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Structure of 70-23-5 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: at 40℃; for 5 h; Stage #2: With hydrogenchloride; sodium nitrite In water for 2 h;
A method for preparing thiazole-4-carboxylic acid,Include the following steps: Mix ethyl bromopyruvate, thiourea, and water,Raise the temperature to 40°C, incubate and stir for 5 hours, then add concentrated hydrochloric acid, and add 30 wtpercent sodium nitrite aqueous solution dropwise.The mixture was further stirred for 2 hours, and the filter cake was filtered to obtain thiazole-4-carboxylic acid. The molar ratio of ethyl bromopyruvate to thiourea was1:1.05, the molar ratio of ethyl bromopyruvate to sodium nitrite is 1:1.5, and the weight ratio of ethyl bromopyruvate to water is1.95:10, the volume ratio of water to concentrated hydrochloric acid is 1:1.
Reference：
[1] Patent: CN107417639, 2017, A, . Location in patent: Paragraph 0023; 0029; 0030; 0031; 0032; 0033; 0034-0041
2
[ 70-23-5 ]
[ 77287-34-4 ]
[ 14527-43-6 ]
Yield
Reaction Conditions
Operation in experiment
87%
With tetraphosphorus decasulfide In 1,4-dioxane for 8 h; Reflux
To a solution of formamide (47 mL, 1.19 mol, 1.5 equiv) in 1,4-dioxane (318 mL), P2S5 (52.70 g, 0.237 mmol, 0.3 equiv) was added in small portions in the course of 0.5 h under vigorous stirring. The reaction mixture was stirred for 0.5 h, and ethyl bromopyruvate (154 g, 0.790 mol) was added dropwise. The reaction mixture was heated at reflux for 8 h, cooled to room temperature and a solution of K2CO3(~100 g) in water (~500 mL) was carefully added to the reaction mixture. The resulted solution was extracted with DCM (3 * 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, evaporated, and the residue was distilled at reduced pressure. bp = 120-130 °C (10 torr). M = 108.3 g. Yield = 87percent. 1H NMR: (CDCl3, 400 MHz) δ = 1.40 (t, J = 7.2 Hz, 3 H), 4.42 (q, J = 7.1 Hz, 2 H), 8.24 (d, J = 2.1 Hz, 1 H), 8.87 (d, J = 2.1 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 14.4, 61.7, 127.3, 148.2, 153.6, 161.3.
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 154, p. 367 - 391
3
[ 70-23-5 ]
[ 14527-43-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 2, p. 533 - 536
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 2, p. 533 - 536
4
[ 115-08-2 ]
[ 70-23-5 ]
[ 14527-43-6 ]
Reference：
[1] Helvetica Chimica Acta, 1951, vol. 34, p. 143,147
5
[ 5600-21-5 ]
[ 70-23-5 ]
[ 7749-47-5 ]
[ 134044-64-7 ]
[ 156756-45-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1994, vol. 29, # 4, p. 279 - 286
6
[ 67-56-1 ]
[ 5600-21-5 ]
[ 70-23-5 ]
[ 7749-47-5 ]
[ 134044-64-7 ]
[ 156756-45-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1994, vol. 29, # 4, p. 279 - 286
To a stirred solution of thioacetamide 7 (2.12 g, 28.27 mmol) in EtOH (40.00 mL), ethyl bromopyruvate (3.40 mL, 25.70 mmol) was added and the reaction was stirred at 80 °C for 12 h. Solvent was removed under reduced pressure. The crude was purified by means of chromatography on silica gel (20 percent ethyl acetate in petroleum ether) to afford title compound (86 percent yield) as a yellow solid. ESI-MS m/z 172 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 4.41 (q, J = 6.9 Hz, 2H), 2.76 (s, 3H), 1.40 (t, J= 7.1 Hz, 3H).
83%
With sodium carbonate In neat (no solvent)Milling
General procedure for the preparation of ethyl 2-methylthiazole-4-carboxylate (12a) An oily mixture of ethyl α-bromopyruvate (9, 2.14 g, 11 mmol) and thioacetamide (10a, 0.75 g, 10 mmol) was ground in presence of Na2CO3 (0.50 g) for 5-6 min. When it becomes solid, the progress of reaction was monitored with TLC. On completion of the reaction, water (20 ml) was added to the reaction followed by extraction with chloroform (20 ml). The organic layer thus separated was dried over anhy. Na2SO4. Excess of solvent was removed by distillation. Filtered the crude product and crystallized from aqueous ethanol (83percent) to give pure solid 12a. Similarly, 12b-12g and 13a-13g were prepared following the above procedure and their formation was confirmed by comparing their melting points with literature values.
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 12, p. 3804 - 3805
[2] Organic Letters, 2008, vol. 10, # 8, p. 1565 - 1568
[3] Journal of Organic Chemistry, 2001, vol. 66, # 19, p. 6410 - 6424
[4] Angewandte Chemie - International Edition, 2008, vol. 47, # 46, p. 8950 - 8953
[5] Patent: US2010/249404, 2010, A1, . Location in patent: Page/Page column 11
[6] Advanced Synthesis and Catalysis, 2014, vol. 356, # 16, p. 3370 - 3376
[7] Tetrahedron Letters, 2016, vol. 57, # 8, p. 920 - 923
[8] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 718 - 726
[9] Tetrahedron Letters, 1997, vol. 38, # 12, p. 2061 - 2064
[10] Chemistry of Heterocyclic Compounds, 2011, vol. 47, # 6, p. 703 - 709
[11] Journal of Organic Chemistry, 2004, vol. 69, # 26, p. 9269 - 9284
[12] Proceedings - Indian Academy of Sciences, Section A, 1945, # 22, p. 362,376
[13] Journal of the Chemical Society, 1946, p. 91
[14] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 9, p. 2243 - 2247
[15] Patent: WO2004/58702, 2004, A2, . Location in patent: Page 29; 23
[16] Patent: WO2004/58763, 2004, A1, . Location in patent: Page 38-39
[17] Patent: EP1445249, 2004, A1, . Location in patent: Page 139
[18] Patent: EP1612204, 2006, A1, . Location in patent: Page/Page column 47
[19] Organic Letters, 2012, vol. 14, # 24, p. 6354 - 6357
9
[ 70-23-5 ]
[ 6436-59-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 8, p. 1203 - 1208
[2] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 5, p. 1449 - 1456
10
[ 70-23-5 ]
[ 17356-08-0 ]
[ 5398-36-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 70℃; for 1 h;
General procedure: A mixture of thiourea (1.2 mmol) and 2-bromoacetophenone (1 mmol) in EtOH (2 mL) was stirred at 70 oC for 1h. The reaction mixture was cooled to room temperature, poured into ice-cold water, and the resulting precipitate was filtered and dried to give the desired compounds: [6a ( 99percent) as a white solid, mp 150-152 oC (Lit.26 149-150 oC) ; 6b (100percent) as a white solid, mp 162-165 oC (Lit.26 163-164 oC); 6c (0.236 g, 93percent) as a white solid, mp 179-181 oC (Lit.26 180-181 oC); 6d (98percent) as a white solid, mp 203.6-204.2 oC (Lit.28/22 204.0-204.5 oC); 6e (94percent) as a bright yellow solid, mp 287-288 oC (Lit.26,27 285-286 oC); 6f (100percent) as a white solid, mp 172-174 oC (Lit.29-31 172 oC).
99.5%
at 120℃; for 0.5 h;
Take 3-bromo-pyruvate (5.0g, 25.6mmol), adding thiourea (1.56g, 20.5mmol, 0.8eq) at 120 °C reflux 0.5h, TLC monitoring of the reaction to completion.The reaction mixture was dissolved in ethyl acetate, washed with distilled water, the organic layer was washed with brine; the organic layer was dried over anhydrous sodium sulfate, suction filtered, the solvent was distilled off under reduced pressure to give a yellow 2-aminothiazol-4-carboxylate (4.39g, 99.5percent).
98%
With potassium carbonate In ethanol at 80℃; for 1 h;
To the stirred solution of thiourea (3.69 g, 1.0 eq) in ethanol (120 mL) was added 3-bromo-2-oxo-propionic acid ethyl ester (9.453 g, 1.0 eq) and the reaction mixture was stirred at 80°C until completion of the reaction. The solvent was evaporated under reduced pressure and the crude prod-uct was dissolved in water, basified with solid K 2 CO 3 and the obtained solid is filtered over Buckner funnel and dried to afford the desired compound. White solid, M.pt.: 176-178°C, yield: 98percent (5.5 g), R f (cyclohexane:ethyl acetate = 6:4): 0.42, Anal (C 6 H 8 N 2 O 2 S) calc. C 41.85 H 4.68 N 16.27 S 18.62, found: C 41.75 H 4.61 N 16.18 S 18.59. 1H-NMR (300 MHz, DMSO-d 6 ) (δ, ppm): 9.12 (brs, 2H, NH 2 ), 7.64 (s, 1H, =CH), 4.27 (q, J = 15.84 Hz, 2H, CH 2 ), 1.28 (t, J = 10.56 Hz, 3H, CH 3 ). 13C-NMR (75 MHz, DMSO) (δ, ppm): 172.31, 165.34, 143.47, 119.64, 68.26, 14.97. IR ν max (neat): 3440 (NH), 3129 (=CH, thia-zole), 1689 (C=O, ester) cm-1. LC-MS: (m/z) [M+H]+ 173.1.
96%
at 80℃; for 1 h;
Thiourea (3.69 g, 48.5 mmol) was added to a solution of ethyl bromopyruvate (10 g, 46 mmol) in EtOH (92 mL), and the reaction mixture was heated to 80 0C for 1 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting solid was dissolved in ice water (100 mL) and brought to pH ~8 with solid K2CO3. The resulting solid was filtered, washed with water (3 x) and air dried. This gave 7.64 g (96percent) of a yellow solid that was used without further purification. LC-MS: RT = 4.85 min, [M+H]+ = 173.0.
96.5%
With Cu2OHKUST-1 nanocatalyst In ethanol for 3 h; Reflux
step 1,In a constant pressure dropping funnel40g of ethyl pyruvate was added to the 500ml three-necked bottle of the thermometer.190g of dichloromethane,1ml of 98percent d concentrated sulfuric acid,Stir the solution; Step 2The water bath is heated to 40 ° C.57.9 g of bromine was added dropwise with stirring.Control the speed of joining,After the first drop of the reaction is completely faded,Add another drop and control the reaction temperature at about 40 °C; Step 3.After the addition,Insulation reaction for 30 min,Distillation under reduced pressure, collecting fractions at 100-120 ° C,To give ethyl bromopyruvate; Step 4,In a 250 ml three-necked flask equipped with a reflux condenser, 90.5 g of ethyl bromopyruvate was added.46.7 g of thiourea,500g of ethanol and 2.0g of Cu2OHKUST-1 nanocatalyst are heated to reflux.Insulation reaction for 3h,After the reaction, the mixture was cooled to room temperature, and concentrated to dryness under reduced pressure to give a crude material. Step 5,Dissolve the remaining solids in 900 ml of ice water.Adjust pH=8 with K2C03,The resulting solid is collected by filtration,Washed in pure water 3 times,The pharmaceutical intermediate 2-aminothiazole-4-carboxylic acid ethyl ester.
92%
at 20℃; for 0.0833333 h;
2-Amino-thiazole-4-carboxylic acid ethyl ester was prepared by a modification to the procedure of Kumar, R.; Rai, D. et al., Heterocyclic Communications 2002, 8, 521-530. Thiourea (18.45 g, 240 mmol) was suspended in absolute ethanol (192 mL) and to this was added ethyl bromopyruvate (52 g, 240 mmol) over 5 minutes. The solution was stirred at room temperature overnight and then concentrated in vacuo and taken into water (400 mL) and 6 N aqueous hydrochloric acid (44 mL). The aqueous mixture was washed with ethyl acetate (2.x.) and back extracted with water (50 mL). The combined aqueous solution was adjusted to pH=10 with sodium hydroxide and extracted with 10percent dichloromethane in tetrahydrofuran (3.x.200 mL). The combined organic extracts were dried over sodium sulfate, concentrated and dried in vacuum. The pale yellow solid was taken into dichloromethane (25 mL) and to the slurry was added hexanes (300 mL). The mixture was vigorously stirred for 15 minutes then filtered on a 9 cm funnel and dried in vacuum to give 2-amino-thiazole-4-carboxylic acid ethyl ester as an off white solid (38 g, 92percent).
90%
at 90℃; for 4 h;
Thiourea (12.93 g, 0.170 mol) was taken in a round bottom flask and charged ethanol (45 mL), stirred for 10 min, slowly added ethyl bromopyruvate (19.36 mL, 0.155 mol). The reaction mass was heated to 90 °C for 4 h. Reaction completion was monitored by TLC. Reaction was complete. The reaction mass was filtered and the ethanol layer was concentrated under reduced pressure to give a pale yellow solid. The crude product was recrystallized in ethylacetate/hexane to afford (1) (23.58 g, 90percent) an off white solid. M.p. = 177-178 °C; 1H NMR (DMSO) δ ppm = 1.26 (t, 3H, CH3), 4.21 (m, 2H, CH2), 7.23 (s, 2H, NH2), 7.46 (s, 1H, ArH); 1H NMR (DMSO-D2O) δ ppm = 1.26 (t, 3H, CH3), 4.21 (m, 2H, CH2), 7.46 (s, 1H, ArH); LC/MS(ESI-MS)m/z = 173.1 (M + 1); Anal. Calcd for C6H8N2O2S; C, 41.85; H, 4.68; N, 16.27; Found C, 41.94; H, 4.69; N, 16.50.
88%
With sodium carbonate In neat (no solvent)Milling
General procedure: General procedure for the preparation of ethyl 2-methylthiazole-4-carboxylate (12a) An oily mixture of ethyl α-bromopyruvate (9, 2.14 g, 11 mmol) and thioacetamide (10a, 0.75 g, 10 mmol) was ground in presence of Na2CO3 (0.50 g) for 5-6 min. When it becomes solid, the progress of reaction was monitored with TLC. On completion of the reaction, water (20 ml) was added to the reaction followed by extraction with chloroform (20 ml). The organic layer thus separated was dried over anhy. Na2SO4. Excess of solvent was removed by distillation. Filtered the crude product and crystallized from aqueous ethanol (83percent) to give pure solid 12a. Similarly, 12b-12g and 13a-13g were prepared following the above procedure and their formation was confirmed by comparing their melting points with literature values.
85%
Reflux
A stirred solution of ethyl bromopyruvate (0.97 g, 0.62 ml, 8.54 mmol) in ethanol was reactedwith thiourea (0.5 g, 6.57 mmol) and the reaction mixture was refluxed overnight. After completion the final solution wasconcentrated under reducedpressure and the resultant residue was extracted with ethyl acetate, washed with brine, and dried over sodium sulphate. The crude mass was purified by flash column chromatography over silica gel with 4percent methanol-DCM eluent to obtain compound A as pale yellow solid (0.88 g, 85percent).1H NMR (DMSO-d6): ö 7.45 (s, 1H, ArH), 7.21 (brs, 2H, NH), 4.19 (q, 2H, JAB = 7.0 Hz, CH2), 1.25 (t, 3H, JAB= 7.5 Hz, CH3).
84%
for 18 h; Reflux
Preparation of ethyl 2-aminothiazole-4-carboxylate hydrochloride salt (3) A suspension of ethyl bromopyruvate (90percent, 33 mL, 0.26 mol, 1 equiv), thiourea (30 g, 0.39 mol, 1.5 equiv) and absolute EtOH (500 mL) was heated to reflux. The resulting solution was refluxed for 18 h, concentrated under reduced pressure, and purified by recrystallization from EtOH/MeOH to afford the title compound as a white solid (56.0 g, 84percent yield). 1H and 13C NMR of the product matched those previously reported (Kelly and Lang 1996).
83%
at 120℃; for 0.5 h; Inert atmosphere; Reflux
3-Bromo taken pyruvate (6.0g, 31mmol), added thiourea (2.3g, 31mmol, 1.0eq), at 120 ° C under nitrogen the reaction was refluxed for 0.5h, the reaction was complete by thin layer chromatography to monitor . 2--4-(4.4g, 83.0percent )0 The reaction mixture was dissolved in ethyl acetate, washed with distilled water, the organic layer was washed with saturated brine; the organic layer was dried over anhydrous sodium sulfate, and filtration, the solvent was distilled off under reduced pressure to give a yellow 2-aminothiazol-4-carboxylate (4.4g, 83.0percent)
74%
at 20℃;
7.8 g (40 mmol) ethyl bromopyruvate and 3.1 g (40 mmol) thiourea were dissolved in 40 ml ethanol, and reacted at room temperature, to precipitate a white solid, which was filtered, washed and dried to obtain 7.5 g ethyl 2-aminothiazol-4-carboxylate (yield 74percent) with mp 177-181°C.
74%
at 20℃;
7.8 g (40 mmol) ethyl bromopyruvate and 3.1 g (40 mmol) thiourea were dissolved in 40 ml ethanol, and reacted at room temperature, to precipitate a white solid, which was filtered, washed and dried to obtain 7.5 g ethyl 2-aminothiazol-4-carboxylate (yield 74percent) with mp 177-181° C.
63%
Stage #1: for 12 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In water for 0.5 h;
Example 11:; WHO EtO2C EtO2C I Et02C C02Et Thiourea N Boc20 OMe Br NH2 g NHBoc n_guLi I /SNHBoc OMe OH Etc Et3SiH/TFA \\ I SNH2TFA OMe; 2-Amino-thiazole-4-carboxylic acid ethyl ester; A mixture of ethyl bromopyruvate (100 g, 80 percent purity, 0.41 mol), thiourea (31 g, 0.41 mol) and ethanol (500 mL) was heated to reflux for 12 hours. The solvent was evaporated to dryness and the residue was washed with ether. The solid was suspended in a saturated aqueous solution of sodium bicarbonate (500 mL) for 30 minutes. The solid was filtered, washed with water, and dried over sodium sulfate to give 2-amino-thiazole-4-carboxylic acid ethyl ester (45 g, 0.26 mol, 63 percent) as an off-white solid
2.25 g
Reflux
After 100 ml round bottom flask, and 30 ml of ethanol was added 1.26 g of thiourea, 16.6 mmol, heated to reflux with stirring until thiourea dissolved, 3.22 g, 16.6 mmol bromopyruvate ethyl IX, after refluxing overnight, the ethanol was removed under reduced pressure and concentrated to give a yellow solid which was washed with saturated sodium carbonate solution was obtained after filtration 2.25 g 2-aminothiazol-4-carboxylic acid ethyl ester X, in a yield of 78.9 percent
Reference：
[1] Arkivoc, 2018, vol. 2018, # 7, p. 110 - 118
[2] Patent: CN104016944, 2016, B, . Location in patent: Paragraph 0014-0015; 0040-0041
[3] Organic and Biomolecular Chemistry, 2012, vol. 10, # 30, p. 5764 - 5768
[4] Letters in Drug Design and Discovery, 2018, vol. 16, # 2, p. 160 - 173
[5] Patent: WO2007/146066, 2007, A2, . Location in patent: Page/Page column 151-152
[6] Patent: CN108218809, 2018, A, . Location in patent: Paragraph 0010; 0012-0030; 0031
[7] Journal of Organic Chemistry, 2018, vol. 83, # 3, p. 1095 - 1105
[8] Patent: US2006/63814, 2006, A1, . Location in patent: Page/Page column 27-28
[9] European Journal of Medicinal Chemistry, 2012, vol. 49, p. 172 - 182
[10] Journal of Medicinal Chemistry, 2002, vol. 45, # 2, p. 533 - 536
[11] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 718 - 726
[12] Patent: WO2017/17631, 2017, A2, . Location in patent: Paragraph 00345
[13] Heterocycles, 1997, vol. 45, # 7, p. 1299 - 1308
[14] Patent: WO2015/57585, 2015, A1, . Location in patent: Page/Page column 27
[15] Synthetic Communications, 2013, vol. 43, # 21, p. 2876 - 2882
[16] Patent: CN104003984, 2016, B, . Location in patent: Paragraph 0012; 0016-0017; 0038-0040
[17] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 5742 - 5750
[18] Patent: EP2039686, 2009, A1, . Location in patent: Page/Page column 23
[19] Patent: US2010/87448, 2010, A1, . Location in patent: Page/Page column 15
[20] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 7, p. 809 - 813
[21] Patent: WO2005/75435, 2005, A1, . Location in patent: Page/Page column 141-142
[22] Journal of Heterocyclic Chemistry, 1989, vol. 26, # 6, p. 1643 - 1647
[23] Justus Liebigs Annalen der Chemie, 1891, vol. 261, p. 26
[24] Tetrahedron Letters, 1995, vol. 36, # 30, p. 5319 - 5322
[25] Journal of Organic Chemistry, 1996, vol. 61, # 14, p. 4623 - 4633
[26] Synlett, 1999, # 8, p. 1239 - 1240
[27] Patent: WO2004/2977, 2004, A1, . Location in patent: Page 22
[28] Patent: US2004/157845, 2004, A1, . Location in patent: Page 16
[29] Medicinal Chemistry Research, 2015, vol. 24, # 8, p. 3194 - 3211
[30] Patent: WO2016/100157, 2016, A2, . Location in patent: Page/Page column 66
[31] Patent: CN102942565, 2016, B, . Location in patent: Paragraph 0032-0035; 0089-0090
[32] Patent: US2008/139558, 2008, A1, . Location in patent: Page/Page column 56
11
[ 70-23-5 ]
[ 5398-36-7 ]
Reference：
[1] Patent: US5498630, 1996, A,
12
[ 70-23-5 ]
[ 41731-52-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 30, p. 5764 - 5768
A solution of benzothioamide (3.00 g, 21.87 mmol) in EtOH (70 mL) was treated dropwise with ethyl bromopyruvate (5.10 g, 26.2 mmol) and stirred at room temperature for 30 min before being heated at reflux for 1.5 h. The cooled mixture was diluted with ethyl acetate (200 mL), washed (aqueous NaHC03, brine), dried over anhydrous MgSO4 and evaporated. The residue was purified on the ISCO using a REDISEP® 80 g column (10 to 20percent EtOAc-hexane) to give the title compound (4.82 g, 94percent) as a yellow oil. LCMS (APCI): calcd for C12H12NO2S [M+H]+ m/z 234.05, found 234.1. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.14 - 8.19 (m, 1H), 7.98 - 8.07 (m, 2H), 7.41 - 7.51 (m, 3H), 4.46 (q, J= 7.2 Hz, 2H), 1.44 (t, J= 7.2 Hz, 3H)
85%
With sodium carbonate In neat (no solvent)Milling
General procedure: General procedure for the preparation of ethyl 2-methylthiazole-4-carboxylate (12a) An oily mixture of ethyl α-bromopyruvate (9, 2.14 g, 11 mmol) and thioacetamide (10a, 0.75 g, 10 mmol) was ground in presence of Na2CO3 (0.50 g) for 5-6 min. When it becomes solid, the progress of reaction was monitored with TLC. On completion of the reaction, water (20 ml) was added to the reaction followed by extraction with chloroform (20 ml). The organic layer thus separated was dried over anhy. Na2SO4. Excess of solvent was removed by distillation. Filtered the crude product and crystallized from aqueous ethanol (83percent) to give pure solid 12a. Similarly, 12b-12g and 13a-13g were prepared following the above procedure and their formation was confirmed by comparing their melting points with literature values.
76%
for 4 h; Reflux
A solution of ethyl bromopyruvate (0.68g, 3.5 mmol) and thiobenzamide(0.40 g, 2.9 mmol) in ethanol (25 mL) was heated to reflux for 4 h. The solvent was removed under reduced pressure, and the residue was washed with water (30ml) and extracted with ethyl acetate (3 × 20 mL). The organic layer was driedover anhydrous Na2SO4 and concentrated. The residue waspurified by silica gel column chromatography using a mixture of petroleum ether/ethyl acetate (20:1, v/v) as eluent to afford the desired product (0.52g, 76percent) as a white solid.1H NMR (300 MHz, DMSO-d6) δ:8.96 (s, 1H, ArH), 7.89 (d, J=8.01Hz, 2H, ArH), 7.31 (m, 3H, ArH), 4.39 (q, J=7.12 Hz, 2H, -OCH2), 1.34 (t, J=7.12 Hz, 3H,-CH3).
70%
for 2 h; Reflux
General procedure: A solution of 2-hydroxy-thiobenzamide 4 (300 mg, 1.96 mmol) and ethyl 3-bromopyruvate (458 mg, 2.35 mmol) in ethanol (15 mL) was heated under reflux for 2h. The reaction progress was monitored by TLC analysis. The solvent was removed in vacuo, and the residue was washed with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (EtOAc:hexane=1:4) to give compound 1 as a colorless needle shaped solid (350 mg, 1.40 mmol) in 71percent yield. Mp 109–111°C (CH2Cl2–hexane); IR (KBr, cm−1) 3140, 2978, 1720, 1474, 1211; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.60 (dd, J=7.8, 8.8Hz, 1H), 7.35 (m, 1H), 7.08 (dd, J=8.4, 8.4Hz, 1H), 6.92 (m, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 160.9, 157.4, 146.5, 132.9, 127.7, 125.4, 119.9, 118.5, 116.7, 62.0, 14.7; Anal. Calcd for C12H11NO3S: C, 57.82; H, 4.45; N, 5.62; S, 12.86, found: C, 57.78; H, 4.36; N, 5.66; S, 13.12. HR-mass Calcd for: C12H11NO3S [M+H]+: 249.0460; found: m/z 249.0457.
69%
at 78℃; for 5 h;
At room temperature,4.1 g (30 mmol) of Intermediate C1 was added to the reaction flask, 40 mL of ethanol was added, stirred to dissolve, 6.44 g (33 mmol) of ethyl bromopyruvate was added slowly, and the temperature was raised to 78 ° C for 5 h. Reaction completed, vacuum distillation solvent, Then, 50 mL of water was added, extracted with dichloromethane (3 x 40 mL), and the combined organic layers were washed successively with saturated sodium bicarbonate (3 x 30 mL), washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 4.8 g of a yellow oil, yield69.0percent.
Reference：
[1] Patent: WO2013/163279, 2013, A1, . Location in patent: Paragraph 00226
[2] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 718 - 726
[3] European Journal of Medicinal Chemistry, 2016, vol. 113, p. 246 - 257
[4] Medicinal Chemistry Research, 2013, vol. 22, # 8, p. 3802 - 3811
[5] Tetrahedron, 2013, vol. 69, # 30, p. 6095 - 6099
[6] Patent: CN107033095, 2017, A, . Location in patent: Paragraph 0133; 0134
[7] Journal of Medicinal Chemistry, 1983, vol. 26, # 6, p. 884 - 891
[8] Helvetica Chimica Acta, 1944, vol. 27, p. 1432,1433
[9] Journal of the Chemical Society. Perkin transactions 1, 1966, vol. 16, p. 1357 - 1360
[10] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 4, p. 437 - 440
[11] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1545 - 1555
[12] European Journal of Medicinal Chemistry, 2017, vol. 137, p. 96 - 107
[13] Medicinal Chemistry Research, 2017, vol. 26, # 10, p. 2557 - 2567
[14] Research on Chemical Intermediates, 2018, vol. 44, # 2, p. 1247 - 1260
17
[ 70-23-5 ]
[ 2227-79-4 ]
[ 59937-01-8 ]
[ 31877-30-2 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 4, p. 1137 - 1146
18
[ 28170-13-0 ]
[ 70-23-5 ]
[ 59937-01-8 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 5, p. 1449 - 1456
19
[ 70-23-5 ]
[ 529-23-7 ]
[ 62235-59-0 ]
Reference：
[1] Tetrahedron, 2004, vol. 60, # 13, p. 2937 - 2942
[2] Journal of Natural Products, 2015, vol. 78, # 10, p. 2398 - 2404
20
[ 504-29-0 ]
[ 70-23-5 ]
[ 38922-77-9 ]
Yield
Reaction Conditions
Operation in experiment
84%
for 4 h; Reflux
Step 1: Preparation of ethyl imidazo[1,2-a]pyridine-2-carboxylate 3 g (31.9 mmol) of 2-aminopyridine were dissolved in 65 ml of tetrahydrofurane with magnetic stirring. The addition of 4.44 ml (31.9 mmol) of ethyl bromopyruvate caused precipitation of a solid. The heterogenous mixture was stirred with reflux for 4 h. After returning to r.t., the solid was isolated by filtration and taken up in 65 ml of ethanol in order to be stirred with reflux in 65 ml of ethanol for 16 h. After returning to r.t., the solid was isolated by filtration. The filtrate was placed in ice in order to facilitate crystallization of the product which was collected by filtration and thus so forth until the liquid phase remained limpid. The solid was rinsed with 30 ml of diisopropyl ether and dried in a vacuum bell jar in order to obtain 5.14 g (yield=84percent) of ethyl imidazo[1,2-a]pyridine-2-carboxylate as a white powder. LC-MS: m/z=191 (MH+); UV purity at 254 nm=99percent. 1H NMR (300 MHz, DMSO) δ 8.95 (s, 1H), 8.84 (d, J=6.8 Hz, 1H), 7.98-7.80 (m, 2H), 7.46 (t, J=7.2 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 1.35 (d, J=7.1 Hz, 3H).
74.3%
for 1 h; Reflux
A solution of 2-amino pyridine (4, 1 mmol) and ethyl bromopyruvate (5, 1.2 mmol) in ethanol (15 mL) was stirred under reflux for 1 h, and concentrated in vacuo to remove the solvent. The residue was partitioned between dichloromethane (15 mL) and saturated aqueous solution of sodium carbonate (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on neutral alumina to afford imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester as a light brown solid (6) in good yield.
60%
for 16 h; Reflux
a. Ethyl imidazo[1,2-a]pyridine-2-carboxylate A solution of 2-aminopyridine (5.0 g, 53.2 mmol) in THF (150 mL) was treated with ethyl bromopyruvate (10.32 g, 57.0 mmol) at room temperature followed by heating the mixture at reflux for 16 h. The resulting white precipitate was collected by filtration and washed with THF (10 mL). Recrystallization of the solids from boiling EtOH (20 mL) gave ethyl imidazo[1,2-a]pyridine-2-carboxylate (6.10 g, 60percent yield). ESI MS: m/z 191 [M+1]+. See, e.g., J. Med. Chem., 2003, 46, 3914-29.
20%
at 20 - 100℃; for 3 h;
Step 1 Synthesis of Imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester A solution of 2-aminopyridine (500 mg, 5.3 mmol) and 2-bromopyruvic acid ethyl ester (824 mg, 4.2 mmol) in DMF (5 ml) was stirred at 100° C. for 2 hours then at room temperature for 1 hr. The reaction mixture was then quenched with cold water and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (using 60-120 silica gel and 50percent ethyl acetate in hexane as eluent) to afford 135 mg (20percent) of imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester.
1.83 g
Stage #1: at 20℃; for 3 h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Step 1. To 2-aminopyridine (12.03 g, 127.8 mmol) in dimethoxyethane (100 mL) was added ethyl 3-bromo-2-oxopropanoate ethyl bromopyruvate (17.9 mL, 128.0 mmol). The mixture was stirred at room temperature for 3 hours. The resulting precipitate was collected on a filter, washed with diethyl ether and dried under vacuum. The residue (33.75 g) was suspended in ethanol (100 mL) and heated for 2 hours at reflux, then cooled to room temperature and the solvent removed on a rotovap to provide ethyl indolizine-2-carboxylate (34.74 g, 100percent) as an HBr salt. A portion of the salt (3.02 g) was taken up in DCM (50 mL) and neutralized to about pH 7 with a saturated aqueous solution of NaHCC>3 (100 mL). The product was then extracted with DCM (3 X 20 mL) and the combined organics were dried over Na2S04, then concentrated and chromatographed on silica (1 to 5 percent MeOH:DCM as eluent) to provide ethyl indolizine-2-carboxylate as a light brown crystalline solid (1.83 g, 86percent).
Reference：
[1] ACS Combinatorial Science, 2018, vol. 20, # 3, p. 164 - 171
[2] Patent: US2015/182507, 2015, A1, . Location in patent: Paragraph 0204; 0205
[3] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 3, p. 359 - 362
[4] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 216 - 231
[5] ChemMedChem, 2017, vol. 12, # 3, p. 257 - 270
[6] Journal of Medicinal Chemistry, 2003, vol. 46, # 18, p. 3914 - 3929
[7] Patent: US2012/178748, 2012, A1, . Location in patent: Page/Page column 49
[8] Journal of Organic Chemistry, 2010, vol. 75, # 9, p. 2776 - 2784
[9] Organic Letters, 2015, vol. 17, # 24, p. 6002 - 6005
[10] Patent: US2010/160323, 2010, A1, . Location in patent: Page/Page column 31
[11] Journal of Heterocyclic Chemistry, 1988, vol. 25, # 1, p. 129 - 137
[12] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 5, p. 1170 - 1176
[13] Journal of Medicinal Chemistry, 1996, vol. 39, # 14, p. 2856 - 2859
[14] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 11, p. 2790 - 2794
[15] Journal of Organic Chemistry, 2008, vol. 73, # 15, p. 5989 - 5992
[16] Patent: EP1813613, 2007, A1, . Location in patent: Page/Page column 92
[17] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 1870 - 1873
[18] Organic Letters, 2012, vol. 14, # 7, p. 1688 - 1691
[19] Patent: WO2015/42397, 2015, A1, . Location in patent: Paragraph 000820
[20] Patent: WO2015/76800, 2015, A1, . Location in patent: Page/Page column 278
[21] Patent: US9284350, 2016, B2,
[22] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 7, p. 1572 - 1575
21
[ 96-50-4 ]
[ 70-23-5 ]
[ 64951-04-8 ]
Yield
Reaction Conditions
Operation in experiment
38.27%
at 20℃; for 8 h;
To a solution of 2-aminothiazole (0.500 g, 5 mmol)In tetrahydrofuran was added ethyl bromopyruvate (90percent, 1.625 g, 7.5 mmol) dropwise,After 8h reaction at room temperature, the resulting precipitate was filtered,The filter cake was washed with tetrahydrofuran.The filter cake was then dissolved in hot ethanol and at 80 under reflux 8h,After cooling, the solvent was distilled off,The residual solid was washed with cold water and filtered,After vacuum drying, the intermediate body weight was 0.375 g,Yield 38.27percent
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 18, p. 3914 - 3929
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 6, p. 2764 - 2778
[3] Patent: CN105985356, 2016, A, . Location in patent: Paragraph 0117; 0118
[4] Farmaco, Edizione Scientifica, 1977, vol. 32, # 10, p. 735 - 746
[5] Patent: US2010/249071, 2010, A1, . Location in patent: Page/Page column 45
22
[ 96-50-4 ]
[ 70-23-5 ]
[ 64951-04-8 ]
[ 244258-92-2 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1999, # 7, p. 1750 - 1760
23
[ 109-12-6 ]
[ 70-23-5 ]
[ 64951-07-1 ]
[ 64951-06-0 ]
Yield
Reaction Conditions
Operation in experiment
30%
at 75℃; for 16 h;
2-Aminopyrimidine (5 g, 52.6 mmol) and bromoethyl pyruvate (90percent, 7.35 mL, 52.6 mmol) were dissolved in ethanol (80 mL) and the reaction was heated to 75 °C for 16 h. The reaction was concentrated under reduced pressure and diluted with CH2Cl2 and sat aq NaHCO3. The organic layer was washed with sat aq NaHCO3 (2x) and the aq layers were extracted with CH2Cl2 (3x). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting brown oil was suspended in cold CH2Cl2 and filtered. The filter cake was washed with cold CH2Cl2 to obtain ethyl imidazo[1,2-a]pyrimidine-2-carboxylate (3 g, 30percent) as a light yellow oil. The mother liquor contains a mixture of ethyl imidazo[1,2-a]pyrimidine-2- carboxylate and ethyl imidazo[1,2-a]pyrimidine-3-carboxylate (6 g, 60percent) in the form of thick, black oil. This black oil was first purified by silica gel chromatography followed by recrystallization from EtOAc to obtain ethyl imidazo[1,2-a]pyrimidine-3- carboxylate (2 g, 20percent).[00236] For 2-isomer: 1H NMR (500 MHz, CDCl3) δ 8.69 (dd, J= 2.2, 6.6 Hz, 1H), 8.67 (dd, J= 2.2, 4.4 Hz, 1H), 8.22 (s, 1H), 7.01 (dd, J= 3.9, 6.6 Hz, 1H), 4.46 (q, J= 7.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H). [00237] 13C NMR (500 MHz, CDCl3) δ 162.8, 152.2, 147.8, 137.7, 134.4, 115.3, 110.0, 61.2, 14.2.[00238] HPLC-MS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100percent B over 4 minutes, 1 minutes hold time, A = 90percent water, 10percent methanol, 0.1percent TFA, B = 10percent water, 90percent methanol, 0.1percent TFA, RT = 0.99 min, 95percent homogeneity index. [00239] LCMS: Anal. Calcd. for C9H9N3O2 191.07 found: 192.13 (M+H)+.[00240] For 3-isomer: HPLC Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100percent B over 4 minutes, 1 minutes hold time, A = 90percent water, 10percent methanol, 0.1percent TFA, B = 10percent water, 90percent methanol, 0.1percent TFA, RT = 1.39 min, 100percent homogeneity index. [00241] LCMS: Anal. Calcd. for C9H9N3O2 191.07 found: 192.19 (M+H)+.
Reference：
[1] Patent: WO2006/71752, 2006, A1, . Location in patent: Page/Page column 83
[2] European Journal of Medicinal Chemistry, 1994, vol. 29, # 4, p. 279 - 286
[3] European Journal of Medicinal Chemistry, 1991, vol. 26, # 1, p. 13 - 18
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5620 - 5628
[5] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00266
24
[ 109-12-6 ]
[ 70-23-5 ]
[ 64951-07-1 ]
[ 64951-06-0 ]
Yield
Reaction Conditions
Operation in experiment
30%
at 75℃; for 16 h;
2-Aminopyrimidine (5 g, 52.6 mmol) and bromoethyl pyruvate (90percent, 7.35 mL, 52.6 mmol) were dissolved in ethanol (80 mL) and the reaction was heated to 75 °C for 16 h. The reaction was concentrated under reduced pressure and diluted with CH2Cl2 and sat aq NaHCO3. The organic layer was washed with sat aq NaHCO3 (2x) and the aq layers were extracted with CH2Cl2 (3x). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting brown oil was suspended in cold CH2Cl2 and filtered. The filter cake was washed with cold CH2Cl2 to obtain ethyl imidazo[1,2-a]pyrimidine-2-carboxylate (3 g, 30percent) as a light yellow oil. The mother liquor contains a mixture of ethyl imidazo[1,2-a]pyrimidine-2- carboxylate and ethyl imidazo[1,2-a]pyrimidine-3-carboxylate (6 g, 60percent) in the form of thick, black oil. This black oil was first purified by silica gel chromatography followed by recrystallization from EtOAc to obtain ethyl imidazo[1,2-a]pyrimidine-3- carboxylate (2 g, 20percent).[00236] For 2-isomer: 1H NMR (500 MHz, CDCl3) δ 8.69 (dd, J= 2.2, 6.6 Hz, 1H), 8.67 (dd, J= 2.2, 4.4 Hz, 1H), 8.22 (s, 1H), 7.01 (dd, J= 3.9, 6.6 Hz, 1H), 4.46 (q, J= 7.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H). [00237] 13C NMR (500 MHz, CDCl3) δ 162.8, 152.2, 147.8, 137.7, 134.4, 115.3, 110.0, 61.2, 14.2.[00238] HPLC-MS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100percent B over 4 minutes, 1 minutes hold time, A = 90percent water, 10percent methanol, 0.1percent TFA, B = 10percent water, 90percent methanol, 0.1percent TFA, RT = 0.99 min, 95percent homogeneity index. [00239] LCMS: Anal. Calcd. for C9H9N3O2 191.07 found: 192.13 (M+H)+.[00240] For 3-isomer: HPLC Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100percent B over 4 minutes, 1 minutes hold time, A = 90percent water, 10percent methanol, 0.1percent TFA, B = 10percent water, 90percent methanol, 0.1percent TFA, RT = 1.39 min, 100percent homogeneity index. [00241] LCMS: Anal. Calcd. for C9H9N3O2 191.07 found: 192.19 (M+H)+.
Reference：
[1] Patent: WO2006/71752, 2006, A1, . Location in patent: Page/Page column 83
[2] European Journal of Medicinal Chemistry, 1994, vol. 29, # 4, p. 279 - 286
[3] European Journal of Medicinal Chemistry, 1991, vol. 26, # 1, p. 13 - 18
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5620 - 5628
[5] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00266
25
[ 109-12-6 ]
[ 70-23-5 ]
[ 64951-06-0 ]
Reference：
[1] ACS Combinatorial Science, 2018, vol. 20, # 3, p. 164 - 171
[2] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 5, p. 1170 - 1176
26
[ 695-34-1 ]
[ 70-23-5 ]
[ 70705-33-8 ]
Reference：
[1] Research on Chemical Intermediates, 2012, vol. 38, # 9, p. 2457 - 2470
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 11, p. 2790 - 2794
[3] Patent: WO2011/38086, 2011, A2, . Location in patent: Page/Page column 107
[4] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 3, p. 359 - 362
27
[ 1603-40-3 ]
[ 70-23-5 ]
[ 67625-40-5 ]
Reference：
[1] Farmaco, Edizione Scientifica, 1983, vol. 38, # 12, p. 911 - 928
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 11, p. 2790 - 2794
28
[ 5469-69-2 ]
[ 70-23-5 ]
[ 64067-99-8 ]
Yield
Reaction Conditions
Operation in experiment
51%
at 0 - 80℃; for 2.75 h;
To slurry of 6-chloropyridazin-3 -amine (10.00 g, 77 mmol) in ethanol (30 mL) at 0 °C was added ethyl 3-bromo-2-oxopropanoate (20.07 g, 93 mmol) in ethanol (5 mL) via pipette. After complete addition, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 15 min., then heated at 80 °C for 30 min. to give a clear solution. After heating for 2 h, the mixture was cooled to room temperature and the resulting precipitated solid was collected and rinsed with cold ethanol to afford beige solid. The solid was suspended in aqueous saturated NaHCC and was stirred for 30 min. before collecting the solid by vacuum filtration. The filter cake was rinsed with water, dried on filter, and further dried under vacuum to afford a tan solid as ethyl 6- chloroimidazo[l ,2-b]pyridazine-2-carboxylate (8.8 g, 39.0 mmol, 51percent yield). NMR (400MHz, chloroform-d3): δ 8.46 (s, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.23 (d, J=9.5 Hz, 1H), 4.49 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H). LC retention time 2.29 min (analytical HPLC Method A). LC/MS (M+H): 226/228 (-3: 1).
46%
for 18 h; Reflux
To a solution of 3-amino-6-chloropyridazine (1, 31 g, 240 mmol) in EtOH (1 L) was added ethylbromopyruvate (39.2 mL, 312 mmol) dropwise. The reaction mixture was refluxed for 18 hours.Upon completion, the reaction mixture was evaporated to dryness. The residue was dissolved inEtOAc (800 mL) and H2O (800 mL) was added. The organic layer was washed with H2O (4 ×800 mL), and the combined organic extracts were dried over MgSO4, filtered and evaporated todryness. H2O (400 mL) was added and stirred at RT for at least 15 min and the solid formed was filtered, washed with H2O to give ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (2) as a beige solid (25 g, 46percent).
39%
Reflux
3-amino-6-chloropyridazine (20 g; 154.4 mmol) and ethyl bromopyruvate (38.9 mL; 308.8 mmol) in EtOH (90 mL) were refluxed overnight. The reaction mixture was cooled to room temperature, water and DCM were added. The organic layer was separated, dried over MgS04, filtered and evaporated. The residue was purified by chromatography over silica gel (Irregular SiOH, 15-40 μιη, 300 g, gradient from 97percent heptane 30percent EtOAc to 50percent Heptane 50percent EtOAc). The fractions containing the product were collected and evaporated to dryness to afford 13.5 g (39percent) of intermediate 102.
39%
Reflux
3-amino-6-chloropyridazine (20 g; 154.4 mmol) and ethyl bromopyruvate (38.9 mL; 308.8 mmol) in EtOH (90 mL) were refluxed overnight. The reaction mixture was cooled to room temperature, water and DCM were added. The organic layer was separated, dried over MgSOzi, filtered and evaporated. The residue was purified by chromatography over silica gel (Irregular SiOH, 15-40 μιη, 300 g, gradient from 97percent heptane 30percent EtOAc to 50percent Heptane 50percent EtOAc). The fractions containing the product were collected and evaporated to dryness to afford 13.5 g (39percent) of intermediate 66.
8.2 g
Reflux
3-amino-6-chloro pyridazine (10 g, 77.2 mmol) was dissolved in absoluteethanol (120 mL), and then slowly added ethyl bromopyruvate (11.70 mL, 92.6mmol) was added thereto, the addition was complete the reaction It was heatedat reflux overnight. After completion of the reaction by TLC, the reactionsolution was cooled to room temperature, most of the solvent was removed underreduced pressure, the residue was dissolved in saturated sodium bicarbonatesolution, and extracted with dichloromethane (50 mLx3), the organic phase waswashed with water, saturated brine, dried over anhydrous dried over sodiumsulfate, filtered, and concentrated under reduced pressure, the residue waspurified by silica gel column chromatography to give Intermediate 6-Chloro -imidazo [l, 2-b] pyridazine-2-carboxylate (pale yellow solid, 8.2 g).
Reference：
[1] Patent: WO2016/149437, 2016, A1, . Location in patent: Page/Page column 58
[2] Journal of Pharmacology and Experimental Therapeutics, 2018, vol. 364, # 2, p. 246 - 257
[3] Patent: WO2016/97347, 2016, A1, . Location in patent: Page/Page column 149
[4] Patent: WO2016/97359, 2016, A1, . Location in patent: Page/Page column 125
[5] Farmaco, 1997, vol. 52, # 4, p. 213 - 217
[6] Patent: CN103420977, 2016, B, . Location in patent: Paragraph 0251-0254
29
[ 4214-76-0 ]
[ 70-23-5 ]
[ 38923-08-9 ]
Yield
Reaction Conditions
Operation in experiment
90%
for 16 h; Reflux
5-Nitropyridine-2-amine (1.5 g, 10.80 mmol) and ethyl 3-bromo-2-oxopropanoate (1.6 mL, 13.00 mmol) were dissolved in EtOH (15.0 mL), followed by refluxing for 16 hours. After completing the reaction, the reaction mixture was filtered to obtain a pale yellow solid. The filtrate was extracted with EtOAc, washed with sat. NaHC03 aqueous solution and brine, dried over anhydrous Na2S04, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 2 : 1) to obtain ethyl 6-nitroimidazo[l,2-a]pyridine-2-carboxylate (2.3 g, 90percent) as a yellow solid. LC/MS ESI (+): 236 (M+l) -NMR (300MHz, CDC13): δ 9.30 (s, 1H), 8.38 (s, 1H), 8.06 (d, 1H, J=10.0Hz), 7.84 (d, 1H, J=10.4Hz), 4.50 (q, 2H, J=7.2Hz), 1.46 (t, 3H, J=7.2Hz)
89%
at 85℃; for 22.75 h; Inert atmosphere
5-Nitropyridin-2-amine (19, 50 g, 359 mmol) was suspended in ethanol (700 ml, 99+percent)and bubbled through with argon. Next, 1.1 equivalents of ethyl bromopyruvate (18, 79 ml,503 mmol) were added and stirred for 45 mm. Then, the reaction mixture was warmed at 85°C for 6 hr, another 0.3 equivalents ethyl bromopyruvate (79 ml, 503 mmol) were added andwarmed to 85 °Cfor 16 hr.Afterwards, the reaction mixture was concentrated, water (300 ml) was added and theresulting suspension was filtered. The solid residue was washed with Et20 (600 ml) and dried to yield ethyl 6-nitroimidazo[1,2-a]pyridine-2-carboxylate (20) (75 g, 319 mmol, 89 percent yield) as a sand coloured solid. UPLC-MS confirmed that the desired product was obtained.
34%
for 18 h; Heating / reflux
A solution of 5-nitropyridin-2-amine (2.0 g, 14.38 mmol) and ethyl bromopyruvate (3.36 g, 17.25 mmol) in ethanol (EtOH) (20 mL) was stirred under reflux for 18 h. The reaction mixture was cooled to room temperature. The precipitated solids were collected by filtration and then suspended in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 solution, dried (Na2SO4) and concentrated under reduced pressure to afford ethyl 6-nitroimidazo[l,2-a]pyridine-2-carboxylate as a brown solid (1.137 g, yield: 34percent ). 1H NMR (400 MHz, CDCl3) δ: 9.320 (IH, s), 8.402 (IH, s), 8.065 (IH, dd, J= 10.0 Hz), 7.905 (IH, d, J= 10.0 Hz), 4.479-4.533 (2H, q, J= 7.2 Hz), 1.469 (3H, t, J= 7.2 Hz).
Reference：
[1] Organic Letters, 2004, vol. 6, # 19, p. 3401 - 3404
[2] Journal of Organic Chemistry, 2005, vol. 70, # 22, p. 8991 - 9001
[3] Chemical Communications, 2004, # 1, p. 102 - 103
[4] Advanced Synthesis and Catalysis, 2014, vol. 356, # 16, p. 3370 - 3376
[5] Tetrahedron Letters, 2016, vol. 57, # 8, p. 920 - 923
[6] Patent: WO2009/147188, 2009, A1,
35
[ 14214-10-9 ]
[ 1113-59-3 ]
[ 70-23-5 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1958, vol. 23, p. 467,472
36
[ 617-35-6 ]
[ 70-23-5 ]
Yield
Reaction Conditions
Operation in experiment
158.1 g
With carbon dioxide; bromine In water at 20℃; for 2 h;
Take 116.12g of ethyl pyruvate and 159.81g of bromine water (80percent by mass), and then dry and carbon dioxide at 20 ° C, stir and react for 2 hours.The reaction product was extracted with dichloromethane.Concentrated and dried at atmospheric pressure,158.1 g of compound 1 were obtained
Reference：
[1] Justus Liebigs Annalen der Chemie, 1949, vol. 564, p. 35
[2] Journal of the Chemical Society, 1947, p. 670
[3] Journal of the American Chemical Society, 1944, vol. 66, p. 1658
[4] Journal of the Chemical Society, 1947, p. 1372,1374
[5] Recueil des Travaux Chimiques des Pays-Bas, 1941, vol. 60, p. 495,500[6] Recueil des Travaux Chimiques des Pays-Bas, 1943, vol. 62, p. 158,160 Anm. 6
[7] Justus Liebigs Annalen der Chemie, 1891, vol. 261, p. 26
[8] Helvetica Chimica Acta, 1942, vol. 25, p. 1075
[9] Journal of Organic Chemistry, 1957, vol. 22, p. 1678
[10] Journal of the Chemical Society, 1923, vol. 123, p. 2208
[11] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 5, p. 1170 - 1176
[12] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 16, p. 4589 - 4593
[13] Organic Letters, 2012, vol. 14, # 24, p. 6354 - 6357
[14] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 718 - 726
[15] Patent: CN107286064, 2017, A, . Location in patent: Paragraph 0041; 0042
[16] Patent: CN108218809, 2018, A, . Location in patent: Paragraph 0010
[17] Patent: CN108329313, 2018, A, . Location in patent: Paragraph 0029; 0040-0042
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 5796
39
[ 97-64-3 ]
[ 70-23-5 ]
Reference：
[1] Journal of Organic Chemistry, 1957, vol. 22, p. 1678
40
[ 14214-10-9 ]
[ 1113-59-3 ]
[ 70-23-5 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1958, vol. 23, p. 467,472
41
[ 56-23-5 ]
[ 128-08-5 ]
[ 97-64-3 ]
[ 617-35-6 ]
[ 70-23-5 ]
Reference：
[1] Journal of Organic Chemistry, 1957, vol. 22, p. 1678
[2] Journal of the American Chemical Society, 1954, vol. 76, p. 5796
42
[ 70-23-5 ]
[ 57-13-6 ]
[ 177760-52-0 ]
Yield
Reaction Conditions
Operation in experiment
85%
Heating / reflux
A stirred solution of ethyl bromopyruvate (50.2 g, 257.2 mmol) in EtOH was treated with urea (23.2 g, 385.8 mmol) refluxed overnight and concentrated under reduced pressure. The resultant residue was dissolved in EtOAC and water. The layers were separated and the aqueous layer washed with EtOAC. The combined organic layers were washed successively with saturated sodium chloride, dried over Mg2SO4 and concentrated under reduced pressure to give the title product in 85percent yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 157.1 (MH+).
85%
Reflux
A stirred solution of ethyl bromopyruvate (2.44 g, 1.32 ml , 2.54 mmol) in ethanol was treated with urea (1 g, 6.5 mmol) and for refluxed overnight. After completion the resultant reaction mixture was concentrated under vacuum resultantresidue and extracted with ethyl acetate, washed with water, brine and finally dried over sodium sulphate. After concentration of the organic layer under reduced pressure, the crude mass was purified by flash column chromatography over silica gel with 4percent methanol-DCM eluent to obtain A as pale yellow solid (0.34 g, 85percent).1H NMR (DMSO): ö 8.07 (s, 1H, ArH), 6.92 (brs, 2H, NH), 4.19 (q, 2H, JAB = 7.0 Hz, CH2), 1.24 (t, 3H, JAB= 7.0 Hz, CH3).
71%
for 24 h; Reflux
Ethyl pyruvate (14.0 mL, 111 mmol) and urea (10.00 g, 167 mmol) were dissolved in ethanol (60 mL). The solution was heated at reflux for 24 h, then the reaction was concentrated in vacuo. Water (40 mL) was added and it was neutralised to pH 7 by the slow addition of HCl (1 M). The aqueous layer was then extracted with CH2Cl2 (3 * 30 mL). The organic layers were combined, washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. The off yellow powder was recrystallised from chloroform affording the product as bright yellow crystals (9.50 g, 55percent). mp = 140-144 °C; νmax = 1266, 1422, 1665, 1726, 2306, 2987, 3055, 3594 cm-1; 1H NMR (300 MHz, CD3OD) δ 7.88 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CD3OD) δ 165.9, 165.6, 141.4, 135.6, 64.6, 17.5 ppm. All the spectroscopic data were in agreement with those reported [ 60 ].
44%
for 2 h; Heating / reflux
Urea (2.91 g, 48.5 mmol) was added to a solution of ethyl bromopyruvate (10 g, 46 mmol) in EtOH (90 mL), and the reaction mixture was heated to reflux for 2 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting thick oil was dissolved in ice water (100 mL) and brought to pH ~8 with solid K2CO3. The resulting solid was filtered, washed with water (2 x) and air dried. This gave 3.16 g (44percent) of a white solid that was used without further purification. LC-MS: RT = 4.47 min, [M+H]+ = 157.0.
2.87 g
Reflux
A mixture of ethyl bromopyruvate (5.00 g), urea (2.31 g) and ethanol (51 mL) was refluxed overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.87 g). 1H NMR (400 MHz, CDCl3) δ 1.36 (3H, t, J = 7.2 Hz), 4.33 (2H, q, J = 7.2 Hz), 5.30 (2H, brs), 7.72 (1H, s)
Reference：
[1] Patent: US2009/23707, 2009, A1, . Location in patent: Page/Page column 33-34
[2] Patent: WO2017/17631, 2017, A2, . Location in patent: Paragraph 00382
[3] European Journal of Medicinal Chemistry, 2019, p. 80 - 108
[4] Patent: WO2007/146066, 2007, A2, . Location in patent: Page/Page column 156-157
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 9, p. 3814 - 3830
[6] Organic and Biomolecular Chemistry, 2012, vol. 10, # 30, p. 5764 - 5768
[7] Journal of medicinal chemistry, 1971, vol. 14, # 11, p. 1075 - 1077
[8] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 10, p. 1379 - 1382
[9] Organic Letters, 2002, vol. 4, # 17, p. 2905 - 2907
[10] Patent: WO2008/57336, 2008, A2, . Location in patent: Page/Page column 43
[11] Patent: US2010/16609, 2010, A1, . Location in patent: Page/Page column 9-10
[12] Journal of the American Chemical Society, 2010, vol. 132, # 30, p. 10286 - 10292
[13] Patent: US2011/166124, 2011, A1, . Location in patent: Page/Page column 40
[14] Patent: EP2818473, 2014, A1, . Location in patent: Paragraph 0601
43
[ 70-23-5 ]
[ 134044-63-6 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1991, vol. 26, # 1, p. 13 - 18
44
[ 5049-61-6 ]
[ 70-23-5 ]
[ 77112-52-8 ]
Yield
Reaction Conditions
Operation in experiment
27%
Stage #1: at 20℃; for 2.5 h; Stage #2: for 2 h; Reflux
[0077] Method A- oxylate [0078] To a stirred solution of 2-aminopyrazine (1.0 g, 10.5 mmol) in dimethoxyethane, ethyl bromopyruvate (2.36 g, 13.0 mmol) was added at room temperature and stirred for 2.5 hours. The reaction mixture was cooled to 0°C and stirred for 30 min to afford a pale brown precipitate. The precipitate was filtered and washed with ethyl acetate to give a pale brown solid. The precipitate was suspended in 50 mL ethyl alcohol and heated at reflux temperature to turn to a clear solution. After refluxing for 2 hours, the reaction mixture was concentrated under reduced pressure and then mixed with CH2CI2 and saturated aqueous NaHCC>3 solution. The mixture was filtered through a pad of Celite, and the separated organic layer was dried by Na2S04 and filtered. The residue was applied to silica gel column chromatography, and the column was eluted with (CH2Cl2:MeOH = 99:1 to 97:3), and the collected fractions were concentrated under reduced pressure. The title compound was obtained as pale yellow crystals (0.546 g, 27percent). *H NMR (400 MHz, CDC13) δ 9.21 (s, 1H), 8.26 (s, 1H), 8.09 (dd, 7 = 4.7, 1.6 Hz, 1H), 7.96 (d, 7 = 4.7 Hz, 1H), 4.49 (q, 7 = 7.1 Hz, 2H), 1.45 (t, 7 = 7.1 Hz, 3H).
22%
Stage #2: for 2 h; Heating / reflux
Step 1: Imidazo [1, 2-a] pyrazine-2-carboxylic acid ethyl ester:; Ethyl bromopyruvate (62.9 g) was added to the DME (258 mL) solution of 2- aminopyrazine (24.8 g) at room temperature and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and stirred for 30 min to afford a pale brown precipitate. The precipitate was filtered and washed with Et20 to give pale brown crystals. The suspension of the precipitate (66.1 g) in EtOH (1.29 L) was heated at reflux temperature to turn to clear solution. After refluxing for 2h, the reaction mixture was concentrated under reduced pressure, then mixed with CHCI3 and saturated NaHCO3aq. The mixture was filtered through a pad of Celite and the separated organic layer was dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCis-MeOH (99/1-97/3), and collected fractions were concentrated under reduced pressure followed by recrystallization from CHCI3- Et20. The titled compound was obtained as pale pink crystals. Yield : 10.9 g, 22percent). 'H NMR (CDCI3) 8 d 1.46 (t, 3H, J = 7.2 Hz), 4.49 (q, 2H, J = 7.2 Hz), 7.96 (d, 1H, J=4. 7Hz), 8.08 (dd, 1 H, J = 1. 2,4. 7 Hz), 8.26 (s, 1 H), 9.21 (d, 1 H, J = 1. 2 Hz).
22%
at 0 - 20℃; for 3 h;
Example 9; Preparation of (5R), (6Z)-6- (7-Methyl-5. 6, 7, 8-tetrahydroimidazor1, 2-alpyrazin-2- vlmethylene)-7-oxo-4-thia-1-aza-bicyclor3. 2. Olhept-2-ene-2-carboxylic acid, sodium salt Step 1 : Imidazo [1, 2-a] pyrazine-2-carboxylic acid ethyl ester: Ethyl bromopyruvate (62.9 g) was added to the DME (258 mL) solution of 2- aminopyrazine (24.8 g) at room temperature and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and stirred for 30 min to afford a pale brown precipitate. The precipitate was filtered and washed with Et20 to give pale brown crystals. The suspension of the precipitate (66.1 g) in EtOH (1.29 L) was heated at reflux temperature to turn to clear solution. After refluxing for 2h, the reaction mixture was concentrated under reduced pressure, then mixed with CHCI3 and saturated NaHCO3aq. The mixture was filtered through a pad of Celite and the separated organic layer was dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCI3- MeOH (99/1-97/3), and collected fractions were concentrated under reduced pressure followed by recrystallization from CHC13-Et20. The titled compound was obtained as pale pink crystals. Yield : 10.9 g, 22percent). 'H NMR (CDCI3) d 1.46 (t, 3H, J = 7.2 Hz), 4.49 (q, 2H, J = 7.2 Hz), 7.96 (d, 1 H, J = 4.7 Hz), 8.08 (dd, 1H, J= 1.2, 4.7 Hz), 8.26 (s, 1H), 9.21 (d, 1 H, J = 1.2 Hz).
22%
Stage #1: at 20℃; for 2.5 h; Stage #2: at 0℃; for 2.5 h; Heating / reflux
Ethyl bromopyruvate (62.9 g) was added to the DME (258 mL) solution of 2-aminopyrazine (24.8 g) at room temperature and stirred for 2.5 h. The reaction mixture was cooled to 0° C. and stirred for 30 min to afford a pale brown precipitate. The precipitate was filtered and washed with Et2O to give pale brown crystals. The suspension of the precipitate (66.1 g) in EtOH (1.29 L) was heated at reflux temperature to turn to clear solution. After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure, then mixed with CHCl3 and saturated NaHCO3aq. The mixture was filtered through a pad of Celite and the separated organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-MeOH (99/1~97/3), and collected fractions were concentrated under reduced pressure followed by recrystallization from CHCl3-Et2O. The titled compound was obtained as pale pink crystals. Yield: 10.9 g, 22percent). 1H NMR(CDCl3)δ d 1.46(t, 3H, J=7.2 Hz), 4.49(q, 2H, J=7.2 Hz), 7.96(d, 1H, J=4.7 Hz), 8.08(dd, 1H, J=1.2, 4.7 Hz), 8.26(s, 1H), 9.21 (d, 1H, J=1.2 Hz).
20%
Stage #1: at 0 - 25℃; for 4.5 h; Stage #2: for 4 h; Heating / reflux
To a solution of 2-amino pyrazine (20 g, 210 mmol) in dimethoxy ethane (400 ml) was added ethyl bromopyruvate (32.8 ml) at 25° C. and the resulting reaction mixture was allowed to stir at the same temperature for 4 hrs. It was then cooled to 0° C. and stirred for 30 minutes. The separated solid was filtered and washed with ether. Solid residue was taken in ethanol (1000 ml) and refluxed for 4 hrs. Solvent was removed completely, residue taken in chloroform (1000 ml), saturated sodium bicarbonate solution (700 ml) was added to it and the mixture was allowed to stir for 45 minutes. The mixture was filtered through celite bed, washed several times with chloroform and filtrate was dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude mass, which was purified by crystallization using ether-methanol mixture.Yield: 20percent
20%
Stage #1: at 0 - 25℃; for 4.5 h; Stage #2: for 4 h; Heating / reflux
To a solution of 2-amino pyrazine (20 g, 210 mmol) in dimethoxy ethane (400 ml) was added ethyl bromopyruvate (32.8 ml) at 25° C. and the resulting reaction mixture was allowed to stir at the same temperature for 4 hrs. It was then cooled to 0° C. and stirred for 30 minutes. The separated solid was filtered and washed with ether. Solid residue was taken in ethanol (1000 ml) and refluxed for 4 hrs. Solvent was removed completely, residue taken in chloroform (1000 ml), saturated sodium bicarbonate solution (700 ml) was added to it and the mixture was allowed to stir for 45 minutes. The mixture was filtered through celite bed, washed several times with chloroform and filtrate was dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude mass, which was purified by crystallization using ether-methanol mixture. Yield: 20percent
20%
Stage #1: at 0 - 25℃; for 4.5 h; Stage #2: for 4 h; Reflux Stage #3: With sodium hydrogencarbonate In chloroform; water for 0.75 h;
To a solution of 2-amino pyrazine (2Og, 210 mmol) in dimethoxy ethane (400 ml) was added ethyl bromopyruvate (32.8 ml) at 25°C and the resulting reaction mixture was allowed to stir at the same temperature for 4 hrs . It was then cooled to O0C and stirred for 30 minutes. The separated solid was filtered and washed with ether. Solid residue was taken in ethanol (1000ml) and refluxed for 4hrs. Solvent was removed completely, residue taken in chloroform (1000ml), saturated sodium bicarbonate solution (700 ml) was added to it and the mixture was allowed to stir for 45 minutes . The mixture was filtered through celite bed, washed several times with chloroform and filtrate was dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude mass, which was purified by crystallization using ether-methanol mixture. Yield : 20percent
20%
at 20℃; for 5 h;
Synthesis of 206-A. A mixture of ethyl 3-bromo-2-oxopropanoate (10.8 g, 55.3 mmol) and pyrazin-2-amine (5.0 g, 52.6 mmol) in DME (150 mL) was stirred at room temperature for 5 h. The precipitate was collected by filtered. Then the cake was dissolved in EtOH (100 mL) and stirred at 80 oC for 2 h. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 2 : 1~ 1 : 2) to give 206-A (2.0 g, 20percent) as a yellow solid.
450 mg
Stage #1: at 20 - 35℃; for 2 h; Stage #2: With ethanol In 1,2-dimethoxyethane for 2 h; Reflux
Ethyl bromopyruvate (2.15 g, 11.04 mmol) was added to stirred solution of 2-aminopyrazine (1 g, 10.5 mmol) in 1,2-Dimethoxy ethane (10 mL). The reaction mixture was stirred at 20-35° C. for 2 h. The mixture was then filtered to obtain a solid precipitate which was dried well, dissolved in EtOH (10 mL) and refluxed for 2 h. This mixture was concentrated, diluted with aqueous saturated sodium bicarbonate solution, extracted with chloroform.-The chloroform layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (using 60-120 silica gel and 60percent EtOAc in Hexane as eluent) to afford 450 mg of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 9.22 (1H, s), 8.28 (1H, s), 8.12-8.08 (1H, m), 8 (1H, d, J=4.8 Hz), 4.52-4.47 (2H, m), 1.5 (3H, t).
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3687 - 3706
[2] Farmaco, Edizione Scientifica, 1981, vol. 36, # 1, p. 61 - 80
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 10, p. 2300 - 2304
[4] Patent: WO2014/113191, 2014, A1, . Location in patent: Paragraph 0077; 0078
[5] European Journal of Medicinal Chemistry, 1983, vol. 18, # 5, p. 413 - 417
[6] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4623 - 4637
[7] Patent: WO2003/93279, 2003, A1, . Location in patent: Page/Page column 50
[8] Patent: WO2003/93277, 2003, A1, . Location in patent: Page/Page column 68-69
[9] Patent: US2006/276445, 2006, A1, . Location in patent: Page/Page column 12
[10] Patent: US2009/186899, 2009, A1, . Location in patent: Page/Page column 45-46
[11] Patent: US2009/186899, 2009, A1, . Location in patent: Page/Page column 46-47
[12] Patent: WO2009/90055, 2009, A1, . Location in patent: Page/Page column 134
[13] Patent: WO2017/7756, 2017, A1, . Location in patent: Paragraph 496
[14] Journal of Chemical Research, Miniprint, 1984, # 2, p. 468 - 480
[15] Patent: US2004/132708, 2004, A1,
[16] Patent: WO2013/134226, 2013, A1, . Location in patent: Page/Page column 96
[17] Patent: US2015/5280, 2015, A1, . Location in patent: Paragraph 0771 - 0773
[18] Patent: WO2004/58266, 2004, A1, . Location in patent: Page/Page column 57
[19] Patent: WO2005/110410, 2005, A2, . Location in patent: Page/Page column 322
45
[ 70-23-5 ]
[ 89226-13-1 ]
[ 96929-05-4 ]
Yield
Reaction Conditions
Operation in experiment
89.6%
Stage #1: at 20 - 25℃; for 5 h; Stage #2: With sodium hydroxide In water; isopropyl alcohol
Method A:; [00082] At 20-25° C., 24.6 mmol of ethyl bromopyruvate were added to 5.0 g (24.2 mmol) of thioamide in 47 ml of isopropanol, and the mixture was stirred for 5 h. 24.0 mmol of NaOH as a 20percent strength aqueous solution of sodium hydroxide were then added, the product was extracted with methyl tert-butyl ether, the organic phase was washed with water and saturated sodium chloride solution and dried over sodium sulfate and the solvent was completely stripped off. This gave 6.2 g of the ethyl thiazole carboxylate, corresponding to a yield of 89.6percent. [00083] 1H-NMR (DMSO-d6, in ppm): 8.41 (s, 1H, Ar-H), 7.86 (t, broad, NH), 4.41 (d, 2H, CH2), 4.30 (q, 2H, CH2), 1.40 (s, 9H, tert-butyl), 1.30 (t, 3H, CH3).
85%
With calcium carbonate In ethanol for 12 h;
Compound 24 (10.53g, 55 . 4mmol) dissolved in anhydrous ethanol (100 ml), added calcium carbonate (11.08g, 111mmol), instillment bromo pyruvic acid ethyl ester (10.4 ml, 83mmol), reaction 12h through the diatomite filter, decompression turns on lathe ethanol, the residue is dissolved in ethyl acetate (300 ml) is dissolved, the organic phase is washed with saturated sodium bicarbonate solution, dried anhydrous sodium sulfate, after concentrating the residue by silica gel column chromatography, the obtained crude product with petroleum ether and ethyl acetate is recrystallized to get white solid compound 25 (13.47g, 85percent).
81.7%
Stage #1: With potassium hydrogencarbonate In ethanol at 20 - 25℃; Stage #2: With sodium hydroxide In ethanol; water
Method B:; [00085] At 20-25° C., 1.07 mol of ethyl bromopyruvate were added to 200 g (1.05 mol) of thioamide in 2.0 l of ethanol and 105 g of KHCO3 powder, and the mixture was stirred overnight. 225 ml of water and 50 g of 20percent strength aqueous sodium hydroxide solution were then added, about 600 ml of ethanol were distilled off, 500 ml of water were added and the mixture was cooled to 0° C. The precipitated solid was filtered off and dried. This gave 246 g of ethyl thiazole carboxylate which, according to NMR, was pure. This corresponds to a yield of 81.7percent.
67%
Stage #1: at 20℃; for 5 h; Stage #2: for 16 h; Heating / reflux Stage #3: With di-<i>tert</i>-butyl dicarbonate; triethylamine In ethanol; dichloromethane at 20℃; for 5 h;
To compound 387 (6.00 g, 31.5 mmol) dissolved in CH2CI2 (150 mL) was added ethyl bromopyruvate (6.76 g, 4.4 mL, 34.7 mmol). Stirred at room temperature for 5 h then concentrated. Added 3 A sieves (6 g) and EtOH (150 mL) and refluxed for 16 h. Filtered and concentrated to give a dark foam. Dissolved foam in 1:1 CH2CI2:EtOH (100 mL) and added triethylamine (6.40 g, 8.8 mL, 63.1 mmol) and tBOC anhydride (7.60 g, 34.7 mmol). Stirred at room temperature for 5 h then concentrated. Added 0.25 N NaOH (100 mL), extracted with CH2CI2, dried combined organic extracts (MgS04), filtered, and concentrated. Purified by silica gel chromatography (eluant: 10percent EtOAc- CH2Cl2 to 30percent EtOAc-CH2Cl2) to give 6.00 g (67percent) of the product 388 as a brown oil. MS m/e: 287 (M+H). For n=2: MS m/e: 301 (M+H)
65%
With pyridine In ethanol for 24 h; Inert atmosphere; Reflux
Ethyl bromopyruvate (1.75 mL, 14.0 mmol) and pyridine (1.69 mL, 21.0 mmol) were added to a solution of 8 (1.33 g, 7.0 mmol) in dry EtOH (60 mL) under N2 atmosphere. The reaction mixture was refluxed 24 hs. The volatile components were removed in vacuo. The resulting residue was dissolved in EtOAc (40 mL), washed with water (30 mL) and brine (30 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo. Purification by column chromatography afforded 5 (1.31g, 65percent) as a brown solid. Rf = 0.5 (hexane/ EtOAc, 1:1); 1H NMR (400MHz, CDCl3) δ 1.39 (t, 3H, J = 7,1 Hz), 1.46 (s, 9H), 4.14 (q, 2H, J = 7.1 Hz), 4.64 (d, 2H, J = 6.3 Hz), 5.31 (bs, 1H), 8.11 (s, 1H5). 13C NMR (100MHz, CDCl3) δ 14.3, 28.3 (3C), 42.4, 61.5, 80.5, 127.9, 146.9, 155.6, 161.3, 170.0.
Reference：
[1] Tetrahedron, 1988, vol. 44, # 18, p. 5833 - 5844
[2] Synlett, 2008, # 15, p. 2379 - 2383
[3] Patent: US6642388, 2003, B1, . Location in patent: Page/Page column 9
[4] Tetrahedron, 2018, vol. 74, # 5, p. 549 - 555
[5] Patent: CN103601742, 2016, B, . Location in patent: Paragraph 0124-0126
[6] Patent: US6642388, 2003, B1, . Location in patent: Page/Page column 9
[7] Tetrahedron, 1986, vol. 42, # 10, p. 2695 - 2702
[8] Journal of Organic Chemistry, 1985, vol. 50, # 15, p. 2787 - 2788
[9] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 16, p. 3475 - 3485
[10] Journal of the American Chemical Society, 2016, vol. 138, # 16, p. 5426 - 5432
[11] Patent: WO2017/132459, 2017, A1, . Location in patent: Page/Page column 105-106
[12] Organic Process Research and Development, 2018, vol. 22, # 2, p. 190 - 199
[13] Journal of Asian Natural Products Research, 2010, vol. 12, # 11, p. 940 - 949
[14] Patent: WO2005/121130, 2005, A2, . Location in patent: Page/Page column 392
[15] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 4994 - 4997
[16] Organic Letters, 2011, vol. 13, # 4, p. 680 - 683
[17] Journal of the American Chemical Society, 2002, vol. 124, # 38, p. 11272 - 11273
[18] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 834 - 864
[19] Bulletin of the Chemical Society of Japan, 1996, vol. 69, # 8, p. 2309 - 2316
[20] Patent: US6642388, 2003, B1, . Location in patent: Page/Page column 8
[21] Patent: US6344562, 2002, B1, . Location in patent: Page column 53
[22] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 1, p. 132 - 136
[23] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 4, p. 401 - 406
46
[ 4530-20-5 ]
[ 70-23-5 ]
[ 543-27-1 ]
[ 96929-05-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 19, p. 7672 - 7680
Step A: Preparation of ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10 C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over a2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 percent) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm.
50.6%
at 110℃; for 3 h;
Step A: Preparation of ethyl 6,8-dibromoimidazo[ 1 , 2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3, 5-dibrompyrazine (20 g, 79mmol) in dimethyicarbonate (1 33 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10° C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 percent) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDC ): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm.
50.6%
at 20 - 110℃; for 3 h;
Intermediate Example 1 -2: Preparation of (6,8-dibromoimidazo[1 ,2-a]pyrazin-2- yl)methanolStep A: Preparation of ethyl 6,8-dibromoimidazo[1 , 2-a]pyrazi'ne-2-carboxylateTo a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10° C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over a2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 percent) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCI3): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm.
50.6%
at 110℃;
Step A: Preparation of ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3,5-di brom pyrazi ne (20 g, 79m mol ) i n dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10° C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 3/4) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm.
50.6%
at 20 - 110℃;
To a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79 mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 110° C. for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(SO4) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6percent) ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz,
50.6%
at 110℃; for 3 h;
To a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79 mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 110° C. for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(SO4) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6percent) ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3: δ=8.30 (s, 1H), 8.27 (s, 1H), 4.48 (q, 2H), 1.43 (tr, 3H) ppm.
A solution of 2,2,2-trifluoroacetamide (14.24 g, 1 eq.) and Lawesson's reagent (30.6 g, 0.6 eq.) in THF (120 mL) was stirred at reflux for 18 hrs. The mixture was cooled, ethyl bromopyruvate (16 mL, 1 eq.) was added and the reaction refluxed for weekend. The reaction was cooled, evaporated in vacuum, and the resulting crude material extracted with dichloromethane and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to give an orange oil. The oil was purified by chromatography on a silica gel (petroleum ether/dichloromethane) to yield compound 251 in 40percent yield. 1H NMR- 161 -SDI-18153v2 (DMSO-J6, 400 MHz): δ (ppm) 1.32 (t, J= 7.10 Hz, 3H), 4.34 (q, J= 7.10 Hz, 2H), 8.9 (s,IH); 119T NMR (DMSO-J6, 376 MHz): δ (ppm) -60.29 (s, 3F); MS (ESI, EI+): m/z = 225.9(MH+).
32%
Stage #1: With Lawessons reagent In tetrahydrofuran for 18 h; Reflux Stage #2: for 18 h; Reflux
A mixture of 2,2,2-trifluoroacetamide (7.12g, 63 mmol) and Lawesson's reagent (15.3 g, 37.8 mmol) in THF (60 mL) was heated at reflux for 18 hours. The reaction was then cooled down to RT and treated with ethyl bromopyruvate (8.0 mL, 63 mmol). The reaction was stirred at reflux for an additional 18 hours, then concentrated under vacuum and diluted with ethyl acetate. This mixture was washed with water (IX) and brine (IX), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (8X1 1 cm, toluene, then second time with 120g silica gel, hexane/ethyl acetate) to give the title material (4.47g, 32percent) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 4.45 (q, J= 7.0 Hz, 2H), 1.41 (t, J= 7.0 Hz, 1H).
Stage #1: With Lawessons reagent In tetrahydrofuran for 18 h; Heating / reflux Stage #2: for 18 h; Heating / reflux
A solution of 2,2,2 -trifluoroacetamide (7.12 g, 63 mmol) and Lawesson's Reagent (15.3 g, 37.8 mmol) in THF (anhydrous, 60 ml) was stirred at reflux for 18 hrs. The reaction mixture was cooled then ethyl bromopyruvate (8 ml, 63 mmol) added, and refluxed for 18 hrs. The reaction was cooled, evaporated in vacuo, and the resulting crude material extracted into ethyl acetate and washed with water. The organic fraction was dried (MgSO^, and condensed to give a yellow/orange oil. The residue was purified by flash column chromatography on silica (eluent: 15percent ethyl acetate in hexane) to provide the title EPO <DP n="45"/>compound as a clear oil (3 g, 21 percent). 1H NMR δ (400MHz, CDCl3) δ 8.39 (1 H, s), 4.47 (2 H, q, J7.1), 1.42 (3 H, t, /7.2).
Stage #1: for 18 h; Heating / reflux Stage #2: for 18 h; Heating / reflux
A solution of 2,2, 2-trifluoroacetamide (7.12 g, 63 mmol) and Lawesson's Reagent (15.3 g, 37.8 mmol) in THF (anhydrous, 60 ml) was stirred at reflux for 18 h. The reaction mixture was cooled, then ethyl bromopyruvate (8 ml, 63 mmol) added, and refluxed for 18 h. The reaction was cooled, evaporated in vacuo, and the resulting crude material extracted into ethyl acetate and washed with water. The organic fraction was dried over MgSO4, and condensed to givea yellow/orange oil. The residue was purified by flash column chromatography on silica eluting with 15 percent ethyl acetate in hexane to provide the title compound as a clear oil (3 g, 21 percent). 1H NMR (400MHz,CDCI3)8 8.39(1H, s), 4.47 (2H, q, J7. 1), 1.42 (3H, t, J7.2).
General procedure: General procedure for the preparation of ethyl 2-methylthiazole-4-carboxylate (12a) An oily mixture of ethyl α-bromopyruvate (9, 2.14 g, 11 mmol) and thioacetamide (10a, 0.75 g, 10 mmol) was ground in presence of Na2CO3 (0.50 g) for 5-6 min. When it becomes solid, the progress of reaction was monitored with TLC. On completion of the reaction, water (20 ml) was added to the reaction followed by extraction with chloroform (20 ml). The organic layer thus separated was dried over anhy. Na2SO4. Excess of solvent was removed by distillation. Filtered the crude product and crystallized from aqueous ethanol (83percent) to give pure solid 12a. Similarly, 12b-12g and 13a-13g were prepared following the above procedure and their formation was confirmed by comparing their melting points with literature values.
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 5742 - 5750
[2] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 718 - 726
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 4979 - 4984
Stage #1: at 75℃; Stage #2: With hydrazine hydrate In ethanol at 75℃;
To a mixture of imidazo[l,2-a]pyrimidine-2-carboxylic acid ethyl ester and imidazo[l,2-a]pyrimidine-3-carboxylic acid ethyl ester (500 mg, 2.62 mmol, 1.0 eq) in EtOH ( 20 mL) was added hydrazine hydrate (180 mg, 2.88 mmol, 1.1 eq). The reaction mixture was heated at 75 °C overnight. The reaction mixture was concentrated and the resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 20/1, v/v) to give 2-amino-lH-imidazole-4-carboxylic acid ethyl ester (220 mg, 54percent) as a yellow solid.
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5620 - 5628
[2] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00267
65
[ 70-23-5 ]
[ 26197-93-3 ]
[ 885278-75-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: at 20℃; for 6 h; Stage #2: at 20℃; Stage #3: With sodium hydrogencarbonate In water; ethyl acetate
Step (i) of Reference Example 4: Ethyl 2-(4-bromophenyl)thiazole-4-carboxylate Ethyl 2-bromopyruvate (0.18 ml) was added to a solution of 529 mg (1.0 mmol) of 4-bromobenzothioamide in ethanol (3 ml), and the mixture was stirred at room temperature for 6 hr. The precipitated crystal was collected by filtration, was dried, and was then added dropwise to 5 ml of concentrated sulfuric acid. The mixture was stirred at room temperature for 3 hr. The solvent was removed by distillation, and the residue was diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous sodium bicarbonate solution and water, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the resultant crystal was collected by filtration and was dried to give 285 mg (yield 91percent) of the title compound. 1H-NMR (300 MHz, CDCl3) δ: 1.30 (3H, t, J = 7.5 Hz), 4.30 (1H, q, J = 7.5 Hz), 7.65 (2H, d, J = 7.8 Hz), 7.85 (2H, d, J = 7.8 Hz), 8.15 (1H, s) MS (FAB) m/z: 313 (M++1).
Reference：
[1] Patent: EP2166015, 2010, A1, . Location in patent: Page/Page column 25
[2] European Journal of Inorganic Chemistry, 2015, vol. 2015, # 29, p. 4935 - 4945
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1545 - 1555
[4] Medicinal Chemistry Research, 2016, vol. 25, # 10, p. 2399 - 2409
[5] Research on Chemical Intermediates, 2018, vol. 44, # 2, p. 1247 - 1260
66
[ 70-23-5 ]
[ 22179-72-2 ]
[ 132089-35-1 ]
Reference：
[1] European Journal of Inorganic Chemistry, 2015, vol. 2015, # 29, p. 4935 - 4945
[2] Medicinal Chemistry Research, 2016, vol. 25, # 10, p. 2399 - 2409
[3] Medicinal Chemistry Research, 2017, vol. 26, # 10, p. 2557 - 2567
[4] Research on Chemical Intermediates, 2018, vol. 44, # 2, p. 1247 - 1260
67
[ 5049-61-6 ]
[ 70-23-5 ]
[ 1286754-14-0 ]
Yield
Reaction Conditions
Operation in experiment
28.9%
at 0 - 30℃; for 4.5 h; Inert atmosphere
Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol). After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0 °C and stirred for 30 minutes until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with ether (10 mLx3). The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9percent) as a brown solid. MS m/z (ESI): 192.1 [M+1]
Into a 250-mL round-bottom flask was placed 2,4-dichlorobenzene-1- carbothioamide (4.0 g, 19 mmol, CAS 2775-38-4), ethyl 3-bromo-2-oxopropanoate (10.0 g, 51 mmol), ethanol (20 mL) and pyridine (4.8 g, 61 mmol). The resulting solution was stirred overnight at 80oC. On completion, the reaction mixture was cooled to rt and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:5). This resulted in 2.0 g (31percent yield) of ethyl 2-(2,4-dichlorophenyl)-1,3-thiazole-4- carboxylate as a yellow solid. LCMS: m/z = 302.0 [M+1]+, tR = 1.3 min.1H-NMR: (300 MHz, Chloroform-d) δ 8.32 (s, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.39 (dd, J = 8.6, 2.1 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H).
Reference：
[1] Patent: WO2018/106636, 2018, A1, . Location in patent: Paragraph 00288
[2] Chemical Biology and Drug Design, 2016, p. 26 - 37
69
[ 70-23-5 ]
[ 2775-38-4 ]
[ 1185155-89-8 ]
[ 1306101-93-8 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 4, p. 1137 - 1146
70
[ 70-23-5 ]
[ 2521-24-6 ]
[ 1185155-89-8 ]
Reference：
[1] Chemical Biology and Drug Design, 2016, p. 26 - 37
A stirred solution of ethyl bromopyruvate (50.2 g, 257.2 mmol) in EtOH was treated with urea (23.2 g, 385.8 mmol) refluxed overnight and concentrated under reduced pressure. The resultant residue was dissolved in EtOAC and water. The layers were separated and the aqueous layer washed with EtOAC. The combined organic layers were washed successively with saturated sodium chloride, dried over Mg2SO4 and concentrated under reduced pressure to give the title product in 85% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 157.1 (MH+).
85%
In ethanol;Reflux;
A stirred solution of ethyl bromopyruvate (2.44 g, 1.32 ml , 2.54 mmol) in ethanol was treated with urea (1 g, 6.5 mmol) and for refluxed overnight. After completion the resultant reaction mixture was concentrated under vacuum resultantresidue and extracted with ethyl acetate, washed with water, brine and finally dried over sodium sulphate. After concentration of the organic layer under reduced pressure, the crude mass was purified by flash column chromatography over silica gel with 4% methanol-DCM eluent to obtain A as pale yellow solid (0.34 g, 85%).1H NMR (DMSO): oe 8.07 (s, 1H, ArH), 6.92 (brs, 2H, NH), 4.19 (q, 2H, JAB = 7.0 Hz, CH2), 1.24 (t, 3H, JAB= 7.0 Hz, CH3).
71%
In ethanol; for 24h;Reflux;
Ethyl pyruvate (14.0 mL, 111 mmol) and urea (10.00 g, 167 mmol) were dissolved in ethanol (60 mL). The solution was heated at reflux for 24 h, then the reaction was concentrated in vacuo. Water (40 mL) was added and it was neutralised to pH 7 by the slow addition of HCl (1 M). The aqueous layer was then extracted with CH2Cl2 (3 * 30 mL). The organic layers were combined, washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. The off yellow powder was recrystallised from chloroform affording the product as bright yellow crystals (9.50 g, 55%). mp = 140-144 C; numax = 1266, 1422, 1665, 1726, 2306, 2987, 3055, 3594 cm-1; 1H NMR (300 MHz, CD3OD) delta 7.88 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CD3OD) delta 165.9, 165.6, 141.4, 135.6, 64.6, 17.5 ppm. All the spectroscopic data were in agreement with those reported [ 60 ].
44%
In ethanol; for 2h;Heating / reflux;
Urea (2.91 g, 48.5 mmol) was added to a solution of ethyl bromopyruvate (10 g, 46 mmol) in EtOH (90 mL), and the reaction mixture was heated to reflux for 2 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting thick oil was dissolved in ice water (100 mL) and brought to pH ~8 with solid K2CO3. The resulting solid was filtered, washed with water (2 x) and air dried. This gave 3.16 g (44%) of a white solid that was used without further purification. LC-MS: RT = 4.47 min, [M+H]+ = 157.0.
A mixture of ethyl bromopyruvate (59.7g, 306mmol) and urea (27.6, 460mmol) in ethanol (220ml) was heated at reflux for 24 hours. The mixture was cooled and evaporated. The residue was taken up in water and treated with IN NaOH until the pH > 9. The mixture was extracted with Et2O (4 x 100ml); the combined Et2O layers were dried over Na2SO4, filtered and evaporated. The residue was purified by MPLC on silica gel eluting with a gradient rising from20 100% hexanes to 90% EtOAc in hexanes. Product containing fractions were combined and evaporated and the residue triturated with EtOAc/hexanes filtered and dried to give the title compound. 1HNMR (500 MHz, DMSO-d6) delta: 8.04 (s, IH), 6.90 (br s, 2H), 4.18 (q, J = 7.1, 2H), 1.22 (t, J = 7.1 3H).
In ethanol;Reflux;
Example 3; Step 1: Preparation of ethyl 2-amino-1,3-oxazole-4-carboxylate; A stirred solution of ethyl bromopyruvate (50.2 g, 257.2 mmol) in EtOH is treated with urea (23.2 g, 385.8 mmol) refluxed overnight and concentrated under reduced pressure. The resultant residue is dissolved in EtOAC and water. The layers are separated and the aqueous layer washed with EtOAC. The combined organic layers are washed successively with saturated sodium chloride, dried over Mg2SO4 and concentrated under reduced pressure to give the title product.
In ethanol;Reflux;
Step 1 Following the procedure, described in J. Med. Chem. 1971, 14, 1075-1077, ethyl bromopyruvate 21a was condensed with urea in ethanol under reflux to provide ethyl-2-amino-4-oxazole carboxylate 21b.
2.87 g
In ethanol;Reflux;
A mixture of ethyl bromopyruvate (5.00 g), urea (2.31 g) and ethanol (51 mL) was refluxed overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.87 g). 1H NMR (400 MHz, CDCl3) delta 1.36 (3H, t, J = 7.2 Hz), 4.33 (2H, q, J = 7.2 Hz), 5.30 (2H, brs), 7.72 (1H, s)
Example 66 Ethyl 10,ll-dimethyl-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-l(8),3,5,9,ll- pentaene-4-carboxylate To a stirred solution of 5,6-dimethyl-l ,3-benzothiazol-2-amine (1.00 g, 5.61 mmol) in DME (13 mL) was added ethyl 3-bromo-2-oxopropanoate (1.93 g, 8.41 mmol) and the solution heated at 85C overnight. The reaction was poured onto ice/water (10 mL) and basified with N (aq). The resulting precipitate was collected by filtration and purified by FCC (eluent: 30% EtOAc in heptane), affording the title compound as a white solid (112 mg, 7% yield); 1H NMR (500 MHz, Chloroform-d) delta 1.45 (t, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 4.45 (q, 2H), 7.46 (s, IH), 7.48 (s, IH), 8.32 (s, IH).
With sodium carbonate; methyloxirane; In 1,2-dimethoxyethane; ethanol; chloroform;
EXAMPLE 25 ethyl 5-bromoimidazo-[1,2-a]-quinoline-2-carboxylate 1 g of <strong>[36825-32-8]2-amino-4-bromoquinoline</strong> was dissolved in 20 ml of dimethoxyethane and a mixture of 1.5 g of ethyl bromopyruvate and 0.5 g of propylene oxide was added thereto. The solution was allowed to stand at room temperature for 1 hour and the quaternary salt thus precipitated was filtered off, was washed with ether and then was dissolved in 20 ml of ethanol. The solution was refluxed for 1 hour, cooled and then was evaporated to dryness under vacuum. The residue was partitioned between 50 ml of chloroform and 50 ml of 2 N sodium carbonate and the organic extract was washed with 50 ml of water, was dried over MgSO4, and was reduced in volume under vacuum. Then, ether was added thereto to give cream needles of ethyl 5-bromoimidazo-[1,2-a]-quinoline-2-carboxylate melting at 205°-207° C. I.R. (KBr Disc): 3150 cm-1 (C--H1 stretch) 1727 cm-1 (Ester C=O) Analysis: C14 H11 BrN2 O2. Calculated: percentC 52.69; percentH 3.48; percentBr 25.04; percentN 8.78; Found: C 52.43; H 3.51; Br 24.81; N 8.66
With sodium hydrogencarbonate; In 1,4-dioxane; at 100℃; for 12h;
To a stirred solution of 6-chloropyridazin-3-amine(A49, 2.0 g, 15.43 mmol) in l,4-dioxane(40 mL) was added ethyl 3-bromo pyruvate(A15, 2.32 mL, 18.51 mmol), followed by NaHC03(1.94 g, 23.14 mmol). The reaction mixture was heated for 12 h at 100 C. After completion of reaction mixture concentrated under reduced pressure. The crude product was triturated with water and washed with n-pentane and dried to afford ethyl 6-chloroimidazo[l,2-b]pyridazine-2-carboxylate 3 as Off white solid Yield: 2.20 g,(64%).LC-MS m/z : 226.05[M+H]+.
57%
In N,N-dimethyl-formamide; at 50℃; for 1.5h;
In a 1L round-botom flask 6-chloropyridazin-3 -amine (30 g, 0.2316 mol) was dissolved in DMF (300 mL). Portionwise addition of ethyl 3-bromo-2-oxo-propanoate (38mL, 0.3 mol) followed. The mixture was maintained at 50 C for l.5h. The mixture was cooled to room temperature with a water/ice bath and water (600mL) was added dropwise over 2h into the reaction mixture. It was then stirred at room temperature overnight. The precipitate formed was filtered off by filtration on Buchner (~30 min). The precipitate was washed with 3 x 500 mL of water and dried under vacuum on the Buchner for 2hrs then 20hrs in vacuum oven at 40C to afford ethyl 6-chloroimidazo[2,l-b]pyridazine-2- carboxylate (29.9g, 57%) as a yellow solid. 1H NMR (401 MHz, DMSO) d 8.85 (s, 2H), 8.27 (d, J = 9.6 Hz, 3H), 7.47 (d, J - 9.6 Hz, 3H), 4.33 (q, J = 7.0 Hz, 6H), 1.32 (t, J = 7.1 Hz, 9H).
51%
In ethanol; at 0 - 80℃; for 2.75h;
To slurry of 6-chloropyridazin-3 -amine (10.00 g, 77 mmol) in ethanol (30 mL) at 0 C was added ethyl 3-bromo-2-oxopropanoate (20.07 g, 93 mmol) in ethanol (5 mL) via pipette. After complete addition, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 15 min., then heated at 80 C for 30 min. to give a clear solution. After heating for 2 h, the mixture was cooled to room temperature and the resulting precipitated solid was collected and rinsed with cold ethanol to afford beige solid. The solid was suspended in aqueous saturated NaHCC and was stirred for 30 min. before collecting the solid by vacuum filtration. The filter cake was rinsed with water, dried on filter, and further dried under vacuum to afford a tan solid as ethyl 6- chloroimidazo[l ,2-b]pyridazine-2-carboxylate (8.8 g, 39.0 mmol, 51% yield). NMR (400MHz, chloroform-d3): delta 8.46 (s, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.23 (d, J=9.5 Hz, 1H), 4.49 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H). LC retention time 2.29 min (analytical HPLC Method A). LC/MS (M+H): 226/228 (-3: 1).
46%
In ethanol; for 18h;Reflux;
To a solution of 3-amino-6-chloropyridazine (1, 31 g, 240 mmol) in EtOH (1 L) was added ethylbromopyruvate (39.2 mL, 312 mmol) dropwise. The reaction mixture was refluxed for 18 hours.Upon completion, the reaction mixture was evaporated to dryness. The residue was dissolved inEtOAc (800 mL) and H2O (800 mL) was added. The organic layer was washed with H2O (4 ×800 mL), and the combined organic extracts were dried over MgSO4, filtered and evaporated todryness. H2O (400 mL) was added and stirred at RT for at least 15 min and the solid formed was filtered, washed with H2O to give ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (2) as a beige solid (25 g, 46%).
39%
In ethanol;Reflux;
3-amino-6-chloropyridazine (20 g; 154.4 mmol) and ethyl bromopyruvate (38.9 mL; 308.8 mmol) in EtOH (90 mL) were refluxed overnight. The reaction mixture was cooled to room temperature, water and DCM were added. The organic layer was separated, dried over MgS04, filtered and evaporated. The residue was purified by chromatography over silica gel (Irregular SiOH, 15-40 muiotaeta, 300 g, gradient from 97% heptane 30% EtOAc to 50% Heptane 50% EtOAc). The fractions containing the product were collected and evaporated to dryness to afford 13.5 g (39%) of intermediate 102.
39%
In ethanol;Reflux;
3-amino-6-chloropyridazine (20 g; 154.4 mmol) and ethyl bromopyruvate (38.9 mL; 308.8 mmol) in EtOH (90 mL) were refluxed overnight. The reaction mixture was cooled to room temperature, water and DCM were added. The organic layer was separated, dried over MgSOzi, filtered and evaporated. The residue was purified by chromatography over silica gel (Irregular SiOH, 15-40 muiotaeta, 300 g, gradient from 97% heptane 30% EtOAc to 50% Heptane 50% EtOAc). The fractions containing the product were collected and evaporated to dryness to afford 13.5 g (39%) of intermediate 66.
8.2 g
In ethanol;Reflux;
3-amino-6-chloro pyridazine (10 g, 77.2 mmol) was dissolved in absoluteethanol (120 mL), and then slowly added ethyl bromopyruvate (11.70 mL, 92.6mmol) was added thereto, the addition was complete the reaction It was heatedat reflux overnight. After completion of the reaction by TLC, the reactionsolution was cooled to room temperature, most of the solvent was removed underreduced pressure, the residue was dissolved in saturated sodium bicarbonatesolution, and extracted with dichloromethane (50 mLx3), the organic phase waswashed with water, saturated brine, dried over anhydrous dried over sodiumsulfate, filtered, and concentrated under reduced pressure, the residue waspurified by silica gel column chromatography to give Intermediate 6-Chloro -imidazo [l, 2-b] pyridazine-2-carboxylate (pale yellow solid, 8.2 g).
To a stirred solution of 4-trifluoromethylthiobenzamide (205 g, 10 mmol) in acetone (10 mL) was added ethyl bromopyruvate (1.95 g, 10 mmol) in acetone (10 mL) dropwise. The mixture was stirred under reflux for 3 h. After cooling to room temperature, the solution was concentrated and purified by column chromatography to give 1.9 g (63%) of cpd Q1 as a white solid: 1H NMR (300 MHz, CDCl3) delta 8.23 (s, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 4.46 (q, J=7.1 Hz, 2H) 1.44(t, J=7.1 Hz, 3H); MS (ES) m/z: 302 (M+H+).
A solution of 4-bromo-2, 4-diaminopyridine (1) (1.09 g, 5. 80 mmol) and ethyl bromopyruvate (0.85 mL of 90% purity, 6.09 mmol) in ethanol (100 mL) was refluxed for 3 h. The ethanol was removed in vacuo and the residue was slurried with saturated aqueous sodium bicarbonate, then diethyl ether to provide the product (2) as a powder (1.24 g, 75%). APCI-MS Found: [M+H] +=286, 284.
In ethanol; for 5h;Reflux;
<strong>[329974-09-6]4-bromopyridine-2,6-diamine</strong> (3 g, 15.96 mmol) was dissolved in EtOH (300 mL). Ethyl bromopyruvate (2.34 mL, 16.8 mmol, 90% tech grade) was added. The mixture was heated at reflux for 5 h. The solvent was evaporated under reduced pressure to give a dark tan foam which was triturated with 200 mL of saturated NaHCO3 overnight. The solids were filtered, washed with 2×10 mL of saturated NaHCO3, then triturated with EtOAc (100 mL) twice, filtered and air dried to give the desired product as a tan powder weighing 3.15 g (70%).
3-[1-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-hydroxy-acrylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53.3%
In ethanol; water; acetonitrile;
35A. Formula Ia where A is N-(propionyl)glycine, X is S, and Z is -O-Ethyl A solution of <strong>[1953-02-2]<strong>[1953-02-2]N-(2-mercaptopropionyl)glycin</strong>e</strong> (1.17 g, 7.17 mmol) and ethyl bromopyruvate (1 mL, 7.17 mmol, 90% purity) in acetonitrile (30 mL) was stirred at room temperature for 3 h. After removal of the solvent, the residue was dissolved in a mixed solvent of ethanol (15 mL) and water (15 mL). After the pH was adjusted to 7-8 with satd. NaHCO3 solution, the mixture was stirred at room temperature overnight. The mixture was acidified to pH 1-2 with concentrated hydrochloric acid and then rotary evaporated to dryness. The residue was purified by column chromatography eluted with EtOAc giving 3-[1-(carboxymethylcarbamoyl)ethylsulfanyl]-2-hydroxyacrylic acid ethyl ester as yellow solid (1.06 g, yield 53.3%). 1H NMR (CDCl3, 300.16 MHz) delta (ppm): 9.10 (broad s, 1H), 7.22 (d, J=0.9 Hz, 1H), 4.62 (d, J=17.7 Hz, 1H), 4.53 (d, J=17.7 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 3.47 (qd, J=6.2 & 0.9 Hz, 1H), 1.48 (d, J=6.2 Hz, 3H) and 1.30 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3, 75.48 MHz) delta (ppm): 174.02, 165.84, 160.57, 130.27, 120.20, 62.04, 46.76, 37.11, 14.45 and 14.09. MS (ESI) m/z: 260 (M+-OH, 100).
53.3%
In ethanol; water; acetonitrile;
35A. Formula Ia where A is N-(Propionyl)glycine, X is S, and Z is -O-Ethyl A solution of <strong>[1953-02-2]<strong>[1953-02-2]N-(2-mercaptopropionyl)glycin</strong>e</strong> (1.17 g, 7.17 mmol) and ethyl bromopyruvate (1 mL, 7.17 mmol, 90% purity) in acetonitrile (30 mL) was stirred at room temperature for 3 h. After removal of the solvent, the residue was dissolved in a mixed solvent of ethanol (15 mL) and water (15 mL). After the pH was adjusted to 7-8 with satd. NaHCO3 solution, the mixture was stirred at room temperature overnight. The mixture was acidified to pH 1-2 with concentrated hydrochloric acid and then rotary evaporated to dryness. The residue was purified by column chromatography eluted with EtOAc giving 3-[1-(carboxymethylcarbamoyl)ethylsulfanyl]-2-hydroxyacrylic acid ethyl ester as yellow solid (1.06 g, yield 53.3%). 1H NMR (CDCl3, 300.16 MHz) delta(ppm): 9.10 (broad s, 1H), 7.22 (d, J=0.9 Hz, 1H), 4.62 (d, J=17.7 Hz, 1H), 4.53 (d, J=17.7 Hz, 1H), 4.28 (q, J=7.1 Hz, 1H), 3.47 (qd, J=6.2 & 0.9 Hz, 1H), 1.48 (d, J=6.2 Hz, 3H) and 1.30 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3, 75.48 MHz) delta(ppm): 174.02, 165.84, 160.57, 130.27, 120.20, 62.04, 46.76, 37.11, 14.45 and 14.09. MS (ESI) m/z: 260 (M+-OH, 100).
Preparation 27 2-Dimethylaminomethylthiazole-4-carboxaldehyde To a slurry of <strong>[27366-72-9]2-<strong>[27366-72-9]dimethylaminothioacetamide hydrochloride</strong></strong> (7.7 g, 50 mmol) in ethanol (100 mL) was added ethyl bromopyruvate (6.3 mL). The mixture was refluxed 6 hours and then cooled to room temperature. More ethyl bromopyruvate (3.2 mL for a total of 75 mmol) was added and the reaction was refluxed 2.5 hours more. The mixture was cooled to ambient temperature and concentrated at reduced pressure. The residue was partitioned between water and ethyl acetate and brought to pH 10 with addition of solid potassium carbonate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with water and brine, then it was dried over sodium sulfate and concentrated to afford an amber oil. This oil was purified by flash chromatography on silica gel (120 g).
With potassium carbonate; In ethanol;
Preparation 27 2-Dimethylaminomethylthiazole-4-carboxaldehyde To a slurry of <strong>[27366-72-9]2-<strong>[27366-72-9]dimethylaminothioacetamide hydrochloride</strong></strong> (7.7 g, 50 mmol) in ethanol (100 mL) was added ethyl bromopyruvate (6.3 mL). The mixture was refluxed 6 hours and then cooled to room temperature. More ethyl bromopyruvate (3.2 mL for a total of 75 mmol) was added and the reaction was refluxed 2.5 hours more. The mixture was cooled to ambient temperature and concentrated at reduced pressure. The residue was partitioned between water and ethyl acetate and brought to pH 10 with addition of solid potassium carbonate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with water and brine, then it was dried over sodium sulfate and concentrated to afford an amber oil. This oil was purified by flash chromatography on silica gel (120 g).
EXAMPLE 1 Preparation of Ethyl 2-Dimethylaminomethyl-4-thiazolecarboxylate A reaction mixture was prepared containing 15.5 g. of <strong>[27366-72-9]dimethylaminothioacetamide hydrochloride</strong>, 20.5 g. of ethyl bromopyruvate and 100 ml. of ethanol. The reaction mixture was heated to refluxing temperature for about four hours after which time the solvent was removed in vacuo in a rotary evaporator. The residue, containing ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate hydrochloride formed in the above reaction, was dissolved in a mixture of ether and water. The aqueous layer was separated. The ether layer was extracted with an equal volume of water and then discarded. The two aqueous layers were combined and washed with ether. The ether layer was again discarded and the aqueous layer cooled to a temperature in the range of 0-5 C. Solid potassium carbonate was added until the aqueous layer gave a basic reaction to litmus. An oil separated comprising ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate free base. The oily layer was extracted with ether and the ether extract separated and dried. The ether was removed by evaporation in vacuo. The resulting residue was purified by gradient high pressure liquid chromatography (silica, ethyl acetate). Ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate thus obtained had the following physical characteristics: Analysis Calculated: C, 50.45; H, 6.59; N, 13.07; S, 14.96 Found: C, 50.13; H, 6.39; N, 12.89; S, 15.04. The nmr spectrum in CDCl3 (TMS internal standard) gave the following signals (delta): 1.43 (triplet, 3H), 2.40 (singlet, 6H), 3.87 (singlet, 2H), 4.47 (quartet, 2H), 8.20 (singlet, 1H).
With triethylamine; In N,N-dimethyl-formamide; at 140℃;Sealed tube;
Example 76 Ethyl 7-thia-2,5-diazatricyclo [6.4.0.02'6] dodeca-1 (8),3,5-triene-4-carboxylate To a solution of 4,5,6,7-tetrahydro-l ,3-benzothiazol-2-amine (690 mg, 4.47 mmol) in DMF (7 mL) in a sealable tube were added triethylamine (453 mg, 4.47 mmol) and ethyl 3-bromo-2-oxopropanoate (1.54 g, 85% purity, 6.71 mmol). The tube was sealed and the mixture stirred at 140C overnight. The cooled reaction mixture was diluted with water (40 mL). The resulting suspension was extracted with EtOAc (40 mL). The organic layer was washed with water (3 x 30 mL), brine (30 mL) and then dried (Na2S04), filtered and concentrated. Partial purification was achieved using FCC (eluent: 30% EtOAc in heptane). Purification was achieved using automated reverse phase HPLC (neutral method), affording the title compound as a white solid (90 mg, 8% yield); 1H NMR (500 MHz, Chloroform-d) delta 1.41 (t, 3H), 1.89 - 2.02 (m, 4H), 2.60 - 2.75 (m, 4H), 4.40 (q, 2H), 7.91 (s, 1H).
Reference Example 8 Production of ethyl 6-iodoimidazo[1,2-b]pyridazine-2-carboxylate Using <strong>[187973-60-0]3-amino-6-iodopyridazine</strong> (2.0 g, 9.05 mmol), N,N-dimethylacetamide (20 mL), ethyl 3-bromo-2-oxopropanate (1.82 mL, 14.5 mmol) and disodium hydrogenphosphate (3.21 g, 22.6 mmol), and in the same manner as in Reference Example 3, the title compound (1.2 g, 44%) was obtained as a green powder. 1H-NMR (DMSO-d6, 300 MHz) delta 1.33 (3H, t, J=7.1 Hz), 4.33 (2H, q, J=7.1 Hz), 7.65 (1H, d, J=9.5 Hz), 7.96 (1H, d, J=9.5 Hz), 8.88 (1H, s).
Step (b) ethyl 2-tert-butylthiazole-4-carboxylateEthyl 3-bromo-2-oxopropanoate (6.20 mL, 49.40 mmol) was added very carefully to a stirred solution of <strong>[630-22-8]2,2-dimethylpropanethioamide</strong> (5.79 g, 49.40 mmol) in ethanol (60 mL). The solution was then heated under reflux for 16h. After cooling, the reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate solution and evaporated in vacuo. Purification by silica gel chromatography (Biotage, 10Og) eluting with EtOAc: iso- hexane, 1 :10 gave the sub-title compound as a yellow oil. Yield: 6.56 g1U NMR (300 MHz, CDCl3) delta 8.03 (s, IH), 4.40 (q, J= 7.1 Hz, 2H), 1.48 (s, 9H), 1.39 (t, J =6.3 Hz, 3H).MS: [M+H]+=214 (MultiMode+)
Step B ethyl 6-chloro-8-(trifluoromethyl)imidazo[l,2-a]pyridine-2-carboxylate[0121] <strong>[79456-33-0]5-chloro-3-(trifluoromethyl)-2-pyridinamine</strong> (3.0 g, 15 mmol) and ethyl bromopyruvate (4.27 mL, 30.5 mmol) in N,N-dimethylformamide (50 mL) were stirred at 60 0C for 3 hours. The mixture was allowed to cool and then poured into stirring iced water. The precipitate was stirred for 5 minutes, collected by filtration, washed with water, and dried under vacuum to give the title compound (3.5 g; 78%). LCMS: m/z 293, 295 (M+l).
78%
at 60℃; for 3.0h;
<strong>[79456-33-0]5-chloro-3-(trifluoromethyl)-2-pyridinamine</strong> (3.00 g, 15.3 mmol) and ethyl bromopyruvate (4.27 mL, 30.5 mmol) in N,/V-dimethylformamide (50 mL) were stirred at 60 C for 3 hours. The mixture was allowed to cool to room temperature and then poured into stirring iced water. The precipitate was stirred for 5 minutes, collected by filtration, washed with water, and dried under vacuum to give the title compound (3.5g, 78%) as a solid. ES-LCMS m/z: 293, 295 (M+1 ).
3-Amino-4-(methylamino)benzonitrile (250 mg; Maybridge) was stirred in ethanol (5 ml_). Ethyl 3-bromo-2-oxopropanoate (0.212 ml; Aldrich) was added and left to stir at room temperature overnight. An orange precipitate had formed overnight, which was filtered off and dried to afford the title compound (253 mg) as a light brown solid, m/z [M+H]+: 278.1 / 280.1. Retention time 0.83 min (LC/MS method 3).
2,3-Diaminobenzonitrile (80 mg; may be prepared as described in intermediate 164) was taken up in ethanol (10 ml). Ethyl 3-bromo-2-oxopropanoate (0.076 ml; Aldrich) was added and left to stir at room temperature overnight. The reaction mixture was filtered, leaving a light orange solid as the residue (15mg). The filtrate was concentrated under vacuum. It was then diluted with DCM and purified, along with the residue, using silica chromatography (10 - 70% EtOAc / isohexane) to give the title compound (70 mg) as an orange solid, m/z [M+H]+: 264.0 / 266.0. Retention time 0.72 min (LC/MS method 3).
Synthesis of 7-cyano-imidazo[l,2-a]pyridine-2-carboxylic acid and 7-carbamoyl- imidazo[l,2-a]pyridine-2-carboxylic acid; To a solution of <strong>[42182-27-4]2-amino-4-cyanopyridine</strong> (4.00 g, 33.6 mmol) in THF (100 mL) add ethyl bromopyruvate (6.55 g, 33.6 mmol). Stir the mixture at rt overnight. A light yellow suspension forms. After filtration and washing with THF, dissolve the light yellow solid in EtOH (50 mL) and heat to reflux for 4 h. Concentrate in vacuo to afford the desired product 7-cyano-imidazo[l,2-a]pyridine-2-carboxylic acid ethyl ester as a solid (6.21 g, 28.9 mmol).
ethyl 9-oxo-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(8),3,5-triene-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide; at 75 - 80℃; for 1h;
Example 83 Ethyl 9-oxo-7-thia-2,5-diazatricyclo[6.4.0.02'6]dodeca-l(8),3,5-triene-4-carboxylate Ethyl 3-bromo-2-oxopropanoate (3.85 mL, 30.5 mmol) was added dropwise to a solution of 2-amino-4,5,6,7-tetrahydro-l,3-benzothiazol-7-one (4.27 g, 25.4 mmol) in anhydrous DMF (90 mL) and stirred at 75-80°C for 60 min. The solution was cooled to room temperature and about half of the solvent was removed under reduced pressure. The remaining solution was diluted with EtOAc (100 mL) and washed with water (5 x 100 mL). The organic layer was concentrated in vacuo to yield a yellow residue which was chromatographed on silica (eluent: 50 to 90percent EtOAc in heptane) to afford the title compound as a yellow solid (2.60g, 74percent purity, 29percent yield); 1H NMR (250 MHz, DMSO-d6) delta 1.31 (t, 3H), 2.23 (p, 2H), 2.57 - 2.70 (m, 2H), 3.12 (t, 2H), 4.30 (q, 2H), 8.69 (s, 1H).
Ethyl bromopyruvate (2.153 g, 11.04 mmol) was added to a solution of 3-aminopyrazine (1 g, 10.51 mmol) in DME (10 mL) and the mixture was stirred continuously at 20-35 C. for 2 h. The reaction mixture was filtered and the solid which precipitated out was dried well, dissolved in EtOH (10 mL) and stirred under reflux for 2 h. This reaction mixture was then concentrated under reduced pressure to obtain a crude residue. The residue was diluted with aqueous sodium bicarbonate solution, and extracted with chloroform. The organic layer separated was washed with water and then with brine solution; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. The crude product was further purified by column chromatography (using Silica gel 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 450 mg of the title compound the as a yellow solid.
ethyl 3-hydroxy-4-oxo-2,3,4,5,6,7-hexahydrofuro[3,2-c]pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a stirred solution of potassium hydroxide (2.97 g, 53 mmol) in methanol (60 mL) under nitrogen at 0° C. was added a solution of the product from Example 1C (6 g, 53 mmol) in methanol (10 mL) dropwise. After the addition was complete, the mixture was stirred at 0° C. for 1 hour, and then a solution of ethyl bromopyruvate (7.01 mL, 55.7 mmol) in methanol (10 mL) was added dropwise. After allowing the mixture to stir at ambient temperature for 2.5 hours, the solvent was removed, and the residue was purified by silica gel column chromatography eluted with methanol/dichloromethane (0-10percent) to afford 3.4 g of crude product which was further purified via Teledyne Isco CombiFlash® Companion® XL eluted with methanol/10 mM ammonium acetate in water (0-50percent) on a 120 g RediSep® C18 column to provide the titled compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.87 (s, 1H), 4.59 (d, J=10.0 Hz, 1H), 4.34 (d, J=10.4 Hz, 1H), 4.11 (m, 2H), 3.27-3.34 (m, 2H), 2.50-2.55 (m, 2H), 1.16 (t, J=7.2 Hz, 3H)
Example 1D ethyl 3-hydroxy-4-oxo-2,3,4,5,6,7-hexahydrofuro[3,2-c]pyridine-3-carboxylate To a stirred solution of potassium hydroxide (2.97 g, 53 mmol) in methanol (60 mL) under nitrogen at 0° C. was added a solution of the product from Example 1C (6 g, 53 mmol) in methanol (10 mL) dropwise. After the addition was complete, the mixture was stirred at 0° C. for 1 hour, and then a solution of ethyl bromopyruvate (7.01 mL, 55.7 mmol) in methanol (10 mL) was added dropwise. After allowing the mixture to stir at ambient temperature for 2.5 hours, the solvent was removed, and the residue was purified by silica gel column chromatography eluted with methanol/dichloromethane (0-10percent) to afford 3.4 g of crude product which was further purified via Teledyne Isco CombiFlash® Companion® XL eluted with methanol/10 mM ammonium acetate in water (0-50percent) on a 120 g RediSep® C18 column to provide the titled compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.87 (s, 1H), 4.59 (d, J=10.0 Hz, 1H), 4.34 (d, J=10.4 Hz, 1H), 4.11 (m, 2H), 3.27-3.34 (m, 2H), 2.50-2.55 (m, 2H), 1.16 (t, J=7.2 Hz, 3H).
With triethylamine; In 1,4-dioxane; at 90℃; for 16h;
To a stirred solution of terf-butyl 4-carbamothioylpiperazine-1-carboxylate (synthesized according to Example 5, Step 1, 3.0 g, 12 mmol) in dioxane (10 mL), TEA (2.6 mL, 16 mmol) and 3-bromo-ethyl pyruvate (2.1 mL, 16 mmol) were added at rt and the mixture was stirred at 90 C for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, concentrated under vacuum and the resulting crude product was taken as such for next step. Yield: 95% (4 g, black solid).
With triethylamine; In 1,4-dioxane; at 90℃; for 16h;
To a stirred solution of <strong>[196811-66-2]tert-butyl 4-carbamothioylpiperazine-1-carboxylate</strong> (synthesized according to Example 5, Step 1, 3.0 g, 12 mmol) in dioxane (10 mL), TEA (2.6 mL, 16 mmol) and 3-bromo-ethyl pyruvate (2.1 mL, 16 mmol) were added at rt and the mixture was stirred at 90 C for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc. The organiclayer was dried over anhydrous Na2504, concentrated under vacuum and the resulting crude product was taken as such for next step. Yield: 95% (4 g, black solid).
ethyl 2-hydrazinylthiazole-4-carboxylate hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 20℃; for 2.0h;Reflux;
[0126] Ethyl bromopyruvate (15.71 ml, 113 mmol) was added to a suspension of 2- acetylhydrazinecarbothioamide (15 g, 113 mmol) in ethanol (200 mL) and stirred at room temperature for 30 minutes until the solution became clear, then refluxed for 1.5 h. The solution was then concentrated and agitated with 20 mL of MeOH and 300 mL of ether. The yellow precipitate was collected by filtration, washed with ether, and dried to obtain a yellow solid (ethyl 2-hydrazinylthiazole-4-carboxylate 3) as HBr salt.
In ethanol; for 1.5h;Reflux;
[0131] Ethyl bromopyruvate (15.71 ml, 113 mmol) was added to a suspension of <strong>[2302-88-7]2-acetylhydrazinecarbothioamide</strong> (15 g, 113 mmol) in ethanol (200 mL) and stirred at room temperature for 30 minutes until the solution became clear, then refluxed for 1.5 h. The solution was then concentrated and agitated with 20 mL of MeOH and 300 mL of ether. The yellow precipitate was collected by filtration, washed with ether, and dried to obtain a yellow solid (ethyl 2-hydrazinylthiazole-4-carboxylate 3) as HBr salt.
ethyl-8-methylimidazo[1,2-a]pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
In 1,2-dimethoxyethane; at 20℃; for 13h;Cooling with ice;
150 g of 3-methylpyrazine 2-amine was reacted with 321 g of ethyl bromopyruvate in 1 liter of ethylene glycol dimethyl ether at room temperature for 12 hours. The mixture was stirred under ice-cooling for 1 hour and then brown solid . The resulting brown solid was refluxed in 1.5 liters of ethanol for 2 hours. After completion of the reaction, the reaction mixture was stirred under ice-cooling for 1 hour and filtered to obtain a white solid in a yield of 72%
General procedure: Amide (1.0 equiv) and ethyl bromopyruvate (1.2 equiv) were dissolved in ethanol and heated to 70C for 5h. The reaction was monitored with TLC until completion. The solvent was evaporated, dried over anhydrous MgSO4. The ethyl ester (1a-1k) was purified by flash column chromatography (ethyl acetate/cyclohexane 3:7 (v/v)).
ethyl 11-bromo-7-thia-2,5,9-triazatricyclo[6.4.0.02,6]dodeca-1(12),3,5,8,10-pentaene-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-methyl-pyrrolidin-2-one; at 20 - 60℃;
6-Bromo-[1 ,3]thiazolo[5,4-b]pyridin-2-amine (0.1 g, 0.43 mmol) was dissolved in N-methyl-2-pyrrolidone (1.5 mE) and ethyl 3-bromo-2-oxopropanoate (64 pi, 0.43 mmol) added dropwise. The reaction was stirred at room temperature for 1 hour then heated to 60 C. overnight. The reaction was cooled then water/ice added. The resulting precipitate was isolated by vacuum filtration. The red solid was further dried in a vacuum oven to give the title compound. ?H NMR(500 MHz, DMSO) 9.05 (s, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H). Tr(MS10)=1.55 mi mlz (ES(M+H)328, 329
ethyl 5-hydroxy-7-methoxyimidazo[1,2-c]pyrimidine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
A 50 mL flask was charged with <strong>[3289-50-7]2,6-dimethoxypyrimidin-4-amine</strong> (1 g, 6.45 mmol). THF (2.5 mL) and diethyl ether (2.5 mL) were added followed by ethyl 3-bromo- 2-oxopropanoate (1.62 mL, 12.9 mmol). The reaction was stirred at rt overnight. The heterogeneous reaction was cooled to 0 C and the precipitated intermediate salt (MW 269) was collected by vacuum filtration and washed with ether. The precipitate was dissolved in MeOH (8 mL) and heated at 60 C for 8h. After cooling to rt, the reaction was concentrated in vacuo. The residue was suspended in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in DCM / MeOH and filtered to give the product (667 mg, 44 % yield) as a white solid.1H NMR (400MHz, METHANOL-d4) delta 8.57 (s, 1H), 6.91 (d, J= 0.6 Hz, 1H), 4.48 (q, J= 7.1 Hz, 2H), 1.44 (t, J= 7.2 Hz, 3H); MS (ESI ) m/z 238.1 (M+H)+
2-tert-butyl thiazole-5-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.0%
In ethanol; at 20℃; for 48h;
A solution of ethyl 3-bromopyruvate (1.95 g, 10 mmol, 1.0 eq) and 2, 2, 2-trimethyl-thioacetamide (1.17 g, 10 mmol, 1.0 eq) in 20 mL of ethanol was stirred at room temperature for 48 h. The solvent was evaporated under reduced pressure, and the residue was extracted with aqueous sodium bicarbonate and DCM. The DCM layer was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was separated by column chromatography to give 2-tert-butyl-thiazole-5-carboxylic acid ethyl ester as a colorless oil (1.15 g, 55.0% yield). 1H NMR (400 MHz, CDCl3) delta 8.01 (s, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.46 (s, 9H), 1.37 (t, J=7.1 Hz, 3H). MS m/z (ESI): 214.0 [M+H].
2-(trifluoromethyl)imidazo[2,1-b][1,3]thiazol-6-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.12 g
4.0 g of <strong>[169260-97-3]5-(trifluoromethyl)thiazol-2-amine</strong> was dissolved in 80 ml of chlorobenzene, and 7.2 g of ethyl 3-bromo-2-oxopropanoate was added at room temperature. After the addition, the reaction mixture was stirred under reflux with heating for 3 hours. After the stirring, 3.09 g of ethyl 3-bromo-2-oxopropanoate was added to the reaction mixture. After the addition, the reaction mixture was stirred under reflux with heating for one hour. After the stirring, 2.4 g of ethyl 3-bromo-2-oxopropanoate was added to the reaction mixture. After the addition, the reaction mixture was stirred under reflux with heating for 2 hours. After the reaction, the solvent was evaporated from the reaction mixture under reduced pressure. The resulting residue was mixed with a 1M sodium hydroxide aqueous solution to adjust the aqueous layer to have a pH of 8, and extracted with ethyl acetate (20 ml*3). The resulting organic layer was dehydrated with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration. The resulting solid was washed with diisopropyl ether to obtain 2.12 g of the desired product as a white solid. 1H-NMR (CDCl3): delta8.14 (s, 1H), 7.92 (s, 1H), 4.42 (q, J=7.5 Hz, 2H), 1.43 (t, J=7.5 Hz, 3H).
Dichloromethane (10 ml) was added to a 50 ml reaction flask.<strong>[14916-63-3]2-Amino-6-nitropyridine</strong> (200 mg, 1.4 mmol) Starting material 1And 3-bromo-2-oxo-propionic acid ethyl ester (280 ml, 1.4 mmol),Magnetic stirring at room temperature for 1-2h,Concentrate under reduced pressure to remove the solvent,The residue is dissolved in 10 ml of ethanol (specifically anhydrous ethanol) and heated to reflux for 3 h.TLC detected the reaction was complete.After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure to remove the ethanol.The residue was washed with saturated sodium hydrogencarbonate solution, the aqueous layer was extracted with dichloromethane, the organic layer solution was dried over anhydrous sodium sulfate overnight, suction filtered and concentrated, and the residue was separated using silica gel column chromatography.Yellow solid, which is Intermediate 2.
A method for preparing thiazole-4-carboxylic acid,Include the following steps: Mix ethyl bromopyruvate, thiourea, and water,Raise the temperature to 40°C, incubate and stir for 5 hours, then add concentrated hydrochloric acid, and add 30 wtpercent sodium nitrite aqueous solution dropwise.The mixture was further stirred for 2 hours, and the filter cake was filtered to obtain thiazole-4-carboxylic acid. The molar ratio of ethyl bromopyruvate to thiourea was1:1.05, the molar ratio of ethyl bromopyruvate to sodium nitrite is 1:1.5, and the weight ratio of ethyl bromopyruvate to water is1.95:10, the volume ratio of water to concentrated hydrochloric acid is 1:1.
With tetraphosphorus decasulfide; In 1,4-dioxane; for 8.0h;Reflux;
To a solution of formamide (47?mL, 1.19?mol, 1.5 equiv) in 1,4-dioxane (318?mL), P2S5 (52.70?g, 0.237?mmol, 0.3 equiv) was added in small portions in the course of 0.5?h under vigorous stirring. The reaction mixture was stirred for 0.5?h, and ethyl bromopyruvate (154?g, 0.790?mol) was added dropwise. The reaction mixture was heated at reflux for 8?h, cooled to room temperature and a solution of K2CO3(~100?g) in water (~500?mL) was carefully added to the reaction mixture. The resulted solution was extracted with DCM (3?*?100?mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, evaporated, and the residue was distilled at reduced pressure. bp?=?120-130?C (10 torr). M?=?108.3?g. Yield?=?87%. 1H NMR: (CDCl3, 400?MHz) delta?=?1.40 (t, J?=?7.2?Hz, 3?H), 4.42 (q, J?=?7.1?Hz, 2?H), 8.24 (d, J?=?2.1?Hz, 1?H), 8.87 (d, J?=?2.1?Hz, 1?H). 13C NMR (CDCl3, 100?MHz): delta?=?14.4, 61.7, 127.3, 148.2, 153.6, 161.3.
ethyl 8-bromo-5-oxo-6H-imidazo[1,2-c]pyrimidine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44.3%
With acetic acid; at 120℃; for 2h;Large scale;
A mixture of compound <strong>[2240-25-7]5-<strong>[2240-25-7]bromocytosine</strong></strong> (150 g, 789 mmol, 1.00 equiv) and ethyl 3- bromo-2-oxo-propanoate (385 g, 1.97 mol, 247 mL, 2.50 equiv) in AcOH (1.5 L) was stirred at 120 C for 2 h. The crude 1H NMR spectrum indicated that the reaction was complete. Three batches were concentrated to provide a residue that was triturated with MTBE (3 L) and filtered. The filter cake was washed with water (1 L x 4) and dried to afford ethyl 8-bromo-5-oxo-5, 6- dihydroimidazo[l, 2-c]pyrimidine-2-carboxylate (300 g, 1.05 mol, 44.3% yield) as a brown solid. 1H NMR (400MHz, DMSO-d6) d 12.47 - 11.64 (m, 1H), 8.33 (s, 1H), 8.06 (s, 2H), 7.73 (s, 1H), 4.31 (q, 7= 7.1 Hz, 2H), 1.32 (t, J= 7.1 Hz, 3H).
Chemistry
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Material Science
Life Science
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