CN113402427A - 一种磺酰脲类化合物的合成方法 - Google Patents
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- 229940100389 Sulfonylurea Drugs 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title description 2
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- 238000000034 method Methods 0.000 claims abstract description 16
- 150000001412 amines Chemical class 0.000 claims abstract description 14
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- 239000011941 photocatalyst Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims abstract description 10
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- 238000006243 chemical reaction Methods 0.000 claims description 47
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- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 1
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- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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Abstract
本发明属于有机化学技术领域,具体涉及一种磺酰脲类化合物的合成方法。本发明在简单、温和的条件下,首先在有机溶剂中,由胺与氯磺酰异氰酸酯作用下生成相应的脲基磺酰氯,再在光催化剂作用下被单电子还原为脲磺酰基自由基,再与烯醇硅醚加成,脱硅后得到目标磺酰脲类化合物。本发明所述方法构建了一系列烷基磺酰脲类化合物,为磺酰脲类化合物的合成提供了崭新的思路,在科研和工业领域具有很好的指导意义和应用前景。
Description
技术领域
本发明属于有机化学技术领域,具体涉及一种磺酰脲类化合物的合成方法。
背景技术
磺酰脲类化合物在药物化学和农业化学中具有广泛的应用。合成磺酰脲类化合物的传统方法有两种,其一为使用磺酰胺与异氰酸酯反应(下式左),其二为使用磺酰异氰酸酯与胺反应(下式右)。然而,方法一依赖于使用现有的磺酰氯制备磺酰胺,而异氰酸酯的合成同样复杂;方法二所使用的磺酰异氰酸酯同样大大限制了其实际应用。由于合成方法受限,目前受到广泛研究的磺酰脲类化合物主要为芳基磺酰脲类,该化合物家族中其他种类具有巨大的开发潜力。
发明内容
本发明目的在于提供一种简便、环保、高效的磺酰脲类化合物的合成方法。
本发明创新性地使用了氯磺酰异氰酸酯作为合成子,从而简单高效地生成磺酰脲类化合物。该类化合物的分子中存在磺酰脲基团,所述化合物的分子结构通式为:
本发明实现发明目的所采用的技术方案是:
一种磺酰脲类化合物的合成方法,所述方法是在有机溶剂中,以胺、氯磺酰异氰酸酯和烯醇硅醚为原料,胺和氯磺酰异氰酸酯先生成脲基磺酰氯中间体,再在光催化剂及光源存在下,进行光催化反应与烯醇硅醚发生加成反应,脱硅后得到磺酰脲类化合物。
优选的,所述反应的反应式为:
式中,R1为含有或不含有吸电子基团或供电子基团的苯基或杂环取代基;R2及R3各自独立,分别为氢、C1-C12烷基或为苯基或杂环取代基,所述苯基或杂环取代基含有或不含有吸电子基团或供电子基团;R4及R5各自独立,分别为氢、氟或C1-C12烷基;R为C1-C6烷基或苯基的任意一种或多种;所述吸电子基团为氟、氯、溴、C1-C12酰基、C1-C12酯基、 C1-C12氰基或三氟甲基取代基团中的一种或多种,供电子基团为C1-C12 烷基、C1-C12烷氧基或氨基基团中的一种或多种,杂环可为缺电子或富电子杂环,例如为含有杂原子的五元环、六元环、七元环或稠环等常见杂环化合物,所述杂原子为N、O或S原子的一种或多种。
优选的,所述方法包括如下步骤:
在室温下,向干燥的反应管中加入光催化剂,惰性气体保护下加入有机溶剂及氯磺酰异氰酸酯,并在冷却条件下依次加入胺和烯醇硅醚,光照条件下搅拌反应;反应后,经后处理得到相应磺酰脲类化合物。
优选的,所述室温为15-40℃,更优选为25℃。
优选的,所述惰性气体为氮气或氩气的任意一种或两种混合。
优选的,所述光催化剂为含双齿配体的金属催化剂或4CzIPN,所述金属催化剂的金属原子为铱或钌,即所述光催化剂为常见的铱催化剂或钌催化剂,具体为Ir(ppy)3、Ir[dF(CF3)ppy]2(bpy)PF6、Ir[dF(CF3)ppy]2(dtbbpy)PF6、 Ru(bpy)3Cl2、Ru(bpy)3(PF6)2、Ru(dtbbpy)3(PF6)2、Ru(dMebpy)3(PF6)2或 Ru(bpm)3Cl2等,更优选为Ir(ppy)3。
优选的,本发明反应体系中,所述胺、氯磺酰异氰酸酯、光催化剂和烯醇硅醚的投料量摩尔比为1:(1.0-2.0):(0.005-0.02):(1.5-5)。
优选的,所述有机溶剂为乙腈、二氯甲烷、二氯乙烷、四氢呋喃、乙醚或丙酮中的一种或多种,更优选为乙腈。
优选的,有机溶剂的用量为以胺计为5-20mL/mmol,更优选为 15mL/mmol。
优选的,冷却温度为-15℃~25℃,更优选为0℃。
优选的,在冷却条件下逐滴加入胺,优选滴加速度为0.1-10μL/s。
优选的,所述烯醇硅醚的硅基为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基或三苯基硅基,更优选为三异丙基硅基。
优选的,光照反应在室温下进行,反应时间为2-10h。
优选的,所述后处理为将反应液减压浓缩去除溶剂,并采用二氯甲烷和甲醇的混合液作为流动相进行柱层析分离后,得到相应磺酰脲类化合物;流动相中二氯甲烷和甲醇的比例依据具体化合物而定,优选体积比为 20:1-8:1。
优选的,所述光源为白色LED。
制备的该类化合物的结构经1H NMR、13C NMR、HRMS等方法表征并得以确认。
在本发明中,由相应的胺、氯磺酰异氰酸酯和烯醇硅醚在光催化下反应,首先生成相应的脲基磺酰氯,经单电子还原、加成脱硅得到目标磺酰脲类化合物。本反应所用的氯磺酰异氰酸酯为廉价易得工业原料,同时直接使用胺作为反应物,无需预先合成异氰酸酯,极大地简化了磺酰脲类化合物的合成,同时产物为目前尚未被广泛研究的烷基磺酰脲,具有一定的潜在利用价值。
与现有技术相比,本发明的有益效果是:本发明在简单、温和的条件下,首先在有机溶剂中,由胺与氯磺酰异氰酸酯作用下生成相应的脲基磺酰氯,再在光催化剂作用下被单电子还原为脲磺酰基自由基,再与烯醇硅醚加成,脱硅后得到目标磺酰脲类化合物。该方法构建了一系列烷基磺酰脲类化合物,为磺酰脲类化合物的合成提供了崭新的思路,在科研和工业领域具有很好的指导意义和应用前景。
具体实施方式
下面通过具体实施例,对本发明的技术方案作进一步的具体说明。
实施例1
在室温下,在干燥的试管反应管中加入0.004mmol的Ir(ppy)3,置于高纯氮气中置换气,使得体系处于无水无氧条件后加入0.21mmol氯磺酰异氰酸酯及1.5mL乙腈并冷却至0℃,之后依次滴加入0.2mmol的苯胺和0.5 mmol的1-对甲苯基-1-三异丙基硅氧乙烯,置于光照反应装置中白色LED 光源下搅拌至完全反应为止。继TLC监测完全反应后,将反应液减压浓缩,并采用二氯甲烷和甲醇的混合液作为流动相进行柱层析分离,即可得到相应化合物2-Oxo-N-(phenylcarbamoyl)-2-(p-tolyl)ethane-1-sulfonamide例1。
化合物例1的结构表征:1H NMR(400MHz,DMSO)δ10.57(broad, 1H),8.82(s,1H),7.96(d,J=8.1Hz,2H),7.42(d,J=7.8Hz,2H),7.39– 7.27(m,4H),7.07(t,J=7.3Hz,1H),5.24(s,2H),2.39(s,3H).
13C NMR(101MHz,DMSO)δ188.46,150.08,144.98,137.95,133.32, 129.38,129.27,128.90,123.39,119.14,58.82,21.23.
实施例2
在室温下,在干燥的试管反应管中加入0.0016mmol的 Ir[dF(CF3)ppy]2(bpy)PF6,置于高纯氮气中置换气,使得体系处于无水无氧条件后加入0.24mmol氯磺酰异氰酸酯及1.0mL乙腈并冷却至0℃,之后依次滴加入0.2mmol的4-氨基苯甲酸甲酯和0.3mmol的1-对甲苯基-1-三异丙基硅氧乙烯,置于光照反应装置中搅拌至完全反应为止。继TLC监测完全反应后,将反应液减压浓缩,并采用二氯甲烷和甲醇的混合液作为流动相进行柱层析分离,即可得到相应化合物Methyl 4-(3-((2-oxo-2-(p-tolyl)ethyl)sulfonyl)ureido)benzoate例2。
化合物例2的结构表征:1H NMR(400MHz,DMSO)δ10.80(broad, 1H),9.22(s,1H),7.96(d,J=8.3Hz,2H),7.92(d,J=8.8Hz,2H),7.58(d,J= 8.8Hz,2H),7.37(d,J=8.1Hz,2H),5.26(s,2H),3.83(s,3H),2.38(s,3H).
13C NMR(101MHz,DMSO)δ188.37,165.73,150.09,144.98,142.59, 133.28,130.35,129.35,129.25,124.02,118.37,58.82,51.88,21.19.
实施例3
在室温下,在干燥的试管反应管中加入0.004mmol的Ir(ppy)3,置于氩气中置换气,使得体系处于无水无氧条件后加入0.45mmol氯磺酰异氰酸酯及4.0mL乙腈并冷却至-10℃,之后依次滴加入0.4mmol的3-氯苯胺和1.0 mmol的1-(4-氟苯基)-1-三异丙基硅氧乙烯,置于光照反应装置中搅拌至完全反应为止。继TLC监测完全反应后,将反应液减压浓缩,并采用二氯甲烷和甲醇的混合液作为流动相进行柱层析分离,即可得到相应化合物 N-((3-Chlorophenyl)carbamoyl)-2-(4-fluorophenyl)-2-oxoethane-1-sulfonamide 例3。
化合物例3的结构表征:1H NMR(400MHz,DMSO)δ10.83(broad, 1H),9.07(s,1H),8.18–8.13(m,2H),7.62(t,J=1.8Hz,1H),7.41(t,J=8.8 Hz,2H),7.35–7.29(m,2H),7.12(dt,J=7.4,1.8Hz,1H),5.30(s,2H).
13C NMR(101MHz,DMSO)δ187.65,165.66(d,JF=254.7Hz),150.19, 139.54,133.21,132.51(d,JF=2.6Hz),132.35(d,JF=9.9Hz),130.56,123.11, 118.63,117.71,115.93(d,JF=22.2Hz),59.03.19F NMR(376MHz,DMSO) δ-104.09.
实施例4
在室温下,在干燥的试管反应管中加入0.002mmol的Ir(ppy)3,置于氩气中置换气,使得体系处于无水无氧条件后加入0.21mmol氯磺酰异氰酸酯及3.0mL乙腈并冷却至0℃,之后依次滴加入0.2mmol的2-氨基嘧啶和0.5mmol的1-对甲苯基-1-三异丙基硅氧乙烯,置于光照反应装置中搅拌至完全反应为止。继TLC监测完全反应后,将反应液减压浓缩,并采用二氯甲烷和甲醇的混合液作为流动相进行柱层析分离,即可得到相应化合物 2-Oxo-N-(pyrimidin-2-ylcarbamoyl)-2-(p-tolyl)ethane-1-sulfonamide例4。
化合物例4的结构表征:1H NMR(400MHz,DMSO)δ12.36(s,1H), 10.85(s,1H),8.70(d,J=4.9Hz,2H),7.92(d,J=8.2Hz,2H),7.34(d,J=8.1 Hz,2H),7.23(t,J=4.9Hz,1H),5.32(s,2H),2.36(s,3H).
13C NMR(101MHz,DMSO)δ188.38,158.35,156.88,145.02,133.23, 129.36,129.18,116.17,58.43,21.21.
实施例5
在室温下,在干燥的试管反应管中加入0.002mmol的Ru(bpy)3Cl2,置于氩气中置换气,使得体系处于无水无氧条件后加入0.21mmol氯磺酰异氰酸酯及1.5mL乙腈并冷却至0℃,之后依次滴加入0.2mmol的3-氯苯胺和0.5mmol的1-(2-噻吩基)-1-三异丙基硅氧乙烯,置于光照反应装置中搅拌至完全反应为止。继TLC监测完全反应后,将反应液减压浓缩,并采用二氯甲烷和甲醇的混合液作为流动相进行柱层析分离,即可得到相应化合物
N-((3-chlorophenyl)carbamoyl)-2-oxo-2-(thiophen-2-yl)ethane-1-sulfonamide 例5。
化合物例5的结构表征:1H NMR(400MHz,DMSO)δ10.87(s,1H), 9.05(s,1H),8.19(d,J=3.7Hz,1H),8.14(d,J=4.9Hz,1H),7.63(s,1H), 7.36–7.29(m,3H),7.16–7.10(m,1H),5.20(s,2H).
13C NMR(101MHz,DMSO)δ181.46,150.45,143.14,139.66,137.35, 136.54,133.18,130.53,129.10,122.98,118.57,117.65,59.29.
实施例6
在室温下,在干燥的试管反应管中加入0.002mmol的Ir(ppy)3,置于氩气中置换气,使得体系处于无水无氧条件后加入0.48mmol氯磺酰异氰酸酯及5.0mL乙腈并冷却至0℃,之后依次滴加入0.3mmol的3-氯苯胺和 0.9mmol的1-苯基-1-三异丙基硅氧-1-丁烯,置于光照反应装置中搅拌至完全反应为止。继TLC监测完全反应后,将反应液减压浓缩,并采用二氯甲烷和甲醇的混合液作为流动相进行柱层析分离,即可得到相应化合物 N-((3-Chlorophenyl)carbamoyl)-1-oxo-1-phenylbutane-2-sulfonamide例6。
化合物例6的结构表征:1H NMR(400MHz,Acetone)δ9.62(s,1H), 8.52(s,1H),8.19(d,J=7.5Hz,2H),7.71–7.66(m,2H),7.56(t,J=7.7Hz, 2H),7.35–7.30(m,2H),7.13(dt,J=4.8,2.1Hz,1H),5.88(dd,J=10.2,4.0 Hz,1H),2.46–2.34(m,1H),2.30–2.20(m,1H),0.96(t,J=7.4Hz,3H).
13C NMR(101MHz,Acetone)δ192.87,150.53,140.30,138.07,134.93, 134.78,131.12,129.96,129.65,124.39,120.12,118.70,68.72,22.54,11.41.
实施例7
在室温下,在干燥的试管反应管中加入0.004mmol的4CzIPN,置于氩气中置换气,使得体系处于无水无氧条件后加入0.5mmol氯磺酰异氰酸酯及4.0mL乙腈并冷却至0℃,之后依次滴加入0.4mmol的3-氯苯胺和 0.8mmol的1-苯基-1-三异丙基硅氧-2,2-二氟乙烯,置于光照反应装置中搅拌至完全反应为止。继TLC监测完全反应后,将反应液减压浓缩,并采用二氯甲烷和甲醇的混合液作为流动相进行柱层析分离,即可得到相应化合物
N-((3-Chlorophenyl)carbamoyl)-1,1-difluoro-2-oxo-2-phenylethane-1-sulfonam ide例7。
化合物例7的结构表征:1H NMR(400MHz,CD3CN)δ7.75(s,1H), 7.62(d,J=7.8Hz,2H),7.42–7.19(m,7H),7.01(d,J=7.1Hz,1H).
13C NMR(101MHz,CD3CN)δ160.31,159.82,156.95,154.04,142.98, 134.49,131.52,131.46,130.65,129.06,128.98,127.43,122.15,119.03,117.59.
19F NMR(376MHz,CD3CN)δ-94.44(d,J=47.6Hz),-105.22(d,J= 47.5Hz).
实施例8
在室温下,在干燥的试管反应管中加入0.002mmol的Ir(ppy)3,置于氩气中置换气,使得体系处于无水无氧条件后加入0.32mmol氯磺酰异氰酸酯及4.0mL乙腈并冷却至5℃,之后依次滴加入0.3mmol的N-甲基苄胺和0.75mmol的1-对甲苯基-1-三异丙基硅氧乙烯,置于光照反应装置中搅拌至完全反应为止。继TLC监测完全反应后,将反应液减压浓缩,并采用二氯甲烷和甲醇的混合液作为流动相进行柱层析分离,即可得到相应化合物N-(benzyl(methyl)carbamoyl)-2-oxo-2-(p-tolyl)ethane-1-sulfonamide例8。
化合物例8的结构表征:1H NMR(400MHz,Acetone)δ9.43(s,1H), 8.00(d,J=8.1Hz,2H),7.34–7.21(m,7H),4.96(s,2H),4.52(s,2H),2.81(s, 3H),2.40(s,3H).
13C NMR(101MHz,Acetone)δ191.16,170.14,145.41,139.53,135.49, 130.48,130.15,129.36,128.68,127.91,60.46,21.75.
以上所述的实施例只是本发明的较佳方案,并非对本发明作任何形式上的限制,在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。
Claims (10)
1.一种磺酰脲类化合物的合成方法,其特征在于,所述方法是在有机溶剂中,以胺、氯磺酰异氰酸酯和烯醇硅醚为原料,胺和氯磺酰异氰酸酯先生成脲基磺酰氯中间体,再在光催化剂及光源下,进行光催化反应与烯醇硅醚发生加成反应,脱硅后得到磺酰脲类化合物。
3.根据权利要求1所述一种磺酰脲类化合物的合成方法,其特征在于,所述光催化剂为含双齿配体的金属催化剂或4CzIPN。
4.根据权利要求1所述一种磺酰脲类化合物的合成方法,其特征在于,所述胺、氯磺酰异氰酸酯、光催化剂和烯醇硅醚的投料量摩尔比为1:(1.0-2.0):(0.005-0.02):(1.5-5)。
5.根据权利要求1所述一种磺酰脲类化合物的合成方法,其特征在于,所述有机溶剂为乙腈、二氯甲烷、二氯乙烷、四氢呋喃、乙醚或丙酮中的一种或多种。
6.根据权利要求1所述一种磺酰脲类化合物的合成方法,其特征在于,有机溶剂的用量为以胺计为5-20mL/mmol。
7.根据权利要求1所述一种磺酰脲类化合物的合成方法,其特征在于,所述烯醇硅醚的硅基为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基或三苯基硅基。
8.根据权利要求1所述一种磺酰脲类化合物的合成方法,其特征在于,光催化反应时间为2-10h。
9.根据权利要求1所述一种磺酰脲类化合物的合成方法,其特征在于,所述方法包括如下步骤:在室温下,向干燥的反应管中加入光催化剂,惰性气体保护下加入有机溶剂及氯磺酰异氰酸酯,并在冷却条件下依次加入胺和烯醇硅醚,光照条件下搅拌反应;反应后,经后处理得到相应磺酰脲类化合物。
10.根据权利要求9所述一种磺酰脲类化合物的合成方法,其特征在于,冷却温度为-15℃~25℃。
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