Structure of 858227-12-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 858227-12-0 |
Formula : | C9H8N2O2 |
M.W : | 176.17 |
SMILES Code : | O=C(C1=NNC2=C1C=CC(C)=C2)O |
MDL No. : | MFCD07378891 |
InChI Key : | PXMCNJOQYWBJDO-UHFFFAOYSA-N |
Pubchem ID : | 24728760 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | 6-methyl-I H-indazole-3-carboxamideTo a solution of 6-methyl-i H-indazole-3-carboxylic acid (440 mg, 2.50 mmol), ammonium chloride (401 mg, 7.49 mmol) and HBTU (1.42 g, 3.75 mmol) in DMF (10 ml) was added DIPEA (1.31 ml, 7.49 mmol) and the reaction mixture was stirred for 16 h at RT. The reaction mixture was concentrated, diluted in EtOAc, washed with iN HCI, dried over Na2504, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (CH2CI2MeOH 1:0 to 8:2). MS (UPLC-MS): 176 [M+H]+; tR (HPLC conditions e): 1.30 mm. | |
With ammonium chloride; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a solution of 6-methyl-1 H-indazole-3-carboxylic acid (440 mg, 2.50 mmol), ammonium chloride (401 mg, 7.49 mmol) and HBTU (1 .42 g, 3.75 mmol) in DMF (10 ml) was added DIPEA (1 .31 ml, 7.49 mmol) and the reaction mixture was stirred for 16 h at RT. The reaction mixture was concentrated, diluted in EtOAc, washed with 1 N HCI, dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (CH2CI2/MeOH 1 :0 to 8:2). MS (UPLC-MS): 176 [M+H]+; tR (HPLC conditions b): 1 .30 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 12h;Inert atmosphere; | 6-Methyl-2H-indazole-3-carboxylic acid (purchased from Sinova, http://www.sinovainc.com; 44 mg, 0.24 mmol) and benzyl amine (31 mL, 0.28 mmol) were dissolved in 2 mL of acetonitrile and treated with EDC (68 mg, 0.36 mmol) and DMAP (87 mg, 0.71 mmol). The resulting solution was stirred for 12 h at room temperature. The reaction mixture was diluted with CH2Cl2, washed with 10% aqueous NaHCO3 solution (2x), water, 5% acetic acid solution (2x). The organic phase was collected, dried over sodium sulfate (Na2SO4), filtered and then concentrated in vacuo. Crude material obtained was purified by silica gel column chromatography with a 20% ethyl acetate : CH2Cl2 solvent system to give 20 mg (32%) of 9 as an off white solid for x-ray diffraction. Mp 159 - 160 C; 1H NMR (300 MHz, CDCl3) δ 10.05 (1H, bs, NH) 8.29 (d, J = 8.1 Hz, 1H), 7.48 - 7.25 (m, 6H), 7.15 (d, J = 8.1 Hz, 1H), 4.70 (d, J = 6.0 Hz, 2H), 2.50 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.98, 142.16, 138.89, 137.89, 136.98, 128.10, 127.03, 127.00, 126.70, 124.29, 120.82, 119.88, 109.22, 42.18, 20.46. HRMS (EI), M+1 calcd. for C16H16N3O, 266.1288; found 266.1299. HPLC tR= 3.5 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(2S,3aR,5R, 7aS)- (6-methyl-lH-indazol-3-yl)(hexahydro-2,5- methanopyrrolo[3,2-c]pyridin-l(6H)-yl)methanone was also prepared by the following alternate method: In a 3000 ml 4 neck flask was charged (2S,3aR,5R, 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.8% | (2R,3aS,5S, 7aR)- (6-methyl-lH-indazol-3-yl)(hexahydro-2,5- methanopyrrolo[3,2-c]pyridin-l(6H)-yl)methanone was also prepared by the following alternate method: (2R,3aS,5S, 7ai?)-octahydro-2,5-methanopyrrolo[3,2-c]pyridine, 2 HCl was prepared in the same manner as (2S,3aR,5R, 7aS)-octahydro-2,5-methanopyrrolo[3,2- c]pyridine, 2 HCl by the method of example la, alternate route, from the opposite enantiomer from the SFC separation of example la, alternate step A To a mixture of 6-methyl-lH-indazole-3-carboxylic acid (11.08 g, 62.9 mmol), l-hydroxypyridin-2(lH)-one (6.99 g, 62.9 mmol) in MeCN (440 ml) was added N 1 -((ethylimino)methylene)-N3 ,N3 -dimethylpropane- 1 ,3 -diamine hydrochloride (12.06 g, 62.9 mmol) in portions over 5 minutes. After addition was complete, the mixture was stirred at rt (3:40 pm) for 2 h 30 min. The mixture was trasferred to an addition funnel. This mixture was added to a solution of (2R,3aS,5S, 7ai?)-octahydro-2,5-methanopyrrolo[3,2-c]pyridine, 2 HCl (13.28 g, 62.9 mmol) and N-ethyl-N-isopropylpropan-2-amine (32.5 g, 252 mmol) in MeCN (220 ml) over 15 min, while maintaining internal temperature between - 30 to - 25 C with acetone/dry ice bath. After addition, the mixture was stirred with an cooling bath and slowly warmed to ambient temperature. After 16 h, the LC/MS was taken and it looked identical to that of 40 min. the reaction was worked up. The solid was filtered off. The solvent in the filtrate was evaporated to dryness. The remaining oil was dissolved in CHCI3 (400 mL), washed with saturated NaHC03 (160 mL). The layers were separated. The aqueous layer was extracted with CHC13 (1 x 100 mL). The combined extracts were washed with saturated NaHC03 (2 x 120 mL), dried (MgS04), evaporated to give the crude material. The crude was purified by silica gel chromatography on a 750g RediSep column, flow rate = 300 mL/min, equilibration volume = 3.0 column volumes. Solvent A was chloroform, solvent B was 20% (2N Ammonia in methanol) in chloroform. The purification was performed by first eluting with 1.OCV of solvent A, followed by a gradient 0-50% B over 10 CV and then holding at 50%B for 5. OCV, affording (2R,3aS,5S, 7aR)- (6-methyl-lH-indazol-3-yl)(hexahydro-2,5- methanopyrrolo[3,2-c]pyridin-l(6H)-yl)methanone (16.2 g) The sample was recrystallized from MeCN (600 mL) at 65 C for 3 h and then slowly cooled to rt overnight. The white solid was collected on a filter, washed with MeCN, dried under house vacuum under a stream of nitrogen. To give (2R,3aS,5S, 7aR)- (6-methyl-lH-indazol-3-yl)(hexahydro-2,5-methanopyrrolo[3,2- c]pyridin-l(6H)-yl)methanone (12.1 g, 64.8 %) with a HPLC purity of 99.8%. LCMS Conditions: Waters BEH CI 8, 1.7um, 150mm (L) x 2.1mm (ID), 35C, Flow rate = 0.35mL/min, Solvent A: 0.1% TFA in water, Solvent B: 0.05% TFA in Acetonitrile. Gradient: 0-15min, gradient 10-25% B, 15-28min, gradient 25-95 %B, 28-30min, 95%B. Injection volume = 2uL of a lmg/mL sample in methanol. Retention time = 9.21min, [M+H]+ at m/z = 297. Accurate mass: [M+H]+ at m/z = 297.1698. Optical Rotation: [a]D25 c = -132.14 (1.66 mg/mL in MeOH). Karl Fischer: 0.75% water. Elemental analysis: (C,H,N) Calculated: (67.77%, 6.45%, 19.74%), found: (68.17%, 6.51%, 19.81%). |
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