* 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] Advanced Synthesis and Catalysis, 2005, vol. 347, # 10, p. 1395 - 1403
2
[ 100-51-6 ]
[ 13504-85-3 ]
[ 13500-53-3 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 24, p. 9353 - 9356
3
[ 100-51-6 ]
[ 13590-42-6 ]
Reference：
[1] Patent: CN107129501, 2017, A,
[2] Chemistry - A European Journal, 2018, vol. 24, # 54, p. 14373 - 14377
4
[ 117811-78-6 ]
[ 100-51-6 ]
[ 13504-85-3 ]
[ 13504-86-4 ]
Reference：
[1] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 8
[2] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9-10
[3] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
[4] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
[5] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
5
[ 117811-78-6 ]
[ 100-51-6 ]
[ 13504-85-3 ]
[ 13504-86-4 ]
Reference：
[1] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 8
[2] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9-10
[3] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
[4] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
[5] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
6
[ 7512-17-6 ]
[ 100-51-6 ]
[ 13343-62-9 ]
Yield
Reaction Conditions
Operation in experiment
74%
With hydrogenchloride In water at 90℃; for 3 h; Inert atmosphere
To a solution of N-acetylglucosamine (6.40 g, 28.9 mmol)in benzyl alcohol (50 mL, 480 mmol), concd aq HCl (3.0 mL) wasadded and the reaction mixture was stirred at 90 C for 3 h. Thecrude mixture was cooled down to rt, poured into Et2O (500 mL)and left to crystallize at 4 C for 18 h. The crystalline product wasfiltered and washed with petroleum ether. Purification by silica gelcolumn chromatography (CH2Cl2/MeOH, 95:5/88:12, v/v) gavebenzyl glycoside 2 (6.67 g, 21.4 mmol, 74percent) as a white foam.Rf0.25 (CH2Cl2/MeOH, 90:10, v/v); mp 182e184 C; [a]D17.8 222(c 0.1, MeOH); IR (film) 3298, 3092, 2938, 2901, 2844, 1648, 1552,1497, 1455, 1375, 1309, 1230, 1156, 1093, 1047, 778, 732, 695 cm1;1H NMR (500 MHz, CD3OD) d 7.40e7.25 (m, 5H, CHarom), 4.85 (d,1H, J10,203.6 Hz, H-10), 4.74 (d, 1H, J1a,1b12.0 Hz, H-1a), 4.49 (d,1H, J1a,1b12.0 Hz, H-1b), 3.89 (dd, 1H, J10,203.6 Hz, J20,3010.8 Hz,H-20), 3.83 (dd, 1H, J50,6a01.6 Hz, J6a0,6b011.4 Hz, H-6a0), 3.73e3.64(m, 3H, H-6b0, H-30, H-40), 3.36 (dd, 1H, J40,50J50,6b09.6 Hz, H-50),1.95 (s, 3H, CH3 Ac); 13C NMR (125 MHz, CD3OD) d 173.6 (C]O Ac),139.0 (Cqarom), 129.4 (C-oarom), 129.3 (C-marom), 128.8 (C-parom),97.5 (C-10), 74.1 (C-40), 72.7 (C-30), 72.5 (C-50), 70.1 (C-1), 62.7 (C-60), 55.4 (C-20), 22.5 (CH3 Ac); HRMS(ESI) m/z calcd for[C15H22NO6]: 312.1442, obsd: 312.1446.
72%
With toluene-4-sulfonic acid In toluene at 130℃; for 4 h; Dean-Stark
N-acetylglucosamine (1) (10 g, 0.045 mol) and benzylalcohol (72 mL) were suspended in toluene (120 mL)and p-toluene sulfonic acid monohydrate (500 mg) wasadded. The reaction mixture was refluxed (130 °C) in aDean-Stark apparatus with water removal by azeotropicmixture. After 4 h, the reaction mixture was cooled toambient temperature and saturated solution of sodiumhydrogen carbonate was added to pH ~ 6. Toluene wasremoved under reduced pressure. Residue was split intoether-hexane (vol. ratio = 2:1, 260 mL) mixture. Reactionmixture was vigorously stirred for 3h and left overnightin refrigerator. The amorphous precipitate wasfiltered off, washed with ether and the crude product recrystallizedfrom 2-propanol to yield colourless crystals2 (10.1 g, 72percent yield). Rf (A) = 0.42; m.p. 186–187 °C(lit. 185–186 °C)20; [α]D = +170 ° c 1, water (lit. [α]D =+168 ° c 1, water)20; 1H NMR (DMSO-d6) δ/ppm: 7.81(d, 1H, J = 8.2 Hz, NH), 7.35–7.28 (m, 5H, Ph), 5.01 (d,1H, J = 5.8 Hz, OH-4), 4.73 (d, 1H, J = 5.8 Hz, OH-3),4.70 (d, 1H, J = 3.2 Hz, H-1), 4.66 (d, 1H, J = 12.3 Hz,CH2b-Ph), 4.54 (t, 1H, J = 5.8 Hz, OH-6), 4.41 (d, 1H,J = 12.3 Hz, CH2a-Ph), 3.68 (m, 1H, H-2), 3.65 (m, 1H,H-6b), 3.53 (m, 1H, H-3), 3.50 (m, 1H, H-6a), 3.45 (m,1H, H-5), 3.16 (m, 1H, H-4), 1.83 (s, 3H, CH3-CON acetyl); 13C NMR (DMSO-d6) δ/ppm: 169.4 (CO acetyl),137.9 (Ph (C)), 128.1–127.4 (Ph(CH)), 95.9 (C-1),73.1 (C-5), 70.9 (C-4), 70.6 (C-3), 67.7 (CH2-Ph), 60.8(C-6), 53.7 (C-2), 22.5 (CH3-CON acetyl); MS-ESI m/z312 [M+H]+.
71%
With hydrogenchloride In water at 90℃; for 3 h; Inert atmosphere
N-Acetyl glucosamine 7 (6.00 g, 27.1 mmol) was dissolved in benzyl alcohol(50 mL) and concentrated HCl (2.9 mL) was added. The mixture was heatedto 90C for 3 h, cooled to rt, and then poured onto 500 mL Et2O and storedovernight at −20C. The resulting precipitate was recovered by filtration andrinsed with Et2O and hexanes to yield 17.64 g of crude material, which waspurified by silica gel chromatography (8percent to 15percent MeOH/CH2Cl2) to provide11 (5.98 g, 71percent) as white foam. Comparison of 1H NMR with literature valuesconfirmed the identity of compound 11.[28] 1H NMR (500 MHz, CD3OD), δ 1.95(s, 3H, COCH3), 3.37–3.39 (m, 1H), 3.69–3.73 (m, 3H), 3.82 (d, 1H, J3 = 9.5 Hz),3.89 (dd, 1H, J3 = 3.5, 11 Hz), 4.49 (d, 1H, J3 = 12 Hz), 4.74 (d, 1H, J3 =11.5 Hz), 7.28–7.40 (m, 5H, aromatic).
27%
at 80℃; for 3.5 h;
A mixture of 2-acetamido-2-deoxy-D-glucopyranose [Compound Ij (15.0 g, 0.068 mol), Amberlite JR 120 [Hj ion exchange resin (15.0 g) in benzyl alcohol (125 mL) was stirred at 80°C for 3.5 hours. The reaction mixture was filtered. The filtrate was evaporated under reduced pressure at 90°C. The residue was taken up in hot isopropanol (60 mL) and filtered. The filtrate was left to crystallize, thewhite crystalline solid was filtered off, washed twice with cold isopropanol (20 mL) and twice with ether (200mL) to give benzyl 2-acetamido-2-deoxy-D- glucopyranoside [Compound JJj (5.62 g, yield 27percent).
15%
Stage #1: With boron trifluoride diethyl etherate In acetonitrile at 20℃; Stage #2: With bacterial β-N-acetyl-hexosaminidase from Zobellia galactanivorans In aq. phosphate buffer at 37℃; for 24 h; Enzymatic reaction
General procedure: The purified α/β mixtures 2a/3a, 2b/3b, 2c/3c, 2d/3d, or 2e/3e were dissolved inNa3PO4/citratebuffer (50mM, pH8.0) and0.1UofZgβHexN2854 hexosaminidasewere added (final volume 5 mL). The reaction mixture was incubated at 37 ° for12 h in the case of 2a/3a, 2b/3b, 2c/3c, and2d/3d and 24 h in the case of 2e/3e. Then,the solvent was evaporated under reduced pressure. The residue was subjected tosilica-gel column chromatography. 2a, 2b, 2c, 2d, and 2e were obtained as whitesolids by eluting them with an AcOEt/MeOH 9:1 mixture (Yields: 2a: 32percent, 2b: 53percent,2c: 44percent, 2d: 9percent, 2e: 15percent).
Reference：
[1] Journal of Organic Chemistry, 2010, vol. 75, # 10, p. 3515 - 3517
[2] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 3, p. 238 - 242
[3] Chemistry - A European Journal, 2016, vol. 22, # 49, p. 17813 - 17819
[4] Journal of the American Chemical Society, 2012, vol. 134, # 22, p. 9343 - 9351
[5] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 11, p. 1853 - 1856
[6] Carbohydrate Research, 2015, vol. 414, p. 1 - 7
[7] Croatica Chemica Acta, 2015, vol. 88, # 2, p. 151 - 157
[8] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1269 - 1275
[9] Journal of Carbohydrate Chemistry, 2013, vol. 32, # 5-6, p. 392 - 409
[10] Collection of Czechoslovak Chemical Communications, 2005, vol. 70, # 10, p. 1615 - 1641
[11] Journal of Medicinal Chemistry, 2016, vol. 59, # 14, p. 6878 - 6890
[12] Synthetic Communications, 2008, vol. 38, # 18, p. 3052 - 3061
[13] Russian Journal of Bioorganic Chemistry, 1999, vol. 25, # 9, p. 628 - 634
[14] Arkivoc, 2012, vol. 2012, # 6, p. 90 - 100
[15] Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 364 - 373
[16] Journal of the American Chemical Society, 2014, vol. 136, # 35, p. 12283 - 12295
[17] Patent: WO2017/98529, 2017, A1, . Location in patent: Page/Page column 18; 34
[18] Journal of Carbohydrate Chemistry, 2016, vol. 35, # 8-9, p. 423 - 434
[19] Journal of the American Chemical Society, 1991, vol. 113, # 21, p. 8137 - 8145
[20] Carbohydrate Research, 1980, vol. 82, p. 71 - 84
[21] Tetrahedron Asymmetry, 2010, vol. 21, # 15, p. 1936 - 1941
7
[ 7512-17-6 ]
[ 100-51-6 ]
[ 13343-62-9 ]
Reference：
[1] Organic Letters, 2011, vol. 13, # 19, p. 5306 - 5309
[2] Liebigs Annalen der Chemie, 1991, # 12, p. 1291 - 1300
[3] Justus Liebigs Annalen der Chemie, 1958, vol. 611, p. 236,239
[4] Collection of Czechoslovak Chemical Communications, 1982, vol. 47, # 11, p. 2989 - 2995
[5] Organic and Biomolecular Chemistry, 2009, vol. 7, # 6, p. 1203 - 1210
8
[ 7512-17-6 ]
[ 100-51-6 ]
[ 3055-51-4 ]
[ 13343-62-9 ]
Yield
Reaction Conditions
Operation in experiment
26 % de
With boron trifluoride diethyl etherate In acetonitrile at 20℃;
General procedure: To a solution of 1 (100 mg, 0.45 mmol) in acetonitrile (15 mL) and the correspondingalcohol (20mmol, methanol (a), ethanol (b), 2-propanol (c), n-butanol (d), orbenzyl alcohol (e)), boron trifluoride diethyl etherate (300μL, 2.3mmol) was added.The reaction mixture was stirred at room temperature overnight. Then, the solventwas evaporated under reduced pressure. The residue was then subjected to silica-gelcolumn chromatography. The α/β mixture of the N-acetyl-D-glucosamine derivativewas obtained as a white solid by eluting the compound with an AcOEt/MeOH9:1 mixture (2a/3a 51:49 mixture: 74percent yield, 2b/3b 80:20 mixture: 68percent yield, 2c/3c82:18 mixture: 58percent yield, 2d/3d 87:13 mixture: 18percent yield, 2e/3e 63:37 mixture: 25percentyield).
Reference：
[1] Liebigs Annalen der Chemie, 1986, vol. 1986, # 1, p. 37 - 45
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 18, p. 5807 - 5812
[3] Carbohydrate Research, 2011, vol. 346, # 14, p. 2294 - 2299
[4] Glycoconjugate Journal, 2010, vol. 27, # 5, p. 549 - 559
[5] Journal of Carbohydrate Chemistry, 2016, vol. 35, # 8-9, p. 423 - 434
9
[ 10036-64-3 ]
[ 100-51-6 ]
[ 13343-62-9 ]
Reference：
[1] Tetrahedron Asymmetry, 2008, vol. 19, # 19, p. 2265 - 2271
[2] Tetrahedron Letters, 2007, vol. 48, # 25, p. 4403 - 4405
[3] Journal of Organic Chemistry, 1990, vol. 55, # 24, p. 6051 - 6054
[4] Chemistry - A European Journal, 2009, vol. 15, # 5, p. 1261 - 1271
Benzyl alcohol (37.5 g, 0.347 mol) and sodium hydroxide (2.96 g, 0.074 mol) were mixed and heated, and sodium hydroxide was dissolved. After cooling, 2-amino-6-chloropurine (6.00 g, 0.035 mol) was added, and the reaction was completed by heating and stirring at 80-90 C for 5 hr. Methyl tert- butyl ether (120 ml) was added to the reaction mixture, and the mixture was extracted twice with queous sodium hydroxide solution (70 ml). The obtained aqueous alkali layers were combined, washed with toluene, and after removing toluene, neutralized with 35percent hydrochloric acid to pH 6-8. The precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to give 2- amino-6-benzyloxypurine (7.60 g, 0.032 mol, yield 92percent) as crude crystals.
62%
With sodium hydride In mineral oil at 60℃; for 12 h; Inert atmosphere
6OBenzylguanine (3). Sodium hydride (1.2 g, 35.4 mmol,55percent suspension in mineral oil) was added to benzyl alcohol(50 mL) with vigorous stirring under argon. Then, 2amino6chloropurin (2.0 g, 11.8 mmol) was added to the suspensionobtained. The reaction mixture was heated to 60 C and stirredfor 12 h. After cooling, glacial acetic acid (1.4 mL, 24.3 mmol)was added to the suspension. The resulting mixture was extracted with 2 M solution of sodium hydroxide (5×5 mL). The organic phase was diluted with diethyl ether (100 mL) and again extracted with 2 M solution of sodium hydroxide (10×10 mL). Theaqueous layers were combined, washed with diethyl ether(50 mL), glacial acetic acid was added to neutralize the solution(pH 7). Then, the solution was allowed to stand for 12 h at 4 C.A precipitate formed was filtered and washed with water. Afterrecrystallization (ethanol—water (1 : 1)), the crystals were driedin vacuo. The yield was 1.76 g (62percent), yellow crystals, m.p.201—202 C. 1H NMR (DMSOd6, 300 MHz), : 12.25 (br.s,1 H, N(9)HGua); 7.82 (s, 1 H, C(8)HGua); 7.56—7.21 (m, 5 H,Ph); 6.29 (s, 2 H, NH2Gua); 5.48 (s, 2 H, CH2Ph(Bn)). 13C NMR(DMSOd6, 75 MHz), : 159.7, 159.6, 156.1, 138.5, 136.8,128.1, 126.5, 112.8, 66.7. Found (percent): C, 56.0; H, 4.8; N, 27.5.C12H11N5O•H2O. Calculated (percent): C, 55.6; H, 5.1; N, 27.0. MS(ESI), found: m/z 243.1033 [M + H]+. C12H12N5O. Calculated:M = 242.1042.
28%
for 4 h; Reflux
General procedure: Sodium or sodium hydride (7-10 mmol) was dissolved inthe appropriate alcohol (5-10 mL). Following the dissolutionand the hydrogen production, 2-amino-6-chloropurine (3) (1-3 mmol) was added and the mixture was refluxed for 4 hthen stirred at room temperature overnight. The reaction was acidified to pH 6 with glacial acetic acid and extracted withdiethylether (3 X 10 mL). The combined organic layers weredried over anhydrous MgSO4, and the solvent was removedunder vacuum. When necessary, the crude product was purifiedwith flash or circular chromatography with a mixture ofdichloromethane/methanol as eluent.
Reference：
[1] Patent: WO2003/84957, 2003, A1, . Location in patent: Page/Page column 9-10
[2] Nucleosides and Nucleotides, 1999, vol. 18, # 10, p. 2219 - 2231
[3] Helvetica Chimica Acta, 2012, vol. 95, # 12, p. 2621 - 2634
[4] Tetrahedron, 2007, vol. 63, # 24, p. 5323 - 5327
[5] Synthetic Communications, 2003, vol. 33, # 6, p. 941 - 952
[6] Russian Chemical Bulletin, 2015, vol. 64, # 5, p. 1100 - 1106[7] Izv. Akad. Nauk, Ser. Khim., 2015, # 5, p. 1100 - 1106,7
[8] Journal of Medicinal Chemistry, 2001, vol. 44, # 24, p. 4050 - 4061
[9] Medicinal Chemistry, 2017, vol. 13, # 1, p. 28 - 39
[10] Tetrahedron Letters, 2000, vol. 41, # 18, p. 3303 - 3307
25
[ 100-51-6 ]
[ 19916-73-5 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: at 80℃; Stage #2: at 90℃; for 5 h;
2-Amino-6-benzyloxypurine, 10; Benzyl alcohol (37.5 g, 347 mmol) and sodium hydroxide (2.96 g, 74 mmol) were mixed and sodium hydroxide was dissolved on heating at 80°C. After cooling, 2-amino- 6-chloropurine (6.0 g, 35 mmol) was added, and the mixture was heated at 900C for 5 h under stirring. After cooling, EtOAc (120 ml) was added to the reaction mixture, and the mixture was extracted twice with 1percent aqueous sodium hydroxide solution (70 mL). The aqueous alkali layers were combined, washed with EtOAc and then treated with 35percent hydrochloric acid until pH 6-8. The precipitated crystals were collected by filtration and dried under reduced pressure, to give 2-amino-6-benzyloxypurine 10 (7.6 g, yield: 92percent) as a white powder: 1H NMR (200 MHz, CDCl3): δ 5.46 (s, 2H), 6.24 (br s, 2H, NH), 7.24 - 7.54 (m, 5 ArH), 7.81 (s, IH), 12.43 (br s, IH, NH).
Reference：
[1] Patent: CN107098906, 2017, A, . Location in patent: Paragraph 0052; 0056; 0057; 0061; 0062; 0063; 0064
27
[ 100-51-6 ]
[ 19916-73-5 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 3, p. 185 - 186
[2] Organic and Biomolecular Chemistry, 2013, vol. 11, # 35, p. 5853 - 5865
28
[ 10310-21-1 ]
[ 100-51-6 ]
[ 19916-73-5 ]
Reference：
[1] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2004, vol. 59, # 7, p. 802 - 806
[2] Collection of Czechoslovak Chemical Communications, 1994, vol. 59, # 5, p. 1153 - 1174
Reference：
[1] Angewandte Chemie - International Edition, 2002, vol. 41, # 21, p. 4059 - 4061
33
[ 3934-20-1 ]
[ 100-51-6 ]
[ 108381-28-8 ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran for 0.5 h; Reflux Stage #2: at -78℃; for 1 h;
Step 1. A mixture formed by 2.26 g (20.1 mmol, 1 equiv.) of potass tert-butoxide and 4.3 g (40.2 mmol, 2 equiv.) of compound phenylmethanol in 10 ml of THF was heated under reflux temperature for half an hour. The reaction mixture was cooled down to 0 0C and slowly added drop-wise to 3 g (20.1 mmol, 1 equiv.) of 2,4-dichloropyrimidine dissolved in 15 ml of N,N- dimethyl formamide, maintaining the temperature below -78 0C. After stirring for one hour, it was left to reach room temperature. The mixture was added drop-wise to 100 ml of cold water, obtaining white solid 4-(benzyloxy)-2-chloropyrimidine (3.3 g, 75percent). The compound was determination by LC-MS (LC-MS (m/z) =222.0 [M+H]+)
24%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 1 - 2℃; for 0.5 h; Stage #2: at 1 - 2℃; for 3.5 h;
To a cooled (1-2° C.) suspension of sodium hydride (60percent in mineral oil) (1.5 equiv) in 250 ml THF, benzyl alcohol (1.0 equiv.) was added dropwise and the mixture stirred 30 min under N2. This suspension was then added in small portions (via syringe, over 1 hr) to a solution of 2,4-dichloropyrimidine (1.5 equiv.) in THF also at 1-2° C. (internal thermometer). The resulting mixture (0.06 M) was stirred at temp <2° C. for 2.5 hrs, then quenched with NH4Cl(sat.) and extracted with EtOAc. Upon separation, the organic layer was washed with NaCl(sat.), dried over Na2SO4, concentrated and purified by silica gel chromatography (hexanes/DCM eluant) to yield 4-(benzyloxy)-2-chloropyrimidine (24percent). LC/MS=221.0 (M+H), LC=3.93 min.
Reference：
[1] Organic Letters, 2017, vol. 19, # 7, p. 1854 - 1857
[2] Chemistry - A European Journal, 2017, vol. 23, # 58, p. 14563 - 14575
[3] Patent: WO2011/19405, 2011, A1, . Location in patent: Page/Page column 107
[4] Patent: US2011/195980, 2011, A1, . Location in patent: Page/Page column 28
[5] Patent: EP1564212, 2005, A1, . Location in patent: Page 13
General procedure: A quantity of 20 mg of catalyst was placed in a 20 mL Schrunkglass bottle (1) which was filled with N2 at a pressure of 1 bar. Benzylalcohols (5 mmol) and nitroarenes (0.5 mmol) were mixed fullyin a Schrunk glass bottle (2) and nitrogen was bubbled to removedissolved oxygen molecules. The mixed solution was transferredto bottle (1) under 1 atm N2 and stirred to make the catalyst blendevenly in the solution. The suspensions were irradiated by a 300WXe arc lamp (PLS-SXE300, Beijing Perfect Light Co.), and an IR-cutfilter was used to remove all wavelengths longer than 800 nm.After the reaction, the mixture was centrifuged to completelyremove the catalyst particles. The remaining solution was determinedby an Agilent online gas chromatograph (GC 6890, FID) withan HP-5973 mass spectrometer. An HP-5 column (length 30 m;inner diameter 320 mm; film thickness 0.25 mm) was applied forseparation of product. Helium (purity 99.999percent) was used as thecarrier gas at a constant flow rate of 20 mL min-1. The temperaturesof the injector and detector were maintained at 280 and300 °C, respectively. The pressure of injection was set at 8.363psi. The column temperature was programmed from 40 to 180 °Cat 15 °C/min, and then up to 280 °C at 15 °C/min, and held 5 min.The injection volume was 5 μl. Conversion of nitroarenes andselectivity for secondary amines were as follows:
Reference：
[1] Journal of Catalysis, 2018, vol. 361, p. 105 - 115
36
[ 100-51-6 ]
[ 2050-16-0 ]
[ 103-14-0 ]
Reference：
[1] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2856 - 2860
37
[ 100-02-7 ]
[ 100-51-6 ]
[ 103-14-0 ]
Reference：
[1] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2467 - 2473
38
[ 123-30-8 ]
[ 100-51-6 ]
[ 103-14-0 ]
[ 588-53-4 ]
Reference：
[1] Green Chemistry, 2010, vol. 12, # 7, p. 1281 - 1287
39
[ 107-15-3 ]
[ 100-51-6 ]
[ 104-71-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 23, p. 5160 - 5164
40
[ 20461-79-4 ]
[ 100-51-6 ]
[ 19910-33-9 ]
Reference：
[1] Chemische Berichte, 1952, vol. 85, p. 168,171
41
[ 100-51-6 ]
[ 2304-94-1 ]
Reference：
[1] Monatshefte fuer Chemie, 1958, vol. 89, p. 61,66,70
42
[ 108-30-5 ]
[ 100-51-6 ]
[ 2304-94-1 ]
Reference：
[1] Angewandte Chemie, 1977, vol. 89, p. 570 - 572
[2] Synthesis, 1976, p. 329 - 330
43
[ 100-51-6 ]
[ 24257-93-0 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 68, p. 17195 - 17198
44
[ 100-51-6 ]
[ 16728-64-6 ]
Reference：
[1] Journal of the American Chemical Society, 1945, vol. 67, p. 1505
45
[ 75-56-9 ]
[ 100-51-6 ]
[ 13807-91-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: at 0℃; for 24 h;
11 g of benzyl alcohol (0.1 mol) and 11.4 g of potassium t-butoxide (first catalyst, 0.1 mol) were added to 150 mL of anhydrous THF at 0 ° C, and stirred for 30 min.The first mixture was obtained. Drop the ring into the first mixture at 0 ° COxypropane is subjected to a ring opening reaction and stirred for 24 hours, wherein benzyl alcohol,The molar ratio of propylene oxide to the first catalyst was 1:1:1. Adjusting the pH of the above ring-opening reaction system to 7 with a 30 wtpercent aqueous solution of dilute acetic acid.After THF was spin-dried, 300 mL of ethyl acetate was added for extraction.The organic phase was washed 3 times with 100 mL of purified water.Then dried with 25 g of anhydrous sodium sulfate for 3 h, after filtering the desiccant,The organic phase was dried to ethyl acetate: n-heptane = 1:5 column chromatographyThere was obtained 13.8 g of a colorless oil (ring-opening product) in a yield of 90percent by weight.
Reference：
[1] Patent: CN108276355, 2018, A, . Location in patent: Paragraph 0110; 0111; 0112; 0113
[2] Journal of the American Chemical Society, 2006, vol. 128, # 16, p. 5360 - 5361
[3] Applied Catalysis A: General, 2011, vol. 408, # 1-2, p. 125 - 129
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 48, p. 12705 - 12708[2] Angew. Chem., 2013, vol. 125, # 48, p. 12937 - 12940,4
56
[ 106-48-9 ]
[ 100-51-6 ]
[ 120-32-1 ]
Reference：
[1] Synthetic Communications, 2008, vol. 38, # 15, p. 2684 - 2691
[2] Journal of the American Chemical Society, 1933, vol. 55, p. 4639,4640
57
[ 100-51-6 ]
[ 17176-77-1 ]
Reference：
[1] Synthesis, 2007, # 22, p. 3553 - 3557
[2] Roczniki Chemii, 1974, vol. 48, p. 277 - 286
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2008, vol. 183, # 2-3, p. 610 - 616
[4] Organic Letters, 2012, vol. 14, # 8, p. 2126 - 2129
[5] Tetrahedron, 2013, vol. 69, # 47, p. 9947 - 9950
[6] European Journal of Organic Chemistry, 2013, # 35, p. 7973 - 7978
58
[ 91-66-7 ]
[ 100-51-6 ]
[ 17176-77-1 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 677
[2] Journal of the Chemical Society, 1945, p. 382,384
[3] Biochemical Preparations, 1957, vol. 5, p. 1,2
59
[ 18108-16-2 ]
[ 100-51-6 ]
[ 17176-77-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 35, p. 7973 - 7978
60
[ 59682-38-1 ]
[ 17176-77-1 ]
[ 97174-13-5 ]
[ 55920-93-9 ]
[ 137095-81-9 ]
[ 100-51-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1991, # 8, p. 1297 - 1304
61
[ 56-84-8 ]
[ 100-51-6 ]
[ 2177-63-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With sulfuric acid In diethyl ether Stage #2: at 25℃; for 24 h;
In a 500mL beaker by adding 100mL of anhydrous ether, and then slowly add 20mL concentrated sulfuric acid, while the side of the edge of the stirring, such as coldBut to room temperature,Add 150mL benzyl alcohol, stir well,The ether was removed under reduced pressure and then 26 g of aspartic acid was added in 5 batchesTo the reaction flask. Room temperature stir the reaction 24h,Then add 300 mL of 95percent ethanol and drop 80 mL with a dropping funnelPyridine, edge dripping vigorously stirring, and then frozen through the refrigerator overnight, filter to get solid, solid 80 ethanol stirring dissolved, heatFiltered, the filtrate was frozen for 8 h, filtered and lyophilized to obtain pure β-aspartic acid benzyl ester (90percent yield).
64%
Stage #1: at 60℃; for 12 h; Stage #2: With ammonia In ethanol; water at 40 - 60℃; for 2 h;
EXAMPLE 3 Preparation of β-benzyl L-aspartate 100 g (0.75 mol, 1 eq.) of L-aspartic acid and 162 g (1.5 mol, 2 eq.) of benzyl alcohol are introduced into a fitted-out 1 litre reactor and the mixture is stirred. 86.4 g (0.9 mol, 1.2 eq.) of methanesulphonic acid are subsequently introduced gradually while allowing the temperature to rise.The temperature is brought by heating to 60° C., stirring of the mixture is continued for 12 hours and then the mixture is cooled to 40° C. 200 ml of water are subsequently added, then 300 ml of ethanol are added and subsequently 95 ml of 22° B aqueous ammonia are added, so as to precipitate the ester at a PH of 6.5-7. The mixture is subsequently heated to 60° C. and is stirred at this temperature for 2 hours to improve the crystalline form of the product. It is cooled to a temperature of 5° C.-10° C. The crystalline precipitate is filtered off and washed twice with 100 ml of ethanol and 3 times with 100 ml of water. A wet product is collected and is dried under vacuum. 108 g (64percent yield) of β-benzyl L-aspartate are thus obtained, the characteristics of which are as follows: Appearance: white powder. Melting point: 212° C. [α]D20: +27.6° (read at 1percent in HCl 1N).
41%
With sulfuric acid In water at 70℃; for 2.5 h;
L-Aspartic acid (1b) (50 g, 0.38 mol), benzyl alcohol (125 g, 1.16 mol), a mixture of concentrated sulfuric acid (40.5 g) and water (10 g) were mixed in a water bath at 70 °C for 0.5 h to give a clear solution, which was stirred for s further 2 h. The resulting solution was evaporated in vacuo to an oily product, which was added to a cold solution containing sodium hydrogen carbonate (70 g) and water (250 mL) at 0 °C. The obtained cooled solution was mixed with ether (150 mL) to give a precipitate, which was filtered and washed with cold water to give another precipitate (88 g). This was recrystallized twice with water to give 34 g (41 percent). m.p. 218-219 °C (lit.23) 222 °C).
Reference：
[1] Journal of Natural Products, 2017, vol. 80, # 7, p. 2136 - 2140
[2] Patent: CN107129501, 2017, A, . Location in patent: Paragraph 0009; 0010; 0011
[3] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2011, vol. 41, # 5, p. 459 - 464
[4] Patent: US2004/133033, 2004, A1, . Location in patent: Page 4-5
[5] Chemistry - A European Journal, 2018, vol. 24, # 54, p. 14373 - 14377
[6] Synthesis, 1987, # 7, p. 635 - 637
[7] Archiv der Pharmazie, 2001, vol. 334, # 6, p. 189 - 193
[8] Archiv der Pharmazie, 2006, vol. 339, # 6, p. 283 - 290
[9] Asian Journal of Chemistry, 2014, vol. 26, # 19, p. 6541 - 6548
[10] Nippon Kagaku Zasshi, 1958, vol. 79, p. 420,423[11] Chem.Abstr., 1960, p. 4408
[12] Canadian Journal of Chemistry, 1962, vol. 40, p. 570 - 572
[13] Bulletin of the Chemical Society of Japan, 1967, vol. 40, # 7, p. 1709 - 1715
[14] Indian Journal of Chemistry, 1965, vol. 3, p. 554 - 558
[15] Journal of pharmaceutical sciences, 1963, vol. 52, p. 847 - 851
[16] Phosphorus, Sulfur and Silicon and the Related Elements, 1995, vol. 105, # 1-4, p. 129 - 144
[17] Doklady Chemistry, 2006, vol. 408, # 1, p. 57 - 60
[18] Patent: CN104725645, 2017, B, . Location in patent: Paragraph 0040-0043
[19] Russian Chemical Bulletin, 2017, vol. 66, # 11, p. 2057 - 2065[20] Izv. Akad. Nauk, Ser. Khim., 2017, vol. 66, # 11, p. 2057 - 2065,9
Reference：
[1] Canadian Journal of Chemistry, 2001, vol. 79, # 8, p. 1238 - 1258
[2] Journal of Organic Chemistry, 1999, vol. 64, # 2, p. 478 - 487
[3] Journal of Chemical Research, 2005, # 5, p. 332 - 334
[4] Recueil des Travaux Chimiques des Pays-Bas, 1938, vol. 57, p. 1234,1246
[5] Journal of Organic Chemistry, 1952, vol. 17, p. 149,153
[6] Bulletin des Societes Chimiques Belges, 1978, vol. 87, p. 721 - 732
[7] Synthesis, 2000, # 12, p. 1749 - 1755
[8] Organic Letters, 2011, vol. 13, # 15, p. 3814 - 3817
64
[ 105-53-3 ]
[ 100-51-6 ]
[ 15014-25-2 ]
[ 42998-51-6 ]
Reference：
[1] Organic Preparations and Procedures International, 2000, vol. 32, # 3, p. 272 - 275
[2] Journal of the Korean Chemical Society, 2010, vol. 54, # 1, p. 131 - 136
[3] Journal of Molecular Catalysis A: Chemical, 2014, vol. 391, # 1, p. 55 - 65
[4] Journal of Molecular Catalysis A: Chemical, 2014, vol. 391, # 1, p. 55 - 65
65
[ 105-53-3 ]
[ 100-51-6 ]
[ 15014-25-2 ]
Reference：
[1] Tetrahedron Asymmetry, 2006, vol. 17, # 22, p. 3111 - 3127
[2] Journal of the Chemical Society, 1950, p. 322,424
[3] Journal of the American Chemical Society, 1953, vol. 75, p. 1094,1096
[4] Journal fuer Praktische Chemie (Leipzig), 1980, vol. 322, # 4, p. 685 - 694
66
[ 108-59-8 ]
[ 100-51-6 ]
[ 15014-25-2 ]
[ 52267-39-7 ]
Reference：
[1] Organic Preparations and Procedures International, 2000, vol. 32, # 3, p. 272 - 275
Reference：
[1] Journal of Nanoscience and Nanotechnology, 2018, vol. 18, # 1, p. 202 - 214
69
[ 100-51-6 ]
[ 22539-93-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 11, p. 3155 - 3157
70
[ 7536-55-2 ]
[ 100-51-6 ]
[ 13512-57-7 ]
[ 95407-39-9 ]
Yield
Reaction Conditions
Operation in experiment
90 %Chromat.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 12 h; Inert atmosphere
General procedure: To a stirred solution of N-protected-L-asparagin 1a-c (0.10 mmol) and alcohol or amine 2a-n (0.12 mmol) inDCM (5 mL), EDC.HCl (0.30 mmol) and DMAP (0.02 mmol) were added at 0 oC. This reaction mixture was stirred for 12h at room temperature. Then the reaction mixture was poured in H2O (10 mL) and extracted with DCM (20 mL). The organic phase was separated, dried, and subjected to flash column chromatography (EtOAc–hexane, 1: 4) to afford the desired compounds as white solids.
Reference：
[1] Synthesis, 2008, # 10, p. 1612 - 1618
77
[ 100-51-6 ]
[ 1234-35-1 ]
Reference：
[1] Chemische Berichte, 1932, vol. 65, p. 1192,1198
78
[ 617-65-2 ]
[ 24424-99-5 ]
[ 104-15-4 ]
[ 100-51-6 ]
[ 13574-13-5 ]
Reference：
[1] Chemical communications (Cambridge, England), 2001, # 19, p. 1908 - 1909
79
[ 100-51-6 ]
[ 13574-13-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2007, vol. 5, # 12, p. 1915 - 1923
80
[ 96-48-0 ]
[ 100-51-6 ]
[ 10385-30-5 ]
Reference：
[1] Journal of Organic Chemistry, 1967, vol. 32, p. 1844 - 1846
81
[ 108-30-5 ]
[ 100-51-6 ]
[ 103-40-2 ]
Yield
Reaction Conditions
Operation in experiment
93.8%
With dmap; triethylamine In dichloromethane at 20℃;
a) Succinic acid monobenzyl ester To the ice-cooled solution of benzyl alcohol (12.96 g, 120 mmol) in methylene chloride (300 mL) was added triethylamine (25 mL, 180 mmol), 4-dimethylaminopyridine (610 mg, 5 mmol) followed by dropwise addition of succinic anhydride (10 g, 100 mmol). The reaction mixture was stirred at room temperature overnight and washed with 1N HCl (2*100 mL) and brine (100 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was dissolved in ethyl acetate (150 mL) and extracted with saturated aqueous NaHCO3 (3*150 mL). The combined aqueous layers were acidified with concentrated HCl to pH=1-2, and extracted with methylene chloride (4*250 mL). The combined organic layers were dried (Na2SO4) and concentrated to give the title acid (19.5 g, 93.8percent). 1H NMR (400 MHz, CDCl3) δ: 11.80-10.50 (br, 1H), 7.35 (m, 5H), 5.15 (s, 2H), 2.70 (m, 4H).
89%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
General procedure: To a solution of succinic anhydride (1.0g, 10mmol) in DMF (4mL) was added benzyl alcohol (0.94mL, 9.09mmol) and DIEA (1.93mL, 11mmol) at 0°C. The reaction mixture was stirred at room temperature overnight and was evaporated in Speed-vac. The residue was dissolved in ethyl acetate (50mL) and washed with saturated NaCl (10mL×2). The organic solution was extracted with aqueous NaHCO3 (5M, 5mL×3) and the aqueous extractions were combined, acidified to pH 4 by adding citric acid (5M), extracted with ethyl acetate (30mL×3). The EtOAc extractions were combined, washed with saturated NaCl, and dried over Na2SO4. Solvent was removed by evaporation in vacuo to give a white solid (1.66g, 89percent); 1H NMR (200MHz, CDCl3) δ 7.38 (s, 5H), 5.18 (s, 2H), 2.73–2.71 (m, 4H); LC–MS (ESI−) 207.0 (100percent).
88%
With dmap In tetrahydrofuran for 18 h; Reflux
A solution of succinic anhydride (1.0 g, 10 mmol), benzyl alcohol (1.14 g,11 mmol), and DMAP (54 mg, 0.44 mmol) in THF (5 mL) was refluxed for 18 h. The mixture was bacified with sat. NaHCO3, and washed with AcOEt. The aqueous layer was then acidified, and the precipiated solid was extracted with AcOEt. The solid was recrystalized to afford succinic acid monobenzyl ester as colorless needles, 1.85 g, 88percent. 1H NMR (400 MHz, CDCl3) d. 2.65–2.73 (m, 4H,CH2CH2), 5.15 (s, 2H, PhCH2), and 7.31–7.38 ppm(s, 5H, aromatic).
85%
With dmap; triethylamine In dichloromethane at 20℃; for 18 h;
Method B: Succinic anhydride (5 g, 50.0 mmol) was dissolved in anhydrous DCM (40 mL). Benzyl alcohol (5.69 mL, 55.0 mmol), triethylamine (7.50 mL, 55.0 mmol), and a catalytic amount of DMAP were added to this solution. The resulting clear solution was stirred at room temperature for 18h, after which the, all the volatiles were removed under vacuum. The crude residue was taken up in diethyl ether (200 mL) and was extracted with 2N NaOH (2 χ 75 mL). The aqueous extracts were carefully acidified to pH 2 with concentrated HC1 and then extracted with diethyl ether (2 χ 100 mL). The organic layer was dried (Na2S04), filtered and concentrated to give the title compound as a white solid (8.84 g, 85 percent). M.p. 52-54 °C, lit. 56-57 °C; 1H NMR (300 MHz, acetone-tfc): δ 2.68-2.71 (m, 4H, 2 χ CH2), 5.14 (s, 2H, CHiAr), 7.34-7.36 (m, 5H, ArH).
77%
With pyridine; dmap In dichloromethane
3-Hydroxyflavone-3-hemisuccinate (15) was produced according to the reaction outlined in Figure 3. Reaction of succinic anhydride (11) and benzyl alcohol (12) in the presence of 4-dimethylaminopyridine (DMAP) and pyridine in dichloromethane produced the succinic acid monobenzyl esteT (13) as white crystalline flakes in 77percent yield. This protected succinic acid derivative was coupled to 3-hydroxyflavone (1) in the presence of DCC and DMAP, forming flavone-3-hemisuccinate monobenzyi ester(14) as yellow or brown oil that solidified upon standing, with yields of up to 96percent produced.The deprotection of the monobenzyl ester to form the corresponding hemisuccinate using a Pd(OAc)2 in the THF:EtOH;acetic acid solvent system, a larger scale reaction was undertaken to yield the requiτed 3-hydrosyflavone-3-hernisuccinate (15).
71%
With dmap In dichloromethane at 0 - 25℃; for 96 h;
Example 14; 1-(((4-(benzyloxy)-4-oxobutanoyl)oxy)methyl)-1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-ium iodide (Compound 14)Synthesis of 4-(benzyloxy)-4-oxobutanoic acidSuccinic anhydride (7 g, 70.0 mmol) and benzyl alcohol (8.7 mL, 83.9 mmol) were combined in dichloromethane (350 mL) at 0° C. and DMAP (0.85 g, 7.0 mmol) was added portion-wise. The reaction was allowed to gradually warm to 25° C. and stirred for 4 days. The reaction mixture was washed with 1M HCl (3.x.200 mL) then water (300 mL). The organic phases were then extracted with aq saturated NaHCO3 (3.x.300 mL). This was then acidified with conc HCl until pH 1 resulting in a solid precipitating which was filtered then dissolved in dichloromethane. The dichloromethane was dried (MgSO4) and concentrated in vacuo to give 4-(benzyloxy)-4-oxobutanoic acid (10.36 g, 71percent).1H-NMR (300 MHz, CDCl3) δ 7.41-7.29 (5H, m), 5.15 (2H, s), 2.74-2.63 (4H, m).
70.47%
at 100℃; for 2 h;
A mixture of 5.0 g (0.05 mol) of succinic acid anhydride, 5.4 g (0.05 mol) of benzyl alcohol, 16.25 g (0.05 mol) of cesium carbonate, and 50 ml of N,N-dimethylforamide was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and then poured into 200 ml of ethyl acetate. The mixture was washed with saturated aqueous NaCl containing 0.35 N HCl (3*100 mL). The ethyl acetate phase, which contains the product, was collected and dried over anhydrous MgSO4. The MgSO4 was removed via filtration, and the ethyl acetate was removed under reduced pressure. The crude product was purified by crystallization in diethyl ether and hexane to provide 7.34 g of succinic acid monobenzyl ester, 70.47percent.
63.29%
With dmap In tetrahydrofuran at 50℃; for 5 h;
Succinic anhydride 1 (5.00 g, 49.96 mmol), benzyl alcohol (5.94 g, 54.96 mmol)And 4-dimethylaminopyridine (DMAP, 61 mg, 0.50 mmol) was added to 50 mL of tetrahydrofuran, and the mixture was heated to 50 ° C and stirred under heating for 5 hours.The solvent was removed under reduced pressure, 100 mL of ethyl acetate was added to the residue, washed with saturated sodium bicarbonate (100 mL) with,Discard the organic layer, adjust the water layer to pH=2 with dilute hydrochloric acid (1 mol/L), and filter.The filter cake was dried to obtain a white solid of 6.58 g, and the yield was 63.29percent.
57%
Stage #1: at 100℃; for 0.5 h; Microwave irradiation Stage #2: With water In ethyl acetate at 20℃; for 2 h;
Succinic acid anhydride (0.66 g, 6.6 mmol) and benzyl alcohol (0.65 g, 6.0 mmol) were dissolved in CH2Cl2 (5 mL) and the mixture was kept under stirring in a microwave reactor (Biotage Initiator 8) at 100 °C (pressure: ca 7 bar) for 30 min. The solvent was removed under reduced pressure and the residue was taken up in EtOAc (80 mL) and water (10 mL). The mixture was stirred at rt for 2 h, washed with 5percent KHSO4 (2 * 20 mL) and brine (20 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the colorless oil was subjected to column chromatography (eluent: CH2Cl2/EtOAc 10:1 to CH2Cl2/EtOAc 2:1). The volatiles were removed from the eluate under reduced pressure, CH2Cl2 (20 mL) was added, the solvent was evaporated, and the process repeated. Product 10 was obtained as colourless oil, which crystallized during drying in vacuo to give a white compact solid (0.71 g, 57percent) mp 55-56 °C (lit.;31 mp 56-57 °C). Rf = 0.3 (CH2Cl2/EtOAc 5:1). 1H NMR (300 MHz, [D4]MeOH): δ (ppm) 2.57-2.68 (m, 4H), 5.13 (s, 2H), 7.26-7.38 (m, 5H). C11H12O4 (208.21).
57.7%
With dmap In tetrahydrofuran at 50℃; for 5 h;
The succinic anhydride (10g, 0.1mol), benzyl alcohol (11.88g, 0.11mol), 4- dimethylaminopyridine (DMAP) (120mg) was added to a 100ml flask, THF (50ml) as solvent, the outside temperature 50 ° C reaction 5h. The reaction solution was concentrated, ethyl acetate was added, the organic layer was successively washed with water, saturated NaHCO3 solution, saturated brine, dried over anhydrous Na2SO4, and concentrated to a solid with isopropyl ether / acetone and recrystallized to give a white solid 12g, yield 57.7percent,
48%
for 4 h; Reflux
Benzyl succinic acid was synthesized by following a known procedure.33 Here, succinic anhydride (30 g, 300 mmol) was dissolved in benzyl alcohol (31.6 mL, 33 g, 300 mmol), and the resulting solutionwas heated at reflux for 4 h. The reaction mixture was dissolvedin ether (100 mL), and the insoluble succinic acid wasremoved by filtration. The filtrate was extracted with saturatedaqueous Na2CO3 (3 100 mL), and the combined aqueous extractswere acidified with 2 M HCl (2.0 L). The precipitate was collectedby filtration and dried under vacuum to give 2 (30 g, 48percent). 1HNMR (CDCl3, 300 MHz) d 7.35 (m, 5H), 5.15 (s, 2H), 2.70 (m, 4H).13C NMR (CDCl3, 75 MHz) d 177.7, 172.1, 135.7, 128.8, 128.5,128.4, 66.9, 29.1, 29.0.
250 g
With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene for 5 h; Reflux
A solution of Succinic anhydride (184 grams, 1.84 mol), Benzyl alcohol (200 grams, 1.849 mol) and PTSA (1 gram, 5.25 mmol) in Xylene (1200 ml) was stirred at reflux temperature for 5 hours. The reaction mixture was cooled to room temperature, poured onto 10percent Sodium bicarbonate solution (2500 ml), aqueous layer washed with Ethyl acetate (500 ml), pH made acidic with dil HCl, extracted with Chloroform, dried over Sodium sulphate, distilled under reduced pressure, precipitated the residue by using Hexane to give pure Succinic acid mono benzyl ester (250 grams) as white powder with a melting point of 61-63° C. The product was characterized by IH NMR (CDCl3) δ 2.70 (m, 4H, CH2X2), 5.20 (s, 2H, CH2), 7.35 (m, 5H, Ar), 10.25 (bs, 1H, COOH).
18.5 g
With pyridine In tetrahydrofuran at 20℃; for 120 h;
10.0 g (100 mmol) of succinic anhydride, 10 ml of THF (tetrahydrofuran), 10.8 g (100 mmol) of benzyl alcohol and 4 ml of pyridine were combined and stirred for 5 days at ambient temperature. The solution was diluted with toluene. The mixture was extracted with a saturated solution of sodium hydrogen carbonate. The water phase was separated, and acidified with hydrochloric acid. The product was extracted with toluene to yield 18.5 g of succinic acid monobenzyl ester.
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[18] Patent: US2007/142331, 2007, A1, . Location in patent: Page/Page column 11
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[20] Patent: CN108743953, 2018, A, . Location in patent: Paragraph 0021
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82
[ 110-15-6 ]
[ 100-51-6 ]
[ 103-40-2 ]
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[1] J. Gen. Chem. USSR (Engl. Transl.), 1963, vol. 33, p. 919 - 922[2] Zhurnal Obshchei Khimii, 1963, vol. 33, p. 934 - 938
83
[ 108-30-5 ]
[ 100-51-6 ]
[ 103-43-5 ]
[ 103-40-2 ]
Reference：
[1] Chemische Berichte, 1902, vol. 35, p. 4080
84
[ 110-15-6 ]
[ 100-51-6 ]
[ 103-50-4 ]
[ 103-43-5 ]
[ 103-40-2 ]
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85
[ 56-86-0 ]
[ 100-51-6 ]
[ 1676-73-9 ]
[ 13030-09-6 ]
Yield
Reaction Conditions
Operation in experiment
95.31%
at 60℃; for 2 h;
The reaction takes place via typical condition, that is 6.8 mmol L-glutamic acid, 10.2 mmol benzyl alcohol (L-glutamic acid/benzyl alcohol molar ratio = 1:1.5) and 0.68 mmol CuCl2 are loaded into a 50 ml single-port reaction flask, and the mixture is stirred at 60 °C for 2 h. After the reaction, the reaction mixture was cooled to be analyzed.
Stage #1: at 0℃; Inert atmosphere Stage #2: at 0 - 20℃; for 50 h; Inert atmosphere
Benzyl alcohol (70 mL, 651 mmol) was cooled to 0 °C under nitrogen and 7.0 mL thionyl chloride (91.2 mmol) was added. l-Proline (5.0 g, 43.4 mmol) was then added and the mixture was stirred at 0 °C under nitrogen for 2 h. The mixture was warmed to room temperature and stirring continued for 48 h. The reaction mixture was then poured into 300 mL diethyl ether and stored at -20 °C for 7 days. The precipitate formed was collected by filtration, washed with diethyl ether, and dried under vacuum to give 8 as white solid (9.88 g, 93percent yield); mp 142.1-144.0 °C; lit: 143-144 °C. 1H NMR (300 MHz, CDCl3): δ 7.41-7.21 (m, 5H), 5.16 (s, 2H), 3.80 (dd, J = 3.83, 5.9 Hz, 1H), 3.15-3.01 (m, 1H), 3.00-2.82 (m, 1H), 2.42-2.21 (m, 1H), 2.13 (dd, J = 12.9 Hz, 7.5 Hz, 1H), 1.92-1.62 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 175.5, 136.0, 128.8, 128.5, 128.3, 66.9, 59.9, 47.2, 30.4, 25.6. Anal. Calcd for C12H16ClNO2: C, 59.63; H, 6.67; N, 5.79. Found: C, 59.50; H, 6.86; N, 5.64. 25
75.3%
Stage #1: With hydrogenchloride; iron(III) chloride In dichloromethane at 20℃; for 0.5 h; Stage #2: for 3 h; Reflux
Will 11 · 5g (0 · lmol) valine,30ml of dichloroethane and 16.2g (0.1mol) of FeCl3 were put into a 250ml three-necked flask,Hydrogen chloride gas is fed at a rate of 1.25 ml/s (hydrogen chloride gas is always fed at this rate for a reaction time of 0.5 h).Reaction at room temperature for 0.5 h. Pass into HC1 total 2250ml, molar amount 0. lmolThen, 11.66 g (0.108 mol) of benzyl alcohol (proline: benzyl alcohol = 1:1.08) was put into a three-necked flask, and hydrogen chloride was introduced at 0.05 ml/s (hydrogen chloride gas was always fed at this rate for a reaction time of 3 h). , Under reflux conditions, distill off the aqueous dichloroethane (ie, the mixture distilled out during azeotropic distillation), and add anhydrous dichloroethane to the reaction system at the same rate to maintain The amount of dichloroethane in the reaction was essentially constant, and the reaction was completed in 3 hours. A total of 120 mL of azeotrope (ie, mixed liquor, ie, aqueous dichloroethane) was distilled out, and HC1 540 mL (0.024 mol) was introduced in total.The reaction solution was filtered while hot to obtain a filter residue containing a catalyst (Note: The "heat filtration reaction liquid" is for the purpose of removing the metal chloride as a catalyst, which can be used in the subsequent step 2).0032] After the filtered reaction solution was cooled to room temperature, the remaining dichloroethane solvent was removed by vacuum distillation (lOmmHg pressure, 40°C temperature), recrystallized at -10°C, and the precipitated solid was cooled with 20 ml of The solution was washed with iced dichloroethane at 0° C., filtered (retain filtrate), and the filter cake was dried at 40° C. for 5 h to obtain 18.20 g of proline benzyl ester hydrochloride. The yield was 75.3percent.[0033] 120ml of the mixed liquor having been distilled out during the water-retention process is obtained, and after dehydration treatment (water is removed with anhydrous sodium sulfate and 5g of anhydrous sodium sulfate is added per 100ml of dichloromethane), anhydrous dichloroethane (118mL) is obtained. Recycle in step 2.The retained filtrate was rotary evaporated (pressure of 10 mmHg, temperature of 40° C.) to 20 ml as a mother liquor for the next cycle (BP, as a raw material, fed into Step 2)..3percent.See also3/4
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 5056 - 5060
[2] Tetrahedron, 2010, vol. 66, # 29, p. 5384 - 5395
[3] Patent: CN105061283, 2017, B, . Location in patent: Paragraph 0030-0032; 0045-0047; 0057
[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1959, p. 1851; engl. Ausg. S. 1768, 1769
[5] Journal of Biological Chemistry, 1951, vol. 193, p. 97,108
[6] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 17, p. 6220 - 6229
93
[ 100-51-6 ]
[ 16652-71-4 ]
Reference：
[1] Patent: WO2012/30160, 2012, A2,
94
[ 6399-81-1 ]
[ 100-51-6 ]
[ 1449-46-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2222 - 2231
[2] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 6, p. 1676 - 1680
[3] Patent: CN105777817, 2016, A, . Location in patent: Paragraph 0103
95
[ 100-51-6 ]
[ 1449-46-3 ]
Reference：
[1] Journal of Steroid Biochemistry and Molecular Biology, 2013, vol. 137, p. 332 - 344
[2] Advanced Synthesis and Catalysis, 2016, vol. 358, # 11, p. 1731 - 1735
96
[ 104-15-4 ]
[ 56-40-6 ]
[ 100-51-6 ]
[ 1738-76-7 ]
Yield
Reaction Conditions
Operation in experiment
88.4%
at 10℃; for 2 h; Autoclave; Reflux; Large scale
To 2000L is put in the reactor 270 kg P-toluenesulfonic acid monohydrate, toluene 550 kg, turning on the agitation, heating to reflux, with the water to drop the generated water, until there is no water generating, glycine is added in to the reaction solution 100 kg, benzalcohol 850 kg, to continue heating to reflux, water constantly by the generated water is separated, water until no, continue to reflux 2 hours, cooling to 10 °C, stirring 1 hour, filtering, with 100 kg of acetone washing the filter cake, drying to be 395 kg glycine benzyl ester P-toluenesulfonate, yield 88.4percent, purity 99.62percent.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 2, p. 519 - 532
[2] Synthesis, 2002, # 8, p. 1017 - 1026
[3] Chemical Communications, 2007, # 36, p. 3711 - 3713
[4] Chemistry - An Asian Journal, 2009, vol. 4, # 2, p. 328 - 335
[5] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 707 - 710
[6] Synthesis, 1991, # 2, p. 141 - 146
[7] Synthesis, 1994, # 2, p. 170 - 172
[8] Chemistry - An Asian Journal, 2017, vol. 12, # 10, p. 1075 - 1086
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5512 - 5517
[10] Patent: CN105503665, 2016, A, . Location in patent: Paragraph 0020; 0021
[11] Synthetic Communications, 1995, vol. 25, # 3, p. 379 - 387
[12] Journal of Chemical Research, 2013, vol. 37, # 3, p. 181 - 185
[13] Chemistry - A European Journal, 2015, vol. 21, # 35, p. 12295 - 12298
[14] Journal of the American Chemical Society, 2012, vol. 134, # 47, p. 19322 - 19325
[15] Organic Letters, 2018, vol. 20, # 1, p. 162 - 165
[16] Patent: US6939973, 2005, B1, . Location in patent: Sheet 1; 3
[17] Dalton Transactions, 2015, vol. 44, # 44, p. 19126 - 19140
[18] Chemical Communications, 2014, vol. 50, # 88, p. 13585 - 13588
[19] Journal of Agricultural and Food Chemistry, 2005, vol. 53, # 20, p. 7899 - 7907
[20] Tetrahedron Asymmetry, 2008, vol. 19, # 24, p. 2816 - 2828
[21] Journal of Organic Chemistry, 2009, vol. 74, # 23, p. 8988 - 8996
[22] Patent: EP1650185, 2006, A1, . Location in patent: Page/Page column 15-16
97
[ 56-40-6 ]
[ 100-51-6 ]
[ 1738-76-7 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 1, p. 121 - 123
[2] Patent: WO2005/33119, 2005, A1, . Location in patent: Page/Page column 76
98
[ 98-59-9 ]
[ 56-40-6 ]
[ 100-51-6 ]
[ 1738-76-7 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 16, p. 1870 - 1875
99
[ 921-26-6 ]
[ 100-51-6 ]
[ 108549-23-1 ]
Yield
Reaction Conditions
Operation in experiment
75.3%
With triethylamine In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere; Cooling with ice
Take compound 3-9, 42g (207.92mmo1) was placed in a 500mL round bottomed flask, was added 300mL of anhydrous tetrahydrofuran, 66mL (455.44mmol, 46g) of anhydrous triethylamine were dissolved with stirring. When the flask was placed in an ice-salt bath until the system temperature was lowered to 0 the right, under nitrogen was added dropwise over anhydrous benzyl alcohol 45mL (416.67mmol, 45g), was added dropwise maintaining temperature of the system is always near 0 , IH complete after the suspension was added dropwise to give a white solid containing the ice bath was removed to room temperature, stirring was continued at room temperature for 3h stirring was stopped to stand 10min, filtered off with suction, washed solid was tetrahydrofuran, the filtrate was collected, rotary evaporated to give tetrahydrofuran was no liquid column liquid chromatography to give an oil 54.0g, a yield of 75.3percent.
Reference：
[1] Tetrahedron, 1991, vol. 47, # 26, p. 4709 - 4722
[2] Patent: CN102977145, 2017, B, . Location in patent: Paragraph 0196; 0197
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 11, p. 1239 - 1246
[4] Journal of Medicinal Chemistry, 1994, vol. 37, # 23, p. 3918 - 3927
[5] Journal of Organic Chemistry, 1996, vol. 61, # 22, p. 7719 - 7726
[6] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 14, p. 1717 - 1727
[7] Tetrahedron, 1999, vol. 55, # 23, p. 7251 - 7270
[8] Carbohydrate research, 2002, vol. 337, # 20, p. 1795 - 1801
General procedure: The esterifications were carried out on L amino acids withthe exception of phenylglycine, the D enantiomer of whichwas used. A mixture of amino acid (0.05 mol), p-toluenesulfonicacid (0.06 mol), benzyl alcohol (0.25 mol) andcyclohexane (30 mL) was refluxed for 4 h using a Dean-Stark apparatus to separate water that was azeotroped outas it formed. The reaction mixture was cooled to roomtemperature and ethyl acetate (80 mL) was added. Afterstirring for 1 h, the precipitate was collected by filtrationand dried to give the corresponding benzyl ester p-toluenesulfonateas a white solid. According to this procedure,the amino acids 1–6 were converted into the correspondingbenzyl ester p-toluenesulfonates 1a–6a. The benzylationof 7 was accomplished in the same manner but in thepresence of more p-toluenesulfonic acid (0.11 mol) to givethe di-p-toluenesulfonate 7a as a white solid. The p-toluenesulfonate8a separated at the end of the reaction as anoil; instead of adding ethyl acetate, the supernatant wasremoved, the oily phase was washed with cyclohexane andthen poured into dichloromethane/aqueous Na2CO3. Afterremoving the water layer and evaporating dichloromethane,the residue was treated with hydrochloric methanol to give the corresponding hydrochloride as a white solid. Thebenzylation of 9 was prolonged over night and, at the endof the reaction, 9a separated as an oil, which was pouredinto dichloromethane/water. After removing the organiclayer, the water phase was made alkaline with NaHCO3 andextracted with ethyl acetate. The organic extract was concentratedto a small volume and a slight excess of p-toluenesulfonicacid was added to precipitate 9a as a white crystallinesolid.
Reference：
[1] Tetrahedron Letters, 2008, vol. 49, # 49, p. 6962 - 6964
[2] Journal of the Indian Chemical Society, 2001, vol. 78, # 3, p. 137 - 141
[3] Amino Acids, 2017, vol. 49, # 5, p. 965 - 974
[4] Chirality, 2012, vol. 24, # 2, p. 188 - 192
[5] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 962 - 977
106
[ 56-87-1 ]
[ 104-15-4 ]
[ 100-51-6 ]
[ 16259-78-2 ]
Yield
Reaction Conditions
Operation in experiment
85%
for 4 h; Dean-Stark; Reflux
General procedure: The esterifications were carried out on L amino acids withthe exception of phenylglycine, the D enantiomer of whichwas used. A mixture of amino acid (0.05 mol), p-toluenesulfonicacid (0.06 mol), benzyl alcohol (0.25 mol) andcyclohexane (30 mL) was refluxed for 4 h using a Dean-Stark apparatus to separate water that was azeotroped outas it formed. The reaction mixture was cooled to roomtemperature and ethyl acetate (80 mL) was added. Afterstirring for 1 h, the precipitate was collected by filtrationand dried to give the corresponding benzyl ester p-toluenesulfonateas a white solid. According to this procedure,the amino acids 1–6 were converted into the correspondingbenzyl ester p-toluenesulfonates 1a–6a. The benzylationof 7 was accomplished in the same manner but in thepresence of more p-toluenesulfonic acid (0.11 mol) to givethe di-p-toluenesulfonate 7a as a white solid. The p-toluenesulfonate8a separated at the end of the reaction as anoil; instead of adding ethyl acetate, the supernatant wasremoved, the oily phase was washed with cyclohexane andthen poured into dichloromethane/aqueous Na2CO3. Afterremoving the water layer and evaporating dichloromethane,the residue was treated with hydrochloric methanol to give the corresponding hydrochloride as a white solid. Thebenzylation of 9 was prolonged over night and, at the endof the reaction, 9a separated as an oil, which was pouredinto dichloromethane/water. After removing the organiclayer, the water phase was made alkaline with NaHCO3 andextracted with ethyl acetate. The organic extract was concentratedto a small volume and a slight excess of p-toluenesulfonicacid was added to precipitate 9a as a white crystallinesolid.
Reference：
[1] Journal of the American Chemical Society, 2000, vol. 122, # 33, p. 7927 - 7935
[2] Amino Acids, 2017, vol. 49, # 5, p. 965 - 974
107
[ 56-40-6 ]
[ 100-51-6 ]
[ 2462-31-9 ]
Reference：
[1] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1928, vol. 176, p. 106
[2] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 17, p. 6220 - 6229
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 1, p. 55 - 67
[4] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 5, p. 1025 - 1030
[5] Patent: WO2014/22807, 2014, A2, . Location in patent: Paragraph 0246; 0247; 0248; 0249
108
[ 63-91-2 ]
[ 100-51-6 ]
[ 2462-32-0 ]
Reference：
[1] Journal of the Chinese Chemical Society, 2009, vol. 56, # 5, p. 1010 - 1017
[2] Journal of the Indian Chemical Society, 1985, vol. 62, # 6, p. 457 - 459
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 17, p. 6220 - 6229
109
[ 100-51-6 ]
[ 2462-32-0 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 9, p. 4235 - 4243
110
[ 29617-66-1 ]
[ 100-51-6 ]
[ 100836-85-9 ]
Reference：
[1] Patent: US6362376, 2002, B1, . Location in patent: Example 1
111
[ 56-41-7 ]
[ 100-51-6 ]
[ 100836-85-9 ]
[ 33106-32-0 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3457 - 3465
112
[ 338-69-2 ]
[ 100-51-6 ]
[ 100836-85-9 ]
[ 33106-32-0 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3457 - 3465
113
[ 6863-73-6 ]
[ 100-51-6 ]
[ 110223-15-9 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With sodium hydride In 1-methyl-pyrrolidin-2-one for 0.5 h; Stage #2: at 80℃; for 24 h;
Benzyl alcohol (4.55 g, 42.15 mmol) was added under an inert atmosphere dropwise to a suspension of sodium hydride (1. 01 g, 42.13 mmol, 80percent) in N-methylpyrrolidinone. Stirring of the reaction mixture was continued for 30 min. 2-Amino-3-chloropyrazine (Compound I in Scheme 1, 5.0 g, 38.6 mmol) was then added in incrememtal portions and the resultant mixture was heated at 80 °C for 24 h. The reaction mixture was subsequently cooled and water (200 mL) was added. The aqueous solution was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (2 x 100 mL), dried (Mg04), and concentrated under reduced pressure to obtain a light brown residue. Addition of cold water to the residue, triggered crystallization of the desired product. The crystals were collected and dried over P2O5 (6.33 g, 82percent). 1H-NMR (CDCl3) No. 7. 54 (d, J 3.1 Hz, 1H), 7.45-7. 32 (m, 6H), 5. 38 (s, 2H), 4. 78 (br s, 2H); MS (ESI) 202.2 ([M+H] +)
82%
Stage #1: With sodium hydride In 1-methyl-pyrrolidin-2-one for 0.5 h; Stage #2: at 80℃; for 24 h;
Benzyl alcohol (4.55 g, 42.15 mmol) was added under an inert atmosphere dropwise to a suspension of sodium hydride (1. 01 g, 42.13 mmol, 80percent) in N-methylpyrrolidinone. Stirring of the reaction mixture was continued for 30 min. 2-Amino-3-chloropyrazine (Compound I in Scheme 1, 5.0 g, 38.6 mmol) was then added in incrememtal portions and the resultant mixture was heated at 80 °C for 24 h. The reaction mixture was subsequently cooled and water (200 mL) was added. The aqueous solution was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (2 x 100 mL), dried (Mg04), and concentrated under reduced pressure to obtain a light brown residue. Addition of cold water to the residue, triggered crystallization of the desired product. The crystals were collected and dried over P2O5 (6.33 g, 82percent). 1H-NMR (CDCl3) No. 7. 54 (d, J 3.1 Hz, 1H), 7.45-7. 32 (m, 6H), 5. 38 (s, 2H), 4. 78 (br s, 2H); MS (ESI) 202.2 ([M+H] +)
53.76%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h; Stage #2: at 100℃; for 15 h;
Sodium hydride (188.6 mg, 4.72 mmol) in N, N- dimethylformamide (3 mL) was slowly added dropwise at room temperature and benzyl alcohol was dissolved in it and it was stirred at room temperature for 1 hour. It was added dropwise slowly to a mixture of 2-amino-3-chloro-pyrazine and heating at 100 °C refluxed for 15 hours. After cooling the reaction to room temperature and the solvent was evaporated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filter and concentrate under reduced pressure . By separation and purification of the residue by column chromatography (ethyl acetate / n-hexane = 1/4) to obtain the objective compound 300 mg at a yield of 53.76percent.
53.8%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1 h; Inert atmosphere; Schlenk technique Stage #2: at 100℃; for 15 h; Inert atmosphere; Schlenk technique
General procedure: Sodium hydride (60percent in mineral oil, 0.04 g, 1 mmol) was addedto a stirred solution of benzyl alcohol derivative (1 mmol) inanhydrous N,N-dimethylformamide (3 mL of DMF) at room temperatureand stirring was continued for 1 h. 2-Amino-3-chloropyrazine (8b, 0.13 g, 1 mmol) was added to the reactionmixture and the reaction mixture was stirred at 100 °C for 15 h.After cooling, the solvent was evaporated and the residue waspartitioned betweenwater and dichloromethane. The organic layer was dried over sodium sulfate anhydrous, filtered, and concentrated.The residue was purified by column chromatography (SiO2,EA/n-Hex 1/5). 4.1.2.1 3-(Benzyloxy)pyrazin-2-amine (9g) Yellow solid, yield: 53.8percent, 1H NMR (400 MHz, CDCl3) δ = 5.45 (2H, s, OCH2Ph), 6.20 (2H, br, NH2), 7.38-7.48 (7H, m, ArH). Reported [ 48,49].
Reference：
[1] Patent: WO2005/34837, 2005, A2, . Location in patent: Page/Page column 43-44
[2] Patent: WO2005/34837, 2005, A2, . Location in patent: Page/Page column 43-44
[3] Patent: KR101481952, 2015, B1, . Location in patent: Paragraph 0797; 0798
[4] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 529 - 543
[5] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1639 - 1643
[6] Journal of Medicinal Chemistry, 1987, vol. 30, # 11, p. 2031 - 2046
[7] MedChemComm, 2014, vol. 5, # 3, p. 333 - 337
[8] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 268 - 278
114
[ 6863-73-6 ]
[ 100-51-6 ]
[ 110223-15-9 ]
[ 132972-99-7 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1639 - 1643
Reference：
[1] Chemical communications (Cambridge, England), 2001, # 19, p. 1908 - 1909
118
[ 100-51-6 ]
[ 150009-58-8 ]
Reference：
[1] Journal of Natural Products, 2017, vol. 80, # 7, p. 2136 - 2140
119
[ 72-18-4 ]
[ 100-51-6 ]
[ 2462-34-2 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: With hydrogenchloride; iron(III) chloride In 1,2-dichloro-ethane at 20℃; for 0.5 h; Stage #2: for 3 h; Reflux
Will 11 · 5g (0 · lmol) valine,30ml of dichloroethane and 16.2g (0.1mol) of FeCl3 were put into a 250ml three-necked flask,Hydrogen chloride gas is fed at a rate of 1.25 ml/s (hydrogen chloride gas is always fed at this rate for a reaction time of 0.5 h).Reaction at room temperature for 0.5 h. Pass into HC1 total 2250ml, molar amount 0. lmolThen, 11.66 g (0.108 mol) of benzyl alcohol (proline: benzyl alcohol = 1:1.08) was put into a three-necked flask, and hydrogen chloride was introduced at 0.05 ml/s (hydrogen chloride gas was always fed at this rate for a reaction time of 3 h). , Under reflux conditions, distill off the aqueous dichloroethane (ie, the mixture distilled out during azeotropic distillation), and add anhydrous dichloroethane to the reaction system at the same rate to maintain The amount of dichloroethane in the reaction was essentially constant, and the reaction was completed in 3 hours. A total of 120 mL of azeotrope (ie, mixed liquor, ie, aqueous dichloroethane) was distilled out, and HC1 540 mL (0.024 mol) was introduced in total.The reaction solution was filtered while hot to obtain a filter residue containing a catalyst (Note: The "heat filtration reaction liquid" is for the purpose of removing the metal chloride as a catalyst, which can be used in the subsequent step 2).0032] After the filtered reaction solution was cooled to room temperature, the remaining dichloroethane solvent was removed by vacuum distillation (lOmmHg pressure, 40°C temperature), recrystallized at -10°C, and the precipitated solid was cooled with 20 ml of The solution was washed with iced dichloroethane at 0° C., filtered (retain filtrate), and the filter cake was dried at 40° C. for 5 h to obtain 18.20 g of proline benzyl ester hydrochloride. The yield was 75.3percent.[0033] 120ml of the mixed liquor having been distilled out during the water-retention process is obtained, and after dehydration treatment (water is removed with anhydrous sodium sulfate and 5g of anhydrous sodium sulfate is added per 100ml of dichloromethane), anhydrous dichloroethane (118mL) is obtained. Recycle in step 2.The retained filtrate was rotary evaporated (pressure of 10 mmHg, temperature of 40° C.) to 20 ml as a mother liquor for the next cycle (BP, as a raw material, fed into Step 2)..3percent.See also3/4
Reference：
[1] Patent: CN105061283, 2017, B, . Location in patent: Paragraph 0047-0049
[2] Journal of the Chinese Chemical Society, 2009, vol. 56, # 5, p. 1010 - 1017
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 17, p. 6220 - 6229
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2011, vol. 50, # 9, p. 1157 - 1164
120
[ 100-51-6 ]
[ 2462-34-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 1, p. 6 - 10
With potassium carbonate In dichloromethane for 2 h;
To a solution of 4-bromobutyryl chloride (Aldrich Chemical Company, Wisconsin), (10.27 g, 55.4 mmol) in 100 mL of dichloromethane was added benzyl alcohol (Aldrich Chemical Company, Wisconsin), (6.29 g, 58.1 mmol), followed by potassium carbonate (8.3 g, 60 mmol) in four portions. After 2 hours, water was added, and the layers were separated. The organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent gave the title compound (11.87 g, 83percent yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 5.14 (s, 2H), 3.46 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 2.20 (quin, J=6.6 Hz, 2H).
82%
With dmap In dichloromethane at 20℃; for 2 h;
[00140] Benzyl alcohol (3.1 ml_, 30 mmol) was added to a solution of Compound 1 (3.47 ml_, 30 mmol) and 4-dimethylaminopyridine (732 mg, 6 mmol) in dichloromethane (100 ml_). The reaction was stirred for 2 hours at room temperature then quenched with 1 M HCI (100 ml_). The organic phase was washed once more with 1 M HCI (100 ml_), dried over MgS04, filtered, dried by rotary evaporation and was dried under vacuum to yield Compound 2 as a colorless oil (6.29 g, 24.5 mmol, 82percent).
Reference：
[1] Patent: US2006/189603, 2006, A1, . Location in patent: Page/Page column 57
[2] Patent: WO2016/86026, 2016, A1, . Location in patent: Paragraph 00140
[3] Journal of Medicinal Chemistry, 1996, vol. 39, # 26, p. 5176 - 5182
[4] Synthesis, 2010, # 6, p. 953 - 958
[5] Patent: EP1724278, 2006, A1, . Location in patent: Page/Page column 44-45
133
[ 2623-87-2 ]
[ 100-51-6 ]
[ 126430-46-4 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With S-phenyl benzenethiosulfinate; diisopropyl-carbodiimide In dichloromethane at 20℃; for 2 h;
General procedure: General Procedure for Benzyl Protection of the Bromo-Acid (1c, 1d) [0103] Diisopropylcarbodiimide (DIC) (3.59 mmol, 1.3 eq) was added to a mixture of the bromo-acid (4-bromobutyric acid or 5-bromovaleric acid) (2.76 mmol, 1 eq) and DPTS (3.04 mmol, 1.1 eq) in dry DCM (30 mL) and was allowed to react for 2 hours at room temperature. Benzyl alcohol (4.14 mmol, 1.5 eq) was added and allowed to react overnight. The reaction was washed water and brine, and the DCM was removed by evaporation. Hexanes was added and the resulting white precipitate was removed by filtration. The hexanes was removed from the filtrate by evaporation resulting in an oil which was purified by silica gel chromatography (Hexanes/Ethyl Acetate 3.5/1). Benzyl 4-bromobutyrate (1c) [0104] 70percent yield [0105] 1H NMR (500 MHz, CDCl3) 2.22 (p 2H), 2.58 (t, 2H), 3.48 (t, 2H), 5.16 (s, 2H), 7.40 (m, 5H) [0106] 13C NMR (125 MHz, CDCl3): 28.0, 32.7, 33.0, 66.7, 128.5, 128.6, 128.9, 136.1, 172.6
Reference：
[1] European Journal of Organic Chemistry, 2008, # 15, p. 2592 - 2600
[2] Advanced Synthesis and Catalysis, 2007, vol. 349, # 3, p. 432 - 440
[3] Journal of Organic Chemistry, 2001, vol. 66, # 12, p. 4115 - 4121
[4] Journal of the American Chemical Society, 2011, vol. 133, # 41, p. 16346 - 16349
[5] Patent: US2013/302258, 2013, A1, . Location in patent: Paragraph 0102; 0103; 0104; 0105; 0106
[6] Chemistry - A European Journal, 2016, vol. 22, # 4, p. 1270 - 1276
[7] Patent: EP1544208, 2005, A1, . Location in patent: Page/Page column 58
134
[ 73731-37-0 ]
[ 100-51-6 ]
[ 175291-56-2 ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: With phosphorus trichloride In tetrahydrofuran at -5 - 5℃; for 0.0833333 h; Inert atmosphere Stage #2: With 2,6-dimethylpyridine In tetrahydrofuran at -5 - 5℃; Inert atmosphere
General Procedure for Amino Acid PhosphorylationIn the following description, a "volume" equivalent is one mL of liquid per gram of the limiting reagent (e.g., the dry amino acid).Amino acid dryingHydrated forms of amino-group-protected amino acids (hydrated specified as >0.5 wtpercent water) are dried prior to use. The amino-group-protected amino acid (1.0 equivalents of dry compound) is charged to a flask. Dry THF (4 volumes, EMD OmniSolv HPLC grade, >99.99percent) is added and the total volume is marked on the outside of the flask. The mixture is heated in a 70°C bath and THF (about 2 volumes) is removed via distillation at 700 mbar. The solution is then diluted to the original, marked volume with dry THF. This distillation and dilution cycle is repeated two additional times. The final water content of the amino acid solution should be <0.20 wtpercent by Karl-Fischer (KF) titration.Step One: Dichlorophosphite preparationTo a flask flushed with nitrogen, THF (8 volumes) is charged. The solvent is cooled to 0°C and PC13 (1.30 equivalents, Aldrich, Reagent Plus grade, 99percent) is charged to the flask at a rate that maintains the solution at 0-5 °C. When the addition is complete and the solution is below 2.5 °C, a suitable base such as pyridine (Aldrich, anhydrous, 99+percent) (1 equivalent) may optionally be added at a rate that keeps the reaction temperature at - 5°C to 5°C. This optional step is especially useful when the dichlorophosphite is prepared from tert-butanol. With the reaction temperature below 2.5°C, a suitable alcohol such as tert-butanol or benzyl alcohol (BnOH; Aldrich, ACS grade, 99+percent) (1.50 equivalents) is added at a rate that keeps the reaction at -5 to 5°C. The solution is then allowed to stir for 5 minutes at 0-5°C and the consumption of PC13 is confirmed by 31P NMR (in CDCI3). A suitable base such as 2,6-lutidine (Aldrich, >99percent) (3.00 equivalents; 2.00 equivalents if a base was added previously) is then added to the flask at a rate that keeps the reaction at -5 to 5 °C. This forms a thick slurry.Step Two: Phosphite ester intermediate preparationA suitable base such as 2,6-lutidine (1.0 equivalents) is added to the dried amino- group-protected amino acid (APG-A.A.) solution. This solution is then added to the mixture from step one at a rate that keeps the reaction at -5 to 5°C. Additional THF (1 volume) is used to rinse the flask containing the APG-A.A. solution into the reaction. HPLC assays (Method 1) are taken at 10 min intervals starting 5 minutes after the addition to confirm reaction completion (no change in the ratio of APG-A.A. to intermediate phosphite ester at 225/210 nm).Step Three: Hydrolysis to phosphite esterAfter three consistent HPLC traces are observed, H20 (3.6 volumes) is added to the flask at a rate that does not allow the reaction to go above 10°C. During the addition, a two-phase solution is formed.Step Four: Oxidation to phosphateA suitable oxidant is then added to the two-phase mixture. When the oxidant isNaBr03/NaBr, solid NaBr (2.32 equivalents, Aldrich, ACS grade, 99+percent) is added to the two-phase mixture in the reactor at 0°C; an aqueous solution (20 wtpercent in water) of NaBr03 (0.48 equivalents, Riedel-de-Haen, puriss grade, 98percent> NaBr03 in DI water) is then added at a rate that keeps the reaction at 0-5°C. After the oxidant addition is complete the cooling is removed to allow the reaction to warm to ambient temperature, being careful not to allow the reaction to exotherm above 30°C. HPLC assays (Method 1) are taken to confirm reaction completion (phosphite ester intermediate <1.5 Apercent at 225/210 nm). When reaction completion is observed an aqueous solution (10 wtpercent> in water) of Na2S205 (1 volume, Sigma- Aldrich, ACS grade, 97+percent> Na2S205 in DI water) is added to the flask in one portion.Example 2. Fmoc (BnO) Phosphothreonine.67percent yield. 1H NMR (400 MHz, DMSO): δ 7.89 (d, 2H), 7.78 (d, 2H), 7.71 (d, 1H), 7.38 (m, 9H), 4.92 (d, 2H), 4.81 (m, 1H), 4.26 (m, 4H), 1.30 (d, 3H); 13C NMR (400 MHz, DMSO): δ 170.95 (s, 1C), 156.51 (s, 1C), 143.74 (d, 2C), 140.65 (d, 2C), 136.96 (d, 1C), 128.29 (s, 2C), 127.89 (s, 1C), 127.61 (s, 2C), 127.50 (s, 2C), 127.03 (s, 2C), 125.40 (d, 2C), 120.04 (s, 2C), 73.10 (d, 1C), 67.35 (d, 1C), 66.05 (s, 1C), 58.59 (d, 1C), 46.59 (s, 1C), 18.17 (d, 1C); 31P NMR (400 MHz, DMSO): δ -2.27; HRMS: [MH+] = 512.14700 (Calc =512.14688); Specific Rotation: +5.99°
Stage #1: With sodium hydride In hexane; N,N-dimethyl-formamide at 20℃; for 2.08333 h; Inert atmosphere; Cooling with ice Stage #2: at 20℃; for 15 h; Inert atmosphere
3-(Benzyloxy)-5-bromopyridine [1099] (Zhu. G.-D. et al., Bioorg. Med. Chem. Lett. 2006, 16, 3150-3155) [1100] A 500 mL three-necked flask was charged with sodium hydride (60percent dispersion in oil; 9.6 g, 240 mmol, 2.0 equiv.) and fitted out with stir bar, dropping funnel, N2 balloon, and septa. The sodium hydride was washed with hexane (2×150 mL), then anhydrous DMF (110 mL) was added. With stifling and intermittent ice cooling, benzyl alcohol (25 mL, 240 mmol, 2.0 equiv.) was added dropwise within 105 min. The temperature was kept high enough to permit efficient stifling and prevent excessive frothing. After the addition was finished, the dropping funnel was rinsed with anhydrous DMF. Stirring was continued at room temperature for 20 min. The flask was briefly opened to add 3,5-dibromopyridine (28.4 g, 120 mmol) all at once. The atmosphere was again replaced with N2, and the reaction mixture was stirred at room temperature for 15 h. A thin layer chromatogram (small aliquot quenched into EtOAc/H2O; silica gel, EtOAc/hexane 15:85) taken shortly before the end of this period demonstrated the near-absence of starting material (Rf 0.6) and the formation of a product (Rf 0.25); benzyl alcohol was detected at Rf 0.15. The bulk of DMF was distilled in an oil pump vacuum at a bath temperature of 40° C. into a receiver cooled with acetone/dry ice. Initial foaming was due to the evaporation of residual hexane. The receiver was subsequently changed to maintain a high vacuum. The residue was taken up in diethyl ether (300 mL) and the resulting suspension poured into ice water (300 mL). The phases were separated, and the aqueous phase was twice extracted with ether (100 mL each). The combined organic phases were washed with brine (100 mL) and dried over MgSO4 (15 g). Evaporation furnished an orange-colored liquid together with a colorless solid. After transfer into a 200 mL flask, benzyl alcohol was distilled off in an oil pump vacuum into a −78° C. receiver. The product began to crystallize after partial cooling, whereon methanol (60 mL) was added. Crystallization was initially allowed to proceed at room temperature, then in the freezer overnight. [1101] The product was isolated by suction filtration, washed with two portions of freezer-chilled methanol (20 mL each), and dried (40° C./oil pump) to obtain 23.2 g (73percent) of light-tan crystals (mp 67-68.5° C.). The mother liquor was concentrated to a few mL, diluted with methanol (15 mL), seeded, and placed in the freezer. Isolation as above gave 1.7 g of a solid which upon TLC examination revealed contamination with polar material. The second mother liquor still contained substantial amounts of benzyl alcohol, which was removed by evaporation into a 50 mL flask and bulb-to-bulb distillation at 80° C. in an oil pump vacuum until by visual appearance no further distillate was formed. The dark residue (2.7 g) together with the impure second crystal fraction was taken up in CH2Cl2 (3 mL) and chromatographed on silica gel (25×3.8 cm, EtOAc/hexane 1:9) to yield, after evaporation and drying, another 2.4 g (8percent) of the product 2. 1H NMR (CDCl3, 300 MHz) δ 8.33 (narrow m, 2H), 7.50-7.32 (m, 6H), 5.11 (s, 2H).
63%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oilInert atmosphere Stage #2: at 180℃; for 2 h; Inert atmosphere
Benzylalcohol (10 mL, 96 mmol) was dissolved in dry DMF (30 mL) and sodium hydride (60percent suspension in mineral oil) (2.5 g, 62.50 mmol) was slowly added. When no more gas evolved, 3,5-dibromopyridine (10 g, 42.21 mmol) was added and the reaction mixture was stirred at 180 °C for 2 h. After addition of water, the aqueous phase was extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The resulting oil was purified by column chromatography eluting with an 8/2 mixture of petroleum ether and diethyl ether and then a second column chromatography eluting with a 9/1 mixture of CH2Cl2 and ethyl acetate to afford 2 (7.02 g, 63percent) as a beige needle. Mp 67-68 °C (lit.:14 64-65 °C); IR (KBr): 1553, 1425, 1259, 990 cm-1; 1H NMR (400 MHz): 5.25 (s, 2H, -OCH2Ph), 7.37-7.51 (m, 5H, Ph-H), 7.84 (dd, J=J'=2.0 Hz, 1H, pyridine-H), 8.33 (d, J=2.0 Hz, 1H, pyridine-H), 8.40 (d, J=2.0 Hz, 1H, pyridine-H); 13C NMR (100 MHz): 70.2, 120.2, 124.3, 128.2, 128.4, 128.7, 136.2, 137.4, 142.5, 155.3; the data are in conformity with the literature.14 MS (ESI) m/z (percent): 265.9 [(M+H)+, 100], 267.9 [(M+H)+2, 100]. Anal. Calcd for C12H10BrNO: C, 54.57; H, 3.82; N, 5.30. Found: C, 54.63; H, 3.83; N, 5.31.
43%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 60℃; for 1 h; Stage #2: at 80℃; for 2 h;
Benzyl alcohol (4.60 g, 42.6 mmol) was slowly added to a stirred solution of NaH (60percent disp., 1.70 g, 42.5 mmol) in DMF (50 mL). The reaction was heated to 60 0C for 1 hours. 3,5-Dibromopyridine (10.0 g, 42.2 mmol) in DMF (20 mL) was added and the mixture was heated at 80 0C for 2 hours. The reaction <n="172"/>mixture was partitioned between ethyl acetate and water. The organic layer was separated and concentrated to give a residue which was purified using flash chromatography to give 3- Benzyloxy-5-bromopyridine (4.75 g, 43percent). MS m/z calculated for (M + H)+ 265, found 265.
26%
Stage #1: With sodium hydride In N,N-dimethyl-formamide for 1.5 h; Reflux Stage #2: at 20℃; for 12 h; Reflux
To a solution of benzyl alcohol (1.04g, 9.66mmol) in anhydrous DMF (80mL) was slowly added 60percent NaH (0.58g, 14.49mmol). The mixture was allowed to react at room temperature for 30min then it was heated to reflux for 1h. 3,5-dibromopyridine (2.41g, 10.17mmol) was added and the reaction was continued for 12h. After cooling down to room temperature, the mixture was poured in water and extracted with ethyl acetate. The organic phase was washed with brine, dried on MgSO4, filtered and evaporated. The crude product was purified by silica gel chromatography (cyclohexane/AcOEt 95:5) affording 10 as a white solid. Yield 26percent. Mp 66–68°C. 1H NMR (400MHz, CDCl3): δ 5.06 (2H, s, OCH2), 7.36–7.44 (6H, m, H-4, H-Ph), 8.30 (1H, d, J=2.3Hz, H-6), 8.31 (1H, d, J=2.3Hz, H-2). 13C NMR (100MHz, CDCl3): δ 155.5, 143.5, 137.0, 135.7, 129.1, 128.8, 127.9, 124.7, 120.7, 71.0.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 12, p. 3150 - 3155
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 717 - 724
[3] Patent: US2013/184313, 2013, A1, . Location in patent: Paragraph 1099; 1100
[4] Tetrahedron, 2011, vol. 67, # 26, p. 4767 - 4773
[5] Tetrahedron, 2001, vol. 57, # 20, p. 4447 - 4454
[6] Patent: WO2007/84560, 2007, A2, . Location in patent: Page/Page column 170-171
[7] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 185 - 198
[8] Patent: WO2010/45212, 2010, A2, . Location in patent: Page/Page column 134; 173-174
[9] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 689 - 697
137
[ 74115-13-2 ]
[ 100-51-6 ]
[ 130722-95-1 ]
Yield
Reaction Conditions
Operation in experiment
97 mg
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 18 h;
Synthesis of 3-Benzyloxy-5-bromo-pyridine To a vial is added 3-bromo-5-hydroxypyridine (200 mg, 1.15 mmol), benzyl alcohol (137 mg, 1.27 mmol) and triphenylphosphine (332 mg, 1.27 mmol) in THF (5 ml) at 0° C., followed by the addition of diisopropyl azodicarboxylate (256 mg, 1.27 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with sat NaHCO3, water, brine, dried under anhy. Na2SO4, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0-5percent MeOH/CH2Cl2) to afford title compound (97 mg); m/z 264.0, 266.0 [M, M+2H]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9929 - 9945
139
[ 623-05-2 ]
[ 100-51-6 ]
[ 151358-47-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
With lithium perchlorate In acetonitrile at 20℃; Electrochemical reaction
General procedure: A 40 cm3 acetonitrile solution of alcohols 1a–1i(1 mmol) in LiClO4 (0.05 g) was electrolyzed at the2.0 V versus SCE. After completion of the electro-oxidationof alcohols to their corresponding aldehydes,indoles 2a, 2b (2 mmol) were added and electrolyzed at-0.9 V versus SCE. In the two mentioned stages, electrosynthesisreactions were done in an undivided cellequipped with graphite rods as the cathode and Pt-anodeat room temperature. The electrolysis was terminatedwhen the current decreased by more than 95 percent. Amagnetic stirrer was employed during the electrolysis.The process was interrupted several times during theelectrolysis and the graphite rod was washed in acetonein order to reactivate it. After completion of the electrocondensation,the solvent was evaporated and theresulting crude product was purified by preparative thinlayerchromatography on silica gel (eluent: n-hexane–EtOAc, 4:1) to afford 3,30-di(indolyl)methanes 3a–3k.All the products were characterized by comparison oftheir melting points and also spectroscopic data (IR, 1HNMR and mass spectra) with those of the authenticsamples in literature
Stage #1: With sodium bis(2-methoxyethoxy)aluminium dihydride In toluene at 30 - 48℃; for 2.66667 h; Stage #2: With sodium hydroxide; water In toluene at 15 - 20℃; for 1 h;
SDMA in toluene (70percent solution, 172 ml, 0.6 mol), diluted with dry toluene (30 ml), was added to a stirred suspension of (R)-2-(5-Bromo-1H-indole-3-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester (60 g, 0.14 mol) in dry toluene (350 ml) at 30-40° C. during 10 min. The reaction temperature was raised to 48° C. and the resulting yellow solution was stirred for 2.5 h. The reaction was cooled to 15° C. and 5percent aqueous NaOH (300 ml) was added dropwise while the temperature was maintained between 15-20° C. The reaction mixture was stirred vigorously for additional 60 min at 20° C. The organic layer was separated and analyzed by HPLC. Crude BIP purity: 66.49 Norm percent. Levels of impurities found (Norm percent): Benzyl-alcohol: 24.11percent; Des-Bromo-BIP: 1.91percent; OH-BIP: 1.38percent; Keto-BIP: 1.90percent.The organic layer was extracted with 2M acetic acid (1.x.250 ml) and (1.x.50 ml). The aqueous layer was combined with toluene (250 ml) in a separatory funnel and 10percent NaOH was added in portions to pH 12 (250 ml) and the product was extracted to the organic phase. The organic phase was separated, the aqueous phase was re-extracted with a fresh portion of toluene (50 ml) and combined toluene extracts were evaporated under reduced pressure. The residue was dissolved in toluene (75 ml) and the product was crystallized upon cooling. The product was filtered off, washed with cold toluene and cold heptane and dried (23.5 g; 57percent). BIP purity: 96.5 Norm percent. Levels of impurities found (Norm percent): Des-Bromo-BIP: 0.85percent; OH-BIP: 0.56percent; Keto-BIP: 1.90percent.; Example 5Preparation of 5-Bromo-3-((R)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indole (BIP)SDMA in toluene (70percent solution, 40 ml, 131.2 mmol), diluted with dry toluene (5 ml), was added to a stirred suspension of (R)-2-(5-Bromo-1H-indole-3-carbonyl)pyrrolidine-1-carboxylic acid benzyl ester (12 g, 28.1 mmol) in dry toluene (70 ml) at 30-40° C. during 10 min. The temperature was raised to 48° C. and the resulting yellow solution was stirred for 2.5 h. The reaction was cooled to 15° C. and 5percent aqueous NaOH (60 ml) was added dropwise while the temperature was maintained between 15-20° C. The reaction mixture was stirred vigorously for additional 60 min at 20° C. Crude BIP purity: 72.36 Norm percent. Levels of impurities found (Norm percent): Benzyl alcohol: 21.50percent; Des-Bromo-BIP: 2.16percent; OH-BIP: 0.47percent; Keto-BIP: 2.14percent.
47%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 39 h; Heating / reflux Stage #2: With sodium hydroxide; water In tetrahydrofuran for 0.5 h;
Example 9 Preparation of 5-Bromo-3-((R)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indole (BIP) according to U.S. Pat. No. 5,545,644, example 27 A solution of (R)-2-(5-Bromo-1H-indole-3-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester (BIPCAM) (3.64 g, 8.55 mmol) in dry THF (70 ml) was added drop-wise to a stirred suspension of lithium aluminium hydride (0.945 g, 24.9 mmol) in dry THF (52.5 ml) at room temperature under an atmosphere of dry nitrogen. The mixture was heated under reflux with stirring for 18 h and then cooled. Additional lithium aluminium hydride (175 mg, 4.61 mmol) was added and refluxing was continued for an additional 3 h. The mixture was again cooled, lithium aluminium hydride (140 mg, 3.69 mmol) was added, and refluxing was continued for a further 18 h. The mixture was cooled and H2O (1.54 ml) was carefully added with stirring, followed by 20percent aqueous NaOH (1.54 ml), followed by more H2O (4.66 ml). The mixture was stirred for 30 min, then diluted with ethyl acetate (50 ml) and filtered through Celite. The filtrate was washed with H2O (50 ml), brine (50 ml) and then dried with Na2SO4. Evaporation of the solvent gave an oil (3.6 g) which was chromatographed on silica gel, eluted with dichloromethane/ethanol/conc. aqueous ammonia (90:10:0.5) to obtain the title compound (1.18 g, 47percent) as a light yellow oil The product precipitated from dichloromethane/hexane (920 mg, 37percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3353 - 3358
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 24, p. 6674 - 6679
[3] Patent: CN108069919, 2018, A,
[4] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 814 - 831
142
[ 100-51-6 ]
[ 3863-11-4 ]
[ 168268-00-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 36, p. 7048 - 7052
143
[ 23761-23-1 ]
[ 100-51-6 ]
[ 130369-36-7 ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: With diphenylphosphoranyl azide; N-ethyl-N,N-diisopropylamine In toluene at 60℃; for 3 h; Inert atmosphere Stage #2: at 60℃;
Compound 8: l-(3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)(methyl)amino)cyclobutyl)-3-(4-(tert- butyl)phenyl)ureaBenzyl (3-oxocyclobutyl)carbamate[0665] To a solution of 3-oxocyclobutanecarboxylic acid (1.0 g, 8.77 mmol) and DIEA (1.92 g, 14.92 mmol) in toluene (8 mL) was added DPPA (2.89 g, 10.52 mmol) at rt. The mixture was heated to 60 °C under Argon for 3 h, then benzyl alcohol (1.14 g, 10.52 mmol) was added. The mixture was stirred at 60 °C overnight. The reaction was concentrated, the residue was purified by SGC (PE : EA = 8 : 1) to afford the desired compound (240 mg, yield 50percent). 1H NMR (500MHz, CDC13): δΗ 7.38-7.33 (m, 5H), 5.12 (d, / = 7.5 Hz, 2H), 4.34-4.33 (brs, 1 H), 3.44-3.39 (m, 2H), 3.10-3.07 (brs, 2H) ppm; ESI-MS (m/z): 220.2 [M+l]+.
25%
Stage #1: With diphenyl phosphoryl azide; triethylamine In toluene at 60℃; for 3 h; Stage #2: at 60℃; for 3 h;
Step A: (3-Oxo-cyclobutyl)-carbamic acid benzyl ester. A solution of 3-Oxo- cyclobutanecarboxylic acid (1.01 g, 8.8 mmol) and Et3N (1.5ml, 10.5mmol) in THF/Toluene (1: 1, 30ml) was treated with DPPA (1.9 ml, 8.8 mmol). The mixture was stirred for 3 hours at 60°C and then BnOH (1 ml, 9.7mmol) added. The reaction mixture was stirred for another 3 hours at the same temperature. The resulting mixture was concentrated under vacuum to remove most THF and then diluted with EtOAc (50 20 ml). This so-obtained mixture was washed with saturated NaHC03 solution, brine, dried over Na2S04 and filtered. The solvent was evaporated and the residue was purified via chromatography eluted with PE/EtOAc (4: 1) to give the desired product as a white solid (yield: 0.48g, 25percent yield). 1H NMR (400 MHz, CDC13): δ 7.35 (m, 5H), 5.12 (m, 3H), 4.33 (m, 1H), 3.41 (m, 2H), 3.07 (m, 2H).
Stage #1: With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 10 - 15℃; for 0.666667 h; Stage #2: at 5 - 25℃; for 61 h;
5-benzyloxy-1H-pyrazol-3-amine, used as starting material, was obtained as follows: i) A solution of 5-amino-2H-pyrazol-3-ol (6.0 g, 60.6 mmol) was stirred in dichloromethane (75 ml). Triphenylphosphine (19.06 g, 72.7 mmol) was added and the mixture was then cooled to 5-10mC. Di-iso-propylazodicarboxylate (14.31 ml, 72.7 mmol) was added dropwise over a period of 20 minutes, maintaining the internal temperature <15° C. The mixture was then held at 10° C. for a further 20 minutes. Benzyl alcohol (7.52 ml, 72.7 mmol) was added dropwise and the mixture stirred at 5-10C for 1 hour and then allowed to warm to room temperature and stirred under nitrogen for 60 hours. The mixture was filtered and the filtrate was then extracted with 1 M hydrochloric acid (3.x.) and the combined extracts washed with dichloromethane (1 5 ml). The aqueous phase was basified with sodium bicarbonate (6.7 g) and the mixture was then extracted with dichloromethane (2.x.40 ml). The combined organic extracts were evaporated to leave a brown oil which was purified by chromatography on silica eluting with a mixture of 0-3percent methanol in dichloromethane. The fractions containing product were combined and then evaporated to leave 5-benzyloxy-1H-pyrazol-3-amine (0.67 g, 6percent yield). 1H NMR (300 MHz, CDCl3): 5.05 (s, 1H), 5.12 (s, 2H), 7.25-7.45 (m, 5H).MS: m/z 190 (MH+).; 5-Phenylmethoxy-2H-pyrazol-3-amine (also named as 5-benzyloxy-1H-pyrazol-3-amine), used as starting material was prepared as in Example 72.
Stage #1: With potassium hydride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere Stage #2: at 20℃; for 18 h; Inert atmosphere
A suspension of KH (1.08 g, 27 mmol) in dry THF (80 mL) at 0 °C under N2, was treated with benzyl alcohol (1.7 mL, 16.2 mmol) and stirred for 1 h. Then, a solution of 2,4-dichloropyridine 5 (1.5 mL, 13.5 mmol) in THF (5 mL) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated NH4Cl (20 mL) and the organic solvent was removed in vacuo. The product was extracted from the residual aqueous layer with CH2Cl2 (3 x 50 mL), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (light petroleum/Et2O 8:2) to yield compound 7 as a pale yellow oil (2.58 g, 87percent); Rf = 0.56 (light petroleum/Et2O 8:2). 1H NMR (300 MHz, CDCl3) δ 5.46 (s, 2H), 6.87-6.89 (m, 2H), 7.33-7.52 (m, 5H), 8.09 (dd, 1H, J = 4.7, 1.8 Hz).
Reference：
[1] European Journal of Medicinal Chemistry, 2013, vol. 64, p. 23 - 34
In a 500mL beaker by adding 100mL of anhydrous ether, and then slowly add 20mL concentrated sulfuric acid, while the side of the edge of the stirring, such as coldBut to room temperature,Add 150mL benzyl alcohol, stir well,The ether was removed under reduced pressure and then 26 g of aspartic acid was added in 5 batchesTo the reaction flask. Room temperature stir the reaction 24h,Then add 300 mL of 95% ethanol and drop 80 mL with a dropping funnelPyridine, edge dripping vigorously stirring, and then frozen through the refrigerator overnight, filter to get solid, solid 80 ethanol stirring dissolved, heatFiltered, the filtrate was frozen for 8 h, filtered and lyophilized to obtain pure beta-aspartic acid benzyl ester (90% yield).
64%
EXAMPLE 3 Preparation of beta-benzyl L-aspartate 100 g (0.75 mol, 1 eq.) of L-aspartic acid and 162 g (1.5 mol, 2 eq.) of benzyl alcohol are introduced into a fitted-out 1 litre reactor and the mixture is stirred. 86.4 g (0.9 mol, 1.2 eq.) of methanesulphonic acid are subsequently introduced gradually while allowing the temperature to rise.The temperature is brought by heating to 60 C., stirring of the mixture is continued for 12 hours and then the mixture is cooled to 40 C. 200 ml of water are subsequently added, then 300 ml of ethanol are added and subsequently 95 ml of 22 B aqueous ammonia are added, so as to precipitate the ester at a PH of 6.5-7. The mixture is subsequently heated to 60 C. and is stirred at this temperature for 2 hours to improve the crystalline form of the product. It is cooled to a temperature of 5 C.-10 C. The crystalline precipitate is filtered off and washed twice with 100 ml of ethanol and 3 times with 100 ml of water. A wet product is collected and is dried under vacuum. 108 g (64% yield) of beta-benzyl L-aspartate are thus obtained, the characteristics of which are as follows: Appearance: white powder. Melting point: 212 C. [alpha]D20: +27.6 (read at 1% in HCl 1N).
41%
With sulfuric acid; In water; at 70℃; for 2.5h;
L-Aspartic acid (1b) (50 g, 0.38 mol), benzyl alcohol (125 g, 1.16 mol), a mixture of concentrated sulfuric acid (40.5 g) and water (10 g) were mixed in a water bath at 70 C for 0.5 h to give a clear solution, which was stirred for s further 2 h. The resulting solution was evaporated in vacuo to an oily product, which was added to a cold solution containing sodium hydrogen carbonate (70 g) and water (250 mL) at 0 C. The obtained cooled solution was mixed with ether (150 mL) to give a precipitate, which was filtered and washed with cold water to give another precipitate (88 g). This was recrystallized twice with water to give 34 g (41 %). m.p. 218-219 C (lit.23) 222 C).
28%
A solution of 167 ml benzyl alcohol, 167 ml diethyl ether and 16.7 ml conc. H2SO4 prepared at room temperaturewas evaporated without heating, by removing diethyl ether. To this solution at room temperature under vigorous stirring22.2 g (166.8 mmol) H-Asp-OH was added in small portions. The resulting suspension was stirred vigorously at 20Cuntil a completely homogeneous clear solution was obtained which was allowed to stand at room temperature for 2 days.Then 335 ml ethyl alcohol and 85 ml pyridine were added under vigorous stirring. The reaction mixture was stirred at20C for 1 h. A gradual formation of a white finely dispersed precipitate took place. The solution containing the precipitatewas allowed to stand at 0C for 1 day. Then the precipitate was filtered off and washed with water. The resulting crystallinemass was recrystallized from 335 ml water supplemented with 335 ml pyridine. The recrystallization was performed froma hot solution (80-85C) by allowing it to cool to room temperature and to stand for 1 day. The resulting crystals werefiltered off, washed with acetone and dried to yield 10.5 g (28%) of the product as white crystals. Rf 0.28 (E), Rf 0.15 (I);m.p. 214-215C. 1H NMR (DMSO-d6 - CF3COOD): 2.95 and 2.99 (2H, 2d, CH2 Asp), 4.24 (1H, m, CH Asp), 5.14 (2H, s,-CH2C6H5), 7.35 (5H, m, -CH2C6H5), 8.42 (av. s, NH2 amide, OH).
Take 500 m L single mouth bottle,Add 100 mL of anhydrous ether,Then add 10 mL of H2SO4 (98%),While adding edge mixing,After cooling to room temperature,Add 100 mL of benzyl alcohol (1 mol, 1.04 g / mL, 108.06 g / mol)Stir well and spin off the ether.A total of 13.3 g (0.1 mol, 133.04 g / mol) of L-aspartic acid was added in multiple portions.After stirring for 24 h at room temperature, 200 mL of 95% ethanol was added, and then 50 mL of pyridine was added dropwise with vigorous stirring.Then placed in the refrigerator frozen overnight, suction filtration, the filter cake was washed with ultrapure water several times, and then washed twice with anhydrous ether.Drained, placed in 500 mL flask, add 300 ~ 400 mL of water, 70 heating and stirring to dissolve, water can be added to 400 ~ 500 mL, all dissolved within 1.5 h, the solution becomes clear.Heat filtration, the filtrate refrigerated overnight. Filtered and recrystallized to obtain pure aspartic acid benzyl ester.
In sulfuric acid; at 70℃; for 0.75h;
L-Aspartic acid (1.33 g,10 mmol) and benzyl alcohol (1.08 g, 10 mmol) were disolved in 60% sulfuric acid (1.65 g) and heated at 70 C for 45 min. Clear gel gained by vacuum concentration at 70 C was neutralized using sodium bicarbonate and the white sample thus obtained was dried over a period of 16 h. The sample (0.60 g)was mixed with salicylaldehyde (0.24 g, 2 mmol) in methanol and the mixture was heated at 40 for 3 h. Copper(II) acetate monohydrate (0.20 g, 1 mmol) was added, the mixture was stirred for an additional 3 h, and a green sample was then obtained by concentration. Complex 3 was recrystallized from MeOH.
With sulfuric acid; In diethyl ether; at 20℃; for 12h;
Synthesis of benzyl beta-aspartate is first synthesized. A 500 mL single-mouth eggplant-shaped flask was taken, and 100 mL of anhydrous diethyl ether, 12 mL of H2SO4 (98%) and 120 mL of benzyl alcohol (1.2 mol, 1.04 g/mL, 108.06 g/mol) were successively added, and the mixture was stirred and evaporated to remove diethyl ether. A total of 16 g (0.12 mol, 133.04 g/mol) of L-aspartic acid was added in three portions with stirring. After stirring for 12 h at room temperature, it was diluted with 240 mL of 95% ethanol, and then 60 mL of pyridine was added dropwise to precipitate a white precipitate. After freezing in a refrigerator overnight, the solid was withdrawn and washed with pure water. The obtained crude product was recrystallized twice with pure water at 80 C to give purified benzyl aspartate.
(1) Prepare a single-mouth bottle (500m L), add 100mL of anhydrous ether,Add 10 mL of H2SO4 (98%) slowly and stir vigorously while adding dropwise.After cooling to room temperature, 100 mL of benzyl alcohol was added, and after stirring well, the ether was distilled off by a rotary evaporator;(2) Then add 13.3 g of L-aspartic acid to the reaction flask in three portions;Stir the reaction evenly at room temperature for 24 h.Then add 200 mL of 95% ethanol, and add 50 mL of pyridine dropwise with a dropping funnel, and vigorously stir while dropping;Then, it was frozen overnight in a refrigerator, and the solid after the reaction was stirred and dissolved at 80 C.Heat filtration, the filtrate was refrigerated overnight, and the solution was recrystallized twice as described above.After lyophilization, pure beta-benzyl-L-aspartate is obtained.The reaction process is as follows:
With toluene-4-sulfonic acid; In toluene;Heating / reflux;
Example 1: Preparation of pentanedioic acid monobenzyl esterGlutaric acid (200 g) was taken along with benzyl alcohol (160 g), p-toluene sulfonic acid (30 g) and toluene (1.0 L). The reaction mass was heated to reflux temperature and water (^ 26 ml) was collected by azeotropic distillation. Reaction completion was checked by TLC/HPLC for absence of benzyl alcohol. After reaction completion, the reaction mass was cooled to ambient temperature and demineralized water (1.0 L) was added and the reaction mass was stirred for 15 minutes. The organic layer was separated and washed with demineralized water (1.0 L).The organic layer was dried over sodium sulfate. Solvent was distilled off fully under vacuum to get the title compound as oil.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0℃;Heating / reflux;
Triphenylphosphine (TPP) (2.9g, ll.16mm.ol, 1.2equiv.) was slowly added to a solution of 3 (2g, 9.30mmol) in dry tetrahydrofuran (2OmL), and the solution was cooled to 0°C in ice bath. Benzyl alcohol (1.2g, ll.l?mmol, 1.2equiv.) was later introduced dropwise followed by diethylazodicarboxylate (DEAD) (1.9g, ll.l6mmol, 1.2equiv.) in the same manner. After refluxing the reaction mixture overnight, the solvent was removed under reduced pressure and the residue was extracted with water. The mixture was adjusted to pH 1 with concentrated hydrochloric acid before washing with diethyl ether (4x). The pH of the aqueous fraction was increased to 8 with sodium hydroxide (2M.), followed by extraction with ethyl acetate (4x). The combined organic fractions were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid. Recrystallisation from chloroform/petroleum spirit gave white crystals, mp 85-87°C. Yield 79percent.vmax (KBr) 3264 (ring C-H), 1589, 1498, 1485 and 1449 (ring C=C), 1218 and 1066 (C-O-C) cm"1. 1H NMR (CDCl3) ? 2.43 (3H, s, CH3), 5.00 (2H, s, 3-OCH2Ph), 5.17 (2H, s, 4- OCH2Ph), 6.79 (1?, d, J=5.6?z, 5-H), 7.30-7.45 (10?, m, 3-OCH2PA and 4- OCH2PA), 8.13 (IH, d, J=5.6Hz, 6-H); mlz (FAB) 306 [(M+H)+]; HRMS (FAB): [(M+H)+], found 306.1504. C20H20NO2 requires 306.1494.
79%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0℃;Reflux;
Triphenylphosphine (TPP) (2.9 g, 11.16 mmol, 1.2 equiv) was slowly added to a solution of 3 (2 g, 9.30 mmol) in dry tetrahydrofuran (20 mL), and the solution was cooled to 0 °C in ice bath. Benzyl alcohol (1.2 g, 11.16 mmol, 1.2 equiv) was later introduced dropwise followed by diethylazodicarboxylate (DEAD) (1.9 g, 11.16 mmol, 1.2 equiv) in the same manner. After refluxing the reaction mixture overnight, the solvent was removed under reduced pressure and the residue was extracted with water. The mixture was adjusted to pH 1 with concentrated hydrochloric acid before washing with diethyl ether (4.x.). The pH of the aqueous fraction was increased to 8 with sodium hydroxide (2 M.), followed by extraction with ethyl acetate (4.x.). The combined organic fractions were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid. Recrystallisation from chloroform/petroleum spirit gave white crystals, mp 85-87 °C. Yield 79percent. numax (KBr) 3264 (ring C-H), 1589, 1498, 1485 and 1449 (ring CC), 1218 and 1066 (C-O-C) cm-1. 1H NMR (CDCl3) delta 2.43 (3H, s, CH3), 5.00 (2H, s, 3-OCH2Ph), 5.17 (2H, s, 4-OCH2Ph), 6.79 (1H, d, J = 5.6 Hz, 5-H), 7.30-7.45 (10H, m, 3-OCH2Ph and 4-OCH2Ph), 8.13 (1H, d, J = 5.6 Hz, 6-H); m/z (ESI): 290.8.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h;
Benzyl 2-(tetrahydropyran-4-yl)acetate To a solution of <strong>[85064-61-5]2-(tetrahydropyran-4-yl)acetic acid</strong> (325 mg, 2.26 mmol) in anhydrous dichloromethane (10 mL) were added benzyl alcohol (439 mg, 2.94 mmol), 1-ethyl-3-(3-dimethylammoniumpropyl)carbodiimide hydrochloride (564 mg, 2.94 mmol) and triethylamine (297 mg, 2.94 mmol) at room temperature, and the mixture was stirred for 12 h. The reaction mixture was diluted with water (1 mL) to separate the phases, and the organic layer was further washed with water (1 mL) and brine (1 mL). The organic layer was concentrated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 7:1) to give 172 mg of the title compound as oil (yield: 32percent). 1H NMR (CDCl3) delta 1.34 (m, 2H), 1.63 (m, 2H), 2.02 (m, 1H), 2.30 (d, J=7.1 Hz, 2H), 3.39 (m, 2H), 3.93 (m, 2H), 5.12 (s, 2H), 7.31-7.40 (m, 5H).
6-(benzyloxy)-5-methylpyridine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In tetrahydrofuran; for 1h;Heating / reflux;
To a solution of <strong>[450844-27-6]2-bromo-6-cyano-3-methylpyridine</strong> (272 mg) and benzyl alcohol (156 mg) in tetrahydrofuran (20 mL) was added sodium hydride (40 mg), and the mixture was heated under reflux for one hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the organic solvent was evaporated off in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=19:1) to give the title compound (161 mg) as a colorless liquid. 1H-NMR (400MHz, CDCl3, deltappm) 2.28(3H, s), 5.40(2H, s), 7.20-7.30(1H, m), 7.30-7.40(3H, m), 7.40-7.50(3H, m)
With hydrogenchloride; triphenylphosphine;SiO2; In tetrahydrofuran; water; ethyl acetate;
EXAMPLE 3b 2-methyl-3,4,bis(phenylmethoxy)pyridine (alternative synthesis) To 154.8 g of the product of Example 2, 86.4 g benzylalcohol and 210 g triphenylphosphine suspended in 1.5 liters (dry) tetrahydrofurane was added a solution of 139.2g diethylazodicarboxylate in 500 ml tetrahydrofuran within 20 minutes. The temperature rose to 53° C. for several hours. After 4.5 hours a clear solution was obtained. After standing overnight, a solution of HCl in ether (28 g) was added. Hydrochlorides of Example 3 and 3 A crystallized from the solution. After cooling they were isolated by filtration and washed with ether and petroleum ether. 230 g of the mixture of HCL salts of 3 and 3A was suspended in 2 liters of ethyl acetate and 1 liter of water. The pH was adjusted to 7.0 with concentrated NaOH solution. The organic phase and two organic was phases were combined and dried over Na2 SO4. Filtration and distilling off the solvent yielded an oily residue which was passed through a column with 600 g SiO2. Ethylacetate as eluent. Only the title compound of Example 3B, 151.8 g, was eluted from the column. Eluation of 3A is possible with CH3 OH. M.P.=92° C. (title comp. 3)
With hydrogenchloride;SiO2; In tetrahydrofuran; (dry) THF; water; ethyl acetate;
3B 2-methyl-3,4,bis(phenylmethoxy)pyridine To 154.8g of the product of Example 2, 86.4g benzylalcohol and 210g TPP (triphenylphosphine) suspended in 1.5 liters (dry) THF was added a solution of 139.2g diethylazodicarboxylate in 500ml tetrahydrofuran within 20 minutes. The temperature rose to 53°C for several hours. After 4.5 hours a clear solution was obtained. After standing overnight, a solution of HCl in ether (28g) was added. Hydrochlorides of Example 3 and 3A crystallized from the solution. After cooling they were isolated by filtration and washed with ether and petroleum ether. 230g of the mixture of HCl salts of 3 and 3A was suspended in 2 liters of ethyl acetate and 1 liter of water. The pH was adjusted to 7.0 with concentrated NaOH solution. The organic phase and two organic wash phases were combined and dried over Na2SO4. Flitration and distilling off the solvent yielded an oily residue which was passed through a column with 600g SiO2. Ethylacetate as eluent. Only the title compound of Example 3B, 151.8g, was eluted from the column. Eluation of 3A is possible with CH3OH. M.P. = 92°C. (title comp. 3)
10 g (0.037 moles) of 6,11-dihydro-11-oxodibenz[b,e] oxepin-2-acetic acid were dissolved in 100 ml of toluene and 2 g (0.01 moles) of p-toluenesulfonic acid (p-TsOH) and 17.5 ml (0.169 moles) of benzyl alcohol were added to this solution. The reaction was equipped with a Dean-Stark, a mixture of water/toluene thus being distilled. The reaction was maintained until 0.7 ml of water were collected. The reaction was left to cool to 20-25°C, at which temperature 1.5 ml (0.011 moles) of Et3N were added. The resulting solution was concentrated under reduced pressure until obtaining a residue which was dissolved in isopropanol (50 ml), giving rise to a suspension. The obtained suspension was stirred at 20-25°C for 30 minutes, then being cooled at 0-5°C. Stirring was maintained at this temperature for 30 minutes. Then, the suspension was filtered and washed, obtaining 12.5 g (0.036 moles, 98percent) of a white solid identified as the compound of the title, the spectroscopic properties of which are: 1H-NMR (CDCl3, 400 MHz), delta: 3.70 (s, 2H); 5.14 (m, 4H), 7.02 (d, 1H), 7.33 (m, 1H); 7.41-7.46 (m, 4H), 7.52 (m, 3H); 7.88 (m, 2H); 8.15 (d, 1H) ppm. 13C-NMR (CDCl3, 400 MHz), delta: 39.95; 66.56; 73.37; 120.88; 124.92; 127.48; 127.64; 128.04 (2); 128.10; 128.39 (2); 129.05; 129.25; 132.32; 132.58; 135.33;135.53; 136.20; 140.60; 160.72; 171.48; 191.01. MS, M++1: 358.12.
With (spiroborate)2n*[(eta5-pentamethylcyclopentadienyl)(N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)iridium(III)]n; In aq. buffer; at 150℃; for 24h;pH 4.0;Microwave irradiation;
General procedure: The appropriate amine 9 (0.5 mmol), the respective alcohol 10 (0.6mmol), PB-Cp*Ir(IPr) (3; 1 molpercent Ir), and H2O (0.5 mL) were mixed in a vial tube at 23 °C under air. The vial was sealed with ascrew cap, and the reaction mixture was stirred at 100 °C for 24 h.After cooling to 23 °C, the mixture was extracted with Et2O orEtOAc (3 × 2 mL) and the combined organic layers were concentrated.The crude product was purified by column chromatographyover silica gel eluting with hexane?EtOAc (98:2 to 85:15) to affordthe corresponding N-alkylated amine 11a?n
With potassium hydroxide; In toluene; at 90℃; for 20h;
General procedure: To an oven-dried 20 cm3 test tube with a ground-in stopperequipped with a stir bar were added anthranilamide (1.0 mmol), benzyl alcohol (1.0 mmol), KOH (2.0 mmol),and 4 cm3 toluene. The test tube was put in an oil bath potpreheated at 90 C and the mixture was stirred for 20 h at90 C. After cooling to room temperature, the reactionmixture was added about 5 g silica gel and directly condensedon a rotator under vacuum. The resulting residualwas transferred to a silica gel chromatography column andeluted with a solution of petroleum ether and ethyl acetate[4/1 (v/v)] to give a white solid 2-phenyl-4(3H)-quinazolinone.For some products (3f, 3g, 3n, and 3t) onlysparingly soluble in ethyl acetate, the reaction mixtureswere condensed in vacuo on a rotary evaporator. Theresiduals were washed three times with water and oncewith ethyl acetate, and then dried in an infrared oven togive the desired products pure enough for NMR analysis.
With pyridine; p-toluenesulfonyl chloride; In toluene; at 0 - 20℃; for 2.0h;
To a stirred solution of <strong>[16176-74-2]2-(1H-indol-4-yl)acetic acid</strong> 45 (11.0 g, 62.9 mmol) in pyridine (45 mL) were added benzyl alcohol (6.9 mL, 66.0 mmol) and a solution of p-toluenesulfonyl chloride (13.2 g, 69.2 mmol) in toluene (38 mL) at 0 °C. After stirring vigorously for 2 h at room temperature, the reaction mixture was diluted with water and extracted with MTBE (.x.2). The combined organic layers were washed with NaHCO3 aq, water and brine, dried over Na2SO4 and concentrated in vacuo to give 46 as a dark brown oil, which was used for the next reaction without further purification; TLC Rf = 0.45 (n-hexane/EtOAc, 2:1).
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20 - 25℃;
General procedure: To a stirred solution of 2-iodobenzoic acids a (10 mmol) in CH2Cl2, was added DCC (dicyclohexylcarbodiimide, 11 mmol), DMAP (Dimethylaminopyridine, 2 mmol) and alcohols b (10 mmol) in sequence. The resulting solution was stirred overnight at room temperature then filtered through a sand core funnel and washed with diethyl ether (2 x 40mL). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography to obtain the pure product c in moderate to good yields. To a soluton of 2-iodobenzoates c in Et3N (5 mL) was added PdCl2 (PPh3)2 (4 mol percent) and CuI (2 mol percent) and the reaction vial was flushed with Ar and the reaction mixture was stirred for 5 minutes. A solution of propargyl alcohols d (1.05 equiv) in Et3N (5 mL) were then added dropwise through a syringe for 5 minutes. The resulting solution was stirred at room temperature overnight. When the reaction was considered complete as determined by TLC analysis, the mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with ethyl ether (3 x 40 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography to give 1.
1.08 g Benzyl alcohol (10 mmol) was dissolved in 15 ml dry dimethylformamide and 480 mg NaH (60% dispersion in mineral oil) (12 mmol) was added at room temperature. After stirring the mixture for 15 minutes 1.54 g <strong>[454-16-0]1-fluoro-2-methoxy-4-nitro-benzene</strong> (obtained in Step 1) (9 mmol) was added and the mixture was stirred at room temperature for an hour. Then it was poured onto 100 g ice and the mixture was extracted three times with 40-40 ml ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and evaporated under reduced pressure. Residue was crystallized from a minimal amount of MeOH to get a yellow solid. Yield: 1.70 g (73%). Ret. time: 4.31 min., very low ion intensity in ESI-MS; 1HNMR (DMSO-d6, 300 MHz), delta (ppm): 7.89 (dd, J3=8.94 Hz, J4=2.61 Hz, 1H), 7.76 (d, J=2.58 Hz, 1H), 7.48-7.31 (m, 5H), 7.27 (d, J=9.00 Hz, 1H), 5.25 (s, 2H), 3.89 (s, 3H).
With sodium sulfide hydrate; iron(III) chloride hexahydrate; at 150℃; for 24h;Inert atmosphere;
General procedure: A 20-mL test-tube equipped with a magnetic stirring bar was charged with o-nitroaniline 1 (2.5 mmol, 1 equiv), alcohol 2 or 5 (3 mmol, 1.2equiv), Na2S·nH2O (?60percent, 130 mg, 1 mmol, 40 molpercent) and FeCl3·6H2O(7 mg, 0.025 mmol, 1 molpercent). The resulting mixture was stirred for 24h under an argon atmosphere at the indicated temperature (see Schemes 2 and 3 and Table 2). After cooling to r.t., the mixture was purified in different ways. (i) For NH benzimidazole products, the mixture was washed with CH2Cl2 (3 × 2 mL) then dissolved in MeOH.The MeOH solution was filtered through a short pad of silica gel. The filtrate was concentrated in vacuo to afford the NH benzimidazole product. Further purification by column or recrystallization was carried out if necessary. (ii) For N-methyl-2-phenylbenzimidazole 3ha and quinoxalines 5, the crude mixture was dissolved in a minimum volume of CH2Cl2 and purified by column chromatography (silica gel or alumina, heptane?EtOAc, EtOAc, EtOAc?MeOH, hexane?Et2O). We noted that some 13C NMR signals of NH-benzimidazoles are missing or difficult to observe.
With tert.-butylhydroperoxide; iron(II) chloride tetrahydrate; calcium carbonate; In water; acetonitrile; at 80℃; for 4h;Sealed tube;
General procedure: In a sealed tube were added FeCl2*4H2O (9.9 mg, 0.05 mmol, 10 mol percent), cyclohexylamine*HCl (67.8 mg, 0.5 mmol, 1 equiv) and CaCO3 (50.1 mg, 0.5 mmol, 1 equiv). 1 mL of CH3CN, benzyl alcohol (67 mL, 0.65 mmol, 1.3 equiv) and tert-butyl hydroperoxide (70percent in H2O, 140 mL, 2 equiv) were then added. After 2 h of stirring at 80°C, another 2 equiv of tert-butyl hydroperoxide (70percent in H2O) were added, and the mixture was further stirred for 2 h. After cooling to rt, HCl 1 N (5 mL) and AcOEt (5 mL) were added. The mixture was extracted with AcOEt (25 mL), and the combined organic phases were washed with saturated aqueous NaHCO3 solution (10 mL), brine (10 mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude mixture was purified by chromatographyon silica gel using mixtures of cyclohexane and ethylacetate as eluant.
5-amino-N-benzyl-2-methylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; caesium carbonate; In tert-Amyl alcohol; at 120℃; for 12h;Inert atmosphere; Schlenk technique;
<strong>[6973-09-7]5-amino-2-methylbenzenesulfonamide</strong> (186 mg, 1 mmol), [Cp * IrCl2] 2 (8 mg, 0.01(10 mgpercent), cesium carbonate (65 mg, 0.2 mmol), benzyl alcohol (130 mg, 1.2 mmol), t-amyl alcohol (1.0ML) were sequentially added to a 25 mL Schlenk reaction flask. The mixture was allowed to react at 120 ° C for 12 hours and then cooledThe solvent was removed under vacuum at room temperature. And then purified by column chromatography (developing solvent: ethyl acetate / n-hexane)Net target compound, yield: 79percent
dibenzyl tricyclo[3.3.1.13,7]decane-1,3-diyldicarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Dibenzyl tricyclo[3.3.1.13,7]decane-1,3-diyldicarbamateA solution of tricyclo[3.3.1.13,7]decane-1,3-dicarboxylic acid (500 mg, 2.230mmo1) in toluene (9 rnL) was treated vvith Et3N (0.68 mL, -
88%
[1431 A solution of tricycio[3.3.i.1?7]decane-1,3-dicarboxylic acid (500 mg, 2230 mmol) in toluene (9 mL) was treated with Et3N (0.68 rnL, 4.91 mrnoi) and DPPA (0.96 mL, 4.46 rnmol) and heated at 110°C for I h. The mixture was cooled down to 80°C and treated with benzyl alcohol (0.580 mL, 5.574 rnmol) and Et3N (0.68 rnL, 4.91 mmol). The resulting mixture washeated at 80°C for 20h. The cooled mixture was then diluted with EtOAc (50 mL) and H20 (50 rnL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organics layers were washed with brine (50 inL), filtered and evaporated to dryness. The residue was purified by 5i02 chromatography (Hex/EtOAc 0 to 70percent gradient) to afford the title compound (800 mg, 1.97 mmol, 88percent) as clear oil.
at 120℃; for 0.333333h;Sealed tube; Microwave irradiation;
General procedure: The 4-substituted methyl (phenylsulfonyl)carbamate was dissolved in the chosen alcohol (2 mL) in a microwave vial, which was closed using an aluminum open-top seal with PTFE-faced septum. The reaction mixture was heated under microwave irradiation at 100-120 oC for 20-60 min. The crude reaction mixture was concentrated under reduced pressure and the residue was purified using silica gel column chromatography to yield the desired (aryl)carbamate.
(methoxy)(benzyloxy)(methyl)(phenyl)silane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With CBV600; at 110℃; for 0.0583333h;Microwave irradiation; Sealed tube;
10236] A mixture of 3.3 mmol of <strong>[3027-21-2]methylphenyldi(methoxy)silane</strong> (Ia), 13.3 mmol of benzyl alcohol (hg) and 10mg of CBV 600 (by Zeolyst International) was charged into a reaction tube that was then sealed, with stirring for 3.5 minutes at 110° C., using a microwave irradiation device (Initiator by Biotage AB). The resulting product was post-processed and distilled in the same way as in Example 101. As a result there were obtained 1.8 mmol (yield 55percent) of methylphenyl(methoxy)(benzyloxy)silane (lilt-i).10237] The physical property values, spectral data and so forth of (lilt-i) were as follows.10238] Boiling point: 105-i 10° C./0.35 mmHg (distillation temperature in short-path distillation)10239] Element analysis: C, 69.52; H, 7.04 (measured value); C, 69.72; H, 7.02 (calculated value C15H18O2Si);j0240] ?H-NMR (CDC13): oe 0.39 (s, 3H, SiCH3), 3.52 (s, 3H, OCH3), 4.83 (s, 1H, OCHCHb), 4.86 (s, 1H, OCHCHb),7.23-7.28 (m, 1H, aromatic ring H), 7.32-7.45 (m, 7H, aromatic ring H), 7.64-7.67 (m, 2H, aromatic ring H)j0241] ?3C-NMR (CDC13): oe ?4.6,50.6,64.7, 126.6, 127.2, 127.9, 128.3, 130.2, 133.9, 134.1, 140.4j0242] 29Si-NMR (CDC13): oe ?15.010243] IR (liquid film): 1592, 1496, 1454, 1429, 1379, 1259,1208,1190,1121,1086, 1028,853,809,777,738,698, 659, 581, 482, 438 cm?j0244] GC-MS (El, 70 eV): mlz (relative intensity) 258 (M, 3.2), 225 (12), 213 (27), 211 (28), 180 (59), 165 (32), 151 (14), 121 (17), 91(100), 65 (17), 59 (ii)
55%
With CBV 600; at 110℃; for 0.0583333h;Sealed tube; Microwave irradiation;
Di(methoxy)(methyl)(phenyl)silane (IIIa) 3.3mmol, benzyl alcohol (IVr) 13.3mmol, CBV600 (Zeolyst Co., Ltd.) 10 mg of mixture into the reaction tube is sealed, a microwave irradiation device using a (Biotage made Initiator), 3.5 minutes at 110 °C by stirring. With a centrifugal separator for separating solid catalyst, after the supernatant liquid is separated, washed with catalyst (2 times at 0.8 ml) hexane, and cleaning of the supernatant liquid concentrated under reduced pressure, as a result of the short path is distilled in a distillation device, (methoxy)(benzyloxyimino)(methyl) (phenyl)silane (Vak-1 (Iak-1)) is, obtd. 1.8mmol (yield 55percent).
(methoxy)(benzyloxy)(methyl)(phenyl)silane[ No CAS ]
[ 86934-36-3 ]
Yield
Reaction Conditions
Operation in experiment
With CBV600; at 110℃; for 0.0833333h;Microwave irradiation;
10096] A mixture of 1.65 mmol of <strong>[3027-21-2]methylphenyldi(methoxy)silane</strong> (Ia), 6.6 mmol of butanol (ha) and 5 mg of CBV 780 (by Zeolyst International) was charged into a reaction tube, with stirring for 1 minute at room temperature (23° C.). The resulting product was analyzed using a gas chromatograph and a gas chromatographlmass spectrometer. The results revealed that a mixture of butoxysilane (lila) (lila-i:methylphenyl(methoxy)(butoxy)silane and IIIa-2: methylphenyldi(butoxy)silane, lila-i :IIIa-2=90: 10) had been generated with a yield of 88.5percent (see Table 1).10097] Reactions and analyses were carried out in the sameway as in Example 1, but modi1,?ing reaction conditions(starting materials, catalysts, temperature, time and so forth).The results of measurements of product yields are given inTable 1.
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; for 12h;
Intermediate 347<strong>[3471-31-6]2-<strong>[3471-31-6](5-methoxy-1H-indol-3-yl)acetic acid</strong></strong> (5 g, 24.4 mmol) and BOP-Cl (7.4 g, 29 mmol) were suspended in DCM (100 mL), and Et3N (5.4 g, 53.7 mmol) was slowly added. The resulting solution was stirred for 30 min. Benzyl alcohol (2.9 g, 26.8 mmol) was added and the mixture was stirred for 12 h. DCM (100 mL) was added, the layers were separated and the organic layer was washed with water (200 mL) and brine. The organic layer was concentrated and purified by chromatography on silica gel (eluent: PE/EtOAc=2/1) to give 347 as a white solid (6.1 g, 85percent).
4-(benzyloxy)-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
In 5 mL of N, N-dimethylformamide (DMF) was added 0.07 mL of benzyl alcohol, 0.05 g of sodium hydride(60%). After stirring at room temperature for 30 minutes, 0.1 g of <strong>[1258861-20-9]LY2940680</strong> was added and reacted for 2 h. After completion of the reaction, 20 mL of saturated ammonium chloride was addedThe solution was quenched, the organic phase was separated and the aqueous phase was extracted three times with dichloromethane and incorporated into an organic phase. The aqueous phase was washed successively with saturated aqueous ammonium chlorideAnd washed with saturated brine, then dried over anhydrous sodium sulfate, filtered to remove sodium sulfate and concentrated to give the crude product. Used for crude productsColumn chromatography (200-300 mesh silica gel, eluent: dichloromethane: methanol = 15: 1) to give pure TC659.
With sodium hydride; In 1-methyl-pyrrolidin-2-one; at 20℃; for 5h;Cooling with ice;
2.3 g of benzyl alcohol was added under ice-cooling to a mixture of 3.0 g of <strong>[19745-07-4]2,5-dichloropyrazine</strong>, 880 mg of sodium hydride (60percent, oil) and 50 mL of NMP.The reaction mixture was warmed to room temperature and stirred at room temperature for 5 hours.Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.The obtained residue was subjected to silica gel chromatography to obtain 3.1 g of Intermediate 1 represented by the following formula.
3.1 g
With sodium hydride; In 1-methyl-pyrrolidin-2-one; mineral oil; at 20℃; for 5h;Cooling with ice;
3.0 g of <strong>[19745-07-4]2,5-dichloropyrazine</strong>,880 mg of sodium hydride (60percent, oil)And 50 mL of NMP,2.3 g of benzyl alcohol was added under ice cooling.The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 5 hours.Water was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate,And concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography,3.1 g of Intermediate 1 represented by the following formula was obtained.Intermediate 1
3.1 g
With sodium hydride; In 1-methyl-pyrrolidin-2-one; mineral oil; at 20℃; for 5h;Cooling with ice;
A mixture of <strong>[19745-07-4]2,5-dichloropyrazine</strong> 3.0 g, sodium hydride (60percent, oil) 880 ml, and NMP 50 ml was added to 2.3 g of benzyl alcohol under ice-cooling. The reaction mixture was warmed to room temperature and stirred at room temperature for 5 hours. The resulting reaction mixture was added with water and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to give 3. lg of an intermediate of the following formula 1 .
With benzyl bromide; at 130℃; for 12h;Green chemistry;
<strong>[4214-79-3]2-hydroxy-5-chloropyridine</strong> (0.259 g, 2 mmol), benzyl alcohol (2.4 mmol,1.2 equiv.) And benzyl bromide (0.0475 ml, 20 molpercent)were added successively to the tube reactor, And then heatedto 130 ° C for 12 hunder solvent-free conditions.After the TLC monitoring reaction was complete, the product was purified by column chromatography and the yield was 90percent.
With 1,1'-bis-(diphenylphosphino)ferrocene; In toluene; at 150℃; for 24h;Inert atmosphere; Sealed tube;
General procedure: The preparation of 2-phenyl-1H-benzoimidazole (3a): A 15 mL capped tube was charged with 2-nitroaniline (0.36 mmol), benzyl alcohol (0.094 mL, 0.90 mmol) and dppf (0.018 mmol). The tube was flushed with argon for 10 min. Then the degassed toluene (3 mL) was added. The tube was flushed with argon, capped, and heated at 150 C for 24 h. After cooling to room temperature, the reaction mixture was then concentrated in vacuo, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 4:1) to afford the pure 3a as a white solid. The product was identified by NMR and MS and the data are identical to the reported values.
General procedure: [0275] To anhydrous DMF was added sodium hydride (1.2 equiv., 60 % dispersion) and allowed to stir for 1 min. To this stirred mixture was added portion wise a solution of benzyl alcohol (1.2 equiv.) in anhydrous DMF (0.1 M). The mixture was stirred at room temperature for 30 min and then a solution of 6-chloropyrazin-2-amine in anhydrous DMF (0.1 M) was added. The reaction was allowed to stir at 100 C for 16 h and upon completion was quenched slowly with isopropanol. The reaction was then partitioned between ethyl acetate and water. The organic layer was washed with water 3X, brine 3X, and then dried over sodium sulfate. The combined organic layers were concentrated under reduced pressure and the product purified via silica gel chromatography.
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