1235036-15-3|tert-Butyl 3-bromo-6-chloropicolinate| Ambeed

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Quality Control of [ 1235036-15-3 ] Purity: 97% SDS Specification

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Product Details of [ 1235036-15-3 ]

CAS No. :	1235036-15-3
Formula :	C₁₀H₁₁BrClNO₂
M.W :	292.56
SMILES Code :	O=C(OC(C)(C)C)C1=NC(Cl)=CC=C1Br
MDL No. :	MFCD19443279
InChI Key :	JKGXLKXQUDHRLL-UHFFFAOYSA-N
Pubchem ID :	59447676

Safety of [ 1235036-15-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P264-P270-P301+P312-P330

Computational Chemistry of [ 1235036-15-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.4
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	62.69
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	39.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.68
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	3.68
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.45
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.	2.53
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	3.24
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.12

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.07
Solubility	0.0249 mg/ml ; 0.0000851 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.19
Solubility	0.0188 mg/ml ; 0.0000641 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	-4.38
Solubility	0.0121 mg/ml ; 0.0000412 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	Yes
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	Yes
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.	-5.47 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<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)	2.25

Application In Synthesis of [ 1235036-15-3 ]

* 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 [ 1235036-15-3 ]

[ 1235036-15-3 ] Synthesis Path-Downstream 1~35

1
[ 929000-66-8 ]
[ 75-65-0 ]
[ 1235036-15-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridine; p-toluenesulfonyl chloride; at 0 - 12℃; for 12.0h;	Tosyl chloride (7.7 g, 40.4 mmol) was added to a solution of 2-chloro-5- bromo picolinic acid (4 g, 17 mmol) and pyridine (9.2 mL, 114 mmol) in 33 mL of t-BuOH at 00C. The reaction was then stirred at room temperature for 12 hours. NaHCO3Sat was then added and the mixture was extracted with ethyl acetate (3 times). The combined organic phases were washed with brine and dried over Na2SO4. Concentration afforded the desired compound 12 IA (quantitative). It was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) £7.85 (d, IH), 7.26 (d, IH), 1.63 (s, 9H).
		Tosyl chloride (7.7 g, 40.4 mmol) was added to a solution of 2-chloro-5- bromo picolinic acid (4 g, 17 mmol) and pyridine (9.2 mL, 114 mmol) in 33 mL of t-BuOH at 00C. The reaction was then stirred at room temperature for 12 hours. NaHCO3 (Sat.) was then added and the mixture was extracted with ethyl acetate (3 times). The combined organic phases were washed with brine and dried over Na2SO4. Evaporation of the organic solvent afforded the desired compound 94A, which is used in the next step without further purification: 1H NMR (300 MHz, DMSO-d6) delta ppm 8.27 (1 H, d), 7.63 (1 H, d), 1.57 (9 H, s).
	With pyridine; p-toluenesulfonyl chloride; In tert-butyl alcohol; at 0 - 20℃; for 12.0h;	Example 1D tert-butyl 3-bromo-6-chloropicolinate Tosyl chloride (7.7 g) was added to a solution of 2-chloro-5-bromo picolinic acid (4 g) and pyridine (9.2 mL) in t-butanol (33 mL) at 0 C. The reaction was then stirred at room temperature for 12 hours. NaHCO3 (aqueous, saturated) was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over Na2SO4. Filtration and evaporation of the organic solvent provided the title compound which was used in the next step without further purification.

	With pyridine; p-toluenesulfonyl chloride; In tert-butyl alcohol; at 0 - 20℃; for 12.0h;	Example 1C tert-butyl 3-bromo-6-chloropicolinate Tosyl chloride (7.7 g) was added to a solution of 2-chloro-5-bromo picolinic acid (4 g) and pyridine (9.2 mL) in t-butanol (33 mL) at 0 C. The reaction was then stirred at room temperature for 12 hours. NaHCO3 (aqueous, saturated) was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over Na2SO4. Filration and evaporation of the organic solvent provided the title compound which was used in the next step without further purification.
	With pyridine; p-toluenesulfonyl chloride; at 0 - 20℃; for 12.0h;	To a solution of 2-chloro-5-bromo picolinic acid (4 g) and pyridine (9.2 mL) in i-butanol (33 mL) at 0 C was added >-toluenesulfonyl chloride (7.7 g). The resulting mixture was stirred at room temperature for 12 hours. Saturated aqueous NaHC03 solution was added, and the resulting mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2S04, filtered and concentrated to provide the title compound.

References: [1]Patent: WO2010/80503,2010,A1 .Location in patent: Page/Page column 232-233.
[2]Patent: WO2010/80503,2010,A1 .Location in patent: Page/Page column 199.
[3]Patent: US2013/96120,2013,A1 .Location in patent: Paragraph 0878.
[4]Patent: US2013/96121,2013,A1 .Location in patent: Paragraph 1224.
[5]Patent: WO2014/28381,2014,A1 .Location in patent: Page/Page column 112.
[6]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 662 - 667.

2
[ 1235036-15-3 ]
N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide dihydrochloride [ No CAS ]
[ 1235036-16-4 ]

Yield	Reaction Conditions	Operation in experiment
80%		Cs2CO3 (4.1 g, 12.6 mmol) and 4A sieves were dried under high vacuum at 1500C for 6 to 10 hours before the start of the reaction. After cooling to room temperature, compound 94A (0.736g, 2.53 mmol) and compound IB (1.62 g, 3 mmol) were transferred to the reaction vessel and the atmosphere was purged with nitrogen. 12 mL of anhydrous DMA were then added and the reaction was stirred at 1200C for 12 hours. The cooled reaction mixture was then diluted with ethyl acetate and 10% citric acid. The organic phase was washed three times with citric acid, once with water and brine, and dried over Na2SO4. Concentration afforded an orange film/foam. Purification on Flash Master (SiO2, ethyl acetate/petroleum ether 0: 100 to 40:60) afforded a white solid (1.15 g, 80 % yield): 1H NMR (300 MHz, DMSO-d6) delta ppm 12.84 (1 H, s), 8.03 (1 H, d), 7.77 (2 H, m), 7.58 (1 H, d), 7.40 (4 H, m), 6.86 (1 H, d), 4.92 (2 H, s), 3.78 (2 H, t), 3.01 (2 H, t), 1.34 (9 H, s).
80%	With caesium carbonate; In ISOPROPYLAMIDE; at 120℃; for 12.0h;Inert atmosphere;	Cs2CO3 (4.1 g, 12.6 mmol) and 4A sieves were dried under high vacuum at 1500C for 6 to 10 hours before the start of the reaction. Once cooled down, compound 121A (0.736 g, 2.53 mmol) and compound IB (1.62 g, 3 mmol) were transferred to the reaction vessel and the atmosphere was purged with nitrogen. 12 mL of anhydrous DMA were then added and the reaction was stirred at 1200C for 12 hours. The cooled reaction mixture was then diluted with ethyl acetate and citric acid 10%. The organic phase was washed three times with citric acid, once with water and brine, and dried over Na2SO4. Concentration of the organic phase afforded an orange film/foam. Purification on Flash Master (SiO2, ethyl acetate/petroleum ether 0:100 to 40:60) afforded a the product 121B as a white solid (1.15 g, 80 % yield): 1H NMR (300 MHz, CDCl3) delta 7.86 (m, IH), 7.71 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 7.42-7.22 (m, 5H), 6.67 (d, IH), 4.99 (s, 2H), 3.95 (t, 2H), 3.01 (t, 2H), 1.56 (s, 9H).
	With caesium carbonate; In N,N-dimethyl acetamide; at 120℃; for 12.0h;	Example 1E tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate EXAMPLE 1D (0.736 g), EXAMPLE 1C (1.62 g), and Cs2CO3 (4.1 g) were stirred in 12 mL of anhydrous N,N-dimethylacetamide at 120 C. for 12 hours. The cooled reaction mixture was then diluted with ethyl acetate and 10% citric acid. The organic phase was washed three times with citric acid, once with water and brine, and dried over Na2SO4. Filtration and concentration afforded crude material, which was chromatographed on silica gel using 0-40% ethyl acetate in hexanes to provide the title compound.

	With caesium carbonate; In N,N-dimethyl acetamide; at 120℃; for 12.0h;	Example 1D tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate EXAMPLE 1C (0.736 g), EXAMPLE 1B (1.62 g), and Cs2CO3 (4.1 g) were stirred in 12 mL of anhydrous N,N-dimethylacetamide at 120 C. for 12 hours. The cooled reaction mixture was then diluted with ethyl acetate and 10% citric acid. The organic phase was washed three times with citric acid, once with water and brine, and dried over Na2SO4. Filtration and concentration afforded crude material, which was chromatographed on silica gel using 0-40% ethyl acetate in hexanes to provide the title compound.
	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12.0h;	A mixture of Example 5C (0.736 g), Example 5B (1.62 g), and Cs2C03 (4.1 g) in N,N- dimethylformamide (15 mL) was heated at 120 C for 12 hours, cooled, diluted with ethyl acetate, and acidified with 10% citric acid. The organic layer was washed with water and brine, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with 0-40% ethyl acetate in hexanes, to provide the title compound.

References: [1]Patent: WO2010/80503,2010,A1 .Location in patent: Page/Page column 199-200.
[2]Patent: WO2010/80503,2010,A1 .Location in patent: Page/Page column 233.
[3]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 662 - 667.
[4]Patent: US2013/96120,2013,A1 .Location in patent: Paragraph 0879; 0880.
[5]Patent: US2013/96121,2013,A1 .Location in patent: Paragraph 1225.
[6]Patent: WO2014/28381,2014,A1 .Location in patent: Page/Page column 112.

3
[ 1235036-15-3 ]
[ 1430846-07-3 ]

References: [1]Patent: US2013/96120,2013,A1 .

4
[ 1235036-15-3 ]
[ 1447273-71-3 ]

References: [1]Patent: US2013/96120,2013,A1 .

5
[ 1235036-15-3 ]
[ 1430844-78-2 ]

References: [1]Patent: US2013/96120,2013,A1 .

6
[ 1235036-15-3 ]
[ 1430844-79-3 ]

References: [1]Patent: US2013/96120,2013,A1 .

7
[ 1235036-15-3 ]
[ 1430845-66-1 ]

References: [1]Patent: US2013/96120,2013,A1 .

8
[ 1235036-15-3 ]
[ 1430845-36-5 ]

References: [1]Patent: US2013/96120,2013,A1 .

9
[ 1235036-15-3 ]
[ 1430750-74-5 ]

References: [1]Patent: US2013/96120,2013,A1 .
[2]Patent: US2013/96121,2013,A1 .

10
[ 1235036-15-3 ]
[ 1430845-73-0 ]

References: [1]Patent: US2013/96120,2013,A1 .

11
[ 1029689-82-4 ]
[ 1235036-15-3 ]
[ 1430847-06-5 ]