942589-45-9|Methyl 3-amino-5-iodo-2-thiophenecarboxylate| Ambeed

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Quality Control of [ 942589-45-9 ] Purity: 98% SDS Specification

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Product Details of [ 942589-45-9 ]

CAS No. :	942589-45-9
Formula :	C₆H₆INO₂S
M.W :	283.09
SMILES Code :	O=C(C1=C(N)C=C(I)S1)OC
MDL No. :	MFCD18157627
InChI Key :	UCHQIMLGNJWRBI-UHFFFAOYSA-N
Pubchem ID :	45480422

Safety of [ 942589-45-9 ]

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

Computational Chemistry of [ 942589-45-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	5
Fraction Csp3	0.17
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	52.72
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	80.56 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.0
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	2.34
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.73
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.	1.24
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	2.65
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.99

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.27
Solubility	0.151 mg/ml ; 0.000532 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.	-3.67
Solubility	0.0604 mg/ml ; 0.000213 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	-2.33
Solubility	1.32 mg/ml ; 0.00468 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	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.	-6.37 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	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)	2.73

Application In Synthesis of [ 942589-45-9 ]

* 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 [ 942589-45-9 ]

[ 942589-45-9 ] Synthesis Path-Downstream 1~35

1
[ 1007171-35-8 ]
[ 942589-45-9 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 39Methyl 3-amino-5-iodo-2-thiophenecarboxylate <n="48"/>Intermediate 38 (4.097 g) was dissolved in 4M HCI in 1 ,4-dioxane solution (40 ml_). The resulting solution was stirred under nitrogen at room temperature for 7 h. The solvent was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and DCM. The organics were separated using a hydrophobic frit and were evaporated in vacuo to give the title compound. 1H NMR (CDCI3) delta 6.73 (1 H, s), 5.46 (2H, br), 3.82 (3H, s).

References: [1]Patent: WO2008/17688,2008,A1 .Location in patent: Page/Page column 46-47.

2
[ 942589-45-9 ]
[ 1007171-36-9 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 40 Methyl 5-iodo-3-(tetrahydro-3-furanylamino)-2-thiophenecarboxylateA solution of Intermediate 39 (3.06 g) in dry DCM (61 ml.) was added to cyclopentanone (1.85 g). To the resulting solution was added glacial acetic acid (1.85 ml_). Sodium triacetoxyborohydride (4.57 g) was added portion-wise, and the resulting solution was stirred under nitrogen at room temperature for 20 h, then at 4O0C for 6 days. The reaction was allowed to cool to room temperature and was quenched with saturated sodium bicarbonate solution. The organic phase was diluted with DCM and the layers were separated. The organics were dried using a hydrophobic frit and were evaporated in vacuo. The crude material was purified by ISCO Companion silica chromatography, eluting with a gradient 5- 100% EtOAc in cyclohexane. The material was purified further by reverse phase ISCO Companion chromatography, using a C18 cartridge, eluting with a gradient 30% MeCN (0.05% formic acid)/water (0.1 % formic acid) to 80% MeCN (0.05% formic acid) to give the title compound. MS calcd for (CI0H12I NO3S + H)+: 354 MS found (electrospray): (M+H)+ = 354

References: [1]Patent: WO2008/17688,2008,A1 .Location in patent: Page/Page column 47.

3
[ 942589-45-9 ]
[ 116-11-0 ]
[ 942589-46-0 ]

Yield	Reaction Conditions	Operation in experiment
		To Intermediate 3 (4.4 g) in dry DCM (80 ml_) was added 2-methoxypropene (6 mL) and acetic acid slowly (3.6 mL), followed by sodium triacetoxyborohydride (6.6 g) added portion wise while controlling the temperature. The mixture was stirred at room temperature under nitrogen overnight. The reaction was neutralised by slowly adding sodium bicarbonate and extracted with DCM. The organics were dried (Na2SO4) and concentrated. The crude product was then purified by Biotage silica chromatography eluting with EtOAc in cyclohexane (2.5%) to give the title compound. MS calcd for (C9H12INO2S+ H)+: 326 MS found (electrospray): (M+H)+ = 326

References: [1]Patent: WO2007/71434,2007,A1 .Location in patent: Page/Page column 27-28.

4
[ 942589-44-8 ]
[ 942589-45-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In methanol; water; at 20℃; for 1h;	Potassium carbonate (8.1 g) was added in one portion to Intermediate 2 (3.7 g) in MeOH (130 mL) and water (18.5 mL) at room temperature. The reaction was stirred for 1 h, then partitioned between water and EtOAc. The organics were washed with brine, dried (Na2SO4 ) and concentrated to give the title compound. MS calcd for (C6H6INO2S + H)+: 284 MS found (electrospray): (M+H)+ = 284
	With potassium carbonate; In methanol; water; at 20℃; for 18h;	Intermediate 8 Methyl S-amino-delta-iodo^-thiophenecarboxylate <n="34"/>A mixture of methyl 5-iodo-3-[(trifluoroacetyl)amino]-2-thiophenecarboxylate (Intermediate 7) (0.98 g, 2.59 mmol) and potassium carbonate (1.8 g, 13 mmol) in methanol (60 ml.) and water (6 ml.) was stirred at room temperature for 18 h. The solvent was evaporated and partitioned between water (30 ml.) and DCM (50 ml_), then passed through a hydrophobic frit and the organic fraction evaporated. The crude material was purified by ISCO Companion silica chromatography, eluting with a gradient of 0-20% ethyl acetate in cyclohexane to give the title compound. Further quantities were obtained by collecting the early eluting fractions and further purification by ISCO Companion silica chromatography, eluting with a gradient 0-50% DCM in cyclohexane.MS calcd for (C6H6INO2S + H)+: 284MS found (electrospray): (M+H)+ = 284

References: [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6293 - 6302.
[2]Patent: WO2007/71434,2007,A1 .Location in patent: Page/Page column 27.
[3]Patent: WO2009/818,2008,A1 .Location in patent: Page/Page column 32-33.

5
[ 942589-45-9 ]
[ 394-39-8 ]
[ 1019338-25-0 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 43 (1 g) was dissolved in DCM (40 mL) and triethylamine (1.3 mL) was added, followed by 4-chloro-2-fluorobenzoyl chloride (1.4 g). The reaction was stirred at room temperature for 2 h. A precipitate was observed. The reaction was acidified with 2N HCI and was stirred at room temperature for 1.5 h. The solid was filtered off to give the title compound.MS calcd for (C13H8CIFINO3S + H)+: 439/441MS found (electrospray): (M+H)+ = 439/441

References: [1]Patent: WO2008/43791,2008,A2 .Location in patent: Page/Page column 50.

6
[ 942589-45-9 ]
[ 5878-19-3 ]
[ 1019338-38-5 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of methyl S-amino-delta-iodo^-thiophenecarboxylate (0.60 g, a synthesis of which is described as Intermediate 43), methoxyacetone (0.39 ml.) and titanium (IV) isopropoxide (0.74 ml.) in dry DCM (30 ml.) was warmed to reflux under nitrogen for 18 h. Sodium triacetoxyborohydride (1.35 g) was added and the reaction was heated at reflux under nitrogen for 4 days. The reaction was evaporated in vacuo and the residue was taken into water (30 ml.) and was extracted with DCM (3 x 30 ml_). The organics were dried by passing through a hydrophobic frit and evaporated in vacuo. The crude material was purified by <n="58"/>ISCO Companion silica chromatography, eluting with a gradient 0-100% EtOAc in cyclohexane to give the title compound.1H NMR (DMSO-d6) delta 7.18 (1 H, s), 3.85-3.77 (1 H, m), 3.69 (3H, s), 3.36-3.33 (2H, m), 3.28 (3H, s), 1.12 (3H, d), amine proton not seen.

References: [1]Patent: WO2008/43791,2008,A2 .Location in patent: Page/Page column 56-57.

7
[ 1019338-24-9 ]
[ 942589-45-9 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 42 (3 g) was dissolved in DCM (30 mL) and TFA (7.5 mL) was added. The reaction mixture was stirred at room temperature for 4 h and was evaporated in vacuo. The residue was partitioned between DCM and saturated sodium bicarbonate solution. The organics were dried by passing through a hydrophobic frit and were evaporated in vacuo to give the title compound.MS calcd for (C6H6INO2S + H)+: 284MS found (electrospray): (M+H)+ = 284

References: [1]Patent: WO2008/43791,2008,A2 .Location in patent: Page/Page column 49-50.

8
[ 942589-45-9 ]
[ 55930-23-9 ]
[ 1027708-01-5 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,2-dichloro-ethane; for 3h;Heating / reflux;	Intermediate 9Methyl 5-iodo-3-[(frans-4-methylcyclohexyl)carbonyl]amino}-2-thiophenecarboxylateTo a mixture of methyl S-amino-delta-iodo^-thiophenecarboxylate (Intermediate 8) (0.54 g) in DCE (25 ml.) was added frans-4-methylcyclohexanecarbonyl chloride1 (910 mg, 5.7 mmol) and the mixture heated under reflux under nitrogen for 3 h. The mixture was cooled, water (20 ml.) was added, and after stirring for 5 mins, the mixture was passed through a hydrophobic frit. The aqueous layer was extracted twice with DCM, the organic fractions combined, dried (hydrophobic frit) and evaporated. The crude material was purified by ISCO Companion silica chromatography, eluting with a gradient 0-50% DCM in cyclohexane to give the title compound. MS calcd for (C14H18INO3S + H)+: 408 MS found (electrospray): (M+H)+ = 408

References: [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6293 - 6302.
[2]Patent: WO2009/818,2008,A1 .Location in patent: Page/Page column 33.

9
trans-4-methylcyclohexanecarbonyl chloride [ No CAS ]
[ 942589-45-9 ]
methyl 5-iodo-3-[(trans-4-methylcyclohexyl)carbonyl]amino}-2-thiophenecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With pyridine; In dichloromethane; 1,2-dichloro-ethane; at 0 - 20℃; for 1.3h;	Alternative Preparation of Compound 6Step 1:The acid chloride was prepared from the carboxylic acid by mixing with oxalyl chloride (1.1 eq.), in toluene (10 volume equivalents) at 0C with a catalytic amount (0.05 eq.) of DMF and slowly warming to RT (gas evolved). After stirring for 16 hours, the toluene was removed at 45C by rotary evaporation until the mixture was ca. two times the mass of the theoretical yield (50% by weight). The acid chloride could be stored at 0C under nitrogen for use as is in subsequent steps. Mixed commercially available methyl 3-amino- 5-iodo-thiophene-2-carboxylate (5 g, 17.49 mmol) at 0C in 10% Pyridine/DCE/DCM (49.5 mL) and Pyridine (2.91 g, 2.97 mL, 36.7 mmol) as solvent, and then added the acid chloride (6.70 g, 21.0 mmol, 50% in toluene) dropwise. After 5 min, removed bath, and stirred as reaction came to RT for 1.25 hours. Worked up by adding brine, and then extraction with DCM (2x100 mL), combined and washed with IN HC1 (50 mL), washed with 1 : 1 IN NaOH (50 mL) / brine (50 mL); back extracted lx, then dried over sodium sulfate, filtered and stripped to give a solid. Triturated the solid with hexanes, filtered and air dried to give desired product, 4.9g (68%). Analysis by LCMS (60-98 MeOH/H20, formic acid modifier, 5/7 minutes, C18); RT = 2.45 min, [M+H] = 407.14.

References: [1]Patent: WO2012/6055,2012,A2 .Location in patent: Page/Page column 108.

10
[ 22288-78-4 ]
[ 942589-45-9 ]

References: [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6293 - 6302.
[2]Patent: WO2008/17688,2008,A1 .

11
[ 79128-68-0 ]
[ 942589-45-9 ]