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CAS No. : | 20826-94-2 | MDL No. : | MFCD00044715 |
Formula : | C9H14O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PJMKFKUFBDXYEC-UHFFFAOYSA-N |
M.W : | 170.21 | Pubchem ID : | 2723663 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.78 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 44.75 |
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) : | -6.9 cm/s |
Log Po/w (iLOGP) : | 2.19 |
Log Po/w (XLOGP3) : | 0.62 |
Log Po/w (WLOGP) : | 1.31 |
Log Po/w (MLOGP) : | 0.9 |
Log Po/w (SILICOS-IT) : | 1.89 |
Consensus Log Po/w : | 1.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.02 |
Solubility : | 16.2 mg/ml ; 0.0951 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.11 |
Solubility : | 13.4 mg/ml ; 0.0785 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.81 |
Solubility : | 2.65 mg/ml ; 0.0156 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.43 |
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 |
---|---|---|
With sulfuric acid;Reflux; | To a solution of 2-(2-oxocyclopentyl)acetic acid (23.6 g, 166 mmol) in absolute ethanol (400 mL) was added H2SO4 (16.28 g, 166 mmol). The resulting solution was refluxed overnight. The reaction mixture was concentrated and ice-water (200 mL) was added. The aqueous mixture was extracted with DCM (3 x 200 mL). The combined organic layers were washed with H2O (300 mL) and brine (300 mL), dried over Na2SO4, decanted, concentrated, and dried under reduced pressure to afford the title compound as a slightly yellowish liquid (27.2 g). LCMS m/z = 171.3 [M + H]+; 1H NMR (400 MHz, CDCl3) delta ppm 1.19 (t, J = 7.14 Hz, 3H), 1.50-1.62 (m, IH), 1.65-1.80 (m, IH), 1.92-2.02 (m, IH), 2.08-2.17 (dd, J = 16.7, 8.86 Hz, IH), 2.19-2.29 (m, 2H), 2.30-2.44 (m, 2H), 2.65 (dd, J = 15.12, 2.6 Hz, IH), 4.07 (q, J = 7.14 Hz, 2H). | |
With sulfuric acid;Reflux; | Step C: Preparation of Ethyl 2-(2-Oxocyclopentyl)acetate. To a solution of 2-(2-oxocyclopentyl)acetic acid (23.6 g, 166 mmol) in absolute ethanol(400 mL) was added H2SO4 (16.28 g, 166 mmol). The resultant solution was heated under reflux overnight. The reaction mixture was concentrated and the liquid residue was added into ice- water (200 mL). The aqueous mixture was extracted with DCM (3 x 200 mL). The combined organic layers were washed with H2O (300 mL), brine (300 mL), dried over Na2SO4, decanted, concentrated and dried under vacuum to afford the title compound as a light yellow liquid (27.2 g). LCMS m/z = 171.3 [M+H]+; 1H NMR (400 MHz, CDCl3) delta ppm 1.19 (t, J = 7.14 Hz, 3 H), 1.50-1.62 (m, 1 H), 1.65-1.80 (m, 1 H), 1.92-2.02 (m, 1 H), 2.12 (dd, / = 16.7, 8.86 Hz, 1 H), 2.19-2.29 (m, 2 H), 2.30-2.44 (m, 2 H), 2.65 (dd, J = 15.12, 2.6 Hz, IH), 4.07 (q, J = 7.14 Hz, 2H). | |
With sulfuric acid;Reflux; | Step C: Preparation of Ethyl 2-(2-Oxocyclopentyl)acetate.To a solution of 2-(2-oxocyclopentyl)acetic acid (23.6 g, 166 mmol) in absolute ethanol (400 mL) was added H2S04 (16.28 g, 166 mmol). The resultant solution was heated under reflux overnight. The reaction mixture was concentrated and the liquid residue was added into ice- water (200 mL). The aqueous mixture was extracted with DCM (3 x 200 mL). The combined organic layers were washed with H20 (300 mL), brine (300 mL), dried over Na2S04, decanted, concentrated and dried under vacuum to afford the title compound as a light yellow liquid (27.2 g). LCMS m/z = 171.3 [M+H]+; NMR (400 MHz, CDC13) delta ppm 1.19 (t, J= 7.14 Hz, 3 H), 1.50-1.62 (m, 1 H), 1.65-1.80 (m, 1 H), 1.92-2.02 (m, 1 H), 2.12 (dd, J = 16.7, 8.86 Hz, 1 H),2.19-2.29 (m, 2 H), 2.30-2.44 (m, 2 H), 2.65 (dd, J= 15.12, 2.6 Hz, 1H), 4.07 (q, J= 7.14 Hz,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20 - 165℃; Hydrogenation.Reaktion ueber mehrere Stufen; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Ethyl bromoacetate (38.3 cm3) was added over 0.25 h to astirred solution of 1-pyrrolidinycyclopentene in benzene(15Ocm3) heated under reflux. The mixture was heated underreflux for a further 1 hr then cooled and evaporated in vacuo. The residue was dissolved in ethanol (100 cm3) containing water (20 cm3) and the resulting solution was heated under reflux for 2 hr, then evaporated to leave a red coloured oil. The oil was diluted with water (100cm3) and then extracted with ether (3x180 cm3). The combined ether extracts were washed successively with 2M-hydrochloric acid (100 cm3), 5% sodium hydrogen carbonate solution (100 cm3) and water (30 cm3), then dried and evaporated. Distillation of the residue gave the keto-ester (19.2 g,38%) as a colourless liquid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate In ethanol at 0 - 5℃; for 1h; Yield given. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With toluene-4-sulfonic acid; In benzene;Reflux; Dean-Stark; | A solution of ethyl 2-oxocyclopentylacetate (7.7 g) in ethyleneglycol (3.23 g) and benzene (20 cm3) containing p-toluenesulphonic acid (25 mg) was heated under reflux for 3 hr using a Dean and Stark separator. The solution was washed with S% sodium hydrogen carbonate solution, then dried and evaporated to leave the corresponding dioxolane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
300 mg | With water; potassium hydroxide; In methanol; at 60℃; for 3h; | Description 402-(2-Oxocyclopentyl)acetic acid (D40)6OHThe mixture of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> (600 mg) and potassium hydroxide (396 mg) inmethanol (20 mL) and water (20 mL) was stirred at 60C for 3 hours and then concentrated undervacuum. The residue was acidified with 2 M HC1 (aq.) to pH = 1 and extracted with EtOAc (10mL). The organic layer was dried and concentrated under vacuum to afford the title compound (300mg) as oil. MS (ESI): C7H,003 requires 142; found 141 [M-H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In benzene; for 24h;Heating / reflux; | A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2- oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24h After this time, the benzene was removed under distillation. Then, 60ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115C for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound.1H NMR (acetone-d6) delta 9.76 (br s, 1H), 7.34 (dd, 1H), 7.03 (d, 1H), 6.78 (td, 1H), 4.14 (q, 2H), 3.57 (m, 1H), 2.85-2.55 (m, 5H), 2.15 (m, 1H), 1.22 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In xylene; for 20h;Heating / reflux; | DP EXAMPLE 17A; Alternative procedure for (+/-)- f5-bromo-4-(4-chlorobenzyl)-7-fluoro-l,2,3,4- tetrahvdrocvclopenta[b]indol-3-yllacetic acid (Example 17, Step 4)Step 1: (+/-)-7-fluoro-l,2,3,4-tetrahvdrocvclopenta|T3lindol-3-yl)acetic acid dicvclohexylamine(OCTLV) saltA 0.526 M solution of 2-bromo-4-fiuoroanilme in xylene along with ethyl (2- oxocyclopentyl) acetate (1.5 eq) and sulfuric acid (0.02 eq) was heated to reflux for 20 hours. Water was azeotropically removed with a Dean-Stark apparatus. The reaction was followed by NMR and after 20 hours, an 80-85% conversion to the desired irnine intermediate was generally observed. The reaction mixture was washed with IM sodium bicarbonate (0.2 volumes) for 15 minutes and the organic fraction was evaporated. The remaining syrup was distilled under vacuum (0.5 mm Hg). Residual xylenes distilled at 3O0C, then excess ketone and unreacted aniline were recovered in the 50-1100C range; the imine was recovered in the 110-18O0C fraction as a light brown clear liquid with 83% purity.The imine intermediate was then added to a degased mixture of potassium acetate (3 eq), tetra-n-butylammonium chloride monohydrate (1 eq), palladium acetate (0.03 eq) and N5N- EPO <DP n="80"/>dimethylacetamide (final concentration of imine = 0.365 M). The reaction mixture was heated to 115C for 5 hours and allowed to cool to room temperature. 3N KOH (3 eq) was then added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (1.0 volume), washed with toluene (3x0.75 volume). The aqueous phase was acidified to pH 1 with 3N HCl and extracted with tertbutyl methyl ether (2x0.75 volume). The combined organic fractions were washed with water (0.75 volume). To the clear light brown solution was added dicyclohexylamine (1 eq) and the solution was stirred at room temperature for 16 hours. The salt was filtered, washed with ethyl acetate, tertbutyl methyl ether and allowed to dry to give the title compound. Assay: 94 A%. IH NMR (500 mHz, CDC13) : delta 9.24 (s, IH), 7.16-7.08 (m, 2H), 6.82 (t, IH), 6.2 (br, 2H), 3.6-3.5 (m, IH), 3.04-2.97 (m, 2H), 2.88-2.70 (m, 3H), 2.66 (dd, IH), 2.45-2.37 (m, IH), 2.13-2.05 (m, 2.05), 1.83 (d, 4H), 1.67 (d, 2H), 1.55-1.43 (m, 4H), 1.33-1.11 (m, 6H). | |
sulfuric acid; In xylene; for 20h;Heating / reflux; | A 0.526 M solution of 2-bromo-4-fluoroaniline in xylene along with <strong>[20826-94-2]ethyl (2-oxocyclopentyl)acetate</strong> (1.5 eq) and sulfuric acid (0.02 eq) was heated to reflux for 20 hours. Water was azeotropically removed with a Dean-Stark apparatus. The reaction was followed by NMR and after 20 hours, an 80-85% conversion to the desired imine intermediate was generally observed. The reaction mixture was washed with IM sodium bicarbonate (0.2 volumes) for 15 minutes and the organic fraction was evaporated. The remaining syrup was distilled under vacuum (0.5 mm Hg). Residual xylenes distilled at 300C, then excess ketone and unreacted aniline were recovered in the 50-1100C range; the imine was recovered in the 110-1800C fraction as a light brown clear liquid with 83% purity.The imine intermediate was then added to a degased mixture of potassium acetate (3 eq), tetra-n-butylammonium chloride monohydrate (1 eq), palladium acetate (0.03 eq) and N,N-dimethylacetamide (final concentration of imine = 0.365 M). The reaction mixture was heated to 115C for 5 hours and allowed to cool to room temperature. 3N KOH (3 eq) was then added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (1.0 volume), washed with toluene (3x0.75 volume). The aqueous phase was acidified to pH 1 with 3N HCl and extracted with tertbutyl methyl ether (2x0.75 volume). The combined organic fractions were washed with water (0.75 volume). To the clear light brown solution was added dicyclohexylamine (1 eq) and the solution was stirred at room temperature for 16 hours. The salt was filtered, washed with ethyl acetate, tertbutyl methyl ether and allowed to dry to give the title compound. Assay: 94 A%., 1H NMR (500 mHz, CDCl3) : delta 9.24 (s, 1H), 7.16-7.08 (m, 2H), 6.82 (t, 1H), 6.2 (br, 2H), 3.6-3.5 (m, 1H), 3.04-2.97 (m, 2H), 2.88-2.70 (m, 3H), 2.66 (dd, 1H), 2.45-2.37 (m, 1H), 2.13-2.05 (m, 2.05), 1.83 (d, 4H), 1.67 (d, 2H), 1.55-1.43 (m, 4H), 1.33-1.11 (m, 6H). | |
Alternative procedure for (+/-)- [5-bromo-4-(4-chlorobenzyl)-7-fluoro-l, 23 A- te1tauahvdrocvclopenta|~b1indol-3-yl1acetic acid (Example 17, Step 4)Step 1 : (+/-)-7-fluoro-l,2,3,4-tetrahvdrocvclopentarb1indol-3-yl)acetic acid dicyclohexylamine(DCHA) salt A 0.526 M solution of 2~bromo-4-fluoroaniline in xylene along with ethyl (2- oxocyclopentyl) acetate (1.5 eq) and sulfuric acid (0.02 eq) was heated to reflux for 20 hours. Water was azeotropically removed with a Dean-Stark apparatus. The reaction was followed by NMR and after 20 hours, an 80-85% conversion to the desired imine intermediate was generally observed. The reaction mixture was washed with IM sodium bicarbonate (0.2 volumes) for 15 minutes and the organic fraction was evaporated. The remaining syrup was distilled under vacuum (0.5 mm Hg). Residual xylenes distilled at 300C, then excess ketone and unreacted aniline were recovered in the 50-1100C range; the imine was recovered in the 110-1800C fraction as a light brown clear liquid with 83% purity.The imine intermediate was then added to a degased mixture of potassium acetate (3 eq), tetra-n-butylammonium chloride monohydrate (1 eq), palladium acetate (0.03 eq) and N,N- dimethylacetamide (final concentration of imine = 0.365 M). The reaction mixture was heated to 1150C for 5 hours and allowed to cool to room temperature. 3N KOH (3 eq) was then added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (1.0 volume), washed with toluene (3x0.75 volume). The aqueous phase was acidified to pH 1 with 3N HCl and extracted with tertbutyl methyl ether (2x0.75 volume). The combined organic fractions were washed with water (0.75 volume). To the clear light brown solution was added dicyclohexylamine (1 eq) and the solution was stirred at room temperature for 16 hours. The salt was filtered, washed with ethyl acetate, tertbutyl methyl ether and allowed to dry to give the title compound. Assay: 94 A%. EPO <DP n="64"/>IH NMR (500 mHz, CDC13) : delta 9.24 (s, IH), 7.16-7.08 (m, 2H), 6.82 (t, IH), 6.2 (br, 2H), 3.6-3.5 (m, IH), 3.04-2.97 (m, 2H), 2.88-2.70 (m, 3H), 2.66 (dd, IH), 2.45-2.37 (m, IH)5 2.13-2.05 (m, 2.05), 1.83 (d, 4H), 1.67 (d, 2H), 1.55-1.43 (m, 4H), 1.33-1.11 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1.1: p-TsOH*H2O / toluene / 20 h / Heating 2.1: 252 g / nBu4NCl / Pd(OAc)2 / dimethylformamide / 1 h / 80 °C 3.1: 92 percent / aq. NaOH / tetrahydrofuran; methanol / 0.25 h / 60 °C 4.1: pyridinium tribromide; pyridine / 0.75 h / -30 - 20 °C 5.1: 117 g / AcOH; Zn / 1 h / 20 °C 6.1: HCl 7.1: NaH / dimethylformamide / 0.33 h / 0 °C 7.2: dimethylformamide / 0.42 h / -50 - 0 °C 8.1: 74.1 g / aq. NaOH / tetrahydrofuran; methanol / 0.25 h / 60 °C 9.1: 42 percent / (S)-(-)-1-(1-naphthyl)ethylamine salt / methanol 10.1: tetrahydrofuran; diethyl ether 11.1: CuI / 1-methyl-pyrrolidin-2-one / 3 h / 150 °C 12.1: 9.8 g / aq. NaOH / methanol; tetrahydrofuran / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 62.3 percent / hydrazine hydrate / ethanol / 1 h / Heating 2: 86.7 percent / CuCl2 / acetonitrile / 1 h / Heating | ||
Multi-step reaction with 2 steps 1: hydrazine hydrate / Heating 2: sodium salt of m-nitrobenzene sulphonic acid, NaOH / H2O / 0.67 h / Heating | ||
Multi-step reaction with 2 steps 1: ethanol; acetic acid; N2H4+H2O 2: bromine; acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a 4.6 M solution of <strong>[88511-27-7]4-amino-3-iodopyridine</strong> in DMF was added 0.05 equiv of PTSA.The solution was degassed by bubbling with N2 and 1.5 equiv of tetraethoxysilane was added, followedby 1.9 equiv of ethyl 2-(2-oxocyclopentyl)acetate. The final mixture was heated in a sealed tube to250C for 600 sec in a microwave heating system (Smith Creator microwave oven set to 150W power).The crude black gum was directly purified by flash chromatography on silica gel, eluting with a gradientfrom 100% hexanes to 50% EtOAc/hexanes. A 0.77 M solution of the resulting semi-pure brown oil inDMF was treated with 0.05 equiv of Pd(OAc)2- The catalyst was dissolved in the reaction mixture withthe help of ultrasound for few min. The solution was degassed by bubbling with N2 and 2.8 equiv ofHunig's base was added. The final mixture was heated in a sealed tube to 150C for 300 sec undermicrowave heating system (Smith Creator microwave oven set to 150W power). The reaction mixturewas cooled to room temperature and poured into a separatory funnel containing diluted aqueous NH4C1/EtOAc. The layers were separated and the aqueous layer was extracted several times with EtOAc. Thecombined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated.A mixture of EtOAc/hexanes was added and the organic phase was filtered through Celite andconcentrated. The crude material was further purified by crystallization at 0C with hexanes containingseveral drops of CH2C12 to yield the title compound as a pale brown solid. The structure of the titlecompound has been confirmed by 2D-COSY, 2D-HMQC and 2D-HMBC NMR experiments. IH NMR(acetone-d6) 6 10.13 (IH, br s), 8.67 (IH, s), 8.14 (IH, d), 7.34 (IH, dd), 4.17 (2H, q), 3.62 (IH, m),2.95-2.75 (3H, m), 2.69 (2H, m), 2.22 (IH, m), 1.24 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphoric acid; triethyl phosphite; In water; at 60℃; for 7h; | A MIXTURE OF ETHYL (2-OXOCYCLOPENTYL) ACETATE (1.0 EQ. ), 2-BROMO-4-FLUOROANILINE (1.05 EQ. ), AND TRIETHYLPHOSPHITE (1.20 EQ. ) IS TREATED WITH 85% PHOSPHORIC ACID (4 MOL%, 0.04 EQ. ) AND THE reaction mixture is then warmed to 60 C under nitrogen. After 7 h the reaction mixture is allowed to cool to room temperature (25-20 C) and is stirred into a 10/90 volume ratio of TRIETHYLAMINE/CYCLOHEXANE (10 L/Kg of the cyclopentylacetate). Water (5 L/Kg of the cyclopentylacetate) is added to the mixture, and the mixture is stirred for 15 minutes. The layers are separated and the organic phase is washed twice with water (2 X 5 L/KG of cyclopentylacetate), then distilled at constant volume under house vacuum at room temp with a half volume (5 L/kg of cyclopentylacetate) of cyclohexane to remove residual water. Finally, the solvent is switched to dimethylacetamide (DMAC, 1 L/mole cyclopentylacetate) for the cyclization step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: (+/-)-('7-Fluoro-l12,3,4-tetrahvdrocyclopenta[b]indol-3-yl)acetic acid ethyl ester.A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2- oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24h. After this time, the benzene was removed under distillation. Then, 60ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg OfPd(OAc)2 were added successively. The solution was heated to 115C for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound.1H NMR (acetone-d6) delta 9.76 (br s, IH), 7.34 (dd, IH), 7.03 (d, IH), 6.78 (td, IH), 4.14 (q, 2H), 3.57 (m, IH), 2.85-2.55 (m, 5H), 2.15 (m, IH), 1.22 (t, 3H). | ||
A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2- oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24h. After this time, the benzene was removed under distillation. Then, 60ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg Of Pd(OAc)2 were added successively. The solution was heated to 1150C for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound. 1H NMR (acetone-d6) delta 9.76 (br s, IH), 7.34 (dd, IH), 7.03 (d, IH), 6.78 (td, IH), 4.14 (q, 2H), 3.57 (m, IH), 2.85-2.55 (m, 5H), 2.15 (m, IH), 1.22 (t, 3H). | ||
Step 1: (+/-)-(7-Fluoro-l,2,3,4-tetrahvdrocvclopentarb]indol-3-yl)acetic acid ethyl ester. A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2- oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24h. After this time, the benzene was removed under distillation. Then, 60ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg OfPd(OAc)2 were added successively. The solution was heated to 115C for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound.1H NMR (acetone-d6) delta 9.76 (br s, IH), 7.34 (dd, IH), 7.03 (d, IH), 6.78 (td, IH), 4.14 (q, 2H), 3.57 (m, IH), 2.85-2.55 (m, 5H), 2.15 (m, IH), 1.22 (t, 3H). |
A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115 C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound. 1H NMR (acetone-d6) delta 9.76 (br s, 1H), 7.34 (dd, 1H), 7.03 (d, 1H), 6.78 (td, 1H), 4.14 (q, 2), 3.57 (m, 1H), 2.85-2.55 (m, 5H), 2.15 (m, 1H), 1.22 (t, 3H). | ||
Step 1: (+/-)-(7-Fluoro-l,2,3,4-tetrahvdrocvclopentarb1indol-3-yl)acetic acid ethyl ester.A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2- oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24h. After this time, the benzene was removed under distillation. Then, 60ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg OfPd(OAc)2 were added successively. The solution was heated to 1150C for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound. 1H NMR (acetone-d6) delta 9.76 (br s, IH), 7.34 (dd, IH), 7.03 (d, IH), 6.78 (td, IH), 4.14(q, 2H), 3.57 (m, IH), 2.85-2.55 (m, 5H), 2.15 (m, IH), 1.22 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; In methanol;Heating / reflux; | Intermediate 5-1A mixture of l-methyl-3, 5-dinitro-2-pyridone (11.7 g, 59 mmol) and ethyl cyclopentanoneacetate (10 g, 59 mmol) in 2 M NH3MeOH (300 niL) was refluxed overnight and then cooled to room temperature. Methanol was removed in vacuo and the residue was partitioned between EtOAc (200 mL) and water (400 mL). The aqueous layer was further extracted with EtOAc (2 x 150 mL). The organic layers were combined, washed with brine (150 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (eluting with a gradient of 0 to 20% EtOAc/hexanes) to give pure product as light yellow oil. LC-MS for C12H15N2O4 [M+H+] : calculated 251.1, found 251.2. EPO <DP n="22"/> |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; toluene-4-sulfonic acid;palladium diacetate; In ethyl acetate; N,N-dimethyl-formamide; benzene; | Step 1 (+-)-(7-Fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid ethyl ester A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115 C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluding with 100% toluene to provide 5.36 g of the title compound as a yellow solid. 1H NMR (acetone-d6) delta9.76 (br s, 1H), 7.34 (dd, 1H), 7.03 (d, 1H), 6.78 (td, 1H), 4.14 (q, 2H), 3.57 (m, 1H), 2.85-2.55 (m, 5H), 2.15 (m, 1H), 1.22 (t, 3H). | |
With toluene-4-sulfonic acid;palladium diacetate; In ethyl acetate; N,N-dimethyl-formamide; benzene; | Step 1: (+-)-(7-Fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid ethyl ester A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115 C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCI and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluding with 100% toluene, to provide the title compound. 1H NMR (acetone-d6) delta 9.76 (br s, 1H), 7.34 (dd, 1H), 7.03 (d, 1H), 6.78 (td, 1H), 4.14 (q, 2H), 3.57 (m, 1H), 2.85-2.55 (m, 5H), 2.15 (m, 1H), 1.22 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; PTSA;palladium diacetate; In Isopropyl acetate; N,N-dimethyl-formamide; | Step 2 (+/-)-Ethyl 2-[7-(methylsulfonyl)-1,2,3-trihydrocyclopenta[2,3-b]indol-3-yl]-acetate To a solution of 150 g of 2-iodo-4-(methylsulfonyl)phenylamine and 4.8 g of PTSA in 30 ml of DMF degassed and kept under a N2 atmosphere, 135 g of tetraethoxysilane and 129 g of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> were added successively. The final mixture was heated to 130-140 C. and stirred for 6 h. Then, 30 ml of DMF was added and the solution was degassed before 270 ml of Hunig's base followed by 3.4 g of Pd(OAc)2 were added successively. The solution was heated to 120 C. for 2 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of isopropyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of isopropyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluding with 50% EtOAc in hexanes to provide 63 g of the title compound as a yellow solid. 1H NMR (acetone-d6) delta10.23 (1H, br s), 7.98 (1H, s), 7.58 (2H, m), 4.14 (2H, q), 3.63 (1H, s), 3.04 (3H, s), 2.90-2.65 (5H, m), 2.19 (1H, m), 1.22 (3H, t). MS (+APCI) m/z 322.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1 (+/-) 2-(7-fluoro-1,2,3-trihydrocyclopenta[2,3-b]indol-3-yl)acetic acid The ethyl ester of the title compound was prepared from 10.00 g of 4-fluoro-2-iodophenylamine and 6.57 g of ethyl 2-(2-oxocyclopentyl)acetate according to example 1, step 2, to yield 5.36 g of a yellow solid. 1H NMR (acetone-d6) delta9.76 (1H, br s), 7.34 (1H, dd), 7.03 (1H, d), 6.78 (1H, td), 4.14 (2H, q), 3.57 (1H, m), 2.85-2.55 (5H, m), 2.15 (1H, m), 1.22 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a 500 mL three-necked round bottom flask containing DMF (195 mL) (deoxygenated with N2 and slight vacuum) were sequentially added 4-amino-3-iodobenzonitrile (12.2 g, 50.0 mmol), pyridine 4-methylbenzenesulfonate (0.477 g, 1.9 mmol), tetraethoxysilane (13.23 g, 63.5 mmol), and <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> (12.76 g, 75.0 mmol) under N2. The reaction mixture was heated at 135 C in the dark overnight. To the mixture were added N- ethyl-N-isopropylpropan-2 -amine (26.2 mL, 150 mmol) and palladium (II) acetate (0.337 g, 1.5 mmol) under N2. The resulting mixture was cooled to 120 0C and stirred for additional 16 h. The reaction mixture was cooled to room temperature and acidified to pH ~ 5 with 1 N aq. HCl. The solvent was evaporated under reduced pressure at 60 0C. To the resulting liquid residue was added water (300 mL) and EtOAc (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 400 mL). The combined organic layers were dried over Na2SO4, decanted and concentrated under reduced pressure to afford a dark brown liquid (22.1 g). The crude liquid was passed through a silica gel plug and eluted with 10%-40% EtOAc in hexanes. Fractions were concentrated and further purified by precipitation in DCM/hexanes to yield the title compound as a light orange solid (4.65 g). LCMS m/z = 269.2 [M + H]+; 1H NMR (400 MHz, DMSO-J6) delta ppm 1.19 (t, J = 7.12 Hz, 3H), 2.05-2.18 (m, IH), 2.54 (dd, J = 16.44, 8.45 Hz, IH), 2.64-2.85 (m, 4H), 3.52-3.63 (m, IH), 4.12 (q, J = 7.12 Hz, 2H), 7.34 (dd, J = 8.45, 1.58 Hz, IH), 7.49 (d, J = 8.45, IH), 7.85 (d, J = 0.81, IH), 11.30 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step D: Preparation of Ethyl 2-(7-Hydroxy-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetate. 2-Iodo-4-methoxyaniline (2.0 g, 8.03 mmol) and <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> (2.05 g,12.1 mmol) were dissolved in DMF (30 mL) and tetraethyl orthosilicate (2.12 g, 10.4 mmol) and pyridinum/7-toluenesulfonate (PPTS) (0.081 g, 0.321 mmol) were added. The reaction mixture was heated and stirred at 135 0C for 4 h. After cooling to 120 0C, DEEA (3.11 g, 24.09 mmol) and palladium (II) acetate (0.054 g, 0.241 mmol) were added. The reaction mixture was stirred for 3 h and then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant solution was diluted with 50% ethyl acetate in hexanes and filtered through a pad of silica gel. The filtrate was concentrated and purified by silica gel column chromatography to give 1.9 g of ethyl 2-(7-methoxy-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetate containing residual <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong>. The mixture was dissolved in DCM (80 mL) and cooled to 0 0C. Boron tribromide (21.0 mL, 21.0 mmol, 1.0 M in DCM) was added and the reaction was stirred for 1.5 h. Ice water was added and the reaction mixture was allowed to reach room temperature. The aqueous mixture was extracted three times with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (650 mg). LCMS m/z = 260.3 [M+H]+; 1H NMR (400 MHz, CDCl3) delta ppm 1.29 (t, J = 7.2 Hz, 3H), 2.05-2.14 (m, IH), 2.50 (dd, J = 16.8, 11.2 Hz, IH), 2.68-2.86 (m, 4H), 3.48-3.58 (m, IH), 4.16-4.24 (m, 2H), 6.66 (dd, J = 8.6, 2.4 Hz, IH), 6.85 (d, J = 2.4 Hz, IH), 7.15 (d, J = 8.7 Hz, IH), 8.4 (s, IH). | ||
Step D: Preparation of Ethyl 2-(7-Hydroxy-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetate.2-Iodo-4-methoxyaniline (2.0 g, 8.03 mmol) and <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> (2.05 g, 12.1 mmol) were dissolved in DMF (30 mL) and tetraethyl orthosilicate (2.12 g, 10.4 mmol) and pyridinum /7-toluenesulfonate (PPTS) (0.081 g, 0.321 mmol) were added. The reaction mixture was heated and stirred at 135 C for 4 h. After cooling to 120 C, DIEA (3.11 g, 24.09 mmol) and palladium (II) acetate (0.054 g, 0.241 mmol) were added. The reaction mixture was stirred for 3 h and then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant solution was diluted with 50% ethyl acetate in hexanes and filtered through a pad of silica gel. The filtrate was concentrated and purified by silica gel column chromatography to give 1.9 g of ethyl 2-(7-methoxy-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetate containing residual <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong>. The mixture was dissolved in DCM (80 mL) and cooled to 0 C. Boron tribromide (21.0 mL, 21.0 mmol, 1.0 M in DCM) was added and the reaction was stirred for 1.5 h. Ice water was added and the reaction mixture was allowed to reach room temperature. The aqueous mixture was extracted three times with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (650 mg). LCMS m/z = 260.3 [M+H]+; NMR (400 MHz, CDC13) delta ppm 1.29 (t, J = 7.2 Hz, 3 H), 2.05-2.14 (m, 1H), 2.50 (dd, J= 16.8, 11.2 Hz, 1H), 2.68-2.86 (m, 4H), 3.48-3.58 (m, 1H), 4.16-4.24 (m, 2H), 6.66 (dd, J = 8.6, 2.4 Hz, 1H), 6.85 (d, J= 2.4 Hz, 1H), 7.15 (d, J= 8.7 Hz, 1H), 8.4 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A 0.526 M solution of 2-bromo4-fluoroaniline in xylene along with ethyl (2-oxocyclopentyl) acetate (1.5 eq) and sulfuric acid (0.02 eq) was heated to reflux for 20 hours. Water was azeotropically removed with a Dean-Stark apparatus. The reaction was followed by NMR and after 20 hours, an 80-85% conversion to the desired imine intermediate was generally observed. The reaction mixture was washed with 1M sodium bicarbonate (0.2 volumes) for 15 minutes and the organic fraction was evaporated. The remaining syrup was distilled under vacuum (0.5 mm Hg). Residual xylenes distilled at 30 C., then excess ketone and unreacted aniline were recovered in the 50-110 C. range; the imine was recovered in the 110-180 C. fraction as a light brown clear liquid with 83% purity.The imine intermediate was then added to a degased mixture of potassium acetate (3 eq), tetra-n-butylammonium chloride monohydrate (1 eq), palladium acetate (0.03 eq) and N,N-dimethylacetamide (final concentration of imine=0.365 M). The reaction mixture was heated to 115 C. for 5 hours and allowed to cool to room temperature. 3N KOH (3 eq) was then added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (1.0 volume), washed with toluene (3×0.75 volume). The aqueous phase was acidified to pH 1 with 3N HCl and extracted with tertbutyl methyl ether (2×0.75 volume). The combined organic fractions were washed with water (0.75 volume). To the clear light brown solution was added dicyclohexylamine (1 eq) and the solution was stirred at room temperature for 16 hours. The salt was filtered, washed with ethyl acetate, tertbutyl methyl ether and allowed to dry to give the title compound. Assay: 94 A %. 1H NMR (500 mHz, CDCl3): delta 9.24 (s, 1H), 7.16-7.08 (m, 2H), 6.82 (t, 1H), 6.2 (br, 2), 3.6-3.5 (m, 1H), 3.04-2.97 (m, 2H), 2.88-2.70 (m, 3H), 2.66 (dd, 1H), 2.45-2.37 (m, 1H), 2.13-2.05 (m, 2.05), 1.83 (d, 4H), 1.67 (d, 2H), 1.55-1.43 (m, 4H), 1.33-1.11 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With diethylamino-sulfur trifluoride; In dichloromethane;Reflux; | Example 68A (+/-)-Ethyl(2,2-difluorocyclopentyl)acetate; At RT, 17.0 g (99.88 mmol) of (+/-)-ethyl 2-oxocyclopentylacetate were added dropwise to a solution of 52.8 ml (399.5 mmol) of diethylaminosulphur trifluoride (DAST) in 150 ml of abs. dichloromethane The mixture was heated under reflux overnight. After cooling, a further 13.2 ml (99.88 mmol) of diethylaminosulphur trifluoride (DAST) were added, and the mixture was once more stirred under reflux for 36 h. After cooling, the mixture was diluted with dichloromethane, saturated sodium bicarbonate solution was added carefully and the mixture was then stirred vigorously. The organic phase was washed successively with saturated sodium bicarbonate solution, twice with 1 N hydrochloric acid and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. From the dark brown residue, the product was isolated by column chromatography on silica gel (mobile phase pentane/dichloromethane 10:1?1:1). This gave 7.52 g (39% of theory) of the title compound.GC-MS (Method 1): Rt=2.88 min; m/z=172.1H-NMR (400 MHz, DMSO-d6): delta [ppm]=1.18 (t, 3H), 1.33-1.48 (m, 1H), 1.61-1.77 (m, 2H), 1.92-2.20 (m, 3H), 2.24-2.38 (m, 1H), 2.43-2.60 (m, 2H), 4.07 (q, 2H). |
39% | With diethylamino-sulfur trifluoride; In dichloromethane;Reflux; | Example 88A(+/-)-Ethyl (2,2-difluorocyclopentyl)acetate; At RT, 17.0 g (99.88 mmol) of (+/-)-ethyl 2-oxocyclopentylacetate were added dropwise to a solution of 52.8 ml (399.5 mmol) of diethylaminosulphur trifluoride (DAST) in 150 ml of abs. dichloromethane. The mixture was heated at reflux overight. After cooling, a further 13.2 ml (99.88 mmol) of diethylaminosulphur trifluoride (DAST) were added, and the mixture was stirred under reflux for another 36 h. After cooling, the mixture was diluted with dichloromethane, saturated aqueous sodium bicarbonate solution was added carefully and the mixture was then stirred vigorously. The organic phase was washed successively with saturated sodium bicarbonate solution, twice with 1 N hydrochloric acid and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. From the dark-brown residue, the product was isolated by column chromatography on silica gel (mobile phase pentane/dichloro-methane 10:1?1:1). This gave 7.52 g (39% of theory) of the title compound.GC-MS (Method 1): Rt=2.88 min; m/z=172.1H-NMR (400 MHz, DMSO-d6): delta [ppm]=1.18 (t, 3H), 1.33-1.48 (m, 1H), 1.61-1.77 (m, 2H), 1.92-2.20 (m, 3H), 2.24-2.38 (m, 1H), 2.43-2.60 (m, 2H), 4.07 (q, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sulfur; diethylamine; In ethanol; at 20℃; for 90h; | To a solution of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> (30.0 g, 169 mmol) in EtOH (300 mL) was added ethyl 2-cyanoacetate (17.2 g, 152 mmol), Et2NH (15.2 g, 208 mmol,) and sulphur (6.62 g, 206 mmol) at rt and the mixture was stirred for 90 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with EA (300 mL) and washed with brine (3×40 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=10:1) to give the title compound (25.0 g, 47% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta 5.95 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.64-3.55 (m, 1H), 2.87-2.11 (m, 6H), 1.35 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H); LC-MS (ESI+) m/z 298.0 (M+H)+. |
45% | With sulfur; diethylamine; In ethanol; at 20℃; | Synthesis of compound 12. Into a 10-L 4-necked round-bottom flask was placed a solution of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> (11, 550 g, 3.23 mol, 1.00 equiv) in ethanol (2200 mL) at room temperature. This was followed by the addition of NCCHaCOOEt (440 g, 1.21 equiv), Et2NH NMR (291.5 g, 1.23 equiv) and S (126.5 g, 1.22 equiv) in portions at room temperature. The solution was stirred overnight at room temperature and then concentrated under vacuum. The resulting solution was diluted with 5000 mL of ethyl acetate and washed with 2 x 1000 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1 : 10) and purified to afford 430 g (45%) of ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)-4H,5H,6H- cyclopenta[b]thiophene-3-carboxylate (12) as an orange oil.[00591] Synthesis of compound 13. To a 10-L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added a solution of 12 (500 g, 1.68 mol, 1.00 equiv) in formamide (5 L) at room temperature. The resulting solution was stirred for 5 h at 180 C in an oil bath. The reaction mixture was cooled to room temperature and then quenched by the addition of 10 L of water/ice. The resulting solution was extracted with 3 x 5 L of ethylPage 265 of 4072009184-0008 acetate and the organic layers were combined. The mixture was washed with 3 x 3000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The solids were collected by filtration to afford 200 g (43%) of ethyl 2-[12-hydroxy-7-thia-9, l l- diazatricyclo[6.4.0.0A[2,6]]dodeca-l(8),2(6),9,l l-tetraen-3-yl]acetate (13) as a yellow solid.[00592] Synthesis of intermediate E. Two 2000-mL 4-necked round-bottom flasks were charged with a solution of 13 (200 g, 718.58 mmol, 1.00 equiv) in POCl3 (2000 mL) at room temperature. The resulting solution was stirred for 2 h at 1 10 C in an oil bath. The reaction mixture was cooled to room temperature and concentrated under vacuum. The reaction was then quenched by the addition of 1000 mL of ice-water. The resulting solution was extracted with 3 x 500 mL of ethyl acetate and the organic layers were combined. The combined organic layers were washed with 2 x 500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 200 g (94%) of ethyl 2-[12-chloro-7-thia-9, l 1- diazatricyclo[6.4.0.0A[2,6]]dodeca-l(12),2(6),8,10-tetraen-3-yl]acetate (E) as a light yellow solid. |
45% | With sulfur; diethylamine; In ethanol; at 20℃; | Into a 10-L 4-necked round-bottom flask was placed a solution of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> (15.1, 550 g, 3.23 mol, 1.00 equiv) in ethanol (2200 mL) at room temperature. This was followed by the addition of NCCH2COOEt (440 g, 1.21 equiv), Et2NH (291.5 g, 1.23 equiv) and S (126.5 g, 1.22 equiv) in portions at room temperature. The solution was stirred overnight at room temperature and then concentrated under vacuum. The resulting solution was diluted with 5000 mL of ethyl acetate and washed with 2 x 1000 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:10) and purified to afford 430 g (45%) of ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)-4H,5H,6H- cyclopenta[b]thiophene-3-carboxylate (15.2) as an orange oil. |
45% | With sulfur; diethylamine; In ethanol; at 20℃; | [00272] Synthesis of compound 1.2. Into a 10-L 4-necked round-bottom flask was placed a solution of 1.1 (550 g, 3.23 mol, 1.00 equiv) in ethanol (2200 mL) at room temperature. This was followed by the addition of NCCH2COOEt (440 g, 1.21 equiv), Et2NH (291.5 g, 1.23 equiv) and S (126.5 g, 1.22 equiv) in portions at room temperature. The solution was stirred overnight at room temperature and then concentrated under vacuum. The resulting solution was diluted with 5000 mL of EA and was washed with 2x1000 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 430 g (45%) of 1.2 as an orange oil. |
45% | With sulfur; diethylamine; In ethanol; at 20℃; | Into a 10-L 4-necked round-bottom flask was placed a solution of 1.1 (550 g, 3.23 mol, 1.00 equiv) in ethanol (2200 mL) at room temperature. This was followed by the addition of NCCH2COOEt (440 g, 1.21 equiv), Et2NH (291.5 g, 1.23 equiv) and S (126.5 g, 1.22 equiv) in portions at room temperature. The solution was stirred overnight at room temperature and then concentrated under vacuum. The resulting solution was diluted with 5000 mL of EA and was washed with 2x1000 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :10). This resulted in 430 g (45%) of 1.2 as an orange oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50%; 16% | In methanol; water; at 90℃; for 0.166667h;Sealed tube; Microwave irradiation; | General procedure: To a stirred solution of corresponding cyclic ketones (1 eq) in a mixture of MeOH/H2O (1/1,3 mL) was added sequentially the ammonium carbonate (3 eq) and the potassium cyanide (1.5 eq). The sealed tube was heated under microwave irradiation for 10 minutes at 90C. The reaction mixture was cooled at RT and the purification by a suitable method afforded the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium tetrahydroborate; ethanol; at 20℃; for 1h; | To a solution of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> (1.0 g, 5.88 mmol) in EtOH (20 mL) at RT was added NaBEE (0.222 g, 5.88 mmol) and the solution was stirred at RT for lh. The reaction mixture was diluted with EhO, then was carefully acidified with 1N aq. HC1 and extracted with EtOAc (2x). The combined organic extracts were washed with EhO, brine, dried (MgSCri), and concentrated in vacuo. The residue was chromatographed (S1O2; continuous gradient from 25-75% EtOAc in hexanes) to give the title compound (741 mg, 73 % yield) as an oil. NMR (500 MHz, CDCh) 5 4.15 (q, J=1.2 Hz, 2H), 3.87 (m, 1H), 2.87 (d, =2.8 Hz, 1H), 2.46 (dd, =l6.2, 5.8 Hz, 1H), 2.38 (dd, =l6.2, 8.8 Hz, 1H), 2.13 - 2.03 (m, 1H), 2.01 - 1.92 (m, 2H), 1.78 - 1.67 (m, 2H), 1.63 - 1.56 (m, 2H), 1.27 (t, J=12 Hz, 3H). |
Tags: 20826-94-2 synthesis path| 20826-94-2 SDS| 20826-94-2 COA| 20826-94-2 purity| 20826-94-2 application| 20826-94-2 NMR| 20826-94-2 COA| 20826-94-2 structure
[ 5400-79-3 ]
Ethyl 3-oxocyclopentanecarboxylate
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[ 24922-00-7 ]
Ethyl 3-cyclopentyl-3-oxopropanoate
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[ 24851-98-7 ]
Methyl 2-(3-oxo-2-pentylcyclopentyl)acetate
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[ 134176-18-4 ]
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[ 611-10-9 ]
Ethyl 2-oxocyclopentanecarboxylate
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[ 5400-79-3 ]
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[ 24922-00-7 ]
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[ 1187-74-2 ]
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[ 24851-98-7 ]
Methyl 2-(3-oxo-2-pentylcyclopentyl)acetate
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[ 611-10-9 ]
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[ 5400-79-3 ]
Ethyl 3-oxocyclopentanecarboxylate
Similarity: 0.97
[ 24922-00-7 ]
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Similarity: 0.94
[ 1187-74-2 ]
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[ 24851-98-7 ]
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[ 611-10-9 ]
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