Peptide deformylase inhibitors containing spiro three-membered rings or spiro five-membered rings
A technology of peptide deformylase and inhibitor, which can be applied in the field of spiro five-membered ring peptide deformylase inhibitor and new spiro three-membered ring, which can solve the problems of toxicity, clinical manifestation and inactivity.
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Embodiment 1
[0122] (S)-5-((R)-2-((N-hydroxycarboxamido)methyl)caproylamido)-N-(1H-pyrazol-3-yl)-5-azaspiro[2.4 ]Synthesis of heptane-6-amide
[0123]
[0124] Step 1: Add 3-aminopyrazole (1.50g, 18.0mmol), trimethylamine (4.5g, 20.6mmol), 4-(dimethylamino)pyridine (0.15g, 1.2mmol) in 60mL dioxane, Add Boc after stirring to dissolve 2 O, heated to reflux for 8h, after the reaction was completed, the solvent was spinned out, then diluted with EA and extracted, washed successively with 10% citric acid and saturated brine, and the organic phase was concentrated to obtain an oil, which was passed through the column (PE / DCM=2 / 1) The product was obtained as a white solid (1.6 g, yield 48%).
[0125]Step 2: the operation is as in step 1 in the synthetic general formula (X1). After adding 20mL of DMF to the acid (2.05g, 8.5mmol) to dissolve, add N-methylimidazole (1.54g, 18.7mmol) under ice cooling, then slowly add MsCl (1.07g, 9.4mmol), stir for 15min and then add Boc Protected amine (1.5...
Embodiment 2
[0136] 5-Fluoro-2-((S)-5-((R)-2-((N-hydroxycarboxamido)methyl)hexylcarbonyl)-5-azaspiro[2.4]heptane-6-amide base) synthesis of pyridine N-oxygen compounds
[0137]
[0138] Step 1: The operation is as in Step 1 in the synthesis of general formula (X1).
[0139] Step 2: The operation is as in step 2 in the synthesis of general formula (X1) (2.1 g, white solid, two-step yield 68%).
[0140] Step 3: The operation is as in step 3 in the synthesis of general formula (X2).
[0141] Step 4: The obtained oil (242mg, 0.46mmol) was dissolved in ethyl acetate (3mL), hydrogen peroxide urea complex (133mg, 1.40mmol) and phthalic anhydride (207mg, 1.40mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with sodium thiosulfate and extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product.
[0142] Step 5: The operation is as in step 4 in the synthesis of gen...
Embodiment 3
[0148] (S)-N-(5-(tert-butyl)isoxazol-3-yl)-5-((R)-2-((N-hydroxycarboxamido)methyl)hexylcarbonyl)-5- Synthesis of Azaspiro[2.4]heptane-6-amide
[0149]
[0150] Step 1: The operation is as in Step 1 in the synthesis of general formula (X1).
[0151] Step 2: The operation is as in step 2 in the synthesis of general formula (X1) (1.4 g, white solid, two-step yield 47%).
[0152] 1 H NMR (400MHz,D 2 O)δ6.14(s,1H),4.44-4.41(m,1H),3.12-2.93(m,2H),2.19(dd,J=13.4,8.9Hz,1H),1.86(dd,J=13.4 ,6.1Hz,1H),0.52-0.29(m,4H).
[0153] 13 C NMR (101MHz,D 2 O) δ183.22, 167.90, 157.06, 93.24, 60.23, 52.67, 37.13, 32.51, 27.67, 20.09, 9.86, 8.49.
[0154] Step 3: The operation is as in step 3 in the synthesis of general formula (X2).
[0155] Step 4: The operation is as in step 4 in the synthesis of general formula (X2), column chromatography (DCM:MeOH=10:1) gives a white solid, and the two-step yield is 28%.
[0156] LC-MS(ESI):[M+1] + =435.24,t R =2.25min.
[0157] 1 H NMR (400MHz,...
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