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CAS No. : | 32249-35-7 | MDL No. : | MFCD00274090 |
Formula : | C7H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RIJWDPRXCXJDPK-UHFFFAOYSA-N |
M.W : | 142.15 | Pubchem ID : | 10130016 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.71 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 35.13 |
TPSA : | 43.37 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.86 cm/s |
Log Po/w (iLOGP) : | 1.44 |
Log Po/w (XLOGP3) : | 0.43 |
Log Po/w (WLOGP) : | 0.47 |
Log Po/w (MLOGP) : | 0.25 |
Log Po/w (SILICOS-IT) : | 1.13 |
Consensus Log Po/w : | 0.74 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.73 |
Solubility : | 26.6 mg/ml ; 0.187 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.91 |
Solubility : | 17.6 mg/ml ; 0.124 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.88 |
Solubility : | 18.6 mg/ml ; 0.131 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.59 |
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: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: With pyridine In chloroform at 10 - 20℃; for 2 h; Stage #2: for 3 h; Heating / reflux |
Reference Example 1 Production of methyl 3-cyclopropyl-3-oxopropionate Merdramic acid (50 g; 347 mmols) was dissolved in chloroform (550 ml), and pyridine (56 g; 700 mmols) was added thereto. Subsequently, a solution of cyclopropanecarboxylic acid chloride (40 g; 383 mmols) in chloroform (50 ml) was added dropwise thereto at a temperature of 10°C or lower while cooling in an ice-bath. After completion of the dropwise addition, the mixture was stirred for further 1 hour under cooling in the ice-bath, then at room temperature for 1 hour. Subsequently, after cooling again using the ice-bath, 1N-HCL aqueous solution (500 ml) was added thereto. The reaction product was extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure. Then, methanol (500 ml) was added thereto to dissolve the residue, and the solution was heated for 3 hours under reflux. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was distilled to obtain 40 g of methyl 3-cyclopropyl-3-oxopropionate. Yield: 80percent Physical properties: bp. 80°C (10mmHg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.1% | With pyridine In dichloromethane at 0 - 20℃; | a.2 2-te/t-Butvl-4-f4-(3-chloro-propvl)-piperazin-1-vll-6-cvclopropvl-pyrimidine; a.2.1: Methyl-2-cvclopropanovl-acetate; 48.6 g of meldrum's acid (337.4 mmol) were dissolved in 200 ml of dichloromethane at room temperature and the solution was cooled to 0°C. 40 g of pyridine (506.1 mmol) were added to said solution. 35.3 g of cyclopropyl carbonic acid chloride (337.4 mmol) were then added at 0°C within 1 h. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCI and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and stirred under reflux for 2h. The reaction mixture was concentrated to dryness and the oily residue was purified by destination at 90 °C bath temperature to yield 42.7 g (71,1 percent) of the title compound.MS (ESI) m/z: 143.1 [M+H]+1H-NMR (CDCI3): 5 [ppm] 3.75 (s, 3H), 3.6 (s, 2H), 2.0 (m, 1H), 1.15 (m, 2H),0.95 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Production of methyl 4-cyclopropyl-1,2,3-thiadiazole-5-carboxylate Methyl 3-cyclopropyl-3-oxopropionate (10 g; 70 mmols) was dissolved in methanol (100 ml), and methyl carbazinate (6.3 g; 70 mmols) and p-toluenesulfonic acid (20 mg; 0.11 mol) were added thereto. After stirring the mixture overnight, methanol was evaporated under reduced pressure. Subsequently, toluene (10 ml) was added thereto, and thionyl chloride (20 ml) was gradually added dropwise thereto under cooling in an ice-bath. After completion of the dropwise addition, the mixture was stirred for 4 hours at room temperature, then poured onto ice to stop the reaction, and neutralized with sodium hydrogencarbonate. After extracting with ethyl acetate and washing with a saturated sodium chloride aqueous solution, the solution was dried over anhydrous sodium sulfate. After the mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10:1) to thereby obtain 9 g of methyl 4-cyclopropyl-1,2,3-thiadiazole-5-carboxylate. Yield: 70% Physical properties: mp. 47C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.13% | 1,1-Dimethoxy-N,N-dimethylmethanamine (1, 24g, 0.2 mol) andmethyl 3-cyclopropyl-3-oxo- propanoate (2, 28g, 0.2 mol) weremixed and heated for 20 h at 60 C. The obtained yellow oil wasfirstly dissolved in methanol (200 mL) and water (100 mL), andthen hydroxylamine hydrochloride (14g, 0.2 mol) was added. Thesolvents were evaporated under vacuum after the mixture washeated for 90 min at 60 C. The residuewas dissolved in the mixtureof acetic acid (100 mL) and concentrated HCl (100 mL) and refluxedfor 4h. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL 3). The organic layer wascombined and washed with brine, and then dried with anhydroussodium sulfate. Ethyl acetate was evaporated under vacuum. Theresidue was subjected to a silica gel column and eluted with themixture of ethyl acetate and petroleum ether at the ratio of 1:3 (v/v) to afford 3. Compound 3 was obtained as white solid (yield80.13%), mp, 163e165 C; 1H NMR (500 MHz, Chloroform-d): d 8.53(s, 1H), 2.91 (m, 1H), 1.38 (m, 2H), 1.3 (m, 2H). 13C NMR (126 MHz,Chloroform-d): d 179.91, 167.63, 150.62, 108.36, 10.86, 8.87. ESI-MS:m/z 152, [M H]-. | |
Methyl 3-cyclopropyl-3-oxopropanoate (0.28 g, 2 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.24 g, 2 mmol) was mixed and heated for 20 h at 60 C. The bright yellow oil was dissolved in methanol (2 mL) and H2O (1 mL) and hydroxylamine hydrochloride (0.14 g, 2 mmol) was added, resulting in a pH of ca 5. The reaction was heated for 90 min at 60 C. The solvents were evaporated and the residue refluxed in acetic acid: conc. HCl (3+3 mL) for 4 h. The mixture was stored at room temperature for 2 days and the solid was filtered off and dried in vacuum to yield the title compound as a grey solid. This compound is also commercially available. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.18-1.28 (m, 2H) 1.28-1.35 (m, 2H) 2.78-2.90 (m, 1H) 8.45 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Reference Example 1 Production of methyl 3-cyclopropyl-3-oxopropionate Merdramic acid (50 g; 347 mmols) was dissolved in chloroform (550 ml), and pyridine (56 g; 700 mmols) was added thereto. Subsequently, a solution of cyclopropanecarboxylic acid chloride (40 g; 383 mmols) in chloroform (50 ml) was added dropwise thereto at a temperature of 10C or lower while cooling in an ice-bath. After completion of the dropwise addition, the mixture was stirred for further 1 hour under cooling in the ice-bath, then at room temperature for 1 hour. Subsequently, after cooling again using the ice-bath, 1N-HCL aqueous solution (500 ml) was added thereto. The reaction product was extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure. Then, methanol (500 ml) was added thereto to dissolve the residue, and the solution was heated for 3 hours under reflux. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was distilled to obtain 40 g of methyl 3-cyclopropyl-3-oxopropionate. Yield: 80% Physical properties: bp. 80C (10mmHg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In isopropyl alcohol; at 79 - 87℃; for 4 - 10h; | 12 g of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> and 25 g of 2-amino-4'-fluorobenzophenone methanesulfonate were added to 146 g of 2-propanol, and 2-propanol was distilled off at 79 to 83C. After distilling off 119 g of 2-propanol over 6 hours, 1.14 g of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> was added and the mixture was heated at 79 to 81C for 4 hours.. An analysis of the mixture with high performance liquid chromatography (HPLC) showed that the residual amount of 2-amino-4'-fluorobenzophenone as a raw material was 0.9%. 146 g of toluene was added into the reaction solution, and the reaction solution was washed with 80 g of 4% aqueous solution of sodium hydroxide and then 35 g of 2% aqueous solution of sodium hydroxide.. The reaction solution was further washed with 25 g of 5% brine solution, and then dried over 5 g of anhydrous magnesium sulfate.. toluene was removed under a reduced pressure, and crystallization was carried out in 180 g of cyclohexane to obtain 22.9 g of methyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-carboxylate. Yield: 89.0% HPLC purity: 99.7% NMR (CDCl3, δ, ppm): 1.04-1.08 (m, 2H, cyclopropane ring), 1.34-1.38 (m, 2H, cyclopropane ring), 2.16-2.2 (m, 1H, cyclopropane ring), 3.63 (S, 3H, methyl), 7.17-7.21 (m, 2H, aromatic nucleus), 7.33-7.39 (m, 3H, aromatic nucleus), 7.477-7.50 (m, 1H, aromatic nucleus), 7.645-7.685 (t, 1H, aromatic nucleus), 7.973-7.993 (d, 1H, aromatic nucleus) 694.1 kg of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> and 1447.8 kg of 2-amino-4'-fluorobenzophenone methanesulfonate were added to 8455 kg of 2-propanol, and 2-propanol was distilled off at 79 to 87C. After distilling off 7553 kg of 2-propanol, 66.1 kg of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> was added and the mixture was heated at 79 to 81C for 4 hours. An analysis of the mixture with HPLC showed that the residual amount of 2-amino-4'-fluorobenzophenone as a raw material was 0.5%. 8455 kg of toluene was added into the reaction solution, and the reaction solution was washed with 4620 kg of 4% aqueous solution of sodium hydroxide, then 2010 kg of 2% aqueous solution of sodium hydroxide, and finally 1585 kg of 5% brine solution. The reaction solution was dried over 158 kg of anhydrous magnesium sulfate to obtain 10220 kg of a toluene solution containing 1350 kg of methyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-carboxylate (converted yield: 90.4%). A part of the solution was concentrated, and the concentrated residue was recrystallized from toluene having the same mass as that of the residue and heptane having five times mass of the residue to obtain methyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-carboxylate of HPLC purity 99.7%. The substance has the same properties as the substance of Example 1. |
85.6% | 47.9 g of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> and 100 g of 2-amino-4'-fluorobenzophenone methanesulfonate were added to 584 g of toluene, and the mixture was dehydrated and refluxed at an internal temperature of 79 to 81C under a reduced pressure of 40 KPa. The reaction mixture was analyzed with HPLC during the reaction, and <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> was added thereto by dividing it into several parts until the residual amount of 2-amino-4'-fluorobenzophenone was less than 2%.. An additional amount of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> was 13.8 g.. After 40 hours of reaction time, the residual amount of 2-amino-4'-fluorobenzophenone was 1.7%.. The reaction solution was washed with 320 g of 4% aqueous solution of sodium hydroxide and then 140 g of 2% aqueous solution of sodium hydroxide.. The reaction solution was further washed with 100 g of 5% brine solution, and then dried over 10 g of anhydrous magnesium sulfate.. toluene was removed under a reduced pressure, and crystallization was carried out in 740 g of cyclohexane to obtain 88.4 g of methyl 2-cyclopropyl-4-(4'-fluorophenyl)quinoline-3-carboxylate. Yield: 85.6% HPLC purity: 98.9% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetic anhydride; at 150℃; for 5h;Heating / reflux; | B] (E,Z)-2-Cyclopropanecarbonyl-3-ethoxy-acrylic Acid Methyl Ester A solution of 10 g (70.34 mmol) 3-cyclopropyl-3-oxo-propionic acid methyl ester, 23.4 ml (140.68 mmol) of triethyl orthoformate in 100 ml acetic anhydride was refluxed at 150 C. for 5 h. The reaction mixture was concentrated at 95 C. under reduced pressure to give 14.35 g of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester. MS: 199.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; at 150℃; for 5h; | C] (E,Z)-2-Cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester A solution of 10 g (70.34 mmol) 3-cyclopropyl-3-oxo-propionic acid methyl ester and of 23.4 ml (140.68 mmol) of triethyl orthoformate in 100 ml acetic anhydride was refluxed at 150 C. for 5 h. The reaction mixture was concentrated at 95 C. under reduced pressure to give 14.35 g of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester. MS: 199.3 (M+H)+. | |
In acetic anhydride; at 150℃; for 5h;Heating / reflux; | C] (E,Z)-2-Cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester A solution of 10 g (70.34 mmol) 3-cyclopropyl-3-oxo-propionic acid methyl ester, 23.4 ml (140.68 mmol) of triethyl orthoformate in 100 ml acetic anhydride was refluxed at 150 C. for 5 h. The reaction mixture was concentrated at 95 C. under reduced pressure to give 14.35 g of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester. MS: 199.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetic anhydride; at 95 - 150℃; for 5h;Heating / reflux; | A solution of 10 g (70.34 mmol) 3-cyclopropyl-3-oxo-propionic acid methyl ester, 23.4 ml (140.68 mmol) of triethyl orthoformate in 100 ml acetic anhydride was refluxed at 150 C. for 5 h. The reaction mixture was concentrated at 95 C. under reduced pressure to give 14.35 g of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester. MS: 199.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium acetate; In acetic acid; for 1.5h;Heating / reflux; | D] 2-Cyclopropyl-6-(4-trifluoromethoxy-phenyl)-nicotinic acid methyl ester (Following the procedure described in Al-Saleh, Balkis; Abdelidalik, Mervat Mohammed; Eltoukhy, Afaf Mohammed; Elnagdi, Mohammed Hilmy. Enaminones in heterocyclic synthesis: A new regioselective synthesis of 2,3,6-trisubstituted pyridines, 6-substituted-3-aroylpyridines and 1,3,5-triaroylbenzenes. Journal of Heterocyclic Chemistry (2002), 39(5), 1035-1038) A mixture of 2.0 g (7.72 mmol) (E)-3-dimethylamino-1-(4-trifluoromethoxy-phenyl)-propenone, 1.32 g (9.26 mmol) <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> and 0.77 (10.0 mmol) ammonium acetate in 8 ml acetic acid were heated under reflux for 1.5 h and cooled to room temperature. The reaction was neutralized with aqueous 10% KHSO4 solution. The mixture was extracted with ether (3×); the organic phase was washed with aqueous 10% KHSO4-solution, aqueous saturated NaHCO3, dried (Na2SO4) and evaporated. The side product ((4-trifluoromethoxy-phenyl)-[6-(4-trifluoromethoxy-phenyl)-pyridin-3-yl]-methanone) was precipitated from ether/pentane and the mother liquor purified by flash chromatography (SiO2, n-heptane/AcOEt=97.5/2.5) to give 1.07 g of the title compound as a yellow oil. MS: 337.1 (M)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium acetate; In methanol; at 20℃; for 18h; | Description 9: 3-Amino-3-cyclopropyl-acrylic acid methyl ester; To a stirred solution of 3-cyclopropyl-3-oxo-propionic acid methyl ester (lOg, ex Butt Park, ) in methanol (200ml) was added ammonium acetate (26g) and the mixture was stirred at room temperature for 18 hours overnight. The methanol was evaporated under reduced pressure, and the residue treated with dichloromethane (100ml). The suspension was stirred for 30 minutes at room temperature. The solid formed was filtered, and washed with dichloromethane. The dichloromethane was evaporated under reduced pressure to afford the title product (lOg) as a clear oil, which solidified on standing. NMRNMR (CDCI3) 8 0.60-0. 85 (4H, m), 1. 29-1.39 (1H, m), 3.55 (3H, s), 4.40 (1H, s), 8.28- 8.85 (bs partially exchanged NH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | at 80℃; for 1h; | [00479] To methyl 4-methyl-3-oxopentanoate (1.98 ml, 13.87 mmol) was added 1,1- dimethoxy-N,N-dimethylmethanamine (2.21 ml, 16.65 mmol) and the solution was stirred at 80 C for 1 h. The reaction mixture was concentrated in vacuo to afford methyl-2- [(dimethylamino)methylidene]-4-methyl-3-oxopentanoate (2.76 g, 95%) as an orange oil. [00480] Method A: LC-MS m/z = 200.0 [M + H]+; RT = 1.00 |
In chloroform; at 60℃; | Example 49: N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-3- [4- (5- cyclopropyl-l-isopropyl-IH-pyrazol-4-yl)- [1, 2,3] triazol-1-yl]-4-methyl-benzamide; 3-Cyclopropyl-3-oxo-propionic acid methyl ester (1.25 g, 8.79 mmol) was dissovled in 6.25 mL of CHC13 and 1.17 mL (8.79 mmol) of dimethylformamide dimethyl acetal was added. The mixture was heated to 60C in a sealed vessel overnight. The mixuture was then cooled and concentrated to provide 1.67 g of 2-cyclopropanecarbonyl-3- dimethylamino-acrylic acid methyl ester. | |
In toluene; for 3h;Reflux; | Step 1 Production of methyl 2-cyclopropylcarbonyl-3-dimethylaminoacrylate Methyl 3-cyclopropyl-3-oxopropionate (2.0 g) was dissolved in toluene (20 ml). To the obtained solution was added dimethylformamide dimethylacetal (3.0 ml) and the mixture was refluxed for 3 hr. The reaction mixture was allowed to cool and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:acetone=2:1) to give the title compound as a yellow oil (2.61 g). |
In toluene; for 3h;Heating / reflux; | Step 1 Production of methyl 2-cyclopropylcarbonyl-3-dimethylaminoacrylate Methyl 3-cyclopropyl-3-oxopropionate (2.0 g) was dissolved in toluene (20 ml). To the obtained solution was added dimethylformamide dimethylacetal (3.0 ml) and the mixture was refluxed for 3 hr. The reaction mixture was allowed to cool and concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:acetone=2:1) to give the title compound as a yellow oil (2.61 g). | |
In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | To a 250 mL round-bottom flask under N2 was added <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (5.00 g, 35.2 mmol) and dioxane (50 ml). N,N-dimethylformamide dimethyl acetal (4.7 mL, 35 mmol) was added at rt, and the resulting mixture was heated to 100 C for 3 h. The mixture was cooled to rt, concentrated, and used in the next step without purification. MS: 198.1 [M+H]+. | |
In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | To a 250 mL round-bottom flask under N2 was added <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (5.00 g, 35.2 mmol) and dioxane (50 ml). N,N-dimethylformamide dimethyl acetal (4.7 mL, 35 mmol) was added at rt, and the resulting mixture was heated to 100 C for 3 h. The mixture was cooled to rt, concentrated, and used in the next step without purification. MS: 198.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium acetate; In methanol; at 20℃; | Intemediate 24: 3-Amino-3-cyclopropyl-acrylic acid methyl ester; To a stirred solution of 3-cyclopropyl-3-oxo-propionic acid methyl ester (lOg, ex Butt Park, ) in methanol (200ml) was added ammonium acetate (26g) and the mixture was stirred at room temperature for 18 hours overnight. The methanol was evaporated under reduced pressure, and the residue treated with dichloromethane (100ml). The suspension was stirred for 30 minutes at room temperature. The solid formed was filtered, and washed with dichloromethane. The dichloromethane was evaporated under reduced pressure to afford the title product (lOg) as a clear oil, which solidified on standing. NMR NMR (CDC13) 8 0. 60-0. 85 (4H, m), 1. 29-1.39 (1H, m), 3. 55 (3H, s), 4.40 (1H, s), 8. 28- 8. 85 (bs partially exchanged NH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine; In methanol; at 20℃; for 48h; | Preparation 19; To a solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (3.00 g) and cyclohexanecarboxaldehyde (2.84 g) in MeOH (30 ml) was added piperidine (0.209 ml) at room temperature. The mixture was stirred for 48 h. The solvent was evaporated off, and the residue was chromatographed on a silicagel column chromatography (EtOAc-hexaens, a linear gradient of EtOAc from 0 to 15% over 60 min) afforded methyl 3-cyclohexyl-2-(cyclopropylcarbonyl)acrylate as a colorless oil (3.72 g). 1H-NMR (CDCl3) δ 0.98 (2H, m), 1.12-1.33 (6H, m), 1.68-13.77 (5H, m), 2.08-2.24 (1H, m), 2.27-2.49 (1H, m), 3.78 and 3.84 (3H, s), 6.71 and 6.71 (1H, d, J=10.2 and 10.6 Hz, respectively) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | at 75℃; for 2h; | Step 1: Synthesis of 2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester The mixture of 3-cyclopropyl-3-oxo-propionic acid methyl ester (15 g, 106 mmol) and N,N-dimethylformamide dimethylacetal (14.7 mL, 111 mmol) was heated at 75 C. for 2 h. The crude mixture was concentrated under high vacuum to give crude 2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester (20.4 g, 91%) which was used without further purification. |
In ethyl acetate; | EXAMPLE 2 5-Cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid A 200 liter glass-lined reactor under nitrogen was charged with ethyl acetate (51 liters), methyl-3-cyclopropyl-3-oxopropanoate (4.90 kg) and N,N-dimethylformamide dimethylacetal (4.31 kg). The reactor was heated to about 75 C. for four hours. Completion of conversion to α-[(dimethylamino)methylene]-β-oxo-cyclopropanepropanoic acid, (αZ)-methyl ester was confirmed using thin-layer chromatography analysis (ethyl acetate/hexanes,1/1). | |
In ethyl acetate; | EXAMPLE 13 Preparation of 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic Acid A 200 liter glass-lined reactor under nitrogen was charged with ethyl acetate (51 liters), methyl-3-cyclopropyl-3-oxopropanoate (4.90 kg) and N,N-dimethylformamide dimethylacetal (4.31 kg). The reactor was heated to about 75 C. for four hours at which time thin-layer chromatography analysis (ethyl acetate/hexanes, 1/1) of the reaction solution indicated that conversion to α-[(dimethylamino)methylene]-β-oxo-cyclopropanepropanoic acid, (αZ)-methyl ester was complete. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.2% | With sodium methylate; In methanol; at 10 - 20℃; | a.2.2: 2-terf-Butvl-4-hvdroxv-6-cyclopropvl-pyrimidine; 16.3 g tert-butyl amidinium chloride (119.6 mmol, Maybridge) were dissolved/suspended in 350 ml of methanol at room temperature. 30.4 g of sodium methanolate (562.8 mmol) were added in portions to the solution at 10C,. After stirring for 30 minutes, a solution of 20 g of methyl-2-cyclopropanoyl acetate (140.7 mmol) in 150 ml of methanol was added over 2 h. The suspension was then stirred at room temperature overnight, concentrated to roughly half the volume, and filtered. 200 ml of dichloromethane were added to the filtrate and theorganic layer was washed 3 times with water. The aqueous phases were combined. The aqueous phase was adjusted to pH 3 with aq. HCI, whereby a white precipitate was formed. The precipitate was collected by filtration, redissolved in dichloromethane, dried over magnesium sulfate and filtered. The solvent was concentrated to dryness to yield 14.8 g (67.2 %) of the title compound.MS (ESI) m/z: 193.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.1% | With pyridine; In dichloromethane; at 0 - 20℃; | a.2 2-te/t-Butvl-4-f4-(3-chloro-propvl)-piperazin-1-vll-6-cvclopropvl-pyrimidine; a.2.1: Methyl-2-cvclopropanovl-acetate; 48.6 g of meldrum's acid (337.4 mmol) were dissolved in 200 ml of dichloromethane at room temperature and the solution was cooled to 0C. 40 g of pyridine (506.1 mmol) were added to said solution. 35.3 g of cyclopropyl carbonic acid chloride (337.4 mmol) were then added at 0C within 1 h. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCI and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and stirred under reflux for 2h. The reaction mixture was concentrated to dryness and the oily residue was purified by destination at 90 C bath temperature to yield 42.7 g (71,1 %) of the title compound.MS (ESI) m/z: 143.1 [M+H]+1H-NMR (CDCI3): 5 [ppm] 3.75 (s, 3H), 3.6 (s, 2H), 2.0 (m, 1H), 1.15 (m, 2H),0.95 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation of Reagent 3-(chloromethyl)-2-cyclopropyl-6-(trifluoromethyl)pyridine; A. Preparation of methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate; To a stirring solution of (Z)-4-amino-1,1,1-trifluorobut-3-en-2-one (3 g, 21.58 mmol) and <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (3.7 g, 26.03 mmol) in toluene (20 mL) at room temperature under argon was added TFA (2.96 g, 25.92 mmol). The reaction mixture was stirred at reflux for 10 h. The reaction mixture was then cooled to room temperature and concentrated under vacuum to obtain a gum. EtOAc (50 mL) and 15% aqueous sodium carbonate solution (50 mL) were added, and the resulting mixture was stirred at room temperature for 10 min. The organic layer was separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to obtain crude product as a yellow oil. This crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to isolate 1 g of the title compound as a pale yellow oil. HPLC/MS: retention time=3.618 min, [M+H]30 =246. | ||
A. Preparation of methyl 2-cyclopropyl-6-(trifluoromethyl)nicotinate To a stirring solution of (Z)-4-amino-1,1,1-trifluorobut-3-en-2-one (3 g, 21.58 mmol) and <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (3.7 g, 26.03 mmol) in toluene (20 mL) at room temperature under argon was added TFA (2.96 g, 25.92 mmol). The reaction mixture was stirred at reflux for 10 h. The reaction mixture was then cooled to room temperature and concentrated under vacuum to obtain a gum. EtOAc (50 mL) and 15% aqueous sodium carbonate solution (50 mL) were added, and the resulting mixture was stirred at room temperature for 10 min. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to obtain crude product as a yellow oil. This crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to isolate 1 g of the title compound as a pale yellow oil. HPLC/MS: retention time=3.618 min, [M+H]+=246. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrazine; In acetic acid; at 100℃; | Step A] 5-Cyclopropyl-2,4-dihydro-pyrazol-3-one To a solution of methyl-3-cyclopropyl-3-oxopropionate (10 g) and acetic acid (28 mL) in a round bottom flask under argon was added hydrazine hydrate (2.25 g). The mixture was immersed into an oil bath and heated to 100 C. overnight. The reaction vessel was then cooled and the acetic acid was evaporated in vacuo and the remaining solid was added to 1 N aqueous sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and cold ether to afford the desired 5-cyclopropyl-2,4-dihydro-pyrazol-3-one (8.2 g) as a beige solid. |
Yield | Reaction Conditions | Operation in experiment |
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With phenylhydrazine; In acetic acid; at 120℃; | Step A] 5-Cyclopropyl-2-phenyl-2,4-dihydro-pyrazol-3-one To a solution of methyl-3-cyclopropyl-3-oxopropionate (17 g) in acetic acid (40 mL) in a round bottom flask under argon was added phenylhydrazine (12.93 g). The mixture was immersed into an oil bath and heated to 120 C. overnight. The reaction vessel was then cooled and the acetic acid was evaporated in vacuo and the remaining solid was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo and azeotroped with toluene (2*). The crude residue was then purified via trituration with a 1:1 mixture of ether/pentane to afford the desired 5-cyclopropyl-2-phenyl-2,4-dihydro-pyrazol-3-one (20.8 g) as a light brown solid. MS (ESI+):201.3 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
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78% | With sodium methylate; In methanol; for 12h; | To a solution of methyl 5-cyclopropyl-5-oxopropionate (2.39 g) and pentylamidine hydrochloride - (1.68 g) in methanol (20 mL) was added 28% sodium methoxide-methanol solution (5.27 mL), and the mixture was stirred for 12 hr. The reaction mixture was concentrated, and the residue was dissolved in water and diethyl ether. The aqueous layer was separated, and weakly acidified with 1 M hydrochloric acid. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (2.02 g, 78%) as a colorless solid. 1H NMR (300 MHz, CDCl3) delta 0.87-0.99 (5H, m) , 1.01-1.10 (2H, m) , 1.29-1.46 (2H, m) , 1.61-1.85 (3H, m) , 2.61 (2H, t, J = 7.5), 6.15 (IH, s), 12.89 (IH, br) |
Yield | Reaction Conditions | Operation in experiment |
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98% | In toluene; for 4h;Heating / reflux; | Reference Example 1495-cyclopropyl-2-methyl-2,4-dihydro-3H-pyrazol-3-oneTo a solution of methyl 3-cyclopropyl-3-oxopropionoate (39.8 g) in toluene (150 mL) was added methylhydrazine (13.0 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound (37.9 g, yield 98%) as colorless crystals.1H-NMR (300 MHz, CDCl3) δ:0.74-0.82 (m, 2H), 0.92-1.01 (m, 2H), 1.71-1.83 (m, 1H), 3.05 (s, 2H), 3.26 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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Carbon tetrachloride was added to a suspension of magnesium turnings (0.107 g, 1.1 equivalents) in methanol. A solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (0.395 g, 1.1 equivalents) in methanol was then added. The mixture was stirred at 60 C. for 0.5 hour, cooled, evaporated and re-evaporated after addition of dry toluene to give the corresponding magnesium enolate. To a toluene solution of half of this magnesium enolate was added a solution of 4-fluoro-3-methoxy-2-methylthiobenzoyl chloride (0.54 g) in toluene and the mixture stirred at 20 C. for 18 hours, washed (2M hydrochloric acid then with water), dried (magnesium sulphate) and evaporated to give the title compound (0.75 g), NMR 1.1 (m, 2H), 1.38 (m, 2H), 2.4 (s, 3H), 2.62 (m, 1H), 3.42 (s, 3H), 4.0 (s, 3H), 6.9 (m, 1H), 7.1 (m, 1H), 17.8 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | To a suspension of magnesium chloride (3.3 g, 35 ml) in CH2Cl2 (15 ml) under argon at 0 C. was added methyl-3-cyclopropyl-oxopropanoate (5.0 g, 35 mmol), followed by pyridine (2.8 ml, 35 mmol). The mixture was stirred for 1 h before the addition of a solution of cyclopropylcarbonylchloride (3.2 ml, 35 mol) in CH2Cl2 (5 ml), followed by more pyridine (2.8 ml, 35 mmol) and the mixture was stirred for a further 1 h. The reaction was washed repeatedly with 6N HCl, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 1:9) afforded the title product (7.4 g, 99%) as a colourless oil. MS: 211.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
C] 2-Cylopropanecarbonyl-4-methoxy-3-oxo-butyric acid methyl ester To an ice-cooled solution of 10 g (70.35 mmol) 3-cyclopropyl-3-oxo-propionic acid methyl ester and 6.69 g (70.35 mmol) anhydrous magnesium chloride was dropped within 10 min 11.3 2ml (140 7 mmol) pyridine. 15 min later, 12.54 g (77.38 mmol) methoxyacetic anhydride was added and the reaction mixture was then stirred at RT over night. The reaction mixture was concentrated under reduced pressure and then taken up in ether and washed with water, 1N HCl and again with water. The ether-phase was concentrated under reduced pressure providing 13.17 g crude 2-cyclopropanecarbonyl-4-methoxy-3-oxo-butyric acid methyl ester. MS: 215.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.2% | With hydroxylamine hydrochloride; triethylamine; In methanol; for 2h;Reflux; | A solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> (4.8 g, 34 mmol) in methanol (80 mL) is mixed with hydroxylamine hydrochloride (2.6 g, 38 mmol) and triethylamine (5.3 mL, 38 mmol), and the mixture is heated under reflux for 2 h. The solvent is distilled out in vacuo. The residue is taken up in EtOAc and filtered through silica gel.Yield: 3.2 g (75.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium nitrate; acetic acid; In water; at 0 - 10℃; for 5h; | methyl 2-amino-3-cyclopropyl-3-oxopropanoate hydrochloride To a solution (15 mL) of methyl 3-cyclopropyl-3-oxopropionoate (10 g, 70 mmol) in acetic acid was slowly added dropwise aqueous solution (15 mL) of sodium nitrate (5.8 g, 84 mmol) at 0C, and the mixture was stirred at 0 - 10C for 5 hr. To the reaction mixture was added saturated sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give residue. 1H NMR (300 MHz, CHLOROFORM-d) δppm 0.97 - 1.09 (2 H, m), 1.15 - 1.24 (2 H, m), 2.59 - 2.83 (1 H, m), 3.91 (3 H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation Example 30 Methyl-3-cyclopropyl-3-oxopropanoate (2.0 g) and magnesium perchlorate (940 mg) were dissolved in ethyl acetate (20 ml), followed by stirring at room temperature for 5 minutes, and N-bromosuccinimide (2.76 g) was added thereto, followed by stirring at room temperature for 4 hours. Water was added thereto, followed by extraction with ethyl acetate, the organic layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain, as a colorless oily product, methyl 2-bromo-3-cyclopropyl-3-oxopropanoate (3.32 g). | ||
The 3 - cyclopropyl -3 - oxo propionic acid methyl ester (2.84 g, 20 mmol), calcium peroxide (1.34 g, 6.0 mmol) and ethyl acetate (50 ml) add 100 ml single-port in the bottle, the reaction mixture stirring at room temperature in 0.1 h after, the reaction bottle in batches and adding N - bromosuccinimide (3.93 g, 22 mmol), after adding, the reaction mixture stirring at room temperature 12 h. To the reaction flask by adding ice water (100 ml), the aqueous phase of ethyl acetate (60 ml × 2), combined with the organic phase, the organic phase with saturated salt water (60 ml × 2) washing, drying with anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/10) to obtain the title compound after purification (pale yellow oily liquid, 3.98 g, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | Example 36.2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-cyclopropanecarbonyl- c clopentyl)-amideStep 1To a solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (2.0 g, 14 mmol) in DMF (70 mL) was added sodium hydride (60% in mineral oil, 1.41 g, 35 mmol). The reaction mixture was stirred for 10 min then 1,4-dibromobutane (1.85 mL, 15 mmol) was slowly added. The reaction mixture was stirred for 2.5 h then carefully quenched with water and extracted with diethyl ether (2x). The combined organics were washed with water (2x) and brine then dried over Na2S04 and concentrated. The residue was purified by chromatography over 60 g Si02 (0% to 10% EtOAc/hexanes) to afford 0.63 g (23%) of 1-cyclopropanecarbonyl-cyclopentane carboxylic acid methyl ester as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With acetic acid; at 100℃; | Intermediate 57Intermediate 4 (5 g, 0.02 mol) in HOAc (20 mL) was treated with 3-cyclopropyl-3- oxopropanoic acid methyl ester (14g, 0.1 mmol) and the mixture was stirred overnight at 100 C. The mixture was concentrated and purified via Si02 column chromatography (40 g Si02 Combiflash HP Gold Column, 0-100% EtOAc/hexanes gradient) to afford intermediate 57 (4 g, 83%).LCMS m/z [M+H]+ C19H26N403 requires: 359.20. Found 359.10HPLC Tr (min), purity %: 2.45, 98% |
83% | With acetic acid; at 100℃; | Example 33 Preparation of Intermediate 34 [0549] [0550] Intermediate 4 (5 g, 0.02 mol) in HOAc (20 mL) was treated with <strong>[32249-35-7]3-cyclopropyl-3-oxopropanoic acid methyl ester</strong> (14 g, 0.1 mmol) and the mixture was stirred overnight at 100 C. The mixture was concentrated and purified via SiO2 column chromatography (40 g SiO2 Combiflash HP Gold Column, 0-100% EtOAc/hexanes gradient) to afford intermediate 34 (4 g, 83%). [0551] LCMS m/z [M+H]+ C19H26N4O3 requires: 359.20. Found 359.10 [0552] HPLC Tr (min), purity %: 2.45, 98% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example-1Preparation of Methyl 3-cyclopropyl-3-oxopropanoateTo the solution of dimethyl carbonate (361 g) in toluene (1250 ml) added cyclopropyl methyl ketone (125 g) and stirred for 15 min at 25 C. Cooled the reaction mixture to 10 C., added potassium tert.butoxide (100 g) to it under nitrogen atmosphere. Heated the reaction mixture to 75 C. and stirred for 14 hrs. Cooled the reaction mixture to 25 C. and slowly poured it into chilled water (750 ml). Cooled the reaction mixture to 0 C. and adjusted the pH to 2.5 by using 50% HCl solution. Raised the temperature to 25 C. and stirred for 45 minutes. Separated the both organic and aqueous layers. Extracted the aqueous layer with toluene (500 ml). Washed the organic layer with water (500 ml). Distilled off the toluene completely from organic layer under reduced pressure to get the title compound.Yield: 130 g; G.C. purity: 93.85% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | at 130℃; for 5h; | Example 384Methyl 3-(4-bromophenylamino)-2-(cyclopropanecarbonyl)acrylate A stirred mixture of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (20 g, 0.141 mol), triethyl orthoformate (28 mL, 0.169 mol), and 4-bromoaniline (24.2 g, 0.141 mol) were heated at 130 C for 5 h with a Dean Stark trap. After this time the reaction was cooled to room temperature, diluted with methylene chloride and filtered through a pad of silica. The filtrate was concentrated to afford the desired product (26.5 g, 55%) as a yellow solid: ESI MS m/z 324[C,4Hi BrN02 + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | at 140℃; | Example 399Methyl 3-(4-bromo-3-fluorophenylamino)-2-(cyclopropanecarbonyl)acrylateA stirred mixture of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (3.49 g, 26.3 mmol), triethyl orthoformate (5.2 mL, 31.6 mmol), and 4-bromo-3-fluoroaniline (4.47 g, 26.0 mmol) was heated at 140 C overnight with a Dean Stark trap. After this time the reaction was cooled to room temperature, diluted with methylene chloride and filtered through a pad of silica. The filtrate was concentrated to afford the desired product (7.5 g, 85%) as a light yellow solid: ESI MS m/z 343 [C|4H13BrFN03 + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In methanol; at 0 - 20℃; for 1h;Inert atmosphere; | Methyl 3- cyclopropropyl-3-oxopropanoate (5.23 g, 36.8 mmol) and (Z)-5-cyclopropyl-N-hydroxy-3-(o- tolyl)isoxazole-4-carbimidoyl chloride (6.23 g, 36.8 mmol) were combined in anhydrous methanol (50 mL) and cooled to 0 C under a nitrogen atmosphere. Sodium methoxide (25 % in methanol, 11.0 mL, 44.2 mmol, 1.2 eq) was added dropwise and the mixture was allowed to warm to RT over 1 hour. The mixture was diluted with ethyl acetate (120 mL) and water (100 mL). The organic layer was separated and washed with brine (75 mL) then dried over magnesium sulfate and concentrated under vacuum. The oil was purified by columnchromatography (Si02, linear gradient, 0-100 % ethyl acetate in hexanes) to afford the desired product. MS m/z 258.0 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; at -5℃; | Methyl 3-cyclopropyl-3-oxopropanoate (189.87 g, 1.34 mol) was added to compound ( T4-c) (160 g, 667.84 mmol), the reaction was stirred at -5C, triethylamine (500 mL) was added dropwise, and the reaction was performed at -5C overnight. The reaction solution was poured into water (20 L), and mechanically stirred for 30 minutes, to result in a solid. A yellow solid was obtained by suction filtration, and dried at 50C overnight, to afford compound (T4-d) (120 g, yield: 55%). |
With potassium carbonate; In tetrahydrofuran; at -10 - 35℃; for 6h; | Potassium carbonate (11 g, 79.7 mmol, 1.09 equiv) was suspended in THF (100 mL) and the mixture was stirred. A solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (11 g, 77.5 mmol, 1.06 equiv) in 50ml THF was added to the above stirred mixture and stirred for 30 min at -10 C. To this reaction mixture was added a solution of (Z)-2-(trifluoromethoxy)benzoyl chloride oxime (17.6 g, 73.3 mmol, 1.00 equiv) in THF (50 mL) at -5 C and then allowed to stir for 6 h at 35 C . The reaction mixture was diluted with 200 mL of H20, extracted with ethyl acetate (2 x 300 mL). The organic layer was washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, concentrated under vacuum, and then purified by silica gel columnchromatography using ethyl acetate/petroleum ether (1: 100-1:20) eluent to afford methyl 5- cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-carboxylate as a white solid. | |
Potassium carbonate (11.0 g, 79.7 mmol, 1.09 equiv) was suspended in THF (100 mL). Then the solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (11.0 g, 77.5 mmol, 1.06 equiv) in 50ml THF was added to the above stirred mixture at -10 C. The resulting solution was stirred for 30 min at -10 C. To this was added a solution of (Z)-2-(trifluoromethoxy)benzoyl chloride oxime (17.6 g, 73.3 mmol, 1.00 equiv) in THF (50 mL) at -5C. The resulting solution was allowed to stir for 6 hours at 35C. The resulting solution was diluted with 200 mL of H20, extracted with 2 x 300 mL of ethyl acetate. The organic layer was washed with 2 x 200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum, then purified by silica gel column with ethyl acetate/petroleum ether (1:100-1:20), which gave methyl 5- cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-carboxylate as a white solid. |
With potassium carbonate; In tetrahydrofuran; at -5 - 35℃; for 6h; | Potassium carbonate (11.0 g, 79.7 mmol, 1.09 equiv) was suspended in THF (100 mL). Then the solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (11.0 g, 77.5 mmol, 1.06 equiv) in 50ml THF was added to the above stirred mixture at -10 C. The resulting solution was stirred for 30 min at -10 C. To this was added a solution of (Z)-2-(trifluoromethoxy)benzoyl chloride oxime (17.6 g, 73.3 mmol, 1.00 equiv) in THF (50 mL) at -5C. The resulting solution was allowed to stir for 6 hours at 35C. The resulting solution was diluted with 200 mL of H20, extracted with 2 x 300 mL of ethyl acetate. The organic layer was washed with 2 x 200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum, then purified by silica gel column with ethyl acetate/petroleum ether (1: 100-1:20). Methyl 5-cyclopropyl-3-(2- (trifluoromethoxy)phenyl)isoxazole-4-carboxylate was obtained as a white solid. | |
Potassium carbonate (11 g, 79.7 mmol, 1.09 equiv) was suspended in THF (100 mL) and the mixture was stirred. A solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (11 g, 77.5 mmol, 1.06 equiv) in 50 ml THF was added to the above stirred mixture and stirred for 30 min at -10C. To this reaction mixture was added a solution of (Z)-2-(trifluoromethoxy)benzoyl chloride oxime (17.6 g, 73.3 mmol, 1.00 equiv) in THF (50 mL) at -5C. and then allowed to stir for 6 h at 35C. The reaction mixture was diluted with 200 mL of H2O, extracted with ethyl acetate (2 x 300 mL). The organic layer was washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, concentrated under vacuum, and then purified by silica gel column chromatography using ethyl acetate/petroleum ether (1 : 100-1 :20) eluent to afford methyl 5-cyclopropyl-3-(2- (trifluoromethoxy)phenyl)isoxazole-4-carboxylate as a white solid. | ||
120 g | With triethylamine; In dimethyl sulfoxide; at -5 - 25℃; | Methyl 3-cyclopropyl-3-oxopropionate compound (189.87g, 1.34mol) and triethylamine (500mL) were dissolved in DMSO (500mL), and the reaction was stirred at -5C,A solution of compound In-3 (160 g, 667.84 mmol) in DMSO (500 mL) was added dropwise,React overnight at 25C.Pour the reaction solution into water (20L),Stir mechanically for 30 minutes,Solids appear,Suction filtration to obtain a yellow solid,Dry overnight at 50C,The title compound In-4 (120 g) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A cold (0C) solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (4.2 g, 0.030 mol) in methanol (100 mL) was treated with the drop wise addition of sodium methoxide in methanol (6.2 mL, 25 wt %). After 10 min., Intermediate I-10C (3.7g, 0.023 mol) was introduced. The reaction stirred for 1 hour and was then concentrated in vacuo, diluted with water and extracted with EtOAc. The organic phase was washed with sat'd NaHC03 (aq) and then dried (MgS04), filtered, and concentrated. The crude residue was purified and isomers separated by column chromatography (SiC"2, linear gradient, 0-15% EtOAc in Hexanes) to afford the desired products. First eluting peak (400 MHz, CDC13): δ 3.87 (s, 3H), 2.75 (m, 1H), 2.16 (dd, J = 3.4, 3.2 Hz, 1H), 1.91 (m, 2H), 1.84 (m, 2H), 1.77 (m, 2H), 1.64 (m, 1H), 1.26 (m, 1H), 1.20 (m, 2H), 1.13 (m, 2H);second eluting peak (400 MHz, CDC13): 3.85 (s, 3H), 2.78 (m, 1H), 1.84-1.72 (m, 7H), 1.42 (m, 1H), 1.22 (m, 2H), 1.14 (m, 2H), 0.37 (m, 1H); MS m/z 248.1 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A cold (0C) solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (1.13 g, 7.93 mmol) in methanol (26 mL) was treated with the dropwise addition of sodium methoxide in methanol (1.65 mL, 25% wt). After 10 min., I-13D (0.97 g, 6.1 mmol) was introduced. The reaction stirred for 1 hour and was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic phase was washed with sat'd NaHC03 (aq) and then dried (MgS04), filtered, and concentrated. The crude residue was purified by column chromatography (Si02, linear gradient, 0-10% EtOAc in hexanes) to afford the desired spirocycle. (400 MHz, CDC13) δ 3.96 (m, 1H), 3.84 (s, 3H), 2.80 (m, 1H), 2.57 (m, 2H), 2.38 (m, 2H), 1.26 (m, 2H), 1.16 (m, 2H), 0.51 (m, 2H), 0.39 (m, 2H); MS m/z 248.2 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A cold (0C) solution of rac-4-C (28.3g, 155 mmol) andtrichloroisocyanuric acid (37.9g, 163 mmol) in CH2C12 (310 mL) was treated with TEMPO (242 mg, 1.55 mmol) and the reaction stirred for 2 h. The reaction was then washed with a solution of saturated Na2C03 (100 mL) followed by 1 M HC1 (50 mL), dried over MgS04, filtered, evaporated and redissolved in ethanol (15 mL). This solution was then cooled to 0C and treated with 50% (aq) hydroxylamine (11.4 mL) and allowed to warm to room temperature and stir overnight. The volatiles were removed in vacuo and extracted with EtOAc. Organics were collected, dried (MgS04), filtered, and concentrated. The crude oxime (27.5 g, 141 mmol) was dissolved in DMF (200 mL) and treated with the portionwise addition of N-chlorosuccinimide (21.1 g, 157 mmol). The reaction slowly warmed to rt and stirred for 1 hour. The reaction was treated with saturated NaCl (aq.) and extracted with Et20. Organics were collected, dried (MgS04), filtered, concentrated and chromatographed (Si02, linear gradient, 0-80% EtOAc in Hex) to afford the chloro-oxime which was dissolved in methanol (5 mL).[0164] In another flask, a cold (0C) solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (23.7g, 170 mmol) in methanol (35 mL) was treated with sodium methoxide (25% wt. solution in methanol, 30 mL). After stirring for 20 minutes, the reaction was treated with the dropwise addition of the chloro-oxime already in methanol. The reaction warmed to rt and stirred for 30 min. The reaction was concentrated in vacuo and diluted with EtOAc. The organics were washed with saturated NaCl (aq) and saturated NaHC03 (aq.). Organics were collected, dried (MgS04), filtered, concentrated, and chromatographed (Si02, linear gradient, 0-80%, EtOAc in Hexanes) to give the desired ester as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In methanol; at 0 - 20℃; for 0.5h; | A cold (0C) solution of (lS,2S)-2-(trifluoromethyl)- cyclopropanecarbaldehyde (J. Chem. Soc, Perkin Trans. 2, 1984, 1907-1915; 2.0 g, 14.5 mmol) in ethanol (5 mL) was treated with 50% (aq) hydroxylamine (1.3 mL) and allowed to warm to rt and stir overnight. The volatiles were removed in vacuo and extracted with EtOAc. Organics were collected, dried (MgS04), filtered, and concentrated. The crude oxime (1.0 g, 6.5 mmol) was dissolved in DMF (11.3 mL) and treated with the portionwise addition of N- chlorosuccinimide (980 mg, 7.3 mmol). The reaction slowly warmed to rt and stirred for 1 hour. The reaction was treated with saturated NaCl (aq.) and extracted with Et20. Organics were collected, dried (MgS04), filtered and concentrated to afford the crude chloro-oxime which was dissolved in methanol (5 mL).[0168] In another flask, a cold (0C) solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (930 mg, 6.5 mmol) in methanol (15 mL) was treated with sodium methoxide (25% wt. solution in methanol, 1.55 mL). After stirring for 15 minutes, the reaction was treated with the dropwise addition of the chloro-oxime already in methanol. The reaction warmed to rt and stirred for an additional 30 min. The reaction was concentrated in vacuo and diluted with EtOAc. The organics were washed with saturated NaCl (aq) and saturated NaHC03 (aq.). Organics were collected, dried (MgS04), filtered, concentrated, and chromatographed (Si02, linear gradient, 0- 80%, EtOAc in Hexanes) to give the desired ester as an oil. 1H NMR (400 MHz, CDC13) δ 3.89 (s, 3H), 2.79 (m, 2H), 2.11 (m, 1H), 1.42 (m, 2H), 1.22 (m, 4H), MS m/z 276.1 (M + 1) |
Yield | Reaction Conditions | Operation in experiment |
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A solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (0.36 mL, 2.9 mmol) in methanol (8 mL) was cooled to 0C and treated with sodium methoxide (0.76 mL of a 25% wt. solution in MeOH). After stirring for 20 minutes, iraw5,-N-hydroxy-2-phenylcyclopropanecarbimidoyl chloride rac-I- 6D (0.57 g, 2.9 mmol) in methanol (0.5 mL) was added dropwise. The reaction mixture was warmed to rt and stirred for lh. The reaction was concentrated in vacuo, diluted with water and extracted with dichloromethane. The aqueous was acidified with 6N HCl to pH=5 and extracted again with dichloromethane. The organics were washed with brine dried over Na2S04, filtered, concentrated to yield 5-cyclopropyl-3-(2phenylcyclopropyl)isoxazole-4-carboxylic acid as clear oil which was directly used in the next step without further purification. MS m/z 270.1 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium methylate; In methanol; at 0 - 20℃; for 0.5h; | In another flask, a cold (0C) solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (23.7g, 170 mmol) in methanol (35 mL) was treated with sodium methoxide (25% wt. solution in methanol, 30 mL). After stirring for 20 minutes, the reaction was treated with the dropwise addition of the chloro-oxime already in methanol. The reaction warmed to rt and stirred for 30 min. The reaction was concentrated in vacuo and diluted with EtOAc. The organics were washed with saturated NaCl (aq) and saturated NaHC03 (aq.). Organics were collected, dried (MgS04), filtered, concentrated, and chromatographed (Si02, linear gradient, 0-80%, EtOAc in Hexanes) to give the desired ester as an oil. |
Yield | Reaction Conditions | Operation in experiment |
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General procedure: MsCl (0.88 mL, 11.4 mmol), under ice cooling, was added to a solution of 4-benzyloxyphenylmethanol (2.33 g, 10.9 mmol) and Et3N (1.67 mL, 11.9 mmol) in 1,2-dimethoxyethane (DME: 10 mL), and the mixture was stirred for 5 min. The insoluble material was removed by filtration and washed with DME (2 mL). The filtrate and washing were added to the mixture prepared by the addition of NaH (478 mg, 12.0 mmol, 60% oil dispersion) into a solution of ethyl 4,4,4-trifluoroacetoacetate (2.00 g, 10.9 mmol) in DME (15 mL) under ice cooling and stirring for 5 min, then the mixture was refluxed for 11 h. After cooling to room temperature, 1 M HCl (20 mL) was added, and the resulting mixture was extracted with EtOAc. The extract was washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give crude ethyl 2-(4-benzyloxyphenylmethyl)-4,4,4-trifluoroacetoacetate (8a). This material was dissolved in toluene (30 mL), and N2H4·H2O (1.05 mL, 21.7 mmol) was added to the solution. After refluxing for 7 h, water was added, and the mixture was extracted with EtOAc. The extract was washed with brine and dried over anhydrous MgSO4. Next, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: CH2Cl2/MeOH = 10:1) to give 9a (2.46 g, 65%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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0.7 g | With 4-pyrrolidin-1-ylpyridine; N-ethyl-N,N-diisopropylamine; In toluene; at 150℃; for 0.75h;Microwave irradiation; | Example 4646-A. 6-(3-Cyclopropyl-l-methyl-lH-pyrazol-5-yl)-2-(5-isopropyl-lH-indazol-4-yl)-4-methyl- 5,6,7,8-tetrahydro-l,6-naphthyridine. Microwave was used to irradiated a suspension of 2-chloro-4-methyl-5,6,7,8-tetrahydro-l,6-naphthyridine hydrochloride (1.00 g, 4.56 mmol), <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (1.298 g, 9.13 mmol), 4- pyrrolidinopyridine (0.068 g, 0.456 mmol) and DIPEA (1.20 mL, 6.85 mmol) in toluene (10 mL) at 150 C for 45 min. The mixture was cooled to rt and diluted with 1 M HClaq (10 mL) and EtOAc. The products were extracted twice with EtOAc. The combined organic layer was washed with a mixed solution of 1M HClaq/brine (lmL/2 mL), dried over Na2S04, filtered, and concentrated to give crude. The residue was purified by flash column chromatography on 12 g of silica gel (eluent: DCM/EtOAc = 90:10 to 0:100) to give crude l-(2-chloro-4-methyl-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)-3- cyclopropylpropane-l,3-dione (0.70 g): MS (ESI+) m/z 293.31 (M+H)+. The obtained material was used without futher purification.Microwave was used to irradiated a solution of crude give crude l-(2-chloro-4-methyl-7,8-dihydro-l,6- naphthyridin-6(5H)-yl)-3-cyclopropylpropane-l,3-dione (0.70 g), pyridine (1.5 mL, 19.1 mmol), Lawesson's reagent (1.064 g, 2.63 mmol) and methyl hydrazine (0.151 mL, 2.87 mmol) in THF (9 mL) at 120 C for 20 min. The mixture was diluted with EtOAc and brine. The organic layer was extracted with EtOAc, washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by flash column chromatography on 80 g of silica gel (eluent: heptane/EtOAc = 80:20 to 0:100) to give 2- chloro-6-(3 -cyclopropyl- 1 -methyl- 1 H-pyrazol-5-yl)-4-methyl-5 ,6,7,8-tetrahydro- 1 ,6-naphthyridine (110 mg): lU NMR (400 MHz, CDC13) δ ppm 7.02 (s, 1 H), 5.56 (s, 1 H), 3.96 (s, 2 H), 3.69 (s, 3 H), 3.08 - 3.23 (m, 4 H), 2.19 (s, 3 H), 1.83 - 1.90 (m, 1 H), 0.86 - 0.91 (m, 2 H), 0.68 - 0.72 (m, 2 H); MS (ESI+) m/z 303.28 (M+H)+.Microwave was used to irradiated a solution of 2-chloro-6-(3-cyclopropyl-l-methyl-lH-pyrazol-5-yl)-4- methyl-5,6,7,8-tetrahydro-l,6-naphthyridine (30 mg, 0.099 mmol), crude 5-isopropyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l//-indazole (38.2 mg, 0.119 mmol), Pd(PPh3)4 (11.45 mg, 9.91 μιηοΐ) and K3P04 (42.1 mg, 0.198 mmol) in 1,4-dioxane (0.5 mL) and H20 (0.05 mL) at 130 C for 1 h under nitrogen. Additional Pd(PPh3)4 (22.90 mg, 0.020 mmol) was added to the mixture. Microwave was irradiated to the mixture at 130 C for further 2 h under nitrogen. The mixture was diluted with brine and EtOAc. The organic layer was separated, dried over Na2S04, filtered, and concentrated.The residue was purified by flash column chromatography on 12 g of silica gel (eluent: DCM/MeOH = 100:0 to 10:1) to give 6-(3-cyclopropyl-l-methyl-lH-pyrazol-5-yl)-2-(5-isopropyl-lH-indazol-4-yl)-4-methyl-5,6,7,8- tetrahydro-l,6-naphthyridine: lU NMR (400 MHz, CDC13) δ ppm 9.98 (br s, 1 H), 7.76 (d, J= 0.76 Hz, 1 H), 7.45 - 7.51 (m, 2 H), 7.12 (s, 1 H), 5.65 (s, 1 H), 4.11 (s, 2 H), 3.75 (s, 3 H), 3.30 - 3.33 (app t, 2 H), 3.15 - 3.24 (m, 3 H), 2.30 (s, 3 H), 1.87 - 1.94 (m, 1 H), 1.25 (d, J= 7.07 Hz, 6 H), 0.89 - 0.94 (m, 2 H), 0.72 - 0.76 (m, 2 H); MS (ESI+) m/z 427.33 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; In toluene; at 150℃; for 0.583333h;Microwave irradiation; | 55-D. (l?)-l-Cyclopropyl-3-(2-(3,5-dimethyl-l-tosyl-lir-indazol-4-yl)-4-(4-methoxy-3,3- dimethylpiperidin-l-yl)-7,8-dihydropyrido [4,3-d]pyrimidin-6(5 )-yl)propane-l,3-dione^ A solution of (R)-2-(3,5-dimethyl-l-tosyl-l//-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-l-yl)- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.200 g, 0.35 mmol), 4-DMAP (0.013 g, 0.10 mmol) and <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (0.13 mL, 1.04 mmol) in toluene (3 mL) was heated at 150 C in a microwave reactor for 35 min. The reaction was then diluted with EtOAc and water. The aqueous phase was extracted further with EtOAc (3x) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduce pressure. The residue was then purified via FCC (0-10% MeOH/DCM) to obtain the title compound. MS (ESI+) m/z 685.6 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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43% | With ytterbium(III) triflate; In ethanol; at 20℃; | To a mixture of (2-amino-5-chlorophenyl)(3-chlorophenyl) methanone (81 mg, 0.31 mmol, leq) and <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (56.2 mg, 0.40 mmol, 1.3eq) in ethanol (3 ml) was added ytterbium triflate (19 mg, 0.03 mmol, O. leq) and the yellow solution was stirred overnight at room temperature. The resultant precipitate was filtered and washed with a small amount of ethanol to give the desired product (49 mg, 43%) as a white solid which did not require any further purification. MS (ESI): 372.1 (M+H)+ |
43% | With ytterbium(III) triflate; In ethanol; at 20℃; | Step A: 6-Chloro-4-(3-chloro-phenyl)-2-cyclopropyl-quinoline-3-carboxylic acid methyl ester To a mixture of (2-amino-5-chlorophenyl)(3-chlorophenyl) methanone (81 mg, 0.31 mmol, 1eq) and <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (56.2 mg, 0.40 mmol, 1.3eq) in ethanol (3 ml) was added ytterbium triflate (19 mg, 0.03 mmol, 0.1 eq) and the yellow solution was stirred overnight at room temperature. The resultant precipitate was filtered and washed with a small amount of ethanol to give the desired product (49 mg, 43%) as a white solid which did not require any further purification. MS (ESI): 372.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With ytterbium(III) triflate; In ethanol; at 20℃; | In a 5 ml round-bottomed flask, (2-amino-5-chlorophenyl)(phenyl)methanone (100 mg, 432 ?????, Eq: 1.00) and <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (79.8 mg, 561 ?????, Eq: 1.3) were combined with EtOH (1.5 ml) to give a light yellow solution. Ytterbium triflate (26.9 mg, 43.2 ?????, Eq: 0.1) was added. The mixture was stirred at room temperature overnight, upon which a white precipitate formed. The precipitate was filtered and washed with ethanol to provide the title compound (67 mg, 46%) as a white powder. |
46% | With ytterbium(III) triflate; In ethanol; at 20℃; | Step A: 6-Chloro-2-cyclopropyl-4-phenyl-quinoline-3-carboxylic acid methyl ester In a 5 ml round-bottomed flask, (2-amino-5-chlorophenyl)(phenyl)methanone (100 mg, 432 μmol, Eq: 1.00) and <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (79.8 mg, 561 μmol, Eq: 1.3) were combined with EtOH (1.5 ml) to give a light yellow solution. Ytterbium triflate (26.9 mg, 43.2 μmol, Eq: 0.1) was added. The mixture was stirred at room temperature overnight, upon which a white precipitate formed. The precipitate was filtered and washed with ethanol to provide the title compound (67 mg, 46%) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium hydroxide; In methanol; at -5 - 0℃; for 0.5h; | General procedure: A 30% solution of potassium hydroxide inmethanol (20 mL) is added to a stirred solution of the 1,3-dicarbonyl compound(30 mmol) in methanol (20 mL) at -5oc . Then, a solution of iodosobenzene diacetate (30mmol) in methanol (50 mL) is added in small portions while the temperature is notallowed to exceed 0oc . Stirring is continued for 30 min at the same temperature,the mixture is poured onto ice water (300 mL), and the product is extracted with dichloromethane (3×100 mL). The organic extract is dried with magnesiumsulfate, the solvent in vacuo, and the solid residue recrystallized from absolute ether. |
Yield | Reaction Conditions | Operation in experiment |
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98% | With sulfuryl dichloride; In dichloromethane; at 0 - 25℃; for 2h; | To a solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (1.00 eq., 20.0 g, 141 mmol) in dichloromethane (150 mL) was added sulfuryl chloride (0.99 eq., 12 mL, 140 mmol) at 0 C. The reaction mixture was stirred at 25 C for 2 hours. Water (200 mL) was added to the mixture and the organic layer was seperated. The organic layer was washed with saturated sodium bicarbonate, brine and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 50: 1, then 20: 1) to give methyl 2-chloro-3-cyclopropyl-3-oxopropanoate (27.0 g, 98%) as yellow oil. 1H NMR (400 MHz, CDCl3): δ [ppm] = 1.07-1.11 (m, 2H), 1.17-1.21 (m, 2H), 2.27-2.33 (m, 1H), 3.86 (s, 3H), 4.95 (s, 1H). LC-MS (Method C): Rt = 0.55 min; MS (ESIpos): m/z = 177 [M+H]+. |
2.48 g | With sulfuryl dichloride; In dichloromethane; at 20℃; for 5h;Cooling with ice; | Preparation Example 7 To a solution of 2 g of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> in 20 ml of dichloromethane was added dropwise 1.24 ml of sulfuryl chloride under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water under ice-cooling, and chloroform was further added thereto to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.48 g of methyl 2-chloro-3-cyclopropyl-3-oxopropanoate. |
With sulfuryl dichloride; In chloroform; at 20℃; for 2h;Inert atmosphere; | A mixture of methyl 3-cyclopropyl-3-oxo-propanoate (5.00 g, 35.17 mmol, 1.00 eg), suifuryl chloride (5.70 g, 42.20 mmol, 4.22 mL, 1.20 eg) in CHCb (50.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20C for 2 hours under N2 atmosphere. Removal of the solvent gave the methyl 2-chloro-3-cyclopropyl-3-oxo- propanoate (5.00 g, crude) as a yellow oil which was used to next step without further purification. |
With sulfuryl dichloride; In chloroform; at 20℃; for 2h;Inert atmosphere; | A mixture of methyl 3 -cyclopropyl-3 -oxo-propanoate (5.00 g, 35.17 mmol, 1.00 eq), sulfuryl chloride (5.70 g, 42.20 mmol, 4.22 mL, 1.20 eq) in CHC13 (50.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20C for 2 hours under N2atmosphere. Removal of the solvent gave the methyl 2-chloro-3-cyclopropyl-3-oxo-propanoate (5.00 g, crude) as a yellow oil which was used to next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | To a mixture of methyl 3 -cyclopropyl-3 -oxopropanoate (15 g, 0.11 mol, 1.0 eq ) in THF (0.10 L) was added CS2CO3 (52 g, 0.16 mol, 1.5 eq). The mixture was stirred at 20 C for 0.5 hours and then was added CH3I (15 g, 0.11 mol, 6.6 mL, 1.0 eq) at 20 C under N2. The mixture was stirred at 40 C for 2.5 hours. The reaction mixture was filtered, and the filtrate cake was washed with EtOAc (150 mL><3). The combined organic phase was concentrated to give 1 (15 g, 91% yield) as a yellow oil. NMR (400 MHz, CD Cl 3 -i ) d ppm 3.75 - 3.73 (m, 3 H), 3.71 - 3.64 (m, 1 H), 2.05 (t, J= 7.6, 4.4 Hz, 1 H), 1.42 - 1.38 (m, 3 H), 1.12 - 1.01 (m, 2 H), 0.97 - 0.86 (m, 2 H). | |
To a slurry of NaH (0.563 g, 60% in mineral oil) in THF (20 mL) was cooled to 10 0 C, then <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (2 g) was added in portions at room temperature over 30 min. Then Mel (0.88 mL) was added over 5 min at room temperature and stirred at room temperature overnight. The reaction was reverse quenched into a half saturated sodium bicarbonate solution (100 mL) and EtOAc (100 mL). The aqueous layer was separated and extracted once with 50 mL EtOAc. The combined organic layers were washed with water and brine, and concentrated to give the title compound, which wast aken on to next the step without further purification. | ||
With sodium hydride; In tetrahydrofuran; mineral oil; at 10 - 25℃; for 0.583333h; | Step 1: methyl 3-cyclopropyl-2-methyl-3-oxopropanoate A slurry of NaH (0.5 63 g, 60% in mineral oil) in THF (20 mL) was cooled to 10 C, then <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (2 g) wasadded in portions at rt over 30 minutes. Then Mel (0.88 mL) was added over 5 minutes at rt and the reaction was stirred at rt overnight. The reaction was then reverse quenched into a half saturated sodium bicarbonate solution (100 mL) and EtOAc (100 mL). The aqueous layer was separated and extracted once with 50 mL EtOAc. The combined organic layers were washed with water and brine, and concentrated to give the title compound, which was used in the next step without furtherpurification. |
A slurry of NaH (0.563 g, 60in mineral oil) in THF (20 mL) was cooled to 10 , and <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (2 g) was added in portions at room temperature over 30 min. Then MeI (0.88 mL) was added over 5 min at room temperature and the reaction was stirred at room temperature overnight. The reaction was then reverse quenched into a half saturated sodium bicarbonate solution (100 mL) and EtOAc (100 mL) . The aqueous layer was separated and extracted once with 50 mL EtOAc. The organic layer was washed with water and brine, and then concentrated to give the title compound, which was used in the next the step without further purification. | ||
A slurry of NaH (0.563 g, 60% in mineral oil) in THF (20 mL) was cooled to 10 C, then <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (2 g) was added in portions at room temperature over 30 minutes. Then Mel (0.88 mL) was added over 5 minutes at room temperature and the reaction was stirred at room temperature overnight. The reaction was then reverse quenched into a half saturated sodium bicarbonate solution (100 mL) and EtOAc (100 mL). The aqueous layer was separated and extracted once with 50 mL EtOAc. The combined organic layers were washed with water and brine, and concentrated to give the title compound, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With stannous chloride; In toluene; for 3h;Reflux; | 40 g of 2-aminobenzonitrile was dissolved in 300 ml of toluene.Add 16 grams of the formula V3-cyclopropyl-3-oxo-propionic acid methyl ester (R=methyl)And 73 grams of tin chloride,Then, the temperature was raised to reflux reaction for 3 hours.After the reaction,Down to room temperature,Add water to dilute the layering,The organic layer was washed twice with saturated brine.Dry over anhydrous sodium sulfate,Filtered, and the filtrate was concentrated to dryness under reduced pressure.27 grams of compound IVMethyl 4-amino-2-cyclopropyl-3-quinolinecarboxylate,The yield was 79%.Send feedbackHistorySaved |
Yield | Reaction Conditions | Operation in experiment |
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With sodium methylate; In methanol; at 16℃; for 48h; | A mixture of AG-1 (50.0 g, 0.35 mol), CHN2H3.AcOH (73 g, 0.70 mol) and NaOMe (133.0 g, 2.4 mol) in MeOH (1.5 L) is stirred at 16 C for 2 days. The reaction mixture is acidified to pH7 with acetic acid and filtered. The filtrate iss concentrated under reduced pressure and the crude product is purified by chromatography on silica gel to yield intermediate AG-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In toluene; at 150℃; for 0.5h;Microwave irradiation; | Step 1 : To a solution of BB-2 (300 mg, 0.898 mmol) and 3-cyclopropyl-3-oxo-propionic acid methyl ester (255 mg, 1.769 mmol) in toluene (6 mL) was added DMAP (22 mg, 0.179 mmol) and the suspension was irradiated in microwave at 150C for 30 min. The RM was concentrated under reduced pressure and crude mixture was purified by CC (Si02, EtOAc/Hex) to afford the desired compound. LC-MS (Method 3): m/z [M+Hf = 445.2 (MW calc. = 444.47); R, = 3.49 min. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium methylate; In methanol; at 16℃; for 48h; | A mixture of AD-1 (100.0 g, 0.70 mol), formamidine acetate (146 g, 1.4 mol) and NaOMe (266.0 g, 4.9 mol) in MeOH (2 L) is stirred at 16 C for 2 days. The reaction mixture is neutralized to pH 7 with acetic acid and filtered. The filtrate is concentrated under reduced pressure and the crude product is purified by Si02 flash chromatography to yield AD-2. |
Yield | Reaction Conditions | Operation in experiment |
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73% | With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; copper diacetate; In tetrahydrofuran;Schlenk technique; Reflux; | General procedure: A Schlenk tube was charged with dialdehyde 1 (0.100 mmol), [Cp*RhCl2]2 (2.0 μmol, 2 mol % dimer, 4 mol % Rh), Cu(OAc)2 (0.150 mmol), and then THF (1.0 mL) and 1,3-dicarbonyl compound 8 (0.200 mmol) were added. The mixture was heated at reflux under air. The reaction mixture was filtered through a plug of Florisil washing with hexane-AcOEt, and the filtrate was concentrated. The residue was purified by preparative TLC on silica gel to afford the following compounds. |
Yield | Reaction Conditions | Operation in experiment |
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87% | To a 50 mL round bottom flask containing <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (1.3 g, 8.9 mmol) was added triethylamine (2.5 mL, 17.8 mmol). The resulting clear solution was stirred at room temperature for 15 minutes and was cooled in an ice water bath. To the stirring solution was added a solution of 2,6-dichloro-N-hydroxybenzimidoyl chloride (2.0 g, 8.9 mmol) in EtOH (4 mL) over the space of 10 minutes giving a white suspension. After addition, the resulting suspension was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on S1O2 (0-10% EtOAc/hexanes, Isco 80 g column) to give methyl 5- cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate (2.4 g, 7.7 mmol, 87% yield) as a white solid. NMR (500 MHz, CDCh) δ 7.45-7.39 (m, 2H), 7.39-7.33 (m, 1H), 3.71 (s, 3H), 2.93 (tt, J=8.5, 5.2 Hz, 1H), 1.47-1.40 (m, 2H), 1.34-1.27 (m, 2H). | |
87% | To a 50 mL round bottom flask containing <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (1.3 g, 8.9 mmol) was added triethylamine (2.5 mL, 17.8 mmol). The resulting clear solution was stirred at room temperature for 15 minutes and was cooled in an ice water bath. To the stirring solution was added a solution of 2,6-dichloro-N-hydroxybenzimidoyl chloride (2.0 g, 8.9 mmol) in EtOH (4 mL) over the space of 10 minutes giving a whitesuspension. After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on 5i02 (0- 10% EtOAc/hexanes, Isco 80 g column) to give methyl 5-cyclopropyl-3-(2,6- dichlorophenyl)isoxazole-4-carboxylate (2.4 g, 7.7 mmol, 87% yield) as a white solid. ‘H NMR (500 MI-Tz, CDC13) ö 7.45-7.39 (m, 2H), 7.39-7.33 (m, 1H), 3.71 (s, 3H), 2.93 (if,J=8.5, 5.2 Hz, 1H), 1.47-1.40 (m, 2H), 1.34-1.27 (m, 2H). | |
87% | With triethylamine; In ethanol; at 20℃;Cooling with ice; | To a 50 mL round bottom flask containing <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (1.3 g, 8.9 mmol) was added triethylamine (2.5 mL, 17.8 mmol). The resulting clear solution was stirred at room temperature for 15 minutes and was cooled in an ice water bath. To the stirring solution was added a solution of 2,6-dichloro-N-hydroxybenzimidoyl chloride (2.0 g, 8.9 mmol, synthesis described in General Method A) in EtOH (4 mL) over the space of 10 minutes giving a white suspension. After addition, the resulting suspension was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on SiO2 (0-10% EtOAc/hexanes, Isco 80 g column) to give methyl 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate (2.4 g, 7.7 mmol, 87% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.45-7.39 (m, 2H), 7.39-7.33 (m, 1H), 3.71 (s, 3H), 2.93 (tt, J=8.5, 5.2 Hz, 1H), 1.47-1.40 (m, 2H), 1.34-1.27 (m, 2H). |
84% | Triethylamine (8.2g) was added to <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> (82mmol), Stir for 30 minutes. Then cool to 10C, Then add a solution of III-1 (18.3g, 82mmol) in absolute ethanol (80mL) dropwise (internal temperature does not exceed 30C), The reaction was overnight at room temperature. Add ethyl acetate (100mL) to dilute the reaction solution, wash with water, The aqueous phase was extracted with ethyl acetate (100 mL each time, 3 times in total). Mix the organic phase, Wash with saturated brine and concentrate. Add 100mL ether to the concentrate and stir, The solvent was removed under vacuum to obtain the solid product IV-1 (21.6 g, yield 84%). | |
65% | 3-Cyclopropyl-3-oxo-propionic acid methyl ester (31.7g, 0.223mol) was dissolved by adding triethylamine (45.1g, 62mL, 0.446mol),Stir at room temperature. After 30 minutes, cool down to 10 C.Slowly add 2,6-dichloro-benzaldehyde-chloro-oxime (50.0g, 0.223mol, dissolved in 300mL ethanol), the temperature during the dropwise addition does not exceed 24 C,After dripping, stir overnight at room temperature, monitor the reaction by thin layer chromatography (TLC), and add 200 mL of water after the reaction.Extracted with 500 mL of ethyl acetate (EA), extracted the aqueous layer three times with 200 mL of ethyl acetate, combined the organic layers, washed the organic layer with 200 mL of saturated brine, and dried over anhydrous Na2SO4.Concentrated in vacuo to 10% solution, a large amount of solids precipitated,The crude product was obtained by suction filtration, followed by grinding with 100 ml of hexane, suction filtration, and drying to obtain 45.0 g of a white solid with a yield of 65%. | |
54% | Triethylamine (10.91 g, 0.11 mol, 2.0 eq) was added to a mixture of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> (7.66 g, 0.054 mol, 1.0 eq) and stirred at room temperature for 30 min, And then cooled to 10 C.The intermediate 1-9 (12.10 g,0.054 mol, 1.0 eq) was dissolved in 24.2 mL of ethanol and slowly added to the above reaction solution, and the internal temperature did not exceed 24 C. In addition,Stir overnight at room temperature.After completion of the reaction, the reaction solution was diluted with 45 ml of ether, washed with 15 ml of water, separated, and the aqueous layer was extracted once with ethyl acetate.And the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to 10% of the total to form a precipitate which was washed with etherMashing beating, filtering, filter cake vacuum dry,To give intermediate 1-10, 8.48 g of a white solid,the yield was 54%. | |
54% | Triethylamine (10.91 g, 0.11 mol, 2.0 eq) was added to <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong>(7.66 g, 0.054 mol, 1.0 eq) mixture was stirred at room temperature for 30 min and then cooled to 10 C.Intermediate 1-9 (12.10 g, 0.054 mol, 1.0 eq) was dissolved in 24.2 mL of ethanol.The reaction solution was slowly added thereto, and the internal temperature did not exceed 24 C. Further, the reaction was stirred at room temperature overnight. After the reaction, the reaction solution was diluted with 45 ml of EA, washed with 15 ml of water, and the mixture was evaporated.The organic layers were combined, washed with brine and dried over anhydrous sodium sulfateFilter and concentrate the filtrate to 10% of the total amount.A precipitate formed, which was beaten with ether and filtered, and the cake was vacuum dried.Intermediate 1-10 was obtained as a white solid, 8.48 g, yield 54%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium cerium (IV) nitrate; sodium carbonate; In acetonitrile; at 0℃;Inert atmosphere; | General procedure: 2. General procedure for the synthesis of 2-butoxy-2,3-dihydrofurans. 1 All reactions were conducted in a 250 mL of three-necked round bottomed flask equipped with magnetic stirring. To a stirred mixture of pentane-2,4-dione (10.0 mmol, 1.0 g), 1-(vinyloxy)butane (10.0 mmol, 1.0 g), and NaHCO3 (30.0 mmol, 2.52 g) in acetonitrile (100 mL), ceric ammonium nitrate (25.0 mmol, 13.7 g) dissolved in acetonitrile (50 mL) was added dropwise at 0 oC under N2. The reaction was stirred until the starting material was consumed totally as screened by TLC. Water was added to the mixture and the product was extracted into ethyl acetate (2 200 mL) and then dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure gave a crude product, which was purified by column chromatography on silica gel, with ethyl acetate-petroleum ether (1/20 (V/V)) as eluent to afford the pure product 1-(5-butoxy-2-methyl-4,5-dihydrofuran-3-yl)ethanone 1a 0.9 g (45%) as a colourless oil. The synthesis of the other 2-butoxy-2,3-dihydrofurans were all performed with an analogous procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a suspension of NaH (0.6 g, 60% in mineral oil, 15 mmol) in THF (50 ml), was added <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (1.42 g, 10 mmol) slowly, then added BnBr (1.7 g, 10 mmol), then heated to reflux for 8 hrs. After evaporation of solvent, the pH was adjusted to 6~7 with 1M HCl, then diluted with ethyl acetate, washed with water, brine. Dried with Na2SO4. The product was purified by chromatogram with a mobile phase of hexane/ethyl acetate (10 : 1) to give title compound (1.86 g, 80%) as a colorless oil. Methyl 2-benzyl-3-cyclopropyl-3-oxopropanoate (1q). 1H NMR (500 MHz, CDCl3) δ 7.30 -7.26 (m, 2H), 7.22-7.18 (m, 3H), 3.93 (t, J = 7.6 Hz, 1H), 3.70 (s, 3H), 3.20 (d, J = 7.6 Hz, 2H), 2.09 - 1.96 (m, 1H), 1.10 - 0.96 (m, 2H), 0.96 - 0.84 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 204.7, 169.9, 138.4, 129.0, 128.7, 126.8, 61.5, 52.6, 34.3, 20.5, 12.0, 11.9. IR (KBr): 2923.0, 1741.4, 1702.1, 1381.7, 699.2 cm-1. ESI (m/z): 233.1 (M + H)+; HRMS (ESI) calcd. for C14H17O3 (M + H)+ 233.1172, found 233.1170. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; at 20℃; for 14h; | Lithium hydroxide monohydrate (0.59 g, 14.7 mmol, 2.0 eq.) was added to a solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (1.0 g, 7.03 mmol, 1.0 eq.) in tetrahydrofuran/water/methanol (15 mL, 1/1/1, v/v/v). The reaction was stirred at 20 C. for 14 hours, and concentrated. The residue was dissolved in water (10 mL), adjusted with 2 N HCl to pH=2, and then extracted with ethyl acetate (20 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated to give the title compound (0.4 g, yield: 44%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.8 g | (1) 3-cyclopropyl-3-oxo-propanoic acid methyl ester (4.9g) in ethyl acetate (50) at room temperature to the solution was added a N, N- dimethylformamide dimethyl acetal (4.31g) at 75 C It was stirred for 3 hours. Then after cooling to room temperature, it was added 4-chlorophenyl hydrazine hydrochloride (7.52g) and triethylamine (7.0), and stirred for 4 hours at 75 C. After the reaction, water was added, extracted with ethyl acetate, washed with water twice. The organic layer was dried, the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (chloroform: methanol) to obtain to obtain a mixture (7.7g). (2) at room temperature in methanol (45) solution of the resulting mixture (7.7g) was added 4N aqueous sodium hydroxide solution (8.4), and stirred for 1 hour under reflux. After the reaction, it cooled to room temperature, and after the addition of water (100) and activated charcoal (1g), the mixture was stirred for 0.25 hours at room temperature. After the reaction, subjected to filtration, and extracted with ethyl acetate twice (until about pH3) in the obtained aqueous layer was added 1N hydrochloric acid aqueous solution. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, the solvent was removed by distillation to some extent. By addition of n- hexane to the obtained solution, and after stirring at 0 C, performing the filtration to obtain the title compound (5.8g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3: To a solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (1.3 g, 9.3 mmol) in THF (60 mL) was added Et3N (6.3 g 62 mmol) and the reaction was stirred at rt for 30 min, then 4,4-difluoro-/V- hydroxycyclohexanecarbimidoyl chloride lnt-1b-1 in THF was added dropwise. The resulting mixture was stirred for 2 h at rt, evaporated and the residue was partitioned with water (100 mL) and EtOAc (50 mL). The organic layer was washed with brine, dried, filtered, concentrated and purified by column chromatography (PE/EtOAc = 10:1 ) to afford methyl 5-cyclopropyl-3-(4,4- difluorocyclohexyl)isoxazole-4-carboxylate lnt-1c-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Step 1: methyl 2-cyclopropyl-4-oxo-4,5-dihydrofuran-3-carboxylate To a solution of magnesiumethanolate (19.32 g, 169 mmol) in toluene (80 mL) was slowly added <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong>l (20 g, 141 mmol) at 0 C. After stirring for 1 hour, acetonitrile (80 mL) was added followed by the addition of 2-chloroacetyl chloride (15.89 g, 141 mmol) at 0 C. The mixture was allowed to warm to room temperature and left to stir for 2 hours. A diluted solution of sulfuric acid (1 mL acid in 30 mL ice/water) was added, followed by extraction with tert-butylmethyl ether. The combined organic fractions were dried over Na2SO4 and filtered. To the filtrate was added a solution of triethylamine (49 mL, 338 mmol) in tert-butylmethyl ether (150 mL). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (200 mL), and extracted with dichloromethane. The organic phase was concentrated under reduced pressure to supply a residue that was purified by chromatography on silica gel and eluted with EtOAc/PE to give the titled compound (24 g, yield 94%). 1H NMR (400 MHz, CDCl3) δ ppm 4.50 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 3.18-3.08 (m, 1H), 1.40-1.32 (m, 5H), 1.29-1.22 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine; In ethanol; at 10 - 20℃; | At room temperature,to3-cyclopropyl-3-Oxypropionic acidMethyl ester (15.8 g, 111 mmol)Triethylamine (32 mL) was added dropwise. 10 C was added (Z) -2,6-dichlorobenzyl to the above system(0.5 g, 111 mmol, dissolved in 60 mL of ethanol) was added and the mixture was stirred overnight at room temperature. plusThe reaction was quenched with water (20 mL) and the reaction system was extracted with ethyl acetate (50 mL x 3)The crude phase was dried and concentrated to a crude product which was recrystallized from ethyl acetate / petroleum ether (1:10)5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4-carboxylate (1-4) (20 g, 58%) was whitesolid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.5% | 203a) Methyl 2-(cyclopropanecarbonyl)-3-oxobutanoate A solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (10 g, 70.3 mmol) in dichloromethane (DCM) (200 mL) was added pyridine (6.12 g, 77 mmol), magnesium chloride (7.03 g, 73.9 mmol) slowly under nitrogen at 0 C. The reaction mixture was stirred at 0 C for 0.5 h. Acetyl chloride (6.07 g, 77 mmol) was added slowly. The reaction mixture was stirred at room temperature for 12 h. 30 mL of water was added and extracted with ethyl acetate (3x). The combined organic layer was concentrated under a stream of nitrogen at 50 C to obtain the title compound methyl 2-(cyclopropanecarbonyl)-3-oxobutanoate (10 g, 48.9 mmol, 69.5 % yield) which was used in next step without further purification. LC-MS m/z 185.1 (M+H)+, 1 .86 min (ret. time). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6. Preparation of methyl 5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl) isoxazol-4-formate Potassium carbonate (10.44 g, 75.52 mmol) was added to THF(100 mL), and the solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropionate</strong> (10.44 g, 73.4 mmol) in THF (50 mL) was added to the reaction system. The system was stirred at -10 C for 30 mins. The solution of N-hydroxy-2-(trifluoromethoxy)benzimidoyl chloride (16.6 g, crude product) in THF (50 mL) was then added to the reaction system at -5 C, and the system reacted at 35 C for 6 hrs. The reaction solution was diluted with water (200 mL), and extracted with ethyl acetate (500 mL x 3). The organic phase was dried, concentrated, and purified by a silica-gel column (petroleum ether : ethyl acetate = 5:1) to obtain a product (11.3 g, yield: 47.1%). | ||
2.5 g | With sodium methylate; In methanol; at -10 - 35℃; for 12h; | Sodium methoxide (2.6 g, 48.9 mmol) was suspended in CH3OH(50 mL), and the mixture was cooled to 10 C and treated with asolution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (5.3 g,37.6 mmol) in CH3OH (20 mL) dropwise over 5 min. To above reactionmixture was then slowly added a solution of compound 3 (4.5 g, 18.8 mmol) in CH3OH at 10 C. The reactionwas warmed to35 C and stirred for 12 h. After completion, the reaction mixturewas diluted with water and extracted with ethyl acetate. Thecombined organic layer was washed with brine, dried over anhydroussodium sulfate, concentrated under vacuum, and then purifiedby silica gel column chromatography using ethyl acetate/petroleum ether to afford compound 4 as a white solid, 2.5 g in 41%yield; 1H NMR (DMSO-d6, 300 MHz) d 7.65e7.60 (m, 1H, Ph),7.53(dd, J 7.6, 2 Hz, 1H, Ph), 7.48e7.43 (m, 2H, Ph), 3.68 (s, 3H,eCOOCH3), 2.89 (m, J 6.8 Hz, 1H, eCH(CH2)2), 1.30 (m, J 6.8 Hz,4H, eCH(CH2)2); MS (ESI) m/z: 328.1 [MH]. |
2.5 g | With sodium methylate; In methanol; at -5 - 35℃; for 12h;Cooling with ice; | Under an ice-salt bath, NaOCH3 (2.64g, 48.9mmol) was dissolved in CH3OH to prepare solution B. Methyl 3-cyclopropyl-3-oxopropionate (5.34 g, 37.6 mmol) was dissolved in CH3OH. The solution B was slowly added to it, and the addition time was longer than 5 minutes. Dissolve 2-trifluoromethoxy-N-hydroxy-chlorobenzaldehyde oxime (4.5g, 18.8mmol) in CH3OH, add dropwise to the above mixture under an ice-salt bath, the reaction temperature should always be less than -5 . After 5 minutes, the ice salt bath was removed, the temperature was raised to 35C, and the reaction was carried out for 12 hours. The excess NaOCH3 was neutralized with CH3COOH, CH3OH was removed under reduced pressure, and extracted with EA and H2O. Dehydrate with saturated brine, dry with anhydrous Na2SO4, and spin dry. Purified by column chromatography, the product was 2.5 g, and the yield was 40.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | To a stirred solution of potassium carbonate (84 mg, 0.605 mmol) in DMF (0.5 mL) was added methyl-3-cycloproyl-3-oxopropionate (0.07 mL, 0.6053 mmol). After stirring at rt for 2 h, 3-methoxyophenyl isothiocyanate (0.08 mL, 0.6053 mmol) was added at 0 C. Then, the mixture was stirred for 60 C for 2 h before addition of 2-(bromomethyl)pyridine hydrobromide (153 mg, 0.6053 mmol). The reaction mixture was stirred at 60 C for 3 h and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The resulting crude residue was purified by column chromatography (ethyl acetate/Hex 10%) to give the thiophene 8ak (186 mg, 81% yield) a yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
880 mg | at 100℃; | 6-Aminoisoquinoline (1.0 g, 6.94 mmol) was heated in methyl 3-cyclopropyl-3-oxopropanoate (5 mL) at 100° C. overnight. The reaction mixture was cooled to RT then applied to a pad of silica and washed with DCM then eluted using 5percent methanol in DCM. This fraction was evaporated and the resultant crude product was chromatographed on a 100 g Si cartridge eluting with 0-5percent methanol in DCM. The product was obtained as a brown oil (880 mg). LCMS (Method 6): Rt=0.67 min, m/z 255.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.7 g | To a solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (2.86 ml, 21.10 mmol) in tetrahydrofuran (THF) (71.9 ml) at 0 C (ice bath) was added NaH (1.266 g, 31.7 mmol, 60% dispersion in mineral oil) in 3 equal portions over 10 mm. The resulting reactionmixture was stirred at RT for 1 h. Following this duration, a thick, white precipitate formed. A solution of 3-iodoprop-1-ene (2.316 ml, 25.3 mmol) in tetrahydrofuran (THF) (23.98 ml) was subsequently added via cannula. After 1 h, the reaction contents were added to 150 mL saturated aqueous NH4CI and diluted with 200 mL EtOAc and 20 mL water. The resulting layers were separated and the aqueous layer was extracted with 3 x 50 mLEtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to give a cloudy orange oil. Purification by silica gel chromatography (120 g column, 0-50% Acetone:Hexane) afforded the title compound as a clear colorless oil (2.7 g, 13.2 mmol,63% yield). LC-MS mlz 183.1 (M+H), 0.70 mm (ret. time). 1H NMR (400 MHz,CHLOROFORM-cl) O ppm 0.96 (dd, J=7.03, 3.01 Hz, 2 H) 1.08 - 1.14 (m, 2 H) 2.01 - 2.17(m, 1 H) 2.66 (t, J=7.03 Hz, 2 H) 3.65 - 3.73 (m, 1 H) 3.77 (s, 3 H) 5.00 - 5.20 (m, 2 H) 5.70- 5.87 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | K2CO3 (3.9 g, 28.3 mmol) and THF (50 mL) were added to a 250 mL three-necked flask, and the nitrogen was replaced three times.A solution of <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (3.9 g, 27.5 mmol) in THF (26 mL) was slowly added dropwise at -10 C, and then reacted at -10 C for 30 min.A solution of (Z)-N-hydroxy-2-(trifluoromethyl)benzeneimidoyl chloride (5.8 g, 25.9 mmol) in THF was added dropwise, stirred at -5 C for 30 min and then transferred to 35 C overnight.The reaction mixture was quenched with water and extracted with EA three times.The organic layers were combined and washed with brine.The title compound (8.2 g, yield 51%) was obtained as a yellow oil. The crude product was purified by column chromatography (PE/EA=20/1~5/1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | at 130℃; for 5h;Dean-Stark; | A solution of m-Chloroaniline (1.36 mL, 12.8 mmol), trimethyl orthoformate (15.37 mmol, 1.68 mL) and <strong>[32249-35-7]methyl 3-cyclopropyl-3-oxopropanoate</strong> (1.82 g, mmol) was heated at 130 C. for 5 hours in the presence of a Dean-Stark apparatus. The crude product is purified on a silica column with dichloromethane. (0266) Yield 49%. White solid. RMN 1H (CDCl3, 400 MHz) δ 0.90-0.94 (2H, m); 1.90-1.11 (2H, m); 3.19-3.25 (1H, m); 3.80 (1H, s); 7.01 (1H, dd, J=8.1, 2.3 Hz); 7.11-7.13 (1H, m); 7.16 (1H, t, J=2.3 Hz); 7.28 (1H, t, J=8.1 Hz); 8.40 (1H, d, J=12.9 Hz); 12.73 (1H, d, J=12.9 Hz). 13C (CDCl3, 100 MHz) δ 11.9; 18.9; 51.6; 103.7; 116.1; 117.8; 125.5; 131.0; 135.9; 140.6; 151.0; 167.6; 202.1. SM (ESI+): m/z=294 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With acetic acid; In isopropyl alcohol; at 100℃; for 19h; | A mixture of thianaphthene-3-carboxaldehyde (0.106 g, 0.65 mmol), methyl 3-cyclopropyl-3-oxopropanoate (0.071 g, 0.72 mmol) and 4-amino-3-penten-2-one (0.088 g, 0.61 mmol) and acetic acid (0.035 mL) in isopropylalcohol (1.5 mL) was heated to 100C and left to stir for 19 hours. The mixture was allowed to cool to RT and was then treated with saturated aqueous sodium bicarbonate solution (10 mL). The solid was filtered off, washed with water, dried and purified by column chromatography (4:1 hexane: ethyl acetate) affording a fine yellow solid (0.075 g, 44 %). 1H-NMR (400 MHz, DMSO-d6) delta = 0.76 (s, 2H), 0.96 (d, 2H), 2.12 (s, 3H), 2.33 (s, 3H), 2.69 (s, 1H), 3.58 (s, 3H), 5.43 (s, 1H), 7.15 (s, 1H), 7.31 (s, 1H), 7.38 (s, 1H), 7.90 (s, 2H), 8.05 (d, 1H). HPLC-MS: Rt 4.302 min, m/z 234.1 (MH+-133). (0600) A second reaction product was isolated by column chromatography: Example J1-a: Dimethyl 4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate (0601) 1H-NMR (400 MHz, DMSO-d6) delta = 0.56 (s, 2H), 0.82 (s, 2H), 0.90 (d, 2H), 1.04 (s, 2H), 2.56 (m, 2H), 3.55 (s, 5H), 5.37 (s, 1 H), 7.05 (s, 1 H), 7.11 (s 1 H), 7.32 (t, 1 H), 7.39 (t, 1H), 7.90 (d, 1 H), 7.98 (s, 1 H). HPLC-MS: Rt 4.935; m/z 276.1 (MH+). |
Tags: 32249-35-7 synthesis path| 32249-35-7 SDS| 32249-35-7 COA| 32249-35-7 purity| 32249-35-7 application| 32249-35-7 NMR| 32249-35-7 COA| 32249-35-7 structure
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P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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