[ CAS No. 1286754-14-0 ] {[proInfo.proName]}

Name: 1286754-14-0|Ethyl imidazo[1,2-a]pyrazine-3-carboxylate|97%
Brand: Ambeed
SKU: A338132
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Quality Control of [ 1286754-14-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1286754-14-0 ]

Product Details of [ 1286754-14-0 ]

CAS No. :	1286754-14-0	MDL No. :	MFCD28142909
Formula :	C₉H₉N₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SQLWTMXBSLVISZ-UHFFFAOYSA-N
M.W :	191.19	Pubchem ID :	68011844
Synonyms :

Calculated chemistry of [ 1286754-14-0 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	49.07
TPSA :	56.49 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.59 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.11
Log Po/w (XLOGP3) :	1.24
Log Po/w (WLOGP) :	0.91
Log Po/w (MLOGP) :	-0.2
Log Po/w (SILICOS-IT) :	0.57
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) :	-2.08
Solubility :	1.57 mg/ml ; 0.00824 mol/l
Class :	Soluble
Log S (Ali) :	-2.02
Solubility :	1.81 mg/ml ; 0.00946 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.2
Solubility :	1.21 mg/ml ; 0.00635 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.11

Safety of [ 1286754-14-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1286754-14-0 ]

* 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 [ 1286754-14-0 ]
Downstream synthetic route of [ 1286754-14-0 ]

[ 1286754-14-0 ] Synthesis Path-Upstream 1~2

1
[ 5049-61-6 ]
[ 70-23-5 ]
[ 1286754-14-0 ]

Yield	Reaction Conditions	Operation in experiment
28.9%	at 0 - 30℃; for 4.5 h; Inert atmosphere	Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol). After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0 °C and stirred for 30 minutes until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with ether (10 mLx3). The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9percent) as a brown solid. MS m/z (ESI): 192.1 [M+1]

Reference： [1] Patent: EP2604610, 2013, A1, . Location in patent: Paragraph 0121; 0122

2
[ 5049-61-6 ]
[ 64-17-5 ]
[ 1113-59-3 ]
[ 1286754-14-0 ]

Yield	Reaction Conditions	Operation in experiment
28.9%	Stage #1: at 20 - 30℃; for 4 h; Stage #2: for 4 h; Reflux	Step 1 ethyl imidazo[1,2-c]pyrazine-3-carboxylate Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol). After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0° C. and stirred for 30 minutes until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with ether (10 mL*3). The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9percent) as a brown solid. MS m/z (ESI): 192.1 [M+1]

Reference： [1] Patent: US2013/131068, 2013, A1, . Location in patent: Paragraph 0176; 0177

[ 1286754-14-0 ] Synthesis Path-Downstream 1~16

1
[ 1286754-14-0 ]
[ 1286753-85-2 ]

Yield	Reaction Conditions	Operation in experiment
87.6%	With palladium 10% on activated carbon; hydrogen; In methanol; for 3h;	Ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (550 mg, 2.76 mmol) was dissolved in 30 mL of methanol, followed by addition of Pd-C (10%, 100 mg), and the reactor was purged with hydrogen for three times. After stirring for 3 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxylate 14b (480 mg, yield 87.6%) as a yellow oil. MS m/z (ESI): 196.1 [M+1]
87.6%	With palladium on activated charcoal; hydrogen; In methanol; for 3h;	Step 2 ethyl 5,6,7,8-tetrahydroimidazo[1,2-c]pyrazine-3-carboxylate Ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (550 mg, 2.76 mmol) was dissolved in 30 mL of methanol, followed by addition of Pd-C (10%, 100 mg), and the reactor was purged with hydrogen for three times. After stirring for 3 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain ethyl 5,6,7,8-tetrahydroimidazo[1,2-c]pyrazine-3-carboxylate 14b (480 mg, yield 87.6%) as a yellow oil. MS m/z (ESI): 196.1 [M+1]
75.3%	With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; at 35℃; for 12h;	The imidazo [1,2 - the a] pyrazine -3 - carboxylic acid ethyl ester (780 mg, 4 . 08 mmol) is dissolved under stirring 20 ml in tetrahydrofuran, then add 10% palladium carbon 400 mg, hydrogen under the protection of the 35 C stirring 12 hours, the reaction to remove the catalyst, concentrated under reduced pressure, column chromatography purification to obtain 5, 6, 7, 8 - tetrahydro imidazo [1,2 - the a] pyrazine -3 - carboxylic acid ethyl ester (600 mg, yield: 75.3%, white solid).

With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In ethanol; ethyl acetate; at 20℃;

To a suspension of <strong>[1286754-14-0]imidazo[1,2-a]pyrazine-3-carboxylic acid ethyl ester</strong> (0.21 g) and a solution of 4 mol/L hydrogen chloride in ethyl acetate (360 muL) in ethanol (3 mL) was added 10% palladium carbon (0.080 g) at room temperature, and the mixture was stirred overnight under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added tetrahydrofuran (3 mL), triethylamine (460 muL) and benzyloxycarbonyl chloride (250 muL), and the mixture was stirred overnight at room temperature. To the reaction mixture were added water and a saturated aqueous solution of sodium bicarbonate, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluent:ethyl acetate/n-hexane=60/40 to 85/15) to afford 5,6-dihydro-8H-imidazo[1,2-a]pyrazine-3,7-dicarboxylic acid 7-benzyl-3-ethyl ester (0.16 g). To a solution of 5,6-dihydro-8H-imidazo[1,2-a]pyrazine-3,7-dicarboxylic acid 7-benzyl-3-ethyl ester (0.16 g) in ethanol (3 mL) was added an aqueous solution of 2 mol/L sodium hydroxide (315 muL). The mixture was stirred for 30 minutes under reflux, and allowed to cool to room temperature. To the mixture was added 2 mol/L hydrochloric acid (315 muL), and concentrated under reduced pressure to afford 5,6-dihydro-8H-imidazo[1,2-a]pyrazine-3,7-dicarboxylic acid 7-benzyl ester (0.146 g). To a solution of (R)-6-chloro-4-fluoroindan-1-ylamine hydrochloride (0.108 g) and triethylamine (0.049 g) in methanol (2 mL) was added benzaldehyde (0.052 g), and the mixture was stirred for 30 minutes at 65 C. The reaction mixture was allowed to cool to room temperature. To the mixture were added 5,6-dihydro-8H-imidazo[1,2-a]pyrazine-3,7-dicarboxylic acid 7-benzyl ester (0.146 g) and 4-phenylcyclohexen-1-ylisocyanide (0.089 g). The mixture was stirred overnight at 65 C., then allowed to cool to room temperature, and concentrated under reduced pressure. To the obtained residue were added tetrahydrofuran (4 mL), water (100 muL) and a solution of 4 mol/L hydrogen chloride in 1,4-dioxane (500 muL), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture were added water and a saturated aqueous solution of sodium bicarbonate, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluent: methanol/ethyl acetate=4/96) to afford 3-{N--[(R)-carbamoylphenylmethyl]-N--[(R)-6-chloro-4-fluoroindan-1-yl]car- bamoyl}-5,6-dihydro-8H-imidazo[1,2-a]pyrazine-7-carboxylic acid benzyl ester (0.038 g) as a low polarity diastereomer. To a suspension of 3-{N--[(R)-carbamoylphenylmethyl]-N--[(R)-6-chloro-4-fluoroindan-1-yl]car- bamoyl}-5,6-dihydro-8H-imidazo[1,2-a]pyrazine-7-carboxylic acid benzyl ester (0.038 g) in tetrahydrofuran (3 mL) was added 10% palladium carbon (0.020 g) at room temperature, and the mixture was stirred for a day under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: methanol/ethyl acetate=0/100 to 20/80) to afford the title compound (0.23 g).

Reference： [1]Patent: EP2604610,2013,A1 .Location in patent: Paragraph 0121; 0123
[2]Patent: US2013/131068,2013,A1 .Location in patent: Paragraph 0178; 079
[3]Patent: CN106478631,2017,A .Location in patent: Paragraph 0152
[4]Patent: CN105263901,2016,A .Location in patent: Page/Page column 104; 105

2
[ 1286754-14-0 ]
[ 1358715-08-8 ]

Reference： [1]Patent: EP2604610,2013,A1
[2]Patent: US2013/131068,2013,A1

3
[ 5049-61-6 ]
[ 70-23-5 ]
[ 1286754-14-0 ]

Yield	Reaction Conditions	Operation in experiment
28.9%	In methanol; 1,2-dimethoxyethane; at 0 - 30℃; for 4.5h;Inert atmosphere;	Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol). After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0 C and stirred for 30 minutes until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with ether (10 mLx3). The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9%) as a brown solid. MS m/z (ESI): 192.1 [M+1]

Reference： [1]Patent: EP2604610,2013,A1 .Location in patent: Paragraph 0121; 0122

4
[ 5049-61-6 ]
[ 64-17-5 ]
[ 1113-59-3 ]
[ 1286754-14-0 ]

Yield	Reaction Conditions	Operation in experiment
28.9%		Step 1 ethyl imidazo[1,2-c]pyrazine-3-carboxylate Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol). After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0 C. and stirred for 30 minutes until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with ether (10 mL*3). The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9%) as a brown solid. MS m/z (ESI): 192.1 [M+1]

Reference： [1]Patent: US2013/131068,2013,A1 .Location in patent: Paragraph 0176; 0177

5
[ 1286754-14-0 ]
5,6-dihydro-8H-imidazo[1,2-a]pyrazine-3,7-dicarboxylic acid 7-benzyl ester [ No CAS ]

Reference： [1]Patent: US2016/115119,2016,A1
[2]Patent: CN105263901,2016,A

6
[ 1286754-14-0 ]
3-{N-[(R)-carbamoylphenylmethyl]-N-[(R)-6-chloro-4-fluoroindan-1-yl]carbamoyl}-5,6-dihydro-8H-imidazo[1,2-a]pyrazine-7-carboxylic acid benzyl ester [ No CAS ]

Reference： [1]Patent: US2016/115119,2016,A1
[2]Patent: CN105263901,2016,A

7
[ 1286754-14-0 ]
N-[(R)-carbamoylphenylmethyl]-N-[(R)-6-chloro-4-fluoroindan-1-yl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide [ No CAS ]

Reference： [1]Patent: US2016/115119,2016,A1
[2]Patent: CN105263901,2016,A

8
[ 1286754-14-0 ]
[ 501-53-1 ]
5,6-dihydro-8H-imidazo[1,2-a]pyrazine-3,7-dicarboxylic acid 7-benzyl-3-ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.16 g		Example 17 N-[(R)-Carbamoylphenylmethyl]-N-[(R)-6-chloro-4-fluoroindan-1-yl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide To a suspension of <strong>[1286754-14-0]imidazo[1,2-a]pyrazine-3-carboxylic acid ethyl ester</strong> (0.21 g) and a solution of 4 mol/L hydrogen chloride in ethyl acetate (360 muL) in ethanol (3 mL) was added 10% palladium carbon (0.080 g) at room temperature, and the mixture was stirred overnight under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added tetrahydrofuran (3 mL), triethylamine (460 muL) and benzyloxycarbonyl chloride (250 muL), and the mixture was stirred overnight at room temperature. To the reaction mixture were added water and a saturated aqueous solution of sodium bicarbonate, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluent:ethyl acetate/n-hexane=60/40 to 85/15) to afford 5,6-dihydro-8H-imidazo[1,2-a]pyrazine-3,7-dicarboxylic acid 7-benzyl-3-ethyl ester (0.16 g).

Reference： [1]Patent: US2016/115119,2016,A1 .Location in patent: Paragraph 1409-1412

9
[ 1286754-14-0 ]
7-acetyl-N-[(R)-carbamoylphenylmethyl]-N-[(R)-6-chloro-4-fluoroindan-1-yl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide [ No CAS ]