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Chemical Structure| 208837-83-6 Chemical Structure| 208837-83-6

Structure of 208837-83-6

Chemical Structure| 208837-83-6

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Product Details of [ 208837-83-6 ]

CAS No. :208837-83-6
Formula : C10H18N2O2
M.W : 198.26
SMILES Code : O=C(N1CC2C(N)C2C1)OC(C)(C)C
MDL No. :MFCD09040607

Safety of [ 208837-83-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of [ 208837-83-6 ]

* 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 [ 208837-83-6 ]

[ 208837-83-6 ] Synthesis Path-Downstream   1~26

  • 1
  • [ 208837-83-6 ]
  • [ 66-99-9 ]
  • C21H24N2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In methanol; at 20℃; for 3h; Intermediate B (200mg, 1.01mml) was stirred in MeOH (10ml) at r.t. under N2 and 2- napthaldehyde (148mg, 0.96mmol) was added. The resultant solution was stirred for 3 h. After this time, NaBH4 (61 mg, 1.62mmol) was added, causing fizzing, and the solution stirred for 10 min. 1 M NaOH (20ml) was then added, forming an opaque white solution which was stirred for 20 min. H2O (50ml) was then added and the solution extracted with Et2O (2 x 100ml). The combined organic extracts were dried (MgSO4) and solvent removed in vacuo to give the title compound as a colourless oil (320mg, 100%). LCMS purity 98%, m/z 339 [M+H]+.
  • 2
  • [ 208837-83-6 ]
  • [ 2243-83-6 ]
  • [ 914937-27-2 ]
YieldReaction ConditionsOperation in experiment
100% With pyridine; at 0℃; for 1h; To a cooled (ice-bath) solution of intermediate B (170mg, 0.86mmol) in pyridine (1 ml) was added 2-naphthoyl chloride (180mg, 0.94mmol). The mixture was stirred for 1 h, then water (8ml) was added. The resulting precipitate was collected by filtration, and dried under vacuum to afford the title compound (314mg, 100%). 1H NMR (300 MHz, CDCI3) δ: 1.47 (9H, s), 1.85 (2H1 s), 2.71 (1 H, d), 3.40-3.50 (2H, m), 3.82 (2H, d), 6.37 (1 H, br s), 7.54-7.60 (2H, m), 7.81 (1 H, dd), 7.88-7.95 (3H, m), 8.26 (1 H, s).
  • 3
  • [ 208837-83-6 ]
  • [ 93-11-8 ]
  • [ 914937-17-0 ]
YieldReaction ConditionsOperation in experiment
82% With triethylamine; In dichloromethane; at 0 - 20℃; 2-Naphtalenesulphonyl chloride (20.07g, 97.39mmol) was added in one portion to a solution of intermediate B (17.53g, 88.54mmol) and Et3N (24.7ml, 177.07mmol) in anhydrous DCM (270ml) at O0C under N2, giving a light brown solution which was allowed to warm to r.t. overnight. The reaction mixture was diluted with DCM (200ml) and sat. NaHCO3 (200ml). The organic phase was separated and washed with H2O (2 x 200ml), dried (Na2SO4), filtered and concentrated in vacuo to give a pale yellow oil. Trituration with TME and heptane gave a solid which was isolated by filtration and washed with heptane to give the title compound as a white solid (27.99g, 82%). LCMS purity 100%, m/z 389 [M+H]+, 1H NMR (300 MHz, CDCI3) δ: 1.35 (9H, s), 1.82 (2H, m), 1.96 (1 H, m), 3.29-3.34 (2H, m), 3.41-3.56 (2H, m), 5.12 (1 H, br s), 7.62- 7.68 (2H, m), 7.85 (1 H, m), 7.93 (1 H, d), 7.99-8.02 (2H, m), 8.47 (1 H, m).
  • 4
  • [ 5414-19-7 ]
  • [ 208837-83-6 ]
  • [ 914937-96-5 ]
YieldReaction ConditionsOperation in experiment
9% With triethylamine; In tetrahydrofuran; for 48h;Heating / reflux; A solution of intermediate B (200mg, 1.01 mmol) in anhydrous THF (5ml) was added to a stirring solution of 1 -bromo-2-(2-bromoethoxy)ethane (234mg, 1.01 mmol) in anhydrous THF (15ml) and triethylamine (323ml, 2.32mmol). The mixture was heated to reflux for 48 h. The reaction mixture was cooled to r.t., diluted with water (10ml) EPO <DP n="73"/>and extracted with EtOAc (3 x 5ml). The combined organic extracts were washed with brine (2 x 5ml), then dried (MgSO4) and evaporated to dryness. The residue was purified by flash chromatography eluting with 100% DCM to 6% MeOH/DCM to give the title compound as a clear oil (24mg, 9%). m/z 269 [M+H]+, 1H NMR (300 MHz, CDCI3) δ: 1.43 (9H, s), 1.58 (2H, br s), 2.58 (4H1 m), 3.33-3.56 (5H1 m), 3.65 (4H, m).
  • 5
  • [ 612-62-4 ]
  • [ 208837-83-6 ]
  • [ 914938-05-9 ]
YieldReaction ConditionsOperation in experiment
97% at 100℃; for 16h; Intermediate B (200mg, 1.01 mmol) was combined with 2-chloroquiniline (328mg, 2.02mmol) and the two solids melted at 10O0C for 16 h. The reaction was then cooled and the residue purified by column chromatography eluting with 0 to 3% MeOH in DCM to give the title compound as a brown oil (320mg, 97%). LCMS purity 94%, m/z 326 [M+H]+.
  • 6
  • [ 208837-83-6 ]
  • [ 148550-51-0 ]
  • [ 914938-12-8 ]
YieldReaction ConditionsOperation in experiment
57% With potassium carbonate; In acetonitrile; at 20℃; for 0.5h; To a solution of intermediate B (150mg, 0.76mmol) in MeCN (0.7ml) was added K2CO3. To this, a solution of intermediate A (174mg, 0.76mmol) in MeCN (0.7ml) was added dropwise resulting in a white suspension. Stirring at r.t. was continued for 30 EPO <DP n="80"/>min after which the white suspension turned pale yellow. The reaction mixture was evaporated, re dissolved in EtOAc (10ml) and washed with water (5ml). The EtOAc layer was dried (Na2SO4) filtered and concentrated to dryness. Purification by flash chromatography (100% DCM to 2% MeOH/DCM) gave the title compound as an off- white solid (0.15g, 57%). LCMS purity 89%, m/z 349 [M+H]+.
  • 7
  • [ 914937-14-7 ]
  • [ 208837-83-6 ]
YieldReaction ConditionsOperation in experiment
95% With hydrogen;palladium 10% on activated carbon; In ethanol; for 18h; tert-Butyl θ-nitro-S-azabicyclofS.I .Ojhexane-S-carboxylate (592mg, 2.59mmol) was reduced in the presence of 10% Pd/C (20mg) in EtOH (5ml) under H2 (balloon pressure) for 18 h. The catalyst was removed by filtration through celite. The celite was washed with EtOH and the filtrate concentrated to give the title compound as a pale yellow oil (487mg, 95%). 1H NMR (300 MHz, c/6-DMSO) δ: 1.40 (9H, s), 1.7-1.9 (2H1 m), 3.2-3.4 (4H, m).
  • 8
  • [ 208837-83-6 ]
  • [ 6160-65-2 ]
  • [ 273207-16-2 ]
YieldReaction ConditionsOperation in experiment
96% In dichloromethane; 2A. 3-(1α,5α,6α-tert-Butoxylcarbonyl)-6-isothiocyanato-3-aza-bicyclo [3.1.0]hexane To a solution of 3-(t-butoxylcarbonyl)-3-aza-bicyclo[3.1.0]hex-6-ylamine (9 g, 45.45 mmol) in methylene chloride (80 ml) was added 1,1-thiocarbonyldiimidazole (8.10 g, 45.45 mmol). The reaction mixture was stirred overnight. It was then partitioned between water and CH2Cl2. After separation, the organic layer was washed with brine, dried over magnesium sulfate and concentrated to afford the crude title compound of 2A, 10.46 g (43.58 mmol, 96% yield).
  • 9
  • [ 755039-56-6 ]
  • [ 208837-83-6 ]
  • [ 1021952-82-8 ]
YieldReaction ConditionsOperation in experiment
81% Stage 1; - terf-butyl 6-[(4-[(7/?)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro pteridin^-ylJaminoJ-S-methoxybenzoyOaminol-S-azabicycloβ.i.Olhexane-S-carboxylate To a stirred solution of 4-[(7f?)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5, 6,7,8- tetrahydropteridin-2-yl] amino}-3-methoxybenzoic acid [Intermediate 2C] (200mg, 0.47mmol) in DCM (1OmL) was added DIPEA (0.16mL, 0.94mmol) and TBTU (167mg, 0.52mmol). The reaction stirred at RT for 30 minutes before addition of terf-butyl 6- amino-3-azabicyclo[3.1.0]hexane-3-carboxylate [WO2006123121] (111mg, 0.56mmol). The reaction was stirred for a further 30 minutes and then the mixture was diluted with DCM (15mL) and washed with water (2 x 5ml_).The organic layer was dried (MgSO4) and concentrated under reduced pressure. The resulting solid was triturated with Et2O to afford the product as a white solid (230mg, 81% yield). ESMS: m/z 606 [M+H]+.
  • 10
  • [ 208837-83-6 ]
  • [ 122-51-0 ]
  • [ 1269429-43-7 ]
YieldReaction ConditionsOperation in experiment
50.3% With sodium azide; acetic acid; at 100℃; for 4h;Inert atmosphere; INTERMEDIATE 106-( 1 H-tetrazol- 1 -y 1 )-3 -azabicyclo [3.1.01 h ( i- 10)Step A: ferf-butyl 6-flH"-tetrazQl-i-yl)-3-azabicvclo[3.1.0]hexane-3-carboxylate; To a solution of iert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (7.3 g, 25.3 mmol) and triethylorothoformate (24 mL, 152 mmol) in acetic acid (200 mL) was added sodium azide (9.9 g, 152 mmol) and the resulting mixture was set under inert atmosphere. The mixture was heated at 100C for 4 h and then cooled to RT at which time the volatiles were removed in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with aqueous sodium bicarbonate solution, followed by brine. The organics were dried over sodium sulfate, filtered, and concentrate to dryness under vacuum. The residue was placed in the refrigerator overnight and the next day a solid white precipitate was observed- The precipitate was triturated with hexane and the solvent was carefully decanted to give the title compound 3.2 g (50.3%) as a white solid. ESI-MS calculated for CnHnNsC^: Exact Mass: 251.28; Found 252.28.
  • 11
  • [ 208837-83-6 ]
  • 5-{4-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(2H-tetrazol-5-yl)phenyl]amino}propyl]phenyl}-6-methylpyridin-2-carboxylic acid [ No CAS ]
  • [ 76-05-1 ]
  • tert-butyl-6-([5-(4-{(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[(4-(2H-tetrazole-5-yl)phenyl)amino]propyl}phenyl)-6-methylpyridin-2-yl]carbonyl}amino)-3-azabicyclo[3.1.0]hexan-3-carboxylate trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% A solution of 100 mg (0.15 mmol) of 5-{4-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(2H-tetrazol-5-yl)phenyl]amino}propyl]phenyl}-6-methylpyridin-2-carboxylic acidand 58.1 mg (0:22 mmol) tert-butyl-6-amino-3-azabicyclo[3.1.0] hexane-3-carboxylate in 25.1 ml of dimethylformamide were treated with 77 μ (0.44 mmol) Ν, Ν-diisopropylethylamine and 83.5 mg (0.22 mmol) of N-[(dimethylamino)(3H-[1,2,3] triazolo [4,5-b] pyridin-3-yloxy)methylidene]-N-methylmethanaminiumhexafluorophosphate and stirred at RT for 24 h.The reaction mixture was filtered and the filtrate purified by preparative HPLC (eluent: AcetonitrilA ater with 0.1% TFA (gradient)) separate.90 mg (57% d. Th.) Of the title compound were obtained.
  • 12
  • [ 208837-83-6 ]
  • 4'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-({4-[5-(2-carboxy-1,1,2,2-tetrafluorethyl)-4H-1,2,4-triazol-3-yl]phenyl}amino)-3-oxopropyl]-2-methylbiphenyl-4-carboxylic acid [ No CAS ]
  • 3-[5-(4-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-(4'-[3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamoyl}-2'-methylbiphenyl-4-yl)propanoyl]amino}phenyl)-4H-1,2,4-triazol-3-yl]-2,2,3,3-tetrafluorpropanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h; A solution of 4 '- [(2S)-2- [(ira Ä 4- [(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) - carbonyl] amino} -3- (4- { [5- (2-carboxy-1, 1, 2,2-tetrafluoroethyl) -4 / i- 1, 2,4-triazol-3-yl] phenyl} - amino) -3-oxopropyl] -2-methylbiphenyl 4-carboxylic acid (80 mg, 0.097 mmol) and Ieri-butyl-6-amino-3-azabicyclo [3.1.0] hexane-3-carboxylate (38 mg, 0:19 mmol) in DMF (1 ml) was treated with N, N - added diisopropylamine (0.05 mL, 0:29 mmol) and HATU (55 mg, 0:15 mmol) was added thereto.The reaction mixture was stirred at RT overnight (ca. 16 h).The residue was diluted / acetonitrile with water and filtered through a Millipore filter, then purified by preparative HPLC (eluent: gradient of acetonitrile / water with 0.1% trifluoroacetic acid).This gave 61.9 mg (60% d. Th.) Of the title compound.
  • 13
  • [ 208837-83-6 ]
  • 4'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-({4-[5-(2-carboxy-1,1,2,2-tetrafluorethyl)-4H-1,2,4-triazol-3-yl]phenyl}amino)-3-oxopropyl]-2-methylbiphenyl-4-carboxylic acid [ No CAS ]
  • 3-{5-[4-({(2S)-2-([trans-4-(aminomethyl)cyclohexyl]carbonyl}amino)-3-[4'-(3-azabicyclo[3.1.0]hex-6-ylcarbamoyl)-2'-methylbiphenyl-4-yl]propanoyl}amino)phenyl]-4H-1,2,4-triazol-3-yl}-2,2,3,3-tetrafluorpropanoic acid dihydrochloride [ No CAS ]
  • 14
  • [ 208837-83-6 ]
  • 4'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(2H-tetrazol-5-yl)phenyl]amino}propyl]-2-methylbiphenyl-4-carboxylic acid [ No CAS ]
  • tert-butyl 6-[({4'-[(2S)-2-[(trans-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(2H-tetrazol-5-yl)phenyl]amino}propyl]-2-methylbiphenyl-4-yl}carbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65 mg With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 16h; A solution of 100 mg (0.15 mmol) of 4'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(2H-tetrazol-5-yl)phenyl]amino}propyl]-2-methyl-biphenyl-4-carboxylic acid and and 35 mg (0:18 mmol) of 3- (feri-butoxycarbonyl) -6-amino- 3-azabicyclo [3.1.0] hexane in 5 ml of tetrahydrofuran and 0.4 ml Ν, Ν-dimethylformamide wastreated with 67 mg (0:18 mmol) of N - [(dimethylamino) (3 / i- [l, 2,3] triazolo [4 , 5-b] pyridin-3-yloxy) methylidene] -N-methyl-methanaminium hexafluorophosphate and 0:03 ml (0:18 mmoles) ofN, N-diisopropylethylamine and stirred at RT for 16 h. The reaction mixture was directly separatedby preparative HPLC (eluent: AcetonitrilA ater gradient, 0.1% trifluoroacetic acid). This gave 65 mgof a mixture of the title compound and the corresponding deprotected amine which was useddirectly in the next stage.
  • 15
  • [ 208837-83-6 ]
  • 3'-[(2S)-2-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-6-methylbiphenyl-3-carboxylic acid [ No CAS ]
  • tert-butyl 6-[({3'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-6-methylbiphenyl-3-yl}carbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
15% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 16h; Example 52A tert-Butyl 6-[({3'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-6-methylbiphenyl-3-yl}carbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate 3'-[(2S)-2-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-6-methylbiphenyl-3-carboxylic acid (100 mg, 0.15 mmol) and <strong>[208837-83-6]tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate</strong> (35 mg, 0.17 mmol) were dissolved in tetrahydrofuran (4 ml), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (67 mg, 0.17 mmol) and N,N-diisopropylethylamine (23 mg, 0.17 mmol) were added and the mixture was stirred at RT for 16 h. Subsequently, the mixture was concentrated and the residue was purified chromatographically by HPLC (Method 10). This gave 18 mg (15% of theory) of the title compound. LC-MS (Method 4): Rt=1.33 min; MS (ESIpos): m/z=862.7 [M+H]+.
  • 16
  • [ 208837-83-6 ]
  • 3'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2-methylbiphenyl-4-carboxylic acid [ No CAS ]
  • tert-butyl 6-[({3'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2-methylbiphenyl-4-yl}carbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; Example 69A tert-Butyl 6-[({3'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2-methylbiphenyl-4-yl}carbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate 3'-[(2S)-2-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2-methylbiphenyl-4-carboxylic acid (100 mg, 0.15 mmol) and <strong>[208837-83-6]tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate</strong> (35 mg, 0.17 mmol) were dissolved in tetrahydrofuran (4 ml), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (67 mg, 0.17 mmol) and N,N-diisopropylethylamine (23 mg, 0.17 mmol) were added and the mixture was stirred at RT overnight. Subsequently, the mixture was concentrated and the residue was purified chromatographically by HPLC (Method 10). This gave 51 mg (41% of theory) of the title compound. LC-MS (Method 4): Rt=1.32 min; MS (ESIpos): m/z=862.7 [M+H]+.
  • 17
  • [ 208837-83-6 ]
  • 5'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2'-methylbiphenyl-3-carboxylic acid [ No CAS ]
  • tert-butyl 6-[({5'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2'-methylbiphenyl-3-yl}carbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; Example 71A tert-Butyl 6-[({5'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2'-methylbiphenyl-3-yl}carbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate 5'-[(2S)-2-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2'-methylbiphenyl-3-carboxylic acid (100 mg, 0.15 mmol) and <strong>[208837-83-6]tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate</strong> (35 mg, 0.18 mmol) were dissolved in tetrahydrofuran (4 ml), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (67 mg, 0.18 mmol) and N,N-diisopropylethylamine (23 mg, 0.18 mmol) were added and the mixture was stirred at RT overnight. Subsequently, the mixture was concentrated and the residue was purified chromatographically by HPLC (Method 10). This gave 50 mg (40% of theory) of the title compound. LC-MS (Method 4): Rt=1.33 min; MS (ESIpos): m/z=862.7 [M+H]+.
  • 18
  • [ 208837-83-6 ]
  • tert-butyl 6-(2-oxoimidazolidin-1-yl)-3-azabicyclo [3.1.0]hexane-3-carboxylate [ No CAS ]
  • 19
  • [ 1943-83-5 ]
  • [ 208837-83-6 ]
  • tert-butyl 6-(3-(2-chloroethyl)ureido)-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; for 1h;Cooling with ice; Step A: tert-butyl 6-(3 -(2-chloroethyl)ureido)-3-azabicyclo [3.1 . Olhexane-3 -carboxylate: To anice-cooled DCM (10 ml) solution of <strong>[208837-83-6]tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate</strong> (1.01 g, 5.09 mmol) was added triethylamine (1.775 mL, 12.74 mmol) and then 2-chloroethyl isocyanate (0.59 1 g, 5.60 mmol). After 1 hour, the reaction mixture was quenched with aqueous sodium bicarbonate and the aqueous layer was extracted with DCM (3 X 10 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 6-(3-(2-chloroethyl)ureido)-3-azabicyclo[3.1 .0]hexane-3-carboxylate which was used without further purification.
  • 20
  • [ 208837-83-6 ]
  • 4-(7-(3-cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)furo[3,2-b]pyridin-2-yl)-3-methoxybenzoic acid [ No CAS ]
  • N-(3-aza-bicyclo[3.1.0]hex-6-yl)-4-{7-[3-cyano-4-(tetrahydro-pyran-4-yloxy)phenyl]furo[3,2-b]pyridin-2-yl}-3-methoxy-benzamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
98 mg General procedure: Example 109 4-{7-[3-Cyano-4-((S)-3-dimethylamino-pyrrolidin-1-yl)-phenyl]-furo[3,2-b]pyridin-2-yl}-N,N-dimethyl-benzamide (173)-EDC-HOBT Method A mixture of 4-{7-[3-Cyano-4-((S)-3-dimethylamino-pyrrolidin-1-yl)-phenyl]-furo[3,2-b]pyridin-2-yl}-benzoic acid (30.00 mg; 0.07 mmol; 1.00 eq.), N-methylmethanamine hydrochloride (10.81 mg; 0.13 mmol; 2.00 eq.), (3-Dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (15.25 mg; 0.08 mmol; 1.20 eq.) (EDCI), Benzotriazol-1-ol (10.75 mg; 0.08 mmol; 1.20 eq.) (HOBt) and Ethyl-diisopropyl-amine (25.71 mg; 0.20 mmol; 3.00 eq.) in DMF (5.0 mL) was stirred at room temperature overnight. The reaction mixture was purified on reverse phase HPLC to obtain the title compound. (21.1 mg, 50%.
  • 21
  • [ 639519-63-4 ]
  • [ 208837-83-6 ]
  • C19H20BrFN4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% To a mixture of 10 (900 mg, 3.1 mmol) in DMF (30 mL) was added HATU (1.55 g, 4.08 mmol)and DIEA (1.22 g, 9.4 mmol) in one portion at 25 C under N2. The mixture was stirred at 25 C for 30min, then 6a (745 mg, 3.7 mmol) was added in portions and the mixture was stirred for 5 h. TLC(petroleum ether:ethyl acetate = 1:1, Rf = 0.6.) showed one main spot was generated. The mixture was poured (30 mL × 2). The combined organic phase was washed with brine (20 mL × 2), dried with anhydrousNa2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography(column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether:ethyl acetate =1:1) to give 11 (2.0 g, 68%) as a yellow solid.
  • 22
  • [ 208837-83-6 ]
  • [ 1422029-67-1 ]
  • C21H24FN5O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of 6 (200 mg, 754 mmol and DIEA (292 mg, 2.26 mmol) in DMF (5 mL) was addedHATU (287 mg, 754 mmol). After stirred at 25 C for 30 min, 6a (150 mg, 754 mmol) was added andthe mixture was stirred at 25 C for 16 h. TLC (petroleum ether: ethyl acetate = 0:1, Rf = 0.3) showedthat the reaction was complete and LCMS showed the desired mass of the product. The mixture wasdiluted with EtOAc (20 mL), washed with water (20 mL), brine (20 mL), dried over Na2SO4, andconcentrated to give 7 (300 mg, crude) as yellow solid.
  • 23
  • [ 208837-83-6 ]
  • [ 31792-47-9 ]
  • C24H25N3O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; General procedure: To a solution of quinoline 4-carboxylic acid (3) (1 equiv) in DMF was added amine (1 equiv) and DIEA (1 equiv). Then HATU (1 equiv) was added in one portion and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with aqueous NaHCO3 solution and brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by silica gel flash column chromatography (0-10% CH3OH/CH2Cl2) to give the final product.
  • 24
  • [ 214707-75-2 ]
  • [ 208837-83-6 ]
  • 6-[(1-isopropyl-1H-indazole-3-carbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester [ No CAS ]
  • 25
  • [ 208837-83-6 ]
  • 7-bromo-N-(tert-butyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5-amine [ No CAS ]
  • 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl [ No CAS ]
  • (1R,5S,6S)-tert-butyl 6-((5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-yl)amino)-3-azabicyclo[3.1.0]hexan-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With palladium diacetate; Step 1: Synthesis of (1R,5S,6S)-tert-butyl 6-((5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-yl)amino)-3-azabicyclo[3.1.0]hexan-3-carboxylate (Compound 84a) Compound 2f (120 mg), (1R,5S,6S)-tert-butyl 6-amino-3-azabicyclo[3.1.0]hexan-3-carboxylate (163.94 mg), potassium tert-butoxide (92.78 mg), Pd(OAc)2 (12.38 mg) and BINAP (68.65 mg) were added to toluene (3 mL), and the reaction proceeded at an elevated temperature of 120C for 2 hours under N2 protection. The reaction solvent was removed by drying in a rotary dryer, and the subsequent purification by flash column chromatography (Eluent System A) gave Compound 84a (110 mg).
  • 26
  • [ 208837-83-6 ]
  • (S)-8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol [ No CAS ]
  • tert-butyl 6-((8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
29% A vial was charged with (S)-8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((l-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (50 mg, 0.12 mmol), N,N-dimethylacetamide (0.50 mL) and N-ethyl-N-isopropylpropan-2-amine (0.10 mL, 0.60 mmol) and the reaction stirred for 15 minutes. 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (0.18 g, 0.48 mmol) was added and the reaction was stirred for 10 minutes. The suspension was cooled in an ice bath and tert-butyl 6-amino-3- azabicyclo[3.1.0]hexane-3-carboxylate (71 mg, 0.36 mmol) was charged to the suspension. The ice bath was removed, and the reaction was warmed to room temperature over 3.5 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (3 x 20 mL), brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 0-5% MeOH/DCM to afford tert-butyl 6-((8-fluoro-7-(3-hydroxynaphthalen-l-yl)- 2-(((S)-l-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate (21 mg, 29% yield). LCMS (MM-ES+APCI, Pos): m/z 601.3 (M+H).
29% A vial was charged with (S)-8-fluoro-7-(3-hydroxynaphthalen-l-yl)-2-((l-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (50 mg, 0.12 mmol), N,N-dimethylacetamide (0.50 mL) and N-ethyl-N-isopropylpropan-2-amine (0.10 mL, 0.60 mmol) and the reaction stirred for 15 minutes. 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (0.18 g, 0.48 mmol) was added and the reaction was stirred for 10 minutes. The suspension was cooled in an ice bath and tert-butyl 6-amino-3- azabicyclo[3.1.0]hexane-3-carboxylate (71 mg, 0.36 mmol) was charged to the suspension. The ice bath was removed, and the reaction was warmed to room temperature over 3.5 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (3 x 20 mL), brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 0-5% MeOH/DCM to afford tert-butyl 6-((8-fluoro-7-(3-hydroxynaphthalen-l-yl)- 2-(((S)-l-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate (21 mg, 29% yield). LCMS (MM-ES+APCI, Pos): m/z 601.3 (M+H).
 

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Technical Information

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