Ing Aminos Anilinoquinoline JAK Signaling Pathway carboxylic acid 4 6 3 Urenitrile 4, which were converted into finished products using both methods. Method 1A, amines 4 were implemented with four bromocrotonyl NaCl 5, and then the bromine with secondary Amines moved to the final compounds seventh 1B method were prepared the final compounds 8 in one step by reaction with amines 4 April crotonyl chloride 6th The two methods described in Scheme 1 were successful in our initial work9 for analog and 86 4 3 anilinoquinoline Carbons Urenitrile as EGFR kinase inhibitors prepare. Our initial preparation of 1a, b nitrocontaining cyclization of a high temperature intermediate.9 Although we never had problems involved with this cyclization, we had some concerns about the Leistungsf Ability of the cyclization of a big scale s. Therefore, we have an alternative synthesis in which the cyclization was carried out in an acetamido intermediate 14 as shown in Figure 2. Commercially Ltliche 2-amino-5-nitrophenol 9 was protected as the acetamide 10th It was then sealed and cut to get to 4 3 acetamido ethoxyaniline 12, the acetate-ethyl cyanoacrylate in the condensation with 13 directed to the acetamido intermediate layer 14. Cyclization of 14 was in Dowtherm carried out at 250 255 to yield 6 acetamido hydroxyquinoline 4 3 carbonitrile 15th The chlorination of 15, the 4-chloro generated between 16th The following are reactions Similar to the previously described, with more than the acetamido group of 18 deacetylated amine 19 prior to reaction with crotonyl chloride 20 to the desired final 21st A third method for the synthesis have been developed, the W rme No page crotonamide 6 was initially Followed Highest on the quinoline characterized carbonitrile 3, by the introduction of anilines at position C 4 are fixed, as shown in Figure 3. 1b 4-chloro 6 nitro compound has been to 22 June 4-chloro amine compound, which was then condensed with 4 to 23 crotonyl chloride give reduced. Was then in the final product 25 by heating with a plurality of anilines 24 to methoxyethanol or 2-propanol using a catalytic amount of pyridine hydrochloride.
Although this method proveduseful in the optimization of four anilino for his two T Activities w During the heat No page 6 crotonic Ureamid constant. For some compounds in which the aniline ring 4 B are REN nitrogen-containing para substituents the syntheses in Figures 4 and 5. The amino group of 26 for the first time with BOC-protected anhydride, the nitro group is reduced to give the aniline 28, and this was with 23 to give chloride by cleavage of the BOC group followed through 29, condensed. Reductive amination of amino-group 29-30 aldehydes with sodium triacetoxyborohydride in acetic Acid and 32 to 31 Another approach was used to prepare the methoxy-7 to 35, as shown in Figure 5. The compound 4-chloro 1a is first condensed with aniline 28 and then the nitro group is reduced followed by reaction 34-4 crotonyl chloride in a Hnlichen manner as shown in Figure 1. After deprotection of the BOC group with TFA, the key is preserved 35th 35 with the condensation S Anhydride, S Acid chloride, isocyanate or phenyl amides yielded 36 and 37 or urea 38th The preparation of substituted anilines, which were necessary.
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