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Chemical Structure| 254882-06-9 Chemical Structure| 254882-06-9

Structure of 254882-06-9

Chemical Structure| 254882-06-9

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Product Details of [ 254882-06-9 ]

CAS No. :254882-06-9
Formula : C12H21NO5
M.W : 259.30
SMILES Code : O=C(N1[C@H](C(OC)=O)C[C@H](O)CC1)OC(C)(C)C
MDL No. :MFCD02259709

Safety of [ 254882-06-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338

Application In Synthesis of [ 254882-06-9 ]

* 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.

  • Downstream synthetic route of [ 254882-06-9 ]

[ 254882-06-9 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 612501-52-7 ]
  • [ 254882-06-9 ]
  • [ 908294-09-7 ]
YieldReaction ConditionsOperation in experiment
69% With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at -15 - 20℃; for 2h;Cooling with acetone-dry ice; Example 1; (2S,4S)-4-({4-[(3-cIiloro-2-fluorophenyl)amiiio]-7-methoxyquinazolin-6-yl}oxy)-l- methylpiperidine-2-carboxamide; The title compound was prepared as shown in scheme A:Scheme AMolecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (25',45)-4-({4-[(3-cMoro-2-fluoiOphenyl)arnino]-7-methoxyquinazolin-6- yl}oxy)rhoiperidine-2-carboxamide (5) (3.1 g, 6.97 ??nol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (2.93 g, 13.9 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCOs(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam The residue was purified by flash chromatography (silica gel, DCM-NH3ZMeOH 2%) to give the title product as a white solid (1.8 g, 56%): 1H NMR Spectrum: (DMSO d6) 1.86-1.91 (m, 3H), 2.07-2.09 (m, IH), 2.20 (s, 3H), 2.47-2.49 (m, IH), 2.71-2.81 (m, 2H), 3.96 (s, 3H), 4.82 (m, IH), 7.02 (s, IH), 7.23 (s, IH), 7.26-7.29 (m, 2H), 7.47-7.53 (m, 2H), 7.82 (s, IH), 8.37 (s, IH), 9.60 (s, IH); Mass Spectrum: (M+H)+ 460.1. The starting material (25,45)-4-({4-[(3-croro-2-fluorophenyl)amiiiotao]-7- methoxyquinazolin-6-yl}oxy)pirhoeridine-2-carboxamide (5) was prepared as follows:DTAD (13.3 g, 57.9 mmol) dissolved in 50 ml of DCM was added over a period of 10 minutes to a stirred suspension of 4-[(3-cMoro-2-fluororhohenyl)arnino]-7-methoxyquinazolin- 6-ol (1) (4.94 g, 15.5 mmol, prepared as described in WO 03/082831, Reference Example 2 therein), triphenylphosphine (18.3 g, 69.5 mmol) and (2S,4R)-N~(te/t-butoxycarbonyi)-4- hydroxypiperidine-2-carboxyric acid methyl ester (ex ACROS, 6 g, 23.2 mmol) in DCM (150 ml) at -150C (acetone/ice). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, concentrated to approximately 50 ml and purified directly by flash chromatography (silica gel, eluting with a gradient from 100% DCM to DCM/EtOAc (80/20) to DCM/EtOAc (50/50) to give 1-tert-butyl 2-methyl (2S,4S)-4-({4-[(3-chloro-2- fluoiOphenyl)amino]-7-methoxyquinazohn-6-yl}oxy)piperidine-l,2-dicarboxylate (2) (6 g, 69%) as a white foam; 1H NMR Spectrum: (DMSO (J6) 1.47-1.53 (m, HH), 1.86-1.91 (m, IH), 2.25-2.36 (m, IH), 2.95-3.13 (m, IH), 3.70 (s, 3H), 3.95 (s, 3H), 3.98-4.04 (m, IH), 4.45 (m, IH), 4.86-4.94 (m, IH), 7.31 (t, IH), 7.51-7.64 (m, 3H), 7.80 (s, IH), 8.39 (s, IH), 9.54 (s, IH): Mass Spectrum: (M+H)÷ 561.1. A stirred solution of 1-f°rr-butyl 2-methyl (25,45)-4-( { 4-[(3-chloro-2- fluorophenyl)amino]-7-methoxyquinazohn-6-yl}oxy)pirhoeridine-l,2-dicarboxylate (2) (6 g, 10.7 mmol) in THF (30 ml) and water (30 ml) was prepared at room temperature then cooled to 00C and solid LiOH-H2O (0.54 g, 12.9 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, acidified with acetic acid and extracted with DCM. The resulting residue was evaporated to dryness, azeotroped with toluene (3 x 50 ml) and dried to a constant weight to give (21Sr,4S)-l-(te7t-butoxycarbonyl)-4-({4-[(3-chloiO-2- fluorophenyl)amino]-7-methoxyquinazoun-6-yl}oxy)piperidine-2-carboxylic acid (3) (5.27 g, 90%), which was used without further purification; Mass Spectrum: (M+H)+ 547.1. A stirred solution of (25',45)-l-(fert-butoxycarbonyl)-4-({4-[(3-chloro-2- fluororhohenyl)amino]-7-methoxyquinazoUn-6-yl}oxy)rhoirhoeridine-2-cai-boxylic acid (3) (5 g, 9.16 mmol) in THF (50 ml) was cooled to -15C (acetone/ice). NMM (1.5 ml, 13.7 mmol) was added to the solution followed by IBCF (1.54 ml, 11.9 mmol). The reaction mixture was held at -150C (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with concentrated aqueous ammonia (3 ml) at -150C and allowed to warm to room temperature. The reaction mixture was diluted with DCM (250 ml), washed with water (2 x 20 ml) and concentrated to give tert-butyl (25',45)-2- (aminocarbonyl)-4-({4-[(3-cMoro-2-fluorophenyl)amino]-7-methoxyquinazorin-6- yl}oxy)piperidine-l-carboxylate (4) (5 g, 100%) as a pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 546.1.TFA (15 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (25,45)-2-(arninocarbonyl)-4-({4-[(3-cMoro-2-fluorophenyl)amino]-7-methoxyquialphaazorJn-6- yl}oxy)piperidine-l-carboxylate (4) (5 g, 9.16 mmol) in DCM (15 ml) at 00C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene and the residue was purified by flash chromatography (silica gel, DCM- NH3ZMeOH 5%) to give (2^4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7- memoxyquinazolin-6-yl}oxy)piperidin...
 

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