N-subsituted aromatic ring-2-amino pyrimidine compound and applications
An aminopyrimidine and compound technology, applied in the direction of organic chemistry, drug combination, antitumor drugs, etc., can solve the problems of reducing the sensitivity of treatment, cell cycle arrest, etc., and achieve the effect of good therapeutic effect
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preparation Embodiment 1
[0125] Preparation Example 1 5-((4-((piperidin-2-ylmethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanopyridine (Compound 1) synthesis
[0126]
[0127] Step 1. Synthesis of 5-trifluoromethyl-4 chloro-2-aminopyrimidine (intermediate 1-2)
[0128]
[0129] Dissolve 2,4-dichloro-5-trifluoromethylpyrimidine (5.2g, 24.07mmol) in ammonia-saturated ethanol (25ml), stir at room temperature for 2h, recover the solvent under reduced pressure to obtain a residue, and use silica gel column layer Analysis and purification, using PE:EA (5:1) as the eluent, gave white solid 1-2 (2.3g, 11.67mmol), yield: 48.5%. 1 H NMR (500MHz, CDCl 3 )δ8.57(s,1H),7.98(s,2H). ESI-MS:m / z=198[M+H] + .
[0130] Step 2.N 4 -Synthesis of (N-tert-butoxycarbonylpiperidin-2-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (intermediate 1-3)
[0131]
[0132] Under ice-bath condition, take intermediate 1-2 (197.0mg, 1.0mmol), 1-Boc-2-aminomethylpiperidine (256.8mg, 1.2mmol), dissolve in m...
preparation Embodiment 2
[0136] Preparation Example 2 5-((4-((piperidin-3-ylmethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanopyridine (Compound 2)
[0137]
[0138] Step 1.N 4 Synthesis of -(N-tert-butoxycarbonylpiperidin-3-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (intermediate 1-4)
[0139]
[0140] For the synthesis steps, refer to Step 2 of Example 1. Intermediate 1-4 was synthesized by replacing 1-Boc-2-aminomethylpiperidine with 1-Boc-3-aminomethylpiperidine. Yield: 70%. 1 H NMR (500MHz, CDCl 3 )δ8.08(s,1H),5.44(s,1H),5.10(s,2H),3.85(m,2H),3.40(m,2H),3.01(m,1H),2.88–2.73(m ,1H),1.91–1.81(m,2H),1.77(m,2H),1.68
[0141] (m,1H),1.47(s,9H).ESI-MS:m / z=376[M+H] + .
[0142] Step 2. Synthesis of 5-((4-((piperidin-3-ylmethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanopyridine (compound 2)
[0143]
[0144] Synthesis steps Refer to step 3 of Example 1 to synthesize compound 2. Yield: 65%. 1 H NMR(500MHz,DMSO)δ10.30(s,1H),9.07(d,J=2.5Hz,1H),8.42(dd,J=9...
preparation Embodiment 3
[0146] Preparation Example 3 (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanopyridine (compound 3)
[0147]
[0148] Step 1. (R)-N 4 Synthesis of -(N-tert-butoxycarbonylmorpholin-2-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (intermediate 1-5)
[0149]
[0150] For the synthesis steps, refer to Step 2 of Example 1. Intermediate 1-5 was synthesized by replacing 1-Boc-2-aminomethylpiperidine with (S)-4-N-Boc-2-aminomethylmorpholine. Yield: 65%. 1 H NMR (500MHz, CDCl 3 )δ8.09(s,1H),5.50(s,1H),5.10(s,2H),4.13–3.67(m,4H),3.66–3.49(m,2H),3.47–3.37(m,1H) ,2.96(s,1H),2.69(s,1H),1.49(s,9H).ESI-MS:m / z=378[M+H] + .
[0151] Step 2. (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanopyridine ( Compound 3) Synthesis
[0152]
[0153] Synthesis steps Referring to Step 3 of Example 1, compound 3 was synthesized. Yield: 70%. 1 H NMR (500MHz, DMSO) δ10.35(s, 1H), 9.04(d, J=2.0Hz, 1H), 8.50–...
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