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Quality Control of [ 446273-59-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 446273-59-2 ]

SDS Specification

Alternatived Products of [ 446273-59-2 ]

Product Details of [ 446273-59-2 ]

CAS No. :	446273-59-2	MDL No. :	MFCD11520891
Formula :	C₄H₃BrClN₃	Boiling Point :	No data available
Linear Structure Formula :	-	InChI Key :	FGOWNGCSUSKHQI-UHFFFAOYSA-N
M.W :	208.44	Pubchem ID :	22024419
Synonyms :

Calculated chemistry of [ 446273-59-2 ] Expand+

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	39.15
TPSA :	51.8 ?2

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) :	-6.76 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.53
Log Po/w (XLOGP3) :	1.15
Log Po/w (WLOGP) :	1.48
Log Po/w (MLOGP) :	1.19
Log Po/w (SILICOS-IT) :	1.67
Consensus Log Po/w :	1.4

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.35
Solubility :	0.931 mg/ml ; 0.00446 mol/l
Class :	Soluble
Log S (Ali) :	-1.83
Solubility :	3.07 mg/ml ; 0.0147 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.77
Solubility :	0.356 mg/ml ; 0.00171 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.9

Safety of [ 446273-59-2 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 446273-59-2 ]

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

Upstream synthesis route of [ 446273-59-2 ]
Downstream synthetic route of [ 446273-59-2 ]

[ 446273-59-2 ] Synthesis Path-Upstream 1~2

1
[ 446273-59-2 ]
[ 598-31-2 ]
[ 1298031-94-3 ]

Yield	Reaction Conditions	Operation in experiment
34%	With sodium carbonate In isopropyl alcohol at 90℃; for 16 h;	4-Bromo-6-chloropyridazin-3-amine (20 g, 97 mmol), Na₂C0₃ (10.2 g, 97 mmol) and 1- bromopropan-2-one (9.7 mL, 116 mmol) were added into isopropyl alcohol (200 mL). The reaction vessel was degassed and then charged with nitrogen three times. The mixture was stirred at 90 °C for 16 h. The mixture was partitioned between EtOAc and H₂0. The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-20percent EtOAc in petroleum ether to yield 8-bromo-6- chloro-2-methylimidazo[l,2-b]pyridazine (8.1 g, 34percent). MS m/z 245.9, 247.9 [M+H]⁺.

Reference： [1] Patent: WO2018/226622, 2018, A1, . Location in patent: Page/Page column 184; 185

2
[ 446273-59-2 ]
[ 78-95-5 ]
[ 1298031-93-2 ]
[ 1298031-94-3 ]

Reference： [1] Patent: WO2011/51342, 2011, A1, . Location in patent: Page/Page column 68
[2] Patent: US2011/269752, 2011, A1, . Location in patent: Page/Page column 28-29
[3] Patent: WO2016/97347, 2016, A1, . Location in patent: Page/Page column 134

[ 446273-59-2 ] Synthesis Path-Downstream 1~10

1
[ 446273-59-2 ]
[ 33142-21-1 ]
[ 1177415-90-5 ]
[ 1177415-89-2 ]

Yield	Reaction Conditions	Operation in experiment
	at 90℃; for 16h;	To a 250 mL round-bottomed flask was added ethyl 2-chloro-3- oxopropanoate (4.33 g, 28.8 mmol) and 4-bromo-6-chloropyridazin-3-amine (5 g, 23.99 mmol). The solution was heated to 90 0C for 16 hours. The solution was quenched with ethyl acetate and washed with water. The organic layer was dried <n="48"/>over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by ISCO (10 % ethyl acetate / dichloromethane; 80 g column) to give a mixture of ethyl 8-bromo-6-chloroimidazo[l,2-b]pyridazine-3-carboxylate and ethyl 6,8-dichloroimidazo[l,2-b]pyridazine-3-carboxylate (2.1 g, 29 % yield). LC/MS, m/z 256.96 (M+l). HPLC Rt, 2.54 min. LC/MS, m/z 303.92 (M+l). HPLC Rt, 2.63 min. Waters Sunfire C18 column (4.6 x 50 mm). 0%-100%B. Solvent B: (90% MeOH, 10 % H2O, 0.1% TFA). Solvent A: (10% MeOH, 90 % H2O, 0.1% TFA). Gradient, start %B = 0, final % B = 100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
	at 90℃; for 16h;	1C: Preparation of ethyl 8-bromo-6-chloroimidazo[l,2-b]pyridazine-3-carboxylate and ethyl 6,8-dichloroimidazo[l,2-b]pyridazine-3-carboxylate[00230] To a 250 mL round-bottomed flask was added IB (4.33 g, 28.8 mmol) and IA (5 g, 24.0 mmol). The solution was heated to 90 0C for 16 hours. The solution was quenched with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography (SiC^, 10 % ethyl acetate / DCM; 80 g column) to give a mixture of IC-I and lC-2 (2.1 g, 29 % yield). [00231] IC-I : HPLC: Rt = 2.54 min (Waters Sunfire C18 column (4.6 x 50 mm). 10-90% aqueous methanol containing 0.1% TF A; 4 min gradient, flow rate = 4 mL/min, detection at 254 nm). MS (ES): m/z = 256.96 [M+H]+. [00232] lC-2: HPLC: Rt = 2.63 min (Waters Sunfire C18 column (4.6 x 50 mm). 10-90% aqueous methanol containing 0.1% TF A, 4 min gradient, flow rate = 4 mL/min, detection at 254 nm). MS (ES): m/z = 303.92 [M+H]+.
	In ethanol; at 80℃; for 16h;	To a solution of 4-bromo-6-chloropyridazin-3-amine (175 g, 840 mmol) in ethanol (2 L) was added <strong>[33142-21-1]ethyl 2-chloro-3-oxopropanoate</strong> (202 g, 1343 mmol) and the reaction was heated to 80 C for 16 hours. The solvent was removed in vacuo and the residual material was diluted with water and dichloromethane. The biphasic mixture was passed through a celite bed and the filtrate was separated into two layers. The dichloromethane layer was separated and then washed with water and saturated aqueous sodium chloride (brine), it was then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified using silica gel chromatography (0 to 20% ethyl acetate in petroleum ether). The product fractions were dried and then triturated with 10% methyl tert-butyl ether in petroleum ether (500 mL). The product was filtered off and rinsed with petroleum ether to provide the product (73 g, 33% yield) as a mixture of the C8-bromo and C8-chloro species (-80:20), the mixture was used as such in the subsequent steps (referred to as the chloride for simplicity). NMR (300 MHz, CDCh): (0447) Chloro: delta 8.37 (s, 1H), 7.38 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). Bromo: delta 8.38 (s, 1H), 7.57 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). LC retention time chloro: 1.04 min [O] ; bromo: 1.07 [O]. Mass Spectrometry ("MS") (E+) m/z: 260 (chloro); 304 (bromo) (MH+).

	In ethanol; at 80℃; for 16h;	To a solution of 4-bromo-6-chloropyridazin-3-amine (175 g, 840 mmol) inethanol (2 L) was added <strong>[33142-21-1]ethyl 2-chloro-3-oxopropanoate</strong> (202 g, 1343 mmol) and thereaction was heated to 80 C for 16 hours. The solvent was removed in vacuo and the residual material was diluted with water and dichloromethane. The biphasic mixture was passed through a celite bed and the filtrate was separated into two layers. The dichloromethane layer was separated and then washed with water and saturated aqueoussodium chloride (brine), it was then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified using silica gel chromatography (0 to 20% ethyl acetate in petroleum ether). The product fractions were dried and then triturated with 10% methyl tert-butyl ether in petroleum ether (500 mL). The product was filtered off and rinsed with petroleum ether to provide la (73 g, 33% yield) as a mixtureof the C8-bromo and C8-chloro species (80:20), the mixture was used as such in the subsequent steps (referred to as the chloride for simplicity).?H NMR (300 MHz, CDC13): Chloro: 8.37 (s, 1H), 7.38 (s, 1H), 4.47 (q, J= 7.2 Hz, 2H), 1.44 (t, J= 7.2 Hz, 3H).Bromo: 8.38 (s, 1H), 7.57 (s, 1H), 4.47 (q, J= 7.2 Hz, 2H), 1.44 (t, J= 7.2 Hz, 3H).LC retention time chloro: 1.04 mm [Bj; bromo: 1.07 [Bj. Mass Spectrometry (?MS?)(E+) m/z: 260 (chloro); 304 (bromo) (MH).
	In ethanol; at 80℃; for 16h;	To a solution of 4-bromo-6-chloropyridazin-3-amine (175 g, 840 mmol) in ethanol (2 L) was added <strong>[33142-21-1]ethyl 2-chloro-3-oxopropanoate</strong> (202 g, 1343 mmol) and the reaction was heated to 80 C for 16 hours. The solvent was removed in vacuo and the residual material was diluted with water and dichloromethane. The biphasic mixture was passed through a celite bed and the filtrate was separated into two layers. Thedichloromethane layer was separated and then washed with water and saturated aqueous sodium chloride (brine), it was then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified using silica gel chromatography (0 to 20% ethyl acetate in petroleum ether). The product fractions were dried and then triturated with 10% methyl tert-butyl ether in petroleum ether (500 mL). The product wasfiltered off and rinsed with petroleum ether to provide the product (73 g, 33% yield) as a mixture of the C8-bromo and C8-chloro species (80:20); the mixture was used as such in the subsequent steps (referred to as the chloride for simplicity).?H NMR (300 MHz, CDC13):Chloro: 8.37 (s, 1H), 7.38 (s, 1H), 4.47 (q, J= 7.2 Hz, 2H), 1.44 (t, J= 7.2 Hz, 3H). Bromo: 8.38 (s, 1H), 7.57 (s, 1H), 4.47 (q, J= 7.2 Hz, 2H), 1.44 (t, J= 7.2 Hz, 3H). LC retention time chloro: 1.04 mm [Gj; bromo: 1.07 [Gj. Mass Spectrometry (?MS?) (E+)m/z: 260 (chloro); 304 (bromo) (MH).

Reference： [1]Patent: WO2009/100375,2009,A1 .Location in patent: Page/Page column 45-46
[2]Patent: WO2010/42699,2010,A1 .Location in patent: Page/Page column 115-116
[3]Patent: WO2017/87590,2017,A1 .Location in patent: Page/Page column 56; 57
[4]Patent: WO2018/67432,2018,A1 .Location in patent: Page/Page column 52; 53
[5]Patent: WO2018/93968,2018,A1 .Location in patent: Page/Page column 47; 48

2
[ 446273-59-2 ]
[ 33142-21-1 ]
[ 1177415-91-6 ]
[ 1177415-92-7 ]

Yield	Reaction Conditions	Operation in experiment
		ID: Preparation of 8-bromo-6-chloroimidazo[l,2-b] pyridazine-3-carboxylic acid and 6,8-dichloroimidazo[l,2-b]pyridazine -3-carboxylic acid[00233] To a vial was added the mixture of 1C (300 mg, 0.98 mmol) in methanol (10 mL). To this mixture was added 6 N HCl (1.64 mL, 9.85 mmol). The solution was heated at 90 0C for 16 hours. The solution was diluted with ethyl acetate, and the product extracted with saturated aqueous sodium bicarbonate solution. The combined aqueous layer was acidified with HCl (IN) to pH 4 and extracted with ethyl acetate (3 times). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give a mixture of ID-I and 1D-2 (150 mg, 55%). [00234] ID-I : HPLC: Rt = 1.67 min (Waters Sunfire Cl 8 column (4.6 x 50 mm). 10-90% aqueous methanol containing 0.1% TF A, 4 min gradient, flow rate = 4 mL/min, detection at 254 nm). MS (ES): m/z = 231.87 [M+H]+.[00235] 1D-2: HPLC: Rt = 1.81 min (Waters Sunfire C18 column (4.6 x 50 mm). 10-90% aqueous methanol containing 0.1% TF A; 4 min gradient, flow rate = 4 mL/min, detection at 254 nm). MS (ES): m/z = 275.79 [M+H]+.

Reference： [1]Patent: WO2010/42699,2010,A1 .Location in patent: Page/Page column 116

3
[ 446273-59-2 ]
[ 33142-21-1 ]
[ 1220631-43-5 ]
[ 1220631-44-6 ]

Yield	Reaction Conditions	Operation in experiment
		ID: Preparation of 8-bromo-6-chloroimidazo[l,2-b] pyridazine-3-carboxylic acid and 6,8-dichloroimidazo[l,2-b]pyridazine -3-carboxylic acid[00233] To a vial was added the mixture of 1C (300 mg, 0.98 mmol) in methanol (10 mL). To this mixture was added 6 N HCl (1.64 mL, 9.85 mmol). The solution was heated at 90 0C for 16 hours. The solution was diluted with ethyl acetate, and the product extracted with saturated aqueous sodium bicarbonate solution. The combined aqueous layer was acidified with HCl (IN) to pH 4 and extracted with ethyl acetate (3 times). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give a mixture of ID-I and 1D-2 (150 mg, 55%). [00234] ID-I : HPLC: Rt = 1.67 min (Waters Sunfire Cl 8 column (4.6 x 50 mm). 10-90% aqueous methanol containing 0.1% TF A, 4 min gradient, flow rate = 4 mL/min, detection at 254 nm). MS (ES): m/z = 231.87 [M+H]+.[00235] 1D-2: HPLC: Rt = 1.81 min (Waters Sunfire C18 column (4.6 x 50 mm). 10-90% aqueous methanol containing 0.1% TF A; 4 min gradient, flow rate = 4 mL/min, detection at 254 nm). MS (ES): m/z = 275.79 [M+H]+.

Reference： [1]Patent: WO2010/42699,2010,A1 .Location in patent: Page/Page column 117

4
[ 446273-59-2 ]
[ 33142-21-1 ]
[ 1220631-46-8 ]
[ 1220631-45-7 ]

Yield	Reaction Conditions	Operation in experiment
		IF: Preparation of 8-bromo-6-chloroimidazo[l,2-b]pyridazine-3-carbonitrile and 6,8- dichloroimidazo[l,2-b]pyridazine-3-carbonitrile[00239] A suspension of ID-I and 1D-2 (8.7 g, 31.6 mmol) in CHCl3 (500 mL) was treated with POCI3 (35.3 mL, 380 mmol) and heated to reflux for 3 days. The resulting solution was cooled to room temperature and poured into cold saturated aqueous NaHCO3 (1 L). Solid Na2CO3 was added until neutral pH was achieved. The resulting layers were separated and the aqueous layer was extracted with CHCl3 (1 L). The combined organics were dried with Na2SO4, filtered and concentrated to dryness to afford a mixture of IF-I and 1F-2 as a yellow powder (5.6 g, 68.9 %). [00240] IF-I: HPLC: Rt = 2.53 min. (YMC S5 ODS 4.6 x 50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm); MS (ES): m/z = 213 [M+H]+.[00241] 1F-2: HPLC: Rt = 2.67 min. (YMC S5 ODS 4.6 x 50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm); MS (ES): m/z = 258.9 [M+H]+.

Reference： [1]Patent: WO2010/42699,2010,A1 .Location in patent: Page/Page column 117-118

5
[ 446273-59-2 ]
[ 33142-21-1 ]
[ 1220631-47-9 ]

Yield	Reaction Conditions	Operation in experiment
90%		IF: Preparation of 8-bromo-6-chloroimidazo[l,2-b]pyridazine-3-carbonitrile and 6,8- dichloroimidazo[l,2-b]pyridazine-3-carbonitrile[00239] A suspension of ID-I and 1D-2 (8.7 g, 31.6 mmol) in CHCl3 (500 mL) was treated with POCI3 (35.3 mL, 380 mmol) and heated to reflux for 3 days. The resulting solution was cooled to room temperature and poured into cold saturated aqueous NaHCO3 (1 L). Solid Na2CO3 was added until neutral pH was achieved. The resulting layers were separated and the aqueous layer was extracted with CHCl3 (1 L). The combined organics were dried with Na2SO4, filtered and concentrated to dryness to afford a mixture of IF-I and 1F-2 as a yellow powder (5.6 g, 68.9 %). [00240] IF-I: HPLC: Rt = 2.53 min. (YMC S5 ODS 4.6 x 50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm); MS (ES): m/z = 213 [M+H]+.[00241] 1F-2: HPLC: Rt = 2.67 min. (YMC S5 ODS 4.6 x 50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm); MS (ES): m/z = 258.9 [M+H]+.

Reference： [1]Patent: WO2010/42699,2010,A1 .Location in patent: Page/Page column 118

6
[ 446273-59-2 ]
[ 78-95-5 ]
[ 1298031-93-2 ]
[ 1298031-94-3 ]

Yield	Reaction Conditions	Operation in experiment
	at 90℃; for 16h;Sealed tube;	Example A3Preparation of intermediate 3: Mixture of 6,8-dichloro-2-methyl-imidazo[l,2- ^lpyridazine and 8-bromo-6-chloro-2-methyl-imidazo [ 1 ,2-&"\|pyridazineA mixture of intermediate 1 (28.57 g, 137.1 mmol) and chloroacetone (76.4 ml, 959.4 mmol) was stirred at 90C for 16 h. in a sealed tube protected from light. After cooling to room temperature, diethylether was added and the solid formed was filtered off and washed with further diethylether. The solid was suspended in a saturated solution of sodium carbonate and extracted with dichloromethane. The organic layer was dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude products were purified by open column chromatography (silica; dichloromethane). The desired fractions were collected and concentrated in vacuo to yield intermediate 3 (19.5 g, 66%) as a white solid, in a 70/30 mixture of 6,8-dichloro-2-methyl-imidazo[l,2- ?]pyridazine and 8-bromo-6-chloro-2-methyl-imidazo[l,2-?]pyridazine. C7H5C12N3 requires 201 ; Found 202 [M+H]+; Rt: 1.25 min and C7H5BrClN3 requires 247; Found 248 [M+H]+; Rt: 1.33 min (method 5).
		Example A3 Preparation of intermediate 3: Mixture of 6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine A mixture of intermediate 1 (28.57 g, 137.1 mmol) and chloroacetone (76.4 ml, 959.4 mmol) was stirred at 90 C. for 16 h. in a sealed tube protected from light. After cooling to room temperature, diethylether was added and the solid formed was filtered off and washed with further diethylether. The solid was suspended in a saturated solution of sodium carbonate and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude products were purified by open column chromatography (silica; dichloromethane). The desired fractions were collected and concentrated in vacuo to yield intermediate 3 (19.5 g, 66%) as a white solid, in a 70/30 mixture of 6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine. C7H5Cl2N3 requires 201; Found 202 [M+H]+; Rt: 1.25 min and C7H5BrClN3 requires 247; Found 248 [M+H]+; Rt: 1.33 min (method 5).
	at 90℃; for 15h;	3-Amino-4-bromo-6-chloropyridazine (23.65 g; 113.46 mmol) in chloro-2-propanone (70.9 mL; 891 mmol) and the mixture was heated at 90 C for 15 hours. The reaction was cooled to room temperature and Et20 was added. The precipitate was filtered, washed with Et20 and dried. The residue was stirred with DCM. The precipitate was filtered and dried to afford 41.1 g of a mixture intermediate 62 (A/B: 75/25 based on Eta NMR).

Reference： [1]Patent: WO2011/51342,2011,A1 .Location in patent: Page/Page column 68
[2]Patent: US2011/269752,2011,A1 .Location in patent: Page/Page column 28-29
[3]Patent: WO2016/97347,2016,A1 .Location in patent: Page/Page column 134

7
[ 446273-59-2 ]
[ 54109-16-9 ]
[ 1431322-42-7 ]

Yield	Reaction Conditions	Operation in experiment
49.8%	In acetonitrile; for 24h;Reflux;	A mixture of 4-bromo-6-chloropyridazin-3-amine (30.0 g, 144.0 mmol) and 2-bromo-l- (2-(trifluoromethyl)phenyl)ethanone (96.0 g, 360.0 mmol) in MeCN (1000.0 mL) was refluxed for 24 h. After cooling, the mixture was filtered and the solid was washed with EtOAc. The solid was poured into bicarb, stirred for 1 h and extracted with EtOAc. The organic layers were combined and concentrated in vacuo to give 8-bromo-6-chloro-2-(2- (trifluoromethyl)phenyl)imidazo[l ,2-b]pyridazine (27.0 g, 71.7 mmol, 49.8 % yield). MS (ESI) calcd for Ci3H6BrClF3N3: 374.94.
	In acetonitrile; at 80℃; for 24h;	A mixture of 4-bromo-6-chloropyridazin-3-amine (207.0 mg, 0.99 mmol, 1.0 equiv.) and <strong>[54109-16-9]2-bromo-1-(2-(trifluoromethyl)phenyl)ethan-1-one</strong> (647.7 mg, 2.42 mmol, 2.5 equiv.) in MeCN (6.5 mL) in a sealed vessel was heated to 80C. After 24 h, the mixture was filtered through celite, rinsed with EtOAc, and the filtrate was concentrated in vacuo. Purification by column chromatography (0-100% DCM in hexanes) afforded 8-bromo-6-chloro-2-(2- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine. ES/MS m/z: 377.90 [M+H].

Reference： [1]Patent: WO2013/59594,2013,A1 .Location in patent: Page/Page column 74-75
[2]Patent: WO2021/222522,2021,A1 .Location in patent: Paragraph 0861
[3]Patent: WO2021/222522,2021,A1 .Location in patent: Paragraph 0861

8
[ 446273-59-2 ]
[ 24424-99-5 ]
[ 301221-79-4 ]
[ 1236355-06-8 ]

Yield	Reaction Conditions	Operation in experiment
66%		3-amino-4-bromo-6-chloropyridazine(0. 5g, 2 4mmol.) Was added to 1- (N- tert-butoxycarbonyl - piperidin-4-yl) bromoacetaldehyde (12mml ) ethyl acetate solution 20ml, heated under reflux for 24h, filtered and dried to give a brown solid 0. 64g, was added to the flask containing 50ml of ethanol, was added potassium carbonate 0. 83g, butyl dicarbonate (B0C20) 1. 7g, room temperature reaction 12h. Filtration, column chromatography to obtain a white solid in 66percent yield

Reference： [1]Patent: CN103360399,2016,B .Location in patent: Paragraph 0016; 0123; 0141; 0142; 0143

9
[ 446273-59-2 ]
[ 33142-21-1 ]
ethyl 6-chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1, 2-b]pyridazine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%		To a solution of 4-bromo-6-chloropyridazin-3-amine (175 g, 840 mmol) inethanol (2 L) was added <strong>[33142-21-1]ethyl 2-chloro-3-oxopropanoate</strong> (202 g, 1343 mmol) and thereaction was heated to 80 C for 16 hours. The solvent was removed in vacuo and the residual material was diluted with water and dichloromethane. The biphasic mixture was passed through a celite bed and the filtrate was separated into two layers. The dichloromethane layer was separated and then washed with water and saturated aqueoussodium chloride (brine), it was then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified using silica gel chromatography (0 to 20% ethyl acetate in petroleum ether). The product fractions were dried and then triturated with 10% methyl tert-butyl ether in petroleum ether (500 mL). The product was filtered off and rinsed with petroleum ether to provide la (73 g, 33% yield) as a mixtureof the C8-bromo and C8-chloro species (80:20), the mixture was used as such in the subsequent steps (referred to as the chloride for simplicity).?H NMR (300 MHz, CDC13): Chloro: 8.37 (s, 1H), 7.38 (s, 1H), 4.47 (q, J= 7.2 Hz, 2H), 1.44 (t, J= 7.2 Hz, 3H).Bromo: 8.38 (s, 1H), 7.57 (s, 1H), 4.47 (q, J= 7.2 Hz, 2H), 1.44 (t, J= 7.2 Hz, 3H).LC retention time chloro: 1.04 mm [Bj; bromo: 1.07 [Bj. Mass Spectrometry (?MS?)(E+) m/z: 260 (chloro); 304 (bromo) (MH).; A solution of ethyl 8-chloro-6-chloroimidazo[ 1 ,2-bj pyridazine-3-carboxylate (la)(7.35 g, 28.3 mmol), 1-(4-methoxyphenyl)-N-methylmethanamine (4.74 g, 31.4 mmol)and triethylamine (6.73 mL, 48.3 mmol) in dioxane (75 mL) was heated in an oil bath at 90 C for 2.5 hours. The reaction was cooled to room temperature and concentrated to provide a sludge that was triturated with water to provide a solid which was filtered, rinsed with water and then collected with dichloromethane. The solution was dried overanhydrous sodium sulfate, filtered and concentrated to provide lb (8.95 g, 84% yield). ?HNMR (400MHz, CHLOROFORM-d) 8.13 (s, 1H), 7.17 (d, J=8.6 Hz, 2H), 6.87 (d,J=8.6Hz, 2H), 6.12 (s, 1H), 5.50 (s, 2H), 4.46 (q,J=7.1 Hz, 2H), 3.81 (s, 3H), 3.18 (s,3H), 1.74 - 1.58 (m, 1H), 1.44 (t, J=7.2 Hz, 3H). LC retention time 1.04 mm [Al. MS(E+) m/z: 375 (MJ-L?)

Reference： [1]Patent: WO2018/67432,2018,A1 .Location in patent: Page/Page column 52; 53

10
[ 446273-59-2 ]
[ 598-31-2 ]
[ 1298031-94-3 ]

Yield	Reaction Conditions	Operation in experiment
34%	With sodium carbonate; In isopropyl alcohol; at 90℃; for 16h;	4-Bromo-6-chloropyridazin-3-amine (20 g, 97 mmol), Na2C03 (10.2 g, 97 mmol) and 1- bromopropan-2-one (9.7 mL, 116 mmol) were added into isopropyl alcohol (200 mL). The reaction vessel was degassed and then charged with nitrogen three times. The mixture was stirred at 90 C for 16 h. The mixture was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in petroleum ether to yield 8-bromo-6- chloro-2-methylimidazo[l,2-b]pyridazine (8.1 g, 34%). MS m/z 245.9, 247.9 [M+H]+.

Reference： [1]Patent: WO2018/226622,2018,A1 .Location in patent: Page/Page column 184; 185

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Technical Information

? Alkyl Halide Occurrence ? Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions ? Chan-Lam Coupling Reaction ? General Reactivity ? Grignard Reaction ? Hiyama Cross-Coupling Reaction ? Hydride Reductions ? Kinetics of Alkyl Halides ? Kumada Cross-Coupling Reaction ? Leuckart-Wallach Reaction ? Mannich Reaction ? Petasis Reaction ? Preparation of Amines ? Reactions of Alkyl Halides with Reducing Metals ? Reactions of Amines ? Reactions of Dihalides ? Specialized Acylation Reagents-Vilsmeier Reagent ? Stille Coupling ? Substitution and Elimination Reactions of Alkyl Halides ? Suzuki Coupling ? Ugi Reaction

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[ CAS No. 446273-59-2 ] {[proInfo.proName]}

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Bromides

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Pyridazines

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