* 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.
With N-Bromosuccinimide In acetonitrile for 2 h; Heating / reflux
A mixture of methyl 3-aminopyrazine-2-carboxylate (6.30 g, 41.14 mmol, 1 eq.) andiV- o bromosuccinimide (7.322 g, 41.14 mmol, 1 eq.) in 100 mL acetonitrile was refiuxed for 2 h until there was no starting material left according to LC/MS. The solvent was removed in vacuo. To the residue was added isopropanol. After filtration, the crude product was collected as a solid. Additional product could be collected from the mother solution. Thus, 12.136 g of crude product was obtained (127 percent). The crude product was used directly in 5 the next step without further purification.1H NMR (400 MHz, DMSO-cfc) δ (ppm) 3.85 (s, 3H)5 7.55 (br s, 2H), 8.42 (s, IH).
94%
Stage #1: at 45℃; for 0.833333 h; Stage #2: at 20℃; for 0.5 h;
Methyl 3-AMINO-2-PYRAZINE-CARBOXYLATE (10 g, 65.3 mmol) was dissolved in glacial acetic acid (50 mL) by warming to approximately 45oC. To the warm solution was added bromine (3-7 MOL) in acetic acid (5 mL) dropwise and the resulting mixture was stirred at room temperature for 20 minutes. The solution was diluted with water (300 ML) and then stirred at room temperature for 30 minutes, which resulted in a precipitate. The precipitate was then filtered, washed with water and dried to afford methyl 3-AMINO-6-BROMO-2-PYRAZINE-CARBOXYLATE as a yellow solid (14. 2 g, 94 percent). IH NMR (300 MHz, CDC13) 63. 99 (s, 3 H), 8.30 (s, 1 H) ; 13C NMR (100 MHZ, CDC13) A 53.02, 123.49, 124.85, 150.24, 154.70, 166.04.
93%
With bromine; acetic acid In water at 25 - 45℃; for 1 h;
Example 58; Step 1; A solution of bromine (10 mL, 190 mmol) in acetic acid (10 mL) was added dropwise to a solution of 1 (20 g, 130 mmol) in glacial acetic acid (100 mL) at 45° C. The resulting mixture was stirred at 25° C. for 30 min. After completion of reaction (reaction progress was monitored by TLC), the solution was diluted with water (600 mL) and then stirred at RT for another 30 min. A yellow solid precipitated out, which was filtered, washed with water and dried to afford compound 2 as yellow solid (28.5 g, 93percent). MS m/z (ES): 232 (M+H)+.
92%
With N-Bromosuccinimide In acetonitrile at 20℃;
Step 1 : Methyl S-amino--bromopyrazine-l-carboxylate[00210] A mixture of methyl 3-aminopyrazine-2-carboxylate (8.35 g, 54.53 mmol) and N- bromo-succinimide (9.705 g, 54.53 mmol) was stirred in MeCN (100 mL) at room temp overnight. The resultant precipitate was filtered, washed with MeCN and dried to give the desired product as a yellow solid (11.68 g, 92percent Yield) 1H NMR (400.0 MHz, DMSO) 3.85 (s, 3H), 7.55 (br s, 2H) and 8.42 (s, IH) ppm; MS (ES+) 233
92%
With N-Bromosuccinimide In acetonitrile at 20℃;
Example 1 : 5-Amino-6-(6-methyl-lH-benzimidazol-2-yl)-N-(tetrahydrofuran-2- ylmethyl)pyrazine-2-carboxamide (Compound 11-52)SCHEME IMETHOD A:Step 1: Methyl 3-amino-6-bromopyrazine-2-carboxylate[00139] A mixture of methyl 3-aminopyrazine-2-carboxylate (8.35 g, 54.53 mmol) and N- bromo-succinimide (9.705 g, 54.53 mmol) was stirred in MeCN (100 mL) at ambient temperature overnight. The resultant precipitate was filtered, washed with MeCN and dried to give the desired product as a yellow solid (1 1.68 g, 92percent Yield)XH NMR (400.0 MHz, DMSO) δ 3.85 (s, 3H), 7.55 (br s, 2H) and 8.42 (s, 1H) ppm; MS (ES+) 233.0
92%
With N-Bromosuccinimide In acetonitrile at 20℃; for 16 h;
Example 1 ; 3-Methyl-6-(4-(methvlsulfonvl)phenyl)-iV-phenvlpvrazine-2-carboxamide (Compound IV-1)SMETHOD A:Step 1: Methyl 3-amino-6-bromopyrazine-2-carboxylate [00141] A mixture of methyl 3-aminopyrazine-2-carboxylate (8.35 g, 54.53 mmol) and N- bromo-succinimide (9.705 g, 54.53 mmol) was stirred in MeCN (100 mL) at RT for 16 hours. The resultant precipitate was filtered, washed with MeCN and dried to give the desired product as a yellow solid (11.68 g, 92percent Yield) XH NMR (400.0 MHz, DMSO) δ 3.85 (s, 3H), 7.55 (br s, 2H) and 8.42 (s, 1H) ppm; MS (ES+) 233.
89%
With N-Bromosuccinimide In acetonitrile at 20℃;
Compound 2 (27.6 g, leq) was added to acetonitrile (276 ml)Stir at room temperature,NBS (25.1 g, 1.01 eq) was added in portions,Stirred at room temperature overnight,TLC showed that after the reaction (20 ~ 30 h)Add water (300 ml)The pH was adjusted to 7 with Na2CO3 solution,Ethyl acetate extraction (3 x 50 ml),Combined organic phase,Dried over anhydrous sodium sulfate and filtered,The solvent was distilled off under reduced pressure,To give crude 3-amino-6-bromopyrazine-2-carboxylic acid methyl ester,30 times the dichloromethane was added (the weight ratio of the crude product to methylene chloride was 1:25 ° C)50) After refluxing for 0.5 h,Filter,The mother liquor was distilled off to dichloromethane,And then 20 times the ethanol (steamed and ethanol weight ratio of 1:5 to 30) recrystallization,Crystallization at 25 to 30 ° C gives a pale yellow solid 3,Yield 89percent.
87%
With N-Bromosuccinimide In acetonitrile at 20℃; for 24 h; Inert atmosphere
Methyl 3-aminopyrazine-2-carboxylate (15 g, 1 eq) wassuspended in 150 mL acetonitrile and NBS (18.3 g, 1 eq)was added in batches under the protection of N2. Then, thesolution was stirred at room temperature for 24 h. Subsequently,the mixture was adjusted to pH 7–8 which wasmonitored by extensive pH indicator paper by progressivelyadding Na2CO3 (20percent, m/m, 10 mL) aqueous solutionat 0 C. Then, the solution was filtered. The filterresidue was collected and dried under reduced pressure toobtain a brown-colored solid. The crude product was thendissolved into 0.8 L dichloromethane by heating to refluxfor 30 min. The suspension was filtered to remove theinsoluble impurities. Then, the solvent was removed underreduced pressure. Afterward, the residue was redissolvedinto 0.7 L EtOH (95percent). The suspension was heated toreflux for 30 min and filtered to crystallize. Then, the filtratewas cooled to 25–30 C which was kept for 4 h. Thecrystal of pure 3 (19.7 g, 87percent) (TLC, EA:PE = 1:2, v/v,Rf = 0.64) could be obtained in open system.Methyl 3-amino-6-bromopyrazine-2-carboxylate (3)Yield: 87percent, yellow crystals, granular, m.p.: 174–176 C(Lit. 175.3–175.9 C) (Caldwell et al. 2012). 1H-NMR(400 MHz, DMSO-d6): d 8.43 (s, 1H), 7.57 (s, 2H) 3.86 (s,3H). 13C-NMR (101 MHz, DMSO-d6): d 165.27, 154.86,150.04, 122.56, 122.31, 52.24. MS (EI): m/z = 232.0 (M?,Br79, 45), 234.0 (M?, Br81, 45), 201.0 (M?, –OCH3, Br79,30), 203.0 (M?, –OCH3, Br81, 20), 173.0 (M?, –COOCH3,Br79, 100), 175.0 (M?, –COOCH3, Br81, 100), 146.0 (Br79,15), 148.0 (Br81, 10).
82%
With N-Bromosuccinimide In acetonitrile at 20℃; for 15 h;
Methyl 3-aminopyrazine-2-carboxylate (100 g, 653.0 mmol) and N- bromosuccinimide (1 16.2 g, 653.0 mmol) were stirred in MeCN (1.198 L) at ambient temperature for 15 hours. The resultant precipitate was isolated by filtration and washed with MeCN (10 mL) and diethyl ether (100 mL) to give the sub-title product as pale yellow flakes (123.73g, 82percent Yield). 1H NMR (400.0 MHz, CDCl3) δ 4.00 (s, 3H), 6.47 (br s, 2H), 7.28 (s, 1H) and 8.31 (s, 1H) ppm; (ES+) 232.0.
Reference：
[1] Patent: WO2007/61360, 2007, A2, . Location in patent: Page/Page column 71
[2] Heterocycles, 2005, vol. 65, # 10, p. 2321 - 2327
[3] Patent: WO2004/92177, 2004, A1, . Location in patent: Page 35-36
[4] Patent: US2011/59118, 2011, A1, . Location in patent: Page/Page column 84-85
[5] Patent: WO2010/54398, 2010, A1, . Location in patent: Page/Page column 90
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2320 - 2330
[7] Patent: WO2011/143419, 2011, A1, . Location in patent: Page/Page column 44
[8] Patent: WO2011/143425, 2011, A2, . Location in patent: Page/Page column 37-38
[9] Patent: CN106866553, 2017, A, . Location in patent: Paragraph 0141; 0142; 0143; 0167; 0168; 0169
[10] Chemical Papers, 2017, vol. 71, # 11, p. 2153 - 2158
[11] Patent: WO2011/143423, 2011, A2, . Location in patent: Page/Page column 52
[12] ACS Combinatorial Science, 2011, vol. 13, # 5, p. 449 - 452
[13] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2784 - 2788
[14] Journal of the American Chemical Society, 1949, vol. 71, p. 2798
[15] Archiv der Pharmazie, 1992, vol. 325, # 12, p. 761 - 767
[16] Patent: WO2008/36272, 2008, A1, . Location in patent: Page/Page column 45
[17] Patent: WO2011/89416, 2011, A1, . Location in patent: Page/Page column 67
[18] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 6, p. 2266 - 2270
[19] Patent: WO2014/209727, 2014, A1, . Location in patent: Page/Page column 66-67
[20] Patent: WO2014/205593, 2014, A1, . Location in patent: Page/Page column 70
[21] Patent: TWI523856, 2016, B, . Location in patent: Paragraph 0067
2
[ 67-56-1 ]
[ 486424-37-7 ]
[ 6966-01-4 ]
Yield
Reaction Conditions
Operation in experiment
80.1%
at 0 - 40℃; for 48 h;
To the 3L into the reaction bottle 50.1g II, 2L methanol. 0 - 5 °C lower, to the slowly dropping 133g 98.3percent concentrated sulfuric acid, then completing, heating up to 40 °C, instead on invitation 48h to raw material II basic reaction end. turns on lathe does methanol, 0 - 5 °C lower, adding 200 ml methanol, 500g ice water mixture, wherein the aqueous solution of sodium bicarbonate to pH=6 - 7 adds by drops full and adjusted to. Filtering, the filter cake 45 °C vacuum drying 12h, get 43.2g brown solid III, yield 80.1percent
Reference：
[1] Patent: CN104496917, 2017, B, . Location in patent: Paragraph 0041; 0042; 0043; 0044; 0045
[2] ACS Chemical Biology, 2013, vol. 8, # 3, p. 519 - 523
3
[ 5424-01-1 ]
[ 6966-01-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 6, p. 2266 - 2270
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2784 - 2788
[3] Patent: CN106866553, 2017, A,
[4] Chemical Papers, 2017, vol. 71, # 11, p. 2153 - 2158
4
[ 6966-01-4 ]
[ 486424-37-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With water; lithium hydroxide In methanol at 90℃; for 5 h; Stage #2: With hydrogenchloride In methanol; water
. Step 2: 3-Amino-6-bromopyrazine-2-carboxylic acid[00140] A mixture of methyl 3-amino-6-bromo-pyrazine-2-carboxylate (5.1 1 g, 22.02 mmol) and lithium hydroxide (2.637 g, 110.1 mmol) in MeOH (20 mL) and Ι3/40 (20 mL) was heated to 90 °C for 2 hours. The reaction mixture was allowed to cool and neutralized with HCl and the resultant precipitate collected by filtration. The sub-title product was taken on to the next step without further purification (4.80g, 99percent Yield).
79%
With water; lithium hydroxide In methanol at 90℃; for 3 h;
To the solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (10.0 g 43.1 mmol) in MeOH (70 mL) was added a solution of Li OH (9.0 g, 215 mmol) in water (70 mL). The mixture was stirred at 90 °C for 3 hours. The reaction mixture was cooled to rt and acidified to PH = 4-5 with HC1 (2 M). The mixture was filtered to afford 7.4 g of 6 (79 percent) as yellow solid. (0170) [0033] LC-MS (M+l): 218.0; 1H MR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.59 (br, 2H).
78%
Stage #1: With water; lithium hydroxide In methanol at 90℃; for 2 h; Stage #2: With hydrogenchloride In methanol; water
Step 2 : 3-amino-6-bromopyrazine-2-carboxylic acid[00211] A mixture of methyl 3-amino-6-bromo-pyrazine-2-carboxylate (3 g, 12.93 mmol) and lithium hydroxide (1.548 g, 64.65 mmol) in MeOH (11.74 mL) and H2O (11.74 mL) was heated to 90 0C for 2 hours. The reaction mixture was allowed to cool, neutralised with HCl and diluted with water, and the resultant precipitate collected by filtration (2.2 g, 78percent Yield). 1H NMR (400.0 MHz, DMSO) 7.57 (br s, 2H) and 8.39 (s, IH), 13.41 (br s, IH) ppm.
64%
Stage #1: With lithium hydroxide; water In tetrahydrofuran at 20℃; for 4 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water
(Step 6-ii) To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (1 g, 4.33 mmol) in 10 mL THF was added a solution of LiOH (540 mg, 12.86 mmol) in 20 mL of water. The mixture was stirred at room temperature for 4 hours and acidified with 6M HCl to a pH of 2. The yellow precipitate was collected by filtration and washed with water. After drying in vacuo, the product, 3-amino-6-bromopyrazine-2-carboxylic acid (600 mg, 2.75 mmol, 64percent yield), can be used directly in the next reaction without further purification.
90 mg
With sodium hydroxide In methanol; water at 50℃; for 4 h;
To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (100 mg, 0.43 mmol) in MeOH (5 mL) was added 2 mL of NaOH aqueous solution (5 N). After being stirred at 50°C for 4 h, the mixture was cooled and acidified with 1 M HCl to a pH of 2. The precipitate was collected by filtration and washed with water to afford the product of 3-amino-6- bromopyrazine-2-carboxylic acid (90 mg, yield: 96percent). XH-NMR (DMSO-ifc, 400 MHz) δ 8.38 (s, 1H), 7.51-7.56 (m, 2H). MS (M+H)+: 218 / 220.
90 mg
With sodium hydroxide In methanol; water at 50℃; for 4 h;
To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (100 mg, 0.43mmol) in MeOH (5 mL) was added 2 mL of NaOH aqueous solution (5 N). After being stirred at50°C for 4 h, the mixture was cooled and acidified with 1 M HC1 to a pH of 2. The precipitate was collected by filtration and washed with water to afford the product of 3-amino-6-bromopyrazine-2-carboxylic acid (90 mg, yield: 96percent). ‘H-NMR (DMSO-d6, 400 MHz) 8.38 (s, 1H), 7.517.56 (m, 2H). MS (M+H): 218 / 220.
Reference：
[1] Patent: WO2011/143419, 2011, A1, . Location in patent: Page/Page column 44-45
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2784 - 2788
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2320 - 2330
[4] Patent: WO2017/123588, 2017, A1, . Location in patent: Paragraph 0031; 0032; 0033
[5] Patent: WO2010/54398, 2010, A1, . Location in patent: Page/Page column 90
[6] Patent: WO2008/36272, 2008, A1, . Location in patent: Page/Page column 45
[7] Journal of the American Chemical Society, 1949, vol. 71, p. 2798
[8] Patent: WO2011/89416, 2011, A1, . Location in patent: Page/Page column 67
[9] Patent: WO2014/209727, 2014, A1, . Location in patent: Page/Page column 67
[10] Patent: WO2014/205593, 2014, A1, . Location in patent: Page/Page column 70; 71
5
[ 6966-01-4 ]
[ 13301-04-7 ]
Yield
Reaction Conditions
Operation in experiment
49%
Stage #1: With hydrogen bromide; bromine; acetic acid In water at 0℃; for 0.75 h; Stage #2: With sodium nitrite In water at 0℃; for 0.5 h;
Step 2; A suspension of compound 2 (28.5 g, 120 mmol) in an aqueous solution of 48percent HBr (120 mL) and acetic acid (30 mL) was cooled to 0° C., and then treated with a solution of bromine (18 mL, 336 mmol) in acetic acid (18 mL) over a period of 45 min. A solution of NaNO2 (8.28 g, 420 mmol) in water (15 ml) was added while maintaining the temperature at 0° C., stirring was continued for further 30 min. After completion of reaction (reaction progress was monitored by TLC), the excess bromine was quenched by the drop wise addition of 30percent aqueous solution of NaHSO3 (180 mL). The resulting precipitate was filtered and purified by column chromatography on silica gel eluted with 10percent ethyl acetate in hexane to afford compound 3 as a white crystalline solid (18 g, 49percent). MS m/z (ES): 294 (M+H)+.
Reference：
[1] Patent: US2011/59118, 2011, A1, . Location in patent: Page/Page column 84-85
[2] ACS Combinatorial Science, 2011, vol. 13, # 5, p. 449 - 452
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 6, p. 2266 - 2270
[4] ACS Chemical Biology, 2013, vol. 8, # 3, p. 519 - 523
[5] Patent: TWI523856, 2016, B, . Location in patent: Paragraph 0068
6
[ 6966-01-4 ]
[ 356783-16-9 ]
Reference：
[1] Patent: CN106866553, 2017, A,
[2] Chemical Papers, 2017, vol. 71, # 11, p. 2153 - 2158
. Step 2: 3-Amino-6-bromopyrazine-2-carboxylic acid[00140] A mixture of <strong>[6966-01-4]methyl 3-amino-6-bromo-pyrazine-2-carboxylate</strong> (5.1 1 g, 22.02 mmol) and lithium hydroxide (2.637 g, 110.1 mmol) in MeOH (20 mL) and Iota¾0 (20 mL) was heated to 90 C for 2 hours. The reaction mixture was allowed to cool and neutralized with HCl and the resultant precipitate collected by filtration. The sub-title product was taken on to the next step without further purification (4.80g, 99% Yield).
79%
With water; lithium hydroxide; In methanol; at 90℃; for 3h;
To the solution of <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (10.0 g 43.1 mmol) in MeOH (70 mL) was added a solution of Li OH (9.0 g, 215 mmol) in water (70 mL). The mixture was stirred at 90 C for 3 hours. The reaction mixture was cooled to rt and acidified to PH = 4-5 with HC1 (2 M). The mixture was filtered to afford 7.4 g of 6 (79 %) as yellow solid. (0170) [0033] LC-MS (M+l): 218.0; 1H MR (400 MHz, DMSO-d6) delta 8.39 (s, 1H), 7.59 (br, 2H).
78%
Step 2 : 3-amino-6-bromopyrazine-2-carboxylic acid[00211] A mixture of <strong>[6966-01-4]methyl 3-amino-6-bromo-pyrazine-2-carboxylate</strong> (3 g, 12.93 mmol) and lithium hydroxide (1.548 g, 64.65 mmol) in MeOH (11.74 mL) and H2O (11.74 mL) was heated to 90 0C for 2 hours. The reaction mixture was allowed to cool, neutralised with HCl and diluted with water, and the resultant precipitate collected by filtration (2.2 g, 78% Yield). 1H NMR (400.0 MHz, DMSO) 7.57 (br s, 2H) and 8.39 (s, IH), 13.41 (br s, IH) ppm.
64%
(Step 6-ii) To a solution of <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (1 g, 4.33 mmol) in 10 mL THF was added a solution of LiOH (540 mg, 12.86 mmol) in 20 mL of water. The mixture was stirred at room temperature for 4 hours and acidified with 6M HCl to a pH of 2. The yellow precipitate was collected by filtration and washed with water. After drying in vacuo, the product, 3-amino-6-bromopyrazine-2-carboxylic acid (600 mg, 2.75 mmol, 64% yield), can be used directly in the next reaction without further purification.
(iv) 3-Amino-6-bromopyrazine-2-carboxylic acid: To a solution of the product of step (iii) (200 g, 0.86 mol) in MeOH (500 mL) was added 5 N-NaOH (500 mL) slowly. The resulting mixture was stirred at 50 C for 3 hours. MeOH was removed under a reduced pressure and water (300 mL) added to the reaction mixture. The solution was acidified to pH 3 with 6N-HC1. The solution was extracted with EtOAc and washed with water. The combined organic extract was dried over Na2S04, filtered and evaporated to dryness to afford the subtitle compound (iv) as a brown yellow solid (180 g). 1H-NMR (400 MHz, CDC13) delta 8.30 (s, 1H);HPLC Retention Time = 0.850min.
90 mg
With sodium hydroxide; In methanol; water; at 50℃; for 4h;
To a solution of <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (100 mg, 0.43 mmol) in MeOH (5 mL) was added 2 mL of NaOH aqueous solution (5 N). After being stirred at 50C for 4 h, the mixture was cooled and acidified with 1 M HCl to a pH of 2. The precipitate was collected by filtration and washed with water to afford the product of 3-amino-6- bromopyrazine-2-carboxylic acid (90 mg, yield: 96%). XH-NMR (DMSO-ifc, 400 MHz) delta 8.38 (s, 1H), 7.51-7.56 (m, 2H). MS (M+H)+: 218 / 220.
90 mg
With sodium hydroxide; In methanol; water; at 50℃; for 4h;
To a solution of <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (100 mg, 0.43mmol) in MeOH (5 mL) was added 2 mL of NaOH aqueous solution (5 N). After being stirred at50C for 4 h, the mixture was cooled and acidified with 1 M HC1 to a pH of 2. The precipitate was collected by filtration and washed with water to afford the product of 3-amino-6-bromopyrazine-2-carboxylic acid (90 mg, yield: 96%). ?H-NMR (DMSO-d6, 400 MHz) 8.38 (s, 1H), 7.517.56 (m, 2H). MS (M+H): 218 / 220.
A mixture of palladium (II) acetate (145 mg, 0.65 mmol) and 1,1'-bis(diphenylphosphino)-ferrocene (493 mg, 0.86 mmol) in DMF (70 ml) was stirred at 50 C. for 15 minutes and cooled to r.t. The mixture was evacuated and vented with argon. 3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (5.0 g, 21.5 mmol), furan-3-yl-boronic acid (2.79 g, 23.7 mmol) and triethylamine (4.51 ml, 32.3 mmol) were added and the reaction mixture was stirred at 90 C. for 16 h. The solvent was evaporated and the product was obtained after purification by silica gel chromatography using a heptane /ethyl acetate gradient as yellow solid (2.92 g, 61.8%). MS: M=220.2 (M+H)+
61.8%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In N,N-dimethyl-formamide; at 90℃; for 16h;Inert atmosphere;
A mixture of palladium (II) acetate (145 mg, 0.65 mmol) and l,l'-bis(diphenylphosphino)- ferrocene (493 mg, 0.86 mmol) in DMF (70 ml) was stirred at 50C for 15 minutes and cooled to r.t. The mixture was evacuated and vented with argon. 3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (5.0 g, 21.5 mmol), furan-3-yl-boronic acid (2.79 g, 23.7 mmol) and triethylamine (4.51 ml, 32.3 mmol) were added and the reaction mixture was stirred at 90C for 16 h. The solvent was evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as yellow solid (2.92 g, 61.8 %). MS: M = 220.2(M+H)+
With potassium acetate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 170℃; for 0.333333h;Microwave irradiation;
(Step 8-iv) Methyl 3-amino-6-bromopyrazine-2-carboxylate (700 mg, 3 mmol) was dissolved in dioxane (4 mL) with 3-furan boronic acid (0.36 g, 3.2 mmol), potassium acetate (980 mg 10 mmol) and tetrakispalladium triphenylphosphine (200 mg, 0.17 mmol) in a microwave vessel. Nitrogen was bubbled through for 5 minutes, followed by sealing the vessel and microirradiating the mixture for 20 minutes at 170 0C. The reaction mixture was diluted with ethyl acetate/saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to give a solid, which was purified by silica gel column chromatography (0 to 70 % EtOAc/hexanes) to give methyl 3-amino-6-(furan-3- yl)pyrazine-2-carboxylate as a solid. This methyl ester was dissolved in THF/MeOH and an aqueous solution of LiOH hydrate (150 mg, 3.6 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature, concentrated to half the volume, and diluted with ethyl acetate/10% aqueous citric acid solution. The organic layer was washed with brine, dried, and concentrated in vacuo to yield 3-amino-6-(furan-3-yl)pyrazine-2- carboxylic acid as a solid (0.46 g, 2.3 mmol, 77 % overall yield).
Methyl 3-AMINO-6-BROMO-2-PYRAZINE-CARBOXYLATE (14.3 g9 61.6 mmol; see Example 16 (a) above) was suspended in 40 % aqueous METHYLAMINE (350 mL) and the resulting mixture was stirred vigorously for 7 hours at room temperature. The precipitate was collected, washed with water, and dried to afford 3-amino-6-bromo- pyrazine-2-carboxylic acid methylamide as a yellow solid (12.7 g, 90 %). H NMR (300 MHz, DMSO-D6) S2. 77 (d, J= 3 Hz, 3 H), 7.70 (br s, 2 H), 8. 33 (s, 1 H), 8. 56 (q, J= 3 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) #27.84, 123.49, 127.69, 150.43, 156.04, 167.18.
90%
In water; at 20℃; for 4h;
Step 1 : 3-amino-6-bromo-N-methylpyrazine-2-carboxamide[00261] Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (7.5 g, 32.32 mmol) was suspended in 40% aqueous methylamine and the resulting mixture stirred vigorously at RT for 4 hours. The resultant precipitate was collected, washed with water and dried to give the desired product(6.73g, 90% Yield). IH NMR (400.0MHz, DMSO) d 2.76 (s, 3H), 7.75 (br s, 2H), 8.34 (s, IH),8.58 (b rs, IH) ppm; MS (ES+) 232.
0.15 eq. palladium (II) acetate and 0.2 eq. 1,1'-bis(diphenylphosphino)-ferrocene were combined in dimethylformamide under nitrogen and heated to 50 C. for 20 minutes. R3 and n are each as defined herein. The reaction was allowed to cool to room temperature and 1.0 eq. of the pyrazine, 1.5 eq. of the boronic acid and 1.15 eq. of triethylamine were added. The reaction was heated to 90 for 12 hours and allowed to cool to room temperature. The DMF was removed by rotary evaporation. The crude reaction mixture was dissolved in chloroform and washed twice with 1N aq. HCl and then twice with saturated aq. NaHCO3 solution. The organic layer was dried over sodium sulfate, filtered and concentrated. Material was purified by silica gel chromatography using 100% chloroform as eluent.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; water; toluene; at 85℃; for 4h;Inert atmosphere;
General Method 9Preparation of (S)-(2-(3-chlorobenzyl)pyrrolidin-1-yl)(3-hydroxy-6-phenylpyrazin-2-yl)methanone (9-6); Step 1: Methyl 3-amino-6-bromopyrazine-2-carboxylate 9-1 (0.85 g, 3.68 mmol), phenylboronic acid (0.56 g, 3.68 mmol) and 2M aqueous sodium carbonate (7.4 mL) were mixed with toluene (8 mL) and methanol (2 mL). Palladium tetrakis(triphenylphosphine) (427 mg, 0.37 mmol) was added. The mixture was degassed and heated under nitrogen at 85 C. for 4 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated and residue was separated by column chromatography (silica gel, gradient elution with DCM to 5% MeOH-DCM), to give desired product 9-2 as a yellow solid.
With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; toluene; at 115℃; for 1h;
Methyl 3-amino-6-bromopyrazine-2-carboxylate (2 g, 8.62 mmol), Pd2(OAc)3 (0.2 g, 0.89 mmol) and Xantphos (0.79 g, 1 .37 mmol) were placed in a closed vessel with toluene (30 mL) and water (1 mL). Methylboronic acid (0.78 g, 13.1 mmol) and potassium phosphate tribasic (3.42 g, 16.1 mmol) were added and the reaction mixture was heated to 1 15 C for 1 h. The reaction mixture was allowed to reach RT, and then it was filtrate on Celite and washed with DCM. The filtrate was concentrate under vacuum and purified through FC on S1O2 column (DCM: EtOAc from 98:2 to 85: 15) affording methyl 3-amino-6-methylpyrazine-2-carboxylate (p125, 870 mg, y= 60 % yield) as a beige solid. MS (mlz): 168.0 [MH]+
With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In water; toluene; for 24h;Heating / reflux;
5. Reactions which are covered by Scheme 12; Example 5.1: Preparation of 3-amino-6-methyl-pyrazine-2-carboxylic acid methyl ester; 3-Amino-6-bromo-pyrazme-2-carboxylic acid methyl ester (1.0 g) (made according to J. Org. Chem. (1988), 59(9), 2052-5), palladium(II) acetate (0.101 g), and 2'-dicyclohexylphosphino-2,6-dimethoxy-l,l'-biphenyl ("S-Phos") were placed in a flask with toluene (15 ml) and water (3 drops). Methyl boronic acid (0.394 g) and potassium phosphate (1.71 g) were added and the reaction mixture was heated to reflux for 24 hours. After allowing the reaction mixture to cool to ambient temperature, the mixture , was diluted with aqueous hydrochloric acid (IM) and extracted with ethyl acetate. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel (eluent: diethyl ether) to give 3-amino-6-methyl-pyrazine- 2-carboxylic acid methyl ester as a yellow solid (0.114 g). 1H-NMR (400 MHz, CDCl3): 2.40 (s, 3H), 3.92 (s, 3H), 6.21 (bs, 2H), 8.03 (s, IH) ppm.
With potassium phosphate; water;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In toluene; for 24h;Heating / reflux;
Example 12.2: Preparation of 3-amino-6-methylpyrazine-2-carboxylic acid methyl ester; 3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (1.0 g), palladium acetate (0.101 g), and S-Phos (2'-dicyclohexylphosphino-2,6-dimethoxy-l,l'-biphenyl) were placed in a flask, with toluene (15 mL) and water (3 drops). Methyl boronic acid (0.394 g) and potassium phosphate (1.71 g) were added and the reaction mixture was refluxed for 24 hours. After allowing the reaction mixture to cool, the mixture was diluted with aqueous hydrochloric acid (IM) and extracted with ethyl acetate. The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluent: diethyl ether) to give 3-amino-6-methylpyrazine-2-carboxylic acid methyl ester as a yellow solid (0.1 14 g).1H NMR (CDCl3): 2.40 (s, 3H), 3.92 (s, 3H), 6.21 (bs, 2H), 8.03 (s, IH) ppm.
With triethylamine;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In N,N-dimethyl-formamide; at 20 - 90℃;
To a solution of <strong>[6966-01-4]3-amino-6-bromo-pyrazine-2-carboxylic acid methyl ester</strong> (3g, 12.9 mmol) in DMF (40ml) was added 3-(hydroxymethyl)benzoic acid (2.16g, 14.22 mmol) followed by Et3N (2.7ml, 19.39 mmol) under nitrogen at room temperature. The mixture was stirred for 10 min before adding 1 ,1'-bis[dit- butylphosphino)ferrocene]paliadium chloride (0.25g, 0.039 mmol) and stirred overnight at 900C. The cooled reaction mixture was condensed. The residue dissolved in THF-EtOAc mixture (200ml, 1 :1), filtered to remove catalyst and evaporated. The filtrated was washed with brine, dried (MgSO4) and <n="18"/>condensed. The resultant brown solid residue was subjected to flash column chromatography on silica eluting gradient of hexane to (3:1 , v/v) ethyl acetate and hexane to give title compound (1.61g, 48%) as a yellow/orange solid; LC/MS: Rt 1.74 (Method A) [M+H]+ 260.
With 1,1'-bis-(diphenylphosphino)ferrocene; triethylamine;palladium diacetate; In N,N-dimethyl-formamide; at 50 - 90℃;Inert atmosphere;
A mixture of Pd(OAc)2 (146 mg, 0.7 mmol) and 1,1-bis(diphenylphosphino)ferrocene (478 mg, 0.9 mmol) in DMF (65 ml) under an argon atmosphere was stirred at 50 for 15 min and cooled to rt. The reaction mixture was evacuated, then flushed with argon. 3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (5.0 g, 21.5 mmol), 2-furanboronic acid (2.65 g, 23.7 mmol) and triethylamine (4.3 ml) were added. The reaction mixture was again evacuated, then flushed with argon. The mixture was heated at 90 overnight. After cooling to rt, the black mixture was concentrated to dryness. The residue was dissolved in dichloromethane (800 ml), washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by silica gel chromatography using a n-heptane /EtOAc gradient for elution, providing the title compound as yellow solid (2.84 g, 60%).MS: M=220.3 (M+H)+
60%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere;
A mixture of Pd(OAc)2 (146 mg, 0.7 mmol) and l,l-bis(diphenylphosphino)ferrocene (478 mg, 0.9 mmol) in DMF (65 ml) under an argon atmosphere was stirred at 50 for 15 min and cooled to rt. The reaction mixture was evacuated, then flushed with argon. 3-Amino-6-bromopyrazine- 2-carboxylic acid methyl ester (5.0 g, 21.5 mmol), 2-furanboronic acid (2.65 g, 23.7 mmol) and triethylamine (4.3 ml) were added. The reaction mixture was again evacuated, then flushed with argon. The mixture was heated at 90 overnight. After cooling to rt, the black mixture was concentrated to dryness. The residue was dissolved in dichloromethane (800 ml), washed with water, dried over MgS04, filtered and evaporated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient for elution, providing the title compound as yellow solid (2.84 g, 60%).MS: M = 220.3 (M+H)+
0.15 eq. palladium (II) acetate and 0.2 eq. 1,1'-bis(diphenylphosphino)-ferrocene were combined in dimethylformamide under nitrogen and heated to 50 C. for 20 minutes. Het is as defined herein. The reaction was allowed to cool to room temperature and 1.0 eq. of the pyrazine, 1.5 eq. of the boronic acid and 1.15 eq. of triethylamine were added. The reaction was heated to 90 for 12 hours and allowed to cool to room temperature. The DMF was removed by rotary evaporation. The crude reaction mixture was dissolved in chloroform and washed twice with 1N aq. HCl and then twice with saturated aq. NaHCO3 solution. The organic layer was dried over sodium sulfate, filtered and concentrated. Material was purified by silica gel chromatography using 100% chloroform as eluent.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 70℃; for 4h;
To 3-aminopyridine (10 g, 106 mmol) at 70 C were added methyl 3-amino-6-bromo-2- pyrazinecarboxylate (1.0 g, 4.3 mmol) and 1, 8-diazabicyclo [5.4. 0] undec-7-ene (645 UL, 4.3 mmol). The reaction solution was stirred for 4 h, diluted with water (75 mL) and extracted with methylene chloride. The combined organic layers were washed with a saturated ammonium chloride solution, dried (MGS04), filtered and evaporated in vacuo. The crude product was purified on a silica gel column using methylene chloride/ethanol, (9: 1), as the eluent to give 750 mg (59% yield) of the title compound as a yellow solid : 1H NMR (CDC13, 400 MHz) 6 9.50 (br s, 1 H), 8.82 (d, J = 3 Hz, 1 H), 8.43 (dd, J = 5 and 1 Hz, 1 H), 8.31 (s, 1 H), 8.23 (ddd, J = 8,3 and 2 Hz, 1 H), 7.34 (dd, J = 8,5 Hz, 1 H); MS (TSP) TYLZ 294 (M++1).
59%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 70℃; for 4h;
To 3-aminopyridine (10 g, 106 mmol) at 70 C were added methyl 3-amino-6-bromo-2- pyrazinecarboxylate (1.0 g, 4.3 mmol) and 1, 8-DIAZABICYCLO [5.4. 0] undec-7-ene (645 UL, 4.3 mmol). The reaction solution was stirred for 4 h, diluted with water (75 mL) and extracted with methylene chloride. The combined organic layers were washed with a saturated ammonium chloride solution, dried (MGS04), filtered and evaporated in vacuo. The crude product was purified on a silica gel column using methylene CHLORIDE/ETHANOL, (9: 1), as the eluent to give 750 mg (59% yield) of the title compound as a yellow solid: 1 H NMR (CDC13, 400 MHz) 8 9.50 (br s, 1 H), 8.82 (d, J = 3 Hz, 1 H), 8.43 (dd, J = 5 and 1 Hz, 1 H), 8.31 (s, 1 H), 8.23 (ddd, J = 8,3 and 2 Hz, 1 H), 7.34 (dd, J = 8,5 Hz, 1 H); MS (TSP) M/Z 294 (M++1).
0.15 eq. palladium (II) acetate and 0.2 eq. 1,1'-bis(diphenylphosphino)-ferrocene were combined in dimethylformamide under nitrogen and heated to 50 C. for 20 minutes. R3 and n are each as defined herein. The reaction was allowed to cool to room temperature and 1.0 eq. of the pyrazine, 1.5 eq. of the boronic acid and 1.15 eq. of triethylamine were added. The reaction was heated to 90 for 12 hours and allowed to cool to room temperature. The DMF was removed by rotary evaporation. The crude reaction mixture was dissolved in chloroform and washed twice with 1N aq. HCl and then twice with saturated aq. NaHCO3 solution. The organic layer was dried over sodium sulfate, filtered and concentrated. Material was purified by silica gel chromatography using 100% chloroform as eluent.
Triisopropyl borate (2.7 mL, 11.6 mmol) was added to a solution of 1- [ (4- bromophenyl) SULFONYL]-4-METHYLPIPERAZINE in (1.24 g, 3.87 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965, 8, 548-550) in anhydrous tetrahydrofuran (25 mL) at-78 C under an atmosphere of nitrogen, followed by dropwise addition of n-butyllithium (9.8 mL, 15.5 mmol). The resulting mixture was stirred at-78 C for 30 min, then allowed to warm to room temperature. HCl (3 M aq, 7.8 mL, 23.2 mmol) was added and the mixture was stirred at room temperature for 10 min. Sodium carbonate (4.1 g, 38.7 mmol) was added followed by the addition of <strong>[6966-01-4]methyl 3-amino-6-bromo-2-pyrazinecarboxylate</strong> (0.79 g, 3.4 mmol; described in: H. Ellingson, J. Amer. Chem. Soc. 1949,2798) and Pd (dppf) Cl2 (95 mg, 0.12 mmol). The resulting mixture was heated at 55 C overnight. Silica was added, the solvent was evaporated and the crude mixture was purified by column chromatography on silica using CHLOROFORM/METHANOL, (99: 1), as the eluent to give 0.923 g (69% yield) of the base as a yellow solid : 1HNMR (DMSO-D6) S 9.0 (s, 1 H), 8.22 (d, J = 7 Hz, 2 H), 7.80 (d, J = 7 HZ, 2 H), 7.62 (BR S, 2 H), 3.90 (s, 3 H) 2.91 (m, 4 H), 2.36 (m, 4 H), 2.12 (s, 3 H); 13CNMR (DMSO-D6) 8 166. 2,155. 1,145. 8,140. 33,127. 5,134. 0,128. 1, 125.7, 109.1, 53.5, 52.3, 45.7, 45.2 ; MS (ESP) M/Z 392 (M++1).
With potassium phosphate tribasic;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 160℃; for 0.5h;heating in a microwave oven;
4- (PYRROLIDIN-1-YLSULFONYL) phenylboronic acid (0.33 g, 1.29 mmol), methyl 3-AMINO-6- bromopyrazine-2-carboxylate (0.25 g, 1.08 mmol; described in: H. Ellingson, J. Amer. CLIENT. Soc. 1949, 2798), K3PO3 (3 M, 1.1 ML, 3.2 mmol), and Pd (dppf) C12 (0.044 g, 54 , UMOL) were suspended in ethylene glycol dimethyl ether/water (1.5 : 0.5 mL) and heated in a microwave oven at 160 C for 10 min. The reaction was repeated 3 times. The combined product mixtures were evaporated with silica gel and the crude product was purified by chromatography on silica gel using a heptane to ethyl acetate gradient to give 0.96 g (82% yield) of the title compound: MS (ES) NAL, Z 363 (M++1).
82%
With potassium phosphate tribasic;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 160℃; for 0.166667h;microwave oven;
4- (PYRROLIDIN-1-YLSULFONYL) PHENYLBORONIC acid (0.33 g, 1.29 mmol), methyl 3-amino-6- BROMOPYRAZINE-2-CARBOXYLATE (0.25 g, 1.08 mmol; described in: H. Ellingson, J. Amer. Chem. Soc. 1949, 2798), K3PO3 (3 M, 1.1 mL, 3.2 mmol), and Pd (dppf) Cl2 (0.044 g, 54 JUMOL) were suspended in ethylene glycol dimethyl ether/water (1.5 : 0.5 mL) and heated in a microwave oven at 160 C for 10 min. The reaction was repeated 3 times. The combined product mixtures were evaporated with silica gel and the crude product was purified by chromatography on silica gel using a HEPTAN/ETHYLACETATE gradient as the eluent to give 0.96 g (82% yield) of the title compound: MS (ES) m/z 363 (M+1).
Palladium acetate (0.145 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium complex with DCM (0.702 g) were dissolved in DMF (65 ml) and heated to 50 C for 15 minutes. After cooling to room temperature <strong>[6966-01-4]3-amino-6-bromo-pyrazine-2-carboxylic acid methyl ester</strong> (5.0 g), 4-fluoro-phenyl boronic acid (3.82 g) and triethylamine (4.5 ml ) were added and the mixture heated to 90 C for 20 hours with stirring. The solvent was evaporated and the residue dissolved in DCM. The organic phase was washed with dilute ammonium hydroxide solution and water. After drying with sodium sulphate and filtration the solvent was evaporated and the residue purified by column chromatography on silica gel eluting with hexane: ethyl acetate, 3: 1 to give 3-amino-6-(4-fluorophenyl)-pyrazine-2- carboxylic acid methyl ester (0.670 g). 'H NMR (CDCI3) 8 ppm: 3.92 (s, 3H), 6.4 (bs,1H), 7.1 (m, 2H), 7.8 (m, 2H), 8.5 (s,1H).
With sodium bicarbonate; sodium chloride; sodium nitrite; In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; chloroform; sulfuric acid; water;
REFERENTIAL EXAMPLE I-1 In 100 mL of concentrated sulfuric acid was dissolved 17.0 g of <strong>[6966-01-4]methyl 3-amino-6-bromo-2-pyrazinecarboxylate</strong>. At an ice-cooled temperature, 10.1 g of sodium nitrite was added and stirred for 30 minutes. The reaction mixture was poured into 920 mL of methanol and heated under reflux for 5 hours. After cooling the reaction mixture, the mixture was concentrated under reduced pressure, the residue thus obtained was added to a mixture of 500 mL of ice water and 600 mL of chloroform, and the mixture thus obtained was separated into layers. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 6.30 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate was obtained as a light yellow oily product. IR (KBr) cm-1: 1735 1H-NMR (CDCl3) delta: 3.97 (3H,s), 4.06 (3H,s), 8.37 (1H,s)
To a solution of <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> prepared in Example 25 J (11.476 g, 49.45 mmol, 1 eq.) in 60 mL anhydrous pyridine was added 3- chlorophenylisocyanate (8.82 g, 57.43 mmol, 1.2 eq.). The mixture was refluxed at 150 0C for 4 h. The solvent was removed in vacuo. To the residue was added brine. The mixture was extracted with three portions of dichloromethane. The organic phase layers were combined, rinsed with aqueous saturated sodium hydrogencarbonate solution, and o evaporated in vacuo. The resulting residue was dissolved in hot ethyl acetate. After standing overnight, the crude product was obtained as a solid. Additional product was extracted from the mother solution. Thus, 8.012 g of the desired product was obtained. The yield from methyl 3-amino-2-pyrazinecarboxylate is 57 % in two steps. 1H NMR (400 MHz, CDCl3) delta (ppm) 7.19 (dt, J-2.0, 4.5 Hz, IH), 7.31 (s, IH), 7.48 (d, s J=4.9 Hz, IH), 8.69 (s, IH).
The 3-( lH-benzimidazol-2-yl)-5-(4-hydroxy-3-methoxyphenyl)pyrazin-2-amine used as a starting material was prepared as follows :- 2-Methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (5.38 g) was added to a solution of <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (5.0 g) and potassium phosphate (16 g) in a 1:1:2 mixture of toluene: water:methanol (120 ml). Nitrogen was bubbled through the solution for 10 minutes before addition of bis(t-tert- butylphosphine)palladium (0.55 g). The mixture was heated to 600C for 1 hour. Ethyl acetate (120 ml) was added and the solution was extracted twice with IN aqueous sodium hydroxide (120 ml). The aqueous extracts were combined and acidified to peta 3 with hydrochloric acid. This solution was extracted with ethyl acetate (120 ml). The organic extract was dried over <n="101"/>magnesiura sulphate and evaporated. The resultant residue was triturated under diethyl ether. The solid so obtained was filtered to give 3-amino-6-(4-hydroxy-3-methoxyrhohenyl)pyrazine- 2-carboxylic acid as a solid (4.65 g).
With cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 60℃; for 4h;
etaATU (2.16 g) was added to a mixture of triethylamine (1.13 ml), 4-fluoro-l,2- diaminobenzene (0.72 g) and 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH- pyrazol-4-yl)pyrazine-2-carboxylic acid (2.1 g) in DMF (25 ml) at ambient temperature and was stirred for 2 hours. The reaction mixture was diluted with dilute aqueous sodium hydrogen carbonate solution. The precipiate was isolated by filtration and dried in a vacuum oven. The material so obtained was added to acetic acid (20 ml), and the resulting mixture was stirred and heated to 1100C for 3 hours. The solvent was then evaporated in vacuo and the residue was added to trifiuoroacetic acid (20 ml) and stirred at ambient temperature for 1 hour. The solvent was evaporated in vacuo and the crude product was purified by SCX ion exchange chromatography. The desired product was eluted from the column using 7M NetaVmethanol and the eluent was evaporated. There was thus obtained the title compound (3.05 g); NMR Spectrum: (DMSOd6) 1.91 (m, 2eta), 2.09 (d, 2H), 2.70 (t, 2H), 3.13 (d, 2H), 4.25 (m, IH), 7.08 (t, IH), 7.43 (brs, IH), 7.54 (s, IH), 7.68 (brs, IH), 8.10 (s, IH), 8.33 (s, IH), 8.47 (s, IH); Mass Spectrum: M+H+ 379; RT 2.16 min.The 3 -amino-6-( 1 -( 1 -(tert-butoxycarbonyl)piperidin-4-yl)- lH-pyrazol-4- yl)pyrazine-2-carboxylic acid used as a starting material was prepared as follows :- l,r-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.245 g) was added to a mixture of caesium fluoride (18.85 g), <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (14.4 g) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine-l-carboxylate (30.4 g) in methanol (450 ml) at ambient temperature. The resulting mixture was stirred at 600C for 1 hour at which time a further portion of tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate (15.0 g) was added and the resultant mixture was stirred for a further 3 hours at 600C. The reaction mixture was evaporated in vacuo and the residue was redissolved in <n="131"/>ethyl acetate (500 ml). The organic solution was washed twice with water (2 x 250 ml), dried with magnesium sulphate, filtered and evaporated in vacuo. The material so obtained was purified by flash silica chromatography on Flash 75 equipment, elution gradient 0 to 4% methanol in dichloromethane. Pure fractions were evaporated to dryness. There was 5 thus obtained methyl 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH-pyrazol-4- yl)pyrazine-2-carboxylate (24.98 g); NMR Spectrum: (DMSOd6) 1.50 (s, 9H), 1.66 (s, 2H), 1.98 (m, 2H), 2.18 (d, 2H), 2.93 (t, 2H), 3.98 (s, 3H), 4.30 (m, IH), 6.37 (brs, 2H), 7.92 (s, IH), 7.95 (s, IH), 8.44 (s, IH); Mass Spectrum: M-H+ 401; RT 2.09 min.2M sodium hydroxide solution (8.70 ml) was added to a solution of methyl 3- i o amino-6-( 1 -( 1 -(tert-butoxycarbonyl)piperidin-4-yl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxylate (3.5 g) in methanol (40 ml) and stirred at ambient temperature for 2 hours. The resultant solution was concentrated in vacuo until half of the methanol had been removed. Water (20 ml) was then added and the solution was acidified to pH4 by addition of 2M hydrochloric acid causing the product to precipitate. This material was filtered and dried is invacuo. There was thus obtained 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)- lH-pyrazol-4-yl)pyrazine-2-carboxylic acid (3.25 g); NMR Spectrum: (DMSOd6) (DMSOd6) 1.45 (s, 9H), 1.82 (m, 2H), 2.06 (d, 2H), 2.95 (t, 2H), 4.07 (d, 2H), 4.40 (m, IH), 7.32 (brs, 2H), 8.07 (s, IH), 8.43 (s, IH), 8.67 (s, IH); Mass Spectrum: M-H+ 387; RT 1.86 min.
With cesium fluoride;bis-triphenylphosphine-palladium(II) chloride; In methanol; at 130℃; for 0.333333h;Microwave irradiation;
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (334 mg), tert-butyl 4-[3-methyl-4- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazol- 1 -yl]piperidine- 1 -carboxylate (563 mg) and bis(triphenylphosphine) palladium (II) chloride (101 mg) and cesium fluoride (656 mg) in MeOH (11 mL) were degassed under vacuum and argon , stirred at 130 0C for 20mn under microwave conditions. The mixture wac concentrated and the residue was dissolved in dichloromethane and filtered. The filtrate was purified by flash chromatography on silica gel eluting with 50 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford methyl 3-amino-6-[l-(l-tert-butoxycarbonyl-4- piperidyl)-3-methyl-pyrazol-4-yl]pyrazine-2-carboxylate (421 mg). Mass spectrum: M+H+ 417. Retention time: 3.47min
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium[ No CAS ]
[ 6966-01-4 ]
[ 877399-74-1 ]
nickel(II) chloride, nickel(II) bromide, bis(triphenylphosphine)nickel(II) chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium[ No CAS ]
[ 1146950-60-8 ]
[ 1122520-91-5 ]
Yield
Reaction Conditions
Operation in experiment
With caesium fluoride; In methanol; dichloromethane; ethyl acetate;
The tert-butyl 4-[4-(5-amino-6-formyl-pyrazin-2-yl)pyrazol-1-yl]piperidine-1-carboxylate used as starting material was made as follows: 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.245 g) was added to a mixture of caesium fluoride (18.85 g), <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (14.4 g) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (30.4 g) in methanol (450 ml). The resulting mixture was stirred at 60 C. for 1 hour at which time a further portion of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (15.0 g) was added. The resultant mixture was stirred for a further 3 hours at 60 C. The reaction mixture was concentrated under reduced pressure and redissolved in ethyl acetate (500 ml), then washed twice with water (2*250 ml). The organic extract was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The material so obtained was purified by flash silica chromatography on Flash 75 equipment, elution gradient 0 to 4% methanol in dichloromethane. There was thus obtained methyl 3-amino-6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxylate (24.98 g); Mass Spectrum: M-H+ 401; RT 2.09 min; NMR Spectrum: (DMSOd6) 8.44 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 6.37 (brs, 2H), 4.30 (m, 1H), 3.98 (s, 3H), 2.93 (t, 2H), 2.18 (d, 2H), 1.98 (m, 2H), 1.66 (s, 2H), 1.50 (s, 9H).
With hydrazine hydrate; In ethanol; at 50℃; for 40h;Inert atmosphere;
Hydrazine hydrate (23.59 mL, 480.75 mmol) was added dropwise to a stirred mixture of <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (100 g, 418.04 mmol) in EtOH (2 L). The mixture was heated at 50 C. under nitrogen. The resulting thick suspension was stirred at 50 C. for 16 hours. Further hydrazine (2.5 mL) was added in one portion and the suspension was stirred at 50 C. for a further 24 hours. Ethanol (500 mL) was charged to the thick reaction mixture and the mixture was allowed to cool to room temperature. The resulting suspension was filtered and the solid washed with ethanol (1 L) and dried in vacuo to give 3-amino-6-bromopyrazine-2-carbohydrazide (98 g, quantitative) as a cream solid: 1H NMR Spectrum; (DMSO-d6) 4.52 (2H, s), 7.59 (2H, s), 8.30 (1H, s), 9.74 (1H, s); Mass Spectrum [M+H]+=232.
100%
With hydrazine hydrate; In ethanol; at 50℃; for 40h;Inert atmosphere;
(4-(5-(5-Amino-6-(5-tert-butyl- 1 ,3,4-oxadiazol-2-yl)pyrazin-2-yl)- 1 -methyl- 1H- 1 ,2,4- triazol-3 -yl)piperidin- 1 -yl)-3 -(tetrahydro-2H-pyran-2-yloxy)propan- 1 -one (Example 2.1) was prepared as follows: Hydrazine hydrate (23.59 mL, 480.75 mmol) was added dropwise to a stirred mixture of <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (100 g, 418.04 mmol) in EtOH (2 L). The mixture was heated at 50C under nitrogen. The resulting thick suspension was stirred at 50 C for 16 hours. Further hydrazine (2.5 mL) was added in one portion and the suspension was stirred at 50 C for a further 24 hours. Ethanol (500 mL) was charged to the thick reaction mixture and the mixture was allowed to cool to room temperature. The resulting suspension was filtered and the solid washed with ethanol (1 L) and dried in vacuo to give 3-amino-6-bromopyrazine-2-carbohydrazide (98 g, quantitative) as a cream solid: 1H NMR Spectrum: (DMSO-d6) 4.52 (2H, s), 7.59 (2H, s), 8.30 (1H, s), 9.74 (1H, s); Mass Spectrum [M+H]+ = 232.
100%
With hydrazine hydrate; In ethanol; at 50℃; for 40h;Inert atmosphere;
Hydrazine hydrate (23.59 mL, 480.75 mmol) was added dropwise to a stirred mixture of <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (100 g, 418.04 mmol) in EtOH (2 L). The mixture was heated at 50 C. under nitrogen. The resulting thick suspension was stirred at 50 C. for 16 hours. Further hydrazine (2.5 mL) was added in one portion and the suspension was stirred at 50 C. for a further 24 hours. Ethanol (500 mL) was charged to the thick reaction mixture and the mixture was allowed to cool to room temperature. The resulting suspension was filtered and the solid washed with ethanol (1 L) and dried in vacuo to give 3-amino-6-bromopyrazine-2-carbohydrazide (98 g, quantitative) as a cream solid: 1H NMR Spectrum: (DMSO-d6) 4.52 (2H, s), 7.59 (2H, s), 8.30 (1H, s), 9.74 (1H, s): Mass Spectrum [M+H]+=232.
100%
With hydrazine hydrate; In ethanol; at 50℃; for 40h;Inert atmosphere;
Hydrazine hydrate (24 mL, 0.48 mol) was added dropwise to a stirred mixture of <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> 29 (100 g, 0.42 mol) in EtOH (2 L). The mixture was heated at 50 C under nitrogen. The resulting thick suspension was stirred at 50 C for 16 h. Further hydrazine hydrate (2.5 mL) was added in one portion and the suspension was stirred at 50 C for a further 24 h. EtOH (500 mL) was charged to the thick reaction mixture and the mixture was allowed to cool to room temperature. The resulting suspension was filtered and the solid washed with ethanol (1 L) and dried in vacuo to give 3-amino-6-bromopyrazine-2-carbohydrazide (98 g, quantitative) as a cream solid. Pivalic anhydride (165 mL, 815 mmol) was added to a stirred mixture of 3-amino-6-bromopyrazine-2-carbohydrazide (172 g, 741 mmol) in acetonitrile (1.8 L) and the mixture was heated at 80 C for 1 h. The reaction was left to stir for 16 h. The required yellow solid material was isolated by filtration. The filtrate was partitioned between EtOAc (2 L) and aqueous sodium bicarbonate (2 L). The organic layer was washed with saturated brine and dried over MgSO4. The solution was filtered and concentrated to give an orange sticky solid which was triturated with MTBE (250 mL). The insoluble yellow solid was isolated by filtration. The combined solids were dried in vacuum at 50 C for 3 days to afford 3-amino-6-bromo-N'-pivaloylpyrazine-2-carbohydrazide (224 g, 96%) as a yellow solid. p-Toluenesulfonyl chloride (164 g, 862 mmol) was added portionwise to a suspension of 3-amino-6-bromo-N'-pivaloylpyrazine-2-carbohydrazide (227 g, 718 mmol) and DIPEA (300 mL, 1.8 mol) in acetonitrile (2.2 L). The mixture was stirred for 2 h at 70 C. The reaction was left to cool to room temperature overnight. The reaction mixture was partitioned between ethylacetate (2 L) and aq. sodium bicarbonate (2 L). The organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown/beige solid was triturated with hot MTBE (1 L), isolated by filtration and dried to afford 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine 30 as a yellow solid (187 g, 87%). The mother liquors were evaporated to dryness. The crude solid was triturated with MTBE (500 mL), filtered and washed with 100 mL of MTBE. The resulting solid was air dried overnight to afford a second crop of 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine 30 (36 g, 17%).
94%
With hydrazine hydrate; In ethanol; at 70℃; for 1.5h;
00154] Step 1 : To a suspension of <strong>[6966-01-4]methyl 3-amino-6-bromo-pyrazine-2-carboxylate</strong> (2.5 g, 10.8 mmol) in ethanol (50 mL) was added hydrazine hydrate (3.2 g, 3 mL, 64.6 mmol) and the reaction mixture heated at 70 C for 1.5 h forming a thick yellow solid. The reaction mixture was filtered and the solid washed with water (20 mL) and ethanol (40 mL). The solid was dried in vacuo to yield 3-amino-6-bromo-pyrazine-2-carbohydrazide (2.7 g, 94% yield) as a light yellow solid. LC/MS m/z 233.1 [M+H]+. XH NMR (400 MHz, DMSO-i¾) delta 9.78 (s, 1H), 8.31 (s, 1H), 7.62 (s, 2H), 4.53 (d, J = 3.5 Hz, 2H).
94%
With hydrazine hydrate; In ethanol; at 70℃; for 1.5h;
Preparation 9. Synthesis of 3-amino-6-bromopyrazine-2-carbohydrazide[00222] Step 1 : To a suspension of <strong>[6966-01-4]methyl 3-amino-6-bromo-pyrazine-2-carboxylate</strong> (2.5 g, 10.8 mmol) in ethanol (50 mL) was added hydrazine hydrate (3.2 g, 3 mL, 64.6 mmol) and the reaction mixture heated at 70 C for 1.5 hours forming a thick yellow solid. The reaction mixture was filtered and the solid washed with water (20 mL) and ethanol (40 mL). The solid was dried in vacuo to yield 3-amino-6-bromo-pyrazine-2-carbohydrazide (2.7 g, 94% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 4.53 (d, J = 3.5 Hz, 2H), 7.62 (s, 2H), 8.31 (s, 1H) and 9.78 (s, 1H) ppm; LC/MS m/z 233.1 [M+H]+
70%
With hydrazine hydrate; In 1,4-dioxane; at 20 - 60℃; for 2h;
Step 2. Methyl 3-amino-6-bromopyrazine-2-carboxylate (15 g, 64.6 mmol) was suspended in 150 mL of dioxane at room temperature. Hydrazine hydrate (6.5 g, 130 mmol) was added and the reaction mixture was stirred at 60 C. for 2 hours. Initially the mixture became clear, but after a while a precipitate formed. The mixture was cooled to ambient temperature and crude product filtered off. The solid was washed with TBME and subsequently stirred in water. The material was filtered and washed with acetone to afford 3-Amino-6-bromopyrazine-2-carbohydrazide 4 as slightly yellow solid. The material was dried in vacuo. (10.5 g, 70%).
With hydrazine hydrate; at 100℃; for 1.5h;
Step 1: S-amino--bromopyrazine-l-carbohydrazide[00541] A mixture of <strong>[6966-01-4]methyl 3-amino-6-bromo-pyrazine-2-carboxylate</strong> (5 g, 21.55 mmol) and hydrazine hydrate (5.397 g, 5.245 niL, 107.8 mmol) were heated to 100 0C for 1.5 hours. Water was added and the product collected by filtration, washed with methanol and dried to give 3- amino-6-bromo-pyrazine-2-carbohydrazide as a yellow solid (5.02g, 100.4% Yield). MS (ES+)
With tert.-butylnitrite; copper dichloride; In acetonitrile; at 20.0℃; for 18.0h;Reflux;
Methyl beta-bromo-S-chloropyrazine-l-carboxylate (1-2)To a suspension of copper (II) chloride (3.48 g, 25.9 mmol, 2.0 equiv) in acetonitrile (43 mL) was added te/t-butylnitrite (3.06 mL, 25.9 mmol, 2.0 equiv). The reaction was heated to 600C for 30 minutes and then cooled to ambient temperature. To this suspension was added <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (Ll, 3.O g, 12.9 mmol, 1.0 equiv, commercially available from SynChem Inc.) as a solid in portions with gas evolution. The reaction mixture was heated to reflux for 18 hours and the reaction was cooled to ambient temperature. The reaction was partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with NaHCO3 and dried over MgSO4. After concentration, the residue was purified by normal phase column chromatography (0 to 50% EtOAc in hexanes) to afford the product CL2) as a clear oil. ESI+ MS [M+H]+ C6H4BrClN2O2: 250.7 found, 250.9 required.
Step 2; A suspension of compound 2 (28.5 g, 120 mmol) in an aqueous solution of 48% HBr (120 mL) and acetic acid (30 mL) was cooled to 0 C., and then treated with a solution of bromine (18 mL, 336 mmol) in acetic acid (18 mL) over a period of 45 min. A solution of NaNO2 (8.28 g, 420 mmol) in water (15 ml) was added while maintaining the temperature at 0 C., stirring was continued for further 30 min. After completion of reaction (reaction progress was monitored by TLC), the excess bromine was quenched by the drop wise addition of 30% aqueous solution of NaHSO3 (180 mL). The resulting precipitate was filtered and purified by column chromatography on silica gel eluted with 10% ethyl acetate in hexane to afford compound 3 as a white crystalline solid (18 g, 49%). MS m/z (ES): 294 (M+H)+.
47.3%
With hydrogen bromide; acetic acid; sodium nitrite; In 1,4-dioxane; at -5℃; for 4h;
The compound <strong>[6966-01-4]3-amino-6-bromopyrazine-2-carboxylic acid methyl ester</strong> 3a (20.0 g, 86.2 mmol) was added to a 500 mL three-necked flask, dioxane (40mL), HBr (200mL) and acetic acid (40mL), stirred and dissolved -5 C dropwise to the reaction system was added NaNO2 (19.6g, 285mmol), the solution was stirred at -5 C (20mL) acetic acid for 4 hours. The system was poured into a solution of Na2SO3 and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and dried under reduced pressure using a rotary evaporator, purified by column to give the title compound 3b (12.0g, 40.8mmol), in a yield of 47.3%
With hydrogen bromide; acetic acid; sodium nitrite; In water; at -5℃; for 1h;
Preparation of methyl 3,6-dibromopyrazine-2-carboxylate A mixture of 3 - amino - 6 - bromopyrazine - 2 - carboxylic acid methyl ester (4 ? 6 2 g '20 mmol), aqueous hydrobromic acid (48%, 24 ml) and acetic acid (3.2 ml) was added to the reactor, -5 C. The solution (20 ml) of the solution of acetic acid (5 ml) and sodium nitrite (4.8 g, 70 ml) was slowly added successively -5 C stirring reaction lh. The reaction was terminated, washed with saturated sodium sulfite solution, extracted with ethyl acetate and water, washed with saturated NaCl solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as an off-white solid.
With potassium phosphate;palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 20h;
A-7: 6-Cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carboxylic acid methyl esterStep 1: 3-amino-6-cyclopropylpyrazine-2-carboxylic acid methyl esterTo a suspension of <strong>[6966-01-4]3-amino-6-bromopyrazine-2-carboxylic acid methyl ester</strong> (17.8 g, 76.7 mmol), cyclopropylboronic acid (8.57 g, 99.7 mmol), potassium phosphate (57.0 g, 268 mmol) and tricyclohexylphosphine (2.15 g, 7.67 mmol) in toluene (445 ml) and water (22 ml) was added palladium(II) acetate (0.86 g, 3.84 mmol). The reaction mixture was heated to 100 C. and stirred for 20 h. Water (200 ml) was added, the organic layer was washed with water and brine and the aqueous layer was back-extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as yellow solid (1.69 g, 11.4%).MS: M=194.1 (M+H)+
11.4%
With potassium phosphate;palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 20h;
A-7: 6-Cvclopropyl-3-fpyrimidin-5-ylamino)-pyrazine-2-carboxylic acid methyl esterStep 1: 3-amino-6-cyclopropylpyrazine-2-carboxylic acid methyl esterTo a suspension of <strong>[6966-01-4]3-amino-6-bromopyrazine-2-carboxylic acid methyl ester</strong> (17.8 g, 76.7 mmol), cyclopropylboronic acid (8.57 g, 99.7 mmol), potassium phosphate (57.0 g, 268 mmol) and tricyclohexylphosphine (2.15 g, 7.67 mmol) in toluene (445 ml) and water (22 ml) was added palladium(II) acetate (0.86 g, 3.84 mmol). The reaction mixture was heated to 100 C and stirred for 20 h. Water (200ml) was added, the organic layer was washed with water and brine and the aqueous layer was back-extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as yellow solid (1.69 g, 11.4 %).MS: M = 194.1 (M+H)+
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