171178-34-0|4-((tert-Butoxycarbonyl)amino)nicotinic acid| Ambeed

CAS No. :	171178-34-0
Formula :	C₁₁H₁₄N₂O₄
M.W :	238.24
SMILES Code :	O=C(O)C1=CN=CC=C1NC(OC(C)(C)C)=O
MDL No. :	MFCD03427724
InChI Key :	FRZDXLXQZVISAQ-UHFFFAOYSA-N
Pubchem ID :	22172623

Safety of [ 171178-34-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H317
Precautionary Statements:	P261-P280

Computational Chemistry of [ 171178-34-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	6
Fraction Csp3	0.36
Num. rotatable bonds	5
Num. H-bond acceptors	5.0
Num. H-bond donors	2.0
Molar Refractivity	61.44
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	88.52 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.62
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	1.49
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.94
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.	-0.63
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	0.61
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.01

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.19
Solubility	1.55 mg/ml ; 0.0065 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.	-2.96
Solubility	0.263 mg/ml ; 0.00111 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.36
Solubility	1.05 mg/ml ; 0.0044 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	0.0 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)	2.27

Application In Synthesis of [ 171178-34-0 ]

* 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 [ 171178-34-0 ]
Downstream synthetic route of [ 171178-34-0 ]

[ 171178-34-0 ] Synthesis Path-Upstream 1~8

1
[ 280115-84-6 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: With sodium hydroxide; water In 1,4-dioxane at 60℃; for 1 h; Stage #2: With hydrogenchloride In 1,4-dioxane; water	4-tert-Butoxycarbonylamino-nicotinic acicL To a solution of 4-tert- butoxycarbonylamino-nicotinic acid methyl ester (6.02g, 23.86 mmol) in dioxane (100 mL) was added aq. sodium hydroxide (0.970 N solution, 28.05 mL, 27.20 mmol). The solution was heated to 6O⁰C for lhr then cooled. Aqueous hydrochloric acid (1.03 IM solution, 26.99mL, 27.20 mmol) was added and the mixture was extracted with chloroform (5x100 mL). The extracts were dried (MgSO₄), filtered, and evaporated to give 4-tert-Butoxycarbonylamino-nicotinic acid, a cream solid (4.7Og, 83percent yield).

References: [1] Patent: WO2006/100310, 2006, A1, . Location in patent: Page/Page column 34.
[2] Patent: WO2005/32481, 2005, A2, . Location in patent: Page/Page column 42-43.

2
[ 24424-99-5 ]
[ 7418-65-7 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
69%	With dmap In tetrahydrofuran; water at 20℃; for 3 h;	Intermediate 6AH: 4- fcr<-Butoxycarbonylamino)pyridine-3-carboxylic acidTo a stirred solution of 4-aminopyridine-3-carboxylic acid (1.0 g, 7.2 mmol), Boc anhydride in THF: water (1: 1, 20mL) was added DMAP and stirred for 3 h at room temperature. To this was added ethyl acetate (25 mL) and water (25 mL). Aqueous layer was separated, extracted with ethyl acetate (25 mL). Combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to furnish 1.2 g (69percent) of 4-(ieri-butoxycarbonylamino)pyridine-3-carboxylic acid.MS (ES) m/z 239.1 (M+l).
69%	With dmap In tetrahydrofuran; water at 20℃; for 3 h;	To a stirred solution of 4-aminopyridine-3-carboxylic acid (1.0 g, 7.2 mmol), Boc anhydride in THF:water (1:1, 20 mL) was added DMAP and stirred for 3 h at room temperature. To this was added ethyl acetate (25 mL) and water (25 mL). Aqueous layer was separated, extracted with ethyl acetate (25 mL). Combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to furnish 1.2 g (69percent) of 4-(tert-butoxycarbonylamino)pyridine-3-carboxylic acid. [0349] MS (ES) m/z 239.1 (M+1)

References: [1] Patent: WO2013/42139, 2013, A1, . Location in patent: Page/Page column 80.
[2] Patent: US2015/65464, 2015, A1, . Location in patent: Paragraph 0348-0349.

3
[ 124-38-9 ]
[ 98400-69-2 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - 20℃; for 2 h;	To a stirred solution of BL (12 g, 0.06 mol) in dry THF (200 mL) under inert atmosphere was added n-butyl lithium (79.12 mL, 0.18 mol) at -78 °C. The reaction was warmed to 0 °C and stirred for 30 min. Carbon dioxide gas was added to the reaction mass at -78 °C for 1 h, then at RT for 1 h. The reaction was monitored by TLC. After complete consumption of the starting material, the reaction mass was diluted with water (200 mL) and washed with diethyl ether (2x150 mL). The aqueous layer was acidified with citric acid to pH~4. The obtained solid was filtered and dried under vacuum to afford BM (5.1 g, 35percent) as a white solid. *H NMR (400 MHz, DMSO-i: δ 11.76 (br s, 1H), 8.96 (s, 1H), 8.52 (d, / = 15.0 Hz, 1H), 8.22 (d, / = 15.0 Hz, 1H), 1.49 (s, 9H).
30%	Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -40 - 20℃; for 0.333333 h; Stage #2: at -78 - 20℃; for 3.25 h;	-Buli (1.6 M soln, 155 mL, 249 mmol) was added to a stirred solution of TMEDA (37.36 mL, 249 mmol) in THF AT-40 °C. The solution was allowed to come at room temperature over 10 min and stirred for another 10 min. The solution was cooled TO-78 °C. A solution OF PYRIDINE-4-YL-CARBAMIC acid-tert-butyl ester (117) (22 g, 113.26 mmol) in THF was added slowly. The solution was allowed to come at room temperature within 3 h. After stirring at room temperature for 15 min the solution was again cooled to -78 OC and a freshly crushed dry ice was added. The solution was allowed to come at room temperature, stirred for 30 min and poured into ice cold 10 percent NH4C1 solution. The solution was basified by IN NaOH solution and washed by dichloromethane. The pH of aqueous phase was adjusted to 4 by cold 10 percent HC1 solution. The solids formed were filtered, washed by water and dried under vacuum at room temperature to yield 16.3 g (30 percent) 4-tert-butoxycarbonylamino-nicotinic acid (118) as white solids. MP: 260 °C ; 1H- NMR (DMSO-d6): d 1.49 (s, 9H), 8.23 (d, J= 6.0 Hz, 1H), 8.55 (D, J= 6.0 Hz, 1H), 8. 96 (s, 1H); EIMS M/Z 238 (M+1).

References: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 16, p. 3023 - 3025.
[2] Patent: WO2014/117090, 2014, A1, . Location in patent: Page/Page column 123-124.
[3] Patent: WO2005/21546, 2005, A1, . Location in patent: Page/Page column 124; 207-208.

4
[ 124-38-9 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: With tert.-butyl lithium In tetrahydrofuran; pentane at -50 - -28℃; for 1 h; Stage #2: for 0.25 h;	To a stirring solution of4- (Boc-amino) pyridine (1.027 g, 5.30 mmol) in THF at-36 C (internal temperature) was added a 1.7 M solution of t-butyl lithium in pentane (6.5 mL, 11 mmol), and the rate of addition was controlled so as to keep the internal temperature below-28 C. After an additional hour (temperature kept between-30 C and- 50 C) carbon dioxide (g) was bubbled through the solution and the cold bath was removed. After about 15 min, the mixture was poured into ice water and the aqueous phase was washed with dichloromethane. The pH was adjusted to 4-5 with citric acid, and the resulting precipitate was washed with dichloromethane and methanol and dried in vacuo to give the title compound (0.811 g, 64percent) as an off-white solid. 1NMR IS-MS, m/e239. 0 (m+l) Analysis forCllH14N2 4 : Calcd: C, 55.46 ; H, 5.92 ; N, 11.76 ; Found: C, 55.73 ; H, 6.07 ; N, 11.75.

References: [1] Patent: WO2005/49604, 2005, A2, . Location in patent: Page/Page column 106.

5
[ 109-72-8 ]
[ 98400-69-2 ]
[ 171178-34-0 ]

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

6
[ 594-19-4 ]
[ 98400-69-2 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
64%	With carbon dioxide In tetrahydrofuran; pentane	B. 4-(Boc-amino)pyridine-3-carboxylic Acid. To a stirring solution of 4-(Boc-amino)pyridine (1.027 g, 5.30 mmol) in THF at -36 °C (internal temperature) was added a 1.7 M solution of t-butyl lithium in pentane(6.5 mL, 11 mmol), and the rate of addition was controlled so as to keep the internal temperature below -28 °C. After an additional hour (temperature kept between -30 °C and -50 °C) carbon dioxide (g) was bubbled through the solution and the cold bath was removed. After about 15 min, the mixture was poured into ice water and the aqueous phase was washed with dichloromethane. The pH was adjusted to 4-5 with citric acid and the resulting precipitate was washed with dichloromethane and methanol and dried in vacuo to give 0.811 g (64percent) of an off-white solid. ¹H-NMR IS-MS, m/e 239.0 (m+1)

References: [1] Patent: EP1140905, 2003, B1, .

7
[ 504-24-5 ]
[ 171178-34-0 ]

References: [1] Patent: WO2014/117090, 2014, A1, .

8
[ 24424-99-5 ]
[ 171178-34-0 ]

References: [1] Patent: WO2014/117090, 2014, A1, .

[ 171178-34-0 ] Synthesis Path-Downstream 1~24

1
[ 124-38-9 ]
[ 98400-69-2 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
35%		To a stirred solution of BL (12 g, 0.06 mol) in dry THF (200 mL) under inert atmosphere was added n-butyl lithium (79.12 mL, 0.18 mol) at -78 C. The reaction was warmed to 0 C and stirred for 30 min. Carbon dioxide gas was added to the reaction mass at -78 C for 1 h, then at RT for 1 h. The reaction was monitored by TLC. After complete consumption of the starting material, the reaction mass was diluted with water (200 mL) and washed with diethyl ether (2x150 mL). The aqueous layer was acidified with citric acid to pH~4. The obtained solid was filtered and dried under vacuum to afford BM (5.1 g, 35%) as a white solid. *H NMR (400 MHz, DMSO-i: delta 11.76 (br s, 1H), 8.96 (s, 1H), 8.52 (d, / = 15.0 Hz, 1H), 8.22 (d, / = 15.0 Hz, 1H), 1.49 (s, 9H).
30%		-Buli (1.6 M soln, 155 mL, 249 mmol) was added to a stirred solution of TMEDA (37.36 mL, 249 mmol) in THF AT-40 C. The solution was allowed to come at room temperature over 10 min and stirred for another 10 min. The solution was cooled TO-78 C. A solution OF PYRIDINE-4-YL-CARBAMIC acid-tert-butyl ester (117) (22 g, 113.26 mmol) in THF was added slowly. The solution was allowed to come at room temperature within 3 h. After stirring at room temperature for 15 min the solution was again cooled to -78 OC and a freshly crushed dry ice was added. The solution was allowed to come at room temperature, stirred for 30 min and poured into ice cold 10 % NH4C1 solution. The solution was basified by IN NaOH solution and washed by dichloromethane. The pH of aqueous phase was adjusted to 4 by cold 10 % HC1 solution. The solids formed were filtered, washed by water and dried under vacuum at room temperature to yield 16.3 g (30 %) 4-tert-butoxycarbonylamino-nicotinic acid (118) as white solids. MP: 260 C ; 1H- NMR (DMSO-d6): d 1.49 (s, 9H), 8.23 (d, J= 6.0 Hz, 1H), 8.55 (D, J= 6.0 Hz, 1H), 8. 96 (s, 1H); EIMS M/Z 238 (M+1).

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3023 - 3025.
[2]Patent: WO2014/117090,2014,A1 .Location in patent: Page/Page column 123-124.
[3]Patent: WO2005/21546,2005,A1 .Location in patent: Page/Page column 124; 207-208.

2
[ 6638-79-5 ]
[ 171178-34-0 ]
[ 244780-32-3 ]

Yield	Reaction Conditions	Operation in experiment
42%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere;	To a stirred solution of BM (5.1 g, 0.02 mol) in DMF (10 mL) under inert atmosphere were added EDCI HC1 (6.14 g, 0.03 mol), HOBt (4.33 g, 0.03 mol), diisopropylethyl amine (5.53 g, 0.04 mol) and Nu,Omicron-dimethylhydroxylamine hydrochloride (4.18 g, 0.04 mol) at 0 C. The reaction was warmed to RT and stirred for 16 h. After complete consumption of the starting material, the reaction mixture was diluted with water (40 mL) and the compound was extracted with diethyl ether (3x40 mL). The combined organic extracts were washed with water (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified through column chromatography eluting with 3% MeOH/CH2Cl2 to afford BN (2.5 g, 42%) as a yellow solid. *H NMR (400 MHz, CDC13): delta 8.98 (br s, 1H), 8.74 (s, 1H), 8.47 (d, / = 15.0 Hz, 1H), 8.25 (d, / = 15.0 Hz, 1H), 3.58 (s, 3H), 3.41 (s, 3H), 1.52 (s, 9H).

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3023 - 3025.
[2]Patent: WO2014/117090,2014,A1 .Location in patent: Page/Page column 123-124.

3
[ 171178-34-0 ]
[ 53277-43-3 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3023 - 3025.
[2]Patent: WO2014/117090,2014,A1 .

4
[ 171178-34-0 ]
[ 244780-21-0 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3023 - 3025.

5
[ 171178-34-0 ]
(3-acetyl-pyridin-4-yl)-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3023 - 3025.
[2]Patent: WO2014/117090,2014,A1 .

6
[ 171178-34-0 ]
4-methyl-[1,6]naphthyridine-2-carboxylic acid 2-methoxy-benzylamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3023 - 3025.

7
[ 171178-34-0 ]
[ 503-38-8 ]
[ 56788-14-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	In 1,4-dioxane; for 4h;Heating / reflux;	Trichloromethyl CHLOROFORMATE (9 mL, 75 mmol) was added slowly to a solution of <strong>[171178-34-0]4-tert-butoxycarbonylamino-nicotinic acid</strong> (118) (16.2 g, 68 mmol) in dioxane and refluxed for 4 h under nitrogen atmosphere. The solution was cooled and the solvent was removed under vacuum. The residue was recrystallized by ether to yield 10.92 g (98 %) of 1H-pyrido [4, 3-d] [1, 3] oxazine-2, 4-DIONE (119) as white solids. MP: 243 C ; 1H- NMR (DMSO-d6) : ), d 7.32 (d, J= 6.0 Hz, 1H), 8. 71 (d, J= 6.0 Hz, 1H), 9.11 (s, 1H); EIMS M/Z 165 (M+1).

References: [1]Patent: WO2005/21546,2005,A1 .Location in patent: Page/Page column 124; 208-209.

8
[ 124-38-9 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
64%		To a stirring solution of4- (Boc-amino) pyridine (1.027 g, 5.30 mmol) in THF at-36 C (internal temperature) was added a 1.7 M solution of t-butyl lithium in pentane (6.5 mL, 11 mmol), and the rate of addition was controlled so as to keep the internal temperature below-28 C. After an additional hour (temperature kept between-30 C and- 50 C) carbon dioxide (g) was bubbled through the solution and the cold bath was removed. After about 15 min, the mixture was poured into ice water and the aqueous phase was washed with dichloromethane. The pH was adjusted to 4-5 with citric acid, and the resulting precipitate was washed with dichloromethane and methanol and dried in vacuo to give the title compound (0.811 g, 64%) as an off-white solid. 1NMR IS-MS, m/e239. 0 (m+l) Analysis forCllH14N2 4 : Calcd: C, 55.46 ; H, 5.92 ; N, 11.76 ; Found: C, 55.73 ; H, 6.07 ; N, 11.75.

References: [1]Patent: WO2005/49604,2005,A2 .Location in patent: Page/Page column 106.

9
[ 171178-34-0 ]
[ 18107-18-1 ]
[ 280115-84-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	In methanol; hexane; for 0.25h;	To a stirring suspension of4- (Boc-amino) pyridine-3- carboxylic acid (1.04 g, 4.37 mmol) in methanol (3.5 mL) was added a 2 M solution of (trimethylsilyl) diazomethane in hexanes (3.5 mL, 7 mmol). After 15 min, acetic acid was added and the solvents were removed in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of 20% ethyl acetate in hexanes through 70% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to give the title compound (0.894 g,81%) as a white solid. 1NMR
0.894 g (81%)	With acetic acid; In methanol; ethyl acetate;	C. Methyl 4-(Boc-amino)pyridine-3-carboxylate. To a stirring suspension of <strong>[171178-34-0]4-(Boc-amino)pyridine-3-carboxylic acid</strong> (1.04 g, 4.37 mmol) in methanol (3.5 mL) was added a 2 M solution of (trimethylsilyl)diazomethane in hexanes (3.5 mL, 7 mmol). After 15 min, acetic acid was added and the solvents were removed in vacuo. The residue was chromatographed over silica gel, eluding with a step gradient of 20 % ethyl acetate in hexanes through 70 % ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to give 0.894 g (81%) of a white solid. 1H-NMR

References: [1]Patent: WO2005/49604,2005,A2 .Location in patent: Page/Page column 107.
[2]Patent: EP1140905,2003,B1 .

10
[ 280115-84-6 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
83%		4-tert-Butoxycarbonylamino-nicotinic acicL To a solution of 4-tert- butoxycarbonylamino-nicotinic acid methyl ester (6.02g, 23.86 mmol) in dioxane (100 mL) was added aq. sodium hydroxide (0.970 N solution, 28.05 mL, 27.20 mmol). The solution was heated to 6O0C for lhr then cooled. Aqueous hydrochloric acid (1.03 IM solution, 26.99mL, 27.20 mmol) was added and the mixture was extracted with chloroform (5x100 mL). The extracts were dried (MgSO4), filtered, and evaporated to give 4-tert-Butoxycarbonylamino-nicotinic acid, a cream solid (4.7Og, 83% yield).
		Example 12 SYNTHESIS of Compound 47 Preparation OF 4-TERT-BUTOXYCARBONYLAMINO-NICOTINIC acid : [0114] To A solution OF 4-TERT-BUTOXYCARBONYLAMINO-NICOTINIC acid methyl ester (6. 02g, 23. 86 MMOL) in dioxane (100 ML) was added AQ. sodium hydroxide (0. 970N solution, 28. 05mL, 27. 20 MMOL). The solution was heated to 60C for Ihr then cooled. Aqueous hydrochloric acid (1. 031M solution, 26. 99mL, 27. 20 mmol) was added and the mixture was extracted with chloroform (SIX100 ML). The extracts were dried (MGS04) and evaporated to give 4-TERT- BUTOXYCARBONYLAMINO-NICOTINIC acid, A cream solid (4. 70g, 83% yield) without further purification.

References: [1]Patent: WO2006/100310,2006,A1 .Location in patent: Page/Page column 34.
[2]Patent: WO2005/32481,2005,A2 .Location in patent: Page/Page column 42-43.

11
[ 75-09-2 ]
[ 171178-34-0 ]
[ 7418-65-7 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid;	4-Amino nicotinic acid. A mixture of 4-(N-t-butoxycarbonylamino) nicotinic acid (2.72 g, 11.4 mmol), TFA (10 mL), and CH2 Cl2 (20 mL) is stirred at room temperature for 12 h. The volatiles are removed under reduced pressure, and the resulting crude 4-amino nicotinic acid is used directly in the next reaction. 3H-Pyrido[4,3-d]pyrimidin-4-one.

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

12
[ 109-72-8 ]
[ 98400-69-2 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
54%	In tetrahydrofuran; water;	4-(N-t-Butoxycarbonylamino)nicotinic acid. n-Butyl lithium (2.18M, 24 mL, 52.51 mmol) is added slowly to a solution of 4-(N-t-butoxycarbonylamino)pyridine (4.08 g, 21 mmol) in THF (50 mL, stirred under N2 at -78 C. The solution is allowed to warm to 0 C., stirred for 3 h, then cooled again to -78 C. and poured into ether (100 mL) containing dry ice. The solution is warmed to room temperature with constant stirring. Water is added and the mixture is neutralized with acetic acid. The resulting solid is collected by vacuum filtration and dried in a vacuum oven to give 4-(N-t-butoxycarbonylamino)nicotinic acid (2.72 g, 54%) as a brown solid. 1 H NMR (DMSO) delta 11.75 (1H, brs), 8.95 (1H, s), 8.50 (1H, d, J=6.0 Hz), 8.20 (1H, d, J=6.0 Hz), 1.49 (9H, s).

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

13
[ 594-19-4 ]
[ 98400-69-2 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
0.811 g (64%)	With carbon dioxide; In tetrahydrofuran; pentane;	B. 4-(Boc-amino)pyridine-3-carboxylic Acid. To a stirring solution of 4-(Boc-amino)pyridine (1.027 g, 5.30 mmol) in THF at -36 C (internal temperature) was added a 1.7 M solution of t-butyl lithium in pentane(6.5 mL, 11 mmol), and the rate of addition was controlled so as to keep the internal temperature below -28 C. After an additional hour (temperature kept between -30 C and -50 C) carbon dioxide (g) was bubbled through the solution and the cold bath was removed. After about 15 min, the mixture was poured into ice water and the aqueous phase was washed with dichloromethane. The pH was adjusted to 4-5 with citric acid and the resulting precipitate was washed with dichloromethane and methanol and dried in vacuo to give 0.811 g (64%) of an off-white solid. 1H-NMR IS-MS, m/e 239.0 (m+1)

References: [1]Patent: EP1140905,2003,B1 .

14
[ 171178-34-0 ]
(3-carbamoyl-pyridin-4-yl)-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		PREPARATION OF 4-AMINO NICOTINAMIDE : [0115] 4-TERT-BUTOXYCARBONYLAMINO-NICOTINIC acid (L. OG, 4. 20 mmol) was suspended in dry DMF (50 ML) followed by CARBONYL-DIIMIDAZOLE (CDI, 1. 36g, 8. 40 MMOL). The mixture was heated to 60C for IH, then cooled. Dry ammonia gas was slowly bubbled through this solution for 1h, followed by evaporation of the mixture. The residue was dissolved in water (20 ML)/ chloroform (50 ML) and shaken then the layers separated. The aqueous layer was extracted further with chloroform (3x50 ML) and the combined organic extracts dried (MGS04) and evaporated to give A yellow oily solid. Silica gel chromatography (CH2C12, 0-15% MEOH gradient) gave the desired product, (3-CARBAMOYL-PYRIDIN-4-YL)-CARBAMIC acid TERT-BUTYL ester, as A yellow solid. This material was directly treated with TRIFLUOROACETIC acid (TFA, 20 ML) stirred at R. t. for 45min., then evaporated to give the desired amine, 4-Amino NICOTINAMIDE, as its TFA salt (892MG, 85% yield over 2 steps).

References: [1]Patent: WO2005/32481,2005,A2 .Location in patent: Page/Page column 43.

15
[ 24424-99-5 ]
[ 7418-65-7 ]
[ 171178-34-0 ]

Yield	Reaction Conditions	Operation in experiment
69%	With dmap; In tetrahydrofuran; water; at 20℃; for 3h;	Intermediate 6AH: 4- fcr<-Butoxycarbonylamino)pyridine-3-carboxylic acidTo a stirred solution of 4-aminopyridine-3-carboxylic acid (1.0 g, 7.2 mmol), Boc anhydride in THF: water (1: 1, 20mL) was added DMAP and stirred for 3 h at room temperature. To this was added ethyl acetate (25 mL) and water (25 mL). Aqueous layer was separated, extracted with ethyl acetate (25 mL). Combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to furnish 1.2 g (69%) of 4-(ieri-butoxycarbonylamino)pyridine-3-carboxylic acid.MS (ES) m/z 239.1 (M+l).
69%	With dmap; In tetrahydrofuran; water; at 20℃; for 3h;	To a stirred solution of 4-aminopyridine-3-carboxylic acid (1.0 g, 7.2 mmol), Boc anhydride in THF:water (1:1, 20 mL) was added DMAP and stirred for 3 h at room temperature. To this was added ethyl acetate (25 mL) and water (25 mL). Aqueous layer was separated, extracted with ethyl acetate (25 mL). Combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to furnish 1.2 g (69%) of 4-(tert-butoxycarbonylamino)pyridine-3-carboxylic acid. [0349] MS (ES) m/z 239.1 (M+1)

References: [1]Patent: WO2013/42139,2013,A1 .Location in patent: Page/Page column 80.
[2]Patent: US2015/65464,2015,A1 .Location in patent: Paragraph 0348-0349.

16
[ 171178-34-0 ]
[ 1664372-00-2 ]