Structure of 32249-35-7
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CAS No. : | 32249-35-7 |
Formula : | C7H10O3 |
M.W : | 142.15 |
SMILES Code : | C1(CC1)C(CC(=O)OC)=O |
MDL No. : | MFCD00274090 |
InChI Key : | RIJWDPRXCXJDPK-UHFFFAOYSA-N |
Pubchem ID : | 10130016 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 ? Topological Polar Surface Area: Calculated from |
43.37 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.44 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.43 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.47 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.25 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.13 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.74 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.73 |
Solubility | 26.6 mg/ml ; 0.187 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.91 |
Solubility | 17.6 mg/ml ; 0.124 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.88 |
Solubility | 18.6 mg/ml ; 0.131 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.86 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.59 |
* 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 |
---|---|---|
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 |
---|---|---|
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 |
---|---|---|
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 |
---|---|---|
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) δ 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 |
---|---|---|
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 |
---|---|---|
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 |
---|---|---|
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]+ |
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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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 |
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