CN106699614B - The halogenated benzsulfamide scalable synthesis methods of 3- nitros -4- - Google Patents
The halogenated benzsulfamide scalable synthesis methods of 3- nitros -4- Download PDFInfo
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- CN106699614B CN106699614B CN201510428095.1A CN201510428095A CN106699614B CN 106699614 B CN106699614 B CN 106699614B CN 201510428095 A CN201510428095 A CN 201510428095A CN 106699614 B CN106699614 B CN 106699614B
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Abstract
A kind of synthetic method of the halogenated benzsulfamides of 3- nitros -4-, is nitrified using the halogenated benzene sulfonyl chlorides of 4- as raw material, the halogenated benzene sulfonyl chlorides of 3- nitros -4- is made, then the halogenated benzsulfamides of 3- nitros -4- are made after ammonolysis.Synthetic method provided by the invention changes the synthetic route using chlorosulfonic acid, significantly improves the safety of production, and reaction condition milder is readily produced control so that the large-scale production of the compound is more easily performed and realizes.
Description
Technical field
The present invention relates to a kind of substituted benzsulfamide synthetic method more particularly to a kind of halogenated benzene sulfonyls of 3- nitros -4-
The synthetic method of amine so that it is safer to the synthesis of this kind of compound, realize scale.
Background technology
3- nitro -4- halogen benzsulfamide series compounds are wide spectrum anti-apoptotic Bcl-2 family protein little molecules in inhibiting
Agent (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 change
It closes object to react with chlorosulfonic acid by halogenated nitrobenzene, then is made through restoring, need that a large amount of chlorosulfonic acid, the reagent is used to belong to acute
Drugs bring hidden danger to the safety in production of product.In large-scale production, the post-processing for producing waste liquid is also costly, also can be right
Environment adversely affects.
With regard to general understanding, sulfuryl chlorio there is passivation, especially phenyl ring also to have halogen substitution simultaneously phenyl ring,
Its nitrifying process seems particularly difficult, does not also there is relevant document announcement.Accordingly, it is difficult to use halogenated benzene sulfonyl chloride for raw material into
Row nitrification, and then the halogenated benzene sulfonyl chloride of nitration is made.
Invention content
It is an object of the present invention to provide a kind of synthetic methods of the halogenated benzsulfamides of 3- nitros -4-, avoid using
Chlorosulfonic acid improves the safety that compound is produced.
It is another object of the present invention to provide a kind of synthetic method of the halogenated benzsulfamides of 3- nitros -4-, realizationizations
The scale for closing object is combined to, and significantly reduces the harmful effect to environment.
A further object of the present invention is to provide a kind of 3- nitros -4- synthetic methods of halogenated benzsulfamide, realizationization
The scale for closing object is combined to, and effectively reduces the production cost of product.
A kind of synthetic method of the halogenated benzsulfamides of 3- nitros -4- provided by the invention, includes the following steps：
It is nitrified as raw material using the halogenated benzene sulfonyl chlorides of 4-, the halogenated benzene sulfonyl chlorides of 3- nitros -4- is made, then made after ammonolysis
Obtain the halogenated benzsulfamides of 3- nitros -4-.
Suitable nitration condition is such as：First be added the concentrated sulfuric acid (1V~10V/g), then be added fuming nitric aicd (0.95~
1.5eq.), the halogenated benzene sulfonyl chlorides of 3- nitros -4- are made overnight in 20 DEG C~100 DEG C.Familiar to those skilled in the art, also
Other reagent combinations can be used and realize 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..
Ammonium hydroxide, and addition solvent appropriate is added to reactant in ammonolysis, such as：But be not limited only to water and isopropanol etc..Ammonia
Xie Hou should also be added acid appropriate and the pH of reaction solution is adjusted to 1-2.
The halogenated benzene sulfonyl chlorides of 4- are selected from 4- fluoro benzene sulfonyl chloride, 4- chlorobenzenesulfonyl chlorides, 4- bromos benzene sulfonyl chloride and 4-
One of iodo benzene sulfonyl chloride kind or several.
The advantageous effect that technical solution of the present invention is realized：
The synthetic method of the halogenated benzsulfamides of 3- nitros -4- provided by the invention is passed through by raw material of the halogenated benzene sulfonyl chlorides of 4-
Nitrification and ammonolysis are produced, and are changed the synthetic route using chlorosulfonic acid, are significantly improved the safety of production so that the compound
Large-scale production be more easily performed and realize.
The synthetic method of the halogenated benzsulfamides of 3- nitros -4- provided by the invention, reaction condition milder are readily produced control
System, generated waste material is few, is significantly reduced to the harmful effect of environment, production cost is also effectively controlled.
Specific implementation mode
Technical scheme of the present invention described in detail below.The embodiment of the present invention be merely illustrative of the technical solution of the present invention and
It is unrestricted, although being described the invention in detail with reference to preferred embodiment, it will be understood by those of ordinary skill in the art that,
The technical solution of invention can be modified or replaced equivalently, without departing from the spirit of the technical scheme of the invention and range,
It should all cover in scope of the presently claimed invention.
1 3- nitro -4- fluoro benzene fulfonic amides of embodiment are produced
The first step：4- fluoro benzene sulfonyl chloride 180g (0.925mol, 1eq) and the concentrated sulfuric acid are added in 1L reaction vessels
540mL (3V/g), stirring rise to 30 DEG C, and fuming nitric aicd 61g (0.925mol, 1eq) is added dropwise, maintains the temperature at 65 DEG C or less.Add
After complete, 56 DEG C are stirred overnight, be made 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：Ammonium hydroxide 1580mL, isopropanol 1L and water 1.5L are added in 5L reaction vessels, stirring is cooled to -40
DEG C, then 3- nitro -4- fluoro benzene sulfonyl chlorides are added dropwise, maintain the temperature at -20 DEG C or less.After dripping, pH value 8, insulated and stirred
Half an hour, then HCl30ml is added dropwise, -20 DEG C are maintained the temperature at hereinafter, adjusting pH=1-2.Isopropanol is removed, 1L is added water, was beaten
Filter, it is dry after 140g 3- nitro -4- fluoro benzene fulfonic amide (1H-NMR(300MHz,d6-DMSO,ppm):δ7.71(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), total recovery：
68%, LC >=99%, m.p.135 DEG C~144 DEG C.
2 3- nitro -4- chloro benzene fulfonic amides of embodiment are produced
500mL dense H2SO4, parachloroben-zenesulfonyl chloride 190g (0.9mol, 1eq) are added in 1L there-necked flasks and is warming up to 30 DEG C, drop
Add fuming nitric aicd 56.7g (0.9mol, 1eq) to maintain the temperature at 60 DEG C to be stirred overnight hereinafter, adding 55 DEG C of temperature in rear, TLC (PE/
EA=10/1) detection has been reacted, and cooling is poured into ice water, and DCM extractions are added, and dry, filtering is concentrated to give 3- nitro -4- chloros
Benzene sulfonyl chloride (1H-NMR(300MHz,CDCl3,ppm):δ 8.09 (2H, s, C-H), 8.50 (1H, m, C-H)), white crystal
163g, yield 71%.
350mL water, 250mL isopropanols are added in 1L there-necked flasks, 47g ammonium hydroxide (0.69mol, 3eq) stirs and is cooled to -40
DEG C, the 3- nitro -4- chlorobenzene sulfonyl chlorides 58g (0.23mol, 1eq) for being dissolved in 100ml are added dropwise, keep T<It -20 DEG C, is kept the temperature after dripping off
0.5h, TLC detect (PE/EA=5/1) without raw material, and hydrochloric acid is added dropwise and adjusts pH=1-2, keeps T<- 20 DEG C, recovery room after having adjusted
Most of isopropanol is removed in temperature, rotation, filters, filter cake washing, and EA dissolving filter cakes are dry, and filtering is spin-dried for obtaining 3- nitro -4- chlorobenzenes
Sulphonyl ammonia (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℃。
3 3- nitro -4- bromo benzene fulfonic amides of embodiment are produced
Concentrated sulfuric acid 500mL (3V/g) and 4- bromobenzene sulfonyl chlorides 200g (0.783mol, 1.0eq) is added in 1L there-necked flasks,
Fuming nitric aicd 52g (0.784mol, 1.0eq) is added dropwise, 60 degree are reacted 2 hours, TLC (PE:EA=5:1) the reaction was complete for raw material, drop
Temperature is poured into 2L ice water, DCM extractions, dry, is threaded to small size, and petroleum ether is added, and cooling crystallization filters, petroleum ether elution,
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, ammonium hydroxide 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) the reaction was complete for raw material, then is added dropwise
Dilute hydrochloric acid to pH=1, rotation removes isopropanol, adds water 1L, filters, filter cake column chromatography is spin-dried for obtaining 3- nitro -4- bromo benzene fulfonic amides
(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 step total recoverys are 61.4%；
LC=97.7%, m.p.181 DEG C~185 DEG C.
Claims (2)
1. a kind of synthetic method of the halogenated benzsulfamides of 3- nitros -4-, which is characterized in that include the following steps：
It is nitrified as raw material using the halogenated benzene sulfonyl chlorides of 4-, the halogenated benzene sulfonyl chlorides of 3- nitros -4- is made, then 3- is made after ammonolysis
The halogenated benzsulfamides of nitro -4-；
The nitrification is that the concentrated sulfuric acid is first added, and adds fuming nitric aicd；The nitrification is reacted in 56 DEG C, overnight；?
After the ammonolysis, acid is added, the pH of reaction solution is adjusted to 1-2.
2. the synthetic method of the halogenated benzsulfamides of 3- nitros -4- according to claim 1, which is characterized in that the 4-
Halogenated benzene sulfonyl chloride is selected from 4- fluoro benzene sulfonyl chloride, 4- chlorobenzenesulfonyl chlorides, 4- bromos benzene sulfonyl chloride and 4- iodo benzene sulfonyls
The one or more of chlorine.
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| 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 |
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| 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 |
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