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Chemical Structure| 41716-18-1 Chemical Structure| 41716-18-1

Structure of 41716-18-1

Chemical Structure| 41716-18-1

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CAS No.: 41716-18-1

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Product Details of [ 41716-18-1 ]

CAS No. :41716-18-1
Formula : C5H6N2O2
M.W : 126.11
SMILES Code : O=C(C1=CN(C)C=N1)O
MDL No. :MFCD02179560
InChI Key :WZTRQGJMMHMFGH-UHFFFAOYSA-N
Pubchem ID :541509

Safety of [ 41716-18-1 ]

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

Computational Chemistry of [ 41716-18-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 5
Fraction Csp3 0.2
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 30.45
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

55.12 ?2

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.72
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

-0.13
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.12
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

-0.8
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-0.26
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.07

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-0.89
Solubility 16.4 mg/ml ; 0.13 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-0.57
Solubility 33.6 mg/ml ; 0.267 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-0.13
Solubility 93.7 mg/ml ; 0.743 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

 High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

 No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

 No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

 No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

 No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

 No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

 No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

 No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.16 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

 0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

 None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

 0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

 0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

 1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.56

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

 No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

 1.46

Application In Synthesis of [ 41716-18-1 ]

* 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 [ 41716-18-1 ]

[ 41716-18-1 ] Synthesis Path-Downstream   1~30

  • 1
  • [ 19485-38-2 ]
  • [ 41716-18-1 ]
  • 2
  • [ 67-56-1 ]
  • [ 41716-18-1 ]
  • [ 17289-19-9 ]
  • 3
  • [ 41716-18-1 ]
  • [ 143165-09-7 ]
YieldReaction ConditionsOperation in experiment
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; A slurry of the 1 -methyl imidazol-4-yl acid (10 g, 79.3 mmol) iin dry DCM (100 ml) at room temperature was treated with dropwise addition of oxalyl chlodide ( 12 ml, mmol) and catalytic DMF ( pipette drops). The reaction bubbled immediately and the slurry was stirred for 1 hr. Removal of the solvent in vacuo followed by drying under high vacuum gave the title compound (9.1 g) as a tan white solid. 1H NMR (400MHz, MD3OD) delta. 9.09 (s, 1H), 8.24 (s, 1H), 3.98 (s, 3H).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 25℃; for 48h; Preparation of Compound 69aAt 0° C., a suspension of <strong>[41716-18-1]1-<strong>[41716-18-1]methyl-1H-imidazole-4-carboxylic acid</strong></strong> (100.9 mg, 0.8 mmol) in CH2Cl2 (8 mL) was added oxalylchloride (305 mg, 0.21 mL, 2.4 mmol) followed by addition of 1 drop of DMF. The mixture was stirred for 2 days at 25° C. All solvent was removed in vacuo to give a crude 69a.
With oxalyl dichloride;N,N-dimethyl-formamide; In chloroform; at 20℃; for 2h;Inert atmosphere; Example 9Methyl N-[(1-methyl-1H-imidazol-4-yl)carbonyl]-N-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethoxy)phenylalaninate To a mixture of <strong>[41716-18-1]1-<strong>[41716-18-1]methyl-1H-imidazole-4-carboxylic acid</strong></strong> (500 mg) and chloroform (5 mL), oxalyl chloride (0.6 mL) was added in a nitrogen atmosphere. A drop of DMF was added to the resulting mixture, which was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure to give a solid (670 mg). The solid (31 mg) was added to methyl N-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethoxy)phenylalaninate (50 mg), diisopropylethylamine (51 muL) and chloroform (0.5 mL) and the resulting mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=95:5 to 0:100) to give the titled compound (19 mg).
  • 5
  • [ 19485-38-2 ]
  • [ 41806-40-0 ]
  • [ 41716-18-1 ]
  • 6
  • [ 19485-35-9 ]
  • [ 41716-18-1 ]
  • 7
  • [ 41716-18-1 ]
  • [ 17289-19-9 ]
  • 8
  • [ 320780-86-7 ]
  • [ 41716-18-1 ]
  • [ 320781-57-5 ]
  • 9
  • [ 41716-18-1 ]
  • [ 17289-25-7 ]
YieldReaction ConditionsOperation in experiment
78.95% With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 50℃; To a suspension of 1-methyl-imidazole-4-carboxylic acid [(11.] 4g, 90 [MMOL)] in THF (500ml) at [0°C,] was added dropwise lithium aluminium hydride (solution 1 M in THF, [117MOL,] 117 [MMOL)] and the mixture was stirred at room temperature overnight and then at [50°C] for 1 hour. Then water (3 mi) was added followed by [NA2S04,] and the resulting precipitate was filtered off on [A] [CELITE PAD. THE FILTRATE] was concentrated under reduced pressure to afford the title compound as a solid (8g, 78.95percent) ;'H NMR (300 MHz, CDCl3, ppm) [8] : 7.25 (s, [1 H),] 6.7 (s, [1H),] 5.25 (m, [1 H),] 4.4 (s, 2H), [3.] 45 (s, 3H).
78.95% To a suspension of [1-METHYL-IMIDAZOLE-4-CARBOXYLIC] acid [(11.] 4g, 90 [MMOL)] in THF (500ml) at [0°C WAS] added dropwise LiAIH4 (solution 1 M in THF, 117ml. 117 [MMOL)] and the mixture was stirred at room temperature overnight and then at [50°C] for 1 hour. On cooling, water (3 [ML)] was added followed by [NA2SO4,] and the resulting precipitate was filtered through a celite pad. The filtrate was concentrated under reduced pressure to afford the title compound as a solid (8g, 78.95percent) [; H] NMR (300 MHz, CDCl3) [] ppm: [7. 25] (s, [1 H),] 6.7 (s, [1 H),] 5.25 (m, [1 H),] 4.4 (s, 2H), 3.45 (s, 3H).
78.95% With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 50℃; To a suspension of [1-METHYL-IMIDAZOLE-4-CARBOXYLIC ACID (11.] 4g, 90 [MMOL)] in THF (500ml) at [0°C,] was added drop-wise a solution of lithium aluminium hydride [(1 M] in THF, [117ML,] 117 [MMOL)] and the mixture was stirred at room temperature overnight and then at [50°C] for 1 hour Water (3 [ML)] was added followed by [NA2SO4] and the mixture was filtered through [CELITETM.] The filtrate was concentrated under reduced pressure to afford the title compound as a solid [(8G,] 78.95percent) ;'H NMR (300 MHz, [CDCI3)] 6 ppm: 7.25 (s, 1 H), 6. 7 (s, 1H), 5.25 (m, 1H), 4.4 (s, 2H), 3.45 (s, 3H).
47.5% With lithium aluminium tetrahydride; In tetrahydrofuran; at 50℃; for 12h;Inert atmosphere; 190a) (1 -Methyl-1 H-imidazol-4-yl)methanol A solution of 1 -methyl-1 H-imidazole-4-carboxylic acid (25 g, 198 mmol) in tetrahydrofuran (THF) (1000 ml_) was added LiAlhU (15.05 g, 396 mmol) slowly under nitrogen at room temperature. The reaction mixture was stirred at 50 °C for 12 h. It was added 15 mL of water, 15 mL of 10percent NaOH, 45 mL of water to the reaction mixture at 0 °C. The solid was filtered and the filtrate was concentrated to obtain the title compound (1 -methyl-1 H- imidazol-4-yl)methanol (13.2 g, 94 mmol, 47.5 percent yield) which was used for next step without further purification. LC-MS m/z 1 13.1 (M+H)+, 0.33 min (ret. time).

  • 10
  • [ 530-62-1 ]
  • [ 41716-18-1 ]
  • [ 883194-84-1 ]
YieldReaction ConditionsOperation in experiment
With Imidazole hydrochloride; In tetrahydrofuran; at 50℃; for 4h; General procedure: To a solution of carboxylic acid (0.1 mmol, 1 equiv.) in anhydrous THF (0.5 mL) in 2 dram screw cap vials was added imidazole hydrochloride (15.7 mg, 1.5 equiv.) and CDI (17.8 mg, 1.1 equiv.). The reactions were stirred for 4 h at 50 oC. A solution of pyrazole amide 23 (17.3 mg, 0.9 equiv.) in THF was added to each of the vials, and the reactions were agitated overnight at 50 oC. The solvent was removed, and the residue was dissolved in absolute EtOH (1 mL). To this was added a solution of NaOEt in EtOH (150 muL, 21percent w/w, 4 equiv.). The reactions were heated to 120 oC for 2 h in a sealed vial. The reactions were cooled to room temperature and 300 muL of 1M HCl was added, and the reactions were concentrated to precipitate the desired product. The solid was washed with 0.5 mL EtOAc and water to provide the final compounds.
  • 11
  • [ 917364-00-2 ]
  • [ 41716-18-1 ]
  • 3-(1-methyl-1H-imidazol-4-yl)-9-phenyl-8-(4-[4-(5-pyrimidin-2-yl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a stirred solution of 11-3 (0.23g, 0.4mMol), HOBT (0.06g, 0.45mMol), and 1- methyl-lH-imidazole-4-carboxylic acid (0.06g, 0.45mMol) in anhydrous DMF (2mL) was added DIEA (0.13mL, 0.8mMol) followed by EDC (0.09g, 0.5mMol). The solution was heated in the microwave reactor for 15 minutes at 800C. Solution was then treated with 0.2mL of acetic acid and was heated to 800C in the microwave reactor for 20 minutes. Upon cooling to room temperature, the solution was passed through a syringe filter and purified on a C18 reverse phase HPLC to give 12-1 as a solid. Mass (M+l) calculated: 632.2742 observed: 632.274 EPO <DP n="105"/>
  • 12
  • [ 917363-83-8 ]
  • [ 41716-18-1 ]
  • 8-[4-(1,3-dioxolan-2-yl)phenyl]-3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a stirred solution of 3-4 (5g, 13mMol), HOBT (1.9g, 14.3mMol), and 1-methyl-lH- imidazole-4-carboxylic acid (2g, 15.6mMol) in anhydrous DMF (10OmL) was added EDC (2.7g, 14.3mMol). The solution was stirred overnight at ambient temperature. The solution was then treated with 24mL of acetic acid and was heated to 800C in an oil bath for 5 hours. Upon cooling to room temperature, an equal volume of water was added and the resulting suspension was filtered and washed with copious amounts of water. The collected solid was dried azeotropically with toluene three times to yield 13-1 as a tan solid. Mass (M+l) calculated: 475.1877 observed: 475.1871
  • 13
  • [ 6638-79-5 ]
  • [ 41716-18-1 ]
  • [ 873221-68-2 ]
YieldReaction ConditionsOperation in experiment
64% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; 1) N-Methoxy-N-methyl-1-methyl-1H-imidazole-4-carboxamide 1-Methyl-1H-imidazole-4-carboxylic acid (1.26 g), N,O-dimethylhydroxylamine hydrochloride (1.17 g), 1-hydroxybenzotriazole (1.84 g), triethylamine (2.09 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g) were dissolved in N,N-dimethylformamide (50 mL), and the solution was stirred overnight at room temperature. The reaction solvent was evaporated under reduced pressure, and ethanol was added to the residue. Insoluble matter was removed through filtration, and the solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform - methanol - water, lower phase), to thereby give N-methoxy-N-methyl-1-methyl-1H-imidazole-4-carboxamide as a solid product (1.08 g, 64percent). 1H-NMR(400MHz,CDCl3)delta:3.45(3H,s), 3.73(3H,s), 3.78(3H,s), 7.45(1H,s),7.54(1H,s).
  • 14
  • [ 41716-18-1 ]
  • [ 214360-73-3 ]
  • [ 1027711-57-4 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 24h; A solution of i-methyl-I H-imidazole^-carboxylic acid (1 g), [4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]amine (1.74 g), HATU (3.62g) and DIPEA (4.15 mL) in DMF (10 ml.) was stirred at room temperature for 24 h. The solvent was evaporated and the residue was dissolved in DCM (50 mL), washed with saturated sodium bicarbonate solution (3 x 10 mL) dried by passing through a hydrophobic frit and evaporated in vacuo. The crude material was purified using a 120 g ISCO Companion.(TM). silica cartridge eluting with a gradient of 0-100percent EtOAc in cyclohexane to give the title compound. MS calcd for (C17H22BN3O3+ H)+ : 328 MS found (electrospray) : (M+H)+ = 328
  • 15
  • methyl 5-(4-aminophenyl)-3-{(cyclopropylmethyl)[(trans-4-methylcyclohexyl)carbonyl]amino}-2-thiophenecarboxylate [ No CAS ]
  • [ 41716-18-1 ]
  • methyl 3-{(cyclopropylmethyl)[(trans-4-methylcyclohexyl)carbonyl]amino}-5-(4-[(1-methyl-1H-imidazol-4-yl)carbonyl]amino}phenyl)-2-thiophenecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1 -Methyl-1 H-imidazole-4-carboxylic acid (48.8 mg) was dissolved in a solution of DMF (3 ml_), DIPEA (182 mul_) and HATU (201 mg), and the reaction was stirred at room temperature for 15 mins. Intermediate 64 (150 mg) in DMF (1 ml_) was added and the mixture was stirred at 5O0C under nitrogen for 22 h. The reaction mixture was evaporated in vacuo and was partitioned between DCM and saturated sodium bicarbonate solution. The organic phase was collected and dried by passing through a hydrophobic frit and evaporated in vacuo. The crude material was purified using a 12 g silica ISCO cartridge eluting with a gradient of 5 - 100percent EtOAc in cyclohexane to give the title compound. MS calcd for (C29H34N4O4S + H)+ : 535 MS found (electrospray) : (M+H)+ = 535
  • 16
  • [ 108-42-9 ]
  • [ 41716-18-1 ]
  • [ 953070-68-3 ]
YieldReaction ConditionsOperation in experiment
76% With triethylamine; HATU; In N,N-dimethyl-formamide; for 18h; N-(3-Chlorophenyl)-1-methyl-1H-imidazole-4-carboxamide O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 912 mg, 2.4 mmol) was added to a stirred mixture of <strong>[41716-18-1]1-<strong>[41716-18-1]methyl-1H-imidazole-4-carboxylic acid</strong></strong> (252 mg, 2.0 mmol), 3-chloroaniline (273 muL, 2.6 mmol), and triethylamine (1.1 mL, 8.0 mmol) in DMF (10 mL). After 18 h, the reaction mixture was diluted with 1:1 hexanes:EtOAc (200 mL), washed with 5percent brine (3*50 mL portions), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by silica gel column chromatography, eluding with 10percent acetonitrile in DCM to afford N-(3-Chlorophenyl)-1-methyl-1H-imidazole-4-carboxamide (358 mg, 76percent) as a tan solid.
  • 17
  • [ 1032085-34-9 ]
  • [ 41716-18-1 ]
  • [ 1032085-43-0 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 120h; A mixture of the amine 32 (500 mg, 1.5 mmol), N-methyl-imidazol-4-yl carboxylic acid ( 212 mg, 1.7 mmol), HOBT (218 mg, 1.6 mmol), DCC (353 mg, 1.8 mmol) and triethyl amine (0.64 ml, 4.6 mmol) in dry dichloromethane (15 ml) was stirred at room temperature for 5 days. The reaction mixture was poured into ethyl acetate and washed with 1 N NaOH (1 X), brine (1 X), dried and concentrated. The crude product was purified by chromatography using the ISCO purification system to provide the desired product 33 (590 mg) as a solid. 1H NMR (400 MHz, CHLOROFORM-d) deltappm 1.25 (s, 2 H) 1.43 (s, 8 H) 1.58 (s, 5 H) 1.85 (s, 2 H) 2.01 (s, 1 H) 2.14 (s, 1 H) 2.50 (s, 3 H) 2.58 (s, 1 H) 2.74 (s, 1 H) 3.69 (s, 5 H) 3.88 (s, 1 H) 5.18 (s, 1 H) 7.25 (S, 2 H) 7.40 (s, 2 H); LCMS (m/z) 435.0 (M+H).
  • 18
  • tert-butyl {2-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate [ No CAS ]
  • [ 41716-18-1 ]
  • C36H37N7O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of 1 -methyl- leta-imidazole-4-carboxylic acid (7.0 g, 56 mmol) in DMA (200 mL) was added EDC (11 g, 56 mmol) and HOBt (8.5 g, 56 mmol) and the reaction mixture was stirred at 600C for 1 hour. Then tert-butyl {2-[4-(5-hydrazino-3-phenyl-l,6- naphthyridin-2-yl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate (1-10) (30 g, 56 mmol) was added and the reaction stirred at 60°C for an additional 2 hours at which time acetic acid (17 g, 280 mmol) was added and the reaction was stirred overnight at 80°C. The reaction mixture was cooled to rt, quenched with IN NaOH, poured into saturated sodium bicarbonate, extracted with chloroform, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography eluting with 10percent methanol in DCM. The appropriate fractions were concentrated and the resulting solid was recrystallized from methanol to give tert-butyl (2-{4-[3- ( 1 -methyl- lH-imidazol-4-yl)-9-phenyl[ 1 ,2,4]triazolo[3,4-/J- 1 ,6-naphthyridin-8-yl]phenyl} -5,8- dioxaspiro[3.4]oct-2-yl)carbamate (1-11) as a white solid. MS (M+eta+): 630
  • 19
  • [ 1032350-00-7 ]
  • [ 41716-18-1 ]
  • [ 1032350-01-8 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 60℃; for 0.75h; tert-butyl{1-[4-(5-{2-[(1-methyl-1H-imidazol-4-yl)carbonyl]hydrazino}-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-7) To a round bottom flask was added tert-butyl{1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (3.94 g, 8.18 mmol), EDC (1.34 g, 10.6 mmol), HOBt (1.44 g, 10.6 mmol), 1-methyl-1H-imidazole-4carboxylic acid (1.34 g, 10.6 mmol), and DMF (40 mL). The reaction mixture was heated to 60° C. while stirring under an atmosphere of nitrogen in a hot oil bath. After 45 minutes the reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl{1-[4-(5-{2-[(1-methyl-1H-imidazol-4-yl)carbonyl]hydrazino}-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-7) as red foam. MS (M+H)+: observed=590.3, calculated=590.69.
  • 20
  • [ 915226-65-2 ]
  • [ 41716-18-1 ]
  • [ 915226-31-2 ]
YieldReaction ConditionsOperation in experiment
57% Example 48 (4-Fluoro-phenyl)-{(S)-3-[5-(1-methyl-1H-imidazol-4-yl)-[1,2,4]oxadiazol-3-yl]-piperidin-1-yl}-methanone A mixture of 1-methyl-imidazole-4-carboxylic acid (0.15 g, 1.2 mmol), HOAT (0.136 g, 1 mmol), EDCI.HCl (0.192 g, 1 mmol) and triethylamine (400 uL) in dry DCM (10 mL) and DMF (5 mL) was stirred at room temperature for 15 min and then (S)-1-(4-fluoro-benzoyl)-N-hydroxy-piperidine-3-carboxamidine (265 mg, 1 mmol), prepared as described in Example 44(D), was added. The reaction mixture was stirred at RT for 2 h. The mixture was diluted with DCM and washed with 0.2 N NaOH. The solvent was removed and the crude residue was purified by passing it through a silica gel cartridge (eluent gradient: from ethyl acetate to methanol/ethyl acetate 1:9). The white solid thus obtained was dissolved in acetonitrile (2 mL) and heated in a microwaves oven at 80° C. for 1 h, then at 95° C. for 1 h, then at 120° C. for 1 h. The solvent was removed and the residue was loaded onto a silica gel cartridge (eluent gradient: from ethyl acetate to methanol/ethyl acetate 6:94) to give (4-fluoro-phenyl)-{(S)-3-[5-(1-methyl-1H-imidazol-4-yl)-[1,2,4]oxadiazol-3-yl]-piperidin-1-yl}-methanone as a colourless glass (120 mg). Yield: 57percent; [alpha]D20=+86° (c=0.55, MeOH); LCMS (Rf): 2.02 min (Method I); MS (ES+) gave m/z: 356.2. 1H-NMR (DMSO-d6, 353K), delta (ppm): 8.01 (d br, 1H); 7.80 (d br, 1H); 7.47 (dd, 2H); 7.23 (dd, 2H); 4.22 (m, 1H); 3.84 (m, 1H); 3.77 (s, 3H); 3.34 (dd, 1H); 3.20 (ddd, 1H); 3.09 (m, 1H); 2.19 (m, 1H); 1.95-1.77 (m, 2H); 1.67 (m, 1H).
  • 21
  • [ 1204738-53-3 ]
  • [ 41716-18-1 ]
  • [ 1204737-09-6 ]
YieldReaction ConditionsOperation in experiment
74% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; EXAMPLE 1 1-Methyl-1H-imidazole-4-carboxylic acid 4-(3-hydroxy-4-isobutyryl-2-trifluoromethyl-phenoxymethyl)-benzylamide Mechanically stir suspensions of 1-[4-(4-aminomethyl-benzyloxy)-2-hydroxy-3-trifluoromethyl-phenyl]-2-methyl-propan-1-one hydrochloride (244 g, 604 mmol), 1-methyl-imidazole-4-carboxylic acid (95 g, 753 mmol), and 1-hydroxybenzotriazole hydrate (118 g, 770 mmol) in tetrahydrofuran (8 L) in two separate 22-L Morton flasks. Treat each solution with diisopropylethylamine (269 mL, 1.54 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 g, 756 mmol) in single portions and stir overnight at room temperature. Dilute each with 4 L of water and extract twice with 4 L of ethyl acetate. Wash organic layers with saturated sodium chloride solution, dry with magnesium sulfate, filter, and evaporate the filtrates to tan foams. Combine the foams and recrystallize from isopropanol (6 L) to afford the title compound (426 g, 74percent yield). m.p. 164.7° C.; HPLC Rt=4.86 min; 1H NMR (DMSO-d6) delta 13.95 (s, 1H), 8.45 (t, J=8.0 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.63 (d, J=12.0 Hz, 2H), 7.33 (ABq, J=12.0, 8.0 Hz, 4H), 6.89 (d, J=8.0 Hz, 1H), 5.32 (s, 2H), 4.39 (d, J=8.0 Hz, 2H), 3.71 (hept, J=8.0 Hz, 1H), 3.67 (s, 3H), 1.12 (d, J=8.0 Hz, 6H); 19F NMR (DMSO-d6) delta-54.10; MS (m/z): 476.0 (M+1).
  • 22
  • [ 1204738-54-4 ]
  • [ 41716-18-1 ]
  • [ 1204737-10-9 ]
YieldReaction ConditionsOperation in experiment
53.4% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; EXAMPLE 2 1-Methyl-1H-imidazole-4-carboxylic acid 4-[3-hydroxy-4-(3-methyl-butyryl)-2-trifluoromethyl-phenoxymethyl]-benzylamide Mix 1-[4-(4-aminomethyl-benzyloxy)-2-hydroxy-3-trifluoromethyl-phenyl]-3-methyl-butan-1-one hydrochloride (120 mg, 287.2 mumol), 1-methyl-1-H-imidazole-4-carboxylic acid (43.5 mg, 344.6 mumol), 1-hydroxybenzotriazole hydrate (52.8 mg, 344.6 mumol) in anhydrous tetrahydrofuran (4.5 mL). Add triethylamine (72.7 mg, 718 mumol, 100 muL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66.1 mg, 344.6 mumol) to the mixture. Stir the reaction mixture at room temperature overnight. Dilute the reaction mixture with water. Extract the mixture with ethyl acetate (3*). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate under reduced pressure. Purify the crude residue by flash chromatography (silica gel) eluding with 5percent methanol/ethyl acetate followed by reverse phase chromatography using 90/10 to 20/80 (water/0. 1percent trifluoroacetic acid)/acetonitrile to provide the product as a white solid (75 mg, 153 mumol, 53.4percent yield). MS (m/z): 490 (M+1).
  • 23
  • [ 34403-46-8 ]
  • [ 41716-18-1 ]
  • [ 1204738-81-7 ]
YieldReaction ConditionsOperation in experiment
Preparation 182 N-(4-(Hydroxymethyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide Stir a mixture of <strong>[41716-18-1]1-<strong>[41716-18-1]methyl-1H-imidazole-4-carboxylic acid</strong></strong> (4.0 g, 31.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.6 g, 34.5 mmol) and 1-hydroxybenzotriazole hydrate (5.29 g, 34.5 mmoles) in anhydrous acetonitrile (150 mL) at room temperature for 1 hr. Add to the reaction mixture (4-aminomethyl-phenyl)-methanol hydrochloride (5.0 g, 28.8 mmol) and triethylamine (8.4 mL, 60.5 mmol). Stir the reaction mixture at room temperature overnight. Quench the reaction mixture with water and extract with ethyl acetate (3*). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the title compound (4.6 g, 18.8 mmol). MS (m/z): 246 (M+1).
  • 24
  • [ 41716-18-1 ]
  • [ 388072-39-7 ]
  • [ 1262237-80-8 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 20℃; for 1h; Preparation Example 6: N-(3-Bromo-4-fluorobenzyl)-l-methyl-lH-imidazole-4- carboxamide [0110] [Formula 18][0111] A mixture of 3-Bromo-4-fluorobenzylamine (1.62 g), l-methyl-lH-imidazole-4- carboxylic acid (1.0 g), HATU (4.52 g), diisopropylethylamine (4.1 mL) and acetonitrile (26 ml) was stirred for 1 hour at room temperature. After addition of water and chloroform, the reaction mixture was stirred, and the chloroform layer was then separated and evaporated under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate = 50:50) and (silica gel cartridge,chloroform:methanol = 99:1 to 90:10) to give the titled compound (1.87 g).IH NMR (600 MHz, CHLOROFORM-d) d ppm 3.74 (s, 3 H) 4.52-4.58 (m, 2 H) 7.03-7.09 (m, 1 H) 7.34-7.56 (m, 4 H)(ESI pos.) m/z: 312, 314 ([M+H]+)
  • 25
  • [ 41716-18-1 ]
  • [ 1262237-81-9 ]
  • 26
  • [ 41716-18-1 ]
  • [ 1262237-18-2 ]
  • 27
  • [ 1019580-43-8 ]
  • [ 41716-18-1 ]
  • [ 1262237-73-9 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 20℃; for 4h; Preparation Example 4: N-(3-Bromo-4-fluorobenzyl)-N-cyclopentyl-l-methyl-lH- imidazole-4-carboxamide[0097] [Formula 16][0098] A mixture of N-(3-bromo-4-fluorobenzyl)cyclopentanamine (1.50 g), 1-methyl-lH- imidazole-4-carboxylic acid (695 mg), 2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (2.72 g), diisopropylethylamine (2.55 mL) and acetonitrile (23 mL) was stirred for 4 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the ethyl acetate solution was washed with water. The organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate = 90:10 to 20:80) to give the titled compound (2.00 g).IH NMR (600 MHz, CHLOROFORM-d) d ppm 1.48-1.95 (m, 8 H) 3.62-3.75 (m, 3 H) 4.42-5.85 (m, 3 H) 6.97-7.21 (m, 2 H) 121-1 Al (m, 2 H) 7.53 (s, 1 H)(ESI pos.) m/z: 380, 382 ([M+H]+)
  • 28
  • [ 1262237-70-6 ]
  • [ 41716-18-1 ]
  • [ 1262237-19-3 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 20℃; for 2.5h; Example 5: N-Cyclobutyl-N-[6-fluoro-3'-(hydroxymethyl)biphenyl-3-yl]methyl}- 1 -methyl- 1 H-imidazole-4-carboxamide[0148] [Formula 27][0149] A mixture of {5'-[(cyclobutylamino)methyl]-2'-fluorobiphenyl-3-yl}methanol (700 mg), l-methyl-lH-imidazole-4-carboxylic acid (340 mg), HATU (1.21 g),diisopropylethylamine (1.13 mL) and acetonitrile (10.5 ml) was stirred for 2.5 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol = 98:2 to 95:5) and (NH silica gel cartridge, chloroform methanol = 100:0 to 98:2) to give the titled compound (758 mg).
  • 29
  • [ 1313440-22-0 ]
  • [ 41716-18-1 ]
  • tert-butyl (1-(4-(3-(1-methyl-1H-imidazol-4-yl)-9-phenyl-5,6-dihydro-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)phenyl)cyclobutyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
5% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere; To a solution of tert-butyl (1-(4-(5-hydrazono-3-phenyl-5,6,7,8-tetrahydro-1,6- naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (22mg, 0.04 mmol) in dry DMF (1 ml_) was added EDCI (11 mg, 0.06 mmol), HOBt.H20(8 mg, 0.06 mmol) and 1-methyl-1H- imidazole-4-carboxylic acid (8 mg, 0.06 mmol) under nitrogen. The reaction mixture was heated at 60 °C overnight. After cooled down to room temperature, the mixture was partitioned between saturated NaHC03 solution and ethyl acetate. The layers were separated and the organic phase washed with water and brine, dried over Na2S04, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (method G, gradient 5 to 95percent 0.1percentFA/ACN in0.1percentFA/H2O) to give the title compound (1 mg, 5percent). NMR (500 MHz, CDCI3): 8.49 (1 H, s), 7.74 (1 H, s), 7.54 (1H, s), 7.38 (2H, d), 7.31 (2H, d), 7.28-7.23 (5H, m), 5.01 (1 H, br s), 4.94 (2H, t), 3.81 (3H, s), 3.49 (2H, t), 2.60-2.30 (4H, m), 2.10-2.01 (1 H, m), 1.85- 1.76 (1 H, m), 1.45-1.20 (9H, br).
  • 30
  • [ 1173177-20-2 ]
  • [ 41716-18-1 ]
  • [ 1173177-23-5 ]
 

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