171178-46-4|5-((tert-Butoxycarbonyl)amino)-2-chloroisonicotinic acid| Ambeed

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Quality Control of [ 171178-46-4 ] Purity: 96% SDS Specification

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HPLC

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Product Details of [ 171178-46-4 ]

CAS No. :	171178-46-4
Formula :	C₁₁H₁₃ClN₂O₄
M.W :	272.69
SMILES Code :	O=C(O)C1=C(NC(OC(C)(C)C)=O)C=NC(Cl)=C1
MDL No. :	MFCD09258838
Boiling Point :	No data available
InChI Key :	KOSPRFUMGCNGFJ-UHFFFAOYSA-N
Pubchem ID :	10564144

Safety of [ 171178-46-4 ]

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

Application In Synthesis of [ 171178-46-4 ]

* 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 [ 171178-46-4 ]

[ 171178-46-4 ] Synthesis Path-Downstream 1~35

1
[ 124-38-9 ]
[ 171178-45-3 ]
[ 171178-46-4 ]

Yield	Reaction Conditions	Operation in experiment
87%		To a 500 ml. oven dried 3 necked round bottom flask, tert- butyl (6-chloropyridin-3- yl)carbamate (Intermediate A) (5 g, 21 .82 mmol, 1 equiv.) was dissolved in anhydrous diethyl ether (200 ml.) giving a yellow solution. TMEDA 0.1 M (1 1 .7 ml_, 76 mmol, 3.5 equiv.) were added and the mixture was cooled to -78C. A solution of n-butyl lithium 2.5 M in hexanes (30.5 ml_, 76 mmol, 3.5 equiv) was dropwise added (the reaction mixture turned brown-red colour). When the addition of the reagent was completed, the reaction mixture was permitted to reach to -10C and stirred at this temperature for 3 h. The reaction mixture was then re-cooled to -78C and a carbon dioxide gas bag (1 gal) was fitted under Ar atmosphere. The system was evacuated and flushed with carbon dioxide for three times. The reaction mixture was stirred at -78C under carbon dioxide atmosphere at atmospheric pressure for 4 h. The reaction was permitted to warm up to 22C and stirred for 18 h. Water was added to the reaction mixture until complete solution of solid materials (300 ml_). The phases were separated and the aqueous phase was washed with diethyl ether (2 x 100 ml_). After that, the pH-value of the aqueous phase was adjusted to 6.32 with HCI 2.7M and extracted with diethyl ether (4 x 200 mL) and EtOAc (5 x 200 ml_). The combined organic phases were dried over anhyd. Na2S04 and concentrated under reduced pressure giving 5 -((tert- butoxycarbonyl)amino)-2-chloroisonicotinic acid as a pale yellow solid, (5.13 g, 87% yield). Purity: 99.1% (UPLC-A); 1H-NMR (DMSO-de), 5(ppm): 10.01 (s, 1 H), 9.12 (s, 1 H), 7.75 (s, 1 H), 1.48 (s, 9H); LR-MS (ESI+): m/z= 273.0 Da [M+H]+, calcd. for C11H13CIN2O4: 272.7.
69.3%		Step (c): 5-TERT-BUTOXYCARBONYLAMINO-2-CHLORO-ISONICOTINIC acid A suspension of (6-CHLORO-PYRIDIN-3-YL)-CARBAMIC acid tert-butyl ester in 800mL of ether was treated with TMEDA, and the mixture cooled TO-75C. To this was added 1.6M BuLi in hexanes dropwise while keeping the temperature BELOW-65C. After the addition was complete, the reaction mixture was allowed to warm to-15C TO-10C, and stirred in this temperature range for 2 hours. The reaction mixture was again cooled TO-75C, and dry carbon dioxide was bubbled into the mixture for 3 hours before allowing the reaction to warm to room temperature overnight with continued bubbling of carbon dioxide. The reaction mixture was carefully quenched with 20% aqueous ammonium hydroxide solution (1.8L), the aqueous portion extracted with ether, then acidified to pH 5 using 50% aqueous HCI. The resulting solid was collected by filtration, washed with water, and dried to give 33.07g (69. 3% yield) of 5-tert- butoxycarbonylamino-2-chloro-isonicotinic acid as a light yellow solid. 1H NMR (400 MHz, DMSO-D6) d ppm 1.5 (s, 9H), 7.7 (s, 1H), 9.1 (s, 1H), 10.0 (s, 1H) MS (APCI) M+1 = 273.1
60%		Step (c): 5-TERT-BUTOXYCARBONYLAMINO-2-CHLORO-ISONICOTINIC acid The reaction was run under Argon. A 20 L jacketed reactor was charged with (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (200 g, 0. 875 moles), THF (5 L), and TMEDA (304 ML, 2.3 equivalents, 2 wt% water), and the mixture was cooled to BETWEEN-70C AND-75C. nBuLi (805 ML, 2.5 M in hexanes, 2.3 mole equivalents) was added via dropping funnel at a rate that kept the reaction temperature BETWEEN-70C AND-75C. The resulting brown solution was warmed to-15C and stirred for 1 hour. The reaction mixture was then cooled back to- 35C, and a lecture bottle of C02 was bubbled through. The reaction mixture was allowed to warm to 20C over 2 hours, during which time the solution became an orange slurry. The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 1.5 L of water. During the quench a precipitate formed in the aqueous layer. The layers were separated, taking the precipitated solid with the aqueous layer. The organic layer was washed once with 1 N NaOH. The aqueous portions were combined, and the pH adjusted to pH 2 with 6 N HC1. The solid was collected by filtration, washed twice with water and dried overnight in the vacuum oven at 45C. The reaction yielded 143 g (60% total yield) of 5-tert-Butoxycarbonylamino-2-chloro-isonicotinic acid as a tan solid that was sufficiently pure by NMR to use in the next reaction. ON (DMSO) 10.06 (1 H, s), 9.07 (1 H, s), 7.71 (1 H, d), 1.42 (9 H, s) MS [M+H] + 273

		[00479] To a stirred solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (5.6 g, 24.6 mmol) in THF (100 mL) was added n-BuLi (29 mL, 74.0 mmol) dropwise at -78 C. The mixture was stirred at this temperature for 1 hors. Then the vessel was charged with carbon dioxide to a pressure of 0.7 Mbar and stirred at - 40 C for 10 min. After warmed to room temperature, the mixture was poured into the ice water and the pH value was adjusted to pH = 3. The aqueous phase was extracted with EA (100 mL x2). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2S04 and filtered. The filtrate was evaporated in vacuum to give the product (crude, 8.0 g) of 5-tert- butoxycarbonylamino-2-chloro-isonicotinic acid as red oil.
		(c) 5-(tert-Butoxycarbonyl)-2-chloroisonicotinic acid. To a solution of tert-butyl 6-chloropyridin-3-ylcarbamate (1O g, 0.045 mol) and N, N, N', N'-tetramethyleethylenediamine (20 mL) in dry Et2O (200 mL) was added n- BuLi (2.5 M solution in hexanes, 84 mL) dropwise with stirring at -78C. After the addition, the reaction mixture was warmed to -15C and stirred at the same temperature for 2 hours. The mixture was cooled to -78C and CO2 gas was bubbled into the reaction solution at -78C for 1 hour. The reaction mixture was then stirred at room temperature overnight, cooled to 0C and quenched with <n="115"/>water. The pH of the aqueous phase was adjusted to pH=3 with IN hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over anhydrous MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the residue was dried in vacuo to give the title compound.
		(c) 5-(tert-Butoxycarbonyl)-2-chloroisonicotinic acid. To a solution of tert-butyl 6-chloropyridin-3-ylcarbamate (10 g, 0.045 mol) and N, N, N',N'-tetramethylethylenediamine (20 mL) in dry diethyl ether (200 mL) was added n-BuLi (2.5 M solution in hexanes, 84 mL) dropwise with stirring at - 78C. After the addition, the reaction mixture was warmed to -15C, and the reaction was stirred at this temperature for 2 hours. The mixture was cooled to - 78C and CO2 gas was bubbled into the reaction solution at -78C for 1 hour. The reaction mixture was then stirred at room temperature overnight, cooled to 0C, and quenched with water. The pH of the aqueous phase was adjusted to pH=3 with IN HCl. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over anhydrous MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the residue was dried in vacuo to give the title compound.
		Step 2: Preparation of 5- tert-butoxycarbonylamino-2-chloro- isonicotinic acid; A solution of ( 6-chloro-pyridin-3-yl) -carbamic acid tert- <n="406"/>butyl ester (4.19 g) in diethyl ether (150 mL) was cooled to -78C and N,N,N' ,N'-tetramethylethylendiamine (6.60 g) was added. After slow addition of n-butyl lithium solution (1.32 M in hexane, 41.6 mL) over a time period of 10 minutes, the mixture was allowed to warm up to -100C, stirred at this temperature for 2 hours and then was re- cooled to -78C. The mixture was poured slowly into a stirred mixture of crushed dry ice in THF and stirred for 30 minutes. The mixture was concentrated on a rotary evaporator and water was added to the residue. The aqueous layer was washed 2x with MTB-ether and acidified with 6N hydrochloric acid to pH ~ 3. The formed precipitate was filtered off, washed with water, ethyl acetate and dried in vacuum to afford 2.46 g of the title compound of the formulaas beige solid.1H-NMR (DMSO-D6) delta (ppm) : 1.48 (9H, s), 7.77 (IH, s), 9.13 (IH, s) , 10.13 (IH, s) .

References: [1]Patent: WO2020/20939,2020,A1 .Location in patent: Page/Page column 32; 34; 36; 37.
[2]Patent: WO2005/16926,2005,A1 .Location in patent: Page/Page column 114-115.
[3]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 256 - 261.
[4]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.
[5]Patent: WO2005/16926,2005,A1 .Location in patent: Page/Page column 122-123.
[6]Journal of the Chemical Society. Perkin transactions I,1996,p. 2221 - 2226.
[7]Patent: WO2015/200534,A2 .Location in patent: Paragraph 00479.
Patent: ,2015, .Location in patent: Paragraph 00479.
[8]Patent: WO2008/76425,2008,A1 .Location in patent: Page/Page column 112-113.
[9]Patent: WO2008/130600,2008,A2 .Location in patent: Page/Page column 57.
[10]Patent: WO2008/130021,2008,A2 .Location in patent: Page/Page column 404-405.

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
[ 171178-46-4 ]
[ 305371-42-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	In tetrahydrofuran;	Step 1: Methyl 5-[(tert-butoxy)carbonylamino]-2-chloropyridine-4-carboxylate <strong>[171178-46-4]5-[(tert-butoxy)carbonylamino]-2-chloropyridine-4-carboxylic acid</strong> (1 equivalent) was dissolved in THF and MeOH. The mixture was heated to 50 C. to completely dissolve the starting material. The solution was then cooled to 0 C., and TMSCHN2 (2 M in THF, 2 equivalents) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was the concentrated to yield the methyl ester (100%) as a brown solid.

References: [1]Patent: US2005/256157,2005,A1 .

4
[ 5326-23-8 ]
[ 171178-46-4 ]

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

5
[ 171178-46-4 ]
[ 171178-47-5 ]

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.

6
[ 171178-46-4 ]
[ 171178-48-6 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1401 - 1405.
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 256 - 261.

7
[ 171178-46-4 ]
[ 189680-99-7 ]

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

8
[ 171178-46-4 ]
[ 189680-98-6 ]

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

9
[ 171178-46-4 ]
[ 202272-67-1 ]

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

10
[ 171178-46-4 ]
[ 202272-97-7 ]

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

11
[ 171178-46-4 ]
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.

12
[ 171178-46-4 ]
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.

13
[ 171178-46-4 ]
[ 202272-71-7 ]

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

14
[ 171178-46-4 ]
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.

15
[ 5350-93-6 ]
[ 171178-46-4 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1996,p. 2221 - 2226.
[2]Patent: WO2008/76425,2008,A1 .
[3]Patent: WO2008/130600,2008,A2 .
[4]Patent: WO2008/130021,2008,A2 .
[5]Patent: WO2020/20939,2020,A1 .

16
[ 24424-99-5 ]
[ 171178-46-4 ]

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 .
[4]Patent: WO2020/20939,2020,A1 .

17
[ 171178-46-4 ]
[ 18107-18-1 ]
[ 305371-42-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen;nickel; In methanol; hexane; chloroform; at 20℃; for 2h;	5-tert-Butoxycarbonylamino-2-chloro-isonicotinic acid, methyl ester To 5.4 g of <strong>[171178-46-4]5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid</strong> in 50 mL of methanol and 100 mL of chloroform was at 0 C. was added 15 mL of 2 M (trimethylsilyl)diazomethane in hexanes. After allowing the reaction to warm to ambient temperature and stirring for 2 hours, the solvents were removed and the crude product purified by passing through a plug of silica gel with chloroform. The product was then recrystallized from hexanes to give 5.8 g (100%) of <strong>[171178-46-4]5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid</strong>, methyl ester: mp=90-96 C. (decomposed); mass spectrum (m/e): M+H 287.1.

References: [1]Patent: US6355636,2002,B1 .Location in patent: Page column 72.

18
[ 171178-45-3 ]
[ 171178-46-4 ]

Yield	Reaction Conditions	Operation in experiment
57%	With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; In diethyl ether;	5-[N-(tert -Butoxycarbonyl)amino]-2-chloropyridine-4-carboxylic acid. A solution of 5-[N-(tert-butoxycarbonyl)amino]-2-chloropyridine (22.87 g, 0.1 mol) and TMEDA (47 mL, 0.31 mol) in dry Et2 O (600 mL) is cooled to -78 C., and n-BuLi (10M in hexanes, 30 mL, 0.3 mol) is added dropwise. The solution is allowed to warm to -10 C. and is then kept at that temperature for 2 h, before being recooled to -78 C. Dry CO2 is then bubbled in, and the resulting mixture is allowed to warm to 20 C., before being quenched with water (300 mL) containing a small amount of NH4 OH. The resulting aqueous layer is washed with EtOAc, then acidified slowly with dilute HCl to precipitate 5-[N-(tert-butoxycarbonyl)amino]-2-chloropyridine-4-carboxylic acid (15.5 g, 57%). 1 H NMR (DMSO) delta 10.00 (1H, s), 9.13 (1H, s), 7.74 (1H, s), 1.47 (9H, s).
	With n-butyllithium; In tetramethylethylenediamine; diethyl ether; hexane; at -78 - 0℃;	To 13 g of (6-chloro-pyridin-3-yl)-carbamic acid, tert-butyl ester in 24 ML of tetramethylethylenediamine and 300 ML of ether at -78 C. under an inert atmosphere was added slowly 68 ML of 2.5 M n-butyllithium/hexanes (3 eq).. After the addition was complete, the reaction was allowed to warm to -15 C. for two hours then recooled to -78 C. Dry ice was allowed to sublime in a separate flask and the vapor was passed over the rapidly stirred reaction mixture while the cooling bath was removed and the reaction allowed to warm to 0 C. Sufficient water was added to dissolve the precipitated product and the resultant aqueous phase was washed twice with ether before acidifying with concentrated HCl. The precipitate was filtered, washed with water, and dried in vacuo to give 10.9 g of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid, which was used as is for the next step: melting point 250 C. and higher (slowly decomposed); mass spectrum (negative mode, m/e): M-H 271.1.

References: [1]Patent: US5654307,1997,A .
[2]Patent: US6355636,2002,B1 .Location in patent: Page column 72.

19
[ 110-18-9 ]
[ 171178-45-3 ]
[ 171178-46-4 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In diethyl ether; at -78 - -15℃; for 2h;	To 13 g of (6-chloro-pyridin-3-yl)-carbamic acid, tert-butyl ester in 24 mL of tetramethylethylenediamine and 300 mL of ether at -78C under an inert atmosphere was added slowly 68 mL of 2.5 M n-butyllithium/hexanes (3 eq). After the addition was complete, the reaction was allowed to warm to -15C for two hours then recooled to -78C. Dry ice was allowed to sublime in a separate flask and the vapor was passed over the rapidly stirred reaction mixture while the cooling bath was removed and the reaction allowed to warm to 0C. Sufficient water was added to dissolve the precipitated product and the resultant aqueous phase was washed twice with ether before acidifying with concentrated HCl. The precipitate was filtered, washed with water, and dried in vacuo to give 10.9 g of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid, which was used as is for the next step: melting point 250C and higher (slowly decomposed); mass spectrum (negative mode, m/e): M-H 271.1.

References: [1]Patent: EP1171440,2004,B1 .Location in patent: Page 59.

20
trimethylsilyl diazomethane [ No CAS ]
[ 171178-46-4 ]
[ 305371-42-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	In methanol; chloroform; at 0 - 20℃; for 2h;	To 5.4 g of <strong>[171178-46-4]5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid</strong> in 50 mL of methanol and 100 mL of chloroform was at 0C was added 15 mL of 2 M (trimethylsilyl)diazomethane in hexanes. After allowing the reaction to warm to ambient temperature and stirring for 2 hours, the solvents were removed and the crude product purified by passing through a plug of silica gel with chloroform. The product was then recrystallized from hexanes to give 5.8 g (100%) of <strong>[171178-46-4]5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid</strong>, methyl ester: mp = 90-96C (decomposed); mass spectrum (m/e): M+H 287.1.

References: [1]Patent: EP1171440,2004,B1 .Location in patent: Page 59.

21
[ 124-38-9 ]
[ 171178-46-4 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (6-chloro-pyridin-3-yl) carbamic acid tert-butyl ester (Method 125; 4.0 g, 17.5 mmol) in ether (40 ml) at -78 0C was treated with A^V^-tetramethyl ethylene diamine (0.78 ml, 5.25 mmol) via a syringe followed by drop-wise addition of a solution of n- BuLi (1.6M, 32.8 ml, 52.5 mmol). The resulting deep coloured solution was kept at - 78 0C for 1 hour. The reaction mixture was then warmed to 0 C for 10 min and then cooled to -78 0C. CO2(g) was bubbled through the solution for 20 min and the resulting mixture was stirred for 10 min at 25 0C. The solvent was removed under reduced pressure. The resulting residue was treated with IN HCl solution (60 ml) resulting in a solid precipitate that was collected by filtration; m/z 273.

References: [1]Patent: WO2006/24834,2006,A1 .Location in patent: Page/Page column 74-75.

22
[ 67-56-1 ]
[ 171178-46-4 ]
[ 305371-42-0 ]

Yield	Reaction Conditions	Operation in experiment
100%		5- [ (TERT-BUTOXY) CARBONYLAMINO]-2-CHLOROPYRIDINE-4-CARBOXYLIC ACID (1 equivalent) was dissolved in THF and MeOH. The mixture was heated to 50 C to completely dissolve the starting material. The solution was then cooled to 0 C, and TMSCHN2 (2 M in THF, 2 equivalents) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was the concentrated to yield the methyl ester (100 %) as a brown solid.
79%		5-((fe/f-butoxycarbonyl)amino)-2-chloroisonicotinic acid (Intermediate B) (4.27 g, 15 mmol, 1 equiv.) was added to a 500 mL two necked oven-dried round bottom flask equipped with a stirring bar and suspended in dichloromethane (187 mL, 0.08M) was added. 4-Dimethylamino pyridine (7.40 g, 60 mmol, 4 equiv.) was added at 22C resulting in an homogeneous solution. /V-(3-dimethylaminopropyl)-/V-ethylcarbodiimide (4.65 g, 30 mmol, 2 equiv.) was added at that temperature and the crude mixture was stirred for 3 h. Anhydrous MeOH (HPLC quality), (5.5 mL, 135 mmol, 9 equiv.) was added to the solution and the mixture was stirred for 1 h at 22C. The resulting mixture was heated to reflux using an aluminium heating block for 72 h. TLC (EtOAc:MeOH 90:10 %v/v) showed complete conversion of Intermediate B into Intermediate C. The reaction was permitted to reach to 22C and volatiles were removed under reduced pressure. Dichloromethane (150 mL) was added to the residue until complete solution was achieved and the mixture was transferred to a separating funnel, washed with H2O (1 x 70 mL), HCI 1 M (2 x 50 mL) and saturated NaCI solution (1 x 50 mL). The organic phase was dried with Na2S04 and filtered through a pad of Na2S04 on a filter plate. The solvent was removed under reduced pressure giving a brown solid, which was purified by automated flash chromatography (Heptane:EtOAc, product elution with EtOAc 100%v/v) giving methyl 5-((fe/f-butoxycarbonyl)amino)-2-chloroisonicotinate as a pale yellow solid (4.04 g, 79% yield). Purity: 99.4% (UPLC-A); mp: 90.0-95.8 C; 1H- NMR (CDCI3), 5(ppm): 9.68 (bs, NH), 9.49 (s, 1 H), 7.73(s, 1 H), 7.20 (s, 1 H), 3.91 (s, 3H), 1.47 (s, 9H); LR-MS (ESI+): m/z= 287.1 Da [M+H]+, calcd. for CI2HI5CIN204: 286.2

References: [1]Patent: WO2004/18419,2004,A2 .Location in patent: Page 314.
[2]Patent: WO2020/20939,2020,A1 .Location in patent: Page/Page column 32; 34; 37.

23
[ 60-29-7 ]
[ 171178-45-3 ]
[ 171178-46-4 ]

Yield	Reaction Conditions	Operation in experiment
35%	With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; at -78 - 0℃; for 2h;	A stirred solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (3.28 g, 14.3 mmol) and TMEDA (6.7 mL, 44.4 mmol) in Et2O (100 mL) at -78 C. was treated with n-BuLi (4.3 mL, 10 M, 43 mmol). After stirring the mixture at -78 C. for 2 hours CO2 was bubbled into the reaction and the solution was warmed to 0 C. Water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified and extracted with Et2O. The Et2O layer was washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The residual solid was triturated with Hexane/Et2O to give 25A (1.38 g, 35%) HPLC Rt=2.98 min.

References: [1]Patent: US2005/192310,2005,A1 .Location in patent: Page/Page column 28.

24
[ 171178-46-4 ]
2-chloro-5-iodo-isonicotinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		Compound 25A (1.0 g, 3.67 mmol) was added slowly to TFA (15 mL) and stirred at room temperature for 30 minutes. The TFA was removed in vacuo and the residue was treated with H2O (100 mL) and H2SO4 (15 mL). The mixture was cooled to 0 C. and KNO2(0.343 g, 4 mmol) was added. The reaction was stirred at 0 C. for 1 hour and then KI (1.2 g, 7.22 mmol) was added. The mixture was heated to 70 C. for 20 minutes then cooled back to 0 C. The solid precipitate was filtered, washed with water and dried in vacuo to give 25B (0.78 g, 75%). HPLC Rt=1.54 min.

References: [1]Patent: US2005/192310,2005,A1 .Location in patent: Page/Page column 28.

25
[ 171178-46-4 ]
[ 74-88-4 ]
[ 1034131-89-9 ]

Yield	Reaction Conditions	Operation in experiment
		(d) Methyl 5-(tert-butoxycarbonylJ-l-chloroisonicotinate. To a solution of 5-(tert-butoxycarbonyl)-2-chloroisonicotinic acid (1 g, 3.7 mmol) in dry DMF (10 mL), was added NaH (60% suspension in mineral oil, 0.37 g, 9.24 mmol) in small portions with stirring and cooling with an ice-bath. After the addition, the reaction mixture was treated with MeI (0.524 mL, 9.24 mmol) dropwise, and then stirred at room temperature for 1 hour. The reaction mixture was poured into water and stirred at room temperature for 3 hours. The precipitate was filtered and dried in vacuo to afford the title compound as a solid.
		(d) Methyl 5-(tert-butoxycarbonyl)-2-chloroisonicotinate. To a solution of 5-(tert-butoxycarbonyl)-2-chloroisonicotinic acid (1 g, 3.7 mmol) in dry DMF (10 mL) was added NaH (60% suspension in mineral oil, 0.37 g, 9.24 mmol) in small portions with stirring and cooling using an ice-bath. After addition, the reaction mixture was treated with MeI (0.524 mL, 9.24 mmol) dropwise, and then stirred at room temperature for 1 hour. The reaction mixture was poured into water and stirred at room temperature for 3 hours. The precipitate was filtered and dried in vacuo to afford the title compound as a solid.

References: [1]Patent: WO2008/76425,2008,A1 .Location in patent: Page/Page column 43.
[2]Patent: WO2008/130600,2008,A2 .Location in patent: Page/Page column 58.

26
[ 171178-46-4 ]
3,3-dimethyl-2,5-dioxo-N-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[3,4-e][1,4]diazepine-7-sulfonamide [ No CAS ]