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[ CAS No. 222530-34-9 ] {[proInfo.proName]}

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Chemical Structure| 222530-34-9
Chemical Structure| 222530-34-9
Structure of 222530-34-9 * Storage: {[proInfo.prStorage]}
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Product Details of [ 222530-34-9 ]

CAS No. :222530-34-9 MDL No. :MFCD06227743
Formula : C12H21NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :JSGHMGKJNZTKGF-DTWKUNHWSA-N
M.W : 243.30 Pubchem ID :2755995
Synonyms :

Calculated chemistry of [ 222530-34-9 ]

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.83
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 63.97
TPSA : 75.63 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.56 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.22
Log Po/w (XLOGP3) : 1.73
Log Po/w (WLOGP) : 2.15
Log Po/w (MLOGP) : 1.31
Log Po/w (SILICOS-IT) : 0.83
Consensus Log Po/w : 1.65

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.11
Solubility : 1.9 mg/ml ; 0.00779 mol/l
Class : Soluble
Log S (Ali) : -2.93
Solubility : 0.283 mg/ml ; 0.00116 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.42
Solubility : 9.29 mg/ml ; 0.0382 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.07

Safety of [ 222530-34-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 222530-34-9 ]

* 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 [ 222530-34-9 ]

[ 222530-34-9 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 222530-34-9 ]
  • N-(6-aminobenzothiazol-2-yl)cyclopentanecarboxamide [ No CAS ]
  • {(1R,3S)-3-[2-(Cyclopentanecarbonyl-amino)-benzothiazol-6-ylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester [ No CAS ]
  • 2
  • (1S,3R)-3-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid ethyl ester [ No CAS ]
  • [ 222530-34-9 ]
  • 3
  • [ 222530-34-9 ]
  • 2-methylamino-propionic acid 9<i>H</i>-fluoren-9-ylmethyl ester [ No CAS ]
  • [ 869081-61-8 ]
  • 4
  • [ 24424-99-5 ]
  • (+/-)-cis-3-aminocyclohexanecarboxylic acid [ No CAS ]
  • [ 222530-39-4 ]
  • [ 222530-34-9 ]
  • 5
  • [ 99-05-8 ]
  • [ 222530-34-9 ]
  • 6
  • [ 222530-34-9 ]
  • [ 869081-63-0 ]
  • 7
  • [ 222530-34-9 ]
  • [ 869081-62-9 ]
  • 9
  • [ 222530-34-9 ]
  • H-[D-γ-Ach-L-MeN-Ala-]2-OH [ No CAS ]
  • 10
  • [ 222530-34-9 ]
  • (S)-2-[((1S,3R)-3-{(R)-2-[((1S,3R)-3-tert-Butoxycarbonylamino-cyclohexanecarbonyl)-methyl-amino]-propionylamino}-cyclohexanecarbonyl)-methyl-amino]-propionic acid [ No CAS ]
  • 11
  • [ 222530-34-9 ]
  • Boc-[D-γ-Ach-L-MeN-Ala-]2-OFm [ No CAS ]
  • 13
  • [ 222530-34-9 ]
  • (S)-2-[((1S,3R)-3-{(S)-2-[((1S,3R)-3-tert-Butoxycarbonylamino-cyclohexanecarbonyl)-methyl-amino]-propionylamino}-cyclohexanecarbonyl)-methyl-amino]-propionic acid [ No CAS ]
  • 15
  • [ 222530-34-9 ]
  • (1S,3R)-3-[(Naphthalen-2-ylmethyl)-amino]-cyclohexanecarboxylic acid [2-(cyclopentanecarbonyl-amino)-benzothiazol-6-yl]-amide [ No CAS ]
  • 16
  • [ 222530-34-9 ]
  • (1S,3R)-3-Amino-cyclohexanecarboxylic acid [2-(cyclopentanecarbonyl-amino)-benzothiazol-6-yl]-amide; compound with trifluoro-acetic acid [ No CAS ]
  • 17
  • [ 62059-56-7 ]
  • [ 222530-34-9 ]
  • 18
  • [ 227783-03-1 ]
  • [ 222530-34-9 ]
  • 19
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-(hydroxymethyl)cyclohexyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; A cooled (0C) solution of (lS,3R)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (prepared following Tetrahedron: Asymmetry 2010 (21), 864-866) (1.24 g, 5.09 mmol) in THF (34 mL) was treated with a 2M solution of BH3 Me2S in THF (3.7 mL, 7.38 mmol) and stirred overnight at rt. The resulting solution was treated with a IM solution of HCl in H20 (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgS04, filtered and evaporated to dryness affording the title compound (1.17 g, 5.09 mmol, 100%) as a colorless oil which was used in the next step without further purification.
100% With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; [3261 A cooled (0 C) solution of(1S,3R-3-ttert-butoxycarbonyiarnino)-cyclohexanecarboxylic acid (prepared following Tetrahedron: Asymmetry 2010 (21), 864-866) (1.24 g, 509 inmol) in THF (34 mL) was treated with a 2M solution of BH3.Me2S in IHF (3.7 mL, 7.38 mmol) and stirred overnight at rt. The resulting solution was treated with a 1M solution of HCI in H20 (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness affording the title compound (1.17 g, 5.09 mmoi, 100%) as a colorless oil which was used in the next step without further purification.
100% With dimethylsulfide borane complex; In tetrahydrofuran; at 20℃;Inert atmosphere; Compound 01500-1 (2.43 g, 10 mmol) was dissolved in 50 mL of tetrahydrofuran, and borane dimethyl sulfide complex (10N, 1.5 mL, 15 mmol) was added under nitrogen protection.The reaction mixture was stirred at room temperature overnight, quenched with ammonium chloride, extracted with ethyl acetate, dried and concentrated to obtain a white solid compound 015010-2 (2.3 g, 100% yield).
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; tert-butyl (1R,3S)-3-(hydroxymethyl)cyclohexylcarbamate[00426] A cooled (0 C) solution of (1S,3R)-3-(tertbutoxycarbonylamino)cyclohexanecarboxylic acid (prepared following Tetrahedron: Asymmetry 2010 (21), 864-866) (1.24 g, 5.09 mmol) in THF (34 mL) was treated with a 2M solution of BH3.Me2S in THF (3.7 mL, 7.38 mmol) and stirred overnight at rt. The resulting solution was treated with a 1M solution of HCl in H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4 , filtered and evaporated to dryness affording the title compound (1.17 g, 5. 09 mmol, 100%) as a colorless oil which was used in the next step without further purification.

  • 20
  • [ 222530-34-9 ]
  • (R)-tert-butyl 3-methylenecyclohexylcarbamate [ No CAS ]
  • 21
  • [ 222530-34-9 ]
  • (R)-tert-butyl 3-oxocyclohexylcarbamate [ No CAS ]
  • 22
  • [ 222530-34-9 ]
  • [ 74-88-4 ]
  • (1S,3R)-methyl 3-(tert-butoxycarbonylamino)cyclohexanecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h; A solution of (lR,3S)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (0815) (prepared following Tetrahedron: Asymmetry 2010 (21), 864-866) (1.0 g, 4.11 mmol), K2C03 (474 mg, 3.43 mmol) and Mel (0.21 mL, 3.43 mmol) in DMF (8 mL) was stirred 72h at rt. The resulting mixture was diluted with H20 (30 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was extracted into EtOAc (3 x 50 mL). The combined organic layers were dried over MgS04, filtered and evaporated to dryness leaving the title compound as a light orange solid (1.35 g, 4.11 mmol, 100%) which was used in the next step without further purification.
1.1 g With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 48h; Add <strong>[222530-34-9](1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid</strong> (1.216g) and methyl iodide (1.4g) into the reaction flask,Potassium carbonate (1.4g), DMF (16mL), stirred at room temperature for 2d, after the reaction, the reaction solution was concentrated,It was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-20%) to obtain 015262A8-1 (1.1 g).
  • 23
  • [ 120278-07-1 ]
  • [ 222530-34-9 ]
  • benzyl 4-[[(1S,3R)-3-(tert-butoxycarbonylamino)cyclohexanecarbonyl]amino]piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
84.6% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 25℃; for 3h;Inert atmosphere; To a mixture of (lS,3R)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (5 g, 20.55 mmol) and benzyl 4-aminopiperidine-l-carboxylate (5.3 g, 22.61 mmol) in DCM (200 mL) was added TEA (4.16 g, 41.10 mmol) and HATU (11.72 g, 30.83 mmol) under N2 at 25 C and stirred for 3 h. The mixture was diluted with DCM, washed with water and brine, and the organic phase wad concentrated under vacuum to afford benzyl4-[[(lS,3R)-3-(tert- butoxycarbonylamino)cyclohexanecarbonyl]amino]piperidine-l-carboxylate (8 g, 84.6%) as a yellow solid.
  • 24
  • [ 222530-34-9 ]
  • [ 84249-14-9 ]
  • tert-butyl ((1R,3S)-3-((4-bromopyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.574 ml, 4.33 mmol) was added to a solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.01 g, 4.16 mmol; prepared according to Example 2) in DCM (40 ml) at 0 C. After 1.5 h, a mixture of 4-bromopyridin-2-amine (0.6 g, 3.47 mmol) and pyridine (1.12 ml, 13.9 mmol) in DCM (33.0 ml) was added via cannula. The resulting yellow mixture was allowed to warm to r.t. and was stirred under these conditions for 72 h. The now white mixture was filtered, rinsed with a cold DCM wash, and the white precipitate was dried under vacuum at 70 C. for 30 min to afford tert-butyl ((1R,3S)-3-((4-bromopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (1.38 g, 100%) of 95% purity as a white solid. 1H NMR (300 MHz, DMSO-d6, 27 C.) 0.99-1.35 (4H, m) 1.38 (9H, s) 1.68-1.80 (3H, m) 1.88 (1H, d) 2.53-2.64 (1H, m) 3.15-3.35 (1H, m) 6.76 (1H, d) 7.34 (1H, dd) 8.21 (1H, d) 8.33 (1H, d) 10.63 (1H, s). m/z: ES+[M+H]+ 398.
  • 25
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(5-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1-carboxamide [ No CAS ]
  • 26
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(4-(4, 5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 27
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(6-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexane-1-carboxamide [ No CAS ]
  • 28
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-pyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 29
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide [ No CAS ]
  • 30
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(4-bromo-5-chloropyridin-2-yl)cyclohexane-1-carboxamide [ No CAS ]
  • 31
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo-[1,2-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 32
  • [ 222530-34-9 ]
  • (1S,3R)-3-amino-N-(4-bromo-5-chloropyridin-2-yl)-cyclohexanecarboxamide dihydrochloride [ No CAS ]
  • 33
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrazolo-[5,1-b][1,3]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 34
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 35
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 36
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-4H-pyrazolo-[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 37
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 38
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 39
  • [ 222530-34-9 ]
  • (1S,3R)-3-amino-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 40
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)-carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 41
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4, 5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 42
  • [ 222530-34-9 ]
  • (1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 43
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexane-1-carboxamide [ No CAS ]
  • 44
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 45
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-pyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 46
  • [ 222530-34-9 ]
  • (1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 47
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 48
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 49
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 50
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-cyclohexanecarboxamide [ No CAS ]
  • 51
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% Carbonyl diimidazole (6.44 g, 39.74 mmol) was added to a solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (3.22 g, 13.3 mmol) in DMF (30 mL) at 40 C. The resulting mixture was stirred at 40 C. for 4 h. The reaction mixture was then cooled to 0 C., and ammonium acetate (7.15 g, 92.7 mmol) was added in one portion with vigorous stirring. This was followed by gas evolution and generation of a foam. A small amount (2 mL) of DCM was added along the sides of the flask to break apart the foam and prevent it from reaching the flask opening. Gradually this foam was reabsorbed by the reaction mixture, which was allowed to warm to r.t. overnight. After a total of 18 h under these conditions, the reaction mixture was poured into ice water, and the resulting mixture was stirred under these conditions for 5 min before being filtered with a water wash. The resulting precipitate was dried under vacuum at 80 C. for 2 h before being cooled to r.t. Vacuum drying was then continued for 18 h to afford tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (2.76 g, 86%) as a white fluffy solid. 1H NMR (DMSO-d6, 27 C.) 0.99-1.31 (4H, m), 1.38 (9H, s), 1.58-1.85 (4H, m), 2.06-2.19 (1H, m), 3.14-3.26 (1H, m), 6.63 (1H, br s), 6.73 (1H, d), 7.17 (1H, br s). m/z: ES+[M+Na]+265. Optical Rotation: (0800) Concentration: 0.1 g/dL Lamp: Sodium Wavelength: 589 nm Temperature: 25 C. (0801) Path length: 10 cm Cell volume: 1 mL Solvent: Methanol (0802) [α]=+51.3
Compound 1a (400mg, 1.6mmol) was dissolved in dry N,N-dimethylformamide (10mL), HATU (950mg, 2.5mmol) and N,N-diisopropylethylamine (413mg, 3.2mmol) were added , Stir for 15 minutes,Add ammonium chloride (101 mg, 1.9 mmol) and stir overnight at room temperature. TLC shows that the reaction is complete. The reaction solution was poured into water, a solid precipitated out, filtered, and the filter cake was washed and dried to obtain the title compound 10c (330 mg, crude product) as an off-white solid, which was used directly in the next step.
  • 52
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(4-chloro-5-cyanopyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 53
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-cyano-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 54
  • [ 222530-34-9 ]
  • (1S,3R)-3-amino-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 55
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 56
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-cyclohexanecarboxamide [ No CAS ]
  • 57
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 58
  • [ 222530-34-9 ]
  • (1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-cyclohexanecarboxamide [ No CAS ]
  • 59
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 60
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(4-(5, 5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 61
  • [ 222530-34-9 ]
  • (1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 62
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)-cyclohexanecarboxamide [ No CAS ]
  • 63
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 64
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
  • 65
  • [ 222530-34-9 ]
  • (1S,3R)-3-amino-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 66
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo-[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 67
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)-cyclohexyl)carbamate [ No CAS ]
  • 68
  • [ 222530-34-9 ]
  • (1S,3R)-3-amino-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)-pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 69
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 70
  • [ 222530-34-9 ]
  • tert-butyl ((1R,3S)-3-((5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)carbamoyl)-cyclohexyl)carbamate [ No CAS ]
  • 71
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(5-(4-hydroxybutyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 72
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(5-chloro-4-(7-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 73
  • [ 222530-34-9 ]
  • (1S,3R)-3-acetamido-N-(4-(5-(4-((tert-butyldimethylsilyl)oxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamide [ No CAS ]
  • 74
  • [ 222530-34-9 ]
  • (1S,3R)-3-amino-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-cyclohexanecarboxamide [ No CAS ]
  • 75
  • [ 222530-34-9 ]
  • [ 1187449-01-9 ]
  • tert-butyl ((1R,3S)-3-((4-bromo-5-chloropyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
A solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.50 g, 6.15 mmol; prepared according to Example 2) dissolved in DCM (20 mL) at 0° C. was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.976 mL, 7.38 mmol). The mixture was stirred at r.t. for 1.5 h before <strong>[1187449-01-9]4-bromo-5-chloropyridin-2-amine</strong> (1.02 g, 4.92 mmol) and pyridine (0.594 mL, 7.38 mmol) were added sequentially. The resulting solution was stirred at r.t. for 16 h. The reaction mixture was diluted with DCM (25 mL), and washed sequentially with water (2×25 mL) and saturated aqueous sodium chloride (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by ion exchange chromatography, using an SCX-2 column. The desired product was eluted from the column using methanol to afford tert-butyl ((1R,3S)-3-((4-bromo-5-chloropyridin-2-yl)carbamoyl)cyclohexyl)carbamate (2.34 g, 110percent) as a white solid. 1H NMR (400 MHz, DMSO-d6, 30° C.) 1.12 (1H, dd), 1.22-1.32 (3H, m), 1.38 (9H, s), 1.72 (3H, dd), 1.83-1.94 (2H, m), 2.11 (1H, dt), 8.48 (1H, s), 8.50 (1H, s), 10.77 (1H, s), one proton not observed. m/z: ES?[M?H]? 430.
  • 76
  • [ 222530-34-9 ]
  • [ 5305-59-9 ]
  • tert-butyl ((1R,3S)-3-((6-chloropyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
14% 1-Chloro-N,N,2-trimethylpropenylamine (3.26 mL, 24.7 mmol) was added to a solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (5.00 g, 20.6 mmol; prepared as in Example 2) in DCM (50 mL) and the resulting mixture stirred for 90 min at r.t. Then 6-chloropyrimidin-4-amine (2.66 g, 20.6 mmol) and pyridine (2.0 mL, 25 mmol) were added, and the resulting mixture was stirred under these conditions for 18 h. The reaction was quenched with saturated aqueous sodium bicarbonate (50 mL), and the layers were separated. The aqueous layer was extracted with DCM (2×50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography, eluting with 0 to 100% (10% methanol in ethyl acetate) in heptane. Product fractions were combined and concentrated under reduced pressure to give tert-butyl ((1R,3S)-3-((6-chloropyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate (1.0 g, 14%) as a white solid. m/z: ES-[M-H]-353.
  • 77
  • [ 222530-34-9 ]
  • [ 1159818-57-1 ]
  • tert-butyl ((1R,3S)-3-((6-bromopyrimidin-4-yl)carbamoyl)cyclohexyl) carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% 1-Chloro-N,N,2-trimethylpropenylamine (0.46 mL, 3.5 mmol) was added dropwsie to a solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (699 mg, 2.87 mmol; prepared according to Example 2) in DCM (10 mL) at 0 C. under nitrogen. The resulting solution was stirred at 0 C. for 1.5 h. <strong>[1159818-57-1]6-Bromopyrimidin-4-amine</strong> (400 mg, 2.30 mmol) and pyridine (0.28 mL, 3.5 mmol) were then added, and the reaction mixture was stirred at r.t. overnight. The crude reaction mixture was concentrated under reduced pressure. To the resulting solid, DCM was then added. The resulting mixture was then filtered, and the resulting precipitate was purified by flash silica chromatography, elution gradient 0 to 2% MeOH in DCM. Pure fractions were concentrated under reduced pressure to afford tert-butyl ((1R,3S)-3-((6-bromopyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate (605 mg, 66%) as a white solid. m/z: ES+[M+H]+ 399
  • 78
  • [ 222530-34-9 ]
  • [ 670253-38-0 ]
  • tert-butyl ((1R,3S)-3-((4-chloro-5-cyanopyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.23 mL, 1.7 mmol) was added to a solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (310 mg, 1.27 mmol; prepared according to Example 2) in DCM (5.5 mL) at r.t., resulting in a colorless solution. The reaction was maintained under these conditions for 2 h, and this reaction was added directly to a solution of 6-amino-4-chloronicotinonitrile (178 mg, 1.16 mmol) and pyridine (0.37 ml, 4.6 mmol) in DCM (11 mL) at 0 C. The reaction was allowed to warm to r.t. and was maintained under these conditions for 18 h. The reaction was then diluted with DCM and washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified flash silica chromatography, elution gradient 0 to 10% methanol in DCM. The resulting material was repurified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in hexanes, to afford tert-butyl ((1R,3S)-3-((4-chloro-5-cyanopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (330 mg, 75%) as a white solid. m/z: ES+[M+Na+]+401.
  • 79
  • [ 222530-34-9 ]
  • [ 1260667-65-9 ]
  • tert-butyl ((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
64.4% 1-Chloro-N,N,2-trimethylpropenylamine (1.149 mL, 8.68 mmol) was added to a stirred solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.41 g, 5.79 mmol; prepared according to Example 2) in DCM (25 mL) cooled in an ice bath under a nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 h. 5-Chloro-4-iodopyridin-2-amine (1.47 g, 5.79 mmol; prepared according to Example 2) and pyridine (0.702 mL, 8.68 mmol) were added, and the resulting mixture was stirred at ambient temperature for 16 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (50 mL). The resulting mixture was extracted with DCM (3×75 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting pale yellow solid was slurried with Et2O (10 mL) and filtered to yield tert-butyl ((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (1.79 g, 3.73 mmol, 64.4%) as a cream-colored solid. 1H NMR (400 MHz, CDCl3, 30 C.) 1.04-1.18 (1H, m), 1.24-1.41 (2H, m), 1.44 (9H, s), 1.92 (2H, dq), 2.00 (1H, d), 2.28 (1H, d), 2.31-2.41 (1H, m), 3.27-3.62 (2H, m), 4.44 (1H, s), 7.80 (1H, s), 8.19 (1H, s), 8.81 (1H, s). m/z: ES- [M-H]-478.
  • 80
  • [ 222530-34-9 ]
  • [ 1227581-81-8 ]
  • tert-butyl ((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.24 mL, 1.8 mmol) was added to a solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (321 mg, 1.32 mmol; prepared according to Example 2) in DCM (2.8 mL) to give a colorless solution. The solution was stirred at r.t. for 2 h and then added a solution of <strong>[1227581-81-8]4-iodo-5-methylpyridin-2-amine</strong> (281 mg, 1.2 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (2.8 mL) at 0 C. The reaction was allowed to warm to r.t. and stirred under these conditions 3 h before being diluted with DCM and washed with saturated aqueous NaHCO3, water, and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, to afford tert-butyl ((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)carbamate (530 mg, 96%) as a white solid. 1H NMR (300 MHz, DMSO-d6, 27 C.) 1.02-1.13 (1H, m), 1.44-1.53 (3H, m), 1.38 (9H, s), 1.65-1.80 (3H, m), 1.87 (1H, br d), 2.29 (3H, s), 2.52-2.61 (1H, m), 3.19-3.34 (1H, m), 6.78 (1H, br d), 8.16 (1H, s), 8.61 (1H, s), 10.43 (1H, s). m/z: ES+[M+H]+ 460.
  • 81
  • [ 222530-34-9 ]
  • 5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine [ No CAS ]
  • tert-butyl ((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-carbamoyl)cyclohexyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (1.12 mL, 8.44 mmol) was added to a solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (2.01 g, 8.24 mmol) in DCM (50 mL) at 0 C. The reaction was maintained under these conditions for 100 minutes. During this time, 5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine (1.64 g, 6.59 mmol), pyridine (2.1 mL, 26.4 mmol) and DCM (20 mL) were combined in a separate flask. The resulting mixture was warmed gently (40 C.) until all solids dissolved. The resulting solution was then cooled to 0 C., whereupon a homogeneous light yellow mixture formed. This mixture was added via cannula rapidly to the previously prepared solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid and 1-chloro-N,N,2-trimethylprop-1-en-1-amine, resulting in a darker yellow solution. The reaction was allowed to warm to r.t. overnight and was then evaporated to dryness. The gray mixture was then taken on to the next step without further purification. m/z: ES+[M+H]+ 474.
  • 82
  • [ 222530-34-9 ]
  • 5-fluoro-4-iodopyridine-2-amine [ No CAS ]
  • tert-butyl ((1R,3S)-3-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.62 mL, 4.7 mmol) was added to a solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (843 mg, 3.47 mmol; prepared according to Example 2) in DCM (15 mL). The colorless solution was stirred at r.t. for 1.5 h. Then a solution of 5-fluoro-4-iodopyridin-2-amine (750 mg, 3.15 mmol) and pyridine (0.51 mL, 6.3 mmol) in DCM (15 mL) was added. The resulting reaction was stirred at r.t. for 18 h before being diluted with DCM (200 mL) and washed with water and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM, to afford tert-butyl ((1R,3S)-3-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (827 mg, 57%) as a white solid. 1H NMR (300 MHz, DMSO-d6, 27 C.) 1.01-1.19 (1H, m), 1.18-1.31 (3H, m), 1.38 (9H, s), 1.61-1.81 (m, 3H), 1.87 (1H, d), 2.53-2.62 (1H, m), 3.16-3.26 (1H, m), 6.78 (1H, br d), 8.26 (1H, s), 8.60 (1H, d), 10.61 (1H, s). m/z: ES+[M+Na+]+486.
  • 83
  • (1S,3R)-benzyl 3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate [ No CAS ]
  • [ 222530-34-9 ]
YieldReaction ConditionsOperation in experiment
99% With palladium 10% on activated carbon; hydrogen; In methanol; under 760.051 Torr; for 18h; A degassed mixture of (1S,3R)-benzyl 3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (11.5 g, 34.6 mmol), palladium on carbon (10 wt %; 3.68 g, 34.5 mmol), and methanol (86 mL) was subjected to a hydrogen atmosphere (1 atm, balloon). After 18 h, the mixture was filtered with a methanol wash. The filtrate was concentrated to a slightly turbid faint gray oil. This oil was taken up in ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting white oily solid was heated under vacuum until all bubbling from solvent evaporation stopped. Cooling to r.t. afforded (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (8.4 g, 99%) as a white solid (See Example 2, Intermediates, for characterization). Optical Rotation: (0795) Concentration: 0.1 g/dL Lamp: Sodium Wavelength: 589 nm Temperature: 25 C. (0796) Path length: 10 cm Cell volume: 1 mL Solvent: DMSO (0797) [α]=+44.6
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; Intermediate IN-3-2 (1.5 g, 4.5 mmol) was dissolved in methanol (25 mL), palladium/carbon (150 mg, 10%) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. TLC showed that the starting material disappeared. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain the title compound 1a (1.1 g, crude product) as a white solid, which was directly used in the next step.
  • 85
  • [ 222530-34-9 ]
  • [ 574729-26-3 ]
  • C24H35N5O5 [ No CAS ]
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