[ CAS No. 33332-28-4 ] {[proInfo.proName]}

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2D 3D

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Quality Control of [ 33332-28-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 33332-28-4 ]

SDS Specification

Alternatived Products of [ 33332-28-4 ]

Product Details of [ 33332-28-4 ]

CAS No. :	33332-28-4	MDL No. :	MFCD00055024
Formula :	C₄H₄ClN₃	Boiling Point :	No data available
Linear Structure Formula :	-	InChI Key :	JTPXVCKCLBROOJ-UHFFFAOYSA-N
M.W :	129.55	Pubchem ID :	118458
Synonyms :

Calculated chemistry of [ 33332-28-4 ] Expand+

Physicochemical Properties

Num. heavy atoms :	8
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 :	31.45
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) :	-6.42 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.11
Log Po/w (XLOGP3) :	0.95
Log Po/w (WLOGP) :	0.72
Log Po/w (MLOGP) :	-0.45
Log Po/w (SILICOS-IT) :	0.98
Consensus Log Po/w :	0.66

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.8
Solubility :	2.07 mg/ml ; 0.016 mol/l
Class :	Very soluble
Log S (Ali) :	-1.62
Solubility :	3.07 mg/ml ; 0.0237 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.87
Solubility :	1.74 mg/ml ; 0.0135 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.02

Safety of [ 33332-28-4 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 33332-28-4 ]

* 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 [ 33332-28-4 ]
Downstream synthetic route of [ 33332-28-4 ]

[ 33332-28-4 ] Synthesis Path-Upstream 1~3

1
[ 544-97-8 ]
[ 33332-28-4 ]
[ 5521-56-2 ]

Yield	Reaction Conditions	Operation in experiment
28%	at 105℃; for 16.25 h;	A. 6-Methylpyrazine-2-ylamine. To a solution containing 6-chloro-2- pyrazineamine (5.0 g, 38.75 mmol) in 1,4-dioxane (70 mL) was added [1,3- bis(diphenylphosphino]Ni(II)Cl₂ (2.10 g, 38.76 mmol), followed by drop-wise addition of dimethylzinc in toluene (38.75 mL, 2.0 M, 77.50 mmol), over 15 min. The solution was allowed stir at 105 °C for 16 hours. The solution was then condensed under reduced pressure, diluted with ethyl acetate and filtered through celite to remove the nickel salts. The resultant slurry was purified via Biotage silica gel chromatography (0-8percent methanol in dichloromethane) to afford the title compound as an orange solid (1.18 g, 28percent yield). MS (ESI) m/z 1 10.3 [M+ 1]⁺.

Reference： [1] Tetrahedron Letters, 2006, vol. 47, # 3, p. 341 - 344
[2] Patent: WO2008/51493, 2008, A2, . Location in patent: Page/Page column 101
[3] Patent: WO2008/83070, 2008, A1, . Location in patent: Page/Page column 85
[4] Patent: US2013/210818, 2013, A1, . Location in patent: Paragraph 0390
[5] Patent: WO2009/115486, 2009, A1, . Location in patent: Page/Page column 25-26
[6] Patent: WO2009/115572, 2009, A2, . Location in patent: Page/Page column 117-118
[7] Patent: WO2004/108692, 2004, A1, . Location in patent: Page 37-38

2
[ 75-16-1 ]
[ 33332-28-4 ]
[ 5521-56-2 ]

Reference： [1] Patent: US2015/175616, 2015, A1, . Location in patent: Paragraph 0242; 0243
[2] Patent: WO2015/100217, 2015, A1, . Location in patent: Page/Page column 99
[3] Patent: WO2016/10809, 2016, A1, . Location in patent: Paragraph 0279
[4] Patent: WO2016/172117, 2016, A1, . Location in patent: Page/Page column 32-33

3
[ 33332-28-4 ]
[ 5158-46-3 ]
[ 5521-56-2 ]

Reference： [1] Tetrahedron Letters, 2006, vol. 47, # 3, p. 341 - 344

[ 33332-28-4 ] Synthesis Path-Downstream 1~19

1
[ 4774-14-5 ]
[ 33332-28-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With ammonia; at 100℃; for 5h;	In the hydrothermal reaction kettle are respectively added with 2, 6 - two chlorine pyrrole qin (10.0 g, 67.1 mmol) and ammonia (100 ml), 100 C lower reaction 5 h. The completion of the reaction, cooling to room temperature, filtered, the filter cake is hexane (16 ml) beating shall 2 - amino -6 - chloropyrazine white solid 8.2 g, yield is 95.0%.
91%	With ammonia; In water; at 100℃; for 18h;Sealed tube;	2,6-Dichloropyrazine (2.89 g, 19.4 mmol) was stirred in aqueous NH3 (28%, 10 ml.) and heated to 100C in a sealed tube for 18 hours. The reaction mixture was cooled and the resultant precipitate was filtered. Trituration with water and then ether gave 6- chloropyrazin-2-amine as a white solid (2.28 g, 17.6 mmol, 91 % yield). 1H NMR (d6-DMSO, 400 MHz) ? 6.9 (brs, 2H), 7.70 (d, J = 0.4, 1 H), 7.80 (d, J = 0.4, 1 H); LC-MS (ZQ, 6 minutes) Rt = 1.05 minutes; m/z (ESI+) 130 (M+H).6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in CH2CI2 (60 ml.) at 0C.A/-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0C for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25% EtOAc-hexanes, gave 5-bromo-6-chloropyrazin-2-amine as a yellow solid (1 .69 g, 8.16 mmol, 42% yield). 1H NMR (de-DMSO, 400 MHz) ? 7.1 (brs, 2H), 7.65 (s, 1 H); LC-MS (ZQ, 4 minutes) Rt = 1.46 minutes; m/z (ESI-) 205 (M-H).A mixture of 5-bromo-6-chloropyrazin-2-amine (1 .00 g, 4.8 mmol), copper (I) iodide (914 mg, 4.8 mmol), 18-crown-6 (95 mg, 0.36 mmol) andtetrakis(triphenylphosphine)palladium (0) (83 mg, 0.072 mmol) was suspended in dry DMF (20 ml.) and a stream of nitrogen was passed through for 5 minutes. Potassium cyanide (312 mg, 4.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, then refluxed at 200C for 3 hours. The mixture was cooled, diluted with EtOAc and absorbed onto silica gel (10 g). DMF was removed by evaporation. The product was purified by flash chromatography, eluting with 1 :1 EtOAc-hexanes, to yield 5- amino-3-chloropyrazine-2-carbonitrile as a yellow solid (607 mg, 3.93 mmol, 82% yield). 1H NMR (d6 DMSO, 400 MHz) ? 7.87 (s, 1 H), 8.1 (brs, 2H); LC-MS (ZQ, 4 minutes) Rt = 1.20 minutes; m/z (ESI-) 153 (M-H).
80%	With ammonia; In water; at 135℃;Autoclave;	A solution of compound 8 4500 g, 302 mol) in conc. aq. NH3 (3.0 L) was stirred at135C overnight in a 10 L sealed pressure vessel. TLC and LC/MS showed completeconversion of the starting material. The reaction mixture was cooled to roomtemperature and filtered to afford a white solid. The solid was washed with water (200mL x 3), and then dried to afford compound 9 (312 g, 80% yield) as a solid.1HNMR (400 MHz, DMSO-d6): 7,82 (s, 1 H), 712 (s, 1 H), 6.93 (s, 2H). MS Calcd.:129 MS Found: 130 ([M+Hj).

80%	With ammonium hydroxide; at 135℃;Sealed tube;	A solution of compound 8 (450.0 g, 3.02 mol) in cone. aq. NH3 (3.0 L) was stirred at 135°C overnight in a 10 L sealed pressure vessel. TLC and LC/MS showed complete conversion of the starting material. The reaction mixture was cooled to room temperature and filtered to afford a white solid. The solid was washed with water (200 mL x 3), and then dried to afford compound 9 (312 g, 80percent yield) as a solid. 1HNMR (400 MHz, DMSO- 6): delta 7.82 (s, 1 H), 7.12 (s, 1 H), 6.93 (s, 2H). MS Calcd.: 129 MS Found: 130 ([M+H]+).
63%	With ammonia; In water; at 20 - 140℃; for 63h;In sealed autoclave;	EXAMPLE 5 2-amino-6-chloropyrazine 120 ml of water, 20.8 ml (0.31 mol, 4.6 eq) of an aqueous 28% ammonia solution and 10 g (0.067 mol, 1 eq) of 2,6-dichloropyrazine were successively added to an autoclave reactor. The autoclave was sealed and the mixture heated at 140 C. for 3 h, then left at room temperature for 60 h. The mixture was filtered, the precipitate washed with water, then vacuum dried. The reaction produced 5.4 g of a fine powder (yield: 63%). 1H NMR (CDCl3) delta (ppm): 7.88 (s, 1H, CH); 7.84 (s, 1H, CH); 4.68 (m, 2H, NH2). HPLC: t=1.07 min MS: 130 (MH+) HPLC purity: 100%
60%	With ammonium hydroxide; In water; at 120℃; for 6h;Large scale;	A solution of 2,6-dichloropyrazine (15kg, 1O1.4mol, 1.00 equiv) in water(20 L), ammonia water (25 L, 25 %) was placed in a 100 L pressure tank reactor. The resulting solution was stirred for 6 h at 120C. The reaction progress was monitored by TLC (EA:PE = 1 : 1) until the starting material was consumed, and cooled to room temperature. Thesolids were collected by filtration. The solid was washed with water and dried. The solidwas washed with petroleum ether to remove the unreacted starting materials. The product (7.8kg, purity = 95 %, 60% yield) was obtained as a white solid.
59.7%	With ammonia; In water; at 140℃; for 14h;	Example B-10: Preparation of (2S)-1-(4-(1-isopropyl-3-(5-methyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)-1H- pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-10) <n="80"/>cr Et3NB-10-1 B-10-2 B-10-3Preparation of 6-chloropyrazin-2-amine (B-10-2). B-10-1 B-10-2A mixture of 2,6-dichloropyrazine (300 g, 2 mol) and 28% aq. NH3 (8 L) was stirred at 14O0C in a sealed system for 14 hours. TLC (petroleum ether/EtOAc 3:1 ) indicated complete consumption of starting material. The reaction mixture was extracted with EtOAc (3 L x 3). The combined organic layers were washed with saturated aqueous NaCI (3 L), dried over Na2SO4 and concentrated in vacuo to give crude compound B-10-2, which was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to yield pure compound B-10-2 (410 g, yield: 59.7%) as a white solid.
41.98 g (48%)	In ammonia;	3. 2-Chloro-6-amino-pyrazine A suspension of 2,6-dichloropyrazine (100 g, 0.67 mole, Lancaster) in 0.880 ammonia (500 ml) was stirred and heated at 150 C. in a glass lined autoclave at 20 atm for 16 hrs. The cooled mixture was filtered, washed well with water (200 ml) and dried. The product was recrystallized from chloroform. Yield 41.98 g (48%), M.p. 150-152 C.
	With ammonia; In water; at 100℃;Autoclave;	Svnthesis 2-1-A 6-Chloropyrazin-2-amine 2,6-Dichloropyrazine (2.89 g, 19.4 mmol) was stirred in aqueous ammonia (28%, 10 mL) and heated to 100C overnight in a sealed tube. The reaction mixture was cooled and the resultant precipitate was filtered. Trituration with water and then ether gave the title compound as a white solid (2.28 g, 17.6 mmol, 91%). 1H NMR (d6-DMSO, 400 MHz) delta 7.80 (d, 1 H1 J = 0.4 Hz), 7.70 (d, 1 H, J = 0.4 Hz), 6.9 (br s, 2H). LC-MS (2) rt 1.05 min; m/z (ESI+) 130/132.

Reference： [1]Patent: CN107857737,2018,A .Location in patent: Paragraph 0011-0013; 0021-0023; 0030-0032; 0040-0042; 0049
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 8328 - 8342
[3]Patent: WO2013/68755,2013,A1 .Location in patent: Page/Page column 67, 68
[4]Patent: WO2017/5786,2017,A1 .Location in patent: Page/Page column 23; 24
[5]Patent: WO2018/9424,2018,A1 .Location in patent: Paragraph 00195; 00198-00199
[6]Tetrahedron,1984,vol. 40,p. 5081 - 5088
[7]Patent: US2005/267126,2005,A1 .Location in patent: Page/Page column 10-11
[8]Patent: WO2017/29602,2017,A2 .Location in patent: Paragraph 75; 133; 134
[9]Patent: WO2009/16460,2009,A2 .Location in patent: Page/Page column 78-79
[10]Patent: US6255307,2001,B1
[11]Patent: WO2009/103966,2009,A1 .Location in patent: Page/Page column 88

2
[ 100-39-0 ]
[ 33332-28-4 ]
6-benzyl-pyrazin-2-ylamine [ No CAS ]