CN105367437A - 一种2-芳氨基乙酰胺类化合物的制备方法 - Google Patents
一种2-芳氨基乙酰胺类化合物的制备方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title abstract description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 title abstract 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- -1 4-chlorphenyl Chemical group 0.000 claims abstract description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 9
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical group OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000460 chlorine Substances 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 8
- 239000001257 hydrogen Chemical group 0.000 claims abstract description 8
- 229910052739 hydrogen Chemical group 0.000 claims abstract description 8
- 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 abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 25
- 238000001953 recrystallisation Methods 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- HUVIYTMXSMOBPC-UHFFFAOYSA-N ClCC(=O)O.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 Chemical group ClCC(=O)O.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 HUVIYTMXSMOBPC-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- SVJXEFIHRCKUJS-UHFFFAOYSA-N 2-chloroacetic acid;pyridine Chemical group [O-]C(=O)CCl.C1=CC=[NH+]C=C1 SVJXEFIHRCKUJS-UHFFFAOYSA-N 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 abstract description 4
- 239000004327 boric acid Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 abstract description 4
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 abstract 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 150000002431 hydrogen Chemical group 0.000 abstract 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 11
- 239000013078 crystal Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 229960000935 dehydrated alcohol Drugs 0.000 description 10
- GTDQGKWDWVUKTI-UHFFFAOYSA-N o-aminoacetophenone Chemical compound CC(=O)C1=CC=CC=C1N GTDQGKWDWVUKTI-UHFFFAOYSA-N 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 6
- XYZMOVWWVXBHDP-UHFFFAOYSA-N cyclohexyl isocyanide Chemical compound [C-]#[N+]C1CCCCC1 XYZMOVWWVXBHDP-UHFFFAOYSA-N 0.000 description 5
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 4
- 0 *c1cc([*+])c(C=O)cc1 Chemical compound *c1cc([*+])c(C=O)cc1 0.000 description 3
- 229940126534 drug product Drugs 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 3
- APHLSUBLNQBFTM-UHFFFAOYSA-N (2-aminophenyl)-(4-chlorophenyl)methanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=C(Cl)C=C1 APHLSUBLNQBFTM-UHFFFAOYSA-N 0.000 description 2
- 102100021752 Corticoliberin Human genes 0.000 description 2
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
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- 238000010189 synthetic method Methods 0.000 description 2
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 239000003589 local anesthetic agent Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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Abstract
本发明涉及一种2-芳氨基乙酰胺类化合物的制备方法,2-芳氨基乙酰胺类化合物的结构通式为,其由化合物Ⅱ、化合物Ⅲ和化合物Ⅳ在化合物Ⅴ作用下反应制备而成,制备反应式为:其中,R1为氯或氢,R2为氯、氢、甲氧基或叔丁基,R3为环己基、叔丁基或正丁基,R4为甲基、乙基或4-氯苯基,化合物V为氯乙酸盐。本发明通过一锅法一步合成2-芳氨基乙酰胺类化合物,简化了反应步骤,同时通过氯乙酸盐做催化剂,避免使用硼酸、四氯化钛等危化药品,提高了反应的安全性。
Description
技术领域
本发明涉及一种有机化合物的合成方法,尤其涉及一种制备2-芳氨基乙酰胺类化合物的方法。
背景技术
2-氨基乙酰胺类化合物(具体结构见下式I)具有广泛的药理活性,如该类衍生物利多卡因是临床引用的局部麻醉药,利多卡因还具有抗心律失常作用,对室性心律失常疗效较好,且作用时间短,无蓄积,不抑制心肌收缩力,是治疗心律失常的首选药物。此外,2-芳氨基乙酰胺类化合物因具有广泛的药理活性而成为近年来的研究热点,如NPPG具有促肾上腺皮质激素释放因子的抑制作用,被应用于神经系统疾病药物的研究中。最近的研究还发现2-芳氨基乙酰胺类化合物还具有较好的抗捻转血矛线虫活性,而且其细胞毒性低,是一类可以进一步开发的结构片段,不久将有望进入市场。
现有的2-芳氨基乙酰胺类化合物的合成方法均需要分两步或者两步以上进行,且过程中使用诸如硼酸、四氯化钛等危化药品作为催化剂,不利于工业化生产。
发明内容
针对现有技术上存在的不足,本发明提供一种一步反应即可制备2-芳氨基乙酰胺类化合物的制备方法。
一种2-芳氨基乙酰胺类化合物的制备方法,2-芳氨基乙酰胺类化合物的结构式为
其由化合物Ⅱ、化合物Ⅲ和化合物Ⅳ在化合物Ⅴ作用下反应制备而成,制备反应式为:
其中,R1为氯或氢,R2为氯、氢、甲氧基或叔丁基,R3为环己基、叔丁基或正丁基,R4为甲基、乙基或4-氯苯基,化合物V为氯乙酸盐。
本发明通过一锅法一步反应合成2-芳氨基乙酰胺类化合物,简化了反应步骤,同时通过氯乙酸盐做催化剂,避免使用硼酸、四氯化钛等危化药品,提高了反应的安全性。
具体实施方式
为使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施方式,进一步阐述本发明。
本发明提供一种2-芳氨基乙酰胺类化合物的制备方法,2-芳氨基乙酰胺类化合物的结构式如式(I)。
其中R1为氯或氢,R2为氯、氢、甲氧基或叔丁基,R3为环己基、叔丁基或正丁基,R4为甲基、乙基或4-氯苯基。
2-芳氨基乙酰胺类化合物的制备是由化合物Ⅱ、化合物Ⅲ及化合物Ⅳ在一定量化合物V作用下反应得到,具体反应式为:
化合物Ⅱ、Ⅲ及Ⅳ中R1、R2、R3和R4与2-芳氨基乙酰胺类化合物中的R1、R2、R3和R4定义相同;化合物Ⅴ为氯乙酸盐,其中R5为吡啶、三苯基膦或4-二甲氨基吡啶。上述反应中,化合物Ⅱ、Ⅲ、Ⅳ、Ⅴ的摩尔配比为1.2:1:0.8:0.5~0.5:0.8:1:1.5,反应过程为:首先将化合物Ⅱ与化合物Ⅳ在室温下混合,以无水甲醇为溶剂,反应2~30分钟后,加入化合物Ⅲ及化合物Ⅴ,然后在室温下搅拌5~15小时。反应完成后,缓慢倒入水中,滤出固体,用甲醇/水重结晶得2-芳氨基乙酰胺类化合物。
实施例1
在室温下,将0.106g(1mmol)的苯甲醛与0.135g(1mmol)的邻氨基苯乙酮混合,加入2ml无水甲醇,搅拌反应5分钟后,向混合体系中加入0.109g(1mmol)的环己基异腈和0.178g(0.5mmol)的三苯基膦氯乙酸盐,反应混合物继续搅拌8小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.315g白色晶体为:产率90%,熔点:188~189℃。检测结果如下:
IR(cm-1)3332,3308,3065,2936,2852,1648,1602,1566,1540,1513,1452,1238,956,769。
1HNMR(600MHz,CDCl3)δ(ppm):9.43(d,J=3.0Hz,1H,Ar-NH),7.82(d,J=7.8Hz,1H,Ar-H),7.48-7.32(m,6H,Ar-H),6.76(t,J=7.8Hz,1H,Ar-H),6.67(d,J=8.4Hz,1H,Ar-H),6.43(d,J=7.8Hz,1H,CONH),4.86(d,J=3.6Hz,1H,COCH),3.82-3.75(m,1H,NCH),2.60(s,3H,CH3),1.86-0.96(m,10H,5CH2)。
13CNMR(150MHz,CDCl3)δ(ppm):201.3,169.8,149.3,137.9,135.2,132.6,129.0,128.3,126.9,118.8,116.3,112.9,63.5,48.1,32.8,32.7,27.9,25.3,24.7,24.6。
MS:m/z(%)=350(3)[M+],224(100),133(42),91(73),77(69)。
实施例2
在室温下,将0.163g(1.2mmol)的4-甲氧基苯甲醛与0.135g(1mmol)的邻氨基苯乙酮混合,加入2ml无水乙醇,搅拌反应2分钟后,向混合体系中加入0.083g(1mmol)的正丁基异腈和0.214g(0.6mmol)的三苯基膦氯乙酸盐,反应混合物继续搅拌10小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.319g白色晶体为产率90%,熔点:155℃。检测结果如下:
IR(cm-1)3331,3302,3060,2929,2851,1646,1600,1563,1542,1511,1459。
1HNMR(600MHz,CDCl3)δ(ppm):9.42(s,1H,Ar-NH),7.80(t,J=7.2Hz,1H,Ar-H),7.40-7.37(m,3H,Ar-H),6.91-6.64(m,5H,4Ar-H+CONH),4.84(d,J=8.4Hz,1H,COCH),3.79(d,J=6.6Hz,3H,OCH3),3.26-3.22(m,2H,NCH2),2.58-2.55(t,J=7.8Hz,3H,COCH3),1.40-1.38(m,2H,CH2),1.22-1.18(m,2H,CH2),0.84-0.81(m,3H,CH3)。
13CNMR(150MHz,CDCl3)δ(ppm):201.0,170.9,159.3,149.1,135.0,132.4,130.0,128.0,118.5,115.9,114.2,112.6,62.4,55.0,38.9,31.3,27.6,19.7,13.4。
MS:m/z(%)=354(1)[M+],254(100),121(51),119(44),107(29),93(68)。
实施例3
在室温下,将0.140g(1mmol)的4-氯苯甲醛与0.135g(1mmol)的邻氨基苯乙酮混合,加入2ml无水乙醇,搅拌反应2分钟后,向混合体系中加入0.083g(1mmol)的正丁基异腈和0.173g(1mmol)的氯乙酸吡啶盐,反应混合物继续搅拌8小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.340g白色晶体为产率95%,熔点:198~199℃。检测结果如下:
IR(cm-1)3333,3309,3061,2940,2822,1650,1610,1569,1541,1519,1454,1229,946。
1HNMR(600MHz,DMSO-d6)δ(ppm):9.42(d,J=3.0Hz,1H,Ar-NH),8.36(t,J=5.1Hz,1H,Ar-H),7.86(d,J=7.8Hz,1H,Ar-H),7.48(d,J=8.4Hz,2H,Ar-H),7.41(d,J=7.8Hz,2H,Ar-H),7.29(t,J=7.8Hz,1H,Ar-H),),6.61(t,J=7.2Hz,1H,CONH),6.42(d,J=8.4Hz,1H,Ar-H),5.18(d,J=6.6Hz,1H,COCH),3.08-3.03(m,2H,NCH2),2.57(s,3H,COCH3),1.35-1.33(m,2H,CH2),1.20-1.17(m,2H,CH2),0.81(t,J=7.2Hz,3H,CH3)。
13CNMR(150MHz,CDCl3)δ(ppm):200.6,169.1,148.0,138.4,133.2,132.3,128.6,128.2,118.0,115.4,115.0,112.2,58.8,38.4,30.9,28.1,19.4,13.6。
MS:m/z(%)=358(5)[M+],258(100),240(15),91(28)。
实施例4
在室温下,将0.140g(1mmol)的4-氯苯甲醛与0.108g(0.8mmol)的邻氨基苯乙酮混合,加入2ml无水乙醇,搅拌反应10分钟后,向混合体系中加入0.0872g(0.8mmol)的环己基异腈和0.178g(0.5mmol)的三苯基膦氯乙酸盐,反应混合物继续搅拌5小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.292g白色晶体为产率95%,熔点:220~221℃。检测结果如下:
IR(cm-1)3337,3302,3027,2916,2857,1647,1604,1569,1543,1511,1456,957,760。
1HNMR(600MHz,CDCl3)δ(ppm):9.40(d,J=3.0Hz,1H,Ar-NH),7.81(d,J=7.8Hz,1H,Ar-H),7.41-7.33(m,5H,Ar-H),6.76(t,J=7.2Hz,1H,Ar-H),6.61(d,J=8.4Hz,1H,Ar-H),6.44(d,J=8.4Hz,1H,CONH),4.83(d,J=3.6Hz,1H,COCH),3.76-3.74(m,1H,NCH),2.60(s,3H,CH3),1.84-0.94(m,10H,5CH2)。
13CNMR(150MHz,CDCl3)δ(ppm):201.5,169.4,149.1,136.5,135.3,134.2,132.6,129.2,128.4,118.9,116.6,112.8,62.7,48.2,32.8,32.6,28.0,25.3,24.7,24.6。
MS:m/z(%)=384(3)[M+],258(100),240(18),128(19),77(16)。
实施例5
在室温下,将0.136g(1mmol)的4-甲氧基苯甲醛与0.135g(1mmol)的邻氨基苯乙酮混合,加入2ml无水乙醇,搅拌反应20分钟后,向混合体系中加入0.109g(1mmol)的环己基异腈和0.250g(0.7mmol)的三苯基膦氯乙酸盐,反应混合物继续搅拌15小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.361g白色晶体为产率95%,熔点:204~205℃。检测结果如下:
IR(cm-1)3330,3303,3061,2942,2860,1641,1600,1567,1544,1532,1450,1233,944,755。
1HNMR(600MHz,CDCl3)δ(ppm):9.36(s,1H,Ar-NH),7.81(d,J=8.4Hz,1H,Ar-H),7.39-7.36(m,3H,Ar-H),6.90(d,J=8.4Hz,2H,Ar-H),6.74(t,J=7.2Hz,1H,Ar-H),6.65(d,J=8.4Hz,1H,Ar-H),6.46(d,J=7.8Hz,1H,CONH),4.81(d,J=3.6Hz,1H,COCH),3.79(s,4H,OCH3+NCH),2.58(s,3H,COCH3),1.90-0.96(m,10H,5CH2)。
13CNMR(150MHz,CDCl3)δ(ppm):201.1,170.0,159.4,149.2,135.0,132.5,130.0,128.1,118.7,116.1,114.3,112.8,62.7,55.1,48.0,32.8,32.6,27.8,25.2,24.7,24.6。
MS:m/z(%)=380(19)[M+],254(100),121(64),107(69),93(38)。
实施例6
在室温下,将0.087g(0.5mmol)的2,4-二氯苯甲醛与0.135g(1mmol)的邻氨基苯乙酮混合,加入2ml无水乙醇,搅拌反应25分钟后,向混合体系中加入0.109g(1mmol)的环己基异腈和0.356g(1mmol)的三苯基膦氯乙酸盐,反应混合物继续搅拌5小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.178g白色晶体为产率85%,熔点:170℃。检测结果如下:
IR(cm-1)3331,3300,3066,2933,2851,1647,1611,1568,1543,1516,1458,1234。
1HNMR(600MHz,CDCl3)δ(ppm):9.61(d,J=3.0Hz,1H,Ar-NH),7.81-7.95(m,1H,Ar-H),7.43-7.22(m,4H,Ar-H),6.72(t,J=7.8Hz,1H,Ar-H),6.49(d,J=8.4Hz,1H,Ar-H),6.32(d,J=8.4Hz,1H,CONH),5.32(d,J=5.4Hz,1H,COCH),3.84-3.79(m,1H,NCH),2.61(s,3H,CH3),1.96-1.03(m,10H,5CH2)。
13CNMR(150MHz,CDCl3)δ(ppm):200.9,167.9,148.5,134.9,134.4,134.0,132.5,132.4,129.4,129.2,127.8,118.8,116.0,112.3,58.4,46.5,32.9,32.3,28.2,27.4,24.9,24.4。
MS:m/z(%)=419(1)[M+],293(100),158(65),144(35)。
实施例7
在室温下,将0.140g(1mmol)的4-氯苯甲醛与0.135g(1mmol)的邻氨基苯乙酮混合,加入2ml无水乙醇,搅拌反应30分钟后,向混合体系中加入0.083g(1mmol)的叔丁基异腈和0.356g(1mmol)的三苯基膦氯乙酸盐,反应混合物继续搅拌8小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.330g白色晶体为产率92%,熔点:159~160℃。检测结果如下:
IR(cm-1)3331,3301,3066,2932,2861,1640,1606,1565,1544,1518,1458,1230,952,763。
1HNMR(600MHz,CDCl3)δ(ppm):9.45(d,J=3.0Hz,1H,Ar-NH),7.83(t,J=8.4Hz,1H,Ar-H),7.42-7.35(m,5H,Ar-H),6.78(t,J=7.8Hz,1H,Ar-H),6.63(d,J=8.4Hz,1H,Ar-H),6.32(s,1H,CONH),4.74(d,J=4.2Hz,1H,COCH),2.62(s,3H,COCH3),1.29(s,9H,3CH3)。
13CNMR(150MHz,CDCl3)δ(ppm):201.4,169.5,149.0,136.7,135.1,134.1,132.6,129.2,128.3,118.9,116.5,112.7,63.2,51.2,28.6,28.5,28.3,28.0。
MS:m/z(%)=358(2)[M+],258(100),124(77),110(60)。
实施例8
在室温下,将0.162g(1mmol)的4-叔丁基苯甲醛与0.135g(1mmol)的邻氨基苯乙酮混合,加入2ml无水乙醇,搅拌反应5分钟后,向混合体系中加入0.083g(1mmol)的叔丁基异腈和0.172g(0.8mmol)的氯乙酸-(4-二甲氨基-)吡啶盐,反应混合物继续搅拌15小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.342g白色晶体为产率90%,熔点:140~141℃。检测结果如下:
IR(cm-1)3330,3302,3069,2929,2869,1649,1605,1563,1539,1518,1453,1233,951,758。
1HNMR(600MHz,CDCl3)δ(ppm):9.37(d,J=3.0Hz,1H,Ar-NH),7.82(t,J=8.4Hz,1H,Ar-H),7.42-7.37(m,5H,Ar-H),6.76(t,J=7.8Hz,1H,Ar-H),6.69(d,J=8.4Hz,1H,Ar-H),6.40(s,1H,CONH),4.73(d,J=4.2Hz,1H,COCH),2.61(s,3H,COCH3),1.31(s,9H,3CH3),1.30(s,9H,3CH3)。
13CNMR(150MHz,CDCl3)δ(ppm):201.2,170.3,151.0,149.3,135.1,134.9,132.6,126.6,126.0,118.8,116.2,116.1,112.9,112.8,63.7,51.1,34.4,31.4,31.2,31.1,28.5,28.4,28.0,27.9。
MS:m/z(%)=380(4)[M+],280(100),133(62),119(41)。;
实施例9
在室温下,将0.162g(1mmol)的4-叔丁基苯甲醛与0.149g(1mmol)的2-氨基苯丙酮混合,加入3ml无水乙醇,搅拌反应5分钟后,向混合体系中加入0.083g(1mmol)的叔丁基异腈和0.172g(0.8mmol)的氯乙酸-(4-二甲氨基-)吡啶盐,反应混合物继续搅拌15小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.347g白色晶体为产率88%,熔点:185~186℃。检测结果如下:
IR(cm-1)3337,3309,3062,2937,2854,1645,1607,1564,1549,1518,1454,1236,925,762。
1HNMR(600MHz,CDCl3)δ(ppm):9.38(s,1H,Ar-NH),7.87(d,J=7.8Hz,1H,Ar-H),7.41-7.38(m,5H,Ar-H),6.75(t,J=7.8Hz,1H,Ar-H),6.69(d,J=8.4Hz,1H,Ar-H),6.41(s,1H,CONH),4.72(d,J=3.6Hz,1H,COCH),3.03(q,J=7.2Hz,2H,COCH2),1.31(s,9H,3CH3),1.29(s,9H,3CH3),1.20(t,J=7.2Hz,3H,CH3)。
13CNMR(150MHz,CDCl3)δ(ppm):203.7,170.4,151.0,149.3,134.9,131.6,126.6,126.0,118.3,116.1,113.0,112.9,63.8,51.0,34.4,32.3,31.4,31.2,31.1,31.0,28.5,28.4,8.6。
MS:m/z(%)=394(11)[M+],294(100),133(21),132(55),119(56)。
实施例10
在室温下,将0.136g(1mmol)的4-甲氧基苯甲醛与0.232g(1mmol)的2-氨基-4'-氯二苯甲酮混合,加入5ml无水乙醇,搅拌反应5分钟后,向混合体系中加入0.083g(1mmol)的正丁基异腈和0.214g(0.6mmol)的三苯基膦氯乙酸盐,反应混合物继续搅拌8小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.419g白色晶体为产率93%,熔点:120~121℃。检测结果如下:
IR(cm-1)3333,3304,3064,2936,2859,1647,1602,1565,1541,1515,1452,1228,946,733。
1HNMR(600MHz,CDCl3)δ(ppm):8.93(d,J=3.6Hz,1H,Ar-NH),7.63-7.31(m,9H,Ar-H),6.91(d,J=8.4Hz,2H,Ar-NH),6.65(d,J=9.0Hz,1H,Ar-NH),6.44(s,1H,CONH),4.86(d,J=4.2Hz,1H,COCH),3.79(s,3H,OCH3),3.27-3.25(m,2H,NCH2),1.75-1.41(m,2H,CH2),1.25-1.21(m,2H,CH2),0.85(t,J=7.2Hz,3H,CH3)。
13CNMR(150MHz,CDCl3)δ(ppm):197.9,170.5,159.4,148.1,139.0,134.4,133.7,131.4,129.7,129.0,128.1,128.0,119.9,119.2,114.3,114.1,61.8,55.0,39.2,31.2,19.7,13.2。
MS:m/z(%)=m/z(%)=450(5)[M+],350(100),135(31),77(39)。
实施例11
在室温下,将0.140g(1mmol)的4-氯苯甲醛与0.232g(1mmol)的2-氨基-4'-氯二苯甲酮混合,加入4ml无水乙醇,搅拌反应5分钟后,向混合体系中加入0.109g(1mmol)的环己基异腈和0.260g(1.5mmol)的氯乙酸4-二甲氨基吡啶盐,反应混合物继续搅拌10小时,反应完成后,倒入水中,滤出固体,用甲醇/水重结晶得0.409g白色晶体为产率90%,熔点:190℃。检测结果如下:
IR(cm-1)3395,3250,3068,2931,2853,1648,1629,1559,1503,1447,1236,892,701。
1HNMR(600MHz,CDCl3)δ(ppm):8.91(d,J=3.6Hz,1H,Ar-NH),7.64-7.33(m,11H,Ar-H),6.64(d,J=9.0Hz,1H,Ar-NH),6.32(d,J=8.4Hz,1H,CONH),4.86(d,J=4.2Hz,1H,COCH),3.81-3.76(m,1H,NCH),1.88-0.97(m,10H,5CH2)。
13CNMR(150MHz,CDCl3)δ(ppm):198.4,168.9,148.0,138.9,136.2,134.7,134.5,134.0,131.8,129.4,129.2,128.3,121.0,119.7,114.3,62.7,48.4,32.8,32.6,25.3,24.7,24.6。
MS:m/z(%)=481(2)[M+],354(100),276(42),255(96),138(39),77(54)。
本发明制备了十一个2-芳氨基乙酰胺类化合物,找到了该类反应的规律及可行的实验方案,通过一锅法一步反应合成,简化了反应步骤,同时通过氯乙酸盐做催化剂,避免使用硼酸、四氯化钛等危化药品,提高了反应的安全性。
以上所述的具体实施例,对本发明的目的、技术方案和有益效果进行了进一步详细说明,所应理解的是,以上所述仅为本发明的具体实施例而已,并不用于限制本发明,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (9)
1.一种2-芳氨基乙酰胺类化合物的制备方法,2-芳氨基乙酰胺类化合物的结构式为
其由化合物Ⅱ、化合物Ⅲ和化合物Ⅳ在化合物Ⅴ作用下反应制备而成,制备反应式为:
其中,R1为氯或氢,R2为氯、氢、甲氧基或叔丁基,R3为环己基、叔丁基或正丁基,R4为甲基、乙基或4-氯苯基,化合物V为氯乙酸盐。
2.如权利要求1所述的2-芳氨基乙酰胺类化合物的制备方法,其特征在于:化合物Ⅱ、化合物Ⅲ、化合物Ⅳ、化合物Ⅴ的摩尔配比为1.2:1:0.8:0.5~0.5:0.8:1:1.5。
3.如权利要求1所述的2-芳氨基乙酰胺类化合物的制备方法,其特征在于:反应过程为首先将化合物Ⅱ与化合物Ⅳ在室温下混合,以无水甲醇为溶剂,反应2~30分钟后,加入化合物Ⅲ及化合物Ⅴ,然后在室温下搅拌5~15小时。
4.如权利要求3所述的2-芳氨基乙酰胺类化合物的制备方法,其特征在于:反应过程为首先将化合物Ⅱ与化合物Ⅳ在室温下混合,以无水甲醇为溶剂,反应5~10分钟后,加入化合物Ⅲ及化合物Ⅴ,然后在室温下搅拌5~8小时。
5.如权利要求3或4所述的2-芳氨基乙酰胺类化合物的制备方法,其特征在于:反应完成后,缓慢倒入水中,滤出固体,用甲醇/水重结晶得2-芳氨基乙酰胺类化合物。
6.如权利要求1所述的2-芳氨基乙酰胺类化合物的制备方法,其特征在于:化合物Ⅴ中的R5为吡啶、三苯基膦或4-二甲氨基吡啶。
7.如权利要求6所述的2-芳氨基乙酰胺类化合物的制备方法,其特征在于:化合物Ⅴ为三苯基膦氯乙酸盐。
8.如权利要求6所述的2-芳氨基乙酰胺类化合物的制备方法,其特征在于:化合物Ⅴ为氯乙酸吡啶盐。
9.如权利要求6所述的2-芳氨基乙酰胺类化合物的制备方法,其特征在于:化合物Ⅴ为氯乙酸4-二甲氨基吡啶盐。
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