[ CAS No. 221295-04-1 ] {[proInfo.proName]}

Name: 221295-04-1|5-Bromopyrazine-2-carbonitrile|97%
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Quality Control of [ 221295-04-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 221295-04-1 ]

Product Details of [ 221295-04-1 ]

CAS No. :	221295-04-1	MDL No. :	MFCD09909652
Formula :	C₅H₂BrN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZPBNABIKZKTQQH-UHFFFAOYSA-N
M.W :	183.99	Pubchem ID :	37818722
Synonyms :

Calculated chemistry of [ 221295-04-1 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	34.45
TPSA :	49.57 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) :	-6.73 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.25
Log Po/w (XLOGP3) :	0.98
Log Po/w (WLOGP) :	1.11
Log Po/w (MLOGP) :	-0.66
Log Po/w (SILICOS-IT) :	1.58
Consensus Log Po/w :	0.85

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.09
Solubility :	1.49 mg/ml ; 0.0081 mol/l
Class :	Soluble
Log S (Ali) :	-1.61
Solubility :	4.53 mg/ml ; 0.0246 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.59
Solubility :	0.472 mg/ml ; 0.00256 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.25

Safety of [ 221295-04-1 ]

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

Application In Synthesis of [ 221295-04-1 ]

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

Upstream synthesis route of [ 221295-04-1 ]
Downstream synthetic route of [ 221295-04-1 ]

[ 221295-04-1 ] Synthesis Path-Upstream 1~2

1
[ 221295-04-1 ]
[ 36070-84-5 ]

Reference： [1] Patent: WO2011/17125, 2011, A1, . Location in patent: Page/Page column 238

2
[ 113305-94-5 ]
[ 221295-04-1 ]

Yield	Reaction Conditions	Operation in experiment
49%	With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 60℃; for 1 h;	ii) 5-Aminopyrazine-2-carbonitrile (0.208 mmol) in acetonitrile (1 mL) was added portionwise to a stirred solution of copper (II) bromide (0.25 mmol) and t-butylnitrite (0.31 mmol) in acetonitrile (2 mL) and the reaction mixture was maintained at 60 ° C. for 1 h. The reaction was diluted with ethyl acetate (15 mL) and washed twice with 1N HCl (aqueous). Purification was done by chromatography (silica, hexane; ethyl acetate) to yield the title compound (49percent). ¹H NMR (CDCl₃) δ (ppm): 8.83 (s, 1H); 8.71 (s, 1H).

Reference： [1] Patent: US2007/37820, 2007, A1, . Location in patent: Page/Page column 15

[ 221295-04-1 ] Synthesis Path-Downstream 1~65

1
[ 113305-94-5 ]
[ 221295-04-1 ]

Yield	Reaction Conditions	Operation in experiment
49%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 60℃; for 1h;	ii) 5-Aminopyrazine-2-carbonitrile (0.208 mmol) in acetonitrile (1 mL) was added portionwise to a stirred solution of copper (II) bromide (0.25 mmol) and t-butylnitrite (0.31 mmol) in acetonitrile (2 mL) and the reaction mixture was maintained at 60 C. for 1 h. The reaction was diluted with ethyl acetate (15 mL) and washed twice with 1N HCl (aqueous). Purification was done by chromatography (silica, hexane; ethyl acetate) to yield the title compound (49%). 1H NMR (CDCl3) delta (ppm): 8.83 (s, 1H); 8.71 (s, 1H).

Reference： [1]Patent: US2007/37820,2007,A1 .Location in patent: Page/Page column 15

2
[ 221295-04-1 ]
[ 57260-71-6 ]
[ 925940-88-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In N,N-dimethyl-formamide; at 85℃; for 4h;	GENERAL PROCEDURE B: Amination of Heteroaryl Halides; i) BOC-Piperazine (2.4 mmol), 5-bromopyrimidine-4-carbonitrile (2 mmol), potassium carbonate (2.8 mmol), 2-dicyclohexylphosphino-2',4',6'triisopropyl-biphenyl (0.16 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.04 mmol) were dissolved in NMP (N-Methylpyrrolidinone) (5 mL) and stirred for 10 min at 200 C. The cooled mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried, filtered and concentrated, then chromatography in 20-50% ethyl acetate in hexane yielded the desired BOC-protected intermediate. Note: The same procedure was used to prepare tert-butyl 4-(5-cyanopyrazin-2-yl)piperazine-1-carboxylate from <strong>[221295-04-1]5-bromopyrazine-2-carbonitrile</strong> except that the reaction was carried out in DMF for 4 h. at 85 C.
58%	With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In 1-methyl-pyrrolidin-2-one; at 20 - 200℃; for 0.333333h;	To a stirred solution of <strong>[221295-04-1]5-bromopyrazine-2-carbonitrile</strong> (350 mg, 1.90 mmol) in NMP (4 mL),tert-butyl piperazine-1-carboxylate (424 mg, 2.28 mmol), Pd2(dba)3 (35 mg, 0.04 mmol), XPhos(72 mg, 0.152 mmol) and K2C03 (367 mg, 2.66 mmol) was added at RT. The reactionmixture was heated at 200 C for 20 min (TLC indicated complete consumption of thestarting material). After completion of reaction, the reaction mixture was diluted with EtOAc(50 mL), washed with cold water (2 x 20 mL), the organic layer was dried over Na2S04 andconcentrated under reduced pressure to give the crude compound. The crude material waspurified by flash chromatography (100-200 silica gel, 5 g, 30% EtOAc-Hexane) to providetert-butyl 4-(5-cyanopyrazin-2-yl)piperazine-1-carboxylate (320 mg, 58%) as a white solid.LCMS: m/z: 290.61 [M+Ht.

Reference： [1]Patent: US2007/37820,2007,A1 .Location in patent: Page/Page column 15
[2]Patent: WO2018/125961,2018,A1 .Location in patent: Page/Page column 95

3
[ 221295-04-1 ]
[ 1137476-11-9 ]
[ 1137476-13-1 ]

Yield	Reaction Conditions	Operation in experiment
20%		5-Chloro-4-morpholinopyridin-2-amine (68 mg, 0.31 mmol), <strong>[221295-04-1]4-bromo-cyanopyrazine</strong> (30 mg, 0.20 mmol), sodium te/f-butoxide (45 mg, 0.47 mmol), Pd(OAc)2 (3 mg, 0.01 mmol) and BINAP (0.030 g, 0.05 mmol) were mixed under argon atmosphere before addition of mixture of DMF in toluene (2:1 , 0.7 mL). The reaction mixture was heated to 1400C by microwave irradiation for 20 minutes. The reaction mixture was purified by ion exchange chromatography on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated. Flash chromoatography on silica, eluting with ethyl acetate - hexane (1:1) gave 5-(5- chloro-4-morpholinopyridin-2-ylamino)pyrazine-2-carbonitrile as a yellow solid (20 mg, 20%).1H NMR (500 MHz, (CD3)2CO) delta 3.14-3.16 (4H, m), 3.76-3.79 (4H, m), 7.52 (1H, s), 8.22 (1H, s), 8.77 (1 H, s), 9.02 (1H1 s), 10.77 (1H, s). LCMS (3) Rt 4.55 min; m/z (ESI+) 317 (MH+).

Reference： [1]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 168

4
[ 221295-04-1 ]
[ 1137477-48-5 ]
[ 1137477-49-6 ]

Yield	Reaction Conditions	Operation in experiment
30%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 20 - 90℃; for 0.666667h;Microwave irradiation;	A solution of 5-chloro-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine (0.080 g, 0.33 mmol), 2-bromo-cyanopyrazine (0.040 g, 0.22 mmol), BINAP (0.005 g, 0.02 mmol), sodium ferf-butoxide (0.030 g, 0.31 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.009 g, 0.01 mmol) in dioxane (1.6 mL) was stirred at r.t. under nitrogen for 10 min before being heated under microwave irradiation for 30 min at 90 0C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) <n="223"/>eluting with methanol / dichloromethane (1 / 1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by preparative thin layer chromatography eluting with methanol / dichloromethane (1 / 9) to give the title compound as a yellow solid (0.023 g, 30%).1H NMR (MeOD-d4, 500 MHz) delta 8.94 (s, 1H), 8.57 (s, 1 H), 7.96 (s, 1 H), 7.18 (s, 1 H), 3.53-3.47 (m, 1H), 3.00-2.98 (m, 2H), 2.40 (s, 3H), 2.38-2.35 (m, 2H), 2.13-2.09 (m, 2H), 1.75-1.67 (m, 2H). LC-MS (3B) Rt = 0.67 min; m/z (ESI+) 344 [MH+].

Reference： [1]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 220-221

5
[ 221295-04-1 ]
[ 1137477-54-3 ]
[ 1137477-56-5 ]

Yield	Reaction Conditions	Operation in experiment
7%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 20 - 90℃; for 6h;	A solution of 5-bromo-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine (0.02O g, 0.070 mmol), 2-bromo-cyanopyrazine (0.013 g, 0.070 mmol), BINAP (0.002 g, 0.005 mmol), sodium tert-butoxide (0.009 g, 0.098 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.003 g, 0.003 mmol) in dioxane (0.5 ml_ was stirred at r.t. under nitrogen for 10 min before being heated for 6 h at 90 0C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) eluting with methanol / dichloromethane (1 / 1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by preparative thin layer chromatography eluting with methanol / dichloromethane (1 / 9) to give the title compound as a yellow solid (0.002 g, 7%).1H NMR (MeOD-d4, 500 MHz) delta 8.87 (s, 1H), 8.60 (s, 1H), 8.12 (s, 1H), 7.31 (s, 1H), 3.86-3.77 (m, 1H), 3.61-3.56 (m, 2H), 2.94 (s, 3H), 2.37-2.31 (m, 2H), 2.03-1.91 (m, 2H), 1.30-1.28 (m, 2H). LCMS (4) Rt = 1.06 min; m/z (ESI+) 387 [MH+].

Reference： [1]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 223

6
[ 221295-04-1 ]
[ 1137477-57-6 ]
[ 1137477-58-7 ]

Yield	Reaction Conditions	Operation in experiment
17%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 20 - 90℃; for 0.666667h;Microwave irradiation;	A solution of N4-(1-methylpiperidin-4-yl)-5-phenylpyridine-2,4-diamine (0.050 g, 0.17 mmol), <strong>[221295-04-1]2-bromo-5-cyanopyrazine</strong> (0.022 g, 0.12 mmol), BINAP (0.003 g, 0.01 mmol), sodium terf-butoxide (0.016 g, 0.16 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.005 g, 0.01 mmol) in toluene (0.7 mL) was stirred at r.t. under nitrogen for 10 min before being heated under microwave irradiation for 30 min at 90 0C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (0.5 g) eluting with methanol / dichloromethane (1 / 1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by preparative thin layer chromatography eluting with methanol / dichloromethane (1 / 9) to give the desired compound as a yellow solid (0.008 g, 17%).1H NMR (500 MHz, MeOD-d4) delta 8.73 (d, 1 H, J =1.2 Hz), 8.63 (d, 1 H, J =1.2 Hz), 7.78 (s, 1H), 7.60-7.46 (m, 5H), 6.89 (s, 1H), 4.06-4.00 (m, 1H), 3.62-3.59 (m, 2H), 3.36-3.30 (m, 2H), 2.91 (s, 3H), 2.31-2.28 (m, 2H), 1.96-1.88 (m, 2H). LCMS (3B) Rt = 1.61 min; m/z (ESI+) 386 [MH+].

Reference： [1]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 224

7
[ 221295-04-1 ]
[ 1137477-72-5 ]
[ 1137477-73-6 ]

Yield	Reaction Conditions	Operation in experiment
20%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In Dimethyl ether; at 100℃; for 1.08333h;Microwave irradiation;	Dry DME (402 muL) was added to a mixture of tert-butyl 4-(2-amino-5-(4- methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate (16 mg, 0.040 mmol), 5- bromopyrazine-2-carbonitrile (7.39 mg, 0.040 mmol), xantphos (1.859 mg, 3.21 mumol), tris(dibenzylideneacetone)dipalladium(0) (1.471 mg, 1.606 mumol), and cesium carbonate (26.2 mg, 0.080 mmol) in a nitrogen purged, sealed microwave vial. Nitrogen gas was <n="234"/>bubbled through the mixture for 5 min. The reaction mixture was heated for 1 hr at 100 0C by microwave irradiation. Upon cooling the mixture was diluted with MeOH and purified by ion exchange on lsolute SCX Il acidic resin (5 g), eluting with MeOH. The eluent was concentrated and further purified by preparative thin layer chromatography, eluting with 7% MeOH, 1% NH3, 92% DCM, to give 5-(5-(4-methoxyphenyl)-4-(1-methylpiperidin-4- ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (4 mg, 7.97 mumol, 20 % yield) as a light yellow powder.1H NMR (500 MHz, CDCI3) delta 8.83 (s, 1H), 8.46 (s, 1H), 7.77 (s, 1 H), 7.29 (d, 2H, J = 8.5 Hz), 7.15 (s, 1 H), 7.05 (d, 2H, J = 8.5 Hz), 4.62 (d, 1 H, J = 7.0 Hz), 4.05-3.94 (m, 2H),3.90 (s, 3H), 3.65-3.55 (m, 1 H), 3.08-2.97 (m, 2H), 2.08-2.00 (d, 2H, J = 12.5 Hz), 1.43 (s, 9H), 1.43-1.32 (m, 2H). LCMS (4) Rt = 2.36 min; m/z (ESI+) 502 (MH+).

Reference： [1]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 231-232

8
[ 221295-04-1 ]
[ 1137477-77-0 ]
[ 1137477-78-1 ]

Yield	Reaction Conditions	Operation in experiment
3%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 20 - 90℃; for 0.666667h;Microwave irradiation;	A solution of (E)-5-(3-methoxyprop-1-enyl)-N4-(1-methylpiperidin-4-yl)pyridine-2,4- diamine (0.090 g, 0.32 mmol), 2-bromo-cyanopyrazine (0.060 g, 0.32 mmol), BINAP (0.007 g, 0.02 mmol), sodium terf-butoxide (0.043 g, 0.45 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.013 g, 0.01 mmol) in dioxane (3 ml_) was stirred at room temperature under nitrogen for 10 min, then heated for 30 min at 90 0C under microwave irradiation. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) eluting with methanol / dichloromethane (1 / 1 ), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by preparative thin layer chromatography, eluting with methanol / dichloromethane (1 / 9), to give the title compound as a yellow solid (0.004 g, 3%). <n="236"/>1H NMR (CDCI3, 500 MHz) delta 8.81 (s, 1 H), 8.76 (s, 1 H), 8.44 (m, 1 H), 7.93 (s, 1 H), 7.02 (s, 1 H), 6.45 (d, 1 H, J = 15.8 Hz)1 6.15 (1 H, dt, J = 15.8, 5.5 Hz), 4.40 (d, 1 H, J = 7.2 Hz), 4.12 (2H, J = 5.5, 1.5 Hz), 3.45 (s, 3H), 2.90-2.88 (m, 2H), 2.37 (s, 3H), 2.23 (t, 2H, J = 11.1 Hz), 2.14-2.11 (m, 2H), 1.66-1.64 (m, 2H). LCMS (4) R, 1.72 min; m/z (ESI+) 380 [MH+].

Reference： [1]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 233-234

9
[ 221295-04-1 ]
[ 1137477-81-6 ]
[ 1137477-83-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 90℃; for 0.583333h;Microwave irradiation;	Dry dioxane (0.45 mL) was added to a microwave reaction vial containing tert-butyl 4-((2- amino-5-chloropyridin-4-ylamino)methyl)piperidine-1 -carboxylate (23 mg, 0.067 mmol), 5- bromopyrazine-2-carbonitrile (8.3 mg, 0.045 mmol), tris(dibenzylideneacetone)- <n="238"/>dipaliadium chloroform complex (1.9 mg, 4 mol%), (+/-)-2,2'-bis(diphenylphosphino)-1 ,1'- binaphthalene (2.2 mg, 8 mol%) and sodium tert-butoxide (6.1 mg, 1.4 eq.) under nitrogen. The vial was sealed and nitrogen gas was bubbled through the suspension with stirring for 5 min. The mixture was heated at 900C for 30 min under microwave irradiation.5 The mixture was diluted with methanol and adsorbed onto lsolute SCX-II acidic resin (2 g). The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were concentrated and the residue was further purified by preparative thin layer chromatography, eluting with 5% MeOH in dichloromethane, to give tert-butyl 4-((5- chloro-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate0 (12mg, 60%) as an off-white solid.1H NMR (500 MHz, CDCI3) delta 8.80 (s, 1H), 8.47 (s, 1H), 8.19 (br s, 1H), 8.00 (s, 1H), 7.09 (s, 1 H), 4.99 (dd, 1 H, J = 5.5, 5.5 Hz), 4.20 (br s, 2H), 3.20 (dd, 2H, J = 6.0, 6.0 Hz), 2.79- 2.69 (m, 2H), 1.91-1.76 (m, 1 H, 2H), 1.48 (s, 9H), 1.31-1.21 (m, 2H). LCMS (4) Rt = 2.21 5 min; m/z (ESI+) 444 (MH+).

Reference： [1]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 235-236

10
[ 221295-04-1 ]
[ 1137477-93-0 ]
[ 1137477-94-1 ]

Yield	Reaction Conditions	Operation in experiment
33%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In Dimethyl ether; at 100℃; for 1.16667h;Microwave irradiation;	Dry DME (0.87 ml_) was added to a microwave reaction vial containing tert-butyl 4-((2-(5- cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)piperidine-1- carboxylate (36 mg, 0.087 mmol), <strong>[221295-04-1]5-bromopyrazine-2-carbonitrile</strong> (19 mg, 0.105 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (3.6 mg, 4 mol%), Xantphos (4.0 mg, 8 mol%) and cesium carbonate (57 mg, 2 eq.) under nitrogen. The vial was sealed and nitrogen was bubbled through the stirred suspension for 10 min. The mixture was heated at 100 0C for 1 hr by microwave irradiation. The mixture was diluted with methanol and adsorbed onto lsolute SCX-II acidic resin (2 g). The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were concentrated and further purified by preparative thin layer chromatography, eluting with 5% MeOH, 0.5% NH3, 94.5% dichloromethane, to give the title compound as a yellow solid (15 mg, 33%).1H NMR (500 MHz, MeOD) delta 8.86 (s, 1 H), 8.55 (s, 1 H), 7.69 (s, 1 H), 7.31 (d, 2H, J = 9.0 Hz), 7.06 (d, 2H, J = 9.0 Hz), 7.01 (s, 1H), 4.13-4.08 (m, 2H), 3.86 (s, 3H), 3.33-3.30 (m, 1 H), 3.11 (d, 2H, J = 7.0 Hz), 2.74 (br s, 2H), 1.94-1.83 (m, 1 H), 1.77-1.69 (m, 2H), 1.46 (s, 9H), 1.19-1.08 (m, 2H). LCMS (4) Rt = 2.22 min; m/z (ESI+) 516 (MH+).

Reference： [1]Patent: WO2009/44162,2009,A1 .Location in patent: Page/Page column 242

11
[ 221295-04-1 ]
[ 1308279-86-8 ]

Reference： [1]Patent: WO2011/79305,2011,A1
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

12
[ 221295-04-1 ]
[ 1308279-80-2 ]

Reference： [1]Patent: WO2011/79305,2011,A1
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

13
[ 221295-04-1 ]
[ 1211534-08-5 ]

Yield	Reaction Conditions	Operation in experiment
28%		The intermediate, ethyl (E)-3-{2-[3-(l-adamantyl)-4-hydroxy]-5-pyrazinyl}-2- propenoate was prepared as follows.; a) 5-Bromo-pyrazine-2-carbaldehyde.; To a solution of 5-cyano-2- bromopyrazine (1.02 g, 5.54 mmol) in anhydrous toluene (15 mL) at -78 C was added 1 M diisobutyl aluminum hydride (8.32 mmol) in CH2C12 (8.3 mL). The reaction mixture was stirred at -78 C for 15 min, warmed to room temperature, stirred for 26 h, and then diluted with MeOH (4 mL) and stirred for 30 min at room temperature before addition of 10% H2S04 (55 mL). The resulting solution was stirred for 1.75 h and extracted with EtOAc (100 mL, 50 mL). After solvent removal at reduced pressure, the residue was chromatographed (1 1% to 14% EtOAc/hexane) to give 289 mg (28%) of 5-bromo-pyrazine-2-carbaldehyde as an orange solid, mp 56-58 C. IR 2960, 1654, 1546, 11 11 cm"1; 1H NMR (CDC13) delta 8.83 (d, J= 1.24 Hz, 1H, 6-PyrH), 8.91 (d, J= 1.24 Hz, 1H, 3-PyrH), 10.13 ppm (s, 1H, CHO). HRMS calcd C5H3BrN20 [M + H]+ 186.9501, found 186.9496.

Reference： [1]Patent: WO2011/79305,2011,A1 .Location in patent: Page/Page column 45
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

14
[ 221295-04-1 ]
[ 1308279-69-7 ]

Reference： [1]Patent: WO2011/79305,2011,A1
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

15
[ 221295-04-1 ]
[ 1308279-74-4 ]

Reference： [1]Patent: WO2011/79305,2011,A1
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

16
[ 221295-04-1 ]
[ 1265357-90-1 ]