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Chemical Structure| 33631-09-3

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Product Details of [ 33631-09-3 ]

CAS No. :33631-09-3
Formula : C6H8N2O
M.W : 124.14
SMILES Code : NC1=C(C=CN=C1)OC
MDL No. :MFCD07374959
Boiling Point : No data available
InChI Key :STWMPIWLSQKHSJ-UHFFFAOYSA-N
Pubchem ID :5200343

Safety of [ 33631-09-3 ]

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

Computational Chemistry of [ 33631-09-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.17
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 35.13
TPSA ?

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

48.14 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.22
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

0.14
Log Po/w (WLOGP)?

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

0.68
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.

-0.48
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

0.64
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.44

Water Solubility

Log S (ESOL):?

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

-1.13
Solubility 9.3 mg/ml ; 0.075 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.

-0.71
Solubility 24.3 mg/ml ; 0.196 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

-1.75
Solubility 2.21 mg/ml ; 0.0178 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

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.

-6.96 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

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)

1.38

Application In Synthesis of [ 33631-09-3 ]

* 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 [ 33631-09-3 ]

[ 33631-09-3 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 31872-62-5 ]
  • [ 33631-09-3 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 2585.81 Torr; for 6h; EXAMPLE 93; Synthesis of 4-Hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-b]pyridine-2-yl)-amide; Step 1: To a mixture of <strong>[31872-62-5]4-Methoxy-3-nitropyridine</strong> (5.0 g, 32.44 mmole) in ethanol (100 mL) was added 10 % palladium on carbon catalyst (200 mg). The resulting mixture was allowed to shake under a hydrogen atmosphere (50 psi) for 6 h. at room temperature. TLC (50% ethyl acetate/hexane) indicated complete consumption of starting material. Filtration through celite to remove the catalyst and concentration gave 3-Amino4 methoxypyridine (4.0 g, 32.44 mmol, 100% yield) as dark red oil.
100% With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; under 2585.81 Torr; Step 1: 4-methoxypyridin-3-amineA solution of 4-methoxy -3-nitropyridine (100 g, 0.65 mol, Ouhe) and 10% Pd/C (10 g) in MeOH (2 L) was stirred under 50 psi of hydrogen. The reaction mixture was stirred at rt overnight. The mixture was filtered and concentrated in vacuo to afford 4-methoxypyridin-3- amine (82.1 g, quantitative) as a yellow solid.
99% With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 48h; Example 26Synthesis of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amineThe compound was synthesized according to Method A.A mixture of 0.475 g (3.08 mmol) of <strong>[31872-62-5]4-methoxy-3-nitropyridine</strong> (Org. Process Res. Dev. 2004, 8, 903-908) and 0.301 g (2.84 mmol) of 10% palladium on carbon in ethanol (30 mL) was stirred under an atmosphere of hydrogen for 48 hrs. The catalyst was removed by filtration through a pad of celite, and the solvent was removed to give 0.380 mg (99%) of 3-amino-4-methoxypyridine as a pink powder, which was used in the next step without further purification: 1H NMR (DMSO-d6) delta8.09 (dd, J=6.4, 1.2 Hz, 1H), 7.93 (d, J=1.2 Hz, 1H), 7.36 (d, J=6.4 Hz, 1H), 6.01 (br s, 2H), 4.06 (s, 3H).To a solution of 0.134 g (1.08 mmol) of 3-amino-4-methoxypyridine in THF (3 mL) was added 0.5 mL of butyllithium (2.5 M solution in hexanes), and the mixture was stirred for 15 min. A solution of 0.133 g (0.36 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried, and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (1:1) and then with CH2Cl2/EtOAc (2:3) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.078 g (48% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 161-163 C.; 1H NMR (DMSO-d6) delta9.43 (br s, 1H), 8.61-8.37 (m, 3H), 7.83-7.81 (m, 2H), 7.41 (br s, 2H), 7.20 (d, J=5.6 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 4H), 3.71 (s, 4H); Anal. Calcd. for C21H20F2N8O2: C, 55.5; H, 4.4; N, 24.7. Found: C, 55.5; H, 4.4; N, 24.5%.
44% With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; under 760.051 Torr; for 10h; To a solution of <strong>[31872-62-5]4-methoxy-3-nitropyridine</strong> (2.5 g, 16.2 mmol) in MeOH (50 mL) was added Pd/C 10% wt/wt (0.5 g) and the mixture was stirred under 1 atm H2 for 10 hours at room temperature. The reaction mixture was filtered through celite and filtrate was concentrated. The crude residue was purified by flash chromatography (0-10% MeOH/CH2Cl2) to give compound 16 (0.875 g, 44%). 1H NMR (400 MHz, DMSO-D6) delta 7.83 (s, 1H) 7.70 (d, 1H) 6.79 (d, 1H) 4.79 (s, 2H) 3.79 (s, 3H).
With hydrogen;palladium 10% on activated carbon; In methanol; under 2068.65 Torr; for 5h; A mixture of <strong>[31872-62-5]4-methoxy-3-nitro-pyridine</strong> (19.2 g, 0.13 mol) and Pd/C (10%, 1.5 g) in MeOH (150 mL) is hydrogenated at 40 psi for 5 h or until no more ¾ is consumed. The mixture is filtered through Celite, and the filtrate is concentrated in vacuo. The residue is dissolved in CH2CI2, and the resulting solution is dried over MgS04, filtered, and concentrated in vacuo to yield 15.0 g of the product as a yellow liquid. 1H NMR (CDC13, 300 MHz) delta 8.00 (s, 1H), 7.98 (d, J= 5.5, 1H), 6.70 (d, J= 5.4, 1H) 3.90 (s, 3H), 3.71 (br s, 2H). LC Rt: 0.57 min; LCMS m/z 125 (M+l, 100%).
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 24h; to a solution of compound 13-1 (10.0 g, 64.9 mmol) in EtOH (400 mL) was added 10% Pd/C (w/w) (4.60 g). The reaction mixture was allowed to stir at rt under an atmosphere of ¾ for 24 hrs. Subsequently, the reaction mixture was filtered through Celite545 and the filtered cake was washed with EtOAc (100 mL x 3). The filtrate was concentrated and the residue was dried in vacuo to give crude compound 13-2 (8.0 g, 99% yield) as a dark red oil, which was used for the next step without further purification. LC-MS (ESI): m/z 125 [M+H]+.

  • 2
  • [ 33631-09-3 ]
  • [ 109613-97-0 ]
YieldReaction ConditionsOperation in experiment
82% To a solution of 4-methoxy-pyridin-3-ylamine (6.76 g, 54.5 mmol) in cone. HC1 (50 mL) is added Br2 (3.36 mL, 65.4 mmol) dropwise over a 30 s period. This mixture is stirred at rt for 1 h,and then heated at 55 C overnight. The mixture is cooled to rt, and then poured into ice. Cone. NH4OH is added until the pH of the solution is basic. The resulting suspension is partitioned between H20 and EtOAc. The two layers are separated, and the aqueous layer is extracted with EtOAc (2X). The combined organic layers are washed with H20 and brine, dried over MgS04, filtered, and concentrated in vacuo. The crude material is purified on silica gelwith EtOAc/MeOH (lOO/o to 80/20) as elant to yield 9.18 g (82%) of the product as a white powder. 1H NMR (CDC13, 300 MHz) 7.75 (d, J= 5.3, 1H), 6.68 (d, J(br s, 2H), 3.91 (s, 3H). LC Rt: 0.89 min; LCMS m/z 203 (M+l, 100%).
77% With N-Bromosuccinimide; trifluoroacetic acid; at 20℃; The solution of 4-methoxypyridin-3-amine (3.1 g, 24.97 mmol) in TFA (38.5 ml, 499 mmol) was stirred at ice bath temperature and to the mixture was added NBS (4.89 g, 27.5 mmol) in several batches. The reaction mixture was stirred at room temperature over night. The reaction mixture was concentrated in vacuo and the residue was diluted with saturated NaHCO3 solution and ethyl acetate. The organic layers (twice extracts) were combined and washed with saturated NaHCO3 solution, dried over MgSO4. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography. The product was eluted with 0-20% ethyl acetate in hexane to give the desired product as a white solid (3.9 g, 77%); HPLC: RT=0.47 min (H2O/ACN with 0.05% TFA, Waters Acquity SDS C18, 2.1×50 mm, 1.7-mum particles, gradient=1.8 min, wavelength=220 nm); MS (ES): m/z=202.8, 204.8 [M+H]+; 1H NMR (400 MHz, CDCl3) delta ppm 7.75 (d, J=5.5 Hz, 1H), 6.69 (d, J=5.5 Hz, 1H), 4.11 (d, J=6.2 Hz, 2H), 3.92 (s, 3H).
2.74 g With hydrogenchloride; bromine; In water; at 20 - 55℃; To a solution of 4-methoxypyridin-3-amine (purchased from Ark Pharm Inc.), (3 g) in concentrated HCl (22.17 mL) was added bromine (1.49 mL) dropwise over a 30 s period and the mixture stirred at rt for 1 h and then at 55 C. over the weekend. The reaction mixture was allowed to cool to rt and then poured into ice (250 g). Concentrated NH4OH was added until the pH of the solution was basic (pH ?9). The resulting solution was then partitioned between H2O and EtOAc and the two layers separated. The aqueous layer was extracted with EtOAc (2*) and the combined organic layers washed with water and brine, dried (MgSO4), filtered and evaporated under vacuum to give a solid which was dissolved in DCM and purified by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL/min, gradient 0-20% EtOAc in n-hexane) to give the desired product (2.74 g). LCMS: m/z 203.37 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 3.93 (s, 3H) 3.95-4.60 (br. s., 2H) 6.69 (d, J=5.4 Hz, 1H) 7.76 (d, J=5.3 Hz, 1H)
2.74 g With hydrogenchloride; bromine; In water; at 20 - 55℃; To a solution of 4-methoxypyridin-3-amine (purchased from Ark Pharm Inc.), (3 g) in concentrated HCl (22.17 mL) was added bromine (1.49 mL) dropwise over a 30 s period and the mixture stirred at rt for 1 h and then at 55 C. over the weekend. The reaction mixture was allowed to cool to rt and then poured into ice (250 g). Concentrated NH4OH was added until the pH of the solution was basic (pH ?9). The resulting solution was then partitioned between H2O and EtOAc and the two layers separated. The aqueous layer was extracted with EtOAc (2*) and the combined organic layers washed with water and brine, dried (MgSO4), filtered and evaporated under vacuum to give a solid which was dissolved in DCM and purified by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL/min, gradient 0-20% EtOAc in n-hexane) to give the desired product (2.74 g). LCMS: m/z 203.37 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 3.93 (s, 3H) 3.95-4.60 (br. s., 2H) 6.69 (d, J=5.4 Hz, 1H) 7.76 (d, J=5.3 Hz, 1H)

 

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Technical Information

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