A kind of macrocyclic jak inhibitor and its application
A technology selected from, alkyl, applied in macrocyclic JAK inhibitors and application fields
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[0220] Compound preparation method
[0221] Methods of preparing compounds of Formula I are described in the following Schemes and Examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise illustrated. In some cases, the order in which the steps of a reaction scheme are performed can be altered to facilitate a reaction or to avoid undesired side reaction products.
[0222] Generally, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 150°C, preferably 10°C to 100°C). The reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.
[0223] The preparation of compound of the present invention comprises steps:
[0224] In an inert solvent, in the presence of a catalyst, compound A 8 reacted to give compound I
[0225]
[0226] In the formula,
[0227] A 1 Selected from the following group: carboxyl group,...
Embodiment 1
[0335] Embodiment 1 preparation: 4 4 -Morpholine-6-oxa-3,11-diaza-2(4,2)-pyrimidina-1(1,4),4(1,3)-diphenylheterocyclododecene-12 - Ketone (A1)
[0336]
[0337] The first step: 2-morpholine-5-nitrobenzyl alcohol (A1-1)
[0338] 2-Fluoro-5-nitrobenzyl alcohol (10.0g, 58mmol) and an equivalent of morpholine were added to DMSO (100ml), heated to 100°C and stirred for 2h. After the completion of the reaction was confirmed by TLC, it was poured into water, extracted with EA, washed three times with deionized water, dried over anhydrous sodium sulfate, concentrated EA, and the residue was purified by column chromatography to obtain 2-morpholine-5-nitrobenzyl alcohol as a yellow solid (A1-1, 13.0 g, yield 94%). MS (ESI) m / z: calcd 239.10 (M+H), found 239.23; 1 H NMR (400MHz, DMSO): δ8.34(d, J=2.7Hz, 1H), 8.10(dd, J=8.9, 2.8Hz, 1H), 7.17(d, J=8.9Hz, 1H), 5.54( t, J = 5.7Hz, 1H), 4.55 (d, J = 5.7Hz, 2H), 3.76 (t, J = 4.0Hz, 4H), 3.01 (t, J = 4.0Hz, 4H).
[0339] The second ste...
Embodiment 2
[0355] Example 2 Preparation 1 2 -Fluoro-4 4 -Cyclopropyl-6-oxa-3,11-diaza-2(4,2)-pyrimidina-1(1,4),4(1,3)-diphenylheterocyclododecano- 12-keto: (A2)
[0356]
[0357] The first step: 1-bromo-2-bromomethyl-4-nitrobenzene (A2-2)
[0358] 2-Bromo-5-nitrobenzyl alcohol (A2-1, 928mg, 4.0mmol) and triphenylphosphine (1.98g, 6.0mmol) were added to DCM (40ml), stirred for 10min, cooled to 0°C in an ice bath, and added dropwise A solution of carbon tetrabromide (1.57 g, 6.0 mmol) in DCM (5 ml) was stirred at room temperature for 2 h after dropping. After the completion of the reaction was confirmed by TLC, the DCM was concentrated, and the residue was purified by column chromatography to obtain yellow solid A2-2 (647 mg, yield 55%). 1 H NMR (400MHz, CDCl 3 ): 8.36(s, 1H), 8.05(d, J=8.8Hz, 1H), 7.81(d, J=8.8Hz, 1H), 4.66(s, 2H).
[0359] The second step: tert-butyl 4-((2-bromo-5-nitro)benzyloxy)butylamine-1-carboxylate (A2-3)
[0360] Under nitrogen protection, 4-(N-tert-buto...
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