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WO2022199124A1 - 一种内酰胺化合物的合成方法 - Google Patents

一种内酰胺化合物的合成方法 Download PDF

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WO2022199124A1
WO2022199124A1 PCT/CN2021/135945 CN2021135945W WO2022199124A1 WO 2022199124 A1 WO2022199124 A1 WO 2022199124A1 CN 2021135945 W CN2021135945 W CN 2021135945W WO 2022199124 A1 WO2022199124 A1 WO 2022199124A1
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product
reaction
lactam compound
compound according
acid chloride
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贾自自
王聪
秦建国
凌芳
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Shanghai Ourchem Bio Technology Co Ltd
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Shanghai Ourchem Bio Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6

Definitions

  • the present invention relates to the technical field of compound synthesis, in particular to a method for synthesizing a five-membered or six-membered cyclic lactam compound.
  • lactam structure is an extremely important part, which widely exists in various natural products and drug molecules. Some lactam compounds have good biological activity and have been verified to have antibacterial, antiviral and anti-senile dementia effects. For example, HIV-1 protease inhibitors containing ⁇ -lactam structure have good water solubility and pharmacological activity. Valerolactam, as an important intermediate in organic synthesis, has also attracted the attention of chemists. It has been reported that inhibitors containing valerolactam structure exhibit good activity. Therefore, it is very meaningful to find an efficient scheme to synthesize five- or six-membered cyclic lactam compounds.
  • the object of the present invention is to provide a simple and convenient lactam synthesis method in view of the disadvantages of the existing synthesis method; the synthesis method of the present invention is simple and low in cost.
  • a kind of synthetic method of lactam compound comprises the steps:
  • step (3) the product A obtained in step (2), cuprous iodide (CuI) and o-phenanthroline are dissolved in a mixed organic solvent and heated to react to obtain an intermediate;
  • CuI cuprous iodide
  • o-phenanthroline o-phenanthroline
  • step (1) under nitrogen protection, N-F benzenesulfonamide and acid chloride were dissolved in dichloromethane (DCM) and stirred uniformly, and the reaction was carried out at room temperature for 2.5 hours to obtain a crude product.
  • the crude product is the crude product of product A.
  • the molar ratio of the N-F benzenesulfonamide to the acid chloride is 1:(1-1.5).
  • the structural formula of described acid chloride is When the acid chloride is When the reaction product A is When the acid chloride is , the reaction product A is In the formula, R represents an aryl group, and R 1 , R 2 and R 3 represent an alkyl group.
  • the molar ratio of the cuprous iodide, the o-phenanthroline and the product A in step (3) is (0.5-1): (1-1.5): 10; the heating temperature is The reaction time is 1.5 hours at 60-80° C.; the mixed organic solvent is a mixture of dichloroethane (DCE) and methanol (MeOH).
  • DCE dichloroethane
  • MeOH methanol
  • step (3) reaction gained intermediate is When the product A is When, step (3) reaction gained intermediate is
  • R represents an aryl group
  • R 1 , R 2 and R 3 represent an alkyl group.
  • volume ratio of the dichloroethane to the methanol is 10:1.
  • step (4) the intermediate is dissolved in tetrahydrofuran (THF), tetrabutylammonium fluoride (TBAF) is added, and the reaction is stirred at room temperature for 16 hours to obtain the target product.
  • THF tetrahydrofuran
  • TBAF tetrabutylammonium fluoride
  • the molar ratio of the intermediate to the tetrahydrofuran is 1:(1-1.5).
  • step (4) reaction gained target product is five-membered ring lactam
  • step (4) the target product obtained from the reaction in step (4) is a six-membered ring lactam
  • R represents an aryl group
  • R 1 , R 2 and R 3 represent an alkyl group.
  • the synthetic route of the present invention is as follows:
  • the five-membered ring lactam can be synthesized through the scheme of the present invention, and its synthetic route is shown in (a) and (b): in the formula, R represents an aryl group, and R 1 , R 2 and R 3 represent an alkyl group;
  • the present invention selects commercially available N-F benzenesulfonamide and acid chloride as starting materials, and its materials are easy to obtain; meanwhile, the synthesis method of the present invention selects commercially cheap and readily available cuprous iodide as a catalyst, avoiding the use of expensive precious metal catalysts , the economy is effectively improved; the reaction conditions of the whole synthesis method of the present invention are mild; the target compound is obtained by free radical cyclization, the use of other oxidants or precious metal catalysts is avoided, and the synthesis cost is low.
  • a synthetic method of a lactam compound comprising the steps: the acid chloride selected in the synthetic method is In the formula, R is an aryl group, and R 1 is a methyl group, that is,
  • NF benzenesulfonamide (Acyl chloride) was dissolved in dichloromethane and stirred uniformly, and the reaction was stirred at room temperature for 2.5 hours to obtain (being the crude product of product A); In this reaction step, NF benzenesulfonamide and The molar ratio is 1:1.2;
  • step (3) dissolving the product A obtained in step (2), cuprous iodide and o-phenanthroline in a mixed solvent of dichloroethane and methanol and heating at 70°C for 1.5 hours to obtain (Intermediate); and the molar ratio of the cuprous iodide, the o-phenanthroline and the product A is 1:1.2:10; the volume ratio of dichloroethane to methanol is 10:1;
  • step (3) gained is dissolved in tetrahydrofuran, and tetrabutylammonium fluoride (TBAF) is added, and the reaction is stirred at room temperature for 16 hours to obtain the target product five-membered ring lactam
  • TBAF tetrabutylammonium fluoride
  • a synthetic method of a lactam compound comprising the steps: the acid chloride selected in the synthetic method is In the formula, R is an aryl group, and R 2 and R 3 are methyl groups, that is,
  • NF benzenesulfonamide (Acyl chloride) was dissolved in dichloromethane and stirred uniformly, and the reaction was stirred at room temperature for 2.5 hours to obtain (being crude product A); In this reaction step, NF benzenesulfonamide and The molar ratio is 1:1.2;
  • step (3) dissolving the product A obtained in step (2), cuprous iodide and o-phenanthroline in a mixed solvent of dichloroethane and methanol and heating at 70°C for 1.5 hours to obtain (Intermediate); and the molar ratio of the cuprous iodide, the o-phenanthroline and the product A is 1:1.2:10; the volume ratio of dichloroethane to methanol is 10:1;
  • step (3) gained is dissolved in tetrahydrofuran and added with tetrabutylammonium fluoride (TBAF), and the reaction is stirred at room temperature for 16 hours to obtain the target product six-membered ring lactam And the molar ratio of the intermediate to tetrahydrofuran is 1:1.2.
  • TBAF tetrabutylammonium fluoride
  • a synthetic method of a lactam compound comprising the steps: the acid chloride selected in the synthetic method is In the formula, R is an aryl group, and R 1 is a methyl group, that is,
  • NF benzenesulfonamide (Acyl chloride) was dissolved in dichloromethane and stirred uniformly, and the reaction was stirred at room temperature for 2.5 hours to obtain (i.e. crude product A); wherein NF benzenesulfonamide and The molar ratio is 1:1;
  • step (3) dissolving the product A obtained in step (2), cuprous iodide and o-phenanthroline in a mixed solvent of dichloroethane and methanol and heating at 80°C for 1.5 hours to obtain (intermediate); and the molar ratio of the cuprous iodide, the o-phenanthroline and the product A is 0.5:1:10; the volume ratio of dichloroethane to methanol is 10:1;
  • step (3) gained is dissolved in tetrahydrofuran, and tetrabutylammonium fluoride (TBAF) is added, and the reaction is stirred at room temperature for 16 hours to obtain the target product five-membered ring lactam And the molar ratio of the intermediate to tetrahydrofuran is 1:1.5.
  • TBAF tetrabutylammonium fluoride
  • a synthetic method of a lactam compound comprising the steps: the acid chloride selected in the synthetic method is In the formula, R is an aryl group, and R 1 is a methyl group, that is,
  • NF benzenesulfonamide (Acyl chloride) was dissolved in dichloromethane and stirred uniformly, and the reaction was stirred at room temperature for 2.5 hours to obtain (i.e. crude product A); wherein NF benzenesulfonamide and The molar ratio is 1:1.5;
  • step (3) dissolving the product A obtained in step (2), cuprous iodide and o-phenanthroline in a mixed solvent of dichloroethane and methanol and heating at 60°C for 1.5 hours to obtain (intermediate); and the molar ratio of the cuprous iodide, the o-phenanthroline and the product A is 0.8:1.5:10; the volume ratio of dichloroethane to methanol is 10:1;
  • step (3) gained is dissolved in tetrahydrofuran, and tetrabutylammonium fluoride (TBAF) is added, and the reaction is stirred at room temperature for 16 hours to obtain the target product five-membered ring lactam And the molar ratio of the intermediate to tetrahydrofuran is 1:1.
  • TBAF tetrabutylammonium fluoride

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明公开一种内酰胺化合物的合成方法，(1)包括在气体保护下，将N-F苯磺酰胺、酰氯溶于有机溶剂中并搅拌均匀，反应得到粗品；(2)将所述粗品重结晶，得到产物A；(3)将步骤(2)得到的产物A、碘化亚铜和邻菲罗啉溶于混合有机溶剂中并加热反应，得到中间体；(4)将中间体溶解并加入四丁基氟化铵，搅拌，得到目标产物。本发明选用商业可得的N-F苯磺酰胺和酰氯作为起始原料，其材料易得；本发明的合成方法选用商业上廉价易得的碘化亚铜作为催化剂，避免了使用昂贵的贵金属催化剂，有效提高了经济性；本发明的整个合成方法反应条件温和；本发明通过自由基环化得到了目标化合物，避免了其它氧化剂或者贵金属催化剂的使用，其合成本低。

Description

一种内酰胺化合物的合成方法 技术领域
本发明涉及化合物的合成技术领域，具体涉及一种五元或六元环内酰胺化合物的合成方法。
背景技术
在杂环化合物中，内酰胺结构是一个极其重要的部分，广泛存在于各种天然产物以及药物分子中。一些内酰胺化合物具有良好的生物活性，已被验证具有抗菌、抗病毒以及抗老年痴呆等作用。例如，含有γ-内酰胺结构的HIV-1蛋白酶抑制剂，具有良好水溶性以及药理活性。戊内酰胺作为一种重要的有机合成中间体，同样备受化学家的关注。已有报道指出含有戊内酰胺结构的抑制剂表现出良好的活性。所以，找到一种有效的方案来合成五元或六元环内酰胺化合物是很有意义的。
目前，已有文献报道了多种合成五元或六元内酰胺化合物的方法。例如有扩环化、4+1环化、或者过渡金属催化环化等。然而，这些方案均存在着一定的弊端,如通过β-内酰胺扩环化来合成γ-内酰胺方法局限于特定的底物类型，并且需用到较强的碱(LDA等)，这就带来了很大的不便和污染；4+1环化或其他的环化方法则需用到较昂贵的催化剂或者需要较高的温度；对于过渡金属催化来得到内酰胺化合物方案，大多是通过贵金属铑(Rh)，铱(Ir)，钯(Pd)，金(Au)等催化完成的，并且一般需要在50-70℃条件下进行。以上方案虽实现了一系列五元或六元环内酰胺化合物的制备，但是都具有一定局限 性或需使用较为昂贵的催化剂。
发明内容
本发明的目的在于针对现有合成方法的劣势，提供一种简便的内酰胺合成方法；本发明的合成方法简便，成本低。
本发明是通过如下技术方案实现的：
一种内酰胺化合物的合成方法，包括如下步骤：
(1)在气体保护下，将N-F苯磺酰胺、酰氯溶于有机溶剂中并搅拌均匀，反应得到粗品；
(2)将所述粗品重结晶，得到产物A；产物A为白色固体状；
(3)将步骤(2)得到的所述产物A、碘化亚铜(CuI)和邻菲罗啉溶于混合有机溶剂中并加热反应，得到中间体；
(4)将所述中间体溶解并加入四丁基氟化铵(TBAF)，搅拌，得到目标产物。
进一步地，步骤(1)在氮气保护下，将N-F苯磺酰胺、酰氯溶于二氯甲烷中(DCM)并搅拌均匀，在室温下反应2.5小时，得到粗品。所述的粗品即为产物A的粗品。
进一步地，所述N-F苯磺酰胺与所述酰氯的摩尔比为1：(1-1.5)。
进一步地，所述的酰氯的结构式为
Figure PCTCN2021135945-appb-000001
当所述酰氯为
Figure PCTCN2021135945-appb-000002
时，反应所得产物A为
Figure PCTCN2021135945-appb-000003
当所述酰氯为
Figure PCTCN2021135945-appb-000004
时，反应得产物A为
Figure PCTCN2021135945-appb-000005
式中R代表芳基，R 1、R 2、R 3代表烷基。
进一步地，步骤(3)中所述碘化亚铜、所述邻菲罗啉和所述产物A的摩尔比为(0.5-1)：(1-1.5)：10；所述加热的温度为60-80℃，反应时间为1.5小时；所述混合有机溶剂为二氯乙烷(DCE)和甲醇(MeOH)的混合物。
进一步地，当所述产物A为
Figure PCTCN2021135945-appb-000006
时，步骤(3)反应所得中间体为
Figure PCTCN2021135945-appb-000007
当所述产物A为
Figure PCTCN2021135945-appb-000008
时，步骤(3)反应所得中间体为
Figure PCTCN2021135945-appb-000009
式中R代表芳基，R 1、R 2、R 3代表烷基。
进一步地，所述二氯乙烷与所述甲醇的体积比为10：1。
进一步地，步骤(4)将所述中间体溶解于四氢呋喃(THF)中并加入四丁基氟化铵(TBAF)，室温下搅拌反应16小时，得到目标产物。
进一步地，所述中间体与所述四氢呋喃的摩尔比为1：(1-1.5)。
进一步地，当所述中间体为
Figure PCTCN2021135945-appb-000010
时，步骤(4)反应所得目标产物即为五元环内酰胺
Figure PCTCN2021135945-appb-000011
当所述中间体为
Figure PCTCN2021135945-appb-000012
时，步骤(4)反应所得目标产物即为六元环内酰胺
Figure PCTCN2021135945-appb-000013
式中R代表芳基，R 1、R 2、R 3代表烷基。
具体的，本发明的合成路线如下所示：
(1)当所述的酰氯为
Figure PCTCN2021135945-appb-000014
时，通过本发明的方案可合成五元环内酰胺，其合成路线如(a)和(b)所示：式中R代表芳基，R 1、R 2、R 3代表烷基；
Figure PCTCN2021135945-appb-000015
(2)当所述的酰氯为
Figure PCTCN2021135945-appb-000016
时，通过本发明的方案可合成六元环内酰胺，其合成路线如(c)和(d)所示：式中R代表芳基，R 1、R 2、R 3代表烷基；
Figure PCTCN2021135945-appb-000017
本发明的有益效果：
本发明选用商业可得的N-F苯磺酰胺和酰氯作为起始原料，其材料易得；同时本发明的合成方法选用商业上廉价易得的碘化亚铜作为 催化剂，避免了使用昂贵的贵金属催化剂，有效提高了经济性；本发明的整个合成方法反应条件温和；本发明通过自由基环化得到了目标化合物，避免了其它氧化剂或者贵金属催化剂的使用，其合成本低。
具体实施方式
下面将结合具体的实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明的一部分实施例，而不是全部的实施例。以下对至少一个示例性实施例的描述实际上仅仅是说明性的，决不作为对本发明及其应用或使用的任何限制。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
一种内酰胺化合物的合成方法，包括如下步骤：该合成方法中选用的酰氯为
Figure PCTCN2021135945-appb-000018
式中R为芳基，R 1为甲基，即
Figure PCTCN2021135945-appb-000019
(1)在氮气保护下，将N-F苯磺酰胺、
Figure PCTCN2021135945-appb-000020
(酰氯)溶解于二氯甲烷中并搅拌均匀，并在室温下搅拌反应2.5小时，得到
Figure PCTCN2021135945-appb-000021
(即为产物A的粗品)；该反应步骤中N-F苯磺酰胺与
Figure PCTCN2021135945-appb-000022
摩尔比为1：1.2；
(2)将步骤(1)所得到的产物A的粗品重结晶，即可得到
Figure PCTCN2021135945-appb-000023
(产物A)；
(3)将步骤(2)得到的产物A、碘化亚铜和邻菲罗啉溶于二氯乙烷和甲醇的混合溶剂中并70℃加热反应1.5小时，即可以得到
Figure PCTCN2021135945-appb-000024
(中间体)；且所述碘化亚铜、所述邻菲罗啉和所述产物A的摩尔比为1：1.2：10；二氯乙烷与甲醇的体积比为10：1；
(4)将步骤(3)所得
Figure PCTCN2021135945-appb-000025
(中间体)溶解于四氢呋喃中并加入四丁基氟化铵(TBAF)，室温下搅拌反应16小时，即得到目标产物五元环内酰胺
Figure PCTCN2021135945-appb-000026
该步骤中间体与四氢呋喃的摩尔比为1：1.2。
该实施例1的合成路线具体如下反应式(1)和(2)所示：
Figure PCTCN2021135945-appb-000027
实施例2
一种内酰胺化合物的合成方法，包括如下步骤：该合成方法中选 用的酰氯为
Figure PCTCN2021135945-appb-000028
式中R为芳基，R 2、R 3为甲基，即
Figure PCTCN2021135945-appb-000029
(1)在氮气保护下，将N-F苯磺酰胺、
Figure PCTCN2021135945-appb-000030
(酰氯)溶解于二氯甲烷中并搅拌均匀，并在室温下搅拌反应2.5小时，得到
Figure PCTCN2021135945-appb-000031
(即粗品产物A)；该反应步骤中N-F苯磺酰胺与
Figure PCTCN2021135945-appb-000032
摩尔比为1：1.2；
(2)将步骤(1)所得到的产物A的粗品重结晶，即可得到
Figure PCTCN2021135945-appb-000033
(产物A)；
(3)将步骤(2)得到的产物A、碘化亚铜和邻菲罗啉溶于二氯乙烷和甲醇的混合溶剂中并70℃加热反应1.5小时，即可以得到
Figure PCTCN2021135945-appb-000034
(中间体)；且所述碘化亚铜、所述邻菲罗啉和所述产物A的摩尔比为1：1.2：10；二氯乙烷与甲醇的体积比为10：1；
(5)将步骤(3)所得
Figure PCTCN2021135945-appb-000035
(中间体)溶解于四氢呋喃中并加入四丁基氟化铵(TBAF)，室温下搅拌反应16小时，即得到 目标产物六元环内酰胺
Figure PCTCN2021135945-appb-000036
且中间体与四氢呋喃的摩尔比为1：1.2。
该实施例2的合成路线具体如下反应式(1)和(2)所示：
Figure PCTCN2021135945-appb-000037
实施例3
一种内酰胺化合物的合成方法，包括如下步骤：该合成方法中选用的酰氯为
Figure PCTCN2021135945-appb-000038
式中R为芳基，R 1为甲基，即
Figure PCTCN2021135945-appb-000039
(1)在氮气保护下，将N-F苯磺酰胺、
Figure PCTCN2021135945-appb-000040
(酰氯)溶解于二氯甲烷中并搅拌均匀，并在室温下搅拌反应2.5小时，得到
Figure PCTCN2021135945-appb-000041
(即粗品产物A)；其中N-F苯磺酰胺与
Figure PCTCN2021135945-appb-000042
摩尔比为1：1；
(2)将步骤(1)所得到的产物A的粗品重结晶，即可得到
Figure PCTCN2021135945-appb-000043
(产物A)；
(3)将步骤(2)得到的产物A、碘化亚铜和邻菲罗啉溶于二氯乙烷和甲醇的混合溶剂中并80℃加热反应1.5小时，即可以得到
Figure PCTCN2021135945-appb-000044
(中间体)；且所述碘化亚铜、所述邻菲罗啉和所述产物A的摩尔比为0.5：1：10；二氯乙烷与甲醇的体积比为10：1；
(6)将步骤(3)所得
Figure PCTCN2021135945-appb-000045
(中间体)溶解于四氢呋喃中并加入四丁基氟化铵(TBAF)，室温下搅拌反应16小时，即得到目标产物五元环内酰胺
Figure PCTCN2021135945-appb-000046
且中间体与四氢呋喃的摩尔比为1：1.5。
实施例4
一种内酰胺化合物的合成方法，包括如下步骤：该合成方法中选用的酰氯为
Figure PCTCN2021135945-appb-000047
式中R为芳基，R 1为甲基，即
Figure PCTCN2021135945-appb-000048
(1)在氮气保护下，将N-F苯磺酰胺、
Figure PCTCN2021135945-appb-000049
(酰氯)溶解于二氯甲烷中并搅拌均匀，并在室温下搅拌反应2.5小时，得到
Figure PCTCN2021135945-appb-000050
(即粗品产物A)；其中N-F苯磺酰胺与
Figure PCTCN2021135945-appb-000051
摩尔比为1：1.5；
(2)将步骤(1)所得到的产物A的粗品重结晶，即可得到
Figure PCTCN2021135945-appb-000052
(产物A)；
(3)将步骤(2)得到的产物A、碘化亚铜和邻菲罗啉溶于二氯乙烷和甲醇的混合溶剂中并60℃加热反应1.5小时，即可以得到
Figure PCTCN2021135945-appb-000053
(中间体)；且所述碘化亚铜、所述邻菲罗啉和所述产物A的摩尔比为0.8：1.5：10；二氯乙烷与甲醇的体积比为10：1；
(4)将步骤(3)所得
Figure PCTCN2021135945-appb-000054
(中间体)溶解于四氢呋喃中并加入四丁基氟化铵(TBAF)，室温下搅拌反应16小时，即得到目标产物五元环内酰胺
Figure PCTCN2021135945-appb-000055
且中间体与四氢呋喃的摩尔比为1：1。
上述实施例1和实施例2的区别在于酰氯的选择不同，其余合成条件均相同；实施例3和实施例4与实施例1合成所用原料相同，其区别在于各组分的添加比例以及反应条件的差异。
上述为本发明的较佳实施例仅用于解释本发明，并不用于限定本发明。凡由本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之中。

Claims (10)

  1. 一种内酰胺化合物的合成方法，其特征在于，该方法包括如下步骤：
    (1)在气体保护下，将N-F苯磺酰胺、酰氯溶于有机溶剂中并搅拌均匀，反应得到粗品；
    (2)将所述粗品重结晶，得到产物A；
    (3)将步骤(2)得到的所述产物A、碘化亚铜和邻菲罗啉溶于混合有机溶剂中并加热反应，得到中间体；
    (4)将所述中间体溶解并加入四丁基氟化铵，搅拌，得到目标产物。
  2. 根据权利要求1所述的一种内酰胺化合物的合成方法，其特征在于，步骤(1)在氮气保护下，将N-F苯磺酰胺、酰氯溶于二氯甲烷中并搅拌均匀，在室温下反应2.5小时，得到粗品。
  3. 根据权利要求2所述的一种内酰胺化合物的合成方法，其特征在于，所述N-F苯磺酰胺与所述酰氯的摩尔比为1：(1-1.5)。
  4. 根据权利要求3所述的一种内酰胺化合物的合成方法，其特征在于，所述的酰氯的结构式为
    Figure PCTCN2021135945-appb-100001
    当所述酰氯为
    Figure PCTCN2021135945-appb-100002
    时，反应所得产物A为
    Figure PCTCN2021135945-appb-100003
    当所述酰氯为
    Figure PCTCN2021135945-appb-100004
    时，反应得产物A为
    Figure PCTCN2021135945-appb-100005
    式中R代表芳基，R 1、R 2、R 3代表烷基。
  5. 根据权利要求4所述的一种内酰胺化合物的合成方法，其特 征在于，步骤(3)中所述碘化亚铜、所述邻菲罗啉和所述产物A的摩尔比为(0.5-1)：(1-1.5)：10；所述加热的温度为60-80℃，反应时间为1.5小时；所述混合有机溶剂为二氯乙烷和甲醇的混合物。
  6. 根据权利要求5所述的一种内酰胺化合物的合成方法，其特征在于，当所述产物A为
    Figure PCTCN2021135945-appb-100006
    时，步骤(3)反应所得中间体为
    Figure PCTCN2021135945-appb-100007
    当所述产物A为
    Figure PCTCN2021135945-appb-100008
    时，步骤(3)反应所得中间体为
    Figure PCTCN2021135945-appb-100009
    式中R代表芳基，R 1、R 2、R 3代表烷基。
  7. 根据权利要求5所述的一种内酰胺化合物的合成方法，其特征在于，所述二氯乙烷与所述甲醇的体积比为10：1。
  8. 根据权利要求6所述的一种内酰胺化合物的合成方法，其特征在于，步骤(4)将所述中间体溶解于四氢呋喃中并加入四丁基氟化铵，室温下搅拌反应16小时，得到目标产物。
  9. 根据权利要求8所述的一种内酰胺化合物的合成方法，其特征在于，所述中间体与所述四氢呋喃的摩尔比为1：(1-1.5)。
  10. 根据权利要求9所述的一种内酰胺化合物的合成方法，其特征在于，当所述中间体为
    Figure PCTCN2021135945-appb-100010
    时，步骤(4)反应所得目标产 物即为五元环内酰胺
    Figure PCTCN2021135945-appb-100011
    当所述中间体为
    Figure PCTCN2021135945-appb-100012
    时，步骤(4)反应所得目标产物即为六元环内酰胺
    Figure PCTCN2021135945-appb-100013
    式中R代表芳基，R 1、R 2、R 3代表烷基。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060052423A1 (en) * 2002-12-18 2006-03-09 Smithkline Beecham Corporation Peptide deformylase inhibitors
JP2007326903A (ja) * 2006-06-06 2007-12-20 Fujifilm Corp 樹脂、該樹脂を含有するポジ型レジスト組成物、該樹脂を含有する保護膜形成組成物、該ポジ型レジスト組成物を用いたパターン形成方法及び該保護膜形成組成物を用いたターン形成方法
CN113045469A (zh) * 2021-03-23 2021-06-29 上海沃凯生物技术有限公司 一种内酰胺化合物的合成方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060052423A1 (en) * 2002-12-18 2006-03-09 Smithkline Beecham Corporation Peptide deformylase inhibitors
JP2007326903A (ja) * 2006-06-06 2007-12-20 Fujifilm Corp 樹脂、該樹脂を含有するポジ型レジスト組成物、該樹脂を含有する保護膜形成組成物、該ポジ型レジスト組成物を用いたパターン形成方法及び該保護膜形成組成物を用いたターン形成方法
CN113045469A (zh) * 2021-03-23 2021-06-29 上海沃凯生物技术有限公司 一种内酰胺化合物的合成方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NAGAMOTO MIDORI, YANAGI TOMOYUKI, NISHIMURA TAKAHIRO, YORIMITSU HIDEKI: "Asymmetric Cyclization of N -Sulfonyl Alkenyl Amides Catalyzed by Iridium/Chiral Diene Complexes", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 18, no. 18, 16 September 2016 (2016-09-16), US , pages 4474 - 4477, XP055970070, ISSN: 1523-7060, DOI: 10.1021/acs.orglett.6b01954 *
ZHAO YI-XIAO, XIE TIAN, YANG SAN-KE, YANG XIAN-JIN: "A Novel C-N Migration Rearrangement Based on N-F Compounds for the Synthesis of N -Alkyl Diaryl Ureas", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, WILEY-VCH, DE, vol. 2020, no. 4, 31 January 2020 (2020-01-31), DE , pages 437 - 445, XP055809435, ISSN: 1434-193X, DOI: 10.1002/ejoc.201901602 *

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