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[ CAS No. 33332-29-5 ] {[proInfo.proName]}

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Chemical Structure| 33332-29-5
Chemical Structure| 33332-29-5
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Product Details of [ 33332-29-5 ]

CAS No. :33332-29-5 MDL No. :MFCD03423596
Formula : C4H4ClN3 Boiling Point : -
Linear Structure Formula :- InChI Key :HWCKAMAVEWVBDO-UHFFFAOYSA-N
M.W : 129.55 Pubchem ID :12808419
Synonyms :

Calculated chemistry of [ 33332-29-5 ]

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 Ų

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) : -6.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.17
Log Po/w (XLOGP3) : 0.67
Log Po/w (WLOGP) : 0.72
Log Po/w (MLOGP) : -0.45
Log Po/w (SILICOS-IT) : 0.98
Consensus Log Po/w : 0.62

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.62
Solubility : 3.11 mg/ml ; 0.024 mol/l
Class : Very soluble
Log S (Ali) : -1.33
Solubility : 6.0 mg/ml ; 0.0463 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 : 2.01

Safety of [ 33332-29-5 ]

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

Application In Synthesis of [ 33332-29-5 ]

* 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 [ 33332-29-5 ]
  • Downstream synthetic route of [ 33332-29-5 ]

[ 33332-29-5 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 33332-29-5 ]
  • [ 19745-07-4 ]
YieldReaction ConditionsOperation in experiment
15% With hydrogenchloride; sodium nitrite In water at -10 - 20℃; for 4 h; Step 2:
Synthesis of 2,5-dichloropyrazine
To a stirred solution of 5-chloropyrazin-2-amine (1 g, 7.751 mmol) in conc. HCl (10 mL) was added aq. solution sodium nitrite (1.1 g, 15.89 mmol) at -10° C. over a period of 1 h, stirred for 1 h 0° C. and then at RT for 2 h.
Progress of reaction was monitored by TLC.
After reaction completion reaction mass neutralised with 50percent NaOH solution and extracted with DCM.
The organic layer was dried over sodium sulphate and concentrated under reduced pressure.
Crude was purified by silica gel (100-200 mesh) column chromatography using 2percent ethyl acetate in hexane as eluent to yield 2,5-dichloropyrazine (0.59 g, 15percent) as colourless oil.
MS: 184.1 [M-1]
Reference: [1] Patent: US2017/291910, 2017, A1, . Location in patent: Paragraph 0565-0567
[2] Patent: WO2008/85316, 2008, A1, . Location in patent: Page/Page column 53-54
[3] Patent: WO2005/97778, 2005, A1, . Location in patent: Page/Page column 15
[4] Patent: WO2004/56369, 2004, A1, . Location in patent: Page/Page column 24
[5] Patent: WO2005/123723, 2005, A1, . Location in patent: Page/Page column 11-12
  • 2
  • [ 6863-77-0 ]
  • [ 6863-73-6 ]
  • [ 33332-29-5 ]
  • [ 33332-28-4 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
[2] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
  • 3
  • [ 5049-61-6 ]
  • [ 33332-29-5 ]
YieldReaction ConditionsOperation in experiment
45% With N-chloro-succinimide In chloroform (pre-treated over basic Al2O3) at 70℃; for 0.166667 h; Microwave irradiation (60W) in a sealed tube Method b:; 2-Amino-pyrazine (0.10 g, 1.05 mmol) and NCS (80 mg, 0.60 mmol) were added in a microwave tube with 1.5 mL of the anhydrous CHCl3 and sealed. The tube was placed in the microwave cavity and heated at 70°C for 10 min. (70C10M60W300Psi). After the workup, the crude (0.15 g) was purified by FCC (Hexane/DCM/ AcOEt = 1 :1 :1) to afford 35 mg (yield 45percent) of the product as yellow solid. 1H NMR (270 MHz; d6-DMSO), δ 7.99 (IH, s, H-6), 7.67 (IH, s, H-3), 6.65 (2H, bs, NH2). m/z (EI-MS): 129 (M+), 99, 94 ([M-Cl]+).; When the distilled chloroform used for the reaction was pre-treated over basic Al2O3, the black polymers formed in the reaction decreased dramatically. When NCS was added slowly into the refluxing 2-aminopyrazine, the product was isolated at 26percent. Moreover, when microwave irradiation was used at 70°C for 10 min., the yield reached 45percent (Figure 4)
26% With N-chloro-succinimide In chloroform (pre-treated over basic Al2O3) at 60℃; for 2 h; 5-chloropyrazin-2-amine (P13).; Method a:; In a double necked dry flask equipped with condenser and dropping funnel, under nitrogen flow, were added 2-amino-pyrazine (0.50 g, 5.25 mmol) and 13 mL of anhydrous CHCl3 previously passed on basic Al2O3. This solution was heated at 600C under stirring. A solution of NCS (0.35 g, 2.12 mmol) in 7 mL of the anhydrous CHCl3 was added to the mixture through dropping funnel during 1.5 hr. After another 30 minutes, the reaction was stopped and the solvent evaporated. The residue was <n="14"/>dissolved in methanol and absorbed on silica (2 g). This crude product was purified by FCC (Hexane/DCM/AcOEt = 1 :1:1) to afford 73 mg (yield 26percent) of product as yellow solid.; When the distilled chloroform used for the reaction was pre-treated over basic Al2O3, the black polymers formed in the reaction decreased dramatically. When NCS was added slowly into the refluxing 2-aminopyrazine, the product was isolated at 26percent. Moreover, when microwave irradiation was used at 70°C for 10 min., the yield reached 45percent (Figure 4)
22% With N-chloro-succinimide In dichloromethane for 5 h; Heating / reflux A 250ml round bottom flask was charged with 2-aminopyrazine (1Og, O.lmol), N-chlorosuccinimide (14g, O.lmol) and dichloromethane (100ml) under nitrogen. The reaction mixture was refluxed for 5h, then allowed to cool to room temperature. The reaction mixture was filtered though a 1 cm thick celite pad, which was then thoroughly washed with dichloromethane. The EPO <DP n="21"/>organic was concentrated in vacuo and the compound was purified by flash chromatography, using as eluent pentane/EtOAc 0percent to 50percent, to give the title compound (3g, 22percent). IHNMR (CDCl3) 4.5-4.8 (2H, brs), 7.8 (IH, s), 8.0 (IH, s).
15% With N-chloro-succinimide In dichloromethane at 40℃; for 2 h; Inert atmosphere Step 1:
Synthesis of 5-chloropyrazin-2-amine
To a stirred solution of pyrazin-2-amine (3 g, 31.545 mmol) in anhydrous DCM (30 mL) was added NCS (4.2 g, 30.545 mmol) under nitrogen and stirred at 40° C. for 2 h.
Progress of reaction was monitored by TLC.
After reaction completion DCM was added and washed with water.
The organic layer was dried over sodium sulphate and concentrated under reduced pressure.
Crude was purified by silica gel (100-200 mesh) column chromatography using 20percent ethyl acetate in hexane as eluent to yield 5-chloropyrazin-2-amine (0.59 g, 15percent) as yellow solid.
MS: 242.08 [M++1]
8.2% With N-chloro-succinimide In dichloromethane at 0℃; for 24 h; [0383] A solution of 2-aminopyrazine (23.86 g, 0.2509 mol) in methylene chloride (420 mL) was cooled to 0° C. and then treated with N-chlorosuccinimide (33.50 g, 0.2509 mol). The reaction mixture was stirred at 0° C. for 24 h. The resulting dark reaction mixture was diluted with water (500 mL) and then concentrated in vacuo to remove methylene chloride. The aqueous layer was continuously extracted with ethyl acetate until product was absence from the aqueous layer as determined by thin layer chromatography. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 25percent ethyl acetate/hexanes) afforded 2-amino-5-chloropyrazine (2.66 g, 8.2percent) as a yellow solid: mp 126-128° C.; EI-HRMS m/e calcd for C4H4ClN3 (M+) 129.0094, found 129.0090. [0384] A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 200 mg, 0.56 mmol) and triphenylphosphine (192 mg, 0.73 mmol) in methylene chloride (4.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (128 mg, 0.73 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-chloropyrazine (145 mg, 1.12 mmol) and 2,6-lutidine (0.28 mL, 2.24 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10percent aqueous hydrochloric acid solution (1.x.20 mL), a saturated aqueous sodium bicarbonate solution (1.x.20 mL) and water (1.x.20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 13/7 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (137 mg, 52percent) as a light yellow foam: [α]23589=-27.35° (c=0.49, chloroform); EI-HRMS m/e calcd for C20H21Cl2N3O4S (M+H)+ 470.0703, found 470.0705.

Reference: [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 36, p. 5937 - 5940
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 19, p. 4746 - 4758
[3] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 12; 27
[4] Journal of Heterocyclic Chemistry, 1982, vol. 19, # 3, p. 673 - 674
[5] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 11-12; 27
[6] Patent: WO2006/58074, 2006, A1, . Location in patent: Page/Page column 19-20
[7] Patent: US2017/291910, 2017, A1, . Location in patent: Paragraph 0562-0564
[8] Patent: US2003/225283, 2003, A1, . Location in patent: Page 49-50
[9] Australian Journal of Chemistry, 1992, vol. 45, # 5, p. 877 - 888
[10] Patent: WO2008/85316, 2008, A1, . Location in patent: Page/Page column 53
[11] Patent: WO2005/97778, 2005, A1, . Location in patent: Page/Page column 15
[12] Patent: WO2004/56369, 2004, A1, . Location in patent: Page/Page column 24
[13] Patent: WO2005/123723, 2005, A1, . Location in patent: Page/Page column 11
  • 4
  • [ 475641-50-0 ]
  • [ 33332-29-5 ]
Reference: [1] Synlett, 2002, # 7, p. 1093 - 1096
[2] Journal of Organic Chemistry, 2008, vol. 73, # 22, p. 8800 - 8807
  • 5
  • [ 1458-03-3 ]
  • [ 33332-29-5 ]
Reference: [1] Patent: US5866568, 1999, A,
  • 6
  • [ 5424-01-1 ]
  • [ 16298-03-6 ]
  • [ 20667-76-9 ]
  • [ 33332-29-5 ]
Reference: [1] Patent: US4293552, 1981, A,
  • 7
  • [ 5049-61-6 ]
  • [ 33332-29-5 ]
  • [ 873-42-7 ]
YieldReaction ConditionsOperation in experiment
4% With N-chloro-succinimide In chloroform for 2 h; Heating / reflux Initial attempt showed that the reaction gave a lot of black polymers after a few <n="29"/>min., with the main product being 3,5-dichloro-2-amino pyrazine. Only small amount of 5- chloro-2-aminopyrazine was isolated (eq 7). This reaction could not be scaled up because it was not reproducible.
Reference: [1] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 26-27
  • 8
  • [ 6863-77-0 ]
  • [ 6863-73-6 ]
  • [ 33332-29-5 ]
  • [ 33332-28-4 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
[2] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
  • 9
  • [ 6863-77-0 ]
  • [ 6863-73-6 ]
  • [ 33332-29-5 ]
  • [ 33332-28-4 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
[2] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
  • 10
  • [ 124-41-4 ]
  • [ 33332-29-5 ]
  • [ 54013-07-9 ]
YieldReaction ConditionsOperation in experiment
67% With copper In methanol at 150℃; for 24 h; Sealed tube General procedure: To a solution of 5-chloropyrazin-2-amine (0.2 g, 1.54 mmol) in MeOH (3 mL) was added Cu powder (0.13 g, 2.07 mmol), followed by a solution of sodium methoxide in MeOH (0.38 mL, 1.75 mmol). The reaction mixture was stirred at 150°C in a sealed tube for 24 h. The reaction mixture was then filtered through Celite, and the filtrate was concentrated in vacuo. The crude product obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3percent) to afford the title compound (0.13 g, 67percent). LCMS (ES+) 126 (M+H)+, RT 1.06 minutes (method 1).
67% With copper In methanol at 150℃; for 24 h; Sealed tube Intermediate 22 5-Methoxypyrazin-2-amine [0242] To a solution of 5-chloropyrazin-2-amine (0.2 g, 1.54 mmol) in MeOH (3 mL) was added Cu powder (0.13 g, 2.07 mmol), followed by a solution of sodium methoxide in MeOH (0.38 mL, 1.75 mmol). The reaction mixture was stirred at 150° C. in a sealed tube for 24 h. The reaction mixture was then filtered through Celite, and the filtrate was concentrated in vacuo. The crude product obtained was purified by column chromatography (silica: 100-200 mesh, MeOH: DCM 2-3percent) to afford the title compound (0.13 g, 67percent). LCMS (ES+) 126 (M+H)+, RT 1.06 minutes (method 1).
Reference: [1] Patent: WO2013/68458, 2013, A1, . Location in patent: Page/Page column 45
[2] Patent: US2014/315885, 2014, A1, . Location in patent: Paragraph 0242
  • 11
  • [ 5049-61-6 ]
  • [ 33332-29-5 ]
  • [ 873-42-7 ]
YieldReaction ConditionsOperation in experiment
4% With N-chloro-succinimide In chloroform for 2 h; Heating / reflux Initial attempt showed that the reaction gave a lot of black polymers after a few <n="29"/>min., with the main product being 3,5-dichloro-2-amino pyrazine. Only small amount of 5- chloro-2-aminopyrazine was isolated (eq 7). This reaction could not be scaled up because it was not reproducible.
Reference: [1] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 26-27
  • 12
  • [ 33332-29-5 ]
  • [ 2032-35-1 ]
  • [ 76537-23-0 ]
YieldReaction ConditionsOperation in experiment
49.75% With hydrogen bromide In isopropyl alcohol at 80℃; compound 5-a (2.6g, 20mmol), 2- bromo-1,1-diethoxyethane (12.0g, 60.89mmol) was dissolved in 30ml isopropanol was then added a solution of hydrogen bromide (10.5g, 62.22mmol), 80 deg. C stirred overnight. Completion of the reaction, cooled to room temperature, adjusted to pH 8 sodium hydrogen carbonate, extracted with dichloromethane, the combined organic phases separated, concentrated under reduced pressure to give a crude product which, by Combi-flash chromatography [DCM: MeOH = 90: 10 ~ 70: 30 ] to give a brown solid compound 16-b (2.3g), was used directly in the next reaction. Yield: 49.75percent, purity 96.63percent.
Reference: [1] Patent: CN105524068, 2016, A, . Location in patent: Paragraph 0286; 0287
[2] Journal of Medicinal Chemistry, 1983, vol. 26, # 3, p. 357 - 363
  • 13
  • [ 107-20-0 ]
  • [ 33332-29-5 ]
  • [ 76537-23-0 ]
YieldReaction ConditionsOperation in experiment
33% at 100℃; for 16 h; To a solution of 5-chloropyrazin-2-amine (2.5 g, 19.3 mmol) in IPA (25 mL) was added 2-chloroacetaldehyde (5.68 g, 28.95 mmol). The resulting mixture was stirred at 100 °C for 16 hours to give a black suspension. The reaction solution was cooled to room temperature and concentrated to give a residue. The residue was dissolved in EtOAc (150 mL) and K2C03 aqueous (60 mL). After separatation, the organic layer was washed with brine (50 mL x 2), dried over anhydrous Na2504, filtered and concentrated to give a crude product. The crudeproduct was purified by silica gel column with EtOAc in PE = (10percent to 50percent) to give 6- chloroimidazo[1,2-alpyrazine (1000 mg, 33percent yield) as a solid. ‘H NMR (400 MHz, CDC13) ö11 8.94 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 7.73 (s, 1H). LCMS R = 0.174 mm in 1.5 mm chromatography, MS ESI calcd. for C6H5C1N3 [M+H1 154.0, found 153.8.
Reference: [1] Patent: WO2018/98500, 2018, A1, . Location in patent: Page/Page column 93; 94; 124
  • 14
  • [ 33332-29-5 ]
  • [ 76537-18-3 ]
YieldReaction ConditionsOperation in experiment
62% With N-Bromosuccinimide In dichloromethane for 1 h; Heating / reflux A 250ml round bottom flask was charged with 5-chloro-pyrazin-2-ylamine (1) (3g, 23mmol, N-bromosuccinimide (4g, 23mmol) and dichloromethane (100ml) under nitrogen. The reaction mixture was refluxed for Ih, then allowed to cool to room temperature and concentrated in vacuo. The compound was purified by flash chromatography, using as eluent pentane/EtOAc 0percent to 50percent, to give the title compound (3g, 62percent). IH NMR (DMSo- d6) 6.8-6.9 (2H, brs), 8.0 (IH, s). MS(ES+): 210, 212.
600 mg With N-Bromosuccinimide In dichloromethane at 40℃; for 1 h; To a solution of 5-chloropyrazin-2-amine (500 mg, 3.86 mmol) in DCM (5mL) was added NBS (686.92 mg, 3.86 mmol), and the brown mixture was stirred at 40 C for 1 hour. After cooling to r.t., the mixture was filtered through silica gel and eluted with EtOAc (20 mL x 3), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20percent to 40percent to 50percent) to give the product (600 mg) as a solid. *H NMR (400MHz, CDC13 ) __ = 7.98 (s, 1H), 5.05 (br s, 2H).
Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 6, p. 996 - 1004
[2] Patent: WO2006/58074, 2006, A1, . Location in patent: Page/Page column 20
[3] Patent: US5866568, 1999, A,
[4] Patent: US5668137, 1997, A,
[5] Patent: WO2018/98499, 2018, A1, . Location in patent: Page/Page column 283
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