158671-29-5|N,2-Dihydroxy-4-methylbenzamide| Ambeed

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Quality Control of [ 158671-29-5 ] Purity: 97% SDS Specification

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Product Details of [ 158671-29-5 ]

CAS No. :	158671-29-5
Formula :	C₈H₉NO₃
M.W :	167.16
SMILES Code :	O=C(NO)C1=CC=C(C)C=C1O
MDL No. :	MFCD09944456
InChI Key :	GWUYSOZDSVVSQU-UHFFFAOYSA-N
Pubchem ID :	23021540

Safety of [ 158671-29-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H312-H332
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P330-P363-P501

Computational Chemistry of [ 158671-29-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	3.0
Molar Refractivity	42.35
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	69.56 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.52
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	2.25
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.82
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.	0.88
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	0.41
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.18

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.53
Solubility	0.491 mg/ml ; 0.00294 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.	-3.35
Solubility	0.0752 mg/ml ; 0.00045 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	-1.63
Solubility	3.94 mg/ml ; 0.0236 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.	-5.72 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	2.0 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)	1.27

Application In Synthesis of [ 158671-29-5 ]

* 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.

Upstream synthesis route of [ 158671-29-5 ]
Downstream synthetic route of [ 158671-29-5 ]

[ 158671-29-5 ] Synthesis Path-Upstream 1~1

1
[ 158671-29-5 ]
[ 66571-26-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 0.533333 h; Inert atmosphere	General procedure: Salicylhydroxamic acid 1a (77 mg, 0.5 mmol, 1 equiv) was dissolved in anhydrous THF (7 mL) under an inert (N₂) atmosphere. Triphenylphosphine (164 mg, 0.625 mmol, 1.25 equiv) was then added. After 2 min, DIAD (123 lL, 0.625 mmol, 1.25 equiv) was added dropwise. TLC (Hex/EtOAc, 1:3) after 30 min revealed the reaction was complete. The THF was removed in vacuo. The residue was partitioned between 0.1 M NaOH (50 mL)and CH₂Cl₂ (100 mL). The organic layer was separated, then the aqueous layerwas washed a further three times with CH₂Cl₂ (100 mL). The aqueous layer was acidified with 1 M HCl (10 mL), then extracted into CH₂Cl₂ (2 100 mL),washed with brine (50 mL), dried (Na₂SO₄), filtered and concentrated to yield the 3-hydroxybenzisoxazole 2a.
56%	Stage #1: With Carbonyldiimidazole In tetrahydrofuran for 0.5 h; Heating / reflux Stage #2: With triethylamine In tetrahydrofuran for 0.333333 h; Heating / reflux	A 50 ml round-bottom flask equipped with a stir bar under a dry nitrogen atmosphere was charged with 2-N-Dihydroxy-4-methyl-benzamide (331 mg, 2.0 mmole, 1.0 eq) and carbonyldiimidazole (1.0 g, 6.0 mmoles, 3.0 eq) followed by dry THF (20 ml). The reaction mixture was stirred at reflux for 30 minutes and then neat TEA (415 μL, 3.0 mmoles, 1.5 eq) was added. The reaction mixture was refluxed for additional 20 hrs, cooled to room temperature and excess THF was removed in vacuo. The residue was dissolved in EtOAc, extracted with aqueous HCl (1.0M/H₂O), the organic layer was dried with MgSO₄, filtered and excess solvent from the filtrate was removed in vacuo. Purification of the crude product by flash chromatography (silica gel, 0percent-->40percent gradient of 2percent AcOH/EtOAc in hexanes) provided 167 mg (56percent) as a white solid. (¹H DMSO-d₆, 400 MHz) δ 12.19 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.34 (sm 1H), 7.12 (d, J=8.0 Hz, 1H), 2.07 (s, 3H); (¹³C DMSO-d₆, 100 MHz) δ 165.09, 163.59, 141.18, 124.588, 120.76, 112.08, 109.80, 21.33.

References: [1] Tetrahedron Letters, 2016, vol. 57, # 48, p. 5301 - 5303.
[2] Patent: US2005/143434, 2005, A1, . Location in patent: Page/Page column 9.
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8541 - 8554.
[4] Patent: EP1988085, 2008, A1, . Location in patent: Page/Page column 29-30.
[5] Journal of Medicinal Chemistry, 2008, vol. 51, # 12, p. 3357 - 3359.
[6] Patent: EP1445249, 2004, A1, . Location in patent: Page 119.

[ 158671-29-5 ] Synthesis Path-Downstream 1~16

1
[ 4670-56-8 ]
[ 158671-29-5 ]

Yield	Reaction Conditions	Operation in experiment
99%		A 250 ml round-bottom flask equipped with a stir bar was charged with hydroxylamine hydrochloride (3.5 g, 50.0 mmoles, 25.0 eq) followed by H2O (35 ml) and by an aqueous solution of NaOH (3.0M/H2O, 38 ml, 114 mmoles, 57.0 eq). In a separate flask, the crude 2-Hydroxy-4-methyl-benzoic acid methyl ester (332 mg, 2.0 mmoles, 1.0 eq) was dissolved in dioxane and added dropwise to the above solution. The reaction mixture was stirred at room temperature for 20 hrs, cooled to 0 C. on an ice bath and neutralized to pH=5 (pH paper strips) with conc. aqueous HCl (10.0M/H20). The reaction was allowed to warm to room temperature, EtOAc was added, the crude product was partitioned in a separatory funnel (3×EtOAc), the organic layer was dried with MgSO4 and filtered. Removal of excess solvent from the filtrate in vacuo provided 331 mg (99%) of the title compound as an off-white solid. (1H DMSO-d6, 400 MHz) δ 12.29 (s, 1H), 11.37 (s, 1H), 9.26 (s, 1H), 7.54 (d, J=8.0 Hz, 1H) 6.70 (s, 1H), 6.648 (d, J=8.1 Hz, 1H), 2.24 (s, 3H).
96%	With hydroxylamine hydrochloride; sodium hydroxide; In 1,4-dioxane; water; at 20℃;	(2)Experimental procedure(105.75 g, 2.64 mol) of sodium hydroxide was dissolved in 800 mL of ice water, and hydroxylamine hydrochloride (71.1 g, 1.02 mol) was added with stirring.Compound 2' (90 g, 0.54 mol) was dissolved in 450 mL of 1,4-dioxane.Slowly drip into the reaction bottle, insoluble matter,The reaction is completely dissolved after a period of time. Stir at room temperature overnight,The solution was yellow, and after concentrating about 600 mL of the solution, pH 1 was adjusted with 1 N hydrochloric acid, and a large amount of solid precipitated. Filtered, washed 4 times with distilled water, dried in vacuum,87 g of a pale pink solid were obtained with a yield of 96%.
	With hydroxylamine hydrochloride; sodium methylate; In methanol; at 20℃; for 5.17h;Heating / reflux;	9.05 g of hydroxylamine hydrochloride was dissolved in 84 ML of methanol, to which 40.64 g of a 28% solution of sodium methoxide in methanol was added at room temperature, and then this mixture was stirred for 10 minutes.. Then, 21 ML of a solution of 7.00 g of methyl 2-hydroxy-4-methylsalicylate in methanol was added dropwise to the reaction mixture, which was stirred for one hour at room temperature and then another four hours while heating it under reflux.. The reaction mixture was added to water, and adjusted to PH 5 with 6M hydrochloric acid, and then resultant precipitate was filtered out thereof.. The resultant solid was washed with water and diisopropyl ether successively to yield 5.95 g of N,2-dihydroxy-4-methylbenzamide as light yellow solid. NMR(400MHz,DMSO-d6) δ value: 2.26(3H,s), 6.68(1H,d,J=8.8Hz), 6.72(1H,s), 7.57(1H,d,J=8.4Hz), 9.27(1H,s), 11.38(1H,brs), 12.29(1H,brs)

4-Methylsalicylic acid (252.5 mg, 1 .66 mmol) was dissolved with 20 mL of MeOH in a 50 mL round bottom flask. 0.5 mL of concentrated sulfuric acid was added while stirring. The flask was connected to a partial condenser (T=5C) and set in an oil bath (T=85C). The solution was stirred and allowed to react under reflux for 24 hours. The reaction wasquenched by adding 100 mL of water to the solution. The intermediate was extracted with ethyl ether (3 x 30 mL). The organic phases were combined and washed with a saturated sodium bicarbonate solution (2 x 100 mL). The ether was evaporated in vacuo and the intermediate was dissolved in 0.5 mL of THF. In a separate vial, 6.72 mL of 1 .64 M hydroxylamine in water was added to 8.38 mL of 3 M NaOH. The intermediate solution was added drop wise to the NaOH/NhbOH solution while stirring. The reaction was allowed to proceed at room temperature for 24 hours. After 24 hours, the reaction was cooled to 0C using an Ice bath, and the pH was adjusted to pH = 5 with 10 M HCI. The solution was allowed to warm to room temperature before extracting the product with ethyl acetate (3 x 15 mL). The organic layers were combined and the solvent was evaporated. Mass spec analysis shows [M+H] = 168.071 1 m/z.

References: [1]Patent: US2005/143434,2005,A1 .Location in patent: Page/Page column 9.
[2]Patent: CN109020912,2018,A .Location in patent: Paragraph 0071; 0077; 0078; 0079; 0080.
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 8541 - 8554.
[4]Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques,1953,vol. <III> 1,p. 319,320.
[5]Journal of Medicinal Chemistry,2008,vol. 51,p. 3357 - 3359.
[6]Patent: EP1445249,2004,A1 .Location in patent: Page 119.
[7]Journal of Medicinal Chemistry,2014,vol. 57,p. 5282 - 5292.
[8]Patent: WO2014/121291,2014,A2 .Location in patent: Page/Page column 44; 45.
[9]Tetrahedron Letters,2016,vol. 57,p. 5301 - 5303.

2
[ 158671-29-5 ]
[ 108-24-7 ]
O-acetyl-N-(2-hydroxy-4-methyl-benzoyl)-hydroxylamine [ No CAS ]

References: [1]Roczniki Chemii,1954,vol. 28,p. 549,554, 555.
Chem.Abstr.,1956,p. 305.

3
[ 158671-29-5 ]
[ 60100-09-6 ]
[ 22876-16-0 ]

References: [1]Roczniki Chemii,1954,vol. 28,p. 549,554, 555.
Chem.Abstr.,1956,p. 305.

6
[ 158671-29-5 ]
[ 66571-26-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 0.533333h;Inert atmosphere;	General procedure: Salicylhydroxamic acid 1a (77 mg, 0.5 mmol, 1 equiv) was dissolved in anhydrous THF (7 mL) under an inert (N2) atmosphere. Triphenylphosphine (164 mg, 0.625 mmol, 1.25 equiv) was then added. After 2 min, DIAD (123 lL, 0.625 mmol, 1.25 equiv) was added dropwise. TLC (Hex/EtOAc, 1:3) after 30 min revealed the reaction was complete. The THF was removed in vacuo. The residue was partitioned between 0.1 M NaOH (50 mL)and CH2Cl2 (100 mL). The organic layer was separated, then the aqueous layerwas washed a further three times with CH2Cl2 (100 mL). The aqueous layer was acidified with 1 M HCl (10 mL), then extracted into CH2Cl2 (2 100 mL),washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to yield the 3-hydroxybenzisoxazole 2a.
56%		A 50 ml round-bottom flask equipped with a stir bar under a dry nitrogen atmosphere was charged with 2-N-Dihydroxy-4-methyl-benzamide (331 mg, 2.0 mmole, 1.0 eq) and carbonyldiimidazole (1.0 g, 6.0 mmoles, 3.0 eq) followed by dry THF (20 ml). The reaction mixture was stirred at reflux for 30 minutes and then neat TEA (415 μL, 3.0 mmoles, 1.5 eq) was added. The reaction mixture was refluxed for additional 20 hrs, cooled to room temperature and excess THF was removed in vacuo. The residue was dissolved in EtOAc, extracted with aqueous HCl (1.0M/H2O), the organic layer was dried with MgSO4, filtered and excess solvent from the filtrate was removed in vacuo. Purification of the crude product by flash chromatography (silica gel, 0%→40% gradient of 2% AcOH/EtOAc in hexanes) provided 167 mg (56%) as a white solid. (1H DMSO-d6, 400 MHz) δ 12.19 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.34 (sm 1H), 7.12 (d, J=8.0 Hz, 1H), 2.07 (s, 3H); (13C DMSO-d6, 100 MHz) δ 165.09, 163.59, 141.18, 124.588, 120.76, 112.08, 109.80, 21.33.
		50.0 g of <strong>[158671-29-5]N,2-dihydroxy-4-methylbenzamide</strong> was added to 350 mL of tert-butylmethylether, and 38.1 g of thionyl chloride was added dropwise at -1-0C. This was stirred for 30 minutes at the same temperature. Then, 164 mL of tributylamine was added dropwise at -5- -3C, and this was stirred for 1.5 hours at -5-5C. To the reaction mixture, 200 mL of 20% sodium hydroxide aqueous solution was added, an organic layer was separated, and 100 mL of water, 42 mL of 20% sodium hydroxide aqueous solution and 5.0 g of celite were added. After insoluble matter was filtered off, the cake was washed with 100 mL of water. The filtrate and the washing solution were combined and an aqueous layer was separated. To the aqueous layer, 10 mL of acetone and 50 mL of acetic acid were added at 40-50C. After stirring at the same temperature for 30 minutes, solids were filtered to obtain 40.1 g of 6-methyl-1,2-benzisoxazol-3-ol in the form of a pale yellow solid. 1H-NMR (CDCl3) δ: 2.51 (3H, s), 7.13 (1H, d, J=8.0Hz), 7.21 (1H, s), 7.65 (1H, d, J=8.0Hz)

With thionyl chloride; triethylamine; In tetrahydrofuran; at 5 - 20℃; for 1h;

44.0 g of [158671-29-5]N,2-dihydroxy-4-methylbenzamide was suspended in 880 ML of tetrahydrofuran, to which 147 ML of triethylamine was added dropwise at room temperature and then 28.7 ML of thionyl chloride was added dropwise at 5 to 10C successively, and this mixture was stirred for one hour at room temperature.. The reaction mixture was added to water, and adjusted to PH 1 with 12M hydrochloric acid, and then resultant precipitate was filtered out thereof.. The resultant solid was washed with water to yield 35.2 g of 6-methyl-1,2-benzisoxazol-3-ol as light yellow solid. NMR(400MHz,DMSO-d6) δ value: 2.45(3H,s), 7.14(1H,d,J=8.0Hz), 7.36(1H,s), 7.59(1H,d,J=8.4Hz), 12.24(1H,brs)

References: [1]Tetrahedron Letters,2016,vol. 57,p. 5301 - 5303.
[2]Patent: US2005/143434,2005,A1 .Location in patent: Page/Page column 9.
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 8541 - 8554.
[4]Patent: EP1988085,2008,A1 .Location in patent: Page/Page column 29-30.
[5]Journal of Medicinal Chemistry,2008,vol. 51,p. 3357 - 3359.
[6]Patent: EP1445249,2004,A1 .Location in patent: Page 119.

7
[ 50-85-1 ]
[ 158671-29-5 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8541 - 8554.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5282 - 5292.
[3]Patent: WO2014/121291,2014,A2 .
[4]Tetrahedron Letters,2016,vol. 57,p. 5301 - 5303.
[5]Patent: CN109020912,2018,A .

8
[ 158671-29-5 ]
[ 16302-64-0 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8541 - 8554.

9
[ 84110-40-7 ]
[ 158671-29-5 ]
[ 1613293-02-9 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5282 - 5292.

10
[ 158671-29-5 ]
[ 98-80-6 ]
[ 1621395-52-5 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; for 2h;Reflux;	General procedure: The boronic acid and the respective molecule (R = A, B, or C) were placed in a flame dried 25 mL flask along with 7 mL of toluene. The flask was placed in an oil bath (T=125C) and connected to a condenser (T=5C). The solution was allowed to reflux for 2 hours before being removed from the heat. The solvent was then evaporated in vacuo. Conjugation was verified using 11B-NMR spectroscopy via Bruker 400 MHz spectrometer.

References: [1]Patent: WO2014/121291,2014,A2 .Location in patent: Page/Page column 45; 46; sheet 26.

11
[ 158671-29-5 ]
[ 947409-01-0 ]