231958-04-6|3-((tert-Butoxycarbonyl)amino)-4-methylbenzoic acid| Ambeed

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Quality Control of [ 231958-04-6 ] Purity: 98% SDS Specification

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Product Details of [ 231958-04-6 ]

CAS No. :	231958-04-6
Formula :	C₁₃H₁₇NO₄
M.W :	251.28
SMILES Code :	O=C(O)C1=CC=C(C)C(NC(OC(C)(C)C)=O)=C1
MDL No. :	MFCD01861378
InChI Key :	ITZUJURBEZPZOD-UHFFFAOYSA-N
Pubchem ID :	10634482

Safety of [ 231958-04-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H317-H319-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 231958-04-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	6
Fraction Csp3	0.38
Num. rotatable bonds	5
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	68.61
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	75.63 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.34
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	2.11
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.85
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.	2.24
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	1.67
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.24

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.64
Solubility	0.571 mg/ml ; 0.00227 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.	-3.33
Solubility	0.118 mg/ml ; 0.000469 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	-3.12
Solubility	0.193 mg/ml ; 0.000767 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.	-6.33 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.	0.56

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<0.0
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)	2.35

Application In Synthesis of [ 231958-04-6 ]

* 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 [ 231958-04-6 ]

[ 231958-04-6 ] Synthesis Path-Downstream 1~35

1
[ 24424-99-5 ]
[ 2458-12-0 ]
[ 231958-04-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; In water; at 20℃; for 18h;	To a solution of 3-amino-4-methyl benzoic acid (2.0 g, 13.2 mmol) in water (25 mL) and 1N sodium hydroxide (25 mL) was added di-tert-butyl dicarbonate (4.3 g, 19.8 mmol) and the reaction was stirred for 18 hours at ambient temperature. The reaction was partitioned between ethyl acetate and 5% aqueous citric acid. The organic layer was washed with water and brine and dried over magnesium sulfate. The material was filtered and concentrated to provide the protected aniline as a pink solid (3.3 g, quantitative yield).
91%	In tetrahydrofuran; at 50℃;	A mixture of commercially-available 4-amino-3-methylbenzoic acid (100 g, 0.66 mol) and di-tertbutyl dicarbonate (150 g, 0.68 mol) in THF (1000 mL) was slowly heated to 50C overnight. The resulting mixture was cooled to rt and the solvent was removed on a rotary evaporator. The resulting solids were triturated with hexanes and dried in vacuo to afford 151 g (91%) of the crude BOC-protected aniline intermediate as a light pink solid. To the above, light-pink solid was added 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (127 g, 0.66 mol), HOBt (90 g, 0.66 mol), and DMF (1000 ml), and the resulting mixture was stirred at rt for 30 minutes followed by addition of methoxyamine hydrochloride (55 g, 0.66 mol) in one portion. After stirring for 10 min, the mixture was cooled using an ice bath. Diisopropyl-ethylamine (250 ml, 1.4 mol) was added at such a rate so as to maintain the internal reaction temperature below 25C. After the addition was complete, the ice bath was removed and the reaction was stirred overnight at rt. The reaction mixture was partitioned between 0.5 L of water and 1.5 L of EtOAc and the resulting layers were separated. The aqueous portion was extracted with additional EtOAc (400 mL x 3), and the combined organic extracts were washed with, water (300 mL x 3), cold 0.5 N aqueous HC1 (400 mL x 2), and water (500 mL). The product was then extracted with cold 0.5 N aqueous NaOH (300 mL x 3) and the combined basic aqueous extracts were neutralized to pH = 8 by a slow addition of cold 0.5 N aqueous HC1. The resulting solid which precipitated was collected by filtration and washed with cold water.'The wet solid was decolorized in hot EtOH with active charcoal to give 106 g of white solid as the BOC-protected N-methoxyamide intermediate. To a slurry of the above solid (91 g, 0.32 mol) in 1,4-dioxane (400 mL) at rt was added a 4M solution of HC1 in dioxane (400 mL), and the resulting mixture was stirred at rt overnight. Diethyl ether (1000 mL) was added and the precipitated solid was collected by filtration and triturated with a hot EtOH/H20 mixture (4: 1 v/v). Drying the resulting solid in vacuo afforded 53 g of the pure hydrochloride salt (1D) as a white solid. 1H NMR (d6-DMSO) : 6 9.5-9. 9 (br. s, 1H), 7.75 (s, 1H), 7.55 (d, 1H), 7.36 (d, 1H), 3.70 (s, 3H), 2.38 (s, 3H).
88%	In tetrahydrofuran; at 50℃;	A suspension of 3-amino-4-methylbenzoic acid (20.0 g, 132 mmol) and N-(tert-butoxycarbonyl)anhydride (30.0 g, 219 mmol) in THF (200 mL) was heated and stirred at 50 C overnight. The resulting mixture was cooled to rt. The solvent was evaporated in vacuo, and the crude product was recrystallized from EtOAc to afford 7 (29.1 g, 88 %) as a pink solid. 1H NMR (DMSO-d6): delta 12.8 (s, 1H), 8.66 (s, 1H), 7.97 (s, 1H), 7.59 (dd, J=2.0, 8.0Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 3.25 (s, 3H), 1.47 (s, 9H).

References: [1]Patent: US2012/142708,2012,A1 .Location in patent: Page/Page column 23.
[2]Patent: WO2005/42537,2005,A1 .Location in patent: Page/Page column 46; 47.
[3]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3700 - 3705.
[4]European Journal of Organic Chemistry,2001,p. 311 - 322.
[5]Journal of Medicinal Chemistry,2008,vol. 51,p. 4 - 16.
[6]Angewandte Chemie - International Edition,2017,vol. 56,p. 14918 - 14922.
Angew. Chem.,2017,vol. 129,p. 15114 - 15118,5.

2
[ 100-39-0 ]
[ 231958-04-6 ]
[ 330807-41-5 ]

References: [1]European Journal of Organic Chemistry,2001,p. 311 - 322.

3
[ 231958-04-6 ]
[ 928123-01-7 ]

References: [1]European Journal of Organic Chemistry,2001,p. 311 - 322.

4
[ 231958-04-6 ]
Boc-(L)-Pro-AB(4-CH₃)-OBn [ No CAS ]

References: [1]European Journal of Organic Chemistry,2001,p. 311 - 322.

5
[ 593-56-6 ]
[ 231958-04-6 ]
[ 607738-98-7 ]

Yield	Reaction Conditions	Operation in experiment
98%		To a stirred solution of compound 7 (5.0 g, 19.9 mmol) in DMF (30 mL) was added EDC (3.9 mL, 21.9 mmol), HOBt (3.35 g, 21.9 mmol). After stirring at rt for 30 min, methoxyamine hydrochloride (1.83 g, 21.9 mmol) was added. The resulting mixture was stirred for another 10 min, and cooled to 0 C. DIPEA (8.09 mL, 46.4 mmol) was added slowly to maintain the internal reaction temperature below 25 C. After finishing the addition, the reaction mixture was allowed to warm to rt and stirred at rt overnight. The resulting mixture was poured into water and extracted with EtOAc. The combined organic layer was washed with cold 0.5 N HCl and water. The organic layer was then extracted with cold 0.5 N NaOH, and the combined basic aqueous extract was adjusted pH to 8 by a slow addition of cold 0.5 N HCl. The resulting precipitate was collected by filtration, and washed with cold water. The crude product was recrystallized in EtOH to afford 8a (5.17 g, 98 %) as a white solid. 1H NMR (DMSO-d6): delta 11.65 (s, 1H), 8.65 (s, 1H), 7.75 (s, 1H), 7.40 (dd, J=1.5, 8.0Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 3.69 (s, 3H), 2.23 (s, 3H), 1.47 (s, 9H).
		A mixture of commercially-available 4-amino-3-methylbenzoic acid (100 g, 0.66 mol) and di-tertbutyl dicarbonate (150 g, 0.68 mol) in THF (1000 mL) was slowly heated to 50C overnight. The resulting mixture was cooled to rt and the solvent was removed on a rotary evaporator. The resulting solids were triturated with hexanes and dried in vacuo to afford 151 g (91%) of the crude <strong>[231958-04-6]BOC-protected aniline intermediate</strong> as a light pink solid. To the above, light-pink solid was added 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (127 g, 0.66 mol), HOBt (90 g, 0.66 mol), and DMF (1000 ml), and the resulting mixture was stirred at rt for 30 minutes followed by addition of methoxyamine hydrochloride (55 g, 0.66 mol) in one portion. After stirring for 10 min, the mixture was cooled using an ice bath. Diisopropyl-ethylamine (250 ml, 1.4 mol) was added at such a rate so as to maintain the internal reaction temperature below 25C. After the addition was complete, the ice bath was removed and the reaction was stirred overnight at rt. The reaction mixture was partitioned between 0.5 L of water and 1.5 L of EtOAc and the resulting layers were separated. The aqueous portion was extracted with additional EtOAc (400 mL x 3), and the combined organic extracts were washed with, water (300 mL x 3), cold 0.5 N aqueous HC1 (400 mL x 2), and water (500 mL). The product was then extracted with cold 0.5 N aqueous NaOH (300 mL x 3) and the combined basic aqueous extracts were neutralized to pH = 8 by a slow addition of cold 0.5 N aqueous HC1. The resulting solid which precipitated was collected by filtration and washed with cold water.'The wet solid was decolorized in hot EtOH with active charcoal to give 106 g of white solid as the BOC-protected N-methoxyamide intermediate. To a slurry of the above solid (91 g, 0.32 mol) in 1,4-dioxane (400 mL) at rt was added a 4M solution of HC1 in dioxane (400 mL), and the resulting mixture was stirred at rt overnight. Diethyl ether (1000 mL) was added and the precipitated solid was collected by filtration and triturated with a hot EtOH/H20 mixture (4: 1 v/v). Drying the resulting solid in vacuo afforded 53 g of the pure hydrochloride salt (1D) as a white solid. 1H NMR (d6-DMSO) : 6 9.5-9. 9 (br. s, 1H), 7.75 (s, 1H), 7.55 (d, 1H), 7.36 (d, 1H), 3.70 (s, 3H), 2.38 (s, 3H).

References: [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3700 - 3705.
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 4 - 16.
[3]Patent: WO2005/42537,2005,A1 .Location in patent: Page/Page column 46; 47.

6
[ 231958-04-6 ]
[ 1117-97-1 ]
[5-(methoxymethylcarbamoyl)-2-methylphenyl]-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		To a solution of the protected aniline of part A (3.0 g, 12.0 mmol) in tetrahydrofuran (20 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (2.5 g, 14.4 mmol) and 4-methylmorpholine (2.6 mL, 24 mmol). After the reaction was stirred for thirty minutes, N,O-dimethylhydroxylamine (1.75 g, 18.0 mmol) was added and the resulting slurry was stirred at ambient temperature for 48 hours. The slurry was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate solution, water, 5% aqueous citric acid and brine and dried over magnesium sulfate. The material was filtered and concentrated to provide the amide as an orange semi-solid (2.6 g, 74% yield).

References: [1]Patent: US2012/142708,2012,A1 .Location in patent: Page/Page column 23-24.

7
[ 231958-04-6 ]
[ 1380281-41-3 ]

References: [1]Patent: US2012/142708,2012,A1 .
[2]Patent: US2012/142708,2012,A1 .

8
[ 231958-04-6 ]
[ 1380281-53-7 ]