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CAS No. : | 611-10-9 | MDL No. : | MFCD00001412 |
Formula : | C8H12O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JHZPNBKZPAWCJD-UHFFFAOYSA-N |
M.W : | 156.18 | Pubchem ID : | 69136 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 39.94 |
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) : | -6.63 cm/s |
Log Po/w (iLOGP) : | 1.82 |
Log Po/w (XLOGP3) : | 0.88 |
Log Po/w (WLOGP) : | 0.92 |
Log Po/w (MLOGP) : | 0.58 |
Log Po/w (SILICOS-IT) : | 1.54 |
Consensus Log Po/w : | 1.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.16 |
Solubility : | 10.7 mg/ml ; 0.0684 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.38 |
Solubility : | 6.58 mg/ml ; 0.0422 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.39 |
Solubility : | 6.32 mg/ml ; 0.0405 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.26 |
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 |
---|---|---|
100% | With sodium methylate; at 150℃; | Example 2; The process was carried out in a corotating twin-shaft extruder model ZSK34 having a shaft diameter of 34 mm. The process section of the machine had a length of 1560 mm. The machine was provided with an opening for the introduction of solids. The liquid was introduced via a drilled hole in the barrel. Mixing of the components is effected by the kneading elements located on the shaft. The volatile reaction products were taken off via an open venting facility. 1.31 kg/h of sodium methoxide as powder and 3.69 kg/h of <strong>[141-28-6]diethyl adipate</strong> as liquid were metered into the machine. The rotational speed of the machine was about 60 l/min. The mixture was heated to about 150 C. by means of the barrel heating. At the end of the machine, a crumbly white solid was discharged. After acidification, aqueous work-up and extraction with an organic solvent (toluene), no starting material in the form of <strong>[141-28-6]diethyl adipate</strong>, monomethyl adipate or adipic acid could be detected. Only ethyl cyclopentanone-2-carboxylate was found. The yield based on <strong>[141-28-6]diethyl adipate</strong> was quantitative. |
~ 99% | With sodium ethanolate; at 120℃; under 7.50075 Torr; for 0.75h; | Example 1; The process was carried out in a high-viscosity reactor model CRP 2,5 Batch from List AG. The high-viscosity reactor is a machine having two horizontal corotating mixing shafts. Kneading devices which intermesh and thus ensure rapid and homogeneous mixing are located on the shafts. In addition, the machine has a discharge screw by means of which the product can be conveyed out of the reaction chamber. It can be operated continuously or batchwise. The reactor has a free volume of about 2.5 l. The reaction chamber of the machine can be heated. Volatile constituents can be taken off via a vent. 1336 g of <strong>[141-28-6]diethyl adipate</strong> and 472 g of sodium ethoxide were placed in the high-viscosity reactor. After start-up of the kneader and commencement of mixing of the starting materials a viscous mass was immediately formed. While kneading slowly, the temperature was slowly increased to 120 C. A vacuum of 10 mbar was slowly built up. The temperature of 120 C. was reached after about 15 minutes. Slow kneading was then continued at a temperature of 120 C. for 30 minutes until a pulverized white solid had been obtained. The powder formed was discharged by means of a transport screw and subsequently hydrolysed using half-strength sulphuric acid. Phase separation and distillation at 120 C./10 mbar gave 1021 g of ethyl cyclopentanone-2-carboxylate, viz. about 99% of theory. Diethyl adipate could no longer be detected. |
85.6% | EXAMPLE 25 Preparation of 2-methylene-5-diphenylmethylenecyclopentanone Step A: Preparation of cyclopentanone-2-carboxylic acid ethyl ester 15.0 g (0.652 mmol) of sodium was placed in 150 mL toluene, heated to reflux, shaken, and made into sodium sand. 81.6 g (0.400 mol) of <strong>[141-28-6]diethyl adipate</strong> was added in drops to the mixture in an outside bath at 105-110C, and the resultant solution changed into a yellow sticky product. After refluxing for 8 h, the solution was cooled by ice bath, and 400 mL of 10% acetic acid solution was added in drops. The mixture was suction filtered and washed with a small amount of toluene. The filtrate was separated into layers. The upper layer was washed with 7% sodium carbonate (260 mL×2) followed by saturated brine (200 mLx2), and dried overnight with anhydrous magnesium sulfate. The solution was filtered, concentrated and distilled under reduced pressure to collect the fractions of bp:142-150C/2660Pa, yielding 53.3 g of colorless liquid with a yield of 85.6%. |
85.6% | With sodium; In toluene; at 105 - 110℃; for 8h; | Example 25; Preparation of 2-methylene-5-diphenylmethylenecyclopentanone; Step A: Preparation of cyclopentanone-2-carboxylic acid ethyl ester 15.0 g (0.652 mmol) of sodium was placed in 150 mL toluene, heated to reflux, shaken, and made into sodium sand. 81.6 g (0.400 mol) of <strong>[141-28-6]diethyl adipate</strong> was added in drops to the mixture in an outside bath at 105-110 C., and the resultant solution changed into a yellow sticky product. After refluxing for 8 h, the solution was cooled by ice bath, and 400 mL of 10% acetic acid solution was added in drops. The mixture was suction filtered and washed with a small amount of toluene. The filtrate was separated into layers. The upper layer was washed with 7% sodium carbonate (260 mL*2) followed by saturated brine (200 mL*2), and dried overnight with anhydrous magnesium sulfate. The solution was filtered, concentrated and distilled under reduced pressure to collect the fractions of bp: 142-150 C./2660 Pa, yielding 53.3 g of colorless liquid with a yield of 85.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With boron trifluoride diethyl etherate; at 135℃; for 0.0833333h;Neat (no solvent); Microwave irradiation; | General procedure: A β-ketoester (1a-5a, 2 mmol), taken in a reactor vessel with BF3 Et2O (339mg, 2.4mmol) was mixed thoroughly for 1 min with urea (156mg, 2.6mmol). The vessel was closed immediately and was subjected to microwave irradiation at 135C. The compound (1-5) was further purified by column chromatography. Yield: as shown in table-1 |
73% | With hydrogenchloride; In ethanol; water; at 80℃; for 24h; | A solution of ethyl 2-oxocyclopentanecarboxylate (15.6 g, 0.10 mol), urea (9.0 g 0.15 mol) and hydrochloric acid (37%, aqueous, 5 mL) in EtOH (100 mL) was heated to 80 0C for 24 h. The mixture was cooled to rt and the precipitate was collected by filtration and dried to afford 6,7-dihydro-lH-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (11.1 g, 73%) as a white solid. <n="209"/>[00603] A stirred mixture of 6,7-dihydro-lH-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (10.0 g, 0.66 mol) and phosphorus oxychloride (300 mL) was heated to 105 0C for 30 min. The reaction mixture was cooled to rt and slowly poured over an ice/water mixture. The solid that formed was collected by filtration, washed with water (50 mL) and dried under reduced pressure to give 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (8.5 g, 74%) as an off-white solid.[00604] To a round bottomed flask containing 2,4-dichloro-6,7-dihydro-5i/- cyclopenta[d]pyrimidine (1.85 g, 10.5 mmol) was added phenylboronic acid (1.43 g, 11.8 mmol), dichloro-((bw-diphenylphosphino)ferrocenyl)-palladium (II) (complex with methylene chloride), (800 mg, 0.98 mmol), triethylamine (4.1 mL, 29 mmol), dimethylformamide (30 mL), and water (2 mL). The reaction mixture was heated to 80 0C for 14 h, then cooled to rt and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The material was purified by flash column chromatography to afford 2-chloro-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.25 g, 52%) as an off-white solid.[00605] To a stirred mixture of 2-chloro-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.3 g, 5.4 mmol) in 2-propanol (30 mL) was added 4-aminobenzoic acid (0.82 g, 6.0 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to rt and the precipitate was collected by filtration, washed with 2-propanol and dried to give the intermediate benzoic acid as a yellow solid (1.5 g, 84%). A portion of this intermediate (1.3 g, 3.9 mmol) was treated with 2,6-dimethylaniline (498 mg, 4.12 mmol), triethylamine (2.1 mL, 15 mmol) and ηATU (1.91 g, 5.00 mmol) in dimethylformamide (10 mL). The stirred mixture was heated to 80 0C overnight, then cooled to rt. The reaction was diluted with ethyl acetate and extracted with water. The organic layer was washed with saturated sodium bicarbonate and concentrated on a rotary evaporator. The resulting residue was purified by preparative reverse phase ηPLC to give N-(2,6-dimethylphenyl)-4-[(4-phenyl-6,7-dihydro-5i7- cyclopenta[d]pyrimidin-2-yl)amino]benzamide (1.18 g, 69%) as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ 7.98 (m, 6H), 7.56 (m, 3H), 7.17 (m, 3H), 3.18 (m, 2H), 2.98 (m, 2H), 2.25 (s, 6H), 2.17 (m, 2H). MS (EI) for C28H26N4O: 435.2 (MH+). |
31% | With hydrogenchloride; In ethanol; water; for 3h;Reflux; | Ethyl-2-oxo-cyclopentane-carboxylate(5 mL, 33.6 mmol, 1.0 eq) was dissolved in ethanol (10 mL), urea (3 g, 50.5 mmol, 1.5 eq) and conc. HCl(0.5 mL) were added and the reaction mixture was refluxed for 3 h. The solvent was decanted and after the addition of 5% NaOH (12.5 mL) the reaction mixture was refluxed for another 12 h before it was cooled to 0 C and the product was filtered and dried under vacuum (Yield: 1.58 g, 31%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.6% | Example 3 Ethyl 1-methyl-2-oxocyclopentane carboxylate Under vigorously agitation, 20.3 g of ethyl 2-oxocyclopentane carboxylate was added to 53.8 g of fine powdery anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 90 ml of acetone. The reaction mixture was further stirred for 15 to 30 minutes at room temperature, then to the mixture was dropwise added 36.9 g of methyl iodide. Upon the completion of the addition, the reaction mixture was heated for reflux for 1 hour. The solvent was removed under reduced pressure, and the solid residue was washed with diethyl ether. The washing liquor was collected and washed with water. After removing the solvent, 22.0 g of pale yellow liquid was obtained. The liquid was distilled under reduced pressure, and 20.9 g of colorless liquid as a distillate cut of 131-133 C./39 mmHg was collected. Yield: 94.6%. 1H NMR(400 MHz, CDCl3): 1.25 (t, 3H, CH2CH3), 1.31 (s, 3H, CH3), 1.85-2.53 (m, 6H, 3CH2), 4.16 (q, 2H, OCH2). | |
94.6% | Example 3; Ethyl l-methyl-2-oxocyclopentane carboxylateUnder vigorously agitation, 20.3 g of ethyl 2-oxocyclopentane carboxylate was added to 53.8 g of fine powdery anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 90 ml of acetone. The reaction EPO <DP n="19"/>mixture was further stirred for 15 to 30 minutes at room temperature, then to the mixture was dropwise added 36.9 g of methyl iodide. Upon the completion of the addition, the reaction mixture was heated for reflux for 1 hour. The solvent was removed under reduced pressure, and the solid residue was washed with diethyl ether. The washing liquor was collected and washed with water. After removing the solvent, 22.0 g of pale yellow liquid was obtained. The liquid was distilled under reduced pressure, and 20.9 g of colorless liquid as a distillate cut of 131-133C/39 mmHg was collected. Yield: 94.6 %.1H NMR(400 MHz, CDCl3): 1.25 (t, 3H5 CH2CH3), 1.31 (s, 3H, CH3), 1.85-2.53 (m, 6H, 3CH2), 4.16 (q, 2H, OCH2). | |
82% | With potassium carbonate; In acetone;Reflux; Inert atmosphere; | To a stirred suspension of dry potassium carbonate (16.64 g, 120.4 mmol) in dry acetone (200 ml_) under argon was added ethyl 2- oxocyclopentanecarboxylate (9.40 g, 60.2 mmol) followed by methyl iodide (7.5 ml_, 120.4 mmol). The reaction was heated to reflux for 3 hours and then another portion of methyl iodide (7.5 ml_, 120.4 mmol) was added and the reaction was refluxed overnight. The cooled reaction mixture was filtered through a silica gel pad and the solid was washed with acetone (100 ml_ x 3). The combined filtrate was concentrated under reduced pressure and the residue dispersed in acetone (200 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1 -> 50/1 ) to afford the title compound as a colorless liquid (8.35 g, Yield: 82%). 1H NMR (400 MHz, CDCI3) δ 4.22-4.10 (m, 2H), 2.57-2.40 (m, 2H), 2.36-2.27 (m, 1 H), 2.11-2.00 (m, 1 H), 1.98-1.83 (m, 2H), 1.31 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H) ppm. |
82% | With potassium carbonate; In acetone;Reflux; | To a stirred suspension of dry potassium carbonate (16.64 g, 120.4 mmol) in dry acetone (200 mL) under argon was added ethyl 2- oxocyclopentanecarboxylate (9.40 g, 60.2 mmol) followed by methyl iodide (7.5 mL, 120.4 mmol). The reaction was heated to reflux for 3 hours and then another portion of methyl iodide (7.5 mL, 120.4 mmol) was added and the reaction was refluxed overnight. The reaction mixture was cooled and then filtered through a silica gel pad and the solid was washed with acetone (100 mL x 3). The organic phase was concentrated under reduced pressure and the residue dispersed in acetone (200 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1 -> 50/1 ) to afford the title compound as a colorless liquid (8.35 g, Yield: 82%). 1 H NMR (400 MHz, CDCI3) δ 4.22-4.10 (m, 2H), 2.57-2.40 (m, 2H), 2.36-2.27 (m, 1 H), 2.1 1 -2.00 (m, 1 H), 1 .98-1 .83 (m, 2H), 1 .31 (s, 3H), 1 .25 (t, J = 7.0 Hz, 3H) ppm. |
82% | With potassium carbonate; In acetone;Inert atmosphere; Reflux; | To a stirred suspension of dry potassium carbonate (16.64 g, 120.4 mmol) in dry acetone (200 mL) under argon was added ethyl 2-oxocyclopentanecarboxylate (9.40 g, 60.2 mmol) followed by methyl iodide (7.5 mL, 120.4 mmol). The reaction was heated to reflux for 3 hours and then another portion of methyl iodide (7.5 mL, 120.4 mmol) was added and the reaction was refluxed overnight. The reaction mixture was cooled and then filtered through a silica gel pad and the solid was washed with acetone (100 mL x 3). The organic phase was concentrated under reduced pressure and the residue dispersed in acetone (200 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1 -> 50/1) to afford the title compound as a colorless liquid (8.35 g, Yield: 82%). 1H NMR (400 MHz, CDCl3) δ 4.22-4.10 (m, 2H), 2.57-2.40 (m, 2H), 2.36-2.27 (m, 1 H), 2.11-2.00 (m, 1H), 1.98-1.83 (m, 2H), 1.31 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H) ppm. |
20% | With potassium carbonate; In acetone; at 20℃; for 1h; | Building block B26: 2-methyl-1 -(methylamino)cvclopentanecarbonitrile B26 a) ethyl 1 -methyl-2-oxocvclopentanecarboxylate To a stirred solution of ethyl 2-oxocyclopentanecarboxylate (1 .0 g, 6 mmol) in acetone (5 mL) was added potassium carbonate (2.65 g, 20 mmol) followed by methyl iodide (0.83 mL, 10 mmol) at room temperature. The reaction mixture was stirred for 1 h at rt. Once the starting material was consumed (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with water, dried over anhydrous Na2S04 and concentrated under reduced pressure. Purification by column chromatography (silica gel, 10% EtOAc in hexane) provided the title compound as a pale yellow liquid (0.2 g, 20%). 1 H NMR (400 MHz, CDCI3): δ 4.19-4.1 1 (m, 2H), 2.54-2.40 (m, 2H), 2.35-2.27 (m, 1 H), 2.09-2.02 (m, 1 H), 1.97-1.82 (m, 2H), 1.24 (s, 3H), 1 .22 (s, 3H); MS (ES-MS): m/z 171 .1 (M + 1 ). |
With sodium hydride; In tetrahydrofuran; for 12.5h;Inert atmosphere; Reflux; | General procedure: 1a-j were synthesized by Method A:2 To a solution of β-ketoester S1 (1.0 equiv) and NaH (2.4 equiv) in dry THF (0.5 M with respect to the S1) was added MeI (S2, 2.4 equiv) dropwise at 0 oC. The reaction mixture was stirred for an additional 0.5 h, and was then refluxed for 12 h under an inert nitrogen atmosphere before water was added to quench the reaction at 0 oC. The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using petroleum ether/EtOAc (50:1 to 15:1) to afford the desired α,α-disubstituted β-ketoesters 1a-j. | |
With sodium hydride; In tetrahydrofuran; at 0℃; for 12.5h;Inert atmosphere; Reflux; | General procedure: 1q, 1r, 1s were synthesized by Method C: To a solution of β-ketoester 1p or S4 (1.0 equiv) and NaH (1.2 equiv) in dry THF (0.5 M with respect to β-ketoester) was added MeI (S2, 1.1 equiv) dropwise at 0 oC. The reaction mixture was stirred for an additional 0.5 h, and was then refluxed for 12 h under an inert nitrogen atmosphere before water was added to quench the reaction at 0 oC. The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using petroleum ether/EtOAc (50:1 to 15:1) to afford the product.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate; In acetone; for 72h;Inert atmosphere; Reflux; | To a mixture of 1,3-diiodopropane (4.4 mL, 38.4 mmol) andethyl 2-oxocyclopentanecarboxylate (0.95 mL, 6.4 mmol) in acetone(16 mL) was added K2CO3 (2.3 g, 16.7 mmol), and the reactionmixture was heated under reflux for 3 days. The mixture was filtered,and the filtrate was then concentrated. The residue was purifiedby silica gel chromatography eluting with 0-50% EtOAc/hexanes to give 28 (1.44 g, 62%). 1H NMR (500 MHz, CDCl3) d4.25-4.10 (m, 2H), 3.16 (qt, J = 9.6, 6.8 Hz, 2H), 2.56-2.40 (m,2H), 2.34-2.24 (m, 1H), 2.08-1.86 (m, 5H), 1.82-1.72 (m, 1H),1.71-1.64 (m, 1H), 1.71-1.64 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H).LC/MS m/z: (M+H)+ calcd for C11H18IO3, 325.03; found 325.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 10 g (64.0 mmol) of ethyl 2-oxocyclopentanecarboxylate in ethanol (130 mL) was added 0.80 mL (9.6 mmol) of concentrated HCl and 5.8 g (96.0 mmol) of urea and the mixture was heated at 80 C. for 4 hours. After cooling to room temperature, a solid was filtered off and washed several times with cold diethyl ether. After drying under high vacuum, the white solid was dissolved in 1N NaOH (100 mL) and heated to 110 C. for 1 hour. The reaction was cooled to room temperature and the acidified with 3N HCl to pH 2 and a solid was collected by filtration. The solid was washed with cold diethyl ether and dried under high vacuum overnight (Procedure slightly modified from Eur. J. Med. Chem. 1980, 15, 317-322). After drying under high vacuum, the solid was dissolved in neat phosphorous oxychloride (55 mL) and heated to 120 C. for 1 hour. The reaction was cooled to room temperature and the excess phosphorous oxychloride was removed via rotary evaporation. The residue was partitioned between EtOAc (400 mL) and water (200 mL) and the organic phase was washed sequentially with saturated NaHCO3 (200 mL) and brine (200 mL). The organic phase was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (EtOAc/hexanes) to afford M-1 as a white solid. Data for M-1: LC/MS: rt=2.40 min; m/z (M+H)=189.1 found; 189.0 required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium acetate; sodium cyanoborohydride; In methanol; at 25℃; for 16h;4A molecular sieves; | 2-Oxo-cyclopentanecarboxylic acid ethyl ester (0.24 mL, 1.64 mmol) and C-<strong>[848497-98-3]cyclobutyl-methylamine hydrochloride</strong> (0.20 g, 1.64 mmol) were dissolved in methanol (8 mL). Sodium acetate (0.27 g, 3.28 mmol) was added followed by 4A powdered molecular sieves (0.20 g) and sodium cyanoborohydride (0.21 g, 3.28 mmol). The reaction was stirred at 25 0C for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The <n="189"/>organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, 2-(cyclobutylmethyl- amino)-cyclopentanecarboxylic acid ethyl ester (0.29 g, 1.30 mmol, 79%) as a clear oil. LC-MS (ESI) calcd for Ci3H23NO2 225.33, found 226.2 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | General procedure: In an open-air tube at room temperature (25 C) the corresponding 1,3-dicarbonyl compound(0.1 mmol) was added to a solution of organocatalyst (0.01 mmol, 10 mol %) in toluene (1 mL).After 5 min, di-tert-butylazodicarboxilate (0.11 mmol, 1.1 equiv.) was added in one portion and thereaction was then allowed to react for 15 h. After this time, water (5 mL) and ethyl acetate were added,and then the aqueous layer was re-extracted twice (2 x 10 mL). The combined organic phases weredried (MgSO4) and evaporated under reduced pressure. Finally, the reaction crude was purified bycolumn chromatography on silica gel or preparative TLC using hexane/ethyl acetate mixtures aseluent. The analytical data shown below correspond to those enantioenriched products (20% ee)as representative compounds. All the compounds are described in the literature. Therefore, only1H-NMR, MS (EI) and enantiomeric excess determination conditions are listed.(R)-Di-tert-butyl 1-[1-(ethoxycarbonyl)-2-oxocyclopentyl]hydrazine-1,2-dicarboxylate (13a) [35]: Colorlessoil; [alpha]D28 = -6.10 (c = 0.49, CHCl3, 91% ee); 1H-NMR (300 MHz, CDCl3) deltaH = 1.28 (t, J = 7.1 Hz,3H), 1.59-1.36 (m, 18H), 2.98-1.75 (m, 6H), 4.24 (m, 2H), 6.53 (br s, 1H) ppm; chiral HPLC analysis:Chiralcel IA column, Hexane/EtOH 96:04, flow rate = 0.7 mL/min, lambda= 210 nm, retention times: 9.9and 11.0 min. | |
73 mg | General procedure: In a tube, open to the atmosphere,in a thermostated bath (25 C) the requisite 1,3-dicarbonylcompound (0.2 mmol) was added to a solution oforganocatalyst II (0.002 mmol, 1 mol%) in Et2O (1 mL). After 5min, di-tert-butylazodicarboxylate (2a; 0.21 mmol, 1.05 equiv)was added in one portion and the reaction was then allowed toreact for 10 h. After this time, H2O (5 mL) and EtOAc wereadded, and then the aqueous layer was re-extracted with EtOAc(2 × 5 mL). The combined organic phases were dried (MgSO4),filtered and the solvent was evaporated under reduced pressure. Finally, the crude product was purified by flash chromatographyusing hexanes-EtOAc mixtures as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | at 160℃;Neat (no solvent); | General procedure: A mixture of equimolar amounts of 3-substituted-5-amino-1H-pyrazoles 1a-h (1 mmol) and 2-ethoxycarbonylcyclopentanone 11 (1 mmol) was thoroughly mixed at room temperature. The mixture was heated in an oil-bath at 160 C for 2-3 min (see Scheme 3), then cooled down to room temperature and the solid material treated with ethanol (8 mL). The solvent was removed and the products were recrystallized from ethanol to give compounds 13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | at 160℃;Neat (no solvent); | General procedure: A mixture of equimolar amounts of 3-substituted-5-amino-1H-pyrazoles 1a-h (1 mmol) and 2-ethoxycarbonylcyclopentanone 11 (1 mmol) was thoroughly mixed at room temperature. The mixture was heated in an oil-bath at 160 C for 2-3 min (see Scheme 3), then cooled down to room temperature and the solid material treated with ethanol (8 mL). The solvent was removed and the products were recrystallized from ethanol to give compounds 13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | General procedure: To a suspension of K2CO3 (2.5 mmol) and KI (0.35 mmol) in anhydrous acetone was added slowly a solution of ethyl-2-oxocyclopentanecarboxylate (1 mmol) in anhydrous acetone. After 10 min, a solution of bromoalkane (1.1 mmol) in acetone (10 ml) was added and the mixture was stirred at reflux. After 20 h, the reaction mixture was cooled to rt, diluted with ether (50 ml) and filtered over Celite pad. The filtrate was concentrated at reduce pressure, dilute with ether and washed with water and brine. The organic layer was dried over MgSO4 and evaporated under reduce pressure. The residue was purified by column chromatography (EtOAc/n-hexane) to give compound 7a-e in 94-99% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With sodium carbonate; In water; at 20℃; | [0588] A mixture of compound VII-2 (0.69 g, 10 mmol), compound VII-3 (1.56 g, 10 mmol), and Na2CO3 (1.06 g, 10 mmol) in water (25 ml) was stirred at rt overnight. And then the mixture was extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel with PE/EtOAc (4/1) to yield compound VII-4 (0.55 g, 24% yield). 1H NMR (CDCl3, 400 MHz) delta 7.13 (s, 1H), 6.63 (d, J=10 Hz, 1H), 5.88 (d, J=10 Hz, 1H), 5.39 (brs, 1H), 4.24-4.15 (m, 2H), 2.50-2.42 (m, 1H), 2.33-2.25 (m, 1H), 2.02-1.95 (m, 1H), 1.92-1.80 (m, 2H), 1.76-1.66 (m, 1H), 1.27-1.18 (m, 3H). |
20% | With sodium carbonate; In water; at 20℃; for 18h; | A mixture of propiolamide (62 g, 898.55 mmol), ethyl 2- oxocyclopentanecarboxylate (140.35 g, 898.55 mmol) and Na2C03 (94.3 g, 898.55 mmol) in water (2.25 L) was stirred at rt for 18 h. The mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried (Na2S04) and concentrated to afford ethyl l-(3-amino-3-oxoprop-l-enyl)-2-oxocyclopentanecarboxylate (40 g, 20%) as an off white solid. MS (LCMS) 226.3 [M+H]+. |
With sodium carbonate; In water; at 20℃; | A mixture of V-2 (0.69 g, 10 mmol), V-3 (1.56 g, 10 mmol), and Na2CO3(1.06 g, 10 mmol) in water (25 ml) was stirred at rt overnight. And then the mixture was extractedwith EtOAc (50 mLx3). The combined organic layer was washed with brine, dried over anhydrousNa2SO4 and concentrated. The residue was purified by flash chromatography on silica gel withPE/EtOAc (4/1) to yield VII-4 (0.55 g, 24% yield). ?H NMR (CDC13, 400 MHz) (57.13 (s, 1 H),6.63 (d, J= 10Hz, 1 H), 5.88 (d, J= 10Hz, 1 H), 5.39 (brs, 1H), 4.24-4.15 (m, 2H), 2.50-2.42 (m,1H), 2.33-2.25 (m, 1H), 2.02-1.95 (m, 1H), 1.92-1.80 (m, 2H), 1.76-1.66 (m, 1H), 1.27-1.18 (m,3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl acetamide; at 65℃; | General procedure: A solution of ethyl 2-oxocyclopentanecarboxylate 8a (0.50 mL, 3.4 mmol) and benzyl bromide (0.50 mL, 4.2 mmol) in N,N-dimethylacetamide (5 mL) is treated with powdered cesium carbonate (1.93 g, 5.9 mmol) and stirred at 65 C overnight. The mixture is cooled, filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography(hexanes/ethyl acetate gradient) affords ethyl 1-benzyl-2-oxocyclopentane carboxylate 8b as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl acetamide; at 65℃; | General procedure: A solution of ethyl 2-oxocyclopentanecarboxylate 8a (0.50 mL, 3.4 mmol) and benzyl bromide (0.50 mL, 4.2 mmol) in N,N-dimethylacetamide (5 mL) is treated with powdered cesium carbonate (1.93 g, 5.9 mmol) and stirred at 65 °C overnight. The mixture is cooled, filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography(hexanes/ethyl acetate gradient) affords ethyl 1-benzyl-2-oxocyclopentane carboxylate 8b as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl acetamide; at 65℃; | General procedure: A solution of ethyl 2-oxocyclopentanecarboxylate 8a (0.50 mL, 3.4 mmol) and benzyl bromide (0.50 mL, 4.2 mmol) in N,N-dimethylacetamide (5 mL) is treated with powdered cesium carbonate (1.93 g, 5.9 mmol) and stirred at 65 C overnight. The mixture is cooled, filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography(hexanes/ethyl acetate gradient) affords ethyl 1-benzyl-2-oxocyclopentane carboxylate 8b as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium acetate; sodium nitrite; In water; at 0 - 20℃; for 2.25h; | To a stirring mixture of <strong>[96558-73-5]2-bromo-3-chloroaniline</strong>(20 mmol) in 1M HCl(25 mL)and water(5 mL) at 0 oc was added NaN02(1.38 g,20 mmol) in water(20 mL),CH3C00Na(9.23 g,112 mmol) in water(25 mL) and ethyl 2-oxocyclopentane carboxylate(3.0 mL,20 mmol) in sequence. The reaction mixture was stirred for 15 min at 0 oc thenwarmed to 20 oc over 2h and extracted with CH2Ch,dried over MgS04,filtered and concentrated in vacuo to give the title compound as a red oil in 7.1 g(90% crude). | |
With hydrogenchloride; sodium acetate; sodium nitrite; In water; at 0℃; for 0.25h; | Step A. Preparation of 5-(2-(2-bromo-3-chlorophenyl)hydrazono)-6-ethoxy-6-oxohexanoic acid To a stirring mixture of <strong>[96558-73-5]2-bromo-3-chloroaniline</strong> (4.1 g, 20 mmol) in 1M HCl (25 mL) and water (5 mL) at 0 C. was added NaNO2 (1.38 g, 20 mmol) in water (20 mL), NaCH3COOH (9.23 g, 112 mmol) in water (25 mL) and ethyl 2-oxocyclopentane carboxylate (3.0 mL, 20 mmol) in sequence. The reaction mixture was stirred for 15 min at 0 C. then warmed to 20 C. over 2 h and extracted with CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a red oil in 7.0 g (90% crude). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With C70H66N8O8; In methanol; at -60℃; for 24h; | General procedure: In a 10 mL round-bottomed flask, the 1,3-dicarbonyl compound 2 (0.24 mmol) was added to the agitated solution of catalyst 1a (0.01 mmol) in 1 mL THF at -78 C and stirred for 15 min, compound 3 (0.20 mmol) in 1 mL THF was added. The reaction was monitored by TLC and condensed under reduced pressure and subjected to flash chromatography column to give the pure product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; potassium iodide; In dimethyl sulfoxide; at 100℃; for 12h; | (1) Ethyl 2-oxocyclopentanecarboxylate (940 mg, 6 mmol) and 2-bromoacetaldehyde ethylene acetal(2 g, 12 mmol) were dissolved in 20 ml of dimethylsulfoxide,Potassium carbonate (2.1 g, 12 mmol) and potassium iodide (996 mg, 6 mmol) were added sequentially. The above reaction was stirred at 100 C for 12 hours. The mixture was extracted with ethyl acetate (20 ml) three times. The combined organic layers were washed successively with saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesium sulfate,And then dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to remove the solvent. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20: 1 by volume) to obtain 940 mg of a colorless oil. Identified as Compound 2 in 65% yield. The correlation analysis data are as follows: |
64% | With potassium carbonate; potassium iodide; In dimethyl sulfoxide; at 100℃; for 12h;Inert atmosphere; | To a solution of ethyl 2-oxocyclopentanecarboxylate (2.0 g, 12.8 mmol)and 2-(bromomethyl)-1,3-dioxolane (4.2 g, 25.6mmol) in DMSO (40ml) under Ar wasadded K2CO3 (3.5g,25.6 mmol) and KI (2.1 g, 12.8 mmol ),the mixture was stirred at 100 C for 12h. After being poured to cold ether/water, the mixture was thoroughly extracted with EtOAc, washed sequentially with saturated aqueous sodium carbonate solution, water, and brine, and dried over Na2SO4. Filtration and concentration afforded the crude product. Purification by column chromatography using EtOAc/Petroleumether (1:10) gave 5(2.0 g, 64%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.9% | To a solution of 74 mg of NaOEt in 1 mL of EtOH is added 180 mg of 3-amino-3-imino-propanoic ethyl ester hydrochloride at room temperature, followed by addition of 200 mg of 2-oxo- cyclopentanecarboxylic acid ethyl ester. The reaction mixture is heated to reflux for 2 h. A total of 860 mg of 20% NaCH aq. solution is added under reflux. The mixture is refluxed for another 1 h, and then cooled to room temperature. It is adjusted to pH = 5-6. The product is precipitated as solid. It is collected by filtration and washed with 1 mL of water twice. A total of 200 mg (yield 82.9%) of the desired product is obtained after being dried at 60C in vacuum oven. ?H NMR (400 MHz, D20 with NaCD): 8 2.68 (t, 2H), 2.61 (t, 2H), 1.95 (m, 2H); ?3C NMR (100 MHz, D20 with NaOD): 8 176.77, 173.75, 165.36, 157.06, 147.52, 122.96, 110.19, 33.51, 28.31, 22.42; MS (m/z+1): 223.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diphenyl hydrogen phosphate; silver carbonate; In hexane; at 40℃; for 36.0h; | General procedure: A dry single-necked flask was charged with 2-alkynylaldehyde 1 (0.4 mmol, 1 equiv), ketone 2 (0.8 mmol, 2 equiv), and diphenylphosphate (10 mg, 0.04 mmol, 10 mol %) in hexane (2.4 mL), and silver carbonate (2.75 mg 0.01 mmol, 2.5 mol%) was added. The mixture was heated to 40 C and stirred until the 2-alkynylaldehyde was completely consumed (progress of the reaction was monitored by TLC). The hexane was evaporated and the mixture was diluted in EtOAc (50 mL) and washed three times with water. The organic layer was dried over anhydrous Na2SO4 and filtered. After evaporating the EtOAc, the crude product was dissolved in dichloromethane and purified by column chromatography (silica gel; pentane/EtOAc, 96:4) to give pure 1H-isochromenes 3 as yellow oils or as colorless solids. In the case of phenylacetone and 2-phenylcyclohexanone as ketone nucleophiles, the crude product was directly purified by flash chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 18-crown-6 ether; potassium carbonate; In acetonitrile; at 50℃; for 8h; | General procedure: A suspension of 0.78 g (5 mmol) of ethyl 2-oxocyclopentanecarboxylate 1a, 0.55 g (5 mmol) of <strong>[10061-02-6](E)-1,3-dichloropropene</strong> 2, 0.83 g (6 mmol) of K2CO3, and 0.02 g of 18-crown-6 in 8 mL of acetonitrile was stirred at 50C for 8 h (GLC monitoring). The reaction mixture was filtered, the precipitate was washed with ethyl acetate, and the combined organic layers were concentrated. The reaction product was purified by column chromatography (SiO2, hexane-diethyl ether, 9 : 1 ? 7 : 3). Yield 0.97 g (84%). |
84% | With 18-crown-6 ether; potassium carbonate; In acetonitrile; at 50℃; for 8h; | A suspension of 0.78 g (5 mmol) of ethyl 2-oxocyclopentane-1-carboxylate(3), 0.55 g (5 mmol) of <strong>[10061-02-6](E)-1,3-dichloropropene</strong>(4), 0.83 g (6 mmol) of K2CO3, and 0.02 g of18-crown-6 in 8 mL of acetonitrile was stirred at 50Cuntil the conversion of 3 was complete (8 h, GCmonitoring). The mixture was filtered, the precipitatewas washed with ethyl acetate, the filtrate was combinedwith the washings and evaporated, and the residuewas purified by silica gel column chromatographyusing hexane-diethyl ether (9 : 1 to 7 : 3) as eluent.Yield 0.97 g (84%). 1H NMR spectrum, delta, ppm: 1.26 t(3H, CH3CH2, J = 7 Hz), 1.87-2.10 m (3H, CH2),2.22-2.52 m (4H, CH2), 2.62-2.70 m (1H, CH2),4.17 q (2H, CH2O, J = 7 Hz), 5.83 d.t (1H, =CHCH2,J = 13.2, 7.6 Hz), 6.05 d (1H, =CHCl, Jtrans = 13.2 Hz).13C NMR spectrum, deltaC, ppm: 13.99 (CH3CH2), 19.42 (C4), 32.24 (C5), 34.49 (=CHCH2), 37.84 (C3), 59.56(C1), 61.57 (CH2O), 120.68 (=CHCl), 128.29(=CHCH2), 170.47 (C=O), 214.10 (C2). Mass spectrum,m/z (Irel, %): 230 (6) [M]+, 157 (37), 121 (100),114 (36), 93 (34), 79 (32), 77 (24), 75 (21), 67 (23), 65(35), 39 (31). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.8 g | To a stirred suspension of <strong>[111721-75-6]2-bromo-3-fluoroaniline</strong> (CAS 1 1 1721 -75-6, 40.0 g, 210 mmol, 1 .00 eq.) in an aqueous hydrochloric acid solution (53.0 ml_ concentrated hydrochloric acid in 339 ml_ water, 630 mmol, 3.00 eq.) was added a 2.5 M solution of sodium nitrite in water (83.9 ml_, 210 mmol, 1 .00 eq.) via dropping funnel at a temperature of 0 <C. After complete addition, a 4.5 M sodium acetate solution (262 ml_, 1.18 mol, 5.62 eq.) in water was added via dropping funnel, followed by addition of ethyl 2-oxocyclopentanecarboxylate (CAS 611 -10-9, 31 .0 ml_, 210 mmol, 1 .00 eq.). The resulting yellow suspension was maintained at 0 for 15 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was extracted four times with dichloromethane (200 ml_ each), and the combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure to give the crude corresponding intermediate hydrazone as an orange solid. The residue was re-suspended in ethanol (210 ml_, 1 .00 M), cooled to 0 , followed by slow addition of concentrated sulfuric acid (27.9 ml_, 525 mmol, 2.50 eq.). The dark red solution was heated at 95 for 13 days, cooled to room tempera ture and partially concentrated under reduced pressure. The dark brown solution was poured onto ice/water (500 ml_) and extracted thrice with dichloromethane (500 ml_ each). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (500 ml_), dried (magnesium sulfate), filtered and concentrated under reduced pressure to give a brown solid. The residue was purified by flash column chromatography (20% ethyl acetate/hexanes) and then recrystallised from hot 10% ethyl acetate/hexanes to give the title compound as a white fluffy solid (40.8 g). (2586) LC-MS (Method 3): Rt = 1 .62 min; MS (ESIpos): m/z = 388 [M+H]+ (2587) 1 H NMR (300 MHz, Chloroform-d) d [ppm]: 8.81 (0.78), 7.63 (1 .03), 6.98 (1 .02), 4.44 (2.08), 4.08 (2.08), 3.36 (2.07), 2.66 (2.08), 1 .44 (3.27), 1 .20 (3.61 ). | |
40.8 g | To a stirred suspension of <strong>[111721-75-6]2-bromo-3-fluoroaniline</strong> (CAS 1 1 1721 -75-6, 40.0 g, 210 mmol, 1 .00 eq.) in an aqueous hydrochloric acid solution (53.0 ml_ concentrated hydrochloric acid in 339 ml_ of water, 630 mmol, 3.00 eq.) was added a 2.5 M solution of sodium nitrite in water (83.9 ml_, 210 mmol, 1 .00 eq.) via dropping funnel at a temperature of 0 . After complete addition, 4.5 M sodium acetate (262 ml_, 1 .18 mol, 5.62 eq.) in water was added via dropping funnel, followed by addition of ethyl 2-oxocyclopentanecarboxylate (CAS 61 1 -10-9, 31 .0 ml_, 210 mmol, 1 .00 eq.). The resulting yellow suspension was maintained at 0 for 15 minutes and was then warmed to room temperature and stirred for 2 hours. The reaction mixture was extracted four times with dichloromethane (200 ml_ each) and the combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure to give the crude hydrazone as a orange solid. The residue was re-suspended in ethanol (210 ml_, 1 .00 M), cooled to 0 , followed by slow addition of co ncentrated sulfuric acid (27.9 ml_, 525 mmol, 2.50 eq.). The dark red solution was heated to 95 C for 13 days, cooled to room temperature and partially concentrated under reduced pressure. The dark brown solution was poured onto ice/water (500 ml_) and extracted with dichloromethane thrice (500 ml_ each). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (500 ml_), dried (magnesium sulfate), filtered and concentrated under reduced pressure to give a brown solid. The residue was purified by flash column chromatography (20% ethyl acetate/hexanes) and was then recrystallised from hot 10% ethyl acetate/hexanes to give the title compound as a white fluffy solid (40.8 g).LC-MS (Method 3): Rt= 1 .62 min; MS (ESIpos): m/z = 388 [M+H]+1H NMR (300 MHz, Chloroform-d) d [ppm]: 8.81 (0.78), 7.63 (1 .03), 6.98 (1 .02), 4.44 (2.08), 4.08 (2.08), 3.36 (2.07), 2.66 (2.08), 1 .44 (3.27), 1 .20 (3.61 ). | |
40.8 g | To a 0 T stirred suspension of 2-bromo-3-fluoroani line (40.0 g, 210 mmol, 1.00 eq.) in an aqueous hydrochloric acid solution (53.0 ml_ concentrated hydrochloric acid in 339 ml_ water, 630 mmol, 3.00 eq.) was added a 2.5 M solution of sodium nitrite in water (83.9 ml_, 210 mmol, 1.00 eq.) via dropping funnel. After complete addition, 4.5 M sodium acetate (262 ml_, 1.18 mol, 5.62 eq.) in water was added via dropping funnel, followed by addition of ethyl 2- oxocyclopentanecarboxylate (31.0 ml_, 210 mmol, 1.00 eq.). The resulting yellow suspension was maintained at 0 for 15 minutes and then warm ed to room temperature and stirred for 2 hours. The reaction mixture was extracted with dichloromethane (4 x 200 ml_) and the combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure to give the crude hydrazone as a orange solid. The residue was re suspended in ethanol (210 ml_, 1.00 M), cooled to 0, followed by slow addition of concentrated sulfuric acid (27.9 ml_, 525 mmol, 2.50 eq.). The dark red solution was heated at 95 for 13 days, cooled to room temperature and p artially concentrated under reduced pressure. The dark brown solution was poured onto ice/water (500 ml_) and extracted with dichloromethane (3 x 500 ml_). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (500 ml_), dried (magnesium sulfate), filtered and concentrated under reduced pressure to give a brown solid. The residue was purified by flash column chromatography (20% ethyl acetate/hexanes) and then recrystallised from hot 10% ethyl acetate/hexanes to give the title compound as a white fluffy solid (40.8 g). LC-MS (Method 3): Rt = 1.62 min; MS (ESIpos): m/z = 388 [M+H]+ 1H NMR (300 MHz, Chloroform-d) d [ppm]: 8.81 (0.78), 7.63 (1.03), 6.98 (1.02), 4.44 (2.08), 4.08 (2.08), 3.36 (2.07), 2.66 (2.08), 1.44 (3.27), 1.20 (3.61). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of <strong>[96558-73-5]2-bromo-3-chloro-aniline</strong> (CAS 96558-73-5, 50 g, 242 mmol) in aqueous hydrochloric acid (2.5 M, 500 ml_) was added sodium nitrite (17 g, 247 mmol) in water (100 ml_) drop-wise at 0 O over 0.5 hour. After add ition, the mixture was stirred at 0 for 0.5 hour. Then sodium acetate (84 g, 1.02 mol) in water (500 ml_) was added into the reaction mixture, followed by ethyl 2-oxocyclopentanecarboxylate (40 g, 256 mmol). The mixture was stirred at 0 6 for 0.5 hour and then it was warmed to 25 O and stirred for 1 hour. Dichloromethane (800 ml_) was added into the reaction mixture. Two layers were separated and the aqueous layer was extracted with dichloromethane (300 ml_ x 3). The combined organic layer was washed with water (300 ml_ x 3), dried over sodium sulfate, filtered and concentrated by evaporation in vacuum to give 5-((2-bromo-3-chlorophenyl)diazenyl)-6-ethoxy- 6-oxohexanoic acid (108 g, crude) as black oil, which was used directly for the next step. | ||
To a stirred solution of <strong>[96558-73-5]2-bromo-3-chloro-aniline</strong> (CAS 96558-73-5, 50 g, 242 mmol) in aqueous hydrochloric acid (2.5 M, 500 ml_) was added sodium nitrite (17 g, 247 mmol) in water (100 ml_) drop-wise at 0 over 0.5 hour. After add ition, the mixture was stirred at 0 for 0.5 hour. Then sodium acetate (84 g, 1.02 mol) in water (500 ml_) was added into the reaction mixture, followed by ethyl 2-oxocyclopentanecarboxylate (40 g, 256 mmol). The mixture was stirred at 0 6 for 0.5 hour and then it was warmed to 25 and stirred for 1 hour. Dichloromethane (800 ml_) was added into the reaction mixture. Two layers were separated and the aqueous layer was extracted with dichloromethane (300 ml_ x 3). The combined organic layer was washed with water (300 ml_ x 3), dried over sodium sulfate, filtered and concentrated by evaporation in vacuum to give 5-((2-bromo-3-chlorophenyl)diazenyl)-6-ethoxy- 6-oxohexaneoic acid (108 g, crude) as black oil, which was used directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | To a stirred solution of <strong>[111721-75-6]2-bromo-3-fluoroaniline</strong> (CAS 111721-75-6, 9.50 g, 50.0 mmol, 1.00eq.) in an aqueous hydrochloric acid solution (12.5 mL conc. HCI in 80.0 mL of water, 150mmol, 3.00 eq.) was added dropwise a 2.5 M solution of sodium nitrite (20.0 mL, 50.0 mmol,1 .00 eq.) in water at a temperature of 0C. After complete addition, a 4.5 M solution of sodiumacetate in water (62.4 mL, 281 mmol, 5.62 eq.) was added via dropping funnel, followed bydropwise addition of ethyl-2-oxocyclopentanecarboxylate (CAS 611-10-9, 7.40 mL, 50.0 mmol,1.00 eq.). The resulting yellow suspension was maintained at 0 C for 15 minutes and thenwarmed to room temperature and stirred for 2 hours. The reaction mixture was extracted thricewith dichloromethane (100 mL each) and the combined organic extracts were dried overmagnesium sulfate, filtered and concentrated under reduced pressure to give the crudehydrazone as a red oil (18.1 g). The residue was dissolved in ethanol (50.0 mL, 1.00 M), afterwhich sulfuric acid (6.63 mL, 125 mmol, 2.50 eq.) was added dropwise. The dark orangesolution was heated at 95 C for 6 days and then cooled to room temperature. The dark brownsolution was poured onto ice/water (200 mL) and extracted thrice with dichloromethane (200mL each). The combined organic extracts were washed with saturated aqueous bicarbonatesolution (200 mL), dried over magnesium sulfate, filtered and concentrated under reducedpressure to give a brown solid. The residue was purified by flash column chromatography (0-30% ethyl acetate/hexane gradient) and then recrystallized from hot ethyl acetate/hexane (9:1)to give the title compound as a light yellow solid (8.35 g, 42%). Rf = 0.22 (15% ethyl acetate/hexane, UV). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | a, 1 ml of 2-p-bromomethylphenylpropionic acid was dissolved in 800 ml of DMF, and then 2-ethoxycarbonyl was added thereto in turn.1.025 ml of cyclopentanone ethyl ester and 1.025 ml of sodium hydroxide, and reacted under normal pressure for 8 hours to obtain a first intermediate product;b. Pour the first intermediate product in the above step a into 300 ml of water, and then dilute the pH of the solution with dilute HCL.Adjust to 5-6, extract with 900ml of toluene three times (300ml each time), and then use 1200ml of water three times (400ml each time)Washing, liquid separation, oil layer, to obtain a light yellow oil A;c. Add 300 ml of industrial HCL to the pale yellow oil A obtained in the above step b, and reflux for 10 hours.After cooling to normal temperature, dilute it in 300 ml of water, then extract it with 900 ml of toluene three times (300 ml each time), then use water.Wash until the pH of the solution is 5-6, separate the liquid, and take the oil layer to obtain a brown liquid;d. The brown liquid obtained in the above step c is subjected to vacuum distillation, and the fraction of 220-250 C is collected to obtain a lightYellow oil B;e, adding ethanol to the pale yellow oil B obtained in the above step d, stirring and dissolving, and then being placed in a refrigerator for refrigerationAfter 5 hours or more, after taking out, it was filtered and air-dried to obtain 210 g of loxoprofen acid solid, and the yield was 85%;f, taking 123 g (0.5 ml) of loxoprofen acid solid, adding 100 ml of acetone thereto and stirring and stirring, maintaining the temperature of 0-5C, into which 67g of NaOH solution with a concentration of 30% was added, and the mixture was dripped in 30 minutes. After the completion of the dropping, the solution was kept for 1 hour, and then taken out for filtration and air-dried.The final product was obtained as a white solid, 135 g of loxoprofen sodium solid in a yield of 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.8% | With sodium carbonate; In water; at 0 - 20℃; for 6h; | Ethyl 2-oxocyclopentanecarboxylate (150 g, 960 mmol) was added to the stirred solution of propiolamide (113 g, 1633 mmol) and Na2C03 (112 g, 1056 mmol) in water (1500 mL) at 0 C and the mixture was stirred at RT for 6 h. The reaction mixture was diluted with water and extracted with DCM, the organic layer was washed with brine solution, dried over anhydrous Na2S04, filtered and filtrate was evaporated under reduced pressure to get crude product. The resulted crude compound was purified by flash column chromatography (100-200 silica mesh, eluent was 80% EtOAc in pet ether) to obtained (E)-ethyl l-(3-amino-3-oxoprop-l-en-l-yl)-2- oxocyclopentanecarboxylate (150 g, 68.8% yield) as an off-white solid. 1H NMR (400 MHz, CDCl ): d 6.58 (d, J= 10.4 Hz, 1H), 5.97 (dd, /= 2.0, 10.0 Hz, 1H), 5.89 (brs, 2H), 4.26 (q, J = 4.8 Hz, 2H), 2.50-2.42 (m, 1H), 2.26-2.19 (m, 1H), 2.08-1.88 (m, 3H), 1.76-1.72 (m, 1H), 1.31 (t, /= 7.2 Hz, 3H). LCMS (ES) m/z 226.23 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of ethyl 2-oxocyclopentane-l -carboxylate (3.56 mL, 26.7 mmol, 1 equiv.) in acetone (62 mL) at r.t. was rapidly added potassium carbonate (8.43 g, 60.4 mmol, 2.25 equiv.) and potassium iodide (1.43 g, 8.55 mmol, 0.32 equiv.). After stirring for 10 min, a solution of 7-bromohept-l-ene (4.23 mL, 26.9 mmol, 1.01 equiv.) in acetone (17 ml) was added and the reaction was refluxed for 23 h. Diethyl ether (100 mL) was added, the mixture was filtered on a Celite pad and the solvent was evaporated. The residue was diluted with ether, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl l-(hept-6-en-l-yl)-2-oxocyclopentane-l -carboxylate as an oil (6.37 g, 88 % purity, 92 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; In acetonitrile; at 70℃; for 16h; | To a solution of Example 51b (538 g, 2.85 mol), Example 51c (296.4 g, 1.9 mol) and K2C03 (522 g, 3.78 mol) in ACN (3 L) was stirred at 70C for 16 h. The reaction was filtered and concentrated, the residue was purified by column chromatography (silica gel, Petroleum Ether/EtOAc = 20/1) to give the product Example 51d (150 g, yield 46%) as yellow oil (NOTE: very weak UV spot is desired; strong UV spot is incorrect). LCMS [M+l]+ = 174.1. *HNMR (400 MHz, CDCl3) d 4.14 (m, 2H), 2.52-2.41 (m, 2H), 2.34-2.24 (m, 1H), 2.08-2.00 (m, 1H), 1.95-1.81 (m, 2H), 1.23 (t, J= 7.2 Hz, 3H). |
Tags: 611-10-9 synthesis path| 611-10-9 SDS| 611-10-9 COA| 611-10-9 purity| 611-10-9 application| 611-10-9 NMR| 611-10-9 COA| 611-10-9 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
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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