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Chemical Structure| 198211-38-0 Chemical Structure| 198211-38-0

Structure of 198211-38-0

Chemical Structure| 198211-38-0

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Product Details of [ 198211-38-0 ]

CAS No. :198211-38-0
Formula : C10H18N2O2
M.W : 198.26
SMILES Code : CC(C)(C)OC(=O)NC1C2CNCC12
MDL No. :MFCD10698578
InChI Key :QIYOMZXJQAKHEK-UHFFFAOYSA-N
Pubchem ID :11148308

Safety of [ 198211-38-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Application In Synthesis of [ 198211-38-0 ]

* 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 [ 198211-38-0 ]

[ 198211-38-0 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 198211-38-0 ]
  • (6-fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine [ No CAS ]
  • (3-{4-[3-Methyl-4-(pyridin-3-yloxy)-phenylamino]-pyrido[3,4-d]pyrimidin-6-yl}-3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.79 g (43%) In ethanol; Part C. (3-{4-[3-Methyl-4-(pyridin-3-yloxy)-phenylamino]-pyrido[3,4-d]pyrimidin-6-yl}-3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester. A solution of 2.71 g (7.83 mmol) of (6-fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine and 31.0 g (156.5 mmol) of <strong>[198211-38-0](3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester</strong> in 20 mL of ethanol in a sealed tube was heated at 105 C. for 24 hours. The mixture was cooled to room temperature and diluted with chloroform. The organics were washed sequentially with 3*150 mL saturated sodium bicarbonate and 1*50 mL of saturated sodium chloride, dried over sodium sulfate and evaporated. Chromatography over silica gel, eluding with 5% methanol/chloroform afforded 1.79 g (43%) of the title compound. 1H NMR (CDCl3): delta8.93 (s,1), 8.53 (s,1), 8.33 (m, 2), 7.60 (m, 3), 7.21 (m, 2), 6.96 (d, 1), 6.24 (m, 1), 4.83 (m, 1), 3.81 (m, 2), 3.51 (m, 2), 3.47 (m, 1), 2.36 (m, 1), 2.26 (s,3), 1.88 (m, 1).
  • 2
  • [ 198211-38-0 ]
  • C20H15FN4O [ No CAS ]
  • C30H32N6O3 [ No CAS ]
  • 3
  • [ 198211-38-0 ]
  • C18H11ClFN5O [ No CAS ]
  • C28H28ClN7O3 [ No CAS ]
  • 4
  • [ 198211-38-0 ]
  • C20H16FN5O [ No CAS ]
  • C30H33N7O3 [ No CAS ]
  • 5
  • [ 198211-38-0 ]
  • C20H14F2N4O [ No CAS ]
  • C30H31FN6O3 [ No CAS ]
  • 6
  • [ 198211-38-0 ]
  • C19H12ClFN4O [ No CAS ]
  • C29H29ClN6O3 [ No CAS ]
  • 7
  • [ 198211-38-0 ]
  • C20H14F2N4O2 [ No CAS ]
  • C30H31FN6O4 [ No CAS ]
  • 8
  • C20H13F3N4O [ No CAS ]
  • [ 198211-38-0 ]
  • C30H30F2N6O3 [ No CAS ]
  • 10
  • [ 198211-38-0 ]
  • [ 1195-45-5 ]
  • [ 888493-42-3 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; for 3h; To a solution of the compound (Example 3, step b) (1.5 g, 7.75 mmol) in dichloromethane (20 ml), was added 4-fluorophenyl isocyanate (1.24 g, 9.09 mmol) and stirred for 3 hours. The reaction mixture was poured into water, extracted with dichloromethane and washed with water. The dichloromethane layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography using methanol in dichloromethane (1:49) solvent mixture as eluent to furnish the title compound. Yield = 2.1 g.
In dichloromethane; at 0℃; for 3h; Example 3; Synthesis of 6-amino-3-azabicyclo[3.1.0]hexane-3-N-(4-fluorophenyl)carboxamide (pTSA salt)Step a: Synthesis of tert-butyl (3-[(4-fluorophenyl)amino]carbonyl}-3-azabicyclo[3.1.0]hex-6-yl)carbamateTo a solution of tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (0.500 g, 2.50 mmol) in dichloromethane (10.0 mL) at 0 C., was added dropwise a solution of 4-fluorophenyl isocyanate (0.34 mL, 3.0 mmol) in dichloromethane (5.0 mL) and stirred at 0 C. for about 3 hours. The reaction mixture was partitioned between water (10.0 mL) and dichloromethane (20.0 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title product, which was used directly in the next step.
  • 11
  • [ 186376-18-1 ]
  • [ 198211-38-0 ]
YieldReaction ConditionsOperation in experiment
To a solution of the compound obtained from step a above (1Og, 34.72 mmole) in methanol (150 ml), was added palladium on carbon (10%, 7 g) and the reaction mixture was refluxed for 30 minutes. To it was added ammonium formate (10.94 g, 173.61 mmol) slowly over a period of 15 minutes and stirred for 15 minutes at 700C. Filtered the reaction mixture through a prewashed celite pad. The organic solvent was evaporated under reduced pressure, added a saturated solution of sodium bicarbonate, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure to furnish the title compound. Yield = 4.3 g.
  • 12
  • [ 198211-38-0 ]
  • 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid lithium salt [ No CAS ]
  • [ 380236-35-1 ]
YieldReaction ConditionsOperation in experiment
A. {3-[7-Chloro-thieno[3,2-b]pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-carbamic Acid tert-butyl Ester The title compound was prepared from <strong>[198211-38-0](3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester</strong> and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 394/396 (MH+); HPLC Rf: 5.30 min.; HPLC purity: 72%.
  • 13
  • [ 198211-38-0 ]
  • 3-[4-(6-Amino-pyridin-2-yl)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-ylamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With trifluoroacetic acid; In dichloromethane; EXAMPLE 123 3-[4-(6-Amino-pyridin-2-yl)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-ylamine Prepared as in Example 122, using <strong>[198211-38-0]6-(t-butoxycarbonylamino)-3-aza-bicyclo[3.1.0]hexane</strong> in the reductive amination in 66% yield, and in 75% yield for the deblocking which included trifluoroacetic acid in methylene chloride to remove the t-butoxycarbonyl group, mp 189-192 C. (dec.) as the hydrochloride salt. 1H-NMR (CDCl3, delta): 1.28 (bs, 2H), 2.34 (m, 2H), 2.51 (bs, 1H), 2.85 (m, 2H), 3.48 (s, 2H), 3.61 (bs), 6.38 (d, J=8, 1H), 6.90 (d, J=7, 1H), 7.23 (m, 2H), 7.39 (t, J=8, 1H), 7.66 (m, 2H). 13C-NMR (MeOD4, delta): 25.2, 32.1, 54.4, 58.9, 107.3, 110.9, 126.7, 128.8, 138.4, 138.5, 139.4, 156.0, 158.5. FAB MS (%): 281 (parent+1, 97), 212 (30), 183 (100). Anal. Calc'd. for C17H19N4.3HCl.1/2H2O: C, 70.56, H, 7.31, N, 19.36. Found: C, 70.76, H, 7.15, N, 19.17.
  • 14
  • [ 198211-38-0 ]
  • [ 224190-76-5 ]
  • [ 224191-25-7 ]
  • [ 224191-36-0 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In acetonitrile; EXAMPLE Y-4 (1alpha,5alpha,6alpha)[3-(3-Benzyloxy-1-(4-fluorophenyl)-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-yl)-3-aza-bicyclo[3.1.0]hex-6-yl]-carbamic Acid tert-butyl Ester Using the method of Example N-4, <strong>[198211-38-0]3-aza-bicyclo[3.1.0]hex-6-yl-carbamic acid tert-butyl ester</strong> (0.1 g, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(4-fluorophenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example Q-2, 0.17 g, 0.42 mmol)) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.25 g of the title compound as a solid, mp 244-245 C.
  • 15
  • [ 198211-38-0 ]
  • [ 224190-91-4 ]
  • [ 224190-97-0 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dimethyl sulfoxide; EXAMPLE J-3 (1alpha,5alpha,6alpha[3-(3-Benzyloxy-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-3-aza-bicyclo[3.1.0]hex-6-yl]-carbamic Acid tert-butyl Ester A solution of 3-benzyloxy-7-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione (Example E-3, 0.20 g, 0.55 mmol) in DMSO (3.0 mL) was reacted with <strong>[198211-38-0]3-aza-bicyclo[3.1.0]hex-6-yl-carbamic acid tert-butyl ester</strong> (0.22 g, 1.1 mmol) and triethylamine (0.76 mL, 5.5 mmol), then heated to 100 C. for 2 days. The mixture was cooled, diluted with H2O, and extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous LiCl, dried with sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide 0.195 g of the title compound as a solid.
  • 16
  • [ 198211-38-0 ]
  • [ 540-51-2 ]
  • tert-butyl [3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; for 0.5h;Microwave irradiation; Intermediate 96: tert-Butyl [3-C2-hvdroxyethyl)-3-azabicyclof3.1.01hex-6- yl] carbamateA mixture of tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (T. F. Braish et al. Synlett, 1996, page 1100 and T. Norris et al. J. Chem. Soc. Perkin I, 2000, page 1615-1622), 2-bromoethanol (669 mg, 3.36 mmol) and N,N-ethyldiisopropyl amine (0.087 niL) in acetonitrile (9 mL) was heated in the microwave at 7O0C for 30 minutes. Chromatography on silica gel with chloroform/ methanol (20:1) gave 376 mg (46%) of the product. MS(EI) 242 for Ci2H22N2O3
  • 17
  • [ 198211-38-0 ]
  • [ 1028202-77-8 ]
  • [ 1028203-23-7 ]
  • 18
  • [ 198211-38-0 ]
  • [ 102614-43-7 ]
  • [ 1028203-22-6 ]
  • 19
  • [ 198211-38-0 ]
  • [ 1885-14-9 ]
  • phenyl 6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃; for 2 - 3h; Example 1; Synthesis of phenyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (pTSA salt)Step a: Synthesis of phenyl 6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylateTo a solution of tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (0.500 g, 2.50 mmol) [prepared following the procedure described in Bioorg. Med. Chem. Lett. 2004, 14(11), 2773-2776)] and triethylamine (0.73 mL, 5.30 mmol) in dichloromethane (10.0 mL) at 0 C., was added dropwise a solution of phenyl chloroformate (0.41 mL, 3.30 mmol) in dichloromethane (5.0 mL) and the reaction mixture was stirred at room temperature for about 2-3 hours and partitioned between water (10.0 mL) and dichloromethane (15.0 mL). The aqueous layer was extracted with dichloromethane (15.0 mL). The combined organic layer was washed water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound, which was used as such in the next step.1H NMR (400 MHz, CDCl3): delta 1.46 (s, 9H), 1.75-1.80 (m, 2H), 2.39 (s, 1H), 3.54-3.58 (m, 1M), 3.63-3.66 (m, 1H), 3.79 (d, 1H, J=12 Hz), 3.91 (br s, 1H), 4.74 (br s, 1H, NH), delta 7.07-7.36 (m, 5H); ESI-MS (m/z): 341 (M++23)
  • 20
  • [ 198211-38-0 ]
  • [ 108-86-1 ]
  • tert-butyl (3-phenyl-3-azabicyclo[3.1.0]hex-6-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 20 - 80℃; for 4h; Example 4; Synthesis of 3-phenol-3-azabicyclo[3.1.0]hexan-6-amine (pTSA salt)Step a: Synthesis of tert-butyl (3-phenyl-3-azabicyclo[3.1.0]hex-6-yl)carbamateTo a solution of tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (0.500 g, 2.52 mmol) in toluene (20.0 mL), was added potassium tert-butoxide (330 mg, 2.95 mmol), bromobenzene (0.444 g, 2.1 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (39.3 mg, 0.063 mmol) and Pd2(dba)3 (40.0 mg, 0.042 mmol) at ambient temperature under argon atmosphere. The reaction mixture was heated to 80 C. for about 4 hours. The reaction mixture was allowed to cool to room temperature and then partitioned between water (20.0 mL) and ether (20.0 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the residue, which was partially purified by column chromatography (silica gel 100-200 mesh, 25% ethyl acetate in hexane).
  • 21
  • [ 198211-38-0 ]
  • [ 727-31-1 ]
  • tert-butyl [3-(4-[(4-methylphenyl)sulphonyl]amino}phenyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; Example 5; Synthesis of N-[4-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-4-methylbenzenesulph onamideStep a: Synthesis of tert-butyl [3-(4-[(4-methylphenyl)sulphonyl]amino}phenyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamateTo a solution of 4-fluoroaniline (1.0 g, 9.0 mmol), and triethylamine (1.32 g, 18.0 mmol) in DCM (25.0 mL) under N2 atmosphere, was added p-toluenesulphonyl chloride (1.88 g, 9.9 mmol) at 0 C. The mixture was warmed to room temperature and stirred overnight. The mixture was diluted with DCM (25.0 mL), washed with water and brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product (1.50 g, 5.66 mmol), obtained, was mixed with tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (1.35 g, 6.79 mmol), and potassium carbonate (1.56 g, 11.32 mmol) in DMF (5.0 mL) and heated at 130 C. overnight. The mixture was partitioned between water (30.0 mL) and ethyl acetate (30.0 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford the residue, which was purified by column chromatography (silica gel 100-200 mesh, 15% ethyl acetate in hexane) to provide the title compound (650 mg, 16%).1H NMR (400 MHz, MeOH-d4): delta 2.12 (s, 2H), 2.36 (s, 3H), 2.40-2.50 (m, 4H), 3.25-3.40 (m, 2H), 3.60-3.70 (m, 2H), 6.4-6.9 (m, 4H), 7.15-7.70 (m, 8H); ESI-MS (m/z): 444.17 (M++1)
  • 22
  • [ 198211-38-0 ]
  • [ 52334-81-3 ]
  • tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl-formamide; at 80℃; for 6h; Example 2; Synthesis of 3-[5-(trifluoromethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexan-6-amine (pTSA salt)Step a: Synthesis of tert-butyl [3-(5-trifluoropyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl] carbamateA solution of tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (0.500 g, 2.50 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (0.38 mL, 3.0 mmol) in dimethylformamide (5.0 mL) was heated at 80 C. for about 6 hours. The solvent was removed under vacuum, and the residue partitioned between dichloromethane (30.0 mL) and water (20.0 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography using 30% ethyl acetate in hexane as eluant (silica gel 100-200 mesh) to yield the title compound.
  • 23
  • [ 198211-38-0 ]
  • [ 54057-46-4 ]
  • tert-butyl (3-{4-[(4-fluorobenzoyl)amino]benzoyl}-3-azabicyclo[3.1.0]hex-6-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; Step c: Synthesis of tert-butyl (3-{4-[(4-fluorobenzoyl)amino]benzoyl}-3-azabicyclo[3.1.0]hex-6-yl)carbamateTo a solution of 4-[(4-fluorobenzoyl)amino]benzoic acid (0.55 g, 2.12 mmol), tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (0.42 g, 2.12 mmol), 1-hydroxybenzotriazole (0.34 g, 2.54 mmol), triethylamine (0.44 ml, 3.18 mmol) in dichloromethane (10.0 mL) at 0 C., was added in portion N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.60 g, 3.18 mmol). The reaction mixture was stirred at room temperature for about 16 hours and then partitioned between water (10.0 mL) and dichloromethane (15.0 mL). The aqueous layer was extracted with dichloromethane (15.0 mL). The combined organic layer was washed water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (30% ethyl acetate in hexane, silica gel 100-200 mesh) to yield the title compound (792 mg, 85%).1H NMR (400 MHz, CDCl3): delta 1.43 (s, 9H), 1.75 (m, 2H), 2.29 (s, 1H), 3.54-3.57 (m, 1H), 3.66-3.81 (m, 2H), 4.19-4.21 (m, 1H), 4.72 (br s, 1H, NH), 7.15-7.94 (m, 8H); ESI-MS (m/z): 440.14 (M++1)
  • 24
  • [ 198211-38-0 ]
  • C16H13N5OS [ No CAS ]
  • C26H29N7O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
The solution of Cul (67 mg, 0.35 mmol), N,N'-dimethylcyclohexane-l,2- diamine (100 mg, 0.70 mmol) in 9 mL of NMP was added to a stirring suspension of him and (Example 2) (229 mg, 1.17 mmol), a proper I-Ar (1.17 mmol), K2C03 (324 mg, 2.35 mmol) and PPh3 (400 mg, 1.53 mmol) in NMP (9 mL). The mixture was heated to 130 C for 2 to 12 hrs monitored by LC-MS for the completion of the reaction. When the reaction completed, the mixture was cooled to 0 C, BOP (621 mg, 1.40 mmol) and Et3N (0.41 mL, 2.93 mmol) was added, stirred for 30 minutes at 0 C, then warmed up to room temperature, a suitable Boc-protected diamine (2.34 mmol) was added. The reaction mixture was heated to 50 C for 30 minutes. LC-MS indicated the completed reaction. At room temperature, N- chlorosuccinimide (NCS, 156 mg, 1.17 mmol) was added in several portions. The mixture was stirred for 2 to 12 hrs for the completion of the reaction, heated to 40 C if the reaction failed to proceed. TFA was finally added to the mixture to remove the Boc protection group. After removal of solvents, Prep HPLC of the resulting residue (eluent: CH3CN/H2O/0.1%TFA) to give the desired S-linked compounds, such as those identified below. Rl and Rl ' in the above scheme together refer to the remainder of an amine- containing moiety, such as the heteralicyclic groups shown in the compounds below. Eta,Nu 7008003-(2-(1 ,5-napht yridin-3-ylthio)-5-chloro-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin4- l)-3-azabicyclo[3.1.0]hexan-6-amine
  • 25
  • [ 198211-38-0 ]
  • [ 488818-70-8 ]
  • (4S,4aS,5aR,12aS)-9-((6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
58 mg In a 25mL single-neck flask, Compound A (1g) and <strong>[198211-38-0]tert-butyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate</strong> (1g) were dissolved in 5mL of DMF, and reacted at room temperature for 0.5h, 1.4g of sodium triacetoxy borohydride was added slowly, and further reacted for 0.5h. Then the reaction solution was mixed with 10g of C18 fillers, packed into a column, separated by a quick preparative chromatography of ISCO (acetonitrile: water = 1-10: 100), collected the fraction which was confirmed by thin layer chromatography (TLC) to contain Compound 26. 10mL of concentrated hydrochloric acid was added and stirred at room temperature for 0.5h. After enrichment, the mixture was concentrated and freeze-dried to give hydrochloride of Compound 26 (58mg, pale yellow powder). 1H NMR(D2O, 400MHz) delta : 7.93 (s, 1H), 4.50 (m, 3H), 3.97 (s, 1H), 3.67(br, 2H), 3.18 (s, 6H), 2.86-3.09(m, 10H), 2.49(t, 1H), 2.32(s, 2H), 2.17(d, 2H), 1.58(m, 1H)
  • 26
  • [ 198211-38-0 ]
  • [ 56553-60-7 ]
  • (4S,4aS,5aR,12aS)-9-((6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,1'-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In N,N-dimethyl-formamide; Example 21 Preparation of (4S,4aS,5aR,12aS)-9-((6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,1'-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide hydrochloride (the hydrochloride of Compound 26) In a 25 mL single-neck flask, Compound A (1 g) and <strong>[198211-38-0]tert-butyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate</strong> (1 g) were dissolved in 5 mL of DMF, and reacted at room temperature for 0.5 h, 1.4 g of sodium triacetoxy borohydride was added slowly, and further reacted for 0.5 h. Then the reaction solution was mixed with 10 g of C18 fillers, packed into a column, separated by a quick preparative chromatography of ISCO (acetonitrile:water=1-10:100), collected the fraction which was confirmed by thin layer chromatography (TLC) to contain Compound 26. 10 mL of concentrated hydrochloric acid was added and stirred at room temperature for 0.5 h. After enrichment, the mixture was concentrated and freeze-dried to give hydrochloride of Compound 26 (58 mg, pale yellow powder). 1H NMR (D2O, 400 MHz) delta: 7.93 (s, 1H), 4.50 (m, 3H), 3.97 (s, 1H), 3.67 (br, 2H), 3.18 (s, 6H), 2.86-3.09 (m, 10H), 2.49 (t, 1H), 2.32 (s, 2H), 2.17 (d, 2H), 1.58 (m, 1H)
  • 27
  • [ 198211-38-0 ]
  • [ 1622091-28-4 ]
  • [ 1622093-04-2 ]
YieldReaction ConditionsOperation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; Step 3: O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (34 mg), <strong>[198211-38-0]tert-butyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate</strong> (21 mg) and iPr2NEt (27 mg) were added into a solution of (R)-4-((4-((4-(3-bromo-2-methylpropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (60 mg) in DMF (1 mL). The reaction was stirred at room temperature for 2 hours. Solvents were removed under vacuum and the residue was purified by preparative HPLC to give tert-butyl (3-(4-((4-((4- ((R)-3-bromo-2-methylpropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate.
  • 28
  • [ 198211-38-0 ]
  • [ 65-85-0 ]
  • tert-butyl (3-benzoyl-3-azabicyclo [3.1.0]hexan-6-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In dichloromethane; at 25℃; for 12h; Synthesis of SC28 (N-{3-benzoyl-3-azabicyclo[3.1.0]hexan-6-yl}-3-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2,3-dioxopropanamide) is shown in Scheme 6. To a solution of compound 27 (200.00 mg, 1.01 mmol, 1.00 eq.), T3P (320.97 mg, 1.01 mmol, 1.00 eq.) and NMM (204.32 mg, 2.02 mmol, 2.00 eq.) in DCM (2 mL) was added benzoic acid (148.01 mg, 1.21 mmol, 1.20 eq.). The mixture was stirred at 25 C for 12 hrs. Then it was washed with water, 5% HCl aqueous solution to give compound 28 (450.00 mg, crude) as yellow oil. To a solution of compound 28 (450.00 mg, 1.49 mmol, 1.00 eq.) in DCM (2 mL) was added HCl/AcOEt (40 mL) at 0 C. The mixture was stirred at 25 C for 2 hrs. Then it was concentrated to dryness to compound 29 (113.00 mg, 558.71 umol, 37.50% yield). A mixture of compound 6 (25.00 mg, 82.98 umol, 1.00 eq.) and compound 29 (16.78 mg, 82.98 umol, 1.00 eq.) in pyridine (3.00 mL) was added EDCI (23.86 mg, 124.47 umol, 1.50 eq.) at 25 C, the mixture was stirred for 3 h our at 25 C. LCMS showed the SM consumed, desired product was formed as major product. The mixture was concentrated, dissolved in to DMF (3 mL) and purified by prep-HPLC (TFA condition). The product was concentrated to give SC28 (33.00 mg, 65.25 umol, 78.64% yield, 96% purity) as yellow gum.
  • 29
  • [ 198211-38-0 ]
  • (6-amino-3-azabicyclo[3.1.0]hexan-3-yl)(phenyl)methanone [ No CAS ]
  • 30
  • [ 198211-38-0 ]
  • C25H23N7O4 [ No CAS ]
  • 31
  • [ 198211-38-0 ]
  • 2-[3‘-(2-bromoethoxy)biphenyl-3-yl]-[1,3]dioxolane [ No CAS ]
  • {(1R*,5S*)-3-[2-(3‘-[1,3]dioxolan-2-ylbiphenyl-3-yloxy)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h; General procedure: Intermediate C17.ii (130 mg) and K2C03 (69 mg) were suspended with DMF. 6-(Boc-amino)-3-azabicyclo[3. 1.0]hexane (81 mg; commercial) was added portionwise and themixture was stirred at rt for 1 day. The mixture was concentrated under reduced pressure and the residue was portioned between EA and water. The aq. layer was extracted with EA and the combined org. layers were washed with water and brine, dried over Mg504 and concentrated under reduced pressure. The title compound was obtained, after purificationby CC (Combiflash; Hept/EA 0:1 to 1:0), as a yellow oil (108 mg; 62% yield). M53 (ESI, mlz): 457.10 [M+H+]; tR = 0.73 mm.
  • 32
  • [ 198211-38-0 ]
  • [ 16004-15-2 ]
  • (2R)-4-(6-((4-((6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methyl)phenyl)ethynyl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide [ No CAS ]
  • 33
  • [ 198211-38-0 ]
  • [ 16004-15-2 ]
  • tert-butyl (3-(4-iodobenzyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
61% With potassium carbonate; potassium iodide; In acetonitrile; at 80℃; for 1h; Preparation G: tert-butyl (3-(4-iodobenzyl)-3-azabicyclo[3.1.0]hexan- 6-yl)carbamate: To a stirred solution of <strong>[198211-38-0]6-(Boc-amino)-3-azabicyclo[3.1.0]hexane</strong> (0.250 g, 1.26 mmol) in MeCN (10 mL) were added K2C03 (0.52 g, 3.78 mmol), 4-iodobenzyl bromide (0.449 g, 1.51 mmol) and KI (0.006 g, 0.0378 mmol). The resulting reaction mixture was heated at 80 C for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between DCM (100 mL) and water (25 mL). The org. layer was separated and the aq. layer was extracted with DCM (2 x 25 mL). The combined org. layers were washed with water (2 x 25 mL). The evaporation residue was purified by CC (DCM-MeOH) to afford the title compound as a beige solid (0.32 g, 61% yield). XH NMR (i/6-DMSO) delta: 7.66 (d, J = 8.3 Hz, 2H); 7.06 (d, J = 8.3 Hz, 2H); 6.90 (m, 1H); 3.48 (s, 2H); 2.88 (d, J = 8.8 Hz, 2H); 2.68 (d, J = 0.3 Hz, 1H); 2.30 (d, J = 8.4 Hz, 2H); 1.37 (s, 9H). MS (ESI, m/z): 414.96 [M+H+] for CnHnNzOzI; tR = 0.68 min.
  • 34
  • [ 198211-38-0 ]
  • 2-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile [ No CAS ]
  • 35
  • [ 198211-38-0 ]
  • methyl 5-(3-(2-cyanophenyl)-3-azabicyclo[3.1.0]hexan-6-ylamino)-2,4-dimethylbenzoate [ No CAS ]
 

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