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Structure of 3012-80-4

Chemical Structure| 3012-80-4

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Product Details of [ 3012-80-4 ]

CAS No. :3012-80-4
Formula : C9H8N2O
M.W : 160.17
SMILES Code : O=CC1=NC2=CC=CC=C2N1C
MDL No. :MFCD00142655
InChI Key :SIRPHJCQZYVEES-UHFFFAOYSA-N
Pubchem ID :762084

Safety of [ 3012-80-4 ]

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

Computational Chemistry of [ 3012-80-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 9
Fraction Csp3 0.11
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 46.38
TPSA ?

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

34.89 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.04
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

1.09
Log Po/w (WLOGP)?

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

1.39
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.

0.67
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

1.56
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.15

Water Solubility

Log S (ESOL):?

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

-2.01
Solubility 1.57 mg/ml ; 0.0098 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-1.41
Solubility 6.16 mg/ml ; 0.0385 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

-2.41
Solubility 0.623 mg/ml ; 0.00389 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

Yes
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

Yes
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.

-6.5 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.

0.55

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

1.0 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)

1.26

Application In Synthesis of [ 3012-80-4 ]

* 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 [ 3012-80-4 ]

[ 3012-80-4 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 3012-80-4 ]
  • [ 7467-35-8 ]
YieldReaction ConditionsOperation in experiment
50.4% 2- hydroxymethyl-l -methyl-1 H-benzimidazole (Compound 49a)A suspension of l -methyl-2-formyl-l H-benzimidazole (500 mg, 3.12 mmol) and NaBH4 (134 mg, 3.43 mmol) in anhydrous THF (25 ml) was stirred for 24 hours at r.t.. The reaction mixture was quenched with water, extracted with EtOAc, dried over Na2S04 and evaporated to dryness in vacuo. The crude was purified by automated flash chromatography (HorizonTM - Biotage) eluting with CHC13 - 1.7M NH3 sol. in MeOH 100:2 giving the title product as white solid. Yield: 50.4 %. MS: [ +H]+ = 163.5
Example 12; (1-Methyl-1H-benzoimidazol-2-yl)-methanol; Sodium borohydride (472 mg, 12.48 mmol) was added to the solution of 1-methyl-1H-benzoimidazole-2-carbaldehyde (1 g, 6.24 mmol) in ethanol (50 mL). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was condensed, the residue was diluted with ethyl acetate; water was added. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and condensed to give off-white solid as product (953 mg, 94%). This product was used in the later steps without further purification.1HNMR (300 MHz, CDCl3): (ppm) 7.63 (m, 1H), 7.21 (m, 3H), 4.84 (s, 2H), 3.75 (s, 3H)
With methanol; sodium tetrahydridoborate; at 0 - 20℃; for 5h; To a 0C solution of 1 -methyl- lH-benzimidazole-2-carbaldehyde (1.1 g, 6.8 mmol) in anhydrous methanol (50 mL) was added sodium borohydride (350 mg, 9.3 mmol). The reaction mixture was stirred at room temperature for 5 hours. Saturated ammonium chloride solution (20 mL) was added. Methanol was evaporated. The resultant mixture was extracted with EtOAc (3 x 50 mL) and CH2Cl2 (1 x 50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. (1 -methyl- lH-benzimidazol-2-yl)methanol was obtained (1.1 g, 99% yield). The product was used without further purification.
With sodium tetrahydridoborate; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere; To a solution of 1-methyl- 1H-benzo[d]imidazole-2-carbaldehyde (5-5a, 150 mg, 936.49 umol, 1 eq) in THF (3 mL) was added NaBH4 (38.97 mg, 1.03 mmol, 1.1 eq) at 20C under N2. The mixture was stirred at 20C for 1 hour. LCMS showed 5-5a was comsumed completely and desired mass was detected. The reaction mixture was quenched by addition water (30 mL) at 20C. The aqueous phase was extracted with ethyl acetate (25 mL*2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (ethyl acetate: methanol = 20:1) to give 5-5b as a white solid.1H NMR (400MHz, CDCl3-d) 7.77-7.67 (m, 1H), 7.34-7.28 (m, 2H), 7.27- 7.23 (m, 1H), 4.91 (s, 2H), 3.83 (s, 3H).

  • 2
  • [ 3012-80-4 ]
  • [ 289037-48-5 ]
  • [3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
In a flask under N2, added 2.15 g (13.4 mmol) of 1-methyl-1 H-benzo[d]imidazole-2- carbaldehyde, 15 mL (107 mmol) of Et3N and 200 mg MgSO4 to a solution of 2.0 g (13.4 mmol) of (3-aza-bicyclo[3.1.0]hex-6-yl)-methanol in 50 mL of anhydrous CH2CI2 at room temperature. After 30 minutes of stirring, 4.25 g (20.1 mmol, 1.5 eq) of sodium triacetoxyborohydride was added and the suspension was stirred at room temperature for 18 hours. The suspension was diluted with CH2CI2 and washed with saturated NaHCO3 aqueous solution and brine. The organic layer was dried with sodium sulfate, filtered and stripped in vacuo to give 3.55 g light yellow solid of [3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-3-aza- bicyclo[3.1.0]hex-6-yl]-methanol, which was used without further purification. 400 MHz 1H NMR (CD3OD) δ 7.7 (d, 1 H), 7.5 (m, 1H), 7.2- 7.3 (m, 2H), 3.9 (s, 2H), 3.8 (s, 3H), 3.3 (d, 2H), 2.9 (d, 2H), 2.5 (broad d, 2H), 1.4 (m, 1 H), 1.3 (s, 2H); MS (M+1 ) 258.
  • 3
  • [ 3012-80-4 ]
  • [ 1378790-75-0 ]
  • 1-methyl-2-(6-phenethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-1H-benzoimidazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a stirred solution of 6-phenethyl-3-aza-bicyclo[3.1.0]hexane (25 mg, 0.13 mmol) in CH2CI2 (2 mL) under N2 at room temperature was added 1-Methyl-1 H-benzoimidazole-2- carbaldehyde (22 mg, 0.13 mmol), Et3N (150 uL, 1.1 mmol) and MgSO4 (5 mg). The mixture was stirred for 30 min and then Na(OAc)3BH (43 mg, 0.20 mmol) was added. After being stirred at room temperature for 12 h, the mixture was diluted with CH2CI2 (30 mL) and washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified with flash column (silica gel, 70% to 100% EtOAc in hexane) to give 26 mg thick oil, which was dissolved in 1 mL MeOH and treated with 50 uL 4N HCI in dioxane. The mixture was concentrated and triturated with ethyl ether to give 31 mg solid as the HCI salt of 1-methyl-2-(6-phenethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-1 H-benzoimidazole. MS (ESI+) for C22H25N3 m/z 332 (M+H)+.
  • 4
  • [ 2249-28-7 ]
  • [ 3012-80-4 ]
  • 1-(1-methyl-1H-benzoimidazol-2-ylmethyl)-4-(3-trifluoromethyl-phenyl)-piperidin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.25 M stock solutions of amines (II) and aldehydes (III) in DCE were prepared. When applicable, the aldehyde salt forms were neutralized by addition of 4 equivalents of DIPEA. A 0.25 M fine suspension of NaBH(OAc)3 in anhydrous DMF/ DCE mixture (20/80) was prepared. To each vial was added 0.2 mL of a solution of amine (II) follwed by 0.2 mL of a solution of aldehyde (III) and 0.5 mL of the NaBH(OAc)3 suspension to each vial. The vials were capped and shaken at room temperature for 16 h. Additional 0.5 mL of the NaBH(OAc)3 suspension was added to each vial, the vials were vortexed, capped, and shaken at room temperature for 16 h. The solvent was removed under reduced pressure. 1 mL of DMSO and 0.1 mL of water were added to each vial. The samples were vortexed for 1 h. 0.05 mL of concentrated NH4OH was added to each vial. The samples were filtered and directly submitted to HPLC purification.
  • 5
  • [ 3012-80-4 ]
  • [ 1004618-99-8 ]
  • 2-((4-(2-methoxy-4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H-benzo[d]imidazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a stirred solution of 4-(2-methoxy-4-(trifluoromethyl)phenyl)piperidine hydrochloride salt (444 mg, 1.5 mmol) in CH2CI2 under N2 at room temperature was added triethylamine (1.7 mL, 12.0 mmol), MgSO4 (20 mg) and 1-methyl-1H-benzo[d]imidazole-2- carbaldehyde (240 mg, 1.5 mmol). The reaction mixture was stirred for 30 min, then <n="79"/>NaBH(OAc)3 (477 mg, 2.25 mmol) was added. The mixture was stirred at room temperature overnight and was then diluted with methylene chloride (50 ml_) and washed with water, brine and dried with Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column with 1-5% MeOH in CH2CI2 to give 546 mg of 2-((4-(2-Methoxy-4- (trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H-benzo[d]imidazole as a white foam. The residue was dissolved in MeOH (3 ml_) and a 4N HCI solution in dioxane (0.4 mL) was added and the mixture was stirred for 10 min. The solvent was removed in vacuo to give 596 mg of 2-((4-(2-Methoxy-4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H- benzo[d]imidazole hydrochloride salt as a white solid. 400 MHz 1H NMR (CD3OD) δ (ppm) 7.75 (dd, 2H), 7.49 (m, 2H), 7.40 (d, 1 H), 7.26 (d, 1 H), 7.21 (s, 1 H), 4.73 (s, 2H), 4.03 (s, 3H), 3.91 (s, 3H), 3.76 (m, 2H), 3.20-3.30 (m, 3H), 2.05-2.20 (m, 4H); MS (m/z) 404.2.
  • 6
  • [ 3012-80-4 ]
  • cis-4-(3,4-difluorophenyl)-3-methylpiperidine hydrochloride [ No CAS ]
  • 2-[cis-4-(3,4-difluoro-phenyl)-3-methyl-piperidin-1-yl]methyl}-1-methyl-1H-benzoimidazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a stirred solution of c/s-4-(3,4-Difluoro-phenyl)-3-methyl-piperidine hydrochloride salt (2.76 g, 11.1 mmol) in CH2CI2 (50 mL) under N2 at room temperature was added triethylamine (11.5 mL), MgSO4 (1.0 g) and 1 -methyl-1 H-benzo[d]imidazole-2-carbaldehyde (1.78 g, 11.1 mmol). The reaction mixture was stirred at rt for 30 min, then NaBH(OAc)3 (3.54g, 16.7 mmol) was added. The mixture was stirred at room temperature overnight and was then diluted with methylene chloride (100 mL) and washed with water, brine and dried with Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column with EtOAc to give 2.93 g of 2-[cis-4-(3,4-Difluoro-phenyl)-3-methyl-piperidin-1-yl]methyl}-1- methyl-1 H-benzoimidazole as a racemic mixture. 400 MHz 1H NMR (CD3OD) δ (ppm) 7.80 (d, H), 7.50 (d, 1 H), 7.28 (m, 2H), 7.10 (m 1H), 7.08 (m, 1H), 6.96 (m, br, 1 H), 3.92 (s, 3H), 3.80 (s, 2H), 3.00 (m, 1H), 2.85 (m, 1 H), 2.78 (d, 1H)1 2.48 (d, 1 H), 2.20 (m, 1 H), 2.10-2.17 (m, 2H), 1.60 (d, br, 1H), 0.76 (d, 3H); MS+ (m/z) 356.1.Two enantiomers were separated using a Chiralpak AD-H column (2.1 CM x 25 CM), with 80/20 CO2/MeOH as Mobile phase at flow rate of 65 g/min to obtain two enantiomers: Example 2a (corresponding to entry 472 in table 7): 2-[Cis-4-(3,4-Difluoro- phenyl)-3-methyl-piperidin-1-yl]methyl}-1 -methyl-1 H-benzoimidazole, Enantiomer No.1 : Retention time: 6.121 min, 100% eeExample 2b (corresponding to entry 473in table 7): 2-[Cis-4-(3,4-Difluoro- phenyl)-3-methyl-piperidin-1 -yl]methyl}-1 -methyl-1 H-benzoimidazole, Enantiomer No.2: Retention time: 9.82 min, 95% ee
  • 7
  • [ 3012-80-4 ]
  • [ 3013-07-8 ]
YieldReaction ConditionsOperation in experiment
94% With hydroxylamine hydrochloride; sodium acetate; In water; at 20℃; for 2h; To a stirred suspension of 1-METHYL-1H-BENZOIMIDAZOLE-2-CARBALDEHYDE (980mg, 6. 61mmol) in H2O (10ML) was added a solution of Sodium Acetate (3. 25g, 39. 68MMOL) and Hydroxylamine hydrochloride (1. 38g, 19. 84MMOL) in 10ml of H2O. The reaction was stirred at rt for 2hr and the thick precipitate was collected by filtration, washed with water and dried under vacuum to give 1. 02g (94%) of a white solid.'H NMR (DMSO-d6) 5 12.06 (1 H, s), 8.28 (1 H, s), 7.65 (1 H, d, J = 7.5 HZ), 7.60 (1 H, d, J = 6.8Hz), 7.32 (1 H, t, J = 7.2 Hz), 7.23 (1 H, t, J = 6.8 Hz), 4.00 (3H, s). Anal. Calcd for C9H9N30 : C, 61.70 ; H, 5.18 ; N, 23.99. Found: C, 61.80 ; H, 5.23 ; N, 23.98.
91% With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; at 20℃; for 8h; To a mixture of l-methyl-l H-benzo[d]imidazole-2-carbaldehyde (2.0 g, 13 mmol) and hydroxylamine hydrochloride (1.3 g, 19 mmol) in ethanol (20 mL) was added sodium hydroxide (0.8 g, 19 mmol. The mixture was stirred at room temperature for 8 hours. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo to give compound B-150 (2.0 g, 91% yield) as a yellow solid. LCMS: (ES+) mix (M+H)+ = 176.1 , tR=0.946
With hydroxylamine hydrochloride; In neat (no solvent); for 0.0833333h;Milling; Green chemistry; General procedure: A Retsch MM200 grinder mill operating at 25 Hz frequency was used for the mechanochemical synthesis. Ball mill experiments were performed in stainless steel jar of 10 mL volume using one ball. Reactions were monitored by TLC (DC-Alufolien Aluminiumoxide 60 F254 plates (Merck) with 9:1 chloroform-methanol as the eluent) and no side products have been detected. FTIR spectra were recorded over the 4000-400 cm-1 range without baseline corrections up to 30 minutes except for compound 4a where the reaction was monitored during 90 minutes. In all reactions 100 mg of FTIR-grade KBr was added. Procedure A: in a jar, 100 mg of the carbonyl compound and equimolar amount of hydroxylamine hydrochloride were grounded together in a mill. Procedure B: (liquid assisted grinding, LAG): 100 mg of carbonyl compound, equimolar amount of hydroxylamine hydrochloride in the presence of 30 μL of methanol were grounded together in a mill. Procedure C: 100 mg of carbonyl compound, equimolar amount of hydroxylamine hydrochloride, equimolar amount of NaOH in the presence of 30 μL of methanol were grounded together in a mill.
  • 8
  • [ 661458-46-4 ]
  • [ 3012-80-4 ]
  • 3-{5-[1-(1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
79.1% With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 0.0833333h; [3-] [{5- [1- ( 1-METHYL-LH-BENZOIMIDAZOL-2-YLMETHYL)-PIPERIDIN-2-YL]- [1,] 2,4] [OXADIAZOL-3-YL}-] benzonitrile (63 mg, 79.1%) was obtained from [3- (5-PIPERIDIN-2-YL- [1,] 2,4] oxadiazol-3-yl) - benzonitrile (50.8 mg, 0.2 mmol) with [1-METHYL-2-FORMYLBENZIMIDAZOLE] (32 mg, 0.2 mmol), sodium triacetoxyborohydride (59.3 mg, 0.28 mmol) and dichloroethane (1 mL) at room temperature for 5 [MIN. 1H] NMR [(CDC13),] 8 (ppm): 8. 30 (s, 1H), 8.27 (d, 1H), 7.76 (d, 1H), 7.62 (d, 1H), 7.59 (t, 1H), 7.30 (d, 1H), 7.20 (m, 2H), 4.02 (t, 1H), 3.90 (dd & s, [SH),] 3.00 (m, 1H), 2.43 (m, 1H), 2.01 (s, 2H), 1.48-1. [88] (m, 4H).
  • 9
  • [ 3012-80-4 ]
  • [ 370594-55-1 ]
  • [ 369654-59-1 ]
YieldReaction ConditionsOperation in experiment
Synthesis Example 6-1: Synthesis of 2-(4-(N-Boc-N-2-picolylamino methyl) benzoyl)-5-((1-methylbenzimidazol-2-ylmethyl) amino) valerate 1-naphthalenemethylamide (Compound XIII-6) 50.3 mg of the compound synthesised in Synthesis Example 1-4 was dissolved in 1 ml of anhydrous methanol, and then 16.1 mg of <strong>[3012-80-4]1-methyl-2-formylbenzimidazole</strong> was added to the solution and the resultant mixture was stirred for 1.5 hours at room temperature. After the solvent was distilled off, 1 ml of anhydrous methanol and a drop of acetic acid were added to the resultant and the resultant mixture was cooled to 0C. Subsequently, 14.2 mg of sodium borohydride was added thereto and the resultant mixture was stirred for 0.5 hour at room temperature. The residue obtained by concentrating the reaction solution was purified by means of silica gel column chromatography (2.5 g, chloroform/methanol = 15/1), and 31.3 mg of the above-mentioned compound was obtained as a white solid product. MS(FAB,Pos.):m/z=740[M+1]+ 1H-NMR(500MHz,CDCl3):δ=1.43 and 1.44(9H,2s),1.52-1.63(1H,m), 1.65-1.78(1H,m),1.89-2.01(2H,m),2.68-2.83(2H,m),3.58(3H,s),3. 75(1H,d,J=14.6Hz),3.81(1H,d,J=14.6Hz),4.41and4.44(2H,2s),4.52 and 4.55(2H,2s)4.69-4.75(1H,m),4.85(1H,dd,J=14.6,5.1Hz),4.98 (1H,dd,J=14.6,5.6Hz),7.10-7.35(7H),7.36(1H,d,J=6.6Hz),7.43-7. 51(2H,m),7.52-7.60(1H,m),7.69-7.78(7H,m),7.80-7.83(1H,m),7.99 -8.01 (1H,m), 8.53 (1H,ddd,J=4.9,2.0,1.0Hz).
  • 10
  • [ 3012-80-4 ]
  • [ 645-36-3 ]
  • [ 854745-40-7 ]
YieldReaction ConditionsOperation in experiment
64% A solution of <strong>[3012-80-4]1-methyl-2-formylbenzimidazole</strong> (1 g) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 eq.) and NaCNBH3 (0.85 g, 2 eq.) at 25 C., stirred for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic phase layer was separated, washed sequentially with saturated NaHCO3 and brine, and concentrated. The residue was chromatographed on silica gel, eluting with 8% methanol/dichloromethane to give the title compound (1.2 g 64% yield).
64% With sodium cyanoborohydride; In methanol; acetic acid; at 25℃; for 1h; A solution of <strong>[3012-80-4]1-methyl-2-formylbenzimidazole</strong> (1 g) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 equivalent) and NaCNBH3 (0.85 g, 2 equivalents) at 25 C., stirred for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed sequentially with saturated NaHCO3 and brine, and concentrated. The residue was chromatographed on silica gel, eluting with 8% methanol/dichloromethane to give 1.2 g (64%) of the title compound.
64% With sodium cyanoborohydride; acetic acid; In methanol; at 25℃; for 1h; EXAMPLE 64A 2,2-dimethoxy-N-[(1-methyl-1H-benzimidazol-2-yl)methyl]ethanamine A solution of <strong>[3012-80-4]1-methyl-2-formylbenzimidazole</strong> (1 g) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 equivalent) and NaCNBH3 (0.85 g, 2 equivalents) at 25 C., stirred for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed sequentially with saturated NaHCO3 and brine, and concentrated. The residue was purified by eluding with 8% methanol/dichloromethane to give 1.2 g (64%) of the title compound.
  • 11
  • [ 3012-80-4 ]
  • [ 22483-09-6 ]
  • [ 854745-40-7 ]
YieldReaction ConditionsOperation in experiment
64% With sodium cyanoborohydride; acetic acid; In methanol; at 25℃; for 1h; Example 64A; 2, 2-dimethoxy-N-[(1-methyl-lH-benzimidazol-2-yl) methyl] ethanamine; A solution of <strong>[3012-80-4]1-methyl-2-formylbenzimidazole</strong> (lg) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 equivalent) and NaCNBH3 (0.85 g, 2 equivalents) at 25C, stirred for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed sequentially with saturated NaHC03 and brine, and concentrated. The residue was purified by eluting with 8% methanol/dichloromethane to give 1.2 g (64%) of the title compound.
  • 12
  • [ 3012-80-4 ]
  • [ 856900-35-1 ]
  • N'-cyclopentyl-N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-({8-[(1-methyl-1H-benzimidazol-2-yl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}methyl) urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% Example 6: N'-Cyclopentyl-N-[3-fluoro-4-(4-morpholinyl)phenyl]-N-({8-[(1-methyl-1H- benzimidazol-2-yl) methyl]-8-azabicyclo [3. 2.1] oct-3-yl} methyl) urea MP-Triacetoxyborohydride resin (ex Argonaut, loading 2.1 mmol/g) (0.25 g, 0.5 mmol) was added to a solution of N- (8-azabicyclo [3.2. 1] oct-3-ylmethyl)-N-cyclopentyl-N- [3- fluoro-4- (4-morpholinyl) phenyl] ureaD12 (90 mg, 0.2 mmol) and 1-methyl-2- formylbenzimidazole (38 mg, 0.24 mmol) in dry THF (0.5 ml). The mixture was shaken at room temperature for 18 h. DCM (1 ml), PS-Isocyanate scavenger resin (ex Argonaut, loading 1.53 mmol/g) (90 mg, 0.14 mmol) and PS-p-toluensulfonyl hydrazide scavenger resin (ex Aldrich, loading 2.5 mmol/g) (128 mg, 0.32) were added. Shaking was continued for 18 h and the mixture filtered. The filtrate was loaded onto a 1g SCX cartridge and washed with methanol. After elution with 2. 0M NH3 in MeOH, the solution was concentrated in vacuo. The crude was purified by mass directed prep HPLC on a Terra MS Cis 5, um column (id 30 x 75 mm) eluting with 10-90% MeCN in water containing 0. 1 % TFA (flow rate 43 ml/min). The HPLC fractions were concentrated and loaded onto a 500 mg SCX cartridge. After elution with 2. 0M NH3 in MeOH, the solution was concentrated in vacuo to afford the title compound (41 mg, 36%). Mass spectrum (API+) : Found 575 (MH+). C33H43FN602 requires 574.
  • 13
  • [ 216686-77-0 ]
  • [ 3012-80-4 ]
  • [ 259861-26-2 ]
YieldReaction ConditionsOperation in experiment
With magnesium sulfate; lithium diisopropyl amide; In tetrahydrofuran; d (+-)-6-[1-Hydroxy-1-(1-methyl-1H-benzimidazol-2-yl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione A solution of lithium diisopropylamide (3.15 mmol) in anhydrous tetrahydrofuran (5 ml) was added to a solution of 3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (500 mg) in anhydrous tetrahydrofuran (20 ml) at -78 C. After 10 minutes, 1-methylbenzimidazole-2-carboxaldehyde (600 mg) was added and the resultant solution kept at -78 C. for 1 hour. The reaction mixture was allowed to warm to ambient temperature and quenched with saturated sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate and washed with saturated sodium hydrogen carbonate and then brine, then dried over a mixture of magnesium sulfate and silica, filtered, and evaporated. Purification by HPLC over silica eluding with an isohexane:ethyl acetate gradient (4:1 to 0:1) gave the title compound (0.13 g). MS (APCI) ((M+H)+) 399; 1H NMR (CDCl3) δ 0.94 (6H, dd); 2.25-2.35 (1H, m); 3.39 (3H, s); 3.60-3.90 (2H, m); 370 (3H, s); 6.19 (1H, s); 7.18 (1H, s); 7.30-7.33 (3H, m); 7.77 (1H, dd).
  • 14
  • [ 3012-80-4 ]
  • 4-(1-methyl-3-{4-[(triphenyl-15-phosphanyl)-methyl]-phenyl}-1H-pyrazol-4-yl)-pyridine bromide [ No CAS ]
  • [ 943656-49-3 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 3h; Preparation 20 1-Methyl-2-{2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-vinyl}-1H-benzoimidazole To a solution of 4-(1-Methyl-3-(4-[(triphenyl-15-phosphanyl)-methyl]-phenyl}-1H-pyrazol-4-yl)-pyridine bromide (300 mg) in dimethyl formamide (3 mL) was added cesium carbonate (290 mg, 3 eq.) and <strong>[3012-80-4]1-Methyl-1H-benzoimidazole-2-carbaldehyde</strong> (52 mg) and the reaction mixture was heated at 40 C. for 3 h. The reaction mixture was poured into 1 N sodium hydroxide, extracted 3* chloroform, dried magnesium sulfate, filtered and concentrated. Purification via MPLC biotage chromatography eluding with 1-3% methanol/0.5% saturated ammonium hydroxide/80% ethyl acetate/hexanes provided the title compound. MS: (M+H m/z=392.0).
  • 15
  • [ 3012-80-4 ]
  • [ 603954-49-0 ]
  • [ 944555-90-2 ]
YieldReaction ConditionsOperation in experiment
A mixture of 2-[4-(aminomethyl)-l-piperidinyl]- 5-pyrimidinecarboxylic acid, ethyl ester (0.0038 mol), 1-methyl- lH-benzimidazole-2-carboxaldehyde (0.0045 mol) and magnesium sulfate (q.s.) in MeOH (80ml) was stirred at 600C overnight, then cooled back to room temperature. Sodium tetrahydroborate (0.0064 mol) was added portionwise. The mixture was stirred at room temperature overnight, then cooled back to room temperature, poured into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (Ig) was purified by column chromatography over silica gel (20-45 μm) (eluent: DCM/MeOH/NH4OH 97/3/0.3). The pure fractions were collected and the solvent was evaporated, yielding 0.32g of intermediate 8.
  • 16
  • [ 3012-80-4 ]
  • [ 1025713-02-3 ]
  • [ 1025712-61-1 ]
YieldReaction ConditionsOperation in experiment
78% Example 171 : l-fer^-Butyl-6-(l-((l-methyl-lH-benzo[dlimidazol-2-yl)methyl)azetidin-3-yl)-lH- pyrazolo[3,4-dlpyrimidin-4(5H)-one; [00320] A solution of Description 6 (80 mg, 0.283 mmol), 1 -methyl-2-carbonyl- benzimidazole (54 mg, 0.339 mmol) and acetic acid (19 mg, 18 mL, 0.311 mmol) in MeOH (2 mL) was stirred at room temperature. After 30 min sodium cyanoborohydride (36 mg, 0.566 mmol) was added and the reaction stirred at room temperature for 16 h. The reaction mixture was evaporated and partitioned between saturated sodium bicarbonate solution and DCM. The organic layer was dried over MgSθ4 and evaporated. The crude product was purified by column chromatography using EtOAc/DCM/MeOH (10:9:1) to elute impurities and then DCM/MeOH (9:1) to elute the product (86 mg, 78 %). 1H NMR (400MHz, CDCl3): δ 11.91 (IH, br s), 8.02 (IH, s), 7.98 (IH, m), 7.35 (IH, m), 7.29 (2H, m), 4.03 (2H, s), 3.86 (3H, s), 3.82 (4H, m), 3.73 (IH, m), 1.76 (9H, s). (MH+, m/z) 392.
  • 17
  • [ 3012-80-4 ]
  • [ 369655-30-1 ]
  • (S)-2-(4-((1-methylbenzimidazol-2-ylmethyl)aminomethyl)benzoylamino)-5-((1-methylbenzimidazol-2-yl)methylamino) valerate 1-naphthalenemethylamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
100.4 mg of the compound obtained in Synthesis Example 19-2 was dissolved in 1 ml of methanol, and then 1 ml of a 4 mol/l hydrochloric acid/dioxane was added to the solution and the whole was stirred for 3 hours at room temperature. On completion of the reaction, the solvent was distilled off and the residue was then dissolved in methanol, followed by neutralizing with amberlite IRA-410 and distilling the solvent off. The residue was dissolved in 1 ml of anhydrous methanol, and 53.8 mg of 1-methyl-2-formyl benzimidazole was then added to the solution, allowing the reaction thereof for 1.5 hours at room temperature. A reaction solution was concentrated and dried under a reduced pressure, followed by dissolving in 2 ml of methanol again. Subsequently, 25.6 mg of sodium cyanoborohydride was added to the solution and the whole was reacted for 0.5 hour at room temperature. On completion of the reaction, the solvent was concentrated, and the residue was then dissolved in chloroform, followed by washing with distilled water and a saturated salt solution. After the solution was dried with anhydrous sodium sulfate, the solvent was distillated off and the resulting residue was then purified by means of silica gel column chromatography (5 g, chloroform/methanol/water = 7/3/0.5). A 1 mol/l hydrochloric acid was added to the resulting compound, and the mixture was then concentrated and azeotropically co-distilled, and 28.2 mg of hydrochloride of the above-mentioned compound was obtained as a white solid product. MS(FAB,Pos.):m/z=693[M+H]+1H-NMR(500MHz,DMSO-d6):δ=1.87-1.97(4H,m),3.93(3H,s),3.97(3H,s) ,4.46(2H,s),4.55-4.62(1H,m),4.64(2H,s),4.67(2H,s),4.76(2H,d,J =5.6Hz),7.36-7.58(6H,m),7.71-7.79(7H,m),7.93-7.95(1H,m),8.01 (2H,d,J=8.5Hz),8.05-8.08(1H,m),8.73-8.76(2H,m),9.94(2H,brs).
  • 18
  • [ 3012-80-4 ]
  • [ 369655-30-1 ]
  • (S)-2-(4-((1-methylbenzimidazol-2-ylmethyl)aminomethyl)benzoylamino)-5-((1-methylpyrrol-2-ylmethyl) amino) valerate 1-naphthalenemethylamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
156.3 mg of the compound obtained in Synthesis Example 29-2 was dissolved in 2 ml of methanol, and then 2 ml of a 4 mol/l hydrochloric acid/dioxane was added to the solution, followed by stirring for 165 minutes at room temperature. On completion of the reaction, the solvent was distilled off. Subsequently, it was dissolved in 4 ml of anhydrous methanol, and then 131.1 µl of triethylamine and 62.8 mg of <strong>[3012-80-4]1-methyl-2-formylbenzimidazole</strong> were added to the solution and the whole was stirred for 12 hours at room temperature. After the solvent was distilled off, subsequently, 4 ml of anhydrous methanol was added thereto and the whole was cooled to 0C. Then, 19.8 mg of sodium borohydride was added to the solution and the whole was stirred for 30 minutes while being gradually returned to room temperature. On completion of the reaction, the solvent was distilled off and the residue was purified by means of silica gel column chromatography (10 g, chloroform/methanol = 10/1). After the resultant compound was dissolved in 2 ml of a 1 mol/l hydrochloric acid, water was distilled off. Consequently, 44.1mg of hydrochloride of the above-mentioned compound was obtained as a white-red solid product. MS(FAB,Pos.):m/z=642[M+1]+1H-NMR(500MHz,DMSO-d6):δ=1.73-1.91(4H,m),2.09(2H,br),3.64(3H,s ),3.85(3H,s),4.08-4.12(2H,m),4.38-4.43(2H,m),4.47-4.59(3H,m), 4.76-4.77(2H,m),5.98-5.99(1H,m),6.22-6.23(1H,m),6.79-6.80(1H, m),7.29-7.59(6H,m),7.60-7.73(2H,m),7.84-7.86(1H,m),7.94-8.08 (4H,m), 8.70-8.72 (2H,m), 8.96 (2H,br).
  • 19
  • [ 3012-80-4 ]
  • [ 4229-44-1 ]
  • [ 1156491-90-5 ]
  • 20
  • [ 3012-80-4 ]
  • [ 25100-12-3 ]
  • [ 1156491-80-3 ]
  • 21
  • [ 7467-35-8 ]
  • [ 3012-80-4 ]
YieldReaction ConditionsOperation in experiment
30% With Dess-Martin periodane; In dichloromethane; at 4℃; for 1h; General procedure: Dess-Martin reagent (1.1 mmol) was added to a solution of benzimidazol-2-ylmethanol 4 or 7(1 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at 4 C for 1 h prior tobeing quenched with saturated aqueous sodium thiosulfate solution (3 mL). The subsequent mixturewas extracted with methylene chloride (3 × 10 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and concentrated in vacuo to provide a crude product, which wascrystallized from methanol to give corresponding product.1-Methyl-1H-benzimidazole-2-carboxaldehyde (1) [3] was obtained as beige solid in 30%yield. M.p. 134-136C from methanol. 1H NMR (500 MHz, CDCl3) δ 4.12 (s, NMe), 7.35-7.39 (m,1Harom.), 7.43-7.48 (m, 2Harom.), 7.90 (d, 1Harom., J = 10.3 Hz), 10.09 (s, 1H, CHO). 13C NMR (125MHz, CDCl3) δ 31.2, 110.5, 122.3, 124.0, 126.8, 136.9, 142.7, 146.1, 185.0.
With manganese(IV) oxide; In ethyl acetate; at 65℃; for 1h; General procedure: A solution of 2a-2d (2 mmol), MnO2 (3.48 g, 40 mmol) was added to EtOAc (120 mL), then refluxedat 65 C for 1 h (monitored by TLC). Afterwards the solution was filtered, and concentrated in vacuoto give pure compounds 3a-3d (in 60%-76% yield) [17].
  • 22
  • [ 1632-83-3 ]
  • [ 33513-42-7 ]
  • [ 3012-80-4 ]
YieldReaction ConditionsOperation in experiment
General procedure: To a solution of 3a (161 mg, 1.20 mmol) in THF (4.0 mL) was added dropwise lithium diisopropylamide(1.93 M solution in THF/heptane/ethylbenzene, 0.68 mL, 1.3 mmol) at dry ice-acetone bath temperaturewith stirring for 1 h. To the solution was added dropwise DMF (0.10 mL, 1.3 mmol), and the reactionmixture was allowed to warm to ice-bath temperature and stirred for 30 min. Trimethyl phosphonoacetate(0.21 mL, 1.5 mmol) was added and stirring at ice-bath temperature was continued for 1 h. Aqueous 5%HCl (2 mL) and water (4 mL) were added successively and the mixture was extracted with EtOAc (10mL). The organic layer was separated and washed with water (10 mL), dried over anhydrous sodiumsulfate, and concentrated. The residual oil was subjected to column chromatography (silica gel) to give 4a(229 mg, 87%) as a white solid;
  • 23
  • [ 3256-27-7 ]
  • [ 3012-80-4 ]
YieldReaction ConditionsOperation in experiment
(b) l-Methyl-lH-benzo[d]imidazole-2-carbaldehyde[00344] To a solution of l ,2-bis(l-methyl-lH-benzo[d]imidazol-2-yl)ethane-l ,2-diol (4.9 g, 15.2 mmol) and NaI04 (3.3 g, 15.2 mmol) in water (150 mL) was added 3 N aqueous H2S04 (18 mL) dropwise. After stirring at ambient temperature overnight, the mixture was adjusted to pH 8 with aqueous Na2C03. The precipitate was collected by vacuum filtration and washed with water and ethanol. The solid was dried to give 3.11 g of the desired product. LC-MS: m/z 161 (M+H+).
  • 24
  • [ 3012-80-4 ]
  • C16H21ClN2O3 [ No CAS ]
  • 2-(((1R,5S,6R)-6-((5-chloropyridin-2-yloxy)methyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)methyl)-1-methyl-1H-benzo[d]imidazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
Prepared a 2 M stock solution of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxyiate (Preparation 1 ) in THF. Prepared 2 M stock solutions of varying phenols of a general formula (III) <n="60"/>in THF. Prepared a 0.5 M stock solution of DEAD in toluene. To each reaction vial, added 0.200 ml_ of the varying phenol followed by 0.075 mL of (1S,5R,6R)-tert-butyl 6- (hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate. Added 0.600 mL of the DEAD solution, followed by 0.750 mL of toluene. Added 140 mg of triphenylphosphine-polystyrene resin. Vials were capped and shaken at room temperature for 17 hours. Added 2.5 mL of THF to each reaction vial. The top layer was transferred to empty 6 mL SPE cartridges over collection tubes. Added 3.0 mL of THF to the reaction vials and then aspirated the top layer to the SPE cartridges over collection tubes. Transferred solutions from collection tubes to new reaction vials and evaporated. Added 0.600 mL of CH3OH followed by 0.300 mL of 4 M HCI in 1 ,4-dioxane to each reaction vial. Vials were capped and shaken at room temperature for 24 hours. The solvent was evaporated and the intermediates used without further purification in the next reaction.Prepared a 0.25 M solution of an aldehyde of general formula (V) in 1 ,2- dichloroethane. Prepared a 0.25 M solution of sodium triacetoxyborohydride in 1 ,2- dichloroethane. Added 0.600 mL of the aldehyde solution to each of the reaction vials from the step above, followed by 0.070 mL of DIPEA. Added 2.0 mL of the sodium triacetoxyborohydride solution, capped vials and shaken at room temperature for 17 hours. Added 1.0 mL of 1 ,2-dichloroethane followed by 2.0 mL of 10% NaOH. Vials were vortexed and/or shaken and removed top layer. Added 2.0 mL of 10% NH4OH, with vials shaken well and/ or vortexed. The bottom layers were aspirated to empty 6 mL SPE cartridges over tared collection tubes. Added 1.0 mL of 1 ,2-dichloroethane to the aqueous layer and aspirated the bottom layer to the SPE cartridge over the collection tubes. Evaporated solutions to dryness. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl) Alternatively, compounds of formula I can be prepared as highlighted below in method D utilizing parallel chemistry or high-speed synthesis methods.
  • 25
  • [ 3012-80-4 ]
  • [ 167484-91-5 ]
  • [ 141-75-3 ]
  • 1-butyryl-5-fluoro-1'-[(1-methyl-1H-benzimidazol-2-yl)methyl]-1,2-dihydrospiro[indole-3,4'-piperidine] [ No CAS ]
YieldReaction ConditionsOperation in experiment
A 2.0 M solution of triethylamine solution in DCE was prepared. 2.0 M stock solutions of amine (XLVII) in this mixture were prepared and sonicated for 10 min. A 0.25 M tetramethylammonium triacetoxyborohydride solution in DCE was prepared and sonicated for 10 min. 0.25 M solutions of aldehyde (III) in DCE were prepared. 1 mL of the solution of amine (XLVII) was dispensed into 2-dram vials. To each vial was added 0.8 mL of the solution of aldehyde (III), and 2.4 mL of the tetramethylammonium triacetoxyborohydride solution. The vials were capped and shaken at room temperature for 16 h. 1.5 mL of 15% NH4OH aqueous solution was added to each vial. The vials were initially slowly then more <n="87"/>vigorously vortexed, centrifuged, and allowed to stand for 2 h. The aqueous layer was discarded and the organic layers were evaporated. 1 mL of DCM and 0.25 mL of TFA was added to each vial. The vials were capped and shaken at room temperature for 16 h. The solvent was evaporated and 1 mL of toluene was added to each vial. The samples were evaporated to dryness. 2 M solution of Et3N and 0.25 M solutions of various acid chlorides in anhydrous DMA were prepared. 1 mL of the Et3N solution was added to each vial and the vials were vortexed until the solutions became clear. 0.96 of the acid chloride solution was added to the corresponding vial and the vials were capped and shaken at room temperature for 16 h. The solvent was evaporated. To each vial was added 3 mL of DCE and 2 mL of water. The vials were vortexed and centrifuged. The orranic layers were transferred into collections vial. The samples were evaporated, dissolved in 1 mL of DMSO, filtered and submitted to HPLC purification.
  • 26
  • [ 50-00-0 ]
  • [ 3012-80-4 ]
  • [ 1004619-35-5 ]
  • 5-bromo-1-methyl-1'-[(1-methyl-1H-benzimidazol-2-yl)methyl]-1,2-dihydrospiro[indole-3,4'-piperidine] [ No CAS ]
YieldReaction ConditionsOperation in experiment
5-Bromo-1 -methyl-1 '-Fd -methyl-1 H-benzimidazole-2-vϖmethvϖ-1 ,2- dihvdrospirofindole-3.4'-piperidine1 ferf-Butyl 5-Bromo-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate (36.7 mg, 0.1 mmol), paraformaldehyde (15 mg), and sodium triacetoxyborohydride (63.6 mg, 0.3 mmol) in DCE (1 mL) were shaken at room temperature overnight. The reaction was washed with 10% NH4OH (1 mL), and the biphasic mixture was loaded onto a 1mL aq. capacity Varian ChemElut cartridge. Cartridge was eluted with DCE (2 x 3 mL), and the solvent removed under a stream of N2 to give 31.8mg residue which was used directly in the next step without further purification. LC/MS (acidic gradient) shows 81 % (UV 215 nm), M+=381.0 (3.62 min). Crude intermediate was dissolved in MeOH (800 uL), 4M HCI/dioxane (200 uL) was added and the reaction shaken at room temperature for 2.5h. Solvents removed under a stream of N2. Residue dissolved in MeOH (1000 uL), loaded onto a Waters Oasis MCX cartridge (400 mg sorbent), which had been preconditioned with 1000 uL MeOH. The cartridge was washed with MeOH (5 mL), and the deprotected intermediate was eluted with 1M NH3 in MeOH (5 mL), and dried under a stream of N2. The free amine was dissolved in DCE (1 mL); 1 -methyl-1 H-benzo[d]imidazole-2-carbaldehyde (13.4 mg, 0.08 mmol) and sodium triacetoxyborohydride (53.0 mg, 0.25 mmol) were added, and the reaction was shaken at room temperature overnight. The reaction was washed with 10% NH4OH (1 mL), and the biphasic mixture was loaded onto a 1 mL aq. capacity Varian ChemElut cartridge. Cartridge eluted with DCE (2 x 3 mL), and the solvent removed under a stream of N2. Crude product was purified using preparative HPLC (TFA conditions) to give 30.7 mg white solid as the bis-TFA salt. LC/MS (acidic gradient) shows 92% (UV 215 nm)/100% (ELSD), M+=426.9 (2.05 min).
  • 27
  • C16H23NO [ No CAS ]
  • [ 3012-80-4 ]
  • 2-[4-(2-cyclobutylmethoxy-phenyl)-piperidin-1-ylmethyl]-1-methyl-1H-benzoimidazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stock solutions of amines (XXIX) (0.15 M in THF), PPh3 (0.5 M in THF), and di-t- butylazodicarboxylate (0.3 M in THF) were prepared. The vials containing alcohols of formula(XXX) was added 1.2 mL of THF and the mixtures was sonicated. To each vial was added0.667 mL of the solution of amine (XXIX)1 0.50 mL of the PPh3 solution, and 0.667 mL of the di-t-butylazodicarboxylate solution. The vials were capped and shaken at room temperature for 16 h. The solvent was evaporated under the reduced pressure and the residues were dissolved in 1 mL of MeOH. The obtained solutions were loaded onto Waters Oasis MCX cartridges (6cc/500mg) previously conditioned with 2 mL of MeOH. The vials were rinsed with1 mL of methanol and the obtained solutions were loaded on the cartridges as well. The <n="85"/>cartridges were eluted using 4.5 ml_ of 1 M NH3 in MeOH into collection vials and the solvents were removed under nitrogen at 35 C.Stock solutions of aldehyde (III) (0.25 M in DCE), and NaBH(OAc)3 (0.25 M in CHCI3) were prepared. The residue in each reaction vial was dissolved in 0.6 mL of DCE. To each vial was added 0.4 mL of the solution of aldehyde (III) and 1.2 mL of NaBH(OAc)3 solution. The vials were capped and shaken at room temperature for 16 h. 2 ml of 10% aqueous NH4OH was added to each vial and the mixtures were vortexed thoroughly. The mixtures were loaded onto Varian ChemElut cartridges and eluted with DCE (2 x 3mL) into collection vials. The solvents were removed under nitrogen at 35 C. The residues were dissolved in 1 mL of DMSO, filtered and submitted to HPLC purification.
  • 28
  • [ 3012-80-4 ]
  • [ 10272-49-8 ]
  • 1-methyl-2-((4-phenylpiperidin-1-yl)methyl)-1H-benzo[d]-imidazole [ No CAS ]
  • 29
  • [ 3012-80-4 ]
  • [ 1080-12-2 ]
  • [ 1357162-25-4 ]
  • 30
  • [ 3012-80-4 ]
  • [ 852443-61-9 ]
  • [ 1694-31-1 ]
  • [ 1369959-32-9 ]
  • 31
  • [ 3012-80-4 ]
  • [ 196929-78-9 ]
  • [ 1421236-68-1 ]
  • 32
  • [ 3012-80-4 ]
  • [ 343338-28-3 ]
  • [ 1421236-74-9 ]
  • 33
  • [ 3012-80-4 ]
  • [ 24424-99-5 ]
  • [ 2516-47-4 ]
  • [ 1429383-54-9 ]
YieldReaction ConditionsOperation in experiment
Step A. tert-Bu yl cyclopropylmethyl((l-methyl-lH-benzo[d]imidazol-2- yl)methyl)carbamate To a mixture of [1 -methyl- lH-benzo[d]imidazole-2-carbaldehyde (1.78 g, 11.11 mmol) and cyclopropylmethanamine (0.790 g, 11.1 1 mmol) was added a 2 mL of anhydrous acetonitrile and the solvent was removed under reduced pressure on a rotary evaporator. This precedure was repeated several times until a chalky solid was obtained. This was then dissolved in 100 mL of DCM, cooled to 0 C, and NaBH(OAc)3 (3.53 g, 16.67 mmol) was added in one portion. After 30 min, the mixture was re-cooled to 0 C and then triethylamine (4.65 mL, 33.3 mmol) and di-ieri-butyl dicarbonate (2.91 g, 13.34 mmol) were added. The reaction mixture was allowed to warm to ambient temperature overnight, at which time it was quenched by addition of 100 mL of water and extracted with DCM (100mLx2). The combined organic layers were dried over Na2S04, filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in acetonitrile and filtered to remove insoluble impurities. The filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 0 to 25% EtOAc/hexane) provided the title compound. Mass Spectrum (ESI) m/z = 316 (M+l).
  • 34
  • [ 3012-80-4 ]
  • [ 1080-12-2 ]
  • C20H18N2O3 [ No CAS ]
  • 35
  • [ 3012-80-4 ]
  • [ 156-87-6 ]
  • [ 1595288-49-5 ]
YieldReaction ConditionsOperation in experiment
30% With acetic acid; In tetrahydrofuran; at 20℃; for 48h;Inert atmosphere; 3-Aminopropanol (174 μl, 2.3 mmol) and acetic acid (260 μl, 4.6 mmol) are added to a solution of methyl-2-formyl benzimidazole (730 mg, 4.6 mmol) in THF anhydride (25 ml). The reaction mixture is then stirred for 48 h at ambient temperature under N2 atmosphere. After concentration of the reaction crude under vacuum, the residue is taken up with CH2Cl2 and then washed with a saturated sodium bicarbonate solution. The aqueous phase is extracted twice with dichloromethane and then the organic phases are pooled, dried over MgSO4 and concentrated. Finally, the reaction crude is purified by silica column flash chromatography (9/1 EtOAc/MeOH) to give the expected product in the form of a colorless oil (245 mg, 0.68 mmol, 30% yield). (0090) 1H NMR (400 MHz, Chloroform-d) δ=7.70 (m, 2H), 7.24-7.19 (m, 6H), 3.96 (s, 4H), 3.82 (t, J=5.8 Hz, 2H), 3.67 (s, 6H), 2.92 (t, J=5.8 Hz, 2H), 1.84 (quin, J=5.8 Hz, 2H) ppm; (0091) 13C NMR (101 MHz, Chloroform-d) δ=151.5 (2C), 141.7 (2C), 135.9 (2C), 122.9 (2C), 122.3 (2C), 119.4 (2C), 109.3 (2C), 60.8, 53.5, 51.4 (2C), 30.1 (2C), 29.5 ppm; (0092) IR (NaCl pellets): 3287, 2938, 1478, 1402, 1333, 174 cm-1.
 

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