205676-84-2|tert-Butyl methyl(6-methylpyridin-2-yl)carbamate| Ambeed

Structure of 205676-84-2

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Quality Control of [ 205676-84-2 ] Purity: 95% SDS Specification

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Product Details of [ 205676-84-2 ]

CAS No. :	205676-84-2
Formula :	C₁₂H₁₈N₂O₂
M.W :	222.28
SMILES Code :	O=C(OC(C)(C)C)N(C)C1=NC(C)=CC=C1
MDL No. :	MFCD08275048
InChI Key :	UZRQBXOOMIFFLB-UHFFFAOYSA-N
Pubchem ID :	10537009

Safety of [ 205676-84-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H312-H332
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P330-P363-P501

Computational Chemistry of [ 205676-84-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	6
Fraction Csp3	0.5
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	64.35
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	42.43 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.08
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	2.33
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.76
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.	1.81
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	1.56
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.31

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.7
Solubility	0.444 mg/ml ; 0.002 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.	-2.86
Solubility	0.307 mg/ml ; 0.00138 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	-3.04
Solubility	0.201 mg/ml ; 0.000906 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	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	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.	-6.0 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	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)	2.4

Application In Synthesis of [ 205676-84-2 ]

* 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 [ 205676-84-2 ]

[ 205676-84-2 ] Synthesis Path-Downstream 1~35

1
[ 205676-84-2 ]
[ 105-58-8 ]
[ 205676-85-3 ]

Yield	Reaction Conditions	Operation in experiment
79%	With n-butyllithium; diisopropylamine; In tetrahydrofuran; dichloromethane;	c) Ethyl-6-[(tert-butoxycarbonyl)methylamino]-2-pyridylacetate LDA was prepared at 0 C. under argon from diisopropylamine (19.5 mL, 139.14 mmole) and 2.5 M n-BuLi in hexanes (46.4 mL, 115.95 mmole) in dry THF (350 mL). This solution was cooled to -78 C. and a solution of 2-[(tert-butoxycarbonyl)methylamino]-6picoline (10.31 g, 46.38 mmole) in dry THF (46 mL) was added dropwise over 10 min. Additional dry THF (2 mL) was used in transfer. The orange solution was stirred at -78 C. for 15 min, then diethyl carbonate (6.2 mL, 51.02 mmole) was added rapidly. The red solution was stirred at -78 C. for 15 min, then was quenched with half-saturated NH4Cl (175 mL). The mixture was warmed to +5 C. and extracted with EtOAc (175 mL) then with CH2Cl2 (2*100 mL). The combined organics were washed with brine (100 mL). dried (MgSO4), and concentrated. The cloudy yellow oil was chromatographed on silica gel (15% EtOAc/hexanes) to afford the title compound (10.72 g, 79%) as a light yellow oil: 1H NMR (250 MHz, CDCl3) δ7.51-7.63 (m, 2 H), 6.91-7.03 (m, 1 H), 4.19 (q, J=7.1 Hz, 2 H), 3.77 (s, 2 H), 3.38 (s, 3 H), 1.27 (t, J=7.1 Hz, 3 H), 1.51 (s, 9 H); MS (ES) m/e 295 (M+H)+.
	With ammonium chloride; In tetrahydrofuran;	c Ethyl-6-[(tert-butoxycarbonyl)methylamino]-2-pyridylacetate LDA (18 mmol) was prepared in THF (30 mL), cooled to -78 C., and 2-[(tert-butoxycarbonyl)methylamino]-6-picoline (2 g, 9 mmol) was added, forming a deep red solution. After 15 min, diethylcarbonate (18 mL, 15 mmol) was added. The burgundy-colored solution was stirred at -78 C. for an additional 15 min, then the reaction was quenched with saturated NH4Cl solution. The mixture was warmed to RT and extracted with EtOAc (3*30 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Silica gel chromatography gave the title compound as a colorless oil: MS (ES) m/e 294 (M+H)+.
	With ammonium chloride; In tetrahydrofuran;	c Ethyl-6-[(tert-butoxycarbonyl)methylamino]-2-pyridylacetate LDA (18 mmol) was prepared in THF (30 mL), cooled to -78 C., and 2-[(tert-butoxycarbonyl)methylamino]-6-picoline (2 g, 9 mmol) was added, forming a deep red solution. After 15 min, diethylcarbonate (18 mL, 15 mmol) was added. The burgundy-colored solution was stirred at -78 C. for an additional 15 min, then the reaction was quenched with saturated NH4Cl solution. The mixture was warmed to RT and extracted with EtOAc (3*30 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Silica gel chromatography gave the title compound as a colorless oil.

	With lithium diisopropyl amide; In tetrahydrofuran; at -15 - -10℃; for 1h;	A 2 L 3-necked flask equipped with air-driven mechanical stirrer, thermometer, addition funnel and nitrogen inlet/outlet was charged with THF (80 mL), 1, 1-dimethylethyl methyl (6-methyl-2-pyridinyl) carbamate (80 g, 0.36 mol) and diethyl carbonate (157.2 ML, 1.30 mol). The flask was cooled until the internal temperature is-15 C. LDA (450 mL, 0.9 mol) was added over lh while maintaining temperature <-10 C. The reaction mixture was transferred to another flask which contain saturated NH4C1 (400 mL). The two layers were separated; the aqueous layer was extracted with ethyl acetate (2 x 150 mL). The organic layers were washed with deionized H20 (4 x 150 mL), combined, and concentrated to provide the title compound. Evaporate the solvent and weigh the product (124.7 g).
		LDA was prepared at 0 C under argon from diisopropylamine (19.5 mL, 139.14 mmole) and 2.5 M n-BuLi in hexanes (46.4 mL, 115.95 mmole) in dry THF (350 mL). This solution was cooled to -78 C and a solution of 2-[(tert-butoxycarbonyl)methylamino]-6-picoline (10.31 g, 46.38 mmole) in dry THF (46 mL) was added dropwise over 10 min. Additional dry THF (2 mL) was used in transfer. The orange solution was stirred at -78 C for 15 min, then diethyl carbonate (6.2 mL, 51.02 mmole) was added rapidly. The red solution was stirred at -78 C for 15 min, then was quenched with half-saturated NH4CI (175 mL). The mixture was warmed to +5 C and extracted with EtOAc (175 mL) then with CH2Cl2 (2 × 100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), and concentrated. The cloudy yellow oil was chromatographed on silica gel (15% EtOAc/hexanes) to afford the title compound (10.72 g, 79%) as a light yellow oil: 1H NMR (250 MHz, CDCl3) δ 7.51 - 7.63 (m, 2 H), 6.91 - 7.03 (m, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 3.77 (s, 2 H), 3.38 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.51 (s, 9 H); MS (ES) m/e 295 (M + H)+.

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 22 - 26.
[2]Patent: US2002/91264,2002,A1 .
[3]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.
[4]Tetrahedron Letters,2008,vol. 49,p. 5946 - 5949.
[5]Patent: US2003/125317,2003,A1 .
[6]Patent: US2002/32187,2002,A1 .
[7]Patent: WO2004/89890,2004,A2 .Location in patent: Page 28-29; 39.
[8]Patent: EP1218005,2004,B1 .Location in patent: Page 20-21.

2
[ 90101-22-7 ]
[ 74-88-4 ]
[ 205676-84-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With NaH; In water; dimethyl sulfoxide; mineral oil;	b) 2-[(tert-Butoxycarbonyl)methylamino]-6-picoline NaH (60% in mineral oil, 3.60 g, 90 mmole) was added in portions over several min to a solution of 2-(tert-butoxycarbonylamino)-6-picoline (15.62 g, 75 mmole) and iodomethane (9.3 mL, 150 mmole) in anhydrous DMSO (75 mL) at 15 C. (cool water bath). The internal temperature rose to 35 C. When gas evolution had subsided, the cool water bath was removed and the reaction was allowed to stir at RT. After 0.5 hr, the dark yellow mixture was poured onto ice/H2O (300 mL) and extracted with Et2O (3300 mL). The combined organic layers were washed sequentially with H2O (275 mL) and brine (75 mL). Drying (MgSO4) and concentration left a yellow oil which was chromatographed on silica gel (7% EtOAc/hexanes). The title compound (13.01 g, 78%) was obtained as a faintly yellow oil: 1H NMR (250 MHz, CDCl3) δ7.51 (app t, 1 H), 7.37 (d, J=8.2 Hz, 1 H), 6.86 (d, J=7.2 Hz, 1 H), 3.38 (s, 3 H), 2.49 (s, 3 H), 1.50 (s, 9 H); MS (ES) m/e 223 (M+H)+.
74%		Step BSodium hydride (0.84 g, 35 mmol) was suspended in N,N'-dimethylformamide (50 mL) and the mixture was cooled to 0 C. At 0 C. a solution of the title compound from Step A above (6 g, 28.8 mmol) in N,N'-dimethylformamide (20 mL) was added over a period of 5 minutes. After the addition was completed, the reaction mixture was stirred at 0 C. for 15 minutes and then 60 minutes at room temperature. Then methyliodide (2.39 mL, 38.5 mmol) was added in one portion and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and 10% citric acid solution (150 mL). The organic phase was separated and the aqueous phase was extracted with ethylacetate (2×100 mL). The combined organic phase was washed with 10% citric acid solution (80 mL), saturated sodium bicarbonate (80 mL) and brine (80 mL). The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed. The residue was purified by chromatography on silica using ethyl acetate/petrolether (10/90) to afford the desired compound as a pale yellow oil (4.75 g, 74%).1H-NMR (400 MHz, CDCl3): δ=1.53 (s, 9H), 2.48 (s, 3H), 3.38 (s, 3H), 6.87 (d, 1H), 7.40 (d, 1H), 7.52 (t, 1H)
74%		Step B ; Sodium hydride (0.84 g, 35 mmol) was suspended in N,N'-dimethylformamide (50 mL) and the mixture was cooled to 0 C. At 0 C a solution of the title compound from Step A above (6 g, 28.8 mnol) in N,N'-dimethylformamide (20 mL) was added over a period of 5 minutes. After the addition was completed, the reaction mixture was stirred at 0 C for 15 minutes and then 60 minutes at room temperature. Then methyliodide (2.39 mL, 38.5 mmol) was added in one portion and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and 10 % citric acid solution (150 mL). The organic phase was separated and the aqueous phase was extracted with ethylacetate (2 x 100 mL). The combined organic phase was washed with 10 % citric acid solution (80 mL), saturated sodium bicarbonate (80 mL) and brine (80 mL). The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed. The residue was purified by chromatography on silica using ethyl acetate/petrolether (10/90) to afford the desired compound as a pale yellow oil (4.75 g, 74 %). 1H-NMR (400 MHz, CDCl3): d = 1.53 (s, 9H), 2.48 (s, 3H), 3.38 (s, 3H), 6.87 (d, 1H), 7.40 (d, 1H), 7.52 (t, 1H)

74%		Sodium hydride (0.84 g, 35 mmol) was suspended in N,N'-dimethylfonnamide (50 mL) and the mixture was cooled to 0 C . At 0 C a solution of the title compound from Step A above (6 g, 28.8 mmol) in Ν,Ν'-dimethylformamide (20 mL) was added over a period of 5 minutes. After the addition was completed, the reaction mixture was stirred at 0 C for 15 minutes and then 60 minutes at room temperature. Then methyliodide (2.39 mL, 38.5 mmol) was added in one portion and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate ( 150 mL) and 10 % citric acid solution ( 150 mL). The organic phase was separated and the aqueous phase was extracted with ethylacetate (2 x 100 mL). The combined organic phase was washed with 10 % citric acid solution (80 mL), saturated sodium bicarbonate (80 mL) and brine (80 mL). The organic phase was separated, dried over Na2S04, filtered and the solvents were removed. The residue was purified by chromatography on silica using ethyl acetate/petrolether (10/90) to afford the desired compound as a pale yellow oil (4.75 g, 74 %).1H- MR (400 MHz, CDC13): d = 1,53 (s, 9H), 2.48 (s, 3H), 3.38 (s, 3H), 6.87 (d, 1 H), 7.40 (d, 1 H), 7.52 (t, 1H)
74%		Sodium hydride (0.84 g, 35 mmol) was suspended in N,N’-dimethylformamide (50 mL) and the mixture cooled to 0C. At 0C a solution of starting material1, (6 g, 28.8 mmol), prepared as described1, in N,N’-dimethylformamide (20 mL) was added over a period of 5 minutes. After the addition was completed, the reaction mixture was stirred at 0C for 15 minutes and then 60 minutes at room temperature. Then methyliodide (2.39 ml, 38.5 mmol) was added in one portion and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and 10 % citric acid solution (150 mL). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2 x 100 mL). The combined organic phase was washed with 10 % citric acid solution (80 mL), saturated sodium bicarbonate (80 mL)and brine (80 mL). The organic phase was separated, dried over Na2SO4,filtered and the solvents removed. The residue was purified by chromatography on silica using ethyl acetate/petrol ether (10/90) to afford the desired compound as a pale yellow oil (4.75 g, 74 %).1H-NMR (400 MHz, CDCl3):δ = 1.53 (s, 9H), 2.48 (s, 3H), 3.38 (s, 3H), 6.87 (d, 1H), 7.40 (d, 1H), 7.52 (t, 1H)
	With NaH; In N,N-dimethyl-formamide; mineral oil;	b 2-[(tert-Butoxycarbonyl)methylamino]-6-picoline To the suspension of NaH (60% dispersion in mineral oil, 0.44 g, 11 mmol) in DMF (20 mL) at 0 C. was added a solution of 2-(tert-butoxycarbonylamino)-6-picoline (2.1 g,10 mmol) in DMF (30 mL). The reaction was stirred at 0 C. for 15 min; then methyl iodide (1.6 g, 11 mmol) was added. The reaction mixture was concentrated in vacuum, diluted with H2O, and extracted with CH2Cl2 (3*50 mL). Drying (MgSO4) and concentration gave the title compound as a colorless oil.
		A 1 L round bottom flask was charged with THF (200 mL) and sodium hydride (60% in mineral oil, 22 g, 0.55 mol). A solution of 2-(tert)-butoxycarbonylamino)-6-picoline (100 g, 99.2% PAR, 0.48 mol) in THF (200 mL) was added over 45 minutes while maintaining temperature 20 ~ 25 C. The resulting mixture was stirred for 15 minutes followed by addition OF IODOMETHANE (102 mL, 1.64 mol) over 1 h, while maintaining temperature 20- 25 C. The resulting mixture was stirred for 3 h at room temperature. Deionized H20 (100 ML) was added and the two layers separated. The aqueous layer was extracted with hexane (150 mL). The combined organic layers were washed with deionized H20 (2 x 100 mL) and concentrated to provide the title product (107.6 g).
	With sodium hydride; In dimethyl sulfoxide; at 15 - 35℃; for 0.5h;	NaH (60% in mineral oil, 3.60 g, 90 mmole) was added in portions over several min to a solution of 2-(tert-butoxycarbonylamino)-6-picoline (15.62 g, 75 mmole) and iodomethane (9.3 mL, 150 mmole) in anhydrous DMSO (75 mL) at 15 C (cool water bath). The internal temperature rose to 35 C. When gas evolution had subsided, the cool water bath was removed and the reaction was allowed to stir at RT. After 0.5 hr, the dark yellow mixture was poured onto ice/H2O (300 mL) and extracted with Et2O (3 × 300 mL). The combined organic layers were washed sequentially with H2O (2 × 75 mL) and brine (75 mL). Drying (MgSO4) and concentration left a yellow oil which was chromatographed on silica gel (7% EtOAc/hexanes). The title compound (13.01 g, 78%) was obtained as a faintly yellow oil: 1H NMR (250 MHz, CDCl3) δ 7.51 (app t, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 6.86 (d, J = 7.2 Hz, 1 H), 3.38 (s, 3 H), 2.49 (s, 3 H), 1.50 (s, 9 H); MS (ES) m/e 223 (M + H)+.

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 22 - 26.
[2]Tetrahedron Letters,2008,vol. 49,p. 5946 - 5949.
[3]Patent: US2002/91264,2002,A1 .
[4]Patent: US2011/92537,2011,A1 .Location in patent: Page/Page column 25.
[5]Patent: EP2311823,2011,A1 .Location in patent: Page/Page column 26; 27.
[6]Patent: WO2011/45383,2011,A2 .Location in patent: Page/Page column 53.
[7]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3330 - 3335.
[8]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.
[9]Patent: US2002/32187,2002,A1 .
[10]Patent: WO2004/89890,2004,A2 .Location in patent: Page 28-29; 39.
[11]Patent: EP1218005,2004,B1 .Location in patent: Page 20.

3
[ 205676-84-2 ]
[ 959991-23-2 ]

Yield	Reaction Conditions	Operation in experiment
17%	With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; at 20 - 50℃;	N-Bromo succinimide (178 mg, 1.0 mmol) and catalytic benzoyl peroxide (1 mg, 0.005 mmol) were added to a solution of <strong>[205676-84-2]tert-butyl methyl(6-methylpyridin-2-yl)carbamate</strong> (222 mg, 1.0 mmol) in CCl4 at room temperature. The reaction was heated at 50C overnight. After evaporation of solvent, the crude mixture was purified by silica gel flash chromatography (0 to 5% diethyl ether in petroleum ether) to afford 2 different brominated compounds, the second one in order of elution being the expected tert-butyl [6- (bromomethyl)pyridin-2-yl]methylcarbamate, obtained as a colorless oil (50 mg, 17%); 1H NMR Spectrum (CDC13) 1.52 (9H, s), 3.40 (3H, s), 4.48 (2H, s), 7.11 (IH, d), 7.61 (2H, m).

References: [1]Patent: WO2007/141473,2007,A1 .Location in patent: Page/Page column 173; 174.

4
[ 205676-84-2 ]
[ 959992-67-7 ]

Yield	Reaction Conditions	Operation in experiment
41%	With 3-chloro-benzenecarboperoxoic acid; In acetic acid; at 20℃;	The starting material tert-butyl [6-(hydroxymethyl)pyridin-2-yl]methylcarbamate was prepared as follows:0 To a solution of <strong>[205676-84-2]tert-butyl methyl(6-methylpyridin-2-yl)carbamate</strong> ( J. Med. Chem.2000, 43, 22)(7.0 g, 31.5 mmol) in acetonitrile (80 ml) was added portionwise w-CPBA <n="273"/>(6.5 g, 37.8 mmol) at room temperature. The reaction mixture was stirred overnight, then washed with an aqueous solution containing 5% OfNa2S2O3, then with water. The organic layer was dried, concentrated and purified by silica gel flash chromatography (50 to 100% ethyl acetate in petroleum ether) to give tert-butyl methyl(6-methyl-l-oxidopyridin-2- yl)carbamate as a white solid (3.1 g, 41%); Mass Spectrum [M+H]+ = 239; 1H NMRSpectrum (DMSO-d6) 1.32 (s, 9H), 2.37 (s, 3H), 3.01 (s, 3H), 7.22 (dd, IH), 7.37 (dd, IH), 7.41 (d, IH).

References: [1]Patent: WO2007/141473,2007,A1 .Location in patent: Page/Page column 271-272.

5
[ 1824-81-3 ]
[ 205676-84-2 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 22 - 26.
[3]Patent: EP2311823,2011,A1 .
[4]Patent: US2011/92537,2011,A1 .

6
[ 24424-99-5 ]
1.) NaH; 2.) SOCl₂ [ No CAS ]
[ 205676-84-2 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.

7
[ 205676-84-2 ]
[ 205676-87-5 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 22 - 26.

8
[ 205676-84-2 ]
[ 205676-86-4 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.

9
[ 205676-84-2 ]
3-(5-(2-(6-(methylamino)pyridin-2-yl)ethoxy)-1H-indol-1-yl)propanoic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.

10
[ 205676-84-2 ]
[ 474658-52-1 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.

11
[ 205676-84-2 ]
3-(6-{2-[6-(methylamino)-pyridin-2-yl]ethoxy}benzo[b]furan-3-yl)propanoic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.

12
[ 205676-84-2 ]
3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-benzo[b]thiophen-3-yl}-propionic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.

13
[ 205676-84-2 ]
[ 848601-25-2 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.

14
[ 205676-84-2 ]
[ 474658-47-4 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.

15
[ 205676-84-2 ]
[ 474658-54-3 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.

16
[ 205676-84-2 ]
[ 474658-53-2 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 926 - 934.

17
[ 24424-99-5 ]
[ 205676-84-2 ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 22 - 26.
[2]Patent: EP2311823,2011,A1 .
[3]Patent: US2011/92537,2011,A1 .

18
[ 205676-84-2 ]
[ 243640-97-3 ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 22 - 26.

19
[ 205676-84-2 ]
(4S)-2,3,4,5-tetrahydro-8-[2-[6-(methylamino)-2-pyridinyl]ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1H-2-benzazepine-4-acetic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 22 - 26.

20
[ 205676-84-2 ]
[ 205677-86-7 ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 22 - 26.

Yield	Reaction Conditions	Operation in experiment
		b 2-[(tert-Butoxycarbonyl)methylamino]-6-picoline To the suspension of NaH (60% dispersion in mineral oil, 0.44 g, 11 mmol) in DMF (20 mL) at 0 C. was added a solution of 2-(tert-butoxycarbonylamino)6-piculine (2.1 g, 10 mmol) in DMF (30 mL). The reaction was stirred at 0 C. for 15 min; then methyl iodide (1.6 g, 11 mmol) was added. The reaction mixture was concentrated in vacuum, diluted with H2O, and extracted with, CH2Cl2 (3*50 mL). Drying (MgSO4) and concentration gave the title compound as a colorless oil: MS (ES) m/e 223 (M+H)+.

22
[ 33513-42-7 ]
[ 205676-84-2 ]
[ 243640-97-3 ]

Yield	Reaction Conditions	Operation in experiment
44%		Step CA solution of LDA was prepared by adding a 2 M solution of n-butyllithium (12 mL, 24 mmol) at 0 C. to a stirred solution of N,N'-diisopropylamine (4 mL, 28.8 mmol) in tetrahydrofuran (60 mL). The mixture was stirred at 0 C. for 1 h and then cooled to -78 C. At -78 C. a solution of the title compound from Step B above (2.13 g, 9.6 mmol) in tetrahydrofuran (15 mL) was added over a period of 5 minutes. The mixture was stirred at -78 C. for 45 minutes and allowed to warm to -50 C. The mixture was then cooled to -78 C. and N,N'-dimethylformamide (0.76 mL, 10.3 mmol) was added. After 15 minutes at -78 C., methanol (8.4 mL) and acetic acid (0.59 mL, 12.8 mmol) were added. Then sodium borohydride (0.34 g, 9.4 mmol) was added at -78 C. and the mixture was stirred overnight and allowed to reach room temperature. The reaction mixture was diluted with ethylacetate (80 mL) and washed with a 10% citric acid solution (50 mL) and brine (50 mL). The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed. The residue was purified by chromatography on silica using ethylacetate/petrolether (20/80) to elute starting material (0.7 g, 35% recovery), followed by ethylacetate/petrolether (60/40) to afford the title compound as a pale orange oil (1.08 g, 44%).1H-NMR (400 MHz, CDCl3): δ=1.56 (s, 9H), 2.98 (t, 2H), 3.37 (s, 3H), 4.05 (t, 2H), 6.88 (d, 1H), 7.53-7.60 (m, 2H)
44%		Step C; A solution of LDA was prepared by adding a 2 M solution of n-butyllithium (12 mL, 24 mmol) at 0 C to a stirred solution of N,N'-diisopropylamine (4 mL, 28.8 mmol) in tetrahydrofuran (60 mL). The mixture was stirred at 0 C for I h and then cooled to -78 C. At -78 C a solution of the title compound from Step B above (2.13 g, 9.6 mmol) in tetrahydrofuran (15 mL) was added over a period of 5 minutes. The mixture was stirred at -78 C for 45 minutes and allowed to warm to -50 C. The mixture was then cooled to -78 C and N,N'-dimethylformamide (0.76 mL, 10.3 mmol) was added. After 15 minutes at -78 C, methanol (8.4 mL) and acetic acid (0.59 mL, 12.8 mmol) were added. Then sodium borohydride (0.34 g, 9.4 mmol) was added at -78 C and the mixture was stirred overnight and allowed to reach room temperature. The reaction mixture was diluted with ethylacetate (80 mL) and washed with a 10 % citric acid solution (50 mL) and brine (50 mL). The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed. The residue was purified by chromatography on silica using ethylacetate/petrolether (20/80) to elute starting material (0.7 g, 35 % recovery), followed by ethylacetate/petrolether (60/40) to afford the title compound as a pale orange oil (1.08 g, 44 %). 1H-NMR (400 MHz, CDCl3): d = 1.56 (s, 9H), 2.98 (t, 2H), 3.37 (s, 3H), 4.05 (t, 2H), 6.88 (d, 1H),7.53-7.60 (m, 2H)
44%		A solution of LDA was prepared by adding a 2 M solution of n-butyllithium (12 mL, 24 mmol) at 0 C to a stirred solution of N,N'-diisopropylamine (4 mL, 28.8 mmol) in tetrahydrofuran (60 mL). The mixture was stirred at 0 C for 1 h and then cooled to -78 C. At -78 C a solution of the title compound from Step B above (2.13 g, 9.6 .mmol) in tetrahydrofuran (15 mL) was added over a period of 5 minutes. The mixture was stirred at -78 C for 45 minutes and allowed to warm to -50 C. The mixture was then cooled to -78 C and N,N'-dimethylformamide (0.76 mL. 10.3 mmol) was added. After 15 minutes at -78 C, methanol (8.4 mL) and acetic acid (0.59 mL, 12,8 mmol) were added. Then sodium borohydride (0.34 g, 9.4 mmol) was added at -78 C and the mixture was stirred overnight and allowed to reach room temperature. The reaction mixture was diluted with ethylacetate (80 mL) and washed with a 10 % citric acid solution (50 mL) and brine (50 mL). The organic phase was separated, dried over Na2S04, filtered and the solvents were removed. The residue was purified by chromatography on silica using ethylacetate/petrolether (20/80) to el Lite starting material (0.7 g, 35 % recover)'), followed by ethylacetate/petrolether (60/40) to afford the title compound as a pale orange oil ( 1.08 g, 44 %).-NMR (400 MHz, CDC13): d = 1 .56 (s, 9H), 2.98 (t, 2H), 3.37 (s, 3H), 4.05 (t. 2H), 6.88 (d, 1 H), 7.53-7.60 (m, 2H)

44%

A solution of LDA was prepared by adding a 2 M solution of n-butyllithium (12 ml,24 mmol) at 0C to a stirred solution of N,N-diisopropylamine (4 mL, 28.8 mmol) in tetrahydrofuran (60 mL). The mixture was stirred at 0C for 1 h and then cooled to -78C. At -78 C a solution of compound 2 (2.13 g, 9.6 mmol) in tetrahydrofuran (15 mL) was added over a period of 5 minutes. The mixture was stirred at -78C for 45 minutes and allowed to warm to -50C. The mixture was then cooled to -78C and N,N-dimethylformamide(0.76 mL, 10. 3 mmol) added. After 15 minutes at -78C, methanol (8.4 mL) and acetic acid (0.59 mL, 12,8 mmol) were added. Then sodium borohydride (0.34 g,9.4 mmol) was added at -78C and the mixture was stirred overnight and allowed to reach room temperature. The reaction mixture was diluted with ethyl acetate (80 mL) and washed with a 10 % citric acid solution (50 mL) and brine (50 mL).The organic phase was separated, dried over Na2SO4, filtered and the solvents removed. The residue was purified by chromatography on silica using ethyl acetate/petrol ether (20/80) to elute starting material (0.7g, 35 % recovery), followed by ethyl acetate/petrol ether (60/40) to afford 3 as pale orange oil (1.08 g, 44 %). 1H-NMR (400 MHz, CDCl3): δ = 1.56 (s, 9H), 2.98 (t, 2H), 3.37 (s, 3H), 4.05 (t,2H), 6.88 (d, 1H), 7.53-7.60 (m,2H).

References: [1]Patent: US2011/92537,2011,A1 .Location in patent: Page/Page column 25.
[2]Patent: EP2311823,2011,A1 .Location in patent: Page/Page column 26; 27.
[3]Patent: WO2011/45383,2011,A2 .Location in patent: Page/Page column 53-54.
[4]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3330 - 3335.

23
[ 205676-84-2 ]
[ 1292955-76-0 ]