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Structure of 387-46-2

Chemical Structure| 387-46-2

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Product Details of [ 387-46-2 ]

CAS No. :387-46-2
Formula : C7H6O3
M.W : 138.12
SMILES Code : O=CC1=C(O)C=CC=C1O
MDL No. :MFCD08061915
Boiling Point : No data available
InChI Key :DGXAGETVRDOQFP-UHFFFAOYSA-N
Pubchem ID :10285801

Safety of [ 387-46-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Computational Chemistry of [ 387-46-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 2.0
Molar Refractivity 35.88
TPSA ?

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

57.53 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.14
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

1.23
Log Po/w (WLOGP)?

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

0.91
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.

0.18
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

1.02
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.9

Water Solubility

Log S (ESOL):?

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

-1.85
Solubility 1.95 mg/ml ; 0.0141 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.

-2.04
Solubility 1.27 mg/ml ; 0.00921 mol/l
Class?

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

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

-1.17
Solubility 9.4 mg/ml ; 0.0681 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

Yes
Log Kp (skin permeation)?

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

-6.27 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)

1.0

Application In Synthesis of [ 387-46-2 ]

* 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 [ 387-46-2 ]

[ 387-46-2 ] Synthesis Path-Downstream   1~6

  • 1
  • [ 387-46-2 ]
  • [ 1446321-95-4 ]
  • [ 1446321-46-5 ]
YieldReaction ConditionsOperation in experiment
88% [0179] A mixture of 2,6-dihydroxybenzaldehyde (1.58 g, 11.47 mmol, 2 eq.) and K2C03 (2.4 g, 17.22 mmol, 3 eq.) in DMF (150 mL) was stirred at rt for 10 min. To this mixture was added 3-(chloromethyl)-2-(l-isopropyI-lH-pyrazol-5-yl)pyridine hydrochloride (1.56 g, 5.74 mmol, leq.) at rt. The mixture was heated at 50 C for 2 h, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-hydroxy-6-((2-(l- isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (1.71 g, 88%) as a pale yellow solid. NMR (400 MHz, CDC13) delta 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J= 4.8, 1.5 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.63 (d, J= 1.8 Hz, 1H), 7.49 - 7.34 (m, 2H), 6.59 (d, J = 8.5 Hz, 1H), 6.37 (d, J= 1.8 Hz, 1H), 6.29 (d, J= 8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J = 6.7 Hz, 1H), 1.50 (d, J= 6.6 Hz, 6H). LRMS (M+rf") m/z 338.1
37% [0178] A mixture of 2,6-dihydroxybenzaldehyde (1.96 g, 14.2 mmol, 2 eq.) and Cs2C03 (7.5 g, 21.3 mmol, 3 eq.) in DMF (180 mL) was stirred at rt for 30 min. To this mixture was added 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine hydrochloride (1.93 g, 7.1 mmol, leq.) at rt. The mixture was continued to stir at rt O/N, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-hydroxy-6- ((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (920 mg, 37%) as a pale yellow oil. NMR (400 MHz, CDCl3) delta 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J= 4.8,7 1.5 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.63 (d, J= 1.8 Hz, 1H), 7.49 - 7.34 (m, 2H), 6.59 (d, J = 8.5 Hz, 1H), 6.37 (d, J= 1.8 Hz, 1H), 6.29 (d, J= 8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J = 6.7 Hz, 1H), 1.50 (d, J= 6.6 Hz, 6H). LRMS (M+H+) m/z 338.1
  • 2
  • [ 387-46-2 ]
  • [ 1446321-93-2 ]
  • [ 1446321-46-5 ]
YieldReaction ConditionsOperation in experiment
37% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere; Example 8: Synthesis of Compound (I) by Mitsunobu couplingInto a 2000-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (7) (70 g, 322.18 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL). 2,6-dihydroxybenzaldehyde (9) (49.2 g, 356.21 mmol, 1.10 equiv) and PPh3 (101 g, 385.07 mmol, 1.20 equiv) were added to the reaction mixture. This was followed by the addition of a solution of DIAD (78.1 g, 386.23 mmol, 1.20 equiv) in tetrahydrofuran (200 ml) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 500 ml of H2O. The resulting solution was extracted with 3x500 ml of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1 :50-l :3) as eluent to yield the crude product. The crude product was re- crystallized from i-propanol/H2O in the ratio of 1/1.5. This resulted in 40 g (37%) of 2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)benzaldehyde as a light yellow solid. The compound exhibited a melting point of 80-82 C. MS (ES, m/z): 338.1 [M+1]. 1H NMR (300 MHz, DMSO-d6) delta 11.72(s, 1H), 10.21(s, 1H), 8.76(d, J=3.6Hz, 1H), 8.24(d, J=2.7Hz, lH),7.55(m, 3H), 6.55(m,3H) ,5.21 (s, 2H), 4.65 (m, 1H), 1.37 (d, J=5.1Hz, 6H). 1H NMR (400 MHz, CDCl3) delta 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J= 4.8, 1.5 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.63 (d, J= 1.8 Hz, 1H), 7.49 - 7.34 (m, 2H), 6.59 (d, J= 8.5 Hz, 1H), 6.37 (d, J= 1.8 Hz, 1H), 6.29 (d, J= 8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J= 6.7 Hz, 1H), 1.50 (d, J= 6.6 Hz, 6H).
37% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 22℃;Inert atmosphere; Example 8 Synthesis of Compound (I) by Mitsunobu Coupling Into a 2000-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (7) (70 g, 322.18 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL). 2,6-Dihydroxybenzaldehyde (9) (49.2 g, 356.21 mmol, 1.10 equiv) and PPh3 (101 g, 385.07 mmol, 1.20 equiv) were added to the reaction mixture. This was followed by the addition of a solution of DIAD (78.1 g, 386.23 mmol, 1.20 equiv) in tetrahydrofuran (200 ml) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 500 ml of H2O. The resulting solution was extracted with 3*500 ml of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1:50-1:3) as eluent to yield the crude product. The crude product was re-crystallized from i-propanol/H2O in the ratio of 1/1.5. This resulted in 40 g (37%) of 2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)benzaldehyde as a light yellow solid. The compound exhibited a melting point of 80-82 C. MS (ES, m/z): 338.1 [M+1]. 1H NMR (300 MHz, DMSO-d6) delta 11.72 (s, 1H), 10.21 (s, 1H), 8.76 (d, J=3.6 Hz, 1H), 8.24 (d, J=2.7 Hz, 1H), 7.55 (m, 3H), 6.55 (m, 3H), 5.21 (s, 2H), 4.65 (m, 1H), 1.37 (d, J=5.1 Hz, 6H). 1H NMR (400 MHz, CDCl3) delta 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J=4.8, 1.5 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.49-7.34 (m, 2H), 6.59 (d, J=8.5 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 6.29 (d, J=8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J=6.7 Hz, 1H), 1.50 (d, J=6.6 Hz, 6H).
  • 3
  • [ 387-46-2 ]
  • 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine dihydrochloride [ No CAS ]
  • [ 1446321-46-5 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; sodium iodide; In 1-methyl-pyrrolidin-2-one; at 40 - 50℃; A suitably equipped reactor was charged with 3-(chloromethyl)-2-(l-isopropyl-lH- pyrazol-5-yl)pyridine dihydrochloride salt (1 equivalent), sodium iodide (0.05 equivalent), sodium bicarbonate (4 equivalent), l-methyl-2-pyrrolidinone (NMP), and 2,6-dihydroxy- benzaldehyde (1 to 1.05 equiv.). The reaction mixture was heated slowly to 40 C to 50 C and stirred until the reaction was complete. Water was then added and the reaction mixture was cooled and maintained at 17 C to 25 C. When the water addition was complete, the reaction mixture was stirred at 17 C to 25 C and slowly cooled to 0C to 5C and the resulting solids were collected by filtration. The solids were washed with a 0 C to 5 C 2: 1 water/NMP solution, followed by 0 C to 5 C water. The solids were filtered and dried to give 2-hydroxy-6- ((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as Form I or a mixture of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as Form I Form I and NMP solvates.
  • 4
  • [ 387-46-2 ]
  • [ 4670-09-1 ]
  • [ 86361-55-9 ]
  • 5
  • [ 387-46-2 ]
  • [ 55876-84-1 ]
  • methyl 5-((2-formyl-3-hydroxyphenoxy)methyl)picolinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; A mixture of 2,6-dihydroxybenzaldehyde (leq) and <strong>[55876-84-1]methyl 5-(bromomethyl)picolinate</strong> (leq) was dissolved in anhydrous N,N-Dimethylformamide (DMF). Anhydrous potassium carbonate (K2CO3) (l .2eq) was added to this mixture and the reaction was stirred at room temperature for 4 hours. The solvent was then evaporated and the reaction mixture extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and the solvent evaporated. The crude product was purified using SiO2 column chromatography and eluted with the solvent system EtOAc: hexanes = 6: 1 to obtain pure product as white powder with a yield of 54%. IR (Diamond, cm-1): 2954, 1731, 1679, 1644, 1618, 1574, 1458, 1440, 1392, 1357, 1289, 1249, 1 177, 1 144, 1 122; 1H-NMR (400 MHz, DMSO-d6): 5 1 1.74 (s, 1H), 10.37 (s, 1 H), 8.86 (s, 1 H), 8.12 (m, 2H), 7.54 (t, J = 8.4 Hz, 1H), 6.72 (d, J = 8.32 Hz, 1H), 6.56 (d, ./ = 8.4 Hz, 1H), 5.40 (s, 2H), 3.89 (s, 3H); 13C-NMR (100 MHz, DMSO-d6): d 193.83, 162.42, 160.69, 148.72, 147.01 , 138.64, 136.32, 135.91, 135.78, 124.64, 109.79, 103.37, 67.31, 52.39. MS (ESI) m/z found 310.08 (M+Na)+, Calculated 301.2940 [M]+. The purity of the compound was checked by HPLC and was found to be 99% pure.
  • 6
  • [ 387-46-2 ]
  • [ 116986-09-5 ]
  • methyl 3-((2-formyl-3-hydroxyphenoxy)methyl)picolinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; A mixture of 2,6-dihydroxybenzaldehyde (leq) and <strong>[116986-09-5]methyl 3-(bromomethyl)picolinate</strong> (leq) was dissolved in anhydrous N,N-Dimethylformamide (DMF). Anhydrous potassium carbonate (K2CO3) ( 1 2eq) was added to this mixture and the reaction was stirred at room temperature for 4 hours. The solvent was then evaporated and the reaction mixture extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and the solvent evaporated. The crude product was purified using SiO2 column chromatography and eluted with the solvent system EtOAc: hexanes = 6: 1 to obtain pure product as pale yellow powder with a yield of 54%. IR (Diamond, cm-1): 3092, 2923, 2851, 1774, 1712, 1632, 1599, 1566, 1515, 1478, 1366, 1276, 1231 , 1 180, 1 136, 1072; 1H-NMR (400 MHz, DMSO-d6): d 1 1.72 (s, 1H), 10.32 (s, 1 H), 8.65 (dd, .7= 4.64, 1.52 Hz, 1H), 8.22 (m, 1 H), 7.66 (dd, J= 7.88, 4.64 Hz, 1 H), 7.54 (t, J= 8.4 Hz, 1H), 6.66 (d, T = 8 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 5.51 (s, 2H), 3.84 (s, 3H), 13C-NMR (100 MHz, DMSO-d6): d 193.59, 166.09, 162.46, 160.68, 148.53, 146.54, 138.72, 136.83, 132.78, 126.44, 1 10.74, 109.79, 103.26, 67.04, 52.35. MS (ESI) m/z found 310.08 (M+Na)+, Calculated 301.2940 [M]+. The purity of the compound was checked by HPLC and was found to be 100% pure.
 

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Technical Information

• Acidity of Phenols • Alkyl Halide Occurrence • Barbier Coupling Reaction • Baylis-Hillman Reaction • Benzylic Oxidation • Birch Reduction • Blanc Chloromethylation • Bucherer-Bergs Reaction • Chan-Lam Coupling Reaction • Clemmensen Reduction • Complex Metal Hydride Reductions • Corey-Chaykovsky Reaction • Corey-Fuchs Reaction • Electrophilic Substitution of the Phenol Aromatic Ring • Etherification Reaction of Phenolic Hydroxyl Group • Fischer Indole Synthesis • Friedel-Crafts Reaction • Grignard Reaction • Halogenation of Phenols • Hantzsch Dihydropyridine Synthesis • Henry Nitroaldol Reaction • Horner-Wadsworth-Emmons Reaction • Hydride Reductions • Hydrogenolysis of Benzyl Ether • Julia-Kocienski Olefination • Knoevenagel Condensation • Leuckart-Wallach Reaction • McMurry Coupling • Meerwein-Ponndorf-Verley Reduction • Mukaiyama Aldol Reaction • Nozaki-Hiyama-Kishi Reaction • Oxidation of Phenols • Passerini Reaction • Paternò-Büchi Reaction • Pechmann Coumarin Synthesis • Petasis Reaction • Pictet-Spengler Tetrahydroisoquinoline Synthesis • Preparation of Aldehydes and Ketones • Preparation of Alkylbenzene • Preparation of Amines • Prins Reaction • Reactions of Aldehydes and Ketones • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reformatsky Reaction • Reimer-Tiemann Reaction • Schlosser Modification of the Wittig Reaction • Schmidt Reaction • Stetter Reaction • Stobbe Condensation • Tebbe Olefination • Ugi Reaction • Vilsmeier-Haack Reaction • Wittig Reaction • Wolff-Kishner Reduction

Categories

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[ 387-46-2 ]

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