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Chemical Structure| 105-45-3
Chemical Structure| 105-45-3
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Product Details of [ 105-45-3 ]

CAS No. :105-45-3 MDL No. :MFCD00008784
Formula : C5H8O3 Boiling Point : -
Linear Structure Formula :- InChI Key :WRQNANDWMGAFTP-UHFFFAOYSA-N
M.W : 116.12 Pubchem ID :7757
Synonyms :
Acetoacetate methyl ester;Methyl 3-oxobutanoate;Methyl 3-oxobutyrate;MAA;Methyl acetoacetate

Calculated chemistry of [ 105-45-3 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.6
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 27.63
TPSA : 43.37 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.03 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.35
Log Po/w (XLOGP3) : -0.03
Log Po/w (WLOGP) : 0.14
Log Po/w (MLOGP) : -0.09
Log Po/w (SILICOS-IT) : 0.34
Consensus Log Po/w : 0.34

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.34
Solubility : 52.7 mg/ml ; 0.454 mol/l
Class : Very soluble
Log S (Ali) : -0.43
Solubility : 43.1 mg/ml ; 0.371 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.64
Solubility : 26.4 mg/ml ; 0.228 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.11

Safety of [ 105-45-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P305+P351+P338 UN#:N/A
Hazard Statements:H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 105-45-3 ]

* 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.

  • Upstream synthesis route of [ 105-45-3 ]
  • Downstream synthetic route of [ 105-45-3 ]

[ 105-45-3 ] Synthesis Path-Upstream   1~102

  • 1
  • [ 75-21-8 ]
  • [ 105-45-3 ]
  • [ 517-23-7 ]
YieldReaction ConditionsOperation in experiment
40.4% With triethylamine In methanol at 5 - 95℃; for 2.15 - 5 h; Example 2: At 5 °C, a solution of MAA (46.9 g 0.40 mol) in MeOH (144.0 g) was treated with EO (25.0 g, 1.4 eq.) and then with triethylamine (TEA, 40.7 g, 1.0 eq.). The reaction mixture was heated to 60 °C within 0.5 h and kept at this temperature for 2.5 h. Quantitative GC analysis indicated that 50.8percent of MAA had been transformed into ABL with a selectivity of 72.9percent.
Example 4: At 5 °C, a solution of MAA (47.0 g, 0.40 mol) in MeOH (144 g) was treated with EO (35.3 g, 2.0 eq.) and then with triethylamine (TEA) (42.4 g, 1.0 eq.). The reaction mixture was heated to 60 °C within 0.5 h and kept at this temperature for 4.5 h. Quantitative GC analysis indicated that 67.7percent of MAA had been transformed into ABL with a selectivity of 75.0percent.
Examples 7-27: The process of example 1, by using an EO amount, optionally a catalyst at an amount as described in Table 1, and an additive at an amount as described in Table 1, and a reaction time as described in Table 1. Turnover and selectivity as described in Table 1.
Table 1: Examples 7-27: Example EO [eq] Catalyst Catalyst [eq] Additive Additive [eq] t [h] Turnover [percent] Sel. [percent] 7 1 TMG 1 --- --- 1 44.7 76.8 8 1 TMG 1BF3*OEt2 0-1 5 46.3 66 9 1 TMG 1Ti(OiPr)4 0.1 5 36.4 59.1 10 1 TMG 1BF3*OEt2 0.1 3 37 75.1 11 1 TMG 1Ti(OiPr)4 0.1 3 42.4 60.6 12 2 TMG 1BF3*OEt2 0.1 5 82.4 41.9 13 2 TMG 1Ti(OiPr)4 0.1 5 76 38.2 14 1 Mim 1 --- --- 5 39.4 57.7 15 2 Mim 1 --- --- 2 43.9 66.2 16 1 DMAP 0.2 --- --- 3 35 48.9 17 1Dec2MeN 1 --- --- 1 21.9 67.9 18 2Dec2MeN 1 --- -- 2 62.9 71.7 19 1Oct2MeN 1 --- --- 1 18 84.2 20 1 TMA 1 --- --- 4 6.6 39 21 2 TMA 1 --- --- 4 62.8 71.2 22 1 TMA 1 --- --- 2 7 87.5 23 2 TMA 1 --- --- 2 48.7 79.7 24 1 TEA 0.2 --- --- 4 27.4 58.6 25 1 Pyridin 0.99 --- --- 1 42.4 41.4 26 1 NMePip 1 --- --- 4 18.4 65.1 27 1 NMeMorph 1 --- --- 4 27.4 83.0 All reactions of examples 7 to 26 reacting 0.40 eq. MMA with the indicated amount EO have been carried out at 60 °C with 11 1 eq. MeOH as solvent. Examples 27 and 28 have been carried out with 0.10 eq. MMA with 1 eq. EO at 60 °C with 11 eq. MeOH as solvent.
Example 28: Example of best mode of a series of reactions with TEA as compound of formula IV: 37 g MeOH were placed in a 250 mL autoclave, pressurized with 2-3 bar nitrogen gas and heated. After reaching 65 °C solution of MMA (39.9 g, 0.34 mol, 1 eq.) and TEA (34.4 g, 0.34 mol, 1 eq.) in methanol (27. g) and EO (30.1 g, 0.68 mol, 2 eq.) were simultaneously fed using two pumps within 11 min. After 2 h additional reaction time ABL was formed (GC analysis) with a selectivity of 77percent, corresponding to 52.3percent based on added MMA. Covered ranges in the series, carried out analogously: Temperature: 65 to 95 °CAddition time: 9 to 13 min.MMA added based on totally added solvent: 1.3 to 2.1 mol/LTEA/MMA molar ratio added to the reaction mixture: 0.7 to 1.3EO/MMA molar ratio added to the reaction mixture: 1.7 to 2.2 Results within the series of Example 28: MMA conversion: 65.6 to 85.0percentSelectivity of ABL formation: 47.5 to 77.4percentABL yield based on MAA: 40.4 to 52.3percent
30.8% With N,N,N',N'-tetramethylguanidine In methanol at 5 - 65℃; for 1.15 - 6.18333 h; Example 1: At 5 °C, a solution of methyl acetoacetate (MAA, 46.7 g, 0.40 mol) in methanol (MeOH, 144.0 g) was treated with ethylene oxide (EO, 17.5 g, 1.0 eq.) and then with 1,1,3,3-tetramethylguanidine (TMG, 46.1 g, 1.0 eq.). The reaction mixture was heated to 40 °C within 0.5 h and kept at this temperature for 4.5 h. Quantitative GC analysis indicated that 53.7percent of MAA had been transformed into α-acetylbutyrolactone (ABL) with a selectivity of 75.2percent.
Examples 7-27: The process of example 1, by using an EO amount, optionally a catalyst at an amount as described in Table 1, and an additive at an amount as described in Table 1, and a reaction time as described in Table 1. Turnover and selectivity as described in Table 1.Table 1: Examples 7-27: Example EO [eq] Catalyst Catalyst [eq] Additive Additive [eq] t [h] Turnover [percent] Sel. [percent] 7 1 TMG 1 --- --- 1 44.7 76.8 8 1 TMG 1BF3*OEt2 0-1 5 46.3 66 9 1 TMG 1Ti(OiPr)4 0.1 5 36.4 59.1 10 1 TMG 1BF3*OEt2 0.1 3 37 75.1 11 1 TMG 1Ti(OiPr)4 0.1 3 42.4 60.6 12 2 TMG 1BF3*OEt2 0.1 5 82.4 41.9 13 2 TMG 1Ti(OiPr)4 0.1 5 76 38.2 14 1 Mim 1 --- --- 5 39.4 57.7 15 2 Mim 1 --- --- 2 43.9 66.2 16 1 DMAP 0.2 --- --- 3 35 48.9 17 1Dec2MeN 1 --- --- 1 21.9 67.9 18 2Dec2MeN 1 --- -- 2 62.9 71.7 19 1Oct2MeN 1 --- --- 1 18 84.2 20 1 TMA 1 --- --- 4 6.6 39 21 2 TMA 1 --- --- 4 62.8 71.2 22 1 TMA 1 --- --- 2 7 87.5 23 2 TMA 1 --- --- 2 48.7 79.7 24 1 TEA 0.2 --- --- 4 27.4 58.6 25 1 Pyridin 0.99 --- --- 1 42.4 41.4 26 1 NMePip 1 --- --- 4 18.4 65.1 27 1 NMeMorph 1 --- --- 4 27.4 83.0 All reactions of examples 7 to 26 reacting 0.40 eq. MMA with the indicated amount EO have been carried out at 60 °C with 11 1 eq. MeOH as solvent. Examples 27 and 28 have been carried out with 0.10 eq. MMA with 1 eq. EO at 60 °C with 11 eq. MeOH as solvent.
Example 29: Example of best mode of a series of reactions with TMG as compound of formula IV: 37 g MeOH were placed in a 250 mL autoclave, pressurized with 2-3 bar nitrogen gas and heated. After reaching 45 °C solution of MMA (35.2 g, 0.30 mol, 1 eq.) and TMG (41.5 g, 0.36 mol, 1.2 eq.) in methanol (27. g) and EO (16.3 g, 0.37 mol, 1.2 eq.) were simultaneously fed using two pumps within 10 min. After 6 h additional reaction time ABL was formed (GC analysis) with a selectivity of 60.4percent, corresponding to 46.0percent total yield based on added MMA. Covered ranges in the series, carried out analogously: Temperature: 45 to 65 °CAddition time: 9 to 11 min.MMA added based on totally added solvent: 1.5 to 1.9 mol/LTEA/MMA molar ratio added to the reaction mixture: 0.8 to 1.2EO/MMA molar ratio added to the reaction mixture: 0.8 to 1.2 Results within the series of Example 29: MMA conversion: 39.5 to 65.0percentSelectivity of ABL formation: 63.8 to 81.2percentABL yield based on MAA: 30.8 to 46.0percent
30.3% With trimethylamine In methanol at 60 - 90℃; for 1.3 - 4 h; Examples 7-27: The process of example 1, by using an EO amount, optionally a catalyst at an amount as described in Table 1, and an additive at an amount as described in Table 1, and a reaction time as described in Table 1. Turnover and selectivity as described in Table 1.
Table 1: Examples 7-27: Example EO [eq] Catalyst Catalyst [eq] Additive Additive [eq] t [h] Turnover [percent] Sel. [percent] 7 1 TMG 1 --- --- 1 44.7 76.8 8 1 TMG 1BF3*OEt2 0-1 5 46.3 66 9 1 TMG 1Ti(OiPr)4 0.1 5 36.4 59.1 10 1 TMG 1BF3*OEt2 0.1 3 37 75.1 11 1 TMG 1Ti(OiPr)4 0.1 3 42.4 60.6 12 2 TMG 1BF3*OEt2 0.1 5 82.4 41.9 13 2 TMG 1Ti(OiPr)4 0.1 5 76 38.2 14 1 Mim 1 --- --- 5 39.4 57.7 15 2 Mim 1 --- --- 2 43.9 66.2 16 1 DMAP 0.2 --- --- 3 35 48.9 17 1Dec2MeN 1 --- --- 1 21.9 67.9 18 2Dec2MeN 1 --- -- 2 62.9 71.7 19 1Oct2MeN 1 --- --- 1 18 84.2 20 1 TMA 1 --- --- 4 6.6 39 21 2 TMA 1 --- --- 4 62.8 71.2 22 1 TMA 1 --- --- 2 7 87.5 23 2 TMA 1 --- --- 2 48.7 79.7 24 1 TEA 0.2 --- --- 4 27.4 58.6 25 1 Pyridin 0.99 --- --- 1 42.4 41.4 26 1 NMePip 1 --- --- 4 18.4 65.1 27 1 NMeMorph 1 --- --- 4 27.4 83.0 All reactions of examples 7 to 26 reacting 0.40 eq. MMA with the indicated amount EO have been carried out at 60 °C with 11 1 eq. MeOH as solvent. Examples 27 and 28 have been carried out with 0.10 eq. MMA with 1 eq. EO at 60 °C with 11 eq. MeOH as solvent.
Example 30: Example of best mode of a series of reactions with TMA as compound of formula IV using a microreactor: A solution A was prepared consisting of MMA (44.6 g, 0.384 mol, 1.0 eq.), TMA (16.8 g, 0.284 mol, 0.74 eq.) and MeOH (81.3 g). 30.6 g/h EO (0.695 mol/h, 1.495 eq.) and 172.8 g/h of solution A (0.465 mol/h MMA) were simultaneously fed using two pumps to a microreactor adjusted to 90 °C, said microreactor having 9.8 mL internal volume, and is acting as mixing and reaction zone. The residence time of the reaction mixture in the microreactor under the current flows was about 2.5 min. After passing through the microreactor the reaction mixture was collected in an autoclave, containing 250 mL MeOH at 60 °C and 2-3 bar under nitrogen gas. After about 1.3 h additional reaction time in the autoclave ABL was formed (GC analysis) with a selectivity of 74.8percent, corresponding to a total yield of 34.8percent based on added MMA, or yield of 61.9percent based on added TMA. 46.6percent MMA has been converted to ABL. Covered ranges in the series, carried out analogously: Temperature of the microreactor: 73 to 107 °CTemperature of the autoclave: 43 to 77 °CDosage rate Solution A: 48.7 to 172 g/hDosage rate EO: 8.6 to 30.6 g/hMMA added based solvent injected to the microreactor: 1.9 mol/LTEA/MMA molar ratio added to the reaction mixture: 0.75EO/MMA molar ratio added to the reaction mixture: 1.5 Results within the series of Example 30: MMA conversion: 38.7 to 66.3percentSelectivity of ABL formation: 50.5 to 78.3percentABL yield based on MAA: 30.3 to 39.7percent
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 2585 - 2598
[2] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 6; 7; 7-8; 8
[3] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 6; 7; 8; 8-9
[4] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7; 8; 9
[5] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7; 8
[6] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7; 8
[7] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7; 8
[8] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7; 8
[9] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7; 8
[10] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7; 8
[11] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7
[12] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7; 8
[13] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7; 8
[14] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7
[15] Patent: EP1911752, 2008, A1, . Location in patent: Page/Page column 7; 8
  • 2
  • [ 105-45-3 ]
  • [ 17356-08-0 ]
  • [ 56-04-2 ]
Reference: [1] Synthetic Communications, 2002, vol. 32, # 6, p. 851 - 855
[2] Canadian Journal of Chemistry, 1986, vol. 64, p. 2087 - 2093
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7180 - 7184
  • 3
  • [ 105-45-3 ]
  • [ 81569-44-0 ]
Reference: [1] Journal of Medicinal and Pharmaceutical Chemistry, 1959, vol. 1, p. 577,594
[2] Journal of the American Chemical Society, 1939, vol. 61, p. 891
  • 4
  • [ 105-45-3 ]
  • [ 95-54-5 ]
  • [ 52099-72-6 ]
Reference: [1] European Journal of Medicinal Chemistry, 1997, vol. 32, # 11, p. 843 - 868
[2] Patent: US5652246, 1997, A,
  • 5
  • [ 105-45-3 ]
  • [ 529-23-7 ]
  • [ 635-79-0 ]
YieldReaction ConditionsOperation in experiment
88% at 110℃; for 24 h; Inert atmosphere To a stirred solution of 2-aminobenzaldehyde (1a, 206 mg, 1.70 mmol) in 15 mL of toluene, was added methyl acetoacetate (2a, 217 mg, 1.87 mmol, 1.1 equiv) and the solution was refluxed for 24 h during which time a light tan precipitate formed. The reaction mixture was cooled to room temperature, evaporated to one-half its volume, and then cooled to 0 °C using an ice bath. The solid was filtered and washed with 1:1 ether:hexane to give acid 3a. The compound obtained was spectroscopically pure and no further purification was necessary. Note: The reaction was also carried out using xylene as the solvent and no change in the yield or purity was observed. Reactions run in benzene, however, gave mixtures of the acid and its corresponding ester.
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 20, p. 3181 - 3183
[2] Green Chemistry, 2017, vol. 19, # 16, p. 3851 - 3855
  • 6
  • [ 105-45-3 ]
  • [ 529-23-7 ]
  • [ 635-79-0 ]
  • [ 30160-03-3 ]
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 20, p. 3181 - 3183
  • 7
  • [ 99-61-6 ]
  • [ 105-45-3 ]
  • [ 21881-77-6 ]
YieldReaction ConditionsOperation in experiment
95% at 70℃; for 2.5 h; Green chemistry; Enzymatic reaction General procedure: Urease (0.05 g) was added to a mixture of aldehyde (5 mmol), 1,3-dicarbonyl (5mmol), and urea (15 mmol), and the mixture was stirred at 70 °C in water, till the product precipitated. After completion of the reaction (thin-layer chromatography (TLC) monitoring, hexane:EtOAc(70:30)), cold water was added and the product was filtered to give the pure 1,4-DHP product.
95% With C23H3BF16N2O; ammonium acetate In toluene at 100℃; for 10 h; In the 100 ml flask is added in a single port 0.01 µM percent Lewis acid-base dual function catalyst I (wherein Rf=CF3; R1, R2, R3, R4, R5, R6=F), 0.1 µM m formaldehyde (R7=3 - NO2- Ph), 0.1 µM methyl acetoacetate (R8=Me; R9=Me), 0.1 µM ammonium acetate, 10 ml toluene, the reaction in the 100 °C stirring for 10 hours, TLC tracking reaction to the reaction is complete. The reaction result is: product II (R7=3 - NO2- Ph; R8=Me; R9=Me) of the yield is 97percent; catalyst system used repeatedly 10 times, its catalytic performance did not decline
90% With uranyl nitrate hexahydrate; ammonium acetate In ethanol at 20℃; for 0.333333 h; Sonication General procedure: To a solution of aldehyde (1.0 mmol), ethyl/methyl acetoacetate/acetylacetone (2.0 mmol) and ammonium acetate (1.0 mmol) in ethanol (3 mL), uranyl nitrate (10 molpercent) was added and the resultant reaction mixture was sonicated at room temperature for the required time (Table 1). The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into crushed ice. The obtained solid was filtered, washed thoroughly with water, dried, and purified by recrystallisation in ethanol.
90% With Er(1,3,5-benzenetricarboxylate)(aqua)(N,N-dimethylformamide)1.1; ammonium acetate In ethanol at 70℃; for 4 h; General procedure: Ammonium acetate (1 mmol), was added to the mixture of benzaldehyde (1 equiv), and ethyl acetoacetate (1.1 equiv) in Ethanol (1.5 mL) along with an appropriate amount of Er-MOF as catalyst (20 mg). The mixture was stirred at 70 °C for 4 h. After completion of the reaction, the catalyst was removed by centrifuge. Then brine (5 mL) and EtOAc (5 mL) was added. The mixture was extracted with EtOAc and the combined organic phase were washed with saturated aqueous solution of NaHCO3 (10 mL), and brine(10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. After removal of the solvent under vacuum, the crude product was purified by column chromatography to afford the desired product, Table 1. It is found that the Er-MOF catalyst can be recovered and reused five times without considerable loss of catalyticactivity.
88% at 100℃; for 0.333333 h; Green chemistry General procedure: To a glassy reactor equipped with a magnetic stir bar, amixture of aromatic aldehyde (1.0 mmol), β-keto ester(2 mmol), ammonium acetate (1.5 mmol) and n-Fe3O4(at)ZrO2/HPW (0.003 g, 15 mol percent) was added. The reactorwas put in an oil bath with the temperature of 100 °C andthe reaction was carried out under solvent-free condition.The progress of the reaction was monitored using TLCplates. When the reaction was completed, the mixture wasallowed to cool to room temperature. Afterwards, the mixturewas triturated with 5mL ethyl acetate and the catalystwas separated by the help of an external magnet. Then thesolvent was evaporated and the crude product was recrystallizedfrom EtOH/H2O to offer the pure product.
84% at 80℃; for 0.216667 h; General procedure: A mixture of the alkyl or aryl aldehyde (1 mmol), -dicarbonyl(2 mmol) and ammonium acetate (1.5 mmol) in the presence ofFe3O4NPs (0.024 g, equal to 10 molpercent) was heated at 80C, withstirring. The progress of the reaction was monitored by TLC (elu-ent: EtOAc:n-hexane). After completion of the reaction, the mixturewas cooled to room temperature and then ethanol was added tothe resulting mixture and separated Fe3O4NPs by a normal mag-net. After evaporation of solvent, the solid product was filtered andrecrystallized from ethanol to give the pure products in 72–95percentyields based on the starting aldehyde.
80% With ammonium hydroxide In ethanol at 120℃; for 0.1 h; Flow reactor General procedure: A 25 mL of stock solutioncontaining aldehyde (1eq), ethyl acetoacetate (3.4eq) 28percent ammonium hydroxide(10eq) and ethanol was prepared. Then, a stainless steel syringe was loaded,the PHD 4400 Hpsi Programmable Syringe Pump was used, and the solution streammerged in a tubular PFA micro reactor [200µL, 0.02’’ (inch = 2.54 cm) innerdiameter, 100 cm length)] and immersed in a heated oil bath at 120oC.The microreactor was equipped with a 100 psi backpressure regulator (BPR) and variableminutes of residence time were used.At the outlet of the microreactor, the pressure was released to ambient conditions and the reactionmixture was collected. Initially a flushwas preceded to ensure steady-state data collection (4x times residence time). Performingthe protocol on the 1 mmol scale, the product was collected as a stream in avial. After that the sample was transferred to a separatory funnel.10 mL of water and 20 mL of diethyl ether was added, then the aqueous layer wasremoved and the organic phase was collected and dried using Na2SO4.The solution was concentrated to obtain a yellow oil. After 10 hours indessicator with P2O5 the sample became a solid, then itwas recrystalized using heptane and diethyl ether. After drying, the solidswere weight to measure the yield.The structure of the products was determined by IR, 1HNMRand 13CNMR spectroscopy, mass analysis.
77.2% With ammonia In methanol; ethanol a)
Preparation of dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
A mixture of 75.5 g (0.50 mole) of 3-nitrobenzaldehyde, 116 g (1.00 mole) of methyl acetoacetate and 55 ml (1.50 mole) of 28percent ammonia in 150 ml of methanol is heated under reflux for 5 hr.
The precipitate is removed by filtration and the cake purified by hot washing in absolute ethanol, giving 133.5 g of a yellow powder.
M.pt.inst. (Kofler)=208° C. Yield=77.2percent
70.9% With ammonium bicarbonate In ethanol; water at 55 - 60℃; Reflux (2)
Preparation of dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
5 g meta-nitrobenzaldehyde (0.033 mol), 8 mL methyl acetoacetate (0.072 mol), 10 mL ethanol, 4 g ammonium bicarbonate (0.05 mol) and 4 mL water were mixed and stirred at 55-60° C. until no bubble formed (about 1 hour).
The mixture was continued to react under reflux for 1-2 hours, cooled, and filtered by suction.
The filter cake was dried in vacuum to produce the title product as a yellow solid (8.1 g) in a yield of 70.9percent.
70.9% With ammonium bicarbonate In ethanol; water at 55 - 60℃; for 2 - 3 h; Reflux (2)
Preparation of dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
5g meta-nitrobenzaldehyde (0.033mol), 8mL methyl acetoacetate (0.072mol), 10mL ethanol, 4g ammonium bicarbonate (0.05mol) and 4mL water were mixed and stirred at 55-60 °C until no bubble formed (about 1 hour).
The mixture was continued to react under reflux for 1-2 hours, cooled, and filtered by suction.
The filter cake was dried in vacuum to produce the title product as a yellow solid (8.1g) in a yield of 70.9percent.
60% Darkness; Reflux General procedure: To a 50-mL round-bottomed flask, ammonium acetate (0.162 g,2.10 mmol) was added to a stirring solution of 2-nitrobenzaldehydeor 3-nitrobenzaldehyde (0.254 g, 1.65 mmol) and thecorresponding alkyl acetoacetate (3.35 mmol) in methanol or2-propanol (10 mL). The reaction mixture was protected fromlight and heated under reflux for 12–24 h. After cooling, theprecipitate was filtered and purified by crystallization frommethanol or 2-propanol to afford the corresponding product.

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[31] Chinese Journal of Chemistry, 2011, vol. 29, # 1, p. 118 - 122
[32] Journal of Heterocyclic Chemistry, 1984, vol. 21, # 6, p. 1849 - 1856
[33] Tetrahedron Letters, 2014, vol. 55, # 13, p. 2090 - 2092
[34] Patent: US5250543, 1993, A,
[35] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 805 - 808
[36] Organic Process Research and Development, 2001, vol. 5, # 4, p. 452 - 455
[37] Patent: US2014/45896, 2014, A1, . Location in patent: Paragraph 0069; 0070
[38] Patent: EP2703398, 2014, A1, . Location in patent: Paragraph 0065; 0066
[39] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2103 - 2107
[40] Journal of Medicinal Chemistry, 1988, vol. 31, # 5, p. 936 - 944
[41] Journal of the Brazilian Chemical Society, 2011, vol. 22, # 3, p. 525 - 531
[42] Angewandte Chemie - International Edition, 2013, vol. 52, # 12, p. 3411 - 3416[43] Angew. Chem., 2013, vol. 125, # 12, p. 3495 - 3500,6
[44] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 10, p. 893 - 903
[45] Journal of the American Chemical Society, 1949, vol. 71, p. 4003,4004
[46] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 10, p. 920 - 922
[47] Synthesis, 2005, # 14, p. 2379 - 2383
[48] European Journal of Medicinal Chemistry, 2010, vol. 45, # 9, p. 3986 - 3992
[49] Australian Journal of Chemistry, 2011, vol. 64, # 10, p. 1390 - 1396
  • 8
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Reference: [1] Organic Process Research and Development, 2001, vol. 5, # 4, p. 452 - 455
[2] Synthetic Communications, 1995, vol. 25, # 6, p. 857 - 862
[3] Biochemical Pharmacology, 2003, vol. 65, # 3, p. 329 - 338
  • 9
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Reference: [1] Archiv der Pharmazie, 1989, vol. 322, # 5, p. 253 - 256
  • 10
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  • [ 39562-70-4 ]
Reference: [1] Archiv der Pharmazie, 1989, vol. 322, # 5, p. 253 - 256
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Reference: [1] Archiv der Pharmazie, 1989, vol. 322, # 5, p. 253 - 256
  • 12
  • [ 105-45-3 ]
  • [ 17758-33-7 ]
  • [ 16135-36-7 ]
YieldReaction ConditionsOperation in experiment
51% With ammonium acetate In methanol at 80℃; for 2 h; Microwave irradiation In a CEM microwave vial, 3-methyl-5-nitro-pyrimidin-4-one (300 mg, 1.94 mmol), methylacetoacetate (2.7 g, 23.27 mmol), ammonium acetate (1.79 g, 23.22 mmol) and MeOH (8.0mL) were added and irradiated at 80 °C for 2 h (TLC indicated complete consumption ofstarting material). The reaction mixture was concentrated under reduced pressure to give thecrude product which was purified by column chromatography (100-200 silica gel, 40 g, 5-10percent MeOH-DCM) to afford methyl 4-aminopyridine-3-carboxylate; this reaction mixturewas carried out in 6 batches (300 mg each), the crude material after work-up was combinedand purified to afford methyl 4-aminopyridine-3-carboxylate (900 mg, 51percent) as a yellowsolid.LCMS (ESI+): m/z: 153.43 [M+Ht.
Reference: [1] Chemical Communications, 2002, # 18, p. 2170 - 2171
[2] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 98; 99
  • 13
  • [ 105-45-3 ]
  • [ 107-02-8 ]
  • [ 65719-09-7 ]
Reference: [1] Chemical Communications, 2008, # 35, p. 4207 - 4209
[2] European Journal of Organic Chemistry, 2013, # 19, p. 4131 - 4145
  • 14
  • [ 105-45-3 ]
  • [ 552-89-6 ]
  • [ 21829-25-4 ]
YieldReaction ConditionsOperation in experiment
95% With C23H3BF16N2O; ammonium acetate In toluene at 100℃; for 10 h; In the 100 ml flask is added in a single port 0.01 µM percent Lewis acid-base dual function catalyst I (wherein Rf=CF3; R1, R2, R3, R4, R5, R6=F), 0.1 µM O-nitrobenzaldehyde (R7=2 - NO2- Ph), 0.1 µM methyl acetoacetate (R8=Me; R9=Me), 0.1 µM ammonium acetate, 10 ml toluene, the reaction in the 100 °C stirring for 10 hours, TLC tracking reaction to the reaction is complete. The reaction result is: product II (R7=2 - NO2- Ph; R8=Me; R9=Me) of yield of 99percent; catalyst system used repeatedly 10 times, its catalytic performance did not decline
91% With ammonium acetate In ethanol; water at 120℃; 10ml of ethanol was 15mmol 15mmol 2- nitrobenzaldehyde and methyl acetoacetate via connecting tubes 50ul / min flow rate injection micromixer, simultaneously, 10ml ammonium acetate solution (25percent) through a connecting pipe of the same diameter at the same flow rate after injection of the micro-mixer into a diameter of 0.5mm, a length of the micro-tube reactor 2m reaction, the micro reactor deg.] C oil bath temperature of 120, at the outlet of the reactor vessel was cooled to collect a crude nifedipine solution of the product, the precipitated solid was nifedipine, nifedipine solid was collected by filtration, and recrystallized from 95percent ethanol was 4.72 g, m.p. 172-173 deg C, 91percent yield.
90% for 0.1 h; microwave irradiation One mmole of 2-nitrobenzaldehyde was taken in a mortar and to it 2.2 mmoles of methyl acetoacetate was added and mixed thoroughly with help of pestle in a mortar. Ammonium acetate (1.2 mmoles) was added to reaction mixture and this mixture was then triturated with help of pestle. To this mixture aluminum oxide was added in small increments with thorough mixing till mixture became free flowing. Mixture was then transferred to a conical flask much larger in capacity compared to volume of adsorbent. A glass funnel was placed on the flask as condenser. Reaction mixture was subjected to microwave irradiation at 400W for 6 min. in a microwave oven placing a heat sink along with it. Reaction mixture was then allowed to cool to room temperature and the compound extracted with 3x50 ml portions of dichloromethane after stirring it thoroughly with adsorbent. The organic solvent extract was filtered through a filter paper on Buchner funnel and the organic solvent layer washed with 2x100 ml portions of water and the organic layer then dried over anhydrous sodium sulphate. Extract was filtered and solvent removed by distillation under vacuum to give residue which was recrystallised in methanol to give yellow coloured crystals of 4- (2-nitro)phenyl-2, 6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine, yield 90percent. m. p. 178 ° C.
89% With ammonium carbonate In neat (no solvent) at 90℃; for 0.5 h; Green chemistry General procedure: A mixture of β-ketoester (4 mmol), aldehyde (2 mmol), ammonium carbonate (1.2 mmol) and sulfated polyborate (5 wtpercent) was heated at 90 °C. The reaction was monitored by thin layer chromatography. After completion of the reaction, reaction mixture was cooled to room temperature and quenched by water; solid precipitated was filtered at vacuum pump, washed with water (3 x 5 mL), dried under vacuum and recrystallized from ethanol to afford the pure product.
88% With [Cp2Zr(H2O)2]+[OSO2C4F9]-2; ammonium acetate In neat (no solvent) at 80℃; for 2 h; General procedure: To a stirred solution of aldehyde (1.0 mmol) and 1,3-diketone compounds (2.0 mmol), ammonium acetate (1.2 mmol) and catalyst 1a (0.05 mmol) were added and heated at 80 °C, until the reaction was completed as indicated by TLC. After completion of the reaction, CH2Cl2 (3×10 mL) was added to the reaction mixture and the catalyst was filtered for the next cycle of the reaction. The combined CH2Cl2 solution was removed by evaporation in vacuum and was then subjected to silica gel column chromatograph with ethyl acetate–n-hexane (1:4) as eluent to afford pure compound.
87% With alumina; ammonium acetate In neat (no solvent) at 120℃; Microwave irradiation; Green chemistry General procedure: A mixture of the aldehyde 1 (2 mmol), the 1,3-dicarbonyl compound 2 (2 mmol) ammonium acetate 5 (5 mmol) and the 3D printed Al2O3 structure (0.350 g) was submitted to microwave irradiation (120 °C) in coated vial. After completion of the reaction, as indicated by TLC, the mixture was cooled and the desired compound solidified. For those 1,4-dihydropyridines that not solidified, the reaction mixture was poured onto crushed ice and stirred for 5-10 min. The solid obtained was filtered under suction, washed with ice-cold water (20 mL) and then purified by column chromatography or recrystallization from the appropriate solvent.
85% With ammonium hydroxide In ethanol at 110℃; Flow reactor General procedure: Diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (4a). EtOH solution (3 mL) ofbenzaldehyde (0.67 M) mixed with ethyl acetoacetate (1.34 M) and the 25percent aqueous NH3 (3 mL) wererespectively transferred into gas-tight syringe 1 and syringe 2. The syringes were placed in a LongerLSP02-1B syringe pump which was set to deliver the reactants into the mixer at identical flow rate of 6.7μL/min. The reaction mixture was then allowed to flow through a stainless steel tube reactor which wasdipped in a 110 C oil bath. The output mixture was collected in a cooled sample vial. After reactioncompletion, rinsed the reactor with ethanol to collect all of the reactant solution and then concentratedunder vacuum. The residue was subjected to silica gel column chromatography with Pet-EA (5:1) aseluent to give 4a (612mg, 93percent yield).
79% Darkness; Reflux General procedure: To a 50-mL round-bottomed flask, ammonium acetate (0.162 g,2.10 mmol) was added to a stirring solution of 2-nitrobenzaldehydeor 3-nitrobenzaldehyde (0.254 g, 1.65 mmol) and thecorresponding alkyl acetoacetate (3.35 mmol) in methanol or2-propanol (10 mL). The reaction mixture was protected fromlight and heated under reflux for 12–24 h. After cooling, theprecipitate was filtered and purified by crystallization frommethanol or 2-propanol to afford the corresponding product.Dimethyl 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (3a)Recrystallization from methanol afforded (0.480 g, 79percent):melting point (mp): 186–188°C.
78% With C21H38N(1+)*Mo11O40PV(4-)*3H(1+); ammonium acetate In ethanol at 78℃; for 8 h; Green chemistry The reaction was performed in a round bottom flask, whichwas equipped with a condenser and immersed in an oil bath. A mixture of methylacetoacetate (232 mg, 2 mmol), 2-nitrobenzaldehyde(151 mg, 1 mmol), ammonium acetate(100 mg, 1.3 mmol), and the selected catalyst (30 mg,1.5 percent mmol), in ethanol (8 mL) was thoroughly mixed andthen heated at 78 °C for 8 h. (to the end point of the reaction,checked by TLC). On cooling, the reaction mixture wasfiltered to separate the catalyst, the ethanol was evaporated,and the crude 1,4-dihydropyidine obtained was dried undervacuum (25 °C). The solid catalyst was washed with hexane(2 x 1 mL) and then, H2O (2 x 1 mL). The crude productwas recrystallized to give the pure 1,4-dihydropyridine.

Reference: [1] Patent: CN107141249, 2017, A, . Location in patent: Paragraph 0138; 0139
[2] Synlett, 2008, # 6, p. 883 - 885
[3] Synthetic Communications, 2012, vol. 42, # 5, p. 627 - 634
[4] RSC Advances, 2015, vol. 5, # 18, p. 13366 - 13373
[5] Patent: CN105348174, 2016, A, . Location in patent: Paragraph 0031
[6] Patent: WO2003/99790, 2003, A1, . Location in patent: Page 17
[7] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2008, vol. 47, # 7, p. 1084 - 1090
[8] Turkish Journal of Chemistry, 2010, vol. 34, # 4, p. 613 - 619
[9] Tetrahedron Letters, 2017, vol. 58, # 12, p. 1240 - 1244
[10] Journal of Organometallic Chemistry, 2015, vol. 785, p. 61 - 67
[11] Heteroatom Chemistry, 2016, vol. 27, # 2, p. 114 - 120
[12] Synthetic Communications, 2012, vol. 42, # 3, p. 454 - 459
[13] Applied Catalysis A: General, 2017, vol. 530, p. 203 - 210
[14] Synthesis, 2007, # 18, p. 2835 - 2838
[15] Journal of the Chinese Chemical Society, 2016, vol. 63, # 4, p. 336 - 344
[16] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 5, p. 969 - 974
[17] New Journal of Chemistry, 2012, vol. 36, # 7, p. 1502 - 1511
[18] Heterocycles, 2016, vol. 93, # 2, p. 755 - 761
[19] Synthetic Communications, 2002, vol. 32, # 4, p. 659 - 663
[20] Organic Letters, 2008, vol. 10, # 16, p. 3627 - 3629
[21] Biochemical Pharmacology, 2003, vol. 65, # 8, p. 1215 - 1226
[22] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 10, p. 893 - 903
[23] Catalysis Letters, 2016, vol. 146, # 9, p. 1634 - 1647
[24] Acta Poloniae Pharmaceutica - Drug Research, 2009, vol. 66, # 2, p. 147 - 153
[25] Chemical and Pharmaceutical Bulletin, 2011, vol. 59, # 9, p. 1153 - 1156
[26] Kinetics and Catalysis, 2010, vol. 51, # 4, p. 566 - 572
[27] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2007, vol. 46, # 2, p. 331 - 335
[28] Archiv der Pharmazie, 1981, vol. 314, # 11, p. 938 - 949
[29] Angewandte Chemie - International Edition, 2013, vol. 52, # 12, p. 3411 - 3416[30] Angew. Chem., 2013, vol. 125, # 12, p. 3495 - 3500,6
[31] Organic Process Research and Development, 2001, vol. 5, # 4, p. 452 - 455
[32] Journal of Medicinal Chemistry, 1988, vol. 31, # 5, p. 936 - 944
[33] Journal of Organic Chemistry, 1996, vol. 61, # 3, p. 924 - 928
[34] Magnetic Resonance in Chemistry, 1996, vol. 34, # 7, p. 495 - 504
[35] Patent: US2003/230478, 2003, A1,
[36] European Journal of Medicinal Chemistry, 2014, vol. 73, p. 97 - 104
[37] Chinese Journal of Chemistry, 2014, vol. 32, # 12, p. 1245 - 1250
[38] Biomedicine and Pharmacotherapy, 2017, vol. 92, p. 356 - 364
  • 15
  • [ 105-45-3 ]
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YieldReaction ConditionsOperation in experiment
76% With ammonium hydroxide In methanol; acetic acid EXAMPLE 5
To a suspension of 43.3 g (0.1 mole) of 1-(2'-nitro-phenyl)-N,N'-bis-(2'-nitro-phenyl)-methylene-methane-diamine and 140 ml of methanol 69.7 g (0.6 mole) of methyl acetoacetate and 8.7 ml of a 25percent ammonium hydroxide solution are added under stirring.
The reaction mixture is stirred at 45° C. for 42 hours, then cooled.
The precipitated product is filtered, dissolved in acetic acid under warming, precipitated with water and dried.
Thus 79.0 g of nifedipine are obtained, yield 76percent, m.p.: 172°-173° C.
Reference: [1] Patent: US5126457, 1992, A,
  • 16
  • [ 1336-21-6 ]
  • [ 105-45-3 ]
  • [ 21829-25-4 ]
Reference: [1] Patent: US4467093, 1984, A,
  • 17
  • [ 105-45-3 ]
  • [ 14205-39-1 ]
  • [ 21829-25-4 ]
Reference: [1] Patent: US5126457, 1992, A,
  • 18
  • [ 126192-87-8 ]
  • [ 105-45-3 ]
  • [ 21829-25-4 ]
YieldReaction ConditionsOperation in experiment
74% With ammonia In methanol; acetic acid EXAMPLE 3
To a mixture of 31.5 g (0.1 mole) of 1-methoxy-1-(2'-nitro-phenyl)-N-(2'-nitro-phenyl)-methylene-methaneamine and 68 ml of methanol first 46.45 g (0.4 mole) of methyl acetoacetate and subsequently a methanolic ammonia solution comprising 1.7 g (0.1 mole) of ammonia are added.
The reaction mixture is heated to boiling for 36 hours, then cooled.
The precipitated product is filtered, sucked dry, dissolved in acetic acid under warming, precipitated with water, filtered, washed with water and dried.
Thus 51.2 g of nifedipine are obtained, yield 74percent, m.p.: 171°-175° C.
71% With ammonia In methanol EXAMPLE 2
31.5 g (0.1 mole) of 1-methoxy-1-(2'-nitro-phenyl)-N-(2'-nitro-phenyl)-methylene-methane-amine are suspended in 100 ml of methanol. 46.45 g (0.4 mole) of methyl acetoacetate are added, whereupon ammonium hydroxide comprising an equivalent amount of ammonia is added dropwise.
The reaction mixture is heated to boiling for 14 hours, then cooled.
The precipitated product is filtered, washed with cold methanol and water and dried.
Thus 49.2 g of nifedipine are obtained, yield 71percent, m.p.: 170°-172° C.
Reference: [1] Patent: US5126457, 1992, A,
[2] Patent: US5126457, 1992, A,
[3] Acta Chimica Hungarica, 1993, vol. 130, # 1, p. 35 - 42
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Reference: [1] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1990, vol. 29, # 3, p. 277 - 279
[2] Organic Process Research and Development, 2001, vol. 5, # 4, p. 452 - 455
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Reference: [1] Patent: US5126457, 1992, A,
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Reference: [1] Russian Journal of Organic Chemistry, 1999, vol. 35, # 9, p. 1372 - 1376
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Reference: [1] Tetrahedron Letters, 1995, vol. 36, # 44, p. 8083 - 8086
  • 23
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Reference: [1] RSC Advances, 2016, vol. 6, # 16, p. 12993 - 13009
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Reference: [1] Synthetic Communications, 1992, vol. 22, # 1, p. 47 - 61
  • 25
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Reference: [1] Synthetic Communications, 1992, vol. 22, # 1, p. 47 - 61
  • 26
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Reference: [1] Synthetic Communications, 1992, vol. 22, # 1, p. 47 - 61
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  • 28
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  • [ 105-45-3 ]
  • [ 21829-09-4 ]
YieldReaction ConditionsOperation in experiment
95% With Er(1,3,5-benzenetricarboxylate)(aqua)(N,N-dimethylformamide)1.1; ammonium acetate In ethanol at 70℃; for 4 h; General procedure: Ammonium acetate (1 mmol), was added to the mixture of benzaldehyde (1 equiv), and ethyl acetoacetate (1.1 equiv) in Ethanol (1.5 mL) along with an appropriate amount of Er-MOF as catalyst (20 mg). The mixture was stirred at 70 °C for 4 h. After completion of the reaction, the catalyst was removed by centrifuge. Then brine (5 mL) and EtOAc (5 mL) was added. The mixture was extracted with EtOAc and the combined organic phase were washed with saturated aqueous solution of NaHCO3 (10 mL), and brine(10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. After removal of the solvent under vacuum, the crude product was purified by column chromatography to afford the desired product, Table 1. It is found that the Er-MOF catalyst can be recovered and reused five times without considerable loss of catalyticactivity.
95% With C23H3BF16N2O; ammonium acetate In toluene at 100℃; for 10 h; In the 100 ml flask is added in a single port 0.01 µM percent Lewis acid-base dual function catalyst I (wherein Rf=CF3; R1, R2, R3, R4, R5, R6=F), 0.1 µM to the nitrobenzene formaldehyde (R7=4 - NO2- Ph), 0.1 µM methyl acetoacetate (R8=Me; R9=Me), 0.1 µM ammonium acetate, 10 ml toluene, the reaction in the 100 °C stirring for 10 hours, TLC tracking reaction to the reaction is complete. The reaction result is: product II (R7=4 - NO2- Ph; R8=Me; R9=Me) of the yield is 94percent; catalyst system used repeatedly 10 times, its catalytic performance did not decline
95% at 100℃; for 0.333333 h; Green chemistry General procedure: To a glassy reactor equipped with a magnetic stir bar, amixture of aromatic aldehyde (1.0 mmol), β-keto ester(2 mmol), ammonium acetate (1.5 mmol) and n-Fe3O4(at)ZrO2/HPW (0.003 g, 15 mol percent) was added. The reactorwas put in an oil bath with the temperature of 100 °C andthe reaction was carried out under solvent-free condition.The progress of the reaction was monitored using TLCplates. When the reaction was completed, the mixture wasallowed to cool to room temperature. Afterwards, the mixturewas triturated with 5mL ethyl acetate and the catalystwas separated by the help of an external magnet. Then thesolvent was evaporated and the crude product was recrystallizedfrom EtOH/H2O to offer the pure product.
94% for 2.25 h; Heating; Green chemistry General procedure: A mixture of aldehyde 1 (1 mmol), 1,3-dicarbonyl compound 2 (2 mmol), and nitrogen source 3 (3 mmol) were mixed and heated in the presence of a low-melting sugar mixture.The progress of the reaction was monitored by thin-layer chromatography (TLC) using n-hexane–ethyl acetate (7:3) as the solvent system. The Rf values of the product spots ranged from 0.5 to 0.6. After completion of the reaction, water was added to the reaction mixture to obtain the solid product as a precipitate. In cases where the product was obtained as a melt, several washings with water followed by bicarbonate solution gave crystalline products. The solids were filtered and washed with cold water. In most of the cases, the product obtained was pure, and when impure, the product was recrystallized from hot ethanol. Further two products were obtained as oils (Table 5, entries 4w and 4x). These products were extracted with ethyl acetate and dried over anhydrous Na2SO4. Evaporation of the solvent gave the pure product as an oil.
92% at 55℃; for 4 h; Green chemistry General procedure: A mixture of aldehyde (1 mmol), β-dicarbonyl compound (1or 2 mmol), NH4OAc (2.5 mmol), dimedone (1 mmol, whenused), and SBA-15/NHSO3H (5 molpercent) was stirred at 55 °C.After complete disappearance of starting material asindicated by TLC, the resulting mixture was diluted with hotEtOAc (10 mL) and filtered. The catalyst was completelyrecovered from the residue.
82% at 80℃; for 0.15 h; General procedure: A mixture of the alkyl or aryl aldehyde (1 mmol), -dicarbonyl(2 mmol) and ammonium acetate (1.5 mmol) in the presence ofFe3O4NPs (0.024 g, equal to 10 molpercent) was heated at 80C, withstirring. The progress of the reaction was monitored by TLC (elu-ent: EtOAc:n-hexane). After completion of the reaction, the mixturewas cooled to room temperature and then ethanol was added tothe resulting mixture and separated Fe3O4NPs by a normal mag-net. After evaporation of solvent, the solid product was filtered andrecrystallized from ethanol to give the pure products in 72–95percentyields based on the starting aldehyde.

Reference: [1] Chemical Communications, 2011, vol. 47, # 32, p. 9230 - 9232
[2] Tetrahedron Letters, 2010, vol. 51, # 8, p. 1187 - 1189
[3] Chemical Papers, 2011, vol. 65, # 6, p. 898 - 902
[4] Catalysis Letters, 2017, vol. 147, # 2, p. 453 - 462
[5] Patent: CN107141249, 2017, A, . Location in patent: Paragraph 0130; 0131
[6] Catalysis Letters, 2017, vol. 147, # 6, p. 1551 - 1566
[7] RSC Advances, 2014, vol. 4, # 21, p. 10514 - 10518
[8] Journal of the Chinese Chemical Society, 2016, vol. 63, # 4, p. 336 - 344
[9] Synthetic Communications, 2016, vol. 46, # 24, p. 1989 - 1998
[10] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 5, p. 969 - 974
[11] Heteroatom Chemistry, 2006, vol. 17, # 4, p. 267 - 271
[12] Journal of Chemical Sciences, 2012, vol. 124, # 5, p. 1091 - 1096
[13] Research on Chemical Intermediates, 2014, vol. 40, # 1, p. 281 - 291
[14] RSC Advances, 2015, vol. 5, # 18, p. 13366 - 13373
[15] Monatshefte fur Chemie, 2006, vol. 137, # 1, p. 77 - 81
[16] Synlett, 2014, vol. 25, # 19, p. 2753 - 2756
[17] Advanced Synthesis and Catalysis, 2012, vol. 354, # 10, p. 2001 - 2008
[18] RSC Advances, 2014, vol. 4, # 100, p. 56658 - 56664
[19] Synthesis, 2007, # 18, p. 2835 - 2838
[20] Journal of Molecular Catalysis A: Chemical, 2014, vol. 382, p. 99 - 105
[21] Canadian Journal of Chemistry, 2017, vol. 95, # 5, p. 530 - 536
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[23] Organic Process Research and Development, 2001, vol. 5, # 4, p. 452 - 455
[24] Journal of Medicinal Chemistry, 1988, vol. 31, # 5, p. 936 - 944
[25] Synthesis, 2006, # 8, p. 1283 - 1288
[26] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 10, p. 920 - 922
[27] Synthetic Communications, 2010, vol. 40, # 16, p. 2457 - 2463
[28] Australian Journal of Chemistry, 2011, vol. 64, # 10, p. 1390 - 1396
  • 29
  • [ 60-35-5 ]
  • [ 555-16-8 ]
  • [ 105-45-3 ]
  • [ 21829-09-4 ]
YieldReaction ConditionsOperation in experiment
82% With Candida antarctica lipase B immobilized on acrylic resin In tert-butyl methyl ether at 50℃; for 72 h; Aldehyde (0.125 mmol), acetamide (0.5 mmol), and CAL-B (100 mg) in the mixed solvent (1 ml, 1,3-dicarbonyl compounds/methyl tert-butyl ether=4:6, by vol) at 50 °C for 72 h. The reaction was terminated by filtering off the enzyme. The crude residue was purified by silica gel column chromatography with an eluent consisting of petroleum ether/ethyl acetate (1/1 v/v). Product-contained fractions were combined, concentrated, and dried to give the product 1,4-dihydropyridine.
Reference: [1] Tetrahedron, 2011, vol. 67, # 14, p. 2689 - 2692
  • 30
  • [ 555-16-8 ]
  • [ 126-81-8 ]
  • [ 105-45-3 ]
  • [ 3357-14-0 ]
  • [ 40588-46-3 ]
  • [ 21829-09-4 ]
YieldReaction ConditionsOperation in experiment
8% With C22H25F6N5S; ammonium acetate In dichloromethane at 20℃; for 1 h; To a mixture of 0.014 g (0.1 mol) of dimedone, 0.01 mL (0.1 mol) of methyl acetoacetate, 0.015 g (0.1 mol) of p-nitrobenzaldehyde, and 0.096 g (0.125 mmol) of ammonium acetate at room temperature was added 1 mL of methylene chloride and 5 mmol of catalyst 5–9, the mixture was stirred for 1 h, then the solution was evaporated on a rotary evaporator. From the residue the reaction products were isolated by column chromatography, eluent ethyl acetate–hexane,1 : 8. Compounds were eluted in the following order: 4, 2, 3, and 1. Yield of compound 1 64–72percent.
Reference: [1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 5, p. 701 - 705[2] Zh. Org. Khim., 2016, vol. 52, # 5, p. 713 - 717,5
  • 31
  • [ 555-16-8 ]
  • [ 105-45-3 ]
  • [ 14205-39-1 ]
  • [ 21829-09-4 ]
Reference: [1] Organic Process Research and Development, 2001, vol. 5, # 4, p. 452 - 455
[2] Synthetic Communications, 1995, vol. 25, # 6, p. 857 - 862
  • 32
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  • [ 105-45-3 ]
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Reference: [1] Journal of Chemical Research, Miniprint, 1986, # 9, p. 2901 - 2915
  • 33
  • [ 555-16-8 ]
  • [ 105-45-3 ]
  • [ 21829-09-4 ]
  • [ 77233-99-9 ]
Reference: [1] RSC Advances, 2016, vol. 6, # 16, p. 12993 - 13009
  • 34
  • [ 631-61-8 ]
  • [ 555-16-8 ]
  • [ 105-45-3 ]
  • [ 21829-09-4 ]
Reference: [1] Dalton Transactions, 2016, vol. 45, # 43, p. 17343 - 17364
  • 35
  • [ 105-45-3 ]
  • [ 60-34-4 ]
  • [ 5203-77-0 ]
YieldReaction ConditionsOperation in experiment
66 g at 20 - 40℃; To a mixture of methyl acetoacetate (70 g, 0.6 mol) in ethanol (500 ml) in a round bottom flask was added drop wise methyl hydrazine (27.6 g, 0.6 mol) with an ice-water bath to keep the temperature below 40° C. The resulting mixture was then stirred at RT for overnight. The solvent was then removed under rotary evaporator to dryness, the solid product was further dried under vacuum, an off-white solid product B (66 grams) was obtained, and used without further purification in next dye formation step.
Reference: [1] Patent: US2016/333210, 2016, A1, . Location in patent: Paragraph 0055; 0058
  • 36
  • [ 105-45-3 ]
  • [ 60-34-4 ]
  • [ 2749-59-9 ]
Reference: [1] Journal of Organic Chemistry, 2015, vol. 80, # 3, p. 1338 - 1348
  • 37
  • [ 50-01-1 ]
  • [ 105-45-3 ]
  • [ 3977-29-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2429 - 2439
  • 38
  • [ 4637-24-5 ]
  • [ 105-45-3 ]
  • [ 23170-45-8 ]
Reference: [1] Patent: WO2016/81918, 2016, A1, . Location in patent: Paragraph 00292
[2] Patent: WO2017/205684, 2017, A1, . Location in patent: Paragraph 00706
  • 39
  • [ 105-45-3 ]
  • [ 23170-45-8 ]
Reference: [1] Patent: WO2006/74281, 2006, A2,
  • 40
  • [ 105-45-3 ]
  • [ 132712-71-1 ]
YieldReaction ConditionsOperation in experiment
88% With hydrazine In water at 20℃; for 0.25 h; Green chemistry General procedure: To a mixture of dicarbonyl compounds (1.0 mmol) and hydrazines/hydrazides (1.0 mmol) Fe3O4(at)SiO2(at)PDETSA MNPs (0.005 g) was added in water (2 mL). The mixture was stirred for the appropriate time at rt, as shown in Tables 3, 4 and 5. Completion of the reaction was indicated by TLC monitoring. After completion of the reaction, Fe3O4(at)SiO2(at)PDETSA MNPs were separated by external magnet. Then, the product was extracted with ethyl acetate (2 x 10 mL). The organic layer was dried (Na2SO4) and evaporated, and the crude product was purified by flash column chromatography (ethyl acetate/n-hexane, 1:20) to provide the pure product.
Reference: [1] RSC Advances, 2014, vol. 4, # 105, p. 61193 - 61199
[2] Research on Chemical Intermediates, 2016, vol. 42, # 4, p. 3169 - 3181
  • 41
  • [ 105-45-3 ]
  • [ 122-51-0 ]
  • [ 3788-94-1 ]
Reference: [1] Journal of the American Chemical Society, 2017, vol. 139, # 46, p. 16458 - 16461
  • 42
  • [ 105-45-3 ]
  • [ 14205-39-1 ]
YieldReaction ConditionsOperation in experiment
85% With ammonia In methanol at 0 - 10℃; for 4 h; Large scale 25kg of methyl acetoacetate and 20kg of methanol were pumped into the ammoniation reaction tank.The internal temperature was controlled to 0 to 10 ° C with iced water, stirred, and ammonia gas was introduced, and white crystals were precipitated, and the ammonia was stopped after 4 hours.After freezing overnight, the mixture was centrifuged to obtain white crystals, which was placed in an ammoniated refining tank, and 15 kg of methanol for purification was added thereto, and the mixture was heated to dissolve, and then freeze-crystallized at 0 to -10 ° C for 20 to 24 hours.The mixture was centrifuged and filtered, and the filter cake was dried in a hot air circulating oven at 50 to 60 ° C for 8 hours to obtain methyl 3-aminocrotonate of 18.6 to 21 kg, and the weight yield range was 74.4 to 84.0percent, and the molar yield range was 75.0 to 85.0percent.
Reference: [1] Chemical and Pharmaceutical Bulletin, 1989, vol. 37, # 8, p. 2117 - 2121
[2] Patent: WO2012/147103, 2012, A2, . Location in patent: Page/Page column 6-7
[3] Patent: CN108164454, 2018, A, . Location in patent: Paragraph 0024; 0026; 0027
[4] Journal of the Chemical Society of Pakistan, 2011, vol. 33, # 6, p. 916 - 921
[5] Journal of the American Chemical Society, 2010, vol. 132, # 28, p. 9585 - 9587
[6] New Journal of Chemistry, 2005, vol. 29, # 12, p. 1567 - 1576
[7] Tetrahedron Letters, 2011, vol. 52, # 34, p. 4412 - 4416
[8] Chemische Berichte, 1887, vol. 20, p. 3054
[9] Chemische Berichte, 1922, vol. 55, p. 2075
[10] Chemische Berichte, 1887, vol. 20, p. 3054
[11] Chemical and Pharmaceutical Bulletin, 1979, vol. 27, # 6, p. 1426 - 1440
[12] Arzneimittel-Forschung/Drug Research, 1981, vol. 31, # 3, p. 407 - 409
[13] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1994, vol. 33, # 5, p. 451 - 454
[14] Journal of Organic Chemistry, 1999, vol. 64, # 18, p. 6907 - 6910
[15] Organic Letters, 2004, vol. 6, # 6, p. 1013 - 1016
[16] Journal of the American Chemical Society, 2002, vol. 124, # 49, p. 14552 - 14553
[17] European Journal of Organic Chemistry, 2008, # 19, p. 3352 - 3362
[18] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 4, p. 1579 - 1586
[19] Organic Letters, 2011, vol. 13, # 7, p. 1754 - 1757
[20] Organic Letters, 2012, vol. 14, # 21, p. 5480 - 5483,4
[21] Organic Letters, 2012, vol. 14, # 21, p. 5480 - 5483
[22] Organic Process Research and Development, 2007, vol. 11, # 3, p. 568 - 577
[23] RSC Advances, 2014, vol. 4, # 37, p. 19111 - 19121
[24] Archives of Pharmacal Research, 2013, vol. 36, # 11, p. 1392 - 1402
[25] Organic Letters, 2014, vol. 16, # 20, p. 5410 - 5413
[26] Journal of the American Chemical Society, 2014, vol. 136, # 46, p. 16120 - 16123
[27] European Journal of Pharmacology, 2015, vol. 746, p. 233 - 244
[28] Tetrahedron, 2015, vol. 71, # 36, p. 6196 - 6203
[29] Advanced Synthesis and Catalysis, 2016, vol. 358, # 13, p. 2035 - 2040
[30] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 1452 - 1458
  • 43
  • [ 7664-41-7 ]
  • [ 105-45-3 ]
  • [ 14205-39-1 ]
Reference: [1] Organic Letters, 2012, vol. 14, # 13, p. 3506 - 3509
  • 44
  • [ 105-45-3 ]
  • [ 5977-14-0 ]
  • [ 14205-39-1 ]
Reference: [1] Monatshefte fuer Chemie, 1907, vol. 28, p. 4
[2] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1905, vol. <5> 14 I, p. 395[3] Chem. Zentralbl., 1905, vol. 76, # I, p. 1559
[4] Chemische Berichte, 1905, vol. 38, p. 1127[5] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1905, vol. <5> 14 I, p. 394[6] Chem. Zentralbl., 1905, vol. 76, # I, p. 1559
  • 45
  • [ 105-45-3 ]
  • [ 74-89-5 ]
  • [ 13412-12-9 ]
YieldReaction ConditionsOperation in experiment
95% With silica gel In water at 20℃; 1.2 g Silicagel was added to 11.6 g (100 mmol, 1 eq.) methyl acetoacetate. To this, 9.25 g (120 mmol, 1.2 eq.) methylamine solution (aqueous; 40percent) was added and the mixture stirred overnight. The reaction mixture was extracted with DCM, dried with MgSO4, filtered and evaporated. Yellow oil, yield: 12.21 g, 95 percent. H1-NMR: [CDCl3] δ = [ppm] 8.47 (s, NH, 1H), 4.47 (s, CH, 1H), 3.61 (s, OCH3, 3H), 2.91 (d, NHCH3, J = 5.22 Hz, 3H), 1.92 (s, CH3, 3H). Compound described in1.
88% at 45℃; for 18 h; Methylamine solution in MeOH (45 g, 517 mmol, 37percentw/w) was added into compound I-la (30 g, 258.6 mmol) at rt, then the mixture was heated to 45 °C for 18 hrs. After being cooled to rt, the mixture was extracted with DCM (250 mLX3), the combined organic layer a washed with water, dried over Na2S04, and concentrated in vacuo to give compound I-2a (29 g, yield 88percent).
Reference: [1] RSC Advances, 2015, vol. 5, # 49, p. 39193 - 39204
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 8, p. 1944 - 1947
[3] Patent: WO2013/25733, 2013, A1, . Location in patent: Paragraph 0402
[4] Chemical and Pharmaceutical Bulletin, 1987, vol. 35, # 12, p. 4819 - 4828
[5] Bulletin de la Societe Chimique de France, 1923, vol. <4> 33, p. 1108
[6] Journal of Organic Chemistry, 1965, vol. 30, p. 3033 - 3037
[7] Patent: WO2010/68775, 2010, A2, . Location in patent: Page/Page column 50; 104
[8] Patent: US2010/152257, 2010, A1, . Location in patent: Page/Page column 17
[9] Patent: WO2010/141761, 2010, A2, . Location in patent: Page/Page column 41-42
[10] Patent: US2011/82164, 2011, A1, . Location in patent: Page/Page column 23
[11] Patent: US2011/82181, 2011, A1, . Location in patent: Page/Page column 15
[12] Patent: WO2011/159550, 2011, A2, . Location in patent: Page/Page column 78-79
[13] Patent: WO2012/30922, 2012, A1, . Location in patent: Page/Page column 44
[14] Patent: WO2012/78805, 2012, A1, . Location in patent: Page/Page column 87
[15] Organic Letters, 2012, vol. 14, # 13, p. 3506 - 3509
[16] Patent: US2012/258987, 2012, A1, . Location in patent: Page/Page column 40
  • 46
  • [ 4091-39-8 ]
  • [ 105-45-3 ]
  • [ 74-89-5 ]
  • [ 13412-12-9 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1923, vol. <4> 33, p. 1108
  • 47
  • [ 67980-06-7 ]
  • [ 105-45-3 ]
  • [ 42825-78-5 ]
  • [ 110512-33-9 ]
  • [ 5234-68-4 ]
Reference: [1] Journal of Organic Chemistry, 1987, vol. 52, # 24, p. 5374 - 5377
  • 48
  • [ 105-45-3 ]
  • [ 17356-08-0 ]
  • [ 3829-80-9 ]
YieldReaction ConditionsOperation in experiment
99% With montmorillonite K10 Clay; iodine In dimethyl sulfoxide at 80℃; for 2 h; Green chemistry General procedure: A mixture of methylcarbonyl (0.5 mmol), thiourea (0.5 mmol), iodine (0.5 mmol), DMSO (2 mL) and 20 mg MMT-K10 was stirred at 80 °C. After completion of the reaction (monitored by TLC, petroleum:ethyl acetate, 4:1), the catalyst was separated by filtration, and then the solvent was removed under reduced pressure. The crude product was dissolved in hot water, extracted with ether (3 9 30 mL), and adjusted to pH = 9–10 by ammonia to give the solid products. Finally, the resulting precipitate was recrystallyzed by EtOH.
96% With iodine In dimethyl sulfoxide at 80℃; for 1 h; Green chemistry General procedure: A mixture of methylcarbonyl (0.5 mmol), thiourea(0.5 mmol), iodine (0.5 mmol), DMSO (2 mL) and 10 mgStarch NPs were stirred at 80 C. After completion of thereaction (monitored by TLC, petroleum:ethyl acetate, 4:1),the reaction was quenched by the addition of 10 mL distilledwater. The aqueous solution was extracted withEtOAc (3 9 10 mL) and the combined extract was driedwith anhydrous Na2SO4. The solvent was vacuumed, andfinally, the resulting precipitate was recrystallized byEtOH.
92% With N-iodo-succinimide In ethanol at 20℃; for 1.5 h; General procedure: A mixture of methyl carbonyl (2 mmol), thiourea (3 mmol), NIS(2 mmol), and NH2-MMT (0.10 g) in EtOH (5 mL) at room temperature was stirred until completion of reaction. The progress of the reaction was monitored by TLC (petroleum ether-ethyl acetate 4:1). After completion of the reaction, the NH2-MMT was separated by filtration. After evaporation of EtOH under vacuum, the crude product was dissolved in boiling water and adjusted to pH 8 withthe amount of ammonia to give the solid products. The solid obtained was recrystallized from a mixture of ethanol-water.
89% With iodine In ethanol for 3 h; Reflux General procedure: A mixture of the acetophenone (2 mmol), thiourea (3 mmol) and iodine (2 mmol), in the presence of 0.03 g nanochitosan was refluxed in EtOH.
The progress of the reaction was monitored by TLC (petroleum ether-ethyl acetate 4:1).
After completion of the reaction, the catalyst was separated by simple filtration.
After evaporation of solvent, the crude product was dissolved in boiling water, extracted with ether (3 * 30 mL), and adjusted to pH = 8 with the amount of ammonia to give the solid products.
The solid was recrystallized with ethanol-water to give pure 2-aminothiazole.
72% With tert.-butylhydroperoxide; 2,2'-azobis(isobutyronitrile) In methanol at 20 - 65℃; General procedure: General procedure: The substrate 1 (1.0 mmol) and thiourea 2(2.0 mmol) were added to solvent (5 mL methanol) at room tem-perature. To the reaction mixture, TBHP (3.0 mmol) and AIBN(0.2 mmol) were added respectively. The reaction mixture wasstirred at room temperature (for substrates 1a-f) or reux tem-perature (for substrates 1g-r) until TLC indicated the total consumption of 1 (for substrates 1p-q, the reaction time is 24 h).The residue was treated with saturated aqueous NaHCO3 (50 mL)and then extracted with EA (30 mL 3). The organic phase waswashed with brine (50 mL 1), dried over anhydrous Na2SO4. Thesolvent was removed and the residue was puried by ash columnchromatography on silica gel (EA/PE) to afford the desired compound 3.
72% With tert.-butylhydroperoxide; 2,2'-azobis(isobutyronitrile) In methanol for 5 h; Reflux 3-carbonyl-Butyric acidMethyl ester(I-i) (116mg)And thiourea (II) (152 mg) were added to methanol (5 mL) at room temperature.Add to reactionPeroxy tert-butyl alcohol (288 μL)And azobisisobutyronitrile (33mg),Stirred at reflux temperature for 5 hours. After the reaction is over, it is cooled to room temperature.Saturated aqueous sodium bicarbonate solution (50 mL) was added and extracted with ethyl acetate.The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product.The crude product was isolated and purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 3:7).The white solid methyl 2-amino-4-methyl-5-carboxylate thiazole (III-i) (124 mg) was obtained in a yield of 72percent.

Reference: [1] RSC Advances, 2016, vol. 6, # 69, p. 64749 - 64755
[2] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 8175 - 8183
[3] Advanced Synthesis and Catalysis, 2018, vol. 360, # 8, p. 1584 - 1589
[4] Monatshefte fur Chemie, 2017, vol. 148, # 4, p. 745 - 749
[5] Journal of Molecular Structure, 2017, vol. 1144, p. 58 - 65
[6] Applied Organometallic Chemistry, 2016, vol. 30, # 12, p. 1043 - 1049
[7] Catalysis Communications, 2016, vol. 77, p. 108 - 112
[8] Tetrahedron, 2018, vol. 74, # 17, p. 2107 - 2114
[9] Patent: CN107739350, 2018, A, . Location in patent: Paragraph 0069; 0070; 0071
  • 49
  • [ 67-56-1 ]
  • [ 77-92-9 ]
  • [ 1830-54-2 ]
  • [ 100009-70-9 ]
  • [ 20820-77-3 ]
  • [ 1587-20-8 ]
  • [ 105-45-3 ]
YieldReaction ConditionsOperation in experiment
87.3%
Stage #1: With chlorosulfonic acid In dichloromethane at 10 - 15℃; for 5 - 6 h;
Stage #2: at 3 - 35℃; for 2 h;
490 kg (370 1) of anhydrous methylene chloride are added to 1320 kg (753 1) of chlorosulphonic acid (the ratio of methylene chloride to chlorosulphonic acid is 0.5 : 1 by volume). The temperature of the mixture is adjusted to 10-15 oC, and 665.0 kg of citric acid monohydrate are added to it at a rate of 1.25 kg/minute, while the temperature of the reaction mixture is kept between 10 oC and 15 oC. When the addition has been completed the reaction mixture is stirred at a temperature between 10 oC and 15 oC until no more gas is liberated (at least 6 hours). The reaction mixture is then cooled to 3-5 oC and 640 kg (800 1) of anhydrous methanol are added to it at such a rate that the inner temperature does not exceed 25 oC. The reaction mixture is then warmed to 30-35 oC and stirred at the same temperature for 2 hours. The esterifying reaction is completed under this period. The reaction mixture is cooled to 10- 12 oC and 1300 1 of water are added to it at such a rate that the temperature does not exceed 15 oC. To the mixture 800 ml of methylene chloride are added and it is stirred for 15 minutes. The two-phase mixture is clarified for 30 minutes and the organic phase is separated. The aqueous layer is extracted three times with 400 ml each of methylene chloride. The organic phases are combined and washed first with 1000 1 of water, then with a solution of 75 kg of sodium hydrocarbonate in 1000 1 of water. The pH of the solution is adjusted to a value of about 7 by the addition of sodium hydrocarbonate. The organic phase is separated, washed twice with 750 ml each of water and evaporated in vacuo. Evaporation is carried out under a pressure of 3-5 kPa until the inner temperature rises at most to 75 oC. Thus 535 kg of dimethyl 3- OXOGLUTARATE are obtained, which can be used for the further reaction steps without purification. Qualification by gas chromatography: Purity by gas chromatography: Apparatus: gas chromatograph of HP-6850 type Method: Column : HP-1.25 m x 0. 32 MM, 0.17 URN of film thickness Carrier gas: hydrogen Program: 80 oC-5 MINUTES-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxoglutarate 5.77 minutes Enol ether 8.15 minutes Trimethyl aconitate 10. 00 minutes Trimethyl citrate 10. 42 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Result: Methyl acetoacetate: 0.31percent Dimethyl 3-oxoglutarate: 98.33percent Enol ether: 0. 81percent Trimethyl aconitate: 0. 28percent Trimethyl citrate : 0. 09percent Isoftalic acid derivative :- Other contamination (higher than 0,2 percent) Example 2 Into a mixture of 100.0 g (58 ml) of chlorosulphonic acid and 30 ml of methylene chloride 50.0 g of citric acid monohydrate are added within 30 minutes at a temperature between 10 oC and 15 oC. The mixture is stirred at the same temperature for 5 hours, cooled to 3-5 oC and 60 ml of methanol are introduced to it within 15 minutes at such a rate that the temperature does not exceed 25 oC. It is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC and 100 ml of water are added to it within 15 minutes. The thus-obtained mixture is extracted three times with 50 ml each of methylene chloride; the organic phases are combined, washed successively with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water and evaporated in vacuo. Thus 40.8 g of dimethyl 3- OXOGLUTARATE are obtained. Yield: 98. 5 percent Apparatus : gas chromatograph of HP-6850 type Method : Column: HP-1.25 m x 0.32 mm, film thickness of 0. 17 Am Carrier gas: hydrogen Program: 80 oC-5 minutes-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxo- glutarate 5. 77 minutes Enol ether 8.15 minutes Trimethyl citrate 10.42 minutes Trimethyl aconitate 10.11 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0. 49percent Dimethyl 3-OXOGLUTARATE : 97. 62percent Enol ether: 0.98percent Trimethyl citrate: 0. 13percent Trimethyl aconitate: 0.29percent Isoftalic acid derivative: 0.07percent Other contamination (more than 0.2 percent) Example 3 (comparative example) Example 1 of the Belgian patent specification No. 879,537 A mixture of 212 ml of chlorosulphonic acid and 600 ml of methylene chloride is prepared (the ratio of methylene chloride to chlorosulphonic acid is 2.83 : 1 by volume). Then 200.0 g of citric acid are added to this mixture within 15-20 minutes, the addition rate of citric acid is 13.3 kg/minute, temperature = 20-22 oC. The reaction mixture is stirred at this temperature for 5 hours, cooled to a temperature between 3"C AND 5 C and 320 ml of methanol are added to it within 15 minutes at such a rate that the temperature remain below 25 oC. The reaction mixture is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC, poured into 800 ml of water, stirred vigorously for 15 minutes, clarified for 15 minutes and the phases are separated. The aqueous phase is extracted three times with 150 ml each of methylene chloride. The organic phases are combined, washed once with 400 ml of saturated sodium hydrogen carbonate solution and twice with 200 ml each of water and evaporated in vacuo. Thus 158.2 g of dimethyl 3-oxoglutarate are obtained. Yield: 87. 3 percent. Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0.21percent Dimethyl 3-oxoglutarate: 91.07percent Enol ether: 4.78percent Trimethyl aconitate 0.46percent Trimethyl citrate : 2.27percent Isoftalic acid derivative: 0.53percent Other contamination (higher than 0. 2percent)
Reference: [1] Patent: WO2004/89867, 2004, A2, . Location in patent: Page 20-26
  • 50
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  • [ 616-38-6 ]
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1989, vol. 108, # 2, p. 51 - 56
  • 51
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  • [ 5977-14-0 ]
  • [ 14205-39-1 ]
Reference: [1] Monatshefte fuer Chemie, 1907, vol. 28, p. 4
[2] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1905, vol. <5> 14 I, p. 395[3] Chem. Zentralbl., 1905, vol. 76, # I, p. 1559
[4] Chemische Berichte, 1905, vol. 38, p. 1127[5] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1905, vol. <5> 14 I, p. 394[6] Chem. Zentralbl., 1905, vol. 76, # I, p. 1559
  • 52
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  • [ 74-88-4 ]
  • [ 30414-53-0 ]
Reference: [1] Tetrahedron, 2015, vol. 71, # 39, p. 7459 - 7469
[2] Journal of the American Chemical Society, 1974, vol. 96, p. 1082 - 1087
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 10, p. 1237 - 1244
  • 53
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  • [ 4755-81-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4660 - 4671
[2] Synthesis, 1987, # 2, p. 188 - 190
[3] Australian Journal of Chemistry, 2007, vol. 60, # 5, p. 358 - 362
[4] Journal of Medicinal and Pharmaceutical Chemistry, 1959, vol. 1, p. 577,594
[5] Journal of the American Chemical Society, 1939, vol. 61, p. 891
[6] Journal of Chemical Research, 2011, vol. 35, # 4, p. 243 - 245
  • 54
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  • [ 2483-57-0 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1904, vol. <3> 31, p. 851
  • 55
  • [ 67-56-1 ]
  • [ 105-45-3 ]
  • [ 81114-96-7 ]
Reference: [1] Tetrahedron, 1988, vol. 44, # 6, p. 1603 - 1608
  • 56
  • [ 105-45-3 ]
  • [ 32807-28-6 ]
Reference: [1] Patent: US2015/133475, 2015, A1, . Location in patent: Paragraph 0105; 0106
  • 57
  • [ 105-45-3 ]
  • [ 41051-15-4 ]
Reference: [1] Patent: US2015/133475, 2015, A1,
  • 58
  • [ 7732-18-5 ]
  • [ 107-08-4 ]
  • [ 105-45-3 ]
  • [ 39815-78-6 ]
YieldReaction ConditionsOperation in experiment
61% With hydrogenchloride; n-butyllithium; diisopropylamine In tetrahydrofuran; hexane EXAMPLE 3
Methyl 3-oxoheptanoate
Under nitrogen atmosphere, 59 ml of butyllithium 1.6M in hexane were added to a solution containing 14 ml of diisopropylamine in 200 ml of anhydrous THF, at
After stirring for 20 minutes, 9.3 ml of methyl acetoacetate were dropped, stirring was continued for 30 minutes at 0° C. and further 54 ml of butyllithium 1.6M in hexane were dropped.
After further 30 minutes 8.4 ml of propyl iodide were dropped into the dark orange solution.
The temperature was allowed to raise to room temperature and after 30 minutes, 50 ml of 37percent HCl diluted with 100 ml of H2 O were continuously dropped while keeping the temperature under 15° C.
The reaction mixture was extracted with Et2 O.
The organic phase was washed with a NaCl saturated solution, dried on Na2 SO4 and evaporated to dryness.
The residue was purified by FC (eluent: AcOEt/hexane 1:9).
8.3 g of a clear oil were obtained (yield 61percent); 1 H-NMR (200 MHz, CDCl3)δ: 0.90 (t, 3H), 1.22-1.65 (m, 4H), 2.53 (t, 2H), 3.44 (s, 2H), 3.73 (s, 3H).
Reference: [1] Patent: US5565464, 1996, A,
  • 59
  • [ 75-30-9 ]
  • [ 105-45-3 ]
  • [ 30414-55-2 ]
Reference: [1] Journal of the American Chemical Society, 1974, vol. 96, p. 1082 - 1087
[2] Canadian Journal of Chemistry, 1984, vol. 62, p. 1709 - 1716
  • 60
  • [ 67-56-1 ]
  • [ 77-92-9 ]
  • [ 1830-54-2 ]
  • [ 100009-70-9 ]
  • [ 20820-77-3 ]
  • [ 1587-20-8 ]
  • [ 105-45-3 ]
YieldReaction ConditionsOperation in experiment
87.3%
Stage #1: With chlorosulfonic acid In dichloromethane at 10 - 15℃; for 5 - 6 h;
Stage #2: at 3 - 35℃; for 2 h;
490 kg (370 1) of anhydrous methylene chloride are added to 1320 kg (753 1) of chlorosulphonic acid (the ratio of methylene chloride to chlorosulphonic acid is 0.5 : 1 by volume). The temperature of the mixture is adjusted to 10-15 oC, and 665.0 kg of citric acid monohydrate are added to it at a rate of 1.25 kg/minute, while the temperature of the reaction mixture is kept between 10 oC and 15 oC. When the addition has been completed the reaction mixture is stirred at a temperature between 10 oC and 15 oC until no more gas is liberated (at least 6 hours). The reaction mixture is then cooled to 3-5 oC and 640 kg (800 1) of anhydrous methanol are added to it at such a rate that the inner temperature does not exceed 25 oC. The reaction mixture is then warmed to 30-35 oC and stirred at the same temperature for 2 hours. The esterifying reaction is completed under this period. The reaction mixture is cooled to 10- 12 oC and 1300 1 of water are added to it at such a rate that the temperature does not exceed 15 oC. To the mixture 800 ml of methylene chloride are added and it is stirred for 15 minutes. The two-phase mixture is clarified for 30 minutes and the organic phase is separated. The aqueous layer is extracted three times with 400 ml each of methylene chloride. The organic phases are combined and washed first with 1000 1 of water, then with a solution of 75 kg of sodium hydrocarbonate in 1000 1 of water. The pH of the solution is adjusted to a value of about 7 by the addition of sodium hydrocarbonate. The organic phase is separated, washed twice with 750 ml each of water and evaporated in vacuo. Evaporation is carried out under a pressure of 3-5 kPa until the inner temperature rises at most to 75 oC. Thus 535 kg of dimethyl 3- OXOGLUTARATE are obtained, which can be used for the further reaction steps without purification. Qualification by gas chromatography: Purity by gas chromatography: Apparatus: gas chromatograph of HP-6850 type Method: Column : HP-1.25 m x 0. 32 MM, 0.17 URN of film thickness Carrier gas: hydrogen Program: 80 oC-5 MINUTES-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxoglutarate 5.77 minutes Enol ether 8.15 minutes Trimethyl aconitate 10. 00 minutes Trimethyl citrate 10. 42 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Result: Methyl acetoacetate: 0.31percent Dimethyl 3-oxoglutarate: 98.33percent Enol ether: 0. 81percent Trimethyl aconitate: 0. 28percent Trimethyl citrate : 0. 09percent Isoftalic acid derivative :- Other contamination (higher than 0,2 percent) Example 2 Into a mixture of 100.0 g (58 ml) of chlorosulphonic acid and 30 ml of methylene chloride 50.0 g of citric acid monohydrate are added within 30 minutes at a temperature between 10 oC and 15 oC. The mixture is stirred at the same temperature for 5 hours, cooled to 3-5 oC and 60 ml of methanol are introduced to it within 15 minutes at such a rate that the temperature does not exceed 25 oC. It is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC and 100 ml of water are added to it within 15 minutes. The thus-obtained mixture is extracted three times with 50 ml each of methylene chloride; the organic phases are combined, washed successively with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water and evaporated in vacuo. Thus 40.8 g of dimethyl 3- OXOGLUTARATE are obtained. Yield: 98. 5 percent Apparatus : gas chromatograph of HP-6850 type Method : Column: HP-1.25 m x 0.32 mm, film thickness of 0. 17 Am Carrier gas: hydrogen Program: 80 oC-5 minutes-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxo- glutarate 5. 77 minutes Enol ether 8.15 minutes Trimethyl citrate 10.42 minutes Trimethyl aconitate 10.11 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0. 49percent Dimethyl 3-OXOGLUTARATE : 97. 62percent Enol ether: 0.98percent Trimethyl citrate: 0. 13percent Trimethyl aconitate: 0.29percent Isoftalic acid derivative: 0.07percent Other contamination (more than 0.2 percent) Example 3 (comparative example) Example 1 of the Belgian patent specification No. 879,537 A mixture of 212 ml of chlorosulphonic acid and 600 ml of methylene chloride is prepared (the ratio of methylene chloride to chlorosulphonic acid is 2.83 : 1 by volume). Then 200.0 g of citric acid are added to this mixture within 15-20 minutes, the addition rate of citric acid is 13.3 kg/minute, temperature = 20-22 oC. The reaction mixture is stirred at this temperature for 5 hours, cooled to a temperature between 3"C AND 5 C and 320 ml of methanol are added to it within 15 minutes at such a rate that the temperature remain below 25 oC. The reaction mixture is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC, poured into 800 ml of water, stirred vigorously for 15 minutes, clarified for 15 minutes and the phases are separated. The aqueous phase is extracted three times with 150 ml each of methylene chloride. The organic phases are combined, washed once with 400 ml of saturated sodium hydrogen carbonate solution and twice with 200 ml each of water and evaporated in vacuo. Thus 158.2 g of dimethyl 3-oxoglutarate are obtained. Yield: 87. 3 percent. Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0.21percent Dimethyl 3-oxoglutarate: 91.07percent Enol ether: 4.78percent Trimethyl aconitate 0.46percent Trimethyl citrate : 2.27percent Isoftalic acid derivative: 0.53percent Other contamination (higher than 0. 2percent)
Reference: [1] Patent: WO2004/89867, 2004, A2, . Location in patent: Page 20-26
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  • 63
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  • 64
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  • 65
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  • [ 105-45-3 ]
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Reference: [1] European Journal of Organic Chemistry, 2009, # 14, p. 2283 - 2288
  • 66
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  • [ 52784-32-4 ]
Reference: [1] Canadian Journal of Chemistry, 1977, vol. 55, p. 996 - 1000
  • 67
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  • [ 105-45-3 ]
  • [ 22027-50-5 ]
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  • 68
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  • [ 74073-22-6 ]
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[2] Applied Catalysis A: General, 2017, vol. 530, p. 203 - 210
  • 69
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  • [ 67333-67-9 ]
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  • 70
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  • 71
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  • 72
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  • 73
  • [ 105-45-3 ]
  • [ 41489-76-3 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 4, p. 1298 - 1308
  • 74
  • [ 105-45-3 ]
  • [ 6289-46-9 ]
Reference: [1] Asian Journal of Chemistry, 2013, vol. 25, # 3, p. 1349 - 1352
  • 75
  • [ 35929-79-4 ]
  • [ 105-45-3 ]
  • [ 73257-49-5 ]
YieldReaction ConditionsOperation in experiment
91% With ammonium hydroxide In ethanol at 110℃; Flow reactor General procedure: Diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (4a). EtOH solution (3 mL) ofbenzaldehyde (0.67 M) mixed with ethyl acetoacetate (1.34 M) and the 25percent aqueous NH3 (3 mL) wererespectively transferred into gas-tight syringe 1 and syringe 2. The syringes were placed in a LongerLSP02-1B syringe pump which was set to deliver the reactants into the mixer at identical flow rate of 6.7μL/min. The reaction mixture was then allowed to flow through a stainless steel tube reactor which wasdipped in a 110 C oil bath. The output mixture was collected in a cooled sample vial. After reactioncompletion, rinsed the reactor with ethanol to collect all of the reactant solution and then concentratedunder vacuum. The residue was subjected to silica gel column chromatography with Pet-EA (5:1) aseluent to give 4a (612mg, 93percent yield).
Reference: [1] Heterocycles, 2016, vol. 93, # 2, p. 755 - 761
  • 76
  • [ 631-61-8 ]
  • [ 104-88-1 ]
  • [ 105-45-3 ]
  • [ 73257-49-5 ]
YieldReaction ConditionsOperation in experiment
96% With iron supported on copper/Zeolite Socony Mobil-5 nanocatalyst In water at 20℃; Sonication General procedure: In a typical experiment, aromatic aldehyde (1 mmol), bketoester(2 mmol), ammonium acetate (1 mmol), and Fe-Cu/ZSM-5 (3 wtpercent) in 2 ml water were introduced in a 20-mL heavy-walled pear-shaped two-necked flask with nonstandard-tapered outer joint. The flask was attached to a12-mm tip diameter probe, and the reaction mixture was sonicated at ambient temperature at 20 percent power of the processor. After completion of the reaction (monitored byTLC, within 5–8 min), the solid product was filtered,washed with water and ethanol, dried, and recrystallized from ethanol. The supported reagent was washed thrice with water and ethanol and dried under vacuum before reuse.
Reference: [1] Journal of the Iranian Chemical Society, 2016, vol. 13, # 2, p. 267 - 277
  • 77
  • [ 104-88-1 ]
  • [ 105-45-3 ]
  • [ 73257-49-5 ]
YieldReaction ConditionsOperation in experiment
95% at 80℃; for 0.3 h; General procedure: A mixture of the alkyl or aryl aldehyde (1 mmol), -dicarbonyl(2 mmol) and ammonium acetate (1.5 mmol) in the presence ofFe3O4NPs (0.024 g, equal to 10 molpercent) was heated at 80C, withstirring. The progress of the reaction was monitored by TLC (elu-ent: EtOAc:n-hexane). After completion of the reaction, the mixturewas cooled to room temperature and then ethanol was added tothe resulting mixture and separated Fe3O4NPs by a normal mag-net. After evaporation of solvent, the solid product was filtered andrecrystallized from ethanol to give the pure products in 72–95percentyields based on the starting aldehyde.
95% With C23H3BF16N2O; ammonium acetate In toluene at 100℃; for 10 h; In a 100 mL single-necked flask, 0.01 molpercent of Lewis acid-base bifunctional catalyst I was added (where Rf = CF3R1,R2, R3, R4, R5, R6 = F), 0.1 mol of p-chlorobenzaldehyde (R7 = 4-Cl-Ph), 0.1 mol of methyl acetoacetate (R8 = Me;Me), 0.1 mol of ammonium acetate, 10 mL of toluene, and the reaction was stirred at 100 ° C for 10 hours. TLC followed the reaction to complete the reaction. anti-The yield of the product II (R7 = 4-Cl-Ph; R8 = Me; R9 = Me) was 95percent; the catalyst system was reused 10 timesAfter its catalytic performance did not decline
94% for 2.25 h; Heating; Green chemistry General procedure: A mixture of aldehyde 1 (1 mmol), 1,3-dicarbonyl compound 2 (2 mmol), and nitrogen source 3 (3 mmol) were mixed and heated in the presence of a low-melting sugar mixture.The progress of the reaction was monitored by thin-layer chromatography (TLC) using n-hexane–ethyl acetate (7:3) as the solvent system. The Rf values of the product spots ranged from 0.5 to 0.6. After completion of the reaction, water was added to the reaction mixture to obtain the solid product as a precipitate. In cases where the product was obtained as a melt, several washings with water followed by bicarbonate solution gave crystalline products. The solids were filtered and washed with cold water. In most of the cases, the product obtained was pure, and when impure, the product was recrystallized from hot ethanol. Further two products were obtained as oils (Table 5, entries 4w and 4x). These products were extracted with ethyl acetate and dried over anhydrous Na2SO4. Evaporation of the solvent gave the pure product as an oil.
91% at 100℃; for 0.25 h; Green chemistry General procedure: To a glassy reactor equipped with a magnetic stir bar, amixture of aromatic aldehyde (1.0 mmol), β-keto ester(2 mmol), ammonium acetate (1.5 mmol) and n-Fe3O4(at)ZrO2/HPW (0.003 g, 15 mol percent) was added. The reactorwas put in an oil bath with the temperature of 100 °C andthe reaction was carried out under solvent-free condition.The progress of the reaction was monitored using TLCplates. When the reaction was completed, the mixture wasallowed to cool to room temperature. Afterwards, the mixturewas triturated with 5mL ethyl acetate and the catalystwas separated by the help of an external magnet. Then thesolvent was evaporated and the crude product was recrystallizedfrom EtOH/H2O to offer the pure product.
90% With uranyl nitrate hexahydrate; ammonium acetate In ethanol at 20℃; for 0.416667 h; Sonication General procedure: To a solution of aldehyde (1.0 mmol), ethyl/methyl acetoacetate/acetylacetone (2.0 mmol) and ammonium acetate (1.0 mmol) in ethanol (3 mL), uranyl nitrate (10 molpercent) was added and the resultant reaction mixture was sonicated at room temperature for the required time (Table 1). The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into crushed ice. The obtained solid was filtered, washed thoroughly with water, dried, and purified by recrystallisation in ethanol.
84% at 55℃; for 3 h; Green chemistry General procedure: A mixture of aldehyde (1 mmol), β-dicarbonyl compound (1or 2 mmol), NH4OAc (2.5 mmol), dimedone (1 mmol, whenused), and SBA-15/NHSO3H (5 molpercent) was stirred at 55 °C.After complete disappearance of starting material asindicated by TLC, the resulting mixture was diluted with hotEtOAc (10 mL) and filtered. The catalyst was completelyrecovered from the residue.
74% With C21H38N(1+)*Mo11O40PV(4-)*3H(1+); ammonium acetate In ethanol at 78℃; for 8 h; Green chemistry General procedure: The reaction was performed in a round bottom flask, whichwas equipped with a condenser and immersed in an oil bath. A mixture of methylacetoacetate (232 mg, 2 mmol), 2-nitrobenzaldehyde(151 mg, 1 mmol), ammonium acetate(100 mg, 1.3 mmol), and the selected catalyst (30 mg,1.5 percent mmol), in ethanol (8 mL) was thoroughly mixed andthen heated at 78 °C for 8 h. (to the end point of the reaction,checked by TLC). On cooling, the reaction mixture wasfiltered to separate the catalyst, the ethanol was evaporated,and the crude 1,4-dihydropyidine obtained was dried undervacuum (25 °C). The solid catalyst was washed with hexane(2 x 1 mL) and then, H2O (2 x 1 mL). The crude productwas recrystallized to give the pure 1,4-dihydropyridine.

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[4] Journal of Molecular Catalysis A: Chemical, 2014, vol. 382, p. 99 - 105
[5] Patent: CN107141249, 2017, A, . Location in patent: Paragraph 0114; 0115
[6] Synthetic Communications, 2016, vol. 46, # 24, p. 1989 - 1998
[7] RSC Advances, 2014, vol. 4, # 21, p. 10514 - 10518
[8] Journal of the Indian Chemical Society, 2009, vol. 86, # 9, p. 996 - 1000
[9] New Journal of Chemistry, 2018, vol. 42, # 15, p. 12539 - 12548
[10] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 3, p. 737 - 739
[11] Catalysis Letters, 2017, vol. 147, # 6, p. 1551 - 1566
[12] Chemical Communications, 2011, vol. 47, # 32, p. 9230 - 9232
[13] Research on Chemical Intermediates, 2015, vol. 41, # 9, p. 6877 - 6883
[14] Journal of the Chinese Chemical Society, 2016, vol. 63, # 4, p. 336 - 344
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Reference: [1] Tetrahedron Letters, 1995, vol. 36, # 44, p. 8083 - 8086
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  • 81
  • [ 626-34-6 ]
  • [ 105-45-3 ]
  • [ 6334-18-5 ]
  • [ 72509-76-3 ]
YieldReaction ConditionsOperation in experiment
94.3%
Stage #1: With piperidine; pyridine In neat (no solvent) at 75 - 80℃; for 9 h;
Stage #2: for 1 h; Reflux
20.0-dichlorobenzaldehyde 70.0 g (0.40 mol), β-aminocrotonate ethyl ester in a 500 mL round bottom flask55.8g (0.48mol),62.0 g (0.48 mol) of methyl acetoacetate, followed by 4.5 g (0.053 mol) of piperidine and 4.2 g (0.053 mol) of pyridine.The heating was started slowly and the temperature was raised. The reaction was maintained at 75-80 ° C for 9 h, and 200 g of absolute ethanol was added while heating, and the mixture was heated to reflux for 1 h, and filtered while hot.The mixture was cooled to 15 ° C and stirred for 1 h, and suction filtered. The filter cake was washed with a small amount of dry ethanol and dried to give 145 g of pale yellow solid.Yield: 94.3percent, purity 99.1percent
Reference: [1] Patent: CN108840819, 2018, A, . Location in patent: Paragraph 0014; 0040-0042; 0045-0048; 0051-0053
  • 82
  • [ 105-45-3 ]
  • [ 6334-18-5 ]
  • [ 72509-76-3 ]
  • [ 91189-59-2 ]
  • [ 79925-38-5 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: at 40 - 45℃; for 6 h;
Stage #2: for 4 h; Heating / reflux
To a solution of 2,3-dichlorobenzaldehyde (8.76 g, 0.05 mol) in isopropanol (80 mL) is added picolinic acid (0.65 g, 5.4 mmol), piperidine (0.45 g, 5.4 mmol) and methyl acetoacetate (86.3 g, 0.06 mol). The solution is stirred at 40-45 C. for 6 h, and then isopropanol is distilled under vacuum. The residue is dissolved in ethyl acetate (80 mL) and washed with water (60 mL). Ethyl acetate is then removed under vacuum. To the residue is added ethyl aminocrotonate (7.74 g, 0.06 mol) and isopropanol (60 mL). The mixture is heated under reflux for 4 hours. Isopropanol is distilled and heptanes (60 mL) is added. The resulting solid is filtered and washed with heptanes. After drying 12.7 g (66percent) felodipine is obtained as pale yellow solid with a purity of 94.4percent (diethyl and dimethyl have a concentration of 2.02percent and 3.38percent (a/a), respectively).
Reference: [1] Patent: US2004/204604, 2004, A1, . Location in patent: Page 5
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Reference: [1] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 1, p. 108 - 116
[2] Patent: CN103242220, 2016, B,
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[2] Chemical Communications, 2015, vol. 51, # 25, p. 5318 - 5321
[3] Chemistry - A European Journal, 2016, vol. 22, # 47, p. 16974 - 16978
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[5] Journal of Organic Chemistry, 1996, vol. 61, # 8, p. 2699 - 2708
[6] Organic Letters, 2007, vol. 9, # 24, p. 5111 - 5114
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Reference: [1] Patent: WO2016/46530, 2016, A1,
  • 90
  • [ 110-89-4 ]
  • [ 459-57-4 ]
  • [ 105-45-3 ]
  • [ 216690-15-2 ]
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[2] Tetrahedron, 2004, vol. 60, # 39, p. 8633 - 8644
  • 92
  • [ 105-45-3 ]
  • [ 350597-49-8 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 1.16 h;
Stage #2: With 1,4-diaza-bicyclo[2.2.2]octane In tetrahydrofuran at 45℃; for 3 h;
Stage #3: With ammonium acetate In tetrahydrofuran at 45 - 80℃; for 5 h;
Example 1.1.68: (5-isopropyl-2-methylpyridin-3-yl)methanamine; To a stirring solution of 1.1 g (9.47 mmol) of methyl acetoacetate in 20 mL of THF at 0 0C was added about 10 mL of 1BuOK (1.0 M) in THF dropwise. The ice bath was removed and stirring was continued at r.t. After 1 h 0.5 mL of 1BuOK was added, and after 10 min. 1.12 g (10 mmol) of DABCO (1,4-Diazabicyclo[2.2.2]octane) and 4.23 g (13.8 mmol) of the vinamidinium hexafluorophosphate salt (Davies, I. W., et al. J. Org. Chem. 2000, 65, 4571) were added. The mixture was heated at 45 0C and after 3 h, 1.35 g (17.5 mmol) of NH4OAc was added. The temperature was increased to 80 0C, and after 1 hour, 130 mg Of NH4OAc was added. After 4 h, the reaction was quenched with 45 mL of water. The aqueous layer was extracted with EtOAc (4x), and the combined extracts were washed with brine , dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (45percent EtOAc/hexanes) provided 1.44 g of methyl 5-chloro-2-methylnicotinate as a yellow orange oil in about 80percent yield.
Reference: [1] Patent: WO2009/42694, 2009, A1, . Location in patent: Page/Page column 106-107
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  • [ 105-45-3 ]
  • [ 3218-36-8 ]
  • [ 1099644-42-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9946 - 9957
  • 98
  • [ 105-45-3 ]
  • [ 1228689-61-9 ]
Reference: [1] Patent: US2011/82164, 2011, A1,
[2] Patent: US2011/82181, 2011, A1,
[3] Patent: WO2011/159550, 2011, A2,
[4] Patent: WO2012/78805, 2012, A1,
[5] Patent: US2012/258987, 2012, A1,
[6] Patent: WO2013/25733, 2013, A1,
  • 99
  • [ 504-29-0 ]
  • [ 105-45-3 ]
  • [ 943112-78-5 ]
Reference: [1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 364 - 369
[2] Organic Letters, 2016, vol. 18, # 5, p. 1016 - 1019
[3] Chemical Communications, 2011, vol. 47, # 40, p. 11333 - 11335
[4] Synthesis, 2011, # 15, p. 2445 - 2453
[5] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 9167 - 9174
  • 100
  • [ 504-29-0 ]
  • [ 105-45-3 ]
  • [ 5231-96-9 ]
  • [ 943112-78-5 ]
Reference: [1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 364 - 369
  • 101
  • [ 105-45-3 ]
  • [ 943112-78-5 ]
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 37, p. 3662 - 3666
  • 102
  • [ 105-45-3 ]
  • [ 1423699-80-2 ]
Reference: [1] Patent: WO2013/25733, 2013, A1,
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