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PROCESS FOR PREPARING N-ALKYLATED DIPEPTIDES AND ESTERS THEREOF

机译:N-烷基化肽及其酯的制备方法

摘要

1. A process for the preparation of compounds of the formula I see diagramm : EP0135182,P12,F1 in which n is 1 or 2, R denotes hydrogen, alkyl having 1-8 carbon atoms, alkenyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C1 -C4 )-alkyl, (C1 -C3 )-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C1 -C4 )-alkylamino, di-(C1 -C4 )-alkylamino, (C1 -C4 )-acylamino, preferably (C1 -C4 )-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy having 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and can be substituted as described above for aryl, mono- or bicyclic heteroaryloxy which has 5-7 or 8-10 ring atoms respectively, 1 to 2 of the ring atoms representing sulfur or oxygen atoms and/or 1 to 4 ring atoms representing nitrogen, and which can be substituted as described above for aryl, amino-(C1 -C4 )-alkyl, (C1 -C4 )-alkanoyl-amino-(C1 -C4 )-alkyl, (C7 -C13 )-aroylamino-(C1 -C4 )-alkyl, (C1 -C4 )-alkoxy-carbonylamino-(C1 -C4 )-alkyl, (C6 -C12 )-aryl-(C1 -C4 )-alkoxycarbonylamino-(C1 -C4 )- alkyl, (C6 -C12 )-aryl-(C1 -C4 )-alkylamino-(C1 -C4 )-alkyl, (C1 -C4 )-alkylamino-(C1 -C4 )-alkyl, di-(C1 -C4 )-alkylamino-(C1 -C4 )-alkyl, guanidino-(C1 -C4 )-alkyl, imidazolyl, indolyl, (C1 -C4 )-alkylthio, (C1 -C4 )-alkylthio-(C1 -C4 )-alkyl, (C6 -C12 )-arylthio-(C1 -C4 )-alkyl which can be substituted in the aryl moiety as described above for aryl, (C6 -C12 )-aryl-(C1 -C4 )-alkylthio which can be substituted in the aryl moiety as described above for aryl, carboxyl-(C1 -C4 )-alkyl, carboxyl, carbamoyl, carbamoyl-(C1 -C4 )-alkyl, (C1 -C4 )-alkoxy-carbonyl-(C1 -C4 )-alkyl, (C6 -C12 )-aryloxy-(C1 -C4 )-alkyl which can be substituted in the aryl moiety as described above for aryl, or (C6 -C12 )-aryl-(C1 -C4 )-alkoxy which can be substituted in the aryl moiety as described above for aryl, R**1 denotes hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, cycloalkenyl having 5-9 carbon atoms, (C3 -C9 )-cycloalkyl-(C1 -C4 )-alkyl, (C5 -C9 )-cycloalkenyl(C1 -C4 )-alkyl, optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted as described above for R, (C6 -C12 )-aryl-(C1 -C4 )-alkyl or (C7 -C13 )-aroyl-(C1 or C2 )-alkyl, both of which can be substituted as the preceding aryl, mono- or bicyclic, optionally partially hydrogenated heteroaryl which has 5-7 or 8-10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 ring atoms representing nitrogen atoms, which can be substituted as the preceding aryl, or, the protected side chain of a naturally occurring alpha-amino acid R**1 -CH(NH2 )-COOH, R**2 and R**3 are identical or different and denote hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, di-(C1 -C4 )-alkylamino-(C1 -C4 )-alkyl, (C1 -C5 )-alkanoyloxy-(C1 -C4 )-alkyl, (C1 -C6 )-alkoxy-carbonyloxy-(C1 -C4 )-alkyl, (C7 -C13 )-aroyloxy-(C1 -C4 )-alkyl, (C6 -C12 )-aryloxycarbonyloxy-(C1 -C4 )-alkyl, aryl having 6-12 carbon atoms, (C6 -C12 )-aryl-(C1 -C4 )-alkyl, (C3 -C9 )-cycloalkyl or (C3 -C9 )-cycloalkyl-(C1 -C4 )-alkyl, and R**4 and R**5, together with the atoms carrying them, form a heterocyclic mono-, bi- or tricyclic ring system having 3 to 15 carbon atoms, which comprises compounds of the formula II see diagramm : EP0135182,P12,F2 in which n, R, R**1 and R**2 have the meanings defined above, being reacted in the presence of a phosphinic anhydride of the formula III see diagramm : EP0135182,P13,F1 in which R**6 , R**7 , R**8 and R**9 are identical or different and represent alkyl and/or aralkyl, with compounds of the formula IV see diagramm : EP0135182,P13,F2 in which R**3 , R**4 and R**5 have the meanings defined above, where appropriate radicals which have been introduced to protect other functional groups being eliminated and, where appropriate, free carboxyl groups being esterified in a manner known per se.
机译:1.制备式I化合物的方法,参见图:EP0135182,P12,F1,其中n为1或2,R表示氢,具有1-8个碳原子的烷基,具有2-6个碳原子的烯基,环烷基具有3-9个碳原子的芳基,具有6-12个碳原子并且可以被(C1-C4)-烷基,(C1-C3)-烷氧基,羟基,卤素,硝基,氨基单,双或三取代,氨基甲基,(C1-C4)-烷基氨基,二-(C1-C4)-烷基氨基,(C1-C4)-酰基氨基,优选(C1-C4)-烷酰基氨基,亚甲基二氧基,羧基,氰基和/或氨磺酰基,具有1的烷氧基-4个碳原子,具有6-12个碳原子的芳氧基,可以如上所述取代分别具有5-7或8-10个环原子的芳基,单环或双环杂芳氧基,其中1至2个环原子代表硫或氧原子和/或代表氮的1至4个环原子,它们可以如上所述被取代为芳基,氨基-(C1-C4)-烷基,(C1-C4)-烷酰基-氨基-(C1-C4) -烷基,(C7 -C13)-芳基氨基-(C1-C4)-烷基,(C1-C4)-烷氧基-羰基氨基-(C1-C4)-烷基,(C6-C12)-芳基-(C1-C4)-烷氧基羰基氨基-(C1-C4)-烷基,(C 6 -C 12)-芳基-(C 1 -C 4)-烷基氨基-(C 1 -C 4)-烷基,(C 1 -C 4)-烷基氨基-(C 1 -C 4)-烷基,二-(C 1 -C 4)-烷基氨基-(C1-C4)-烷基,胍基-(C1-C4)-烷基,咪唑基,吲哚基,(C1-C4)-烷硫基,(C1-C4)-烷硫基-(C1-C4)-烷基,(C6 -C12)-芳硫基-(C1-C4)-烷基,其可如上文关于芳基所述被取代,(C6-C12)-芳基-(C1-C4)-烷硫基,其可被芳基部分取代如上文关于芳基,羧基-(C1-C4)-烷基,羧基,氨基甲酰基,氨基甲酰基-(C1-C4)-烷基,(C1-C4)-烷氧基-羰基-(C1-C4)-烷基,(C6 -C12)-芳氧基-(C1-C4)-烷基,其可以如上文关于芳基所述在芳基部分中被取代,或(C6-C12)-芳基-(C1-C4)-烷氧基,其可以在芳基中被取代如上对于芳基所述的部分,R ** 1表示氢,具有1-6个碳原子的烷基,具有2-6个碳原子的烯基碳原子,具有2-6个碳原子的炔基,具有3-9个碳原子的环烷基,具有5-9个碳原子的环烯基,(C3-C9)-环烷基-(C1-C4)-烷基,(C5-C9)-环烯基(C1-C4)-烷基,具有6-12个碳原子并且可以如上文关于R,(C6-C12)-芳基-(C1-C4)-烷基或(C7-C13)所述被取代的任选地部分氢化的芳基-芳酰基-(C1或C2)-烷基,它们都可以被取代为分别具有5-7或8-10个环原子的单环或双环,任选地部分氢化的杂芳基,其中这些环中的1-2个代表硫或氧原子的原子和/或代表氮原子的1-4个环原子,可以被取代为之前的芳基,或者是天然存在的α-氨基酸R ** 1-CH(NH2)的保​​护侧链-COOH,R ** 2和R ** 3相同或不同,表示氢,具有1-6个碳原子的烷基,具有2-6个碳原子的烯基,二-(C1-C4)-烷基氨基-(C1-C4 )-烷基,(C1-C5)-烷酰氧基-(C1 -C 4)-烷基,(C 1 -C 6)-烷氧基-羰氧基-(C 1 -C 4)-烷基,(C 7 -C 13)-芳酰氧基-(C 1 -C 4)-烷基,(C 6 -C 12)-芳氧基羰基氧基-(C1 -C4)-烷基,具有6-12个碳原子的芳基,(C6-C12)-芳基-(C1-C4)-烷基,(C3-C9)-环烷基或(C3-C9)-环烷基-(C1-C4烷基,以及R ** 4和R ** 5与携带它们的原子一起形成具有3至15个碳原子的杂环单环,双环或三环系统,该环系统包含式II的化合物,请参见示意图:其中n,R,R ** 1和R ** 2具有以上定义的含义,在式III的次膦酸酐存在下反应的EP0135182,P12,F2,参见图:EP0135182,P13,F1,其中R ** 6,R ** 7,R ** 8和R ** 9相同或不同,并且代表烷基和/或芳烷基,其中式IV的化合物参见图:EP0135182,P13,F2,其中R **在图3中,R ** 4和R ** 5具有上面定义的含义,其中引入适当基团以保护其他官能团被消除。然后以合适的方式将游离羧基酯化,并以本身已知的方式酯化。

著录项

  • 公开/公告号HUT36145A

    专利类型

  • 公开/公告日1985-08-28

    原文格式PDF

  • 申请/专利权人 HOECHST AGDE;

    申请/专利号HU19840003415

  • 申请日1984-09-10

  • 分类号C07K5/06;

  • 国家 HU

  • 入库时间 2022-08-22 08:15:35

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