16870-28-3|2-Hydroxy-4-iodobenzoic acid| Ambeed

CAS No. :	16870-28-3
Formula :	C₇H₅IO₃
M.W :	264.02
SMILES Code :	OC(=O)C1=C(O)C=C(I)C=C1
MDL No. :	MFCD00061127
InChI Key :	UQOZVZTUJNRMBV-UHFFFAOYSA-N
Pubchem ID :	72874

Safety of [ 16870-28-3 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H302-H311-H318-H400
Precautionary Statements:	P264-P270-P273-P280-P301+P312+P330-P302+P352+P312-P305+P351+P338+P310-P391-P405-P501
Class:	9
UN#:	3077
Packing Group:	Ⅲ

Computational Chemistry of [ 16870-28-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
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	48.14
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.	1.12
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	3.34
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.69
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.	1.91
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	1.71
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.95

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.92
Solubility	0.0318 mg/ml ; 0.000121 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.	-4.23
Solubility	0.0157 mg/ml ; 0.0000595 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-2.15
Solubility	1.88 mg/ml ; 0.00711 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.	-5.54 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.	0.56

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	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<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)	1.72

Application In Synthesis of [ 16870-28-3 ]

* 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 [ 16870-28-3 ]

[ 16870-28-3 ] Synthesis Path-Downstream 1~54

1
[ 89942-34-7 ]
[ 16870-28-3 ]

References: [1]Journal of the Chemical Society,1927,p. 1742,3042.

2
[ 730977-57-8 ]
[ 16870-28-3 ]

References: [1]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1924,vol. 178,p. 1011.

3
[ 65-49-6 ]
[ 16870-28-3 ]

Yield	Reaction Conditions	Operation in experiment
85 - 90%		Step A: 4-Aminosalicylic acid (4.0 g, 26 mmol) was suspended in H2SO4 (26 mL, 2.7M) at -50C. Sodium nitrite (1.8 g, 26.1 mmol) in H2O (6.5 mL) was cooled to ice bath temperature and was added dropwise to the aminosalicylic acid mixture over 5 minutes. The resulting suspension was stirred at -5 C for 15 minutes. A solution of KI (6.8 g, 41 mmol) in H2SO4 (13 mL, IM) was added dropwise to the diazonium salt, with considerable evolution of N2. The reaction mixture was heated at 7O0C for 20 minutes. The reaction mixture was then partitioned between H2O and EtOAc. The organic layer was dried and concentrated. Purification by silica gel chromatography (7/3, hexanes/acetone, 1% acetic acid) yielded 4-iodosalicylic acid (5.33g, 85-90% pure).
39.8%		In a 0.5 L 3 necked flask, 4-aminosalicylic acid 45 (15.3 g, 100 mmol) was mixed with H2O (100 ml), Conc. H2SO4 (14 ml, 25.8 g, 263 mmol). The mixture was stirred and cooled to 3-5 C. and diazotated by gradual addition of cold solution of NaNO2 (6.9 g, 100 mmol) in 20 ml water with control with iodine:starch paper of excess NaNO2. Dark solution was obtained. The diazotated solution was added to cold solution of KI (26 g, 156.6 mmol) in 25 ml 1N H2SO4. After 1 min, strong and rapid evolution of nitrogen was observed without heating. Ether (10-20 ml) was added to destroy the foam. The beaker with reaction mixture was heated at 75-80 C. for 10 min. The precipitate was filtered and washed with water and dried in air to obtain 17 g of raw product, which was purified by column chromatography: 340 g SiO2, 2% MeOH in CHCl3. 10.5 g, Yield: 39.8%.
35%.	With potassium iodide; sodium nitrite;copper(I) iodide; In sulfuric acid; water;	(b) Preparation of 2-hydroxy-4-iodobenzoic acid: To 20% sulfuric acid solution (650 ml) were added 4-amino-2-hydroxybenzoic acid and 200 ml of 20% sulfuric acid solution. The solution was cooled to -10 C. and a solution of sodium nitrite (47 g, 0.34 mol) in water (100 ml) was added over 5 hours. The solution obtained was added dropwise to a suspension of potassium iodide (69.5 g, 0.42 mol) and copper(I) iodide (69.5 g, 0.36 mol) in 370 ml of 20% sulfuric acid. The mixture was stirred for 36 hours at room temperature and was then filtered. The filtrate was extracted with ethyl acetate, washed twice with saturated sodium sulfite solution and twice with water. The organic phase was concentrated on a rotary evaporator under vacuum at 40 C. The properties of the final product were as follows: White solid. Mass: 24.25 g. Yield: 35%. m.p.: 192 C. 1 H NMR (DMSO, 250 MHz): 7.17 (1H, Ar, d, J=8.25 Hz), 7.25 (1H, Ar, s), 7.42 (1H, Ar, d, J=8.25 Hz).

		A suspension of 4-aminosalicylic acid (60.6 g) , water (240 mL), C-H2SO4 (90 mL) and acetic acid (240 mL) was cooled with an ice-bath. A solution of sodium nitrite (30.0 g) in water (60 mL) was added dropwise to the suspension over 30 min and the mixture was stirred at 00C for 1 hr. Then a solution of potassium iodide (200 g) in water (160 mL) was added dropwise over 30 min and the cooling-bath was removed. The mixture was stirred at room temperature for 20 hr, diluted with water and extracted with ethyl acetate (three times) . The extracts were combined, washed with 5% Na2S2Oa solution and brine, dried over MgSO4 and concentrated. The residue was suspended in acetonitrile and collected by filtration to give the title compound as a powder (35.0 g) .1H-NMR (300 MHz, DMSO-d6) delta: 7.30 (dd, J = 8.1, 1.8 Hz, IH), 7.38 (d, J = 1.8 Hz, IH), 7.51 (d, J = 8.1 Hz, IH).
		A sample of 4-amino-2-hydroxysalicylic acid (10 g, 65.3 mmol) is charged to a 2 liter Erlenmeyer flask equipped with a large stir bar, cooled in an ice/water bath and treated with concentrated sulfuric acid (20 mL) and enough water to make a free flowing suspension (50 mL). After stirring for 20 minutes, the reaction is treated with a solution of sodium nitrite (4.55 g, 66.0 mmol) in water (20 mL) over the course of 10 minutes. After stirring an additional 3 minutes, the reaction is treated with a solution of potassium iodide (16.9 g, 101 mmol) in water (30 mL) over the course of 15 minutes. The cooling bath is removed and the reaction is carefully monitored and stirred as it generates a significant amount of nitrogen gas. After the reaction subsides, it is briefly heated to 70 C. after which it is allowed to cool to room temperature and sit overnight. The resulting solid is collected by filtration, washed with water and dried to give crude 2-hydroxy-4-iodo-benzoic acid that is used in the next reaction without further purification: ESMS m/z 265.0 (M+H+).
		Example 1 Synthesis of 4-[2-(4-carboxy-3-hydroxy-phenyl)ethynyl]-2-hydroxy-benzoic acid (I) Synthesis of Compound 2 11.0 g (72.0 mmol) of 4-aminosalicylic acid (1) was taken in 110.0 ml 50% H2SO4 and cooled to -5 C. and stirred for 20 minutes. To this NaNO2 solution (5.5 g, 80 mmol of NaNO2 in 6.5 ml deionized water) was added drop wise maintaining temperature below 0 C. and stirred for 20 minutes. This diazonium salt solution was added drop wise to the freshly prepared CuI solution* at -5 C. After addition, temperature of the reaction mixture was raised to room temperature and then heated to 90 C. for 1 h. After completion of reaction, the reaction mixture was cooled to room temperature and filtered to obtain yellow solid which was washed with water and dried. This solid was dissolved in hot ethanol and filtered. The inorganic residue remained was washed with ethanol and the filtrate was evaporated to dryness under vacuum to obtain 16.0 g of crude Compound 2 as a brown solid. *(CuI solution: 17.95 g (72.0 mmol) CuSO4.5H2O, 5.5 g (86.0 mmol) Cu-powder and 55.0 g (332.0 mmol) KI were taken in 100.0 ml deionized water. To this 100.0 ml 20% H2SO4 was added with constant stirring. Reaction mixture was allowed to stirred at room temperature for 1 h and then it was cooled to -5 C. CuI gets precipitated out as off-white solid. The above solution of CuI is directly used for the preparation of Compound 2. Yield: 84.6% Analysis: 1H NMR (300 MHz, MeOD): delta 7.48 (d, 1H); 7.24 (d, 1H); 7.19 (dd, 1H). MS (m/z): 263 (M+-H)
		Example 1 Synthesis of 4-[2-(4-carboxy-3-hydroxy-phenyl)ethynyl]-2-hydroxy-benzoic acid (I) Synthesis of Compound 2 11.0 g (72.0 mmol) of 4-aminosalicylic acid (1) was taken in 110.0 ml 50% H2SO4 and cooled to -5 C. and stirred for 20 minutes. To this NaNO2 solution (5.5 g, 80 mmol of NaNO2 in 6.5 ml deionized water) was added drop wise maintaining temperature below 0 C. and stirred for 20 minutes. This diazonium salt solution was added drop wise to the freshly prepared CuI solution* at -5 C. After addition, temperature of the reaction mixture was raised to room temperature and then heated to 90 C. for 1 h. After completion of reaction, the reaction mixture was cooled to room temperature and filtered to obtain yellow solid which was washed with water and dried. This solid was dissolved in hot ethanol and filtered. The inorganic residue remained was washed with ethanol and the filtrate was evaporated to dryness under vacuum to obtain 16.0 g of crude Compound 2 as a brown solid. *(CuI solution: 17.95 g (72.0 mmol) CuSO4.5H2O, 5.5 g (86.0 mmol) Cu-powder and 55.0 g (332.0 mmol) KI were taken in 100.0 ml deionized water. To this 100.0 ml 20% H2SO4 was added with constant stirring. Reaction mixture was allowed to stirred at room temperature for 1 h and then it was cooled to -5 C. CuI gets precipitated out as off-white solid. The above solution of CuI is directly used for the preparation of Compound 2. Yield: 84.6% Analysis: 1H NMR (300 MHz, MeOD): delta 7.48 (d, 1H); 7.24 (d, 1H); 7.19 (dd, 1H). MS (m/z): 263 (M+-H)

References: [1]Patent: WO2006/19831,2006,A1 .Location in patent: Page/Page column 445.
[2]Russian Journal of Organic Chemistry,2008,vol. 44,p. 1243 - 1244.
[3]Il Farmaco,2003,vol. 58,p. 173 - 183.
[4]Patent: US2016/2269,2016,A1 .Location in patent: Paragraph 0236; 0237.
[5]Nippon Kagaku Zasshi,1957,vol. 78,p. 1608,1612.
Chem.Abstr.,1959,p. 21342.
[6]Journal of Medicinal Chemistry,1997,vol. 40,p. 2474 - 2481.
[7]Patent: US5849798,1998,A .
[8]Patent: WO2007/77961,2007,A2 .Location in patent: Page/Page column 320.
[9]Patent: US2008/194668,2008,A1 .Location in patent: Page/Page column 7.
[10]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 6567 - 6582.
[11]Patent: US2014/81044,2014,A1 .Location in patent: Paragraph 0145-0149.
[12]Patent: WO2014/45135,2014,A1 .Location in patent: Page/Page column 16.

4
[ 81505-61-5 ]
[ 16870-28-3 ]
C₂₁H₁₄I₂O₁₁ [ No CAS ]

References: [1]Journal of Pharmaceutical Sciences,1984,vol. 73,p. 418 - 420.

5
[ 16870-28-3 ]
[ 105417-09-2 ]
2-Hydroxy-4-trifluorovinyl-benzoic acid [ No CAS ]

References: [1]Journal of Fluorine Chemistry,1991,vol. 54,p. 160.

6
[ 16870-28-3 ]
[ 74-88-4 ]
[ 148490-97-5 ]

References: [1]Journal of the American Chemical Society,2011,vol. 133,p. 51 - 55.
[2]Journal of Medicinal Chemistry,1992,vol. 35,p. 734 - 740.

7
[ 69-72-7 ]
[ 16870-28-3 ]

References: [1]Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical,1983,vol. 22,p. 770 - 773.

8
[ 38170-02-4 ]
[ 16870-28-3 ]

References: [1]Bulletin of the Chemical Society of Japan,2000,vol. 73,p. 417 - 422.
[2]Chemical and pharmaceutical bulletin,1963,vol. 11,p. 123 - 126.

9
[ 16870-28-3 ]
[ 77-78-1 ]
[ 89942-34-7 ]

References: [1]Chemical and pharmaceutical bulletin,1963,vol. 11,p. 123 - 126.

10
[ 292638-84-7 ]
[ 16870-28-3 ]
[ 193803-84-8 ]

References: [1]European Journal of Medicinal Chemistry,1997,vol. 32,p. 409 - 423.

11
[ 16870-28-3 ]
[ 89011-19-8 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide; In toluene; at 20℃; for 1h;Inert atmosphere;	Under nitrogen atmosphere, <strong>[16870-28-3]2-hydroxy-4-iodo-benzoic acid</strong> (975 mg, 3.69 mmol) is dissolved in toluene and oxalyl dichloride (3.693 mL of 2 M, 7.39 mmol) is added. The reaction is stirred for 2 minutes and dimethylformamide (13.5 mg, 15 mu, 0.185 mmol) is added. The reaction is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure to afford the title compound. The latter is used as is for the next step

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2474 - 2481.
[2]Patent: WO2013/134415,2013,A1 .Location in patent: Page/Page column 161.

12
[ 16870-28-3 ]
[ 100-39-0 ]
[ 170282-08-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In acetone; for 24h;Inert atmosphere; Reflux;	In a 50 mL dry, two necked round bottom flask, under N 2 atmosphere was added <strong>[16870-28-3]2-hydroxy-4-iodobenzoic acid</strong> 4 (5 mmol, 1.32 g), anhydrous acetone (25 mL), K 2 CO 3 (11 mmol, 1.52 g), and benzyl bromide (11 mmol, 1.30 mL) dropwise and the reaction was stirred overnight under reflux. The volatiles are evaporated and the residue was diluted with water (25 mL). The content was transferred to a separation funnel and extracted with EtOAc (3 x 25 mL). The organic combined was dried over MgSO 4 , filtered off and volatiles were evaporated. It was recovered a white solid with enough purity to further steps. Yield: 85% m.p.: 75-77C 1 H NMR: (300 MHz, CDCl 3 ): delta (ppm) 7.54 (d, J= 8.1 Hz, 1H), 7.50-7.30 (m, 12H), 5.31 (s, 2H), 5.10 (s, 2H). 13 C NMR: (75 MHz, CDCl 3 ): delta (ppm) 165.7, 158.4, 136.0, 136.0, 133.1, 130.0, 128.7, 128.6, 128.3, 128.2, 128.1, 127.3, 123.2, 120.4, 100.0, 71.0, 66.9. IR: max (neat, cm -1 ): 3064, 3030, 2944, 1726, 1601, 1568, 1492, 1456, 1432, 1380, 1274, 1259, 1223, 1160, 1091, 1000, 823, 756, 723, 693. HRMS: (ESI) m/z, calcd for [C 21 H 17 IO 3 + Na]: 467,0120; found: 467,0126.
	In N-methyl-acetamide; mineral oil;	Sodium hydride (4.7 g, 60% dispersion in mineral oil) is added portionwise over 15 minutes to a solution of <strong>[16870-28-3]4-iodosalicylic acid</strong> (15.4 g) in dry dimethylformamide (150 mL). After stirring for 40 minutes benzyl bromide (19.9 g) is added and the mixture heated at 60 C. for 1.5 hours. The reaction mixture is evaporated and the residue partitioned between chloroform and water. The organic phase is dried over magnesium sulphate, evaporated and the residue triturated with ether to give benzyl 2-benzyloxy-4-iodobenzoate (14.2 g) as a cream coloured solid.

References: [1]Tetrahedron,2018,vol. 74,p. 6866 - 6872.
[2]European Journal of Medicinal Chemistry,1997,vol. 32,p. 409 - 423.
[3]Patent: US6211234,2001,B1 .

13
[ 16870-28-3 ]
[ 70744-47-7 ]
3-hydroxy-4'-methoxy-biphenyl-4-carboxylic acid [ No CAS ]

References: [1]Tetrahedron Letters,1999,vol. 40,p. 415 - 418.

14
[ 16870-28-3 ]
[ 67-63-0 ]
2-hydroxy-4-iodo-benzoic acid isopropyl ester [ No CAS ]

References: [1]Bulletin of the Chemical Society of Japan,2000,vol. 73,p. 417 - 422.

16
[ 16870-28-3 ]
4-(tributyltin)benzoic acid on Merrifield resin [ No CAS ]
3-hydroxy-biphenyl-4,4'-dicarboxylic acid-4'-methyl ester [ No CAS ]

References: [1]Tetrahedron Letters,1999,vol. 40,p. 415 - 418.

17
[ 52898-32-5 ]
[ 16870-28-3 ]
4-[(E)-4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-but-1-enyl]-2-hydroxy-benzoic acid [ No CAS ]