474432-56-9|Methyl 5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate| Ambeed

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Quality Control of [ 474432-56-9 ] Purity: 95% SDS Specification

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Product Details of [ 474432-56-9 ]

CAS No. :	474432-56-9
Formula :	C₁₀H₁₀N₂O₃
M.W :	206.20
SMILES Code :	O=C(OC)C1=C2C=C(C=CN2N=C1)CO
MDL No. :	MFCD16987697
InChI Key :	KSBXLXBYELWDNC-UHFFFAOYSA-N
Pubchem ID :	11030983

Safety of [ 474432-56-9 ]

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

Computational Chemistry of [ 474432-56-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	9
Fraction Csp3	0.2
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	52.6
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	63.83 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.95
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.03
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.46
Log P_o/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.	0.78
Log P_o/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	0.61
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.76

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.38
Solubility	8.53 mg/ml ; 0.0414 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.	-0.92
Solubility	24.6 mg/ml ; 0.119 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	-2.0
Solubility	2.07 mg/ml ; 0.01 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.	-7.54 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	0.0
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)	1.81

Application In Synthesis of [ 474432-56-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 474432-56-9 ]

[ 474432-56-9 ] Synthesis Path-Downstream 1~35

1
[ 922-67-8 ]
1-amino-4-hydroxymethyl-pyridinium; methanesulfonate [ No CAS ]
[ 474432-56-9 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4594 - 4597.

2
[ 474432-56-9 ]
[ 474432-57-0 ]

Yield	Reaction Conditions	Operation in experiment
69%	With hydrogen bromide; at 120.0℃; for 12.0h;	A mixture of compound B-246 (2.0 g, 9.7 mmol) in 40% hydrobromic acid (20 mL) was heated to 120 C and stirred for 12 hours. On completion, the mixture was concentrated, neutralized with sodium carbonate, and extracted with dichloromethane (3 chi 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography (dichloromethane: methanol = 100: 1-10: 1 ) to give compound B-247 (1.0 g, 69% yield) as a yellow solid. LCMS: (ES+ ) m/z (M+H)+ = 149.0, tR = 1.146
60%		5-Hydroxymethylpyrazolo[1,5-a]pyridine (C4e); A mixture of 402 mg (1.95 mmol) methyl 5-hydroxymethylpyrazolo[1,5-a]pyridine-3-carboxylate (C3d) and 13.6 ml sulphuric acid (40%) was refluxed for 3 hrs and neutralized with 5N NaOH solution after cooling to room temperature. The solution was extracted with dichloromethane, the organic layers were dried with Na2SO4, evaporated and purified by flash-chromatography (EtOAc). Yield: 289 mg (60 %) yellow solid. Mp.: 47C. MS (EI): m/z 148 (M)+. IR (NaCl) v (cm-1): 3335; 2849; 1648; 1439; 1339; 1054; 774. 1H NMR (CDCl3, 360 MHz) delta (ppm): 2.12 (br s, 1H, OH); 4.70 (s, 2H, CH2); 6.46 (dd, J = 2.2 Hz, 0.8 Hz, 1H, H-3); 6.71 (dd, J = 7.2 Hz, 1.7 Hz, 1 H, H-6); 7.48 (dd, J = 1.7 Hz, 0.8 Hz, 1 H, H-4); 7.92 (d, J = 2.2 Hz, 1H, H-2); 8.40 (d, J = 7.2 Hz, 1 H, H-7).
		A suspension of methyl 5-(hydroxymethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylate Y-6 (1.9 g, 9.1 mmol ) in 40% H2S04 was stirred at 80C for 24 h, then neutralized with 3N NaOH to pH=7-8. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography to afford the title compound (1.1g). MS (m/z): 149(M+1 ) +.

Pyrazolo[1,5-a]pyridin-5-ylmethanol (Y-7) A suspension of methyl 5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate Y-6 (1.9 g, 9.1 mmol) in 40% H2SO4 was stirred at 80 C. for 24 h, then neutralized with 3N NaOH to pH=7-8. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford the title compound (1.1 g). MS (m/z): 149 (M+1)+.

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4594 - 4597.
[2]Patent: WO2015/66371,2015,A1 .Location in patent: Paragraph 00490-00491.
[3]Patent: EP1972628,2008,A1 .Location in patent: Page/Page column 30.
[4]Patent: WO2011/79804,2011,A1 .Location in patent: Page/Page column 44.
[5]Patent: US2012/245178,2012,A1 .Location in patent: Page/Page column 27.
[6]Journal of Medicinal Chemistry,2014,vol. 57,p. 7577 - 7589.

3
[ 474432-56-9 ]
[ 474432-59-2 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4594 - 4597.
[2]Patent: WO2015/66371,2015,A1 .

4
[ 474432-56-9 ]
[ 104468-87-3 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4594 - 4597.

5
[ 474432-56-9 ]
pyrazolo[1,5-a]pyridine-5-carboxylic acid methyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4594 - 4597.

6
[ 474432-56-9 ]
pyrazolo[1,5-<i>a</i>]pyridine-5-carboxylic acid {4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butyl}-amide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4594 - 4597.

7
[ 876379-84-9 ]
[ 922-67-8 ]
[ 474432-56-9 ]

References: [1]Patent: WO2006/15737,2006,A1 .Location in patent: Page/Page column 53.

8
[ 474432-56-9 ]
methyl 5-formylpyrazolo[1,5-a]pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With manganese(IV) oxide; In dichloromethane; at 20℃; for 12.0h;	A solution of methyl 5-(hydroxymethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylate (prepared by the method of Bettinetti, L.; Schlotter, K.; Hbner, H.; Gmeiner, P. J. Med. Chem., 2002, 45, 21, 4594-4597)(0.110 g, 0.538 mmol) in methylene chloride (2.0 mL) was treated with manganese dioxide (0.460 g, 5.38 mmol) at ambient temperature. Following stirring for 12 h, the solution was filtered, concentrated in vacuo, and purified via flash column chromatography (10% methanol in dichloromethane) to afford the title compound as a white solid (0.111 g, 100%). 1H NMR (400 MHz, DMSO-Cf6) δ ppm 10.1 (s, 1 H), 8.70 (s, 1 H), 8.62 (d, J=7.1 Hz, 1 H), 8.52 (s, 1 H), 7.47 (dd, J=7.1, 1.8 Hz, 1 H),4.00 (s, 3 H). MS(ES+) m/e 205 [M+H]+.

References: [1]Patent: WO2007/56683,2007,A2 .Location in patent: Page/Page column 22.

10
[ 586-95-8 ]
[ 474432-56-9 ]

References: [1]Patent: WO2011/79804,2011,A1 .
[2]Patent: US2012/245178,2012,A1 .
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 7577 - 7589.
[4]Patent: WO2015/66371,2015,A1 .

11
[ 117423-41-3 ]
[ 474432-56-9 ]

References: [1]Patent: WO2011/79804,2011,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 7577 - 7589.

12
[ 1313726-18-9 ]
[ 474432-56-9 ]

References: [1]Patent: WO2011/79804,2011,A1 .

13
[ 1313726-19-0 ]
[ 474432-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 0.166667h;	To a solution of methyl 5-((tert-butyldimethylsilyloxy)methyl)pyrazolo[1 ,5-a]pyridine-3- carboxylate Y-5 (2.9 g, 9.1 mmol) in dry THF (20 mL) was added TBAF (3.5 g, 13.7 mmol).The reaction mixture was stirred at room temperature for 10 mins, then treated with ethyl acetate. The resulting mixture was washed with brine, dried over Na2S04 and concentrated to afford the title compound (1.9 g).
	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 0.166667h;Product distribution / selectivity;	Methyl 5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (Y-6) To a solution of methyl 5-((tert-butyldimethylsilyloxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate Y-5 (2.9 g, 9.1 mmol) in dry THF (20 mL) was added TBAF (3.5 g, 13.7 mmol). The reaction mixture was stirred at room temperature for 10 mins, then treated with ethyl acetate. The resulting mixture was washed with brine, dried over Na2SO4 and concentrated to afford the title compound (1.9 g).

References: [1]Patent: WO2011/79804,2011,A1 .Location in patent: Page/Page column 44.
[2]Patent: US2012/245178,2012,A1 .Location in patent: Page/Page column 27.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 7577 - 7589.

14
[ 592-55-2 ]
[ 474432-56-9 ]
[ 1355460-21-7 ]

Yield	Reaction Conditions	Operation in experiment
18%	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at 0 - 70℃;	To a solution of 9 (62 mg, 0.3 mmol) and 2-bromoethyl ethyl ether (0.2 mL, 1.8 mmol) in dry THF (2.5 mL) was added dropwise KHMDS (1.8 mL, 0.5 M in toluene, 0.9 mmol) at 0 C. After being stirred at ambient temperature for 2 h, the mixture was heated to 70 C over night. After being cooled to room temperature the mixture was treated with water and extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4. After evaporation the crude product was purified by flash chromatography (hexane/EtOAc 3:2) to give 11a in 18% yield (15 mg). APCI-MS: m/z 279 (M++1); 1H NMR: (CDCl3, 600 MHz) δ (ppm): 1.24 (t, J = 7.0 Hz, 3H), 3.56 (q, J = 7.0 Hz, 2H), 3.64-3.67 (m, 2H), 3.68-3.71 (m, 2H), 3.91 (s, 3H), 4.67 (s, 2H), 7.01 (dd, J1 = 7.0 Hz, J2 = 2.0 Hz, 1H), 8.08-8.11 (m, 1H), 8.38 (s, 1H), 8.46-8.50 (m, 1H); 13C NMR: (CDCl3, 90 MHz) δ (ppm): 15.2, 51.2, 66.8, 69.9, 70.2, 72.0, 103.5, 113.4, 116.6, 129.2, 139.1, 140.7, 145.1, 163.9.

References: [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 455 - 466.

15
[ 474432-56-9 ]
[ 1355460-22-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 455 - 466.

16
[ 474432-56-9 ]
[ 1355460-23-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With phosphorus tribromide; In dichloromethane; at 0 - 20℃;	A solution of 9 (124 mg, 0.6 mmol) in CH2Cl2 (2 mL) was cooled to 0 C. PBr3 (0.11 mL, 1.2 mmol) was added dropwise and the mixture was stirred at room temperature over night. After evaporation of the solvent the crude product was treated with a saturated solution of NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (hexane/EtOAc 3:1) yielded pure 13 (118 mg, 90%). EI-MS: m/z 269 (M+); 1H NMR: (CDCl3, 600 MHz) δ (ppm): 3.96 (s, 3H), 4.56 (s, 2H), 7.02 (dd, J1 = 7.0 Hz, J2 = 2.0 Hz, 1H); 8.18 (dd, J1 = 2.0 Hz, J2 = 1.0 Hz, 1H), 8.43 (s, 1H), 8.52 (dd, J1 = 7.0 Hz, J2 = 1.0 Hz, 1H); 13C NMR: (CDCl3, 150 MHz) δ (ppm): 31.4, 51.3, 104.3, 114.7, 118.3, 129.5, 137.6, 140.4, 145.4, 163.6; IR: (NaCl) ν (cm-1): 2359, 1691, 1643, 1536, 1367, 1274, 1243, 1049, 778.

References: [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 455 - 466.

17
[ 474432-56-9 ]
[ 1355460-33-1 ]

References: [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 455 - 466.

18
[ 474432-56-9 ]
[ 1355460-40-0 ]

References: [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 455 - 466.

19
[ 474432-56-9 ]
[ 1355460-41-1 ]

References: [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 455 - 466.

20
[ 474432-56-9 ]
[ 1355460-54-6 ]

References: [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 455 - 466.

21
[ 474432-56-9 ]
[ 1355460-28-4 ]

References: [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 455 - 466.

22
[ 474432-56-9 ]
[ 1355460-55-7 ]

References: [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 455 - 466.

23
1-amino-4-((tert-butyldimethylsilyloxy)methyl)pyridinium 2,4-dinitrophenolate [ No CAS ]
[ 474432-56-9 ]