58483-95-7|5-Amino-2-chloropyridine-4-carboxylic acid| Ambeed

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Quality Control of [ 58483-95-7 ] Purity: 98% SDS Specification

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Product Details of [ 58483-95-7 ]

CAS No. :	58483-95-7
Formula :	C₆H₅ClN₂O₂
M.W :	172.57
SMILES Code :	NC1=CN=C(C=C1C(=O)O)Cl
MDL No. :	MFCD06659499
InChI Key :	WCZUTMZMEAPPIX-UHFFFAOYSA-N
Pubchem ID :	22736791

Safety of [ 58483-95-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 58483-95-7 ] 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	40.61
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	76.21 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.89
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	1.21
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.02
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.	-1.1
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	0.68
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.54

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.01
Solubility	1.69 mg/ml ; 0.00978 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.	-2.41
Solubility	0.676 mg/ml ; 0.00392 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	-1.65
Solubility	3.85 mg/ml ; 0.0223 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	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.	-6.49 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	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)	1.65

Application In Synthesis of [ 58483-95-7 ]

* 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 [ 58483-95-7 ]

[ 58483-95-7 ] Synthesis Path-Downstream 1~35

1
[ 77287-34-4 ]
[ 58483-95-7 ]
[ 171178-47-5 ]

Yield	Reaction Conditions	Operation in experiment
83.9%	at 140℃;Product distribution / selectivity;	Step (e): 6-CHLORO-3H-PYRIDO [3, 4-D] PYRIMIDIN-4-ONE A suspension of 5-amino-2-chloro-isonicotinic acid in formamide (240 mL) was heated at an internal temperature of 140°C overnight with stirring. The mixture was cooled to room temperature, diluted with water (600mL), and stirred for 1 hour. The resulting solid was collected by filtration, washed with water, and dried to give 17. 20g of 6-chloro-3H-pyrido [3, 4-d] PYRIMIDIN-4-ONE as a brown solid (83. 9percent yield). 1H NMR (400 MHz, DMSO-D6) d ppm 7.9 (s, 1H), 8.2 (s, 1H), 8.9 (s, 1H), 12.7 (bs, 1H) MS (APCI) M+1 = 182.0
	at 140℃; for 12h;	a) Method for synthesising P-1 a:; delta-amino^-chloro-isonicotinic acid (4 g, 23.18 mmol) is taken up in the form of the amide (50 ml.) and stirred for 12 h at 140 0C. The reaction mixture is cooled to RT and mixed with water. The precipitate formed is filtered off, washed with water and then dried at 60 0C for 24h in the vacuum drying cupboard.The intermediate product obtained, 6-chloro-3/-/-pyrido[3,4-c/]pyrimidin-4-one (745 mg, 4.1 mmol), is suspended in thionyl chloride (10 ml_), mixed with one drop of DMF and refluxed for 16 h. The excess thionyl chloride is distilled off. The residue is taken up in DCM, washed 1x with semisaturated NaHCC>;3 solution and saturated NaCI solution, dried on Na2SC>;4 and concentrated to dryness by rotary evaporation. The crude product P-1a is further used directly.

References: [1]Journal of the Chemical Society. Perkin transactions I,1996,p. 2221 - 2226.
[2]Patent: WO2005/16926,2005,A1 .Location in patent: Page/Page column 116.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 3484 - 3493.
[4]Patent: WO2010/94695,2010,A1 .Location in patent: Page/Page column 35.

2
[ 171178-46-4 ]
[ 58483-95-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With trifluoroacetic acid; In dichloromethane;	5-Amino-2-chloropyridine-4-carboxylic acid. A stirred suspension of <strong>[171178-46-4]5-[N-(tert-butoxycarbonyl)amino]-2-chloropyridine-4-carboxylic acid</strong> (1.91 g, 7 mmol) in CH2 Cl2 (200 mL) is treated slowly with trifluoroacetic acid until homogeneous (ca. 12 mL). The solution is stirred overnight and extracted with dilute NH4 OH, and the aqueous layer is then acidified with dilute HCl to gave a precipitate of 5-amino-2-chloropyridine-4-carboxylic acid (1.05 g, 87percent yield). 1 H NMR (DMSO) delta 9.01 (2H, m), 8.03 (1H, s), 7.48 (1H, s).
80 - 93.6%	With trifluoroacetic acid; In dichloromethane; at 20℃;	Step (d): 5-AMINO-2-CHLORO-ISONICOTINIC acid A suspension of <strong>[171178-46-4]5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid</strong> in methylene chloride (600mL) was treated dropwise at room temperature with TFA until the solid had dissolved into solution (95 mL). The reaction mixture was stirred overnight under nitrogen at room temperature, evaporated to dryness, diluted with water, and the solid collected by filtration. The solid was washed with water, dried under low heat and house vacuum, to afford 19.55g of 5-amino- 2-chloro-isonicotinic acid as a yellow solid (93.6percent yield). 1H NMR (400 MHz, DMSO-D6) 8 ppm 7.5 (s, 2H), 8.0 (s, 2H) MS (APCI) M+1= 173.0; Step (d): 5-AMINO-2-CHLORO-ISONICOTINIC acid A 3 L round bottomed flask was charged with 5-tert- BUTOXYCARBONYLAMINO-2-CHLORO-ISONICOTINIC acid (138 g, 0.51 moles), 1 L of CH2C12, and 400 mL of TFA. The resulting orange solution was stirred overnight at room temperature. One liter of H20 was added to the reaction solution, which caused a solid to precipitate out. The solid was collected, washed once with H2O and dried overnight in the vacuum oven at 45°C. The reaction yielded 69.6 g (80percent total yield) of 5-amino-2-chloro-isonicotinic acid as a pale yellow solid, which was pure enough by NMR to use in the next reaction. ON (DMSO) 7.99 (1 H, d), 7.45 (1 H, d) MS [M+H] + 173
		Step 3: Preparation of 5-amino-2-chloroisonicotinic acid; A suspension of 5- tert-butoxycarbonylamino-2-chloro- isonicotinic acid (2.46 g) in aqueous 2N potassium hydroxide solution (45 mL) was stirred at 90°C for 5 hours, <n="407"/>After cooling to room temperature, the solution was acidified by slow addition of 6N hydrochloric acid. The formed precipitate was filtered off, washed with water, MTB-ether and hexane and dried in vacuum to afford 700 mg of the title compound of the formulaas beige solid .1H-NMR ( DMSO-D6) delta (ppm) : 7 . 47 ( IH , s ) , 8 . 02 ( IH, s ) .

References: [1]Journal of the Chemical Society. Perkin transactions I,1996,p. 2221 - 2226.
[2]Patent: US5654307,1997,A .
[3]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.
[4]Patent: WO2005/16926,2005,A1 .Location in patent: Page/Page column 115-116; 123.
[5]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 256 - 261.
[6]Patent: WO2008/130021,2008,A2 .Location in patent: Page/Page column 405-406.

3
[ 3473-63-0 ]
[ 58483-95-7 ]
[ 171178-47-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	In 2-methoxy-ethanol; for 18h;Heating / reflux;Product distribution / selectivity;	Step (e) 6-Chloro-3H-pyrido [3,4-d] pyrimidin-4-one A 1 L round bottomed flask was charged with 5-amino-2-chloro- isonicotinic acid (69.5 g, 0.40 moles), formamidine acetate (84 g, 0.81 moles, 2 mole equivalents), and 600 mL of methoxyethanol. The resulting solution was heated at reflux for 18 hours. After cooling to 5°C, a precipitate was collected by filtration, washed twice with methoxyethanol, and dried overnight in the vacuum oven at 45°C. The reaction yielded 67 g (92percent total yield) of 6-chloro-3H- pyrido [3, 4-D] PYRIMIDIN-4-ONE as a tan solid that was sufficiently pure by NMR to use in the next reaction. 8H (DMSO) 12.70 (1 H, s), 8.86 (1 H, d), 8. 19 (1 H, s), 7.93 (1 H, d) MS [M+H3+ 182

References: [1]Patent: WO2005/16926,2005,A1 .Location in patent: Page/Page column 123-124.
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.

4
[ 5326-23-8 ]
[ 58483-95-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.

5
[ 58483-95-7 ]
[ 171178-48-6 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3484 - 3493.
[3]Patent: TWI525093,2016,B .
[4]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 256 - 261.
[5]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3619 - 3633.

6
[ 58483-95-7 ]
[ 189680-99-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.

7
[ 58483-95-7 ]
[ 189680-98-6 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.

8
[ 58483-95-7 ]
[ 202272-67-1 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.

9
[ 58483-95-7 ]
[ 202272-97-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.

10
[ 58483-95-7 ]
GW₂₉₇₄ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.

11
[ 58483-95-7 ]
N₄-(1-Benzyl-1H-indol-5-yl)-N₆,N₆-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.

12
[ 58483-95-7 ]
[ 202272-71-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.

13
[ 58483-95-7 ]
N₄-(2-Benzyl-1H-benzimidazol-5-yl)-N₆,N₆-dimethyl-pyrido[3,4-d]-pyrimidine-4,6-diamine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.

14
[ 171178-45-3 ]
[ 58483-95-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.
[2]Journal of the Chemical Society. Perkin transactions I,1996,p. 2221 - 2226.
[3]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 256 - 261.
[4]Patent: WO2008/130021,2008,A2 .

15
[ 5350-93-6 ]
[ 58483-95-7 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1996,p. 2221 - 2226.
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 256 - 261.
[3]Patent: WO2008/130021,2008,A2 .

16
[ 58483-95-7 ]
[ 171178-47-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	In formamide;	6-Chloro-3H-pyrido[3,4-d]pyrimidin-4-one. A solution of 5-amino-2-chloropyridine-4-carboxylic acid (8.1 g, 4.7 mmol) in formamide (100 mL) is stirred at 140° C. for 12 h. Dilution of the cooled mixture with water gives a precipitate of 6-chloro-3H-pyrido[3,4-d]pyrimidin-4-one (7.3 g, 86percent yield). 1 H NMR (DMSO) delta 12.73 (1H, m), 8.90 (1H, d, J=0.7 Hz), 8.23 (1H, s), 7.97 (1H, d, J=0.7 Hz).

References: [1]Patent: US5654307,1997,A .

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; methanol; In 1,4-dioxane; at 0 - 25℃; for 1h;	A solution of 5-tert-butoxycarbonyl amino-2-chloro-isonicotinic acid (Method 126; 2.06 g, 7.6 mmol) in methanol (10 ml) at 0 °C was treated with a solution of HCl in dioxane (4N, 2.3 ml). The resulting cloudy solution stirred at 25 °C for 1 hour. The solvent was evaporated under reduced pressure to afford the desired product; m/z 173.

18
[ 58483-95-7 ]
[ 18107-18-1 ]
[ 1073182-59-8 ]

Yield	Reaction Conditions	Operation in experiment
67.7%	In methanol; hexane; ethyl acetate; at 24 - 30℃; for 0.5h;Inert atmosphere;	To a solution of compound 6a (4.0 g, 23.2 mmol) in EtOAc/MeOH=1: 1 (60 mL) was added TMSCH 2N 2 (23.2 mL, 46.4 mmol, 2 M in hexane). The resulting mixture was stirred at 24-30C for 30 min. The reaction mixture was poured into H2O (30 mL), and extracted with EtOAc (50 mL 3). The combined organic layers were washed with water (20 mL 3) and brine (20 mL), dried over Na 2SO 4 and concentrated in vacuo to give the title compound 6b (3.1 g, 67.7% yield) as a yellow solid. LCMS: Rt = 0.672 min in 5-95AB_220&254. lcm chromatography (ACSSH-LCMS-AB MERCK RP18 2.5-2mm), MS (ESI) m/z=186.9 [M+H] +. 1H NMR (400MHz, DMSO-d 6) delta 8.06 (s, 1H), 7.50 (s, 1H), 6.79 (br s, 2H), 3.84 (s, 3H).
	In methanol; diethyl ether; toluene; at 20℃; for 2h;	Step 4 : Preparation of S-amino-S-chloroisonicotinic acid methyl ester; 5-Amino-2-chloroisonicotinic acid (1.72 g) was suspended in methanol (20 mL) and toluene (60 mL) was added. A solution of (trimethylsilyl ) diazomethane (2.0 M in diethyl ether, 6.5 mL) was added slowly to the suspension. Within 5 to 10 minutes after addition, the suspension turned into a solution. After 2 hours stirring at room temperature, the reaction mixture was quenched with water and extracted 3x with ethyl acetate. The combined organic layer was washed with saturated bicarbonate solution and brine, dried over MgSO4 and concentrated in vacuum.The residue was purified by column chromatography (silica gel 60, chloroform/ethyl acetate = 20:1, Rf = 0.30 in chloroform/ethyl acetate = 3:1) to afford 1.50 g of the <n="408"/>title compound of the formulaas a white solid.1H-NMR (DMSO-D6) delta (ppm) : 3.83 (3H, s) , 6.77 (2H, s), 7.48 (IH, s) , 8.05 (IH, s) .

References: [1]Patent: WO2019/149164,2019,A1 .Location in patent: Page/Page column 73-74; 60.
[2]Patent: WO2008/130021,2008,A2 .Location in patent: Page/Page column 406-407.

19
[ 1336910-15-6 ]
[ 58483-95-7 ]
[ 1381862-66-3 ]