323578-38-7|tert-Butyl (6-(hydroxymethyl)pyridin-3-yl)carbamate| Ambeed

Structure of 323578-38-7

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Quality Control of [ 323578-38-7 ] Purity: 95% SDS Specification

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Product Details of [ 323578-38-7 ]

CAS No. :	323578-38-7
Formula :	C₁₁H₁₆N₂O₃
M.W :	224.26
SMILES Code :	O=C(OC(C)(C)C)NC1=CC=C(CO)N=C1
MDL No. :	MFCD12031249
InChI Key :	FVXMQFNZAQVKAK-UHFFFAOYSA-N
Pubchem ID :	40151875

Safety of [ 323578-38-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 323578-38-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	6
Fraction Csp3	0.45
Num. rotatable bonds	5
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	60.61
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	71.45 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.2
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	0.57
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.58
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.	0.3
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	1.04
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.14

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.54
Solubility	6.51 mg/ml ; 0.029 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.64
Solubility	5.1 mg/ml ; 0.0227 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-2.81
Solubility	0.344 mg/ml ; 0.00153 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	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.	-7.26 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)	2.37

Application In Synthesis of [ 323578-38-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 323578-38-7 ]
Downstream synthetic route of [ 323578-38-7 ]

[ 323578-38-7 ] Synthesis Path-Upstream 1~10

1
[ 1078129-19-7 ]
[ 323578-38-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 6.5 h;	To a stirred solution of ethyl 5-(tert-butoxycarbonylarnino)picolinate (112; 8.9 g, 24.0 mmol) in ethyl ether (200 mL) was added LiAlH4 (1.80 g, 48 mmol) in ethyl ether (100 mL) over a period of 30 min at 0 ⁰C. The resulting reaction mixture was stirred at 0 ⁰C for 3 h and then carefully quenched by carefully adding water (1.0 mL) and 10percent NaOH solution (2.0 mL). The mixture was filtered; the filtrate was dried (Na₂SO₄) and concentrated under reduced pressure to afford tert-butyl 6-(hydroxymethyl)pyridin-3- ylcarbamate 113 (4.20 g, 78percent)
78%	Stage #1: With lithium aluminium tetrahydride In diethyl ether at 0℃; for 3.5 h; Inert atmosphere Stage #2: With water; sodium hydroxide In diethyl ether at 0℃; Inert atmosphere	To a stirred solution of ethyl 5-(tert-butoxycarbonylamino)picolinate (18; 8.9 g, 24 mmol) in ethyl ether (200 mL) under nitrogen was added l ithium aluminum hydride (LAH) ( 1 .8 g, 48 mmol) in ethyl ether ( 100 mL) over a period of 30 min at 0 °C. The reaction mixture was stirred for 3 h, water ( 1 mL) and 1 0percent NaOH solution (2 mL) was added and the mixture was filtered and the filtrate was dried over a2SC>4 and concentrated under reduced pressure to give compound tert-butyl 6-(hydroxymethyl)pyridin-3-ylcarbamate (19; 4.2 g, 78percent). M S (ESI) calcd for C 1 1 H 16N2O3 (m/z) 224.26.
78%	With lithium aluminium tetrahydride In diethyl ether at 0℃; for 3.5 h; Inert atmosphere	To a stirred solution of ethyl 5-(tert-butoxycarbonylamino)picolinate (8.9 g, 24 mmol) in ethyl ether (200 mL) under nitrogen was added LAH (1.8 g, 48 mmol) in ethyl ether (100 mL) over a period of 30 min at 0 °C. The reaction mixture was stirred for 3 h, water (1 mL) and 10percent NaOH solution (2 mL) was added and the mixture was filtered and the filtrate was dried over Na₂SO₄ and concentrated under reduced pressure to give compound tert-butyl 6-(hydroxymethyl)pyridin-3-ylcarbamate (4.2 g, 78percent). MS (ESI) calcd for C₁₁H₁₆N₂O₃ (m/z): 224.26

78%

With lithium aluminium tetrahydride In diethyl ether at 0℃; for 3.5 h;

To a stirred solution of ethyl 5-(tert-butoxycarbonylamino)picolinate (8.9 g, 24 mmol) in ethyl ether (200 mL) under nitrogen was added LAH (1.8 g, 48 mmol) in ethyl ether (100 mL) over a period of 30 min at 0 °C. The reaction mixture was stirred for 3 h, water (1 mL) and 10percent NaOH solution (2 mL) was added and the mixture was filtered and the filtrate was dried over Na₂SO₄ and concentrated under reduced pressure to give compound tert-butyl 6-(hydroxymethyl)pyridin-3-ylcarbamate (4.2 g, 78percent). MS (ESI) calcd for C₁₁H₁₆N₂O₃ (m/z): 224.26.

References: [1] Patent: WO2010/3048, 2010, A1, . Location in patent: Page/Page column 115.
[2] Patent: WO2011/59839, 2011, A1, . Location in patent: Page/Page column 71-72.
[3] Patent: WO2013/59587, 2013, A1, . Location in patent: Page/Page column 159.
[4] Patent: EP2768509, 2017, B1, . Location in patent: Paragraph 0581; 0582.

2
[ 131052-40-9 ]
[ 323578-38-7 ]

Yield	Reaction Conditions	Operation in experiment
67%	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 12 h; Inert atmosphere	Step 3. tert-Butyl (6-(hydroxymethyl)pyridin-3-yl)carbamate. LAH powder (36 g, 0.96 mol) was suspended in dry THF (1000 ml) under N₂atmosphere and cooled to 0° C. To the mixture was added compound 3 (150 g, 0.60 mol) in dry THF (1000 ml) slowly at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 12 h. TLC (PE/EA, 1:1) showed that the reaction was complete, and the reaction was quenched with dropwise addition of THF-Water (9:1, 400 mL) followed by 90 ml 15percent NaOH aqueous and 50 ml of water at 0° C., stirred for 0.5 h at room temperature, and filtered through a pad of Celite®, and then washed with THF (4×1000 ml). The filtrate was concentrated under reduced pressure to give the crude which was purified by column chromatography over silica gel eluting with PE/EA (2:1-1:2). The desired fraction was concentrated to afford tert-butyl (6-(hydroxymethyl)pyridin-3-yl)carbamate (450 g, 67percent) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.58-9.40 (m, 1H), 8.59-8.45 (m, 1H), 7.95-7.78 (m, 1H), 7.42-7.22 (m, 1H), 5.42-5.21 (m, 1H), 4.58-4.40 (m, 2H), 1.48 (s, 9H).
60%	With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0 - 20℃; for 12 h; Inert atmosphere	To a stirred solution of methyl 5-[(tert-butoxy)carbonyl]amino}pyridine-2- carboxylate (EV-AX4571-001, 2.73 g, 10.82 mmol) in THF (60 ml) at 0 °C under an atmosphere of nitrogen was added 4M lithium tetrahydridoaluminate(l-) in diethyl ether (4.1 ml) drop-wise, the reaction was allowed to warm to room temperature and stirred for a further 12h. The reaction was quenched by addition of THF:water (9: 1, 15 ml), followed by 10percent sodium hydroxide (10 ml) and then water (10 ml). The reaction mixture was then filtered through a pad of Kieselguhr, rinsing with THF (3 x 50 ml). The filtrate was concentrated in vacuo and the crude was purified by flash column chromatography (50-100percent) EtOAc/heptane then 0-10percent Methanol/EtOAc) to obtain 1.50 g (60percent) of tert-butyl N-[6- (hydroxymethyl)pyridin-3-yl]carbamate EV-AX4573-001 as an off-white solid. LCMS (method D): retention time 0.70min, M/z = 224 (M + 1).

References: [1] European Journal of Inorganic Chemistry, 2010, # 13, p. 1913 - 1928.
[2] Patent: US2015/158864, 2015, A1, . Location in patent: Paragraph 0295.
[3] Patent: WO2017/100594, 2017, A1, . Location in patent: Paragraph 00304.
[4] Patent: WO2006/51270, 2006, A1, . Location in patent: Page/Page column 146.

3
[ 323578-37-6 ]
[ 323578-38-7 ]

References: [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 26, p. 5017 - 5029.
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 18, p. 4136 - 4142.

4
[ 24242-20-4 ]
[ 323578-38-7 ]

References: [1] Patent: WO2011/59839, 2011, A1, .
[2] Patent: US2015/158864, 2015, A1, .
[3] Patent: EP2768509, 2017, B1, .
[4] Patent: WO2013/59587, 2013, A1, .

5
[ 119830-47-6 ]
[ 323578-38-7 ]

References: [1] Patent: WO2011/59839, 2011, A1, .
[2] Patent: EP2768509, 2017, B1, .
[3] Patent: WO2013/59587, 2013, A1, .

6
[ 3222-47-7 ]
[ 323578-38-7 ]

References: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 18, p. 4136 - 4142.
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 26, p. 5017 - 5029.

7
[ 67515-76-8 ]
[ 323578-38-7 ]

References: [1] Patent: US2015/158864, 2015, A1, .
[2] Patent: WO2017/100594, 2017, A1, .
[3] Patent: WO2018/165611, 2018, A1, .

8
[ 100-26-5 ]
[ 323578-38-7 ]

References: [1] European Journal of Inorganic Chemistry, 2010, # 13, p. 1913 - 1928.

9
[ 17874-76-9 ]
[ 323578-38-7 ]

References: [1] European Journal of Inorganic Chemistry, 2010, # 13, p. 1913 - 1928.

10
[ 24424-99-5 ]
[ 323578-38-7 ]

References: [1] Patent: WO2017/100594, 2017, A1, .

[ 323578-38-7 ] Synthesis Path-Downstream 1~35

1
[ 3222-47-7 ]
[ 323578-38-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4136 - 4142.
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 5017 - 5029.

2
[ 323578-38-7 ]
[ 882425-82-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4136 - 4142.

3
[ 323578-38-7 ]
<i>N</i>-(6-azidomethyl-pyridin-3-yl)-methanesulfonamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4136 - 4142.

4
[ 323578-38-7 ]
[ 401909-23-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4136 - 4142.

5
[ 323578-38-7 ]
[ 866005-45-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium azide; carbon tetrabromide; triphenylphosphine; In N,N-dimethyl-formamide; at 20℃; for 2h;	Synthesis of fe -Butyl (6-azidomethylpyridin-3-yl')carbamate.[0302] tert-Buty (6-(hydroxymethyl)pyridin-3-yl)carbamate (24 mg, 0.107 mmol) was dissolved in DMF (2 mL) and sodium azide (35 mg, 0.54 mmol) was added followed by the simultaneous addition of carbon tetrabromide (179 mg, 0.54 mmol) and triphenylphosphine (142 mg, 0.54 mol). The mixture was stirred for 2 hours at ambient temperature, then diluted in ethyl acetate (20 mL) and saturated NaHCC solution (20 mL). The layers were separated, and the organic layer was dried with MgSC>4, filtered, and concentrated to a yellow oil, which was chromatographed (1 5- 90% ethyl acetate/hexanes on silica gel) to afford this compound as a film 16.8 mg (63%). Rf = 0.92 (ethyl acetate, 254nm UV). MS (ESI +): 250.0 (M + H+, 100%; 194.0, 25%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4136 - 4142.
[2]Patent: WO2012/121973,2012,A1 .Location in patent: Page/Page column 100-101.

6
[ 323578-38-7 ]
1-(4-t-butylbenzyl)-3-(3-methanesulfonylamino-6-pyridinyl)methylthiourea [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4136 - 4142.

7
[ 323578-38-7 ]
(R)-N-[1-(5-Amino-pyridin-2-ylmethyl)-piperidin-4-yl]-2-((R)-3,3-difluoro-cyclopentyl)-2-hydroxy-2-phenyl-acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 5017 - 5029.

8
[ 323578-38-7 ]
(2R)-N-[1-(5-tert-butoxycarbonylamino-2-pyridylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 5017 - 5029.

9
[ 131052-40-9 ]
[ 323578-38-7 ]

Yield	Reaction Conditions	Operation in experiment
67%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere;	Step 3. tert-Butyl (6-(hydroxymethyl)pyridin-3-yl)carbamate. LAH powder (36 g, 0.96 mol) was suspended in dry THF (1000 ml) under N2 atmosphere and cooled to 0 C. To the mixture was added compound 3 (150 g, 0.60 mol) in dry THF (1000 ml) slowly at 0 C. The reaction mixture was gradually warmed to room temperature and stirred for 12 h. TLC (PE/EA, 1:1) showed that the reaction was complete, and the reaction was quenched with dropwise addition of THF-Water (9:1, 400 mL) followed by 90 ml 15% NaOH aqueous and 50 ml of water at 0 C., stirred for 0.5 h at room temperature, and filtered through a pad of Celite, and then washed with THF (4×1000 ml). The filtrate was concentrated under reduced pressure to give the crude which was purified by column chromatography over silica gel eluting with PE/EA (2:1-1:2). The desired fraction was concentrated to afford tert-butyl (6-(hydroxymethyl)pyridin-3-yl)carbamate (450 g, 67%) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 9.58-9.40 (m, 1H), 8.59-8.45 (m, 1H), 7.95-7.78 (m, 1H), 7.42-7.22 (m, 1H), 5.42-5.21 (m, 1H), 4.58-4.40 (m, 2H), 1.48 (s, 9H).
60%	With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 12h;Inert atmosphere;	To a stirred solution of methyl 5-[(tert-butoxy)carbonyl]amino}pyridine-2- carboxylate (EV-AX4571-001, 2.73 g, 10.82 mmol) in THF (60 ml) at 0 C under an atmosphere of nitrogen was added 4M lithium tetrahydridoaluminate(l-) in diethyl ether (4.1 ml) drop-wise, the reaction was allowed to warm to room temperature and stirred for a further 12h. The reaction was quenched by addition of THF:water (9: 1, 15 ml), followed by 10% sodium hydroxide (10 ml) and then water (10 ml). The reaction mixture was then filtered through a pad of Kieselguhr, rinsing with THF (3 x 50 ml). The filtrate was concentrated in vacuo and the crude was purified by flash column chromatography (50-100%) EtOAc/heptane then 0-10% Methanol/EtOAc) to obtain 1.50 g (60%) of tert-butyl N-[6- (hydroxymethyl)pyridin-3-yl]carbamate EV-AX4573-001 as an off-white solid. LCMS (method D): retention time 0.70min, M/z = 224 (M + 1).
		Methyl 5-tert-butoxycarbonylaminopyridine-2-carboxylate (J. Med. Chem., 1991, 34, 1594; 5 g) was dissolved in THF (75 mL) and the mixture was cooled to 00C. Lithium aluminium hydride (IM in THF, 19.8 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. The mixture was re-cooled to 0C and water (0.75 mL) was carefully added followed in turn by 2Nu aqueous sodium hydroxide solution (0.75 mL) and water (2.25 mL). The resultant mixture was stirred for 30 minutes and filtered. The filtrate was dried over magnesium sulfate and evaporated. There was thus obtained 5-tert-butoxycarbonylamino-2-hydroxymethylpyridine as a solid (2.8 g); 1H NMR Spectrum: (DMSOd6) 1.47 (s, 9H), 4.46 (d, 2H), 5.24 (t, IH), 7.33 (d, IH), 7.84 (m, IH), 8.49 (d, IH), 9.44 (s, IH); Mass Spectrum: M+H+ 225.

References: [1]European Journal of Inorganic Chemistry,2010,p. 1913 - 1928.
[2]Patent: US2015/158864,2015,A1 .Location in patent: Paragraph 0295.
[3]Patent: WO2017/100594,2017,A1 .Location in patent: Paragraph 00304.
[4]Patent: WO2006/51270,2006,A1 .Location in patent: Page/Page column 146.

10
[ 323578-38-7 ]
[ 1088711-73-2 ]

Yield	Reaction Conditions	Operation in experiment
	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0℃; for 0.5h;	A mixture of carbon tetrabromide (3.19 g) and dichloromethane (15 mL) was added slowly to a stirred mixture of <strong>[323578-38-7]5-tert-butoxycarbonylamino-2-hydroxymethylpyridine</strong> (1.8 g), triphenylphosphine (2.53 g) and dichloromethane (80 mL) that had been cooled to 0C. The resultant mixture was stirred at 0C for 30 minutes. The mixture was evaporated and the residue was purified by column chromatography on silica using a 200: 1 mixture of dichloromethane and methanol as eluent. There was thus obtained 2-bromomethyl- 5-te7^-butoxycarbonylaminopyridine.

References: [1]Patent: WO2006/51270,2006,A1 .Location in patent: Page/Page column 146.

11
[ 1078129-19-7 ]
[ 323578-38-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 6.5h;	To a stirred solution of ethyl 5-(tert-butoxycarbonylarnino)picolinate (112; 8.9 g, 24.0 mmol) in ethyl ether (200 mL) was added LiAlH4 (1.80 g, 48 mmol) in ethyl ether (100 mL) over a period of 30 min at 0 0C. The resulting reaction mixture was stirred at 0 0C for 3 h and then carefully quenched by carefully adding water (1.0 mL) and 10% NaOH solution (2.0 mL). The mixture was filtered; the filtrate was dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl 6-(hydroxymethyl)pyridin-3- ylcarbamate 113 (4.20 g, 78%)
78%		To a stirred solution of ethyl 5-(tert-butoxycarbonylamino)picolinate (18; 8.9 g, 24 mmol) in ethyl ether (200 mL) under nitrogen was added l ithium aluminum hydride (LAH) ( 1 .8 g, 48 mmol) in ethyl ether ( 100 mL) over a period of 30 min at 0 C. The reaction mixture was stirred for 3 h, water ( 1 mL) and 1 0% NaOH solution (2 mL) was added and the mixture was filtered and the filtrate was dried over a2SC>4 and concentrated under reduced pressure to give compound tert-butyl 6-(hydroxymethyl)pyridin-3-ylcarbamate (19; 4.2 g, 78%). M S (ESI) calcd for C 1 1 H 16N2O3 (m/z) 224.26.
78%	With lithium aluminium tetrahydride; In diethyl ether; at 0℃; for 3.5h;Inert atmosphere;	To a stirred solution of ethyl 5-(tert-butoxycarbonylamino)picolinate (8.9 g, 24 mmol) in ethyl ether (200 mL) under nitrogen was added LAH (1.8 g, 48 mmol) in ethyl ether (100 mL) over a period of 30 min at 0 C. The reaction mixture was stirred for 3 h, water (1 mL) and 10% NaOH solution (2 mL) was added and the mixture was filtered and the filtrate was dried over Na2SO4 and concentrated under reduced pressure to give compound tert-butyl 6-(hydroxymethyl)pyridin-3-ylcarbamate (4.2 g, 78%). MS (ESI) calcd for C11H16N2O3 (m/z): 224.26

78%

With lithium aluminium tetrahydride; In diethyl ether; at 0℃; for 3.5h;

To a stirred solution of ethyl 5-(tert-butoxycarbonylamino)picolinate (8.9 g, 24 mmol) in ethyl ether (200 mL) under nitrogen was added LAH (1.8 g, 48 mmol) in ethyl ether (100 mL) over a period of 30 min at 0 C. The reaction mixture was stirred for 3 h, water (1 mL) and 10% NaOH solution (2 mL) was added and the mixture was filtered and the filtrate was dried over Na2SO4 and concentrated under reduced pressure to give compound tert-butyl 6-(hydroxymethyl)pyridin-3-ylcarbamate (4.2 g, 78%). MS (ESI) calcd for C11H16N2O3 (m/z): 224.26.

References: [1]Patent: WO2010/3048,2010,A1 .Location in patent: Page/Page column 115.
[2]Patent: WO2011/59839,2011,A1 .Location in patent: Page/Page column 71-72.
[3]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 159.
[4]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0581; 0582.

12
[ 24242-20-4 ]
[ 323578-38-7 ]

References: [1]Patent: WO2011/59839,2011,A1 .
[2]Patent: US2015/158864,2015,A1 .
[3]Patent: EP2768509,2017,B1 .
[4]Patent: WO2013/59587,2013,A1 .

13
[ 119830-47-6 ]
[ 323578-38-7 ]

References: [1]Patent: WO2011/59839,2011,A1 .
[2]Patent: EP2768509,2017,B1 .
[3]Patent: WO2013/59587,2013,A1 .

14
[ 323578-38-7 ]
[ 1203486-73-0 ]

References: [1]Patent: WO2011/59839,2011,A1 .
[2]Patent: EP2768509,2017,B1 .
[3]Patent: WO2013/59587,2013,A1 .

15
[ 323578-38-7 ]
[ 1147181-18-7 ]

References: [1]Patent: WO2011/59839,2011,A1 .
[2]Patent: EP2768509,2017,B1 .
[3]Patent: WO2013/59587,2013,A1 .

16
[ 100-26-5 ]
[ 323578-38-7 ]