CN112047899A - Method for synthesizing 3-substituted aminobenzo [ c ] isothiazole derivative - Google Patents
Method for synthesizing 3-substituted aminobenzo [ c ] isothiazole derivative Download PDFInfo
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- -1 3-substituted aminobenzo [ c ] isothiazole Chemical class 0.000 title claims abstract description 68
- 238000000034 method Methods 0.000 title claims abstract description 51
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000003960 organic solvent Substances 0.000 claims description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- 238000007280 thionation reaction Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 abstract description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 229910052717 sulfur Inorganic materials 0.000 abstract description 2
- 239000011593 sulfur Substances 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 2
- 150000003854 isothiazoles Chemical class 0.000 abstract 2
- 238000013341 scale-up Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- FEBARMACRVKUOJ-UHFFFAOYSA-N N-phenyl-2,1-benzothiazol-3-amine Chemical compound N(c1snc2ccccc12)c1ccccc1 FEBARMACRVKUOJ-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HPZKAJRFABCGFF-UHFFFAOYSA-N 2-aminobenzenecarbothioamide Chemical compound NC(=S)C1=CC=CC=C1N HPZKAJRFABCGFF-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention provides a method for synthesizing 3-substituted aminobenzene [ c ] isothiazole derivatives, which takes amide N-substituted benzamide compounds as starting materials and obtains the 3-substituted aminobenzene [ c ] isothiazole derivatives through sulfur replacement reaction of carbonyl oxygen and ring closing reaction for 2 steps; the method for synthesizing the 3-substituted aminobenzo [ c ] isothiazole derivative has the advantages of short steps of the whole synthetic route, good repeatability, mild operating conditions and high safety, is favorable for scale-up production and industrial popularization, is favorable for application of green and environment-friendly industrial production, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of organic compound synthesis, in particular to a method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative.
Background
The 3-substituted aminobenzo [ c ] isothiazole derivative comprises an isothiazole heterocycle, and is an important intermediate compound for synthesizing various heterocyclic pharmaceutical compounds. The structure of the 3-substituted aminobenzo [ c ] isothiazole derivative is shown as the following formula:
currently, there are few reports on the synthesis of 3-substituted aminobenzo [ c ] isothiazole derivatives in the prior published documents, and the prior published synthesis method is to perform ring closure by 2-aminothiobenzamide, and then perform substitution reaction of substituted amino group after substituting halogen for unsubstituted amino group. The existing synthesis method has the defects of multiple steps, multiple side reactions, low conversion rate and yield, difficult separation and purification, harsh reaction conditions, poor operation safety and the like.
Accordingly, those skilled in the art have been devoted to developing a method for synthesizing 3-substituted aminobenzo [ c ] isothiazole derivatives, aiming at solving the drawbacks of the preparation methods of such compounds in the prior art.
Disclosure of Invention
The technical problem to be solved by the invention is that the preparation method of the 3-substituted aminobenzo [ c ] isothiazole derivative in the prior art has the defects of multiple steps, multiple side reactions, low conversion rate and yield, difficult separation and purification, harsh reaction conditions and poor operation safety.
To achieve the above objects, the present invention provides a method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative, comprising the steps of:
step 1, heating a compound A-1 and phosphorus pentasulfide in the presence of alkali and an organic solvent to raise the temperature for a thionation reaction, and carrying out post-treatment to obtain a compound A-2;
step 2, adding NBS and an organic solvent into the compound A-2, performing normal-temperature ring-closing reaction, and performing post-treatment to obtain a target product, namely the 3-substituted aminobenzo [ c ] isothiazole derivative;
wherein, the structure of the 3-substituted aminobenzo [ c ] isothiazole derivative is shown as the following formula A:
the synthetic method comprises the following route:
wherein R is1、R2Each independently selected from hydrogen, alkyl, aryl;
or, R1And R2And together with the N to which they are attached form a five to six membered ring;
further, the alkyl is C1-C10 straight chain or branched chain alkyl;
further, the aryl is aliphatic aryl of C5-C15, heterocyclic aryl containing 1-10 carbon atoms;
further, the alkyl, aryl groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, alkyl, cyano, amino, carbonyl, mercapto, alkylthio, acylamino, aryl;
further, said R1、R2Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl; wherein said methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl is unsubstituted or substituted by one or more substituents selected from the group consisting of: alkyl, halogen, aryl;
further, said R1、R2Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, pyridyl;
further, the organic solvent is one or more of tetrahydrofuran and dioxane;
further, in the step 1, the alkali is NaHCO3、Na2CO3、K2CO3One or more of (a);
further, in the step 1, the heating temperature is 50-80 ℃;
further, in the step 1, the reaction is carried out under an inert gas environment;
according to the method for synthesizing the 3-substituted aminobenzo [ c ] isothiazole derivative, in the step 1, the molar ratio of the compound A-1 to phosphorus pentasulfide is 1: 1.2-1: 1.6;
according to the method for synthesizing the 3-substituted aminobenzo [ c ] isothiazole derivative, in the step 1, the molar ratio of the compound A-1 to the alkali is 1: 1.5-1: 3;
according to the method for synthesizing the 3-substituted aminobenzo [ c ] isothiazole derivative, in the step 1, the weight-volume ratio (g: mL) of the compound A-1 to the organic solvent is 1: 10-1: 20;
according to the method for synthesizing the 3-substituted aminobenzo [ c ] isothiazole derivative, in the step 2, the molar ratio of the compound A-2 to NBS is 1: 1-1: 1.5;
according to the method for synthesizing the 3-substituted aminobenzo [ c ] isothiazole derivative, in the step 2, the weight-to-volume ratio (g: mL) of the compound A-2 to the organic solvent is 1: 10-1: 20;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the molar ratio of the compound a-1 to the phosphorus pentasulfide is 1: 1.2;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the molar ratio of the compound a-1 to the phosphorus pentasulfide is 1: 1.4;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the molar ratio of the compound a-1 to the phosphorus pentasulfide is 1: 1.6;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the molar ratio of the compound a-1 to the base is 1: 1.5;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the molar ratio of the compound a-1 to the base is 1: 2;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the molar ratio of the compound a-1 to the base is 1: 3;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the weight-to-volume ratio (g: mL) of the compound A-1 to the organic solvent is 1: 10;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the weight-to-volume ratio (g: mL) of the compound A-1 to the organic solvent is 1: 18;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the weight-to-volume ratio (g: mL) of the compound A-1 to the organic solvent is 1: 20;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the heating temperature is 50 ℃;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the heating temperature is 60 ℃;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 1, the heating temperature is 80 ℃;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, the step 1, the reaction is performed under an argon atmosphere;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, the step 1, the reaction is performed under a nitrogen atmosphere;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, said step 2, the molar ratio of compound a-2 to NBS is 1: 1;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 2, the molar ratio of the compound a-2 to NBS is 1: 1.3;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 2, the molar ratio of the compound a-2 to NBS is 1: 1.5;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 2, the weight to volume ratio (g: mL) of the compound A-2 to the organic solvent is 1: 10;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 2, the weight-to-volume ratio (g: mL) of the compound A-2 to the organic solvent is 1: 18;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, in the step 2, the weight-to-volume ratio (g: mL) of the compound A-2 to the organic solvent is 1: 20;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, the step 1 is specifically operated as follows: adding a compound A-1 and sodium bicarbonate into tetrahydrofuran, then adding phosphorus pentasulfide, replacing inert gas in a reaction system, heating to 50-80 ℃, stirring for reacting for 2-6 hours, and performing post-treatment to obtain a compound A-2; wherein the molar ratio of the compound A-1 to the sodium bicarbonate is 1: 1.5-1: 2; the molar ratio of the compound A-1 to the phosphorus pentasulfide is 1: 1.4-1: 1.6; the weight-to-volume ratio (g: mL) of the compound A-1 to tetrahydrofuran is 1: 18-1: 20;
according to a preferred embodiment of the method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative according to the present invention, the step 2 is specifically operated as follows: adding the compound A-2 into tetrahydrofuran, then adding NBS (N-bromosuccinimide) in batches, stirring at room temperature for reaction for 10-60 minutes, and carrying out aftertreatment to obtain a target product, namely the 3-substituted aminobenzo [ c ] isothiazole derivative (shown in a formula A); wherein the weight-to-volume ratio (g: mL) of the compound A-2 to tetrahydrofuran is 1: 18-1: 20; the molar ratio of the compound A-2 to NBS is 1: 1-1: 1.2; adding the mixture in batches into 2-4 batches;
the technical parameter characteristics in the above synthesis method of the invention can be combined at will.
In the above-mentioned operations, the post-treatment includes, but is not limited to, quenching with a quenching agent, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc., or one or more of water quenching, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc.
In a preferred embodiment of the invention, the extraction solvent is dichloromethane or ethyl acetate;
in a preferred embodiment of the present invention, the filtration refers to a process of separating solids and liquids in a reaction solution, or a process of separating solids and liquids in a post-treatment operation; the filtration comprises common filtration and separation and centrifugal separation; wherein, the common filtration separation includes but is not limited to filtration using filter cloth, membrane filtration, and diatomite filtration;
in a preferred embodiment of the present invention, the water washing, alkali washing, and acid washing include, but are not limited to, using a saturated sodium bicarbonate solution, a 5% potassium carbonate aqueous solution, a saturated brine;
in a preferred embodiment of the present invention, the drying comprises anhydrous sodium sulfate drying, vacuum drying of the filtrate;
in a preferred embodiment of the present invention, the concentration refers to a process of removing a liquid solvent, including concentration under reduced pressure, concentration under normal pressure, low-temperature spin-drying, etc.;
the steps, solvents, reagents, filtration, drying, concentration, extraction, washing, separation and the like in the preparation method of the formaldehyde-substituted aza-condensed ring compound can be combined or separated at will, and the purpose of the invention can be achieved.
The room temperature is 15 ~ 30 ℃.
The 3-substituted aminobenzo [ c ] isothiazole derivative is prepared by taking an amide N-substituted benzamide compound as an initial raw material and carrying out sulfur replacement reaction and ring closing reaction of carbonyl oxygen for 2 steps, and the whole synthetic method has the advantages of short route, mild reaction conditions and high safety; the operation repeatability of the route steps is good, the conversion rate and the yield are high, the energy consumption of post-treatment is low, and the purification operation is suitable for the operation of an enlarged workshop; the method does not produce a large amount of toxic wastewater, is environment-friendly, has no pollution to the environment, reduces the safety level and the production cost of production, is beneficial to the application of environment-friendly industrial production, and has wide application prospect.
Detailed Description
The following describes preferred embodiments of the present invention to make the technical contents thereof clearer and easier to understand. The invention may be embodied in many different forms of embodiments, which are intended to be illustrative only, and the scope of the invention is not intended to be limited to the embodiments shown herein.
If there is an experimental method not specified specific conditions, it is usually carried out according to conventional conditions, such as the relevant instructions or manuals.
Example 1, R1、R2And together with the N to which they are attached form a six-membered ring
Step 1, adding sodium bicarbonate (230mg) into a tetrahydrofuran (5mL) solution of A1-1(278mg), then adding phosphorus pentasulfide (424mg), replacing the reaction system with argon, heating to 60 ℃, and stirring for 3 hours; after the reaction was completed, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried at low temperature, and the residue was purified by column chromatography to give (2-aminophenyl) (piperidin-1-yl) methylsulfan) compound (a1-2) (reddish brown oily substance, 142mg, yield 47%).
Step 2, adding N-bromosuccinimide (NBS) (115mg) in two portions to a tetrahydrofuran (2.5mL) solution of A1-2(142mg), and stirring at room temperature for 15 minutes; after the reaction was completed, the reaction mixture was extracted with ethyl acetate, the organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was dried by spinning at low temperature, and the residue was purified by high performance liquid chromatography to give the objective compound 3- (piperidin-1-yl) benzo [ c ] isothiazole (a1) (pale yellow oily substance, 108mg, yield 77%).
The 3- (piperidin-1-yl) benzo [ c ] isothiazole (a1) obtained above was subjected to structural NMR measurement, and the measurement results were as follows:
1H NMR(400MHz,DMSO-d6)7.80(d,J＝8.7Hz,1H),7.44(d,J＝8.9Hz,1H),7.34–7.22(m,1H),6.95(dd,J＝8.3,6.7Hz,1H),3.55–3.40(m,4H),1.86–1.71(m,4H),1.66–1.55(m,2H)。
the detection result shows that the synthesized compound 3- (piperidine-1-yl) benzo [ c ] isothiazole has a correct structure.
Example 2, R1、R2Each independently selected from hydrogen and phenyl
Step 1, adding sodium bicarbonate (222mg) into a tetrahydrofuran (5mL) solution of a compound A2-1(280mg), then adding phosphorus pentasulfide (411mg), replacing a reaction system with nitrogen, heating to 50 ℃, and stirring for 6 hours; after the reaction was completed, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried at low temperature, and the residue was purified by column chromatography to give the compound 2-amino-N-benzothioamide (a2-2) (reddish brown solid, 138mg, yield 46%).
Step 2, adding N-bromosuccinimide (NBS) (106mg) into a tetrahydrofuran (2.5mL) solution of A2-2(138mg) in two portions, and stirring at room temperature for 30 minutes; after the reaction was completed, ethyl acetate was added to the reaction solution to extract, the organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was dried by spinning at low temperature, and the residue was purified by high performance liquid chromatography to give the objective compound N-phenylbenzo [ c ] isothiazol-3-amine (a2) (pale yellow solid, 104mg, yield 76%).
The structure NM detection is carried out on the obtained N-phenylbenzo [ c ] isothiazol-3-amine (A2), and the detection result is as follows:
1H NMR(400MHz,DMSO-d6)10.35(s,1H),8.11(d,J＝8.6Hz,1H),7.55–7.41(m,5H),7.39–7.33(m,1H),7.10(t,J＝7.0Hz,1H),7.06–6.96(m,J＝8.2,6.8Hz,1H)
the detection result shows that the synthesized compound N-phenylbenzo [ c ] isothiazole-3-amine has a correct structure.
Example 3, R1、R2Each independently selected from methyl and ethyl
Step 1, adding sodium carbonate (706mg) into a dioxane (10mL) solution of a compound A3-1(1g), then adding phosphorus pentasulfide (1.5g), replacing a reaction system with nitrogen, heating to 80 ℃, and stirring for 2 hours; after the reaction was completed, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried at low temperature, and the residue was purified by column chromatography to give the compound 2-amino-N-methyl-N-ethylthiobenzamide (a3-2) (red oil, 741mg, yield 68%).
Step 2, adding N-bromosuccinimide (NBS) (555mg) into a tetrahydrofuran (5mL) solution of A3-2(500mg) in two portions, and stirring at room temperature for 60 minutes; after the reaction, ethyl acetate was added to the reaction solution to extract, the organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was dried by spinning at low temperature, and the residue was purified by high performance liquid chromatography to give the target compound N-methyl-N-ethylbenzo [ c ] isothiazol-3-amine (a3) (pale yellow oily substance, 420mg, yield 85%).
Example 4, R1、R2Each independently selected from methyl and pyridyl
Step 1, adding potassium carbonate (1.1g) into a tetrahydrofuran (20mL) solution of a compound A4-1(1g), then adding phosphorus pentasulfide (1.55g), replacing the reaction system with argon, heating to 50 ℃, and stirring for 4 hours; after the reaction was completed, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried at low temperature, and the residue was purified by column chromatography to give the compound 2-amino-N-2-pyridothioamide (a4-2) (reddish brown solid, 630mg, yield 59%).
Step 2, adding N-bromosuccinimide (NBS) (556mg) into a tetrahydrofuran (10mL) solution of A4-2(500mg) in three portions, and stirring at room temperature for 10 minutes; after the reaction was completed, the reaction mixture was extracted with ethyl acetate, the organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was spun dry at low temperature, and the residue was purified by high performance liquid chromatography to give the objective compound N-2-pyridylbenzo [ c ] isothiazol-3-amine (a4) (pale yellow solid, 395mg, yield 82%).
Purity detection is carried out on the 3-substituted aminobenzo [ c ] isothiazole derivative (shown in the formula A) of the product compound obtained in the embodiments 1 to 4, and the detection result shows that the purity of the 3-substituted aminobenzo [ c ] isothiazole derivative (shown in the formula A) of the product compound obtained in the embodiments 1 to 4 is more than 99.5%;
in conclusion, the 3-substituted aminobenzo [ c ] isothiazole derivative (shown in the formula A) obtained in the embodiment of the invention has the advantages of correct structure, high purity, low impurity content and excellent quality.
The 3-substituted aminobenzo [ c ] isothiazole derivative (formula A) obtained by the method of other embodiments and technical schemes of the invention has similar beneficial effects as described above.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (10)
1. A method for synthesizing a 3-substituted aminobenzo [ c ] isothiazole derivative, comprising the steps of:
step 1, heating a compound A-1 and phosphorus pentasulfide in the presence of alkali and an organic solvent to raise the temperature for a thionation reaction, and carrying out post-treatment to obtain a compound A-2;
step 2, adding NBS and an organic solvent into the compound A-2, performing normal-temperature ring-closing reaction, and performing post-treatment to obtain a target product, namely the 3-substituted aminobenzo [ c ] isothiazole derivative;
wherein, the structure of the 3-substituted aminobenzo [ c ] isothiazole derivative is shown as the following formula A:
the synthetic method comprises the following route:
wherein R is1、R2Each independently selected from hydrogen, alkyl, aryl;
or, R1And R2And together with the N to which they are attached form a five to six membered ring.
2. The method of claim 1,
the alkyl is C1-C10 straight chain or branched chain alkyl;
the aryl is C5-C15 aliphatic aryl and heterocyclic aryl containing 1-10 carbon atoms.
3. The method of claim 1,
the alkyl, aryl groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, alkyl, cyano, amino, carbonyl, mercapto, alkylthio, acylamino, aryl.
4. The method of claim 1,
the R is1、R2Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl; wherein said methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl is unsubstituted or substituted by one or more substituents selected from the group consisting of: alkyl, halogen, aryl.
5. The method of claim 1, wherein R is1、R2Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, pyridyl.
6. The method according to claim 1, wherein the organic solvent is one or more of tetrahydrofuran and dioxane.
7. The method according to claim 1, wherein in the step 1,
the base is NaHCO3、Na2CO3、K2CO3One or more of (a);
the heating temperature is 50-80 ℃;
the reaction is carried out under an inert gas environment.
8. The method according to claim 1, wherein in the step 1,
the molar ratio of the compound A-1 to the phosphorus pentasulfide is 1: 1.2-1: 1.6;
the molar ratio of the compound A-1 to the alkali is 1: 1.5-1: 3;
the weight-volume ratio of the compound A-1 to the organic solvent is 1: 10-1: 20.
9. The method according to claim 1, wherein, in the step 2,
the molar ratio of the compound A-2 to NBS is 1: 1-1: 1.5;
the weight-volume ratio of the compound A-2 to the organic solvent is 1: 10-1: 20.
10. The 3-substituted aminobenzo [ c ] isothiazole derivative synthesized by the method of any one of claims 1-9 is characterized in that the purity of the 3-substituted aminobenzo [ c ] isothiazole derivative product is more than 99.5%.
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