CN113912509B - 酰胺类化合物的制备方法 - Google Patents
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- -1 amide compound Chemical class 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- SVOSGILHJQWIHT-UHFFFAOYSA-N bromomethanesulfonyl fluoride Chemical compound BrCS(=O)(=O)F SVOSGILHJQWIHT-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000001412 amines Chemical class 0.000 claims abstract description 13
- 150000001408 amides Chemical class 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 230000008878 coupling Effects 0.000 claims abstract description 11
- 238000010168 coupling process Methods 0.000 claims abstract description 11
- 238000005859 coupling reaction Methods 0.000 claims abstract description 11
- 238000000746 purification Methods 0.000 claims abstract description 8
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- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
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- 238000006243 chemical reaction Methods 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
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- 125000000217 alkyl group Chemical group 0.000 description 7
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- HXELGNKCCDGMMN-UHFFFAOYSA-N [F].[Cl] Chemical group [F].[Cl] HXELGNKCCDGMMN-UHFFFAOYSA-N 0.000 description 2
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
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- FBRJYBGLCHWYOE-UHFFFAOYSA-N 2-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(F)(F)F FBRJYBGLCHWYOE-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- 239000005740 Boscalid Substances 0.000 description 1
- 150000001265 acyl fluorides Chemical class 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
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- 125000002619 bicyclic group Chemical group 0.000 description 1
- WYEMLYFITZORAB-UHFFFAOYSA-N boscalid Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=C1NC(=O)C1=CC=CN=C1Cl WYEMLYFITZORAB-UHFFFAOYSA-N 0.000 description 1
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- BQIVJVAZDJHDJF-LURJTMIESA-N ethyl (2s)-2-amino-3-methylbutanoate Chemical compound CCOC(=O)[C@@H](N)C(C)C BQIVJVAZDJHDJF-LURJTMIESA-N 0.000 description 1
- BQIVJVAZDJHDJF-UHFFFAOYSA-N ethyl 2-amino-3-methylbutanoate Chemical compound CCOC(=O)C(N)C(C)C BQIVJVAZDJHDJF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ZKPGLQPSAPAFAP-UHFFFAOYSA-N n-phenyl-2-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC=CC=C1C(=O)NC1=CC=CC=C1 ZKPGLQPSAPAFAP-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005254 oxyacyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
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- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
本发明涉及一种酰胺类化合物的制备方法，以胺和羧酸为原料，以溴甲基磺酰氟为偶联试剂，在碱和溶剂存在条件下，进行脱水缩合反应，最后分离纯化得到酰胺类化合物。本发明制备方法具有操作简单、制备成本低廉、产物容易分离纯化等特点，且底物范围广，不仅可用于氨基酸之间的缩合，而且可用于生物活性分子的合成和修饰，有望用于大规模合成酰胺。
Description
技术领域
本发明属于通过与氨或胺反应从羧酸或从它们的酯、酐或卤化物来制备羧酸酰胺技术领域，涉及一种酰胺类化合物的制备方法。
背景技术
作为有机化学中最普遍和最重要的官能团之一，酰胺键不仅在多肽、蛋白质、生物活性化合物、农用化学品和聚合物中作为关键连接物出现，而且广泛存在于市场上约25％的药物中。尽管已经有很多从醇类、醛类、腈类等合成酰胺的方法，但胺和羧酸直接脱水缩合仍然是最直接的方法。胺和羧酸的直接缩合往往需要苛刻的条件，为了规避这些问题，人们开发出了多种偶联试剂在温和的反应条件下介导胺和羧酸的脱水缩合。然而现有方法存在偶联试剂成本高、化学废物多、工业生产中工序繁琐和提纯困难等问题，鉴于人们对酰胺类产品的需求与日俱增，亟需开发一种高效、经济、环保、可再生的偶联试剂用于酰胺的生产。
本发明采用一种新型的偶联试剂溴甲基磺酰氟用于介导胺和羧酸的脱水缩合。该试剂具有分子量小、价格低廉、原料易得、可再生等特点，通过氢氧化钠溶液洗涤便可以将其转化为溴甲基磺酸钠，再经过氯化和氟氯交换便可重新转化为溴甲基磺酰氟。采用该偶联试剂制备酰胺类化合物的方法具有操作简单、反应条件温和、产率高、产物容易分离纯化等特点，且底物范围广。
发明内容
本发明所要解决的技术问题是针对现有技术中存在的上述不足，提供一种酰胺类化合物的制备方法，以溴甲基磺酰氟(BMF)为偶联试剂，偶联试剂易于制备，成本低，操作简单、反应条件温和、产率高、底物范围广、产物容易分离纯化，有望用于酰胺的大规模生产。
为解决上述技术问题，本发明提供的技术方案是：
一种酰胺类化合物的制备方法，以胺和羧酸为原料，以溴甲基磺酰氟为偶联试剂，在碱和溶剂存在条件下，进行脱水缩合反应，最后分离纯化得到酰胺类化合物，其反应式如下：
其中R1、R2、R3为相同或不同基团，各自独立选自以下基团：氢、烷基、芳基。
本申请所述烷基是指任选取代的饱和脂肪族烃类，为直链结构，环状结构或者支链结构，优选具有1-约20个碳原子，例如具有1-约10个碳原子，具有1-约8个碳原子，或1-约6个碳原子，或1-约4个碳原子或1-约3个碳原子。本申请的烷基实施例包括但不限于甲基、乙基、正丙基、异丙基、2-甲基-1-丙基、2-甲基-2丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基和己基，以及更长的烷基基团，如庚基和辛基等。这些烷基上可以含有一个或多个取代基，这些取代基可以但不仅限于氨基，芳基，烷基，芳酰基，烷酰基，取代氧酰基，烷氧基，卤素，烷氧基等，烯基，炔基，杂芳基，这些取代基可以在烷基的不同位置，可以为一个，也可以为多个，多个官能团取代时，官能团种类可以相同也可以不同，位置可以相同也可以不相同。
本申请所述芳基是指任选取代的芳香烃基，其具有6-约20个，如6-12个或6-10个成环碳原子，其可以是单环芳基、双环芳基或更多环芳基。双环芳基或更多环芳基可以是一个单环芳基与其它独立环，如脂环、杂环、芳环、芳杂环相稠合。
按上述方案，所述溴甲基磺酰氟CAS号为1378749-82-6。
按上述方案，所述碱为氢氧化钾或氢氧化钠。优选碱为氢氧化钠。
按上述方案，所述胺、羧酸、溴甲基磺酰氟、碱的摩尔比为1:2～3:1.5～2:2～3。优选的摩尔比为1：3：1.5：3。
按上述方案，所述溶剂为乙腈，N,N-二甲基甲酰胺、四氢呋喃、丙酮中的一种或几种的混合物。优选溶剂为乙腈。
按上述方案，所述胺在溶剂中的浓度为0.1～2M(mol/L)。
按上述方案，所述脱水缩合反应条件为：50～80℃下反应12～18h。
本发明的反应原理如下：
羧酸在碱性条件下与溴甲基磺酰氟发生SN2亲核取代反应，生成中间体酸酐，生成的酸酐可以进一步转化为中间体酰氟，这两种中间体都可以与
胺反应生成酰胺
本发明的有益效果在于：本发明制备方法具有操作简单、制备成本低廉、产物容易分离纯化等特点，且底物范围广，不仅可用于氨基酸之间的缩合，而且可用于生物活性分子的合成和修饰，有望用于大规模合成酰胺。
具体实施方式
为使本领域技术人员更好地理解本发明的技术方案，下面结合实施例对本发明作进一步详细描述。
实施例1
一种酰胺类化合物的制备方法，反应式如下：
具体步骤如下：
向100mL耐压瓶中加入二乙胺(10mmol)、苯甲酸(30mmol)、氢氧化钠(30mmol)、溴甲基磺酰氟(15mmol)、乙腈(25mL)，于50℃油浴下回流反应18h，反应结束后，向反应液中加入30mL 1M的氢氧化钠溶液，然后用20mL乙酸乙酯萃取3次，萃取液用20mL 1M盐酸溶液洗涤，然后加入无水硫酸钠干燥后减压蒸馏，即得白色固体N,N-二乙基苯甲酰胺氟(1.41g，80％yield)。
本实施例所得酰胺类化合物的氢谱数据如下：1H-NMH(500MHz,CDCl3)δ＝7.40-7.36(m,5H),3.56(s,2H),3.26(s,2H),1.26(s,3H),1.11(s,3H).
实施例2
一种酰胺类化合物的制备方法，反应式如下：
具体步骤如下：
向100mL耐压瓶中加入苯胺(10mmol)、邻三氟甲基苯甲酸(30mmol)、氢氧化钠(30mmol)、溴甲基磺酰氟(15mmol)、乙腈(25mL)，于50℃油浴下回流反应18h，反应结束后，向反应液中加入30mL 1M的氢氧化钠溶液，然后用20mL乙酸乙酯萃取3次，萃取液用20mL 1M盐酸溶液洗涤，然后加入无水硫酸钠干燥后减压蒸馏，即得白色固体N-苯基-2-(三氟甲基)苯甲酰胺(2.20g,83％yield)。
本实施例所得酰胺类化合物的氢谱数据如下：1H-NMH(500MHz,DMSO-d6)δ＝10.55(s,1H),7.85(d,J＝7.6Hz,1H),7.80(t,J＝7.3Hz,1H),7.73-7.70(m,4H),7.36(t,J＝7.6Hz,2H),7.12(t,J＝7.3Hz,1H).19F-NMH(500MHz,DMSO-d6),δ＝－57.94(s,3F).
实施例3
一种酰胺类化合物的制备方法，反应式如下：
具体步骤如下：
向100mL耐压瓶中加入L-缬氨酸乙酯(10mmol)、苯甲酸(30mmol)、氢氧化钠(30mmol)、溴甲基磺酰氟(15mmol)、乙腈(25mL)，于50℃油浴下回流反应18h，反应结束后，向反应液中加入30mL 1M的氢氧化钠溶液，然后用20mL乙酸乙酯萃取3次，萃取液用20mL 1M盐酸溶液洗涤，然后加入无水硫酸钠干燥后减压蒸馏，即得白色固体苯甲酰-L-缬氨酸乙酯(2.17g,87％yield,99％ee)。
本实施例所得酰胺类化合物的氢谱数据如下：1H-NMR(500MHz,CDCl3)δ＝7.81(d,J＝7.3Hz,2H),7.50(t,J＝7.3Hz,1H),7.44(t,J＝7.5Hz,2H),6.68(d,J＝7.7Hz,1H),4.76(dd,J1＝8.6Hz,J2＝4.8Hz,1H),4.27-4.20(m,2H),2.31-2.25(m,1H),1.30(t,J＝7.1Hz,3H),1.00(dd,J1＝12.4Hz,J2＝6.9Hz,6H).
实施例4
一种酰胺类化合物的制备方法，反应式如下：
具体步骤如下：
向25mL耐压管中加入DL-缬氨酸乙酯(1mmol)、Boc-甘氨酸(3mmol)(Boc指叔丁氧羰基，为保护基团)、氢氧化钠(3mmol)、溴甲基磺酰氟(1.5mmol)、乙腈(2.5mL)，于50℃油浴下回流反应18h，反应结束后，反应液中加入10mL水稀释，然后用10mL乙酸乙酯萃取3次，萃取液用无水硫酸钠干燥后减压蒸馏，残余物用硅胶柱层析纯化(洗脱剂为石油醚:乙酸乙酯＝2:1(v/v))，即得白色固体(叔丁氧羰基)甘氨酰缬氨酸乙酯(242.7mg,80％yield)。本实施例所得酰胺类化合物的氢谱数据如下：1H-NMR(500MHz,CDCl3)δ＝6.74(s,1H),5.33(s,1H),4.51(s,1H),4.17(m,2H),3.82-3.79(m,2H),2.16-2.15(m,1H),1.43(s,9H),1.26(m,3H),0.93-0.87(m,6H).
实施例5
一种酰胺类化合物的制备方法，反应式如下：
具体步骤如下：
向25mL耐压管中加入4'-氯-[1,1'-联苯]-2-胺(1mmol)、2-氯烟酸(3mmol)、氢氧化钠(3mmol)、溴甲基磺酰氟(1.5mmol)、四氢呋喃(2.5mL)，于50℃油浴下回流反应18h，反应结束后，反应液中加入10mL水稀释，然后用10mL乙酸乙酯萃取3次，萃取液用无水硫酸钠干燥后减压蒸馏，残余物用硅胶柱层析纯化(洗脱剂为石油醚:乙酸乙酯＝1:1(v/v))，即得白色固体啶酰菌胺(242.8mg,71％yield)。
本实施例所得酰胺类化合物的氢谱数据如下：1H-NMR(500MHz,DMSO-d6)δ＝10.15(s,1H),8.48(d,J＝4.6Hz,1H),7.88(d,J＝7.5Hz,1H),7.61(d,J＝7.8Hz,1H),7.53-7.45(m,6H),7.40(d,J＝4.0Hz,2H).
采用本发明的方法合成酰胺类化合物，其典型结构及反应产率如下所示，所公开的酰胺类化合物分子结构式不作为对本发明保护范围的限制。
本发明旨在新型的酰胺偶联试剂，该试剂具有分子量小、价格低廉、原料易得、可再生等特点，并且通过氢氧化钠溶液洗涤便可以将其转化为溴甲基磺酸钠，再经过氯化和氟氯交换便可重新转化为溴甲基磺酰氟。该酰胺合成方法具有操作简单、反应条件温和、产率高、产物容易分离纯化等特点，且底物范围广，不仅可用于氨基酸之间的缩合，而且可用于生物活性分子的合成和修饰，有望用于大规模合成酰胺和多肽，应用于有机化学、药物化学、生命科学等领域。
Claims (3)
1.一种酰胺类化合物的制备方法，其特征在于，以胺和羧酸为原料，以溴甲基磺酰氟为偶联试剂，在碱和溶剂存在条件下，进行脱水缩合反应，最后分离纯化得到酰胺类化合物，其反应式如下：
所述碱为氢氧化钾或氢氧化钠；
所述溶剂为乙腈；
所述脱水缩合反应条件为：50～80℃下反应12～18h；
所述酰胺类化合物结构式如下：
2.根据权利要求1所述的酰胺类化合物的制备方法，其特征在于，所述胺、羧酸、溴甲基磺酰氟、碱的摩尔比为1:2～3:1.5～2:2～3。
3.根据权利要求1所述的酰胺类化合物的制备方法，其特征在于，所述胺在溶剂中的浓度为0.1～2M。
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