ALK (anaplastic lymphoma kinase) protein degradation agent and anti-tumor application thereof
An inhibitor and solvate technology, applied in the field of ALK protein degrader and its anti-tumor application, can solve the problems of ALK protein drug resistance and inability to clear ALK protein, etc.
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[0277] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. The present invention may be practiced without some or all of these specific details. In other instances, well known process operations have not been described in detail in order not to unnecessarily obscure the present invention. While the invention will be described in conjunction with specific embodiments, it will be understood that they are not intended to limit the invention to those embodiments.
[0278] The following abbreviations are used throughout the specification and examples:
[0279] Boc tert-butoxycarbonyl
[0280] Con. Concentration
[0281] DCM dichloromethane
[0282] DMF N,N-Dimethylformamide
[0283] DMSO dimethyl sulfoxide
[0284] DIPEA N,N-Diisopropylethylamine
[0285] EDCI carbodiimide
[0286] ESI electrospray ionization
[0287] equiv equivalent
[0288] EtOH ethanol
[0289] HOAT 1-Hydroxy-7-azobenzot...
preparation Embodiment 1
[0357] Intermediate Preparation Example 1: Preparation of Brigatinib Derivative A (SIAIS1197135)
[0358] Brigatinib derivative A (SIAIS1197135) was prepared according to Scheme 1.
[0359] Preparation of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (SIAIS1197111):
[0360] Under open conditions, 5-fluoro-2-nitroanisole (7g, 40.9mmol) was dissolved in 60mL of DMF solution, followed by adding K 2 CO 3 (8.4g, 60.8mmol), N-tert-butoxycarbonylpiperazine (9.1g, 48.9mmol), stirred overnight at room temperature. After the reaction was completed, quenched with water, extracted with ethyl acetate, washed the organic phase with water, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, beating with a mixed solvent of petroleum ether:ethyl acetate=5:1, and filtered through a sand core 11.1 g of yellow target solid SIAIS1197111 was obtained with a yield of 80%. 1 H NMR (500MHz, DMSO) δ7.89(d, J=9.3Hz, 1H), 6.57(d, J=9.5 Hz, 1H), 6.52(s, 1H),...
preparation Embodiment 2
[0366] Intermediate Preparation Example 2: Preparation of Brigatinib Derivative B
[0367] Using a method similar to that of the brigatinib derivative A in Example 1 of intermediate preparation, the brigatinib derivative B was prepared according to Scheme 1, and the intermediate synthesis data and structural characterization data are as follows:
[0368]
[0369] tert-Butyl(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)carbamate (SIAIS151054).(Yellow solid, 1.81g, 88%) 1 H NMR (500MHz, CDCl 3 )δ7.99(t, J=8.9Hz, 1H), 6.41(dd, J=9.4, 2.5Hz, 1H), 6.30(d, J=2.5Hz, 1H), 4.49(s, 1H), 3.94( s,3H),3.86–3.82(m,2H),3.71(s,1H),3.09–3.00(m,2H),2.11–2.03(m,2H),1.89–1.75(m,2H),1.45( s,9H).
[0370]
[0371] tert-Butyl(1-(4-amino-3-methoxyphenyl)piperidin-4-yl)carbamate (SIAIS151062).(gray purple solid, 411.6mg, 90%) 1 H NMR (500MHz, DMSO) δ6.82(d, J=7.6Hz, 1H), 6.50(d, J=8.5Hz, 1H), 6.48(d, J=2.5Hz, 1H), 6.28(dd, J =8.4,2.4Hz,1H),4.20(s,2H),3.73(s,3H),3.33–3.26(m,3H),2.56–2.50(m,2H),...
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