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Structure of 2033-24-1 * 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: With orthoformic acid triethyl ester In ethanol for 2.5 h; Reflux Stage #2: at 20 - 280℃;
To a solution of p-fluoroaniline (3.03 mL, 31.5 mmol, 1 equiv) in ethanol (30 mL) were added Meldrum's acid (5.54 g, 38.4 mmol, 1.2 equiv) and triethyl orthoformate (12.4 mL, 74.5 mmol, 2.4 equiv). The mixture was heated to reflux for 2.5 h. The reaction was cooled to 0 °C and the solid was filtered and washed with cold ethanol. The dried solid was added portiowise over 5 mins to boiling diphenyl ether (100 mL). Reflux was maintained for an additional 3 mins. The reaction was stirred at room temperature for 30 mins before petroleum ether (25 mL) was added and the solid was filtered and dried. The crude product was purified by column chromatography on silica gel (EtOAc/MeOH 95:5), to afford 6-fluoroquinolin-4-ol (2.36 g, 14.5 mmol, 46percent). The analyses were consistent with the data reported in the literature. Ref: WO2010/123995 (2010) TLC Rf 0.41 (EtOAc/MeOH 95:5) 1HNMR (400MHz, DMSO-de) δ (ppm) 11.90 (s, 1H, OH), 7.94 (d, J=7.6, 1H, NCH), 7.73 (m, 1H, NCCH), 7.53-7.67 (m, 2H, FCCH, FCCH), 6.04 (d, J=7.3, 1H, OHCCH) ppm CNMR (101 MHz, DMSO-de) δ (ppm) 159.9 (7), 157.7 (5), 140.0 (2), 137.2 (10), 127.3 (4), 121.1 (6), 120.8 (1), 109.5 (3), 108.3 (8) ppm IR (neat) v max 2768 (br), 1594 (m) cm"1 LCMS (ESI+) m/z 164.1 [M+H]+, 186.1 [M+Na]+ 11 RMS (ESI+) m/z calcd. 164.0506 m/z meas. 164.0509 [M+H] Mpt 227 - 228 °C
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 6, p. 2232 - 2235
7
[ 527-72-0 ]
[ 2033-24-1 ]
[ 13669-10-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 2 h; Stage #2: With toluene-4-sulfonic acid In ethanol for 1 h; Heating / reflux
Step 1. Preparation of ethyl-2-(thiophene-2-oyl)acetate. A solution of thiophene-2-carboxylic acid (8.9 g, 68.5 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (12.0 g, 81.6 mmol), and 4-dimethylaminopyridine (17.0 g, 138 mmol) in dry CH2Cl2 (100 mL) was cooled to 0° C. and treated with a solution of 1,3-dicyclohexylcarbodiimide (75 mL, 1.0 M in CH2Cl2, 75 mmol). The reaction was allowed to stir at room temperature for 2 h and the dicyclohexylurea was then filtered and washed with CH2Cl2. The filtrate was concentrated at reduced pressure and the residue was dissolved in absolute ethanol (400 mL). The solution was then treated with a solution of p-toluenesulfonic acid monohydate (32 g, 168 mmol) in absolute ethanol (100 mL) and refluxed under argon for 1 h. At this time, the ethanol was removed at reduced pressure and the residue was dissolved in EtOAc and washed sequentially with H2O (300 mL), saturated NaHCO3 (200 mL), 1 N HCl (200 mL), saturated NaCl, and dried (MgSO4). The solvent was removed at reduced pressure and the residue was filtered through a pad of silica with 10percent EtOAc/90percent hexanes to afford the desired product as an oil (13 g, 96percent). TLC (20percent EtOAc/80percent hexane) Rf 0.21; 1H-NMR (DMSO-d6) δ 1.17 (t, J=7.01, 3H), 4.06-4.14 (m, 4H), 7.25 (t, J=5.1 Hz, 1H), 7.98 (d, J=3.8 Hz, 1H), 8.06 (d, J=4.9 Hz, 1H).
96%
Stage #1: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 2 h; Stage #2: With toluene-4-sulfonic acid In ethanol for 1 h; Heating / reflux
A solution of thiophene-2-carboxylic acid (8.9 g, 68.5 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (12.0 g, 81.6 mmol), and 4-dimethylaminopyridine (17.0 g, 138 mmol) in dry CH2Cl2 (100 mL) was cooled to 0° C. and treated with a solution of 1,3-dicyclohexylcarbodiimide (75 mL, 1.0 M in CH2Cl2, 75 mmol). The reaction was allowed to stir at room temperature for 2 h and the dicyclohexylurea was then filtered and washed with CH2Cl2. The filtrate was concentrated at reduced pressure and the residue was dissolved in absolute ethanol (400 mL). The solution was then treated with a solution of p-toluenesulfonic acid monohydate (32 g, 168 mmol) in absolute ethanol (100 mL) and refluxed under argon for 1 h. At this time, the ethanol was removed at reduced pressure and the residue was dissolved in EtOAc and washed sequentially with H2O (300 mL), saturated NaHCO3 (200 mL), 1 N HCl (200 mL), saturated NaCl, and dried (MgSO4). The solvent was removed at reduced pressure and the residue was filtered through a pad of silica with 10percent EtOAc/90percent hexanes to afford the desired product as an oil (13 g, 96percent). TLC (20percent EtOAc/80percent hexane) Rf0.21; 1H-NMR (DMSO-d6) δ1.17 (t, J=7.01, 3H), 4.06-4.14 (m, 4H), 7.25 (t, J=5.1 Hz, 1H), 7.98 (d, J=3.8 Hz, 1H), 8.06 (d, J=4.9 Hz, 1H).
27%
Stage #1: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 2 h; Stage #2: With toluene-4-sulfonic acid In ethanol for 1 h; Heating / reflux
Intermediate 1D : Preparation of 4-chloro-6- (2-thienyl) pyrimidin-2-amine; Step 1: Preparation of ethyl 3-oxo-3- (2-thienyl) propanoate; A solution of 2, 2-dimethyl-1, 3-dioxane-4,6-dione (12 g, 83.26 mmol) and thiophene- 2-carboxylic acid (8.97 g, 70.0 mmol) and DMAP (17.10 g, 140 mmol) in methylene chloride (100 mL) was cooled in an ice bath and treated with a solution of DCC (15.88 g, 76.96 mmol) in methylene chloride (50 mL). The reaction was stirred at rt for 2 h. The resulting precipitate was filtered and the filtrate was concentrated and re-dissolved in EtOH (400 mL). To this solution was addedp-toluenesulfonic acid (32 g) and the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo to afford the crude organic concentrate which was dissolved in ethyl acetate (1000 mL) and washed with water (300 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (200 mL), IN hydrochloric acid (200 mL), saturated aqueous sodium chloride, dried (Na2S04), and concentrated. The residue was purified using silica gel column chromatography (0-7percent ethyl acetate in hexane) to furnish the desired product as a colorless oil (3.67 g, 27percent). MS ES 199 (M+H) +, calcd 199; RT = 2.12 min; TLC (25percent ethyl acetate in hexane) Rf= 0.50.
27%
Stage #1: With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2 h; Stage #2: With toluene-4-sulfonic acid In ethanol for 1 h; Heating / reflux
A solution of 2,2-dimethyl-l,3-dioxane-4,6-dione (12 g, 83.26 mmol) and thiophene- 2-carboxylic acid (8.97 g, 70.0 mmol) and DMAP (17.10 g, 140 mmol) in methylene chloride (100 rnL) was cooled in an ice bath and treated with a solution of DCC (15.88 g, 76.96 mmol) in methylene chloride (50 mL). The reaction was stirred at rt for 2 h. The resulting precipitate was filtered and the filtrate was concentrated and re-dissolved in EtOH (400 mL). To this solution was added /?-toluenesulfonic acid (32 g) and the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo to afford the crude organic concentrate which was dissolved in ethyl acetate (1000 mL) and washed with water (300 EPO <DP n="40"/>mL). The organic layer was washed with saturated aqueous sodium bicarbonate (200 niL), IN hydrochloric acid (200 mL), saturated aqueous sodium chloride, dried (Na2SO4), and concentrated. The residue was purified using silica gel column chromatography (0-7percent ethyl acetate in hexane) to furnish the desired product as a colorless oil (3.67 g, 27percent). MS ES 199 5 (M+H)+, calcd 199; RT = 2.12 min; TLC (25percent ethyl acetate in hexane) Rf = 0.50.
Reference：
[1] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2004, vol. 59, # 2, p. 129 - 133
[2] Synthetic Communications, 1996, vol. 26, # 22, p. 4195 - 4209
[3] Journal of the American Chemical Society, 1958, vol. 80, p. 1942
With tomato juice In water at 20℃; for 0.0833333 h; Sonication; Green chemistry
General procedure: 2-Hydroxybenzaldehyde (acetophenone, or benzaldehydes) (1.0 mmol) and Meldrum’s acid (1.01 mmol) were suspended in the aqueous medium (juice or waste water) (2 mL). The resulting mixture was subjected to ultrasound irradiation at room temperature for 5 min (15 min). The precipitate so formed was filtrated under vacuum. Structural assignments (NMR) was made by comparison of the recorded analytical data with those of commercially available sample or those already reported for the same compounds.2-6 The aqueous medium (juice or waste water) was recovered by filtration and re-used as such to perform further processes.
92%
at 60℃; for 4 h; Schlenk technique; Green chemistry
General procedure: A mixture of Meldrum’s acid (0.5 mmol) and salicylaldehydes (0.55 mmol) was placed in a 10-mL Schlenk tube, then Et3N (0.015 mmol) and 50 μL water were added. The reaction mixture was stirred at the indicated temperature for 4 h. After completion of the reaction, 3 mL aqueous ethanol was added to the mixture and vigorously stirred for a moment. The pH was adjusted to 2–3 with dilute hydrochloric acid. Finally, the precipitate was separated by filtration and washed with aqueous ethanol without further purification to afford the corresponding pure adducts.
90%
for 10 h; Reflux
General procedure: In a round-bottomed flask the selected salicylaldehyde (1 mmol) and Meldrum's acid (1.2 mmol) in water (2 mL) were heated at reflux under stirring for 10 h; then, the reaction mixture was cooled and filtered on Büchner funnel. The products were purified by recrystallization from methanol.
77%
With ammonium acetate In water at 20℃; for 0.1 h;
A suspension of 2,4-dihydroxybenzaldehyde (1.30 g, 9.5 mmol) in 21 mL of water was added Meldrum's acid (1.55 g, 10.8 mmol) and ammonium acetate (150 mg, 1.9 mmol). The suspension was stirred at room temperature for about 1 h. The precipitate formed was filtered and washed with cold water (2 x 10 mL) and vacuum drying (1.5 g, yellow-orange solid, 77percent). m.p. 260-264 °C; 1H NMR (DMSO-d6): δ 11.93 (bs, 2H, OH), 8.66 (s, 1H, =CH), 7.73 (d, 1H, Ar-H, J = 8.6 Hz ), 6.83 (dd, 1H, Ar-H, J = 8.6, 2.1 Hz), 6.72 (d, 1H, Ar-H, J = 2.1 Hz)
Reference：
[1] Tetrahedron Letters, 2016, vol. 57, # 43, p. 4795 - 4798
[2] Research on Chemical Intermediates, 2016, vol. 42, # 9, p. 7057 - 7063
[3] New Journal of Chemistry, 2018, vol. 42, # 11, p. 8831 - 8842
[4] European Journal of Medicinal Chemistry, 2014, vol. 84, p. 1 - 7
[5] Tetrahedron Letters, 2003, vol. 44, # 9, p. 1755 - 1758
[6] Central European Journal of Chemistry, 2010, vol. 8, # 2, p. 370 - 374
[7] Helvetica Chimica Acta, 2012, vol. 95, # 3, p. 455 - 460
[8] Synthetic Communications, 2008, vol. 38, # 20, p. 3508 - 3513
[9] Organic and Biomolecular Chemistry, 2012, vol. 10, # 27, p. 5258 - 5265
[10] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 23, p. 5732 - 5735
[11] Organic Letters, 2004, vol. 6, # 20, p. 3561 - 3564
[12] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 8, p. 1157 - 1160
11
[ 2033-24-1 ]
[ 779-27-1 ]
Yield
Reaction Conditions
Operation in experiment
86%
for 0.25 h; Reflux; Green chemistry
General procedure: A mixture of nitrone (10 mmol) and Meldrum’sacid (10 mmol) was refluxed in ethanol (15 mL) for a given time (see Table I). The progress of reaction was monitored via thin layer chromatography. After reaction completion, the reaction mass was cooledand excess solvent was removed under vacuum. Obtained crude product was washed with cold water (5 mL × 3). The solid product was filtered and dried. For further purification, products were recrystallized from EtOH. The products were characterized by comparison of their melting points and spectral (IR,1H NMR) data with those of authentic samples (authentic samples were obtained via direct Knoevenagel reaction of aldehydes with Meldrum’s acid). The representative characterization data of products was identical with those described in the literature and as shown below.
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 8, p. 1157 - 1160
12
[ 2033-24-1 ]
[ 64-17-5 ]
[ 3535-37-3 ]
[ 4687-37-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With pyridine In dichloromethane at -5 - 0℃; for 0.5 h; Stage #2: at -5 - 25℃; for 1.5 h;
[Reference Example 1] Ethyl 3-(3,4-dimethoxyphenyl)-3-oxopropionate To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (14.4 g 10 mmol) in dichloromethane (30 mL), pyridine (0.81 mL, 10 mmol) was added at 0°C or less, and this was stirred at -5°C for 0.5 hours. Subsequently, 3,4-dimethoxybenzoylchloride (2.00 g 10 mmol) was added at 0°C or less, stirred at -5°C for 0.5 hours, 0°C for 0.5 hours, and 25°C for 0.5 hours, and then 1 M hydrochloric acid (30 mL) was added while cooling on ice. This was then extracted with dichloromethane. After drying over magnesium sulfate, dichloromethane was distilled off, this was redissolved in ethanol (30 mL), refluxed for 1.5 hours, stirred at room temperature for 10 hours. It was then stirred at 60°C for 14 hours, ethanol was distilled off, and this was purified by silica gel column chromatography (elude: hexane: tetrahydrofuran = 3:1) which resulted in a colorless oily material (2.27 g, 90percent yield).
To a preheated (—100 00) mixture of 3-aminopyridine (0.37g, 4.0 mmol) and 2,2-dimethyl-[1 ,3}dioxane-4,6-dione (Meidrum’s acid, 0.69 g, 4.8 mmol) was added triethyl orthoformate (4.0 mL, 24.0 mmol). The solution was stirred at 100 °C for 2 h. The reaction proceeded by changing color from yellow to wine red accompanying the formation of yellow precipitate. After cooling to room temperature, the excess liquid of triethyl orthoformate was removed via vacuumdistillation. The resulting solid was purified via silica gel chromatography using a gradient of 70 to 100percent EtOAc in hexanes.
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 2, p. 763 - 777
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 4, p. 1343 - 1361
[3] Patent: WO2017/31255, 2017, A1, . Location in patent: Paragraph 0086
With 4-toluenesulfonyl azide In tetrahydrofuran at 25℃; for 22 h; Molecular sieve
General procedure: To a solution of the 1,3-dicarbonyl compound 1 (1.00 mmol) and p-toluenesulfonyl azide (0.197 g, 1.00 mmol) in THF (2.0 mL) was added the MS (0.300 g) and the mixture was stirred at 25°C for the time stated in Table 2. After the reaction was completed (monitoredby TLC [8:2 hexane:EtOAc] by following the consumption of the starting 1,3-dicarbonyl compound 1), the catalyst was separated by filtration followed by sequential washing with 10 mL CH2Cl2 and10 mL EtOAc. The filtrate was concentrated under reduced pressure and the residue was taken up in ethyl ether. The mixture was concentrated again and the final residue was triturated with hexane (3 × 20 mL). The solid material formed (TsNH2) was filtered andthe solvent was removed under reduced pressure to give the diazocarbonyl compound 2 in >95percent purity.
66%
With 4-acetamidobenzenesulfonyl azide In acetonitrile at -15 - 20℃;
General procedure: Procedure A: Dimedone (2.24 g, 16.0 mmol, 1 eq) was dissolved in acetonitrile (7.50 mL, 2 M)and stirred vigorously at room temperature. To this solution was addedp-acetamidobenzenesulfonyl azide (p-ABSA, 3.60 g, 16.0 mmol, 1 eq) and the solution wascooled in an ice-salt bath to -15 C. Triethylamine (2.45 mL, 17.6 mmol, 1.1 eq) was added tothe solution dropwise and the reaction was allowed to warm naturally to room temperature. Afterconsumption of starting material was determined by TLC analysis, the reaction material wasfiltered and the precipitate washed with 10 mL of cold diethyl ether. The diazo product was obtained from the filtrate through trituration using diethyl ether. Pure diazo compound could alsobe obtained through silica gel chromatography following concentration of the filtrate en vacuo.
40%
With sodium azide; N-benzyl-N,N,N-triethylammonium chloride; <i>tert</i>-butylamine; p-acetylaminobenzenesulfonyl chloride In water; acetone at 0 - 25℃; for 2 h; Green chemistry
General procedure: To a solution of the corresponding 1,3-dicarbonyl compound 1 (1.0 mmol) and ABSCl (304 mg, 1.3 mmol) in acetone (2.0 mL) under stirring at 0-5 °C was added a cold solution of NaN3 (71 mg, 1.1 mmol) in H2O (1.0 mL) followed by BTEAC (45 mg, 0.20 mmol) and t-BuNH2 (73 mg, 1.0 mmol) [or β-CD (57 mg, 0.05 mmol and i-Pr2NH (101 mg, 1.0 mmol); see Table2]. Then the reaction mixture was stirred at room temperature until consumption of the starting material (monitored by TLC: 2-24 h, see Table 2). Next, the mixture was diluted in 5 mL of EtOAc and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. After complete removal of the solvent, the residue was triturated in ethyl ether and the resulting mixture was again concentrated under reduced pressure. The final solid residue was repeatedly triturated with hexane to separate out the insoluble ABSNH2 by decantation. The resulting supernatants were filtered and concentrated under reduced pressure to give diazo compounds9,10d,26 2 as oils with high degree of purity in 40-92percent yield.
Reference：
[1] Gazzetta Chimica Italiana, 1992, vol. 122, # 5-7, p. 249 - 251
[2] Synlett, 2009, # 18, p. 2943 - 2944
[3] Synthesis, 2011, # 7, p. 1037 - 1044
[4] Synthetic Communications, 2010, vol. 40, # 11, p. 1574 - 1579
[5] Synthetic Communications, 1989, vol. 19, # 13-14, p. 2567 - 2572
[6] Synthetic Communications, 2004, vol. 34, # 5, p. 951 - 959
[7] Journal of Organic Chemistry, 2016, vol. 81, # 17, p. 7760 - 7770
[8] Chemical Communications, 2017, vol. 53, # 2, p. 443 - 446
[9] Tetrahedron Letters, 2008, vol. 49, # 17, p. 2704 - 2709
[10] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 735 - 737
[11] Organic Letters, 2012, vol. 14, # 2, p. 440 - 443
[12] Journal of Molecular Catalysis A: Chemical, 2014, vol. 386, p. 35 - 41
[13] Journal of Organic Chemistry, 2001, vol. 66, # 7, p. 2509 - 2511
[14] Synlett, 2015, vol. 26, # 8, p. 1003 - 1007
[15] Synthetic Communications, 1981, vol. 11, # 12, p. 947 - 956
[16] Synthetic Communications, 1987, vol. 17, # 14, p. 1709 - 1716
[17] Journal of the American Chemical Society, 2003, vol. 125, # 6, p. 1456 - 1457
[18] Russian Journal of Organic Chemistry, 2006, vol. 42, # 6, p. 815 - 827
[19] Tetrahedron, 2017, vol. 73, # 31, p. 4549 - 4559
[20] Synthetic Communications, 1987, vol. 17, # 8, p. 983 - 992
[21] Chemical Communications, 2014, vol. 50, # 49, p. 6483 - 6486
[22] Organic Letters, 2016, vol. 18, # 12, p. 2828 - 2831
[23] European Journal of Organic Chemistry, 2016, vol. 2016, # 34, p. 5637 - 5641
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 46, p. 14153 - 14162
[2] Journal of the American Chemical Society, 2003, vol. 125, # 6, p. 1456 - 1457
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 6, p. 2232 - 2235
23
[ 2033-24-1 ]
[ 106-40-1 ]
[ 54675-23-9 ]
Reference：
[1] Patent: KR2016/68948, 2016, A, . Location in patent: Paragraph 0290-0293
24
[ 2033-24-1 ]
[ 75-36-5 ]
[ 85920-63-4 ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: With pyridine In dichloromethane at 0℃; for 0.25 h; Stage #2: at 0 - 20℃; for 3 h;
General procedure: Method A: Adapted from the procedure of Srensen et al.14 To a solution of Meldrum’s acid (1equiv) in dichloromethane at 0°C was added pyridine (2equiv) drop wise, and the resulting solution was stirred for 15min. The corresponding acid chloride (1equiv) was added to this reaction mixture. Thereafter, the reaction was stirred for 1.5h at 0°C, and for an additional 1.5h at room temperature. The reaction was quenched with 2M hydrochloric acid, and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient from 5percent to 10percent ethyl acetate in hexane, 1percent acetic acid to yield acyl Meldrum’s acids (11a–e, j, l, p).
7.44 g
Stage #1: With pyridine In dichloromethane at -5℃; for 0.166667 h; Stage #2: at 20℃; for 1.33333 h;
Meldrum's acid (7.2g, 0.05M) and was dissolved in dichloromethane (60mL), was added pyridine inner temperature as -5°C (7.9g, 0.1M) and slowly mixed and stirred for about 10 minutes to obtain a liquid.Then, to the resulting mixture was added dropwise acetyl chloride (4.3g, 0.055M) in dichloromethane (20mL) solution of over 20 minutes. Thereafter, the resulting solution was reacted at room temperature for 1 hour, the reaction mixture was acidified with 1N-HCl, washed with water, after performing drying over MgSO4,evaporated, red-brown oil was obtained.The oil was repeated twice purified by silica gel chromatography (Hexane: AcOEt = 10: 1 ~ 5: 1), to give 7.44g of compound A.
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 4, p. 1003 - 1007
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 6, p. 1321 - 1340
[3] Acta Chimica Slovenica, 2013, vol. 60, # 2, p. 403 - 410
[4] Canadian Journal of Chemistry, 1992, vol. 70, # 5, p. 1427 - 1445
[5] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 10, p. 1303 - 1306
[6] Tetrahedron Letters, 1998, vol. 39, # 41, p. 7487 - 7490
[7] Chemical Communications, 1999, # 12, p. 1113 - 1114
[8] European Journal of Organic Chemistry, 2003, # 3, p. 537 - 541
[9] Synthetic Communications, 2005, vol. 35, # 16, p. 2139 - 2141
[10] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 2, p. 365 - 369
[11] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 12, p. 3203 - 3214
[12] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 20, p. 9349 - 9358
[13] Tetrahedron Letters, 2010, vol. 51, # 3, p. 548 - 549
[14] Tetrahedron, 2011, vol. 67, # 17, p. 3062 - 3070
[15] Patent: KR2015/43489, 2015, A, . Location in patent: Paragraph 0278-0280; 0283
[16] Organic Syntheses, 2000, vol. 77, p. 114 - 114
25
[ 2033-24-1 ]
[ 78-39-7 ]
[ 85920-63-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 2, p. 365 - 369
26
[ 2033-24-1 ]
[ 64-19-7 ]
[ 85920-63-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 10, p. 3117 - 3121
[2] Journal of the American Chemical Society, 2012, vol. 134, # 4, p. 1962 - 1965
27
[ 2033-24-1 ]
[ 149-73-5 ]
[ 15568-85-1 ]
Yield
Reaction Conditions
Operation in experiment
68%
for 1 h; Reflux
The Meldrum's acid [1] (50.0 g, 347 mmol) and trimethyl orthoformate [2] (184 g) were charged into a 500 mL four-necked flask and heated under reflux for 1 hour. After completion of the reaction, the solvent was removed by an evaporator, and the crude product was recrystallized in a hexane / tetrahydrofuran mixed solvent to give 43.7 g of the compound [66] (yield: 68percent).
59%
at 110℃; for 3 h;
A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (10.0g, 69.4mmol) disolved in trimethoxymethane (40mL, 366mmol) was refluxed at 110°C for 3 hours.Then the reaction mixture was cooled to room temperatue and yellow crystalformed, the crystal was filtered out, washed with petroleum ether and dried in the air to give the titled compound as a light yellow crystaline solid (7.5g,59percent). 1H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 4.27 (s, 3H), 1.72(s, 6H).
Reference：
[1] Synthetic Communications, 1997, vol. 27, # 3, p. 483 - 492
[2] Patent: TWI588139, 2017, B, . Location in patent: Paragraph 71; 72
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 12, p. 2900 - 2906
[4] Tetrahedron, 2002, vol. 58, # 44, p. 9095 - 9100
[5] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 1015 - 1018
[6] Journal of Molecular Structure, 2005, vol. 752, # 1-3, p. 32 - 39
[7] Magnetic Resonance in Chemistry, 2005, vol. 43, # 2, p. 171 - 173
[8] Journal of Organic Chemistry, 2000, vol. 65, # 23, p. 8001 - 8010
[9] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 477 - 479
[10] Patent: WO2004/113303, 2004, A1, . Location in patent: Page 28
[11] Patent: WO2003/101981, 2003, A1, . Location in patent: Page 40
[12] Heterocycles, 2009, vol. 78, # 10, p. 2477 - 2488
[13] New Journal of Chemistry, 2010, vol. 34, # 2, p. 236 - 242
[14] Journal of Medicinal Chemistry, 2010, vol. 53, # 5, p. 2114 - 2125
[15] Patent: WO2010/17132, 2010, A1, . Location in patent: Page/Page column 53-54
[16] Organic and Biomolecular Chemistry, 2011, vol. 9, # 19, p. 6559 - 6565
[17] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
[18] Patent: WO2013/12915, 2013, A1, . Location in patent: Paragraph 00658
[19] Journal of Molecular Structure, 2013, vol. 1038, p. 170 - 176
[20] ChemMedChem, 2015, vol. 10, # 11, p. 1846 - 1862
[21] New Journal of Chemistry, 2018, vol. 42, # 3, p. 1832 - 1839
[22] ChemCatChem, 2018, vol. 10, # 5, p. 965 - 970
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6836 - 6840
[2] MedChemComm, 2013, vol. 4, # 9, p. 1297 - 1304
34
[ 2033-24-1 ]
[ 75-65-0 ]
[ 40052-13-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
for 6 h; Reflux
A 200 mL round-bottom flask equipped with a stirring bar was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione 5 (Meldrum's acid, 5.0 g, 34.7 mmol) and tert-butyl alcohol (40 mL). The reaction was allowed to stir for 6 h at reflux conditions. The reaction mixture was concentrated in vacuo to afford the desired product 6 (5.56 g, 100percent) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 10.51 (br s, 1H), 3.35 (s, 2H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.8, 166.3, 81.9, 42.1, 27.9; HR-FAB MS calcd for C7H13O4 [M+H]+ 161.0814, found 161.0809.
Reference：
[1] Tetrahedron Asymmetry, 2015, vol. 26, # 4, p. 214 - 218
[2] Journal of Organic Chemistry, 2010, vol. 75, # 9, p. 3085 - 3096
[3] Tetrahedron Letters, 2011, vol. 52, # 46, p. 6072 - 6075
[4] Tetrahedron Letters, 1984, vol. 25, # 41, p. 4623 - 4626
[5] Tetrahedron Letters, 1997, vol. 38, # 38, p. 6689 - 6692
[6] Tetrahedron Letters, 2003, vol. 44, # 40, p. 7499 - 7502
[7] Journal of Chemical Research, 2006, # 9, p. 586 - 588
[8] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6553 - 6557
[9] Organic Letters, 2012, vol. 14, # 23, p. 5864 - 5867
[10] Organic Letters, 2013, vol. 15, # 10, p. 2426 - 2429
[11] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4367 - 4371
[12] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 1153 - 1169
[13] Chemical Communications, 2017, vol. 53, # 13, p. 2170 - 2173
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 8, p. 2955 - 2956
38
[ 67-56-1 ]
[ 2033-24-1 ]
[ 79-30-1 ]
[ 42558-54-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6836 - 6840
39
[ 2033-24-1 ]
[ 89-98-5 ]
[ 1643-28-3 ]
Yield
Reaction Conditions
Operation in experiment
67%
at 10 - 100℃; for 4 h;
General procedure: A three-necked flask fitted with a dropping funnel, reflux condenser and thermometer was charged with 85percent formic acid (8 mL, 180 mmol). After cooling the solution to 5 °C, triethylamine (2.7 mL, 27 mmol) was added dropwise maintaining the temperature below 10 °C. Subsequently, 2-bromobenzaldehyde (7a, 5 g, 27 mmol) and Meldrums acid (3.9 g, 27 mmol) were added to the solution and the mixture was refluxed for 4 h. Afterwards the mixture was cooled to an ambient temperature and poured onto ice-cold water (30 mL). The resulting suspension was acidified by 5.5M HCl until pH ≈ 1 and stored in a refrigerator overnight. The precipitated crystals were filtered with suction, washed with water (3 20 mL), dried in desiccator and dissolved in chloroform (100 mL). Undissolved impurities were filtered off. The filtrate was concentrated to the volume of about 10 mL and petroleum ether (15 mL) was added under stirring and heating the solution. After gradual cooling a white solid was formed. Yield 4.17 g (67percent) of solid with mp 93–95 °C (ref. [8] reports 99–100 °C). Proton NMR spectrum is in accordance with ref.[8]
Reference：
[1] Synthetic Communications, 1995, vol. 25, # 19, p. 3067 - 3074
[2] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 884 - 892
[3] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 3, p. 670 - 684
40
[ 2033-24-1 ]
[ 123-11-5 ]
[ 1929-29-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 35, p. 7374 - 7379
41
[ 2033-24-1 ]
[ 100-51-6 ]
[ 40204-26-0 ]
Yield
Reaction Conditions
Operation in experiment
48%
at 80℃; Inert atmosphere
To a flame dried 150 mL pressure tube under argon was added Meldrum’s acid (2.00 g, 13.8 mmol) and anhydrous MeCN (40 mL).To the resulting solution was added benzyl alcohol (1.44 mL, 13.8 mmol), the tube was tightly capped, and refluxed overnight. The reaction was concentrated under reduced pressure and purified with column chromatography (70/30 hexanes/EtOAc) to give 16b (1.28 g, 6.59 mmol) as a colorless oil in 48percent yield.
Reference：
[1] Helvetica Chimica Acta, 2002, vol. 85, # 1, p. 288 - 319
[2] Heterocycles, 1993, vol. 35, # 2, p. 1205 - 1235
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1143 - 1148
[4] Journal of Organometallic Chemistry, 2001, vol. 619, # 1-2, p. 179 - 193
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 21, p. 4933 - 4936
[6] Tetrahedron, 1993, vol. 49, # 17, p. 3479 - 3488
[7] Tetrahedron Letters, 1997, vol. 38, # 44, p. 7737 - 7740
[8] Tetrahedron Letters, 2003, vol. 44, # 40, p. 7499 - 7502
[9] Journal of Chemical Research, 2006, # 9, p. 586 - 588
[10] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6553 - 6557
[11] Organic Letters, 2013, vol. 15, # 10, p. 2426 - 2429
[12] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4367 - 4371
[13] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 1153 - 1169
[14] Chemical Communications, 2017, vol. 53, # 13, p. 2170 - 2173
With formic acid; triethylamine In N,N-dimethyl-formamideLarge scale
General procedure: NEt3 (56.6 g, 0.56 mol) was added dropwise to stirred formicacid (64.4 g, 1.4 mol) at 5 8C. To the resulting reagent were addedDMF (150 ml), Meldrum’s acid (57.6 g, 0.4 mol) and aldehyde 2a–c(60.4 g, 0.4 mol). The reaction mixture was heated at reflux for 4 h.The solvent was evaporated under vacuum.The residue was triturated with water (1000 ml) and acidifiedwith conc. aq HCl to pH = 2. The formed product was filtered off,dried on air, and crystallized from EtOAc (3a) or CCl4 (3b,c) toobtain the pure material.
Reference：
[1] Journal of Fluorine Chemistry, 2015, vol. 171, p. 174 - 176
[2] Archiv der Pharmazie, 2011, vol. 344, # 12, p. 840 - 842
With formic acid; triethylamine In N,N-dimethyl-formamideLarge scale
General procedure: NEt3 (56.6 g, 0.56 mol) was added dropwise to stirred formicacid (64.4 g, 1.4 mol) at 5 8C. To the resulting reagent were addedDMF (150 ml), Meldrum’s acid (57.6 g, 0.4 mol) and aldehyde 2a–c(60.4 g, 0.4 mol). The reaction mixture was heated at reflux for 4 h.The solvent was evaporated under vacuum.The residue was triturated with water (1000 ml) and acidifiedwith conc. aq HCl to pH = 2. The formed product was filtered off,dried on air, and crystallized from EtOAc (3a) or CCl4 (3b,c) toobtain the pure material.
Reference：
[1] Journal of Fluorine Chemistry, 2015, vol. 171, p. 174 - 176
50
[ 2033-24-1 ]
[ 64-17-5 ]
[ 3721-95-7 ]
[ 24922-01-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 34, p. 5629 - 5632
51
[ 67-56-1 ]
[ 2033-24-1 ]
[ 4023-34-1 ]
[ 32249-35-7 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With pyridine In chloroform at 10 - 20℃; for 2 h; Stage #2: for 3 h; Heating / reflux
Reference Example 1 Production of methyl 3-cyclopropyl-3-oxopropionate Merdramic acid (50 g; 347 mmols) was dissolved in chloroform (550 ml), and pyridine (56 g; 700 mmols) was added thereto. Subsequently, a solution of cyclopropanecarboxylic acid chloride (40 g; 383 mmols) in chloroform (50 ml) was added dropwise thereto at a temperature of 10°C or lower while cooling in an ice-bath. After completion of the dropwise addition, the mixture was stirred for further 1 hour under cooling in the ice-bath, then at room temperature for 1 hour. Subsequently, after cooling again using the ice-bath, 1N-HCL aqueous solution (500 ml) was added thereto. The reaction product was extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure. Then, methanol (500 ml) was added thereto to dissolve the residue, and the solution was heated for 3 hours under reflux. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was distilled to obtain 40 g of methyl 3-cyclopropyl-3-oxopropionate. Yield: 80percent Physical properties: bp. 80°C (10mmHg)
Reference：
[1] Patent: EP1852428, 2007, A1, . Location in patent: Page/Page column 31
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6836 - 6840
52
[ 2033-24-1 ]
[ 4023-34-1 ]
[ 32249-35-7 ]
Yield
Reaction Conditions
Operation in experiment
71.1%
With pyridine In dichloromethane at 0 - 20℃;
a.2 2-te/t-Butvl-4-f4-(3-chloro-propvl)-piperazin-1-vll-6-cvclopropvl-pyrimidine; a.2.1: Methyl-2-cvclopropanovl-acetate; 48.6 g of meldrum's acid (337.4 mmol) were dissolved in 200 ml of dichloromethane at room temperature and the solution was cooled to 0°C. 40 g of pyridine (506.1 mmol) were added to said solution. 35.3 g of cyclopropyl carbonic acid chloride (337.4 mmol) were then added at 0°C within 1 h. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCI and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and stirred under reflux for 2h. The reaction mixture was concentrated to dryness and the oily residue was purified by destination at 90 °C bath temperature to yield 42.7 g (71,1 percent) of the title compound.MS (ESI) m/z: 143.1 [M+H]+1H-NMR (CDCI3): 5 [ppm] 3.75 (s, 3H), 3.6 (s, 2H), 2.0 (m, 1H), 1.15 (m, 2H),0.95 (m, 2H)
Reference：
[1] Journal of Combinatorial Chemistry, 2010, vol. 12, # 2, p. 260 - 265
54
[ 2033-24-1 ]
[ 619-73-8 ]
[ 77359-11-6 ]
Yield
Reaction Conditions
Operation in experiment
83%
at 80℃; Inert atmosphere
To a flame dried 150 mL pressure tube under argon was added Meldrum’s acid (5.00 g, 34.7 mmol) and anhydrous MeCN (40 mL). To the resulting solution was added p-nitrobenzyl alcohol (5.58 g, 36.4 mmol), the tube was tightly capped, and refluxed overnight. The reaction was concentrated under reduced pressure and purified with column chromatography (55/45 hexanes/EtOAc) to give 16a (6.86 g, 27.1 mmol) as an off-white solid in 83percent yield. A small crop of this material (1.00 g) was recrystallized from t-butanol/hexanes to give 16a (225 mg, 0.889 mmol) as a white solid.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 21, p. 4933 - 4936
[2] Tetrahedron, 2001, vol. 57, # 9, p. 1837 - 1847
[3] Tetrahedron Letters, 2003, vol. 44, # 40, p. 7499 - 7502
55
[ 2033-24-1 ]
[ 619-73-8 ]
[ 28509-24-2 ]
[ 77359-11-6 ]
Reference：
[1] Patent: US4576746, 1986, A,
56
[ 2033-24-1 ]
[ 94569-84-3 ]
[ 135832-52-9 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6752 - 6755
57
[ 2033-24-1 ]
[ 103718-15-6 ]
[ 158577-01-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
With acetic acid; ethylenediamine In methanol at 0 - 20℃;
2,2-Dimethyl-[1,3]dioxane-4,6-dione, commonly Meldrum's acid, (166.9 g, 1.16 mol) was added to a stirred solution of 2-isopropylaminobenzaldehyde (105 g, 0.64 mol), acetic acid (73.6 mL, 1.29 mol) and ethylenediamine (43.0 mL, 0.64 mol) in methanol (1 L) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then at room temperature overnight. The resulting suspension was filtered and the solid washed with methanol and collected to yield the title intermediate, 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (146 g, 98percent) as an off-white solid. 1H NMR (CDCl3; 300 MHz): 1.72 (d, 6H, CH(CH3)2), 5.50 (bs, 1H, CH(CH3)2), 7.44 (t, 1H, ArH), 7.75-7.77 (m, 2H, ArH), 7.82 (d, 1H, ArH), 8.89 (s, 1H, CH).
98%
With acetic acid; ethylenediamine In methanol at 0 - 20℃;
First, acetone (228.2 mL, 3.11 mol) was added to a stirred suspension of 2-aminophenylmethanol (255.2 g, 2.07 mol) and acetic acid (3.56 mL, 62 mmol) in water (2 L) at room temperature. After 4 h, the suspension was cooled to 0° C. and stirred for an additional 2.5 h and then filtered. The solid was collected and washed with water and the wet solid cooled and dried by lyophilisation to yield 2,2,-dimethyl-1,4-dihydro-2H-benzo[1,3]oxazine (332.2 g, 98percent) as an off-white solid. 1H NMR (CDCl3; 300 MHz): 1.48 (s, 6H, C(CH3)2), 4.00 (bs, 1H, NH), 4.86 (s, 2H, CH2), 6.66 (d, 1H, ArH), 6.81 (t, 1H, ArH), 6.96 (d, 1H, ArH), 7.10 (t, 1H, ArH). A solution of 2,2,-dimethyl-1,4-dihydro-2H-benzo[1,3]oxazine (125 g, 0.77 mol) in THF (1 L) was filtered through a scintillation funnel and then added dropwise via an addition funnel, over a period of 2.5 h, to a stirred solution of 1.0 M LiAlH4 in THF (800 mL) at 0° C. The reaction was quenched by slow portionwise addition of Na2SO4.10H2O (110 g), over a period of 1.5 h, at 0° C. The reaction mixture was stirred overnight, filtered and the solid salts were washed thoroughly with THF. The filtrate was concentrated under reduced pressure to yield 2-isopropylaminophenylmethanol (120 g, 95percent) as a yellow oil. 1H NMR (CDCl3; 300 MHz): 1.24 (d, 6H, CH(CH3)2), 3.15 (bs, 1H, OH), 3.61 (sept, 1H, CH(CH3)2), 4.57 (s, 2H, CH2), 6.59 (t, 1H, ArH), 6.65 (d, 1H, ArH), 6.99 (d, 1H, ArH), 7.15 (t, 1H, ArH). Manganese dioxide (85percent 182.6 g, 1.79 mol) was added to a stirred solution of 2-isopropylaminophenylmethanol (118 g, 0.71 mol) in toluene (800 mL) and the reaction mixture was heated to 117° C. for 4 h. The reaction mixture was allowed to cool to room temperature overnight and then filtered through a pad of Celite which was eluted with toluene. The filtrate was concentrated under reduced pressure to yield 2-isopropylaminobenzaldehyde (105 g, 90percent) as an orange oil. 1H NMR (CDCl3; 300 MHz): 1.28 (d, 6H, CH(CH3)2), 3.76 (sept, 1H, CH(CH3)2), 6.65 (t, 1H, ArH), 6.69 (d, 1H, ArH), 7.37 (d, 1H, ArH), 7.44 (t, 1H, ArH), 9.79 (s, 1H, CHO). 2,2-Dimethyl-[1,3]dioxane-4,6-dione, commonly Meldrum's acid, (166.9 g, 1.16 mol) was added to a stirred solution of 2-isopropylaminobenzaldehyde (105 g, 0.64 mol), acetic acid (73.6 mL, 1.29 mol) and ethylenediamine (43.0 mL, 0.64 mol) in methanol (1 L) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then at room temperature overnight. The resulting suspension was filtered and the solid washed with methanol and collected to yield the title intermediate, 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (146 g, 98percent) as an off-white solid. 1H NMR (CDCl3; 300 MHz): 1.72 (d, 6H, CH(CH3)2), 5.50 (bs, 1H, CH(CH3)2), 7.44 (t, 1H, ArH), 7.75-7.77 (m, 2H, ArH), 7.82 (d, 1H, ArH), 8.89 (s, 1H, CH).
98%
With acetic acid; ethylenediamine In methanol at 0 - 20℃;
2,2-Dimethyl-[1,3]dioxane-4,6-dione, commonly Meldrum's acid, (166.9 g, 1.16 mol) was added to a stirred solution of 2-isopropylaminobenzaldehyde (105 g, 0.64 mol), acetic acid (73.6 mL, 1.29 mol) and ethylenediamine (43.0 mL, 0.64 mol) in methanol (1 L) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then at room temperature overnight. The resulting suspension was filtered and the solid washed with methanol and collected to yield the title intermediate, 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (146 g, 98percent) as an off-white solid. 1H NMR (CDCl3; 300 MHz): 1.72 (d, 6H, CH(CH3)2), 5.50 (bs, 1H, CH(CH3)2), 7.44 (t, 1H, ArH), 7.75-7.77 (m, 2H, ArH), 7.82 (d, 1H, ArH), 8.89 (s, 1H, CH).
98%
With acetic acid; ethylenediamine In methanol at 0 - 20℃;
2,2-Dimethyl-[1,3]dioxane-4,6-dione, commonly Meldrum's acid, (166.9 g, 1.16 mol) was added to a stirred solution of 2-isopropylaminobenzaldehyde (105 g, 0.64 mol), acetic acid (73.6 mL, 1.29 mol) and ethylenediamine (43.0 mL, 0.64 mol) in methanol (1 L) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then at room temperature overnight. The resulting suspension was filtered and the solid washed with methanol and collected to yield the title intermediate, 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (146 g, 98percent) as an off-white solid. 1H NMR (CDCl3; 300 MHz): 1.72 (d, 6H, CH(CH3)2), 5.50 (bs, 1H, CH(CH3)2), 7.44 (t, 1H, ArH), 7.75-7.77 (m, 2H, ArH), 7.82 (d, 1H, ArH), 8.89 (s, H, CH).
98%
With acetic acid; ethylenediamine In methanol at 0 - 20℃;
2,2-Dimethyl-[1,3]dioxane-4,6-dione, commonly Meldrum's acid, (166.9 g, 1.16 mol) was added to a stirred solution of 2-isopropylaminobenzaldehyde (105 g, 0.64 mol), acetic acid (73.6 mL, 1.29 mol) and ethylenediamine (43.0 mL, 0.64 mol) in methanol (1 L) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then at room temperature overnight. The resulting suspension was filtered and the solid washed with methanol and collected to yield the title intermediate, 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (146 g, 98percent) as an off-white solid. 1H NMR (CDCl3; 300 MHz): 1.72 (d, 6H, CH(CH3)2), 5.50 (bs, 1H, CH(CH3)2), 7.44 (t, 1H, ArH), 7.75-7.77 (m, 2H, ArH), 7.82 (d, 1H, ArH), 8.89 (s, 1H, CH).
Reference：
[1] Patent: US2005/228014, 2005, A1, . Location in patent: Page/Page column 17
[2] Patent: US2006/100426, 2006, A1, . Location in patent: Page/Page column 19
[3] Patent: US2006/100236, 2006, A1, . Location in patent: Page/Page column 21
[4] Patent: US2006/199839, 2006, A1, . Location in patent: Page/Page column 24
[5] Patent: US2006/229332, 2006, A1, . Location in patent: Page/Page column 9
[6] Heterocycles, 2000, vol. 53, # 11, p. 2471 - 2485
[7] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 1, p. 29 - 39
58
[ 7521-41-7 ]
[ 2033-24-1 ]
[ 64-17-5 ]
[ 5174-90-3 ]
Yield
Reaction Conditions
Operation in experiment
76%
at 60 - 80℃; for 7 h;
General procedure: Anhydrous FeCl3 (0.05 mmol) was added to a stirred solution of 2-aminonicotinaldehyde (1, 0.01 mmol) and Meldrum’s acid (2, 0.01 mmol) in alcohol 3a–3k(3 mL). The mixture was heated on an oil bath at 60–80°C for 6-8 h. The mixture was then cooled down to room temperature, and excess alcohol was removed under reduced pressure. The residue was purified by column chromatography on silica gel with ethylacetate and petroleum ether (1 : 6, v/v) as eluent. Th eyields and melting points of compounds 4a–4k are given in Table 1.
Reference：
[1] Russian Journal of General Chemistry, 2018, vol. 88, # 6, p. 1224 - 1227[2] Zh. Obshch. Khim.,
Stage #1: With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20 - 50℃; for 2 - 3 h; Stage #2: With hydrogenchloride In acetonitrile at 0℃; for 1 h;
2,4,5-Trifluorophenylacetic acid (2-1) (available from several commercial supplers) (25 g, 0.132 mol), Meldrum's acid (21 g, 0.145 mol), and DMAP (1.29 g, 0.0011 mol) were charged into a 1000 mL three-neck flask. Acetonitrile (75 mL) was added in one portion at room temperature. N,N-diisopropylethylamine (49.2 mL, 0.283 mol) was added in one portion at room temperature while maintaining the temperature below 40 C. Pivaloyl chloride (17.8 mL, 0.145 mol) was added dropwise over 1 to 2 h while maintaining the temperature below 50 C. The reaction was aged at 45-50 C for 2-3 h and cooled to 0 C. 1N HCl (300 mL) was added dropwise over 1 h while the Meldrum's adduct 2-2 was crystallized out. The product was collected by filtration and washed with 20percent MeCN/ water. After drying, 36.5 g of the Meldrum's acid adduct was obtained (88percent yield). 1H-NMR (400 MHz, CDCl3): δ 15.50 (s, 1H), 7.14 (m, 1H), 6.96 (m, 1H), 4.45 (s, 2H), 1.76 (s, 6H) ppm. 13C-NMR (100 MHz, CDCl3): δ 192.76, 170.66, 160.42, 156.47 (ddd, J CF = 245.7, 9.6, 2.4 Hz), 149.79 (ddd, J CF = 251.4, 14.5, 12.0 Hz), 146.90 (ddd, J CF = 244.9, 12.0, 3.2 Hz), 119.40 (dd, J CF = 19.3, 5.6 Hz), 117.41 (ddd, J CF = 18.5, 5.6, 4.0 Hz), 105.80 (dd, J CF = 28.1, 20.9 Hz), 105.63, 91.99, 34.59, 27.06 ppm.
85%
Stage #1: With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 0.75 h; Cooling with ice Stage #2: at 45℃;
Under ice bath conditions,To a 2 L three-necked reaction flask equipped with 800 mL of acetonitrile,2,4,5-trifluorophenylacetic acid was added(285.2 g, 1.5 mol, 1 eq),Pivaloyl chloride(199.0 g, 1.65 mol, 1.1 eq), DMAP (1.8 g, 0.015 mol, 0.01 eq),DIPEA (387.6 g, 3.0 mol, 2.0 eq),Stirred at room temperature for 45min,Meldrum's acid (237.8, 1.65 mol, 1.1 eq) was added and the temperature was raised to 45 ° C. to react overnight.TLC detection of the reaction process. After the reaction was completed, cooled to room temperature,1M hydrochloric acid was slowly added, Solid generation. The resulting solid was washed with water and recrystallized from acetonitrile-water to give a white solid,Yield 85percent.
80%
With 1,1'-carbonyldiimidazole In tetrahydrofuran at 51℃; for 3.08333 h;
2,4,5-Trifluorophenylacetic acid (2-1) (11.4 g, 60 mmol) was dissolved in THF (60 mL) and 1,1'-carbonyldiimidazole (10.7 g, 66 mmol) was added over 5 min. The mixture was warmed to 51 C, Meldrum's acid (9.51 g, 66 mmol) was added, and the mixture was aged for 3 h. The reaction mixture was diluted with IPAc (60 mL) and water (60 mL), and the pH was adjusted to 2.4 with concentrated hydrochloric acid (11.5 mL). The aqueous layer was separated, and the orgnic layer was washed at 36 C with 0.1 N HCl (60 mL). The organic layer was concentrated, flushed with IPAc, and the residue was slurried in 2:1 heptane/IPAc (70 mL). the mixture was cooled over an ice-bath, then filtered, rinsing the solid with 2:1 heptane/IPAc. After drying, the Meldrum's acid adduct was obtained as a solid (15.1 g) in 80percent yield. The Meldrum's acid adduct (22.1 g, 70 mmol) and the triazole hydrochloride 1-4 (16.0 g, 70 mmol) were sluuried in IPAc (220 mL) and N,N-diisopropylethylamine (12.8 mL) was added. After aging for 3.5 h at 85 C, water (175 mL) was added and the mixture was transferred to a separatory funnel with a 40-mL rinse with IPAc. The aqueous layer was separated and the organic layer was washed with water (100 mL). The organic layer was partially concentrated under reduced pressure to give a 65 g of solution of the ketoamide 2-3 in IPAc. n-Heptane (30 mL) was added at roo temperature, followed by seed crystals of ketoamide. Additional heptane (20 mL) was added dropwise, and the mixture was stirred overnight. Additional heptane (50 mL) was added slowly and after aging for 2 h, the solids were filtered and washed with 2.2:1 heptane/IPAc (30 mL). After drying, the ketoamide 2-3 was obtained in 92percent yield (26.3 g).
80.7%
at 0 - 45℃; Inert atmosphere
Under nitrogen protection,Compound A was added sequentially to a 1000 mL three-necked flask(100 g, 0.524 mol),Compound B (84 g, 0.583 mol),DMAP (5.2 g, 0.042 mol),Acetonitrile (250 mL),Cooling to 0 ~ 5 .Temperature control 0 ~ 30 ,Triethylamine was added dropwise to the system(150 mL, 1.079 mol).Cooling to 0 ~ 5 ,To the system, pivaloyl chloride was added dropwise(76 mL, 1.17 mol),Dropping temperature below 30 , plus complete,And the temperature was raised to 40 to 45C. 3 to 5 hours later,At the end of the reaction,Cooling to 25 ~ 30 .filter, The filter cake was washed twice with 200 mL of methyl tert-ether,The solvent was distilled off under reduced pressure (<30C) to 3-fold volume (viscous).600 mL of methylene chloride was added,The mixture was stirred for 5 minutes (25 to 30 ° C)Approximately 300 mL of 1.5 M hydrochloric acid was added dropwise over 15 minutes,Adjust the pH = 2 ~ 3.The DCM phase was washed with 100 mL of saturated brine, and the organic phase was evaporated in vacuo for 2 times the volume of the solvent (<15C)200 mL of n-heptane was added,The solvent was distilled off under reduced pressure (<15C)50 mL of ethyl acetate was added,Heptane 300 mL was beaten for 2 hours.Filtration,100 ml (n-heptane:Ethyl acetate = 10: 1)Dried to obtain 134.23 g of product,Yield 80.7percent.
65%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 25 - 30℃; Stage #2: at 50 - 55℃; for 6 h;
Meldrum's Adduct (19)2,4,5-Trifluorophenylacetic acid (500.0 gm, 2.63 mol) (18) was suspended in tetrahydrofuran (5.26 vol, 2.63 Ltr) at 25-30° C. and the reaction mixture was stirred for 10-15 minutes. To this clear solution, 1,1'-carbonyldiimidazole (1.5 eq, 639.68 gm) was charged in four lots and the reaction mixture was stirred for 2-3 hours at 25-30° C. After 2-3 hours stirring, Meldrum's acid (1.2 eq, 454.87 gm) was charged and the reaction mixture was heated for 6 hours at 50-55° C. After 6 hours heating at 50-55° C., the tetrahydrofuran was distilled out completely at 50-55° C. under reduced pressure to give a dark yellow coloured residue. The dark yellow residue was acidified by using a 1:1 mixture of 35percent hydrochloric acid:water (0.5 vol, 250.0 ml) at 0-5° C. The product was extracted from the aqueous solution by using dichloromethane (3.x.5.0 vol, 3.x.2.5 Ltr). The combined dichloromethane layers were further washed with water (3.x.10.0 vol, 3.x.5.0 Ltr). After water washing, the dichloromethane was completely distilled under reduced pressure to give a dark yellow fluffy solid. The product was further washed with methanol (2.0 vol, 1.0 Ltr) at 0-5° C.Molar Yield: 60-65percent (505.0 gm)Chemical Purity: 98-99.5percent (as measured by HPLC)
60.1%
With 1,1'-carbonyldiimidazole In tetrahydrofuran at 50℃; for 5 h;
2,4,5-trifluorophenylacetic acid (30 g), tetrahydrofuran (360 ml_), 1 ,1 -carbonyl diimidazole (25.5 g) at about 5O0C, and meldrums acid (22.7 g) are combined. The mixture is stirred for about five hours at the same temperature. The reaction mass is then cooled to about 3O0C. Isopropyl acetate (180 ml_) and water (180 ml_) are added and stirred for about 30 minutes. The reaction mass is cooled to about O0C and pH is adjusted to about 2.4 using 36percent aqueous hydrochloric acid. The organic layer is separated, washed with 0.1 N aqueous hydrochloric acid and distilled off completely. To the residue obtained, n-heptane (140 ml_) and isopropyl acetate (70 ml_) are charged at about 3O0C and stirred at about O0C for about 90 minutes. The separated solid is filtered and washed with a mixture of n-heptane (20 ml_) <n="30"/>and isopropyl acetate (10 ml_). The wet cake is dried at about 5O0C for about 4 hours to afford the title compound. (Yield: 60.1 percent; purity by HPLC: 98.0percent)
60%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 25 - 30℃; Stage #2: at 50 - 55℃; for 6 h;
Meldrum's adduct (19)2,4,5-Trifluorophenylacetic acid (500.0 gm, 2.63 mol) (18) was suspended in tetrahydrofuran (5.26 vol, 2.63 Ltr) at 25-30°C and the reaction mixture was stirred for 10- 15 minutes. To this clear solution, l,r-carbonyldmidazole (1.5 eq, 639.68 gm) was charged in four lots and the reaction mixture was stirred for 2-3 hours at 25-300C. After 2- 3 hours stirring, Meldrum's acid (1.2 eq, 454.87 gm) was charged and the reaction mixture was heated for 6 hours at 50-550C. After 6 hours heating at 50-55°C, the tetrahydrofuran was distilled out completely at 50-55°C under reduced pressure to give a dark yellow coloured residue. The dark yellow residue was acidified by using a 1:1 mixture of 35percent hydrochloric acid : water (0.5 vol, 250.0 ml) at 0-50C. The product was extracted from the aqueous solution by using dichloromethane (3 x 5.0 vol, 3 x 2.5 Ltr). The combined dichloromethane layers were further washed with water (3 x 10.0 vol, 3 x 5.0 Ltr). After water washing, the dichloromethane was completely distilled under reduced pressure to give a dark yellow fluffy solid. The product was further washed with methanol (2.0 vol, 1.0 Ltr) at 0-50C.Molar Yield: 60-65percent (505.0 gm) Chemical Purity: 98-99.5percent (as measured by HPLC)
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2622 - 2628
[2] Journal of the American Chemical Society, 2004, vol. 126, # 40, p. 13002 - 13009
[3] Journal of the American Chemical Society, 2009, vol. 131, # 25, p. 8798 - 8804
[4] Patent: WO2004/83212, 2004, A1, . Location in patent: Page 11-12
[5] Patent: CN107501112, 2017, A, . Location in patent: Paragraph 0061; 0062; 0063; 0064
[6] Patent: WO2004/83212, 2004, A1, . Location in patent: Page 12
[7] Patent: CN105566138, 2016, A, . Location in patent: Paragraph 0042; 0043; 0044
[8] Patent: US2012/108598, 2012, A1, . Location in patent: Page/Page column 9
[9] Patent: WO2009/85990, 2009, A2, . Location in patent: Page/Page column 27-28
[10] Patent: WO2010/131025, 2010, A1, . Location in patent: Page/Page column 25-26
[11] Patent: WO2004/85378, 2004, A1, . Location in patent: Page 16
[12] Patent: WO2005/97733, 2005, A1, . Location in patent: Page/Page column 23
[13] Patent: WO2006/33848, 2006, A1, . Location in patent: Page/Page column 11
[14] Patent: WO2007/35198, 2007, A2, . Location in patent: Page/Page column 10-11
[15] Patent: WO2007/50485, 2007, A2, . Location in patent: Page/Page column 34-35
[16] Patent: WO2005/20920, 2005, A2, . Location in patent: Page/Page column 11-12
[17] Patent: WO2009/84024, 2009, A2, . Location in patent: Page/Page column 22-23
[18] Patent: WO2005/72530, 2005, A1, . Location in patent: Page/Page column 11-12
[19] Patent: WO2006/65826, 2006, A2, . Location in patent: Page/Page column 21; 22
[20] Patent: US2010/317856, 2010, A1, . Location in patent: Page/Page column 11
[21] Patent: WO2012/42534, 2012, A2, . Location in patent: Page/Page column 26-27
[22] Patent: CN102363599, 2016, B, . Location in patent: Paragraph 0025; 0026
[23] Patent: CN103923087, 2016, B, . Location in patent: Paragraph 0054-0056
[24] Patent: WO2006/119260, 2006, A2, . Location in patent: Page/Page column 43-44
[25] Patent: WO2005/20920, 2005, A2, . Location in patent: Page/Page column 11-12
61
[ 2033-24-1 ]
[ 209995-38-0 ]
[ 764667-65-4 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20 - 50℃; for 2 - 3 h; Stage #2: at 40 - 70℃; Stage #3: With sodium hydrogencarbonate In N,N-dimethyl acetamide; water at 20 - 45℃;
2,4,5-Trifluorophenylacetic acid (2-1) (150 g, 0.789 mol), Meldrum's acid (125 g, 0.868 mol), and DMAP (7.7 g, 0.0063 mol) were charged into a 5 L three-neck flask. DMAc (525 mL) was added in one portion at room temperature. N,N-diisopropylethylamine (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 C. Pivaloyl chloride (107 mL, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature below 50 C. The reaction was aged at 45-50 C for 2-3 h. Triazole hydrochliride 1-4 (180 g, 0.789 mol) was added in one portion at 40-50 C. The reaction solution was aged at 70 C for several h. 5percent Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20 - 45 C. The batch was seeded and aged at 20 - 30 C for 1-2 h. Then the additional 525 mL of 5percent aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was further cooled to 0-5 C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20percent aqueous DMAc (300 mL), followed by an aditional two batches of 20percent aqueous DMAc (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. The isolated yield of final product was 89percent.In CD3CN solutiob, 2-3 exists as a 4:3 mixture of amide rotamers (hindered rotation around the Nitrogen-Carbonyl bond). Severe overlap of signals does not permit unequivocal assignment of each rotamer. Assignments are grouped (when necessary) and rotamers (major/minor/both) denoted. Complexity due to 19F spin-spin coupling does not permit assignment of all 13C resonances, therefore, select 13C data are presented. The structure shown is the major rotamer in solution. 1H-NMR (400 MHz, CD3CN): δ 7.23-7.07 (overlaping m, 2H, both), 4.91 (s, 2H, major), 4.81 (s, 2H, minor), 4.16 (t, J = 5.6 Hz, 2H, major), 4.11 (t, J = 5.6 Hz, 2H, minor), 4.00 (t, J = 5.6 Hz, 2H, minor), 3.92 (s, 2H, major), 3.91 (s, 2H, minor), 3.83 (t, J = 5.6 Hz, 2H, major), 3.80 (s, 2H, major), 3.78 (s, 2H, major), 3.91 (s, 2H, minor) ppm. 13C NMR (100 MHz, CD3CN, selected data): δ 201.43 (both), 167.37 (minor), 167.27 (major), 151.88 (major), 151.53 (minor), 48.88 (minor), 48.81 (major), 44.65 (major), 44.19 (minor), 43.86 (minor), 43.08 (major), 43.00 (both), 39.82 (major), 38.81 (minor) ppm.
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 25, p. 8798 - 8804
[2] Patent: WO2004/83212, 2004, A1, . Location in patent: Page 10-11
[3] Patent: WO2004/83212, 2004, A1, . Location in patent: Page 10
[4] Patent: US2006/270722, 2006, A1, . Location in patent: Page/Page column 18
[5] Patent: WO2011/25932, 2011, A2, . Location in patent: Page/Page column 17-18
62
[ 2033-24-1 ]
[ 764667-65-4 ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: With 1,1'-carbonyldiimidazole In Isopropyl acetate at 45℃; for 0.166667 h; Stage #2: at 20 - 40℃; for 25.5 h; Stage #3: at 90℃; for 12 h;
To 45 mL of IPAc was added the trifluorophenylacetic acid (5 g), CDI (4.3 g), and the resulting mixture was heated to 45 C for 10 min. The reaction was allowed to cool to 20 C and degassed. Meldrum's acid (4.2 g) was added and the mixture was aged 24 h at 20 C, and then 1.5 h at 40 C. The triazole hydrochloride 1-4 (6 g) was added and the reaction mixture was stirred for 12 h at 90 C. The reaction mixture was washed with water (2 x 50mL). The solution ontained 7.8 g pf the product 2-3 (71percent yield).
69%
Stage #1: With 1,1'-carbonyldiimidazole In ISOPROPYLAMIDE at 45℃; for 0.166667 h; Stage #2: at 20 - 50℃; for 25 h; Stage #3: at 90℃; for 12 h;
To 25 mL of DMAc was added the trifluorophenylacetic acid (5 g), CDI (4.3 g), and the resulting mixture was heated to 45 C for 10 min. The reaction was allowed to cool to 20 C and degassed. Meldrum's acid (4.2 g) was added and the mixture was aged 24 h at 20 C and then 1 h at 50 C. The triazole hydrochloride 1-4 (6 g) was added and the reaction mixture was stirred for 12 h at 90 C. The reaction mixture was cooled to 50 C and water (40 mL) was added crystallizing the product. The slurry was cooled to 20 C and stirred for 12 h and water (35 mL) was added over 3 h. After 2 h, the solid was isolated by filtration and dried to give 7.4 g of 2-3 (69percent yeild).
Stage #1: With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 50 - 55℃; Stage #2: With trifluoroacetic acid In N,N-dimethyl acetamide at 55℃; for 6 h;
In 2000 mL of three necked flask , 150g(0.789mil)2,4,5- Trifluorophenylacetic acid,125g(0.86mol) isopropylidene malonate and 7.7g(63mol)DMAP(4-dimethylaminopyridine) were addded , plus 525 ml DMA (N,N- Dimethylacetamide) was dissolved with magnetic stirring .296mL(1.696mol)DIPEA(N,N-Diisopropylethylamine) was added at room temperature . The oil bath was heated to a reaction temperature of 50 ° C and 107 mL (0.868 mol) of pivaloyl chloride was added dropwise,Keeping the temperature above 55 ° C (1-2h). After completion of the dropwise addition at 55 ° C for 2 h, 3- (trifluoromethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyrazine (0.789 mol) was added, followed by 18 mL (0.237 mol) of trifluoroacetic acid was added dropwise, keeping the temperature at 55° C for 6 h. After cooling, 625 mL of 5percent sodium bicarbonate solution was added, after adding 5g of the compound shown in the formula I keep temperature at 20 ~ 30 ° C and stirring for 2h,add 5percent of sodium bicarbonate solution dropwise for 3 h, Stir at room temperature until no more solids are produced, after cooling to 5 ° C for 1 h, filtered and washed using three times with 200 mL of 20percent DMA solution, washed with 400 mL of water and vaccum drying to obtain 269 g of solid which was tested as a compound of formula I in 84percent yield,m/z:407.15[M+H]+.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 2047 - 2057
65
[ 2033-24-1 ]
[ 99-09-2 ]
[ 933486-43-2 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 6, p. 2232 - 2235
66
[ 2033-24-1 ]
[ 3303-84-2 ]
[ 845267-78-9 ]
Yield
Reaction Conditions
Operation in experiment
71%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 12 h;
Step ii: tert-butyl 2,4-dioxopiperidine-l-carboxylate To a 250 mL round bottom flask, were added 3-((tert-butoxycarbonyl)amino)propanoic acid (4 g, 0.0211 mol), Meldrum's acid (3.66 g, 0.0253 mol), 4-dimethylaminopyridine (3.92 g, 0.0316 mol) and anhydrous dichloromethane (100 mL). The reaction mixture was cooled to 0 °C. To the same flask, EDCI.HC1 (6.01 g, 0.0316 mol) was added. The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with dichloromethane and washed with 5 percent aqueous potassium hydrogen sulfate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get residue. The residue was dissolved in ethyl acetate (100 mL) and refluxed for 4 h. The volatiles were evaporated under reduced pressure to get the title compound [3.2 g, 71 percent].1H NMR (300 MHz, CDCls): δ 4.12 (t, 2H), 3.51 (s, 2H), 2.64 (t, 2H), 1.55 (s, 9H). LCMS: 211.9 (M-H)+.
Reference：
[1] Patent: WO2015/101928, 2015, A1, . Location in patent: Page/Page column 52; 53
[2] Angewandte Chemie - International Edition, 2014, vol. 53, # 14, p. 3594 - 3598[3] Angew. Chem., 2014, vol. 126, # 14, p. 3668 - 3672,5
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 34, p. 7651 - 7657
67
[ 2033-24-1 ]
[ 27492-84-8 ]
[ 149-73-5 ]
[ 205448-64-2 ]
Yield
Reaction Conditions
Operation in experiment
89.62%
at 90℃; for 1 h;
Methyl 2-methoxy-4-amino-benzoate (500.00 g, 2.76 mol), 2,2-dimethyl-1,3-dioxane-4,6-dione (397.73 g, 2.76 mol) and trimethyl orthoformate (292.84 g, 2.76 mol) were added to isopropanol (5.00 L). The reaction solution was heated up to an outer temperature of 90 °C and kept refluxing for 1 hour. The completion of the reaction was detected by TLC. The reaction solution was cooled to an outer temperature of 20 °C in an ice bath and then filtered. The solid was washed with MTBE (300 ml * 2) and then concentrated to dryness in a water bath. Compound 1A (873.00 g, 2.47 mol, the yield was 89.62percent and the purity was 95percent) was obtained as a light red powder. NMR (DMSO) demonstrated that the product was correct. 1H NMR (400 MHz, DMSO-d6) ppm 1.67 (s, 6 H) 3.76 (s, 3 H) 3.86 (s, 3 H) 7.19 (dd, J=8.41, 1.63 Hz, 1 H) 7.43 (d, J=1.25 Hz, 1 H) 7.71 (d, J=8.28 Hz, 1 H) 8.69 (d, J=10.04 Hz, 1 H) 11.25 (d, J=9.03 Hz, 1 H)
Stage #1: With pyridine; thionyl chloride In dichloromethane at 25℃; for 0.333333 h; Stage #2: With dmap In dichloromethane for 1 h; Stage #3: for 4 h; Heating / reflux
SOCl2 (18.5 mL) was added slowly under N2 to a stirred mixture of the acid (50.0 g, 218 mmol) and pyridine (44.0 mL) in anhydrous CH2Cl2 (300 mL). The mixture was stirred at 25° C. for 20 min, then Meldrum's acid (35.0 g, 243 mmol) and DMAP (66.6 g, 546 mmol) were added and the mixture was stirred under N2 for 1 hr. Then Et2O (2 L) was added, the mixture was washed with 1 M HCl (3.x.500 mL), brine (500 mL), and the organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was dissolved in MeOH (580 mL), and the mixture was refluxed for 4 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 10:1 CH2Cl2/EtOAc as eluent. Pale yellow oil (26.5 g, 43percent) was obtained.
43%
Stage #1: With pyridine; thionyl chloride In dichloromethane at 25℃; for 0.333333 h; Inert atmosphere Stage #2: With dmap In dichloromethane for 1 h; Inert atmosphere Stage #3: for 4 h; Reflux
SOCl2 (18.5 mL) was added slowly under N2 to a stirred mixture of the acid (50.0 g, 218 mmol) and pyridine (44.0 mL) in anhydrous CH2Cl2 (60 mL). The mixture was stirred at 25 °C for 20 min, then Meldrum's acid (35.0 g, 243 mmol) and DMAP (66.6 g, 546 mmol) were added and the mixture was stirred under N2 for 1 hr. Then Et2O (2 L) was added, the mixture was washed with 1 M HC (3 x 500 mL), brine (500 mL), and the organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was dissolved in MeOH (580 mL), and the mixture was refluxed for 4 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 10:1 CH2Cl2/EtOAc as eluent. Pale yellow oil (26.5 g, 43 percent) was obtained.
Stage #1: With pyridine; thionyl chloride In dichloromethane at 25℃; for 0.333333 h; Stage #2: With dmap In dichloromethane for 1 h; Stage #3: for 4 h; Heating / reflux
SOCl2 (18.5 mL) was added slowly under N2 to a stirred mixture of the acid (50.0 g, 218 mmoi) and pyridine (44.0 mL) in anhydrous CH2CI2 (300 mL). The mixture was stirred at 250C for 20 min, then Meldrum's acid (35.0 g, 243 mmol) andDMAP (66.6 g, 546 mmol) were added and the mixture was stirred under N2 for 1 hr.Then Et2O (2 L) was added, the mixture was washed with 1 M HCI (3x500 mL), brine(500 mL), and the organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was dissolved in MeOH (580 mL), and the mixture was reffuxed for 4 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 10:1 CH2CI2ZEtOAc as eiuent. Pale yellow oil (26.5 g, 43 percent) was obtained.
Description 34; 5-[(4-Fluoro-3-methoxvphenvl) aminolmethvlene}-2, 2-dimethvl- 1 3-dioxane-4, 6-dione; To a stirred solution of <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (20 g, 142 mmol) in acetonitrile (200 ml) was added 2, 2-dimethyl-1, 3-dioxane-4,6-dione (Meldrum's acid) (22.5 g, 156 mmol) followed by trimethyl orthoformate (18.6 ml, 170 mmol). The mixture was heated to reflux for 3 hours. The cooled mixture was filtered to give the title compound (30.9 g, 74%). 1H NMR (400 MHz, CDCl3) 1.76 (6 H, s), 3.94 (3 H, s), 6.76-6. 83 (2 H, m), 7.14 (1 H, dd, J10. 5 and 8.4), 8.56 (1 H, d, J14. 4), 11.23 (1 H, d, J14.4).
In acetonitrile; at 80℃; for 16h;
[0579] Procedure: To a stirred solution of <strong>[64465-53-8]4-fluoro-3-methoxyaniline</strong> (3 g, 21.25 mmol) in ACN (30 mL), Meldrum's acid (3.9 g, 27.63 mmol) and trimethyl orthoformate (3.25 mL, 29.75 mmol) were added at room temperature. The resulting mixture was heated to 80 C for 16 h. The progress of the reaction was monitored by TLC. Reaction mixture was cooled to room temperature and evaporated the solvent under reduced pressure. The crude product was triturated with n-pentane (3 x 50 mL) and decanted, dried to afford 5-(((4-fluoro-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as brown solid (6 g , crude). LC-MS (ES) m/z = 293.9 [M-H]+.
With pyridine; In N-methyl-acetamide; methanol; dichloromethane;
1-Methyl, 8-tert-butyl 3-oxo-1,8-octanedioate A solution of <strong>[52221-07-5]mono-tert-butyl adipate</strong> (7.8 g, 37.5 mmol) in dichloromethane (175 ml) was treated with oxalyl chloride (9.8 ml, 112.5 mmol) followed by ten drops of dimethylformamide. The reaction was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was dried under vacuum. To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (5.42 g, 37.6 mmol) in dichloromethane (30 ml) at 0° C. was added pyridine (6.1 ml, 75 mmol) followed by the crude acid chloride in a solution of dichloromethane (30 ml). The reaction was stirred at 0° C. for 1 hour and at room temperature for 2 hours. The reaction was then washed with water and dried over anhydrous magnesium sulfate, filtered and concentrated. The crude residue was then dissolved in methanol and refluxed for 3 hours. The solvent was evaporated and the residue was purified by silica gel chromatography to give the title material (5.82 g, 60percent) as an oil.
To a solution of p-fluoroaniline (3.03 mL, 31.5 mmol, 1 equiv) in ethanol (30 mL) were added Meldrum's acid (5.54 g, 38.4 mmol, 1.2 equiv) and triethyl orthoformate (12.4 mL, 74.5 mmol, 2.4 equiv). The mixture was heated to reflux for 2.5 h. The reaction was cooled to 0 °C and the solid was filtered and washed with cold ethanol. The dried solid was added portiowise over 5 mins to boiling diphenyl ether (100 mL). Reflux was maintained for an additional 3 mins. The reaction was stirred at room temperature for 30 mins before petroleum ether (25 mL) was added and the solid was filtered and dried. The crude product was purified by column chromatography on silica gel (EtOAc/MeOH 95:5), to afford 6-fluoroquinolin-4-ol (2.36 g, 14.5 mmol, 46percent). The analyses were consistent with the data reported in the literature. Ref: WO2010/123995 (2010) TLC Rf 0.41 (EtOAc/MeOH 95:5) 1HNMR (400MHz, DMSO-de) delta (ppm) 11.90 (s, 1H, OH), 7.94 (d, J=7.6, 1H, NCH), 7.73 (m, 1H, NCCH), 7.53-7.67 (m, 2H, FCCH, FCCH), 6.04 (d, J=7.3, 1H, OHCCH) ppm CNMR (101 MHz, DMSO-de) delta (ppm) 159.9 (7), 157.7 (5), 140.0 (2), 137.2 (10), 127.3 (4), 121.1 (6), 120.8 (1), 109.5 (3), 108.3 (8) ppm IR (neat) v max 2768 (br), 1594 (m) cm"1 LCMS (ESI+) m/z 164.1 [M+H]+, 186.1 [M+Na]+ 11 RMS (ESI+) m/z calcd. 164.0506 m/z meas. 164.0509 [M+H] Mpt 227 - 228 °C
With orthoformic acid triethyl ester; In ethanol; for 2.5h;Heating / reflux;
To a mixture of 4-fluoro-aniline (25.O g, 224.9 mmol) in EtOH (17O mL) were added successively Meldrum's acid (35.69 g, 247.6 mmol) and triethyl orthoformate (40.O mL, 240.4 mmol). The reaction mixture was then refluxed for 2 h 30 min. The reaction mixture was cooled to 00C and the solid was filtered and washed with cold EtOH. The solid was dried under HV to give 54.62 g of a yellow powder. To a boiling solution of diphenyl ether (230 g) was added the latter solid portion wise over 5 min. The reflux was maintained for further 3 min and the reaction mixture was allowed to stir at rt. After 30 min at rt, ether was added and the desired solid was filtered, thoroughly washed with ether and dried under HV to afford the title compound as a brown solid (11.11 g, 68.1 mmol). MS (ESI, mix): 164.1 [M+H+].
Intermediate 12: 5-([3-iodo-4-(methoxy)phenyl]amino}methylidene)-2,2-dimethyl- 1 ,3-dioxane-4,6-dione; A mixture of 2,2-dimethyl-1 ,3-dioxane-4,6-dione (203g, 1.4mol) and trimethoxymethane (1 -51) was heated to reflux for 1 h, then the <strong>[74587-12-5]3-iodo-4-methoxy-aniline</strong> (349.2g, 1 .402mol) was added portionwise. The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature. The resulting precipitate was filtered off, washed with diisopropyl ether and dried to give the title compound as a beige powder (485g, 85.9%)1H NMR (300 MHz, DMSO-d6, ppm) delta : 1 1.2 (d, J=14.6Hz, 1 H), 8.50-8.39 (m,1 H), 8.05 (d, J=2.7Hz, 1 H), 7.60 (dd, J=8.9, 2.7Hz, 1 H), 7.05 (d, J=8.9Hz, 1 H), 3.84 (s, 3H), 1.67 (s,6H).
85.9%
Intermediate 12: 5-([3-iodo-4-(methoxy)phenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (203 g, 1.4 mol) and trimethoxymethane (1.51) was heated to reflux for 1 h, then the <strong>[74587-12-5]3-iodo-4-methoxy-aniline</strong> (349.2 g, 1.402mol) was added portionwise. The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature. The resulting precipitate was filtered off, washed with diisopropyl ether and dried to give the title compound as a beige powder (485 g, 85.9%) 1H NMR (300 MHz, DMSO-d6, ppm) delta: 11.2 (d, J=14.6 Hz, 1H), 8.50-8.39 (m, 1H), 8.05 (d, J=2.7 Hz, 1H), 7.60 (dd, J=8.9, 2.7 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 3.84 (s, 3H), 1.67 (s, 6H).
80%
In ethanol; for 2h;Reflux;
To a solution of compound 50 (22.0 g, 883 mmol) in ethanol (120 ml) were added trimethyl orthoformate (10.6 ml, 97.1 mmol) and Meldrums acid (15.2 g, 106 mmol). The resulting mixture was heated to reflux for 2 h, cooled to room temperature and filtered. The filtrate was washed with ethanol and dried under vacuum to give the title compound 63 (29.0 g, 80%) . 1HNMR (400 MHz, DMSO-dc) delta : 11.15 (d, J = 14.8 Hz, IH) , 8.42 (d, J = 14.4 Hz, IH) , 8.01 (d, J = 2.8 Hz, IH) , 7.56 (dd, J = 6.0, 8.8 Hz, IH) , 7.01 (d, J = 9.2 Hz, IH) , 3.81 (s, 3H) , 1.64 (s, 6H) .
With laccase; benzotriazol-1-ol; In aq. phosphate buffer; at 5 - 20℃; for 12h;pH 7;Green chemistry; Enzymatic reaction;
General procedure: Catechol or hydroquinone (1 mM) and Meldrum?s acid(2 mM) were taken in 15 mL of phosphate/citrate bufferpH 7 solution. Then, purified laccase (400 U) and0.01 mmol of HBT were added to the resultant solutionand stirred well at 5 8C with a magnetic stirrer. Thetemperature of the reaction mixture was graduallyincreased up to room temperature. The progress of thereaction was monitored by TLC examination at intervals of30 min. Upon completion of the reaction, approximatelyafter 12 h, the reaction mixture was extracted withethylacetate (3 15, i.e. three-time extraction with 15 mLof ethylacetate). The organic layer was dried overanhydrous Na2SO4. The aqueous phase was further usedfor another run without any pre-treatment. The productwas purified by column chromatography using aluminiumoxide as a stationary phase and hexane:ethyl acetate(80:20) as a mobile phase. Products were unambiguouslycharacterized by spectral data
With triethylammonium formate; at 20 - 95℃; for 16h;
3-(4-Bromo-2,5-difluorophenyl)acrylic acid To a solution of <strong>[357405-75-5]4-bromo-2,5-difluorobenzaldehyde</strong> (15.0 g) in triethylamine formiate (80 mL) at room temperature was added 2,2-dimethyl-1,3-dioxane-4,6-dione (9.77 g). After being stirred for 1 h, the mixture was heated at 95° C. with stirring for 15 hours. After cooling down, ice water was added. The mixture was adjusted to pH ?1 with HCl (6 M) and then extracted with ethyl acetate (200 mL*3). The organic phase was washed with brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with DCM/petroleum ether (7:1) to give the subtitle compound as a white solid. MS ESI+: m/z=263 [M+H]+.
With triethylammonium formate; at 20 - 95℃; for 16h;
To a solution of <strong>[357405-75-5]4-bromo-2,5-difluorobenzaldehyde</strong> (15.0 g) in triethylamine formiate (80 ml_) at room temperature was added 2,2-dimethyl-1 ,3-dioxane-4,6-dione (9.77 g). After being stirred for 1 h, the mixture was heated at 95°C with stirring for 15 hours. After cooling down, ice water was added. The mixture was adjusted to pH ~1 with HCI (6 M) and then extracted with ethyl acetate (200 ml_ x 3). The organic phase was washed with brine (50 ml_) and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with DCM/petroleum ether (7:1 ) to give the subtitle compound as a white solid. MS EST: m/z = 263 [M+H]+.
With 1,2-dimethyl-1H-imidazol-3-ium-3-butanesulfonic acid hydrogensulfate; at 80℃; for 0.1h;Green chemistry;
General procedure: A mixture of equimolar amounts of <strong>[1074-41-5]6-amino-2-(methylthio)pyrimidin-4(3H)-one</strong> (1) (1 mmol), ethylcyanoacetateor meldrum?s acid (2 or 5) (1 mmol) and aldehyde(3 or 6) (1 mmol) was added to a vial containinga magnetic stirring bar and [DMBSI]HSO4 (0.18 mmol,0.06g) and heated at 80 C in an oil bath. Stirring at 80C was continued until disappearance of the startingmaterials. At this stage, due to the poor solubility in theionic liquid, the product appears as a precipitate. Thereaction mixture was cooled and washed with water toextract the ionic liquid. The solid obtained was recrystallizedfrom ethanol to furnish the desired pure product.The ionic liquid was recovered from the aqueous extractsby evaporation under reduced pressure, and reusedin the next run.
With 1,2-dimethyl-1H-imidazol-3-ium-3-butanesulfonic acid hydrogensulfate; at 80℃; for 0.1h;Green chemistry;
General procedure: A mixture of equimolar amounts of <strong>[1074-41-5]6-amino-2-(methylthio)pyrimidin-4(3H)-one</strong> (1) (1 mmol), ethylcyanoacetateor meldrum?s acid (2 or 5) (1 mmol) and aldehyde(3 or 6) (1 mmol) was added to a vial containinga magnetic stirring bar and [DMBSI]HSO4 (0.18 mmol,0.06g) and heated at 80 C in an oil bath. Stirring at 80C was continued until disappearance of the startingmaterials. At this stage, due to the poor solubility in theionic liquid, the product appears as a precipitate. Thereaction mixture was cooled and washed with water toextract the ionic liquid. The solid obtained was recrystallizedfrom ethanol to furnish the desired pure product.The ionic liquid was recovered from the aqueous extractsby evaporation under reduced pressure, and reusedin the next run.
With 1,2-dimethyl-1H-imidazol-3-ium-3-butanesulfonic acid hydrogensulfate; at 80℃; for 0.0833333h;Green chemistry;
General procedure: A mixture of equimolar amounts of <strong>[1074-41-5]6-amino-2-(methylthio)pyrimidin-4(3H)-one</strong> (1) (1 mmol), ethylcyanoacetateor meldrum?s acid (2 or 5) (1 mmol) and aldehyde(3 or 6) (1 mmol) was added to a vial containinga magnetic stirring bar and [DMBSI]HSO4 (0.18 mmol,0.06g) and heated at 80 C in an oil bath. Stirring at 80C was continued until disappearance of the startingmaterials. At this stage, due to the poor solubility in theionic liquid, the product appears as a precipitate. Thereaction mixture was cooled and washed with water toextract the ionic liquid. The solid obtained was recrystallizedfrom ethanol to furnish the desired pure product.The ionic liquid was recovered from the aqueous extractsby evaporation under reduced pressure, and reusedin the next run.
3‑( 3‑nitrophenyl)-1‑phenyl‑1H‑pyrazole‑4‑carbaldehyde[ No CAS ]
[ 1569612-97-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
With 1,2-dimethyl-1H-imidazol-3-ium-3-butanesulfonic acid hydrogensulfate; at 80℃; for 0.0666667h;Green chemistry;
General procedure: A mixture of equimolar amounts of <strong>[1074-41-5]6-amino-2-(methylthio)pyrimidin-4(3H)-one</strong> (1) (1 mmol), ethylcyanoacetateor meldrum?s acid (2 or 5) (1 mmol) and aldehyde(3 or 6) (1 mmol) was added to a vial containinga magnetic stirring bar and [DMBSI]HSO4 (0.18 mmol,0.06g) and heated at 80 C in an oil bath. Stirring at 80C was continued until disappearance of the startingmaterials. At this stage, due to the poor solubility in theionic liquid, the product appears as a precipitate. Thereaction mixture was cooled and washed with water toextract the ionic liquid. The solid obtained was recrystallizedfrom ethanol to furnish the desired pure product.The ionic liquid was recovered from the aqueous extractsby evaporation under reduced pressure, and reusedin the next run.
With 1,2-dimethyl-1H-imidazol-3-ium-3-butanesulfonic acid hydrogensulfate; at 80℃; for 0.0666667h;Green chemistry;
General procedure: A mixture of equimolar amounts of <strong>[1074-41-5]6-amino-2-(methylthio)pyrimidin-4(3H)-one</strong> (1) (1 mmol), ethylcyanoacetateor meldrum?s acid (2 or 5) (1 mmol) and aldehyde(3 or 6) (1 mmol) was added to a vial containinga magnetic stirring bar and [DMBSI]HSO4 (0.18 mmol,0.06g) and heated at 80 C in an oil bath. Stirring at 80C was continued until disappearance of the startingmaterials. At this stage, due to the poor solubility in theionic liquid, the product appears as a precipitate. Thereaction mixture was cooled and washed with water toextract the ionic liquid. The solid obtained was recrystallizedfrom ethanol to furnish the desired pure product.The ionic liquid was recovered from the aqueous extractsby evaporation under reduced pressure, and reusedin the next run.
To the solution of N-methyl indole (200 mg, 1.52 mmol), Meldrum?s acid (220 mg, 1.52 mmol),<strong>[3364-80-5]1,3-<strong>[3364-80-5]thiazole-4-carbaldehyde</strong></strong> (171.3 mg, 1.52 mmol) in acetonitrile (2 mL), was added cholinechloride-urea ionic liquid (20 molpercent). The resultant mixture was stirred at 80 °C. After 6hr, water(1 mL) was added and continued the heating. After 7hr, reaction completion was monitored byTLC which shows absence of starting material. The reaction mixture was cooled to ambienttemperature and diluted with water (2 mL). The precipitate obtained was filtered and furtherpurified by recrystallization with diethyl ether to obtain yellow solid (365 mg, 84 percent).
With formic acid; triethylamine; at 0 - 100℃; for 2h;
To a solution of formic acid (3.7 mL) was added triethylamine (5.4 mL) at 0 C. followed by compound 33-5 (1.85 g. 12 mmol) and 2.2-dimethyl-l.3-dioane-4.6-dione (1.73 g. 12 mmol). At the end of the addition, the mixture was stirred at 100 C for 2.0 hrs. A ter the reaction was completed.20 mL of ice water was added to the mixture, and the resulting mixture was adjusted to pH 1 with hydrochloric acid (2 M) and extracted with EtOAc (25 mL x 3). The combined organic layers were dried over anhydrous and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give the title compound as a white solid (2.02 g.85%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 199.5 [M+H] '; and NMR (400 MHz. CDCh) delta (ppm) : 9.60 (brs.1H ).7.13-7.09 (m.1 H), 6.82-6.81.6.79-6.77 (m. m, 1H). 6.76-6.71 (m.1H).3.79 (d, 3H).2.90-2.85 (m.211).2.62.2.60.2.58 (d. d. d.2H).
2-methylthio-5,6-dihydro-5-((E)-5-(2-(4-chlorophenyl)diazenyl)-2-hydroxyphenyl)pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dion[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With [gamma-Fe2O3-encapsulated-HAp-SO3H]; at 60℃; for 0.0666667h;
General procedure: [gamma-Fe2O3Hap-SO3H] was synthesized according to the procedures reported in Ref. [2]. Then to a mixture of 6-amino-2-(methylthio or ethylthio)pyrimidin-4(3H)-one (1 mmol), Meldrum?s acid (1 mmol) and aryl aldehydes (1 mmol) was added [gamma-Fe2O3Hap-SO3H] (10 mg, 0.9 mol%) and the reaction mixture was stirred mechanically at 60 C. After the completion of the reaction, which was monitored by TLC analysis, the reaction mixture was diluted with hot ethanol and the catalyst was easily separated from the reaction mixture by an external magnet. The product obtained was collected by filtration, washed with ethanol and recrystallized from appropriate solvent to furnish the desired pure product (4a-n).
With [gamma-Fe2O3-encapsulated-HAp-SO3H]; at 60℃; for 0.0166667h;
General procedure: [gamma-Fe2O3Hap-SO3H] was synthesized according to the procedures reported in Ref. [2]. Then to a mixture of 6-amino-2-(methylthio or ethylthio)pyrimidin-4(3H)-one (1 mmol), Meldrum?s acid (1 mmol) and aryl aldehydes (1 mmol) was added [gamma-Fe2O3Hap-SO3H] (10 mg, 0.9 mol%) and the reaction mixture was stirred mechanically at 60 C. After the completion of the reaction, which was monitored by TLC analysis, the reaction mixture was diluted with hot ethanol and the catalyst was easily separated from the reaction mixture by an external magnet. The product obtained was collected by filtration, washed with ethanol and recrystallized from appropriate solvent to furnish the desired pure product (4a-n).
With [gamma-Fe2O3-encapsulated-HAp-SO3H]; at 60℃; for 0.05h;
General procedure: [gamma-Fe2O3Hap-SO3H] was synthesized according to the procedures reported in Ref. [2]. Then to a mixture of 6-amino-2-(methylthio or ethylthio)pyrimidin-4(3H)-one (1 mmol), Meldrum?s acid (1 mmol) and aryl aldehydes (1 mmol) was added [gamma-Fe2O3Hap-SO3H] (10 mg, 0.9 mol%) and the reaction mixture was stirred mechanically at 60 C. After the completion of the reaction, which was monitored by TLC analysis, the reaction mixture was diluted with hot ethanol and the catalyst was easily separated from the reaction mixture by an external magnet. The product obtained was collected by filtration, washed with ethanol and recrystallized from appropriate solvent to furnish the desired pure product (4a-n).
2-methylthio-5,6-dihydro-5-((E)-5-(2-(4-nitrophenyl)diazenyl)-2-hydroxyphenyl)pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With [gamma-Fe2O3-encapsulated-HAp-SO3H]; at 60℃; for 0.0666667h;
General procedure: [gamma-Fe2O3Hap-SO3H] was synthesized according to the procedures reported in Ref. [2]. Then to a mixture of 6-amino-2-(methylthio or ethylthio)pyrimidin-4(3H)-one (1 mmol), Meldrum?s acid (1 mmol) and aryl aldehydes (1 mmol) was added [gamma-Fe2O3Hap-SO3H] (10 mg, 0.9 mol%) and the reaction mixture was stirred mechanically at 60 C. After the completion of the reaction, which was monitored by TLC analysis, the reaction mixture was diluted with hot ethanol and the catalyst was easily separated from the reaction mixture by an external magnet. The product obtained was collected by filtration, washed with ethanol and recrystallized from appropriate solvent to furnish the desired pure product (4a-n).
5-(((3-bromo-4-hydroxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
2,2-Dimethyl-1 ,3-dioxane-4,6-dione (31.2 g, 216 mmol) and 1,171 -trimethoxyethane(150 mL) were mixed together and heated to reflux for 1 h. 4-Amino-2-bromophenol(37 g, 197 mmol) was added in portions and heated at 110 C for 2.5 h. The reactionmixture was cooled to room temperature and the solid obtained was filtered and washed with diethyl ether (200 mL) to obtain the title compound. Yield: 55 g (82 %); 1H NMR (300 MHz, DMSO-d6): O 1.75 (s, 6H, CH3), 6.96 (d, 1H, J=8.7 Hz, CH), 7.40 (d, 1H, J= 8.7 Hz, Ar), 7.84 (s, 1H, Ar), 8.41 (d, 1H, J= 14.4 Hz, CH),1O.46 (s, 1H, OH, exchangeable with D20), 11.17 (d, 1H, J= 14.7Hz, NH, exchangeable with D20); MS (El, 70 eV): mlz 341.0 (M-Hj; HPLC purity: 98.92 %.
With kiwi juice; In water; at 20℃; for 0.0833333h;Sonication; Green chemistry;
General procedure: 2-Hydroxybenzaldehyde (acetophenone, or benzaldehydes) (1.0 mmol) and Meldrum?s acid (1.01 mmol) were suspended in the aqueous medium (juice or waste water) (2 mL). The resulting mixture was subjected to ultrasound irradiation at room temperature for 5 min (15 min). The precipitate so formed was filtrated under vacuum. Structural assignments (NMR) was made by comparison of the recorded analytical data with those of commercially available sample or those already reported for the same compounds.2-6 The aqueous medium (juice or waste water) was recovered by filtration and re-used as such to perform further processes.
Step 1 (0503) A mixture of <strong>[109179-31-9]2-bromo-3-methylbenzaldehyde</strong> (3.15 g), 2,2-dimethyl-[1,3]dioxane-4,6-dione (2.28 g), triethylamine (3 mL) and formic acid (2 mL) was stirred at an external temperature of 100° C. for 2 hours. The mixture was cooled to room temperature. The mixture was poured into ice water, and the resulting mixture was diluted with hydrochloric acid (2 mol/L) and ethyl acetate. The ethyl acetate layer was washed with brine, and concentrated under reduced pressure to give 3-(2-bromo-3-methylphenyl)propionic acid (3. 90 g).
The product of Example 10, Step 2, was added to thionyl chloride (200 mL)Heated to 90 degrees Celsius,The reaction system is dissolved,Stirring was continued for 1 hour.Cooling,After the reaction system was reduced to room temperature,The unreacted thionyl chloride was evaporated to dryness under reduced pressure,Add 100mLDCM,Once again evaporated,Repeated twice,The residual thionyl chloride was removed.To the residue was added DCM (300 mL) and triethylamine (150 g, 15 mmol)Then added to Medrum & apos; s acid (144 g, 100 mmol)Stir overnight at room temperature.Water (400 mL) was added to the reaction system,Extraction,The organic phase was dried over anhydrous sodium sulfate for 2 hours,filter,Remove the desiccant.The resulting filtrate was evaporated to dryness under reduced pressure using a rotary evaporator,To the resulting residue was added anhydrous ethanol (200 mL)And trifluoroacetic acid (1 mL),50 degrees Celsius reaction 8 hours.Cooling,To the reaction system was added 50 mL of saturated sodium bicarbonate solution,The ethanol was evaporated to dryness on a rotary evaporator,To the residue was added 300 mL of purified water,Ethyl acetate extraction (300 mL x 3).Combine organic phase,Dried over anhydrous sodium sulfate for 2 hours.filter,Filter out desiccant,The filtrate was evaporated to dryness on a rotary evaporator,The residual oily liquid was purified by flash column chromatography (0-50percentEthyl acetate n-hexane solution as mobile phase)C-10-C (14 g, 45percent),White powder.
45%
The product of Example 13, Step 2, was added to thionyl chloride (200 mL)Heated to 90 degrees Celsius, the reaction system dissolved, continue stirring for 1 hour.Cooling, the reaction system to be reduced to room temperature, the unreacted sodium sulfoxide reduced pressure evaporated,Add 100mLDCM, again evaporated,Repeat twice to remove the residual thionyl chloride.To the residue was added DCM (300 mL) and triethylamine (150 g, 15 mmol)Medrum's acid (144 g, 100 mmol) was then added and stirred at room temperature overnight.Water (400 mL) was added to the reaction system,The organic phase was dried over anhydrous sodium sulfate for 2 hours, filtered and the desiccant was filtered off.The resulting filtrate was evaporated to dryness under reduced pressure using a rotary evaporator,To the resulting residue was added anhydrous ethanol (200 mL)And trifluoroacetic acid (1 mL) at 50 ° C for 8 hours.Cooling, adding 50 mL of saturated sodium bicarbonate solution to the reaction system,The ethanol was evaporated to dryness on a rotary evaporator,To the residue was added 300 mL of purified water, extracted with ethyl acetate (300 mL x 3).The combined organic phases were dried over anhydrous sodium sulfate for 2 hours.Filtering, filtering the desiccant, the filtrate in the rotary evaporator on the vacuum drying,The residual oily liquid was purified by flash column chromatography (0-50percent ethyl acetate n-hexane solution as mobile phase)A-13-C (14 g, 45percent), an off-white powder.
45%
The product obtained in Example 7, Step 2, was added to thionyl chloride (200 mL)Heated to 90 degrees Celsius,The reaction system is dissolved,Stirring was continued for 1 hour.Cooling, until the reaction system to room temperature,The unreacted thionyl chloride was evaporated to dryness under reduced pressure, 100 mLDCM was added,Evaporated again, twice, to remove the residual thionyl chloride.To the residue was added DCM (300 mL) and triethylamine (150 g, 15 mmol)Then add Medrum's acid (144 g, 100 mmol)Stir overnight at room temperature. Water (400 mL) was added to the reaction system,The organic phase was dried over anhydrous sodium sulfate for 2 hours, filtered,Remove the desiccant. The resulting filtrate was evaporated to dryness under reduced pressure using a rotary evaporator,To the resulting residue was added absolute ethanol (200 mL) and trifluoroacetic acid (1 mL)50 degrees Celsius reaction 8 hours. Cooling, adding 50 mL of saturated to the reaction systemSodium bicarbonate solution, and the ethanol was evaporated to dryness on a rotary evaporator, 300 mL of purified water was added to the residue,Ethyl acetate extraction (300 mL x 3). Combined organic phase,Dried over anhydrous sodium sulfate for 2 hours. Filter, filter desiccant,The filtrate was evaporated to dryness on a rotary evaporator,The residual oily liquid was purified by flash column chromatography (0-50percent ethyl acetate n-hexane as the mobile phase) to give C-07-C (14 g, 45percent) as an off-white powder.
5-[(4,6-dichloropyridin-3-yl)amino]methylene}-2,2-dimethyl-1,3-dioxane-4,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of <strong>[7321-93-9]5-amino-2,4-dichloropyridine</strong> (818 mg, 5.02 mmol) and 2,2- dimethyl-l,3-dioxane-4,6-dione (889 mg, 6.05 mmol) was heated to 100°C. After 2 minutes, trimethyl orthoformate (2.32 mL, 30.1 mmol) was added to the melt. A white suspension formed over 25 minutes and reflux was observed. The mixture was cooled to ambient temperature and the suspension was diluted with diethyl ether (10 mL). The reaction was filtered to afford the title compound (90percent purity, 1.40 g, 79percent) as an off- white powder. deltaEta (DMSO-d6, 300 MHz) 11.40 (d, J 10.9 Hz, 1H), 8.92 (s, 1H), 8.86-8.73 (m, 1H), 7.99 (s, 1H), 1.70 (s, 6H). LCMS (ES-) [Mu-EtaGamma 315, RT 1.41 minutes (method 2)·
The product of Example 13, Step 2, was added to thionyl chloride (200 mL)Heated to 90 degrees Celsius,The reaction system is dissolved,Stirring was continued for 1 hour.Cooling,After the reaction system was reduced to room temperature,The unreacted thionyl chloride was evaporated to dryness under reduced pressure,Add 100mLDCM,Once again evaporated,Repeated twice,The residual thionyl chloride was removed.To the residue was added DCM (300 mL) and triethylamine (150 g, 15 mmol)Was then added Medrum's acid (144g, 100mmol),Stir overnight at room temperature.Water (400 mL) was added to the reaction system,Extraction,The organic phase was dried over anhydrous sodium sulfate for 2 hours,filter,Remove the desiccant.The resulting filtrate was evaporated to dryness under reduced pressure using a rotary evaporator,To the resulting residue was added anhydrous ethanol (200 mL) and trifluoroacetic acid (1 mL)50 degrees Celsius reaction 8 hours.Cooling,To the reaction system was added 50 mL of saturated sodium bicarbonate solution,The ethanol was evaporated to dryness on a rotary evaporator,To the residue was added 300 mL of purified water,Ethyl acetate extraction (300 mL x 3).Combine organic phase,Dried over anhydrous sodium sulfate for 2 hours.filter,Filter out desiccant,The filtrate was evaporated to dryness on a rotary evaporator,The residual oily liquid was subjected to flash column chromatography(0-50percent ethyl acetate n-hexane solution as mobile phase) to give B-13-C (14 g, 45percent),White powder.
The Meldrum's acid [1] (23.6 g, 164 mmol) and trimethyl orthoformate [2] (100 g) were added to a 30 mL four-necked flask and heated under reflux for 1 hour. Followed by the addition of 3-aminobenzylamine [26] (10.0 g, 81.9 mmol) followed by heating under reflux for 2 hours. After completion of the reaction, the solvent was removed with an evaporator and dried to give 36.2 g of compound [27] (yield 100percent).
3-oxo-3-(tetrahydropyran-3-yl)propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Thionyl chloride (0.17 mL, 2.4 mmol) was added to a stirred solution of tetrahydro-pyran-3- carboxylic acid (0.26 g, 2.0 mmol) in DCM (4 mL) and DMF (0.1 mL). The mixture was stirred at room temperature for 30 min then Meldrum's acid (0.576 g, 4.0 mmol) was added and the mixture was left to stir at room temperature for 1 hour. The reaction mixture was washed with a 2 N HC1 (aq) solution and evaporated under reduced pressure. The residue was dissolved in methanol and heated to reflux for 6 h. The mixture was then concentrated under reduced pressure to give the title compound (0.27 g, 75percent yield) which was used in the next step without further purification.
General procedure: 2-hydroxybenzaldehydes (1) (0.02mol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (2) (0.02mol) were first reacted at room temperature in the presence of a catalytic amount of piperidinyl acetate and then refluxed in ethanol. The product then crystallizes in the solvent. After filtration and washing with ethanol, coumarin-3-carboxylic acid (4) was obtained in comparable yield and purity.
5-[1-(4-chlorophenyl)cyclopropanecarbonyl]-2,2-dimethyl-1,3-dioxane-4,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 20℃; for 19h;
To a solution of l -(4-chlorophenyl)cyclopropanecarboxylic acid (2.00 g, 10.2 mmol) in DMA (20.0 mL) were added 2,2-dimethyl-l,3-dioxane-4,6-dione (1.76 g, 12.2 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.92 g, 15.3 mmol) and DMAP (1.86 g, 15.3 mmol) at room temperature. The mixture was stirred at room temperature for 19 h. The mixture was diluted with IN HC1 and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give 5-[l-(4-chlorophenyl)cyclopropanecarbonyl]-2,2-dimethyl-l,3- dioxane-4,6-dione (1.84 g, 5.70 mmol, 56percent yield) as colorless solid. NMR (500 MHz, Chloroform- delta 15.53 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 7.7 Hz, 2H), 1.65 (d, J = 1.5 Hz, 6H), 1.58 (s, 2H), 1.47 (d, J = 5.7 Hz, 2H). MS m/z: 321 [M-H]\
In 1,4-dioxane; at 140℃; for 0.0833333h;Microwave irradiation;
General procedure: A mixture of Meldrum?s acid (4.8 mmol, 1.2 equiv., 0.69 g) and the corresponding alcohol (4 mmol, 1.0 equiv.) in dioxane (3 mL) was heated by microwave irradiation at 140 °C for 5 min. After the removal of the dioxane by rotatory evaporation, the residue was separated using a column of Diaion HP-20, eluting with H2O, 30percent CH3OH/H2O and CH3OH to give the desired malonic acid monoesters as a light yellow oil.
5-(((6-methoxypyridin-2-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
[0602] Procedure: A solution of Meldrum?s acid (3,49g, 24 mmol) in triethyl orthoformate (40 mL) was heated at 105° C for 2 h. 6-methoxypyridin-2-amine (3.0 g, 24.1 mmol) was added and the resulting reaction mixture was further heated at 105°C for 10 h. The progress of the reaction was monitored by TLC using 30percent ethyl acetate in hexane as eluent. The reaction mixture was cooled to room temperature. The solid formed in the reaction mixture was filtered and dried under vacuum pressure to afford 5-(((6-methoxypyridin-2-yl)amino) methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as brown solid (3.5 g, 52 percent).1HNMR (400 MHz, DMSO-d6): delta 11.30 (d, J = 10.0 Hz, 1H), 9.16 (d, J = 11.6 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 3.89 (s, 3H), 1.66 (s, 6H). LC-MS (ES) m/z = 279 [M+H]+.
5-[(3-bromo-2,4-difluoroanilino)methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
A mixture of 106 2,2-dimethyl-1,3-dioxane-4,6-dione (7.62 g, 52.88 mmol) in 107 trimethoxymethane (26.3 mL, 240.38 mmol) was heated at 85 C. and stirred for 1.5 h. 498 3-Bromo-2,4-difluoroaniline (10 g, 48.08 mmol) in 33 ethanol (42.4 mL) was added and the reaction mixture was stirred at 85 C. for 3 h. The mixture was cooled with the resulting solid was filtered and washed with IPA (2×50 mL) and diethyl ether (4×50 mL). The solid was dried under vacuum overnight to afford 499 5-[(3-bromo-2,4-difluoroanilino)methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (14.62 g, 84%) as a beige solid; 1H NMR (400 MHz, DMSO, 30 C.) 1.69 (6H, s), 7.33-7.43 (1H, m), 7.86-7.97 (1H, m), 8.56-8.64 (1H, m), 11.24 (1H, s); m/z: ES+ [M+H]+ 362.0.
5-[1-hydroxy-2-(5-methoxy-2-nitrophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 40℃; for 4h;
To a mixture of 2.27 g (10.7 mmol) of (5-methoxy-2-nitrophenyl) acetic acid (Intermediate 7), 40 mL of dry acetonitrile, 1.70 g (11.8 mmol) of Meldrum?s acid, 131 mg (1.07 mmol) of DMAP and 4.21 mL (24.2 mmol) of DIPEA, 1.46 mL (11.8 mmol) trimethyiacetyi chloride was added dropwise and the reaction mixture was stirred at 40C for 4 hours. The mixture was cooled to OX, 26 mL of 1 N hydrochloric acid was added dropwise and diluted with 60 mL of water. The precipitated product was filtered off, washed with water and dried over phosphorus pentoxide in a vacuum desiccator. Thus, 2.45 g (68%) of the title product was obtained which was used without further purification.
5-[(2,2-difluorocyclopropyl)carbonyl]-2,2-dimethyl-1,3-dioxane-4,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;
To a stirred solution of 2,2-difluorocyclopropanecarboxylic acid (14.0 g, 114.7 mmol) in DCM (150 ml.) were added 4-dimethylaminopyridine (14.0 g, 114.7 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (16.5 g, 114.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.9 g, 114.69 mmol) at 0 C. The reaction temperature was allowed to rise to RT. After stirring overnight, the reaction mixture was quenched with water (120 ml) and extracted with DCM (2 x 150 ml). The organic phase was washed with 1 M sodium hydrogen sulfate (2 x 150 ml) and brine (2 x 150 ml) and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: DCM 100%) to give 20.0 g (63% of theory, 90% purity) of the title compound. LC/MS [Method 42]: Rt = 1.03 min; MS (ESIpos): m/z = 247 [M-H] 1H-NMR (300 MHz, DMSO-d6): d [ppm] = 3.87-4.18 (m, 1H), 2.11-2.35 (m, 2H), 1.85-2.07 (m, 1H), 1.69 (s, 6H).
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