CN1053921A - Therapeutical agent - Google Patents
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- CN1053921A CN1053921A CN 90101419 CN90101419A CN1053921A CN 1053921 A CN1053921 A CN 1053921A CN 90101419 CN90101419 CN 90101419 CN 90101419 A CN90101419 A CN 90101419A CN 1053921 A CN1053921 A CN 1053921A
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Abstract
The present invention relates to the method for preparation I compound
Description
The present invention relates to prepare the also method of (4,3-C) pyrazoles of new (1) chromene, and relate to their therapeutic activities as immunomodulator.
In United States Patent (USP) 4268516, disclose some and can suppress immunoreactive compound in the mammalian body.These compounds are groups 1,2,3, and 4-tetrahydrochysene (1) benzo thiapyran is (4,3-C) pyrazoles-3-ketone and 2 also, and 3-dihydro (1) benzo thiapyran is (4,3-C) pyrazoles-3-ketone compound also, is respectively structure A and B.
Wherein n is an integer 0 to 2; R is a phenyl; By the mono-substituted phenyl of chlorine, bromine, fluorine, methyl, methoxyl group, nitro or trifluoromethyl; Or by the disubstituted phenyl of chlorine; X is hydrogen or chlorine.
The present invention relates to the compound of formula I:
R wherein
1Expression hydrogen or and R
2Represent a key together; R
2With R
1And R
3In one represent a key together; R
3With R
2And R
4In one represent a key together; R
4Expression hydrogen or and R
3Represent a key together; R
5Expression hydrogen or methyl; R
6Expression hydrogen, halogen, a C
2～6Alkyloyl, a C
2～6Alkoxy carbonyl, a C
1～6Alkylthio, a C
1～6The alkyl sulfinyl, a C
1～6Alkyl sulphonyl, formamyl, carboxyl, perhaps R
5And R
6Represent a cyclopropyl with the carbon atom that they connected; R
7Expression hydrogen, halogen, trifluoromethyl, methoxyl group, a C
1～6Alkyl, a C
1～6Alkylthio or a C
1～6The alkyl sulfinyl; R
8Expression hydrogen, halogen or trifluoromethyl; R
9And R
10Can be identical or different, represent halogen respectively; Perhaps R
9Expression hydrogen, R
10Expression hydrogen, halogen, trifluoromethyl, hydroxyl, nitro, a C
2～6Alkanoyloxy, a C
1～6Alkyl or C
1～6Alkoxyl group.Have now found that these compounds have immunoregulatory activity.
In " Tetrahedron Letters " (1987, Vol.28, No.43 PP5165～5168), a formula I compound has been described, R wherein
1And R
2Represent a key, R
3And R
4Represent a key, R
5, R
6, R
7, R
8, R
9And R
10Each represents hydrogen.But this piece document is disclosed is the non-pharmaceutical activity of this compound.
The inventive method provides new formula I compound, wherein R
1Expression hydrogen or and R
2Represent a key together; R
2With R
1And R
3In one represent a key together; R
3With R
2And R
4In one represent a key together; R
4Expression hydrogen or and R
3Represent a key together; R
5Expression hydrogen or methyl; R
6Expression hydrogen, halogen, a C
2～6Alkyloyl, a C
2～6Alkoxy carbonyl, a C
1～6Alkylthio, a C
1～6The alkyl sulfinyl, a C
1～6Alkyl sulphonyl, formamyl, carboxyl or R
5And R
6Represent a cyclopropyl with the carbon atom that they connected; R
7Expression hydrogen, halogen, trifluoromethyl, methoxyl group, a C
1～6Alkyl, a C
1～6Alkylthio or a C
1～6The alkyl sulfinyl; R
8Expression hydrogen, halogen or trifluoromethyl; R
9And R
10Can be identical or different, represent halogen separately; Or R
9Expression hydrogen, R
10Expression hydrogen, halogen, trifluoromethyl, hydroxyl, nitro, a C
2～6Alkanoyloxy, a C
1～6Alkyl or a C
1～6Alkoxyl group is if work as R
1And R
2Represent a key, R
3And R
4Represent a key, R
6, R
7, R
8, R
9And R
10When representing hydrogen respectively, R
5Not hydrogen.
Will be appreciated that the group that contains 3 or more a plurality of carbon atom chains can be straight chain or side chain, for example propyl group is just comprising-propyl group and sec.-propyl, butyl just comprising-butyl, the second month in a season-butyl isobutyl-and tert-butyl.Term " halogen " comprises fluorine, chlorine or bromine.
One group of formula I compound more preferably, R wherein
1And R
2Represent a key, R
3And R
4Represent a key, represent by the formula II:
R wherein
5, R
6, R
7, R
8, R
9And R
10Definition as above.
Further preferred one group of formula I compound, R wherein
1Expression hydrogen, R
2And R
3Represent a key, R
4Expression hydrogen, represent by formula III or its tautomer:
R wherein
5, R
6, R
7, R
8, R
9And R
10Definition as above.
In the compound of formula I, work as R
5During the expression methyl, R
6Preferably represent a substituting group rather than hydrogen, for example a C
1～6Carbalkoxy.In preferred formula I compound, R
5Expression hydrogen or and R
6The carbon atom that is connected with them is represented a cyclopropyl together.R most preferably
5Expression hydrogen.
Preferred R
6Expression hydrogen, halogen, a C
2～4Alkyloyl (for example ethanoyl (acetyl), ethanoyl (ethanoyl) or propionyl), a C
2～6Carbalkoxy (for example methoxycarbonyl, ethoxycarbonyl, third oxygen carbonyl or the butoxy carbonyl), a C
1～4Alkylthio (for example methylthio group, ethylmercapto group or rosickyite base), a C
1～4Alkyl sulfinyl (for example methyl sulfinyl, ethylsulfinyl-1 base or propyl group sulfinyl), a C
1～4Alkyl sulphonyl (for example methyl sulphonyl, ethylsulfonyl or sulfonyl propyl base), formamyl, carboxyl or R
6With R
5The carbon atom that is connected with them is represented a cyclopropyl together.In further preferred one group of compound, R
6Expression hydrogen, a C
2～6Carbalkoxy, a C
1～4Alkylthio, a C
1～4The alkyl sulfinyl, a C
1～4Alkyl sulphonyl, formamyl, carboxyl or R
6With R
5The carbon atom that is connected with them is represented a cyclopropyl together, especially hydrogen or a C
2～6Carbalkoxy.Most preferred R
6Expression hydrogen, chlorine, bromine, ethanoyl, a C
2～4Carbalkoxy, methylthio group, ethylmercapto group, methyl sulfinyl, methyl sulphonyl, formamyl or carboxyl, or R
6With R
5The carbon atom that is connected with them is represented a cyclopropyl together.Particularly preferably be R wherein
6Expression hydrogen, methoxycarbonyl, ethoxycarbonyl, third oxygen carbonyl or methylthio group, especially hydrogen or the C
2～4Carbalkoxy, the compound of the third oxygen carbonyl (promptly just-third oxygen carbonyl and the different third oxygen carbonyl) for example.
Suitable R
7Expression hydrogen, halogen, trifluoromethyl, a C
1～6Alkyl, preferably a C
1～4Alkyl (for example methyl, ethyl or propyl group), a C
1～6Alkylthio (for example methylthio group or ethylmercapto group) or a C
1～6Alkyl sulfinyl (for example methyl sulfinyl or ethylsulfinyl-1 base).In preferred formula I compound, R
7Expression hydrogen, fluorine, chlorine, trifluoromethyl, a C
1～6Alkylthio or a C
1～6The alkyl sulfinyl.R more preferably
7Expression hydrogen, fluorine, chlorine, trifluoromethyl, a C
1～4Alkylthio or a C
1～4The alkyl sulfinyl.R most preferably
7Expression hydrogen, fluorine, chlorine, trifluoromethyl, methylthio group or methyl sulfinyl.Particularly preferred formula I compound is those R wherein
7The expression fluorine, chlorine, trifluoromethyl or methylthio group, satisfactory is fluorine, the compound of chlorine or trifluoromethyl, especially fluorine or chlorine.
In preferred formula I compound, R
8Expression hydrogen, fluorine or chlorine, even more preferably hydrogen or chlorine, most preferably hydrogen.
Substituent R
9And R
10Can be on any position of benzo ring, i.e. the position 6-of benzo ring, 7-, 8-, and/or on the 9-.Therefore at this specified each R
9And R
10Substituting group should be considered to specify in that each is locational.
In preferred formula I compound, R
9Expression hydrogen.
Suitable R
10Expression hydrogen, fluorine, trifluoromethyl, hydroxyl, nitro, a C
2～6C of alkanoyloxy (especially at the position of benzo ring 8-or 9-)
1～6Alkyl (especially at the position of benzo ring 8-or 9-) or a C
1～6Alkoxyl group (especially at the position of benzo ring 9-).According to regulation above, R
10Can be on the 6-position, especially for substituting group 6-fluorine.6-hydroxyl or 6-methoxyl group.Also can be with a substituting group on the 7-position, as 7-fluorine or 7-hydroxyl.In preferred formula I compound, R
10Be positioned on the position 8-or 9-of benzo ring expression hydrogen, fluorine, trifluoromethyl, hydroxyl, nitro, a C
2～6Alkanoyloxy (for example acetoxyl group, propionyloxy, butyryl acyloxy or penta acyloxy) or a C
1～4Alkyl (for example methyl, ethyl or propyl group).Preferred R
10Also represent C
1～6Alkoxyl group is positioned on the 9-position of benzo ring (for example methoxyl group, oxyethyl group, propoxy-or butoxy), even more preferably C
1～4Alkoxyl group.R more preferably
10Expression hydrogen, fluorine, hydroxyl or nitro, and C
2～6Alkanoyloxy is also suitable.Most preferred R
10Expression hydrogen, fluorine, hydroxyl, a C
2～4Alkanoyloxy, or R
10Represent a C
1～4Alkoxyl group is positioned on the 9-position of benzo ring.In particularly preferred compound, R
10Expression hydrogen, fluorine or a C
2～4Alkanoyloxy is positioned on the 8-position of benzo ring, or expression hydroxyl or a C
1～4Alkoxyl group is positioned on the 9-position of benzo ring, for example the 9-oxyethyl group.Especially preferred is wherein R
10The compound of expression hydrogen or 8-fluorine.
According to the present invention, one group of preferred compound is those wherein R
1Expression hydrogen or and R
2Represent a key together; R
2With R
1And R
3In one represent a key together; R
3With R
2And R
4In one represent a key together; R
4Expression hydrogen or and R
3Represent a key together; R
5Expression hydrogen; R
6Expression hydrogen, halogen, a C
2～6Alkyloyl, a C
2～6The alcoxyl carbon back, a C
1～6Alkylthio, a C
1～6The alkyl sulfinyl, a C
1～6Alkyl sulphonyl, formamyl, carboxyl, or R
6With R
5The carbon atom that is connected with them is represented a cyclopropyl together; R
7Expression hydrogen, fluorine, chlorine, trifluoromethyl, a C
1～6Alkylthio or a C
1～6The alkyl sulfinyl; R
8Expression hydrogen or chlorine; R
9And R
10Represent fluorine separately, or R
9Expression hydrogen, and R
10Be a substituting group, be positioned on the 8-or 9-position of benzo ring, expression hydrogen, fluorine, trifluoromethyl, hydroxyl, nitro, a C
2～6Alkanoyloxy, a C
1～6Alkyl, or R
10Represent a C
1～6Alkoxyl group is positioned at the compound on the 9-position of benzo ring.
More preferably one group of formula I compound is those wherein R
1, R
2, R
3, R
4, R
5, R
7, R
8And R
9As described in top final stage, R
6Expression hydrogen, a C
2～6The alcoxyl carbon back, a C
1～6Alkylthio, a C
1～6The alkyl sulfinyl, a C
1～6Alkyl sulphonyl, formamyl, carboxyl or R
6With R
5The carbon atom that is connected with them is represented a cyclopropyl together; R
10Be a substituting group, be positioned on the 8-or 9-position of benzo ring, expression hydrogen, fluorine, trifluoromethyl, hydroxyl, nitro, a C
1～6Alkyl, or R
10Represent a C
1～6Alkoxyl group is positioned at the compound on the 9-position of benzo ring.
In formula II compound, substituent R
5, R
6, R
7, R
8, R
9And R
10Can define as above.In one group of compound that preferably is expressed as the formula II, R
5Expression hydrogen, R
6Expression hydrogen, methoxycarbonyl, ethoxycarbonyl, oxygen carbonyl just-third, different third oxygen carbonyl or the methylthio group, R
7The expression fluorine, chlorine, bromine, trifluoromethyl or methylthio group, especially fluorine, chlorine or trifluoromethyl, R
8Expression hydrogen or chlorine, R
9Expression hydrogen, R
10Expression hydrogen, 9-hydroxyl, 9-oxyethyl group, 8-propionyloxy or 8-fluorine.
In formula III compound, substituent R
5, R
6, R
7, R
8, R
9And R
10Can define as above.At one group of compound that preferably is expressed as the formula III, R
5And R
6Represent hydrogen separately, R
7Expression hydrogen or chlorine, R
8Expression hydrogen or chlorine, R
9And R
10Represent hydrogen separately.
Formula I compound can contain one or more chiral centres and exist with different optically active forms.When formula I compound contained a chiral centre, compound existed with two enantiomeric forms, the present invention includes the mixture of two kinds of enantiomorphs and corresponding body.Enantiomorph can adopt method well known in the prior art to split, and for example by high performance liquid chromatography, on a kind of chiral support, for example splits having on the silica in conjunction with chiral ligand.Following formula I compound exists with the form of (R)-and (S)-enantiomorph, for example:
The 2-(4-chlorophenyl)-and Alpha-Methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-C) pyrazoles-4-ethyl acetate also
The 2-(4-chlorophenyl)-4-methyl sulfinyl methyl (1) chromene (4,3-C) pyrazoles-3(2H)-ketone also
4-methyl-2-(4-trifluoromethyl)-1,4-dihydro (1) chromene is (4,3-C) pyrazoles-3(2H)-ketone also
The 2-(3-chlorophenyl)-and the 4-methyl isophthalic acid, 4-dihydro (1) chromene is (4,3-C) pyrazoles-3(2H)-ketone also
2-(3,4-dichloro-phenyl)-and the 4-methyl isophthalic acid, 4-dihydro (1) chromene is (4,3-C) pyrazoles-3(2H)-ketone also
The 2-(4-chlorophenyl)-and the 4-methyl isophthalic acid, 4-dihydro (1) chromene is (4,3-C) pyrazoles-3(2H)-ketone also
2-(4-fluoro phenyl)-and the 4-methyl isophthalic acid, 4-dihydro (1) chromene is (4,3-C) pyrazoles-3(2H)-ketone also
When formula I compound contained more than one chiral centre, compound can exist with the diastereo-isomerism form.The present invention includes the mixture of each diastereomer and diastereomer.Diastereomer can for example by crystallization, and then split and make their separation by method well known in the prior art again.
In therepic use, active compound can be oral, rectum, non-enteron aisle or localized forms medication, preferably oral or local application.Therefore, therapeutic composition can be got any known oral, rectum, the pharmaceutical compositions of non-enteron aisle or local application.The pharmaceutically acceptable carrier that is applicable to this composition is known in the pharmaceutical field.
The composition of oral medication is a preferred compositions, and for this medication, these are known medicinal forms, tablet for example, capsule, syrup and water-based or oily suspensions.
Formula I compound is an immunomodulatory reagent, generally shows as immunosuppressor, but is under the some diseases state, and some compound can demonstrate immunostimulatory activity.According to the present invention, these compounds can be used for treating the disease that produces because of the distortion immune response.Therefore the pharmaceutical composition that contains the formula I compound for the treatment of significant quantity can be used for treatment and immunology diseases associated, and for example tissue rejection rejects as kidney; Autoimmune disorders is as rheumatoid arthritis and systemic lupus erythematosus; Tetter, as contact allergy, eczema and psoriasis; And tumorigenesis, as melanoma.
In this treatment, the amount of the formula I compound of using every day should be effective therapeutic dose, generally in 0.1～2000mg scope, and 1～500mg preferably.
The preparation method of formula I compound will be described now.
The formula I compound of representing with the formula II can prepare by the formula I compound that oxidation is represented with the formula III, for example by reacting with chloranil.
Can through type IV compound or the ortho ester of its tautomer and formula V (a) or the thio-orthoester prepared in reaction of formula V (b) with the formula I compound that the formula II is represented.
Wherein y represents a C
1～4Alkyl or a benzyl.For example by heating down at 50～200 ℃.Perhaps, the R wherein that represents with the formula II
6Represent a C
2～6The formula I compound of alkyloyl can through type IV compound and one 2,2,6-three (C
1～6Alkyl)-and 4H-1,3-dioxy-5-alkene-4-reactive ketone prepares C wherein
1～6Alkyl can be identical or different, for example by heating down at 50～200 ℃ in an organic liquid.
The formula I compound of representing with the formula II can through type VI compound and a kind of alkali, as piperidines, in an appropriate solvent, prepares as reacting in the ethanol.
R wherein
11Expression hydrogen, or its tautomer, or R wherein
11Expression group COR
13R wherein
13Expression hydrogen, a benzyl or a C
1～4Alkyl, and R
12Expression COCHR
5R
6
The formula I compound of representing with the formula III can prepare by the formula I compound that reduction is represented with the formula II, for example by reacting with sodium borohydride.
The formula I compound of representing with the formula III can through type VII compound and formula VIII compound react and prepare.
R wherein
14Represent a C
1～4Alkyl or a benzyl,
For example by in an organic liquid, as toluene, 50～200 ℃ of heating down.
Formula IV compound can through type IX compound and formula VIII compound react and prepare,
For example by in an organic liquid, as toluene, 50～200 ℃ of heating down.Preferably use the formula VII compound that surpasses stoichiometric quantity.
Formula IV compound can through type X compound and a kind of acid, example hydrochloric acid, or with a kind of alkali, as sodium hydroxide solution, react and prepare.
Formula V (a) compound can through type R
5R
6The alcohol that compound that CHCN represents and formula YOH represent is having an anhydrous acid, reacts down as the existence of hydrogenchloride to prepare, and obtains formula R earlier
5R
6CHC(=NH) compound represented of OY is their acid-salt, hydrochloride for example, then it more further with the alcohol reaction of formula YOH.
The compound of formula V (b) can be from formula R
5R
6The compound that CHCOCL represents, the mercaptan by representing with formula YSH is having a Lewis acid, reacts under the existence as zinc chloride to prepare.
R wherein
11Expression COR
13And R
12Expression COCHR
6R
5Formula VI compound can be by wherein R
11Expression COR
13And R
12The acylation of formula VI compound of expression hydrogen prepares, for example by with an acyl halide, suc as formula R
5R
6CHCOCL reacts.
R wherein
11Expression COR
13And R
12The formula VI compound of expression hydrogen can through type IV compound acylation prepare, for example by with a kind of formula (R
13CO)
2The acid anhydrides that O represents, have the salt of respective acids (as sodium salt) in the presence of react.
R wherein
11And R
12Identical, and expression R
5R
6The formula VI compound of CHCO can through type IV compound acylation prepare, for example by use formula (R
5R
6CHCO)
2O represents acid anhydrides, and has the salt (as sodium salt) of respective acids.
R wherein
12Expression COCHR
6R
5And R
11The formula VI compound of expression hydrogen, or its tautomer can be by R wherein
11Expression COR
13And R
12Expression COCHR
5R
6Formula VI compound and a kind of alkali, as piperidines,, prepare as reacting in the ethanol at an appropriate solvent.
Formula VII compound can through type XI compound alkylating or cycloalkylation be used for preparation,
For example by reacting with dialkyl group copper lithium.
Formula VIII compound can be by currently known methods preparation of the prior art.
Formula IX compound can through type XII compound, wherein R
15Expression hydrogen with propanedioic acid, is having a kind of acyl chlorides, as phosphoryl chloride and a kind of Lewis acid, as zinc chloride, existence under react and prepare.
Formula IX compound can be by R wherein
15The formula XII compound of expression ethanoyl is represented C with y wherein
1～4The formula of alkyl or benzyl (YO)
2The dialkyl carbonate that CO represents reacts and prepares, for example, with dimethyl carbonate, have alkali such as sodium hydride in the presence of react.
Formula X compound can react by the hydrazine of IX compound and formula VIII and prepare, for example by in appropriate solvent, as toluene, 50～200 ℃ of heating down.If obtained the mixture of formula IV and formula X compound, can use a kind of organic liquid, as methylene dichloride, they are separated by its different solvability.
Formula XI compound can be by method preparation well known in the prior art.
Formula XII compound can be by currently known methods preparation of the prior art.
R wherein
10The formula II compound of expression hydroxyl can be by R wherein
10Expression C
1～6The formula II compound of alkoxyl group and a kind of Lewis acid as aluminum chloride, react and prepare.R wherein
10Expression C
2～6The formula II compound of carbalkoxy can be by R wherein
10The formula II compound of expression hydroxyl carries out acylation reaction and prepares, and for example uses corresponding acyl halide.R wherein
5And R
6The formula II compound of expression hydrogen can be by R wherein
5Represent hydrogen and R
6The formula II compound of expression carboxyl carries out decarboxylic reaction and prepares, perhaps by hydrolysis R wherein
6Expression can be hydrolyzed into the group of carboxyl, as C
2～6The formula II compound of carbalkoxy or formamyl, for example by with sulfuric acid reaction, carry out decarboxylic reaction then and prepare.R wherein
6Expression C
1～6Alkyl sulfinyl or C
1～6The formula II compound of alkyl sulphonyl can be by R wherein
6Expression C
1～6The formula II compound of alkylthio and 3-chloroperoxybenzoic acid carry out oxidizing reaction and prepare.
Formula IV compound can through type X III compound and formula VIII compound react and prepare.
R wherein
19The expression formamyl.
R wherein
19The formula X III compound of expression formamyl can be by R wherein
19The hydrolysis of formula X III compound of expression cyano group prepares, for example by with the saturated methyl alcohol reaction of hydrogenchloride, and then react with water.
R wherein
19The formula X III compound of expression cyano group can through type X IV compound and an alkali, as sodium ethylate, reacts and prepare.
Formula X IV compound can through type X V compound and hydroxyl hydrochloride react and prepare.
Formula X V compound can be from R wherein
19The formula X III compound of expression hydrogen, for example by with ethyl formate, have alkali in the presence of, as sodium ethylate, heat and prepare.
Some formula I compounds, as work as R
5And R
6During expression hydrogen, 2-(4-chlorophenyl for example)-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone, 2-(4-fluoro phenyl)-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone or 2-(3,4-dichloro-phenyl)-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone have for example a kind of alkanol of buck and a kind of organic liquid such as Virahol in the presence of, can reset the dipolymer of accepted way of doing sth X VI.
Under superincumbent three kinds of situations, the dimer of generation is respectively:
The 1-(4-chlorophenyl)-4-1-(2-(4-chlorophenyl)-3-hydroxyl-2,4-dihydro (1) chromene is (4,3-C) pyrazoles-4-ylidenylmethyl also) ethylidene }-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one.
1-(4-fluoro phenyl)-4-1-(2-(4-fluoro phenyl)-3-hydroxyl-2,4-dihydro (1) chromene is (4,3-C) pyrazoles-4-ylidenylmethyl also) ethylidene }-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one.
1-(3,4-dichloro-phenyl)-4-1-(2-(3,4-dichloro-phenyl)-3-hydroxyl-2,4-dihydro (1) chromene is (4,3-C) pyrazoles-4-ylidenylmethyl also) ethylidene }-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one.
Proposition formula X VI compound is the further content of the present invention.
The midbody compound of be sure oing some formula II, III, IV, V, VI, VII, IX, X, X III, X IV and X V is new compound, is the further contents of the present invention at all new compounds of this proposition.
By following non-limiting examples invention is described.
The therapeutic activity of The compounds of this invention has obtained confirmation by skin anaphylactic test (CH test), in the test with the non-enterally administer of compound on BALB/C mouse body.Carry out this test with following manner.
Female BALB/C mouse, weight range 16～24g, 8 one group.The hair of every mouse belly is scraped off, and with the sensitiser solution of 20 μ l, the 4-oxyethyl group methylene radical of 5%w/v-2-phenyl-2-oxazoline-5-ketone (oxazolone) is at acetone: the solution in the ethanol (1: 1 volume ratio) imposes on the area of scraping.After sensitization produces, at once with test compound by a kind of dosage of listing below, with the Isosorbide Dinitrate of 1.5%v/v, commodity be called Tween80, the form of the suspension of formation is carried out peritoneal injection in sterilized water (100 μ l).By with the same suspension of quadrat method injection in per 24 hours 100 μ l, injected again 7 days.The dosage that uses is selected from following numerical value: 50,30,10,3,1,0.3,0.1,0.03 or 0.01mg/kg.
Each test selects for use two groups of BALB/C mouse (8 group) in contrast, to be undertaken by above-mentioned similar methods simultaneously, does not just contain test compound in the injection liquid of every day.
After the sensitization the 7th day, with the oxazolone of 10 μ l1%W/V at acetone: the solution in the sweet oil (or 1: 1, or 3: 1, volume ratio) is applied on the ear of every test mouse and contrast mouse (ear of irriate).After 24 hours, measure same the animal irriate ear and the thickness of irriate ear not with the engineering micometer screw, same animal irriate ear and not the difference between the irriate ear thickness be the yardstick of that animal of measurement to oxazolone sensitivity.Comparison sheet between mouse of handling with test compound and the mouse sensitivity handled with contrast is understood the usefulness of test compound as immunomodulator.If under a given dose, there are two (perhaps to carry out the test more than three in three CH tests, great majority tests) increase that has obtained mouse ear between treatment group and the control group has reduced 20% or more result, think that so compound has activity under this dosage, it is to have (P＜0.05) of statistical significance (referring to Int.Arch.Allergy according to Dunnett ' s test, 38, P246-259(1970))
The formula I compound that illustrates in the Table A below each under 50mg/Kg, has two tests to have activity (notes that see the following form) at 50mg/Kg unless otherwise indicated in three tests.Provided the minimum effective dose (that is, as above defining the lowest dose level that uses when compound has activity) of each compound in the Table A.The embodiment numeral of listing near each compound illustrates the method for that compound in an embodiment.
Table A
Ex compound title subliminal dose
（mg/kg）
36 2-(3,4-dichloro-phenyl)-the 4-methyl
(1) chromene (4,3-C) pyrazoles-0.3 also
3(2H)-ketone
37 2-(4-fluoro phenyl)-4-methyl (1)
Chromene is (4,3-C) pyrazoles-3 1 also
(2H)-ketone
38 2-(3-chlorophenyls)-4-methyl (1)
Chromene is (4,3-C) pyrazoles-3 3 also
(2H)-ketone
39 2-(4-p-methoxy-phenyls)-4-methyl (1)
Chromene is (4,3-C) pyrazoles-3 50 also
(2H)-ketone
40 2-(4-chlorophenyls)-4-ethyl (1)
Chromene is (4,3-C) pyrazoles-3 50 also
(2H)-ketone
41 2-(4-chlorophenyls)-3-oxo-2,
3-dihydro (1) chromene is (4,3-C) 3 also
Pyrazoles-4-ethyl acetate
Table A (continuing)
42 4-methyl-2-phenyl (1) chromene also
(4.3-C) pyrazoles-3(2H)-ketone 50(a)
43/4-methyl-2-(4-aminomethyl phenyl) (1)
96 chromenes are (4,3-C) pyrazoles-3 10 also
(2H)-ketone
44 2-(4-bromo phenyl)-4-methyl (1)
Chromene is (4,3-C) pyrazoles-3 1 also
(2H)-ketone
45 2-(3-chloro-4-fluoro phenyl)-the 4-first
Base (1) chromene is (4,3-C) pyrazoles 0.3 also
-3(2H)-ketone
46 2-(3-chloro-4-aminomethyl phenyls)-the 4-first
Base (1) chromene is (4,3-C) pyrazoles 3 also
-3(2H)-ketone
47 4-methyl-2-(4-trifluoromethyl)-
(1) chromene (4,3-C) pyrazoles 1 also
-3(2H)-ketone
48 2-(4-chlorophenyls)-7-fluoro-4-first
Base (1) chromene is (4,3-C) pyrazoles 50 also
-3(2H)-ketone
49 8-chloro-2-(4-chlorophenyls)-the 4-first
Base (1) chromene is (4,3-C) pyrazoles 50 also
-3(2H)-ketone
Table A (continuing)
50 2-(4-chlorophenyls)-4, the 8-dimethyl
(1) chromene (4,3-C) pyrazoles-50 also
3(2H)-ketone
51 2-(4-chlorophenyls)-9-methoxyl group-4
-methyl (1) chromene is (4,3-C) 50 also
Pyrazoles-3(2H)-ketone
52 2-(4-chlorophenyls)-4, the 9-dimethyl
(1) chromene (4,3-C) pyrazoles 50 also
-3(2H)-ketone
53 2-(4-fluoro phenyl)-3-oxo-2,
3-dihydro (1) chromene is (4,3-C) 3 also
Pyrazoles-4-ethyl acetate
54 2-(4-chlorophenyls)-8-fluoro-4-first
Base (1) chromene is (4,3-C) pyrazoles 0.1 also
-3(2H)-ketone
55 7-chloro-2-(4-chlorophenyls)-the 4-first
Base (1) chromene is (4,3-C) pyrazoles 50 also
-3(2H)-ketone
56 2-(4-chlorophenyls)-8-hydroxyl-4-
Methyl (1) chromene is (4,3-C) pyrrole 50 also
Azoles-3(2H)-ketone
57 4-methyl-2-(4-methylthio group phenyl) (1)
Chromene is (4,3-C) pyrazoles-3(2H) 3 also
-ketone
Table A (continuing)
58 2-(4-chlorophenyls)-9-oxyethyl group-4
-methyl (1) chromene is (4,3-C) 3 also
Pyrazoles-3(2H)-ketone
59 2-(4-chlorophenyls)-4-methyl-8-
Nitro (1) chromene is (4,3-C) pyrrole 50 also
Azoles-3(2H)-ketone
60 2-(4-chlorophenyls)-8-ethyl-4-
Methyl (1) chromene is (4,3-C) pyrrole 50 also
Azoles-3(2H)-ketone
61 6-chloro-4-methyl-2-phenyl (1) benzo
Pyrans is (4,3-C) pyrazoles-3(2H) 50 also
-ketone
62 2-(4-chlorophenyls)-6-fluoro-4-first
Base (1) chromene is (4,3-C) pyrazoles 50 also
-3(2H)-ketone
63 2-(4-chlorophenyls)-6,8-two fluoro-4
-methyl (1) chromene is (4,3-C) pyrrole 50 also
Azoles-3(2H)-ketone
64 4-bromomethyl-2-(4-chlorophenyl)
(1) chromene (4,3-C) pyrazoles 50 also
-3(2H)-ketone
65 4-chloro methyl-2-(4-chlorophenyls)
(1) chromene (4,3-C) pyrazoles 3 also
-3(2H)-ketone
Table A (continuing)
66 2-(4-chlorophenyls)-6-methoxyl group-4
-methyl (1) chromene is (4,3-C) 50 also
Pyrazoles-3(2H)-ketone
67 4-methyl-2-(4-methyl sulfinyl phenyl)
(1) chromene (4,3-C) pyrazoles-3 50 also
(2H)-ketone
69 2-(4-chlorophenyls)-the 4-methylthiomethyl
(1) chromene (4,3-C) pyrazoles 3 also
-3(2H)-ketone
74 2-(4-chlorophenyls)-3-oxo-2,
3-dihydro (1) chromene is (4,3-C) 50 also
Pyrazoles-4-ethanamide
75 2-(4-chlorophenyls)-Alpha-Methyl-3-
Oxo-2,3-dihydro (1) chromene and 50
(4,3-C) pyrazoles-4-ethyl acetate
76 2-(4-chlorophenyls)-3-oxo-2,
3-dihydro (1) chromene is (4,3-C) 0.3 also
Pyrazoles-4-ethyl acetate
77 2-(4-chlorophenyls)-3-oxo-2,
3-dihydro (1) chromene is (4,3-C) 0.3 also
Pyrazoles-4-isopropyl acetate
78 2-(4-chlorophenyls)-4-cyclopropyl (1)
Chromene is (4,3-C) pyrazoles-3 50 also
(2H)-ketone
Table A (continuing)
79 2-(4-chlorophenyls)-3-oxo-2,
3-dihydro (1) chromene is (4,3-C) 3 also
Pyrazoles-4-methyl acetate
80 2-(4-chlorophenyls)-4-ethylmercapto group methyl
(1) chromene (4,3-C) pyrazoles 50 also
-3(2H)-ketone
81 2-(4-chlorophenyls)-4-methyl-3-
Oxo-2,3-dihydro (1) chromene and 50
(4,3-C) pyrazoles-9-yl acetate
82 2-(4-chlorophenyls)-4-methyl-3-
Oxo-2,3-dihydro (1) chromene and 50(b)
(4,3-C) pyrazoles-8-yl acetate
83 2-(4-chlorophenyls)-the 4-(2-oxo
Propyl group) (1) chromene (4,3-C) 3 also
Pyrazoles-3(2H)-ketone
84 2-(4-chlorophenyls)-9-hydroxyl-4-
Methyl (1) chromene is (4,3-C) pyrrole 3 also
Azoles-3(2H)-ketone
85 2-(4-chlorophenyls)-7-hydroxyl-4-
Methyl (1) chromene is (4,3-C) pyrrole 50 also
Azoles-3(2H)-ketone
86 2-(4-chlorophenyls)-6-hydroxyl-4-
Methyl (1) chromene is (4,3-C) pyrrole 50 also
Azoles-3(2H)-ketone
Table A (continuing)
87 2-(4-chlorophenyls)-the 4-methyl sulphonyl
Methyl (1) chromene is (4,3-C) 50 also
Pyrazoles-3(2H)-ketone
88 2-(4-chlorophenyls)-4-methyl thionyl
Ylmethyl (1) chromene is (4,3-C) 50 also
Pyrazoles-3(2H)-ketone
89 2-(4-chlorophenyls)-4-methyl-3-
Oxo-2,3-dihydro (1) chromene and 3
(4,3-C) pyrazoles-8-base propionic ester
90 2-(4-chlorophenyls)-4-methyl-3-
Oxo-2,3-dihydro (1) chromene and 3
(4,3-C) pyrazoles-8-base butyric ester
91/ 2-(4-chlorophenyl)-4-methyl (1)
92/ chromene is (4,3-C) pyrazoles-3 0.1 also
93/ (2H)-ketone
95
97 4-methyl-2-(4-trifluoromethyl)
-1,4-dihydro (1) chromene and 3
(4,3-C) pyrazoles-3(2H)-ketone
98 2-(3-chlorophenyls)-the 4-methyl isophthalic acid,
4-dihydro (1) chromene is (4,3-C) 3 also
Pyrazoles-3(2H)-ketone
Table A (continuing)
99 2-(3,4-dichloro-phenyl)-the 4-methyl
-1,4-dihydro (1) chromene also (4,3 50
-C) pyrazoles-3(2H)-ketone
100 2-(4-chlorophenyls)-the 4-methyl isophthalic acid,
4-dihydro (1) chromene is (4,3-C) 3(C also)
Pyrazoles-3(2H)-ketone
101 2-(4-fluoro phenyl)-the 4-methyl isophthalic acid,
4-dihydro (1) chromene is (4,3-C) 50 also
Pyrazoles-3(2H)-ketone
102 2-(4-chlorophenyls)-3-oxo-2,
3-dihydro (1) chromene is (4,3-C) 50 also
Pyrazoles-4-acetate
103 1-(4-chlorophenyls)-4-{ 1-(2-
(4-chlorophenyl)-3-hydroxyl-2,4-23
Hydrogen (1) chromene also (4,3-C) pyrazoles-
The 4-ylidenylmethyl) ethylidene }-the 3-(2-hydroxyl
Phenyl)-the 2-pyrazolin-5-one
104 1-(3,4-dichloro-phenyl)-4-{ 1-
(2-(3,4-dichloro-phenyl)-3-hydroxyl
-2,4-dihydro (1) chromene also (4,3 50
-C) ethylidene pyrazoles-4-ylidenylmethyl) }-3
-(2-hydroxy phenyl)-2-pyrazoline-5-
Ketone
Annotate
A): during 50mg/Kg in 5 tests 3 activity is arranged.
B): the activity of the activity of a 50mg/Kg test and a 18mg/Kg test.
C): the activity of the activity of a 50mg/Kg test and two 30mg/Kg tests.
The compounds of this invention has also shown the activity of covert in all other bodies, and this shows that compound can be used as immunomodulator, is particularly suppressing in the immune response.The use of compound is undertaken by forms such as oral, non-enteron aisle or parts.Some compounds have activity in measuring their tests to the influence of humoral immunity, this test collected serum that is chemical examination when above-mentioned skin allergy test (CH test) end that is caused by oxazolone for the amount of the anti-oxazolone antibody that changes generation.And these compounds are similar in appearance to Smith SR, Terminelli C, Kipilman CT and Smith Y., and J.Immunopharmacology 1981; 3(2), also has activity in the employed Graft versus of the 133-170 Host test.
In an embodiment, umber and percentage ratio are weight unit, and the composition of mixed solvent provides with volume, and the compound property list is shown ultimate analysis and one or more following spectroscopic techniques: nucleus magnetic resonance, infrared and mass spectrum.
Embodiment 1
Stirring Powdered aluminum chloride (97.4g) is being joined in the acetate 2-fluorobenzene yl acetate (74.9g) in batches.Reaction mixture slowly is heated to 150 ℃, and under this temperature, kept 2 hours.Reaction mixture is cooled to 40 ℃, and the solid that generates is added in the frozen water (300ml) that contains concentrated hydrochloric acid (5ml).Reaction mixture carries out vapor distillation, with the overhead product cooling, uses ethyl acetate extraction.With extract drying, evaporation, obtain 3 '-fluoro-2 '-glycoloyl benzene, m.p.75～77 ℃.
Embodiment 2
In 20 minutes, with 5 '-fluoro-2 '-mixture of glycoloyl benzene (10g) in dry toluene (130ml) dropwise join the sodium hydride (6.17g that is stirring, 60% mineral oil dispersion system) in the suspension in dry toluene (130ml), the latter is reflux under nitrogen.After boiling 10 minutes again, continue heating, in 25 minutes, dropwise add the solution of diethyl carbonate (15.7ml) in dry toluene (130ml) simultaneously.This mixture is stirred, and under refluxing, heated 4 hours.Cooling is in the 2M hydrochloric acid (700ml) that the reaction mixture impouring is ice-cooled.Filter and collect the solid that obtains, then it is dissolved in the aqueous sodium hydroxide solution (325ml) of 4M.This solution washs with ether, uses the hcl acidifying of 5M then.Filter and collect the solid that obtains, wash with water and drying, obtain 6-fluoro-4 hydroxy coumarin, M.P.250-251 ℃.
Embodiment 3～6
With the similarity method of describing among the embodiment 2,, summarize in the following tabulation 1 from formula XII compound formula IX compound.
In each initiated XII compound, R
15Expression COCH
3, R
9And R
10Definition is as table 1.
The formula IX compound of preparation is as follows in embodiment 3～6:
Embodiment 3 8-fluoro-4 hydroxy coumarins
Embodiment 4 6-ethyl-4 hydroxy coumarins
Embodiment 5 4-hydroxyl-8-methoxy coumarin
Embodiment 66,8-two fluoro-4 hydroxy coumarins
Embodiment 7
A) under the nitrogen, in 10～15 minutes, 2-fluoro-6-HOMOVERATRONITRILE (34g) is joined in the methyl magnesium iodide suspension of being made in toluene (300ml) by magnesium (6.5g) and methyl-iodide (38.4g) that is stirring in batches, mixture stirred and heating 18 hours under refluxing, the 3M hydrochloric acid (200ml) of cool to room temperature, and adding then.The heating 18 hours that stirs the mixture and reflux down, cool to room temperature then, and isolate organic layer.The water layer extracted with diethyl ether, the ether extract and the toluene extract of merging wash with water, and dry and evaporation obtains an oily matter (41.1g).Under-70 to-80 ℃ temperature, in 25 minutes, dropwise handle methylene dichloride (250ml) solution of above-mentioned oily matter (36g) with methylene dichloride (60ml) solution of boron tribromide (35.7g).Mixture stirred 10 minutes down at-80 ℃, made it be warmed to 0 ℃ then.Add entry (100ml), maintain the temperature at below 10 ℃.Isolate organic layer, washing, drying, and evaporation obtain an oily matter, and it is under reduced pressure distilled, obtain 2 '-fluoro-6 '-glycoloyl benzene, b.p.170～172 ℃ (0.2mmHg).
B). under the nitrogen, in 30 minutes, with 2 '-fluoro-6 '-glycoloyl benzene (30g) dropwise joins under the backflow of stirring just in dry toluene (400ml) suspension of ebullient sodium hydride (17.1g, 60% mineral oil dispersion system).After seething with excitement again 20 minutes, continue heating, in 10 minutes, dropwise add diethyl carbonate (50.8g) simultaneously.The mixture that stirring obtains, and the heating down 20 hours that refluxes.With the reaction mixture cool to room temperature, and dropwise add entry (150ml).After the separation, water washs with ether, uses the concentrated hydrochloric acid acidifying then.Filter the collecting precipitation thing, and wash with water.After re-crystallizing in ethyl acetate and drying, obtain 5-oxyethyl group-4 hydroxy coumarin, m.p.110-111 ℃
C). heating was 6 hours under the mixture in dimethylbenzene (20ml) refluxed with 5-oxyethyl group-4 hydroxy coumarin (4.2g) and 4-chloro phenylhydrazine (3.7g), and removed the water that generates in the dereaction.With the mixture cool to room temperature, and under reduced pressure remove removal xylene.Residuum is with methyl alcohol (50ml) and concentrated hydrochloric acid (50ml) reflux 2.5 hours, cool to room temperature then.Under reduced pressure mixture is evaporated to driedly, uses the water treatment residuum, obtain a solid after the drying, the 1-(4-chlorophenyl)-3-(6-oxyethyl group-2-hydroxy phenyl)-the 2-pyrazolin-5-one.
Embodiment 8
With the 4 hydroxy coumarin (17.2g) and 3 that is stirring, the mixture heating up of 4-dichloro-phenylhydrazine (18.8g) in dry toluene (174ml) refluxed 4.25 hours, removed the water that generates in the dereaction.After making its cooling, mixture at room temperature being kept 16 hours, filter then and obtain a solid, is 1-(3,4-dichloro-phenyl)-the 3-(2-hydroxy phenyl)-2-pyrazolin-5-one and 4-(2-(3,4-dichloro-phenyl) diazanyl) mixture of tonka bean camphor.The same methylene dichloride of this solid (approximately 500ml) heating together.Behind the heat filtering, the filtrate cooling being settled out solid product, is 1-(3,4-dichloro-phenyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one, m.p.196-200 ℃.
Embodiment 9-32
With the similarity method of describing among the embodiment 8, through type VIII compound and formula IX compound prepared in reaction formula IV compound are as summarizing in the following table 2.The substituent R of formula VIII compound
7And R
8, and the substituent R of formula IX compound
9And R
10In table 2, provide.
Annotate:
(1): make reflux solution cooling, and boil off solvent and obtain solid, heat with methylene dichloride then.
(2): use the acetonitrile recrystallization.
(3): use the hexanaphthene recrystallization.
(4): dichloromethane extract is evaporated to dried.
(5): initiator is the mixture of 5-methyl-4 hydroxy coumarin and 7-methyl-4 hydroxy coumarin.
(6): required compound IV obtains by with methylene dichloride isomer mixture being carried out fractional crystallization.
(7): make reaction mixture cooling and filtration, filtrate concentrating crystallized out until product.
(8): the reaction mixture filtration is obtained IV.
(9): dichloromethane extract is evaporated, and develop residuum with ether.
(10): make catalyzer with tosic acid.
(11): make the reaction mixture cooling and boil off solvent.The residuum re-crystallizing in ethyl acetate.
(12): crude product replaces methylene dichloride to carry out recrystallization with toluene.
The formula IV compound for preparing among the embodiment 9-32 is as follows:
The embodiment compound
9 1-(4-fluoro phenyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one.
10 1-(3-chlorophenyls)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one.
11 3-(2-hydroxy phenyls)-the 1-(4-p-methoxy-phenyl)-the 2-pyrazolin-5-one.
12 3-(2-hydroxy phenyls)-1-phenyl-2-pyrazolin-5-one.
13 3-(2-hydroxy phenyls)-the 1-(4-aminomethyl phenyl)-the 2-pyrazolin-5-one.
14 1-(4-bromophenyls)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one.
15 1-(3-chloro-4-fluoro phenyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one.
16 1-(3-chloro-4-aminomethyl phenyls)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one.
17 3-(2-hydroxy phenyls)-the 1-(4-trifluoromethyl)-the 2-pyrazolin-5-one.
18 1-(4-chlorophenyls)-3-(4-fluoro-2-hydroxy phenyl)-the 2-pyrazolin-5-one.
19 1-(4-chlorophenyls)-3-(5-chloro-2-hydroxy phenyl)-the 2-pyrazolin-5-one.
20 1-(4-chlorophenyls)-3-(2-hydroxy-5-methyl base phenyl)-the 2-pyrazolin-5-one.
21 1-(4-chlorophenyls)-3-(2-hydroxyl-6-aminomethyl phenyl)-the 2-pyrazolin-5-one.
22 1-(4-chlorophenyls)-3-(5-fluoro-2-hydroxy phenyl)-the 2-pyrazolin-5-one.
23 3-(4-chloro-2-hydroxy phenyls)-the 1-(4-chlorophenyl)-the 2-pyrazolin-5-one.
24 1-(4-chlorophenyls)-3-(2-hydroxy-5-methyl oxygen base phenyl)-the 2-pyrazolin-5-one.
25 3-(2-hydroxy phenyls)-1-(4-methylthio group phenyl)-the 2-pyrazolin-5-one.
26 1-(4-chlorophenyls)-3-(2-hydroxyl-4-p-methoxy-phenyl)-the 2-pyrazolin-5-one.
27 1-(4-chlorophenyls)-3-(2-hydroxyl-5-nitrophenyl)-the 2-pyrazolin-5-one.
28 1-(4-chlorophenyls)-3-(5-ethyl-2-hydroxy phenyl)-the 2-pyrazolin-5-one.
29 3-(3-chloro-2-hydroxy phenyls)-1-phenyl-2-pyrazolin-5-one.
30 1-(4-chlorophenyls)-3-(3-fluoro-2-hydroxy phenyl)-the 2-pyrazolin-5-one.
31 1-(4-chlorophenyls)-3-(2-hydroxy 3-methoxybenzene base)-the 2-pyrazolin-5-one.
32 1-(4-chlorophenyls)-and 3-(3,5-two fluoro-2-hydroxy phenyls)-the 2-pyrazolin-5-one.
Embodiment 33
A) 4 hydroxy coumarin (10.8g) and 4-chlorophenyl hydrazine (9.5g) mixture in dry toluene (110ml) is stirred and reflux 1.5 hours, remove the water that generates in the dereaction.With mixture standing over night at room temperature, filter then and collect the solid that obtains.It is boiled in methylene dichloride (approximately 200ml), and heat filtering, with obtaining 4-(2-(4-chlorophenyl) diazanyl behind the industrial methylated spirit recrystallization) tonka bean camphor, m.p.226-229 ℃.
B) with 4-(2-(4-chlorophenyl) diazanyl) tonka bean camphor (2.86g), the mixture of the hydrochloric acid (2ml) of ethanol (250ml) and 5M stirs, and boiling reflux 21.5 hours.Reaction mixture is filtered in cooling.Evaporated filtrate, and residuum is distributed between methylene dichloride and water.Dichloromethane extraction liquid is merged, dry and concentrated, obtain the 1-(4-chlorophenyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one.m.p.182-187℃。
Embodiment 34
A). the 4-hydroxy-5-methyl oxygen basic note legumin (6.5g) that will stir, the mixture heating up of 4-chloro phenylhydrazine (7.3g) and dry toluene (66ml) refluxes, and removes the water that generates in the dereaction.The solid that obtains filter is collected in cooling, obtains 4-(2-(4-chlorophenyl) diazanyl)-the 5-methoxy coumarin, m.p.206～209 ℃.
B). with 4-(2-(4-chlorophenyl) diazanyl)-5-methoxy coumarin (1.58g), the mixture boiled of 5M aqueous sodium hydroxide solution (1ml) and industrial methylated spirit (100ml) refluxed 4 hours.Mixture is filtered in cooling.Filtrate is evaporated to dried, and residuum is distributed between methylene dichloride and water.Isolate dichloromethane layer, dry and concentrated, obtain the 1-(4-chlorophenyl after the filtration)-3-(2-hydroxyl-6-p-methoxy-phenyl)-the 2-pyrazolin-5-one, m.p.185-188 ℃.
Embodiment 35
With the 3-(2-hydroxy phenyl)-1-(4-methylthio group phenyl)-2-pyrazolin-5-one (2.3g) (embodiment 25), the mixture of 3-chloro-peroxy benzoic acid (1.7g, 80%) and methylene dichloride (172ml) at room temperature stirred 66 hours.Use the saturated solution of sodium bicarbonate purging compound, wash with water then.Dry then also evaporation.Residuum obtains the 3-(2-hydroxy phenyl with toluene/sherwood oil (b.p.62～68 ℃) recrystallization)-1-(4-methyl sulfinyl phenyl)-the 2-pyrazolin-5-one, m.p.76～80 ℃.
Embodiment 36
With the 1-(3 that is stirring, 4-dichloro-phenyl)-the 3-(2-hydroxy phenyl)-mixture of 2-pyrazolin-5-one (2.0g) (embodiment 8) and triethly orthoacetate (3.41ml) heated 10 minutes under 130～135 ℃ temperature.Make mixture be cooled to room temperature, and under this temperature, kept 16 hours.With ether development, collect solid product and dry then, obtain 2-(3,4-dichloro-phenyl)-4-methyl (1) chromene (4,3-C) pyrazoles-3(2H)-ketone also, m.p.207-211 ℃.
Embodiment 37～68
With the similarity method of describing among the embodiment 36, through type IV compound and formula V (a) compound prepared in reaction formula II compound, as summarized in Table 3.The substituent R of formula IV compound
7, R
8, R
9And R
10In table 3, provide.In formula V (a) compound, except other has explanation, R
18Expression R
5R
6CH, Y represents C
2H
5On an embodiment number hurdle, embodiment number of the numeral preparation formula IV compound that provides in the bracket.Except other has explanation, the amount of compound V (a) is that unit provides with ml.
Annotate:
(1): use the Virahol recrystallization.
(2): use the acetonitrile recrystallization.
(3): use the propyl alcohol recrystallization.
(4): reactant heats under 135～145 ℃ temperature.
(5): reactant is 125 ℃ of heating down.
(6): by being dissolved in methylene dichloride and diluting with industrial methylated spirit, filtering also, evaporated filtrate carries out purifying.
(7): use re-crystallizing in ethyl acetate.
(8): in reactant, add toluene, and mixture boiled is refluxed.
(9): Y=CH in formula V (a)
3
Embodiment 69
A) steps A is under 0～5 ℃, with saturated methylthio group acetonitrile of hydrogenchloride (100g) and the solution of methyl alcohol (47ml) in anhydrous diethyl ether (644ml).In 16 hours, make mixture be warmed to room temperature.Filter and collect the solid product that generates, washing is also dry, obtains the methylthio group imido by the methyl acetate hydrochloride, is viscous solid.
B) step B stirs the mixture of methylthio group imido by methyl acetate hydrochloride (69a preparation) and methyl alcohol (551ml) 3 hours down at 35～45 ℃, at room temperature places then 72 hours.Mixture being filtered and evaporated filtrate, obtain containing some solid oily matter, by the velveteen solids removed by filtration, obtain former (methylthio group) 3-acetic acid methyl ester, is an oily matter, b.p.96-104 ℃ (5mmHg).
C) step c joins the 1-(4-chlorophenyl with former (methylthio group) 3-acetic acid methyl ester (5ml))-the 3-(2-hydroxy phenyl)-2-pyrazolin-5-one (2.87g) (embodiment 91a) in, mixture heated 10 minutes down at 135～145 ℃, with ether (10ml) development, filter then.Residuum with excessive ether washing, obtains the 2-(4-chlorophenyl then with excessive water washing)-4-methylthiomethyl (1) chromene (4,3-C) pyrazoles-3(2H)-ketone also, m.p.215-217 ℃.
Embodiment 70-73
With the similarity method of describing among embodiment 69 steps A and the B, preparation formula V (a) compound, as summarized in Table 4.
Annotate:
(1): reaction adds diethyl ether when finishing.
(2): add anhydrous dioxan (110ml) and improve solubleness, reaction adds diethyl ether when finishing.
(3): evaporation reaction mixture, remaining polyurethane.
(4): use the ether crystallization.
(5): add diethyl ether during the reaction beginning (290ml).
The compound for preparing among the table 4 step B is as follows:
Embodiment 70 former (formamyl) triethyl acetate.
Embodiment 71 former (2-ethoxycarbonyl) propionic acid triethyl.
Embodiment 72 former (the third oxygen carbonyl) acetate three propyl ester.
Embodiment 73 former (the different third oxygen carbonyl) 3-acetic acid methyl ester.
Embodiment 74-77
With the similarity method of describing among the embodiment 69 step c, from formula V (a) compound and formula IV compound formula II compound, as summarizing in the following table 5.In formula V (a) compound, R
18Expression R
6R
5CH, the R in the formula IV compound
7, R
8, R
9And R
10In table 5, provide.
Embodiment 78
A). handle the 1-(4-chlorophenyl with anhydrous sodium acetate (0.41g))-the 3-(2-hydroxy phenyl)-mixture of 2-pyrazolin-5-one (1.43g) (embodiment 91a) and diacetyl oxide (7.5ml), and at room temperature stirred 2.5 hours.In the mixture (b.p.62-68 °, 9: 1) with reaction mixture impouring water and gasoline.The solid product that water and gasoline (b.p.62-68 °) washing is collected, dry then, obtain the 1-(4-chlorophenyl)-the 3-(2-hydroxy phenyl)-5-pyrazolyl acetic ester, m.p.108-110 ℃.
B). under 0～5 ℃, cyclopropane carbonyl chlorine (2ml) is added drop-wise to the 1-(4-chlorophenyl that is stirring)-the 3-(2-hydroxy phenyl)-solution of 5-pyrazolyl acetic ester (3.29g) in anhydrous tetrahydro furan (50ml) and triethylamine (3ml) in, and stirred the mixture 16 hours, make temperature rise to room temperature.Then with in the mixture impouring water (10 volume), and use ethyl acetate extraction.Extract washes with water, and dry and evaporation obtains cyclopropane-carboxylic acid 2-(5-acetoxyl group-1-(4-chlorophenyl)-3-pyrazolyl) phenylester is an oily matter.
C). with cyclopropane-carboxylic acid 2-(5-acetoxyl group-1-(4-chlorophenyl)-3-pyrazolyl) phenylester (78b preparation), the mixture heating up of piperidines (1ml) and dehydrated alcohol (30ml) refluxed 2 hours.The solid product that collection obtains with washing with alcohol and dry, obtains the 2-(4-chloro-phenyl-)-4-cyclopropyl (1) chromene (4,3-C) pyrazoles-3(2H)-ketone also, m.p.240-243 ℃.
Embodiment 79
A). with the similarity method of embodiment 78a, from the 1-(4-chlorophenyl)-the 3-(2-hydroxy phenyl)-2-pyrazolin-5-one (1.9g) (embodiment 91a), the mixture of butyryl oxide (10ml) and Sodium propanecarboxylate (0.73g) obtains the 1-(4-chlorophenyl)-the 3-(2-hydroxy phenyl)-5-pyrazolyl butyric ester, m.p.119-122 ℃.
B). under 0-5 ℃, methyl malonyl chloride (1.2ml) is added drop-wise to the 1-(4-chlorophenyl that is stirring)-the 3-(2-hydroxy phenyl)-mixture of 5-pyrazolyl butyric ester (3.57g) in anhydrous tetrahydro furan (50ml) and triethylamine (1.5ml) in.Mixture at room temperature stirs 24 hours, and then adds some methyl malonyl chlorides (0.6ml) and triethylamine (0.75ml).Reaction mixture at room temperature stirred 24 hours, handled with embodiment 78b similar methods then, obtained an oily matter, by removing wherein unreacted starting raw material with the ether development.
C). above-mentioned product boiling reflux 1.5 hours in dry toluene (25ml) and piperidines (1ml).Product filter is collected in cooling, obtains the 2-(4-chlorophenyl)-3-oxo-2,3-dihydro (1) chromene is (4,3-C) pyrazoles-4-methyl acetate also, m.p.170～172 ℃.
Embodiment 80
Under 0～5 ℃, ethylmercapto group Acetyl Chloride 98Min. (1ml) is added drop-wise to the 1-(4-chlorophenyl that is stirring)-the 3-(2-hydroxy phenyl)-mixture of 5-pyrazolyl butyric ester (3.57g) (embodiment 79a) in anhydrous tetrahydro furan (50ml) and triethylamine (1.5ml) in.Mixture was at room temperature stirred 2 days, be cooled to 0～5 ℃ then, and add some triethylamines (0.75ml) and ethylmercapto group Acetyl Chloride 98Min. (0.5ml) again.Mixture was at room temperature stirred 16 hours, handle with the similarity method of embodiment 78b then, obtain a jelly, with its boiling reflux 35 minutes in the dehydrated alcohol that contains piperidines (1ml) (20ml).Cooling, filtering mixt obtains the 2-(4-chlorophenyl)-4-ethylmercapto group methyl (1) chromene (4,3, C) pyrazoles-3(2H)-ketone also, m.p.167 ℃.
Embodiment 81
A). with the 1-(4-chlorophenyl)-3-(2-hydroxyl-6-p-methoxy-phenyl)-2-pyrazolin-5-one (1.52g) (embodiment 34), the mixture of aluminum chloride (2.54g) and anhydrous dimethyl benzene (16ml) stirred 35 minutes down at 100～110 ℃.Cooling, decant goes out dimethylbenzene, with the hydrochloric acid (32.6ml) of 2M with ice and join in the remaining brown jelly.The solid collected by filtration product, washing is also dry, with aqueous industrial methylated spirit recrystallization, obtains the 1-(4-chlorophenyl)-3-(2, the 6-dihydroxy phenyl)-the 2-pyrazolin-5-one, m.p.290～293 ℃.
B). with the 1-(4-chlorophenyl)-3-(2, the 6-dihydroxy phenyl)-2-pyrazolin-5-one (1.36g), diacetyl oxide (6.75ml) and sodium acetate (0.37g) at room temperature stirred 3 hours, add some sodium acetates (0.74g) again, and continue to stir 16 hours, mixture is joined in the mixture (b.p.60～80 °, 9: 1) of water and gasoline.The solid collected by filtration product, after the drying, make it in the mixture of anhydrous tetrahydro furan (26ml) and triethylamine (1.42ml), stir on ice-water bath, dripping acetyl chloride (0.74ml) stirs mixture 3.3 hours simultaneously, joins then in the water (10 volume), leach the solid and the drying that obtain, obtain the 1-(4-chlorophenyl)-3-(2,6-diacetoxy phenyl)-5-pyrazolyl acetic ester, m.p.140～142 ℃.
C). with the 1-(4-chlorophenyl)-3-(2,6-diacetoxy phenyl)-5-pyrazolyl acetic ester (1.2g), the mixture boiled of piperidines (0.28ml) and ethanol (5.5ml) refluxed 30 minutes, cooling, filter to collect the solid that obtains, obtain the 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro (1) chromene also (4,3-O) pyrazoles-9-yl acetate, m.p.233～236 ℃.
Embodiment 82
A). with the 1-(4-chlorophenyl)-3-(2-hydroxy-5-methyl oxygen base phenyl)-2-pyrazolin-5-one (5.5g) (embodiment 24), aluminum chloride (9.35g) and anhydrous dimethyl benzene (66ml) were 100 ℃ of following stirring heating 1 hour, handle with the similarity method among the embodiment 81a then, after recrystallizing methanol, obtain the 1-(4-chlorophenyl)-3-(2, the 5-dihydroxy phenyl)-and the 2-pyrazolin-5-one, m.p.220～225 ℃.
B). with the 1-(4-chlorophenyl)-3-(2, the 5-dihydroxy phenyl)-2-pyrazolin-5-one (0.6g), boil under diacetyl oxide (3ml) and anhydrous sodium acetate (0.5g) reflux and stirred 2 hours.In mixture impouring water, and product is extracted in the ethyl acetate, ethyl acetate steamed fall to obtain an oily matter, make its boiling reflux 3 hours in dehydrated alcohol (4ml) and piperidines (0.2ml).Filter and collect the solid that obtains after the cooling, obtain the 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-C) pyrazoles-8-yl acetate also, m.p.192-194 ℃.
Embodiment 83
Under 130～135 ℃, in 15 minutes, with 2,2,6-trimethylammonium-4H-1, the 3-dioxane oneself-the 5-alkene-mixture of 4-ketone (2.85g) in dimethylbenzene (15ml) be added drop-wise to the 1-(4-chlorophenyl that is stirring)-the 3-(2-hydroxy phenyl)-mixture of 2-pyrazolin-5-one (3.8g) (embodiment 91b) in dimethylbenzene (20ml) in, any lower boiling material is all steamed.With mixture stirring heating 30 minutes, and then add again in 10 minutes some 2,2,6-trimethylammonium-4H-1, the 3-dioxane oneself-the 5-alkene-mixture of 4-ketone (1.4g) in dimethylbenzene (7.5ml).With mixture stirring heating 1 hour, under reduced pressure steam then and remove dimethylbenzene.With the solid residue that the propan-2-ol recrystallization obtains, obtain the 2-(4-chlorophenyl)-the 4-(2-oxopropyl) also (4,3-C) pyrazoles-3(2H)-ketone m.p.167-168 ℃ of (1) chromene.
Embodiment 84
With the 2-(4-chlorophenyl)-also (4,3-C) pyrazoles-3(2H)-ketone (0.50g) (embodiment 51) and the mixture of aluminum chloride (0.78g) in anhydrous dimethyl benzene (4.8ml) place the oil bath of 100～110 ℃ preheating to place 35 minutes to 9-methoxyl group-4-methyl (1) chromene.Cooling, the hydrochloric acid (10ml) of adding 2M and ice in reaction mixture.The yellow solid that filtration obtains obtains the 2-(4-chlorophenyl)-9-hydroxy-4-methyl (1) chromene (4,3-C) pyrazoles-3(2H)-ketone also, m.p.213～215 ℃.
Embodiment 85
With the similarity method among the embodiment 84, with the 2-(4-chlorophenyl)-7-methoxyl group-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone (1.0g) (embodiment 68), anhydrous dimethyl benzene (12ml) and aluminum chloride (1.7g) heated 2 hours down at 100 ℃, obtain the 2-(4-chlorophenyl)-7-hydroxy-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone, m.p.＞300 ℃
Embodiment 86
Similarity method with embodiment 84, with the 2-(4-chlorophenyl)-6-methoxyl group-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone (1.0g) (embodiment 66), aluminum chloride (1.7g) and anhydrous dimethyl benzene (12ml) heated 3 hours down at 100 ℃, use N, behind the dinethylformamide recrystallization, obtain the 2-(4-chlorophenyl)-6-hydroxy-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone, m.p.＞300 ℃
Embodiment 87
With the 2-(4-chlorophenyl)-4-methylthiomethyl (1) chromene also (4; 3-C) pyrazoles-3(2H)-ketone (1.5g) (embodiment 69C) and 3-chloro-peroxy benzoic acid (80%; 1.8g) mixture in methylene dichloride (265ml) at room temperature stirred 48 hours; add some 3-chloro-peroxy benzoic acids (80% again; 0.2g) mixture in methylene dichloride (25ml); and with reaction mixture stirring 48 hours; with saturated solution of sodium bicarbonate washing reaction mixture; wash with water then; dry and concentrated; the solid collected by filtration product; obtain the 2-(4-chlorophenyl)-4-sulfonyloxy methyl ylmethyl (1) chromene also (4; 3-C) pyrazoles-3(2H)-ketone, m.p.240～243 ℃.
Embodiment 88
With the 2-(4-chlorophenyl)-4-methylthiomethyl (1) chromene also (4; 3-C) pyrazoles-3(2H)-ketone (1.5g) (embodiment 69C) and 3-chloro-peroxy benzoic acid (80%; 0.9g) mixture in methylene dichloride (172ml) at room temperature stirred 66 hours; filtration obtains the 2-(4-chlorophenyl)-4-methyl sulfinyl methyl (1) chromene also (4; 3-C) pyrazoles-3(2H)-ketone, m.p.193～194 ℃.
Embodiment 89
In 16 hours, with the 2-(4-chlorophenyl)-8-hydroxy-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone (1.5g) (embodiment 56), the mixture of anhydrous pyridine (45ml) and propionyl chloride (0.9ml) stirs in ice bath, makes it be warmed to room temperature then.Mixture is poured in the water, and uses ethyl acetate extraction.The extract that merges washes with water for several times, dry and evaporation obtains a solid, with ether it is developed, methylate with industry then and spill smart recrystallization, obtain the 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-C) pyrazoles-8-base propionic ester also, m.p.191～193 ℃.
Embodiment 90
Under 0-5 ℃, butyryl chloride (1.64ml) is added drop-wise to the 2-(4-chlorophenyl that is stirring)-8-hydroxy-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone (2.0g) (embodiment 56) is in the mixture of methylene dichloride (50ml) and triethylamine (2.2ml).Mixture was at room temperature stirred 20 hours, wash with water then, dry and vapourisation under reduced pressure.Develop residuum with ether, obtain the 2-(4-chlorophenyl after the filtration)-4-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-C) pyrazoles-8-base butyric ester also, m.p.170-173 ℃.
Embodiment 91
A). 4 hydroxy coumarin that will stir (14.3g) and 4-chloro phenylhydrazine (18.9g) mixture heating up in dry toluene (150ml) refluxed 2.5 hours, remove the water that generates in the dereaction, make reaction mixture be cooled to room temperature, filter and collect solid product then, obtain the 1-(4-chlorophenyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one; M.p.183-185 ℃.
B). the 1-(4-chlorophenyl that will stir)-the 3-(2-hydroxy phenyl)-mixture of 2-pyrazolin-5-one (1.43g) and triethly orthoacetate (2.74ml) is 130～135 ℃ of heating 10 minutes down, make reaction mixture be cooled to room temperature, develop with ether (10ml), collect solid product and dry, obtain the 2-(4-chlorophenyl)-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone, m.p.204～206 ℃.
Embodiment 92
With the 1-(4-chlorophenyl that is stirring)-the 3-(2-hydroxy phenyl)-2-pyrazolin-5-one (0.29g) (embodiment 91a), the mixture heating up of sodium acetate (0.25g) and diacetyl oxide (1.5ml) refluxed 0.5 hour, make reaction mixture be cooled to room temperature, dilute with water, and use extracted with diethyl ether.Wash extract with water, dry and evaporation obtains a semi-crystalline jelly.Mixture heating up in ethanol (2ml) refluxed 1.5 hours with this jelly and piperidines (0.08ml), cooling then, and dilute with water, and use the concentrated hydrochloric acid acidifying.The solid collected by filtration product obtains the 2--(4-chlorophenyl)-4-methyl (1) chromene (4,3-C) pyrazoles-3(2H)-ketone also, m.p.202-205 ℃.
Embodiment 93
With the 2-(4-chlorophenyl)-3-oxo-2,3-dihydro (1) chromene is (4,3-C) pyrazoles-4-ethanamide (0.8g) (embodiment 74) also, and sulfuric acid (75%, 25ml) 100-120 ℃ of following stirring heating 9 hours.Mixture is poured into (10 volume) in the ice, filter collects the solid that obtains, obtain the 2-(4-chlorophenyl)-4-methyl (1) chromene (4,3-C) pyrazoles-3(2H)-ketone also, m.p.204-206 ℃.
Embodiment 94
A). with sodium (2.24g) liquid in A.R. methyl alcohol (24ml), and with A.R. methyl alcohol (52ml) solution-treated of ethyl formate (8.1ml).Under 0-5 ℃, stir the mixture, in 5 minutes, add 6-fluoro-2-methyl-4-chromanone (8.78g) simultaneously in batches.This mixture was stirred 1 hour, at room temperature place then and spend the night.Boil off solvent, after the sodium hydroxide solution of adding 5M makes PH＞10 in residuum, make it between toluene and water, distribute.The water layer of separating obtains 6-fluoro-3-hydroxyl methylene radical-2-methyl-4-chromanone, m.p.68-73 ℃ with the hcl acidifying of 2M.
B). with 6-fluoro-3-hydroxyl methylene radical-2-methyl-4-chromanone (1.8g), boiling reflux was 10 minutes under the mixture of hydroxyl hydrochloride (0.49g) and Glacial acetic acid (41ml) stirred.Add entry (40ml), and the filtered and recycled product, also (3,4-d) isoxzzole of 8-fluoro-4-methyl-4H-(1) chromene obtained, m.p.84-87 ℃.
C). 8-fluoro-4-methyl-4H-(1) chromene that is stirring also dehydrated alcohol (2ml) suspension of (3,4-d) isoxzzoles (0.125g) is dropwise used ethanol (0.4ml) solution-treated of sodium (0.017g).With the solution stirring that obtains 3 hours, use the hcl acidifying of 5M then, and dilute with water.Cooled and filtered is collected solid and the drying that obtains, and obtains 6-fluoro-2-methyl-4-oxo-3-chroman formonitrile HCN, m.p.125-128 ℃.
D). under 0-5 ℃,, and placed 66 hours with the mixture of the saturated 6-fluoro-of hydrogenchloride 2-methyl-4-oxo-3-chroman formonitrile HCN (1.1g) and A.R. methyl alcohol (50ml).With the mixture evaporation, residuum distributes between water and ethyl acetate.The acetic acid ethyl ester extract that merges is dry and concentrated, obtain a solid, filter and collect this solid, obtain 6-fluoro-2-methyl-4-oxo-3-chroman methane amide, m.p.161-165 ℃.
E). the mixture in Glacial acetic acid (1ml) adds some 4-chloro phenylhydrazines (0.075g) again 110-115 ℃ of following heated and stirred 1 hour in the time of 45 minutes with 6-fluoro-2-methyl-4-oxo-3-chroman methane amide (0.467g) and 4-chloro phenylhydrazine (0.298g).With the mixture cooling,, wash dry and evaporation with water with the ether dilution.Residuum prepares thin-layer chromatography with silicon-dioxide purifies, and toluene/Glacial acetic acid (9: 1) is made moving phase, obtains the 1-(4-chlorophenyl)-3-(5-fluoro-2-hydroxy phenyl)-the 2-pyrazolin-5-one, m.p.178-182 ℃.
Embodiment 95
Under nitrogen, under-10 to-15 ℃, lithium methide (74ml, the diethyl ether solution of 1.4M) is joined in the suspension of methyl-sulfide-cupric bromide (I) title complex (21.1g) in anhydrous diethyl ether (800ml) that is stirring with 25 minutes.The mixture that obtains is cooled to-40 ℃, dropwise adds the 4-oxo-4H-chroman-solution of 3-methyl-formiate (7.0g) in anhydrous diethyl ether (100ml), and in the time of-40 ℃, mixture was stirred 30 minutes.Dropwise add ammonium chloride saturated aqueous solution (100ml) and maintain the temperature between-40 to-20 ℃, make mixture be warmed to room temperature then, and use ethyl acetate extraction.The extract that washing merges, dry and evaporation obtains a yellow oil (8.6g).This oily matter is dissolved in the toluene (250ml) that contains 4-chloro phenylhydrazine (4.3g), and, removes the water of generation mixture boiling reflux 3 hours under nitrogen.Make mixture be cooled to room temperature, and add a chlorine anil (8.3g).Under nitrogen, with mixture heating up and stirring and refluxing 2 hours, be cooled to room temperature then, and left standstill 16 hours, filter the solid of collecting precipitation, wash with ether, then with the washing of industrial methylated spirit, and then, obtain the 2-(4-chlorophenyl with the ether washing)-4-methyl (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone, m.p.203-206 ℃.
Embodiment 96
With 4-methyl-2-(4-aminomethyl phenyl)-1,4-dihydro (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone (200mg) (embodiment 105) at room temperature stirred 3 hours the mixture of a chlorine anil (0.15g) and methyl-sulphoxide (2ml), filtered then.Make the product of collection become slurries with methyl-sulphoxide, cooling is also filtered, and obtains 4-methyl-2-(4-aminomethyl phenyl) (1) chromene (4,3-C) pyrazoles-3(2H)-ketone also, m.p.157-160 ℃.
Embodiment 97
Under 0-5 ℃, handle the 4-methyl-2-(4-trifluoromethyl stirring with sodium borohydride (0.24g)) (1) chromene (4,3-C) pyrazoles-the 3(2H)-suspension of ketone (1.10g) (embodiment 47) in ethanol (22ml) also.Mixture was stirred 20 minutes, make it be warmed to room temperature simultaneously.Decant falls ethanol, add entry (180ml) and gasoline (b.p.60-80 ℃, mixture 20ml).With Glacial acetic acid the pH value is transferred to 4～5, solid collected by filtration.The silicon-dioxide flash chromatography purification (removal starting material) of this solid, with ethyl acetate/Glacial acetic acid (9: 1) wash-out pillar, obtain 4-methyl-2-(4-trifluoromethyl)-1,4-dihydro (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone, m.p.143～145 ℃.
Embodiment 98
Under 0～5 ℃, handle the 2-(3-chlorophenyl stirring with sodium borohydride (0.33g))-4-methyl (1) chromene (4,3-C) pyrazoles-the 3(2H)-suspension of ketone (1.3g) (embodiment 38) in ethanol (31ml) also.Under this temperature, reaction mixture was stirred 22 minutes, be poured into then in the mixture of the water (9 volume) that stirring and gasoline (b.p.60-80 ℃, 1 volume).After decant is removed insoluble initial substance, the pH value of mixture is transferred to 4-5, mixture is filtered, obtain the 2-(3-chlorophenyl with Glacial acetic acid)-the 4-methyl isophthalic acid, 4-dihydro (1) chromene is (4,3-C) pyrazoles-3(2H)-ketone also, m.p.140-141 ℃.
Embodiment 99
Under 0-5 ℃, use sodium borohydride (0.29g) to handle the 2-(3 that is stirring in batches, 4-dichloro-phenyl)-4-methyl (1) chromene also (4,3-C) pyrazoles-the 3(2H)-mixture of ketone (1.31g) (embodiment 36) in ethanol (28.5ml), and the mixture that obtains stirred 22 minutes under this temperature.Decanted solution is removed a spot of solid, and joins refrigerative, in the mixture of water that is stirring and gasoline (b.p.60-80 ℃, 9: 1).With Glacial acetic acid the pH value of mixture is transferred to 4-5, filters then.With the washing of the solid product collected, drying, and with industrial methylated spirit recrystallization, obtain 2-(3,4-dichloro-phenyl)-and the 4-methyl isophthalic acid, 4-dihydro (1) chromene is (4,3-C) pyrazoles-3(2H)-ketone also, m.p.147-150 ℃.
Embodiment 100
Under 0-5 ℃, the 2-(4-chlorophenyl of in batches using sodium borohydride (0.76g) to handle to stir)-4-methyl (1) chromene (4,3-C) pyrazoles-the 3(2H)-suspension of ketone (2.04g) (embodiment 91b) in ethanol (49ml) also.Reaction mixture was stirred 15 minutes under this temperature, be poured into then in the ice-cooled water.With Glacial acetic acid the pH value of mixture is transferred to 4-5, and mixture is filtered.Wash the solid product of collecting with water, dry and use recrystallizing methanol, obtain the 2-(4-chlorophenyl)-the 4-methyl isophthalic acid, 4-dihydro (1) chromene is (4,3-C) pyrazoles-3(2H)-ketone also, m.p.143-147 ℃.
Embodiment 101
Under 0-5 ℃, in 5 minutes, the 2-(4-fluoro phenyl of in batches using sodium borohydride (0.67g) to handle to stir)-4-methyl (1) chromene (4,3-C) pyrazoles-the 3(2H)-mixture of ketone (2.63g) (embodiment 37) in ethanol (67ml) also.Reaction mixture was stirred 0.5 hour under this temperature, join then in the mixture of water cold, that stirring and gasoline (b.p.62-68 ℃, 9: 1).With Glacial acetic acid the pH value of mixture is transferred to 4-5, and filters the mixture that obtains.With the solid product washing of collecting and dry, obtain 2-(4-fluoro phenyl)-the 4-methyl isophthalic acid, 4-dihydro (1) chromene is (4,3-C) pyrazoles-3(2H)-ketone also, is its monohydrate, m.p.114-117 ℃.
Embodiment 102
A). with the 2-(4-chlorophenyl)-3-oxo-2,3-dihydro (1) chromene also the mixture of (4,3-C) pyrazoles-4-ethyl acetate (100mg) (embodiment 41) and 4-methoxyl group benzylalcohol (0.32ml) 150 ℃ of following stirring heating 50 minutes.With the mixture cool to room temperature,, obtain the 2-(4-chlorophenyl with ether dilution and filtration)-3-oxo-2,3-dihydro (1) chromene is (4,3-C) pyrazoles-4-acetate 4-methoxy benzyl ester also, m.p.161-163 ℃.
B). under 0 ℃, stir the 2-(4-chlorophenyl)-3-oxo-2,3-dihydro (1) chromene is the mixture of (4,3-C) pyrazoles-4-acetate 4-methoxy benzyl ester (1.38g) and methylene dichloride (7ml) also, and adds anisole (0.28ml) and trifluoroacetic acid (3.45ml).Mixture was stirred 110 minutes down at 0 ℃, filter then.Filtrate is diluted with ice-cooled water, and filters and collect the solid that generates, and washes with water and drying.This solid stirred 5 minutes with ether (10ml), filtered then, obtained the 2-(4-chlorophenyl)-3-oxo-2,3-dihydro (1) chromene is (4,3-C) pyrazoles-4-acetate also, m.p.195-198 ℃.
Embodiment 103
At room temperature, stir down handle the 2-(4-chlorophenyl with the sodium hydroxide (3.2ml) of 2M)-4-methyl (1) chromene (4,3-C) pyrazoles-the 3(2H)-mixture of ketone (2.0g) (embodiment 91b) in propan-2-ol (36ml) also.Stir after 10 minutes, in mixture impouring water, and with the hcl acidifying of 5M.This mixture dichloromethane extraction, and wash the extract of merging with water, filter and collect solid and the drying that generates, obtain the 1-(4-chlorophenyl)-4-{ 1-(2-(4-chlorophenyl)-3-hydroxyl-2,4-dihydro (1) chromene also (4,3-C) ethylidene pyrazoles-4-ylidenylmethyl) }-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one, m.p.220-222 ℃.
Embodiment 104
Similarity method with embodiment 103, stir the sodium hydroxide (2.1ml) of using 2M and handling 2-(3,4-dichloro-phenyl)-4-methyl (1) chromene (1.43g) mixture in propan-2-ol (23.5ml) 15 minutes of (4,3-C) pyrazoles-3(2H)-ketone (embodiment 36) also.The acidifying after-filtration is collected solid and the drying that generates.Solid was stirred 10 minutes with methylene dichloride (10ml), filter then to collect and obtain 1-(3,4-dichloro-phenyl)-4-{ 1-(2-(3,4-dichloro-phenyl)-3-hydroxyl-2,4-dihydro (1) chromene also (4,3-C) ethylidene pyrazoles-4-ylidenylmethyl) }-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one, m.p.213～215 ℃.
Embodiment 105
Similarity method with embodiment 101, make 4-methyl-2-(4-aminomethyl phenyl) (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone (embodiment 43) ethanol (50ml) solution and sodium borohydride (0.56g) reaction (2.12g), with obtaining 4-methyl-2-(4-aminomethyl phenyl behind the industrial methylated spirit recrystallization)-1,4-dihydro (1) chromene also (4,3-C) pyrazoles-3(2H)-ketone, m.p.118-121 ℃.
Claims (5)
1, a kind of method of preparation:
Wherein: R
1And R
2Form a key, R
3And R
4Form a key; R
5Expression hydrogen or methyl; R
6Expression hydrogen, halogen, a C
2～6Alkyloyl, a C
2～6Carbalkoxy, a C
1～6Alkylthio, a C
1～6The alkyl sulfinyl, a C
1～6Alkyl sulphonyl, formamyl, carboxyl, or R
5And R
6Represent a cyclopropyl with the carbon atom that they are connected; R
7Expression hydrogen, halogen, trifluoromethyl, methoxyl group, a C
1～6Alkyl, a C
1～6Alkylthio or a C
1～6The alkyl sulfinyl; R
8Expression hydrogen, halogen or trifluoromethyl; R
9And R
10Can be identical or different, represent halogen respectively; Or R
9Expression hydrogen and R
10Expression hydrogen, halogen, trifluoromethyl, hydroxyl, nitro, a C
2～6Alkanoyloxy, a C
1～6Alkyl or a C
1～6Alkoxyl group, this method comprises:
A). oxidation R wherein
1Expression hydrogen, R
2And R
3Represent a key and R
4Expression hydrogen.R
5, R
6, R
7, R
8, R
9And R
10Definition formula I compound as above;
B). formula IV compound or its tautomer:
React with the ortho ester of formula V (a) or the thio-orthoester of formula V (b)
Y wherein represents a C
1～4Alkyl or a benzyl;
Perhaps
C). formula VI compound and a kind of alkali reaction
R wherein
11Expression hydrogen, or its tautomer, or R wherein
11Expression group COR
13, R
12Expression COCHR
5R
6, R
13Expression hydrogen, a C
1～4Alkyl or a benzyl.
2, a kind of method of preparation, R wherein
1Expression hydrogen, R
2And R
3Represent a key, R
4Expression hydrogen and R
5, R
6, R
7, R
8, R
9And R
10Definition is as claim 1, and this method comprises:
A). reduction R wherein
1And R
2Represent a key, R
3And R
4Form a key, R
5, R
6, R
7, R
8, R
9And R
10Definition formula I compound as above;
Perhaps
B). formula VII compound
R wherein
14Represent a C
1～4Alkyl reacts with formula VIII compound;
3, according to the method for claim 1 or 2, R wherein
6Expression hydrogen, a C
2～6Carbalkoxy, a C
1～6Alkylthio, a C
1～6The alkyl sulfinyl, a C
1～6Alkyl sulphonyl, formamyl, carboxyl, or R
5And R
6Represent a cyclopropyl with the carbon atom that they connected; R
7Expression hydrogen, fluorine, chlorine, trifluoromethyl, a C
1～6Alkylthio or a C
1～6The alkyl sulfinyl; R
8Expression hydrogen or chlorine; R
9And R
10Represent fluorine respectively; Or R
9Expression hydrogen.R
10Be at the 8-of benzo ring or the substituting group on the 9-position, expression hydrogen, fluorine, trifluoromethyl, hydroxyl, nitro, a C
1～6Alkyl, or R
10C of expression on the 9-position of benzo ring
1～6Alkoxyl group.
4, the compound of representing according to the method preparation formula II of claim 1:
R wherein
5Expression hydrogen, R
6Expression hydrogen, methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, or methylthio group, R
7Expression fluorine, chlorine, bromine, trifluoromethyl or methylthio group, R
8Expression hydrogen or chlorine, R
9Expression hydrogen, R
10Expression hydrogen, 8-fluorine, 8-propionyloxy, 9-hydroxyl or 9-oxyethyl group.
5, the compound of representing according to the method preparation formula III of claim 2
R wherein
5And R
6Expression hydrogen, R
7Expression hydrogen or chlorine, R
8Expression hydrogen or chlorine, R
9And R
10Represent hydrogen respectively.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 90101419 CN1053921A (en) | 1990-02-08 | 1990-02-08 | Therapeutical agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 90101419 CN1053921A (en) | 1990-02-08 | 1990-02-08 | Therapeutical agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1053921A true CN1053921A (en) | 1991-08-21 |
Family
ID=4877058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 90101419 Pending CN1053921A (en) | 1990-02-08 | 1990-02-08 | Therapeutical agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1053921A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0624567A2 (en) * | 1993-05-11 | 1994-11-17 | Hoechst Aktiengesellschaft | Derivatives of 3-fluorophenol, process for their preparation and their use |
-
1990
- 1990-02-08 CN CN 90101419 patent/CN1053921A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0624567A2 (en) * | 1993-05-11 | 1994-11-17 | Hoechst Aktiengesellschaft | Derivatives of 3-fluorophenol, process for their preparation and their use |
| EP0624567A3 (en) * | 1993-05-11 | 1995-03-22 | Hoechst Ag | Derivatives of 3-fluorophenol, process for their preparation and their use. |
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