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HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 14508-49-7 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
6
[ 6863-76-9 ]
[ 14508-49-7 ]
[ 19745-07-4 ]
[ 4858-85-9 ]
[ 4774-14-5 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
7
[ 290-37-9 ]
[ 7732-18-5 ]
[ 7782-50-5 ]
[ 14508-49-7 ]
[ 19745-07-4 ]
[ 4858-85-9 ]
[ 4774-14-5 ]
Reference：
[1] Patent: US2540476, 1948, ,
8
[ 14508-49-7 ]
[ 6270-63-9 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 400
9
[ 14508-49-7 ]
[ 56423-63-3 ]
Reference：
[1] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
10
[ 14508-49-7 ]
[ 5049-61-6 ]
Reference：
[1] Organic Letters, 2013, vol. 15, # 14, p. 3734 - 3737
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 400
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 1137 - 1140
The starting compound 3-chloropyrazine-2-carboxamide was synthesized using two published procedures. The first method was classified as less effective and was based on the homolytic amidation of 2-chloropyrazine. Thus, 2-chloropyrazine (0.17 mol) was dissolved in formamide (3.7 mol), heated to 90 °C and ammonium peroxodisulphate (0.18 mol) was added portionwise over one hour period. This mixture reacted for another one hour at 90 °C and then it was left to stand for 24 h at laboratory temperature. Dilution with 100 mL of water was followed by filtration and this filtrate was extracted continuously with chloroform for 16 h [34,42]. The mixture of three positional isomers was separated by flash chromatography using silica gel as stationary phase. The second process used 3-chloropyrazine-2-carbonitrile, which was submitted to partial hydrolysis of the nitrile group. The powdered carbonitrile (0.104 mol) was added little by little into the reaction mixture of concentrated hydrogen peroxide (0.95 mol) and water (195 mL) heated to 50 °C. The pH was adjusted and regulated around a value of 9 using an 8percent solution of sodium hydroxide and the temperature of the reaction was regulated between 55 and 60 °C. The reaction was stopped after 2.5 h and was cooled to 5 °C. Newly-emerged crystals were removed by suction and recrystallized from ethanol [42].
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 10, p. 2493 - 2501
[2] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 10, p. 2493 - 2501
39
[ 616-47-7 ]
[ 67-66-3 ]
[ 14508-49-7 ]
[ 17180-94-8 ]
[ 51269-82-0 ]
[ 38180-46-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
40
[ 616-47-7 ]
[ 67-66-3 ]
[ 14508-49-7 ]
[ 17180-94-8 ]
[ 51269-82-0 ]
[ 68325-15-5 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1431 - 1435
41
[ 14508-49-7 ]
[ 32111-21-0 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: With acetic acid; sodium iodide In acetonitrile for 4.5 h; Reflux Stage #2: With sodium hydrogencarbonate In water
A reaction mixture of chloropyrazine (7.5 ml, 83 mmol), NaI (30.3 g, 202 15 mmol), HOAc (9.6 ml, 168 mmol) and H2SO4 (0.5 ml) in MeCN (105 ml) was heated at reflux for 4.5 hours. The solvent was removed and water (120 ml) was added. After the solution was basified with saturated NaHCO3, it was extracted with dichloromethane (DCM) (2 x 125 ml). The DCM layers were combined, washed with saturated Na2S2O3, brine and dried. The removal of solvent gave crude iodopyrazine as an oil (12.33 g, 20 71percent). Analysis by 1H NMR showed there was less than about 10 molpercent of chloropyrazine in the oil. Another batch of chloropyrazine (50 g, 437 mmol) was also converted into crude iodopyrazine (about 65 g) by the same procedure. These two batches of crude iodopyrazine were combined and distillation of the crude iodopyrazine under reduced pressure (about 0.75 torr, bp 47°C) gave pure compound 64 g (60percent). 251H-NMR (CDCl3, 300MHz) 8.40 (dd, /=1.8, 2.4Hz, IH), 8.51 (d, /=2.4Hz,lH), 8.87 (d, /=1.5Hz,lH).
EXAMPLE 1 This Example illustrates the preparation of 2-iodopyrazine. 2-Chloropyrazine (6.18 g, 54 mmol) was added to a saturated solution of sodium iodide in acetone (100 ml) and water (3 ml) at reflux temperature under a nitrogen atmosphere. A solution of hydroiodic acid (3 ml of 55) in water (6 ml) was added and the mixture was heated at reflux temperature for 19 hours. The precipitated solids were removed by filtration and the filtrate concentrated under reduced pressure. Water (100 ml) was added to the residue and then solid sodium sulphite until a negative starch iodide test was obtained. Sodium hydroxide pellets were added until the pH was greater than pH 11 and the mixture was continuously extracted with diethylether. The extract was concentrated under reduced pressure and the residue fractionated to give the product as a clear oil (65percent, b. pt. 83°-85° C./18 mm Hg). NMR (90 MHz, CDCl3): 8,88 (1H,m), 8.53 (1H,m), 8.40 (1H, m). m/z: 206 (M+), 127, 79 (100percent).
Reference：
[1] Patent: US4975112, 1990, A,
43
[ 14508-49-7 ]
[ 2234-82-4 ]
[ 18138-03-9 ]
Yield
Reaction Conditions
Operation in experiment
82.4%
Stage #1: With iron(III)-acetylacetonate In tetrahydrofuranInert atmosphere Stage #2: Cooling with ice-water Stage #3: With ammonium chloride In tetrahydrofuran; water at 20℃; Inert atmosphere
EXAMPLE 1Synthesis of the compound of Formula I5 2-[4-(7-Ethyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)- phenyl]-propan-2-ol. 80 - 95percent2-chloropyrazine 2-n-propylpyrazineKHMDS4-acetylbenzonitrile 4-(1-hydroxy-1-methylethyl)benzonitrile TBME 70percentFormula IScheme 2The title compound was synthesized by the reactions of Scheme 2, shown above. 2-Propylpyrazine was first prepared by the following. This was accomplished by adding to a stirred round bottom flask 8.0 mL of 2-chloropyrazine, 1.58 g Fe(acac)3 (also known as iron acetylacetonate) and 100 mL THF (tetrahydrofuran). This was stirred under nitrogen giving a red solution. The flask was cooled in an ice-water bath for ten minutes. Then the addition of 49 mL of n-propylmagnesium chloride to the flask was begun. This resulted in a dark purple solution. After 1.5 hours 10 mL of n-propylmagnesium chloride were added over ten minutes. After an additional 20 minutes, an additional 5 mL of n-propylmagnesium chloride were added. After about 30 minutes of stirring, 22 mL of saturated aqueous NH4Cl were added over 7 minutes. After an additional 7 mL of the NH4Cl were added, the stirring was stopped and the mixture was allowed to stand at room temperature overnight under nitrogen.After adding 125 mL EtOAc and 450 mL water, the contents of the flask were filtered through polypropylene and poured into a separatory funnel. The phases were separated, and the aqueous phase was extracted twice more with 125 mL portions of EtOAc. The combined organic phase was filtered through Celite.(R). and subsequently concentrated by rotary evaporation (200 mbar, 40 0C). After a short-path distillation, the distillate was distilled (200 mbar, 90-110 0C) through a Vigreux column to give 9.0 g (82.4percent yield) of 2-n- propylpyrazine. HPLC of the final product gave a retention time of 3.0 minutes using an Elipse XDB-C8 column, 4.6 x 150 mm, 5 microns, using 60:40 acetonitrile/water, with 1percent TFA, isocratically at 1 niL/minute at 350C.
Reference：
[1] Patent: WO2010/107969, 2010, A1, . Location in patent: Page/Page column 6-7
[2] Journal of the American Chemical Society, 1992, vol. 114, # 13, p. 5269 - 5280
[3] Organic Process Research and Development, 2015, vol. 19, # 7, p. 806 - 811
44
[ 14508-49-7 ]
[ 4949-13-7 ]
Reference：
[1] Tetrahedron, 1998, vol. 54, # 19, p. 4899 - 4912
[2] Chemistry Letters, 1993, # 3, p. 509 - 512
[3] Heterocycles, 1992, vol. 34, # 8, p. 1507 - 1510
[4] Angewandte Chemie - International Edition, 2006, vol. 45, # 17, p. 2720 - 2725
[5] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
[6] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12137 - 12145
45
[ 14508-49-7 ]
[ 54608-52-5 ]
Yield
Reaction Conditions
Operation in experiment
75%
With hydrazine hydrate In water at 63 - 65℃;
Step 1: 2-hydrazinylpyrazine [0204] 2-Chloropyrazine (2.0 g, 17.5 mmol) was added dropwise to a 35percent aqueous solution of hydrazine hydrate (25.8 g, 97.8 mmol) at 63-65 °C, the addition rate was carefully monitored to ensure that the reaction temperature did not exceed 65 °C. Following the addition, the mixture was heated to 65 °C. After stirring overnight, the reaction was cooled to room temperature. The solvent was evaporated to afford the title compound as a yellow powder (1.5 g, 75percent). MS (ESI) calcd for C4H6N4: 110.1; found: 111.4 [M+H]. *H NMR (400 MHz, CD3OD) δ 8.10 (d, J = 1.6 Hz, 1H), 8.00 (dd, J = 3.2, 1.6 Hz, 1H), 7.73(d, J = 3.2 Hz, 1H).
67%
at 100℃; for 2 h;
General procedure: (0.1mole) of 2-halo nitrogen heterocycle and (0.5 mole) of hydrazine hydrate were mixed together in a 250mL round bottom flask equipped with reflux condenser and wereheated at 100oC, progress of the reaction was monitored byTLC. After completion of the reaction the reaction mixture was cooled to (-5-0oC) for 14hr and the precipitated solid was filtered and washed with two 5ml portions of ice coldwater and dried to give the compound 1 in good yield.
60%
at 20 - 110℃; for 1 h;
A mixture of 2-chloropyrazine (4.00 g) andhydrazine hydrate was heated at 1 10 °C for 1 h, and then cooled to room temperature. The mixture was filtered to give the title compound as a solid (2.30 g, 60.00 percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 1 1 1.0 (M+ l).
60%
at 110℃; for 1 h;
A mixture of 2-chloropyrazine (4.00 g) and hydrazine hydrate was heated at 110° C. for 1 h, and then cooled to room temperature. The mixture was filtered to give the title compound as a solid (2.30 g, 60.00percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 111.0 (M+1).
60.5%
at 60℃; for 10 h;
1)Will be 31.3 grams(80 wtpercent, 50 mmol)Hydrazine hydrate was added to 100 ml three-necked flask,Heating up to 60 ,Under magnetic stirring, 11.5 g was slowly added dropwise(100 mmol)2-chloropyrazine,The reaction was carried out at a temperature of 60 ° C for 10 hours,After completion of the reaction, the mixture was cooled to 2 ° C,Precipitation of solids,filter,Dried to afford 6.63 g of a white solid,Yield 60.5percent;
51%
With hydrazine In water at 20 - 67℃; for 53 h; Inert atmosphere
The reaction was run under nitrogen atmosphere. 2-chloropyrazine (96 mL, 1073 mmol) was added dropwise to 35 wt aqueous hydrazine (544 mL, 6009 mmol) at 65 °C over 1 h. After the addition, stirring was continued at 63-67 °C for 16 h then let stand at room temperature for two days. The mixture was filtered to remove a small amount of precipitate, then extracted with 10percent iPrOH/dichloromethane (5 x 250 mL). The combined organic extracts were dried (MgS04), filtered, then concentrated under reduced pressure. The resulting solid was triturated with isopropyl acetate (600 mL). The solid was collected by filtration, rinsed with isopropyl acetate and dried under vacuum to give 2-hydrazinylpyrazine (60 g, 51 percent) as a pale yellow solid. LCMS m/z = 111.2 [M+H]+. lU NMR (400 MHz, DMSO-i ) δ 4.21 (s, 2H), 7.70 (d, = 2.8 Hz, 1H), 7.89 (s, 1H), 7.93 (dd, = 2.8, 1.5 Hz, 1H), 8.10 (d, = 1.5 Hz, 1H).
47%
With hydrazine In ethanol at 20℃; for 17 h; Heating / reflux
[Referential Example 33] 2-Hydrazinopyrazine; [Show Image] Hydrazine monohydrate (21.80 g) was added to a solution of 2-chloropyrazine (10.44 g) in ethanol (65 ml) at room temperature, and the mixture was heated under reflux for 17 hours. After cooling with air, the reaction solvent was evaporated under reduced pressure, and benzene was added to the residue, then the insoluble content was' removed by decantation. After evaporation of the benzene solution under reduced pressure, hexane was added to the resulting solid, and the product was collected by filtration to give the title compound (4.67 g, 47percent). 1H-NMR (400 MHz, CDCl3)δ: 7.89 (1H, d, J = 2.7 Hz), 7.99-8.05 (1H, m), 8.20 (1H, d, J = 1.5 Hz). ESI-MSm/z: 111 (M+H)+.
47%
With hydrazine In ethanol at 20℃; for 17 h; Heating / reflux
[Referential Example 2] 2-Hydrazinopyrazine [Show Image] Hydrazine monohydrate (21.80 g) was added to 2-chloropyrazine (10.44 g) in ethanol (65 mL) at room temperature, and the resultant mixture was refluxed for 17 hours, followed by cooling in air. The reaction solvent was evaporated under reduced pressure, and then benzene was added to the residue. The resultant mixture was subjected to decantation, to thereby remove an insoluble matter. The benzene was evaporated under reduced pressure. Hexane was added to the resultant solid, and the mixture was subjected to filtration, to thereby give the title compound (4.67 g, 47percent). 1H-NMR(400MHz,CDCl3)δ:7.89(1H,d,J=2.7Hz), 7.99-8.05(1H,m), 8.20(1H,d,J=1.5Hz). ESI-MS m/z:111(M+H)+.
46%
With hydrazine In ethanol at 80℃;
Using Procedure AU-3 (Table 5) with 2-chloropyrazine the title compound 476 was obtained (4.4 g, 46percent) as a yellow solid. MS (m/z): 111.0 (M+H)
34%
at 120℃; for 0.75 h;
20.0 g (174.6 mmol) 2-chloropyrazine are added dropwise to 60.0 ml (61.7 g, 1.2 mol) hydrazine hydrate. The mixture is stirred at a bath temperature of 120° C. for 45 min. For working up, the cooled reaction mixture is left to stand at 2° C. for 12 h, the crystals which have precipitated out are filtered off and the residue on the filter is washed twice with petroleum ether. The residue is then recrystallized from toluene.Yield: 6.5 g (34percent of th.)LC-MS (Method 1): Rt=0.49 min; MS (ESIpos): m/z=111 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ=8.11 (s, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.70 (d, 1H), 4.29 (br. s, 2H).
34%
at 120℃; for 0.75 h;
20.0 g (174.6 mmol) of chloropyrazine are added dropwise to 61.7 g (1.2 mol) of hydrazine hydrate, and the mixture is stirred at 120° C. for 45 min. The mixture is then allowed to stand at 2° C. for 24 h. The solid is filtered off and washed twice with petroleum ether. The solid is initially air-dried and then dried under high vacuum. The solid is then recrystallized from toluene and again dried under high vacuum.Yield: 6.5 g (34percent of theory)LC-MS (Method 1): Rt=0.41 min; MS (ESIpos): m/z=111 [M+H]+.
Reference：
[1] Patent: WO2016/100349, 2016, A2, . Location in patent: Paragraph 0204
[2] Letters in Organic Chemistry, 2013, vol. 10, # 5, p. 348 - 352
[3] Patent: WO2013/71697, 2013, A1, . Location in patent: Paragraph 00198
[4] Patent: US2014/228361, 2014, A1, . Location in patent: Paragraph 0279-0280
[5] Patent: CN106749262, 2017, A, . Location in patent: Paragraph 0035
[6] Patent: WO2012/116276, 2012, A1, . Location in patent: Page/Page column 59
[7] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 12, p. 1309 - 1313
[8] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 141 - 151
[9] Patent: EP1698626, 2006, A1, . Location in patent: Page/Page column 47
[10] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 22
[11] Patent: US2017/749, 2017, A1, . Location in patent: Paragraph 0713
[12] Patent: US2010/305085, 2010, A1, . Location in patent: Page/Page column 20
[13] Patent: US2012/264704, 2012, A1, . Location in patent: Page/Page column 17
[14] ChemMedChem, 2018, vol. 13, # 10, p. 988 - 1003
[15] Journal of Medicinal Chemistry, 1988, vol. 31, # 9, p. 1719 - 1728
[16] Patent: US6316464, 2001, B1,
[17] Patent: WO2010/125102, 2010, A1, . Location in patent: Page/Page column 132
[18] Patent: WO2012/116279, 2012, A1, . Location in patent: Page/Page column 96-97
[19] Organic Process Research and Development, 2005, vol. 9, # 5, p. 634 - 639
[20] Patent: US2015/359793, 2015, A1, . Location in patent: Paragraph 0208
46
[ 14508-49-7 ]
[ 68-12-2 ]
[ 89283-32-9 ]
Yield
Reaction Conditions
Operation in experiment
60 g
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran at -78 - 0℃; for 0.666667 h; Inert atmosphere Stage #2: at -78 - 70℃; for 2.16667 h; Inert atmosphere Stage #3: With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃; for 2 h; Inert atmosphere
Under nitrogen protection,To a solution of 2,2,6,6-tetramethylpiperidine (72.8 g, 516.3 mmol)In 500 mL of dry THF solution,N-BuLi (346 mL, 553.7 mmol, 1.6 mol / L THF) was slowly added dropwise at -78 &After completion of the reaction, the reaction mixture was warmed to 0 ° C and the reaction was continued for 20 min.The reaction mixture was then cooled to -78 ° C,A solution of 2-chloropyrazine (50 g, 436.3 mmol) in THF (100 mL) was added dropwise to the reaction mixture,30min plus finished,The color of the reaction mixture changed from light yellow to dark brown,The reaction was continued for 10 min at -78-0 degC.DMF (84 ml, 1092 mmol)Was dissolved in THF (50 mL) dropwise dropwise into the reaction mixture,Control the reaction system temperature at -70 ~ -78 ,10min plus finished,The reaction was stirred at -78 ° C for 2 h.To the reaction mixture was then added MeOH (800 mL)To the reaction mixture, NaBH4 (33 g, 868 mmol) was added portionwise,After the addition, the reaction mixture was allowed to rise to room temperature and stirring continued for 2 h,TLC shows the raw material reaction is complete,The reaction solution was quenched with saturated NH4Cl,DCM (1 L x 3) was extracted three times,The organic phase was washed with water,Anhydrous Na2SO4 fully dried,After vacuum evaporation, the residue was purified by silica gel column (PE / EA = 100/1 to 5/1) to give 60 g of the title compound
Reference：
[1] Patent: CN106831787, 2017, A, . Location in patent: Paragraph 0145; 0146; 0147; 0148
47
[ 14508-49-7 ]
[ 5188-07-8 ]
[ 21948-70-9 ]
Reference：
[1] Tetrahedron, 2002, vol. 58, # 5, p. 887 - 890
[2] Journal of Organic Chemistry, 2010, vol. 75, # 6, p. 2131 - 2133
Reference：
[1] Synthesis, 1988, # 11, p. 881 - 884
56
[ 14508-49-7 ]
[ 59016-93-2 ]
[ 127406-08-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h;
General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n.
90%
With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h;
General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n.
90%
With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h;
General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n.
Reference：
[1] Inorganica Chimica Acta, 2014, vol. 423, # PART A, p. 11 - 15
[2] Inorganica Chimica Acta, 2014, vol. 423, # 1, p. 11 - 15
[3] Inorganica Chimica Acta, 2014, # PA, p. 11 - 15
57
[ 14508-49-7 ]
[ 87199-17-5 ]
[ 127406-08-0 ]
Yield
Reaction Conditions
Operation in experiment
97%
With sodium carbonate In ethanol; toluene for 18 h; Heating / reflux
Step A Ethanol (13 ml) and 1.0M Na2CO3 (27.5 ml) were added to a suspension of 2-chloropyrazine (4.0 g, 34.6 mmole), 4-formylphenylboronic acid (6.8 g, 45.0 mmole), and tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.7 mmole) in toluene (55 ml). The mixture was refluxed for 18 hours then cooled, diluted with EtOAc, washed with NaHCO3, washed with brine, dried (MgSO4) and concentrated. Purification by chromatography (SiO2, 4:1 hexanes/EtOAc) yielded 6.2 g (97percent) of 4-(2-pyrazinyl)benzaldehyde.
42%
Stage #1: With sodium carbonate In ethanol; water; toluene for 18 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In ethanol; water; ethyl acetate; toluene
[0410] Step A: [0411] 1M aq. Na2CO3 (20 mL) and ethanol (10 mL) were added to a solution of 2-chloropyrazine (2.30 g, 20.06 mmol), 4-formylphenylboronic acid (3.90 g, 26.01 mmol) and [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (0.60 g, 0.99 mmol) in toluene (40 mL) and the mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 1.56 g (42percent) of 4-pyrazinylbenzaldehyde.
Reference：
[1] Patent: US2005/250713, 2005, A1, . Location in patent: Page/Page column 29-30
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 35, p. 6944 - 6952
[3] Patent: US2004/18994, 2004, A1, . Location in patent: Page/Page column 61
With hydrazine hydrate; sodium carbonate; at 120 - 130℃;
The mixture of 2-chloropyrazine (7) (20.0 g, 0.175 mol),hydrazine hydrate (60 mL) and sodium carbonate (27.84 g,0.264 mol) was stirred for 2 h at 120-130 C. After completionof the reaction that was checked by TLC, the reactionmass was allowed to cool at 50-60 C and then water(60.0 mL) followed by isopropyl alcohol (IPA) (40.0 mL)were added. The reaction mass was maintained for 16 h at 0-3 C and then the precipitated white solid was separatedby filtration. The wet solid was dried under vacuum at 45-50 C to obtain desired 2-hydrazinopyrazine (14.8 g, 77.8%).1H NMR (400 MHz; CD3OD), d, ppm (J, Hz): 7.94-8.14(2H, m, Ar-H); 7.69 (1H, s, Ar-H). ESI-MS m/z (rel, %):111.07 (M+H+) (100). HRMS (FAB) Calc.: C4H6N4:110.059246; Found: 111.0592 [M+H+].
75%
With hydrazine hydrate; In water; at 63 - 65℃;
Step 1: 2-hydrazinylpyrazine [0204] 2-Chloropyrazine (2.0 g, 17.5 mmol) was added dropwise to a 35% aqueous solution of hydrazine hydrate (25.8 g, 97.8 mmol) at 63-65 C, the addition rate was carefully monitored to ensure that the reaction temperature did not exceed 65 C. Following the addition, the mixture was heated to 65 C. After stirring overnight, the reaction was cooled to room temperature. The solvent was evaporated to afford the title compound as a yellow powder (1.5 g, 75%). MS (ESI) calcd for C4H6N4: 110.1; found: 111.4 [M+H]. *H NMR (400 MHz, CD3OD) delta 8.10 (d, J = 1.6 Hz, 1H), 8.00 (dd, J = 3.2, 1.6 Hz, 1H), 7.73(d, J = 3.2 Hz, 1H).
67%
With hydrazine hydrate; at 100℃; for 2h;
General procedure: (0.1mole) of 2-halo nitrogen heterocycle and (0.5 mole) of hydrazine hydrate were mixed together in a 250mL round bottom flask equipped with reflux condenser and wereheated at 100oC, progress of the reaction was monitored byTLC. After completion of the reaction the reaction mixture was cooled to (-5-0oC) for 14hr and the precipitated solid was filtered and washed with two 5ml portions of ice coldwater and dried to give the compound 1 in good yield.
60%
With hydrazine hydrate; at 20 - 110℃; for 1h;
A mixture of 2-chloropyrazine (4.00 g) andhydrazine hydrate was heated at 1 10 C for 1 h, and then cooled to room temperature. The mixture was filtered to give the title compound as a solid (2.30 g, 60.00 %). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 1 1 1.0 (M+ l).
60%
With hydrazine hydrate; at 110℃; for 1h;
A mixture of 2-chloropyrazine (4.00 g) and hydrazine hydrate was heated at 110 C. for 1 h, and then cooled to room temperature. The mixture was filtered to give the title compound as a solid (2.30 g, 60.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 111.0 (M+1).
60.5%
With hydrazine hydrate; at 60℃; for 10h;
1)Will be 31.3 grams(80 wt%, 50 mmol)Hydrazine hydrate was added to 100 ml three-necked flask,Heating up to 60 ,Under magnetic stirring, 11.5 g was slowly added dropwise(100 mmol)2-chloropyrazine,The reaction was carried out at a temperature of 60 C for 10 hours,After completion of the reaction, the mixture was cooled to 2 C,Precipitation of solids,filter,Dried to afford 6.63 g of a white solid,Yield 60.5%;
51%
With hydrazine; In water; at 20 - 67℃; for 53h;Inert atmosphere;
The reaction was run under nitrogen atmosphere. 2-chloropyrazine (96 mL, 1073 mmol) was added dropwise to 35 wt aqueous hydrazine (544 mL, 6009 mmol) at 65 C over 1 h. After the addition, stirring was continued at 63-67 C for 16 h then let stand at room temperature for two days. The mixture was filtered to remove a small amount of precipitate, then extracted with 10% iPrOH/dichloromethane (5 x 250 mL). The combined organic extracts were dried (MgS04), filtered, then concentrated under reduced pressure. The resulting solid was triturated with isopropyl acetate (600 mL). The solid was collected by filtration, rinsed with isopropyl acetate and dried under vacuum to give 2-hydrazinylpyrazine (60 g, 51 %) as a pale yellow solid. LCMS m/z = 111.2 [M+H]+. lU NMR (400 MHz, DMSO-i ) delta 4.21 (s, 2H), 7.70 (d, = 2.8 Hz, 1H), 7.89 (s, 1H), 7.93 (dd, = 2.8, 1.5 Hz, 1H), 8.10 (d, = 1.5 Hz, 1H).
47%
With hydrazine; In ethanol; at 20℃; for 17h;Heating / reflux;
[Referential Example 33] 2-Hydrazinopyrazine; [Show Image] Hydrazine monohydrate (21.80 g) was added to a solution of 2-chloropyrazine (10.44 g) in ethanol (65 ml) at room temperature, and the mixture was heated under reflux for 17 hours. After cooling with air, the reaction solvent was evaporated under reduced pressure, and benzene was added to the residue, then the insoluble content was' removed by decantation. After evaporation of the benzene solution under reduced pressure, hexane was added to the resulting solid, and the product was collected by filtration to give the title compound (4.67 g, 47%). 1H-NMR (400 MHz, CDCl3)delta: 7.89 (1H, d, J = 2.7 Hz), 7.99-8.05 (1H, m), 8.20 (1H, d, J = 1.5 Hz). ESI-MSm/z: 111 (M+H)+.
47%
With hydrazine; In ethanol; at 20℃; for 17h;Heating / reflux;
[Referential Example 2] 2-Hydrazinopyrazine [Show Image] Hydrazine monohydrate (21.80 g) was added to 2-chloropyrazine (10.44 g) in ethanol (65 mL) at room temperature, and the resultant mixture was refluxed for 17 hours, followed by cooling in air. The reaction solvent was evaporated under reduced pressure, and then benzene was added to the residue. The resultant mixture was subjected to decantation, to thereby remove an insoluble matter. The benzene was evaporated under reduced pressure. Hexane was added to the resultant solid, and the mixture was subjected to filtration, to thereby give the title compound (4.67 g, 47%). 1H-NMR(400MHz,CDCl3)delta:7.89(1H,d,J=2.7Hz), 7.99-8.05(1H,m), 8.20(1H,d,J=1.5Hz). ESI-MS m/z:111(M+H)+.
46%
With hydrazine; In ethanol; at 80℃;
Using Procedure AU-3 (Table 5) with 2-chloropyrazine the title compound 476 was obtained (4.4 g, 46%) as a yellow solid. MS (m/z): 111.0 (M+H)
34%
With hydrazine hydrate; at 120℃; for 0.75h;
20.0 g (174.6 mmol) 2-chloropyrazine are added dropwise to 60.0 ml (61.7 g, 1.2 mol) hydrazine hydrate. The mixture is stirred at a bath temperature of 120 C. for 45 min. For working up, the cooled reaction mixture is left to stand at 2 C. for 12 h, the crystals which have precipitated out are filtered off and the residue on the filter is washed twice with petroleum ether. The residue is then recrystallized from toluene.Yield: 6.5 g (34% of th.)LC-MS (Method 1): Rt=0.49 min; MS (ESIpos): m/z=111 [M+H]+;1H-NMR (400 MHz, DMSO-d6): delta=8.11 (s, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.70 (d, 1H), 4.29 (br. s, 2H).
34%
With hydrazine hydrate; at 120℃; for 0.75h;
20.0 g (174.6 mmol) of chloropyrazine are added dropwise to 61.7 g (1.2 mol) of hydrazine hydrate, and the mixture is stirred at 120 C. for 45 min. The mixture is then allowed to stand at 2 C. for 24 h. The solid is filtered off and washed twice with petroleum ether. The solid is initially air-dried and then dried under high vacuum. The solid is then recrystallized from toluene and again dried under high vacuum.Yield: 6.5 g (34% of theory)LC-MS (Method 1): Rt=0.41 min; MS (ESIpos): m/z=111 [M+H]+.
With hydrazine; In ethanol;
Step 1 To a solution of chloropyrazine (11.5 g, 0.1 mmol) in absolute ethanol (50 ml) was added anhydrous hydrazine (16 ml, 0.5 mmol) and the reaction mixture was refluxed for 3 h. The organics were removed in vacuo and the residue was extracted with benzene to give hydrazinopyrazine (4.2 g).
With hydrazine hydrate; In ethanol; for 6h;Reflux;
2-Chloropyrazine (7.79 mL, 87 mmol, commercially available e.g. from Sigma- Aldrich or Haiso PharmChem) was dissolved in ethanol (50 mL), and hydrazine hydrate (6.85 mL, 218 mmol) was added. The solution was refluxed for 6 hours. The mixture was cooled to room temperature and the solvent was partially evaporated. The residue was diluted with water and extracted with 10% (v/v) of 2-propanol/Dichloromethane solution (5 extractions). The combined organic phases were then dried and evaporated to give a yellow solid which was triturated with diethyl ether to give 2-hydrazinopyrazine as a yellow solid (3.32 g).
With hydrazine; In water; at 20 - 67℃; for 65h;Inert atmosphere;
Step B: Preparation of 2-Hydrazinylpyrazine.Under nitrogen atmosphere, 2-chloropyrazine (96 mL, 1073 mmol) was added dropwise to 35 wt aqueous hydrazine (544 mL, 6009 mmol) at 65 C over 1 h. After the addition, stirring was continued at 63-67 C for 16 h and the reaction mixture was let stand at room temperature for two days. The mixture was filtered to remove a small amount of precipitate, then extracted with 10% iPrOH/dichloromethane (5 x 250 mL). The combined organic extracts were dried (MgS04), filtered, then concentrated under reduced pressure. The resulting solid was triturated with isopropyl acetate (600 mL). The solid was collected by filtration, rinsed with isopropyl acetate, then dried in vacuo to give the title compound (60 g) as a pale yellow solid. LCMS m/z = 111.2 [M+H]+; lU NMR (400 MHz, DMSO- ) delta 4.21 (s, 2H), 7.70 (d, 7 = 2.8 Hz, 1H), 7.89 (s, 1H), 7.93 (dd, 7 = 2.8, 1.5 Hz, 1H), 8.10 (d, 7 = 1.5 Hz, 1H).
With hydrazine;
A mixture of 2-hydrazinopyrazine (820 mg, 7.45 mmol), prepared from 2-chloropyrazine and hydrazine using a procedure analogous to that described in the literature (P. J. Nelson and K. T. Potts, J. Org. Chem. 1962, 27, 3243, except that the crude product was extracted into 10% methanol/dichloromethane and filtered, and the filtrate was concentrated and purified by flash chromatography on silica gel, eluting with 100% ethyl acetate followed by 10% methanol in dichloromethane), TFA (2.55 g, 22.4 mmol), and polyphosphoric acid (10 mL) was heated to 140 C. with stirring for 18 h. The solution was added to ice and neutralized by the addition of ammonium hydroxide. The aqueous solution was extracted with ethyl acetate (3×), washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography (silica gel, 1:1 hexane:ethyl acetate, then 100% ethyl acetate) afforded the title compound as a solid (861 mg). 1H NMR (500 MHz, CDCl3) delta 8.17-8.20 (m, 2H), 9.54 (s, 1H). LC/MS (M+1) 189.
With hydrazine hydrate; In ethanol; for 10h;Reflux;
General procedure: 2,6-dichloropyrazine (10.49 g, 70.38 mmol) was dissolved in 150 mL of ethanol. After stirring for 5 min, 80% hydrazine hydrate (7.05 g, 0.147 mol) was added. The reaction was heated to 80 C and refluxed for 10 h until the solution became clear. The resulting mixture was cooled to room temperature, and a yellow solid was precipitated. The suspension was filtered, and the filtrate was concentrated under reduced pressure to afford a yellow solid 9.1 g.
A reaction mixture of chloropyrazine (7.5 ml, 83 mmol), NaI (30.3 g, 202 15 mmol), HOAc (9.6 ml, 168 mmol) and H2SO4 (0.5 ml) in MeCN (105 ml) was heated at reflux for 4.5 hours. The solvent was removed and water (120 ml) was added. After the solution was basified with saturated NaHCO3, it was extracted with dichloromethane (DCM) (2 x 125 ml). The DCM layers were combined, washed with saturated Na2S2O3, brine and dried. The removal of solvent gave crude iodopyrazine as an oil (12.33 g, 20 71%). Analysis by 1H NMR showed there was less than about 10 mol% of chloropyrazine in the oil. Another batch of chloropyrazine (50 g, 437 mmol) was also converted into crude iodopyrazine (about 65 g) by the same procedure. These two batches of crude iodopyrazine were combined and distillation of the crude iodopyrazine under reduced pressure (about 0.75 torr, bp 47C) gave pure compound 64 g (60%). 251H-NMR (CDCl3, 300MHz) 8.40 (dd, /=1.8, 2.4Hz, IH), 8.51 (d, /=2.4Hz,lH), 8.87 (d, /=1.5Hz,lH).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃;Inert atmosphere;
To degassed dioxane (10ml_) were added sequentially 3-amino-1 ,2,4- triazine (2) (205mg, 2.1 mmol), 2-chloropyrazine (1) (0.23mL, 2.6mmol), Pd2(dba)3 (59mg, 0.06mmol), XantPhos (74mg, 0.13mmol) and Cs2C03 (1.4g, 4.3mmol) with continued degassing. The reaction mixture was heated up to 90C overnight. Once cooled down to rt, it was poured into a brine solution (50%, 20ml_) and extracted with EtOAc (3 x 20ml_). The combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1 :0-0: 1 ) afforded a residue. It was re-dissolved in CH2CI2/MeOH (4:1 , 50ml_) and swirled with MP-TMT resin (500mg, 1.3mmol/g) at rt overnight. The solution was filtered, the resin washed with CH2CI2/MeOH (4:1 , 100ml_) and the filtrate concentrated in vacuo to yield (3) as an orange solid (69mg, 18%). (0797) LCMS (ES): Found 175.0 [M+Hf. (0798) 1H NMR (300 MHz, DMSO-cf6), d: 10.86 (s, 1 H), 9.38 (d, J=1.5 Hz, 1 H), 8.99 (d, J= 2.3 Hz, 1 H), 8.61 (d, J= 2.3 Hz, 1 H), 8.40 (dd, J= 2.5, 1.6 Hz, 1 H), 8.30 (d, J= 2.6 Hz, 1 H).
4-tert-butoxycarbonylamino-4-methyl-1-(2-pyrazinyl)piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate; In 1,4-dioxane; for 96h;Heating / reflux;
(1) To a solution of 4-tert-butoxycarbonylamino-4-methyl-piperidine (856 mg, 4.00 mmol) described in European Patent 647,639 in 1,4-dioxane (16 mL) were added potassium carbonate (2.21 g, 16.0 mmol) and 2-chloropyrazine (0.764 mL, 8.00 mmol), and the mixture was refluxed for 4 days. After the reaction mixture was stand for cooling, the mixture was added with water and extracted three times with chloroform. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain 4-tert-butoxycarbonylamino-4-methyl-1-(2-pyrazinyl)piperidine (1.04 g, 3.55 mmol).yield: 89 %<1>H NMR (CDCl3) delta (ppm): 8.15 (1H, d, J = 1.4 Hz), 8.04 (1H, dd, J = 2.7, 1.4 Hz), 7.82 (1H, d, J = 2.7 Hz), 4.43 (1H, br s), 3.87 (2H, ddd, J = 13.5, 4.7, 4.7 Hz), 3.33 (2H, ddd, J = 13.5, 10.5, 3.0 Hz), 2.11 (2H, d, J = 13.8 Hz), 1.66 (2H, ddd, J = 13.8, 9.6, 4.2 Hz), 1.44 (9H, s), 1.40 (3H, s).APCIMS (m/z): 293 (M + H)<+>
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 24h;
Example 10-6 tert-Butyl [4-methyl-1-(2-pyrazinyl)-4-piperidinyl]- carbamate To a mixture of tert-butyl (4-methyl-4-piperidinyl) carbamate obtained in Example 10-5 (415mg) and potassium carbonate (321mg) in N, N-dimethylformamide (4. 5mL), was added chloropyrazine (665mg). The mixture was heated at 100C with stirring for 24hrs. The resulting mixture was partitioned betwwen saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with water and brine, dried over MgS04, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, and ethyl acetate (2: 1) to give the title compound as a pale yellow oil (566mg). H-NMR (300MHz, CDCl3) : No. 1.40 (3H, s), 1.44 (9H, s), 1.66 (2H, ddd, J=14, 10,4Hz), 2. 11 (2H, br-d, J=14Hz), 3.33 (2H, ddd, J=14,10, 3Hz), 3.87 (2H, ddd, J=14,4, 4Hz), 4.43 (1H, br-s), 7.82 (1H, d, J=2. 6Hz), 8.05 (1H, dd, J=2. 6, 1. 5Hz), 8.16 (1H, d, J=1. 5Hz). Mass (ES+) m/z : 293 (M+l).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 18h;Heating / reflux;
Step A Ethanol (13 ml) and 1.0M Na2CO3 (27.5 ml) were added to a suspension of 2-chloropyrazine (4.0 g, 34.6 mmole), 4-formylphenylboronic acid (6.8 g, 45.0 mmole), and tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.7 mmole) in toluene (55 ml). The mixture was refluxed for 18 hours then cooled, diluted with EtOAc, washed with NaHCO3, washed with brine, dried (MgSO4) and concentrated. Purification by chromatography (SiO2, 4:1 hexanes/EtOAc) yielded 6.2 g (97%) of 4-(2-pyrazinyl)benzaldehyde.
42%
[0410] Step A: [0411] 1M aq. Na2CO3 (20 mL) and ethanol (10 mL) were added to a solution of 2-chloropyrazine (2.30 g, 20.06 mmol), 4-formylphenylboronic acid (3.90 g, 26.01 mmol) and [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (0.60 g, 0.99 mmol) in toluene (40 mL) and the mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 1.56 g (42%) of 4-pyrazinylbenzaldehyde.
Example 3; (2S)-4,4-Difluoro-1-(2-[1-(2-pyrazinyl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile dihydrochloride; The meaning of Rl is 2-pyrazinyl group, B means a group of formula (1), R2 and R3 mean fluorine atom in general formula (I). a. ) 1- .-4-acetamino-piperidine with (V) general formula-where Ru ils 2- pyrazinyl, Y is COCH3, B is (1) group; 0,45 ml of chloropyrazine (5 mmol) and 1,6 g of 4-acetaminopyperidine (10 mmol) are dissolved in 15 ml of 1-pentanol and heated under reflux for 14 hours. The solvent are evaporated and the residue is purified by column chromatography using ethyl acetate- methanol-25 % aqueous NH3 solution (17: 3: 1) as eluent to result 0,81 g (76 %) of the above crystalline product. M. p.: 158-160C. 1H-NMR (200 MHz, DMSO-d6) : 3 1.34 (dq, 2H), 1.78 (m, 5H), 3.03 (dt, 2H), 3.74-3. 89 (m, lH), 4.21 (td, 2H), 7.77 (d, 1H, 3'-H), 7.80 (s, 1H, NH), 8. 05 (dd, 1H, 5'-H), 8.31 (d, 1H, 6'-H).
A mixture of chloropyrazine 3 (5.0 mmol) and HNR1R2 (10.0 mmol) was heated at 100 C. in a sealed tube for 15 h. The reaction mixture was cooled to room temperature, diluted with methylene chloride (50 mL), washed with saturated sodium bicarbonate solution (10 mL), dried over sodium sulfate and concentrated to provide the product 4, which could be purified by column chromatography, but was usually used in the next step without purification.; Prepared from 2-chloropyrazine and diethanolamine according to general procedure 2 providing the aminopyrazine (700 mg, quant.) as an oil; 1H NMR (300 MHz, CDCl3) delta 7.80-7.99 (dd, J=2.7, 1.5 Hz, 1H), 7.90-7.89 (d, J=1.5 Hz, 1H), 7.79-7.80 (d, J=2.8 Hz, 1H), 4.78 (br s, 1H), 2.80-2.79 (d, J=4.9 Hz, 3H).
77%
In ethanol; at 95℃; for 1.0h;Inert atmosphere; Sealed tube;
In a sealed tube, 2-chloropyrazine (1.0 g, 8.7 mmol, 1 equiv) was heated withethanolic methylamine (33% w/w; 4.0 g, 43.6 mmol, 5 equiv) at 95 C for 1 h.Solvent and excess of methylamine were then removed under reduced pressure. Theresidue was then dissolved in dichloromethane and washed three times with water.The organic phase was then evaporated under reduced pressure and the crude productwas further purified by flash chromatography on silica gel (EtOAc/Et2O= 1:6 to 1:4).The product S2 was obtained as a colorless oil (0.73 g, 6.7 mmol, 77% yield), whichsolidified as a light brown solid. The spectra are in agreement with the literaturereport.1
Step 1: 2-methylaminopyrazine. To a stirred solution of 2M methylamine in 1 mL of methanol, at room temperature, was added 2-chloropyrazine. The reaction was sealed and heated to 60 C. for 24 hours. The reaction was concentrated to a mixture of starting material and the desired 2-methylaminopyrazine in a 1:2 ratio. The material was used crude in a urea forming reaction. 1H-NMR (400 MHz, CDCl3) delta7.97 (d, 1H), 7.85 (s, 1H), 7.73 (d, 1H), 2.96 (s, 3H)
N-(aminoethyl)-3,5-diamino-6-chloropyrazine-2-carboxamide[ No CAS ]
[ 14527-26-5 ]
[ 57-13-6 ]
N-(2-guanidinoethyl)-3,5-diamino-6-chloropyrazine-2-carboxamide hydrochloride trihydrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In hydrogenchloride; methanol; ethanol; water;
Step 2: Dissolve the product of Step 1 (100 mg) and 2-methyl-2-thiopseudourea sulfate (122 mg) in water (0.5 ml) and MeOH (0.5 ml) and heat on a steam bath for 1 hour. If all the starting chloropyrazine is not reacted, add more pseudourea and repeat the procedure. Triturate the resulting residue in EtOH to obtain the sulfate salt of the title compound. Chromatograph the product on a high pressure reversed phase prep C18 column (Dynamax), eluding with MeOH:H2 O (40:60), 0.2% TFA, at 10 ml/min., followed by a C18 Magnum 20 column (Whatman), eluding with MeOH:H2 O (30:70), 0.2% TFA. Dissolve the resultant residue in 1N HCl, evaporate the solvent, redissolve in water and lyophilize to obtain the title compound as a yellow solid, m.p. 100 (d), M+ =272.
With sodium sulfide nonahydrate; In N,N-dimethyl-formamide;
EXAMPLE 1 Preparation of ((5-nitro-2-thiazolyl)thio)Pyrazine (Compound 1) To a solution of 60.0 g (0.25 mol) of sodium sulfide nonahydrate in 500 ml of dimethyl formamide was gradually added 29 g (0.25 mol) of chloropyrazine in 100 ml of dimethyl formamide. The solution was stirred overnight at approximately 40° C. following which 52.5 g (0.25 mol) of <strong>[3034-48-8]<strong>[3034-48-8]2-bromo-5-nitrothiazol</strong>e</strong> was added as a solid. This reaction mixture was stirred at room temperature for 4 hours. After this period it was poured into water. The resulting precipitate was collected by suction filtration, washed with water and dried. The crude product was crystallized from methanol to yield 38 g (72percent yield) of yellowish-gold crystals, m.p. 129°-130° C. A sample was subjected to elemental analysis. The results obtained were as follows: Analysis. for C7 H4 N4 O2 S2: Calcd.: C, 35.00; H, 1.67; N, 23.33. Found: C, 34.80; H, 1.71; N, 23.27.
EXAMPLE 8 1-Acetyl-azetidine-3-carboxylic Acid [(S)-3-[5-(3,5-dimethyl-1-pyrazin-2-yl-1H-pyrazole-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-amide (III-25) 3,5-Dimethyl-1-pyrazin-2-yl-1H-pyrazole-4-carboxylic acid-To a solution of <strong>[35691-93-1]3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (1 g, 5.95 mmol) in DMF (20 mL) cooled to 0 C. was added portionwise NaH (60% in mineral oil, 171 mg, 7.13 mmol). After hydrogen evolution ceased, 2-chloro-pyrazine (0.64 mL, 7.13 mmol) was added and the reaction was stirred at 50 C. for 24 h. The reaction mixture was cooled to RT, partitioned between EtOAc and saturated NH4Cl. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified via SiO2 chromatography eluding with hexane/EtOAc to afford 0.64 g (44%) of 3,5-dimethyl-1-pyrazin-2-yl-1H -pyrazole-4-carboxylic acid ethyl ester.
44%
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 50℃; for 24h;
step 1 - To a solution of 3,5-dimethyl-lff-pyrazole-4-carboxylic acid ethyl ester (1 g, 5.95 mmol) in DMF (20 mL) cooled to 0 C was added portionwise NaH (60% in mineral oil, 171 mg, 7.13 mmol). After hydrogen evolution ceased, 2-chloro-pyrazine (0.64 mL, 7.13 mmol) was added and the reaction was stirred at 50 C for 24 h. The reaction mixture was cooled to RT, partitioned between EtOAc and saturated NH4Cl. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified via SiO2 chromatography eluting with hexane/EtOAc to afford 0.64 g (44%) of 3,5-dimethyl- 1 - pyrazin-2-yl-lff-pyrazole-4-carboxylic acid ethyl ester (124a). The ethyl ester was hydrolyzed to the corresponding acid with KOH in aqueous EtOH as described in step 2 of example 31.
A flame dried and cooled 100 mL round bottom flask was charged with 2,2,6,6-tetramethylpiperidine (2.5 mL, 14.96 mmol) and anhydrous THF (25 mL) under a nitrogen atmosphere. The contents were cooled to -78 C. and n-butyllithium (2.5 M in hexane, 5.7 mL, 14.28 mmol) was added dropwise over a 5 minute period. The reaction mixture was stirred at -78 C. for 5 minutes, bought to 0 C. and stirred at 0 C. for 25 minutes. The reaction mixture was recooled to -78 C. and 2-chloropyrazine (0.78 g, 1 mL, 6.8 mmol) was added over a 3 minute period. After 30 minutes at -78 C., anhydrous DMF (0.99 mL, 13.6 mmol) was added over 3 minutes and the contents stirred at -78 C. for a further 30 minutes. The reaction mixture was bought to 0 C., stirred at 0 C. for 15 minutes, recooled to -78 C. and quenched by the addition of acetic acid (4 mL) in THF (10 mL). The reaction mixture was stirred at room temperature for 10 minutes and partitioned between ethyl acetate (60 mL) and brine (30 mL). The ethyl acetate layer is separated, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel flash chromatography using dichloromethane and ethyl acetate (9.5:0.5, 400 mL) to yield the title compound a (950 mg). 1H-NMR of the compound was consistent with the desired structure.
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;palladium diacetate; In toluene; at 70℃;Sealed tube;
In a sealed tube, 40 mL of dry toluene was degazed with Argon during 15 minutes, palladium acetate (165 mg, 0.24 mmol, 0.04 eq.) and racemic-2,2'-bis(diphenylphosphino)-,1'-binaphthyl (152 mg, 0.24 mmol, 0.04 eq.) were added and the mixture was degazed with Argon for 10 minutes. Then 2-chloropyrazine (700 mg, 6.11 mmol, 1.0 eq.), <strong>[270912-72-6]3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester</strong> (1.5 g, 7.33 mmol, 1.2 eq.) and sodium tert-butoxide (822 mg, 8.55 mmol, 1.4 eq.) were added and the mixture was stirred at 70 C. overnight. The reaction was concentrated in vacuum. The resulting crude product was purified by flash chromatography on silica gel, eluting with cyclohexane-ethyl acetate (1:1 to 0:1) to afford a mixture of 3a and 3b (900 mg, 2:1, over yield 38%).
In a sealed tube, 40 mL of dry toluene was degazed with Argon during 15 minutes, palladium acetate (165 mg, 0.24 mmol, 0.04 eq.) and racemic-2,2'-bis(diphenylphosphino)-,1'-binaphthyl (152 mg, 0.24 mmol, 0.04 eq.) were added and the mixture was degazed with Argon for 10 minutes. Then 2-chloropyrazine (700 mg, 6.11 mmol, 1.0 eq.), <strong>[270912-72-6]3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester</strong> (1.5 g, 7.33 mmol, 1.2 eq.) and sodium tert-butoxide (822 mg, 8.55 mmol, 1.4 eq.) were added and the mixture was stirred at 70 C. overnight. The reaction was concentrated in vacuum. The resulting crude product was purified by flash chromatography on silica gel, eluting with cyclohexane-ethyl acetate (1:1 to 0:1) to afford a mixture of 3a and 3b (900 mg, 2:1, over yield 38%).Step B: Preparation of 4a and 4b The mixture of 3a and 3b (900 mg) was dissolved in dichloromethane (25 mL) and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 6 hours. The reaction was concentrated in vacuum and co-evaporated with toluene and methanol. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane-7N NH3 methanol (gradient from 5% to 100% of 7N NH3 methanol) 4a and 4b were separated during the flash chromatography purification to afford quantitatively 4a and 4b as colorless oils.4a: MS (ESI+) (+0.1% HCOOH): 179.21 [C9H14N4+H]+ (m/z)4b: MS (ESI+) (+0.1% HCOOH): 257.14 [C13H16N6+H]+ (m/z)
Preparation 1; 4-Methyi-3,4,5,6-tetrahydro-2H-[1,2'lbip(at)rrazinyl-3'-carbaldehyde; n-BuLi (56 mmol, 22.4 mL, 2.5 M in hexanes) was added to tetrahydrofuran (300 mL) cooled to-78 C followed by the addition of 2,2-6,6-tetramethylpiperidine (52 mmol, 8.71 mL). The solution was removed from the cooling bath and stirred for 30 minutes and then cooled back to -78C. 2-chloropyrazine (40 mmol, 3.65 mL) was added dropwise, and the solution turned a reddish-brown color. After stirring 30 minutes, methylformate (60 mmol, 3.7 mL) was added and the reaction mixture was stirred for 2.25 hrs at -78C. Acetic acid (8 mL) was added and the mixture was warmed to 0C, was washed 3 times with 1: 1 brine-water, dried over sodium sulfate, and then concentrated in vacuo. The residue was dissolved in 1,4- dioxane (250 mL) and 1-methylpiperazine (60 mmol, 6.6mL) and potassium carbonate solution (8.28g in 60 mL of water) were added and the mixture was heated at 100C for 1.5 hours. After cooling to room temperature, the mixture was filtered through a Celite pad which was then washed with chloroform. The filtrate was concentrated in vacuo and purified by silica gel chromatography (100: 1:1 chloroform-methanol-ammonium hydroxide) to yield 3.3 g (40% yield for two steps) of 4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-carbaldehyde; ¹3C NMR (100 MHz, CDC13) d 191.7,154.3, 145.3,134.5, 133.2, 55.1, 48.7, 46.3; MS (AP/CI) 207.2 (M+H)+.
With potassium fluoride; copper(l) iodide; palladium diacetate; catacxium A; In N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere;
General procedure: 2-Trimethylsilylpyridine (1.2mmol), the aryl halide (1mmol), palladium acetate (0.10mmol), CataXCium A (0.2mmol), CuI (76mg, 0.4mmol) and KF (2.20mmol) were combined in reaction tubes in a Radleys green-house parallel synthesiser under a flow of nitrogen and degassed DMF (1ml) was added. The resulting suspensions were stirred at 90 oC under nitrogen for 12 hours. Reactions were analysed by LC-MS at 1mg/1ml in methanol to determine the yield.
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In Isopropyl acetate; water; at 64.0℃; for 2.0h;Inert atmosphere;
[0243] fer^Butyl-5-(pyrazin-2-yl)-picolinate (34h- 1). The 250 mL flask was charged with tert-butyl 5-bromopicolinate 34h-4 (12.9 g, 50 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (13.9 g, 55 mmol), KOAc (9.8 g, 100 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.408 g, 0.5 mmol) and THF (80 mL). The flask was sealed under nitrogen and the mixture was stirred at 80 C for 24 hours. After completion of the reaction, it was cooled to room temperature and filtered through Celite. The filtrate was taken in 500 mL 4-necked RB flask and charged with aqueous K2C03 solution (13.8 g in 100 ml Of water), 2-chloropyrazine (6.8 g, 60 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.204g, 0.25 mmol). The reaction mixture was stirred at 64 C for 2 h under nitrogen, cooled to room temperature and filtered through Celite. The filtrate was diluted with i-PrOAc (100 mL) and the aqueous layer separated. The organic layer was washed with water (2 X 100 mL), concentrated to -20 mL of volume and diluted with heptane (200 mL). The solid was collected by filtration, washed with heptane (50 mL), and dried at 40 C to obtain 34h-l as a pale yellow solid.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 1h;Inert atmosphere; Microwave irradiation;
General procedure: To an oven-dried microwave vial was added ethyl <strong>[4570-45-0]2-amino-1,3-oxazole</strong>-5-carboxylate (546 mg, 3.50 mmol), Cs2CO3 (2279 mg, 6.99 mmol), Pd2(dba)3 (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. 2,4-Dichloropyridine (0.378 mL, 3.50 mmol) was added via syringe, followed by 1,4-dioxane (18 mL) (degassed) and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. CH2Cl2 (40 mL) was added to the crude reaction mixture together with silica (5 g). The solvents were removed under reduced pressure and the crude product was purified by flash silica chromatography with CH2Cl2 (containing 1% methanolic ammonia) as eluent.The resulting brown solid was triturated with Et2O to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (626 mg, 67%) as a pale yellow solid, which was collected by filtration and dried under vacuum.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 1.0h;Inert atmosphere; Microwave irradiation;
General procedure: To an oven-dried microwave vial was added <strong>[113853-16-0]ethyl 2-amino-1,3-oxazole-5-carboxylate</strong> (546 mg, 3.50 mmol), Cs2CO3 (2279 mg, 6.99 mmol), Pd2(dba)3 (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. 2,4-Dichloropyridine (0.378 mL, 3.50 mmol) was added via syringe, followed by 1,4-dioxane (18 mL) (degassed) and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. CH2Cl2 (40 mL) was added to the crude reaction mixture together with silica (5 g). The solvents were removed under reduced pressure and the crude product was purified by flash silica chromatography with CH2Cl2 (containing 1% methanolic ammonia) as eluent.The resulting brown solid was triturated with Et2O to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (626 mg, 67%) as a pale yellow solid, which was collected by filtration and dried under vacuum.
With (R)-(-)-di-tert-butyl-{1-(S)-[2-(dicyclohexylphosphanyl)ferrocenyl]ethyl}phosphine; palladium diacetate; sodium t-butanolate; In 1,2-dimethoxyethane; at 100℃; for 4h;
w-[(3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(1 H-indol-5-yl)-A -2- pyrazinylbenzamide(a) 1 ,1 -Dimethylethyl (3S)-3-[(2-pyrazinylamino)methyl]-1 -pyrrolidinecarboxylateA 20 mL tube-shaped pressure bottle was charged with 3-chloropyridine (0.200 g) and dimethylethyl (3S)-3-(aminomethyl)-1 -pyrrolidinecarboxylate (0.437g) in 1 ,2- dimethoxyethane (DME) (5 mL), followed by sodium tert-butoxide (0.252 g), palladium (II) acetate (12 mg, 0.040 mmol) and (R)-(-)-di-tert-butyl-{1 -(S)-2- [(dicyclohexylphosphanyl)ferrocenyl]ethyl}phosphine (29 mg) to give a yellowsuspension.The reaction vessel was sealed and heated with stirring at 100 C for 4 hr. The crude reaction mixture was poured directly onto a 20 g silica gel pad and eluted with 10 x 100 mL EtOAc/hexanes 1 :1. The appropriate fractions were pooled and evaporated to dryness to afford 240 mg of the titled compound, which was used without furtherpurification.
With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110.0℃; for 24h;
General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n.
90%
With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110.0℃; for 24h;
General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n.
90%
With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110.0℃; for 24h;
General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a-k, and4m are known compounds [6,9] except for 4l and 4n.
With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110℃; for 24h;
General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a?k, and4m are known compounds [6,9] except for 4l and 4n.
78%
With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110℃; for 24h;
General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a?k, and4m are known compounds [6,9] except for 4l and 4n.
78%
With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate; In 1,4-dioxane; at 110℃; for 24h;
General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a?k, and4m are known compounds [6,9] except for 4l and 4n.
With ammonium peroxodisulphate; at 90℃; for 26.0h;
The starting compound 3-chloropyrazine-2-carboxamide was synthesized using two published procedures. The first method was classified as less effective and was based on the homolytic amidation of 2-chloropyrazine. Thus, 2-chloropyrazine (0.17 mol) was dissolved in formamide (3.7 mol), heated to 90 C and ammonium peroxodisulphate (0.18 mol) was added portionwise over one hour period. This mixture reacted for another one hour at 90 C and then it was left to stand for 24 h at laboratory temperature. Dilution with 100 mL of water was followed by filtration and this filtrate was extracted continuously with chloroform for 16 h [34,42]. The mixture of three positional isomers was separated by flash chromatography using silica gel as stationary phase. The second process used 3-chloropyrazine-2-carbonitrile, which was submitted to partial hydrolysis of the nitrile group. The powdered carbonitrile (0.104 mol) was added little by little into the reaction mixture of concentrated hydrogen peroxide (0.95 mol) and water (195 mL) heated to 50 C. The pH was adjusted and regulated around a value of 9 using an 8% solution of sodium hydroxide and the temperature of the reaction was regulated between 55 and 60 C. The reaction was stopped after 2.5 h and was cooled to 5 C. Newly-emerged crystals were removed by suction and recrystallized from ethanol [42].
With C37H44ClN2O3PPd; caesium carbonate; In water; at 100℃; for 12h;Schlenk technique; Inert atmosphere;
General procedure: In a Schlenk tube, a mixture of the required amount of catalyst, plus the aryl chloride (1.0 mmol), aryl boronic acid (1.5 mmol) and the selected base (2.0 mmol) in water was evacuated and charged with nitrogen. The reaction mixture was heated at 100°C for 12 h. After cooling, the mixture was extracted with CH2Cl2 and the extract was evaporated. The resulting residue was purified by flash chromatography on silica gel using a mixture of CH2Cl2/ethyl acetate (5/1) as eluent. The known products 5, 6a [17,18], 6b [22], 6c [23], 6e [24], 6g [19], 6h [25] and 7a [26] were characterized by comparison of data with those in the literature. The products 6d, 6f and 7b?h were new compounds and characterized by elemental analysis, MS, 1H and 13C NMR.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 125℃; for 6h;
A mixture of K2C03 (29.19 g, 211.2 mmol), <strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (25 g, 169.0 mmol) and 2-chloropyrazine (19.36 g, 169.0 mmol) inNMP (130 mL) was heated at 125 °C for 6 hrs. The reaction was quenched with water (300 mL) and stined for lh. The solids were collected, washed with water, ether and dried to give 2-(3-bromo-1,2,4-triazol-1-yl)pyrazine (32 g, 83.8percent). ?H NMR (300 MHz, CD3OD+CDC13) oe 9.40 - 9.05 (m, 2H), 8.70 (d, J = 2.5 Hz, 1H), 8.56 (dd, J = 2.5, 1.5 Hz, 1H) ppm. ESI-MS m/z calc. 224.97, found 226.29 (M+1)+; Retention time: 0.75 minutes
1-(2'-pyrazinyl)-4-(N-Boc-N-methyl)aminopiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;
General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.
Under nitrogen protection,To a solution of 2,2,6,6-tetramethylpiperidine (72.8 g, 516.3 mmol)In 500 mL of dry THF solution,N-BuLi (346 mL, 553.7 mmol, 1.6 mol / L THF) was slowly added dropwise at -78 &After completion of the reaction, the reaction mixture was warmed to 0 C and the reaction was continued for 20 min.The reaction mixture was then cooled to -78 C,A solution of 2-chloropyrazine (50 g, 436.3 mmol) in THF (100 mL) was added dropwise to the reaction mixture,30min plus finished,The color of the reaction mixture changed from light yellow to dark brown,The reaction was continued for 10 min at -78-0 degC.DMF (84 ml, 1092 mmol)Was dissolved in THF (50 mL) dropwise dropwise into the reaction mixture,Control the reaction system temperature at -70 ~ -78 ,10min plus finished,The reaction was stirred at -78 C for 2 h.To the reaction mixture was then added MeOH (800 mL)To the reaction mixture, NaBH4 (33 g, 868 mmol) was added portionwise,After the addition, the reaction mixture was allowed to rise to room temperature and stirring continued for 2 h,TLC shows the raw material reaction is complete,The reaction solution was quenched with saturated NH4Cl,DCM (1 L x 3) was extracted three times,The organic phase was washed with water,Anhydrous Na2SO4 fully dried,After vacuum evaporation, the residue was purified by silica gel column (PE / EA = 100/1 to 5/1) to give 60 g of the title compound
2-(4'-N,N-diphenylamino[1,1'-biphenyl]-4-yl)pyrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 15h;Reflux; Schlenk technique;
General procedure: A stirred mixture of halogeno derivative (1mmol), arylboronic acid (1.2mmol), Pd(PPh3)4 (0.05mmol), aqueous 1M sodium carbonate (2.2mmol, 2.2mL) and ethanol (1.5mL) in degassed toluene (10mL) was heated at reflux under nitrogen for 15h in Schlenk tube. The reaction mixture was cooled, filtered, and dissolved with a mixture of AcOEt and water 1:1(50mL) and the organic layer was separated. The aqueous layer was extracted with AcOEt (2×25mL). The combined organic extracts were dried with MgSO4 and the solvents evaporated.
tert-butyl (1-(pyrazin-2-yl)azetidin-3-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 1h;
To a reaction vial with terf-butyl azetidin-3-ylcarbamate hydrochloride (902 mg, 5.24 mmol) in acetonitrile (15 mL) was added 2-chloropyrazine (600 mg, 5.24 mmol) and N,N- diisopropylethylamine (1 .37 mL, 7.86 mmol). The mixture was heated to 100 C for 1 h, heated to 90 C overnight, cooled, and concentrated. The resulting residue was purified on silica gel eluting with a 5%-20% MeOH in DCM gradient to give the title compound (595 mg, 45%) as a white solid. 1H NMR (400 MHz, CD3OD) delta 1 .47 (s, 9 H), 3.94 (dd, J = 8, 6 Hz, 2 H), 4.38 (t, J = 8 Hz, 2 H), 4.58 (d, J = 6 Hz, 1 H), 7.83 (dd, J = 1 1 , 2 Hz, 2 H), 8.03 (dd, J = 3, 2 Hz, 1 H); LC- MS (LC-ES) M+H = 251 .
tert-butyl 3-(hydroxymethyl)-4-(pyrazin-2-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 18h;Inert atmosphere; Sealed tube;
2-Chloropyrazine (250 mg, 2.18 mmol), <strong>[301673-16-5]tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate</strong> (495 mg, 2.29 mmol), (+/?) BINAP (14 mg, 0.02 mmol), Pd(OAc)2 (25 mg, 0.11 mmol) and cesium carbonate (1.4 g, 4.4 mmol) were suspended in anhydrous de-gassed toluene (10 ml). The mixture was de-gassed with nitrogen for 5 minutes then sealed under a nitrogen atmosphere and stirred at 100° C. for 18 h. The reaction mixture was cooled to rt and filtered through Celite, washing with EtOAc. The filtrate was concentrated in vacuo. The resultant orange oil was purified by flash column chromatography eluting with gradient from 0-100percent EtOAc in heptane followed by 0-100percent MeOH in EtOAc. The product containing fractions were combined and concentrated in vacuo to give a yellow oil. The oil was purified by preparative HPLC [UV-Directed High pH prep method]. The fractions containing product were combined and concentrated in vacuo to yield the title compound as a clear gel (170 mg, 25percent). 1H NMR (250 MHz, Chloroform-d) delta 8.17-8.12 (m, 1H), 8.06-7.99 (m, 1H), 7.86 (d, J=2.6 Hz, 1H), 4.54-4.42 (m, 1H), 4.35-3.90 (m, 3H), 3.78-3.59 (m, 2H), 3.18 (s, 4H), 1.49 (s, 9H). LCMS Method 1?Tr=1.03 min (ES+) (M+H)+ 295.3
tert-butyl (1R,3s,5S)-3-pyrazin-2-yloxy-8-azabicyclo[3.2.1]octane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With potassium tert-butylate; In tetrahydrofuran; for 16h;Reflux;
General procedure: . Following GP2, t-BuOK (0.1 g, 1 eq., 0.88 mmol) was added to a solution of <strong>[194222-05-4]tert-butyl (1R,3s,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate</strong> (0.2 g, 1 eq., 0.88 mmol), and 2-chloropyrazine (0.08 mL, 1 eq., 0.88 mmol) in dry THF (7 mL). The reaction mixture was refluxed for 16 h. Then, the mixture was quenched with water (15 mL) and extracted with DCM (210 mL). The organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with DCM/MeOH (95:5) to give the pure title compound as white solid (0.096 g, 36%). UPLC-MS: tR=2.27 min (generic method); MS (ESI) m/z calcd for C16H24N3O3 (M+H)+: 306.2, found: 306.2.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃;Inert atmosphere;
To degassed dioxane (10mL) were added sequentially 5- trifluoromethylpyridin-3-amine (2) (309mg, 1.9mmol), 2-chloropyrazine (1) (0.26mL, 2.86mmol), Pd2(dba)3 (52mg, 0.06mmol), XantPhos (66mg, 0.1 1 mmol) and Cs2C03 (1.24g, 3.8mmol) with continued degassing. The reaction mixture was heated up to 90C overnight. An additional portion of 2-chloropyrazine (0.17ml_, 1.91 mmol) was then added and the reaction mixture was heated up to (0304) 90C overnight. Once cooled down to rt, it was poured into H20 (20ml_) and extracted with EtOAc (3 x 20ml_). The combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel column chromatography with hexane/EtOAc (1 :0-1 :2) gave a residue which was re- dissolved in CH2CI2/MeOH (4:1 , 50ml_) and swirled with MP-TMT resin (440mg, 1.3mmol/g) at rt overnight. The solution was filtered, the resin washed with CH2CI2/MeOH (4:1 , 100ml_) and the filtrate concentrated in vacuo to yield (3) as a yellow solid (202mg, 44%). (0305) LCMS (ES): Found 241.0 [M+Hf. (0306) 1H NMR (300 MHz, DMSO-cf6), d: 10.14 (s, 1 H), 9.00 (d, J=2.4 Hz, 1 H), 8.69 (t, J= 2.0 Hz, 1 H), 8.52 (d, J=0.9 Hz, 1 H), 8.32 (d, J=1.5 Hz, 1 H), 8.25 (dd, J= 2.8, 1.5 Hz, 1 H), 8.08 (d, J= 2.8 Hz, 1 H). (0307) 19F NMR (282 MHz, DMSO-cf6), d: -61.09 (s, 3F).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere;
Under Ar(g), to a mixture of pyrazin-2-amine (1) (209mg, 2.2mmol), 2- chloro-4-methoxypyrimidine (2) (289mg, 2.0mmol), Cs2C03 (1.30g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13ml_). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt and concentrated in vacuo, CH2CI2 (15ml_) and H20 (15mL) were added. The organic phase was separated and the water layer was extracted with CH2CI2 (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (55mg, 14%).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere;
Under Ar(g), to a mixture of 2-chloropyrazine (1) (252mg, 2.2mmol), 2- amino-4,6-dimethylpyrimidine (2) (246mg, 2.0mmol), Cs2C03 (1.3g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13ml_). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt and concentrated in vacuo, CH2CI2 (15ml_) and H20 (15ml_) were added. The organic phase was separated and the water layer was extracted with CH2CI2 (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (159mg, 39%).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃;Inert atmosphere;
A suspension of 2-chloropyrazine (1) (250mg, 2.3mmol), 2-amino-3- methylpyrazine (2) (0.23mL, 2.5mmol), Cs2C03 (1.5g, 4.6mmol), Pd2(dba)3 (105mg, 0.12mmol) and Xantphos (148mg, 0.26mmol) in dioxane (15ml_) was degassed with Ar(g) for 20min. The reaction mixture was then heated up to 90C overnight. Once cooled down to rt, it was partitioned between EtOAc (35mL), H20 (10mL) and brine (5ml_). The organic phase was separated and the aqueous phase extracted with EtOAc (2 x 10ml_). The combined organics extracts were dried (MgS04) and concentrated in vacuo. Purification by SCX-2 with CH2CI2/MeOH (1 :0-1 :4) then 0.3M NH3 gave a residue. Pre-washed MP- TMT (ca. 400mg, 1.3mmol/g) was added to the residue dissolved in CH2CI2/MeOH (1 : 1 , 30ml_), which was then agitated overnight. The resin was removed by filtration and the solution concentrated in vacuo. Purification by silica gel column chromatography with hexane/EtOAc (1 :0-3:7) yielded (3) as a light yellow solid (310mg, 72%). (0401) LCMS (ES): Found 188.1 [M+Hf. (0402) 1H NMR (300 MHz, DMSO-cfe), d: 9.24 (s, 1 H), 9.10 (d, J=1.3 Hz, 1 H), 8.30 (dd, (0403) J= 2.6, 1.5 Hz, 1 H), 8.18 (d, J= 2.6 Hz, 1 H), 8.08-8.16 (m, 2H), 2.55 (s, 3H).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃;Inert atmosphere;
4.8mmol), Pd2(dba)3 (184mg, 0.20mmol), XantPhos (233mg, 0.40mmol) and Cs2C03 (2.6g, 8.0mmol) were added sequentially with continued degassing. The reaction mixture was degassed with Ar(g) for a further 15min then heated up to 90C overnight. Once cooled down to rt, the reaction mixture was poured into H20 (20ml_) and extracted with EtOAc (5 x 30ml_). The combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel column chromatography with hexane/EtOAc (1 :0-0: 1 ) then CH2CI2/EtOAc (1 :0-1 :1 ), then re-dissolved in CH2CI2/MeOH (4:1 , 50mL) and swirled with MP-TMT resin (1.2g, 1.1 mmol/g) at rt overnight. The solution was filtered, the resin washed with CH2CI2/MeOH (4:1 , 100ml_) and the filtrate concentrated in vacuo to yield (3) as an off-white solid (600mg, 73%). (0436) LCMS (ES): Found 204.1 [M+Hf. (0437) 1H NMR (300 MHz, DMSO-cf6), d: 10.05 (s, 1 H), 8.81 (d, J=1.3 Hz, 1 H), 8.65 (d, J=1.5 Hz, 1 H), 8.19 (dd, J= 2.6, 1.5 Hz, 1 H), 8.06 (d, J=1.3 Hz, 1 H), 8.03 (d, J= 2.6 Hz, 1 H), 3.88 (s, 3H).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 21h;Inert atmosphere;
Dioxane (10mL) was degassed with Ar(g) for 20min before 2-amino-6- methoxypyrazine (2) (310mg, 2.48mmol), 2-chloropyrazine (1) (0.026mL, 2.97mmol), Pd2(dba)3 (68mg, 0.074mmol), XantPhos (86mg, 0.15mmol) and Cs2C03 (1.6g, 4.96mmol) were added sequentially with continued degassing. The reaction mixture was degassed with Ar(g) for a further 10min then heated up to 90C for 21 h. After cooling to rt, the reaction mixture was poured into a brine solution (50%, 20ml_) and extracted with EtOAc (4 x 30ml_). The combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with hexane/EtOAc (1 :0-1 :4), then re-dissolved in CH2CI2/MeOH (4:1 , 50ml_) and swirled with MP- TMT resin (600mg, 1.1 mmol/g) at rt overnight. The solution was filtered, the resin washed with CH2CI2/MeOH (4:1 , 100ml_) and the filtrate concentrated in vacuo. A second purification by silica gel column chromatography with hexane/EtOAc (1 :0-2: 1 ) yielded (3) as an off-white solid (385mg, 64%). (0510) LCMS (ES): Found 204.1 [M+Hf. (0511) 1H NMR (300 MHz, DMSO-cf6), d: 10.27 (s, 1 H), 9.03 (d, J=1 .5 Hz, 1 H), 8.59 (s, (0512) 1 H), 8.30 (dd, J= 2.6, 1.5 Hz, 1 H), 8.16 (d, J= 2.6 Hz, 1 H), 7.82 (s, 1 H), 3.94 (s, (0513) 3H).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere;
Under Ar(g), to a mixture of 2-chloropyrazine (1) (252mg, 2.2mmol), 4- Amino-2-methoxypyrimidine (2) (250mg, 2.0mmol), Cs2C03 (1.3g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13mL). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt. EtOAc (15ml_), H20 (10mL) and brine (5ml_) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (45mg, 1 1 %).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere;
Under Ar(g), to a mixture of 2-chloropyrazine (1) (252mg, 2.2mmol), 4- amino-6-methoxypyrimidine (2) (250mg, 2.0mmol), Cs2C03 (1.3g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13ml_). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt. EtOAc (15ml_), H20 (10mL) and brine (5mL) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (177mg, 44%). (0636) LCMS (ES): Found 204.2 [M+Hf.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere;
aminopyrimidine (2) (504mg, 5.0mmol), 2-chloropyrazine (1) (0.54mL, 6.0mmol), Pd2(dba)3 (138mg, 0.15mmol), XantPhos (175mg, 0.30mmol) and Cs2C03 (3.29g, 10.1 mmol) were added sequentially with continued degassing. The reaction mixture was degassed with Ar(g) for a further 10min then heated up to 90C overnight. Once cooled down to rt, it was poured into H20 (25ml_) and extracted with EtOAc (3 x 35ml_). The combined organic extracts were dried over MgS04, filtered, concentrated in vacuo and purified by silica gel column chromatography with CH2CI2/MeOH (1 :0-12: 1 ). The residue was re-dissolved in CH2CI2/MeOH (4: 1 , 50ml_) and swirled with MP-TMT resin (1.2g, 1.3mmol/g) at rt overnight. The solution was filtered, the resin washed with CH2CI2/MeOH (4:1 , 100ml_) and the filtrate concentrated in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1 :0-16:1 ) then reverse-phase column chromatography with H20/MeCN (1 :0-9: 1 ) yielded (3) as an off-white solid (66mg, 8%). (0709) LCMS (ES): Found 174.1 [M+Hf.1H NMR (300 MHz, DMSO-cf6), d: 9.13 (s, 2H), 8.77 (s, 1 H), 8.30 (d, J=1.3 Hz, 1 H), 8.20 (dd, J= 2.8, 1.3 Hz, 1 H), 8.04 (d, J= 2.8 Hz, 1 H).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90.0℃; for 40.0h;Inert atmosphere;
Under Ar(g), to a mixture of 2-chloropyrazine (1) (193mg, 1.7mmol), 2- (trifluoromethyl)pyrimidin-5-amine (2) (250mg, 1.5mmol), Cs2C03 (0.99g, 3.0mmol) was added degassed dry 1 ,4-dioxane (13mL). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (70mg, 0.08mmol) and Xantphos (98mg, 0.17mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt and concentrated in vacuo, CH2CI2 (15ml_) and H20 (15mL) were added. The organic phase was separated and the water layer was extracted with CH2CI2 (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (17mg, 5%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90.0℃; for 40.0h;Inert atmosphere;
Under Ar(g), to a mixture of 2-chloropyrazine (1) (252mg, 2.2mmol), 2,4- dimethyl-5-pyrimidinamine (2) (246mg, 2.0mmol), Cs2C03 (1.30g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13mL). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt. EtOAc (15mL), H20 (10mL) and brine (5mL) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15mL). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4mL) and purified by basic prep LCMS to yield (3) as a solid (92mg, 23%). (0777) LCMS (ES): Found 202.4 [M+Hf.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere;
To a mixture of 2-chloropyrazine (1) (252 mg, 2.20 mmol, 1.1 eq), 3- (trifluoromethyl)pyridin-2-amine (2) (324 mg, 2.00 mmol, 1.0 eq) and Cs2C03 (1.30 g, 4.00 mmol, 2.0 eq) was added predegassed 1 ,4-dioxane (13 ml_) and the resulting suspension was degassed with Ar(g) for 1 min. Pd2(dba)3 (91.6 mg, 0.100 mmol, 5 mol%) and XantPhos (127 mg, 0.220 mmol, 1 1 mol%) were then added and the reaction was stirred at 90 C for 40 h. After cooling to room temperature, H20 (10 ml_) and brine (5 ml_) were added and the mixture was extracted with EtOAc (2 x 15 ml_). To the combined organic extracts was added MP-TMT resin (1.3 mmol g-1 , -400 mg) and the mixture was swirled for several hours then filtered and the filtrate concentrated in vacuo. Purification by basic prep LCMS yielded intermediate 3 (138 mg, 29%). (1226) LCMS (ES): Found 241.2 [M+Hf.
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