1072-97-5|5-Bromopyridin-2-amine| Ambeed

Structure of 1072-97-5

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Quality Control of [ 1072-97-5 ] Purity: 98% SDS Specification

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Product Details of [ 1072-97-5 ]

CAS No. :	1072-97-5
Formula :	C₅H₅BrN₂
M.W :	173.01
SMILES Code :	C1=CC(=NC=C1Br)N
MDL No. :	MFCD00006323
InChI Key :	WGOLHUGPTDEKCF-UHFFFAOYSA-N
Pubchem ID :	70622

Safety of [ 1072-97-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1072-97-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	8
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	36.34
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.41
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.51
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.43
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.	0.99
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	1.41
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.35

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.42
Solubility	0.659 mg/ml ; 0.00381 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.	-1.94
Solubility	2.01 mg/ml ; 0.0116 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	-2.51
Solubility	0.531 mg/ml ; 0.00307 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.	-6.28 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	1.0
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)	1.53

Application In Synthesis of [ 1072-97-5 ]

* 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 [ 1072-97-5 ]
Downstream synthetic route of [ 1072-97-5 ]

[ 1072-97-5 ] Synthesis Path-Upstream 1~4

1
[ 1072-97-5 ]
[ 356560-80-0 ]

References: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3614 - 3627.
[2] European Journal of Organic Chemistry, 2005, # 17, p. 3761 - 3765.
[3] Patent: WO2013/127266, 2013, A1, .
[4] Patent: WO2013/127267, 2013, A1, .
[5] Patent: WO2013/127268, 2013, A1, .
[6] Patent: WO2013/130935, 2013, A1, .
[7] Patent: WO2013/130943, 2013, A1, .
[8] Patent: WO2008/128953, 2008, A1, .
[9] Patent: WO2004/43940, 2004, A1, .
[10] Patent: WO2005/116029, 2005, A1, .
[11] Patent: KR2018/131662, 2018, A, .

2
[ 1072-97-5 ]
[ 19255-60-8 ]
[ 603311-76-8 ]

References: [1] Patent: WO2004/50659, 2004, A1, . Location in patent: Page 39.

3
[ 1072-97-5 ]
[ 947248-52-4 ]

References: [1] Patent: WO2018/17435, 2018, A1, .

4
[ 1072-97-5 ]
[ 97674-02-7 ]
[ 1189169-37-6 ]

Yield	Reaction Conditions	Operation in experiment
66%	With bis-triphenylphosphine-palladium(II) chloride In toluene at 130℃; for 16 h; Inert atmosphere	5-Bromo-2-iodopyrimidine (10 g, 35.1 mmol) and tributyl(1-ethoxyethenyl)- stannane (15.85 g, 43.88 mmol) were dissolved in anhydrous toluene (500 mL) and purged with nitrogen for 10 minutes. Dichlorobis(triphenylphosphine)palladium(II) (1.23 g, 1.76 mmol) was added and the mixture was stirred at 130°C for 16 h. The reaction mixture was cooled to room temperature and water (29 mL) was added, followed by 6MHC1 (106 mL), then the mixture was stirred vigorously at room temperature for 4 h. The solvent was removed in vacuo and the pH of the mixture was adjusted to pH 7 by the addition of saturated aqueous sodium hydrogencarbonate solution (500 mL). The mixture was extracted with ethyl acetate (3 x 350 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material waspurified on silica gel, eluting with 20-100percent ethyl acetate in heptane, to afford the title compound (2.99 g, 66 percent) as a gold-coloured solid. LCMS m/z 20 1/203.

References: [1] Patent: WO2015/86506, 2015, A1, . Location in patent: Page/Page column 125.

[ 1072-97-5 ] Synthesis Path-Downstream 1~26

1
[ 1072-97-5 ]
[ 38923-13-6 ]
[ 38923-02-3 ]

References: [1]Journal of Medicinal Chemistry,1972,vol. 15,p. 982 - 985.

2
[ 1072-97-5 ]
[ 124-41-4 ]
[ 10167-97-2 ]

Yield	Reaction Conditions	Operation in experiment
36%	copper; In methanol; at 135℃; for 14h;Product distribution / selectivity;	5-methoxypyridin-2-amine (P5).; Method a: 2-Amino-4-bromopyridine (0.10 g; 0.58 mmol), sodium methoxide (0.16 g; 2.9 mmol) and copper powder nanosized activated (0.11 g; 1.74 mmol) were introduced in a screw cap vial (Pyrex glass) together with 2.0 mL of anhydrous MeOH and a stirrer bar. The vial was closed and put in an oil bath at 135°C and stirred for 14 h. The mixture was cooled, diluted with MeOH (5.0 mL) and filtered through an SPE silica gel cartridge and the product eluted with AcOEt. The fractions were <n="13"/>collected and evaporated obtaining a crude of 92 mg of product which was further purified by FCC (DCM/AcOEt = 1:1) to give 26 mg (yield 36percent) of the title compound as brown oil.; Attempts to improve the result were made by increasing the equivalents of catalyst used. It was believed that copper could be coordinated and thus inactivated by the nitrogen atoms of the substrate. By this means the expected product was achieved in 36percent yield (eq 3). The reaction mixture, after being heated for 14 hrs, still contained a significant amount of starting material together with black polymers. The reaction was quenched to avoid further formation of polymers and degradation of the formed product.
34.3%	copper; In methanol; at 100℃; for 48h;Sealed tube;	A mixture of 2-amino-5-bromopyridine (5.0 g, 28.9 mmol), sodium methoxide (6.3 g, 116.6 mmol) and copper powder (1.85 g, 28.9 mmol) in methanol (30 mL) was heated in sealed tube for 48 h at 100° C. The reaction mixture was cooled to room temperature, diluted with dichloromethane (50 mL), filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was diluted with water, extracted with dichloromethane (2.x.100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude material was purified over silica gel column chromatography eluting with EtOAc:Hexane (6:4) to afford Int-1 (1.2 g, 34.3percent) as brown color oil. To a solution of Int-1 (3.0 g, 24.2 mmol) in dimethoxy ethane (30 mL) was added 3-chloro-2,4-pentanedione (4.9 g, 36.4 mmol) at room temperature and the mixture was stirred at reflux temperature for 16 hours. The volatile was concentrated under reduced pressure. The residue was purified over silica gel column chromatography eluting with MeOH:DCM (1:9) to afford Int-2 (2.3 g, 46.6percent) as brown color oil. A solution of Int-2 (1.5 g, 7.35 mmol) in DMF DMA (15 mL) was stirred at reflux temperature for 24 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether (15 mL) and stirred for 15 minutes. The precipitated solid was filtered, washed with ether (2.x.10 mL) and dried under vacuum to afford Int-3 (1.2 g, 63percent) as brown solid. Mass (m/z): 260 [M++1]. 1H NMR (200 MHz, CDCl3): delta 9.43 (d, J=2.2 Hz, 1H), 7.8 (d, J=12.4 Hz, 1H), 7.44 (d, J=9.8 Hz, 1H), 7.09 (dd, J=2.2, 9.6 Hz, 1H), 5.58 (d, J=12 Hz, 1H), 3.86 (s, 3H), 3.06 (brs, 6H), 2.75 (s, 3H). To a solution of Int-3 (1.6 g, 6.17 mmol) in DMF (25 mL) was added Int-3B (2.38 g, 12.3 mmol) followed by K2CO3 (2.13 g, 15.4 mmol) at room temperature under inert atmosphere and the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, poured into ice water (70 mL) and stirred for 15 minutes. The precipitated solid was filtered, washed with water (2.x.10 mL) and dried under vacuum to afford Int-4 (1.2 g, 50percent) as brown solid. Mass (m/z): 390 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 10.13 (s, 1H), 9.17 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.-6.90 (m, 4H), 7.55 (d, J=10 Hz, 1H), 7.25-7.14 (m, 2H), 3.8 (s, 3H), 3.66 (s, 3H), 2.6 (s, 3H). A mixture of Int-4 (0.8 g, 2.05 mmol) and 4 N HCl (30 mL) was stirred at reflux temperature for 4 hours. The reaction mixture was cooled to room temperature and pH adjusted to about 5 using NaHCO3 and stirred for 20 minutes. The precipitated solid was filtered, washed with water (2.x.10 mL) and dried under vacuum to afford Int-5 (0.7 g, 90.9percent yield) as brown color solid. Mass (m/z): 376 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 10.29 (s, 1H), 9.18 (d, J=1.8 Hz, 1H), 8.72 (d, J=5.2 Hz, 1H), 8.-7.78 (m, 6H), 7.64 (dd, J=2.2, 10 Hz, 1H), 3.71 (s, 3H), 2.69 (s, 3H). To a stirred solution of Int-5 (0.7 g, 1.86 mmol) in DMF (10 mL) were added HOBt (0.25 g, 1.86 mmol), EDCI (0.71 g, 3.7 mmol), N-ethyldiisopropylamine (0.7 mL, 5.58 mmol) at 0° C. After being stirred for 10 minutes, and then added o-phenylenediamine (0.2 g, 1.86 mmol) to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirring was continued for 16 hours. The reaction mixture was poured into ice cold water (50 mL) and stirred for 10 minutes. The precipitated solid was filtered, washed with water (3.x.10 mL) and dried under vacuum. The crude material was purified over silica gel column chromatography eluting with 4percent MeOH/DCM to afford the title compound (0.27 g, 31.1percent yield) as off white solid. Mass (m/z): 465.2 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 10.02 (s, 1H), 9.53 (s, 1H), 9.18 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 7.86-7.98 (m, 4H), 7.60 (d, J=9.6 Hz, 1H), 7.13-7.25 (m, 3H), 6.85-7.0 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.45-6.61 (m, 1H), 4.86 (brs, 2H), 3.69 (s, 3H), 2.60 (s, 3H). 13C NMR (125 MHz, dmso-d6): delta 164.69, 159.26, 158.17, 156.83, 148.74, 146.45, 143.33, 143.03, 142.42, 128.49, 127.05, 126.55, 126.21, 123.65, 120.66, 118.59, 118.10, 116.37, 116.29, 116.15, 110.27, 110.15, 55.90, 16.36.
17%	copper; In N,N-dimethyl-formamide; at 140℃; under 15514.9 Torr; for 0.5h;Microwave irradiation (75W) in a sealed tube;Product distribution / selectivity;	Method b:; 2-Amino-4-bromopyridine (0.10 g; 0.58 mmol), sodium methoxide (0.16 g; 2.9 mmol) and copper powder nanosized activated (0.11 g; 1.74 mmol) were introduced in a microwave glass tube with 1.5 mL of anhydrous DMF and sealed. The tube was introduced in the microwave cavity and heated for 30 min at 140°C (140C30M75W300Psi). Although DMF is a high boiling solvent, high pressure was observed, probably caused by the partial methanolysis of the DMF resulting in low boiling products such as methyl formate and dimethylamine. The mixture was diluted with 10 mL of 2 M NH4Cl solution and extracted 3 times with AcOEt. The organic phase was washed 2 times with 2 M NH4Cl solution and 1 time with water to remove the remaining DMF, dried on NaSO4, and filtered. After the solvent was removed, the crude product was purified by FCC (AcOEt) to afford 12 mg (yield 17percent) of the title compound as brown oil. 1H NMR (270 MHz; CDCl3), delta 7.74 (1 H, d, 3JHH = 3.0 Hz), 7.06 ( IH, dd, 3JHH = 9.0 Hz, 4JHH = 3.0 Hz), 6.45 (1 H, d, 3JHH = 9.0 Hz), 3.95 (2H, bs, NH2), 3.74 (3H, s, OCH3); m/z (EI-MS): 124 (M+), 109 ([M-CH3]+).; Substitution of halide by OCH3 and SEt group is more challenging. The first attempts to prepare P5 by a nucleophilic aromatic displacement of the bromide with a methoxy group catalyzed by Cu powder in a conventional way11 or with microwave heating or an ultrasound bath were frustrated by the apparent unreactivity of the substrate.; In order to decrease the reaction time, the transformation in eq 3 was carried out with microwave irradiation according to Table 3.

	With copper; In methanol; at 160℃; for 72h;Heating in a sealed tube;	Preparation 177; 2-amino-5-methoxypyridine; Add 2-amino-5-bromopyridine (5.0 g, 29 mmol) to a freshly prepared solution of sodium methoxide (1.3 g, 58 mmol) in methanol (50 mL) and then add copper powder (1.8 g, 2.9 mmol). Heat and stir the mixture in a sealed tube at 160 °C for 3 days. Cool, filter through celite and concentrate under reduced pressure. Dissolve the residue in dichloromethane, then wash with water and saturated aqueous sodium chloride. Dry over magnesium sulfate, concentrate under reduced pressure, and subject the residue to silica gel chromatography, eluting with hexane/ethyl acetate; 3: 1 to 0: 1 to provide the title compound (1.5 g). MS (ES): m/z = 125 (M++H).
	copper; In methanol; at 140℃; for 1h;Microwave irradiation;Product distribution / selectivity;	In order to decrease the reaction time, the transformation in eq 3 was carried out with microwave irradiation according to Table 3.

References: [1]Heterocycles,2002,vol. 57,p. 55 - 71.
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 4746 - 4758.
[3]Patent: WO2007/124345,2007,A2 .Location in patent: Page/Page column 10; 25.
[4]Patent: US2010/29638,2010,A1 .Location in patent: Page/Page column 96.
[5]Patent: WO2007/124345,2007,A2 .Location in patent: Page/Page column 11; 24-25.
[6]Patent: WO2003/76442,2003,A1 .Location in patent: Page/Page column 83.
[7]Patent: WO2007/124345,2007,A2 .Location in patent: Page/Page column 25.

3
[ 1072-97-5 ]
[ 79-10-7 ]
[ 167837-43-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	With sodium carbonate;palladium dichloride; In water;	a) (E)-3-(6-Aminopyridin-3-yl)acrylic acid Acrylic acid (23 mL, 0.33 mole) was added carefully to a solution of 2-amino-5-bromopyridine (25.92 g, 0.15 mole) and Na2CO3 (55.64 g, 0.53 mole) in H2O (600 mL). PdCl2 (0.53 g, 0.003 mole) was then added, and the mixture was heated at reflux. After 24 hr, the reaction was cooled to RT and filtered, and the filtrate was adjusted to pH 6 with aqueous HCl. Additional H2O (0.5 L) was added to improve mixing, and the mixture was stirred for 1 hr. The pH was readjusted to 6, then the solid was collected by suction filtration. The filter pad was washed sequentially with H2O (2 x 0.5 L), cold absolute EtOH (100 mL), and Et2O (2 x 250 mL). Drying in high vacuum at elevated temperature gave the title compound (15.38 g, 62%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) delta 8.11 (d, J = 2.0 Hz, 1 H), 7.75 (dd, J = 8.7, 2.0 Hz, 1 H), 7.43 (d, J = 15.8 Hz, 1 H), 6.53 (s, 2 H), 6.45 (d, J = 8.7 Hz, 1 H), 6.22 (d, J = 15.8 Hz, 1 H); MS (ES) m/e 165 (M + H)+.

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3246 - 3256.
[2]Patent: EP1226138,2004,B1 .
[3]RSC Advances,2018,vol. 8,p. 23698 - 23710.

4
[ 1072-97-5 ]
[ 2032-35-1 ]
[ 865156-68-9 ]

Yield	Reaction Conditions	Operation in experiment
62%		A suspension of 2-amino-5-bromopyrimidine (3.0 g, 17.2 mmol), bromoacetaldehyde diethyl acetal (3.2 mL, 20.7 mmol) and 48% HBr (1.7 mL) in EtOH was heated was heated to 80 0C in a sealed tube for 16 h. After cooling to rt, the reaction was adjusted to pH ~12 with 6N NaOH and the resultant precipitate was collected by filtration, rinsed with water followed by hexanes and dried to a constant weight to give 2.12 g (62%) of 6-bromoimidazo[l,2-alpha]pyrimidine as a white solid. MS(ES)+ m/e 199.7 [M+H]+.

References: [1]Patent: WO2008/14219,2008,A2 .Location in patent: Page/Page column 48.

5
[ 1072-97-5 ]
[ 356560-80-0 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3614 - 3627.
[2]European Journal of Organic Chemistry,2005,p. 3761 - 3765.
[3]Patent: WO2013/127266,2013,A1 .
[4]Patent: WO2013/127267,2013,A1 .
[5]Patent: WO2013/130935,2013,A1 .
[6]Patent: WO2013/130943,2013,A1 .
[7]Patent: WO2008/128953,2008,A1 .
[8]Patent: WO2004/43940,2004,A1 .
[9]Patent: KR2018/131662,2018,A .

6
[ 1072-97-5 ]
[ 167837-43-6 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3246 - 3256.

7
[ 1072-97-5 ]
[ 50-00-0 ]
[ 26163-07-5 ]

Yield	Reaction Conditions	Operation in experiment
43%		37 % Aqueous formaldehyde (13.55 ml, 180.3 mmol) was added dropwise to a solution of 2-amino-5-bromopyrydine (2.0 g, 11.56 mmol) in methanol (465 ml)at room temperature. To the mixture was added dropwise a solution of zinc chloride (3.94 g, 28.90 mmol) and sodium cyanoborohydride (3.63 g, 57.80 mmol) in methanol (155 ml)and the mixture was stirred at room temperature for 4 hrs. To the reaction mixture was added ice water (300 ml) at 5 C and then methanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate - tetrahydrofuran (1/1) and the extract was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 24 and 5) to give 5-bromo-2-dimethylamino-pyridine (1.00 g, 43 %) as colorless crystals. m.p.: 39 - 41 C; IR (Nujol): 1588 cm-1; APCI-MS m/z: 201/203 [M+H]+.
43%	With sodium cyanoborohydride; zinc(II) chloride; In methanol; water; at 20℃; for 4h;	(Preparation 27) (0109) 1) 37% Aqueous formaldehyde (13.55 ml, 180.3 mmol) was added dropwise to a solution of 2-amino-5-bromopyrydine (2.0 g, 11.56 mmol) in methanol (465 ml)at room temperature. To the mixture was added dropwise a solution of zinc chloride (3.94 g, 28.90 mmol) and sodium cyanoborohydride (3. 63 g, 57.80 mmol) in methanol (155 ml) and the mixture was stirred at room temperature for 4 hrs. To the reaction mixture was added ice water (300 ml) at 5 C. and then methanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate-tetrahydrofuran (1/1) and the extract was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=24 and 5) to give 5-bromo-2-dimethylamino-pyridin- e (1.00 g, 43%) as colorless crystals. m.p.: 39-41 C.; IR (Nujol): 1588 cm-1; APCI-MS m/z: 201/203 [M+H]+.

References: [1]Patent: EP1481965,2004,A1 .Location in patent: Page 29.
[2]Patent: EP2959918,2015,A1 .Location in patent: Paragraph 0109.

8
[ 1072-97-5 ]
[ 140-88-5 ]
[ 227963-57-7 ]

Yield	Reaction Conditions	Operation in experiment
82%	With dichlorobis(tri-O-tolylphosphine)palladium; triethylamine; In N,N-dimethyl-formamide; at 100℃; for 6h;	To a solution of 5-bromopyridin-2-amine (0.568 g) in dimethylformamide (6 mL) were added ethyl acrylate (0.429 mL), triethylamine (0.682 mL), and dichloro di(tri(o-tolylphosphine))palladium (0.262 g). The mixture was stirred at 100 C. for 6 hours, and then thereto was added aqueous saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.520 g) (yield 82%). (0387) LC/MS, Condition D, Retention time 0.59 min, obs MS[M+1]193.1
81%	With palladium diacetate; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere; Sealed tube;	Step 1. (E)-ethyl 3-(6-aminopyridin-3-yl)acrylate To a glass bomb were charged with 5-bromopyridin-2-amine (10.0 g, 57.8 mmol), ethyl acrylate (8.14 mL, 75 mmol) and DIEA (25.2 mL, 144 mmol) in DMF (40 mL). The mixture was purged with argon, followed by addition of Pd(OAc)2 (0.649 g, 2.89 mmol) and (o-Tol)3P (3.87 g, 12.72 mmol), and finally purged thoroughly with argon. The mixture was sealed, and heated with 100 C. oil bath overnight. The reaction mixture was cooled down to room temperature, and the precipitates were removed by filtering through a thin layer of Celite. The filtrate was concentrated as much as possible via rotavap, and the residue was partitioned between EtOAc/water (150 mL/100 mL). EtOAc layer was washed with water (2*100 mL), dried over Na2SO4, and concentrated. A brown slid was obtained as crude product. The crude product was triturated with EtOAc (40 mL) and the yellow solid was collected via filtration. The filter cake was rinsed with small amount of EtOAc and dried under vacuum as the first crop of product (5.0 g). The mother liquor from trituration was stripped by dilute aqueous 1 N HCl (30 mL) and water (70 mL). Aqueous layer was transferred to a clean separate funnel, basicified with 20 mL sat. Na2CO3, and extracted with EtOAc (60 mL). EtOAc layer was dried over Na2SO4, concentrated and provided the second portion of product (4.0 g). The two crops of product were combined to afford 81% yield. LCMS (m/z) 193.2 (MH+), 0.39 min.
	With triethylamine;tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine; In dichloromethane; at 20 - 80℃;Heating / reflux;	Ethyl acrylate (0.47 mL, 4.33 mmol) was added into a stirred suspension of the amine (0.50 g, 2.89 mmol), Pd2(dba)3 (0.2646 g, 0.289 mmol), P(o-tol)3 (0.1583 g, 0.52 mmol), Et3N (0.62 mL, 4.45 mmol) and CH2CI2 (12 mL) at room temp. The reaction was heated to reflux at ~ 8O0C. When the starting material had fully depleted (monitored by LCMS), the reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was then washed with NaHCO3 (2 x 10 mL) and brine (2 x 10 mL). The organic layer was dried in Na2SO4 before being filtered and concentrated in vacuo. The crude product was EPO <DP n="66"/>purifed by the Bison system and was isolated as a light yellow solid [trifluoroacetic acid (TFA) salt] (75%, 0.63 g).3-(2-Amino-pyridin-4-yl)-acrylic acid ethyl esterHPLC: 97.5 %; tR = 1.114 min; LCMS (ESI) Calcd for C10H12N2O2 [M+]: 192.0899, found 193.08 [MH]+; 1H NMR (400 MHz, CDCI3): δ 8.36 (brs, 1 H), 8.29 (s, 1 H), 8.26 (dd, J = 2.00, 9.27 Hz, 1 H), 7.56 (dd, J = 16.02 Hz, 1 H), 6.92 (d, J = 9.20 Hz, 1 H), 6.55 (d, J = 16.00 Hz, 1 H), 4.17 (q, J = 7.08 Hz, 2H), 1.24 (t, J = 7.10 Hz, 3H);13C NMR (100.5 MHz, CDCI3): 8 165.9, 155.3, 139.9, 139.5, 139.3, 119.1 , 118.1 , 117.2, 115.2, 113.1 , 60.0, 14.1.

References: [1]Patent: US10898469,2021,B2 .Location in patent: Page/Page column 43.
[2]Patent: US9242996,2016,B2 .Location in patent: Page/Page column 358; 359.
[3]Patent: WO2006/101455,2006,A1 .Location in patent: Page/Page column 64-65.

9
[ 1072-97-5 ]
[ 74-88-4 ]
[ 84539-30-0 ]
[ 26163-07-5 ]

Yield	Reaction Conditions	Operation in experiment
34%	With NaH; In N,N-dimethyl-formamide; mineral oil;	a) 5-Bromo-2-(methylamino)pyridine and 5-bromo-2-(dimethylamino)pyridine To a suspension of NaH (60% dispersion in mineral oil, 0.44 g, 11 mmole) in dry DMF (40 mL) was added solid 2-amino-5-bromopyridine (1.73 g, 10 mmole) in portions over 5-10 min. Gas evolution was allowed to subside between additions. The resulting amber mixture was stirred for 15 min, then' methyl iodide (0.61 mL, 10 mmole) was added all at once. The reaction mixture was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 5% NH4Cl (30 mL) and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) separated the products. 5-Bromo-2-(methylamino)pyridine (0.60 g, 32 %) was obtained as a semisolid: TLC (3% MeOH/CH2Cl2) Rf 0.35; MS (ES) m/e 187 (M + H)+. 5-Bromo-2-(dimethylamino)pyridine (0.70 g, 34%) was obtained as a semisolid: TLC (3% MeOH/CH2Cl2) Rf 0.77; MS (ES) m/e 201 (M + H)+.

References: [1]Patent: EP1226138,2004,B1 .

10
[ 1072-97-5 ]
[ 19255-60-8 ]
[ 603311-76-8 ]

Yield	Reaction Conditions	Operation in experiment
		Reflux a solution of 4, 4-dimethoxy-but-2-enoic acid ethyl ester (3.3 g, 19.12 mmol) and toluene-4-sulfonic acid (0.02 g, 0.12 mmol) in a solution of 2: 1 acetonitrile: water (90 mL) for 30 min. Add 2-AMINO-5-BROMO-PYRIDINE (1.65 g, 9.56 mmol) and reflux for 15 h. Cool and concentrate TO-20 ML. Dilute the reaction with saturated aqueous sodium bicarbonate and extract into ethyl acetate. Combine and concentrate organic extracts. Flash chromatography using ethyl acetate/dichloromethane/methanol mixtures gives the subtitled compound as a brown oil (2. 9 G). TOF MS ES+ exact mass calculated for CLLHNBRN202 (P+1) : m/z = 283.0075 Found: 283. 0082. 1H NMR (400 MHz, DMSO-d6) B 8.68 (s, 1H), 7.55 (d, J = 10 Hz, 1H), 7.49 (s, 1H), 7.34 (d, J = 10 Hz, 1H), 4.15 (s, 2H), 4.09 (q, J = 4 Hz, 2H), 1.18 (t, J = 4 Hz, 3H). EA Calcd. For CLLHLLBRN202 : C, 46.66 ; H, 3.92 ; N, 9.89 ; Found C, 46.56 ; H, 4.02 ; N, 9.60.

References: [1]Patent: WO2004/50659,2004,A1 .Location in patent: Page 39.

11
[ 1072-97-5 ]
[ 474706-74-6 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2455 - 2466.
[2]Tetrahedron,2011,vol. 67,p. 7128 - 7138.
[3]Patent: WO2015/188369,2015,A1 .

12
[ 1072-97-5 ]
[ 74-88-4 ]
[ 26163-07-5 ]

Yield	Reaction Conditions	Operation in experiment
94%		Step 64a: 5-Bromo-N,N-dimethylpyridin-2-amine (cCompound 0601-114)To a solution of 5-bromopyridin-2-amine (1.0 g, 5.8 mmol) in THF (25 mL) was added NaH (0.92 g, 23.1 mmol) at 0 C and stirred for 10 min. followed by the addition of CH3I (1 mL, 16 mmol) and stirred fori h. Water (30 mL) was added and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2S04, concentrated and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give the title compound (1.1 g, 94%) as a white solid LCMS: 203 [M+2]+; 1HNMR (400 MHz, DMSO-<¾) delta 2.99 (s, 6H), 6.61 (d, J= 9.6 Hz, 1H), 7.62 (dd, J= 9.2, 2.8 Hz, 1H), 8.12 (d, J= 2.4 Hz, 1H).
94%		Step 64a: 5-Bromo-N,N-dimethylpyridin-2-amine (compound 0601-114)[0486]To a solution of 5-bromopyridin-2-amine (1.0 g, 5.8 mmol) in THF (25 mL) was added NaH (0.92 g, 23.1 mmol) at 0 C. and stirred for 10 min. followed by the addition of CH3I (1 mL, 16 mmol) and stirred for 1 h. Water (30 mL) was added and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give the title compound (1.1 g, 94%) as a white solid LCMS: 203 [M+2]+; 1HNMR (400 MHz, DMSO-d6) delta 2.99 (s, 6H), 6.61 (d, J=9.6 Hz, 1H), 7.62 (dd, J=9.2, 2.8 Hz, 1H), 8.12 (d, J=2.4 Hz, 1H).
94%		THF (25mL) in 5-bromo-2-amine (1.0g, 5.8mmol) to a solution of NaH (0.92g, 23.1mmol) was stirred addition to 10 minutes at 0 , then CH3I (1mL, 16mmol) and the mixture was stirred for 1 hour with the addition of. With the addition of water (30mL) and extracted with ethyl acetate (3x30mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated and purified by column chromatography (petroleum ether in ethyl acetate, 10% v / v) on silica gel to give the white solid title compound obtained as (1.1g, 94%).

References: [1]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 206.
[2]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0485; 0486.
[3]Patent: JP2015/187145,2015,A .Location in patent: Paragraph 0418.
[4]European Journal of Organic Chemistry,2020.
[5]Organic and Biomolecular Chemistry,2019,vol. 17,p. 1749 - 1753.

13
[ 1072-97-5 ]
[ 33142-21-1 ]
[ 372198-69-1 ]

Yield	Reaction Conditions	Operation in experiment
21%	In ethanol;Reflux;	To a solution of ethyl formylchloroacetate (prepared according to the procedure described by Plouvier et al. Heterocycles 1991, 32, 693) (2.41 g, 16.0 mmol) in ethanol (60 mL) was added 5-bromopyridin-2-amine (2.77 g, 16.0 mmol), and the mixture was heated to reflux overnight. After cooling, the solvent was removed by rotary evaporation, and the residue was treated with CHCI3 (50 mL) and a saturated solution of aqueous NaHC03. The layers were separated and the aqueous layer was further extracted with CHC13 (2 x 30 mL). The combined organic layer was dried over Na2S04, filtered, and concentrated to dryness. Purification by flash column chromatography (20-35% ethyl acetate in hexane) gave the title compound (0.9 g, 21%). 1H-NMR (DMSO-d6, 400 MHz) delta 9.61 (s, 1 H), 8.32 (s, 1 H), 8.00 (d, J = 9.6 Hz, 1 H), 7.74 (d, J = 9.6 Hz, 1 H), 4.48 (q, J = 7.2 Hz, 2 H), 1.45 (t, J = 7.2 Hz, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C10H10BrN2O2: 269, obtained: 269.
	In ethanol; at 80℃; for 5h;	A solution of <strong>[33142-21-1]ethyl 2-chloro-3-oxopropanoate</strong> (261 g, 1.74mol) 5-bromopyridin-2-amine (100 g, 581 mmol) in ethanol (2L) was heated to 80 C for 5h and concentrated under vacuum. The residue was applied to silica gel column (EA/PE, 1/2) for purification to afford ethyl 6-bromoH-imidazo[l,2- a]pyridine-3-carboxylate as white solid.
	In ethanol; at 20 - 78℃;Inert atmosphere; Reflux; Large scale;	[002981 Example 4[00299] Preparation of compound 8:[00300] 1. Anethanol solution of compound 5 (12400 g in 51 L of ethanol) was added to an appropriately sized stainless steel reactor at room temperature under nitrogen atmosphere.[00301] 2. Compound 6 (9500 g) was added as a solid in one portion at room temperature.[00302] 3. The reaction mixture was heated to reflux (~78C) and stirred for 1-2 days.[00303] 4. The reaction was monitored by HPLC.[00304] 5. Upon completion, the reaction mixture was allowed to cool to room temperature.[00305] 6. NaOH solution (9884 g solid pellets dissolved in 38 L of water) was added as a stream over a30 min period at an internal temperature below 35 C.[00306] 7. The reaction mixture was heated to reflux (~78C) for 3 to 4 hours.[00307] 8. The reaction was monitored by HPLC.[00308] 9. Upon completion, the reaction mixture was cooled to an appropriate temperature to start solvent removal.[00309] 10. All ethanol (approximately 5 volumes of ethanol) was removed under vacuum at 40 to 45 C.[00310] 11. The reaction mixture was cooled to room temperature.[00311] 12. Water (57 L; 6 vol) was added at room temperature.[00312] 13. The aqueous solution was washed with ethyl acetate (2 x 38 L) to remove all organic impurities.[00313] 14. The lower aqueous layer was cooled to 0-5 C and acidified with cone. HCl (~15 L) until reaching pH 1-2.[00314] 15. The reaction mixture was stirred for 1 to 2 hours at 0 to 5 C.[00315] 16. The mixturewas filtered and the cake was washed with water (2 x 38 L) and acetone (2 x 19L) followed by drying for 1-2 hours.[00316] 17. The solid collectedwas transferred back into an appropriately sized reactor.[00317] 18. Heptane (95 L; 10 vol) was addedto the reactor; the suspension was stirred for 4 to 5 hours at roomtemperature.[00318] 19. The solidwas collected by filtration and washed with heptane (2 x 19 L).[00319] 20. The solid (15 kg) was suspended in methanol (75 L; 5 vol) at room temperature for 2 hours.[00320] 21. The suspension was filtered and the solid collected was washed with methanol (2x 5L).22. The solid was dried under vacuum at 50C to constant weight to give compound 8 as an off-white to white solid (10169 g, 83.3 % yield; HPLC purity 99.2%;1HNMR (DMSO-d6, 300 MHz) ? 9.4 (s, 1H), 8.3(s, 1H), 7.85-7.67 (m, 2H)).

References: [1]Patent: WO2011/50245,2011,A1 .Location in patent: Page/Page column 104-105.
[2]Patent: WO2012/87519,2012,A1 .Location in patent: Page/Page column 112; 113.
[3]Patent: WO2013/71272,2013,A1 .Location in patent: Paragraph 00298-00320.
[4]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641.
[5]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 67.
[6]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 345.

14
[ 1072-97-5 ]
[ 1897-41-2 ]
[ 1416422-05-3 ]

Yield	Reaction Conditions	Operation in experiment
2.5 g	With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 5h;	0.60g (0.015 mol) of sodium hydroxide was added to a solution of 1.3g(0.0075 mol) of 5-bromopyridin-2-aminein 40 mL of DMF, followed by addition of 2g (0.0075 mol) of <strong>[1897-41-2]2,3,5,6-<strong>[1897-41-2]tetrachloroterephthalonitrile</strong></strong> under stirring, the mixturewas stirred for 5 hours after addition at room temperature. After the reaction was over by Thin-Layer Chromatographymonitoring, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washedwith water and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reducedpressure. The residue was purified through silica column (ethyl acetate/petroleum ether (boiling point range 60-90°C)= 1:3, as an eluent) to give 2.5 g of compound C-109 as yellow solid, m.p. 154-156°C.[0126] 1H-NMR (300MHz, internal standard TMS, solvent CDCl3) delta(ppm): 9.78(s, 1H, NH), 6.62(d, 1H, Py-3-1H), 7.73(dd, 1H, Py-4-1H), 8.27 (d, 1H, Py-6-1H)
2.5 g	With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 5h;	0.60 g (0.015 mol) of sodium hydroxide was added to a solution of 1.3 g (0.0075 mol) of 5-bromopyridin-2-amine in 40 mL of DMF, followed by addition of 2 g (0.0075 mol) of <strong>[1897-41-2]2,3,5,6-<strong>[1897-41-2]tetrachloroterephthalonitrile</strong></strong> under stirring, the mixture was stirred for 5 hours after addition at room temperature. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column (ethyl acetate/petroleum ether (boiling point range 60-90° C.)=1:3, as an eluent) to give 2.5 g of compound C-109 as yellow solid, m.p. 154-156° C. [0191] 1H-NMR (300 MHz, internal standard TMS, solvent CDCl3) delta (ppm): 9.78 (s, 1H, NH), 6.62 (d, 1H, Py-3-1H), 7.73 (dd, 1H, Py-4-1H), 8.27 (d, 1H, Py-6-1H).

References: [1]Patent: EP2757092,2014,A1 .Location in patent: Paragraph 0124 - 0126.
[2]Patent: US2014/213598,2014,A1 .Location in patent: Paragraph 0189-0191.

15
[ 1072-97-5 ]
[ 33142-21-1 ]
[ 944896-42-8 ]

Yield	Reaction Conditions	Operation in experiment
83.3%		Example 4 Preparation of compound 8: 1. An ethanol solution of compound 5 (12400 g in 51 L of ethanol) was added to an appropriately sized stainless steel reactor at room temperature under nitrogen atmosphere. 2. Compound 6 (9500 g) was added as a solid in one portion at room temperature. 3. The reaction mixture was heated to reflux (?78C) and stirred for 1-2 days. 4. The reaction was monitored by HPLC. 5. Upon completion, the reaction mixture was allowed to cool to room temperature. 6. NaOH solution (9884 g solid pellets dissolved in 38 L of water) was added as a stream over a 30 min period at an internal temperature below 35 C. 7. The reaction mixture was heated to reflux (?78C) for 3 to 4 hours. 8. The reaction was monitored by HPLC. 9. Upon completion, the reaction mixture was cooled to an appropriate temperature to start solvent removal. 10. All ethanol (approximately 5 volumes of ethanol) was removed under vacuum at 40 to 45 C. 11. The reaction mixture was cooled to room temperature. 12. Water (57 L; 6 vol) was added at room temperature. 13. The aqueous solution was washed with ethyl acetate (2 x 38 L) to remove all organic impurities. 14. The lower aqueous layer was cooled to 0-5 C and acidified with cone. HCl (?15 L) until reaching pH 1-2. 15. The reaction mixture was stirred for 1 to 2 hours at 0 to 5 C. 16. The mixturewas filtered and the cake was washed with water (2 x 38 L) and acetone (2 x 19L) followed by drying for 1-2 hours. 17. The solid collectedwas transferred back into an appropriately sized reactor. 18. Heptane (95 L; 10 vol) was addedto the reactor; the suspension was stirred for 4 to 5 hours at roomtemperature. 19. The solidwas collected by filtration and washed with heptane (2 x 19 L). 20. The solid (15 kg) was suspended in methanol (75 L; 5 vol) at room temperature for 2 hours. 21. The suspension was filtered and the solid collected was washed with methanol (2x 5L). 22. The solid was dried under vacuum at 50C to constant weight to give compound 8 as an off-white to white solid (10169 g, 83.3 % yield; HPLC purity 99.2%;1HNMR (DMSO-d6, 300 MHz) delta 9.4 (s, 1H), 8.3 (s, 1H), 7.85-7.67 (m, 2H)).

References: [1]Patent: EP2792360,2014,A1 .Location in patent: Paragraph 0223-0224.

16
[ 1072-97-5 ]
[ 628-36-4 ]
5-bromo-2-(4H-1,2,4-triazol-4-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 190℃; for 1.5h;	A mixture of 5-bromopyridin-2-amine (9.43 g, 54.5 mmol) and 1 ,2-<strong>[628-36-4]diformylhydrazine</strong> (4.8 g, 54.5 mmol) was heated at 190 °C for 1.5h. After cooling to rt, the residue was treated with DCM, the solid was collected by filtration, and washed with DCM to give the title compound. LC/MS [M+l]+ = 224.93, 226.93.
	at 165 - 190℃; for 0.5h;	2.2 g of 5-bromo-2-aminopyridine and 4.0 g of diformylhydrazin mixed, heated to 165 °C, reacted at 185-190 °C for 30 minutes, After recrystallization with benzene and ethanol, respectively, a white acicular ligand L was obtained.

References: [1]Patent: WO2016/10801,2016,A1 .Location in patent: Page/Page column 41.
[2]Patent: CN104844636,2016,B .Location in patent: Paragraph 0029-0034.

17
[ 1072-97-5 ]
[ 1142197-14-5 ]