CN106699614A - Amplified synthesis method of 3-nitro-4-halogeno-benzenesulfonamide - Google Patents
Amplified synthesis method of 3-nitro-4-halogeno-benzenesulfonamide Download PDFInfo
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- CN106699614A CN106699614A CN201510428095.1A CN201510428095A CN106699614A CN 106699614 A CN106699614 A CN 106699614A CN 201510428095 A CN201510428095 A CN 201510428095A CN 106699614 A CN106699614 A CN 106699614A
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Abstract
An amplified synthesis method of 3-nitro-4-halogeno-benzenesulfonamide is disclosed. According to the method, 4-halogeno-benzenesulfonyl chloride which is used as a raw material undergoes nitration to prepare 3-nitro-4-halogeno-benzenesulfonyl chloride; and after aminolysis, 3-nitro-4-halogeno-benzenesulfonamide is prepared. By the synthesis method provided by the invention, the synthesis route by the adoption of chlorosulfonic acid is changed, and production safety is remarkably raised. The reaction condition is milder and is easy for production control. Thus, mass production of the compound is easier to implement and realize.
Description
Technical field
The present invention relates to a kind of substituted benzsulfamide synthetic method, more particularly to a kind of 3- nitros -4- halo benzsulfamides
Synthetic method so that the synthesis to this kind of compound is safer, realizes scale.
Background technology
3- nitro -4- halogen benzsulfamide series compounds are wide spectrum anti-apoptotic Bcl-2 family protein micromolecular inhibitors
(Bioorganic and Medicinal Chemistry Letters, 2012,22 (1), 39-44, Journal of Medicinal
Chemistry, 2006,49 (3), 1165-1181, and US2002/55631A1) important intermediate.The compound leads to
Cross halogenated nitrobenzene to be reacted with chlorosulfonic acid, then be obtained through reduction, it is necessary to using substantial amounts of chlorosulfonic acid, the reagent belongs to severe toxicity
Product, the safety in production to product brings hidden danger.In large-scale production, the post processing for producing waste liquid is also costly, also can
Environment is adversely affected.
With regard to general understanding, sulfuryl chlorio has passivation to phenyl ring, and especially phenyl ring also simultaneously there is halogen to replace,
Its nitrifying process seems particularly difficult, the document announcement for also not having correlation.Accordingly, it is difficult to use halo benzene sulfonyl chloride for former
Material is nitrified, and then the halo benzene sulfonyl chloride of nitration is obtained.
The content of the invention
It is an object of the present invention to provide a kind of synthetic method of 3- nitros -4- halo benzsulfamides, it is to avoid use chlorine sulphur
Acid, improves the security that compound is produced.
It is another object of the present invention to provide a kind of synthetic method of 3- nitros -4- halo benzsulfamides, compound is realized
Scale be combined to, significantly reduce the harmful effect to environment.
A further object of the present invention is to provide a kind of synthetic method of 3- nitros -4- halo benzsulfamides, realizes compound
Scale be combined to, effectively reduce product production cost.
A kind of synthetic method of 3- nitros -4- halo benzsulfamides that the present invention is provided, comprises the following steps：
Nitrified by raw material of 4- halos benzene sulfonyl chloride, 3- nitro -4- halo benzene sulfonyl chlorides are obtained, then be obtained after ammonolysis
3- nitro -4- halo benzsulfamides.
Suitable nitration condition is such as：The concentrated sulfuric acid (1V~10V/g) is first added, fuming nitric aicd (0.95~1.5eq.) is subsequently adding,
3- nitro -4- halo benzene sulfonyl chlorides are overnight obtained in 20 DEG C~100 DEG C.Familiar to those skilled in the art, can also use it
Its agent combination realizes nitrification, such as：But it is not limited only to NaNO3/ dense H2SO4、KNO3/ dense H2SO4, concentrated nitric acid/tri-
Fluoroacetic acid, concentrated nitric acid/acetic acid, concentrated nitric acid/dichloromethane, concentrated nitric acid/dichloroethanes and concentrated nitric acid/chloroform etc..
Ammonolysis are to add ammoniacal liquor, and appropriate addition solvent to reactant, such as：But it is not limited only to water and isopropanol etc..Ammonia
Xie Hou, should also add appropriate acid that the pH of reaction solution is adjusted into 1-2.
4- halos benzene sulfonyl chloride is selected from 4- fluoro benzene sulfonyl chloride, 4- chlorobenzenesulfonyl chlorides, 4- bromos benzene sulfonyl chloride and 4- iodine
One or more for benzene sulfonyl chloride.
The beneficial effect that technical solution of the present invention is realized：
The present invention provide 3- nitro -4- halo benzsulfamides synthetic method, with 4- halos benzene sulfonyl chloride be raw material through nitrify
Produced with ammonolysis, changed using the synthetic route of chlorosulfonic acid, significantly improve the security of production so that the compound
Large-scale production be more easily performed and realize.
The synthetic method of the 3- nitro -4- halo benzsulfamides that the present invention is provided, reaction condition milder, it is easy to production control,
Produced waste material is few, and the harmful effect to environment is significantly reduced, and production cost is also effectively controlled.
Specific embodiment
Technical scheme described in detail below.The embodiment of the present invention be merely illustrative of the technical solution of the present invention rather than
Limitation, although being described in detail to the present invention with reference to preferred embodiment, it will be understood by those within the art that,
The technical scheme invented can be modified or equivalent, without deviating from the spirit and scope of technical solution of the present invention,
It all should cover in scope of the presently claimed invention.
Embodiment 1 3- nitro -4- fluoro benzene fulfonic amides are produced
The first step：4- fluoro benzene sulfonyl chlorides 180g (0.925mol, 1eq), and the concentrated sulfuric acid are added in 1L reaction vessels
540mL (3V/g), stirring rises to 30 DEG C, and fuming nitric aicd 61g (0.925mol, 1eq) is added dropwise, and maintains the temperature at 65 DEG C
Below.After adding, 56 DEG C are stirred overnight, be obtained 3- nitro -4- fluoro benzene sulfonyl chloride (1H-NMR(300MHz,CDCl3,ppm):
δ7.64(1H,t,C-H),8.34-8.39(1H,m,C-H),8.80(1H,dd,C-H)；GC 97%；EI:239).
Second step：Ammoniacal liquor 1580mL, isopropanol 1L and water 1.5L are added in 5L reaction vessels, stirring is cooled to -40 DEG C,
3- nitro -4- fluoro benzene sulfonyl chlorides are added dropwise again, less than -20 DEG C are maintained the temperature at.After dripping, pH value is 8, insulated and stirred
Half an hour, then HCl30ml is added dropwise, less than -20 DEG C are maintained the temperature at, adjust pH=1-2.Removal isopropanol, adds water 1L,
Mashing filtering, dried 140g 3- nitros -4- fluoro benzene fulfonic amide (1H-NMR(300MHz,d6-DMSO,ppm):δ
7.71(2H,m,N-H),7.78(1H,t,C-H),8.17-8.19(1H,m,C-H),8.51(1H,d,C-H)；ESI-:219.3), always
Yield：68%, LC >=99%, m.p.135 DEG C~144 DEG C.
Embodiment 2 3- nitro -4- chloro benzene fulfonic amides are produced
500mL dense H2SO4, parachloroben-zenesulfonyl chloride 190g (0.9mol, 1eq) is added to be warming up to 30 DEG C in 1L there-necked flasks,
Fuming nitric aicd 56.7g (0.9mol, 1eq) is added dropwise and maintains the temperature at less than 60 DEG C, interior 55 DEG C of temperature is stirred overnight after adding, TLC
(PE/EA=10/1) detection has been reacted, and cooling is poured into frozen water, adds DCM extractions, is dried, and filtering is concentrated to give 3-
Nitro -4- chlorobenzenesulfonyl chlorides (1H-NMR(300MHz,CDCl3,ppm):δ8.09(2H,s,C-H),8.50(1H,m,
C-H)), white crystal 163g, yield 71%.
350mL water is added in 1L there-necked flasks, 250mL isopropanols, 47g ammoniacal liquor (0.69mol, 3eq), stirring is cooled to -40 DEG C,
Dropwise addition is dissolved in 3- nitros -4- chlorobenzene sulfonyl chlorides 58g (0.23mol, 1eq) of 100ml, keeps T<- 20 DEG C, it is incubated after dripping off
0.5h, TLC detect (PE/EA=5/1) without raw material, and hydrochloric acid regulation pH=1-2 is added dropwise, and keep T<- 20 DEG C, after having adjusted
Recover room temperature, most of isopropanol is removed in rotation, is filtered, filter cake washing, EA dissolving filter cakes are dried, filtering is spin-dried for obtaining 3-
Nitro -4- chloros benzene fulfonic amide (1H-NMR(400MHz,d6-DMSO,ppm):δ7.77(2H,m,N-H),8.03(1H,d,
C-H),8.09(1H,d,C-H),8.47(1H,s,C-H)；ESI-:235.2), pale yellow crystals 36g, yield 66%, LC=99.7%,
M.p.177 DEG C~179 DEG C.
Embodiment 3 3- nitro -4- bromo benzene fulfonic amides are produced
Concentrated sulfuric acid 500mL (3V/g) and 4- bromobenzene sulfonyl chlorides 200g (0.783mol, 1.0eq), drop are added in 1L there-necked flasks
Plus fuming nitric aicd 52g (0.784mol, 1.0eq), 60 degree are reacted 2 hours, TLC (PE:EA=5:1) raw material reaction is complete,
Cooling, pours into 2L frozen water, DCM extractions, dries, and is threaded to small size, adds petroleum ether, cooling crystallization to filter,
Petroleum ether drip washing, obtain 3- nitro -4- bromos benzene sulfonyl chloride (1H-NMR(300MHz,CDCl3,ppm):δ8.09(2H,s,C-H),
8.50 (1H, m, C-H)), yellow solid 225g, yield：95.7%.
Isopropanol 500mL, ammoniacal liquor 100mL, water 500mL are added in 2L there-necked flasks, -20 degree are lower to be added dropwise above-mentioned product 79g
(0.264mol, 1.0eq) is dissolved in 100mlDCM, drips off stirring 1 hour, TLC (PE:EA=1:1) raw material reaction is complete
Entirely, then it is added dropwise watery hydrochloric acid to pH=1, isopropanol is removed in rotation, and add water 1L, and filtering, filter cake column chromatography is spin-dried for obtaining 3- nitros -4-
Bromo benzene fulfonic amide (1H-NMR(400MHz,d6-DMSO,ppm):δ8.38(1H,s,C-H),8.14(1H,d,C-H),7.95
(1H,d,C-H),7.71(2H,m,N-H)；ESI-:279.1,281.1), yellow solid 47.5g, yield 64.2%, two steps are always received
Rate is 61.4%；LC=97.7%, m.p.181 DEG C~185 DEG C.
Claims (6)
1. a kind of synthetic method of 3- nitros -4- halo benzsulfamides, comprises the following steps：
Nitrified by raw material of 4- halos benzene sulfonyl chloride, 3- nitro -4- halo benzene sulfonyl chlorides are obtained, then be obtained after ammonolysis
3- nitro -4- halo benzsulfamides.
2. the synthetic method of 3- nitros -4- halo benzsulfamides according to claim 1, it is characterised in that described
4- halos benzene sulfonyl chloride is selected from 4- fluoro benzene sulfonyl chloride, 4- chlorobenzenesulfonyl chlorides, 4- bromos benzene sulfonyl chloride and 4- iodobenzene sulphurs
One or more of acyl chlorides.
3. the synthetic method of 3- nitros -4- halo benzsulfamides according to claim 1, it is characterised in that described
Nitrification first adds the concentrated sulfuric acid, adds fuming nitric aicd.
4. the synthetic method of 3- nitros -4- halo benzsulfamides according to claim 1, it is characterised in that described
Nitrification should be in 56 DEG C, overnight.
5. the synthetic method of 3- nitros -4- halo benzsulfamides according to claim 1, it is characterised in that described
The agent combination that nitrification is used is selected from NaNO3/ dense H2SO4、KNO3/ dense H2SO4, concentrated nitric acid/trifluoroacetic acid, dense nitre
One or more of acid/acetic acid, concentrated nitric acid/dichloromethane, concentrated nitric acid/dichloroethanes and concentrated nitric acid/chloroform.
6. the synthetic method of 3- nitros -4- halo benzsulfamides according to claim 1, it is characterised in that described
Ammonolysis after, add acid the pH of reaction solution is adjusted to 1-2.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456231A (en) * | 2018-12-13 | 2019-03-12 | 临海市奥特休闲用品股份有限公司 | A kind of preparation method of 2- nitro-chlorobenzene -4- sulfonamide |
| CN109942434A (en) * | 2019-03-26 | 2019-06-28 | 山东世纪阳光科技有限公司 | A kind of production method of large red-based g |
| CN115872963A (en) * | 2022-12-27 | 2023-03-31 | 南京哈柏医药科技有限公司 | Synthetic method of Venetork intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020055631A1 (en) * | 2000-09-20 | 2002-05-09 | Augeri David J. | N-acylsulfonamide apoptosis promoters |
| CN1660800A (en) * | 2004-12-04 | 2005-08-31 | 浙江工业大学 | 2(2-chlorine-4-phenyl fluoride) bisulfide, preparation and aplication |
| CN101119981A (en) * | 2004-12-21 | 2008-02-06 | 阿斯利康(瑞典)有限公司 | New benzothiazolesulfonamides |
| CN104592064A (en) * | 2014-12-30 | 2015-05-06 | 青岛双桃精细化工（集团）有限公司 | Synthetic method of 2-aminophenol-4-sulfonamide |
-
2015
- 2015-07-20 CN CN201510428095.1A patent/CN106699614B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020055631A1 (en) * | 2000-09-20 | 2002-05-09 | Augeri David J. | N-acylsulfonamide apoptosis promoters |
| CN1660800A (en) * | 2004-12-04 | 2005-08-31 | 浙江工业大学 | 2(2-chlorine-4-phenyl fluoride) bisulfide, preparation and aplication |
| CN101119981A (en) * | 2004-12-21 | 2008-02-06 | 阿斯利康(瑞典)有限公司 | New benzothiazolesulfonamides |
| CN104592064A (en) * | 2014-12-30 | 2015-05-06 | 青岛双桃精细化工（集团）有限公司 | Synthetic method of 2-aminophenol-4-sulfonamide |
Non-Patent Citations (1)
| Title |
|---|
| TRIFILENKOV A. S.等: "Synthesis of new sulfonamide derivatives of 2H-1,4-benzothiazine-3(4H)-one", 《IZVESTIYA VYSSHIKH UCHEBNYKH ZAVEDENII, KHIMIYA I KHIMICHESKAYA TEKHNOLOGIYA》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456231A (en) * | 2018-12-13 | 2019-03-12 | 临海市奥特休闲用品股份有限公司 | A kind of preparation method of 2- nitro-chlorobenzene -4- sulfonamide |
| CN109942434A (en) * | 2019-03-26 | 2019-06-28 | 山东世纪阳光科技有限公司 | A kind of production method of large red-based g |
| CN115872963A (en) * | 2022-12-27 | 2023-03-31 | 南京哈柏医药科技有限公司 | Synthetic method of Venetork intermediate |
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