907545-47-5|2-Chloro-5-nitroisonicotinic acid| Ambeed

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Quality Control of [ 907545-47-5 ] Purity: 98% SDS Specification

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Product Details of [ 907545-47-5 ]

CAS No. :	907545-47-5
Formula :	C₆H₃ClN₂O₄
M.W :	202.55
SMILES Code :	O=C(O)C1=C([N+]([O-])=O)C=NC(Cl)=C1
MDL No. :	MFCD14584664
InChI Key :	YIKBSICAFIIUER-UHFFFAOYSA-N
Pubchem ID :	18440622

Safety of [ 907545-47-5 ]

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

Computational Chemistry of [ 907545-47-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	2
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	45.03
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	96.01 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	-0.3
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	1.17
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.34
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.	-1.54
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	-0.69
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.0

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.04
Solubility	1.84 mg/ml ; 0.00907 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.	-2.78
Solubility	0.335 mg/ml ; 0.00165 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	-1.4
Solubility	8.05 mg/ml ; 0.0397 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.	-6.7 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	3.0 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)	2.05

Application In Synthesis of [ 907545-47-5 ]

* 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.

Upstream synthesis route of [ 907545-47-5 ]
Downstream synthetic route of [ 907545-47-5 ]

[ 907545-47-5 ] Synthesis Path-Upstream 1~5

1
[ 907545-47-5 ]
[ 88482-17-1 ]

References: [1] Patent: WO2016/29454, 2016, A1, .

2
[ 23056-33-9 ]
[ 907545-47-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	at 0 - 20℃;	2-chloro-4-methyl-5-nitropyridine (31 g, 180 mmol) was dissolved in conc.H2SO4 (300mL) and the resulting mixture was cooled to 0 °C. CrO3 (59.4 g, 594 mmol) was added to the solution. After stirring for 1 h at 0 °C, the mixture was warmed up to room temperature and stirred overnight. It was poured into ice-water (1 L). The mixture was warmed up to room temperature and filtered. The solid was then washed with water ( 2 L) and dried in vacuo to afford the desired product as a white solid (28.5g, 78percent); LC/MS: MS(ES) m/e 203 (MH=); 1H NMR (300 MHz, DMSO-d6) δ ppm 8.04 (s, 1 H), 9.16 (s, 1 H).
75%	at 0 - 20℃; for 13 h;	(Step 1) 2-Chloro-5-nitro-pyridine-4-carboxylic acid (0167) (0168) 2-Chloro-4-methyl-5-nitro-pyridine (20.5 g, 119 mmol) was dissolved in concentrated sulfuric acid (200 ml), the resulting solution was cooled to 0° C., then chromium(VI) oxide (40.0 g, 400 mmol) was added thereto, and the resulting mixture was stirred at 0° C. for 1 hour and then at room temperature for 12 hours. The reaction liquid was diluted with water (2,000 ml), and the precipitated solid was filtered and dried to obtain the title compound (18.0 g, 75percent). (0169) ¹H NMR (400 MHz, CD₃OD): δ 10.8 (br, s, 1H), 9.13 (s, 1H), 7.70 (s, 1H).
73%	at 0 - 20℃; for 1 h; Inert atmosphere	[00610] Step 1: To a solution of 2-chloro-4-methyl-5-nitro-pyridine (10.35 g, 60 mmol) in H₂S0₄ (100 mL), Cr0₃ (19.8 g, 198 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 h and then was allowed to warm to room temperature and stirred overnight. The mixture was poured into ice water (500 mL). The resulting solid was filtered and dried to give 2-chloro-5-nitro-isonicotinic acid (8.89 g, yield: 73percent) as a white solid. MS: m/z 200.9 (M-H⁺).

18 g

at 0 - 20℃; for 13 h;

2-Chloro-4-methyl-5-nitropyridine (20.5 g, 119 mmol) was dissolved in concentrated sulfuric acid (200 ml), and chromium trioxide (40.0 g, 400 mmol) was added thereto, followed by stirring at 0° C. for 1 hour. Then, the temperature was gradually raised from 0° C. to room temperature, followed by stirring for 12 hours. The reaction solution was poured into ice-water (2000 ml), and the temperature was raised from 0° C. to room temperature. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (18 g, 750). [0144] ¹H NMR (CD3OD, 400 MHz): δ 10.8 (1H, br, s), 9.13 (1H, s), 7.70 (1H, s)

References: [1] Patent: WO2013/95761, 2013, A1, . Location in patent: Page/Page column 39.
[2] Patent: US2016/244451, 2016, A1, . Location in patent: Paragraph 0167; 0168; 0169.
[3] Patent: WO2015/200534, , A2, . Location in patent: Paragraph 00610[3] Patent: , 2015, , . Location in patent: Paragraph 00610.
[5] Patent: US2006/122236, 2006, A1, . Location in patent: Page/Page column 20.
[6] Patent: US2006/106011, 2006, A1, . Location in patent: Page/Page column 23.
[7] Patent: WO2011/45258, 2011, A1, . Location in patent: Page/Page column 53-54.
[8] Patent: EP2366691, 2011, A1, . Location in patent: Page/Page column 13.
[9] Patent: US2015/51395, 2015, A1, . Location in patent: Paragraph 0143-0144.
[10] Patent: WO2016/29454, 2016, A1, . Location in patent: Page/Page column 46.

3
[ 21901-41-7 ]
[ 907545-47-5 ]

References: [1] Patent: EP2366691, 2011, A1, .

4
[ 695-34-1 ]
[ 907545-47-5 ]

References: [1] Patent: EP2366691, 2011, A1, .

5
[ 21901-40-6 ]
[ 907545-47-5 ]

References: [1] Patent: EP2366691, 2011, A1, .

[ 907545-47-5 ] Synthesis Path-Downstream 1~35

1
[ 907545-47-5 ]
[ 18107-18-1 ]
[ 777899-57-7 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; chloroform;	To a stirred solution of the above acid (5.3 g, 26.17 mmol) in methanol (50 ml) was added chloroform (200 ml). 2M TMS-diazomethane solution in hexanes was added to the solution dropwise until the color of the solution remained yellow (apprx. 20 ml). The residual TMS-diazomethane was quenched by addition of acetic acid, and the solvent was removed under reduced pressure. The oily residue was subjected to silica gel chromatography eluted with 50-70percent ethyl acetate in hexanes to provide methyl 2-chloro-5-nitroisonicotinate.

References: [1]Patent: US2006/106011,2006,A1 .Location in patent: Page/Page column 23.

2
[ 23056-33-9 ]
[ 907545-47-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	With chromium(VI) oxide; sulfuric acid; at 0 - 20℃;	2-chloro-4-methyl-5-nitropyridine (31 g, 180 mmol) was dissolved in conc.H2SO4 (300mL) and the resulting mixture was cooled to 0 C. CrO3 (59.4 g, 594 mmol) was added to the solution. After stirring for 1 h at 0 C, the mixture was warmed up to room temperature and stirred overnight. It was poured into ice-water (1 L). The mixture was warmed up to room temperature and filtered. The solid was then washed with water ( 2 L) and dried in vacuo to afford the desired product as a white solid (28.5g, 78%); LC/MS: MS(ES) m/e 203 (MH=); 1H NMR (300 MHz, DMSO-d6) delta ppm 8.04 (s, 1 H), 9.16 (s, 1 H).
77%	With chromium(VI) oxide; sulfuric acid; at 0 - 20℃;	Chromium trioxide (40.0 g, 40 mmol) was added to a solution of 2-chloro-4-methyl-5-nitropyridine (20.0 g, 11.6 mmol) in sulfuric acid (200 mL) at 0 C. After the addition was completed, the mixture was stirred at 0 C. for 1 h, then slowly warmed to room temperature and stirred overnight, and then poured into ice water (1 L) and filtrated to obtain 2-chloro-5-nitroisonicotinic acid (18 g, yield: 77%). MS (ESI): m/z 201.1 [M-1]-.
75%	With chromium(VI) oxide; sulfuric acid; at 0 - 20℃; for 13h;	(Step 1) 2-Chloro-5-nitro-pyridine-4-carboxylic acid (0167) (0168) 2-Chloro-4-methyl-5-nitro-pyridine (20.5 g, 119 mmol) was dissolved in concentrated sulfuric acid (200 ml), the resulting solution was cooled to 0 C., then chromium(VI) oxide (40.0 g, 400 mmol) was added thereto, and the resulting mixture was stirred at 0 C. for 1 hour and then at room temperature for 12 hours. The reaction liquid was diluted with water (2,000 ml), and the precipitated solid was filtered and dried to obtain the title compound (18.0 g, 75%). (0169) 1H NMR (400 MHz, CD3OD): delta 10.8 (br, s, 1H), 9.13 (s, 1H), 7.70 (s, 1H).

73%	With chromium(VI) oxide; sulfuric acid; at 0 - 20℃; for 1h;Inert atmosphere;	[00610] Step 1: To a solution of 2-chloro-4-methyl-5-nitro-pyridine (10.35 g, 60 mmol) in H2S04 (100 mL), Cr03 (19.8 g, 198 mmol) was added at 0 C. The mixture was stirred at 0 C for 1 h and then was allowed to warm to room temperature and stirred overnight. The mixture was poured into ice water (500 mL). The resulting solid was filtered and dried to give 2-chloro-5-nitro-isonicotinic acid (8.89 g, yield: 73%) as a white solid. MS: m/z 200.9 (M-H+).
	With chromium(VI) oxide; sulfuric acid; at 0 - 20℃;	A solution of 2-chloro-4-methyl-5-nitropyridine (5.13 g, 29.73 mmol) in concentrated sulfuric acid (42 mL) was cooled to 0 C., and chromium trioxide (9.81 g, 98.1 mmol) was added. The mixture was stirred at 0 C. for 1 hour and then warmed to room temperature, with an oil bubbler attached, for overnight stirring. The reaction mixture was poured onto ice (300 ml) and diluted with water (150 ml). The mixture was warmed to room temperature, and the solid was filtered and then dried under vacuum to yield 2-chloro-5-nitroisonicotinic acid. To a stirred solution of the above material (5.3 g, 26.17 mmol) in methanol (50 ml) was added chloroform (200 ml). TMS-diazomethane as a solution in hexane (2M) was added dropwise until the color of the reaction mixture remained yellow (20 mL). The residual TMS-diazomethane was quenched by addition of acetic acid, and the solvent was removed under reduced pressure. The oily residue was subjected to silica gel chromatography eluted with 50-70% ethyl acetate in hexane to provide methyl 2-chloro-5-nitroisonicotinate. A solution of the above material (5.66 g, 26.13 mmol), methyl 4'-(aminomethyl)-3,3'-difluorobiphenyl-2-carboxylate (7.971 g, 28.75 mmol, prepared according to procedures described in WO 03/066577), and triethylamine (3.97 g, 39.20 mmol) in methanol (100 ml) was stirred at room temperature overnight. The solution was then heated at 60 C. for 4 hours and cooled to ambient temperature for continued stirring over the weekend. Solvent was removed, and the residue was subjected to silica gel chromatography eluted with 25-50% ethyl acetate in hexane to provide methyl 2-([3,3'-difluoro-2'-(methoxycarbonyl)biphenyl-4-yl]methyl}amino)-5-nitroisonicotinate as a yellow solid. A solution of the above material (9.3 g, 20.33 mmol) in methanol (330 ml) was purged with nitrogen, and 10% Pd/C catalyst (1 g) was added. The reaction vessel was again purged with nitrogen and then with hydrogen from a balloon. After 23 hours of stirring under hydrogen, nitrogen was bubbled through the solution for 10 minutes prior to filtration through a celite pad. The filtrate was concentrated under reduced pressure to provide methyl 5-amino-2-([3,3'-difluoro-2'-(methoxycarbonyl)biphenyl-4-yl]methyl}amino)isonicotinate. Into a solution of the above material (8.45 g, 19.77 mmol) in THF (440 ml) at 0 C. were added hypophosphorous acid (50% solution in water, 110 ml) and sodium nitrite (2.73 g, 39.54 mmol). After 10 minutes of stirring, a catalytic amount of copper (I) oxide was added every 30 minutes for 7.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluted with 20-40% ethyl acetate in hexane to provide methyl 2-([3,3'-difluoro-2'-(methoxycarbonyl)biphenyl-4-yl]methyl}amino)isonicotinate. To a stirred solution of the above material (3.96 g, 9.60 mmol) in methanol (85 ml) was added 1N NaOH (11.5 ml), and the solution was heated at 40 C. for 3.5 hours. Solvent was removed under reduced pressure prior to dilution with water. The aqueous solution was washed with diethyl ether twice, and the residual diethyl ether in the aqueous solution was removed under reduced pressure. The aqueous solution was neutralized by addition of 1N HCl (11.5 ml), and the resulting thick suspension was heated (70 C.) and then slowly cooled to ambient temperature before being cooled to 0 C. for 30 minutes. The solid was filtered and dried under vacuum, providing the title compound as a white solid. LRMS (ES, M+H+): 399. 1H NMR (CD3OD, 400 MHz) delta 8.04 (d, J=5.6 Hz, 1H), 7.55 (m, 1H), 7.44 (t, J=8 Hz, 1H), 7.23 (m, 3H), 7.10 (m, 3H), 4.65 (s, 2H), 3.66 (s, 3H).
	With chromium(VI) oxide; sulfuric acid; at 0 - 20℃;	EXAMPLE 10 Methyl 3,3,'-difluoro-4'-([2-(4-pyridin-4-ylpiperazin-1-yl)isonicotinoyl]amino}-methyl)biphenyl-2-carboxylate Commercially available 2-chloro-4-methyl-5-nitropyridine (5.13 g, 29.73 mmol) was dissolved in 42 ml conc. sulfuric acid. The resulting solution was cooled to 0 C., and chromium trioxide (9.81 g, 98.1 mmol) was added to the solution. After 1 hour of stirring at 0 C., the mixture was warmed to room temperature with a bubbler attached to the flask. After overnight stirring, the reaction mixture was poured onto ice (300 ml) and diluted with water (150 ml). The mixture was allowed to warm to room temperature and the solid was filtered and dried under vacuum overnight to get 2-chloro-5-nitroisonicotinic acid as a light green solid.
	With sodium dichromate; sulfuric acid; at 15 - 20℃;Cooling with ice;	Intermediate 25A: 2-Chloro-5-nitroisonicotinic acid 2-chloro-4-methyl-5-nitropyridine (1 .0 g, 5.8 mmol) was cooled using an ice water bath. Sodium dichromate dihydrate (3.45 g, 1 1 .6 mmol) dissolved in sulphuric acid (50 mL) was added dropwise, ensuring reaction temperature does not exceed 15C. After complete addition, reaction allowed to warm to room temperature and stirred overnight. Quenched with ice, extracted into ethylacetate and concentrated under reduced pressure to afford 2- chloro-5-nitroisonicotinic acid (1.3 g, 6.4 mmol).
	With sodium dichromate; sulfuric acid; at 60℃; for 6h;	Synthesis of the compound 33 The compound 32 (9.45 g, 0.055 mol) was dissolved in a concentrated sulphuric acid (80mL) with agitation, a sodium dichromate (19.2 g, 0.065 mol) was added slowly in batches into the system, and the reaction was run at 60C for 6 h. The above reaction liquid was added slowly into broken ice (250 g) and extracted with ethyl acetate (300 mL) three times. The extracts were combined and washed with a saturated aqueous solution of table salt. The solvent was evaporated off and 8.65 g of the crude product was obtained with a yield of 77.6%. The crude product was recrystallized in a mixture of ethanol and petroleum ether (1:2) to obtain a white solid product with the melting point of 193.3-193.6C (ethanol/petroleum ether).
18 g	With chromium(VI) oxide; sulfuric acid; at 0 - 20℃; for 13h;	2-Chloro-4-methyl-5-nitropyridine (20.5 g, 119 mmol) was dissolved in concentrated sulfuric acid (200 ml), and chromium trioxide (40.0 g, 400 mmol) was added thereto, followed by stirring at 0 C. for 1 hour. Then, the temperature was gradually raised from 0 C. to room temperature, followed by stirring for 12 hours. The reaction solution was poured into ice-water (2000 ml), and the temperature was raised from 0 C. to room temperature. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (18 g, 750). [0144] 1H NMR (CD3OD, 400 MHz): delta 10.8 (1H, br, s), 9.13 (1H, s), 7.70 (1H, s)
	With potassium dichromate; sulfuric acid; at 60℃; for 14h;	To a solution of 2-chloro-4-methyl-5-nitropyridine (46 g, 267 mmol) in H2SO4(400 ml) was added K2Cr2O7(98 g, 333 mmol) in several portions at 60 . The resulting mixture was stirred at the same temperature for 14 h to give a dark green solution. After cooling, the mixture was poured into ice (250 g) carefully and the aqueous was extracted with EtOAc (500 ml*3) . The organic phase was concentrated under reduced pressure to give the product as a solid which was used in next step without further purification. MS (ESI) calcd. for (C6H4ClN2O4) [M+H] +, 203.0, found, 203.0

References: [1]Patent: WO2013/95761,2013,A1 .Location in patent: Page/Page column 39.
[2]Patent: US2019/270742,2019,A1 .Location in patent: Paragraph 0160-0161.
[3]Patent: US2016/244451,2016,A1 .Location in patent: Paragraph 0167; 0168; 0169.
[4]Patent: WO2015/200534,A2 .Location in patent: Paragraph 00610.
Patent: ,2015, .Location in patent: Paragraph 00610.
[5]Patent: US2006/122236,2006,A1 .Location in patent: Page/Page column 20.
[6]Patent: US2006/106011,2006,A1 .Location in patent: Page/Page column 23.
[7]Patent: WO2011/45258,2011,A1 .Location in patent: Page/Page column 53-54.
[8]Patent: EP2366691,2011,A1 .Location in patent: Page/Page column 13.
[9]Patent: US2015/51395,2015,A1 .Location in patent: Paragraph 0143-0144.
[10]Patent: WO2016/29454,2016,A1 .Location in patent: Page/Page column 46.

3
[ 67-56-1 ]
[ 907545-47-5 ]
[ 777899-57-7 ]

Yield	Reaction Conditions	Operation in experiment
98%		Oxalyl chloride (12.7 g, 100 mmol) was added to a suspension of <strong>[907545-47-5]2-chloro-5-nitroisonicotinic acid</strong> (16 g, 80 mmol) in dichloromethane (150 mL) at 0 C. After the addition was completed, the mixture was stirred at room temperature for 3 h. Methanol (100 mL) was added, the reaction mixture was stirred at room temperature for another 4 h and then concentrated. The crude product was dissolved in dichloromethane (200 mL), the mixture was washed with sodium bicarbonate solution (100 mL*2), dried over anhydrous sodium sulfate and concentrated to obtain methyl 2-chloro-5-nitroisonicotinate (17.2 g, yield: 98%).
		A solution of 2-chloro-4-methyl-5-nitropyridine (5.13 g, 29.73 mmol) in concentrated sulfuric acid (42 mL) was cooled to 0 C., and chromium trioxide (9.81 g, 98.1 mmol) was added. The mixture was stirred at 0 C. for 1 hour and then warmed to room temperature, with an oil bubbler attached, for overnight stirring. The reaction mixture was poured onto ice (300 ml) and diluted with water (150 ml). The mixture was warmed to room temperature, and the solid was filtered and then dried under vacuum to yield <strong>[907545-47-5]2-chloro-5-nitroisonicotinic acid</strong>. To a stirred solution of the above material (5.3 g, 26.17 mmol) in methanol (50 ml) was added chloroform (200 ml). TMS-diazomethane as a solution in hexane (2M) was added dropwise until the color of the reaction mixture remained yellow (20 mL). The residual TMS-diazomethane was quenched by addition of acetic acid, and the solvent was removed under reduced pressure. The oily residue was subjected to silica gel chromatography eluted with 50-70% ethyl acetate in hexane to provide methyl 2-chloro-5-nitroisonicotinate. A solution of the above material (5.66 g, 26.13 mmol), methyl 4'-(aminomethyl)-3,3'-difluorobiphenyl-2-carboxylate (7.971 g, 28.75 mmol, prepared according to procedures described in WO 03/066577), and triethylamine (3.97 g, 39.20 mmol) in methanol (100 ml) was stirred at room temperature overnight. The solution was then heated at 60 C. for 4 hours and cooled to ambient temperature for continued stirring over the weekend. Solvent was removed, and the residue was subjected to silica gel chromatography eluted with 25-50% ethyl acetate in hexane to provide methyl 2-([3,3'-difluoro-2'-(methoxycarbonyl)biphenyl-4-yl]methyl}amino)-5-nitroisonicotinate as a yellow solid. A solution of the above material (9.3 g, 20.33 mmol) in methanol (330 ml) was purged with nitrogen, and 10% Pd/C catalyst (1 g) was added. The reaction vessel was again purged with nitrogen and then with hydrogen from a balloon. After 23 hours of stirring under hydrogen, nitrogen was bubbled through the solution for 10 minutes prior to filtration through a celite pad. The filtrate was concentrated under reduced pressure to provide methyl 5-amino-2-([3,3'-difluoro-2'-(methoxycarbonyl)biphenyl-4-yl]methyl}amino)isonicotinate. Into a solution of the above material (8.45 g, 19.77 mmol) in THF (440 ml) at 0 C. were added hypophosphorous acid (50% solution in water, 110 ml) and sodium nitrite (2.73 g, 39.54 mmol). After 10 minutes of stirring, a catalytic amount of copper (I) oxide was added every 30 minutes for 7.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluted with 20-40% ethyl acetate in hexane to provide methyl 2-([3,3'-difluoro-2'-(methoxycarbonyl)biphenyl-4-yl]methyl}amino)isonicotinate. To a stirred solution of the above material (3.96 g, 9.60 mmol) in methanol (85 ml) was added 1N NaOH (11.5 ml), and the solution was heated at 40 C. for 3.5 hours. Solvent was removed under reduced pressure prior to dilution with water. The aqueous solution was washed with diethyl ether twice, and the residual diethyl ether in the aqueous solution was removed under reduced pressure. The aqueous solution was neutralized by addition of 1N HCl (11.5 ml), and the resulting thick suspension was heated (70 C.) and then slowly cooled to ambient temperature before being cooled to 0 C. for 30 minutes. The solid was filtered and dried under vacuum, providing the title compound as a white solid. LRMS (ES, M+H+): 399. 1H NMR (CD3OD, 400 MHz) delta 8.04 (d, J=5.6 Hz, 1H), 7.55 (m, 1H), 7.44 (t, J=8 Hz, 1H), 7.23 (m, 3H), 7.10 (m, 3H), 4.65 (s, 2H), 3.66 (s, 3H).

References: [1]Patent: US2019/270742,2019,A1 .Location in patent: Paragraph 0162-0163.
[2]Patent: US2006/122236,2006,A1 .Location in patent: Page/Page column 20.

4
[ 907545-47-5 ]
[ 73874-95-0 ]
[ 1051383-19-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With triethylamine; In tetrahydrofuran; at 50℃; for 2h;	Reference Example 35 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-5-nitropyridine-4-carboxylic acid [Show Image] A solution of <strong>[907545-47-5]2-chloro-5-nitropyridine-4-carboxylic acid</strong> (1.50 g, 7.41 mmol), tert-butyl piperidin-4-ylcarbamate (1.48 g, 7.41 mmol) and triethylamine (3.1 mL, 22.2 mmol) in THF (19 mL) was stirred with heating at 50°C for 2 hr. After completion of the reaction, the mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=4:1 to 1:0) to give the title compound (1.57 g, yield 58percent) as a powder. EI(pos) 311.1 [M+H-tBu]+

References: [1]Patent: EP2123652,2009,A1 .Location in patent: Page/Page column 55.

5
[ 907545-47-5 ]
[ 74-88-4 ]
[ 777899-57-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Cooling with ice;	Intermediate 26A: Methyl 2-chloro-5-nitroisonicotinateTo a solution of <strong>[907545-47-5]2-chloro-5-nitroisonicotinic acid</strong> (Intermediate 25A) (0.64 g, 3.17 mmol) in DMF (15 mL) under nitrogen was added sodium carbonate (1.0 g, 9.51 mmol). Reaction cooled in an ice bath and methyliodide (1 .35 g, 9.51 mmol) was added dropwise. After complete addition, reaction allowed to warm to room temperature and stirred overnight under nitrogen. The reaction mixture was filtered and concentrated. The resultant crude material was purified by a 20g silica column eluting with 40percent ethylacetate in hexane to afford methyl 2-chloro-5-nitroisonicotinate (0.62 g, 2.86 mmol).
	In N,N-dimethyl-formamide; at 0 - 15℃; for 15h;	To a solution of <strong>[907545-47-5]2-chloro-5-nitroisonicotinic acid</strong> (20.2g, 100 mmol) in DMF (500 mL) was added dropwise iodomethane (10 mL, 160 mmol) at 0 . After addition, the mixture was gradually warmed to 15 and stirred for 15 h. The reaction was quenched with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (300 mL 3) . The combined organic phase was washed with 10aqueous LiCl (50 mL2) , dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel: 200-300 mesh, petroleum ether/EtOAc 50/1to 10/1, v/v) to give the product as a solid.1HNMR(400 MHz, CDCl3) delta 9.04 (s, 1H) , 7.59 (s, 1H) , 3.97 (s, 3H)

References: [1]Patent: WO2011/45258,2011,A1 .Location in patent: Page/Page column 54.
[2]Patent: WO2016/29454,2016,A1 .Location in patent: Page/Page column 46; 47.

6
[ 907545-47-5 ]
[ 1290634-42-2 ]

References: [1]Patent: WO2011/45258,2011,A1 .

7
[ 907545-47-5 ]
[ 1290634-44-4 ]

References: [1]Patent: WO2011/45258,2011,A1 .

8
[ 907545-47-5 ]
[ 1290634-47-7 ]

References: [1]Patent: WO2011/45258,2011,A1 .

9
[ 907545-47-5 ]
[ 1290634-49-9 ]

References: [1]Patent: WO2011/45258,2011,A1 .

10
[ 21901-41-7 ]
[ 907545-47-5 ]

References: [1]Patent: EP2366691,2011,A1 .

11
[ 695-34-1 ]
[ 907545-47-5 ]

References: [1]Patent: EP2366691,2011,A1 .

12
[ 21901-40-6 ]
[ 907545-47-5 ]

References: [1]Patent: EP2366691,2011,A1 .

13
[ 907545-47-5 ]
C₆H₂Cl₂N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;N,N-dimethyl-formamide; for 2h;Reflux;	Synthesis of the compound 34 The compound 33 (3 g, 0.017 mol) was added into thionyl chloride (20 mL), two drops of DMF was added to the above mixture, and then refluxed for 2 h. The thionyl chloride was evaporated off, an acetone (20mL) was added and stirred in an ice bath, ammoniae gas was charged, and then the reaction was run for 1 h before completed. Acetone was evaporated off, 30 mL of water and 30 mL of ethyl acetate were added to the residue, and then extraction was performed. The ethyl acetate layer was washed with the saturated aqueous solution of table salt and evaporated to being dry. The resulted product was recrystallized in ethanol (95percent) to obtain 0.8 g of a white solid product with a yield of 23.5percent. The melting point is 193.4-193.7°C(ethanol).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃;Inert atmosphere;	[00611] Step 2: To a solution of 2-chloro-5-nitro-isonicotinic acid (4.64 g, 23 mmol) in DCM (200 mL), 5 drops of DMF was added. Then (COCl)2 (7.27g, 57.3 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature overnight. The solvent was removed and dry THF (200 mL) was added. NH3 gas was bubbled into the solution for 0.5 h. The mixture was filtered and the filtrate was concentrated to give 2-chloro-5-nitro-isonicotinamide (4.61 g, 95percent) as a white solid. lH NMR (400 MHz, DMSO-i/6): delta = 9.12 (s, 1H), 8.32 (brs, 1H), 8.07 (brs, 1H), 7.90 (s, 1H).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 0.5h;	<strong>[907545-47-5]2-chloro-5-nitroisonicotinic acid</strong> (0.100 g, 0.494 mmol) was dissolved in DCM (4.94 mL) and oxalyl chloride (0.043 mL, 0.494 mmol) was added. To the stirred reaction mixture was added 2 drops of DMF. The reaction mixture was stirred for 30 mmand concentrated under reduced pressure. The compound was used without further purification in the next step. The residue was dissolved in tetrahydrofuran (4.98 mL) and sodium methoxide (3.98 mL, 1.991 mmol) was added. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was diluted with water and EtOAc. 1 N HC1 was added and the layers were separated. The organic layer waswashed brine, dried with sodium sulfate, and concentrated under reduced pressure to yieldIntermediate 192A (0.078 g, 0.394 mmol, 79 percent yield) as a white solid. ?H NMR(400MHz, CHLOROFORM-d) 8.97 (s, 1H), 6.95 (s, 1H), 4.08 (s, 3H). LC-MS: methodH, RT = 0.82 mm, MS (ESI) m/z: 198.9 (M+H)t

References: [1]Patent: EP2366691,2011,A1 .Location in patent: Page/Page column 14.
[2]Patent: WO2015/200534,A2 .Location in patent: Paragraph 00611.
Patent: ,2015, .Location in patent: Paragraph 00611.
[3]Patent: WO2018/13774,2018,A1 .Location in patent: Page/Page column 624.

14
[ 907545-47-5 ]
[ 1224637-08-4 ]

References: [1]Patent: EP2366691,2011,A1 .

15
[ 907545-47-5 ]
[ 1224636-83-2 ]

References: [1]Patent: EP2366691,2011,A1 .

16
[ 907545-47-5 ]
C₈H₈N₄O₃*(x)ClH [ No CAS ]

References: [1]Patent: EP2366691,2011,A1 .

17
[ 907545-47-5 ]
[ 1445877-17-7 ]