[ CAS No. 779345-37-8 ] {[proInfo.proName]}

Name: 779345-37-8|5-Fluoro-2-nitropyridine|97%
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SKU: A225131
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Quality Control of [ 779345-37-8 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 779345-37-8 ]

CAS No. :	779345-37-8	MDL No. :	MFCD03092917
Formula :	C₅H₃FN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CGFYNRVHPARGFY-UHFFFAOYSA-N
M.W :	142.09	Pubchem ID :	16748109
Synonyms :

Calculated chemistry of [ 779345-37-8 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	33.02
TPSA :	58.71 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) :	-6.38 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.0
Log Po/w (XLOGP3) :	1.11
Log Po/w (WLOGP) :	1.55
Log Po/w (MLOGP) :	1.3
Log Po/w (SILICOS-IT) :	-0.3
Consensus Log Po/w :	0.93

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.8
Solubility :	2.26 mg/ml ; 0.0159 mol/l
Class :	Very soluble
Log S (Ali) :	-1.94
Solubility :	1.65 mg/ml ; 0.0116 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.66
Solubility :	3.11 mg/ml ; 0.0219 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.16

Safety of [ 779345-37-8 ]

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

Application In Synthesis of [ 779345-37-8 ]

* 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 [ 779345-37-8 ]
Downstream synthetic route of [ 779345-37-8 ]

[ 779345-37-8 ] Synthesis Path-Upstream 1~5

1
[ 779345-37-8 ]
[ 571189-49-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2018,

2
[ 779345-37-8 ]
[ 571188-59-5 ]

Reference： [1] Patent: WO2012/97682, 2012, A1,
[2] Journal of Medicinal Chemistry, 2018,

3
[ 779345-37-8 ]
[ 57260-71-6 ]
[ 571189-16-7 ]

Reference： [1] Patent: WO2012/97682, 2012, A1, . Location in patent: Page/Page column 158

4
[ 21717-96-4 ]
[ 779345-37-8 ]

Yield	Reaction Conditions	Operation in experiment
39.45%	at 0 - 20℃; for 16 h;	Synthesis of compound 207.2. A solution of 207.1 (6.0g, 53.51mmol, l .Oeq) in concentrated H₂SO₄ (60 ml) was cooled at 0 °C (A). Further in another flask hydrogen peroxide (13 ml) was added to concentrated sulphuric acid at 0 °C (B). Further solution (A) was added dropwise to solution (B) at 0 °C. The reaction was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was poured in ice cold water and product was extracted with EtOAc. Organic layers were combined, dried over sodium sulphate and evaporated to obtain pure compound 207.2 (3.0g, 39.45percent). MS (ES): m/z 142.09 [M+H]⁺.

Reference： [1] Patent: US2004/209886, 2004, A1,
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3627 - 3644
[3] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 001083; 001084
[4] Patent: US2010/160340, 2010, A1, . Location in patent: Page/Page column 7
[5] Patent: WO2012/97682, 2012, A1, . Location in patent: Page/Page column 158

5
[ 779345-37-8 ]
[ 108-01-0 ]
[ 1346675-75-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With caesium carbonate In tetrahydrofuran at 80℃; for 16 h;	2-Dimethylaminoethanol (0.32 mL, 3.17 mmol) was dissolved in DMF (4 mL) and cesium carbonate (1.03 g, 3.17 mmol) was added thereto, and the resultant suspension was stirred at room temperature for 10 minutes. 5-Fluoro-2-nitropyridine (0.30 g, 2.11 mmol) was added to the suspension at room temperature, and the mixture then was stirred at 80°C for 16 hours. The reaction was monitored by LC/MS. After completion of the reaction, the reaction was quenched through addition of ice water, and the reaction mixture was extracted with ethyl acetate. The resultant organic phase was dried over anhydrous sodium sulfate, and the solid was separated by filtration. The filtrate was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to yield the title compound (0.40 g, 90percent).

Reference： [1] Patent: EP3305785, 2018, A1, . Location in patent: Paragraph 0199; 0200

[ 779345-37-8 ] Synthesis Path-Downstream 1~88

1
[ 21717-96-4 ]
[ 779345-37-8 ]

Yield	Reaction Conditions	Operation in experiment
77%	With sulfuric acid; dihydrogen peroxide;	429A-Preparation of 5-Fluoro-2-nitro-pyridine To concentrated H2SO4 at 0 C. was added 4 ml of 3% H2O2. To this solution at 0 C. was added 5-fluoro-2-amino-pyridine (250 mg, 2.23 mmol). The mixture was warmed to room temperature and stirred for 20 hr, then poured onto ice. The aqueous solution was extracted with EtOAc (3*30 ml). The combined organic layers were washed with water, brine and dried with Na2SO4. Removal of the solvent gave a light brown oil (245 mg, 77%). The product was used for next step without further purification.
76%	With sulfuric acid; dihydrogen peroxide; at 0℃; for 24h;	H2O2 (37%, 50ml) was drop wise added to concentrated H2SO4 (200 ml) at 0 C in open air and after 5 min stirring at same temperature, 5-fluoropyridin-2-amine (11, 20.0 g, 0.139 mol) in conc. H2SO4 (200 ml) was slowly added and stirred for 24 h. The reaction mixture was diluted with water (300 ml) and extracted with DCM (3 x 300 ml). The organic layers were combined, washed with 5% of aqueous sodium bi-sulphate (200 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh) and gradient 3% to10% ethyl acetate in hexane] and then triturated with pentane (100 ml) to give 5-fluoro-2-nitropyridine (12, 14.0 g, 76%) as an off-white solid.1H-NMR (400 MHz; CDCl3): d 7.70 - 7.77 (m, 1H), 8.32 - 8.38 (m, 1H), 7.48 (d, J = 2.6 Hz,1H).
39.45%	With sulfuric acid; dihydrogen peroxide; at 0 - 20℃; for 16h;	Synthesis of compound 207.2. A solution of 207.1 (6.0g, 53.51mmol, l .Oeq) in concentrated H2SO4 (60 ml) was cooled at 0 C (A). Further in another flask hydrogen peroxide (13 ml) was added to concentrated sulphuric acid at 0 C (B). Further solution (A) was added dropwise to solution (B) at 0 C. The reaction was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was poured in ice cold water and product was extracted with EtOAc. Organic layers were combined, dried over sodium sulphate and evaporated to obtain pure compound 207.2 (3.0g, 39.45%). MS (ES): m/z 142.09 [M+H]+.

		Preparation 25-Fluoro-2-nitro-pyridineTo sulfuric acid (46 mL) at 0 C. add 25% hydrogen peroxide (26.98 mL) in the open air. After 5 min add a cold solution of 2-amino-5-fluoropyridine (9 g) in concentrated sulfuric acid (46 mL) drop wise with an addition funnel Stir the resulting dark solution at 0 C. to RT in the bath overnight. Pour over 200 mL ice-water and extract with DCM. Wash combined organic layers with 5% aqueous solution of sodium bisulfite and dry over anhydrous sodium sulfate. Remove the solvent under vacuum and purify by silica gel column chromatography eluting with DCM to afford 7.5 g of the title compound. MS (ES+): m/z=143 (M+H)+.
	With sulfuric acid; dihydrogen peroxide; In water; at 0 - 20℃; for 16h;	EXAMPLE 103 7-(2-chlorophenoxy)-5-{ [5-(piperazin-l-yl)pyridin-2-yl]amino}pyrido[3,4-d]pyridazin-4(3H)-one EXAMPLE 103 A 5 -fluoro-2-nitropy ridine To concentrated sulfuric acid (6 mL) at 0C was added dropwise 30% aqueous hydrogen peroxide (2.5 mL). To the mixture was added a pre-cooled solution of 5- fluoropyridin-2-amine (1 g, 8.9 mmol) in concentrated sulfuric acid (6 mL). The mixture was stirred at ambient temperature for 16 hours, poured into ice-water and extracted with ethy l acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 98/2 dichloromethane/methanol to give the title compound. MS: 143 (Mu+Iota-Gamma).

Reference： [1]Patent: US2004/209886,2004,A1
[2]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29
[3]Journal of Medicinal Chemistry,2007,vol. 50,p. 3627 - 3644
[4]Patent: WO2015/131080,2015,A1 .Location in patent: Paragraph 001083; 001084
[5]Patent: US2010/160340,2010,A1 .Location in patent: Page/Page column 7
[6]Patent: WO2012/97682,2012,A1 .Location in patent: Page/Page column 158

2
[ 779345-37-8 ]
[ 113451-59-5 ]
[ 286946-14-3 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3627 - 3644

3
[ 779345-37-8 ]
(1S,4S)-2-(6-nitro-3-pyridinyl)-2,5-diazabicyclo[2.2.1]heptane p-toluenesulfonate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3627 - 3644

4
[ 779345-37-8 ]
(1S,4S)-2-(6-aminopyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane p-toluenesulfonate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3627 - 3644

5
[ 779345-37-8 ]
[ 108-95-2 ]
[ 779345-38-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In 2,4-dichlorophenoxyacetic acid dimethylamine; ethyl acetate;	429B-Preparation of 2-nitro-5-phenoxy-pyridine To a mixture of phenol (175 mg, 1.86 mmol) and t-BuOK (208 mg, 1.86 mmol) in DMA (4 ml) was added a solution of 5-fluoro-2-nitro-pyridine (240 mg, 1.69 mmol) in DMA (2 ml) under argon. The deep brown mixture was stirred at rt for 1 h. Treated with EtOAc (50 ml), the mixture was washed with H2O (4*10 ml) and brine (20 ml), dried with Na2SO4. Removal of the solvent under reduced pressure gave 429A (345 mg, 94%) as a brown oil. It has a retention time of 7.25 min (standard LC1 method, 8 min run). MS Found: (M+H)+=217.0

Reference： [1]Patent: US2004/209886,2004,A1

6
[ 779345-37-8 ]
(4s)-4-(1-azatricyclo[3.3.1.13,7]decan-4-ol) N-borane complex [ No CAS ]
(4s)-4-(6-nitropyridin-3-yloxy)-1-azatricyclo[3.3.1.13,7]decane N-borane complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at -20 - 20℃; for 1.25 - 2.25h;	A solution of 1-azaadamantan-4-ol N-borane complex (1 eq.) and a heteroaryl halide (1.1 eq.) in anhydrous DMF (0.5-1 M) was chilled to between -20 and 0 C and treated with sodium hydride (1.5 equiv; 95%, Aldrich). After 15 minutes, the cooling bath was removed and the mixture was allowed to warm to room temperature. When 1 -azaadamantan-4-ol N-borane complex was consumed as determined by TLC analysis (generally 1-2 hours), the mixture was diluted with water and stirred for 1 hour. The resulting solid product was collected by filtration, washed with water, and dried under reduced pressure to afford the desired product; (4s)-4-(6-Nitropyridin-3-yloxy)-1-azatricyclo[3.3.1.13,7]decane N-borane complex Prepared from the product of Example 10A (419 g, 2.51 mmol) and <strong>[779345-37-8]5-fluoro-2-nitropyridine</strong> (420 mg, 2.9 mmol; see US Patent Appl. 20040209886) according to Method A: 1H NMR (300 MHz, chloroform-D) delta ppm 1.68 - 1.78 (m, 2 H), 2.07 (s, 1 H), 2.20 - 2.35 (m, 4 H), 3.19 - 3 34 (m, 6 H), 4.74 (t, J=3.4 Hz, 1 H), 7.42 (dd, J=9.0, 2.9 Hz, 1 H), 8.26 - 8.31 (m, 2 H). MS (DCI/NH3) m/z= 290 (M+H)+

Reference： [1]Patent: WO2008/58096,2008,A2 .Location in patent: Page/Page column 61; 77

7
[ 779345-37-8 ]
[ 109384-19-2 ]
[ 1231930-18-9 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 104-(6-Nitro-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl esterAdd potassium tert-butoxide (4.84 g) to a solution of tert-butyl 4-hydroxy-1-piperidine-carboxylate (8.76 g) in dimethylacetamide (DMA, 39 mL) at 0 C. under nitrogen. Stir for 1 h and add drop wise a solution 5-fluoro-2-nitro-pyridine (5 g) in DMA (78 mL). Let the reaction stir at RT overnight. Add water and stand for 1 h. Filter, wash with water. Purify by silica gel column chromatography eluting with DCM/EA (0-15%) to afford 5.65 g of the title compound. MS (ES+): m/z=324 (M+H)+.
		To a solution of compound 82 (564 mg, 4.2 mmol, 1.2 eq) in dimethylacetamide (5 mL) was added potassium tert-butoxide (910 mg, 4.6 mmol, 1.3 eq) at 0 C under nitrogen and then stirred for 1 h before a solution of compound 61 (500 mg, 3.5 mmol, 1.0 eq) in DMA (2mL) was added drop wise. After addition, the reaction mixture was stirred at RT overnight. Water (15 mL) was added and the reaction mixture was extracted with EA (5 mL X 3). The combined organic layers was dried over NaiSCU, filtered and concentrated to give a crude product (800 mg crude), which was used into next step without further purification. NMR (300 MHz, CDCb): delta 8.30-8.25 (m, 2 H), 7.43-7.39 (m, 1 H), 4.69-4.66 (m, 1 H), 3.77-3.69 (m, 2 H), 3.45- 3.40 (m, 2 H), 2.03-1.97 (m, 2 H), 1.85-1.80 (m, 2 H), 1.49 (s, 9 H). LCMS: (M-56+H)+ = 268.6.

Reference： [1]Patent: US2010/160340,2010,A1 .Location in patent: Page/Page column 8
[2]Patent: WO2019/35008,2019,A1 .Location in patent: Paragraph 742-744

8
[ 779345-37-8 ]
(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane bishydrochloride [ No CAS ]
(1R,5S)-3-methyl-8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.8%	With triethylamine; In dimethyl sulfoxide; at 80℃; for 2h;	Step 1. Preparation of (1R,5S)-3-methyl-8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane A solution of (1R,5S)-3-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (981 mg, 4.93 mmol), <strong>[779345-37-8]5-fluoro-2-nitropyridine</strong> (100 mg, 4.93 mmol), and triethylamine (4.99 g, 49.3 mmol) in DMSO (8 ml) was heated to 80 C. for 2 hr. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with saturated ammonium chloride, and water. The organic phase was then concentrated and triturated with ether to give desire product as an yellow solid (1 g, 81.8%).

Reference： [1]Patent: US2012/40949,2012,A1 .Location in patent: Page/Page column 130

9
[ 779345-37-8 ]
(1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ No CAS ]
[ 1360056-11-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dimethyl sulfoxide; at 80℃; for 2h;	tert-butyl 8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate Triethylamine (6.87 mL, 49.3 mmol) was added to a stirred solution of <strong>[779345-37-8]5-fluoro-2-nitropyridine</strong> (700 mg, 4.93 mmol) and (1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.05 g, 4.93 mmol) in 8 mL of DMSO at room temperature. The reaction mixture was heated to 80 C. for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with, saturated ammonium chloride, water (3*), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1.21 g (73.5%) of tert-butyl 8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as yellow solid.

Reference： [1]Patent: US2012/40949,2012,A1 .Location in patent: Page/Page column 61

10
[ 779345-37-8 ]
(1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ No CAS ]
tert-butyl 8-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ No CAS ]

Reference： [1]Patent: US2012/40949,2012,A1

11
[ 779345-37-8 ]
[ 13425-93-9 ]
[ 1000850-78-1 ]

Yield	Reaction Conditions	Operation in experiment
40%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h;Microwave irradiation;	Step 1 : 6,7-dimethoxy-4-[(6-nitro-3-pyridyl)oxy]quinoline (W1)A mixture of 6,7-dimethoxyquinolin-4-ol (2.02g, 9.8mmol, 1.0eq.), 5-fluoro-2-nitro- pyridine (1.96g, 13.78mmol, 1.4eq.) and cesium carbonate (4.8g, 14.7mmol, 1.5eq.) in dry DMF (10mL) was heated for 1 h at 80C in a microwave oven. After cooling to RT the mixture was diluted with water and extracted with DCM. The combined organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH = 100:0 to 10:1 ) to yield the desired product W1 (1.28g, 40%) as a yellow solid. 1H NMR (400MHz, d6-DMSO, 300K) delta 3.88 (s, 3H), 3.94 (s, 3H), 6.92 (d, J = 5.2 Hz, 1 H), 7.41 (s, 1 H), 7.45 (s, 1 H), 7.98 (dd, J = 2.7 Hz, J = 9.0 Hz, 1 H), 8.40 (d, J = 9.0 Hz, 1 H), 8.60 (d, J = 5.2 Hz, 1 H), 8.66 (d, J = 2.7 Hz, 1 H). MS (ES) C16H13N3O5 requires: 327, found: 328 (M+H)+.
40%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h;Microwave irradiation;	Step 1: 6,7-dimethoxy-4-[(6-nitro-3-pyridyl)oxy]quinoline (W1) A mixture of 6,7-dimethoxyquinolin-4-ol (2.02g, 9.8mmol, 1.0eq.), 5-fluoro-2-nitropyridine (1.96g, 13.78mmol, 1.4eq.) and cesium carbonate (4.8g, 14.7mmol, 1.5eq.) in dry DMF (10mL) was heated for 1 h at 80C in a microwave oven. After cooling to RT the mixture was diluted with water and extracted with DCM. The combined organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH = 100:0 to 10:1) to yield the desired product W1 (1.28g, 40%) as a yellow solid. 1H NMR (400MHz, d6-DMSO, 300K) delta 3.88 (s, 3H), 3.94 (s, 3H), 6.92 (d, J = 5.2 Hz, 1H), 7.41 (s, 1H), 7.45 (s, 1H), 7.98 (dd, J = 2.7 Hz, J = 9.0 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 8.60 (d, J = 5.2 Hz, 1H), 8.66 (d, J = 2.7 Hz, 1H). MS (ES) C16H13N3O5 requires: 327, found: 328 (M+H)+.

Reference： [1]Patent: WO2012/28332,2012,A1 .Location in patent: Page/Page column 108
[2]Patent: EP2423208,2012,A1 .Location in patent: Paragraph 0145

12
[ 779345-37-8 ]
[ 571188-59-5 ]

Reference： [1]Patent: WO2012/97682,2012,A1
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 9371 - 9385
[3]International Journal of Molecular Sciences,2019,vol. 20

13
[ 779345-37-8 ]
[ 57260-71-6 ]
[ 571189-16-7 ]

Yield	Reaction Conditions	Operation in experiment
90%		5-Fluoro-2-nitropyridine (13, 7.1 g, 50 mmol), potassium carbonate (8.3 g, 60 mmol) was dissolved in 200 mL of THF and stirred at room temperature for 1 hour, then tert-butyl piperazine-1-carboxylate was added ( 149.3 g, 50 mmol), the mixture was heated to 50 C for 8 hours, the solvent was evaporated, and then the mixture was evaporated to ethyl acetate / water (100 mL / 100 mL). Wash once with saturated sodium bicarbonate (30 mL), brine (30 mL), dry A yellow oil 15 (14.0 g, 90%) was obtained.
	With triethylamine; In toluene; at 100℃; for 16h;	EXAMPLE 103B ter/-butyl 4-(6-nitropyridin-3-yl)piperazine-l -carboxylate A mixture of EXAMPLE 103A (3.84 g, 27 mmol), tert-butyl piperazine-l -carboxylate (6.04 g, 2.4 mmol) and triethylamine (8.20, 81 mmol) in toluene (150 mL) was heated at 100"C for 16 hours. The mixture was concentrated and the residue was washed with petroleum ether and dried under vacuum to give the title compound. MS: 309 (M+H+).

Reference： [1]Patent: CN110156754,2019,A .Location in patent: Paragraph 0046-0049
[2]Patent: WO2012/97682,2012,A1 .Location in patent: Page/Page column 158
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 9371 - 9385
[4]International Journal of Molecular Sciences,2019,vol. 20

14
[ 779345-37-8 ]
[ 1407831-58-6 ]

Reference： [1]Patent: WO2012/151512,2012,A2

15
[ 779345-37-8 ]
[ 1407834-77-8 ]

Reference： [1]Patent: WO2012/151512,2012,A2

16
[ 779345-37-8 ]
[ 1407835-60-2 ]
[ 1407834-74-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium tert-butylate; In dimethyl sulfoxide; at 120℃; under 2400.24 Torr; for 1h;Microwave irradiation;	(R)-8-bromo-l,4-dimethyl-6-(6-nitropyridin-3-yl)-5,6-dihydro-4H-benzo[b][l,2,4]triazolo[4,3-d][l,4]diazepine (Step 1). To a solution of <strong>[779345-37-8]5-fluoro-2-nitropyridine</strong> (284 mg, 2 mmol) and (R)-8-bromo-l,4-dimethyl-5,6- dihydro-4H-benzo[b][l,2,4]triazolo[4,3- d][l,4]diazepine (292 mg, 1 mmol) in dimethyl sulfoxide (5 mL) was added potassium tert- butanolate (223 mg, 2 mmol). The reaction mixture was heated at 120C for 1 hour under microwave (pressure: 3.2 bar, equipment power : 150W). The mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 2:1) to give (R)-8-bromo- l,4-dimethyl-6-(6-nitropyridin-3-yl)-5,6-dihydro-4H-benzo[b][l,2,4]triazolo[4,3- d][l,4]diazepine (320 mg, 77%) as a light yellow solid.

Reference： [1]Patent: WO2012/151512,2012,A2 .Location in patent: Page/Page column 167

17
[ 779345-37-8 ]
[ 13425-93-9 ]
[ 417722-21-5 ]

Reference： [1]Patent: EP2423208,2012,A1

18
[ 779345-37-8 ]
[ 1253911-54-4 ]

Reference： [1]Patent: US2013/116246,2013,A1
[2]Patent: EP2773638,2015,B1

19
[ 779345-37-8 ]
[ 1346673-20-8 ]

Reference： [1]Patent: US2013/116246,2013,A1
[2]Patent: EP2773638,2015,B1

20
[ 779345-37-8 ]
[ 1433856-24-6 ]

Reference： [1]Patent: US2013/116246,2013,A1

21
[ 779345-37-8 ]
[ 1433848-08-8 ]

Reference： [1]Patent: US2013/116246,2013,A1

22
[ 779345-37-8 ]
[ 18621-18-6 ]
[ 1211443-63-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate; In acetonitrile; at 60℃; for 1h;	Example 147a 1-(6-Nitropyridin-3-yl)azetidin-3-ol 147a A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetonitrile (50 mL), <strong>[779345-37-8]5-fluoro-2-nitropyridine</strong> (1.2 g, 7.9 mmol), K2CO3 (2.1 g, 15.8 mmol), and azetidin-3-ol hydrochloride (1.3 g, 11.9 mmol). The mixture was heated at 60 C. for 1 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 147a (1.1 g, 73%) as a yellow solid. MS-ESI: [M+H]+ 196.0.
73%	With potassium carbonate; In acetonitrile; at 60℃; for 1h;	Example 314a 1-(6-Nitropyridin-3-yl)azetidin-3-ol 314a A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetonitrile (50 mL), <strong>[779345-37-8]5-fluoro-2-nitropyridine</strong> (1.2 g, 7.9 mmol), K2CO3 (2.1 g, 15.8 mmol), and azetidin-3-ol hydrochloride(1.3 g, 11.9 mmol). The mixture was heated at 60C for 1 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 314a (1.1 g, 73%) as a yellow solid. MS-ESI: [M+H]+196.0.

Reference： [1]Patent: US2013/116246,2013,A1 .Location in patent: Paragraph 0486
[2]Patent: EP2773638,2015,B1 .Location in patent: Paragraph 1284

23
[ 779345-37-8 ]
C₉H₇F₃N₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3051 - 3058

24
[ 779345-37-8 ]
[ 1432500-06-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3051 - 3058

25
[ 779345-37-8 ]
C₂₅H₂₈F₃N₅O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3051 - 3058

26
[ 779345-37-8 ]
C₂₀H₁₉F₃N₄O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3051 - 3058

27
[ 779345-37-8 ]
C₂₂H₂₃F₃N₄O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3051 - 3058

28
[ 779345-37-8 ]
[ 52222-73-8 ]
C₉H₅F₃N₄O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3051 - 3058

29
[ 779345-37-8 ]
[ 75-64-9 ]
C₉H₁₃N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.59%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 1h;	Synthesis of compound 224.1. To a solution of 220.1 (0.300g, 2.1 lmmol, l .Oeq) in DMSO(5ml) was added 2-methylpropan-2-amine (0.185g, 2.533mmol, 1.2eq.) and DIPEA (2.72g, 21.1 lmmol, lO.Oeq.). The reaction mixture was heated at 100 C for lh. After completion of reaction, mixture was poured in water, quenched with NH4C1 solution and extracted with EtOAc. Organic layers were combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by chromatography to get pure 224.1 (0.225g, 54.59%). MS(ES): m/z 195.22 [M+H]+.

Reference： [1]Patent: WO2015/131080,2015,A1 .Location in patent: Paragraph 001174; 001175

30
[ 779345-37-8 ]
[ 766-17-6 ]
C₁₂H₁₇N₃O₂ [ No CAS ]