[ CAS No. 947249-14-1 ] {[proInfo.proName]}

Name: 947249-14-1|3-(Difluoromethoxy)pyridin-2-amine|95%
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SKU: A251188
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Quality Control of [ 947249-14-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 947249-14-1 ]

SDS Specification

Alternatived Products of [ 947249-14-1 ]

Product Details of [ 947249-14-1 ]

CAS No. :	947249-14-1	MDL No. :	MFCD12405788
Formula :	C₆H₆F₂N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	URJOUYRTHKWERB-UHFFFAOYSA-N
M.W :	160.12	Pubchem ID :	28981901
Synonyms :

Calculated chemistry of [ 947249-14-1 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.24
TPSA :	48.14 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.26 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.17
Log Po/w (XLOGP3) :	1.43
Log Po/w (WLOGP) :	2.11
Log Po/w (MLOGP) :	0.28
Log Po/w (SILICOS-IT) :	1.06
Consensus Log Po/w :	1.21

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.01
Solubility :	1.58 mg/ml ; 0.00988 mol/l
Class :	Soluble
Log S (Ali) :	-2.05
Solubility :	1.44 mg/ml ; 0.00899 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.0
Solubility :	1.59 mg/ml ; 0.00995 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.96

Safety of [ 947249-14-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 947249-14-1 ]

* 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 [ 947249-14-1 ]
Downstream synthetic route of [ 947249-14-1 ]

[ 947249-14-1 ] Synthesis Path-Upstream 1~5

1
[ 1111637-77-4 ]
[ 947249-14-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydrogen In ethanol at 20℃;	A mixture of3-(diflυoroinetho?ty)-2-ιiitropyridine(, 5.428 g, 28.6 mmol) in absolute EtOH (50 ml) solution with catalytic Pd/C (0.55 g, lψwtpercent Palladium on activated carbon) was stirred under 1 atm Hj at ambient temperature. LCMS aliquot indicated reaction completion after overnight stirring. Catalyst Pd/C was removed by filtration through a celite pad, filtrate was concentrated and desired product 7 (4.41 g, 27.5 mmol, 96percent yield, [IVWI] ^:... 161.1, /R ^... 0.28 min) was obtained as a colorless solid. ¹H NMK (400 MHz, CDCI₃) δ ppxn 7,90-7.97 (m, 1 H), 7.24-7.31 (m, I H), 6.61-6.68 (m, 1 H), 6.49 (t, J^r 64.4 Hz, 1 H), 4.73 (br s, 2 H).
95%	With iron; ammonium chloride In ethanol; waterHeating / reflux	Step 2:8182 <n="57"/>To a solution of compound 81 (10 g, 0.0526 mol) in EtOH/H₂O (2:1 , 450 mL) was added iron powder (15 g, 0.268 mol), followed by addition of NH₄CI (7.5 g, 0.14 mol) in one portion. After addition, the mixture was refluxed overnight. TLC (Petroleum ether/EtOAc 2:1 ) indicated the reaction was complete. EtOH was removed under reduced pressure and the residue was partitioned between saturated aq. NaHCO₃ (500 mL) and EtOAc (400 mL). The aqueous layer was extracted with EtOAc (2300 mL) and the combined organic layers were washed with brine (2300 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo to give compound 82 (8.0 g, 95percent) as a yellow solid.
66%	With iron; acetic acid In ethanol at 100℃;	3-(Difluoromethoxy)-2-nitropyridine (450 mg, 2.37 mmol) obtained in step 1 was dissolved in ethanol (2 mL)-acetic acid (2 mL), reduced iron (397 mg, 7.10 mmol) was added, and the mixture was stirred at 100°C overnight. Since the starting material did not disappear, reduced iron (397 mg, 7.10 mmol) was added, and the mixture was further stirred at 100°C overnight. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (chloroform/methanol = 9/1 v/v) to give 3-(difluoromethoxy)pyridin-2-amine (250 mg, 66percent). ESIMS m/z: 161 (M + H)⁺; ¹H NMR (270 MHz, CDCl₃, δ): 4.79 (br s, 2H), 6.14-6.80 (m, 2H), 7.19-7.35 (m, 1H), 7.85-7.98 (m, 1H)

55%	With iron; ammonium chloride In ethanol; water at 90℃; for 1 h;	To a stirred solution of 3-(difluoromethoxy)-2-nitropyridine (5 g, 2.63 mmol) and ammonium chloride (4.22 g, 78.9 mmol) in ethanol (40 mL) and water (30 mL) was added iron powder (7.34 g, 131.51 mmol). The reaction mixture was heated to 90 °C for 1 h. After cooling down the reaction mixture was filtered and the solid was washed with ethyl acetate. The mother liquid was concentrated to dryness in vacuo. The residue was diluted with water and extracted with ethyl acetate (3 x 70 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo affording 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 55percent). The residue was used in next step directly without further purification. NMR (400 MHz, DMSO-d6) δ 7.90 (dd, Jj = 4.8 Hz, J₂ = 1.6 Hz, 1H), 7.28 (dd, Jj = 8.0 Hz, J₂ = 0.8 Hz, 1H), 7.07 (t, / = 74.0 Hz, 1H), 6.53 (dd, J_} = 8.0 Hz, J₂ = 0.8 Hz, 1H), 6.01 (s, 2H).
55%	With iron; ammonium chloride In ethanol; water at 90℃; for 1 h;	To a stirred solution of 3-(difluoromethoxy)-2-nitropyridine (5 g, 2.63 mmol) and ammonium chloride (4.22 g, 78.9 mmol) in ethanol (40 mL) and water (30 mL) was added iron powder (7.34 g, 131.51 mmol). The reaction mixture was heated to 90 °C for 1 h. After cooling down the reaction mixture was filtered and the solid was washed with ethyl acetate. The mother liquid was concentrated to dryness in vacuo. The residue was diluted with waterand extracted with ethyl acetate (3 x 70 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo affording 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 55percent). The residue was used in next step directly without further purification. 1H NMR (400 MHz, DMSO-d6) ö: 7.90 (dd, 11 = 4.8 Hz, 12=1.6 Hz, 1H), 7.28 (dd, 11 = 8.0 Hz, 12 = 0.8 Hz, 1H), 7.07 (t, I = 74.0 Hz, 1H), 6.53 (dd, 11 =8.0 Hz, 12 = 0.8 Hz, 1H), 6.01 (s, 2H).
55%	With iron; ammonium chloride In ethanol; water at 90℃; for 1 h; Inert atmosphere	To a stirred solution of 3-(difluoromethoxy)-2-nitropyridine (5 g, 2.63 mmol) and ammonium chloride (4.22 g, 78.9 mmol) in ethanol (40 mL) and water (30 mL) was added iron powder (7.34 g, 131.51 mmol). The reaction mixture was heated to 90° C. for 1 h. After cooling down the reaction mixture was filtered and the solid was washed with ethyl acetate. The mother liquid was concentrated to dryness in vacuo. The residue was diluted with water and extracted with ethyl acetate (3*70 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo affording 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 55percent). The residue was used in next step directly without further purification. ¹H NMR (400 MHz, DMSO-d6) δ7.90 (dd, J₁=4.8 Hz, J₂=1.6 Hz, 1H), 7.28 (dd, J₁=8.0 Hz, J₂=0.8 Hz, 1H), 7.07 (t, J=74.0 Hz, 1H), 6.53 (dd, J₁=8.0 Hz, J₂=0.8 Hz, 1H), 6.01 (s, 2H).

Reference： [1] Patent: WO2010/100127, 2010, A1, . Location in patent: Page/Page column 73
[2] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 55-56
[3] Patent: EP2740730, 2014, A1, . Location in patent: Paragraph 0346
[4] Patent: WO2014/111496, 2014, A1, . Location in patent: Page/Page column 108
[5] Patent: WO2015/91889, 2015, A1, . Location in patent: Page/Page column 73; 74
[6] Patent: US2015/175619, 2015, A1, . Location in patent: Paragraph 0219; 0220
[7] Patent: WO2016/142310, 2016, A1, . Location in patent: Page/Page column 74-75

2
[ 947249-27-6 ]
[ 947249-14-1 ]

Reference： [1] Patent: US2013/210818, 2013, A1, . Location in patent: Paragraph 0415
[2] Patent: WO2009/115572, 2009, A2, . Location in patent: Page/Page column 125-126

3
[ 15128-82-2 ]
[ 947249-14-1 ]

Reference： [1] Patent: EP2740730, 2014, A1,
[2] Patent: WO2014/111496, 2014, A1,
[3] Patent: WO2015/91889, 2015, A1,
[4] Patent: US2015/175619, 2015, A1,
[5] Patent: WO2016/142310, 2016, A1,

4
[ 6602-32-0 ]
[ 947249-14-1 ]

Reference： [1] Patent: US2013/210818, 2013, A1,
[2] Patent: WO2009/115572, 2009, A2,

5
[ 947249-14-1 ]
[ 947249-13-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-Bromosuccinimide In acetonitrile at 0℃; for 0.383333 h;	To a solution of 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 14.36 mmol) in acetonitrile (15 was added N-bromosuccinimide (2.61 g, 14.65 mmol) over 3 min at 0 °C. The reaction mixture was stirred at the same temperature for another 20 min and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20percent ethyl acetate in hexane) affording 5-bromo-3-(difluoromethoxy)pyridin-2-amine (3.2 g, 93percent): NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.51 (s, 1H), 7.16 (t, / = 73.6 Hz, 1H), 6.34 (s, 2H).
93%	With N-Bromosuccinimide In acetonitrile at 0℃; for 0.383333 h;	To a solution of 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 14.36 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (2.61 g, 14.65 mmol) over 3 mm at 0 °C. The reaction mixture was stirred at the same temperature for another 20 mm and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were driedover sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20percent ethyl acetate in hexane) affording 5-bromo-3-(difluoromethoxy)pyridin-2-amine (3.2 g, 93percent): 1H NMR (400 MHz, DMSO-d6) ö: 7.89 (s, 1H), 7.51 (s, 1H), 7.16 (t, I = 73.6 Hz, 1H), 6.34 (s, 2H).
93%	With N-Bromosuccinimide In acetonitrile at 0℃; for 0.383333 h; Inert atmosphere	To a solution of 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 14.36 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (2.61 g, 14.65 mmol) over 3 min at 0° C. The reaction mixture was stirred at the same temperature for another 20 min and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (3*60 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20percent ethyl acetate in hexane) affording 5-bromo-3-(difluoromethoxy)pyridin-2-amine (3.2 g, 93percent): ¹H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.51 (s, 1H), 7.16 (t, J=73.6 Hz, 1H), 6.34 (s, 2H).

91.2%	Stage #1: at 20℃; for 2 h; Stage #2: With water; sodium hydrogencarbonate In ethyl acetate	Step 3:⁸² M ⁸³To a solution of compound 82 (8.0 g, 0.05 mol) in AcOH (100 mL) was added dropwise bromine (8.0 g, 0.05 mol) at room temperature. The mixture was stirred at ambient temperature for 2 h. TLC (Petroleum ether/EtOAc 2:1 ) indicated the reaction was complete. AcOH was removed under reduced pressure and the residue was partitioned between saturated aq. NaHCO₃ (200 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (200 mL) and the combined organic layers were washed with brine (2*300 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo to give crude product, which was purified via column chromatography (petroleum ether/EtOAc 8:1-4:1 ) to afford the product 83 (10.9 g, 91.2percent) as a yellow solid.
80%	With N-Bromosuccinimide In acetonitrile at 0℃; for 0.166667 h;	N-Bromosuccinamide (1.00 g, 5.62 mmol) was added portionwise over 10 min to a cooled solution of 3-(difluoromethoxy)pyridin-2-amine (1.12 g) in dry acetonitrile (20 ml) at 0° C. The reaction mixture was further stirred at 0° C. for 10 min. The mixture was concentrated, and residue was partitioned between EtOAc/sat. Na₂CO₃/H₂O (30 ml/15 ml/15 ml). The organic phase was sequentially washed with sat. aqueous Na₂CO₃/H₂O (15 ml/15 ml) and brine (30 ml), dried (Na₂SO₄), and concentrated. The resulting residue was extracted with EtOAc/hexanes (6 ml/30 ml), and the resulting suspension was filtered through Celite, and the resulting filtrate was concentrated to provide 1.32 g (80percent) of 5-bromo-3-(difluoromethoxy)pyridine-2-amine. LCMS (m/z, MH⁺): 238.9, t_R=0.52 min; ¹H NMR (CDCl₃, 400 MHz) δ 7.99 (d, J=2.0 Hz, 1H), 7.41 (m, 1H), 6.50 (t, J=72.8 Hz, 1H), 4.75 (br s, 2H).
80%	With N-Bromosuccinimide In acetonitrile at 0℃; for 0.333333 h;	Bromosuccinamide (1.0Og, 5.62 mmol) was added portionwise over 10 min to a cooled solution of 3-(difiuoromethoxy)pyridin-2-amine (1.12 g) in dry acetonitrile (20ml) at 0 ⁰C. The reaction mixture was further stirred at 0 ⁰C for lOmin. The mixture was concentrated, and residue was partitioned between EtO Ac/sat. Na₂CO₃ZH₂O(S OmI/ 15ml/ 15ml). The organic phase was sequentially washed with sat. aqueous Na₂CO₃ZH₂O(15ml/l 5ml) and brine(30ml), dried (Na₂SO^, and concentrated. The resulting residue was extracted with EtOAc/hexanes(6ml/30ml), and the resulting suspension was filtered through Celite, and the resulting filtrate was concentrated to provide 1.32 g (80percent) of 5-bromo-3-(difiuoromethoxy)pyridine-2-amine. LCMS (m/z, MH⁺): 238.9, t_R = 0.52min; ¹H NMR (CDCl₃, 400 MHz) δ 7.99 (d, J = 2.0 Hz, 1 H), 7.41 (m, 1 H), 6.50 (t, J = 72.8 Hz, 1 H), 4.75 (br s, 2 H).
3.2 g	With N-Bromosuccinimide In acetonitrile at 0℃; for 0.383333 h;	Step 3: 5-bromo-3-(difluoromethoxy)pyridin-2-amine To a solution of 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 14.36 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (2.61 g, 14.65 mmol) over 3 min at 0 °C. The reaction mixture was stirred at the same temperature for another 20 min and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20percent ethyl acetate in hexane) affording 5-bromo-3-(difluoromethoxy)pyridin-2-amine (3.2 g, 93percent): NM (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.51 (s, 1H), 7.16 (t, / = 73.6 Hz, 1H), 6.34 (s, 2H).

Reference： [1] Patent: WO2014/111496, 2014, A1, . Location in patent: Page/Page column 108; 109
[2] Patent: WO2015/91889, 2015, A1, . Location in patent: Page/Page column 74, 75
[3] Patent: US2015/175619, 2015, A1, . Location in patent: Paragraph 0221; 0222
[4] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 56
[5] Patent: US2013/210818, 2013, A1, . Location in patent: Paragraph 0416
[6] Patent: WO2009/115572, 2009, A2, . Location in patent: Page/Page column 126
[7] Patent: WO2010/100127, 2010, A1, . Location in patent: Page/Page column 73-74
[8] Patent: WO2016/142310, 2016, A1, . Location in patent: Page/Page column 75

[ 947249-14-1 ] Synthesis Path-Downstream 1~26

1
[ 1111637-77-4 ]
[ 947249-14-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 760.051 Torr;	A mixture of3-(diflupsilonoroinetho?ty)-2-iotaiitropyridine(, 5.428 g, 28.6 mmol) in absolute EtOH (50 ml) solution with catalytic Pd/C (0.55 g, lthetawt% Palladium on activated carbon) was stirred under 1 atm Hj at ambient temperature. LCMS aliquot indicated reaction completion after overnight stirring. Catalyst Pd/C was removed by filtration through a celite pad, filtrate was concentrated and desired product 7 (4.41 g, 27.5 mmol, 96% yield, [IVWI] :... 161.1, /R ... 0.28 min) was obtained as a colorless solid. 1H NMK (400 MHz, CDCI3) delta ppxn 7,90-7.97 (m, 1 H), 7.24-7.31 (m, I H), 6.61-6.68 (m, 1 H), 6.49 (t, J^r 64.4 Hz, 1 H), 4.73 (br s, 2 H).
95%	With iron; ammonium chloride; In ethanol; water;Heating / reflux;	Step 2:8182 <n="57"/>To a solution of compound 81 (10 g, 0.0526 mol) in EtOH/H2O (2:1 , 450 mL) was added iron powder (15 g, 0.268 mol), followed by addition of NH4CI (7.5 g, 0.14 mol) in one portion. After addition, the mixture was refluxed overnight. TLC (Petroleum ether/EtOAc 2:1 ) indicated the reaction was complete. EtOH was removed under reduced pressure and the residue was partitioned between saturated aq. NaHCO3 (500 mL) and EtOAc (400 mL). The aqueous layer was extracted with EtOAc (2300 mL) and the combined organic layers were washed with brine (2300 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give compound 82 (8.0 g, 95%) as a yellow solid.
66%	With iron; acetic acid; In ethanol; at 100℃;	3-(Difluoromethoxy)-2-nitropyridine (450 mg, 2.37 mmol) obtained in step 1 was dissolved in ethanol (2 mL)-acetic acid (2 mL), reduced iron (397 mg, 7.10 mmol) was added, and the mixture was stirred at 100C overnight. Since the starting material did not disappear, reduced iron (397 mg, 7.10 mmol) was added, and the mixture was further stirred at 100C overnight. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (chloroform/methanol = 9/1 v/v) to give 3-(difluoromethoxy)pyridin-2-amine (250 mg, 66%). ESIMS m/z: 161 (M + H)+; 1H NMR (270 MHz, CDCl3, delta): 4.79 (br s, 2H), 6.14-6.80 (m, 2H), 7.19-7.35 (m, 1H), 7.85-7.98 (m, 1H)

55%	With iron; ammonium chloride; In ethanol; water; at 90℃; for 1h;	To a stirred solution of 3-(difluoromethoxy)-2-nitropyridine (5 g, 2.63 mmol) and ammonium chloride (4.22 g, 78.9 mmol) in ethanol (40 mL) and water (30 mL) was added iron powder (7.34 g, 131.51 mmol). The reaction mixture was heated to 90 C for 1 h. After cooling down the reaction mixture was filtered and the solid was washed with ethyl acetate. The mother liquid was concentrated to dryness in vacuo. The residue was diluted with water and extracted with ethyl acetate (3 x 70 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo affording 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 55%). The residue was used in next step directly without further purification. NMR (400 MHz, DMSO-d6) delta 7.90 (dd, Jj = 4.8 Hz, J2 = 1.6 Hz, 1H), 7.28 (dd, Jj = 8.0 Hz, J2 = 0.8 Hz, 1H), 7.07 (t, / = 74.0 Hz, 1H), 6.53 (dd, J} = 8.0 Hz, J2 = 0.8 Hz, 1H), 6.01 (s, 2H).
55%	With iron; ammonium chloride; In ethanol; water; at 90℃; for 1h;	To a stirred solution of 3-(difluoromethoxy)-2-nitropyridine (5 g, 2.63 mmol) and ammonium chloride (4.22 g, 78.9 mmol) in ethanol (40 mL) and water (30 mL) was added iron powder (7.34 g, 131.51 mmol). The reaction mixture was heated to 90 C for 1 h. After cooling down the reaction mixture was filtered and the solid was washed with ethyl acetate. The mother liquid was concentrated to dryness in vacuo. The residue was diluted with waterand extracted with ethyl acetate (3 x 70 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo affording 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 55%). The residue was used in next step directly without further purification. 1H NMR (400 MHz, DMSO-d6) oe: 7.90 (dd, 11 = 4.8 Hz, 12=1.6 Hz, 1H), 7.28 (dd, 11 = 8.0 Hz, 12 = 0.8 Hz, 1H), 7.07 (t, I = 74.0 Hz, 1H), 6.53 (dd, 11 =8.0 Hz, 12 = 0.8 Hz, 1H), 6.01 (s, 2H).
55%	With iron; ammonium chloride; In ethanol; water; at 90℃; for 1h;Inert atmosphere;	To a stirred solution of 3-(difluoromethoxy)-2-nitropyridine (5 g, 2.63 mmol) and ammonium chloride (4.22 g, 78.9 mmol) in ethanol (40 mL) and water (30 mL) was added iron powder (7.34 g, 131.51 mmol). The reaction mixture was heated to 90 C. for 1 h. After cooling down the reaction mixture was filtered and the solid was washed with ethyl acetate. The mother liquid was concentrated to dryness in vacuo. The residue was diluted with water and extracted with ethyl acetate (3*70 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo affording 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 55%). The residue was used in next step directly without further purification. 1H NMR (400 MHz, DMSO-d6) delta7.90 (dd, J1=4.8 Hz, J2=1.6 Hz, 1H), 7.28 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.07 (t, J=74.0 Hz, 1H), 6.53 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 6.01 (s, 2H).
	With iron; ammonium chloride; In ethanol; water; at 90℃; for 1h;	Step 2: 3-(difluoromethoxy)pyridin-2-amine To a stirred solution of 3-(difluoromethoxy)-2-nitropyridine (5 g, 2.63 mmol) and ammonium chloride (4.22 g, 78.9 mmol) in ethanol (40 mL) and water (30 mL) was added iron powder (7.34 g, 131.51 mmol). The reaction mixture was heated to 90 C for 1 h. After cooling down the reaction mixture was filtered and the solid was washed with ethyl acetate. The mother liquid was concentrated to dryness in vacuo. The residue was diluted with water and extracted with ethyl acetate (3 x 70 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo affording 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 55%). The residue was used in next step directly without further purification. lU NMR (400 MHz, DMSO-d6) delta 7.90 (dd, Jj = 4.8 Hz, J2 = 1.6 Hz, 1H), 7.28 (dd, Jj = 8.0 Hz, J2 = 0.8 Hz, 1H), 7.07 (t, / = 74.0 Hz, 1H), 6.53 (dd, Jj = 8.0 Hz, J2 = 0.8 Hz, 1H), 6.01 (s, 2H).

Reference： [1]Patent: WO2010/100127,2010,A1 .Location in patent: Page/Page column 73
[2]Patent: WO2009/16460,2009,A2 .Location in patent: Page/Page column 55-56
[3]Patent: EP2740730,2014,A1 .Location in patent: Paragraph 0346
[4]Patent: WO2014/111496,2014,A1 .Location in patent: Page/Page column 108
[5]Patent: WO2015/91889,2015,A1 .Location in patent: Page/Page column 73; 74
[6]Patent: US2015/175619,2015,A1 .Location in patent: Paragraph 0219; 0220
[7]Patent: WO2016/142310,2016,A1 .Location in patent: Page/Page column 74-75

2
[ 947249-14-1 ]
[ 947249-13-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-Bromosuccinimide; In acetonitrile; at 0℃; for 0.383333h;	To a solution of 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 14.36 mmol) in acetonitrile (15 was added N-bromosuccinimide (2.61 g, 14.65 mmol) over 3 min at 0 C. The reaction mixture was stirred at the same temperature for another 20 min and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in hexane) affording 5-bromo-3-(difluoromethoxy)pyridin-2-amine (3.2 g, 93%): NMR (400 MHz, DMSO-d6) delta 7.89 (s, 1H), 7.51 (s, 1H), 7.16 (t, / = 73.6 Hz, 1H), 6.34 (s, 2H).
93%	With N-Bromosuccinimide; In acetonitrile; at 0℃; for 0.383333h;	To a solution of 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 14.36 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (2.61 g, 14.65 mmol) over 3 mm at 0 C. The reaction mixture was stirred at the same temperature for another 20 mm and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were driedover sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in hexane) affording 5-bromo-3-(difluoromethoxy)pyridin-2-amine (3.2 g, 93%): 1H NMR (400 MHz, DMSO-d6) oe: 7.89 (s, 1H), 7.51 (s, 1H), 7.16 (t, I = 73.6 Hz, 1H), 6.34 (s, 2H).
93%	With N-Bromosuccinimide; In acetonitrile; at 0℃; for 0.383333h;Inert atmosphere;	To a solution of 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 14.36 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (2.61 g, 14.65 mmol) over 3 min at 0 C. The reaction mixture was stirred at the same temperature for another 20 min and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (3*60 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in hexane) affording 5-bromo-3-(difluoromethoxy)pyridin-2-amine (3.2 g, 93%): 1H NMR (400 MHz, DMSO-d6) delta 7.89 (s, 1H), 7.51 (s, 1H), 7.16 (t, J=73.6 Hz, 1H), 6.34 (s, 2H).

91.2%		Step 3:82 M 83To a solution of compound 82 (8.0 g, 0.05 mol) in AcOH (100 mL) was added dropwise bromine (8.0 g, 0.05 mol) at room temperature. The mixture was stirred at ambient temperature for 2 h. TLC (Petroleum ether/EtOAc 2:1 ) indicated the reaction was complete. AcOH was removed under reduced pressure and the residue was partitioned between saturated aq. NaHCO3 (200 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (200 mL) and the combined organic layers were washed with brine (2*300 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give crude product, which was purified via column chromatography (petroleum ether/EtOAc 8:1-4:1 ) to afford the product 83 (10.9 g, 91.2%) as a yellow solid.
80%	With N-Bromosuccinimide; In acetonitrile; at 0℃; for 0.166667h;	N-Bromosuccinamide (1.00 g, 5.62 mmol) was added portionwise over 10 min to a cooled solution of 3-(difluoromethoxy)pyridin-2-amine (1.12 g) in dry acetonitrile (20 ml) at 0 C. The reaction mixture was further stirred at 0 C. for 10 min. The mixture was concentrated, and residue was partitioned between EtOAc/sat. Na2CO3/H2O (30 ml/15 ml/15 ml). The organic phase was sequentially washed with sat. aqueous Na2CO3/H2O (15 ml/15 ml) and brine (30 ml), dried (Na2SO4), and concentrated. The resulting residue was extracted with EtOAc/hexanes (6 ml/30 ml), and the resulting suspension was filtered through Celite, and the resulting filtrate was concentrated to provide 1.32 g (80%) of 5-bromo-3-(difluoromethoxy)pyridine-2-amine. LCMS (m/z, MH+): 238.9, tR=0.52 min; 1H NMR (CDCl3, 400 MHz) delta 7.99 (d, J=2.0 Hz, 1H), 7.41 (m, 1H), 6.50 (t, J=72.8 Hz, 1H), 4.75 (br s, 2H).
80%	With N-Bromosuccinimide; In acetonitrile; at 0℃; for 0.333333h;	Bromosuccinamide (1.0Og, 5.62 mmol) was added portionwise over 10 min to a cooled solution of 3-(difiuoromethoxy)pyridin-2-amine (1.12 g) in dry acetonitrile (20ml) at 0 0C. The reaction mixture was further stirred at 0 0C for lOmin. The mixture was concentrated, and residue was partitioned between EtO Ac/sat. Na2CO3ZH2O(S OmI/ 15ml/ 15ml). The organic phase was sequentially washed with sat. aqueous Na2CO3ZH2O(15ml/l 5ml) and brine(30ml), dried (Na2SO^, and concentrated. The resulting residue was extracted with EtOAc/hexanes(6ml/30ml), and the resulting suspension was filtered through Celite, and the resulting filtrate was concentrated to provide 1.32 g (80%) of 5-bromo-3-(difiuoromethoxy)pyridine-2-amine. LCMS (m/z, MH+): 238.9, tR = 0.52min; 1H NMR (CDCl3, 400 MHz) delta 7.99 (d, J = 2.0 Hz, 1 H), 7.41 (m, 1 H), 6.50 (t, J = 72.8 Hz, 1 H), 4.75 (br s, 2 H).
	With N-Bromosuccinimide; In acetonitrile; at 0 - 10℃; for 0.25h;	A solution of 3-(difluoromethoxy)pyridin-2-amine (7, 4.402 g, 27.5 mmol) in ACN (50 ml) was cooled to OC5 followed by treatment of NBS(4,89 g, 27.5 mmol) with internal reaction mixture temperature controlled between 0-1O0C during 5 minutes, and the reaction mixture was further stirred at OC for an additional 10 minutes, LCMS of an aliquot indicated absence of starting material (7) indicating that, the reaction was complete. Reaction mixture was concentrated; residue was partitioned between EtOAc/sat. NaHCOj(30 ml/20 ml); EtOAc layer was sequentially washed with saturated NaHCO3 (20 ml) and brine (20 ml), dried over Na2SO,,, concentrated, Crude residue was triturated with EtOAc/hcptane (10 ml/40 ml), suspension was removed via filtration, and filtrate was concentrated to afford 8 (6.212 g, 26.0 mmol, \|M+I-ty=24L.O, /R « 0.5Smin) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta ppm 7.99 (d, J« 2.0 Hz, 1 I I), 7.41 (d, J- 2.1 Mz, 1 H), 6,50 (l, Jr. ,/- 72J Hz, III), 4.74 (br s, 2 H).
3.2 g	With N-Bromosuccinimide; In acetonitrile; at 0℃; for 0.383333h;	Step 3: 5-bromo-3-(difluoromethoxy)pyridin-2-amine To a solution of 3-(difluoromethoxy)pyridin-2-amine (2.3 g, 14.36 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (2.61 g, 14.65 mmol) over 3 min at 0 C. The reaction mixture was stirred at the same temperature for another 20 min and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in hexane) affording 5-bromo-3-(difluoromethoxy)pyridin-2-amine (3.2 g, 93%): NM (400 MHz, DMSO-d6) delta 7.89 (s, 1H), 7.51 (s, 1H), 7.16 (t, / = 73.6 Hz, 1H), 6.34 (s, 2H).

Reference： [1]Patent: WO2014/111496,2014,A1 .Location in patent: Page/Page column 108; 109
[2]Patent: WO2015/91889,2015,A1 .Location in patent: Page/Page column 74, 75
[3]Patent: US2015/175619,2015,A1 .Location in patent: Paragraph 0221; 0222
[4]Patent: WO2009/16460,2009,A2 .Location in patent: Page/Page column 56
[5]Patent: US2013/210818,2013,A1 .Location in patent: Paragraph 0416
[6]Patent: WO2009/115572,2009,A2 .Location in patent: Page/Page column 126
[7]Patent: WO2010/100127,2010,A1 .Location in patent: Page/Page column 73-74
[8]Patent: WO2016/142310,2016,A1 .Location in patent: Page/Page column 75

3
[ 947249-27-6 ]
[ 947249-14-1 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(I) oxide; ammonium hydroxide; In 2-methoxy-ethanol; water; at 100℃; for 23h;	To a steel bomb were charged with 2-methoxyethanol (20 ml), <strong>[947249-27-6]2-bromo-3-(difluoromethoxy)pyridine</strong> (1.95 g, 8.7 mmol), conc. aqueous NH4OH (28-30%, 5 ml, 79 mmol) and Cu2O (0.25 g, 1.7 mmol). The reaction mixture was heated at 100 C. for 23 h, then cooled to 0 C., and partitioned between mixture of EtOAc/aq. 3 N NaOH/H2O (40 ml/10 ml/30 ml). The organic phase layer was collected, washed with saturated aqueous NaHCO3 solution (30 ml), brine (40 ml), dried (Na2SO4), and concentrated to produce 1.12 g of 3-(difluoromethoxy)pyridin-2-amine which was carried forward without further purification: LCMS (m/z, MH+): 161.0, tR=0.31 min.
	With ammonium hydroxide; 2-methoxy-ethanol;copper(I) oxide; In water; at 100℃; for 23h;	To a steel bomb were charged with 2-methoxyethanol (20ml), <strong>[947249-27-6]2-bromo-3-(difluoromethoxy)pyridine</strong> (1.95g, 8.7 mmol), cone. <n="127"/>aqueous NH4OH (28-30%, 5 ml, 79 mmol) and Cu2O (0.25 g,, 1.7 mmol). The reaction mixture was heated at 100 0C for 23 h, then cooled to 0 0C, and partitioned between mixture of EtOAc/aq. 3 N NaOHZH2O (40ml/10ml/30ml). The organic phase layer was collected, washed with saturated aqueous NaHCO3 solution (30ml), brine (40ml), dried (Na2SO^, and concentrated to produce 1.12 g of 3-(difiuoromethoxy)pyridin-2-amine which was carried forward without further purification: LCMS (m/z, MH+): 161.0, tR = 0.31min.

Reference： [1]Patent: US2013/210818,2013,A1 .Location in patent: Paragraph 0415
[2]Patent: WO2009/115572,2009,A2 .Location in patent: Page/Page column 125-126

4
[ 6602-32-0 ]
[ 947249-14-1 ]

Reference： [1]Patent: US2013/210818,2013,A1
[2]Patent: WO2009/115572,2009,A2

5
[ 947249-14-1 ]
[ 1188302-00-2 ]

Reference： [1]Patent: US2013/210818,2013,A1
[2]Patent: WO2014/111496,2014,A1
[3]Patent: WO2015/91889,2015,A1
[4]Patent: US2015/175619,2015,A1
[5]Patent: WO2016/142310,2016,A1
[6]Patent: WO2009/115572,2009,A2

6
[ 15128-82-2 ]
[ 947249-14-1 ]

Reference： [1]Patent: EP2740730,2014,A1
[2]Patent: WO2014/111496,2014,A1
[3]Patent: WO2015/91889,2015,A1
[4]Patent: US2015/175619,2015,A1
[5]Patent: WO2016/142310,2016,A1

7
[ 947249-14-1 ]
3-(difluoromethoxy)-5-(1-isopropyl-5-((1R,5S,6r)-spiro[bicyclo[3.1.0]hexane-3,2’-oxetan]-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine [ No CAS ]