CN100577659C - Processes for producing indole compound - Google Patents
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- CN100577659C CN100577659C CN200610106266A CN200610106266A CN100577659C CN 100577659 C CN100577659 C CN 100577659C CN 200610106266 A CN200610106266 A CN 200610106266A CN 200610106266 A CN200610106266 A CN 200610106266A CN 100577659 C CN100577659 C CN 100577659C
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Abstract
A process for producing an indole compound represented by the formula (2) which comprises reducing a 2-nitrobenzylcarbonyl compound represented by the formula (1) (wherein R1 and R2 each independently represents hydrogen or optionally substituted alkyl or phenyl; R3 represents alkyl, halogeno, etc.; and n is an integer of 0 to 4) with a hydrogen donor in the presence of a reduction catalyst, characterized in that an acylating agent and a base are caused to coexist in the reduction step; the process in which the 4-fluoro-2-nitrophenylacetone produced from 2-chloro-4-fluoronitrobenzene is used; and a process for producing a sulfamoyltriazole compound which comprises reacting the indole compound with 1-(N,N-dimethylsulfamoyl)-3-chlorosulfonyl-1,2,4-triazole.
Description
The application is to be on March 28th, 2003 applying date, and application number is 03807772.8, and denomination of invention is the dividing an application of preparation method of benzazolyl compounds.
Technical field
The present invention relates to conduct based on the preparation method of the useful benzazolyl compounds of the various fine chemicals intermediates of physiologically active substances such as medical agricultural chemicals and the new 2-nitrophenyl acetonide that in this preparation method, becomes intermediate.
Background technology
As the preparation method of benzazolyl compounds, known have a following method.
In DE262327, have to make N-o-tolyl-ethanamide react the example that obtains 2 methyl indole with barium oxide at 360 ℃.Equally, use sodium amide (Block Le チ Application デ ラ オ Block ソ サ イ エ テ チ ミ ケ デ Off ラ Application ス (Bull.Soc.Chim.Fr.) is also arranged, 4,1039 (1924) or sodium methylate (オ one ガ ニ Star Network シ Application セ セ ス (Org.Syn.), 27,94 (1942)) example, but they all need high temperature of reaction, by product is many, and yield is not high yet.
Though have phenylhydrazone to react the example that obtains 2 methyl indole with sodium hydroxide, by product many and yield low (ケ ミ カ Le ベ リ ヒ テ (Chem.Ber.), 81,266,270 (1948) at 240 ℃ with acetone.
Make 2-nitro-1-(2-nitrophenyl) propane in the presence of 10% palladium catalyst that is stated from the gac with H-H reaction, the preparation 2 methyl indole, but yield is 81% (ヘ テ ロ サ イ Network Le ス (Heterocycles), 55,95 (2001)).
Though make aniline and three (2-hydroxypropyl) amine hydrochlorate at tindichloride at 180 ℃, there are reaction down in ruthenium trichloride, triphenylphosphine, and the yield with 64% obtains 2 methyl indole, but low (the テ ト ラ ヘ De ロ Application (Tetrahedron, 3321 (2001)) of yield.
As the preparation method who begins from 2-nitrobenzyl carbonyl compound, for example have 2-nitrophenyl acetone at acetic acid, sodium-acetate reduces with iron under existing, yield with 68% obtains record (ジ ヤ one Na Le オ Block オ one ガ ニ Star Network ケ ミ ス ト リ one (J.Org.Chem.) of 2 methyl indole, 48,2066 (1983)) or make 4-fluoro-2-nitrophenyl acetone in aqueous acetic acid, obtain the record (spy opens clear 47-38963) etc. of 6-fluoro-2 methyl indole with 95% yield with zinc reaction, but during post-reaction treatment, a large amount of ferric oxide or zinc oxide are discharged from as refuse, and are bigger for environmental influence.In addition, have in the latter, even at palladium, there are catalytic reduction down in Raney nickel, catalyzer such as platinum, also can obtain the record of same product, but do not have the record embodiment corresponding with it.
As mentioned above, also reducing catalyst such as the catalysis by using the carrying precious metal and hydrogen are supplied with the method to the environment gentleness of body, prepare the example of the benzazolyl compounds that 2-replaces with high yield in a stage.In fact, if 4-fluoro-2-nitrophenyl acetone is used hydrogen reducing in the presence of the palladium catalyst that is stated from the gac, because by-product is given birth to 6-fluoro-2 methyl indole, so the yield of 6-fluoro-2 methyl indole is about 70%.This be because, the relation that there are tautomerism in the 1-hydroxy-2-methyl indoles that generates as reaction intermediate and 2-methyl pseudo-indole N-oxide compound, this 2-methyl pseudo-indole N-oxide compound further is reduced generation 6-fluoro-2-methyl indoline.
The synthetic example of 1-hydroxyl-2-alkyl indoles as the reduction intermediate, have example (the Block Le チ Application デ ラ オ Block ソ サ イ エ テ チ ミ ケ デ Off ラ Application ス (Bull.Soc.Chim.Fr.) of 2-nitrophenyl acetone with zinc and the synthetic 1-hydroxy-2-methyl indoles of ammonium chloride reduction, 1296 (1967)), or electrochemically from synthetic (Block Le チ Application デ ラ オ Block ソ サ イ エ テ チ ミ ケ デ Off ラ Application ス (Bull.Soc.Chim.Fr.), 121 (1974)) that α-(o-hydroxyl amino phenyl) propane begins.In addition, there be tautomeric relation (ジ ヤ one Na Le オ Block ザ ケ ミ カ Le ソ サ イ エ テ イ one (J.Chem.Soc.) in known 1-hydroxy-2-methyl indoles and 2-methyl pseudo-indole N-oxide compound, 1067 (1970), ス ペ Network ト ロ チ ミ カ ア Network タ (Spectrochim.Acta), 23,717 (1967).
Secondly; example as its acidylate; have from example (ジ ヤ one Na Le オ Block ザ ケ ミ カ Le ソ サ イ エ テ イ one (J.Chem.Soc.) of 1-hydroxyl-2-phenylindone class with diacetyl oxide or the synthetic 1-acetoxyl group of Benzoyl chloride-2-phenylindone class or 1-benzoyloxy-2-phenylindone class; 3466 (1960)) or 1-acetoxyl group-2 methyl indole (Block Le チ Application デ ラ オ Block ソ サ イ エ テ チ ミ ケ デ Off ラ Application ス (Bull.Soc.Chim.Fr.), 3040 (1973) synthesis example.
And then; as example from the reduction reaction of its acidylate body; have 1-benzoyloxy-2-phenylindone or 1-acetoxy-3-cyano group-2-phenylindone in ethanol; with the palladium catalyst reduction that is stated from the gac; obtain example ((ジ ヤ one Na Le オ Block ザ ケ ミ カ Le ソ サ イ エ テ イ one (J.Chem.Soc.), 3466 (1960) of 2-phenylindone or 3-cyano group-2-phenylindone.But, this method, obtaining the object benzazolyl compounds from initial substance 2-nitrobenzyl carbonyl compound needs a plurality of stages, is not efficient method.
In addition, in the past, the phenyl-acetone compound has been developed all cpds or preparation method as the important intermediate of fine chemicals manufacturing.2-nitrophenyl acetonide is owing to have nitro, 2 kinds of functional groups of carbonyl at intramolecularly, therefore be the important intermediate during various heterogeneous ring compounds are made, known for example have, 2-nitrophenyl acetone (テ ト ラ ヘ De ロ Application レ タ one ズ (TetrahedronLett.), 42,1387 (2001)), 4-chloro-2-nitrophenyl acetone (ケ ミ カ Le ア Application De Off ア one マ ソ イ テ イ カ Le Block Le チ Application) (Chem.Pharm.Bull.), 17,605 (1969), 4-fluoro-2-nitrophenyl acetone (spy opens clear 47-38947).
, just be that all cpds has been synthesized at the center since ancient times particularly with the physiologically active compound from the benzazolyl compounds of these compound derivings.
Put down in writing the availability of the compound group of the benzazolyl compounds preparation that obtains with its described method in the open WO99/21851 brochure of international patent application as sterilant.6-fluoro-2 methyl indole particularly, it is the intermediate of the high benzazolyl compounds of one of them availability of preparation, preparation method as corresponding important source material 3-(4-fluoro-2-nitrophenyl) acetone, though it is known that known above-mentioned spy opens the method for clear 47-38947 record, but, therefore need easier and excellent preparation method owing to need the multistage.
In addition; by making benzazolyl compounds and 1-(N; N-dimethylamino alkylsulfonyl)-3-chlorosulfonyl-1; 2; the reaction of 4-triazole is as the method for the sterilant of putting down in writing in the open WO99/21851 brochure of preparation international patent application, though except that the open WO99/21851 brochure of international patent application; known spy opens the method for putting down in writing in the 2001-187786 communique, but also needs the higher preparation method of yield.
The problem that the present invention will solve provides preparation method and its intermediate at industrial useful benzazolyl compounds.
Summary of the invention
Present inventors; for solving found that of above-mentioned problem further investigation; 2-nitrobenzyl carbonyl compound is being supplied with the body reductive in the stage with hydrogen in the presence of reducing catalyst; by acidylating the coexistence of agent and alkali; can prepare benzazolyl compounds with high yield in a stage; the various preparation methods that in the 6-fluoro-2 methyl indole of preparation, become 3-(the 4-fluoro-2-nitrophenyl) acetone of important source material have been studied simultaneously as one of benzazolyl compounds; found that new preparation method as new 2-nitrophenyl acetonide and process this compound 3-(4-fluoro-2-nitrophenyl) acetone of key intermediate; and find; by benzazolyl compounds is made an alkali metal salt; make itself and 1-(N then; N-dimethylamino alkylsulfonyl)-3-chlorosulfonyl-1; 2; the reaction of 4-triazole; can prepare the compound of putting down in writing in the open WO99/21851 brochure of international patent application with high yield, until having finished the present invention.
That is, the present invention relates to following [1] to [23]
[1], passes through formula (2)
(in the formula, R
1And R
2Represent hydrogen atom respectively independently, can substituted alkyl or phenyl, R
3Expression can substituted alkyl, phenyl, alkoxyl group, alkoxy carbonyl or halogen atom; n represents 0 to 4 integer) represented benzazolyl compounds forms an alkali metal salt, then, makes itself and 1-(N; N-dimethylamino alkylsulfonyl)-and 3-chlorosulfonyl-1,2, the 4-triazole reacts preparation formula (3)
The method of represented sulfamyl triazole compounds,
(in the formula, R
1, R
2, R
3Represent definition same as described above with n).
[2], the preparation method of record in [1], wherein use by with formula (1)
(in the formula, R
1And R
2Represent hydrogen atom respectively independently, can substituted alkyl or phenyl, R
3Expression can substituted alkyl; phenyl; alkoxyl group; alkoxy carbonyl or halogen atom; n represents 0 to 4 integer) represented 2-nitrobenzyl carbonyl compound supplies with the body reductive in the stage with hydrogen in the presence of reducing catalyst, acidylate the coexistence of agent and alkali and the represented benzazolyl compounds of above-mentioned formula (2) for preparing.
[3], the preparation method of the benzazolyl compounds shown in above-mentioned (2), it is characterized in that the 2-nitrobenzyl carbonyl compound shown in the above-mentioned formula (1) is being supplied with the body reductive in the stage with hydrogen in the presence of reducing catalyst, acidylating agent and alkali and coexisting.
[4], the preparation method of the described benzazolyl compounds of claim 3, wherein above-mentioned acylating agent is an organic acid anhydride.
[5], the preparation method of the benzazolyl compounds described in [3], wherein above-mentioned acylating agent is an acetic anhydride.
[6], the preparation method of the benzazolyl compounds described in [3], wherein above-mentioned alkali is an alkali metal salt or alkali metal hydroxide.
[7], the preparation method of the benzazolyl compounds described in [3], wherein above-mentioned alkali is alkali-metal organic acid salt, carbonate, supercarbonate or oxyhydroxide.
[8], the preparation method of the benzazolyl compounds described in [3], wherein above-mentioned reducing catalyst is the catalyzer of carrying precious metal.
[9], the preparation method of the benzazolyl compounds described in [3], wherein above-mentioned reducing catalyst is the palladium that is stated from the gac.
[10], the preparation method of the benzazolyl compounds described in [3], it is hydrogen that wherein above-mentioned hydrogen is supplied with body.
[11], above-mentioned formula (3) (wherein, R
2Expression chlorine atom, bromine atoms or iodine atom) shown in the preparation method of sulfamyl triazole compounds, this method is by with above-mentioned formula (2) (wherein, R
2The expression hydrogen atom) represented benzazolyl compounds halogenation, make it become an alkali metal salt then after, again with 1-(N, N-dimethylamino alkylsulfonyl)-3-chlorosulfonyl-1,2,4-triazole reaction and preparation.
[12], the preparation method described in [11], wherein above-mentioned benzazolyl compounds is 2-methyl-6-fluoro indole.
[13], the described preparation method of claim 12, wherein above-mentioned halogenation is a bromination.
[14], the preparation method described in [13], wherein above-mentioned bromination is undertaken by sodium hypobromite.
[15], the preparation method described in [13], wherein above-mentioned bromination is in the presence of sodium hydroxide, is undertaken by bromine.
[16], the preparation method described in [12], use by 3-(4-fluoro-2-nitrophenyl) acetone is being supplied with the body reductive in the stage with hydrogen in the presence of reducing catalyst, by acidylating 2-methyl-6-fluoro-indoles that agent and alkali coexist and prepares.
[17], the preparation method of 2-methyl-6-fluoro indole, it is characterized in that, above-mentioned 3-(4-fluoro-2-nitrophenyl) acetone is being supplied with the body reductive in the stage with hydrogen in the presence of reducing catalyst, acidylating the coexistence of agent and alkali.
[18], the preparation method described in [16], it is characterized in that using by with formula (I)
(in the formula, R represents methyl, methoxy or ethoxy) represented 2-nitrophenyl acetonide is handled in the presence of acid or alkali and 3-(the 4-fluoro-2-nitrophenyl) acetone for preparing.
[19], [17] described preparation method, wherein use and in the presence of acid or alkali, handle 3-(the 4-fluoro-2-nitrophenyl) acetone for preparing by the 2-nitrophenyl acetonide that above-mentioned formula (I) is represented.
[20], the preparation method of 3-(4-fluoro-2-nitrophenyl) acetone, handle in the presence of acid or alkali by the 2-nitrophenyl acetonide that above-mentioned formula (I) is represented.
[21], [18], [19] or [20] described preparation method wherein uses by making formula (II)
Oil of mirbane that (in the formula, X represents fluorine atom, chlorine atom or bromine atoms) is represented and formula (III)
2-nitrophenyl acetonide shown in the above-mentioned formula (I) of the reaction of (in the formula, R represents methyl, methoxy or ethoxy) represented dicarbonyl compound and preparation.
[22], the preparation method of the 2-nitrophenyl acetonide shown in the above-mentioned formula (I), this method is by making the described dicarbonyl compound reaction of oil of mirbane shown in the above-mentioned general formula (II) and above-mentioned formula (III).
[23], the 2-nitrophenyl acetonide shown in the above-mentioned formula (I).
If to being further described by the preparation method of the 2-nitrobenzyl carbonyl compound shown in the formula (1) to the benzazolyl compounds shown in the formula (2), then the present invention is the preparation method of the benzazolyl compounds shown in the formula (2),
It is characterized in that, with formula (1)
(in the formula, R
1And R
2Represent hydrogen atom respectively independently, can substituted alkyl or phenyl, R
3Expression can substituted alkyl, phenyl, alkoxyl group; alkoxy carbonyl or halogen atom; n represents 0 to 4 integer) represented 2-nitrobenzyl carbonyl compound supplies with the body reductive in the stage with hydrogen in the presence of reducing catalyst, by acidylating the coexistence of agent and alkali, make intermediate formula (3)
The formula (4) of shown 1-oxyindole and its tautomer
Shown pseudo-indole N-oxide compound acidylate is via formula (5)
(in the formula, R
4The carboxyl groups of representing above-mentioned acylating agent) the 1-acyloxy indoles shown in.
According to the present invention, produce reduction by product dihydroindole compounds hardly, can prepare benzazolyl compounds with high yield.
Embodiment
As suitable compound of the present invention, in the benzazolyl compounds shown in 2-nitrobenzyl carbonyl compound shown in the formula (1) and the formula (2), can enumerate R
1And R
2Represent hydrogen atom respectively independently, can substituted alkyl or phenyl, R
3Expression can substituted alkyl, and phenyl, alkoxyl group, alkoxy carbonyl or halogen atom, n are represented the situation of 0 to 4 integer, can enumerate R
1And R
2Represent hydrogen atom or can substituted alkyl, R respectively independently
3The expression halogen atom, n represents the situation of 0 or 1 integer, can enumerate R
1The expression methyl, R
2The expression hydrogen atom, R
3The expression fluorine atom, n represents the situation of 0 or 1 integer.
2-nitrobenzyl carbonyl compound as shown in the formula (1) of starting raw material of the present invention can prepare by currently known methods.For example, can enumerate 2-nitrophenyl acetone (テ ト ラ ヘ De ロ Application レ タ one ズ (Tetrahedron Lett.), 42,1387 (2001)), 4-chloro-2-nitrophenyl acetone (ケ ミ カ Le ア Application De Off ア one マ ソ イ テ イ カ Le Block Le チ Application) (Chem.Pharm.Bull.), 17,605 (1969), 4-fluoro-2-nitrophenyl acetone (spy opens clear 47-38947).
The reagent and the reaction conditions that use in the stage of reductase 12-nitrobenzyl carbonyl compound are as follows, but are not limited thereto.
As acylating agent; organic acid anhydride compound with acyl group of reactive behavior is effectively, is preferably acetic anhydride, trifluoro-acetic anhydride; propionic anhydride; butyryl oxide, caproic anhydride, crotonic anhydride; maleic anhydride; benzoyl oxide, succinyl oxide or by acetic anhydride and formic anhydride synthetic mixed acid anhydride etc. also can use their mixture.Wherein from economic aspect, preferred especially acetic anhydride.
As the usage quantity of acylating agent, with respect to 1 mole of 2-nitrobenzyl carbonyl compound, be preferably 0.01～10 mole, more preferably 1～5 mole.
As alkali, can enumerate organic basess such as amine or pyridine, or the metal organic acid salt of basic metal or alkaline-earth metal etc., carbonate, supercarbonate, phosphoric acid salt, sulphite, oxyhydroxide, mineral alkalis such as oxide compound, but preferably can enumerate alkali-metal organic acid salt, or in reaction solution with organic acid anhydride or generate the alkali-metal carbonate of basic metal organic acid salt by the organic acid reaction that their generate, supercarbonate, alkali such as oxyhydroxide.Wherein special preferable formic acid sodium, potassium formiate, sodium-acetate, Potassium ethanoate, Sodium Propionate, potassium propionate, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide etc.Also these alkali can be mixed and use.
As the usage quantity of alkali, with respect to 1 mole of 2-nitrobenzyl carbonyl compound, be preferably 0.01～5 mole, more preferably 0.1～2 mole.
As reductive agent, be preferably the nickel catalyzator that in hydrogenation, uses usually, palladium catalyst, platinum catalyst, rhodium catalyst, metal catalysts such as ruthenium catalyst, homogeneous system and heterodisperse system all can use.Wherein, especially preferably carry noble metal catalyst, and then, more preferably be stated from the palladium on the gac from economic aspect.
The usage quantity of reducing catalyst is preferably 0.01%～50%, and more preferably 1%～10%.
Supply with body as hydrogen, except that hydrogen, can also be set forth in to become the sodium formiate that hydrogen is supplied with body, potassium formiate in the reaction system, ammonium formiate, sodium phosphite, potassium phosphite, diphosphorous acid potassium, diphosphorous acid sodium etc., but from economic aspect, wherein preferred especially hydrogen.
As the usage quantity of hydrogen supply body, be 2～5 moles with respect to 1 mole of 2-nitrobenzyl carbonyl compound, be preferably 3～4 moles.
As solvent, so long as just being not particularly limited of reactionlessness can be enumerated for example benzene, toluene, the fragrant same clan such as dimethylbenzene, ether, dibutyl ether, tetrahydrofuran (THF), 1,4-diox, glycol dimethyl ether, ethers such as diglyme, methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, butylacetate, ester classes such as ethyl propionate, acetone, methylethylketone, methyl iso-butyl ketone (MIBK), ketones such as pimelinketone, hexane, heptane, octane, hydro carbons such as nonane, formic acid, acetate, organic acids such as propionic acid, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone isopolarity solvent and water etc. also can use these mixed solvent.
As the usage quantity of solvent, be preferably 1～2 times of amount with respect to 2-nitrobenzyl carbonyl compound, more preferably 3～10 times of amounts.
Reaction can make 2-nitrobenzyl carbonyl compound, acylating agent, and alkali, the mixture of reducing catalyst and solvent and hydrogen are supplied with precursor reactant and are carried out.
As temperature of reaction, can preferably under boiling point from room temperature to reaction solvent or the temperature below it, carry out in the scope of hundreds of degree, carrying out from room temperature or the low temperature below it.
As the reaction total pressure, can be from the normal pressure to 100kg/cm
2Deng high pressure under carry out, but preferably at normal pressure～10kg/cm
2Scope in, be preferably 0.01～10kg/cm as the hydrogen dividing potential drop in addition
2Scope, under any situation, reaction under high pressure is rapid more.
Reaction times is influenced by stirring velocity, normal pressure 4～50 hours, just can finish reaction in pressurized conditions following a few hours under common agitation condition.
Treatment process as reaction afterreaction liquid, after removing by filter reducing catalyst, reaction solution is washed with water, can obtain benzazolyl compounds solution, but as required, can by with alkaline aqueous solution such as sodium hydroxide or, reagent that acidic aqueous solution washing reaction liquid such as sulfuric acid, hydrochloric acid and removing uses in the dereaction or by product etc.
The reducing catalyst that reclaims is not poisoned and just can repeatedly be used repeatedly.
The new 2-nitrophenyl acetonide that provides among the present invention is by formula (I) expression,
(in the formula, R represents methyl, methoxyl group, oxyethyl group).
In addition, in the above-mentioned new 2-nitrophenyl acetone mixture, there is the keto-enol tautomerism body, with common
1H-NMR etc. can be observed both blended forms, also comprise the enol body in this application, and unification is represented with the structure of formula (I).
In addition, above-mentioned 2-nitrophenyl acetonide can be by making (II)
(in the formula, X represents fluorine atom, chlorine atom or bromine atoms.) shown in oil of mirbane and formula (III)
(in the formula, R represents methyl, methoxy or ethoxy.) shown in the dicarbapentaborane mixture reaction novel method and prepare.
In addition, the structure of formula (III) also comprises enol body and unified with formula (III) expression.
Reaction is carried out in the presence of alkali usually.
Alkali as using in the reaction can use various alkali, for example can enumerate lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrated barta, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, lithium hydride, sodium hydride, potassium hydride KH, sodium methylate, sodium ethylate, sodium isopropylate, various alkali such as potassium tert.-butoxide, but operability from reacting, economy etc. are set out, preferred sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood etc.
These alkali can be used alone or in combination.
With respect to the dicarbonyl compound of 1 mole of formula (III), the usage quantity of alkali is generally 0.3～10 mole, preferred especially 0.5～5 mole.
In addition, in order to make reaction carry out smoothly also can in reaction system, adding additive.As additive, can enumerate tetramethyl ammonium chloride, 4 bromide, Tetramethylammonium iodide, etamon chloride, tetraethylammonium bromide, tetraethyl ammonium iodide, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide, palmityl trimethyl ammonium chloride, cetyl trimethylammonium bromide, benzyltriethylammoinium chloride, quarternary ammonium salt classes such as benzyl triethyl ammonium bromide, trityl group phosphonium iodide, the trityl group phosphonium bromide, the trityl group phosphonium chloride, triphenyl allyl group iodate Phosphonium, triphenyl allyl group bromination Phosphonium, triphenyl allyl group chlorination Phosphonium, the tetraphenyl phosphonium iodide, 4-phenyl phosphonium bromide, phosphonium salt classes such as tetraphenyl phosphonium chloride etc.
These additives are 0.0001～1 mole with respect to the dicarbonyl compound of 1 mole of formula (III) usually, are preferably 0.001～0.5 mole usage quantity especially.
For the reaction that makes the dispersing and mixing that is included in all ingredients that uses in the reaction is carried out smoothly, reaction is preferably with carrying out behind the solvent cut.As the solvent that uses in the reaction,, for example can enumerate ether in this reaction as long as be that the inert solvent just is not particularly limited, methyl tertiary butyl ether, tetrahydrofuran (THF), Methylal(dimethoxymethane), methylene diethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, the ethylene glycol bisthioglycolate butyl ether, diglyme, diethyl carbitol, the glycol ether dibutyl ether, triglyme, 1, ethers such as 4-diox, methyl alcohol, ethanol, the 1-propyl alcohol, 2-propyl alcohol, 1-butanols, the 2-butanols, isopropylcarbinol, 2-methyl-2-propyl alcohol, methylcyclohexane, ethyl cellosolve, ispropyl cellosolve, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diglycol monotertiary butyl ether, hexalin, alcohols such as benzyl alcohol, pentane, hexane, hexanaphthene, methylcyclohexane, heptane, octane, aliphatic hydrocarbons such as decane, benzene, toluene, dimethylbenzene, chlorobenzene, neighbour-dichlorobenzene ,-dichlorobenzene, right-dichlorobenzene, oil of mirbane, naphthanes etc. are aromatic hydrocarbon based, acetonitrile, nitriles such as propionitrile, methyl acetate, ethyl acetate, butylacetate, ester classes such as ethyl propionate, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, amidess such as N-Methyl pyrrolidone, 1,3-methylimidazole alkane ketone, N, N, N ', N '-urea classes such as 4-methyl urea, dimethyl sulfoxide (DMSO), sulfur-bearing class polar solvents such as tetramethylene sulfone, pyridine, 2-picoline, the 3-picoline, 4-picoline, pyridines or water such as aldehydecollidine.They can be used alone or in combination.
This reaction can be carried out in wide temperature range.As the situation of considering economic preparation and preferred temperature range, usually preferably at 0～150 ℃, particularly preferably in carrying out in 10～100 ℃ the scope.
Reaction times, according to used amount of reagent, concentration, temperature of reaction etc. and difference, but the preferred settings condition preferably finishes reaction for making it at 1～200 hour usually in 1～70 hour scope.
After reaction finishes, distillation removes and to desolvate as required, in the crude reaction thing, add then entry and with the immiscible solvent extraction of water after, by organic layer is distilled, recrystallization, conventional processing such as column chromatography can purifying, separate the 2-nitrophenyl acetonide of purpose formula (I).
In addition, handle in the presence of acid or alkali by the 2-nitrophenyl acetonide of formula (I) that above-mentioned reaction is obtained, can easily derive obtains 3-(4-fluoro-2-nitrophenyl) acetone as the important intermediate of indoles preparation etc.
As the alkali that can in reaction, use, can use various alkali, for example can enumerate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, hydrated barta, yellow soda ash, sodium bicarbonate, salt of wormwood, various alkali such as saleratus, operability from reaction, economy etc. are set out, preferred sodium hydroxide, potassium hydroxide.
In addition, as the acid that can in this reaction, use, can enumerate sulfuric acid, nitric acid, inorganic acids such as hydrochloric acid, formic acid, acetate, trifluoroacetic acid, aliphatic carboxylic acid classes such as propionic acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, organic sulfonic acid classes such as toluenesulphonic acids etc., but from practicality, economy etc. are set out, preferably can use sulfuric acid separately, hydrochloric acid, or be that the basis is used in combination other acids with it.
With respect to the 2-nitrophenyl acetone of 1 mole of formula (I), above-mentioned alkali or acid are generally 0.01～50 mole, preferred especially 0.1～20 mole usage quantity.
From operability, reaction is preferably with carrying out behind the solvent cut.As the solvent that uses in the reaction, as long as in reaction, just be not particularly limited for the inert solvent, for example, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), Methylal(dimethoxymethane), diethoxyethane, glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol bisthioglycolate butyl ether, diglyme, diethyl carbitol, glycol ether dibutyl ether, triglyme, 1, ethers such as 4-diox, methyl alcohol, ethanol, 1-propyl alcohol, the 2-propyl alcohol, 1-butanols, 2-butanols, isopropylcarbinol, 2-methyl-2-propyl alcohol, methylcyclohexane, ethyl cellosolve, ispropyl cellosolve, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diglycol monotertiary butyl ether, hexalin, alcohols such as benzyl alcohol, acetone, methylethylketone, metacetone, metacetone, 2 pentanone, methyl iso-butyl ketone (MIBK), ketones such as pimelinketone, pentane, hexane, hexanaphthene, methylcyclohexane, heptane, octane, aliphatic hydrocarbons such as decane, chloroform, ethylene dichloride, halogenated hydrocarbons such as tetrachloroethane, benzene, toluene, dimethylbenzene, chlorobenzene, neighbour-dichlorobenzene ,-dichlorobenzene, right-dichlorobenzene, oil of mirbane, naphthanes etc. are aromatic hydrocarbon based, formic acid, acetate, organic acid or water such as propionic acid.They can be used alone or in combination.
This reaction can be carried out in very wide temperature range.But, as the optimal temperature scope of the situation of the usage quantity of having considered to comprise reaction reagent and economic preparation, usually at 20～200 ℃, particularly preferably in carrying out in 50～150 ℃ the scope.
Reaction times, according to used amount of reagent, concentration, temperature of reaction etc. and difference, but the preferred settings condition preferably finishes reaction for making it at 1～50 hour usually in 1～30 hour scope.
After reaction finishes, distillation removes and desolvates as required, directly obtain object by distilling then, perhaps in the crude reaction thing, add entry and with the immiscible solvent thorough washing of water after, by organic layer is distilled, conventional processing such as column chromatography can purifies and separates obtain object 3-(4-fluoro-2-nitrophenyl) acetone.
The reaction of above-mentioned 2 operations of the application can operate continuously, has boost productivity etc. with the obvious advantage like this.
For example, after the reaction of the 1st operation finishes, under the situation of use and any dissolved solvent of water, distillation removes and desolvates, with with the immiscible solvent exchange of water, with its primary state, add water and from organic solvent, extract the intermediate 2-nitrophenyl acetonide that makes new advances under the situation of use and the immiscible solvent of water.Like this under the situation that needs are further purified, from containing the organic solvent of 2-nitrophenyl acetonide, alkali aqueous solution with requirement, concentration changes molten in the aqueous solution with this compound, then with its acidifying, adds new organic solvent and this compound commentaries on classics is dissolved in the organic solvent again.Then, direct in the solution that contains 2-oil of mirbane acetonide, or concentrated back adds acid or alkali reacts, and can obtain object 3-(4-fluoro-2-nitrophenyl) acetone with high yield.According to present method, the reaction of 2 operations need not to use methods such as recrystallization or column chromatography, can be undertaken by operate continuously under solution state substantially.
Benzazolyl compounds shown in the formula (2) is made an alkali metal salt, then, make itself and 1-(N, N-dimethylamino alkylsulfonyl)-3-chlorosulfonyl-1,2, the reaction of 4-triazole compounds can prepare the compound shown in the formula (3).
Compound shown in the formula (3) is the sterilant of putting down in writing in the open WO99/21851 specification sheets of international patent application.
Method when the benzazolyl compounds shown in the formula (2) is become an alkali metal salt for example can be enumerated, in solvent, with the alkali metal compound stirring method.
As the solvent in this stage, for example can enumerate ether, propyl ether, diglyme, glycol dimethyl ether, diglyme, diethyl carbitol, tetrahydrofuran (THF), tetrahydropyrans, 1, ring-type or non-annularity ether solvents such as 4-diox.
As alkali metal compound, can enumerate alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline carbonates such as yellow soda ash or salt of wormwood etc., sodium methylate, pure salt such as potassium tert.-butoxide, sodium hydride etc.
In this stage, in order to make an alkali metal salt of the balanced deflection indoles in the reaction system, generation by alkali metal compound deutero-water during preferred limit will react, acid, alcohol etc. are discharged to outside the system, and react on the limit, from such viewpoint, perhaps, be preferably alkoxide, particularly preferred example such as sodium methylate as alkali metal compound from the viewpoint of economy.
The amount of employed alkali metal compound is 0.5～20 mole with respect to 1 mole of benzazolyl compounds, is preferably 1～2 mole especially.
Temperature of reaction changes according to the kind of employed benzazolyl compounds or reaction raw materials etc., but selects in 0～100 ℃ scope usually, is preferably 20～50 ℃.
As reaction conditions, for example preferably under reduced pressure reflux.
As the reaction times, according to used matrix and difference, but be generally 5 minutes～24 hours, be preferably 1 hour to 3 hours.But if react till the abundant generation in reaction system up to salt, condensation reaction thereafter sometimes can not be carried out smoothly.
In addition, can use phase-transfer catalyst in the reaction.As the phase-transfer catalyst in this stage, can enumerate 4 grades of ammonium salts such as tetrabutylammonium chloride etc. or 18-hat 6 etc.
As making gained an alkali metal salt and 1-(N, N-dimethylamino alkylsulfonyl)-3-chlorosulfonyl-1,2; the solvent of 4-triazole step of reaction can be enumerated for example ether, propyl ether; diglyme; glycol dimethyl ether, diglyme, diethyl carbitol; tetrahydrofuran (THF); tetrahydropyrans, 1, ring-type or non-annularity ether solvents such as 4-diox.
Reaction is added drop-wise to this reaction solution and contains 1-(N, N-dimethylamino alkylsulfonyl)-3-chlorosulfonyl-1,2 preferably after an alkali metal salt generates in system, and the system of 4-triazole compounds makes its reaction in the time of interior.
As temperature of reaction, be preferably 0～100 ℃, preferred especially 0～20 ℃.
In addition, in the formula (2), for R
2Be the compound of halogeno-group, can pass through R
2After the benzazolyl compounds halogenation for hydrogen atom, with above-mentioned itself and 1-(N, N-dimethylamino the alkylsulfonyl)-3-chlorosulfonyl-1,2 of similarly making, 4-triazole reaction and preparing.
Solvent as the halogenation stage, can enumerate methylene dichloride, chloroform and 1, the halogenated hydrocarbon of 2-ethylene dichloride etc., ether, ethers such as isopropyl ether ， diox and tetrahydrofuran (THF), acetone, ketone such as methylethylketone and mibk, nitrile such as acetonitrile and propionitrile, N, dinethylformamide and N, amidess such as N-N,N-DIMETHYLACETAMIDE, the solvent that not influenced by halogenating agent can be used, but also the benzene that influenced by halogenating agent can be used, toluene, aromatic hydrocarbon solvents such as dimethylbenzene, for example, from the viewpoint of industrial operation, toluene is preferred solvent.
As halogenating agent, can enumerate chlorine, bromine, iodine, N-chloro-succinimide, N-bromine succinimide, N-iodine succinimide, sodium hypobromite etc.
Halogenation preferably makes the alkali metal compound coexistence and is carrying out under alkaline condition.As the alkali metal compound in this stage, preference such as sodium hydroxide.
The amount of employed halogenating agent for example, with respect to 1 mole of benzazolyl compounds, is preferably about 1 mole or its.
The amount of sodium hydroxide for example, with respect to 1 mole of benzazolyl compounds, is preferably about 1.1 moles or its.
Use under the situation of sodium hypobromite as halogenating agent, sodium hydroxide and bromine are coexisted in reaction system, in reaction system, react again behind the generation sodium hypobromite in advance.
Temperature of reaction is according to the kind of employed benzazolyl compounds and reaction raw materials etc. and different, but selects in 0～100 ℃ scope usually, is preferably 0～10 ℃.
In the reaction times, according to employed matrix and difference is generally 5 minutes to 24 hours, be preferably 1 hour to 3 hours.
The halogenide of gained can be direct with solution, or as required with after the washings such as aqueous solution of sodium bisulfite, supply in the formation reaction of next step an alkali metal salt.
Below, enumerate embodiment and illustrate in greater detail the present invention, but the present invention is not limited to this.
Embodiment 1
In with nitrogen metathetical reaction flask, add 5.00g (0.0254 mole) 4-fluoro-2-nitrophenyl acetone, 35g toluene, (2.10g 0.0254 mole) sodium acetate, 10.4g (0.101 mole) diacetyl oxide and 0.25g 5% are stated from the palladium [NE ケ system キ ヤ Star ト society's system (50% moisture product)] of gac, with after the hydrogen displacement, hydrogen supply and reacting 6 hours under 50 ℃ of normal pressures.After the disappearance of liquid-phase chromatographic analysis affirmation 4-fluoro-2-nitrophenyl acetone,, use the diatomite filtration catalyzer with the nitrogen displacement.Reaction solution is used 35g water successively, 10g water, the aqueous sodium hydroxide solution of 14g 5%, 10g water and 10g water washing behind the separatory, obtain the toluene solution of 6-fluoro-2 methyl indole.Behind chromatogram quantitative analysis of the liquid phase, confirm to have generated 3.60g (yield 95.0%) 6-fluoro-2 methyl indole.
Embodiment 2
In with nitrogen metathetical reaction flask, add 500g (2.54 moles) 4-fluoro-2-nitrophenyl acetone, 3500g toluene, 208g (2.54 moles) sodium acetate, 1036g (10.1 moles) diacetyl oxide and 25g5% are stated from the palladium [NE ケ system キ ヤ Star ト society's system (50% moisture product)] of gac, with after the hydrogen displacement, hydrogen supply and reacting 30 hours under 50 ℃ of normal pressures.After the disappearance of liquid-phase chromatographic analysis affirmation 4-fluoro-2-nitrophenyl acetone, with the nitrogen displacement, drip 2000g water, the aqueous sodium hydroxide solution of 2705g 30% stirred after 1 hour, used the diatomite filtration catalyzer, then, separated water layer.Use 1000g water successively, the aqueous sulfuric acid of 1000g 0.5%, 1000g water and 1000g water washing, carry out separatory after, obtain the toluene solution of 6-fluoro-2 methyl indole.Behind chromatogram quantitative analysis of the liquid phase, confirm to have generated the 6-fluoro-2 methyl indole of 353g (yield 93.4%).
Embodiment 3
In with nitrogen metathetical reaction flask, add 0.50g (0.00254 mole) 4-fluoro-2-nitrophenyl acetone, 3.5g toluene, (0.21g 0.00254 mole) sodium acetate, 1.32g (0.0102 mole) propionic anhydride and 0.025g 5% are stated from the palladium [NE ケ system キ ヤ Star ト society's system (50% moisture product)] of gac, with after the hydrogen displacement, hydrogen supply and reacting 5 hours under 50 ℃ of normal pressures.After the disappearance of liquid-phase chromatographic analysis affirmation 4-fluoro-2-nitrophenyl acetone,, use the diatomite filtration catalyzer with the nitrogen displacement.With reaction solution with chromatogram quantitative analysis of the liquid phase after, confirm to have generated 0.36g (yield 95%) 6-fluoro-2 methyl indole.
Embodiment 4
In with nitrogen metathetical reaction flask, add 0.50g (0.00254 mole) 4-fluoro-2-nitrophenyl acetone, 3.5g toluene, (0.21g 0.00254 mole) sodium acetate, 1.61g (0.0102 mole) butyryl oxide and 0.025g 5% are stated from the palladium [NE ケ system キ ヤ Star ト society's system (50% moisture product)] of gac, with after the hydrogen displacement, hydrogen supply and reacting 5 hours under 50 ℃ of normal pressures.After the disappearance of liquid-phase chromatographic analysis affirmation 4-fluoro-2-nitrophenyl acetone,, use the diatomite filtration catalyzer with the nitrogen displacement.With reaction solution with chromatogram quantitative analysis of the liquid phase after, confirm to have generated 0.37g (yield 97%) 6-fluoro-2 methyl indole.
Embodiment 5
In with nitrogen metathetical reaction flask, add 0.50g (0.00254 mole) 4-fluoro-2-nitrophenyl acetone, 3.5g toluene, (0.18g 0.00127 mole) salt of wormwood, 1.29g (0.0127 mole) diacetyl oxide and 0.025g 5% are stated from the palladium [NE ケ system キ ヤ Star ト society's system (50% moisture product)] of gac, with after the hydrogen displacement, hydrogen supply and reacting 7.5 hours under 50 ℃ of normal pressures.After the disappearance of liquid-phase chromatographic analysis affirmation 4-fluoro-2-nitrophenyl acetone,, use the diatomite filtration catalyzer with the nitrogen displacement.With reaction solution with chromatogram quantitative analysis of the liquid phase after, confirm to have generated 0.36g (yield 95%) 6-fluoro-2 methyl indole.
Embodiment 6
In with nitrogen metathetical reaction flask, add 0.50g (0.00254 mole) 4-fluoro-2-nitrophenyl acetone, 3.5g toluene, (0.21g 0.00254 mole) sodium bicarbonate, 1.29g (0.0127 mole) diacetyl oxide and 0.025g 5% are stated from the palladium [NE ケ system キ ヤ Star ト society's system (50% moisture product)] of gac, with after the hydrogen displacement, hydrogen supply and reacting 7.5 hours under 50 ℃ of normal pressures.After the disappearance of liquid-phase chromatographic analysis affirmation 4-fluoro-2-nitrophenyl acetone,, use the diatomite filtration catalyzer with the nitrogen displacement.With reaction solution with chromatogram quantitative analysis of the liquid phase after, confirm to have generated 0.37g (yield 97%) 6-fluoro-2 methyl indole.
Embodiment 7
In with nitrogen metathetical reaction flask, add 0.50g (0.00254 mole) 4-fluoro-2-nitrophenyl acetone, 3.5g toluene, (0.13g 0.00127 mole) yellow soda ash, 1.29g (0.0127 mole) diacetyl oxide and 0.025g 5% are stated from the palladium [NE ケ system キ ヤ Star ト society's system (50% moisture product)] of gac, with after the hydrogen displacement, hydrogen supply and reacting 8 hours under 50 ℃ of normal pressures.After the disappearance of liquid-phase chromatographic analysis affirmation 4-fluoro-2-nitrophenyl acetone,, use the diatomite filtration catalyzer with the nitrogen displacement.With reaction solution with chromatogram quantitative analysis of the liquid phase after, confirm to have generated 0.35g (yield 92%) 6-fluoro-2 methyl indole.
Embodiment 8
In with nitrogen metathetical reaction flask, add 0.50g (0.00254 mole) 4-fluoro-2-nitrophenyl acetone, 3.5g toluene, (0.10g 0.00254 mole) yellow soda ash, 1.29g (0.0127 mole) diacetyl oxide and 0.025g 5% are stated from the palladium [NE ケ system キ ヤ Star ト society's system (50% moisture product)] of gac, with after the hydrogen displacement, hydrogen supply and reacting 9 hours under 50 ℃ of normal pressures.After the disappearance of liquid-phase chromatographic analysis affirmation 4-fluoro-2-nitrophenyl acetone,, use the diatomite filtration catalyzer with the nitrogen displacement.With reaction solution with chromatogram quantitative analysis of the liquid phase after, confirm to have generated 0.36g (yield 95%) 6-fluoro-2 methyl indole.
Comparative example
In with nitrogen metathetical reaction flask, add 0.30g (0.00152 mole) 4-fluoro-2-nitrophenyl acetone, 2.1g ethanol and 0.030g 5% is stated from the palladium [NE ケ system キ ヤ Star ト society's system (50% moisture product)] of gac, hydrogen supply and reacting 90 hours under 20 ℃ of normal pressures.After the disappearance of liquid-phase chromatographic analysis affirmation 4-fluoro-2-nitrophenyl acetone,, use the diatomite filtration catalyzer with the nitrogen displacement.With reaction solution with chromatogram quantitative analysis of the liquid phase after, confirm to have generated 0.16g (yield 72%) 6-fluoro-2 methyl indole.
Embodiment 9
The preparation of 3-(4-fluoro-2-nitrophenyl)-4-hydroxyl-3-amylene-2-ketone
At 5.00g 2, the 5-difluoro nitrobenzene in the mixing solutions of 50mL dimethyl sulfoxide (DMSO), adds the 3.45g methyl ethyl diketone, adds 9.09g salt of wormwood then.Under the room temperature, stir after 43 hours, in reaction mixture, add 150mL toluene and stirring, and it is added in the 150mL water.The separation and Extraction toluene layer carries out 2 times at aqueous phase adding 100mL toluene and with extracting operation then.The toluene phase that merges gained is after 150mL water washing 3 times, with the water washing of 100mL saturated common salt, anhydrous sodium sulfate drying.After the filter operation, except that desolvating and the mixed solvent of gained crude product with 15mL hexane and 2mL ether being washed, obtain 4.81g (yield 64%) 3-(4-fluoro-2-nitrophenyl)-4-hydroxyl-3-amylene-2-ketone after the vacuum-drying by distillation.
1H-NMR(CDCl
3)：1.86ppm(s，6H，CH
3)，7.3～7.8ppm(m，3H，ArH)，16.55ppm(s，1H，OH)
Fusing point: 98-100 ℃
Embodiment 10
The preparation of 3-(4-fluoro-2-nitrophenyl)-4-hydroxyl-3-amylene-2-ketone
With the 7.65g potassium carbonate powder, 4.00g 2, and 5-difluoro nitrobenzene and 20mLN after the mixing suspension of dinethylformamide is heated to 40 ℃, add the 2.90g methyl ethyl diketone.Reaction soln is heated to 80 ℃, under nitrogen atmosphere, stirs a night.After the cooling, in reaction mixture, add 20mL toluene and stirring, it is added in 50mL cold water (10 ℃).Separation and Extraction toluene phase adds 30mL toluene at aqueous phase then and also this extracting operation is carried out 3 times.The toluene phase that merges gained is after 50mL water washing 3 times, by silica gel (10.0g) (using the 40mL toluene wash).Distillation removes the mixed solvent washing of desolvating and the gained crude product being used 30mL hexane and 2mL ether, after filtering (filtrate hexane wash), by vacuum-drying, obtain 4.07g (yield 68%) 3-(4-fluoro-2-nitrophenyl)-4-hydroxyl-3-amylene-2-ketone.
Embodiment 11
The preparation of 2-(4-fluoro-2-nitrophenyl)-3-hydroxyl-2-butylene acid methyl esters [2-(4-fluoro-2-nitrophenyl)-3-ketobutyric acid methyl esters]
With the 19.0g potassium carbonate powder, 10.0g 2, and 5-difluoro nitrobenzene and 50mLN after the mixing suspension of dinethylformamide is heated to 50 ℃, add the 8.39g methyl acetoacetate.Then, under nitrogen atmosphere, stir 19 hours postcooling to 22 ℃ at 49-51 ℃.In reaction mixture, add 150mL toluene and stirring, it is added in the cold water of 10 ℃ of 300mL.Separation and Extraction toluene phase adds 150mL toluene at aqueous phase then and also this extracting operation is carried out 2 times.The toluene phase that merges gained after the water washing of 150mL 3 times, adds 150mL 5% aqueous sodium hydroxide solution water is carried out extracting operation (2 times).Making pH at gained aqueous phase adding 35mL 35% hydrochloric acid is 3, carries out extracting operation 2 times with 150mL toluene.After gained toluene solution usefulness 200mL water washing 3 times, by the liquid phase separation filter paper filtering, with 20mL toluene wash filter paper, distillation removes and desolvates, by drying, obtain 12.1g (yield 76%) 2-(4-fluoro-2-nitrophenyl)-3-hydroxyl-2-butylene acid methyl esters [2-(4-fluoro-2 nitrophenyls)-3-ketobutyric acid methyl esters] (CDCl
3Middle ketoboidies: enol body=1: 9).
1H-NMR (CDCl
3): 1.83ppm (s, 3H, enol body C=C (OH) CH
3), 2.38ppm (s, ketoboidies COCH
3), 3.64ppm (s, 3H, enol body CO
2CH
3), 3.79ppm (s, 3H, ketoboidies CO
2CH
3), 5.35ppm (s, 1H, ketoboidies CH
3COCHCO
2CH
3), 7.2-8.0ppm (m, 3H, ArH), 12.95ppm (s, 1H, enol body OH),
Fusing point: 72-75 ℃
Embodiment 12
The preparation of 2-(4-fluoro-2-nitrophenyl)-3-hydroxyl-2-butylene acetoacetic ester [2-(4-fluoro-2-nitrophenyl)-ethyl 3-oxobutanoate]
At 5.00g 2,5-difluoro nitrobenzene and 30mL N in the mixing solutions of dinethylformamide, add the 4.49g methyl aceto acetate, add 9.09g salt of wormwood then under the room temperature.Under the room temperature, stir after 67 hours, in reaction mixture, add 100mL toluene and stirring, it is added in the 200mL frozen water.Separation and Extraction toluene phase adds 100mL toluene at aqueous phase then and also this extracting operation is carried out 2 times.The toluene phase that merges gained, the potassium hydroxide aqueous solution that adds 100mL 1N carries out extracting operation 2 times to water.Making pH at gained aqueous phase adding 25mL 35% hydrochloric acid is 2, carries out extracting operation 2 times with 150mL toluene.After gained toluene used 150mL water washing 3 times mutually, with the water washing of 100mL saturated common salt, anhydrous sodium sulfate drying.After the filter operation,, obtain 7.10g (yield 84%) 2-(4-fluoro-2-nitrophenyl)-3-hydroxyl-2-butylene acetoacetic ester [2-(4-fluoro-2 nitrophenyls)-ethyl 3-oxobutanoate] (CDCl by reducing pressure down distillation except that desolvating
3Middle ketoboidies: enol body=1: 9).
1H-NMR (CDCl
3): 1.13ppm (t, J=7.2Hz, 3H, enol body CO
2CH
2CH
3), 0.9-1.5ppm (ketoboidies CO
2CH
2CH
3), 1.87ppm (s, 3H, enol body COCH
3), 2.42ppm (s, ketoboidies COCH
3), 3.8-4.6ppm (m, 2H, CO
2CH
2CH
3), 5.33ppm (s, 1H, ketoboidies CH
3COCHCO
2Et), and 7.2-8.1ppm (m, 3H, ArH), 13.05ppm (s, 1H, enol body OH),
Fusing point: 48-49 ℃
Embodiment 13
The preparation of 1-(4-fluoro-2-nitrophenyl) acetone (beginning preparation) by 3-(4-fluoro-2-nitrophenyl)-4-hydroxyl-3-amylene-2-ketone
In 1.03g 3-(4-fluoro-2-nitrophenyl)-4-hydroxyl-3-amylene-2-ketone, add 10g acetate under the room temperature, add 8.0g 50% aqueous sulfuric acid then.With mixture slowly heating while stirring, finally under reflux temperature, reacted 3 hours.After reaction mixture was cooled to room temperature, portion water and acetate were removed in distillation, dropped into 20mL toluene, dropped into 40mL water then.Separation of methylbenzene mutually after, with water with 30mL toluene extraction 2 times.Merge gained toluene phase,, after the 20mL saturated common salt water washing 1 time, use anhydrous sodium sulfate drying with 30mL water washing 3 times.After the filter operation, except that desolvating, obtain 0.76g (yield 89%) 1-(4-fluoro-2 nitrophenyls) acetone by distillation.
1H-NMR(CDCl
3)：2.32ppm(s，3H，CH
2C(O)CH
3)，4.11ppm(s，CH
2C(O)CH
3)，7.2-7.9ppm(m，3H，ArH)
Fusing point: 49-50 ℃
Embodiment 14
The preparation of 1-(4-fluoro-2-nitrophenyl) acetone (beginning preparation) by 2-(4-fluoro-2-nitrophenyl)-3-hydroxyl-2-butylene acid methyl esters [2-(4-fluoro-2-nitrophenyl)-3-ketobutyric acid methyl esters]
In 18.1g 2-(4-fluoro-2-nitrophenyl)-3-hydroxyl-3-M Cr [2-(4-fluoro-2-nitrophenyl)-3-ketobutyric acid methyl esters], add 110g acetate under the room temperature, add 26.0g 50% aqueous sulfuric acid then.With mixture slowly heating while stirring, finally under reflux temperature, make its reaction 4.7 hours.Portion water and acetate are removed in distillation from reaction mixture, slowly drop into 100mL water behind the adding 100mL toluene.Separation of methylbenzene mutually after, add 100mL toluene, separation of methylbenzene phase again at aqueous phase.Gained toluene is washed 4 times in 100mL water, use diatomite filtration.Underpressure distillation removes and desolvates, and after adding 100mL normal hexane becomes slurries, filters, and gained crystallization drying under reduced pressure is obtained 12.8g (yield 92%) 1-(4-fluoro-2 nitrophenyls) acetone.
Embodiment 15
The preparation of 1-(4-fluoro-2-nitrophenyl) acetone (beginning preparation) by 2-(4-fluoro-2-nitrophenyl)-3-hydroxyl-2-butylene acetoacetic ester [2-(4-fluoro-2-nitrophenyl)-ethyl 3-oxobutanoate]
In 4.00g 2-(4-fluoro-2-nitrophenyl)-3-hydroxyl-2-butylene acetoacetic ester [2-(4-fluoro-2-nitrophenyl)-ethyl 3-oxobutanoate], add 24g acetate under the room temperature, add 6.0g 50% aqueous sulfuric acid then.With mixture slowly heating while stirring, finally under reflux temperature, reacted 4.6 hours.Portion water and acetate are removed in distillation from reaction mixture, slowly drop into 40mL water behind the adding 40mL toluene.Separation of methylbenzene mutually after, water is with 40mL toluene extraction 2 times.Gained toluene is used the 40mL water washing 3 times mutually, after 40mL saturated common salt water washing 1 time, pass through silica gel.Underpressure distillation removes and desolvates, and obtains 2.40g (yield 82%) 1-(4-fluoro-2 nitrophenyls) acetone thus.
Embodiment 16
The preparation [successive method] of 1-(4-fluoro-2-nitrophenyl) acetone
With 10.0g 2, the 5-difluoro nitrobenzene, 19.0g potassium carbonate powder and 52mL N after the mixing solutions of dinethylformamide is heated to 53 ℃, continue to add the 8.4g methyl acetoacetate, under nitrogen atmosphere, stir 15 hours at 48-53 ℃.After the cooling, in reaction mixture, add 150mL toluene and stirring, it is added in 300mL cold water (6 ℃).The separation of methylbenzene phase extracts water 2 times with 150mL toluene then.Merge gained toluene phase, after the water washing of 150mL 3 times, by liquid phase separation filter paper filtering (with 20mL toluene wash filter paper), distillation adds 40mL toluene after removing and desolvating, and obtains the toluene solution of the 2-nitrophenyl acetonide shown in the 56g embodiment 11.
This solution is supplied with following decarbonate operation continuously.Add 20mL acetate, 20mL 50% aqueous sulfuric acid, gently heating up also, reflux was cooled to 24 ℃ after 45 hours.Further add 20mL acetate and 50% aqueous sulfuric acid respectively and under reflux temperature the reaction 25 hours.Cooling back (22 ℃) adds 150mL toluene, and 200mL water stirs.Separation of methylbenzene mutually after, water is with 150mL toluene extraction 2 times.Merge gained toluene phase, add 200mL 5% aqueous sodium hydroxide solution, after the stirring, carry out diatomite filtration.The separation of methylbenzene phase, after washing with water, by the liquid phase separation filter paper filtering, distillation removes and desolvates.With the solid of separating out with the dissolving of 33mL toluene after, drop into hexane (300mL), stir a night after, with the solid filtering that generates.After filtrate concentrated, use 1mL toluene, the 30mL hexane carries out purifying, with the solid merging of front, carry out vacuum-drying after, obtain 9.8g (yield 79% (from 2, the 5-difluoro nitrobenzene begins 2 stage successive yields)) 1-(4-fluoro-2-nitrophenyl) acetone.
Embodiment 17
The preparation of 3-bromo-6-fluoro-2 methyl indole
Under nitrogen atmosphere, in 0.58g (3.9mmol) 6-fluoro-2 methyl indole, add 8.7g toluene and 0.17g (4.25mmol) sodium hydroxide, be cooled to 5 ℃.In this solution, drip 0.6g (3.9mmol) bromine with 1 hour, further stirred 1 hour.Behind HPLC affirmation generation object, the aqueous solution of sodium bisulfite of solution with 8.7g 0.2mol/L to be washed 1 time, 8.7g pure water washing 1 time imports subsequent processing then.Quantitative yield 96.6%.
1HNMR(CDCl
3)
2.4(s，3H)，6.90-7.00(m，2H)，7.45-7.51(m，1H)，7.85-8.05(br，s，1H)
Embodiment 18
1-(N, N-dimethylamino alkylsulfonyl)-3-(3-bromo-6-fluoro-2 methyl indole-1-yl) alkylsulfonyl-1,2, the preparation of 4-triazole
Under nitrogen atmosphere, in the toluene solution of the 3-bromo-6-of embodiment 17 gained fluoro-2 methyl indole, add 0.17g (4.25mmol) sodium hydroxide, 0.11g (0.39mmol) tetrabutylammonium chloride and 5.8g diglyme, at 30 ℃, the reduced-pressure backflow of 30mmHg stirred 2 hours down, had synthesized the sodium salt of 3-bromo-6-fluoro-2 methyl indole.With 15 minutes this drips of solution is added to other 1.04g (3.9mmol) 1-(N for preparing under 5 ℃ nitrogen atmosphere; N-dimethylamino alkylsulfonyl)-3-chlorosulfonyl-1; 2; restir is 1 hour in the 5.8g diglyme solution of 4-triazole; confirm to have generated object 1-(N by HPLC; N-dimethylamino alkylsulfonyl)-and 3-(3-bromo-6-fluoro-2 methyl indole-1-yl) alkylsulfonyl-1,2, the 4-triazole.Quantitative yield 94.0%.
Embodiment 19
The preparation of 3-bromo-6-fluoro-2 methyl indole
Under the nitrogen atmosphere, in 1g (6.7mmol) 6-fluoro-2 methyl indole, add 7g toluene and 0.3g (7.5mmol) sodium hydroxide, be cooled to 5 ℃.With in this solution, dripping 1.1g (6.7mmol) bromine, restir 1 hour in 1 hour.After confirming to have generated object by HPLC, solution with 8g 0.2mol/L sodium sulfite aqueous solution washing 1 time, with 8g pure water washing 1 time, is imported subsequent processing.Quantitative yield 95.5%.
Embodiment 20
1-(N, N-dimethylamino alkylsulfonyl)-3-(3-bromo-6-fluoro-2 methyl indole-1-yl) alkylsulfonyl-1,2, the preparation of 4-triazole
Under nitrogen atmosphere, the toluene solution of the 3-bromo-6-fluoro-2 methyl indole that embodiment 19 is obtained is cooled to 5 ℃, is added drop-wise to the 11.8g diglyme solution of 0.8g (7.2mmol) potassium tert.-butoxide, with the sylvite of 30 minutes synthetic 3-bromo-6-fluoro-2 methyl indoles.With 15 minutes this drips of solution is added to other 1.8g (6.7mmol) 1-(N for preparing under 5 ℃ of nitrogen atmosphere; N-dimethylamino alkylsulfonyl)-3-chlorosulfonyl-1; 2; the 10.7g diglyme solution of 4-triazole; behind the restir 30 minutes, confirm to have generated object 1-(N, N-dimethylamino alkylsulfonyl)-3-(3-bromo-6-fluoro-2 methyl indole-1-yl) alkylsulfonyl-1 by HPLC; 2, the 4-triazole.Quantitative yield 95.2%.
Industrial utilizability
If according to the present invention, can easily obtain with new 2-nitrobenzophenone acetone class intermediate Useful intermediate 1-(the 4-fluoro-2-nitro in indoles preparation etc. that prior art is difficult to prepare Phenyl) acetone can prepare indoles chemical combination with high yield from 2-nitrobenzyl carbonyls Thing, and then can from benzazolyl compounds, obtain as the useful sulfamoyl three of bactericide with high yield Azole compounds.
Claims (16)
1, by making the represented benzazolyl compounds of formula (2) make an alkali metal salt,
In the formula, R
1The expression methyl, R
2The expression hydrogen atom, R
3The expression halogen atom, n represents 0 to 4 integer,
Then, make itself and 1-(N, N-dimethylamino alkylsulfonyl)-3-chlorosulfonyl-1,2, the reaction of 4-triazole, the method for the sulfamyl triazole compounds shown in the preparation formula (3),
In the formula, R
1, R
2, R
3Represent as hereinbefore definition with n.
2, preparation method as claimed in claim 1 wherein uses and passes through at the 2-nitrobenzyl carbonyl compound that formula (1) is represented
In the formula, R
1The expression methyl, R
2The expression hydrogen atom,, R
3The expression halogen atom, n represents 0 to 4 integer,
In the presence of reducing catalyst, supply with the body reductive in the stage, acidylate the coexistence of agent and alkali and the represented benzazolyl compounds of above-mentioned formula (2) of preparation with hydrogen.
3, preparation method as claimed in claim 2, wherein above-mentioned acylating agent is an organic acid anhydride.
4, preparation method as claimed in claim 2, wherein acylating agent is a diacetyl oxide.
5, preparation method as claimed in claim 2, wherein above-mentioned alkali is an alkali metal salt or alkali metal hydroxide.
6, preparation method as claimed in claim 2, wherein above-mentioned alkali is alkali-metal organic acid salt, carbonate, supercarbonate or oxyhydroxide.
7, preparation method as claimed in claim 2, wherein above-mentioned reducing catalyst is to support noble metal catalyst.
8, preparation method as claimed in claim 2, wherein above-mentioned reductive agent is the palladium that is stated from gac.
9, preparation method as claimed in claim 2, it is hydrogen that wherein above-mentioned hydrogen is supplied with body.
10, R in the above-mentioned formula (3)
2Expression chlorine atom, the preparation method of the sulfamyl triazole compounds shown in bromine atoms or the iodine atom, this method are by with R in the above-mentioned formula (2)
2The represented benzazolyl compounds halogenation of expression hydrogen atom, and after making it become an alkali metal salt, again with 1-(N, N-dimethylamino alkylsulfonyl)-3-chlorosulfonyl-1,2, the reaction of 4-triazole.
11, preparation method as claimed in claim 10, wherein above-mentioned benzazolyl compounds is 2-methyl-6-fluoro indole.
12, preparation method as claimed in claim 11, wherein above-mentioned halogenation is a bromination.
13, preparation method as claimed in claim 12, wherein above-mentioned bromination is undertaken by sodium hypobromite.
14, preparation method as claimed in claim 12, wherein above-mentioned bromination are by in the presence of sodium hydroxide, carry out with bromine.
15, preparation method as claimed in claim 11 wherein uses 3-(4-fluoro-2-nitrophenyl) acetone is being supplied with the body reductive in the stage with hydrogen in the presence of reducing catalyst, acidylates the coexistence of agent and alkali and the 2-methyl-6-fluoro indole of preparation.
16, preparation method as claimed in claim 15 wherein uses by the 2-nitrophenyl acetonide that formula (I) is represented
In the formula, R represents methyl, methoxy or ethoxy,
In the presence of acid or alkali, handle and 3-(the 4-fluoro-2-nitrophenyl) acetone of preparation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP98813/2002 | 2002-04-01 | ||
| JP2002098813 | 2002-04-01 | ||
| JP188929/2002 | 2002-06-28 |
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| CN 03807772 Division CN1286832C (en) | 2002-04-01 | 2003-03-28 | Processes for producing indole compound |
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| CN1896075A CN1896075A (en) | 2007-01-17 |
| CN100577659C true CN100577659C (en) | 2010-01-06 |
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| CN200610106266A Expired - Lifetime CN100577659C (en) | 2002-04-01 | 2003-03-28 | Processes for producing indole compound |
| CN2008101728773A Expired - Lifetime CN101468964B (en) | 2002-04-01 | 2003-03-28 | Processes for producing indole compound |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000302781A (en) * | 1999-04-22 | 2000-10-31 | Nissan Chem Ind Ltd | Indole compound and agricultural/horticultural fungicide |
| JP2001192381A (en) * | 2000-01-11 | 2001-07-17 | Nissan Chem Ind Ltd | Indole compound and germicide for agriculture and horticulture |
-
2003
- 2003-03-28 CN CN200610106266A patent/CN100577659C/en not_active Expired - Lifetime
- 2003-03-28 CN CN2008101728773A patent/CN101468964B/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000302781A (en) * | 1999-04-22 | 2000-10-31 | Nissan Chem Ind Ltd | Indole compound and agricultural/horticultural fungicide |
| JP2001192381A (en) * | 2000-01-11 | 2001-07-17 | Nissan Chem Ind Ltd | Indole compound and germicide for agriculture and horticulture |
Non-Patent Citations (2)
| Title |
|---|
| The chemistry of Indole. Masanori Somei et al.CHEM. PHARM. BULL,Vol.29 No.3. 1981 |
| The chemistry of Indole. Masanori Somei et al.CHEM. PHARM. BULL,Vol.29 No.3. 1981 * |
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|---|---|
| CN101468964B (en) | 2011-05-11 |
| CN101468964A (en) | 2009-07-01 |
| CN1896075A (en) | 2007-01-17 |
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