Home Cart 0 Sign in  
X

[ CAS No. 2985-33-3 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 2985-33-3
Chemical Structure| 2985-33-3
Chemical Structure| 2985-33-3
Structure of 2985-33-3 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 2985-33-3 ]

Related Doc. of [ 2985-33-3 ]

Alternatived Products of [ 2985-33-3 ]

Product Details of [ 2985-33-3 ]

CAS No. :2985-33-3 MDL No. :MFCD02684780
Formula : C6H10O4 Boiling Point : -
Linear Structure Formula :- InChI Key :REGOCDRDNZNRMC-UHFFFAOYSA-N
M.W : 146.14 Pubchem ID :295972
Synonyms :

Calculated chemistry of [ 2985-33-3 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.67
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 34.01
TPSA : 63.6 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) : -6.66 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.28
Log Po/w (XLOGP3) : 0.75
Log Po/w (WLOGP) : 0.27
Log Po/w (MLOGP) : 0.25
Log Po/w (SILICOS-IT) : 0.06
Consensus Log Po/w : 0.52

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.85

Water Solubility

Log S (ESOL) : -0.95
Solubility : 16.2 mg/ml ; 0.111 mol/l
Class : Very soluble
Log S (Ali) : -1.67
Solubility : 3.16 mg/ml ; 0.0216 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.15
Solubility : 104.0 mg/ml ; 0.71 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.04

Safety of [ 2985-33-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2985-33-3 ]

* 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.

  • Downstream synthetic route of [ 2985-33-3 ]

[ 2985-33-3 ] Synthesis Path-Downstream   1~84

  • 1
  • [ 2985-33-3 ]
  • [ 14794-31-1 ]
  • [ 759-68-2 ]
YieldReaction ConditionsOperation in experiment
With tetrahydrofuran; isopropylmagnesium bromide
  • 2
  • [ 2985-33-3 ]
  • [ 22955-75-5 ]
  • [ 101499-64-3 ]
YieldReaction ConditionsOperation in experiment
With tetrahydrofuran; isopropylmagnesium bromide
  • 3
  • [ 2985-33-3 ]
  • [ 920-39-8 ]
  • [ 10488-87-6 ]
YieldReaction ConditionsOperation in experiment
With tetrahydrofuran anschliessend Umsetzen mit Benzoylchlorid;
  • 4
  • [ 2985-33-3 ]
  • [ 50496-34-9 ]
YieldReaction ConditionsOperation in experiment
96% With thionyl chloride at 0 - 40℃; 2.12. Ethyl a-methylmalonyl chloride 3 Thionyl chloride (4.76 mL, 65.2 mmol) was added dropwise to the mono-acid (4.767 g, 32.6 mmol) at 0 °C and the reaction mixture was stirred at 40 °C for overnight. The excess thionyl chloride was removed in vacuo to give acid chloride 3, which was used directly in the next step. Yield 96% (5.15 g); orange oil; nmax/ cm-1 2988 (C-H), 2945 (C-H), 1789 (C]O), 1736 (C]O); dH (400 MHz, CDCl3): 1.24 (3H, t, J 7.1, C(5)H3), 1.46 (3H, d, J 7.2, C(2) CH3), 3.78 (1H, q, J 7.2, C(2)H), 4.19 (2H, q, J 7.1, C(4)H2); dC (100 MHz, CDCl3): 13.9 (C(5)), 14.0 (C(2)CH3), 57.0 (C(2)), 62.3 (C(4)), 167.5 (C(3)), 170.7 (C(1)).
91% With thionyl chloride at 40℃; for 4h;
With thionyl chloride
With thionyl chloride
With phosphorus pentachloride In dichloromethane at 20℃; for 3h;
With thionyl chloride In benzene for 1.5h; Heating;
With phosphorus pentachloride In dichloromethane at 20℃; for 3h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere;
With oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether at 0 - 20℃; Inert atmosphere;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 6h; Inert atmosphere;
With thionyl chloride at 80℃; for 2h; Inert atmosphere;
166.1 mg With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; Synthetic procedure of 1 To a stirring solution of 2-methylmalonic acid ethyl ester (186.2 mg, 1.10 mmol, 1.0 equiv) in CH2Cl2 (2 mL) were added oxalyl chloride (200 μL, 1.68 mmol, 1.5 equiv) and a few drops of DMF, and the resulting mixture was kept stirred for 3 h at ambient temperature. After concentration, the generated ethyl 2-methylmalonyl chloride (166.1 mg, 1.0 mmol, 1.0 equiv) was dissolved in CH2Cl2 (1.5 mL) and condensed with aniline (66 μL, 1.0 mmol, 1.0 equiv) under the catalysis of Et3N (150 μL) first at 0 , and then at room temperature over 6 h. The reaction was quenched with 0.1 M HCl (500 μL) and extracted with CH2Cl2 (500 μL). The CH2Cl2 layer was washed with saturated NaHCO3 and NaCl solution, dried over anhydrous MgSO4, filtered, and evaporated to give of ethyl 2-methyl-3-oxo-3-(phenylamino)propanoic acid (176.5 mg, 0.72 mmol, 72%).
With thionyl chloride at 80℃; for 2h; Inert atmosphere; Schlenk technique; Sealed tube;

Reference: [1]Bagum, Halima; Christensen, Kirsten E.; Genov, Miroslav; Pretsch, Alexander; Pretsch, Dagmar; Moloney, Mark G. [Tetrahedron, 2019, vol. 75, # 40]
[2]Danieli, Bruno; Lesma, Giordano; Palmisano, Giovanni; Passarella, Daniele; Silvani, Alessandra [Tetrahedron, 1994, vol. 50, # 23, p. 6941 - 6954]
[3]Marguery [Bulletin de la Societe Chimique de France, 1905, vol. <3> 33, p. 550]
[4]Andrews, Mark D.; Brewster, Andrew G.; Crapnell, Katherine M.; Ibbett, Ashley J.; Jones, Tim; Moloney, Mark G.; Prout, Keith; Watkin, David [Journal of the Chemical Society. Perkin transactions I, 1998, # 2, p. 223 - 235]
[5]Roma, Giorgio; Cinone, Nunzia; Di Braccio, Mario; Grossi, Giancarlo; Leoncini, Giuliana; Signorello, Maria Grazia; Carotti, Angelo [Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 4, p. 751 - 768]
[6]Nagashima; Akamatsu; Kawaminami; Kawazoe; Ogami; Matsumoto; Okada; Suzuki; Tsukamoto [Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 11, p. 1420 - 1432]
[7]Di Braccio, Mario; Grossi, Giancarlo; Ceruti, Maurizio; Rocco, Flavio; Loddo, Roberta; Sanna, Giuseppina; Busonera, Bernardetta; Murreddu, Marta; Marongiu, Maria Elena [Il Farmaco, 2005, vol. 60, # 2, p. 113 - 125]
[8]Basak, Ashok K.; Shimada, Naoyuki; Bow, William F.; Vicic, David A.; Tius, Marcus A. [Journal of the American Chemical Society, 2010, vol. 132, # 24, p. 8266 - 8267]
[9]Shimada, Naoyuki; Stewart, Craig; Bow, William F.; Jolit, Anais; Wong, Kahoano; Zhou, Zhe; Tius, Marcus A. [Angewandte Chemie - International Edition, 2012, vol. 51, # 23, p. 5727 - 5729]
[10]Dhanjee, Heemal H.; Kobayashi, Yutaka; Buergler, Jonas F.; McMahon, Travis C.; Haley, Matthew W.; Howell, Jennifer M.; Fujiwara, Koichi; Wood, John L. [Journal of the American Chemical Society, 2017, vol. 139, # 42, p. 14901 - 14904]
[11]Santra, Surojit; Maji, Ujjwal; Guin, Joyram [Organic Letters, 2020, vol. 22, # 2, p. 468 - 473]
[12]Igarashi, Yasuhiro; Kurokawa, Yoichi; Li, Dandan; Oku, Naoya; Shinozaki, Yukiko [Beilstein Journal of Organic Chemistry, 2020, vol. 16, p. 1489 - 1494]
[13]Porey, Arka; Mondal, Bhaskar Deb; Guin, Joyram [Angewandte Chemie - International Edition, 2021, vol. 60, # 16, p. 8786 - 8791][Angew. Chem., 2021, vol. 133, # 16, p. 8868 - 8873,6]
  • 5
  • [ 105-37-3 ]
  • [ 2985-33-3 ]
YieldReaction ConditionsOperation in experiment
With diethyl ether; ammonia; sodium amide Verdampfen des NH3 und Behandeln des Rueckstands mit festem CO2;
  • 6
  • [ 609-08-5 ]
  • [ 2985-33-3 ]
YieldReaction ConditionsOperation in experiment
100% With potassium hydroxide In ethanol at 0 - 20℃; for 2h; To a cooled (0°C), stirred solution of diethyl methylmalonate (13) (2.00 ml, 11.7mmol) in EtOH (40ml), KOH(789 mg, 14.1mmol) was added. After being stirred at rt for 2 hours, the mixture was diluted with H2O (60 ml) and washed with hexane/THF (2:3,100ml). 1M aqueous HCl (30ml) was added to the aqueous layer. The mixture was extracted with CH2Cl2 (20ml3). The combined extracts were dried and concentrated in vacuo to provide 1.70 g (100%) of 14 as a colorless oil, which was used in the next step without further purification: TLC Rf 0.50 (EtOAc/hexane, 3:1); 1H-NMR (300MHz, CDCl3) d 1.28 (t, 3H, J7.1Hz), 1.45 (d,3H, J7.4Hz), 3.47 (q, 1H, J7.4Hz), 4.22 (q, 2H, J7.1Hz); 13C-NMR(125MHz, CDCl3) d 13.5, 14.0, 45.9, 61.7, 169.9, 175.8.
96% With sodium hydroxide In tetrahydrofuran at 0℃; for 1.5h;
96% Stage #1: Diethyl methylmalonate With potassium hydroxide; water In tetrahydrofuran at 0℃; for 1h; Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃; 44; 58 EXAMPLES 38-53[0049] These examples illustrate the application of the methodologies described herein to a wide range of dialkyl malonates and their derivatives using aqueous NaOH or KOH as a base.[0050] EXAMPLE 1 was repeated using the various diesters depicted in TABLE5. The results are summarized in TABLE 5. Most of these diesters are commercially available. Some diesters were prepared by the standard Fischer esterification. [0051] Unlike classical monosaponiflcation, which tends to yield a complex yellowish reaction mixture, in all cases in these reactions, only pure half esters, starting diesters, and (in rare cases) diacids, if extant, were isolated. In some cases, based on the percentage of the yield of the half ester and recovered diester, a small amount of the diacid appeared to have formed. However, these diacids were not extracted when the reaction mixture was worked up. All the obtained half esters had excellent purity, giving sharp elemental analysis data. No decarboxylated products were detected in any of the monohydrolysis reactions.[0052] Overall, KOH tends to be more reactive and slightly more selective than NaOH, as was obseryed in the results, depicted Jn TABLEs5. Thisstendency may be best illustrated in the monohydrolysis of diethyl phenymalonate (EXAMPLES 50-51), which showed1 enhanced reactivity and selectivity with the use of KOH, compared to the'results previously obtained with the useiof NaOH.for. monohydrolysis of the same diester:(see Id.). . } ''• p[0053] - '.Thec'results in TABLE '5 suggest that selectivity may increase with the hydrophobichy of the molecule. For example, the yields ofthe half ester increase with ester groups that are more hydrophobic in comparison to the monohydrolysis of diesters (see TABLE 5, EXAMPLES 50-53). The yields of half esters become even higher when the additional methyl or phenyl group is introduced (EXAMPLES 42- 53). Without wishing to be bound by^ theory, it is believed that, in this monohydrolysis reaction, upon the monohydrolysis of the two identical ester groups, inter- and/or intramolecular hydrophobic attractive interactions within the remaining portion of the molecule may play an important role for this high selectivity, as such aggregates may be protected from further hydrolysis. Therefore, this trend may explain such potential hydrophobic interaction. [0054] The only noted exception to the foregoing observation is in the monohydrolysis of dipropyl phenylmalonate (EXAMPLES 52 and 53). This result may be due to the extended period of the reaction time, which also sometimes allowed isolation of a visible amount of the corresponding diacid. Here, the use of acetonitrile (another slightly polar aprotic solvent that is slightly miscible with water) instead of THF as a co-solvent helped accelerate the reaction time to some extent, increasing the yield of the half ester by about 10%. Previously, the influence of the co-solvent in this monohydrolysis was studied and it was found that a slightly polar aprotic solvent with a small degree of miscibility with water appears to be an effective co-solvent. It may also be possible that the introduction of several bulky groups prohibited adoption of a preferable conformation for this selectivity.; EXAMPLE 58[0069] This example illustrates the synthesis of monoethyl methylmalonate. [0070] Diethyl methylmalonate (209 mg, 1.2 mmol) was dissolved in 2 mL of THF, and 2OmL of water was added. The reaction mixture was cooled to O0C in an ice-water bath. To this mixture was added the 1.2 equivalents of a 0.25 M aqueous NaOH, or KOH solution dropwise with stirring. The reaction mixture was stirred for 1.5 hours, and acidified with IM HCl at O0C, saturated with NaCl, extracted with ethyl acetate (X4), and dried over Na2SO4. This extract was concentrated in vacuo and purified by silica gel column chromatography, first with hexane:ethyl acetate (3:1) and then with ethyl acetate, to afford monoethyl methylmalonate. [0071] Oil. 1H NMR (300MHz, CDCl3) δ= 1.24 (3H, t, J = 7.2), 1.40 (3H, d, J = 7.5), 3.44 (IH, q, J= 7.2), 4.18 (2H, q, J= 7.2), 11.21 (IH, br, s); 13C NMR (75MHz, CDCl3) δ= 13.44, 13.90, 45.93, 61.70, 169.83, 176.00; IR (neat, cm"1) 1722, 1735, 2946-3200; Anal. Calcd for C6Hi0O4: C, 49.31 ; H, 6.90. Found: C, 49.68; H, 6.75.
96% Stage #1: Diethyl methylmalonate With sodium hydroxide; water In tetrahydrofuran at 0℃; for 1h; Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃; 45; 58 EXAMPLES 38-53[0049] These examples illustrate the application of the methodologies described herein to a wide range of dialkyl malonates and their derivatives using aqueous NaOH or KOH as a base.[0050] EXAMPLE 1 was repeated using the various diesters depicted in TABLE5. The results are summarized in TABLE 5. Most of these diesters are commercially available. Some diesters were prepared by the standard Fischer esterification. [0051] Unlike classical monosaponiflcation, which tends to yield a complex yellowish reaction mixture, in all cases in these reactions, only pure half esters, starting diesters, and (in rare cases) diacids, if extant, were isolated. In some cases, based on the percentage of the yield of the half ester and recovered diester, a small amount of the diacid appeared to have formed. However, these diacids were not extracted when the reaction mixture was worked up. All the obtained half esters had excellent purity, giving sharp elemental analysis data. No decarboxylated products were detected in any of the monohydrolysis reactions.[0052] Overall, KOH tends to be more reactive and slightly more selective than NaOH, as was obseryed in the results, depicted Jn TABLEs5. Thisstendency may be best illustrated in the monohydrolysis of diethyl phenymalonate (EXAMPLES 50-51), which showed1 enhanced reactivity and selectivity with the use of KOH, compared to the'results previously obtained with the useiof NaOH.for. monohydrolysis of the same diester:(see Id.). . } ''• p[0053] - '.Thec'results in TABLE '5 suggest that selectivity may increase with the hydrophobichy of the molecule. For example, the yields ofthe half ester increase with ester groups that are more hydrophobic in comparison to the monohydrolysis of diesters (see TABLE 5, EXAMPLES 50-53). The yields of half esters become even higher when the additional methyl or phenyl group is introduced (EXAMPLES 42- 53). Without wishing to be bound by^ theory, it is believed that, in this monohydrolysis reaction, upon the monohydrolysis of the two identical ester groups, inter- and/or intramolecular hydrophobic attractive interactions within the remaining portion of the molecule may play an important role for this high selectivity, as such aggregates may be protected from further hydrolysis. Therefore, this trend may explain such potential hydrophobic interaction. [0054] The only noted exception to the foregoing observation is in the monohydrolysis of dipropyl phenylmalonate (EXAMPLES 52 and 53). This result may be due to the extended period of the reaction time, which also sometimes allowed isolation of a visible amount of the corresponding diacid. Here, the use of acetonitrile (another slightly polar aprotic solvent that is slightly miscible with water) instead of THF as a co-solvent helped accelerate the reaction time to some extent, increasing the yield of the half ester by about 10%. Previously, the influence of the co-solvent in this monohydrolysis was studied and it was found that a slightly polar aprotic solvent with a small degree of miscibility with water appears to be an effective co-solvent. It may also be possible that the introduction of several bulky groups prohibited adoption of a preferable conformation for this selectivity.;EXAMPLE 58[0069] This example illustrates the synthesis of monoethyl methylmalonate. [0070] Diethyl methylmalonate (209 mg, 1.2 mmol) was dissolved in 2 mL of THF, and 2OmL of water was added. The reaction mixture was cooled to O0C in an ice-water bath. To this mixture was added the 1.2 equivalents of a 0.25 M aqueous NaOH, or KOH solution dropwise with stirring. The reaction mixture was stirred for 1.5 hours, and acidified with IM HCl at O0C, saturated with NaCl, extracted with ethyl acetate (X4), and dried over Na2SO4. This extract was concentrated in vacuo and purified by silica gel column chromatography, first with hexane:ethyl acetate (3:1) and then with ethyl acetate, to afford monoethyl methylmalonate. [0071] Oil. 1H NMR (300MHz, CDCl3) δ= 1.24 (3H, t, J = 7.2), 1.40 (3H, d, J = 7.5), 3.44 (IH, q, J= 7.2), 4.18 (2H, q, J= 7.2), 11.21 (IH, br, s); 13C NMR (75MHz, CDCl3) δ= 13.44, 13.90, 45.93, 61.70, 169.83, 176.00; IR (neat, cm"1) 1722, 1735, 2946-3200; Anal. Calcd for C6Hi0O4: C, 49.31 ; H, 6.90. Found: C, 49.68; H, 6.75.
87% With potassium hydroxide In tetrahydrofuran; water at 0 - 20℃; Synthetic procedure of 1 Diethyl methyl malonate (220 mg, 1.26 mmol, 1.0 equiv) was dissolved in THF (1.4 mL) and 0.25 M KOH (6.28 mL, 157 mmol, 1.25 equiv) was added to the solution dropwise at 0 . After stirring at room temperature for 2 h, the reaction solution was acidified with 1 M HCl (pH 3.0) and extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated to give 2-methylmalonic acid ethyl ester (186.2 mg, 1.10 mmol, 87%).
84% With potassium hydroxide In ethanol at 110℃; for 4h; Inert atmosphere;
81% With potassium hydroxide In ethanol at 110℃; for 4h;
81% With potassium hydroxide In ethanol at 20℃; for 72h; 2 4.3.2. 2-(Ethoxycarbonyl)propionic acid (2b). General procedure: Malonate 1a (7.5 g, 30.0 mmol) was added to a solution of KOH (1.68 g, 30.0 mmol) in 45 mL of EtOH at room temperature and the solution was stirred for 72 h. For the work-up the solvent was evaporated and the resulting residue was dissolved in NaHCO3 5% (20 mL) and washed with ethyl acetate (15 mL). The aqueous layer was acidified and extracted with ethyl acetate (3*15 mL). The combined organic layers were dried over Na2SO4, filtered, and solvent evaporated to give monoacid 2a as a colorless oil (89%). Monoacid 2a was obtained as a chromatographically pure compound and no further purification was required. Its spectroscopic behavior was consisted with reported data. 2-(Ethoxycarbonyl)propionic acid (2b). Colorless oil, 81% yield. 1H NMR (300 MHz, CDCl3) δ 10.80 (br s, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.47 (q, J=7.3 Hz, 1H), 1.42 (d, J=7.3 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.1, 170.1, 61.7, 46.0, 13.7, 13.4; IR (cm-1): 3100, 1716.
72% With water; potassium hydroxide at 18 - 25℃; for 2h; General procedure 4 (GP4) - monosaponification: General procedure: In a manner similar to 19, a RBF equipped with a stirring bar was charged with themalonate derivative 3 (1.0 equiv) and the solvent (c = 0.5 M, V mL). A 5 M aqueous solution of KOH (1.0 equiv) was added with asyringe and the reaction mixture was stirred at rt for 2 h. Then, the mixture was concentrated, diluted with water (V mL), and the mresulting aqueous layer was washed with Et2O (3*V/4 mL), acidified to pH 1 by the addition of 1 M aq HCl, saturated with NaCl, and extracted with EA (3*V/4 mL). The combined organic layers were dried (Na2SO4) and evaporated to afford the expected product 4.
71% With potassium hydroxide In ethanol at 20℃; for 4h;
68% With potassium hydroxide In ethanol at 0 - 20℃; for 24h; 2.11. Ethyl a-methylmalonic acid Diethyl methylmalonate (9.0 mL, 53 mmol) was added to a solution of KOH (2.99 g, 53.3 mmol) in EtOH (55 mL) at 0 °C and stirred at room temperature for 24 h or refluxed for 90 min. The resulting mixture was filtered and concentrated to give white solid. Water was then added, acidified the solution with HCl (pH 3.0) and extracted with diethyl ether. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the desired mono-acid. Yield 68% (5.28 g); colorless oil; nmax/cm-1 3183 (O-H), 2989 (C-H), 2947 (C-H), 1717 (C]O); dH (400 MHz, CDCl3): 1.21 (3H, t, J 7.1, C(5)H3), 1.38 (3H, d, J 7.3, C(2)CH3), 3.42 (1H, q, J 7.3, C(2)H), 4.15 (2H, q, J 7.1, C(4)H2), 11.35 (1H, s, COOH); dC (100 MHz, CDCl3): 13.4 (C(2)CH3), 13.9 (C(5)), 46.0 (C(2)), 61.7 (C(4)), 169.9 (C(3)), 176.0 (C(1)); m/z ([ESI]+) 147.0 ([M+H]+, 90%), 169.0 ([M+Na]+, 100%); HRMS ([ESI]+) found 147.0653, C6H11O4 ([M+H]+) requires 147.0652.
53% With potassium hydroxide In ethanol for 24h; Ambient temperature;
With sodium ethanolate at 120℃;
With potassium hydroxide; ethanol
With sodium ethanolate at 50 - 60℃;
With potassium hydroxide
With potassium hydroxide In ethanol
95 % Turnov. With sodium hydroxide In water at 40℃; for 5.5h; titrisol buffer pH 8, carboxylesterase NP;
With potassium hydroxide In ethanol at 0℃; for 48h;
Stage #1: Diethyl methylmalonate With potassium hydroxide In ethanol for 4h; Heating / reflux; Stage #2: With hydrogenchloride In water 20.a To a solution of 6.44 g (115 mmol) potassium hydroxide in 200 ml of ethanol 20.0 g diethyl methyl-malonate (115 mmol) was added and the mixture was refluxed for 4 hours. After cooling the reaction mixture was concentrated on a rotary evaporator, 50 ml of water was added and the mixture was extracted with ether (two times 50 ml). The aqueous solution was acidified with 4M hydrochloric acid and extracted with ethyl acetate (three times 50 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and used without further purification. MS m/e (%): 101.1 (M-EtO, 100), 147.1 (M+H+, 8).
With hydrogenchloride; sodium hydroxide In ethanol; hexane; water 3 Production of malonic acid monoester compound Reference Example 3 Production of malonic acid monoester compound First, 20.0 g of methylmalonic acid diethyl ester was dissolved in a mixed solution of 30 g of water and 30 g of ethanol. To this solution was added dropwise 9.6 g of 48% aqueous NaOH solution, and the mixture was vigorously stirred at room temperature for 7 hours. After completion of the reaction, the reaction solution was adjusted to pH 3 by the addition of 35% hydrochloric acid and concentrated under reduced pressure. To the residue was added 80 g of water, and the mixture was extracted twice with 40 g of ethyl acetate. The organic layers were combined and concentrated under reduced pressure. To the residue was added 100 g of n-hexane, and the precipitated crystals were collected by filtration. The filtrate was concentrated under reduced pressure to give 16.1 g of methylmalonic acid monoethyl ester. 1H-NMR (250 MHz, CDCl3, TMS) δ (ppm): 1.29 (t, 3H, J=7.1 Hz), 1.44 (d, 3H, J=7.3 Hz), 3.48 (q, 1H, J=7.3 Hz), 4.22 (q, 2H, J=7.1 Hz), 10-13 (brs, 1H).
Stage #1: Diethyl methylmalonate With potassium hydroxide In ethanol for 4h; Heating / reflux; Stage #2: With hydrogenchloride In water Acidic aqueous solution; 1.a Example 1 (N- (3, 5-DIFLUORO-BENZYL)-2-METHYL-N - (L-METHYL-2-OXO-5-PHENYL-2, 3-DIHYDRO-LH- benzo [e] [1,4] diazepin-3-yl) -malonamide a) 2-METHYL-MALONIC acid monoethyl ester To a solution of 6.44 g (115 mmol) potassium hydroxide in 200 ml of ethanol 20.0 g diethyl methyl-malonate (115 mmol) was added and the mixture was refluxed for 4 hours. After cooling the reaction mixture was concentrated on a rotary evaporator, 50 ml of water was added and the mixture was extracted with ether (two times 50 ml). The aqueous solution was acidified with 4M hydrochloric acid and extracted with ethyl acetate (three times 50 ml). The combined organic layers were dried (MGS04), concentrated under reduced pressure and used without further purification. MS m/e (%): 101.1 (M-EtO, 100), 147.1 (M+H+, 8).
With potassium hydroxide In ethanol
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 16 h / Inert atmosphere; Reflux 2.1: N1,N1,N12,N12-tetramethyl-7,8-dihydro-6H-dipyrido[1,2-a:2,1'-c][1,4]diazepine-2,12-diamine / N,N-dimethyl-formamide / 72 h / 20 °C / Inert atmosphere; Glovebox; UV-irradiation 2.2: 0 °C / pH < 3 / Inert atmosphere
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 16 h / Inert atmosphere; Reflux 2.1: N1,N1,N12,N12-tetramethyl-7,8-dihydro-6H-dipyrido[1,2-a:2,1'-c][1,4]diazepine-2,12-diamine / N,N-dimethyl-formamide / 72 h / 20 °C / Inert atmosphere; Glovebox; UV-irradiation 2.2: 0 °C / pH < 3 / Inert atmosphere
With potassium hydroxide In ethanol at 70℃; for 12h; B Step B: 3-ethoxy-2-methyl-3-oxopropanoic acid A suspension of diethyl 2-methylmalonate (500.00 g, 2.87 mol, 1.00 eq) and KOH (177.16 g, 3.16 mol, 1.10 eq) in EtOH (5000 mL) was stirred at 70 for 12 hr. The reaction mixture was concentrated under vacuum. The resulting residue was diluted with water and the aqueous layer was extracted with EtOAc. The organic layer was separated, dried and concentrated to provide 3-ethoxy-2-methyl-3-oxopropanoic acid.
Stage #1: Diethyl methylmalonate With potassium hydroxide In ethanol at 20℃; for 24h; Stage #2: With hydrogenchloride In water
Stage #1: Diethyl methylmalonate With potassium hydroxide; ethanol; water for 4h; Heating / reflux; Stage #2: With hydrogenchloride In water 1.a a) a) 2-Methyl-malonic acid monoethyl ester To a solution of 6.44 g (115 mmol) potassium hydroxide in 200 ml of ethanol 20.0 g diethyl methyl-malonate (115 mmol) was added and the mixture was refluxed for 4 hours. After cooling the reaction mixture was concentrated by distillation, 50 ml of water were added and the mixture was extracted with ether (two times 50 ml). The aqueous solution was acidified with 4M hydrochloric acid and extracted with ethyl acetate (three times 50 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and used without further purification, MS m/e (%): 101.1 (100), 147.1 (M+H+, 8).
With water; potassium hydroxide In tetrahydrofuran at 0℃; for 3h;
With water; potassium hydroxide In tetrahydrofuran at 0 - 25℃; for 4h; Schlenk technique; Sealed tube;

Reference: [1]Sasaki, Shu; Samejima, Suguru; Uruga, Tomoki; Anzai, Kai; Nishi, Natsumi; Kawakita, Eriko; Takao, Ken-Ichi; Tadano, Kin-Ichi [Journal of Antibiotics, 2013, vol. 66, # 3, p. 147 - 154]
[2]Niwayama, Satomi; Cho, Hanjoung; Lin, Chunlei [Tetrahedron Letters, 2008, vol. 49, # 28, p. 4434 - 4436]
[3]Current Patent Assignee: TIMES THREE WIRELESS - WO2008/150487, 2008, A2 Location in patent: Page/Page column 17-21; 24
[4]Current Patent Assignee: TIMES THREE WIRELESS - WO2008/150487, 2008, A2 Location in patent: Page/Page column 17-21; 24
[5]Igarashi, Yasuhiro; Kurokawa, Yoichi; Li, Dandan; Oku, Naoya; Shinozaki, Yukiko [Beilstein Journal of Organic Chemistry, 2020, vol. 16, p. 1489 - 1494]
[6]Liu, Yang; Mao, Zhongyi; Pradal, Alexandre; Huang, Pei-Qiang; Oble, Julie; Poli, Giovanni [Organic Letters, 2018, vol. 20, # 13, p. 4057 - 4061]
[7]Klahn, Philipp; Erhardt, Hellmuth; Kotthaus, Andreas; Kirsch, Stefan F. [Angewandte Chemie - International Edition, 2014, vol. 53, # 30, p. 7913 - 7917][Angew. Chem., 2014, vol. 126, # 30, p. 8047 - 8051,5]
[8]Tellitu, Imanol; Beitia, Itziar; Díaz, Marta; Alonso, Argiñe; Moreno, Isabel; Domínguez, Esther [Tetrahedron, 2015, vol. 71, # 43, p. 8251 - 8255]
[9]Condon, Sylvie; Le Gall, Erwan; Pichon, Christophe; Presset, Marc; Xavier, Tania [Beilstein Journal of Organic Chemistry, 2021, vol. 17, p. 2085 - 2094]
[10]Location in patent: experimental part Flipo, Marion; Charton, Julie; Hocine, Akila; Dassonneville, Sandrine; Deprez, Benoit; Deprez-Poulain, Rebecca [Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6790 - 6802]
[11]Bagum, Halima; Christensen, Kirsten E.; Genov, Miroslav; Pretsch, Alexander; Pretsch, Dagmar; Moloney, Mark G. [Tetrahedron, 2019, vol. 75, # 40]
[12]Danieli, Bruno; Lesma, Giordano; Palmisano, Giovanni; Passarella, Daniele; Silvani, Alessandra [Tetrahedron, 1994, vol. 50, # 23, p. 6941 - 6954]
[13]Roland; McElvain [Journal of the American Chemical Society, 1937, vol. 59, p. 134]
[14]Marguery [Bulletin de la Societe Chimique de France, 1905, vol. &lt;3&gt; 33, p. 550]
[15]Roland; McElvain [Journal of the American Chemical Society, 1937, vol. 59, p. 134]
[16]Curd; Robertson [Journal of the Chemical Society, 1933, p. 437,440]
[17]Carpino,L.A. et al. [Journal of Organic Chemistry, 1966, vol. 31, p. 2867 - 2873] Ruwet,A. et al. [Bulletin des Societes Chimiques Belges, 1970, vol. 79, p. 631 - 637]
[18]Smeets, J. W. H.; Kieboom, A. P. G. [Recueil des Travaux Chimiques des Pays-Bas, 1992, vol. 111, # 11, p. 490 - 495]
[19]Bellier; Million; DaNascimento; Meudal; Kellou; Maigret; Garbay [Journal of Medicinal Chemistry, 2000, vol. 43, # 20, p. 3614 - 3623]
[20]Current Patent Assignee: ROCHE HOLDING AG - US2005/54633, 2005, A1 Location in patent: Page/Page column 10
[21]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - US6204380, 2001, B1
[22]Current Patent Assignee: ROCHE HOLDING AG - WO2004/69826, 2004, A1 Location in patent: Page 19
[23]Shimada, Naoyuki; Stewart, Craig; Bow, William F.; Jolit, Anais; Wong, Kahoano; Zhou, Zhe; Tius, Marcus A. [Angewandte Chemie - International Edition, 2012, vol. 51, # 23, p. 5727 - 5729]
[24]Doni, Eswararao; Mondal, Bhaskar; O'Sullivan, Steven; Tuttle, Tell; Murphy, John A. [Journal of the American Chemical Society, 2013, vol. 135, # 30, p. 10934 - 10937]
[25]Doni, Eswararao; Mondal, Bhaskar; O'Sullivan, Steven; Tuttle, Tell; Murphy, John A. [Journal of the American Chemical Society, 2013, vol. 135, # 30, p. 10934 - 10937]
[26]Current Patent Assignee: MERCK &amp; CO INC - WO2016/19863, 2016, A1 Location in patent: Page/Page column 68
[27]Hermant, Paul; Bosc, Damien; Piveteau, Catherine; Gealageas, Ronan; Lam, Baovy; Ronco, Cyril; Roignant, Matthieu; Tolojanahary, Hasina; Jean, Ludovic; Renard, Pierre-Yves; Lemdani, Mohamed; Bourotte, Marilyne; Herledan, Adrien; Bedart, Corentin; Biela, Alexandre; Leroux, Florence; Deprez, Benoit; Deprez-Poulain, Rebecca [Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 9067 - 9089]
[28]Current Patent Assignee: ROCHE HOLDING AG - US2006/122168, 2006, A1 Location in patent: Page/Page column 10-11
[29]Santra, Surojit; Maji, Ujjwal; Guin, Joyram [Organic Letters, 2020, vol. 22, # 2, p. 468 - 473]
[30]Porey, Arka; Mondal, Bhaskar Deb; Guin, Joyram [Angewandte Chemie - International Edition, 2021, vol. 60, # 16, p. 8786 - 8791][Angew. Chem., 2021, vol. 133, # 16, p. 8868 - 8873,6]
  • 7
  • [ 2949-92-0 ]
  • [ 2985-33-3 ]
  • ethyl α,α-bis(methylthio)propionate [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With sodium hydride In dimethyl sulfoxide; paraffin for 10h; Ambient temperature;
  • 8
  • [ 2985-33-3 ]
  • [ 93-04-9 ]
  • [ 1875-53-2 ]
  • 2-(2-Methoxy-naphthalen-1-yl)-2-methyl-malonic acid monoethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 7% 2: 35% With sodium acetate; manganese triacetate In acetic acid at 30℃; for 9h;
  • 9
  • [ 2985-33-3 ]
  • [ 16874-17-2 ]
  • [ 100431-51-4 ]
YieldReaction ConditionsOperation in experiment
97% With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In tetrahydrofuran; chloroform Ambient temperature;
  • 10
  • [ 2985-33-3 ]
  • [ 110720-19-9 ]
  • ethyl O-benzyl-α-(α-hydroxyisovaleryl)propionate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With magnesium Multistep reaction;
  • 11
  • [ 2985-33-3 ]
  • [ 100431-27-4 ]
  • [ 100431-34-3 ]
YieldReaction ConditionsOperation in experiment
85% With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In tetrahydrofuran; chloroform Ambient temperature;
  • 12
  • [ 2985-33-3 ]
  • [ 58207-46-8 ]
  • (S)-N-<(R,S)-2-carbethoxy-1-oxopropyl>phenylalanine N'-(benzyloxy)amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-hydroxybenzotriazol-hydrate; triethylamine; dicyclohexyl-carbodiimide In chloroform 1.) 0 deg C, 1 h, 2.) room temperature, overnight;
  • 13
  • [ 2985-33-3 ]
  • [ 115364-52-8 ]
  • (R)-N-<(R,S)-2-carbethoxy-1-oxopropyl>phenylalanine N'-(benzyloxy)amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With 1-hydroxybenzotriazol-hydrate; triethylamine; dicyclohexyl-carbodiimide In chloroform 1.) 0 deg C, 1 h, 2.) room temperature, overnight;
  • 14
  • [ 2985-33-3 ]
  • [ 115364-67-5 ]
  • (R)-N-<(R,S)-2-carbethoxy-1-oxopropyl>-3-amino-4-phenyl-N'-(benzyloxy)butanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With 1-hydroxybenzotriazol-hydrate; triethylamine; dicyclohexyl-carbodiimide In chloroform 1.) 0 deg C, 1 h, 2.) room temperature, overnight;
  • 15
  • [ 2985-33-3 ]
  • H-D-Phe-NH2 hydrobromide [ No CAS ]
  • EtO(RS)-mAla-D-Phe-NH2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide 0 deg C, 1 h; room temp., 8 h;
  • 16
  • [ 103362-70-5 ]
  • [ 2985-33-3 ]
YieldReaction ConditionsOperation in experiment
96% With hydrogenchloride In water at -10℃;
  • 17
  • [ 2985-33-3 ]
  • [ 2592-95-2 ]
  • 2-Methyl-malonic acid benzotriazol-1-yl ester ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 0℃; for 0.333333h;
  • 18
  • [ 2985-33-3 ]
  • [ 2216-69-5 ]
  • 2-(4-Methoxy-naphthalen-1-yl)-propionic acid ethyl ester [ No CAS ]
  • 2-(4-Methoxy-naphthalen-1-yl)-2-methyl-malonic acid monoethyl ester [ No CAS ]
  • [ 118657-14-0 ]
YieldReaction ConditionsOperation in experiment
1: 24% 2: 1% 3: 1% With sodium acetate; manganese triacetate In acetic acid at 80℃; for 0.5h;
  • 19
  • [ 2985-33-3 ]
  • [ 15186-48-8 ]
  • [ 81997-76-4 ]
  • [ 81997-75-3 ]
YieldReaction ConditionsOperation in experiment
1: 13% 2: 61% With piperidine; pyridine at 5℃; for 96h;
1: 39% 2: 15% With diethylamine In toluene at 5℃; for 48h;
  • 20
  • [ 2985-33-3 ]
  • [ 64314-29-0 ]
  • [ 81684-83-5 ]
YieldReaction ConditionsOperation in experiment
59% With triethylamine In acetonitrile at 65 - 70℃; for 2h;
  • 21
  • [ 2985-33-3 ]
  • [ 75-65-0 ]
  • [ 56834-42-5 ]
YieldReaction ConditionsOperation in experiment
87% With dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 0.25h;
60% With dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 0.25h;
50% With dmap; dicyclohexyl-carbodiimide In dichloromethane 0 deg C, 1.5 h, then at r.t., 12 h;
  • 22
  • [ 2985-33-3 ]
  • Boc-Val-gPhe-H*TFA [ No CAS ]
  • N-[(S)-1-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-2-phenyl-ethyl]-2-methyl-malonamic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 3h; Ambient temperature;
  • 23
  • [ 292638-85-8 ]
  • 2-methyl-malonic acid ethyl ester 2-thioxo-2<i>H</i>-pyridin-1-yl ester [ No CAS ]
  • [ 2127-03-9 ]
  • [ 2985-33-3 ]
  • [ 114827-49-5 ]
  • 4-methyl-2-(2'-thiopyridyl)pentanedioic acid 5-ethyl 1-methyl diester [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 5% 2: 31% 3: 25% 4: 9% In benzene Irradiation;
  • 24
  • 2-methyl-malonic acid ethyl ester 2-thioxo-2<i>H</i>-pyridin-1-yl ester [ No CAS ]
  • [ 2127-03-9 ]
  • [ 2985-33-3 ]
  • [ 114827-49-5 ]
YieldReaction ConditionsOperation in experiment
1: 35% 2: 8% 3: 30% In benzene Irradiation;
  • 25
  • [ 2985-33-3 ]
  • H-Trp-(NMe)Nle-Asp(OBzl)-Phe-NH2 trifluoroacetate [ No CAS ]
  • C2H5O2C-CH(CH3)-CONH-Trp-(NMe)Nle-Asp(OBzl)-Phe-NH2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;
  • 26
  • [ 2985-33-3 ]
  • [ 538-75-0 ]
  • 3-cyclohexyl-2-(cyclohexylimino)-6-ethoxy-5-methyl-2H-1,3-oxazine-4(3H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% In dichloromethane at 20℃; for 1h;
59% With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h;
  • 27
  • [ 2985-33-3 ]
  • [ 67-63-0 ]
  • 1-ethyl 3-isopropyl 2-methylmalonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 11.5h;
With dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 0.25h;
  • 28
  • [ 82218-06-2 ]
  • [ 2985-33-3 ]
  • 2-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-propionic acid ethyl ester [ No CAS ]
  • 2-(6,8-dimethoxy-1-oxo-1H-isochromen-3-ylmethyl)-4,6-dimethoxybenzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% With triethylamine; 1,1'-carbonyldiimidazole In acetonitrile for 24.5h;
  • 29
  • [ 15761-39-4 ]
  • [ 2985-33-3 ]
  • ethyl (4S,2S)-3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-oxo-2-methylpropanoate [ No CAS ]
  • ethyl (4S,2R)-3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-oxo-2-methylpropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1-(tert-butoxycarbonyl)-L-proline With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 4h; Stage #2: monoethyl methylmalonate With isopropylmagnesium bromide In tetrahydrofuran; diethyl ether at -10 - 20℃; Further stages. Title compound not separated from byproducts.;
  • 30
  • [ 2985-33-3 ]
  • [ 91243-90-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (i) iPrMgBr, (ii) /BRN= 1099817/ 2: H2 / Raney-Ni / ethanol
  • 31
  • [ 753-90-2 ]
  • [ 2985-33-3 ]
  • [ 847926-36-7 ]
YieldReaction ConditionsOperation in experiment
61% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 18h; 20.b To a solution of 1.56 g (10.6 mmol) methyl-malonic acid monoethyl ester in 20 ml of tetrahydrofuran 1.06 g (10.6 mmol) of 2,2,2-trifluoroethylamine, 2.05 g (10.6 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 1.44 g (10.6 mmol) of 1-hydroxybenzotrizole hydrate and 2.75 g (21.2 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. The mixture was poured onto 0.5 N HCl (50 ml) and afterwards extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by column filtration (hexane/ethyl acetate=2:1) to yield 1.48 g (61%) of the title compound as white crystalline solid. MS m/e (%): 226,1 (M-H+, 100).
  • 32
  • [ 2985-33-3 ]
  • [ 90390-27-5 ]
  • N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 18h; 1.b b) N- (3, 5-DIFLUORO-BENZYL)-2-METHYL-MALONAMIC acid ethyl ester To a solution of 2.92 g (20 mmol) methyl-malonic acid monoethyl ester in 100 ml of tetrahydrofuran 2.86 g (20 mmol) of 3, 5-difluorobenzylamine, 3.83 g (20 mmol) of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, 2.70 g (20 mmol) of 1- hydroxybenzotrizole hydrate and 2.58 g (20 mmol) of N, N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. After concentration in vacuo 0.5 N HCl (50 ml) was added and the mixture was extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NAHCO3 solution, dried (MGS04) and evaporated on the rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate = 3: 1) to yield 4.29 g (79 %) of the title compound as white crystalline solid. MS m/e (%): 272.2 (M+H+, 100).
  • 33
  • [ 422-03-7 ]
  • [ 2985-33-3 ]
  • [ 2592-95-2 ]
  • [ 25952-53-8 ]
  • [ 7087-68-5 ]
  • [ 889458-71-3 ]
YieldReaction ConditionsOperation in experiment
81% b) 2-Methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid ethyl ester To a solution of 1.56 g (10.6 mmol) methyl-malonic acid monoethyl ester in 20 ml of tetrahydrofuran 1.58 g (10.6 mmol) of 2,2,3,3,3-pentafluoropropylamine, 2.05 g (10.6 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 1.44 g (10.6 mmol) of 1-hydroxybenzotrizole hydrate and 2.75 g (21.2 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. The mixture was poured onto 0.5 N HCl (50 ml) and afterwards extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and the solvent was removed by distillation. The residue was purified by column filtration (hexane/ethyl acetate=2:1) to yield 2.38 g (81%) of the title compound as white crystalline solid, MS m/e (%): 276.1 (M-H+, 100).
  • 34
  • 4-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)-2-methylaminoaniline [ No CAS ]
  • [ 2985-33-3 ]
  • [ 138032-47-0 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane 15.C Step C Step C 4-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)-2-methylaminoaniline (0.48 g), monoethyl 2-methylmalonate (0.38 g), DMAP (20 mgs) were dissolved in stirred, dry dichloromethane (5cm3). The mixture was cooled with cold water, dicyclohexylcarbodiimide (0.34 g) added, and left overnight at room temperature. The mixture was filtered (hyflo) and the filtrate concentrated under vacuum. The residue was purified using preparative plates (SiO2, CH2 C12 diethyl ether, 9:1) to give ethyl 2-[2-methylamino-4-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)phenylcarbamoyl] propionate (0.38 g) as a white solid. NMR(CDCl3) δ1.3(t); 1.55(d); 2.82(s)3H; 3.48(q)1H; 4.25(q+br.s)3H; 6.05(dd)1H; 7.08(d)1H; 7.39(dd)1H; 7.58(s)1H; 7.86(s)1H.
  • 35
  • [ 2985-33-3 ]
  • [ 530-62-1 ]
  • [ 116023-06-4 ]
YieldReaction ConditionsOperation in experiment
R.7.1 REFERENCE EXAMPLE 7-1 STR70 REFERENCE EXAMPLE 7-1 STR70 In the same manner as in Reference Example 1-2 but using ethyl 2-carboxypropionate (3.65 g; 25 mmole), 1,1'-carbonyldiimidazole (4.455 g; 27.5 mmole) and malonic acid monobenzyl ester magnesium salt (11.275 g; 27.5 mmole), there was produced benzyl 4-ethoxycarbonyl-3-oxopentanoate. IR (neat): 1730, 1445, 1370, 1315, 1230, 740, 690 (cm-1). NMR δ (CDCl3) 7.35 (s, 5H), 5.17 (s, 2H), 4.16 [q (J=7.0 Hz), 2H], 3.70 [q (J=7.0 Hz), 1H], 3.67 (s, 2H), 1.35 [d (J=7.0 Hz), 3H)], 1.24 [t (J=7.0 Hz), 3H].
  • 36
  • [ 2985-33-3 ]
  • [ 516-05-2 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide In methanol; water P.1 Preparation of α-[4-(4-Trifluoromethylphenoxy)phenoxy], α-Methyl Malonic Acid PREPARATION EXAMPLE 1 Preparation of α-[4-(4-Trifluoromethylphenoxy)phenoxy], α-Methyl Malonic Acid 3.6 g of α-[4-(4-trifluoromethylphenoxy)phenoxy], α-methyl malonic acid ethyl ester was dissolved in 20 ml of methanol, and an alkaline aqueous solution consisting of 2 ml of water and 0.7 g of sodium hydroxide was then dropwise added to the resulting mixture, followed by allowing the mixture to reflux for 1 hour. The reaction product was thrown into an appropriate amount of water to obtain crystals under acidic conditions with hydrochloric acid. The thus obtained crystals were filtered and recrystallized from acetic acid to obtain 3 g of the desired product having a melting point of 72° to 75° C.
  • 37
  • [ 2985-33-3 ]
  • [ 140-75-0 ]
  • [ 1193364-98-5 ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: monoethyl methylmalonate With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: para-fluorobenzylamine In N,N-dimethyl-formamide at 20℃;
  • 38
  • [ 2985-33-3 ]
  • [ 190080-34-3 ]
  • (2R,4S)-2-tert-Butyl-3-(2-ethoxycarbonyl-propionyl)-oxazolidine-4-carboxylic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;
  • 39
  • [ 1447797-53-6 ]
  • [ 2985-33-3 ]
YieldReaction ConditionsOperation in experiment
73% Stage #1: diethyl 2-methyl-2-(4-(trifluoromethyl)benzyl)malonate With N1,N1,N12,N12-tetramethyl-7,8-dihydro-6H-dipyrido[1,2-a:2,1'-c][1,4]diazepine-2,12-diamine In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; Glovebox; UV-irradiation; Stage #2: With hydrogenchloride In water at 0℃; Inert atmosphere; chemoselective reaction;
  • 40
  • [ 1447797-55-8 ]
  • [ 2985-33-3 ]
YieldReaction ConditionsOperation in experiment
57% Stage #1: diethyl 2-(3,5-di-tert-butylbenzyl)-2-methylmalonate With N1,N1,N12,N12-tetramethyl-7,8-dihydro-6H-dipyrido[1,2-a:2,1'-c][1,4]diazepine-2,12-diamine In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; Glovebox; UV-irradiation; Stage #2: With hydrogenchloride In water at 0℃; Inert atmosphere; chemoselective reaction;
  • 41
  • [ 2985-33-3 ]
  • [ 347384-33-2 ]
  • methyl 2,3-di-O-(tert-butyldimethylsilyl)-6-deoxy-4-O-(2-(ethoxycarbonyl)propanoyl)-α-D-glucopyranoside [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% Stage #1: methyl 6-deoxy-2,3-di-O-(tert-butyldimethylsilyl)-α-D-glucopyranoside With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 15h; Stage #2: monoethyl methylmalonate In dichloromethane at 20℃; for 3h; To a stirred solution of 12 (1.90 g,4.67mmol) in CH2Cl2 (38ml), DMAP (57.1 mg, 0.467mmol), a solution of14 (818mg, 5.60mmol) in CH2Cl2 (10ml) and dicyclohexylcarbodiimide(1.16 g, 5.60mmol) were added. The mixture was stirred at rt for 15 h, and a solution of 14 (273mg, 1.87mmol) in CH2Cl2 (2.4 ml) and dicyclohexylcarbodiimide(387 mg, 1.87mmol) were added. After being stirred at rt for 3 h,the mixture was diluted with H2O (80 ml) and extracted with CH2Cl2(20ml3). The combined extracts were dried and concentrated in vacuo The residue was purified by column chromatography on silica gel (EtOAc/hexane, 1:40) to provide 2.44 g (98% from 12) of 15 (ca. 1:1 diastereomericmixture) as a colorless oil: TLC Rf 0.60 (EtOAc/hexane, 1:5); IR (neat) 2931,1757 cm1; 1H-NMR (300MHz, CDCl3) d 0.05 (s, 3H), 0.07 (s, 3H), 0.10 (s,6H), 0.83 (s, 9H1/2), 0.86 (s, 9H1/2), 0.92 (s, 9H), 1.13 (d, 3H1/2,J6.6Hz), 1.18 (d, 3H1/2, J6.6Hz), 1.27 (t, 3H1/2, J7.2Hz), 1.28(t, 3H1/2, J7.2Hz), 1.42 (d, 3H1/2, J7.2Hz), 1.46 (d, 3H1/2,J7.2Hz), 3.36 (s, 3H1/2), 3.37 (s, 3H1/2), 3.42-3.52 (m, 1H), 3.66 (dd,1H, J3.5, 8.9Hz), 3.91 (t, 1H1/2, J8.9Hz), 3.92 (t, 1H1/2, J8.9Hz), 4.19 (q, 2H, J7.2Hz), 4.61 (d, 1H, J3.5Hz), 4.69 (dd, 1H1/2,J6.0, 8.9Hz), 4.72 (dd, 1H1/2, J6.0, 8.9Hz); 13C-NMR (125MHz,CDCl3) d 4.5 (3/2C), 4.4 (1/2C), 3.4, 3.0 (1/2C), 2.9 (1/2C), 13.6(1/2C), 14.0 (1/2C), 14.0 (1/2C), 14.1 (1/2C), 17.4 (1/2C), 17.6 (1/2C), 17.8 (1/2C), 17.8 (1/2C), 18.4, 25.8 (3/2C), 25.9 (3/2C), 26.1 (3C), 46.3 (1/2C), 46.3(1/2C), 55.0 (1/2C), 55.0 (1/2C), 61.3 (1/2C), 61.5 (1/2C), 65.3 (1/2C), 65.5(1/2C), 71.6 (1/2C), 71.7 (1/2C), 74.4, 77.6 (1/2C), 77.6 (1/2C), 100.0, 169.0(1/2C), 169.6 (1/2C), 169.7 (1/2C), 170.2 (1/2C); HRMS (EI) calculated forC21H41O8Si2 (M t-C4H9) m/z 477.2340, found 477.2349.
  • 42
  • [ 2985-33-3 ]
  • [ 71754-74-0 ]
YieldReaction ConditionsOperation in experiment
98% With sodium azide; potassium 1-hydroxy-1,3-dioxo-1,3-dihydro-1λ(5)-benziodoxol-5-sulfonate; sodium iodide In dimethyl sulfoxide at 10 - 60℃; for 2h;
  • 43
  • [ 2985-33-3 ]
  • [ 100-61-8 ]
  • [ 1174045-74-9 ]
YieldReaction ConditionsOperation in experiment
77% With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 0 - 20℃; for 2.5h; Inert atmosphere;
77% With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 0 - 20℃; for 2.5h; Ethyl 2-methyl-3-(methyl(phenyl)amino)-3-oxopropanoate[1] (21) To a stirred solutionof 3-ethoxy-2-methyl-3-oxopropanoic acid(2.41 g, 16.4 mmol) in CH2Cl2 (100 mL) was added at 0 °C,N-methylaniline (1.94 mL, 18.0 mmol),2-chloro-1-methylpyridinium iodide (6.23 g, 24.5 mmol), and Et3N(11.3 mL, 72.6 mmol). The reaction mixture was stirred at 0 °C for 30 min andallowed slowly to warm to room temperature and stirred for a further 2 h. A solutionof HCl (10%, 75 mL) was added and the organic phase was extracted with CH2Cl2(2 × 75 mL). The combined organic portions werewashed with water (2 × 75 mL) and brine (2 × 75 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude yellow oil was thenpurified by column chromatography (SiO2, Hexane/EtOAc, 6:1) to givethe title compound 21 (3.26 g, 77%)as a yellow oil.
With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 0 - 20℃; for 2.5h;
  • 44
  • [ 2985-33-3 ]
  • [ 105-37-3 ]
YieldReaction ConditionsOperation in experiment
91% With 1H-imidazole In neat (no solvent) at 115℃; for 0.0666667h; Microwave irradiation; 2 4.4.2. Ethyl propionate (3b). General procedure: A cap closed-vessel that has been charged with monoacid 2a (52 mg, 0.23 mmol) and imidazole (28 mg, 0.23 mmol) was irradiated for the programmed time and temperature (see Table 2). For the work-up, the residue was diluted with CH2Cl2 and washed with water (to remove imidazole), the organic layer was dried over Na2SO4, and the solvent evaporated under vacuum to render chromatographically pure ester 3a as a colorless oil (82% yield). Ethyl propionate (3b). Yellowish oil, 91% yield. 1H NMR (300 MHz, CDCl3) δ 4.16 (q, J=7.1 Hz, 2H), 2.32 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.8, 60.3, 27.6, 14.2, 9.1.
  • 45
  • [ 2985-33-3 ]
  • (S)-N-phenyl-1-phenylethylamine [ No CAS ]
  • ethyl 2-methyl-2{phenyl[(1S)-1-phenylethyl]carbamoyl}acetate [ No CAS ]
  • ethyl 2-methyl-2{phenyl[(1S)-1-phenylethyl]carbamoyl}acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 0℃; for 1h; Inert atmosphere; Overall yield = 68 %; Overall yield = 0.148 g; Optical yield = 20 %de; Ethyl 2-methyl-2{phenyl[(1S)-1-phenylethyl]carbamoyl}acetate (17) Toa stirred solution of N-[(1S)-1-phenylethyl]aniline (0.101 g, 0.514mmol) in CH2Cl2 (2 mL) was added at 0 °C 3-ethoxy-2-methyl-3-oxopropanoicacid (0.066 g, 0.453 mmol), 2-chloro-1-methylpyridinium iodide(0.167 g, 0.654 mmol) and Et3N (0.298 mL, 2.14 mmol). The resultingyellow mixture was stirred at 0 °C for 1 h and allowed to warm to roomtemperature and stirred for a further 1 h. HCl (10% solution in water, 5 mL)was added, the organic layer wasseparated, and the aqueous layer was extracted with EtOAc (2 × 10mL). The combined organic layers were washed with brine (10 mL), dried overMgSO4, and concentrated invacuo. The residual oil was loaded on a silica gel column and eluted with8:1 Hexane/EtOAc to afford the titlecompound 17 (0.148 g, 68%) as athick colourless oil in a 1:1.5 ratio of inseparable diastereoisomers.
  • 46
  • [ 2985-33-3 ]
  • 1-ethyl 3-(2,2,2-trifluoroethyl) 2-methyl-2-(2-(2-tosylhydrazono)propanoyl)malonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 12 h 2.1: sodium hydride / tetrahydrofuran; mineral oil / -78 - 55 °C / Cooling with ice; Inert atmosphere 2.2: 0.67 h / -78 - 20 °C / Inert atmosphere 3.1: dmap; dicyclohexyl-carbodiimide / tetrahydrofuran / 15 h / 55 °C / Inert atmosphere
  • 47
  • [ 2985-33-3 ]
  • C11H13F3O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 12 h 2.1: sodium hydride / tetrahydrofuran; mineral oil / -78 - 55 °C / Cooling with ice; Inert atmosphere 2.2: 0.67 h / -78 - 20 °C / Inert atmosphere
  • 48
  • [ 2985-33-3 ]
  • ethyl 3-(2,2,2-trifluoroethyl) 2-(2-diazopropanoyl)-2-methylmalonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 12 h 2.1: sodium hydride / tetrahydrofuran; mineral oil / -78 - 55 °C / Cooling with ice; Inert atmosphere 2.2: 0.67 h / -78 - 20 °C / Inert atmosphere 3.1: dmap; dicyclohexyl-carbodiimide / tetrahydrofuran / 15 h / 55 °C / Inert atmosphere 4.1: aluminum oxide / dichloromethane / 21.5 h / Inert atmosphere
  • 49
  • [ 2985-33-3 ]
  • 2-methyl 6-(2,2,2-trifluoroethyl) 1-ethoxy-4,6-dimethyl-5-oxo-7-oxabicyclo[2.2.1]hept-2-ene-2,6-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 12 h 2.1: sodium hydride / tetrahydrofuran; mineral oil / -78 - 55 °C / Cooling with ice; Inert atmosphere 2.2: 0.67 h / -78 - 20 °C / Inert atmosphere 3.1: dmap; dicyclohexyl-carbodiimide / tetrahydrofuran / 15 h / 55 °C / Inert atmosphere 4.1: aluminum oxide / dichloromethane / 21.5 h / Inert atmosphere 5.1: dirhodium tetraacetate / benzene / 24 h / 50 °C / Inert atmosphere
  • 50
  • [ 2985-33-3 ]
  • 2,3-dimethyl 5-(2,2,2-trifluoroethyl) 4-ethoxy-1,5-dimethyl-6-oxo-7-oxabicyclo[2.2.1]hept-2-ene-2,3,5-tricarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 12 h 2.1: sodium hydride / tetrahydrofuran; mineral oil / -78 - 55 °C / Cooling with ice; Inert atmosphere 2.2: 0.67 h / -78 - 20 °C / Inert atmosphere 3.1: dmap; dicyclohexyl-carbodiimide / tetrahydrofuran / 15 h / 55 °C / Inert atmosphere 4.1: aluminum oxide / dichloromethane / 21.5 h / Inert atmosphere 5.1: dirhodium tetraacetate / benzene / 24 h / 50 °C / Inert atmosphere
  • 51
  • [ 2985-33-3 ]
  • 2-methyl 6-(2,2,2-trifluoroethyl) 1-ethoxy-4,6-dimethyl-5-oxo-3-propyl-7-oxabicyclo[2.2.1]hept-2-ene-2,6-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 12 h 2.1: sodium hydride / tetrahydrofuran; mineral oil / -78 - 55 °C / Cooling with ice; Inert atmosphere 2.2: 0.67 h / -78 - 20 °C / Inert atmosphere 3.1: dmap; dicyclohexyl-carbodiimide / tetrahydrofuran / 15 h / 55 °C / Inert atmosphere 4.1: aluminum oxide / dichloromethane / 21.5 h / Inert atmosphere 5.1: dirhodium tetraacetate / benzene / 24 h / 50 °C / Inert atmosphere
  • 52
  • [ 2985-33-3 ]
  • 1-ethyl 3-isopropyl 2-methyl-2-(2-(2-tosylhydrazono)propanoyl)malonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 11.5 h 2.1: sodium hydride / tetrahydrofuran; mineral oil / -78 - 55 °C / Cooling with ice; Inert atmosphere 2.2: 0.83 h / -78 - 20 °C / Inert atmosphere 3.1: dmap; dicyclohexyl-carbodiimide / tetrahydrofuran / 16 h / 55 °C / Inert atmosphere
  • 53
  • [ 2985-33-3 ]
  • C12H18O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 11.5 h 2.1: sodium hydride / tetrahydrofuran; mineral oil / -78 - 55 °C / Cooling with ice; Inert atmosphere 2.2: 0.83 h / -78 - 20 °C / Inert atmosphere
  • 54
  • [ 2985-33-3 ]
  • 1-ethyl 3-isopropyl 2-(2-diazopropanoyl)-2-methylmalonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 11.5 h 2.1: sodium hydride / tetrahydrofuran; mineral oil / -78 - 55 °C / Cooling with ice; Inert atmosphere 2.2: 0.83 h / -78 - 20 °C / Inert atmosphere 3.1: dmap; dicyclohexyl-carbodiimide / tetrahydrofuran / 16 h / 55 °C / Inert atmosphere 4.1: aluminum oxide / dichloromethane / 16.5 h / Inert atmosphere
  • 55
  • [ 2985-33-3 ]
  • 5-isopropyl 2,3-dimethyl 4-ethoxy-1,5-dimethyl-6-oxo-7-oxabicyclo[2.2.1]hept-2-ene-2,3,5-tricarboxylate [ No CAS ]
  • 5-ethyl 2,3-dimethyl 4-isopropoxy-1,5-dimethyl-6-oxo-7-oxabicyclo[2.2.1]hept-2-ene-2,3,5-tricarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 11.5 h 2.1: sodium hydride / tetrahydrofuran; mineral oil / -78 - 55 °C / Cooling with ice; Inert atmosphere 2.2: 0.83 h / -78 - 20 °C / Inert atmosphere 3.1: dmap; dicyclohexyl-carbodiimide / tetrahydrofuran / 16 h / 55 °C / Inert atmosphere 4.1: aluminum oxide / dichloromethane / 16.5 h / Inert atmosphere 5.1: dirhodium tetraacetate / benzene / 24 h / 50 °C / Inert atmosphere
  • 56
  • [ 75-89-8 ]
  • [ 2985-33-3 ]
  • 1-ethyl 3-(2,2,2-trifluoroethyl) 2-methylmalonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h;
  • 57
  • [ 2985-33-3 ]
  • [ 105-10-2 ]
  • diethyl 3,3'-(benzene-1,4-diylbis(methylimino))bis(2-methyl-3-oxopropanoate) [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 0 - 20℃; for 17.1667h; Inert atmosphere;
  • 58
  • [ 2985-33-3 ]
  • diethyl (2-(methyl(4-(methylamino)phenyl)amino)-2-oxoethyl)propanedioate [ No CAS ]
  • 1,3-diethyl 2-(((4-(3-ethoxy-N,2-dimethyl-3-oxopropanamido)phenyl)(methyl)carbamoyl)methyl)propanedioate [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 0 - 20℃; for 19h; Inert atmosphere;
  • 59
  • [ 2985-33-3 ]
  • [ 758640-21-0 ]
  • [ 1236055-92-7 ]
YieldReaction ConditionsOperation in experiment
68% With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere;
With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 0 - 20℃; for 2.5h;
  • 60
  • [ 953077-11-7 ]
  • [ 2985-33-3 ]
  • ethyl 3-cyclobutyl-2-methyl-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: monoethyl methylmalonate With magnesium ethylate In tetrahydrofuran at 70℃; for 12h; Stage #2: cyclobutyl (1H-imidazol-1-yl)methanone In tetrahydrofuran for 20h; Reflux; C Step C: ethyl 3-cyclobutyl-2-methyl-3-oxopropanoate A suspension of 3-ethoxy-2-methyl-3-oxopropanoic acid (400 g, 2.74 mol) and Mg (C2H5O) 2 (313 g, 2.74 mol) in THF (4000 mL) was stirred at 70 for 12 hr. After the cooling down to 10 , cyclobutyl (1H-imidazol-1-yl) methanone (702 g, crude) was added and the mixture was heated at reflux for 20 h. Then the mixture was filtered and the filtrate was concentrated. The resulting residue was diluted with DCM, washed with water and brine, dried and concentrated. The resulting residue was purified by silica gel chromatography to afford ethyl 3-cyclobutyl-2-methyl-3-oxopropanoate.
  • 61
  • [ 2985-33-3 ]
  • 1-(2,6-difluorophenyl)cyclopropane-1-carbonyl chloride [ No CAS ]
  • ethyl 3-[1-(2,6-difluorophenyl)cyclopropyl]-2-methyl-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% Stage #1: monoethyl methylmalonate With isopropylmagnesium bromide In tetrahydrofuran Cooling; Stage #2: 1-(2,6-difluorophenyl)cyclopropane-1-carbonyl chloride In tetrahydrofuran at -8 - 20℃; for 19h; Ethyl 3-[1-(2,6-difluorophenyl)cyclopropyl]-2-methyl-3-oxopropanoate (7a) A solution of the Grignard reagent prepared from 9 g (≈370 mol) of Mg and 35 mL (45.9 g, 372 mmol) of i-PrBr in 400 mL of anhydrous THF was added dropwise to a solution of 27 g (184.8 mmol) of 2-(ethoxycarbonyl)propanoic acid in 200 mL of anhydrous THF at stirring and cooling, preventing the contact with air moisture and carbon dioxide. The resulting mixture was stirred during 15-20 min, cooled to -8° with an ice/NaCl mixture, and treated with a solution of 13.5 g (58.2 mmol) of acyl chloride 6a in 175 mL of anhydrous THF at stirring. Upon addition of the acyl chloride, the reaction mixture was stirred during 18 h on a cooling bath, then the temperature was raised to ambient, and stirring was continued during further 1 h at room temperature. The prepared solution was cooled with icy water and treated at stirring with 110 mL of 12% HCl. The reaction product was extracted with t-BuOMe (3×200 mL). The organic extracts were washed from acids with 10% aqueous solution of K2CO3 (during the phases separation, the mixture was filtered on a Buchner funnel to remove small amount of MgCO3 precipitate), washed with water to neutral reaction, and dried with anhydrous MgSO4. The filtrate was evaporated, and the residue was purified by fractional distillation under reduced pressure using a short Vigreaux column. Yield 15.3 g (93%), bp 127- 128°C (2.5 mmHg). Major component content 95% (GLC/MS). 1H NMR spectrum (300 MHz, CDCl3), δ, ppm: 1.05-1.42 m (7H, CH3CH2, CH2, c-Pr), 1.72- 1.83 m (3H, CH3), 3.51-3.59 m (1H, CH), 3.85-4.01 m (2H, CH2), 6.76-6.89 m (2H, 3,5H), 7.18-7.29 m (1H, 4H). The product was a mixture of the keto and the (E,Z)-enol form in dynamic equilibrium. The keto form: fraction 81.1%. Mass spectrum, m/z ( Irel, %): 284/ 283/282 (9/64/42) [M]+, 254 (15), 209 (15), 188 (10), 181 (33), 153 (100), 133 (34), 127 (30); tR 13.92 min. The enol form: fraction 18.9%. Mass spectrum (EI), m/z (Irel, %): 283/282 (21/70) [M]+, 237/236/235 (48/100/24), 207 (21), 153 (14), 127 (19), 83 (35); tR 15.00 min. Found, %: C 64.20; H 6.00. C15H16F2O3. Calculated, %: C 63.82; H 5.71.
93% Stage #1: monoethyl methylmalonate With magnesium; isopropyl bromide In tetrahydrofuran Cooling; Stage #2: 1-(2,6-difluorophenyl)cyclopropane-1-carbonyl chloride In tetrahydrofuran at -8 - 20℃; for 2h; Cooling; Ethyl 3-[1-(2,6-difluorophenyl)cyclopropyl]-2-methyl-3-oxopropanoate (6). To a soluton of 27 g(184.8 mmol) of 2-(ethoxycarbonyl)propanoic acid in200 mL of anhydrous THF at cooling with runnin gwater and stirring avoiding contact with moisture and carbon dioxide of air we added dropwise Grignard reagent obtained from 9 g (~370 mg-atom) of Mg and 35 mL (45.9 g, 372 mmol) of i-PrBr in 400 mL of anhydrous THF. On completion of the addition the obtained mixture was stirred for 15-20 min, cooled to 8° with a bath filled with ice and salt, and to the reaction mixture was added at stirring 12.6 g (58.2 mmol) of acid chloride 5 in 175 mL of anhydrous THF. On completion of the addition of the acid chloride solution the reaction mixture was stirred for 1 h at cooling, then the bath was removed, the mixture was stirred at warming to room temperature and 1 h more at this temperature. The solvent obtained was cooled with ice water, treated at stirring with 110 mL of 12% HCl, the product was extracted with t-BuOMe (3 × 200 mL). The extracts were washed from acids with 10% water solution of K2CO3 (at separating the phases the mixture was filtered through a Büchner funnel to remove the little quantity of MgCO3), washed with water (till neutral reaction by litmus), and dried with anhydrous MgSO4. The drying agent was filtered off,the filtrate was evaporated at atmospheric pressure while heating on a water bath, the residual solvent was removed at a reduced pressure while heating on a boiling water bath, and the reaction product was purified by fractional distillation at the reduced pressure using a short Vigreux column. Yield 15.3 g (93%), bp 127128°C (2.5 mm Hg). Content of the main product 95% (GC-MS). 1H NMR spectrum (300 MHz,CDCl3), δ, ppm: 1.051.42 m (7H, CH3CH2, 2CH2 cyclopropyl), 1.721.83 m (3H, C2H3), 3.513.59 m (1H, CH),3.854.01 m (2H, CH2), 6.766.89 m (2H, Ha3r,5om), 7.187.29 m (1H, H4arom).
  • 62
  • [ 2985-33-3 ]
  • 1-(2-fluoro-6-chlorophenyl)cyclopropane-1-carbonyl chloride [ No CAS ]
  • ethyl 3-[1-(2-fluoro-6-chlorophenyl)cyclopropyl]-2-methyl-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% Stage #1: monoethyl methylmalonate With isopropylmagnesium bromide In tetrahydrofuran Cooling; Stage #2: 1-(2-fluoro-6-chlorophenyl)cyclopropane-1-carbonyl chloride In tetrahydrofuran at -8 - 20℃; for 19h; Ethyl 3-[1-(2,6-difluorophenyl)cyclopropyl]-2- methyl-3-oxopropanoate (7a) General procedure: A solution of the Grignard reagent prepared from 9 g (≈370 mol) of Mg and 35 mL (45.9 g, 372 mmol) of i-PrBr in 400 mL of anhydrous THF was added dropwise to a solution of 27 g (184.8 mmol) of 2-(ethoxycarbonyl)propanoic acid in 200 mL of anhydrous THF at stirring and cooling, preventing the contact with air moisture and carbon dioxide. The resulting mixture was stirred during 15-20 min, cooled to -8° with an ice/NaCl mixture, and treated with a solution of 13.5 g (58.2 mmol) of acyl chloride 6a in 175 mL of anhydrous THF at stirring. Upon addition of the acyl chloride, the reaction mixture was stirred during 18 h on a cooling bath, then the temperature was raised to ambient, and stirring was continued during further 1 h at room temperature. The prepared solution was cooled with icy water and treated at stirring with 110 mL of 12% HCl. The reaction product was extracted with t-BuOMe (3×200 mL). The organic extracts were washed from acids with 10% aqueous solution of K2CO3 (during the phases separation, the mixture was filtered on a Buchner funnel to remove small amount of MgCO3 precipitate), washed with water to neutral reaction, and dried with anhydrous MgSO4. The filtrate was evaporated, and the residue was purified by fractional distillation under reduced pressure using a short Vigreaux column. Yield 15.3 g (93%), bp 127- 128°C (2.5 mmHg).
  • 63
  • [ 2985-33-3 ]
  • 1-(2,6-dichlorophenyl)cyclopropane-1-carbonyl chloride [ No CAS ]
  • ethyl 3-[1-(2,6-dichlorophenyl)cyclopropyl]-2-methyl-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% Stage #1: monoethyl methylmalonate With isopropylmagnesium bromide In tetrahydrofuran Cooling; Stage #2: 1-(2,6-dichlorophenyl)cyclopropane-1-carbonyl chloride In tetrahydrofuran at -8 - 20℃; for 19h; Ethyl 3-[1-(2,6-difluorophenyl)cyclopropyl]-2- methyl-3-oxopropanoate (7a) General procedure: A solution of the Grignard reagent prepared from 9 g (≈370 mol) of Mg and 35 mL (45.9 g, 372 mmol) of i-PrBr in 400 mL of anhydrous THF was added dropwise to a solution of 27 g (184.8 mmol) of 2-(ethoxycarbonyl)propanoic acid in 200 mL of anhydrous THF at stirring and cooling, preventing the contact with air moisture and carbon dioxide. The resulting mixture was stirred during 15-20 min, cooled to -8° with an ice/NaCl mixture, and treated with a solution of 13.5 g (58.2 mmol) of acyl chloride 6a in 175 mL of anhydrous THF at stirring. Upon addition of the acyl chloride, the reaction mixture was stirred during 18 h on a cooling bath, then the temperature was raised to ambient, and stirring was continued during further 1 h at room temperature. The prepared solution was cooled with icy water and treated at stirring with 110 mL of 12% HCl. The reaction product was extracted with t-BuOMe (3×200 mL). The organic extracts were washed from acids with 10% aqueous solution of K2CO3 (during the phases separation, the mixture was filtered on a Buchner funnel to remove small amount of MgCO3 precipitate), washed with water to neutral reaction, and dried with anhydrous MgSO4. The filtrate was evaporated, and the residue was purified by fractional distillation under reduced pressure using a short Vigreaux column. Yield 15.3 g (93%), bp 127- 128°C (2.5 mmHg).
  • 64
  • [ 2985-33-3 ]
  • 3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidine hydrochloride [ No CAS ]
  • ethyl 3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2-methyl-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 19 ethyl 3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2-methyl-3-oxopropanoate Example 19 ethyl 3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2-methyl-3-oxopropanoate To a mixture of 3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidine hydrochloride (400 mg), 3-ethoxy-2-methyl-3-oxopropanoic acid (205 mg) and DMF (10 mL) were added HATU (730 mg) and N,N-diisopropylethylamine (660 mg) at 0° C., and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (200 mg). MS: [M+H]+ 392.2.
  • 65
  • [ 2985-33-3 ]
  • [ 615-36-1 ]
  • [ 1259439-90-1 ]
YieldReaction ConditionsOperation in experiment
90% With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; Inert atmosphere;
  • 66
  • [ 2985-33-3 ]
  • ethyl 4-methyl-1,5-dioxo-1,2,3,3a,3a1,4,5,10b-octahydropyrrolo[3,2,1-jk]carbazole-4-carboxylate [ No CAS ]
  • ethyl 4-methyl-1,5-dioxo-1,2,3,3a,3a1,4,5,10b-octahydropyrrolo[3,2,1-jk]carbazole-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C / Inert atmosphere 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; palladium diacetate; 1,4-di(diphenylphosphino)-butane / toluene / 0.17 h / 0 - 20 °C / Inert atmosphere; Sealed tube 2.2: 2 h / 145 °C / Inert atmosphere; Sealed tube
  • 67
  • [ 2985-33-3 ]
  • [ 123-11-5 ]
  • ethyl (E)-3-(4-methoxyphenyl)-2-methylpropenoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With morpholine In toluene for 4h; Reflux; Green chemistry; stereoselective reaction;
  • 68
  • [ 2985-33-3 ]
  • [ 100-52-7 ]
  • [ 7042-33-3 ]
YieldReaction ConditionsOperation in experiment
83% With morpholine In toluene for 24h; Reflux; Green chemistry; stereoselective reaction;
  • 69
  • [ 2985-33-3 ]
  • [ 104-87-0 ]
  • ethyl (E)-2-methyl-3-(o-tolyl)acrylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With morpholine In toluene for 4h; Reflux; Green chemistry; stereoselective reaction;
  • 70
  • [ 2985-33-3 ]
  • [ 591-31-1 ]
  • [ 1524157-79-6 ]
YieldReaction ConditionsOperation in experiment
80% With morpholine In toluene for 24h; Reflux; Green chemistry; stereoselective reaction;
  • 71
  • [ 455-19-6 ]
  • [ 2985-33-3 ]
  • [ 890648-41-6 ]
YieldReaction ConditionsOperation in experiment
65% With morpholine In toluene for 4h; Reflux; Green chemistry; stereoselective reaction;
  • 72
  • [ 2985-33-3 ]
  • [ 105-07-7 ]
  • [ 302571-72-8 ]
YieldReaction ConditionsOperation in experiment
57% With morpholine In toluene for 24h; Reflux; Green chemistry; stereoselective reaction;
  • 73
  • [ 98-01-1 ]
  • [ 2985-33-3 ]
  • (E)-3-(furan-2-yl)-2-methylacrylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% With morpholine In toluene for 4h; Reflux; Green chemistry; stereoselective reaction;
  • 74
  • [ 924-44-7 ]
  • [ 2985-33-3 ]
  • [ 2418-31-7 ]
YieldReaction ConditionsOperation in experiment
50% With morpholine In toluene for 17h; Reflux; Green chemistry; stereoselective reaction;
  • 75
  • [ 107-75-5 ]
  • [ 2985-33-3 ]
  • C15H28O3 [ No CAS ]
  • C15H28O3 [ No CAS ]
  • 76
  • [ 2985-33-3 ]
  • [ 13949-93-4 ]
  • C12H18O4 [ No CAS ]
  • 77
  • [ 2985-33-3 ]
  • [ 90-02-8 ]
  • [ 85-90-5 ]
  • [ 112021-87-1 ]
YieldReaction ConditionsOperation in experiment
30% With morpholine In toluene for 4h; Reflux; Green chemistry;
  • 78
  • [ 64-17-5 ]
  • [ 609-08-5 ]
  • [ 2985-33-3 ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: ethanol; Diethyl methylmalonate With potassium hydroxide In water at 18 - 25℃; Stage #2: With hydrogenchloride In water
  • 79
  • [ 2985-33-3 ]
  • [ 456-06-4 ]
  • C13H15FN2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 8h; General procedure: Ethyl hydrogen malonate (0.70g, 5.25 mmol) was added dropwiseto a solution of 4-fluoro-N-hydroxybenzimidamide (17,0.78g, 5.0 mmol), EDCI (1.5eq.) and triethylamine (1.01g,10.0 mmol) in dichloromethane in an ice bath. Upon completion ofthe addition, the reaction mixture was removed from the ice bathand placed in room temperature for 8h and monitored by thin-layerchromatography (TLC). The mixture was washed with 10% K2CO3(150 mL3) followed by brine (150 mL1), and the organic phasewas separated, dried and evaporated to yield ethyl 3-((4-fluorobenzimidamido)oxy)-3-oxopropanoate as yellow solid.
  • 80
  • [ 2985-33-3 ]
  • C24H37N3O7 [ No CAS ]
  • C24H37N3O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: thionyl chloride / 2 h / 80 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 12 h / 0 - 20 °C 3.1: C27H34N3O(1+)*BF4(1-); lithium hexamethyldisilazane / toluene; tetrahydrofuran / 0.42 h / -45 - 25 °C / Schlenk technique; Molecular sieve; Inert atmosphere; Sealed tube 3.2: 24 h / -40 °C / Schlenk technique; Molecular sieve; Inert atmosphere; Sealed tube
  • 81
  • [ 2985-33-3 ]
  • ethyl 3-((2-ethylphenyl)amino)-2-methyl-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 80 °C / Inert atmosphere 2: triethylamine / dichloromethane / 12 h / 0 - 20 °C
Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 80 °C / Inert atmosphere; Schlenk technique; Sealed tube 2: triethylamine / dichloromethane / Inert atmosphere; Schlenk technique; Sealed tube
  • 82
  • [ 105-53-3 ]
  • [ 2985-33-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydride / mineral oil; tetrahydrofuran / 0 °C / Inert atmosphere 1.2: 12 h / 0 - 20 °C / Inert atmosphere 2.1: potassium hydroxide; water / tetrahydrofuran / 3 h / 0 °C
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.25 h / Inert atmosphere 1.2: 2 h / 0 - 25 °C / Inert atmosphere 2.1: water; potassium hydroxide / 2 h / 18 - 25 °C
  • 83
  • [ 2985-33-3 ]
  • [ 1126-78-9 ]
  • ethyl 3-(n-butyl(phenyl)amino)-2-methyl-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 0 - 20℃; for 2.5h;
  • 84
  • [ 2985-33-3 ]
  • [ 768-52-5 ]
  • ethyl 3-(isopropyl(phenyl)amino)-2-methyl-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane at 0 - 20℃; for 2.5h;
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 2985-33-3 ]

Aliphatic Chain Hydrocarbons

Chemical Structure| 609-08-5

[ 609-08-5 ]

Diethyl 2-methylmalonate

Similarity: 1.00

Chemical Structure| 6279-86-3

[ 6279-86-3 ]

Triethyl methanetricarboxylate

Similarity: 1.00

Chemical Structure| 40516-46-9

[ 40516-46-9 ]

Diethyl 2-(ethoxymethyl)malonate

Similarity: 1.00

Chemical Structure| 23904-38-3

[ 23904-38-3 ]

Diethyl 2-(hydroxymethyl)malonate

Similarity: 1.00

Chemical Structure| 1619-62-1

[ 1619-62-1 ]

Diethyl 2,2-dimethylmalonate

Similarity: 0.96

Esters

Chemical Structure| 609-08-5

[ 609-08-5 ]

Diethyl 2-methylmalonate

Similarity: 1.00

Chemical Structure| 6279-86-3

[ 6279-86-3 ]

Triethyl methanetricarboxylate

Similarity: 1.00

Chemical Structure| 40516-46-9

[ 40516-46-9 ]

Diethyl 2-(ethoxymethyl)malonate

Similarity: 1.00

Chemical Structure| 23904-38-3

[ 23904-38-3 ]

Diethyl 2-(hydroxymethyl)malonate

Similarity: 1.00

Chemical Structure| 1619-62-1

[ 1619-62-1 ]

Diethyl 2,2-dimethylmalonate

Similarity: 0.96

Carboxylic Acids

Chemical Structure| 5471-77-2

[ 5471-77-2 ]

3-Ethoxy-2,2-dimethyl-3-oxopropanoic acid

Similarity: 0.96