CN103922975B - Synthesis method of sulfonamide compound - Google Patents
Synthesis method of sulfonamide compound Download PDFInfo
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- CN103922975B CN103922975B CN201410144073.8A CN201410144073A CN103922975B CN 103922975 B CN103922975 B CN 103922975B CN 201410144073 A CN201410144073 A CN 201410144073A CN 103922975 B CN103922975 B CN 103922975B
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Abstract
The invention relates to a synthesis method of a sulfonamide compound, which comprises the following steps of by taking mercaptan and an amide compound as raw material in open air environment, carrying out reaction under the synergistic action of a catalyst, an oxidant and an assistant to prepare the sulfonamide compound. The method is capable of widening the application range of the substrates, has the advantages of high reaction yield, high product purity and the like, and has wide industrial application prospect and market potential.
Description
Technical field
The present invention relates to a kind of synthetic method of sulfamide compound, relate more specifically to a kind of synthetic method being prepared sulphonamide by mercaptan and Carbox amide, belong to organic chemical synthesis field.
Background technology
Sulfamide compound has biological activity widely, and it is as the very important pharmaceutical intermediate of one, has now been widely used in the fields such as industry medicine, organic synthesis.
Traditional sulphonamide synthetic method relates generally to: the reaction of (1) SULPHURYL CHLORIDE or sulphonate and amine is [see " Facile One-Pot Synthesis of Aromatic and HeteroaromaticSulfonamides ", J.Org.Chem., 2003,68,8274-8276]; (2) the substituted or non-substituted sulphonamide of N-and amine or organic halogen compound react [see " Palladium-CatalyzedIntermolecular Coupling of Aryl Halides and Amides ", Organic Letters, 2000,2 (8), 1101-1104]; (3) reaction [see " Hydrous zinc halide-catalyzed aminosulfonation of hydrocarbon ", Chem.Commun., 2008,4291-4293] of sulphonamide and hydrocarbon compound.
Although these methods all relate to constructing of S-N key, but there is inherent defect, the such as substrate scope of application is narrower, reaction relates to multiple step, needs strong oxidizer or high toxicity reagent.As can be seen here, the industrial synthetic process developing a kind of novel, efficient sulfamide compound is the key issue that organic, chemical industry, medicine and other fields face.
Nowadays, organic catalysis synthetic chemistry becomes the new way of the numerous chemical industry of synthesis, medicine intermediate gradually, and the synthesis of sulfamide compound is no exception.Such as:
Tang Xiaodong etc. (" Copper-catalyzed sulfonamides formation fromsodium sulfinates and amines ", Chem.Commun., 2013,49, what 6102-6104) report a kind of copper catalysis prepares the method for sulphonamide by-sulfinic acid sodium and amine through oxidative coupling reaction, it has higher yield and chemo-selective, and reaction formula is as follows:
Nobukazu Taniguchi etc. (" Copper-Catalyzed Formation of Sulfur-Nitrogen Bonds by Dehydrocoupling of Thiols with Amines ", Eur.J.Org.Chem., 2010,2670-2673) report a kind of formation method of S-N key, it adopts aryl mercaptan and amine to be raw material, under the effect of copper catalyst in air or oxygen atmosphere, reaction prepares sulfamide compound, and its reaction formula is as follows:
Although there is the synthetic method of many sulfone amide derivatives in prior art, but, these methods are limited to the kind of substrate and range of application is extensive not, there is reaction yield excellent not simultaneously, still fully can not adapt to the needs of current chemical industry, medicine intermediate synthesis field development.As can be seen here, effectively widened the source of substrate or raw material by scientific exploration with the preparation technology of development of new sulphonamide, and improve reaction yield further, this has become a large target of numerous researcher.
The problems that the present inventor exists for prior art, are intended to the Novel synthesis technology developing a kind of sulfamide compound, thus reach the object widened substrate source, improve product yield, fully meet the widespread demand of current industrial synthesis application.
Summary of the invention
In order to overcome above-mentioned pointed many defects, the present inventor, to this has been further investigation, after having paid a large amount of creative work, thus develops a kind of synthetic method of novel sulfonyl aminated compounds, and then completes the present invention.
Specifically, technical scheme of the present invention and content relate to the synthetic method of a kind of formula (III) sulfamide compound, described method is: under open air ambient, formula (I) compound and formula (II) compound is added successively in reactor, then in system, catalyzer, oxygenant and auxiliary agent is added under stirring, temperature reaction, after completion of the reaction through aftertreatment certainly, can obtain formula (III) compound:
Wherein:
R is H, halogen, C
1-C
6alkyl, C
1-C
6alkoxyl group, nitro or cyano group;
R
1, R
2be H, C independently of one another
1-C
6alkyl; Or R
1, R
2be connected to form together with N and comprise 1-3 heteroatomic 5-10 unit heterocycle, described heteroatoms is N, O, S atom.
In described synthetic method of the present invention, described halogen is fluorine, chlorine, bromine or iodine atom.
In described synthetic method of the present invention, described C
1-C
6alkyl refers to the alkyl with 1-6 carbon atom, and it can be straight or branched, such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, n-hexyl etc. in non-limiting manner.
In described method of the present invention, C
1-C
6alkoxyl group then refers to " C defined above
1-C
6alkyl " be connected with O atom after group.
In described synthetic method of the present invention, described catalyzer is triphenylphosphine compound, described triphenylphosphine compound is any one in iodate (N-methyl-N-anilino) triphenylphosphine, chlorination methoxyl methyl triphenylphosphine, butyltriphenylphosphonium phosphine, is preferably chlorination methoxyl methyl triphenylphosphine.
In described synthetic method of the present invention, described oxygenant is Cu (OAc)
2.
In described synthetic method of the present invention, described auxiliary agent is the mixture of Whitfield's ointment, beta-cyclodextrin and 1-ethoxyethyl group-3-Methylimidazole chlorate, wherein the mass ratio of Whitfield's ointment, beta-cyclodextrin and 1-ethoxyethyl group-3-Methylimidazole chlorate is 1:1.1-1.3:1.2-1.5, preferred 1:1.2:1.4.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and formula (II) compound is 1:1-4, such as, can be 1:1,1:2,1:3,1:4 or 1:5, is preferably 1:1.5-2.5.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and catalyzer is 1:0.05-0.15, can be 1:0.05,1:0.06,1:0.07,1:0.08,1:0.09,1:0.1,1:0.11,1:0.12,1:0.13,1:0.14 or 1:0.15 in non-limiting manner, be preferably 1:0.06-0.08.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and oxygenant is 1:1.1-1.3, such as, can be 1:1.1,1:1.15,1:1.2,1:1.25 or 1:1.3.
In described synthetic method of the present invention, described formula (I) compound compares 1:15-20mol/g with the molar mass of auxiliary agent, namely formula (I) compound in the mole number of mol and auxiliary agent in the ratio between the quality of g for 1:15-20, also namely every 1mol formula (I) compound uses 15-20g auxiliary agent, can be 1:15mol/g, 1:16mol/g, 1:17mol/g, 1:18mol/g, 1:19mol/g or 1:20mol/g in non-limiting manner.
In described synthetic method of the present invention, temperature of reaction is 60-100 DEG C, such as can be 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C, 80 DEG C, 85 DEG C, 90 DEG C, 95 DEG C or 100 DEG C in non-limiting manner, preferred 80-100 DEG C.
In described synthetic method of the present invention, the reaction times is without particular limitation, such as, can be 8-18h, can be 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h or 18h in non-limiting manner.
In described synthetic method of the present invention, when aftertreatment is after completion of the reaction: reaction mixture naturally cools to room temperature, through washing, acetone extract, anhydrous magnesium sulfate drying, then get organic layer in vacuo concentrated after pillar layer separation again, formula (III) compound can be obtained.
Wherein, pillar layer separation adopts volume ratio to be that the mixed solution of the petrol ether/ethyl acetate of 5:1 is as elutriant.
Compared with prior art, the present invention achieves following beneficial effect:
1, having expanded the kind of the reaction substrate for building sulfamide compound, having efficiently solved the limitation problem of prior art by substrate range of application.
2, provide a kind of compound system of catalyzer/auxiliary agent, it efficiently promotes that reaction is carried out and improves target product yield.
3, screen the kind of catalyzer and auxiliary agent, optimize the best of breed being suitable for this reaction.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Embodiment 1
Under open air ambient, in reactor, add 1mol formula (I) compound and 1.5mol formula (II) compound successively, under then stirring, in system, add the chlorination methoxyl methyl triphenylphosphine of 0.06mol, the Cu (OAc) of 1.1mol
2, and mass ratio is the mixture of the Whitfield's ointment of 1:1.2:1.4, beta-cyclodextrin and 1-ethoxyethyl group-3-Methylimidazole chlorate, this mixture total mass is 18g, is warming up to 100 DEG C of reaction 15h.
After completion of the reaction, reaction mixture naturally cools to room temperature, through washing, acetone extract, anhydrous magnesium sulfate drying, then get organic layer in vacuo concentrated after pillar layer separation again, wherein, pillar layer separation adopt volume ratio be the mixed solution of the petrol ether/ethyl acetate of 5:1 as elutriant, formula (III) compound can be obtained, productive rate is 95.6%, and purity is 98.9% (HPLC).
1H NMR(500MHz,CDCl
3)δ7.64(d,J=8.5Hz,2H),7.58(d,J=7.5Hz,2H),2.66(s,6H)；
MS[M+H]
+:263.9。
Embodiment 2
Under open air ambient, in reactor, add 1mol formula (I) compound and 2mol formula (II) compound successively, under then stirring, in system, add the chlorination methoxyl methyl triphenylphosphine of 0.08mol, the Cu (OAc) of 1.2mol
2, and mass ratio is the mixture of the Whitfield's ointment of 1:1.2:1.4, beta-cyclodextrin and 1-ethoxyethyl group-3-Methylimidazole chlorate, this mixture total mass is 15g, is warming up to 80 DEG C of reaction 12h.
After completion of the reaction, reaction mixture naturally cools to room temperature, through washing, acetone extract, anhydrous magnesium sulfate drying, then get organic layer in vacuo concentrated after pillar layer separation again, wherein, pillar layer separation adopts volume ratio to be that the mixed solution of the petrol ether/ethyl acetate of 5:1 is as elutriant, formula (III) compound can be obtained, can obtain formula (III) compound, productive rate is 95.8%, and purity is 98.7% (HPLC).
1H NMR(500MHz,CDCl
3)δ8.35(d,J=7.5Hz,2H),7.91(d,J=7.5Hz,2H),2.73(s,6H)；
MS[M+H]
+:231.1。
Embodiment 3
Under open air ambient, in reactor, add 1mol formula (I) compound and 2.5mol formula (II) compound successively, under then stirring, in system, add the chlorination methoxyl methyl triphenylphosphine of 0.07mol, the Cu (OAc) of 1.3mol
2, and mass ratio is the mixture of the Whitfield's ointment of 1:1.2:1.4, beta-cyclodextrin and 1-ethoxyethyl group-3-Methylimidazole chlorate, this mixture total mass is 16g, is warming up to 90 DEG C of reaction 10h.
After completion of the reaction, reaction mixture naturally cools to room temperature, through washing, acetone extract, anhydrous magnesium sulfate drying, then get organic layer in vacuo concentrated after pillar layer separation again, wherein, pillar layer separation adopt volume ratio be the mixed solution of the petrol ether/ethyl acetate of 5:1 as elutriant, formula (III) compound can be obtained, productive rate is 95.3%, and purity is 98.6% (HPLC).
1H NMR(500MHz,CDCl
3)δ=7.38-7.34(m,1H),7.25(d,J=7.5Hz,1H),7.21(s,1H),7.07(d,J=8.5Hz,1H),3.76(s,3H),2.61(s,6H)；
MS[M+H]
+:216.1。
Embodiment 4
Under open air ambient, in reactor, add 1mol formula (I) compound and 2mol formula (II) compound successively, under then stirring, in system, add the chlorination methoxyl methyl triphenylphosphine of 0.07mol, the Cu (OAc) of 1.2mol
2, and mass ratio is the mixture of the Whitfield's ointment of 1:1.2:1.4, beta-cyclodextrin and 1-ethoxyethyl group-3-Methylimidazole chlorate, this mixture total mass is 20g, is warming up to 90 DEG C of reaction 14h.
After completion of the reaction, reaction mixture naturally cools to room temperature, through washing, acetone extract, anhydrous magnesium sulfate drying, then get organic layer in vacuo concentrated after pillar layer separation again, wherein, pillar layer separation adopt volume ratio be the mixed solution of the petrol ether/ethyl acetate of 5:1 as elutriant, formula (III) compound can be obtained, productive rate is 95.4%, and purity is 98.4% (HPLC).
1H NMR(500MHz,CDCl
3)δ=7.61(d,J=7.5Hz,2H),7.44(d,J=7.5Hz,2H),3.70-3.67(m,4H),2.95-2.92(m,4H)；
MS[M+H]
+:262.0。
Embodiment 5-8
Replace with except following component except by catalyzer chlorination methoxyl methyl triphenylphosphine, implement embodiment 5-8 respectively in the mode identical with embodiment 1-4, the corresponding relation of component and experimental result is as shown in table 1 below.
Table 1
From the result of embodiment 1-4 and table 1, like this as known by organic catalysis field, the kind of catalyzer has very material impact to reaction system catalytic performance and efficiency.In view of this, present inventor has performed a large amount of experimental exploring, the optimum catalyst of chlorination methoxyl methyl triphenylphosphine as reaction has been filtered out from numerous compound, its catalytic performance is obviously better than other triphenylphosphine, triphenylphosphine or trialkyl phosphine compound, shows technique effect beyond expectation.
Embodiment 9-12
Replace with except following component except by the Whitfield's ointment in auxiliary agent, implement embodiment 9-12 respectively in the mode identical with embodiment 1-4, the corresponding relation of component and experimental result is as shown in table 2 below.
Table 2
Embodiment 13-16
Replace with except following component except by the beta-cyclodextrin in auxiliary agent, implement embodiment 13-16 respectively in the mode identical with embodiment 1-4, the corresponding relation of component and experimental result is as shown in table 3 below.
Table 3
Embodiment 17-20
Except not adding 1-ethoxyethyl group-3-Methylimidazole chlorate in auxiliary agent, implement embodiment 17-20 respectively in the mode identical with embodiment 1-4, experimental result is as shown in table 4 below.
Table 4
"--" indicates without 1-ethoxyethyl group-3-Methylimidazole chlorate.
From the result of embodiment 1-4 and table 2-4, adjuvant component kind is also the key factor affecting material reactivity worth, have studied the catalyzed reaction result in component 1 and 2 between different sorts by experiment of single factor, wherein only the combination of Whitfield's ointment and beta-cyclodextrin can impel reaction to reach high yield.In addition, component 3 is investigated, i.e. 1-ethoxyethyl group-3-Methylimidazole chlorate, the practical function played in auxiliary agent, experimental result shows: there is significantly synergy between each component, and when lacking any component or change the kind of certain component, reaction yield all occurs significantly to reduce.
In sum; the present inventor is by a large amount of creative works; have developed a kind of novel preparation process closing sulfamide compound; its with mercaptan and Carbox amide for reaction raw materials; achieve the object that high yield prepares sulfonamide compounds, there is large-scale production prospect widely and marketable value.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (11)
1. the synthetic method of formula (III) sulfamide compound, described method is: under open air ambient, formula (I) compound and formula (II) compound is added successively in reactor, then in system, catalyzer, oxygenant and auxiliary agent is added under stirring, temperature reaction, after completion of the reaction through aftertreatment, formula (III) compound can be obtained:
Wherein:
R is H, halogen, C
1-C
6alkyl, C
1-C
6alkoxyl group, nitro or cyano group;
R
1, R
2be H, C independently of one another
1-C
6alkyl; Or R
1, R
2be connected to form together with N and comprise 1-3 heteroatomic 5-10 unit heterocycle, described heteroatoms is N, O, S atom;
Described catalyzer is any one in iodate (N-methyl-N-anilino) triphenylphosphine, chlorination methoxyl methyl triphenylphosphine, butyltriphenylphosphonium phosphine;
Described oxygenant is Cu (OAc)
2;
Described auxiliary agent is the mixture of Whitfield's ointment, beta-cyclodextrin and 1-ethoxyethyl group-3-Methylimidazole chlorate, and wherein the mass ratio of Whitfield's ointment, beta-cyclodextrin and 1-ethoxyethyl group-3-Methylimidazole chlorate is 1:1.1-1.3:1.2-1.5.
2. synthetic method as claimed in claim 1, is characterized in that: described catalyzer is chlorination methoxyl methyl triphenylphosphine.
3. synthetic method as claimed in claim 1 or 2, it is characterized in that: in described auxiliary agent, the mass ratio of Whitfield's ointment, beta-cyclodextrin and 1-ethoxyethyl group-3-Methylimidazole chlorate is 1:1.2:1.4.
4. synthetic method as claimed in claim 1 or 2, is characterized in that: the mol ratio of described formula (I) compound and formula (II) compound is 1:1-4.
5. synthetic method as claimed in claim 4, is characterized in that: the mol ratio of described formula (I) compound and formula (II) compound is 1:1.5-2.5.
6. synthetic method as claimed in claim 1 or 2, is characterized in that: the mol ratio of described formula (I) compound and catalyzer is 1:0.05-0.15.
7. synthetic method as claimed in claim 6, is characterized in that: the mol ratio of described formula (I) compound and catalyzer is for being 1:0.06-0.08.
8. synthetic method as claimed in claim 1 or 2, is characterized in that: the mol ratio of described formula (I) compound and oxygenant is 1:1.1-1.3.
9. synthetic method as claimed in claim 1 or 2, is characterized in that: described formula (I) compound compares 1:15-20mol/g with the molar mass of auxiliary agent.
10. synthetic method as claimed in claim 1 or 2, is characterized in that: temperature of reaction is 60-100 DEG C; Reaction times is 8-18h.
11. synthetic methods as claimed in claim 1 or 2, it is characterized in that: aftertreatment is after completion of the reaction: reaction mixture naturally cools to room temperature, through washing, acetone extract, anhydrous magnesium sulfate drying, then get organic layer in vacuo concentrated after pillar layer separation again, formula (III) compound can be obtained.
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