CN102040563B - Preparation method for 3-aryl benzo [d] isothiazole - Google Patents
Preparation method for 3-aryl benzo [d] isothiazole Download PDFInfo
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- CN102040563B CN102040563B CN200910197259.9A CN200910197259A CN102040563B CN 102040563 B CN102040563 B CN 102040563B CN 200910197259 A CN200910197259 A CN 200910197259A CN 102040563 B CN102040563 B CN 102040563B
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- boric acid
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- alkali
- phenylo boric
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- -1 amino, hydroxyl Chemical group 0.000 claims abstract description 14
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 239000004327 boric acid Substances 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000003513 alkali Substances 0.000 claims description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 11
- CUXQLKLUPGTTKL-UHFFFAOYSA-M microcosmic salt Chemical compound [NH4+].[Na+].OP([O-])([O-])=O CUXQLKLUPGTTKL-UHFFFAOYSA-M 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- 239000011261 inert gas Substances 0.000 claims description 8
- LBBMOAOCCQOIAQ-UHFFFAOYSA-N methoxy(phenyl)borinic acid Chemical compound COB(O)C1=CC=CC=C1 LBBMOAOCCQOIAQ-UHFFFAOYSA-N 0.000 claims description 8
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 239000003880 polar aprotic solvent Substances 0.000 claims description 5
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 claims description 4
- OPPWASLOVKWHCT-UHFFFAOYSA-N boric acid;phenol Chemical compound OB(O)O.OC1=CC=CC=C1 OPPWASLOVKWHCT-UHFFFAOYSA-N 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
- KNPNGMXRGITFLE-UHFFFAOYSA-N methylperoxy(phenyl)borinic acid Chemical compound COOB(O)C1=CC=CC=C1 KNPNGMXRGITFLE-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- UTHULKKJYXJZLV-UHFFFAOYSA-N (3-aminophenoxy)boronic acid Chemical compound NC1=CC=CC(OB(O)O)=C1 UTHULKKJYXJZLV-UHFFFAOYSA-N 0.000 claims description 2
- ZPKSAIWDCQVXSQ-UHFFFAOYSA-N (4-aminophenoxy)boronic acid Chemical compound NC1=CC=C(OB(O)O)C=C1 ZPKSAIWDCQVXSQ-UHFFFAOYSA-N 0.000 claims description 2
- PSIGFRPUHBNDEW-UHFFFAOYSA-N (4-nitrophenoxy)boronic acid Chemical compound OB(O)OC1=CC=C([N+]([O-])=O)C=C1 PSIGFRPUHBNDEW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 5
- WGMRIHBMPBDMMG-UHFFFAOYSA-N 3-(3-methylphenyl)-1,2-benzothiazole Chemical compound CC1=CC=CC(C=2C3=CC=CC=C3SN=2)=C1 WGMRIHBMPBDMMG-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 2
- UYLILQQAXFPQJW-UHFFFAOYSA-N 3-(4-methoxyphenyl)-1,2-benzothiazole Chemical compound COC1=CC=C(C=C1)C1=NSC2=C1C=CC=C2 UYLILQQAXFPQJW-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method for 3-aryl benzo [d] isothiazole shown in formula I. The method comprises the following step: subjecting a compound II and a compound III to coupling reaction to obtain the compound I. In formula I, R1, R2, R3, R4, R5 are separately C1 to C3 alkyl, C1 to C3 alkyloxy, amino substituted by one or two C1-C4 alkyls, amino, hydroxyl, nitro or carbonyl connecting C1 to C3 alkyloxy. The preparation method provided by the invention has the advantages that: the raw material is cheap and easily available, the step is simple, the condition is mild, and the yield is high generally which can reach 70% to 80%.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, be specifically related to the preparation method of a kind of 3-aryl benzo [d] isothiazole.
Background technology
3-aryl benzo [d] isothiazole (I), structural formula specific as follows:
The type compound is a kind of important medicine and chemical intermediate.
In existing synthetic method, (as shown below, Chemische Berichte 1979,112,3286-3292), independently react through three steps, and use the acute product such as phosphorus oxychloride, and environmental pollution is serious; Temperature of reaction is very high, dangerous large; Aftertreatment complexity.So need development step brief, environmental friendliness, and lower-cost method.
Summary of the invention
Technical problem to be solved by this invention is in the method in order to overcome the existing 3-of preparation aryl benzo [d] isothiazole, reactions steps is long, and use the highly toxic product such as phosphorus oxychloride, environmental pollution is serious, temperature of reaction is very high, dangerous large, and the defect such as aftertreatment complexity, and the preparation method of a kind of 3-aryl benzo [d] isothiazole is provided.Preparation method's raw material of the present invention is cheap and easy to get, and step is simple, mild condition, and product yield is higher, generally can reach 70%-80%.
The present invention relates to a kind of preparation method suc as formula 3-aryl benzo [d] isothiazole shown in I, it comprises the following step: in solvent, Compound I I and compound III are carried out linked reaction, make Compound I;
Wherein, R
1, R
2, R
3, R
4and R
5alone be C
1～C
3alkyl, C
1～C
3alkoxyl group, by 1 or 2 C
1～C
4amino, amino, hydroxyl, nitro or connection C that alkyl replaces
1～C
3the carbonyl of alkoxyl group.
Preferably, compound III is to methylphenylboronic acid, a methylphenylboronic acid, to methoxyphenylboronic acid, meta-methoxy phenylo boric acid, to dimethylin phenylo boric acid, a dimethylin phenylo boric acid, to diethylin phenylo boric acid, a diethylin phenylo boric acid, to methylamino phenylo boric acid, a methylamino phenylo boric acid, to ethylamino-phenylo boric acid, an ethylamino-phenylo boric acid, p-aminophenyl boric acid, m-aminophenyl boric acid, para hydroxybenzene boric acid, a hydroxybenzene boric acid, p-nitrophenyl boric acid, m-nitro boric acid or to ethoxycarbonyl phenylo boric acid.
Wherein, the method for described reaction and condition all can be method and the condition of this area microcosmic salt linked reaction, and preferred method and condition are as follows:
(1) in polar aprotic solvent, under protection of inert gas, Compound I I and microcosmic salt and alkali effect;
(2), under protection of inert gas, product and compound III that step (1) is obtained are carried out linked reaction.
Wherein, described microcosmic salt is preferably tripyrrole alkyl bromide phosphine hexafluoro microcosmic salt (PyBroP) and/or phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus (PyBOP), preferably PyBroP; Described alkali can be mineral alkali and/or organic bases, preferably organic bases; Mineral alkali is preferably sodium tert-butoxide, and organic bases is preferably triethylamine and/or diethyl propyl group ethylamine, preferably triethylamine; The mol ratio of described Compound I I and microcosmic salt, alkali is preferably 1: 1: 1～1: 2: 10, and better is 1: 1.1: 2.5～1: 1.5: 6; The mol ratio of compound III and Compound I I is preferably 0.8: 1～2: 1, and better is 1: 1～1.2: 1; Described polar aprotic solvent is preferably one or more in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), acetonitrile and glycol dimethyl ether, preferably Isosorbide-5-Nitrae-dioxane; Described Compound I I is 0.01～1mol/L with the molecular volume of solvent than preferably, and that better is 0.05～0.5mol/L.
In described step (1), the temperature of effect is preferably 0～50 ℃, and better is 10～30 ℃, in step (1) time of effect preferably with detection effect completely till, preferably 0.5～4 hour, better was 1.5～2.5 hours;
The method of the linked reaction in described step (2) and condition can be ordinary method and the condition of this area Suzuki linked reaction; particularly preferably following method and condition: in solvent; under protection of inert gas; under the effect of palladium catalyst and alkali; step (1) products therefrom and compound III are reacted.Wherein, described palladium catalyst is preferably tetrakis triphenylphosphine palladium, two (triphenylphosphine) Palladium Diacetate and two (triphenylphosphine) palladium chloride [Pd (PPh
3)
2cl
2] in one or more, preferably Pd (PPh
3)
2cl
2; The consumption of palladium catalyst is preferably 0.1～20mol% of Compound I I, and that better is 1～10mol%; Described alkali is preferably mineral alkali, as one or more in sodium carbonate, salt of wormwood and cesium carbonate, and preferably sodium carbonate; The consumption of alkali is preferably 1～10 equivalent of Compound I I, and better is 3～5 equivalents; In step (2), can continue to use the solvent in step (1), also can be with an organic solvent and the mixed solvent of water, preferably mixed solvent, the preferred Isosorbide-5-Nitrae-dioxane of organic solvent in mixed solvent; Compound I I is 0.01～1mol/L with the molecular volume of solvent than preferably, and that better is 0.05～0.5mol/L; The temperature of described reaction is preferably 50～150 ℃, and better is 80～110 ℃; The time of reaction preferably with detection reaction completely till, preferably 4～8 hours.
In preparation method of the present invention, the optimum condition of above-mentioned each processing step can arbitrary combination, obtains each preferred embodiments of the present invention.
Except specified otherwise, the raw material the present invention relates to and reagent is commercially available obtaining all.
Positively effect of the present invention is:
(1) in preparation method of the present invention, raw material is all cheap and easy to get, and does not use and poison large raw material reagent.
(2) preparation method's reactions steps of the present invention is simple, easily operation, and mild condition, aftertreatment is also simpler, and cost is lower, and the total recovery of product is higher, reaches 70～80%, and product purity is also higher, is easy to realize suitability for industrialized production.
Embodiment
With embodiment, further illustrate the present invention below, but the present invention is not limited.
In following embodiment, " equivalent " of correlated response thing is all the equivalents with respect to Compound I I.
Embodiment 1
By benzisothia oxazolone (II) (0.5mmol); PyBroP (1.2 equivalent) and triethylamine (3.0 equivalent) join 1; in 4-dioxane (4mL), room temperature under nitrogen protection (25 ℃) stirs 2 hours.Then add to methylphenylboronic acid (2.0 equivalent) two (triphenylphosphine) palladium chloride (Pd (PPh
3)
2cl
2) (5% equivalent), sodium carbonate (5.0 equivalent) and water (1 milliliter).Reaction mixture is heated to 100 ℃, stirs 4 hours.Cool to room temperature, adds ethyl acetate dilution, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Be concentrated into dryly, column chromatography obtains compound 3-tolyl benzo [d] isothiazole, yield: 78%.Nuclear magnetic resonance data is consistent with bibliographical information, and HPLC purity assay is 92%.
Embodiment 2
By benzisothia oxazolone (II) (0.5mmol); PyBroP (1.2 equivalent) and triethylamine (3.0 equivalent) join 1; in 4-dioxane (4mL), room temperature under nitrogen protection (25 ℃) stirs 2 hours.Then add to dimethylin phenylo boric acid (2.0 equivalent) two (triphenylphosphine) palladium chloride (Pd (PPh
3)
2cl
2) (5% equivalent), sodium carbonate (5.0 equivalent) and water (1 milliliter).Reaction mixture is heated to 100 ℃, stirs 4 hours.Cool to room temperature, adds ethyl acetate dilution, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Be concentrated into dryly, column chromatography obtains 3-(to dimethylamine phenyl) benzo [d] isothiazole, yield: 70%.Nuclear magnetic resonance data is consistent with bibliographical information, and HPLC purity assay is 95%.
Embodiment 3
By benzisothia oxazolone (II) (0.5mmol); PyBroP (1.2 equivalent) and triethylamine (3.0 equivalent) join 1; in 4-dioxane (4mL), room temperature under nitrogen protection (25 ℃) stirs 2 hours.Then add to methoxyphenylboronic acid (2.0 equivalent) two (triphenylphosphine) palladium chloride (Pd (PPh
3)
2cl
2) (5% equivalent), sodium carbonate (5.0 equivalent) and water (1 milliliter).Reaction mixture is heated to 100 ℃, stirs 4 hours.Cool to room temperature, adds ethyl acetate dilution, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Be concentrated into dryly, column chromatography obtains 3-(p-methoxyphenyl) benzo [d] isothiazole, yield: 68%.Nuclear magnetic resonance data is consistent with bibliographical information, and HPLC purity assay is 90%.
Embodiment 4
By benzisothia oxazolone (II) (0.5mmol); PyBroP (1.2 equivalent) and triethylamine (3.0 equivalent) join 1; in 4-dioxane (4mL), room temperature under nitrogen protection (25 ℃) stirs 2 hours.Then add to ethoxycarbonyl phenylo boric acid (2.0 equivalent) two (triphenylphosphine) palladium chloride (Pd (PPh
3)
2cl
2) (5% equivalent), sodium carbonate (5.0 equivalent) and water (1 milliliter).Reaction mixture is heated to 100 ℃, stirs 4 hours.Cool to room temperature, adds ethyl acetate dilution, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Be concentrated into dryly, column chromatography obtains 3-(to carbethoxy phenyl) benzo [d] isothiazole, yield: 72%.Nuclear magnetic resonance data is consistent with bibliographical information, and HPLC purity assay is 94%.
Embodiment 5
By benzisothia oxazolone (II) (0.5mmol), PyBoP (1 equivalent) and sodium tert-butoxide (1.0 equivalent) join in tetrahydrofuran (THF) (4mL), the lower 0 ℃ of stirring of nitrogen protection 2 hours.Then add to methylphenylboronic acid (0.8 equivalent) tetrakis triphenylphosphine palladium (0.1% equivalent), cesium carbonate (1.0 equivalent) and water (1 milliliter).Reaction mixture is heated to 80 ℃, stirs 4 hours.Cool to room temperature, adds ethyl acetate dilution, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Be concentrated into dryly, column chromatography obtains compound 3-tolyl benzo [d] isothiazole, yield: 76%.Nuclear magnetic resonance data is consistent with bibliographical information, and HPLC purity assay is 93%.
Embodiment 6
By benzisothia oxazolone (II) (0.5mmol), PyBroP (2 equivalent) and diethyl propyl group ethylamine (10 equivalent) join in acetonitrile (4mL), the lower 50 ℃ of stirrings of nitrogen protection 2 hours.Then add to methylphenylboronic acid (1 equivalent) two (triphenylphosphine) palladium chloride (Pd (PPh
3)
2cl
2) (20% equivalent), salt of wormwood (3 equivalent) and water (1 milliliter).Reaction mixture is heated to 150 ℃, stirs 4 hours.Cool to room temperature, adds ethyl acetate dilution, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Be concentrated into dryly, column chromatography obtains compound 3-tolyl benzo [d] isothiazole, yield: 75%.Nuclear magnetic resonance data is consistent with bibliographical information, and HPLC purity assay is 92%.
Embodiment 7
By benzisothia oxazolone (II) (0.5mmol); PyBroP (1.5 equivalent) and diethyl propyl group ethylamine (6 equivalent) join in glycol dimethyl ether (4mL), the lower 30 ℃ of stirrings of nitrogen protection 2 hours.Then add to methylphenylboronic acid (1.2 equivalent) two (triphenylphosphine) Palladium Diacetate (1% equivalent), sodium carbonate (1 equivalent) and water (1 milliliter).Reaction mixture, at 50 ℃, stirs 10 hours.Cool to room temperature, adds ethyl acetate dilution, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Be concentrated into dryly, column chromatography obtains compound 3-tolyl benzo [d] isothiazole, yield: 71%.Nuclear magnetic resonance data is consistent with bibliographical information, and HPLC purity assay is 90%.
Embodiment 8
By benzisothia oxazolone (II) (0.5mmol); PyBroP (1.1 equivalent) and triethylamine (2.5 equivalent) join 1; in 4-dioxane (4mL), room temperature under nitrogen protection (25 ℃) stirs 2 hours.Then add to methoxyphenylboronic acid (2.0 equivalent) two (triphenylphosphine) palladium chloride [Pd (PPh
3)
2cl
2] (10% equivalent), sodium carbonate (10 equivalent) and water (1 milliliter).Reaction mixture is heated to 100 ℃, stirs 4 hours.Cool to room temperature, adds ethyl acetate dilution, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Be concentrated into dryly, column chromatography obtains 3-(p-methoxyphenyl) benzo [d] isothiazole, yield: 67%.Nuclear magnetic resonance data is consistent with bibliographical information, and HPLC purity assay is 90%.
Claims (8)
1. suc as formula a preparation method for 3-aryl benzo [d] isothiazole shown in I, it is characterized in that comprising the following step:
(1) in polar aprotic solvent, under protection of inert gas, Compound I I and microcosmic salt and alkali effect; Described microcosmic salt is tripyrrole Wan base phosphonium bromide hexafluorophosphate and/or phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus; Described alkali is sodium tert-butoxide and/or triethylamine;
(2), under protection of inert gas, product and compound III that step (1) is obtained are carried out linked reaction;
Wherein, R
1, R
2, R
3, R
4and R
5alone be C
1～C
3alkyl, C
1～C
3alkoxyl group, by 1 or 2 C
1～C
4amino, amino, hydroxyl, nitro or connection C that alkyl replaces
1～C
3the carbonyl of alkoxyl group.
2. suc as formula a preparation method for 3-aryl benzo [d] isothiazole shown in I, it is characterized in that comprising the following step:
(1) in polar aprotic solvent, under protection of inert gas, Compound I I and microcosmic salt and alkali effect; Described microcosmic salt is tripyrrole Wan base phosphonium bromide hexafluorophosphate and/or phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus; Described alkali is sodium tert-butoxide and/or triethylamine;
(2), under protection of inert gas, product and compound III that step (1) is obtained are carried out linked reaction;
Described compound III is to methylphenylboronic acid, between methylphenylboronic acid, to methoxyphenylboronic acid, meta-methoxy phenylo boric acid, to dimethylin phenylo boric acid, between dimethylin phenylo boric acid, to diethylin phenylo boric acid, between diethylin phenylo boric acid, to methylamino phenylo boric acid, between methylamino phenylo boric acid, to ethylamino-phenylo boric acid, between ethylamino-phenylo boric acid, p-aminophenyl boric acid, m-aminophenyl boric acid, para hydroxybenzene boric acid, between hydroxybenzene boric acid, p-nitrophenyl boric acid, m-nitro boric acid, or to ethoxycarbonyl phenylo boric acid.
3. preparation method as claimed in claim 1 or 2, is characterized in that: the mol ratio of described Compound I I and microcosmic salt, alkali is 1:1:1 ~ 1:2:10; The mol ratio of described compound III and Compound I I is 0.8:1 ~ 2: 1.
4. preparation method as claimed in claim 3, is characterized in that: the mol ratio of described Compound I I and microcosmic salt, alkali is 1:1.1:2.5 ~ 1:1.5:6; The mol ratio of described compound III and Compound I I is 1:1 ~ 1.2: 1.
5. preparation method as claimed in claim 1 or 2, is characterized in that: described polar aprotic solvent is one or more in Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), acetonitrile and glycol dimethyl ether; In described step (1), the temperature of effect is 0 ~ 50 ℃; Till the time acting in described step (1) is complete with detection effect.
6. preparation method as claimed in claim 1 or 2; it is characterized in that: the method for the linked reaction in described step (2) comprises the following step: in solvent, under protection of inert gas, under the effect of palladium catalyst and alkali; step (1) products therefrom and compound III are reacted.
7. preparation method as claimed in claim 6, is characterized in that: described palladium catalyst is one or more in tetrakis triphenylphosphine palladium, two (triphenylphosphine) Palladium Diacetate and two (triphenylphosphine) palladium chloride; The consumption of described palladium catalyst is 0.1 ~ 20 mol% of Compound I I; Described alkali is one or more in sodium carbonate, salt of wormwood and cesium carbonate; The consumption of described alkali is 1 ~ 10 equivalent of Compound I I; Solvent in described step (2) is the solvent in step (1), or is the mixed solvent of organic solvent and water; The temperature of described reaction is 50 ~ 150 ℃; Till the time of reaction is complete with detection reaction.
8. preparation method as claimed in claim 7, is characterized in that: the consumption of described palladium catalyst is 1 ~ 10 mol % of Compound I I; The consumption of described alkali is 3 ~ 5 equivalents of Compound I I; Described organic solvent is Isosorbide-5-Nitrae-dioxane; The temperature of described reaction is 80 ~ 110 ℃.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4590196A (en) * | 1984-08-23 | 1986-05-20 | Bristol-Myers Company | Analgesic 1,2-benzisothiazol-3-ylpiperazine derivatives |
| CN1246114A (en) * | 1996-12-20 | 2000-03-01 | 曾尼卡有限公司 | Process for making benzisothiazolin-3-ones |
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2009
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4590196A (en) * | 1984-08-23 | 1986-05-20 | Bristol-Myers Company | Analgesic 1,2-benzisothiazol-3-ylpiperazine derivatives |
| CN1246114A (en) * | 1996-12-20 | 2000-03-01 | 曾尼卡有限公司 | Process for making benzisothiazolin-3-ones |
Non-Patent Citations (2)
| Title |
|---|
| Horst Boshagen et al..Uber die Umsetzung von 3-Chlor-l,2-benzisothiazolium-chloriden mit N-Mono- und N,N-Dialkylanilinen.《Chem. Ber.》.1979,第112卷3286-3292. |
| Uber die Umsetzung von 3-Chlor-l,2-benzisothiazolium-chloriden mit N-Mono- und N,N-Dialkylanilinen;Horst Boshagen et al.;《Chem. Ber.》;19791231;第112卷;3286-3292 * |
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