* 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] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1987, vol. 26, p. 341 - 343
4
[ 105-50-0 ]
[ 40296-46-6 ]
Reference：
[1] Tetrahedron Letters, 2011, vol. 52, # 4, p. 512 - 514
[2] Patent: WO2011/97526, 2011, A1,
[3] Patent: WO2013/91011, 2013, A1,
[4] Patent: US8461179, 2013, B1,
[5] Patent: WO2013/184119, 2013, A1,
[6] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495
[7] Patent: WO2014/52365, 2014, A1,
[8] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 31 - 38
[9] European Journal of Medicinal Chemistry, 2014, vol. 87, p. 52 - 62
[10] Patent: WO2015/38417, 2015, A1,
[11] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495
[12] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 3, p. 403 - 427
[13] European Journal of Medicinal Chemistry, 2016, vol. 119, p. 17 - 33
[14] Antimicrobial Agents and Chemotherapy, 2016, vol. 60, # 8, p. 4442 - 4452
[15] Patent: WO2007/136465, 2007, A2,
[16] Patent: WO2009/105712, 2009, A1,
[17] Patent: WO2005/34869, 2005, A2,
5
[ 122-51-0 ]
[ 105-50-0 ]
[ 6975-44-6 ]
Yield
Reaction Conditions
Operation in experiment
81.6%
Stage #1: at 120℃; for 2 h; Stage #2: With ammonia In water at 0℃; for 1 h;
Diethyl 3-oxopentanedioate (1, 10.00 g, 49.45 mmol), triethyl orthoformate (7.33 g, 49.45 mmol) and acetic anhydride (10.10 g, 98.93 mmol) were combined and stirred at 120 °C for 2 h then allowed to cool to ambient temperature. The volatiles were removed under vacuum. The residue was then cooled in an ice bathand aqueous ammonia (25 mL) was added in portions with stirring. The reaction mixture was stirred at 0 C for 1 h and was then acidified with 2N hydrochloric acid to pH < 5. The precipitate was collected by filtration and allowed to dry to provide 2 as yellowsolid. Yield: 81.6percent. Mp: 207-210 °C. 1H NMR (400 MHz, DMSO-d6,ppm) d: 11.78 (s, br, 1H), 10.74 (s, br, 1H), 8.02 (s, 1H), 5.61 (s, 1H), 4.27 (q, 2H, J 7.1), 1.29 (t, 3H, J 7.1). 13C NMR (100 MHz, DMSOd6,ppm) d: 166.57, 166.40, 164.00, 142.97, 100.44, 98.96, 61.35, 14.46.
55.7%
Stage #1: at 130℃; for 3 h; Stage #2: With ammonium hydroxide In water at 20℃; for 0.5 h;
Step 1: Preparation of ethyl 4,6-dihydroxy-5-nitronicotinate (14) A mixture of diethyl 1,3-acetonedicarboxylate (80.0 g, 0.40 mol), acetic anhydride (80.8 g, 0.79 mol) and ethyl orthoformate (59.2 g, 0.40 mol) was heated to 130 °C for 3 h. Volatile components were removed under reduced pressure and the remaining mixture was treated with aqueous ammonia 160 ml. The resulting mixture was stirred for another 30 min at ambient temperature. Subsequently the pH of the mixture was adjusted to 2 with 6 mol/L hydrochloric acid aqueous. The solid was filtered off, washed with cold water and dried in vacuum overnight. Toluene (120 ml) was then added to the crude product before the mixture was stirred at 0 °C for 30 min, filtered and dried to give 14 40.4 g as red solid, yield 55.7percent. Mp 214-216 °C. 1H NMR (300 MHz, CDCl3), δ (ppm): 8.21 (s, 1H), 5.95 (s, 1H), 4.37 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). MS (ESI+) m/z: 184 [M+H]+.
50%
Stage #1: at 120℃; for 2 h; Stage #2: With ammonia In water at 20℃; for 0.5 h;
A mixture of 5.0 g (24.73 mmol) diethyl 1,3-acetonedicarboxylate, 5.05 g (49.45 mmol) acetic anhydride and 3.7 g (24.73 mmol) ethyl orthoformate was heated to 12O0C for 2 hours. Volatile components were removed under reduced pressure and the remaining mixture was treated with 10 ml of aqueous ammonia (25percent). The mixture was stirred for 30 minutes at room temperature. Subsequently the pH of the mixture was adjust to pH 2 with aqueous HCl (2N). The solid was filtered off, washed with cold water and dried. 8 ml of toluene were added to the crude product, the mixture was stirred at O0C for 30 minutes and then filtered and dried to give 2.26 g (50percent) of a red solid. 1H-NMR (DMSOd6): 11.77 (s, br, IH); 10.74 (s, br, IH); 8.01 (s, IH); 5.60 (s, IH); 4.26 (q, 2H); 1.28 (t, 3H).
50%
Stage #1: at 120℃; for 2 h; Stage #2: at 20℃; for 0.5 h;
G] Preparation of compound 5 -G A mixture of 5.0 g (24.73 mmol) diethyl 1,3-acetonedicarboxylate, 5.05 g (49.45 mmol) acetic anhydride and 3.7 g (24.73 mmol) ethyl orthoformate is heated to 1200C for 2 hours. Volatile components are removed under reduced pressure and the remaining mixture is treated with 10 ml of aqueous ammonia (25percent). The mixture is stirred for 30 minutes at room temperature. Subsequently the pH of the mixture is adjust to pH 2 with aqueous HCl (2N). The solid is filtered off, washed with cold water and dried. 8 ml of toluene are added to the crude product, the mixture is stirred at 00C for 30 minutes and then filtered and dried to give 2.26 g (50percent) of a red solid.1H-NMR (DMSO-de): 11.77 (s, br, IH); 10.74 (s, br, IH); 8.01 (s, IH); 5.60 (s, IH); 4.26 (q, 2H); 1.28 (t, 3H).
50%
Stage #1: at 120℃; for 2 h; Stage #2: With ammonia In water at 20℃; for 0.5 h;
A mixture of 5.0 g (24.73 mmol) diethyl 1,3-acetonedicarboxylate, 5.05 g (49.45 mmol) acetic anhydride and 3.7 g (24.73 mmol) ethyl orthoformate was heated to 12O0C for 2 hours. Volatile components were removed under reduced pressure and the remaining mixture was treated with 10 ml of aqueous ammonia (25percent). The mixture was stirred for 30 minutes at room temperature. Subsequently the pH of the mixture was adjust to pH 2 with aqueous HCl (2N). The solid was filtered off, washed with cold water and dried. 8 ml of toluene were added to the crude product, the mixture was stirred at O0C for 30 minutes and then filtered and dried to give 2.26 g (50percent) of a red solid. 1H-NMR (DMSOd6): 11.77 (s, br, IH); 10.74 (s, br, IH); 8.01 (s, IH); 5.60 (s, IH); 4.26 (q, 2H); 1.28 (t, 3H).
22%
Stage #1: at 120℃; for 1.5 h; Stage #2: With ammonium hydroxide In water at 0℃; for 1 h; Stage #3: With hydrogenchloride In water
A mixture of scheme 1 compound 1 (50.0 g, 247.5 mmol), triethyl orthofomate (40.3 g, 272.3 mmol) and acetic anhydride (50.5 g, 495.0 mmol) was heated at 120 °C for 1.5h with vigorous stirring. The dark yellow solution was cooled in an ice bath, and mixed with ammonia (20 mL, 30percent water solution). The resulting mixture was stirred at 0 °C for lh. A yellow solid formed in the mixture. After the mixture was acidified with 2N HC1 to pH = 5, a white solid formed. The mixture was filtered, washed with water and air dried to give scheme 1 compound 2 (10.0 g, yield: 22.0percent) as a white solid. 1H NMR (400 MHz, MeOD): δ 8.16 (s, 1H, ArH), 5.79 (s, 1H, ArH), 4.38 (q, J= 7.2 Hz, 2H, CH2), 1.37 (t, J= 7.2 Hz, 3H, CH3).
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 87, p. 52 - 62
[2] Antimicrobial Agents and Chemotherapy, 2016, vol. 60, # 8, p. 4442 - 4452
[3] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495
[4] European Journal of Medicinal Chemistry, 2016, vol. 119, p. 17 - 33
[5] Tetrahedron Letters, 2011, vol. 52, # 4, p. 512 - 514
[6] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 20, p. 6551 - 6559
[7] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 3, p. 403 - 427
[8] Patent: WO2008/17696, 2008, A1, . Location in patent: Page/Page column 50-51
[9] Patent: WO2009/106419, 2009, A1, . Location in patent: Page/Page column 78
[10] Patent: WO2008/17696, 2008, A1, . Location in patent: Page/Page column 50-51
[11] Patent: WO2014/52365, 2014, A1, . Location in patent: Page/Page column 165-166
[12] Patent: WO2008/51757, 2008, A1, . Location in patent: Page/Page column 31
[13] Patent: WO2005/34869, 2005, A2, . Location in patent: Page/Page column 39
[14] Patent: WO2011/97526, 2011, A1, . Location in patent: Page/Page column 30
[15] Patent: WO2007/136465, 2007, A2, . Location in patent: Page/Page column 33
[16] Patent: WO2009/105712, 2009, A1, . Location in patent: Page/Page column 35-36
[17] Patent: WO2005/34869, 2005, A2, . Location in patent: Page/Page column 39
6
[ 105-50-0 ]
[ 149-73-5 ]
[ 6975-44-6 ]
Yield
Reaction Conditions
Operation in experiment
55%
With ammonia; acetic anhydride In water at 0 - 120℃; for 20 h; Inert atmosphere
(E. Wallace, B. Hurley, H. W. Yang, J. Lyssikatos and J. Blake, Int. Pat. App. WO200523759, 2005): Trimethylorthoformate (5.95 mL, 54.4 mmol) was added to a solution of diethyl 1,3-acetonedicarboxylate (i) (8.98 mL, 49.5 mmol) in acetic anhydride (9.34 mL, 99.0 mmol). The reaction mixture was heated under N2(g) to 120°C for 2 h, cooled to room temperature and the excess solvent removed in vacuo. The resulting dark orange residue was cooled to 0°C and treated with an aqueous solution of ammonia (33percent, 4 mL) followed by water (15 mL). The mixture was stirred at room temperature for 18 h and the resulting heavy tan precipitate filtered, washed with water (20 mL) and air dried to give compound ii. (5.00 g, 27.3 mmol, 55percent) as a light tan solid, [M+H]+ m/z = 184.1.
55%
Stage #1: at 120℃; for 2 h; Inert atmosphere Stage #2: With ammonia In water; acetic anhydride at 0 - 20℃; for 18 h; Inert atmosphere
Trimethylorthoformate (5.95 mL, 54.4 mmol) was added to a solution of diethyl 1,3-acetonedicarboxylate 34 (8.98 mL, 49.5 mmol) in acetic anhydride (9.34 mL, 99.0 mmol). The reaction mixture was heated under N2(g) to 120 °C for 2 h, cooled to room temperature and the excess solvent removed in vacuo. The resulting dark orange residue was cooled to 0 °C and treated with an aqueous solution of ammonia (33percent, 4 mL) followed by water (15 mL). The mixture was stirred at room temperature for 18 h and the resulting heavy tan precipitate filtered, washed with water (20 mL) and air dried to give the title compound17 (5.00 g, 27.3 mmol, 55percent) as a light tan solid, m.p. 200-204 °C (from EtOH–water, lit.18 m.p. 213 °C); Rf 0.27 (EtOAc); δH (300 MHz, DMSO-d6); 8.02 (1H, s, 2-H), 5.60 (1H, s, 5-H), 4.27 (2H, q, J 7.2, 3-CO2CH2CH3), 1.28 (3H, t, J 7.2, 3-CO2CH2CH3); δC (75 MHz, DMSO-d6); 166.4 (3-CO2CH2CH3), 166.3 (6-C), 163.9 (4-C), 143.0 (2-C), 100.4 (5-C), 98.8 (3-C), 61.2 (3-CO2CH2CH3), 14.4 (3-CO2CH2CH3); νmax/cm-1 (solid); 3053, 2689, and 1658; m/z (ES) 184.1 (100percent, MH+); (Found MH+, 184.0606. C8H9NO4 requires MH 184.0610); LC-MS; RT= 1.23min, m/z (ES+) found MH+, 184.1.
Reference：
[1] Patent: WO2013/91011, 2013, A1, . Location in patent: Page/Page column 66; 67
[2] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 31 - 38
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 7, p. 2355 - 2361
[4] Patent: US2007/60577, 2007, A1, . Location in patent: Page/Page column 30; 43
7
[ 108-24-7 ]
[ 105-50-0 ]
[ 6975-44-6 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: at 120℃; for 2 h; Stage #2: With ammonia In dichloromethane at 0 - 20℃;
3-Oxo-pentanedioic acid diethyl ester (101 g, 0.5 mmol), triethyl orthoformate (81.4 g, 0.55 mol) and acetic anhydride (102 g, 1 mol) were combined and heated to 120° C. for 2 h. The resulting mixture was cooled to RT and dissolved in DCM (1 L). After further cooling to 0° C., ammonia (30percent, 80 mL) was added and the reaction mixture was allowed to warm to RT overnight. The product was extracted with water (2*) and the aqueous layer was acidified to pH 5 with conc. HCl. The precipitate was collected by filtration to afford ethyl 4,6-dihydroxynicotinate (60.0 g, 60percent yield). 1H NMR (400 MHz, DMSO-d6): δ 7.99 (s, 1H), 5.58 (s, 1H), 4.23 (q, J=6.8, 14.0 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 184.1 [M+H]+.
Stage #1: at 120℃; for 3 h; Stage #2: at 0℃; for 1 h;
Diethyl 1,3-acetonedicarboxylate (2 x 50 g, 1.0 eq, Aldrich) was added in portions to acetic anhydride (2 x 58.6 g, 2.0 eq) in a round bottomed flask. To this solution, triethyl orthoformate (2 x 51 g, 1.2 eq) was added slowly and the contents heated under a reflux condenser at 120°C for 3 h. The contents were cooled to 0°C and 25percent aqueous ammonia was added slowly while stirring. The mixture continued stirring for 1 h at 0°C and the mixture acidified with 3N HC1 solution. The solid that separated out was filtered and dried under vacuum to obtain product as white solid ethyl 4,6-dihydroxynicotinate (75.1 g, 82.8percent). LCMS: Purity: 99.84percent, MS: 184.18 (M+H).
Example C3: 3-0xo-pentanedioic acid diethyl ester (101 g, 0.5 mmol), triethylorthoformate (81.4 g, 0.55mol) and acetic anhydride (102 g, 1 mol) were combined andheated to 120°C for 2 h. The resulting mixture was cooled toRT and dissolved in DCM (1L). After further cooling to 0°C, ammonia (30percent, 80 mL) was added and the reaction mixturewas allowed to warm to RT overnight. The product was extracted with water (2x) and theaqueous layer was acidified to pH 5 with cone. HCl. The precipitate was collected byfiltration to afford ethyl 4,6-dihydroxynicotinate (60.0 g, 60percent yield). 1H NMR (400 MHz,DMSO-d6): 8 7.99 (s, 1 H), 5.58 (s, 1 H), 4.23 (q, J = 6.8, 14.0 Hz, 2 H), 1.25 (t, J = 7.2 Hz, 3H); MS (ESI) mlz: 184.1 [M+Ht.
Reference：
[1] Journal of Medicinal Chemistry, 1986, vol. 29, # 6, p. 1094 - 1099
14
[ 105-50-0 ]
[ 62935-72-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6349 - 6362
15
[ 105-50-0 ]
[ 80883-54-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6349 - 6362
[2] Journal of the Chemical Society, 1915, vol. 107, p. 1637
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 5022 - 5034
Reference：
[1] European Journal of Organic Chemistry, 2012, # 29, p. 5818 - 5827,10
[2] Gazzetta Chimica Italiana, 1891, vol. 21 I, p. 306
[3] Chemische Berichte, 1916, vol. 49, p. 2704[4] Chemische Berichte, 1920, vol. 53, p. 1917
21
[ 64-17-5 ]
[ 77-92-9 ]
[ 105-50-0 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 29, p. 5818 - 5827
[2] Journal of Organic Chemistry, 2018,
[3] Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft, 1967, vol. 300, # 1, p. 53 - 61
22
[ 542-05-2 ]
[ 64-17-5 ]
[ 105-50-0 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1921, vol. 422, p. 11
[2] Journal of the Chemical Society, 1922, vol. 121, p. 1644
[3] Organic Syntheses 5 <New York 1925>, S. 53,
[4] Journal of Organic Chemistry USSR (English Translation), 1988, vol. 24, p. 101 - 104[5] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 1, p. 116 - 119
[6] Russian Journal of Organic Chemistry, 2010, vol. 46, # 4, p. 517 - 519
23
[ 542-05-2 ]
[ 105-50-0 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1921, vol. 422, p. 11
[2] Journal of the Chemical Society, 1922, vol. 121, p. 1644
[3] Chemische Berichte, 1890, vol. 23, p. 3757
[4] Journal of the American Chemical Society, 1944, vol. 66, p. 1658
[5] Bulletin des Societes Chimiques Belges, 1945, vol. 54, p. 80
[6] Organic Syntheses, Coll. Vol. I <2. Ausg. 1941> 237,
24
[ 619-67-0 ]
[ 105-50-0 ]
Reference：
[1] Patent: US6034099, 2000, A,
25
[ 115996-74-2 ]
[ 105-50-0 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1988, vol. 24, p. 101 - 104[2] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 1, p. 116 - 119
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1954, vol. 19, p. 1231,1236
28
[ 64-17-5 ]
[ 77570-27-5 ]
[ 105-50-0 ]
Reference：
[1] Synthesis, 1981, # 2, p. 130 - 133
29
[ 64-17-5 ]
[ 5780-52-9 ]
[ 105-50-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1972, p. 3151 - 3156
30
[ 5780-52-9 ]
[ 141-52-6 ]
[ 105-50-0 ]
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[1] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1966, vol. 262, p. 135 - 138
31
[ 542-05-2 ]
[ 64-17-5 ]
[ 6202-45-5 ]
[ 105-50-0 ]
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[1] Chemische Berichte, 1898, vol. 31, p. 2015
32
[ 90927-60-9 ]
[ 105-50-0 ]
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[1] Recueil des Travaux Chimiques des Pays-Bas, 1964, vol. 83, p. 513 - 514
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[ 79353-42-7 ]
[ 105-50-0 ]
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[1] Roczniki Chemii, vol. 6, p. 24[2] Chem. Zentralbl., 1926, vol. 97, # II, p. 2906
34
[ 21269-49-8 ]
[ 105-50-0 ]
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[1] Chemische Berichte, 1899, vol. 32, p. 1285
35
[ 463-51-4 ]
[ 67-66-3 ]
[ 1663-67-8 ]
[ 105-50-0 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1955, vol. 20, p. 593,595[2] Chemicke Listy, 1955, vol. 49, p. 78
[3] Collection of Czechoslovak Chemical Communications, 1955, vol. 20, p. 285,289
[4] Collection of Czechoslovak Chemical Communications, 1954, vol. 19, p. 1231,1236
36
[ 7647-01-0 ]
[ 64-17-5 ]
[ 101875-39-2 ]
[ 21269-49-8 ]
[ 105-50-0 ]
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[1] Nippon Kagaku Zasshi, 1957, vol. 78, p. 1780,1783[2] Chem.Abstr., 1960, p. 1505
37
[ 105-50-0 ]
[ 109-77-3 ]
[ 58168-20-0 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With triethylamine In ethanol at 20 - 45℃; for 1 h; Stage #2: With sulfur In ethanolReflux
Example 1 : Preparation of ethyl 5-amino-4-cvano-3-(2-ethoxy-2-oxoethyl)-2-thiophene carboxylate compound of formula HI Triethylamine (25 g) was added to a solution of malononitrile (16.33 g) and diethyl-3- oxogutarate (50 g) in ethanol (75 ml) at ambient temperature. The reaction mixture was stirred at 40-45°C for 1 hour. Sulphur (7.9 g) was added into the reaction mass and was heated to reflux till the completion of reaction. The reaction mass was cooled at ambient temperature and added water (400 ml) slowly. Stirred the reaction mixture for 1 hour and filtered the product, washed with water (200 ml) and dry the product at 40-50°C. Yield 82percent.
With sodium tetrahydroborate; ethanol; at 0℃; for 0.05h;
Sodium borohydride (190 mg, 5 mmol) was added to a solution of compound 1,3-acetone dicarboxylic acid diethyl ester (1.01 g, 5 mmol) in ethanol (30 mL) at 0 C.After 3 minutes of reaction, saturated ammonium chloride solution (15 mL) was added to quench the reaction. Extract with ethyl acetate (3 × 50 mL), combine the organic phases and wash with saturated brine (3 × 30 mL),Dry over anhydrous magnesium sulfate. After removing the solvent,The residue was uploaded onto 100-200 mesh silica gel, and the washing solution was a mixed solvent of petroleum ether and ethyl acetate (5: 1). The diethyl 1,3-isopropanol dicarboxylate compound (970 mg, 95%) was collected.
With sodium tetrahydroborate; ethanol; at 0 - 20℃; for 0.166667h;
To a solution of diethyl-3-oxopentanedioate (5.0 g, 24 mmol, 1 .0 equiv) in ethanol (50 mL) was added sodium borohydride (0.93 g, 24 mmol, 1 .0 equiv.) at 0 C in portions over a period of 15 minutes and the reaction mixture was maintained for 10 minutes at room temperature. The reaction mixture was quenched with saturated aqueous solution of NH4CI (30 mL) at 0 C, extracted with DCM (2 X 250 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford diethyl-3- hydroxypentanedioate (3.5 g, crude) as a viscous liquid. LCMS (ES) m/z = 205.0 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1.16 (t, J = 7.0 Hz, 6 H), 2.31 - 2.38 (m, 2 H), 2.43 - 2.48 (m, 2 H), 4.03 (q, J = 7.2 Hz, 4 H), 4.20 - 4.25 (m, 1 H), 5.01 (d, J = 6.4 Hz, 1 H).
Triethylamine is added to a mixture of 5-methoxy-3,4-dihydro-2H-pyrrole (73 g, 0.73 mmol) and 3-oxopentanedioic acid diethyl ester (200 g, 0.99 mmol) at room temperature. The resulting solution is stirred for 5 days after which the reaction mixture is filtered to give 39 g (24% yield) of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester as a white solid. The NMR spectrum of the title compound is according to theory.1H NMR (CDCl3, 300 MHZ): δ 11.4 (s, 1H), 5.80 (s, 1H), 4.40 (q, 2H), 4.15 (t, 2H), 3.50 (t, 2H), 2.3-2.15 (m, 2H), 1.40 (t, 3H).
24%
With triethylamine; at 20℃; for 120.0h;
Triethylamine is added to a mixture of 5 -methoxy-3,4-dihydro-2H- pyrrole (SM-2: 73 g, 0.73 mmol) and 3-oxopentanedioic acid diethyl ester (200 g, 0.99 mmol) at room temperature. The resulting solution is stirred for 5 days after which the reaction mixture is filtered to give 39 g (24% yield) of 7-hydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethyl ester as a white solid. The NMR spectrum of the title compound is consistent with the structure.1H NMR (CDCI3, 300 MHZ): δ 11.4 (s, 1H), 5.80 (s, 1H), 4.40 (q, 2H), 4. 15 (t, 2H), 3.50 (t, 2H), 2.3-2.15 (m, 2H), 1.40 (t, 3H).
2.52 g
With triethylamine; at 20 - 35℃;
To a flask containing 18-1 (2.87 g, 28.9 mmol) at room temperature, diethyl 1,3-acetonedicarboxylate (7.90 mL, 43.4 mmol) and triethylamine (0.45 mL, 3.2 mmol) were added. The mixture was stirred at room temperature overnight then was heated to 35 C. for 3 days. The mixture was cooled to room temperature and diluted with ether. The resulting suspension was filtered, washing with ether. Additional solid precipitated from the filtrate which was collected by filtration. The combined solids were dried under vacuum to give ethyl 7-hydroxy-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate (18-2, 2.52 g) as a white solid.
With hydrogenchloride; methyl orange; In ethanol; water; at 20℃; for 72h;
Compound 93 (100 g, 0.625 mol), 800 mL of ethanol and 0.15 g (0.45 mmol) of helianthin (methyl orange) were mixed. To the stirred mixture, 225 mL of a dilute hydrochloric acid (2.74 M) was slowly added followed by 45.8 ml (0.625 mol) of a formaldehyde solution, 124.8 g (0.625 mol) of compound 94 and 150 mL of ethanol were added. The mixture was stirred at room temperature for 3 days. The mixture was concentrated in vacuo to ca.500 mL. The mixture was cooled in an ice bath before the addition of IN NaOH (625 mL) which cause the separation of an oily solid. The aqueous phase was separated and the residue was triturated in ether (250 mL). After 30 min, the precipitate was collected by filtration, washed with ether (2x60 mL), and dried in vacuo to afford 95 as a pale yellow solid (1 10 g, 62%). LCMS:m z 284 (M+l)+.
1 General
5.1.1 Synthesis of ethyl 2-(4,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-3-yl)etanoate 4 In a 500 mL three neck round bottomed flask equipped with a condenser and a thermometer, phenylhydrazine 3 (10.8 g, 99.4 mmol, 1.1 equiv, 10.1 mL) was diluted in EtOH (140 mL) under magnetic stirring at 20 °C. Diethyl-3-oxopentandionate 2 (18.3 g, 90.4 mmol) was added and the resulting mixture was brought to reflux temperature for 2 h. The solution was then cooled to 20 °C and the solvent evaporated under reduced pressure. The residue was triturated with PE (200 mL) and kept under stirring for 6 h. The suspension was filtered in vacuo, obtaining the title compound (18.9 g, 85%) as pale yellow solid, mp 79-80 °C, lit. 14 75-76 °C; Rf (10% EtOAc/CH2Cl2) 0.43; λmax (ɛ) (MeOH) 244 nm (16,559 M-1 cm-1); νmax (KBr disk): 3140, 2972, 2893, 2794, 1743, 1595, 1535, 1451, 1402, 1318, 1249, 1194 cm-1; δH (200 MHz, CDCl3) 7.86-7.82 (2H, m, Ar-H), 7.43-7.36 (2H, m, Ar-H), 7.24-7.16 (1H, m, Ar-H), 4.23 (2H, q, J 7.2 Hz, CO2CH2CH3), 3.64 (2H, s, CH2CONPh), 3.58 (2H, s, CH2CO2CH2CH3), 1.31 (3H, t, J 7.2 Hz, CO2CH2CH3); δC (50.3 MHz, CDCl3) 170.5, 168.2, 152.7, 137.7, 128.8 (2C), 125.2, 118.8 (2C), 61.7, 42.0, 37.0, 14.2; ESI (m/z, -c) 245.2 [M-1]-.
56%
Stage #1: phenylhydrazine; diethyl 1,3-acetonedicarboxylate at 20 - 70℃;
Stage #2: at 100℃; for 1.5h;
Example 2.1: Ethyl 2-{2-ethoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3- cartooxylate; Propiolamide (20.0 g, 289.6 mmol), diethyl 3-oxopentanedioate (87.8 g, 434.4 mmol) and sodium carbonate (24.6 g, 231.7 mmol) were mixed in water (800 mL) at 0 0C and then warmed to r.t. over 4 hours. The reaction was allowed to continue t? stir at r.t. for 3 days. The reaction was neutralized with aqueous hydrochloric acid (5M) at 0 0C with vigorous stirring. A solid precipitate was collected by filtration and washed with diethyl ether/hexanes (2:1) to yield a first batch of the title compound (43g). The filtrate was further extracted with ethyl acetate and the combined organic phases were dried over sodium sulphate and purified by column chromatography (10-80% ethyl acetate/hexanes) to yield another batch of the title compound (7g), in total gave 50 g (68%). 1H NMR (300 MHz, CDCI3): delta(ppm) 13-12 (br S, 1 H)1 8.08 (d, 1H), 6.52 (d, 1H), 4.3 (q, 2H), 4.21 (q, 2H)1 4.13 (s, 2H)1 1.29 (m, 6H).
68%
With sodium carbonate; In water; at 0 - 20℃; for 76h;
Example 2.1: Ethyl 2-(2-ethoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3- carboxylate; Propiolamide (20.0 g, 289.6 mmol), diethyl 3-oxopentanedioate (87.8 g, 434.4 mmol) and sodium carbonate (24.6 g, 231.7 mmol) were mixed in water (800 <n="67"/>ml_) at 0 C and then warmed to RT over 4 h. The reaction was allowed to continue to stir at RT for 3 days. The reaction was neutralized with aqueous hydrochloric acid (5 M) at 0 C with vigorous stirring. A solid precipitate was collected by filtration and washed with diethyl ether/hexanes (2:1) to yield a first batch of the title compound (43 g). The filtrate was further extracted with ethyl acetate and the combined organic phases were dried over sodium sulphate and purified by column chromatography (10-80% ethyl acetate/hexanes) to yield another batch of the title compound (7 g), in total gave 50 g (68%). 1H NMR (300 MHz, CDCI3): delta (ppm) 13.12 (br s, 1 H), 8.08 (d, 1 H), 6.52 (d, 1 H), 4.3 (q, 2H), 4.21 (q, 2H), 4.13 (s, 2H), 1.29 (m, 6H).
Example 1 : Preparation of ethyl 5-amino-4-cvano-3-(2-ethoxy-2-oxoethyl)-2-thiophene carboxylate compound of formula HI Triethylamine (25 g) was added to a solution of malononitrile (16.33 g) and diethyl-3- oxogutarate (50 g) in ethanol (75 ml) at ambient temperature. The reaction mixture was stirred at 40-45C for 1 hour. Sulphur (7.9 g) was added into the reaction mass and was heated to reflux till the completion of reaction. The reaction mass was cooled at ambient temperature and added water (400 ml) slowly. Stirred the reaction mixture for 1 hour and filtered the product, washed with water (200 ml) and dry the product at 40-50C. Yield 82%.
3 grams of phenanthrene-9,10-diketone (manufactured by Aldrich Co., 95%) was dissolved in 60 ml HBr and 20 ml H2SO4, and heated to 80 C., and a small amount of Br2 (manufactured by ACROS Co.) was added slowly, after which the mixture was allowed to react for 24 hours. After precipitation and filtration, dibromophenanthrene-9,10-diketone was obtained at a yield of more than 90%. 2 grams of NaOH and 200 ml methanol was mixed and heated to about 60 C. After NaOH was dissolved completely, 3 grams of dibromophenanthrene-9,10-diketone and 4 grams of diethyl 1,3-acetonedicarboxylate (manufactured by ACROS Co., 95%) were added and the temperature was maintained at 60 C. After 36 hours of reaction, 10% HCl aqueous solution was added to the reaction mixture for neutralization, and then the mixture precipitated and filtered. The precipitate collected was dissolved by acetic acid, 300 ml 10% HCl aqueous solution was added, and reaction took place for 18 hours at an elevated temperature. Then, acetic acid and water were removed, and the product neutralized with sodium hydrogen carbonate aqueous solution, precipitated, and filtered, giving Reactant 1 at a yield of 17%. The following reaction scheme illustrates the preparation of Reactant 1: 3 grams of Reactant 1 and 150 ml ethylene glycol were mixed, 0.5 grams of N2H4 (manufactured by Lancaster Co., 98%) was added, and the resulting mixture was stirred for 10 minutes, then 0.5 grams of KOH was added, and heated to about 180 C. for reaction. After 15 hours, the reaction mixture was cooled to room temperature and diluted with water, resulting in a white solid product (Compound 1), at a yield of 61%, herein referred as 9,10:9,10-bis(trimethylene)-2,7-dibromo-9,10-dihydrophenanthrene. This Compound 1 is the novel phenanthrene compound of the present invention, and is also a mediate for the synthesis of various phenanthrene compounds of the present invention. 1H NMR (CDCl3): delta (ppm) about 1.40 (m, 2H), about 1.70 (m,2H), 1.88-1.96(m, 4H), 2.10-2.16(m, 4H), 7.23-7.26(m, 2H), 7.23-7.26(m, 2H), 7.92(s, 2H). The following reaction scheme illustrates the preparation of Compound 1:
Z-3-(4-phenyl-thiophen-2-ylamino)-pent-2-enedioic acid diethyl ester[ No CAS ]
E-3-(4-phenyl-thiophen-2-ylamino)-pent-2-enedioic acid diethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In chloroform for 12h; Molecular sieve; Heating / reflux;
38
Amino thiophene (1.39g, 7.94mmol), p-Toluenesulfonic acid (7.5mg, 0.4mmol) and diethylacetonedicarboxylate (1.73ml, 9.53mmol) were refluxed for 12h in chloroform in the presence of 3A molecular sieves. On cooling, the reaction was filtered, treated with activated charcoal, refiltered through a pad of celite and concentrated. The residue was triturated with petroleum ether (bp.40-60°) until crystallisation was complete to give (E/Z)-3-(4-Phenyl-thiophen-2-ylamino)-pent-2-enedioic acid diethyl ester as a brown powder. Yield = 2.4g (84%, mixture of E and Z isomers).
7.a a
a Diethyl 4-chloro-3,5-pyridinedicarboxylate Following a similar procedure to that described in Example 1, Step a, except using diethyl 1,4-dihydro-4-oxo-3,5-pyridinedicarboxylate (prepared from diethyl 1,3-acetonedicarboxylate as described in J. Heterocyclic Chem. 1980, 17, 359-368) instead of ethyl 1,4-dihydro-4-oxo-3-phenyl-5-pyridinecarboxylate, the title compound was prepared, after purification by flash chromatography (silica gel, 10% EtOAc/hexane), in quantitative yield; 1H NMR (250 MHz, CDCl3) δ1.43 (6H, t, J 7.1 Hz), 4.46 (4H, q, J 7.1 Hz), 8.98 (2H, s); MS (ES+) m/z 258/260 [MH]+.
Multi-step reaction with 3 steps
1.1: acetic anhydride / 1.5 h / 120 °C
1.2: 0 °C / Cooling
1.3: pH < 5
2.1: trichlorophosphate / 3 h / 110 °C
3.1: acetonitrile; water / 3.5 h / 0 - 20 °C
Multi-step reaction with 3 steps
1.1: orthoformic acid triethyl ester / 2 h / 120 °C
1.2: 0 - 20 °C
2.1: trichlorophosphate / 2 h / Reflux
3.1: water; acetonitrile / 8 h / 0 - 20 °C
Multi-step reaction with 3 steps
1: 2 h / 120 °C
2: trichlorophosphate / 2 h / Reflux
3: water; acetonitrile / 8 h / 0 - 20 °C
Multi-step reaction with 3 steps
1.1: acetic anhydride / 3 h / 120 °C
1.2: Cooling with ice
2.1: trichlorophosphate / 2 h / Reflux
3.1: water; acetonitrile / 3.5 h / 0 - 20 °C
Multi-step reaction with 3 steps
1.1: orthoformic acid triethyl ester; acetic anhydride / 3 h / 120 °C
1.2: 0.25 h / 0 °C
2.1: trichlorophosphate / 2 h / 110 °C
3.1: acetonitrile; water / 3.5 h / 0 - 20 °C
Multi-step reaction with 3 steps
1.1: acetic anhydride / 1.5 h / 120 °C
1.2: 0 °C
2.1: trichlorophosphate / 2 h / 110 °C
3.1: acetonitrile / 3.5 h / 0 - 20 °C
Multi-step reaction with 3 steps
1.1: acetic anhydride / 1.5 h / 120 °C
1.2: 1 h / Ice cooling
2.1: trichlorophosphate
2.2: Ice cooling
3.1: water; acetonitrile / 0 - 20 °C
Multi-step reaction with 3 steps
1.1: acetic anhydride / 1.5 h / 120 °C
1.2: 1 h / 0 °C
2.1: trichlorophosphate / 2 h / 110 °C
3.1: acetonitrile / 2.5 h / 0 - 20 °C
Multi-step reaction with 4 steps
1.1: acetic anhydride / 1.5 h / 120 °C
1.2: 0 °C / Cooling
1.3: pH < 5
2.1: trichlorophosphate / 3 h / 110 °C
3.1: acetonitrile; water / 3.5 h / 0 - 20 °C
4.1: lithium aluminium tetrahydride / tetrahydrofuran / -78 °C
4.2: 20 °C
Multi-step reaction with 4 steps
1.1: orthoformic acid triethyl ester / 2 h / 120 °C
1.2: 0 - 20 °C
2.1: trichlorophosphate / 2 h / Reflux
3.1: water; acetonitrile / 8 h / 0 - 20 °C
4.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.33 h / 0 °C / Inert atmosphere
Multi-step reaction with 4 steps
1: 2 h / 120 °C
2: trichlorophosphate / 2 h / Reflux
3: water; acetonitrile / 8 h / 0 - 20 °C
4: lithium aluminium tetrahydride / tetrahydrofuran / 0.33 h / 0 °C / Inert atmosphere
Multi-step reaction with 4 steps
1.1: acetic anhydride / 3 h / 120 °C
1.2: Cooling with ice
2.1: trichlorophosphate / 2 h / Reflux
3.1: water; acetonitrile / 3.5 h / 0 - 20 °C
4.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / -78 °C
Multi-step reaction with 4 steps
1.1: orthoformic acid triethyl ester; acetic anhydride / 3 h / 120 °C
1.2: 0.25 h / 0 °C
2.1: trichlorophosphate / 2 h / 110 °C
3.1: acetonitrile; water / 3.5 h / 0 - 20 °C
4.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / -78 °C
Multi-step reaction with 4 steps
1.1: acetic anhydride / 1.5 h / 120 °C
1.2: 1 h / Ice cooling
2.1: trichlorophosphate
2.2: Ice cooling
3.1: water; acetonitrile / 0 - 20 °C
4.1: lithium aluminium tetrahydride / tetrahydrofuran / -78 °C
4.2: 20 °C
Multi-step reaction with 4 steps
1.1: acetic anhydride / 1.5 h / 120 °C
1.2: 1 h / 0 °C
2.1: trichlorophosphate / 2 h / 110 °C
3.1: acetonitrile / 2.5 h / 0 - 20 °C
4.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 78 °C
Step-I: Preparation of crude Ethyl 5-amino-3-ethoxycarbonylmethyl-4-cyano-2- thiophenecarboxylateA solution of morpholine (76.9 g) in dimethylformamide (175 ml) was added to a solution of diethyl 3-oxoglutarate (175 g) and malononitrile (59.46 g) in dimethylformamide (262 ml) for 30-45 minutes while maintaining the temperature at below 35C. The reaction mass was cooled to 25-30C and stirred for 2 to 3 hours. A mixture of sulfur powder (30.56 g) in dimethylformamide (87.5 ml) was added to the reaction mass at 25-30C, followed by heating the mass at 50-55C and maintaining for 2 to 4 hours. Water (1750 ml) was added to the hot reaction mixture at 50-55C for 30 to 45 minutes. The reaction mass was then cooled to 25-30C and stirred for 3 to 4 hours. The precipitated product was filtered, washed with water (2 x 700 ml) and then dried at 50-60C in air oven for 4 to 5 hours to produce 201.5 g of crude ethyl 5-amino-3-ethoxycarbonylmethyl-4-cyano-2-thiophenecarboxylate [Yield: 82.5%; Purity by HPLC: 92.3%; Content of ethyl 5-amino-3-methyl-4-cyano-2- thiophenecarboxylate (Impurity- A): 6.9%].
Multi-step reaction with 4 steps
1.1: orthoformic acid triethyl ester / 2 h / 120 °C
1.2: 0 - 20 °C
2.1: trichlorophosphate / 2 h / Reflux
3.1: water; acetonitrile / 0 - 20 °C
4.1: lithium aluminium tetrahydride / water; tetrahydrofuran / 1 h / -50 - 0 °C
Multi-step reaction with 4 steps
1: 2 h / 120 °C
2: trichlorophosphate / 2 h / Reflux
3: water; acetonitrile / 20 °C
4: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / -50 - 0 °C
Multi-step reaction with 4 steps
1.1: acetic anhydride / 1.5 h / 120 °C
1.2: 1 h / 0 °C
1.3: pH 5
2.1: trichlorophosphate / 2 h / 110 °C
3.1: tetrahydrofuran / 16.5 h / 0 - 20 °C
4.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / -78 °C
Multi-step reaction with 4 steps
1.1: acetic anhydride / 1.5 h / 120 °C
1.2: 1 h / Cooling with ice bath
1.3: pH < 5
2.1: trichlorophosphate / 2 h / 110 °C
3.1: water; acetonitrile / 2.5 h / 0 - 20 °C
4.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / -78 °C
Example 1A ethyl 4-(2-ethoxy-2-oxoethyl)-2-(methylthio)pyrimidine-5-carboxylate To a solution of diethyl 3-oxopentanedioate (4.03 ml, 22.19 mmol) in ethanol (44.4 ml), 1,1-dimethoxy-N,N-dimethylmethanamine (2.95 ml, 22.19 mmol) was added and the mixture was stirred at ambient temperature for 45 minutes. Methyl carbamimidothioate sulfate (3.08 g, 22.19 mmol) was then added and the mixture was stirred under refluxing conditions for 3 hours. After cooling to ambient temperature, the solution was concentrated and the residue was dissolved in 200 mL of ethyl acetate. The solution was poured into a separatory funnel, washed with saturated aqueous sodium bicarbonate (1*150 mL) and brine (1*150 mL), dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (Isco, Redi-Sep column, 0-100% ethyl acetate/hexane, linear gradient) afforded the title compound. MS (ESI) m/z 285 (M+H)+.
With acetic acid; In water; at 200℃; for 0.05h;Microwave irradiation;
General procedure: Acetonedicarboxylate (1.5mmol), 1,2-aryldiamine 1 (1.0mmol), water (5mL) and two drops of acetic acid were mixed thoroughly and were irradiated in a Biotage Initiator 2.0 microwave oven at 200C for 3min. The crude product was filtered by Gooch funnel, washed on the funnel with diethyl ether and recrystallized from ethanol.
Multi-step reaction with 3 steps
1: water / 1 h / 15 - 40 °C
2: sodium hydroxide / water / 3 h / 100 °C
3: acetyl chloride / 16 h / 52 °C / Inert atmosphere
2
(2) Dissolving sodium (4.0 g, 174 mmol) in 120 mL of absolute ethanol,Further compound diethyl 1,3-acetone dicarboxylate (4.34 g, 21.5 mmol) was added.A milky white solution was obtained.A solution of S2 (2.0 g, 14.3 mmol) dissolved in 10 mL of absolute ethanol was quickly added to the above system.The system turns into a brick red solution.After stirring the reaction for 12 h at room temperature,Add 200 mL of water, precipitate with an orange solid, then filter.Obtained an orange solid, which was then dissolved in 30 mL of glacial acetic acid and diluted with 100 mL of water.Extract three times with dichloromethane, combine the organic phases, and concentrate.Column chromatography [V (petroleum ether): V (ethyl acetate) = 5: 1] to give an orange-yellow solid was isolated S3 2.03g,The yield was 49%.
38%
Stage #1: diethyl 1,3-acetonedicarboxylate With ethanol; sodium
Stage #2: 2-chlorotropone at 20℃; for 12h;
diethyl 5,7-dioxospiro[2.5]octane-4,6-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a slurry of NaH (0.96 g, 60% in oil) in THF (5.0mL), was added diethyl 1,3-acetonedicarboxylate (2.4 g) slowly at 0-15 oC. After the mixture was stirred for 0.5 h, a total of 1.4 g of Compound 9 was added slowly at 0-15 oC. The mixture was stirred at 20-30 oCfor 1 h, and then heated to reflux. 5 mL of EtOH and 2.4 g of NaOEt solution(20% in EtOH) were added respectively. The resulting mixture was refluxed for 5h. After that, a total of 11.2 g of KOH solution (20% in water) was added slowly, and the reaction mixture was refluxed for another 5 h. The organic solvent in reaction mixture was removed at reduced pressure. The aqueous solution was extracted with MTBE (2 x 10 mL) and then heated to 50-60 oCwith addition of conc. HCl until pH at 2.5-3.5. The resulting mixture wasstirred at 50-60 oC for 2 h and then cooled to 20-30 oC.It was extracted with dichloromethane (3 x 25 mL). The combined organic phase was concentrated at reduced pressure. Then 5.0 mL of MTBE was added to the residue and the resulting slurry was stirred for 0.5 h at 0-10 oC.The solid was collected by filtration, washed with MTBE (5.0 mL), and dried under vacuum. A total of 0.68 g (45% yield) of 2 was obtained as a white solid.
To a slurry of NaH (0.96 g, 60 in oil) in THF (5.0 mL) , was added diethyl acetonedicarboxylate (2.4 g) slowly at 0-15 . After it was stirred for 0.5 h, a total of 1.4 g of Compound 12 was added slowly at 0-15 . The mixture was stirred at 20-30 for 1 h, and then heated to reflux. 5 mL of EtOH and 2.4 g of NaOEt solution (20 in EtOH) were added respectively. The resulting mixture was refluxed for 5 h. After that, a total of 11.2 g of KOH solution (20 in water) was added slowly, and the reaction mixture was continuously refluxed for another 5 h. The organic solvent in reaction mixture was removed under vacuum. The aqueous solution was extracted with MTBE (2 x 10 mL) and then heated to 50-60 with addition of conc. HCl until pH at 2.5-3.5. The resulting mixture was stirred at 50-60 for 2 h and then cooled to 20-30 . It was extracted with dichloromethane (3 x 25 mL) . The combined organic phase was concentrated under vacuum. Then 5.0 mL of MTBE was added to the residue and the resulting slurry was stirred for 0.5 h at 0-10 . The solid was collected by filtration, washed with MTBE (5.0 mL) , and dried under vacuum. A total of 0.68 g (45 yield, 98 purity) of Compound 6 was obtained as a white solid.1HNMR(400 MHz, DMSO-d6) delta11.02 (br s, 1H) , 5.17 (s, 1H) , 2.45-2.25 (m, 4H) , 1.90-1.75 (m, 2H) , 1.75-1.65 (m, 4H) 13CNMR(100 MHz, DMSO-d6) delta186.22, 103.55, 44.69, 38.35, 31.48, 14.61 MS (m/z) 152.1.
Step 1 (Synthesis of Compound 107-2) (0550) Compound 107-1 (8.0 g, 39.6 mmol) was dissolved in anhydrous ethanol (200 mL), and 2-bromo-4-fluorobenzaldehyde (8.0 g, 39.6 mmol), thiazoledicarboxamidine hydrochloride (6.5 g, 39.6 mmol), sodium acetate (6.5 g, 79.2 mmol) were added. The reaction mixture was slowly warmed to reflux, and the reaction was stirred under reflux overnight. The reaction mixture was concentrated under reduced pressure and then extracted with (500 mL×3) EtOAc. The organic layer was washed with saturated saline solution (300 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and purified by silica gel column: chromatography with an eluent system (PE: EtOAc=10:1) to obtain 5.0 g product 107-2, yield: 25.5%. (0551) LCMS (ESI) m/z: 496.0 [M+H].
With ammonium cerium (IV) nitrate In methanol at 20℃;
2. General procedure for the synthesis of symmetrical bispyrrole derivatives 1under solvent-free high-speed vibration milling (HSVM) conditions
General procedure: The suitable ketone (1 mmol), N-iodosuccinimide (NIS, 1 mmol) and ptoluenesulphonic acid (PTSA, 10 mol %) were added to a commercially availablesnap closure grinding jar, along with a zirconium oxide ball. This ball mill vessel wasfitted to one of the horizontal vibratory arms of the ball mill, while the other arm wasoccupied with an empty vessel. The ball mill was set to vibrate at a frequency of20 s-1 for 60 min at room temperature. Then, a mixture of the corresponding diamine(0.85 mmol), the suitable -dicarbonyl compound (1.3 mmol) and cerium(IV)ammonium nitrate (CAN, 0.13 mmol) in 0.5 mL of methanol was stirred at roomtemperature during 30-60 min (judged by TLC), and the solvent was evaporated.The residue was transferred to the milling vessel with a Pasteur pipette or a spatulaand silver nitrate (1 mmol) was added. The reaction was subjected to the vibratorymovement at 20 s-1 for 60 min, affording a dark paste. Then, the reaction vessel wascleansed with ethyl acetate or dichloromethane and the suspension was filtered toremove the silver iodide precipitate. The organic layer was washed with water (2 mL),dried over anhydrous sodium sulfate and the solvent was removed under reducedpressure. Purification by flash column chromatography on silica gel eluting with agradient from petroleum ether to 8:2 petroleum ether-ethyl acetate afforded thedesired pyrrole derivatives. Compounds 1h, 1i and 1j were purified by flashchromatography eluting with a 98/2 dichloromethane/methanol mixture.
diethyl 3-(1-(tert-butyl)-1H-tetrazol-5-yl)-3-((1R,5S)-8-oxo-5,6-dihydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-3(2H,4H,8H)-yl)pentanedioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With trimethylsilylazide; In methanol; at 20℃; for 24.0h;
General procedure: The <strong>[485-35-8]cytisine</strong> (0.2mmol) was dissolved in MeOH (5mL). The aldehyde (0.22mmol) (2a-h), TMSN3 (0.22mmol) and isocyanide (3a-g) (0.22mmol) were added. The resulting solution was kept for 24h (TLC control) at the room temperature. When the reaction was completed, solvent was evaporated and the product was purified via column chromatography (dichloromethane/methanol 20:1).
With sodium hydride In tetrahydrofuran; ethanol at 60 - 70℃;
1.2 Step 2 Synthesis of Compound A-3
At room temperature, THF (400 mL) was added to the reactor, sodium hydride (24 g) was added first, diethyl 1,3-acetonedicarboxylate(61 g) was added, and stirred,Then compound A-2 (35g), and absolute ethanol (12g) were added, and then the reaction solution was heated to 60°C-70°C, stirred for 1-2 hours, Cool to room temperature, add methanol, then add 20% potassium hydroxide aqueous solution (280 g), heat the reaction mixture to 60°C-70°C, continue stirring for 12 hours, Cool to room temperature, add methyl tert-butyl ether for extraction, discard the organic layer to obtain an aqueous layer, acidify the aqueous layer with concentrated hydrochloric acid below 40°C, and then continue to heat the reaction to 45°C-50°C and stir for 3 hours, After the reaction was completed, it was cooled to 0°C-10°C, filtered and concentrated to obtain the crude product, which was slurried with demineralized water, centrifuged, and dried in vacuo to obtain off-white solid compound 3 (18 g, yield 53%).
53%
Stage #1: α-(ethoxycarbonyl)methylenecyclobutane; diethyl 1,3-acetonedicarboxylate With ethanol; sodium hydride In tetrahydrofuran at 60 - 70℃;
Stage #2: With water; potassium hydroxide In tetrahydrofuran; methanol at 25 - 70℃; for 12h;
Stage #3: With hydrogenchloride In tetrahydrofuran; tert-butyl methyl ether; water at 25 - 50℃; for 3h;
1.2 Step 2 synthesis of the compound A-3
At room temperature, THF (400 mL) was added to a reactor, sodium hydride (24 g) was added at first, and then diethyl acetonedicarboxylate (61 g) was added, the mixture was stirred, after that the compound A-2 (35 g) and anhydrous ethanol (12 g) were added. Then the reaction solution was heated to 60 -70 , stirred for 1-2 hours, then cooled to room temperature, added with methanol and 20%potassium hydroxide aqueous solution (280 g) successively. And the mixture was heated to 60 -70 and continued to stir for 12 hours, then cooled to room temperature, added with methyl tert-butyl ether for extraction, the organic phase was discarded to obtain an aqueous phase, which was acidified with concentrated hydrochloric acid at 40 . Then the reaction solution was heated to 45 -50 and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to 0 -10 , filtered and concentrated to obtain a crude product by slurrying with demineralized water, concentrated, dried under vacuum to obtain the compound 3 as an off-white solid (18 g, yield 53%). 1HNMR (300MHz, CDCl3) : δ ppm 2.94 (2H, d, J=1.6) , 2.52 (2H, s) , 1.792.03 (6H, m).
32%
Stage #1: diethyl 1,3-acetonedicarboxylate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere;
Stage #2: α-(ethoxycarbonyl)methylenecyclobutane In tetrahydrofuran at 0 - 20℃; for 2h; Further stages;
15.2 Step 2: Synthesis of Compound spiro[3.5]nonane-6,8-dione
Under the protection of nitrogen atmosphere, NaH (60%, 960 mg, 24 mmol) was added portionwise at 0° C. to a solution of diethyl 3-oxopentanedioate (2.53 g, 12.5 mmol) in anhydrous THF (50 mL) and stirred at this temperature for 30 mins, ethyl 2-cyclobutylideneacetate (1.4 g, 10 mmol) in anhydrous THF (10 mL) solution was then added, reacted at RT for 2 hours, then EtONa (816 mg, 12 mmol) in anhydrous EtOH (5 mL) solution was added. The above mixture was refluxed and reacted for 5 hours, then cooled to 50° C., 20% KOH solution (10 mL) was added. The resulting mixture was stirred at this temperature overnight. After the reaction was completed, the reaction mixture was cooled to RT and extracted with EA, the aqueous phase was adjusted to 1-2 and stirred at 70° C. for 2 hours. The reaction mixture was cooled to RT and extracted with DCM. The combined organic phase was washed with water, dried with sulfate and concentrated. The crude product was separated and purified by column chromatography to give the desired product (483 mg, yield 32%).
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