75056-97-2|4-Hydroxy-2,6-dimethylbenzoic acid| Ambeed

CAS No. :	75056-97-2
Formula :	C₉H₁₀O₃
M.W :	166.17
SMILES Code :	O=C(O)C1=C(C)C=C(O)C=C1C
MDL No. :	MFCD00963146
InChI Key :	FFUMDYCIOSWRLV-UHFFFAOYSA-N
Pubchem ID :	1514302

Safety of [ 75056-97-2 ]

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

Computational Chemistry of [ 75056-97-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	45.36
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	57.53 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.2
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	1.82
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.71
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.	1.64
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	1.66
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.61

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.32
Solubility	0.794 mg/ml ; 0.00478 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.	-2.65
Solubility	0.374 mg/ml ; 0.00225 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	-1.96
Solubility	1.81 mg/ml ; 0.0109 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.	-6.02 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.	0.56

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<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)	1.08

Application In Synthesis of [ 75056-97-2 ]

* 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 [ 75056-97-2 ]

[ 75056-97-2 ] Synthesis Path-Downstream 1~46

1
[ 75056-98-3 ]
[ 75056-97-2 ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1980,vol. 19,p. 191 - 194.
[2]Justus Liebigs Annalen der Chemie,1905,vol. 342,p. 349.

2
[ 51-28-5 ]
[ 75056-97-2 ]
[ 87513-48-2 ]

References: [1]Journal of the Chemical Society. Chemical communications,1983,p. 529 - 530.

3
[ 124-38-9 ]
[ 95741-44-9 ]
[ 75056-97-2 ]

References: [1]Journal of the Chemical Society. Chemical communications,1983,p. 529 - 530.

4
[ 37934-89-7 ]
[ 75056-97-2 ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1980,vol. 19,p. 191 - 194.

5
[ 76139-75-8 ]
[ 13509-08-5 ]
[ 75056-97-2 ]
[ 76139-77-0 ]
[ 108-68-9 ]

References: [1]Chemical and pharmaceutical bulletin,1980,vol. 28,p. 2129 - 2135.

6
[ 87513-48-2 ]
[ 51-28-5 ]
[ 75056-97-2 ]

References: [1]Journal of Organic Chemistry,1985,vol. 50,p. 1867 - 1872.

7
[ 87513-48-2 ]
[ 75056-97-2 ]

References: [1]Journal of the Chemical Society. Chemical communications,1983,p. 529 - 530.

8
[ 75056-97-2 ]
[ 75-65-0 ]
[ 306296-71-9 ]

References: [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 771 - 777.

9
[ 75056-97-2 ]
4-(3,3-Diethyl-4-oxo-azetidin-2-yloxy)-2,6-dimethyl-benzoic acid tert-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 771 - 777.

10
[ 75056-97-2 ]
4-(1-Benzylcarbamoyl-3,3-diethyl-4-oxo-azetidin-2-yloxy)-2,6-dimethyl-benzoic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 771 - 777.

11
[ 75056-97-2 ]
4-(1-Benzylcarbamoyl-3,3-diethyl-4-oxo-azetidin-2-yloxy)-2,6-dimethyl-benzoic acid tert-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 771 - 777.

12
[ 70547-87-4 ]
[ 75056-97-2 ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1980,vol. 19,p. 191 - 194.
[2]Synthesis,2016,vol. 48,p. 3917 - 3923.

13
[ 19447-00-8 ]
[ 75056-97-2 ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1980,vol. 19,p. 191 - 194.

14
[ 75056-97-2 ]
[ 306298-11-3 ]
[ 887333-94-0 ]

References: [1]Patent: US6391865,2002,B1 .Location in patent: Page column 101-102.

15
C₂₆H₃₄F₃N₃O [ No CAS ]
[ 75056-97-2 ]
[ 306296-06-0 ]

References: [1]Patent: US6391865,2002,B1 .Location in patent: Page column 103-104.

16
[ 75056-97-2 ]
[ 306298-16-8 ]
C₃₀H₄₀F₃N₃O₂ [ No CAS ]

References: [1]Patent: US6391865,2002,B1 .Location in patent: Page column 106.

17
[ 75056-97-2 ]
[ 696600-31-4 ]
C₃₁H₄₂F₃N₃O₂ [ No CAS ]

References: [1]Patent: US6391865,2002,B1 .Location in patent: Page column 112.

18
[ 75056-97-2 ]
[ 696601-20-4 ]
C₃₀H₄₀F₃N₃O₃ [ No CAS ]

References: [1]Patent: US6391865,2002,B1 .Location in patent: Page column 116.

19
C₂₀H₃₀F₃N₃*3ClH [ No CAS ]
[ 75056-97-2 ]
[ 760162-74-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25.0℃; for 20.0h;	The tri-hydrochloride salt of the product of Example 8, step 3 (75 mg, 0.16 mmol), EDC (61 mg, 0.32 mmol), HOBT (49 mg, 0.32 mmol), iPr2NEt (0.16 ml, 0.96 mmol), and <strong>[75056-97-2]2,6-dimethyl-4-hydroxy-benzoic acid</strong> (53 mg, 0.32 mmol) were taken up in CH2Cl2 and stirred at 25 C. for 20 h. The solution was concentrated. Purification via preparative TLC (EtOAc, SiO2) gave the title compound as a yellow oil. m.p. (2×HCl salt) 210-220 C. HRMS (MH+) calcd. for C29H39O2N3F3, 518.2994; Found, 518.2997.

References: [1]Patent: US6391865,2002,B1 .Location in patent: Page column 39-40.

20
[ 306297-33-6 ]
[ 75056-97-2 ]
C₂₈H₃₆F₃N₃O₂ [ No CAS ]

References: [1]Patent: US6391865,2002,B1 .Location in patent: Page column 67-68.

21
C₁₉H₂₈F₃N₃O [ No CAS ]
[ 75056-97-2 ]
C₂₈H₃₆F₃N₃O₃ [ No CAS ]

References: [1]Patent: US6391865,2002,B1 .Location in patent: Page column 65-66.

22
C₂₀H₃₀F₃N₃*3ClH [ No CAS ]
[ 75056-97-2 ]
C₂₉H₃₈F₃N₃O₂*2ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25.0℃; for 20.0h;	The tri-hydrochloride salt of the product of Example 8, step 3 (75 mg, 0.16 mmol), EDC (61 mg, 0.32 mmol), HOBT (49 mg, 0.32 mmol), iPr2NEt (0.16 ml, 0.96 mmol), and <strong>[75056-97-2]2,6-dimethyl-4-hydroxy-benzoic acid</strong> (53 mg, 0.32 mmol) were taken up in CH2Cl2 and stirred at 25 C for 20 h. The solution was concentrated. Purification via preparative TLC (EtOAc, SiO2) gave the title compound as a yellow oil. m.p. (2xHCl salt) 210-220 C. HRMS (MH+) calcd. for C29H39O2N3F3 , 518.2994; Found, 518.2997

References: [1]Patent: EP1175401,2005,B1 .Location in patent: Page/Page column 26.

23
C₁₈H₁₉Cl₃N₂ [ No CAS ]
[ 75056-97-2 ]
C₂₇H₂₇Cl₃N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20.0℃;	Preparation of Example 90; To a solution of Example 85 (35 mg, 0.095 mmol) in MeCN (1.5 mL) was added EDCl (27 mg, 0.14 mmol), HOBt (20 mg, 0.14 mmol), iPr2NEt (61 mg, 0.48 mmol) and 4-hydroxy-2,6-dimethyl benzoic acid (31 mg, 0.19 mmol). 4-hydroxy-2,6-dimethyl benzoic acid was prepared by the method described in U.S. Pat. No. 6,391,865B1, which is herein incorporated by reference. The solution was allowed to stir at RT overnight. The solution was concentrated and partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (1:1 EtOAc:hexanes) to afford 37 mg of Example 90.

References: [1]Patent: US2007/203183,2007,A1 .Location in patent: Page/Page column 84.

24
[ 75056-97-2 ]
[ 1356963-69-3 ]