorus Halides, thionyl halide or sulfonic acid halide through the compound that hydrolysis can generate mineral acid.
5. the method for claim 1, this method are implemented reaction in acetate.
6. the process of claim 1 wherein that the Ar in formula (1) and the formula (4) is the optional phenyl that is replaced by listed substituting group.
7. the process of claim 1 wherein that the Ar in formula (1) and the formula (4) is the optional indyl that is replaced by listed substituting group.
8. the process of claim 1 wherein that compound shown in the formula (1) is a compound shown in the formula (5):
In the formula, R
1Optional phenyl, the hydrogen or alkyl that is replaced by halogen of expression, R
2Expression alkyl or the optional phenyl that is replaced by halogen;
Aromatic unsaturated compound shown in the formula (4) is an aromatic unsaturated compound shown in the formula (6):
R in the formula
1And R
2Represent meaning same as described above.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1984002131A1 (en) * | 1982-11-22 | 1984-06-07 | Sandoz Ag | Analogs of mevalolactone and derivatives thereof, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals |
| US5118853A (en) * | 1988-10-13 | 1992-06-02 | Sandoz Ltd. | Processes for the synthesis of 3-disubstituted aminoacroleins |
| JP2001081057A (en) * | 1999-09-09 | 2001-03-27 | Sumitomo Chem Co Ltd | Production of aromatic alkenes |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1984002131A1 (en) * | 1982-11-22 | 1984-06-07 | Sandoz Ag | Analogs of mevalolactone and derivatives thereof, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals |
| US5118853A (en) * | 1988-10-13 | 1992-06-02 | Sandoz Ltd. | Processes for the synthesis of 3-disubstituted aminoacroleins |
| JP2001081057A (en) * | 1999-09-09 | 2001-03-27 | Sumitomo Chem Co Ltd | Production of aromatic alkenes |
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