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CAS No. : | 609-14-3 | MDL No. : | MFCD00009164 |
Formula : | C7H12O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FNENWZWNOPCZGK-UHFFFAOYSA-N |
M.W : | 144.17 | Pubchem ID : | 701 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.71 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 37.25 |
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) : | -6.53 cm/s |
Log Po/w (iLOGP) : | 1.8 |
Log Po/w (XLOGP3) : | 0.91 |
Log Po/w (WLOGP) : | 0.77 |
Log Po/w (MLOGP) : | 0.64 |
Log Po/w (SILICOS-IT) : | 0.96 |
Consensus Log Po/w : | 1.02 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.04 |
Solubility : | 13.1 mg/ml ; 0.0905 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.41 |
Solubility : | 5.66 mg/ml ; 0.0392 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.11 |
Solubility : | 11.2 mg/ml ; 0.0778 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.96 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P210-P280-P370+P378-P403+P235-P501-P264-P337+P313-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319-H227 | 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 |
---|---|---|
25% | Stage #1: With hydrogenchloride; sodium nitrite In water at -5℃; for 0.25 h; Stage #2: With potassium hydroxide; sodium acetate In ethanol; water at 0℃; for 18 h; Stage #3: With toluene-4-sulfonic acid In toluene at 110℃; for 5 h; |
7.2 g (0.104 mol) of sodium nitrite dissolved in 40 ml of water are added, at 5 C., to a mixture of 10.7 g (0.1 mol) of 4-methylaniline, 74 ml of 12 N hydrochloric acid and 140 ml of water. The reaction mixture is stirred for 15 minutes at 5 C. and is neutralized by addition of 8.1 g of sodium acetate. 12.33 g (0.085 mol) of ethyl a-methyl acetoacetate and 80 ml of ethanol are introduced into a three-necked Uask, followed, at 0 C., by 4.8 g (0.085 mol) ofpotassium hydroxide dissolved in 20ml ofwater and 100 g of ice. The diazonium solution prepared above is added dropwise, at 0 C., to this reaction mixture and the resulting mixture is left for 18 hours at 0 C. The aqueous phase is extracted 4 times with 50 ml of ethyl acetate and the organic phases are combined and dried over anhydrous sodium sulphate. The residue is taken up in 100 ml of toluene and 16.3 g (0.085 mol) of para-toluene sulphonic acid monohy drate. The mixture is then heated slowly to 110 C. and maintained at this temperature for S hours. After cooling and then addition of saturated sodium carbonate solution, the insoluble material is removed by ltration and the organic phase is separated out after settling has taken place, dried over anhydrous sodium sulphate and concentrated. The residue is chromatographed on a column of silica gel, eluent:30/70 (v/v) dichloromethane/cyclohexane, to give beige coloured crystals; m.p.=94 C.; yield=25percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With sodium hydroxide; sodium nitrite In hydrogenchloride; ethanol; water; ethyl acetate | (i) Ethyl 2-acetyl-2-N'-(3-chloro-methoxylphenyl)hydrazino)propionate Ethereal HCl (60 ml) was added to a solution of 3-chloro-p-anisidine in ethyl acetate (300 ml) to precipitate the salt, which was isolated by filtration and air dried. The salt (18.5 g) was suspended in 1.5 N HCl (230 ml) at -5° C. under argon. A solution of sodium nitrite (6.9 g) in water (50 ml) was added over 15 minutes to form a solution/slurry, which was stirred at -5° C. for a further 1 hour. (solution A) A solution of sodium hydroxide (5.36 g) in water (10 ml) was added to a solution of ethyl-2-methylacetoacetate (13.5 ml) in ethanol (80 ml) at 5° C. The reaction was stirred at 5° C. for a further 1 hour and the pH was then adjusted to 4 by addition of sodium acetate (20 g).(solution B) Solution B was added to solution A at -5° C. and the mixture was allowed to warm to ambient temperature over 3 hours before partitioning between water (250 ml) and ethylacetate (250 ml). The organic phase was dried (MgSO4), concentrated under vacuo and purified by column chromatography using 15percent ethylacetate/isohexane as the eluant to yield the desired product (7 g, 21percent); NMR (CDCl3) δ 1.24 (t, 3H), 1.63 (s, 3H), 2.34 (s,3), 3.98 (s, 3H), 4.22-4.35 (m, 2H), 7.02 (d, 1H), 7.72 (dd, 1H), 7.83 (d, 1H) m/z 270(M-CH3COH)+ In a similar manner but starting from 3-fluoro-4-methoxyaniline was prepared: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With bromine; In chloroform; at 0 - 130℃; for 4h; | Example 13: Synthesis of 4-hydroxy-3-methyl-5H-furan-2-one.; [Show Image] A solution of bromine (11.60 g, 71.00 mmol) in chloroform (20 ml) was added dropwise to a solution of ethyl 2-methylacetoacetate (10.00 g, 69.00 mmol) in chloroform (75 ml) at 0C. After addition, stirring was kept for 2 hours at room temperature. The solvent was evaporated to dryness and the residue was heated at 130C for 2 hours. A crude solid was obtained which was purified by silica gel chromatography (CH2Cl2 / MeOH, 12/1) to give 5.50 g (70%) of the aimed productas a white solid. TLC (UV 254 nm): AcOEt / n-hexane / acetic acid, 5 / 10 / 0,5 Rf=0,1. 1H RMN (400 MHz, MeOD): 1.6 (t, 3H, J=1.17 Hz, CH3); 4.6 (q, 2H, J= 1.17 Hz, CH2) allylic coupling (AB system). 13C RMN (100 MHz, MeOD): 5.8 (CH3); 68.3 (CH2); 96.7 (3-C(Me)=); 175.0 (C-OH); 179.1 (C=O). |
51% | With bromine; In water; at 0 - 20℃; | To a three neck 100 mL round bottom flask, ethyl 2-methyl-3-oxo-butanoate (20 g, 138.72 mmol) was suspended in water (40 mL) and cooled to 0C. Bromine (7.100 mL, 138.70 mmol) was added to the reaction mixture slowly. The reaction mixture was stirred at room temperature for overnight. After the completion of the reaction, tertiary-butyl methyl ether (100 mL) was added and organic layer was separated which was washed with aqueous sodium thiosulfate (1 M, 50 mL), dried over sodium sulfate, concentrated on rotovap to give colorless liquid (27 g) to which (0.5 mL) was added and the reaction mass was refluxed for overnight. The solid formed was filtered and washed with tertiary-butyl methyl ether (10 mL x 3) to give the desired product (8.0 g, 51 %) as a white solid. H NMR (DMSO-D6, 400MHz): δ 1 1.78 (s, 1 H), δ 4.56 (dd, 2H), δ 1 .57 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With poly(4-vinylpyridinium)perchlorate In neat (no solvent) at 20℃; for 0.366667h; Irradiation; | 2.5 General procedure for the preparation of coumarins General procedure: In a 25 mL batch reactor equipped with a distillation condenser the mixture of phenols (1 mmol), β-keto esters (2 mmol) and P(4-VPH)ClO4 (50 mg) was stirred and irradiated under ultrasonic irradiation (with a frequency of 35 kHz and a nominal power 200 W) at ambient temperature for the time mentioned in the Table 1. Ethyl acetoacetate was taken 2 equiv. for the proper solubility of phenol and ease of proper stirring of the reaction mixture. After completion of the reaction (monitored by TLC), ethanol was added to the reaction mixture and the catalyst was recovered by filtration. The filtrate was concentrated in vacuum, and the crude product was washed with water, dried and slowly re-crystallized in ethanol or ethanol-water system. The melting point, IR, 1H NMR and mass spectroscopic techniques were used to analyze the products and compared with the authentic samples. |
83% | With perchloric acid at 20℃; | 6.2.2. General method for 4-substituted 7-hydroxycoumarins (2, 4-22) General procedure: 30 mmol of properly substituted resorcinol was dissolved in 30 ml of perchloric acid. 30 mmol of β-ketoester was added and the reaction mixture was stirred at room temperature until TLC showed that resorcinol had reacted. The mixture was poured into 250 ml of cold water and the precipitate was filtered and dried at room temperature and recrystallised from ethanol. Analytical data of compounds 2-13, 15, 16, 19 and 20 is presented in refPreviewPlaceHolderSupplementary data. |
65% | In toluene for 6h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 2-acetylpropanoic acid ethyl ester With sodium hydride In toluene at 20℃; for 1h; Stage #2: 4,4,5,5-tetramethyl-2-(propa-1,2-dien-1-yl)-1,3,2-dioxaborolane; iodobenzene With tris(para-trifluoromethyl)phenyl phosphine In toluene at 80℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 2-acetylpropanoic acid ethyl ester; methyl 2-(aminosulfonyl)benzoate With N,N,N,N,-tetramethylethylenediamine; lithium diisopropyl amide In tetrahydrofuran at 0℃; for 3.5h; Stage #2: With hydrogenchloride In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Example 7 5-(2-(Morpholin-4-yl)ethoxy)-1H-indole-2-carboxylic acid ethyl ester (12): A stirred solution of 4-(2-(morpholin-4-yl)ethoxy)phenylamine (11) (4.00 g, 18.0 mmol) in water (38 mL) and concentrated HCl (12 mL) was treated dropwise at 0 C. with a solution of NaNO2 (1.36 g, 19.8 mmol) in water (3.8 mL) and the resulting mixture was stirred for 30 min at 0 C. (solution A). Ethyl 2-methylacetoacetate (2.75 mL, 18.9 mmol) was added dropwise to a suspension of NaOAc (15.3 g) in EtOH (29 mL) at 0 C. After stirring for 30 min at this temperature, ice (18 g) was added (solution B). Then, solution A was added to solution B by a transfer cannula at 0 C., the mixture was allowed to warm to room temperature and was stirred for a further 2.5 h. After that, the reaction mixture was basified by slow addition of a saturated aqueous solution of Na2CO3 at 0 C. and extracted with CH2Cl2 (3*200 mL). The combined organic layers were washed with water (300 mL), dried (MgSO4), and the solvent was removed in vacuo. The residue was then dissolved in absolute EtOH (15 mL), treated with a freshly prepared saturated solution of HCl in absolute EtOH (15 mL) and heated at reflux for 40 min. After cooling to room temperature the solvent was removed under reduced pressure and the residue was partitioned between water (50 mL) and CH2Cl2 (100 mL). The aqueous layer was basified using a saturated aqueous solution of Na2CO3 and extracted with CH2Cl2 (3*100 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), and concentrated in vacuo. Purification by crystallization from iPr2O and column chromatography (CH2Cl2/MeOH, 20:1) of the residue after evaporation of the mother liquor provided 12 (4.07 g, 71% overall yield) as a yellow solid. 1H NMR (300 MHz, CDCl3): delta 1.41 (t, J=7.1 Hz, 3H, OCH2C3), 2.61 (mc, 4H, 3"-H2, 5"-H2), 2.84 (t, J=5.7 Hz, 2H, 2'-H2), 3.76 (mc, 4H, 2"-H2, 6"-H2), 4.15 (t, J=5.7 Hz, 2H, 1'-H2), 4.40 (q, J=7.1 Hz, 2H, OC2CH3), 6.99 (dd, J=9.0, 2.4 Hz, 1H, 6-H), 7.08 (d, J=2.4 Hz, 1H, 4-H), 7.13 (d, J=1.3 Hz, 1H, 3-H), 7.30 (d, J=9.0 Hz, 1H, 7-H), 9.13 (sbr, 1H, NH) ppm; 13C NMR (50.3 MHz, CDCl3): delta=14.4 (OCH2H3), 54.1 (C-3", C-5"), 57.7 (C-2'), 60.9 (OH2CH3) 66.2 (C-1'), 66.9 (C-2", C-6"), 103.7 (C-4), 108.1 (C-3), 112.7 (C-7), 117.3 (C-6), 127.7, 127.9 (C-2, C-3a), 132.3 (C-7a), 153.7 (C-5), 162.0 (C=O) ppm; MS (70 eV, EI): m/z (%)=318 (14) [M]+, 100 (100) [CH2N(CH2)4O]+; C17H22N2O4 (318.37): calcd. C, 64.13; H, 6.97; found C, 63.85; H, 7.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 93 percent / ammonium hydroxide; Bentonite K-10 / 24 h / 20 °C 2.1: sodium; ethanol / toluene / 1 h 2.2: 65 percent / ethanol; toluene / 96 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium hydride; In 1,2-dimethoxyethane; at 70℃; for 18.75h;Heating / reflux; | 60%-NaH (4.65g, 0. 116MOL) was suspended in DME (70mL) and then heated to 70C under reflux. Subsequently, a solution of cyclohexane carboxylic acid methyl ester (5. 00g, 0. 0352MOL) and 2-methyl-3-oxo-butyric acid ethyl ester (90%, 6.20g, 0. 0387MOL) diluted with DME (30mL) was added thereto over 45 minutes and then heated under reflux for 18 hours. After the resulting solution was cooled down to room temperature, the solvent was distilled off under reduced pressure. Then, water (50mL) was added thereto and the resulting solution was stirred for 2 hours. After a 2N HCl solution was added thereto for acidification followed by extraction with ethyl acetate (50MLX 2), the resulting organic layer was washed with a saturated NACI solution (50ML). The organic layer was dried over MGSO4, filtered, and then concentrated under a reduced pressure. The resulting residue was purified by recrystallization from ethyl acetate/n-hexane to obtain white solid (4.80g, 66%). 'H-NMR (CDCL) ; 6 = 8. 46 (brs, 1H), 6.02 (s, 1H), 2.35 (m, 1H), 1.96 (s, 3H), 1.90- 1. 15 (m, 10H). MS = 209 [M+H], 231 [M+Na] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In diphenylether; benzene | 1 Synthesis of 4-hydroxy-2,3-dimethyl-6-n-pentyl-quinoline Compound No. 97) Example 1 Synthesis of 4-hydroxy-2,3-dimethyl-6-n-pentyl-quinoline Compound No. 97) 1.63 Grams of 4-n-pentylaniline and 1.44 g of ethyl 2-methylacetoacetate were refluxed in benzene in the presence of a Lewis acid catalyst for 3 hours. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution and a saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated, the resultant intermediate was refluxed in diphenyl ether for 30 minutes and allowed to cool to produce precipitates, which were collected by filtration under reduced pressure to obtain 1.01 g of 4-hydroxy-2,3-dimethyl-6-n-pentyl-quinoline (yield 42%). Its NMR spectral data are shown in the following Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium tert-butylate; In ethyl acetate; tert-butyl alcohol; | Example 9 Synthesis of 3-[3-(5-carboxypentyl)-5-iodo-2,3-dimethyl-3H-1-indoliumyl]-1-propanesulfonate (2) A mixture of 13.4 g (0.12 mol) of potassium tert-butoxide and 100 g of tert-butanol was stirred and heated until the tert-butoxide totally dissolved. The solution was cooled to about 50 C. and 17 g (0.12 mmol) of ethyl 2-methylacetoacetate was added dropwise. Ethyl-6-bromohexanoate (30 g, 0.13 mmol) was then added dropwise and the reaction mixture was stirred and refluxed for 5 hours. The mixture was filtered and the solvent was removed under reduced pressure. The residue was partitioned between 1M HCl and chloroform. The organic layer was dried over magnesium sulfate and purified on silica gel using 1:10 ethyl acetate/hexane as the eluent to yield 25 g (75%) of diethyl 2-acetyl-2-methyloctanedioate (3) as yellow liquid. |
75% | With potassium tert-butylate; In tert-butyl alcohol; at 50℃; for 5h;Reflux; | A mixture of 13.4 g (0.12 mol) of potassium tert-butoxide and 100 g of tert-butanol was stirred and heated until the tert-butoxide totally dissolved. The solution was cooled to about 50 C. and 17 g (0.12 mmol) of ethyl 2-methylacetoacetate was added dropwise. Ethyl-6-bromohexanoate (30 g, 0.13 mmol) was then added dropwise and the reaction mixture was stirred and refluxed for 5 hours. The mixture was filtered and the solvent was removed under reduced pressure. The residue was partitioned between 1M HCl and chloroform. The organic layer was dried over magnesium sulfate and purified on silica gel using 1:10 ethyl acetate/hexane as the eluent to yield 25 g (75%) of diethyl 2-acetyl-2-methyloctanedioate (3) as yellow liquid. |
63.4% | With sodium ethanolate; In ethanol; at 120℃; for 12h; | Example 9.1 (0321) (0322) Ethyl 2-methyl acetoacetate (29.2 mL, 0.203 mol. 1 eq), 21% sodium ethoride solution (64 mL, 0.816 mol, 4 eq), <strong>[25542-62-5]ethyl 6-bromohexanoate</strong> (34 mL, 0.192 mol, 1 eq) and ethanol (200 mL) are added and the mixture is subjected to reflux at 120 C. for 12 hours. Next, the solvent is neutralized with 1M hydrochloric acid and extraction is carried out by using chloroform and distilled water. The extracted solvent is dried under reduced pressure and purification is carried out by normal phase chromatography to obtain the target compound (36.8 g, 63.4%). (0323) Rf=0.34 (Silica gel, hexane/ethyl acetate=10:1 v/v) |
With sodium ethanolate; In ethanol; ethyl acetate; | EXAMPLE 1 Preparation of 3-(5-carboxypentyl)-2,3-dimethyl-5-sulfoindolium, Inner Salt (Compound 1) A mixture of 25 g of ethyl 2-methylacetoacetate, 64 mL of a 21% sodium ethoxide solution in ethanol and 34 mL of <strong>[25542-62-5]ethyl 6-bromohexanoate</strong> is refluxed in 200 mL of ethanol overnight. The mixture is filtered and solvent is evaporated. The residue is partitioned between 1 M HCl and chloroform. The organic layer is dried over magnesium sulfate and purified on silica gel using 1:10 ethyl acetate/ hexanes as eluant to yield 22 g of ethyl 2-(5-carbethoxypentyl)-2-methylacetoacetate. The acetoacetate thus obtained is dissolved in 300 mL of methanol. | |
22 g | With sodium ethanolate; In ethanol;Reflux; | 10103] A mixture of 25 g of ethyl 2-methylacetoacetate, 64 mL of a 21% sodium ethoxide solution in ethanol and 34 mL of <strong>[25542-62-5]ethyl 6-bromohexanoate</strong> is refluxed in 200 mL of ethanol overnight. The mixture is filtered and solvent is evaporated. The residue is partitioned between 1 M HC1 and chloroform. The organic layer is dried over magnesium sulfate and purified on silica gel using 1:10 ethyl acetate/hexanes as eluant to yield 22 g of ethyl 2-(5-carbethoxypentyl)-2-methylacetoac- etate. |
15 g | With sodium ethanolate; In ethanol; for 12h;Reflux; | To the solution of sodium ethoxide (173.4 mmol, prepared from 4.0 g sodium in 200 mL dry ethanol) is added ethyl 2-methylacetoacetate (25.0 g, 173.4 mmol), followed by ethyl 6-bromohexanonate (44.5 g, 190.7 mmol). The mixture is heated to reflux for 12 hours. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated. The residue is treated with 1M HCl to pH 1 and the aqueous solution is extracted with chloroform twice. The organic layer is washed with brine and dried over Na2SO4. After removal of solvent, the residue is purified on silica gel to afford 15 g ethyl 2-(5-ethoxycarbonyl)pentyl-2-methylacetoacetate. |
With sodium ethanolate; In ethanol; for 48h;Reflux; | To prepare compound 1, shown below, to the solution of sodium ethoxide (40 g sodium in 500 mL dry ethanol) was added ethyl 2-methylacetoacetate (250 g), followed by ethyl 6-bromohexanonate (445 g). The mixture was heated to reflux for 2 days. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was treated with 1M HCl to pH 1 and the aqueous solution was extracted with chloroform twice. The organic layer was washed with brine and dried over Na2SO4. After removal of solvent, the residue was purified on silica gel to give ethyl 2-(5-ethoxycarbonyl)pentyl-2-methylacetoacetate. | |
47.7 g | With sodium ethanolate; In ethanol; at 80℃; for 10h; | The compound represented by Formula 8-a was synthesized by Reaction 8-1.Ethyl 2-methylacetatoacetate (23.5 g, 163 mmol) and <strong>[25542-62-5]ethyl 6-bromohexanoate</strong> (40.0 g, 179 mmol) were stirred in 200 ml of ethanol and liquid sodium ethoxide was added dropwise thereto. The mixture was stirred at 80 C. for 10 h. After completion of the reaction, the solid was filtered off. The filtrate was distilled under reduced pressure and extracted with dichloromethane and a 2 N aqueous solution of hydrochloric acid. The organic layer was treated with anhydrous sodium sulfate and distilled under reduced pressure (47.7 g). After removal of the solvent, 300 ml of water was added, followed by stirring under reflux for 10 h. After completion of the reaction, the reaction solution was extracted with dichloromethane, treated with sodium sulfate, and distilled under reduced pressure (25 g, 71%).1H NMR (400 MHz, CDCl3): delta=10.85 (1H, s), 2.52 (1H, m), 2.36 (2H, m) 2.30 (3H, s), 1.65 (4H, m), 1.35 (4H, m), 1.09 (3H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; potassium hydroxide; sodium nitrite; In ethanol; water; | Solid NaNO2 (0.35 g, 5 mmol) was added to a suspension of the p-phenethylaniline hydrochloride (1.1 g, 5 mmol) and concentrated HCl (2 ml) in H2 O (3 ml) under an icewater bath. The solution was kept at -5 C. with stirring while ethyl 2-methylacetoacetate (0.72 g, 5 mmol)in EtOH 95% (5 ml) was treated at -10 C. with a solution of 50% KOH (1.7 ml) followed at once by ice (10 g). The diazo-solution was then added immediately, stirred at room temperature for 20 min, and extracted with Et2 O (2*20 ml). The combined Et2 O portions were dried (MgSO4) and the solvent was removed under reduced pressure to give a red oil which was taken up in anhydrous EtOH (10 ml), and dry hydrogen chloride gas was passed through the solution until ammonium chloride was precipitated. The mixture was heated at reflux for 20 min, and then stirred at room temperature for 2 h. The suspension was poured into ice water (100 ml) and extracted with Et2 O (2*30 ml). The combined Et2 O portions were dried (MgSO4) and the solvent was removed under reduced pressure to give a solid which was recrystallized from EtOH 95% to provide 3-ethyloxycarbonyl-5-(2-phenylethyl)indole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In methanol; | PREPARATION 1 Methyl 4,5-dimethyl-3-hydroxythiophene-2-carboxylate Dry hydrogen chloride gas was bubbled through a mixture of ethyl 2-methyl-3-oxobutanoate (7.6 g, 50 mmol) and methyl 2-mercaptoacetate (11.2 g, 100 mmol) at -10 C. until saturated. The oil was allowed to stand for 3 hours at room temperature, diluted with dichloromethane and washed with brine. After drying with sodium sulphate and evaporation of solvent the oil was dissolved in methanol (10 ml) and added dropwise to methanolic potassium hydroxide (2N; 75 ml), stirring at room temperature for 1 hour. The solution was diluted with iced water (125 ml) and acidified with 3N hydrochloric acid at -3 to 0 C. to pH1. The precipitate was filtered and washed with water (5.5 g, m.p. 50-51 C., methanol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; | EXAMPLE 2 Methyl 3-hydroxy-4,5-dimethyl-2-thiophenecarboxylate Prepared by the method described in Example 1 from ethyl alpha-methyl acetoacetate (29 g, 0.20 moles), methyl thioglycolate (45 g, 0.40 moles) and sodium (10.2 g, 0.44 moles). Recrystallization from methanol gave the product (15.2 g); mp 52-54 C. | |
With sodium; | EXAMPLE 2 Methyl 3-hydroxy-4,5-dimethyl-2-thiophenecarboxylate. Prepared by the method described in Example 1 from ethyl alpha-methyl acetoacetate (29 g, 0.20 moles), methyl thioglycolate (45 g, 0.40 moles) and sodium (10.2 g, 0.44 moles). Recrystallization from methanol gave the product (15.2 g); mp 52-54C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In PPA; | EXAMPLE 1 2-amino-thiazole-5-carboxylic acid, methyl ester (5 g) was reacted with ethyl 2-methyl-acetoacetate (9.11 g) in polyphosphoric acid (25 g:13.3 g of H3 PO4 and 11.7 g of P2 O5) under stirring at 100 C. for three hours. After cooling, dilution with ice water and neutralization with 20% NaOH, the precipitate was filtered, washed with water and crystallized from CH2 Cl2 -hexane to give 6,7-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester, m.p. 158-159 C. (5.46 g), which was reacted with benzaldehyde (3.52 g) in methanol (120 ml) in the presence of sodium methylate (2.7 g) under stirring at reflux temperature for 120 hours. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium nitrite; In diethyl ether; ethanol; hexane; water; | Production Example 1 Ethyl pyruvate N-(5-methyl-2-nitrophenyl) hydrazone 75.0 g (493 mmol) of <strong>[578-46-1]5-methyl-2-nitroaniline</strong> was added to a mixed solution of 160 ml of water and 170 ml of concentrated hydrochloric acid and the mixture was stirred. To the mixturewas added dropwise 80 ml of an aqueous solution containing 36.0 g (517 mmol) of sodium nitrite at -20C. The reaction solution was added to a solution obtained by dissolving ethyl 2-methylacetoacetate in 100 ml of ethanol and then adding 200 ml of a 12N aqueous potassium hydroxide thereto, at -20C over 30 minutes under stirring. After stirring at the same temperature for 30 minutes, 100 ml of concentrated hydrochloric acid was added thereto. The resulting precipitates were collected by filtration, washed with water and dried under reduced pressure overnight. A mixed solution of diethyl ether and hexane was added thereto and the crystals were collected by filtration, to give 130 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm): 1.29 (3H, t, J=7.2Hz), 2.16 (3H, s), 2.40 (3H, s), 4.25 (2H, q, J=7.2Hz), 6.91 (1H, dd, J=8.8, 2.0Hz), 7.63 (1H, s), 8.07 (1H, d, J=8.8Hz), 10.69 (1H, s) | |
With concentrated hydrochloric acid; sodium nitrite; In diethyl ether; ethanol; hexane; water; | PRODUCTION EXAMPLE 1 Ethyl Pyruvate N-(5-methyl-2-nitrophenyl)hydrazone 75.0 g (493 mmol) of <strong>[578-46-1]5-methyl-2-nitroaniline</strong> was added to a mixed solution of 160 ml of water and 170 ml of concentrated hydrochloric acid and the mixture was stirred. To the mixture was added dropwise 80 ml of an aqueous solution containing 36.0 g (517 mmol) of sodium nitrite at -20 C. The reaction solution was added to a solution obtained by dissolving ethyl 2-methylacetoacetate in 100 ml of ethanol and then adding 200 ml of a 12N aqueous potassium hydroxide thereto, at -20 C. over 30 minutes under stirring. After stirring at the same temperature for 30 minutes, 100 ml of concentrated hydrochloric acid was added thereto. The resulting precipitates were collected by filtration, washed with water and dried under reduced pressure overnight. A mixed solution of diethyl ether and hexane was added thereto and the crystals were collected by filtration, to give 130 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm): 1.29 (3H, t, J=7.2 Hz), 2.16 (3H, s), 2.40 (3H, s), 4.25 (2H, q, J=7.2 Hz), 6.91 (1H, dd, J=8.8, 2.0 Hz), 7.63 (1H, s), 8.07 (1H, d, J=8.8 Hz), 10.69 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; sodium methylate; In methanol; diethyl ether; ethanol; water; | (1) Sodium methoxide (17.5g, 28% in MeOH, 91mmol) was dropwise added to ethanol (55ml) solution of 2-methylacetoacetic acid ethyl ester (4.33g, 30mmol) and formamidine hydrochloride(3.62g, 45mmol), followed by refluxing under heating for 15 hours. After cooling diluted sulfuric acid (concentrated sulfuric acid 4.53g + water 4g) was added, followed by refluxing under heating for 1 hour. After cooling insolubles were filtered off and the filtrate was concentrated. Water was added to the residue, followed by neutralization to pH 7 with aqueous sodium hydrogen carbonate. The mixture was extracted 3 times with chloroform, and the extract was dried and concentrated by evaporation of the solvent. Diethyl ether was added to the residue, and the crystals were collected by filtration to obtain 4-hydroxy-5,6-dimethylpyrimidine (1.82g). m.p.120-121ØC 1H-NMR(DMSO-d6) delta 1.91(3H, s), 2.20(3H, s), 7.92(1H, s), 12.20-12.40(1H, br) IR(Nujol) 1652, 1636, 1609, 1378, 1240, 1200, 1142, 861 cm-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | 7.2 g (0.104 mol) of sodium nitrite dissolved in 40 ml of water are added, at 5 C., to a mixture of 10.7 g (0.1 mol) of 4-methylaniline, 74 ml of 12 N hydrochloric acid and 140 ml of water. The reaction mixture is stirred for 15 minutes at 5 C. and is neutralized by addition of 8.1 g of sodium acetate. 12.33 g (0.085 mol) of ethyl a-methyl acetoacetate and 80 ml of ethanol are introduced into a three-necked Uask, followed, at 0 C., by 4.8 g (0.085 mol) ofpotassium hydroxide dissolved in 20ml ofwater and 100 g of ice. The diazonium solution prepared above is added dropwise, at 0 C., to this reaction mixture and the resulting mixture is left for 18 hours at 0 C. The aqueous phase is extracted 4 times with 50 ml of ethyl acetate and the organic phases are combined and dried over anhydrous sodium sulphate. The residue is taken up in 100 ml of toluene and 16.3 g (0.085 mol) of para-toluene sulphonic acid monohy drate. The mixture is then heated slowly to 110 C. and maintained at this temperature for S hours. After cooling and then addition of saturated sodium carbonate solution, the insoluble material is removed by ltration and the organic phase is separated out after settling has taken place, dried over anhydrous sodium sulphate and concentrated. The residue is chromatographed on a column of silica gel, eluent:30/70 (v/v) dichloromethane/cyclohexane, to give beige coloured crystals; m.p.=94 C.; yield=25percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; chloropyridinecobaloxime(III) In acetonitrile at 20℃; Irradiation; | |
30% | With tris(2,2'-bipyridyl)ruthenium dichloride; oxygen; copper(II) bis(trifluoromethanesulfonate) In toluene at 20℃; Irradiation; Optical yield = 33.333 %de; | |
With copper(II) bis(trifluoromethanesulfonate); 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With toluene-4-sulfonic acid In toluene for 20h; Inert atmosphere; Reflux; | 4.2.39. (S)-(-)-Ethyl 4-oxo-1,2,3-trimethyl-2-cyclohexene-1-carboxylate [(-)-53]26b A mixture of 13.4 g of (S)-(-)-α-methylnaphthylamine (78 mmol), 11.3 g (78 mmol) of ethyl 2-methylacetoacetate and a catalytic amount (75 mg) of p-toluensulfonic acid in 100 mL of dry toluene was heated at reflux for 20 h with azeotropic removal of water using a Dean-Stark trap. After cooling to rt, ∼200 mg of solid NaHCO3 was added and the solution was filtered through a pad of silica gel using hexanes/EtOAc 4:1 containing 2% Et3N as eluent. Evaporation of the solvent at reduced pressure afforded 20.7 g (89%) of vinylogous carbamate ( +299 (c 5.5, CH3OH)).26b |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In 1,4-dioxane at 150℃; for 1.5h; Microwave irradiation; | 41 Preparation of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-oxobutanamide (Compound 499) Example 41 Preparation of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-oxobutanamide (Compound 499) To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine, HCl (259 mg, 1 mmol) and ethyl 2-methyl-3-oxobutanoate (144 mg, 1.000 mmol) in dioxane (1 mL) was added 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (181 mg, 1.30 mmol) and the mixture was heated in a microwave (CEM Discover) at 150° C. for 1.5 h, with external IR-sensor temperature monitoring from the bottom of the vessel. LCMS (ELSD) indicated a 40% conversion to the desired product. The mixture was diluted with ethyl acetate (50 mL) and saturated aqueous NH4Cl (15 mL), and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL) and the combined organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to give an oily residue. This residue was purified on silica gel eluting with mixtures of ethyl acetate and hexanes to give N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methyl-3-oxobutanamide (37 mg, 11% yield, 96% purity) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 9.02-8.92 (dd, J=2.6, 0.8 Hz, 1H), 8.68-8.60 (dd, J=4.8, 1.5 Hz, 1H), 8.09-7.98 (m, 1H), 7.96-7.87 (s, 1H), 3.87-3.58 (d, J=3.0 Hz, 2H), 3.49-3.38 (m, 1H), 2.16-2.08 (s, 3H), 1.39-1.32 (d, J=7.0 Hz, 3H), 1.22-1.13 (m, 3H); EIMS (m/z) 321 ([M+1]+), 319 ([M-1]-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With boron trifluoride diethyl etherate; at 135℃; for 0.0833333h;Neat (no solvent); Microwave irradiation; | General procedure: A beta-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 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-acetylpropanoic acid ethyl ester; 2,4-difluoroethynylbenzene In toluene at 90℃; for 60h; Molecular sieve; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran at 23℃; for 18h; | 2.A Example 2; Preparation of 5-bromo-4-(2,4-difluorophenyl)-3,6-dimethyl-2H-pyran-2-oneStep A: Preparation of 4-(2,4-difluorophenyl)-3,6-dimethyl-2H-pyran-2-oneTo a mixture solution of ethyl 2-methylacetoacetate (1.25 g, 8.68 mmol) and 2,4-difluorophenylacetylene (1.3 g, 6.1 mmol) in toluene (10 mL) was added 4 molecular sieves (400 mg) and ReBr(CO)3(thf)2 (180 mg, 0.21 mmol). The reaction mixture was heated at 90° C. for 60 h, after which time tetrabutylammonium fluoride (0.5 M in tetrahydrofuran, 0.5 mL) was added and stirring was continued at 23° C. for 18 h. The reaction mixture was concentrated onto silica gel and then purified by column chromatography (10:1 hexanes/ethyl acetate as eluant) to provide the title compound as a solid (1.3 g).1H NMR (CDCl3) δ 1.95 (s, 3H), 2.26 (s, 3H), 5.89 (s, 1H), 6.97 (m, 2H), 7.22 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetic acid; at 20℃; for 2h; | General procedure: A mixture of 2-hydrazino-5-methyl-benzimidazole (3, 1.0g, 6.17mmol) and ethyl 2-acetyl-3-phenylpropanoate (4, 1.4mL, 6.59mmol) in acetic acid (20mL) was stirred for 2h at ambient temperatures. To a mixture of acetonitrile (100mL) and water (100mL) was added the reaction mixture. After stirring at ambient temperatures, the resulting precipitates were collected by filtration and washed with acetonitrile in water (1:1). The precipitates was purified by recrystallization from ethanol (95mL) to generate 3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-4-benzyl-1H-pyrazol-5-ol (35, 0.64g, 32.6%). The other compounds studied in this work (5-52) were prepared in a similar manner. The typical experimental procedure for synthesizing and evaluating the compounds used in this study, in addition to the analytical data and the estimated purity (HPLC) of the biologically relevant compounds, are provided in Supplemental data and Table S1, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetic acid at 20℃; for 2h; | The representative procedure for synthesizing the compounds studied in this work is as follows: General procedure: A mixture of 2-hydrazino-5-methyl-benzimidazole (3, 1.0g, 6.17mmol) and ethyl 2-acetyl-3-phenylpropanoate (4, 1.4mL, 6.59mmol) in acetic acid (20mL) was stirred for 2h at ambient temperatures. To a mixture of acetonitrile (100mL) and water (100mL) was added the reaction mixture. After stirring at ambient temperatures, the resulting precipitates were collected by filtration and washed with acetonitrile in water (1:1). The precipitates was purified by recrystallization from ethanol (95mL) to generate 3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-4-benzyl-1H-pyrazol-5-ol (35, 0.64g, 32.6%). The other compounds studied in this work (5-52) were prepared in a similar manner. The typical experimental procedure for synthesizing and evaluating the compounds used in this study, in addition to the analytical data and the estimated purity (HPLC) of the biologically relevant compounds, are provided in Supplemental data and Table S1, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetic acid; at 20℃; for 2h; | General procedure: A mixture of 2-hydrazino-5-methyl-benzimidazole (3, 1.0g, 6.17mmol) and ethyl 2-acetyl-3-phenylpropanoate (4, 1.4mL, 6.59mmol) in acetic acid (20mL) was stirred for 2h at ambient temperatures. To a mixture of acetonitrile (100mL) and water (100mL) was added the reaction mixture. After stirring at ambient temperatures, the resulting precipitates were collected by filtration and washed with acetonitrile in water (1:1). The precipitates was purified by recrystallization from ethanol (95mL) to generate 3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-4-benzyl-1H-pyrazol-5-ol (35, 0.64g, 32.6%). The other compounds studied in this work (5-52) were prepared in a similar manner. The typical experimental procedure for synthesizing and evaluating the compounds used in this study, in addition to the analytical data and the estimated purity (HPLC) of the biologically relevant compounds, are provided in Supplemental data and Table S1, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; for 16h;Reflux; | Synthesis of 3,4-Dimethyl Pyrazalinone Compounds [00375] 3,4-Dimethyl pyrazalinone compounds were synthesized as illustrated in Scheme 3, below: Scheme 3 [00376] Compound 140 (4-(3,4-dimethyl-5-oxo-4,5-dihydro-lH-pyrazol-l-yl)benzoic acid) was synthesized from Compounds 60 and 130 as follows. A 40mL vial was charged with 400mg 4- hydrazine benzoic acid hydrochloride (2.13 mmol, 1 equiv) followed by 5mL acetic acid and 2.13 mmol of ethyl 2-methyl-3-oxobutanoate and heated to reflux. The reaction was allowed to stir for 16hr and then cooled to room temperature, upon which pink crystals formed. The crystals were collected by filtration, washed with cold acetic acid, and pumped on overnight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 25℃; for 26h; | To a mixture of ethyl acetoacetate (5.0 mmol) and phenyl trifluoromethyl ketone (0.5mmol) was added DBU (0.1 mmol), and the mixture was stuffed at RT (25 C) until 1 was consumed (monitored by TLC), 24h. The reaction mixture was diluted with hexane-EtOAc and purified by silica gel flash column chromatography (hexane/EtOAc = 8:1 to 4:1) to give 4a (126.0 mg, 83%).To a mixture of ethyl acetoacetate (9.48 mL, 75.0 mmol, 5.0 equiv) and la (2.11 mL, 15.0 mmol, 1.0 equiv) was added DBU (224 1iL, 1.50 mmol, 0.1 equiv), and the mixture was stirred at RT (25 C) for 4 days. The reaction mixture was diluted with hexane-EtOAc and purified by silica gel flash column chromatography (hexane/EtOAc = 15:1 to 8:1) to give 4a (3.29 g, 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dmap In toluene at 20℃; for 0.25h; Microwave irradiation; | |
71% | With dmap In toluene at 20℃; for 0.25h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (2R,2'R)-2,2'-((2-iodo-1,3-phenylene)bis(oxy))bis(1-(piperidin-1-yl)propan-1-one); 3-chloro-benzenecarboperoxoic acid; trifluoroacetic acid; In chloroform; at -20℃; for 48h;Inert atmosphere; | General procedure: In an oven-dried flask equipped with a stir bar were placed the alpha-substituted beta-keto ester 2 (0.5 mmol, 1 equiv), catalyst 1d (24.5 mg, 0.05 mmol, 10 mol%), the corresponding sulfonic acid (0.55 mmol, 1.1 equiv), and trifluoroacetic acid (0.115 mL, 1.5 mmol, 3 equiv) in CHCl3 (1 mL) under an inert atmosphere. MCPBA (77%, 202 mg, 0.9 mmol, 1.8 equiv) was then added at -20 C and the reaction mixture was stirred for 24 h or 48 h. At the end of the reaction, H2O (5 mL) was added to the mixture, which was stirred at r.t. for 15 min. The mixture was diluted with CH2Cl2, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 ×). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (pentane-EtOAc) to afford the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium carbonate; In water; at 20℃; for 0.25h;Microwave irradiation; | General procedure: The corresponding amidine hydrochloride (2.54 mmol) and powdered K2CO3 (5.76 mmol) were dissolved in water (5.0 mL) in a 20-mL vessel. The beta-keto ester (2.31 mmol) was added and the resulting mixture was irradiated for 5-15 min (see Table 2). Upon the end of the reaction (TLC, hexanes/EtOAc, 5:1), the mixture was diluted with sat. aq NH4Cl (5.0 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were dried (anhyd Na2SO4) and filtered. The filtrate was rotary evaporated and the obtained crude product was purified by column chromatography [silica gel, hexane/EtOAc mixtures or recrystallized (EtOH)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: 2-acetylpropanoic acid ethyl ester; (E)-tert-butyl 3-(2-ethoxy-2-oxoethylidene)-2-oxoindoline-1-carboxylate With 3-((3,5-bis(trifluoromethyl)benzyl)amino)-4-(((1S)-(6-methoxyquinolin-4-yl)((2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)amino)cyclobut-3-ene-1,2-dione In tetrachloromethane at 0℃; for 24h; Stage #2: 4-oxo-but-2-enoic acid ethyl ester With morpholine In tetrachloromethane at 0℃; for 24h; | General Procedure for the Synthesis of Spirocyclohexane Oxindoles General procedure: A suspension of oxoindole derivative (2, 0.20 mmol) and cat. 6a (0.01 mmol, 5 mol %) in anhydrous CCl4 (0.2 mL, 1 M) was cooled to 0 oC before added with 1,3-dicarbonyl compound (1, 0.4 mmol). The reaction mixture was stirred vigurously for 24 hours at 0 oC, then α,β-unsaturated aldehyde (3, 0.6 mmol) and morpholine (cat. 7e, 50 mol %) were added successfully. After 24 hours, the reaction mixture was purified on silica gel to afford the desired product directly. The racemic samples were prepared by using the mixture of quinine and quinidine (1:1, 20 mol %), morpholine (50 mol %) as the catalyst combination. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-acetylpropanoic acid ethyl ester; (E)-tert-butyl 3-(2-ethoxy-2-oxoethylidene)-2-oxoindoline-1-carboxylate With quinindine; quinine In tetrachloromethane at 0℃; for 24h; Stage #2: 4-oxo-but-2-enoic acid ethyl ester With morpholine In tetrachloromethane at 0℃; for 24h; | General Procedure for the Synthesis of Spirocyclohexane Oxindoles General procedure: A suspension of oxoindole derivative (2, 0.20 mmol) and cat. 6a (0.01 mmol, 5 mol %) in anhydrous CCl4 (0.2 mL, 1 M) was cooled to 0 oC before added with 1,3-dicarbonyl compound (1, 0.4 mmol). The reaction mixture was stirred vigurously for 24 hours at 0 oC, then α,β-unsaturated aldehyde (3, 0.6 mmol) and morpholine (cat. 7e, 50 mol %) were added successfully. After 24 hours, the reaction mixture was purified on silica gel to afford the desired product directly. The racemic samples were prepared by using the mixture of quinine and quinidine (1:1, 20 mol %), morpholine (50 mol %) as the catalyst combination. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of <strong>[53324-38-2]4-bromo-3-nitroaniline</strong> (4.00 g, 18.4 mmol) in water (8 mL) and concentrated aqueous hydrochloric acid solution (9.5 mL) at 0 C was added dropwise a solution of sodium nitrite (1.40 g, 20.3 mmol) in water (6.5 mL). In a separate flask, a solution of aqueous 50% (w/w) potassium hydroxide (3.10 g, 55.3 mmol) was added to a solution of ethyl 2- methyl-3-oxobutanoate (2.70 g, 18.4 mmol) in ethanol (24 mL) at 0 C, followed by cold water (48 mL). The resulting solution was stined at 0 C for 10 mm before the aforementioned solution of the diazonium saltwas added. After 10 mm, the precipitate was filtered, washed by water and dried to give the title compound.MS: m/z = 329.9, 331.9 (M + 1).?H NMR (400 MHz, CD3OD) oe7.73-7.83 (m, 1H), 7.60-7.69 (m, 1H), 7.37-7.51 (m, 1H), 4.29 (q, J = 7.3 Hz, 2H), 2.12 (s, 3H), 1.34 (t,J= 7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of <strong>[7138-15-0]3-bromo-2-nitroaniline</strong> (20 g, 92 mmol) in water (32 mL) and concentrated aqueous hydrochloric acid solution (38 mL) at 23 C was added a solution of sodium nitrite (6.68 g, 97 mmol) in water (25 mL) dropwise. In a separate flask, an aqueous solution of 50% (w/w) potassium hydroxide (15.5 g, 276 mmol) was slowly added to a solution of ethyl 2-methyl-3-oxobutanoate (13 g, 92 mmol) in ethanol (95 mL) at 0 C, followed by ice- cold water (190 mL). The resulting mixture was stined for 10 mm before the aforementioned solution of the diazonium salt was added. The resulting mixture was stined for 10 mm. The precipitate was filtered and washed with water until the filtrate was pH 7 by a litmus test. The solid was dissolved in acetonitrile and water and lyophilized to give the title compound. MS:m/z = 330.1, 332.1 (M + 1). ?H NMR (400 MHz, CD3OD) oe 7.27-7.35 (m, 2H), 6.84-6.89 (m, 1H), 4.23 (q,J= 6.8 Hz, 2H), 2.07 (s, 3H), 1.33 (t,J= 6.8 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 57% 2: 71 % ee | With 1-hydroxy-1,2-benzodioxol-3-(1H)-one; tris(bipyridine)ruthenium(II) dichloride hexahydrate; CHF3O3S*C10H24N2 In dichloromethane at 20℃; for 48h; Inert atmosphere; Schlenk technique; Irradiation; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With boron trifluoride diethyl etherate; at 0 - 20℃; for 2.0h; | General procedure: A mixture of N-(hydroxymethyl)-4-methoxybenzamide (2.0 g, 11 mmol, 1 equiv) and ethylbenzoylacetoacetate (1.9 mL, 11 mmol, 1 equiv) was cooled to 0 C and BF3·OEt2 solution(2.7 mL, 22 mmol, 2 equiv) was added slowly with stirring. The reaction mixture was left tostir at room temperature for 2 h. The resulting mixture was added to a solution of sodiumacetate (4 g) in water (8 mL) mixed well and allowed to separate. The aqueous layer wasextracted twice with CH2Cl2 (10 mL). The organic layers were dried over anhydrous MgSO4and the solvents were removed under vacuum to provide 7b as a yellow wax (3.7 g, 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100 g | With polyphosphoric acid; at 170℃; for 4h; | Ethyl 2-methylacetoacetate 144.1 g and equimolar2-Methyl-4-heptafluoroisopropylaniline added to 2000mlIn a three-necked flask,Add 1.5 times the amount of polyphosphoric acid to the system,The reaction system was slowly heated to 100 C under stirring, and the system was reacted for 1 h.Then the temperature is raised to 170 C, and the reaction system continues to react for 3 h.The system is then cooled to 80 C, then slowly poured into cold water, filtered, washed,Drying gave 100 g of a white solid. After testing, the obtained white solid is2,3,8-trimethyl-6-heptafluoroisopropyl-4-hydroxyquinoline,The nuclear magnetic data is as follows: |
100 g | With polyphosphoric acid; at 100 - 170℃; for 4h; | Adding 144.1 g of ethyl 2-methylacetoacetate and equimolar <strong>[238098-26-5]2-methyl-4-heptafluoroisopropylaniline</strong> toIn a 2000 ml three-necked flask, 1.5 times the amount of polyphosphoric acid was added to the system, and the reaction system was slowly heated to 100 C under stirring, and the system was reacted for 1 h.Then the temperature is raised to 170 C, the reaction system continues to react for 3 h, and then the system is cooled to 80 C.Then slowly pour into cold water, filter, wash,Drying gave 100 g of a white solid. Tested,The white solid obtained was 2,3,8-trimethyl-6-heptafluoroisopropyl-4-hydroxyquinoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With PPA; at 150℃; for 4h; | The mixture of <strong>[42265-67-8]4-(tert-butyl)-2-chloroaniline</strong> (7.32g, 0.04mol), ethyl 2-methyl-3-oxobutanoate (5.76 g, 0.04 mol)) and PPA (8.30 g) was stirred at 150 C for 4 h, TLC monitor. Then it was poured into water, the intermediate 1 was afforded with yield 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Weigh 500 mg of <strong>[52068-30-1]4-benzyloxyphenylhydrazine hydrochloride</strong> (2 mmol),Add to 10 mL of H2O, stir for 30 min, add 80 mg of equimolar amount of NaOH, and stir for 30 min.To the above reaction solution, 2-methylacetoacetate (247 mg,1.9mmol), the temperature was raised to reflux reaction for 2.5h, and the heating was stopped.Cool to room temperature, filter, and filter residue with petroleum ether: EtOAc (5:1).Petroleum ether: EtOAc (3:1) washed, dried,A pale yellow solid of 350 mg was obtained. Yield: 63percent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of sodium nitrite (9.95?g, 144?mmol) in water (27?mL) was added to a mixture of 23 (29.0?g, 131?mmol), water (223?mL) and conc. HCl (65.7?mL, 657?mmol) at 0?C. The mixture was stirred for a further 10?min?at 0?C, then added to a stirred mixture of ethyl 2-methylacetoacetate (19.8?g, 138?mmol), sodium acetate (112?g, 1.37?mol), EtOH (163?mL), and ice (133?g, freshly added just before mixing) at 0?C (bath temperature). The final reaction mixture was stirred at 0?C for 5?min, then at 20?C for 1?h 40?min. Solid Na2CO3 was added to give a pH of approximately 7-8. The mixture was extracted with CH2Cl2 (2?*?300?mL) and the extracts were washed with cold water (400?mL), then dried (Na2SO4) and evaporated to give a red oil. To the oil was added EtOH (60?mL) and HCl-saturated EtOH (100?mL). The mixture was stirred at reflux for 30?min, then cooled and evaporated under reduced pressure to give a dark solid. Water (200?mL) was added and the aqueous mixture was basified at 0?C with 10% aqueous Na2CO3 solution to a pH of approximately 7-8. The resulting pale orange solid was filtered off, washed with water (5?*?80?mL), and dried to give 24 as a yellow solid (35.9?g, 86%); mp 130-132?C; deltaH (CDCl3) 8.78 (br s, 1H), 7.30 (d, J?=?8.9?Hz, 1H), 7.13 (dd, J?=?2.1, 0.8?Hz, 1H), 7.08 (d, J?=?2.4?Hz, 1H), 7.01 (dd, J?=?8.9, 2.4?Hz, 1H), 4.40 (q, J?=?7.1?Hz, 2H), 4.15 (t, J?=?5.8?Hz, 2H), 3.77-3.71 (m, 4H), 2.83 (t, J?=?5.7?Hz, 2H), 2.63-2.57 (m, 4H), 1.41 (t, J?=?7.1?Hz, 3H); consistent with that reported [11]. [Found: C, 63.82; H, 7.23; N, 8.91. C17H22N2O4 requires C, 64.14; H, 6.97; N, 8.80]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
585 mg | A solution of NaN02 (2.320 g, 33.6 mmol) in water (NaN02) (8.69 ml, 482 mmol) was added dropwise over 20 minutes to 4-fluoro-2-nitroaniline (5 g, 32.0 mmol) in water (aniline) (11.14 ml, 618 mmol) and HCI cone. (13.15 ml, 160 mmol. In a separate containing ethyl 2-methylacetoacetate (4.66 ml, 32.0 mmol) in EtOH (33.1 ml, 567 mmol) cooled to 0-5 C was added dropwise KOH 45%wt. in water (8.23 ml, 96 mmol) followed by ice-cold water (66.1 ml, 3667 mmol) and It was stirred for 10 minutes. To this solution was added the 1st solution dropwise and stirred overnightAn orange suspension and big black chunks were formed. The reaction mixture was extracted with Et20 (3 x 100 mL) and the combined organic layers were washed with water (2 x 100 mL) then with brine (100 mL). The organic layer was dried over MgS04, filtered and concentrated to dryness to give crude ethyl (E)-ethyl 2-(2-(4-fluoro-2- nitrophenyl)hydrazono)propanoate (7.30 g, 27.1 mmol, 85 % yield). The previous compound in polyphosphoric acid (41.5 ml, 873 mmol) was heated to 110 C for 1 hour then cooled to 75 C. After 3 hrs, the mixture was cooled to 20 C and water (100 mL) was added and stirred for 30 minutes. EA was then added (600 mL) and the aqueous phase was neutralized with sat. NaHC03 (300 mL) (not close to neutral pH). More water was added (500 mL) and then solid NaHC03 (ca. 250 g). More water (500 mL) and EtOAc (500 mL) were added and the mixture was filtered. The solid was washed solids with Water (500 mL) and EtOAc (500 mL). The layers were separated and the organic layer was washed with water (500 mL) and with brine (300 mL). The organic layer was dried over MgSC>4, filtered and concentrated to give 3.42 g as a brown solid. The residue was purified on ISCO using a RediSep Gold column (Hex/EtOAc) . The crude product was dissolved and loaded onto a pre-column (dissolved crude in EtOAc). A second purification was needed to yield ethyl 5-fluoro-7-nitro-1 H-indole-2-carboxyiate (585 mg, 8.55 % yield). 1H NMR (DMSO-d6) delta: 11.59 (br. s., 1 H), 8.18 (dd, J = 9.0, 2.3 Hz, 1 H), 8.12 (dd, J = 8.6, 2.3 Hz, 1 H), 7.44 (s, 1 H), 4.39 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | To a mixture of <strong>[5228-61-5]5-bromo-2-nitroaniline</strong> (5 g, 23 mmol) in 9 mL water and 8 mL concentrated aqueous hydrochloric acid in the ice bath was added a solution of sodium nitrite (1.7 g, 30 mmol) in 5 mL water dropwise. Then, another flask, 50% potassium hydroxide (3.1 g, 69 mmol) was slowly added to a solution of ethyl-2-methyl-3-oxobutanoate (3.3 g, 23 mmol) in 20 mL EtOH. To this mixture was added 40 mL ice water, stirred for 30 min. The diazonium solution was dropped to the later solution, continue stirring 30 min. The precipitate was filtered and wash with water, the solid was dried by vacuum drier to give title compound S2-2 (3.9 g, 53%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hydrogencarbonate; In dimethyl sulfoxide; at 110.0℃; for 48h; | A solution of l-(7-methoxy-4-methylquinazolin-2-yl) guanidine (compound 2) (3.2 g, 13.8 mmol), ethyl 2-methyl-3-oxobutanoate (2.3 inL, 16.2 mmol), NaHC03(1.43 g, 17 mmol) in DMSO (22 inL) was heated at 110 C for 48 h. After cooling at room temperature cold water was added. The precipitate formed was filtered off and purified by column chromatography (DCM/ MeOH 100:0 -> 98:2) to afford the madrasin 3 as a beige powder. Yield: 83% (3.58 g, 11.5 mmol). Mp 216.4-217.5 C. TLC R f: 0.26 (DCM/MeOH 98:2). *H NMR (300 MHz, CDC13) d 13.25 (s, 1H), 8.54 (s, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.17 (d, / = 2.5 Hz, 1H), 7.07 (dd, / = 9.1, 2.5 Hz, 1H), 3.98 (s, 3H), 2.80 (s, 3H), 2.27 (s, 3H), 2.06 (s, 3H). HRMS (ESI) (M + H)+ m/z calculated for C16H18N5O2312.1462, found 312.1458. |
Tags: 609-14-3 synthesis path| 609-14-3 SDS| 609-14-3 COA| 609-14-3 purity| 609-14-3 application| 609-14-3 NMR| 609-14-3 COA| 609-14-3 structure
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