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CAS No. : | 1679-47-6 | MDL No. : | MFCD00005396 |
Formula : | C5H8O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QGLBZNZGBLRJGS-UHFFFAOYSA-N |
M.W : | 100.12 | Pubchem ID : | 98323 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 25.32 |
TPSA : | 26.3 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) : | -6.38 cm/s |
Log Po/w (iLOGP) : | 1.39 |
Log Po/w (XLOGP3) : | 0.75 |
Log Po/w (WLOGP) : | 0.57 |
Log Po/w (MLOGP) : | 0.5 |
Log Po/w (SILICOS-IT) : | 1.32 |
Consensus Log Po/w : | 0.91 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.93 |
Solubility : | 11.7 mg/ml ; 0.117 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.88 |
Solubility : | 13.1 mg/ml ; 0.131 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.7 |
Solubility : | 20.2 mg/ml ; 0.201 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.51 |
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 |
---|---|---|
55% | Stage #1: at 130℃; Stage #2: With hydroxylamine hydrochloride In water at 40 - 130℃; for 12 h; |
Next, an internal volume of 100 ml equipped with a thermometer, cooling tube and receiver Was charged with 30 ml of the above reaction solution. Next, 1000 ppm of sodium hydroxide was added to the mass of the reaction solution, The reaction pressure was adjusted to 13 kPa and the reaction temperature to 130 ° C., The reaction was carried out while distilling off the methanol formed. 1.5 hours after the start of the reaction, the reaction solution in the flask was subjected to gas chromatography As a result of analyzing by analysis, the conversion of methyl 4-hydroxy-2-methylbutyrate was 95.6percent, and the selectivity to α-methyl-γ-butyrolactone was 98percent. At this time, methyl 3-formyl-2-methylpropionate and Methyl 2-formyl-2-methylpropionate The combined concentration was 1.6 wtpercent (0.04 mmol). (Example 1) 20 ml of the reaction solution obtained in the cyclization step (C) of Production Example 1 was charged in a 100 ml three-necked flask equipped with a thermometer, a cooling tube and a receiver, and 9 mg of hydroxylamine hydrochloride dissolved in 5 ml of distilled water ( 0.16 mmol), and the mixture was stirred at 40 ° C. for 12 hours. Distillation was performed on the obtained reaction liquid using a 10-stage distillation column at a heat medium temperature of 130 ° C., a reflux ratio of 30, and a reduced pressure degree of 1.3 kPa. as a result, Α-methyl-γ-butyrolactone having a purity of not less than 99.9percent It can be obtained with a distillation yield of 55percent Methyl 3-formyl-2-methylpropionate and 2- The combined content of methyl formyl-2-methylpropionate is It was 10 ppm or less, which was below the detection limit |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.9 - 21.5 %Chromat. | at 300 - 348℃; for 3 h; | A mixture of isopropanol (38.73percent), water (36.74percent), and FTHF (23.81percent) was fed into a one inch tubular reactor filled with Cu/ZrO2 catalyst (130ml catalytic bed) at 37.3-39.4 ml/hr rate at 300-344°C and 800 psi hydrogen pressure. The product was collected every 3 hrs and analyzed by GC. The yield and production rates at full conversion are shown in the Table 3. EXAMPLE 6Reduction of FTHF with Hydrogen, Continuous Run, Repetition of Example 5 Copper / Zirconia Catalyst and secondary alcohol A mixture of isopropanol (21.91percent), water (44.81percent), FTHF (30.86percent) was fed into a one inch tubular reactor filled with Cu/ZrO2 catalyst (130ml catalytic bed) at 37.7-38.8 ml/hr rate at 310-348°C and 800 psi hydrogen pressure. The product was collected every 3hrs and analyzed by GC. The selectivity and production rates are shown in the Table 4. EXAMPLE 7Reduction of FTHF with Hydrogen, Continuous Run, Repetition of Example 5 Copper / Zirconia Catalyst and secondary alcohol A mixture of isopropanol (10.91percent), water (50.88percent), FTHF (35.2percent) was fed into a one inch tubular reactor filled with Cu/ZrO2 catalyst (130ml catalytic bed) at 39.4 ml/hr rate at 310-320°C and 800 psi hydrogen pressure. The product was collected after 3hrs run and analyzed by GC. The selectivity and production rates are shown in the Table 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With thionyl chloride; zinc(II) chloride at 65℃; for 65h; | |
With hydrogenchloride; thionyl chloride | ||
With hydrogenchloride; thionyl chloride for 504h; |
With thionyl chloride; zinc(II) chloride | ||
With thionyl chloride | 1.A A. A. 2-Methyl-4-chlorobutyric acid chloride To a stirring solution of 77 g of α-methyl-γ-butyrolactone and 1 g of zinc chloride was added 120 g of thionyl chloride. The reaction was allowed to stir at room temperature for about 16 hours and then was heated to 75°-80° C. for 24 hours. The reaction mixture was distilled at 10 mm pressure to provide 2-methyl-4-chlorobutyric acid chloride. bp=57°-60° C. | |
With thionyl chloride; zinc(II) chloride at 80℃; for 15h; | 22.22a Example 22; 1- (4-{(2S)-3-[(6-Chloronaphthalen-2-yl)sulfonyl]-2- hydroxypropanoyl} piperazin-1-yl)-3-methylpyrrolidin-2-one; 22a) 1-(4-Benzylpiperazin-1-yl)-3-methylpyrrolidin-2-one; A mixture of 3-methyldihydrofuran-2 (3H)-one g), thionyl chloride (1.5 ml) and zinc chloride (10 mg) was stirred at 80°C for 15 hours. The mixture was cooled to room temperature, and the reaction mixture was added dropwise to a solution of 4-benzylpiperazin-1-amine (3.8 g) in THF (50 mL) at 0°C, followed by stirring at 0°C for 2 hours. Sodium hydride (60% in oil; 2.4 g) was added thereto and the mixture was stirred at room temperature for 15 hours. Ice was. added thereto, and then the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by basic silica gel column chromatography (ethyl acetate/hexane = 1/5) to obtain the title compound (2.0 g, 37%) as a yellow oil. NMR (CDC13) 5: 1.18 (3H, d, J = 7.2), 1.48-1.63 (lH, m), 2.12-2.29 (lH, m), 2.28-2.49 (lH, m), 2.62 (4H, dd), 2.84- 3.08 (4H, m), 3.26-3.47 (2H, m), 3.48-3.64 (2H, m), 7.20- 7.40 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrogen bromide for 72h; Ambient temperature; | |
84% | With hydrogen bromide for 17h; Ambient temperature; | |
(i) aq. HBr, (ii) /BRN= 1718733/, HCl; Multistep reaction; |
With hydrogen bromide at 20℃; for 72h; | 15.A Step A: ethyl 4-bromo-2-methylbutanoateTo a HBr saturated solution of EtOH (100 mL) at 0 °C was added a-methyl~y- butyrolactone (3.0 mL, 31.7 mmol). The mixture was allowed to stir at rt for 3 days and then poured onto ice (500 g). After warming to rt, the mixture was extracted with Et20 (2x200 mL). The combined organic layer was further washed with H20 (300 mL) sat. NaHC03 (3x300 mL) and brine (300 mL), dried over MgSC>4, and concentrated to give the title compound, which was used without further purification: 1H NMR (500 MHz, CDC13) δ 4.15 (q, J= 7.1 Hz, 2H), 3.43 (dt, J= 1.1, 6.9 Hz, 2H), 2.68 (m, 1H), 2.26 (m, 2H)5 1.93 (m, 2H), 1.26 (t, J= 7.0 Hz, 3H), 1.19 (d, J= 7.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogenchloride at 0 - 20℃; | |
95% | With hydrogenchloride for 17h; Ambient temperature; | |
With hydrogenchloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With hydrogenchloride; oxygen; copper dichloride In tetrahydrofuran Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; tin(ll) chloride; palladium dichloride; 1,3,5-trimethyl-benzene 1) acetonitrile, 90 deg C, 100 psi, 2 h; 2) 18.5 h; Yield given. Multistep reaction. Yields of byproduct given; | ||
54.6 mg | Stage #1: homoalylic alcohol for 0.5h; Inert atmosphere; Molecular sieve; Stage #2: carbon monoxide With (acetylacetonato)dicarbonylrhodium (l); diphenylphosphinous acid methyl ester; hydrogen; lithium chloride In toluene at 40℃; for 20h; Molecular sieve; Stage #3: With aluminum oxide; sodium acetate; pyridinium chlorochromate In dichloromethane at 20℃; for 12h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In benzene at 80℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In benzene Heating; | |
1: 55% 2: 45% | With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In neat (no solvent) Heating; | |
With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride at 80℃; for 0.5h; Yield given. Yields of byproduct given. Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 3-methyltetrahydro-2-furanone With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.533333h; Inert atmosphere; Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; Enzymatic reaction; | |
67% | With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 20℃; for 2h; | |
With n-butyllithium; diisopropylamine 1.) THF, -78 deg C, 10 min, 2.) 3 h, warm. to RT; Yield given. Multistep reaction; |
Stage #1: 3-methyltetrahydro-2-furanone With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1.08333h; Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane at -78 - 20℃; for 6h; | ||
Stage #1: 3-methyltetrahydro-2-furanone With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane at -78 - 20℃; for 20h; Inert atmosphere; | ||
Stage #1: 3-methyltetrahydro-2-furanone With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane at -78 - 22℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With n-butyllithium In tetrahydrofuran at -78℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylsilane In dichloromethane 1) -78 deg C, 2) -23 deg C; | |
71% | With triethylsilane In dichloromethane -78 deg C -> 23 deg C-r.t.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With aluminum (III) chloride In dichloromethane | |
69% | Stage #1: N-methylaniline With aluminium trichloride In dichloromethane at 0℃; Stage #2: 3-methyltetrahydro-2-furanone In dichloromethane at 20℃; for 5h; | |
With aluminium trichloride 1.) 1,2-dichloroethane, 15-25 deg C, 2.) r.t., 3 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 3-methyltetrahydro-2-furanone With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1.5h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at -78 - 20℃; Inert atmosphere; | |
65% | Stage #1: 3-methyltetrahydro-2-furanone With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran at -78 - 20℃; Inert atmosphere; | |
With lithium diisopropyl amide 1.) THF, -78 deg C, 30 min, 2.) THF, HMPA, a) -78 deg C, 4 h, b) RT, overnight; Yield given. Multistep reaction; |
With sodium hydride In 1,4-dioxane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid In methanol at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With diisobutylaluminium hydride In tetrahydrofuran; diethyl ether at -20℃; | |
92% | With diisobutylaluminium hydride In dichloromethane; toluene at -78℃; for 1h; | |
92% | With diisobutylaluminium hydride In hexanes; dichloromethane at -78℃; Inert atmosphere; |
81% | With diisobutylaluminium hydride In dichloromethane at -78℃; for 0.5h; Inert atmosphere; | |
80% | With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 1h; Inert atmosphere; | |
80% | Stage #1: 3-methyltetrahydro-2-furanone With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 1h; Inert atmosphere; Stage #2: With water; Rochelle's salt In hexane; dichloromethane; ethyl acetate at 23℃; for 2h; Inert atmosphere; | |
78% | With diisobutylaluminium hydride In toluene at -78℃; for 3h; | |
75% | With diisobutylaluminium hydride In dichloromethane at -78℃; for 4h; | |
With diisobutylaluminium hydride In tetrahydrofuran; toluene | ||
With diisobutylaluminium hydride In hexane | ||
With diisobutylaluminium hydride In toluene at -70℃; for 1h; | ||
With diisobutylaluminium hydride In hexane; n-heptane at -78 - 20℃; | ||
With diisobutylaluminium hydride In dichloromethane at -70℃; for 0.5h; | ||
With diisobutylaluminium hydride In tetrahydrofuran at -20℃; | ||
With diisobutylaluminium hydride In tetrahydrofuran; methanol | 1 (EXAMPLE 1) Synthesis of 2-chloro-3-methyltetrahydrofuran Subsequently, 50 mL of a THF solution (1.0 mol/L) of diisobutylaluminum hydride was added to an ether solution (50 mL) of the 3-methyltetrahydrofuran-2-one (4 g) at -20°C, and the resulting mixture was stirred for 1.5 hours. The internal temperature was returned to room temperature and methanol (35 mL) was added to the mixture. A precipitated solid was separated by filtetration, and the filtetrate was concentrated to prepare 3-methyltetrahydrofuran-2-ol (4.6 g). | |
With diisobutylaluminium hydride In dichloromethane at -78℃; for 6h; | ||
With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 1h; Inert atmosphere; | ||
With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 5h; Inert atmosphere; | 2.1 Step 1: Synthesis of 3-methyloxacyclopentan-2-ol of the formula (10) from α-methyl-γ-butyrolactone of the formula (9) 5.0 g (50 mmol) of α-methyl-γ-butyrolactone of the formula (9) and 150 ml of dichloromethane were charged in a 300 ml three-necked flask,And the mixture was cooled and stirred at -78 ° C. under a nitrogen atmosphere.70 ml (1.0 M, 70 mmol) of a hexane solution of diisobutylaluminum hydride (DIBAL) was added dropwise thereto,And the mixture was stirred at the same temperature for 5.0 hours.After disappearance of the raw material was confirmed by TLC, 48 ml of methanol was added dropwise at a rate keeping the in-system temperature -50 ° C. or lower.After stirring overnight while gradually raising the temperature, filtration under reduced pressure was carried out, and the filtrate obtained was concentrated under reduced pressure to obtain 4.15 g of a crude product of 3-methyloxacyclopentan-2-ol of the formula (10). This was used in the next step without further purification. | |
With diisobutylaluminium hydride In tetrahydrofuran; dichloromethane at -78℃; for 1h; Schlenk technique; Inert atmosphere; | ||
With diisobutylaluminium hydride In dichloromethane at -78℃; for 2.5h; | 33 PREPARATION 33: 3-methyltetrahydrofuran-2-ol To a stirred solution of 3-methyldihydrofuran-2(3H)-one (14 g, 139.84 mmol, 13.21 mL) in DCM (250 mL) at -78°C was added DIBAL-H (1.0 M, 167.81 mL) dropwise over 1.5 hours. The solution was stirred at -78°C for 1.0 hour. TLC (petroleum ether/EtOAc = 3:1) showed a new spot was formed. Next, a solution of sodium tartrate dihydrate (96.52 g, 419.52 mmol, 144.06 mL) in water (50 mL) and DCM (200 mL) was added and the resulting mixture was stirred at 10°C for 10 minutes. The aqueous layer was separated and extracted with DCM (200 mL). The organic layers were combined, dried over MgSO4 and concentrated to give the title compound as a yellow oil (14.5 g, crude).1H NMR (CDCl3) δ ppm 5.19 (t, J = 3.2 Hz, 1 H), 3.91 - 3.73 (m, 2 H), 2.44 (d, J = 3.2 Hz, 2 H), 2.15 - 2.10 (m, 1 H), 1.03 (d, J = 6.8 Hz, 3 H). | |
With diisobutylaluminium hydride In dichloromethane at -78℃; for 2.5h; | 33 PREPARATION 33: 3-methyltetrahydrofuran-2-ol To a stirred solution of 3-methyldihydrofuran-2(3H)-one (14 g, 139.84 mmol, 13.21 mL) in DCM (250 mL) at -78°C was added DIBAL-H (1.0 M, 167.81 mL) dropwise over 1.5 hours. The solution was stirred at -78°C for 1.0 hour. TLC (petroleum ether/EtOAc = 3:1) showed a new spot was formed. Next, a solution of sodium tartrate dihydrate (96.52 g, 419.52 mmol, 144.06 mL) in water (50 mL) and DCM (200 mL) was added and the resulting mixture was stirred at 10°C for 10 minutes. The aqueous layer was separated and extracted with DCM (200 mL). The organic layers were combined, dried over MgSO4 and concentrated to give the title compound as a yellow oil (14.5 g, crude).1H NMR (CDCl3) δ ppm 5.19 (t, J = 3.2 Hz, 1 H), 3.91 - 3.73 (m, 2 H), 2.44 (d, J = 3.2 Hz, 2 H), 2.15 - 2.10 (m, 1 H), 1.03 (d, J = 6.8 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With phosphorus tribromide at 140℃; for 2.5h; | a a) 4-Bromo-2-methyl-bιιtyryl bromide2-niethylbutyrolactone (50 mmol, 5.0 g) and phosphorous tribromide (41 mmol, 3.7 niL) were heated at 140°C for 2.5 hours. The reaction mixture was transferred into a Kugelrohr distillation apparatus and distilled under reduced pressure (40 mmHg, T=128°C) to obtain 6.21 g (yield: 51%) of 4-bromo-2-methyl- butyryl bromide as a clear oil.C5H8Br2O1H-NMR (CDCl3): 3.45 (2 H5 t, J=6.8 Hz); 3.22-3.18 (1 H5 m); 2.42-2.36 (1 H5 m); 1.99-1.94 (1 H5 m); 1.32 (3 H5 d, J=7.2 Hz). |
With phosphorus tribromide at 140℃; for 2h; | ||
With phosphorus tribromide at 140℃; for 2h; | 373.a a) 4-Bromo-2-methyl-butyric acid methyl ester; [0462] 3-Methyl-dihydro-furan-2-one (5.0 g, 1.20 equiv.) was heated at 140 °C in neatPBr3 (3.90 mL, 1.0 equiv.) for 2 hrs. The reaction mixture was transferred to a Kugelrohr apparatus and distilled under reduced pressure (130 °C at 40 mm Hg). The product was then transferred in a flask, dissolved in DCM (10 mL) and cooled with an ice bath to 0 °C. The mixture was treated slowly with CH3OH (10 mL), due to the strong exotherm produced. The reaction mixture was stirred under nitrogen for 24 hrs and the solvents evaporated in vacuo. The title product (6.1O g, 75% yield) was obtained as an oil.C6HnBrO2 1H-NMR (400 MHz, CDC13): 1.19 (d, J=7.09 Hz, 3H); 1.92 (m, 1H), 2.25 (m, 1H), 2.70 (m,1H), 3.40 (m, 2H), 3.68 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tetraphosphorus decasulfide In acetonitrile for 1.5h; Reflux; | 5.2 General procedure for thionation using P4S10/HMDO (Method A) General procedure: Lactone 1a-5a (1.0mmol), P4S10 (0.25mmol), CH3CN (1.0mL) and HMDO (1.67mmol) were combined, refluxed and stirred for appropriate time. After this time, the reaction mixture was cooled to 0°C and an aqueous K2CO3 solution (1.26mL of 5.3M/mmol of P4S10 taken) was added. Then acetone (equal to one-half of the reaction solvent) and water (1mL/mmol of P4S10 taken) were added to the reaction mixture. The reaction mixture was stirred vigorously for 30min at 0°C. After this time, water and an extraction solvent were added, the layers were separated, and the organic phase was washed with an aqueous solution of K2CO3, water, and brine. The organic extract was dried over MgSO4 and evaporated, and the crude product was purified by column chromatography using hexanes/ethyl acetate as an eluent to give the desired product. |
78% | With tetraphosphorus decasulfide; Hexamethyldisiloxane In acetonitrile Heating; | |
71% | With Lawessons reagent In toluene for 4h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 4 % Chromat. 2: 96 % Chromat. | With carbon monoxide; hydrogen In dichloromethane at 100℃; for 18h; | |
1: 61 % Chromat. 2: 39 % Chromat. | With carbon monoxide; hydrogen In dichloromethane at 130℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: 3-methyltetrahydro-2-furanone With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.166667h; Stage #2: tert-butyldimethylsilyl chloride With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran; hexane at -78 - 20℃; for 0.25h; | |
59% | With N,N,N,N,N,N-hexamethylphosphoric triamide; lithium diisopropyl amide In tetrahydrofuran 1.) -78 deg C, 10 min, 2.) 20 deg C, 10 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33 % Chromat. | With sodium hexamethyldisilazane; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); zinc dibromide In tetrahydrofuran; toluene at 60℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hexamethyldisilazane; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); zinc dibromide In tetrahydrofuran; toluene at 80℃; for 17h; Title compound not separated from byproducts.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hexamethyldisilazane; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); zinc dibromide In tetrahydrofuran; toluene at 60℃; for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hexamethyldisilazane; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); zinc dibromide In tetrahydrofuran; toluene at 60℃; for 20h; Title compound not separated from byproducts.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hexamethyldisilazane; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); zinc dibromide In tetrahydrofuran; toluene at 60℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hexamethyldisilazane; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); zinc dibromide In tetrahydrofuran; toluene at 60℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hexamethyldisilazane; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); zinc dibromide In tetrahydrofuran; toluene at 60℃; for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hexamethyldisilazane; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); zinc dibromide In tetrahydrofuran; toluene at 60℃; for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hexamethyldisilazane; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); zinc dibromide In tetrahydrofuran; toluene at 60℃; for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 3-methyltetrahydro-2-furanone With lithium diisopropyl amide In tetrahydrofuran; cyclohexane at -78 - 20℃; for 2h; Stage #2: carbon disulfide In tetrahydrofuran; cyclohexane at -78℃; for 1h; Stage #3: methyl iodide In tetrahydrofuran; cyclohexane at -78 - 2℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 3-methyltetrahydro-2-furanone With lithium diisopropyl amide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: benzyl bromide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium hexamethyldisilazane In toluene at 0 - 20℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium hexamethyldisilazane In toluene at 0 - 20℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 33 percent Chromat. / (S)-BINAP; NaHMDS; ZnBr2 / Ni(COD)2 / toluene; tetrahydrofuran / 60 °C 2: 73 percent / Me3Al / CH2Cl2; hexane / 20 h / 80 °C | ||
Multi-step reaction with 2 steps 1: Pd2(dba)3; (S)-BINAP; NaHMDS / toluene / 50 °C 2: 73 percent / Me3Al / CH2Cl2; hexane / 20 h / 80 °C | ||
Multi-step reaction with 2 steps 1: (S)-BINAP; NaHMDS; ZnBr2 / Ni(COD)2 / toluene; tetrahydrofuran / 20 h / 60 °C 2: 73 percent / Me3Al / CH2Cl2; hexane / 20 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium hexamethylsilazane; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl In toluene at 100 - 105℃; for 24h; | Typical Procedure: Palladium acetate (45 mg, 0.2 mmol, 0.1 eq.) and R-(+)-BINAP (156 mg, 0.25 mmol, 0.125 eq.) in dry toluene (30 mL, degased with dry nitrogen) were stirred at room temperature under nitrogen for 60 minutes. Aryl bromide (4 mmol, 2.0 eq.) and α-methyl-γ-butyrolactone (2 mmol) were added via syringe. KN(TMS)2 in toluene (0.5 M, 7 mL, 3.5 mmol, 1.75 eq.) was added dropwise and the resultant dark red solution was then stirred at 100-105° C. for 24 hours. The reaction mixture was cooled to room temperature before treating with 1N HCl (15 mL) and water (50 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phase was washed with water (25 mL) and brine (40 mL) and dried over MgSO4. After removal of the solvent, the residue was chromatographed on silica gel (heptane: ethyl acetate=8:1→2:1) to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a 2 L, 3-neck round bottom flask, equipped with a mechanic stirrer and an internal temperature controller, is added a solution of <strong>[1193-72-2]2,4-dichlorobromobenzene</strong> (65.5 g, 290.7 mmol) in 1.1 L [OF THF] under nitrogen. The solution is cooled to-95 C with a [MEOH/LIQUID] nitrogen bath. To this solution is added t-BuLi (400 mL, 1.6 M in pentane, 639.5 mmol) slowly via syringe pump followed by the addition of a solution of [OC-METHYL-Y-BUTYROLACTONE] (43.5 g, 434.8 mmol) in THF (100 mL). The internal temperature is controlled <-80 [C.] After 1 h stirring [<-80 C,] the reaction mixture is quenched with saturated NH4C1 solution and warmed to room temperature. Water (2 L) and EtOAc (1 L) are added and separated. The aqueous layer is extracted with EtOAc (2 x 2 L). The combined organic solutions is dried [(MGSO4)] and filtered. The filtrate is concentrated in vacuo to dryness to give 80.9 g of [1- (2,] 4-dichlorophenyl) -4- hydroxy-2-methylbutan-1-one as light yellow oil. The residue is used for Swern oxidation. To a 2 L, 3-neck round bottom flask, equipped with a mechanic stirrer and an internal temperature controller, is added DMSO (104.1 mL, 1465.7 mmol) and [CH2C12] (1.1 L). The solution is cooled to-80 C with a [MEOH/LIQUID] nitrogen bath. To this solution is added oxalyl chloride (63.9 mL, 732.9 mmol) slowly via syringe pump. The mixture is stirred at-80 C for 15 min followed by the addition of a solution of the above obtained crude [1- (2,] 4-dichlorophenyl) -4-hydroxy-2- methylbutan-1-one in [CH2C12] (150 mL) slowly via syringe pump. After stirring <-70 [C] for 1 h, to the mixture is added [ET3N] (456 mL, 3271.7 mmol). The cooling bath is removed after 5 min and the mixture is stirred at room temperature for 1.5 h. The mixture is diluted with hexanes (6 L) and washed with water (6 L). The aqueous layer is extracted with hexanes (6 L). The combined organic solutions is concentrated in vacuo to dryness and the residue is subjected to column chromatography (silica gel, 1/6 EtOAc/heptane) to give 36 g (50% for two steps) of light yellow oil as the title compound [:'H] NMR (400 MHz, CDCl3) 8 9.86 (s, 1H), 7.61 (d, J= 8.3 Hz, 1H), 7.49 (d, J=2. 0 Hz, 1H), 7.37 (dd, J=2. 0,8. 3 Hz, 1H), 3.81-3. 76 (m, 1H), 3.18 (dd, [J =] 8.2, 18.6 Hz, 1H), 2.65 (dd, [J =] 5.0, 18.6 Hz, 1H), 1.21 (d, [J =] 7.3 Hz, 3H) ; 13C NMR (100 MHz, [CDC13)] [# 206. ] 1,202. 4,139. 5,139. 2,134. 4,132. 7,132. 4,129. 6,48. 8, 42.0, 18.6 ; IR (liq. ) 2974,2936, 1996,1910, 1708,1585, 1457,1374, 1228, [1191,] 1106,1064, 978,828, [810 CM'' ;] MS (CI) [NZLZ] 247 (M+), 245 (M+). | ||
With tert.-butyl lithium; In tetrahydrofuran; pentane; at -80℃; for 1h; | To a 2 L, 3-neck round bottom flask, equipped with a mechanic stirrer and an internal temperature controller, is added a solution OF 2, 4-DICHLOROBROMOBENZENE (65.5 g, 290.7 MMOL) in 1.1 L of THF under nitrogen. The solution is cooled to-95 C with a MeOH/liquid nitrogen bath. To this solution is added t-BuLi (400 mL, 1.6 M in pentane, 639.5 MMOL) slowly via syringe pump followed by the addition of a solution of a-methyl-y-butyrolactone (43.5 g, 434.8 MMOL) in THF (100 mL). The internal temperature is controlled <-80 C. After 1 h stirring <-80 C, the reaction mixture is quenched with saturated NH4CI solution and warmed to room temperature. Water (2 L) and EtOAc (1 L) are added and separated. The aqueous layer is extracted with EtOAc (2 x 2 L). The combined organic solutions is dried (MGS04) and filtered. The filtrate is concentrated in vacuo to dryness to give 80.9 g of 1-(2, 4-dichlorophenyl)-4- HYDROXY-2-METHYLBUTAN-1-ONE as light yellow oil. The residue is used for Swern oxidation. To a 2 L, 3-neck round bottom flask, equipped with a mechanic stirrer and an internal temperature controller, is added DMSO (104.1 mL, 1465.7 MMOL) and CH2CI2 (1.1 L). The solution is cooled to-80 C with a MeOH/liquid nitrogen bath. To this solution is added oxalyl chloride (63.9 mL, 732.9 MMOL) slowly via syringe pump. The mixture is stirred at-80 C for 15 min followed by the addition of a solution of the above obtained crude 1- (2, 4-dichlorophenyl)-4- HYDROXY-2-METHYLBUTAN-1-ONE in CH2CI2 (150 mL) slowly via syringe pump. After stirring <-70 C for 1 h, to the mixture is added Et3N (456 mL, 3271.7 MMOL). The cooling bath is removed after 5 min and the mixture is stirred at room temperature for 1.5 h. The mixture is diluted with hexanes (6 L) and washed with water (6 L). The aqueous layer is extracted with hexanes (6 L). The combined organic solutions is concentrated in vacuo to dryness and the residue is subjected to column chromatography (silica gel, 1/6 EtOAc/heptane) to give 36 G (50% for two steps) of light yellow oil as the title compound : H NMR (400 MHz, CDCI3) E 9.86 (s, 1 H), 7.61 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 2. 0 Hz, 1H), 7.37 (dd, J = 2. 0,8. 3 Hz, 1H) 3.81-3. 76 (m, 1H), 3. 18 (dd, J = 8.2, 18.6 Hz, 1H), 2.65 (dd, J = 5.0, 18.6 Hz, 1H), 1.21 (d, J = 7.3 Hz, 3H) ; 13C NMR (100 MHz, CDCI3) 8 206.1, 202.4, 139.5, 139.2, 134.4, 132.7, 132.4, 129.6, 48.8, 42.0, 18.6 ; IR (LIQ.) 2974,2936, 1996, 1910,1708, 1585, 1457, 1374,1228, 1191,1106, 1064,978, 828,810 cm-1 ; MS (CL) M/Z247 (M), 245 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tert.-butyl lithium; In tetrahydrofuran; pentane; at -85 - -80℃; for 1h;Cooling with methanol-liquid nitrogen; | Step 1: Preparation of 4-hydroxy-1-(2-chloro-4-methoxyphenyl)-2-methylbutan-1-one [0064] To a 1.0 L, 3-neck round bottom flask, equipped with a mechanical stirrer and an internal thermometer, was added a solution of <strong>[50638-46-5]4-bromo-3-chloroanisole</strong> (12.0 g, 54.0 mmol) in 350 mL of THF under nitrogen. The solution was cooled to -85 C. with a MeOH/liquid nitrogen bath. To this solution was added t-BuLi (72.0 mL, 1.6 M in pentane, 122 mmol) slowly followed by the addition of a solution of alpha-methyl-gamma-butyrolactone (9.25 g, 92.0 mmol) in THF (30.0 mL). The internal temperature was controlled <-80 C. After 1 h stirring at <-80 C., the reaction mixture was quenched with saturated NH4Cl solution and warmed to room temperature. Water and EtOAc were added and separated. The aqueous layer was extracted with EtOAc (2×). The combined organic solutions was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (E:H, 1:3) to give 10.4 g (79%) of brown oil as the title compound: 1H NMR (400 MHz, CDCl3) delta 7.53 (d, J =8.6 Hz, 1H), 6.97 (d, J =2.4 Hz, 1H), 6.85 (dd, J =8.6, 2.4 Hz, 1H), 3.88 (s, 3H), 3.77-3.69 (m, 2H), 3.64-3.56 (m, 1H), 2.16-2.07 (m, 1H), 1.76-1.67 (m, 1H), 1.23 (d, J=7.0 Hz, 3H); MS (El m/z 241.16 (M+-H). |
10.4 g (79%) | With ammonium chloride; tert.-butyl lithium; In tetrahydrofuran; water; ethyl acetate; pentane; | Step 1: Preparation of 4-hydroxy-1-(2-chloro-4-methoxyphenyl)-2-methylbutan-1-one To a 1.0 L, 3-neck round bottom flask, equipped with a mechanical stirrer and an internal thermometer, was added a solution of <strong>[50638-46-5]4-bromo-3-chloroanisole</strong> (12.0 g, 54.0 mmol) in 350 mL of THF under nitrogen. The solution was cooled to -85 C. with a MeOH/liquid nitrogen bath. To this solution was added t-BuLi (72.0 mL, 1.6 M in pentane, 122 mmol) slowly followed by the addition of a solution of alpha-methyl-gamma-butyrolactone (9.25 g, 92.0 mmol) in THF (30.0 mL). The internal temperature was controlled <-80 C. After 1 h stirring at <-80 C., the reaction mixture was quenched with saturated NH4Cl solution and warmed to room temperature. Water and EtOAc were added and separated. The aqueous layer was extracted with EtOAc (2*). The combined organic solutions was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (E:H, 1:3) to give 10.4 g (79%) of brown oil as the title compound: 1H NMR (400 MHz, CDCl3) delta7.53 (d, J=8.6 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.85 (dd, J=8.6, 2.4 Hz, 1H), 3.88 (s, 3H), 3.77-3.69 (m, 2H), 3.64-3.56 (m, 1H), 2.16-2.07 (m, 1H), 1.76-1.67 (m, 1H), 1.23 (d, J=7.0 Hz, 3H); MS (EI) m/z 241.16 (M+-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.45 g (77%) | Preparation of 1-Methylycyclopropylamine Hydrochloride Water (190 mL) and 50percent sodium hydroxide (104.9 mL; 160 g; 2.0 mol) were combined and cooled to below 5° C. 1-Methylcyclopropanecarboxamide (60.4 g; 82percent solids; 49.6 g 100percent basis; 0.5 mol) was added and washed in with 60 mL water. The reaction was placed in an ice-acetone bath and the addition of aqueous sodium hypochlorite (12.68percent aqueous solution; 268 mL; 0.55 mol; 1.1 equiv) was begun. The addition was carried out over 30 minutes such that the temperature was maintained between 0 and 5° C. The mixture was stirred at 0-5° C. for 1 hour. The reaction mixture was allowed to warm to ambient temperature and stir for 2 hours at which point all solids had dissolved. GC analysis of an aliquot indicated no caboxamide reactant present. One mL of 2 M sodium thiosulfate was added to destroy any excess oxidant and the reaction mixture was heated to 60° C. for 2 hours to decompose the carbamate intermediate. A distillation head was fitted to the flask and material boiling from ambient temperature up to a head temperature of 91° C. (43.78 g) was collected. The distillate contained an approximate 84:16 weight:weight mixture of 1-methylcyclopropylamine and water, respectively. The distillate was dissolved in 173 mL of n-butanol and cooled in an ice-water bath. Concentrated hydrochloric acid was added such that the temperature remained below 20° C. A Dean-Stark trap was placed on the flask and the mixture heated. A total of 39 mL of water were removed (head temperature at end of water removal was 111.5° C.). The trap was drained and an additional 77 mL of butanol distilled (final pot temperature was 125° C.). The heating mantle was removed from the flask and heptane (228 mL) was slowly added to the hot solution. Product crystallized at 109° C. The temperature at end of the heptane addition was 70° C. The resulting slurry was allowed to cool to ambient temperature and then cooled to 0-5° C. for 1 hour. The resulting glistening white solid was collected, washed with heptane (3*50 mL) and air-dried to afford 41.45 g (77percent) of 1-methylcyclopropaneamine hydrochloride, mp 203-204° C. 1H NMR (DMSO) delta8.35(bs, 3H); 1.38(s, 3H); 0.9 (t, 2H); 0.62(t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen cyanide; In tetrahydrofuran; water; | EXAMPLE 16 Reductive hydrolysis of methyl 3-cyano-isobutyrate A mixture of 0.05 mmol RuHCi(H2)(PCy3)2, 0.54 mmol methyl-3-cyanoisobutyrate (prepared by addition of HCN to methyl methacrylate), 17.7 g THF, 15.3 g water, and 0.0596 g <strong>[294-62-2]cyclododecane</strong> (internal standard for gc analysis) was stirred in an autoclave and heated to 100 C. under 7000 kPa H2. After 3.2 hours, the nitrile was completely and cleanly converted to methyl-butyrolactone, which formed by transesterification/cyclization of the intermediate hydroxyester, methyl 2-methyl-4-hydroxybutyrate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; diisopropylamine In tetrahydrofuran | 1.c (c) (c) Dihydro-3,3-dimethyl-2(3H)furanone1 The dihydro-3-methyl-2(3H)furanone (10.0 g, 0.1 mol) was slowly added to a cold (-78° C.), THF solution (150 ml) of LDA (0.11 mol) so that the internal temperature did not exceed -65° C. After stirring for an additional 30 minutes, the acetone/CO2 bath was replaced with a CH3 CN/CO2 bath and CH3 I (21.3 g, 0.15 mol) was added at a rate sufficient to maintain the internal temperature at -30° C. After stirring at -30° C. for another hour the reaction mixture was allowed to warm to 0° C. and quenched by the dropwise addition of 10% HCl (40 ml, 0.116 mol). The resulting mixture was poured into ether (700 m) and the ether layer was washed with brine (2*50 ml), dried (MgSO4), and evaporated to a yellow oil. The oil was distilled to give desired product as a colorless liquid, bp18 80°-82° C. | |
With hydrogenchloride; diisopropylamine In tetrahydrofuran | 1.c (c) (c) Dihydro-3,3-dimethyl-2(3H)furanone1 The dihydro-3-methyl-2(3H)furanone (10.0 g, 0.1 mol) was slowly added to a cold (-78° C.), THF solution (150 ml) of LDA (0.11 mol) so that the internal temperature did not exceed -65° C. After stirring for an additional 30 minutes, the acetone/CO2 bath was replaced with a CH3 CN/CO2 bath and CH3 I (21.3 g, 0.15 mol) was added at a rate sufficient to maintain the internal temperature at -30° C. After stirring at -30° C. for another hour the reaction mixture was allowed to warm to 0° C. and quenched by the dropwise addition of 10% HCl (40 ml, 0.116 mol). The resulting mixture was poured into ether (700 ml) and the ether layer was washed with brine (2*50 ml), dried (MgSO4), and evaporated to a yellow oil. The oil was distilled to give desired product as a colorless liquid, bp18 80°-82° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: indole; 3-methyltetrahydro-2-furanone With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: With copper(II) 2-ethylhexanoate In tetrahydrofuran at -78 - 20℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With phosphorus tribromide at 140℃; for 8h; | 4-Bromo-2-methylbutanoic acid (18) To α-methyl-γ-butyrolactone (130 g, 1.3 mol) was added phosphoroustribromide (101 mL, 1.13 mol) and this was then heated at reflux for 8 hours. The reaction was slowly poured onto iced water (500 mL). Dichloromethane (500 mL) was added and this was stirred overnight at ambient temperature. The layers were separated, dried over magnesium sulphate, filtered, and evaporated to dryness. The resultant yellow oil was passed through a pad of silica (3:1 hexane:ethyl acetate). This gave 18 (158.5 g, 67%) as an oil. |
With hydrogen bromide; acetic acid at 20 - 70℃; for 4h; | ||
With hydrogen bromide; acetic acid at 20℃; for 6h; Inert atmosphere; Cooling with ice; | 1 Example 1 Synthesis of (±)-2-methyl-4-bromobutyric acid (II) Under nitrogen protection, (±)-α-methyl-γ-butyrolactone (I) (7.33 g, 73.3 mmol) was transferred to a reaction flask in ice water. Under a bath condition, slowly add 33% HBr acetic acid solution (51.3 mL, 147 mmol, 2.0 eq.) to the reaction flask. After stirring for 6 hours at room temperature, TLC monitoring showed that the conversion of the starting material I was completed, stirring was stopped, and the reaction solution was placed in a fume hood. After pouring into 250 mL of CH2Cl2 cooled in an ice water bath, a large amount of white smoke emerged and the resulting solution was successively treated with water (50 mL x 2). After washing with saturated NaHSO 3 solution (100 mL×2) and saturated brine (50 mL), the solid was dried over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure to give 12.5 g of pale yellow oil II (yield 94.2%). The product was not purified. Can be used for the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Stage #1: 4-bromo-3-methylanisole With tert.-butyl lithium In tetrahydrofuran; pentane at -68℃; Stage #2: 3-methyltetrahydro-2-furanone In tetrahydrofuran; pentane at -55℃; for 1h; Stage #3: With ammonium chloride In water at -55 - 20℃; | 1.1 EXAMPLE 1 : 7-(4-methoxy-2-methylphenyl-2,6-dimethyl-N-[(1S)-1-methylpropyl]pyrrolo[1, 2-b]pyridazin-4-amine; Step 1 : Preparation of 4-(4-methoxy-2-methylphenyl)-3-methyl-4-oxobutanal; EXAMPLE 1 : 7-(4-methoxy-2-methylphenyl-2,6-dimethyl-N-[(1S)-1-methylpropyl]pyrrolo[1, 2-b]pyridazin-4-amine; Step 1 : Preparation of 4-(4-methoxy-2-methylphenyl)-3-methyl-4-oxobutanal; To a 200 mL, 3-neck round bottom flask, equipped with an internal temperature controller, was added a solution of 4-bromo-3-methylanisole (2. 77 g, 16.3 mmoL) in 40 mL of THF under nitrogen. The solution was cooled to -68 °C with a dry ice/acetone bath. To this solution was slowly added t-BuLi (21.0 mL, 1.70 M in pentane, 35.8 mmol) followed by the addition of a solution of α-methyl-γ-butyrolactone (2.30 mL, 24.4 mmoL) in THF (10.0 mL). The internal temperature was controlled |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.7%Chromat. | With potassium tert-butylate; hydrogen;[tris(mu-chloro)bis((triphos)ruthenium(II))] chloride; In methanol; at 100℃; under 30003 Torr; for 13.0h;Inert atmosphere; Autoclave; | Example 11 Hydrogenation of alpha-methyl-gamma-butyrolactone [Ru2(mu-Cl)3(triphos)2]Cl (3.0 mg), potassium tert-butoxide (5.5 mg), and 1. 5 ml of methanol were added into a 20-ml Schlenk tube under a nitrogen atmosphere, and the mixture was stirred for 20 minutes at room temperature. This solution and alpha-methyl-gamma-butyrolactone (0.12 g) were added into a 100-ml autoclave having a stirrer placed inside, under a nitrogen atmosphere. The autoclave was purged with hydrogen, and then hydrogen was further included in the autoclave up to 4.0 MPa. The contents of the autoclave were heated and stirred at 100C for 13 hours. After cooling, the reaction liquid was analyzed by gas chromatography, and it was found that 1,4-pentanediol was produced at a yield of 39.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 3-methyltetrahydro-2-furanone With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: allyl bromide In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: 3-methyltetrahydro-2-furanone With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.666667h; Stage #2: With 2-chloro-2-fluoro-2-phenylacetonitrile In tetrahydrofuran at -78℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With Λ(+)-tris(pentane-2,5-dionato)ruthenium; hydrogen; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In 1,4-dioxane at 195℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Stage #1: 3-methyltetrahydro-2-furanone With potassium hydroxide In 1,4-dioxane; water at 20 - 90℃; for 0.75h; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.583333h; Stage #3: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 18h; | 51.1 To a solution of 3-methyldihydrofuran-2-one (2.0 g, 20.0 mmol) in dioxane (15 mL) was added a solution of KOH (1.32 g, 20.0 mmol in 5 mL of water) and the mixture was stirred at RT for 30 min, then at 90° C. for 15 min. After cooling to RT, volatiles were removed under reduced pressure and the residue was azeotroped with toluene and heated at 190° C. affording a white residue. The resulting residue was suspended in DMF (25 mL) and NaH (800 mg, 20 mmol) was added at RT over 5 min. The mixture was stirred at RT for 30 min, then bromomethylbenzene (5.94 mL, 50 mmol) was added over 5 min. Stirring at RT was continued for 18 h then the mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. Half of the resulting residue was purified by column chromatography (Si-PCC, gradient 2-30% EtOAc in cyclohexane) affording 4-Benzyloxy-2-methylbutyric acid benzyl ester as a colorless oil (0.738 g, 25%). 1H NMR (CDCl3, 400 MHz): δ 7.38-7.22 (10H, m), 5.08 (2H, s), 4.44 (2H, s), 3.51-3.44 (2H, m), 2.78-2.64 (1H, m), 2.12-1.97 (1H, m), 1.79-1.64 (1H, m), 1.19 (3H, d, J=7.06 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With C24H38Cl2N3PRu; hydrogen; sodium methylate In isopropyl alcohol at 25℃; for 6h; Autoclave; | |
With C21H24N4Ru(1+)*F6P(1-); potassium <i>tert</i>-butylate; hydrogen In tetrahydrofuran at 50℃; for 4h; | ||
With 5 wt% ruthenium/carbon; hydrogen In water at 100℃; for 6.3h; | 1 2 wt. % MGBL in 60 mL H2O, 1.0 g 5 wt. % Ru/C, 140 bar. Data reported at time of maximum MBDO selectivity: 80° C. (71 h-did not reach maximum), 100° C. (6.3 h), 120° C. (3.5 h), 140° C. (1.8 h), 160° C. (0.3 h), 200° C. (0.3 h). Pd/C (1.5 h), Pt/C (1.5 h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: benzyl bromide; 3-methyltetrahydro-2-furanone With potassium hydroxide In toluene at 110℃; for 5h; Stage #2: With methanol; potassium hydroxide In water for 16h; Reflux; | |
81% | Stage #1: benzyl bromide; 3-methyltetrahydro-2-furanone With potassium hydroxide In toluene at 110℃; for 5h; Stage #2: With water; potassium hydroxide In methanol for 16h; Reflux; | 43.1 Step-1 Powdered KOH (6.0 g, 0.10 mol) was added to a solution of 3-methyltetrahydrofuran-2-one(2.0 g, 0.02 mol) and benzyl bromide (14.0 g, 0.08 mol) in toluene (36 mL). The resultantreaction mixture was stirred at 110 °C for 5 hand toluene was removed under vacuum to givethe crude residue which was dissolved in MeOH (40 mL). KOH (2.0 g, 0.035 mol) and water(20 mL) were added to the above solution and the reaction mixture was refluxed for 16 h. Thereaction mixture was brought toRT, washed with Et20 (2 x 50 mL), the aqueous layer wasacidified to pH= 2-3 with cone. HCl, and extracted with DCM (3 x 50 mL). The combinedorganic extracts were dried over Na2S04, filtered, and concentrated under vacuum to afford4-benzyloxy-2-methyl-butanoic acid (3.4 g, 81%) as a pale yellow oil. 1H NMR [400 MHz, CDCh]: 8 7.37-7.26 (m, 5H), 4.53-4.50 (m, 2H), 3.54 (t, J = 6.4 Hz,2H), 2.73-2.64 (m, 1H), 2.09-2.00 (m, 1H), 1.76-1.68 (m, 1H), 1.21 (d, J = 7.2 Hz, 3H). |
Stage #1: benzyl bromide; 3-methyltetrahydro-2-furanone With potassium hydroxide In toluene at 110℃; for 5h; Stage #2: With water; potassium hydroxide In methanol for 7h; Reflux; | 1.2.1 Preparation of Intermediate Compound A Method 2 Step 1: Crushed KOH (28.0 g, 499 mmol) was added to a solution of a-methyl-y-butyrolactone (9.43 mL, 100 mmol) and benzyl bromide (47.5 mL, 400 mmol) in toluene (200mL). The reaction was allowed to stir at 110 °C for 5 hours, then toluene was removed in vacuo. Methanol (200 mL) was added to the reaction mixture followed by KOH (10 g, 178 mmol), and water (100 mL), then the reaction mixture was allowed to stir at reflux for 7 hours. The reaction mixture was extracted with diethyl ether (3 x 200 mL), the aqueous layer was acidified with concentrated HC1, and extracted with DCM (3 x 200 mL). The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo at room temperature to provide the intermediate compound 4-(benzyloxy)-2-methylbutanoic acid as oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-methyltetrahydro-2-furanone With boron tribromide In dichloromethane at 0 - 20℃; for 19h; Stage #2: With methanol In dichloromethane at 0 - 20℃; for 0.5h; | Boron tribromide solution (44.4 mL, 1.0M in DCM, 44.4 mmol) was added dropwise to alpha-methyl-gammabutyrolactone (commercial) (4.23 g, 42.3 mmol) in DCM (47 mL) at 0° C. The mixture was warmed to room temperature and stirred for 19 hours. The reaction was quenched with methanol (10.5 mL) at 0° C. and stirred at room temperature for 30 minutes, then diluted with water (100 mL) and extracted with DCM (1×50 mL). The organic extracts were washed with saturated NaHCO3(aq) (2×50 mL) dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica afforded the title compound. [1915] 1H NMR (400 MHz, CDCl3) δ 3.72 (3H, s), 3.44 (2H, br t), 2.74 (1H, mult), 2.29 (1H, mult), 1.94 (1H, mult), 1.22 (3H, mult) | |
Multi-step reaction with 2 steps 1: hydrogen bromide; acetic acid / 6 h / 20 °C / Inert atmosphere; Cooling with ice 2: acetyl chloride / 3 h / Inert atmosphere; Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium on activated charcoal; hydrogen In ethyl acetate at 20℃; | General procedure: Authentic standards for each reduction product by stirring ethyl acetate solutions under an atmosphere of H2 in the presence of Pd/C. Reactions were stirred at room temp until GC/MS indicated complete consumption of starting materials, the solvent was removed by rotary evaporation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In water at 200℃; for 20h; Autoclave; | Catalytic hydrogenation of IA was performed in a 50 ml autoclave. After 1 wt.% IA aqueous solution and 1.5 mol% Pd catalysts were introduced into the reactor, the reactor was purged with H2 for five times and then pressurized to the desired pressure at room temperature. After reaction, unconsumed IA was detected by high performance liquid chromatography (HPLC) and products were quantified by gas chromatography (GC). The products were also analyzed by GC or LC coupled with a mass spectrometer (MS). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogen In water at 180℃; for 20h; Autoclave; | Catalytic hydrogenation of IA was performed in a 50 ml autoclave. After 1 wt.% IA aqueous solution and 1.5 mol% Pd catalysts were introduced into the reactor, the reactor was purged with H2 for five times and then pressurized to the desired pressure at room temperature. After reaction, unconsumed IA was detected by high performance liquid chromatography (HPLC) and products were quantified by gas chromatography (GC). The products were also analyzed by GC or LC coupled with a mass spectrometer (MS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; potassium hydroxide In tetrahydrofuran; methanol at 20℃; for 3h; | 32.32.A Example 32-A. (±)-Potassium 4-hydroxy-2-methylbutanoate To a solution of (±)-3-methyldihydrofuran-2(3H)-one (CAS 1679-47-6) (0.95 mL, 10 mmol) in THF (25 mL) and MeOH (25 mL) was added 1 M aq. KOH (10.5 mL, 10.5 mmol). The mixture was then stirred at room temperature for 3 h, and then concentrated. The resulting residue was triturated with acetone, and then the resulting white solid was collected by filtration to furnish the title compound. 1H NMR (400 MHz, D20) δ 3.58 (t, J=7.0 Hz, 2 H) 2.24- 2.53 (m, 1 H) 1 .79 (dq, J=14.8, 6.9 Hz, 1 H) 1 .58 (dq, J=13.6, 6.9 Hz, 1 H) 1 .08 (d, J=7.0 Hz, 3 H). | |
With potassium hydroxide In water for 3h; Reflux; | 1 Intermediate E: Isopropyl 4-hydroxy-2-methylbutanoate: Step 1: A solution of a-methyl-ybutyrolactone (50.0 g, 499 mmol) in 1M aqueous potassium hydroxide solution (499 mL, 499 mmol) was stirred under reflux for 3 hours, then cooled to RT and concentrated under reducedpressure. The crude solid was triturated in diethyl ether, filtered off and washed with diethyl ether. The solid was then dried in vacuo over P205 at 45°C. Step 2: To a solution of the product of step 1(25.0 g, 160.0 mmol) in DMF (200 mL) was added dropwise at RT under nitrogen 2- iodopropane (31.9 mL, 320 mmol). The reaction mixture was stirred at RT for 5h. 2- iodopropane (8.0 mL, 80 mmol) was added, and the reaction mixture was stirred at RTovernight. The mixture was diluted with EtOAc, and the organic layer was washed with a metabisulfite solution and brine. The organic layer was dried, filtered and concentrated under reduced pressure at 20-30°C to provide the expected intermediate. 1H NMR (400 MHz, CDC13)ö4.97 (heptuplet, J= 6.23Hz, 1H), 3.66-3.60 (m, 2H), 2.59-2.50 (m, 1H), 1.92-1.84 (m, 1H), 1.67-1.59 (m, 1H), 1.195 (d,J= 6.23Hz, 3H), 1.19 (d,J= 6.23Hz, 3H),1.14 (d,J= 7.09Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In water at 180℃; for 2h; Autoclave; | 2.4. Catalytic reaction General procedure: IA hydrogenation reactions were conducted in a 50 mL stain-less steel autoclave with magnetic stirring. In every experiment,0.2 g IA, 0.1 g catalyst and 20 mL deionized water were placed inthe autoclave. Afterwards, the autoclave was purged with hydro-gen for five times to remove air and pressured up to the desiredhydrogen pressure and then heated to the reaction temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In water at 180℃; for 2h; Autoclave; | 2.4. Catalytic reaction General procedure: IA hydrogenation reactions were conducted in a 50 mL stain-less steel autoclave with magnetic stirring. In every experiment,0.2 g IA, 0.1 g catalyst and 20 mL deionized water were placed inthe autoclave. Afterwards, the autoclave was purged with hydro-gen for five times to remove air and pressured up to the desiredhydrogen pressure and then heated to the reaction temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 5 wt% ruthenium/carbon; hydrogen In water at 100℃; for 6.3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen at 100℃; for 2h; Autoclave; | 1.b Hydrogen reduction step (step (B)) Next, a thermometer, a magnetic stirrer, Content volume 100 ml equipped with gas blowing inlet and sampling port In a stainless steel autoclave, 39 ml of methyl 3-formyl-2-methylpropionate obtained above was added to Raney nickel (Evonik Degussa Japan Co., Ltd. B K 113 AW) 1 g. Then, Hydrogen gas was introduced into the autoclave, Adjust the pressure inside the autoclave to 0.8 MPa, The inner temperature was raised to 100 ° C. while stirring, The reaction was carried out for 2 hours. After the reaction, Raney nickel was separated from the reaction solution by filtration, As a result of analyzing by chromatography, The conversion rate of methyl 3-formyl-2-methylpropionate was 99.3% The selectivity to methyl 4-hydroxy-2-methylbutyrate is It was 94.9%. Incidentally, α-methyl-γ-butyrolactone was produced at a selectivity of 2.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Next, an internal volume of 100 ml equipped with a thermometer, cooling tube and receiver Was charged with 30 ml of the above reaction solution. Next, 1000 ppm of sodium hydroxide was added to the mass of the reaction solution, The reaction pressure was adjusted to 13 kPa and the reaction temperature to 130 C., The reaction was carried out while distilling off the methanol formed. 1.5 hours after the start of the reaction, the reaction solution in the flask was subjected to gas chromatography As a result of analyzing by analysis, the conversion of methyl 4-hydroxy-2-methylbutyrate was 95.6%, and the selectivity to alpha-methyl-gamma-butyrolactone was 98%. At this time, methyl 3-formyl-2-methylpropionate and Methyl 2-formyl-2-methylpropionate The combined concentration was 1.6 wt% (0.04 mmol). (Example 1) 20 ml of the reaction solution obtained in the cyclization step (C) of Production Example 1 was charged in a 100 ml three-necked flask equipped with a thermometer, a cooling tube and a receiver, and 9 mg of hydroxylamine hydrochloride dissolved in 5 ml of distilled water ( 0.16 mmol), and the mixture was stirred at 40 C. for 12 hours. Distillation was performed on the obtained reaction liquid using a 10-stage distillation column at a heat medium temperature of 130 C., a reflux ratio of 30, and a reduced pressure degree of 1.3 kPa. as a result, Alpha-methyl-gamma-butyrolactone having a purity of not less than 99.9% It can be obtained with a distillation yield of 55% Methyl 3-formyl-2-methylpropionate and 2- The combined content of methyl formyl-2-methylpropionate is It was 10 ppm or less, which was below the detection limit |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With palladium 10% on activated carbon; W(OTf)6; hydrogen; at 180℃; under 760.051 Torr; for 12h; | Specific methods are as follows: propiolactone was added (0.36g, 5mmol), palladium on carbon (10%, 26.5mg, 0.025mmol, 0.5mol%) in the reactor and W (OTf)6(107.8mg, 0.1mmol, 2mol%). A hydrogen balloon connected to the top of the reactor, and the reactor was purged with hydrogen gas atmosphere. Hydrogen atmosphere at normal pressure, the reaction was stirred at 135 deg.] C after 12h, detected by gas, gamma- valerolactone complete conversion of starting material, and only n-valeric acid. The method carried out as follows completion of the hydrogenation reaction of the ring-opening reaction system separation, to obtain the desired product n-valeric acid: The reaction was completed reaction mixture was dissolved with methylene chloride, filtered to remove the palladium on carbon catalyst and W (OTf)699% yield measured propionic acid, purity of the product was 99%. NMR data for the product using the embodiment of the present invention is the NMR identified the product as follows:The specific reaction procedure and operation method were the same as in Example 27 except that the reaction temperature was changed to 180 C, the yield 33%, the purity of the product is 99%. The product was subjected to nuclear magnetic identification using the manner described in the present invention, and the NMR data of the product were as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 23% 2: 35% | With C45H45P3Ru; hydrogen; bis(trifluoromethanesulfonyl)amide at 200℃; for 0.0833333h; Autoclave; | General Procedure for Hydrogenation Experiments General procedure: For the hydrogenation experiments the following general procedure, here exemplified with Ruthenium (Triphos-Xyl)TMM (lb) was used except where noted.A 20 mE stainless steel autoclave with a glass inlet was charged with Dimethyl itaconate (3.7258 g, 23.6 mmol), Ruthenium(Triphos-Xyl)TMM (lb) (0.0095 g, 0.01 mmol) and HRTA=Ris(trifluormethylsulfon)imid (0.0028 g, 0.01 mmol). It should be noted that the ratio of catalyst/HETA is always set 1:1 (mol/mol), also when different concentration of catalyst were used.The autoclave was sealed, evacuated at high vacuum and refilled with argon at least 3 times and subsequently pressurized with 100 bar H2 and placed into a steel cone preheated to 200° C. on a magnetic stir plate. Stirring speed was increased from 0 rpm to 700 rpm within 5 minutes to assure the movement of the stirring bar. Due to the high substrate loading the autoclave needed to be repressurized several times with H2 to 100 bat After no pressure drop was observable, the autoclave was cooled to 0° C. in an ice bath and was than depressurized to ambient pressure.Using the general procedure, a series of test hydrogenations were made. The results are listed in the following table (average results out of three test reactions): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With C57H69P3Ru; hydrogen; bis(trifluoromethanesulfonyl)amide at 200℃; for 0.0833333h; Autoclave; | General Procedure for Hydrogenation Experiments General procedure: For the hydrogenation experiments the following general procedure, here exemplified with Ruthenium (Triphos-Xyl)TMM (lb) was used except where noted.A 20 mE stainless steel autoclave with a glass inlet was charged with Dimethyl itaconate (3.7258 g, 23.6 mmol), Ruthenium(Triphos-Xyl)TMM (lb) (0.0095 g, 0.01 mmol) and HRTA=Ris(trifluormethylsulfon)imid (0.0028 g, 0.01 mmol). It should be noted that the ratio of catalyst/HETA is always set 1:1 (mol/mol), also when different concentration of catalyst were used.The autoclave was sealed, evacuated at high vacuum and refilled with argon at least 3 times and subsequently pressurized with 100 bar H2 and placed into a steel cone preheated to 200° C. on a magnetic stir plate. Stirring speed was increased from 0 rpm to 700 rpm within 5 minutes to assure the movement of the stirring bar. Due to the high substrate loading the autoclave needed to be repressurized several times with H2 to 100 bat After no pressure drop was observable, the autoclave was cooled to 0° C. in an ice bath and was than depressurized to ambient pressure.Using the general procedure, a series of test hydrogenations were made. The results are listed in the following table (average results out of three test reactions): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-methyltetrahydro-2-furanone With water; potassium hydroxide for 3h; Reflux; Stage #2: 2-iodo-propane In N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere; | 1.1 Preparation of Intermediate Compound A Method 1 Step 1: A solution of a-methyl-y-butyrolactone (9.90 mL, 88 mmol) in 1M aqueous potassium hydroxide solution (88 mL, 88 mmol) was heated under reflux for 3 hours, then cooled to room temperature and concentrated in vacuo. The crude solid was triturated in diethyl ether, filtered off and washed with diethyl ether. The solid was then dried in vacuo over P205 at 40°C. Step 2: To a solution of the product of step 1 (10 g, 64.0 mmol) in DMF (80 mL) was added dropwise at room temperature under nitrogen 2-iodopropane (12.78 mL, 128 mmol). The reaction was allowed to stir at room temperature for 5 hours. 2-iodopropane (3.2 mL, 32 mmol) was added, and the reaction mixture was allowed to stir at room temperature for about 15 hours. The mixture was diluted with EtOAc, and the organic layer was washed with a metabisulfite solution and brine. The organic layer was dried, filtered and concentrated in vacuo at 20-30°C to provide intermediate compound A. 1H MR (400 MHz, CDC13) δ 5.02 (heptuplet, J= 6.30Hz, 1H), 3.71-3.66 (m, 2H), 2.63-2.54 (m, 1H), 1.96-1.87 (m, 1H), 1.73-1.65 (m, 2H), 1.24 (d, J= 6.30Hz, 3H), 1.235 (d, J= 6.30Hz, 3H),1.18 (d, J= 6.91Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 40% 2: 10.1% | With hydrogen In 1,2-dimethoxyethane at 80℃; for 4h; | 2C Example 2C (Synthesis of 1,4-pentanediol) In the same apparatus as in Example 1, The residue (Ir-Pt -Re catalyst (1)) obtained in Example 1, and 0.342 g (3.0 mmol) of ε-caprolactone were added, It was made up with 1,2-dimethoxyethane to make ε-caprolactone 5%. Pressurized to 8.0 MPa with hydrogen gas, the mixture was reacted at 80 °C. for 2 hours with stirring. After completion of the reaction, the resulting reaction solution was cooled to room temperature, And then filtered through a syringe equipped with a membrane filter (0.45 μm). When the obtained filtrate was analyzed by gas chromatography, The conversion of ε-caprolactone is 100% The yield of 1,6-hexanediol was 92.3%. The selectivity was 92.3% The yield of 1-hexanol was 8.0% The selectivity was 8.0%. In Example 1A, The catalyst was added to the Ir-Pt-Re catalyst (2) prepared in Example 2, A 1,2-dimethoxyethane solution of 5% ε-caprolactone was added to 50% γ-valerolactone 1, To a 2-dimethoxyethane solution (7.5 mmol of γ-valerolactone) Except for changing the reaction time to 4 hours, The reaction was carried out in the same manner as in Example 1A. When the obtained filtrate was analyzed by gas chromatography, The conversion of γ-valerolactone was 50.0% . The yield of 1,4-pentanediol was 40.0%. The selectivity was 80.0%. The yield of 2-pentanol was 10.1% . The same selectivity was 20.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: furan With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5h; Stage #2: 3-methyltetrahydro-2-furanone In tetrahydrofuran; hexane | 4.2.1. Furan S1 A flame-dried 25mL round-bottom flask was charged with furan (300 μL, 4.12 mmol, 2 equiv) and THF (3 mL). The resulting solution was cooled to -78°C and n-BuLi (0.83 mL, 2.06 mmol, 1 equiv, 2.5M in hexane) was added over 30 min. After stirring for 1h at -78°C, the furyl lithium solution was added dropwise to α-methyl-γ-butyrolactone (18) (195 μL, 2.06 mmol, 1 equiv) in THF (9 mL). Stirring at-78°C was continued for 5h at which point conversion was judged complete by TLC. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL), warmed to room temperature, and extracted with Et2O (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Column chromatography (SiO2 neutralized with Et3N, 30%-70% EtOAc/hexanes gradient) gave furan S1 (225 mg, 65% yield) as a colorless oil: Rf=0.26 (50% EtOAc/hexane); 1H NMR (600MHz, C6D6) δ 6.92 (dd, J=3.5, 0.8Hz, 1H), 6.84 (dd, J=1.7, 0.8Hz, 1H), 5.85 (dd, J=3.5, 1.7Hz, 1H), 3.36-3.29 (m, 3H), 2.01-1.92 (m, 1H), 1.47-1.40 (m, 1H), 1.06 (d, J=7.0Hz, 3H), 0.71 (d, J=26.4Hz, 1H); 13C NMR (150MHz, C6D6) δ 192.4, 153.3, 145.8, 116.8, 112.1, 60.4, 38.5, 36.2, 17.1; IR (thin film, cm-1) 3423, 2934, 1664, 1566, 1466, 1397; HRMS (EI) calcd. for [C9H12O3]: m/z 168.0786, found 168.0788 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In water at 180℃; for 6h; | 1 0.1 g of reduced catalystAnd 20g of 5wt% aqueous itaconic acid solutionInto the reaction kettle,Stir well and disperse evenly.After hydrogen replacement,Filled with 50bar H2,Heated to 180 ° C,Stop after 6h reaction,Sampled for gas chromatography after cooling to room temperatureAnd liquid chromatography analysis.The reaction results are shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 3-methyltetrahydro-2-furanone With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at 0℃; for 0.25h; Stage #2: 2,6-dichloropyrazine In tetrahydrofuran; hexane at 20℃; | 46.1 Step 1: 3- (6-Chloropyrazin-2-yl) -3-methyldihydrofuran-2 (3H) -one. To a solution of diisopropylamine (2.3 mL, 16.16 mmol) in tetrahydrofuran (THF) (37 mL),N-Butyllithium (2.5 M in hexanes, 5.92 mL, 14.81 mmol) was added with stirring at -78 ° C. After stirring for 5 minutes,Alpha-methyl-gamma-butyrolactone(1.416 mL, 14.81 mmol) was added dropwise.After stirring at 0 ° C for 15 minutes,The reaction mixture is cooled to -75 ° C.2,6-Dichloropyrazine (2.0059 g, 13.46 mmol) was added dropwise as a solution in THF (7.5 mL). The mixture was stirred overnight while warming to room temperature.Dilute the reaction mixture with saturated aqueous sodium bicarbonate solution,Extracted with dichloromethane (2 × 10 mL).The combined extracts are dehydrated with anhydrous sodium sulfate,Filter and concentrate under reduced pressure. ProductPurify by silica gel chromatography eluting with 0-40% ethyl acetate / heptane,The desired product (2.5 g, 76% yield) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | Stage #1: nitromethane; 3-methyltetrahydro-2-furanone With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 40 - 45℃; for 5h; Green chemistry; Stage #2: With methanesulfonyl chloride; triethylamine In dichloromethane at 20 - 25℃; for 4h; Green chemistry; Stage #3: With 5%-palladium/activated carbon; hydrogen at 30 - 35℃; for 4h; Autoclave; Green chemistry; | 1-2 Example 1: Preparation of 4-methylpiperidin-3-one To the agitator, thermometer, A 500 ml four-necked flask with a reflux condenser, Add 150 grams of dichloromethane, 20.0 g (0.2 mole) of α-methyl-γ-butyrolactone, 12.5 grams (0.2 moles) of nitromethane, 0.5 g DBU, Stir the reaction at 40-45 ° C for 5 hours. After the gas phase detection reaction is completed, Cool to 20 , Add 25.0 grams of triethylamine, 24.5 g (0.22 mol) of methylsulfonyl chloride, Stir the reaction at 20-25 ° C for 4 hours. Cool to 0-5 ° C and filter, Wash the filter cake twice with dichloromethane, 20 grams each time, Combined filtrates, The resulting filtrate was transferred to a 500 ml stainless steel autoclave, Add 0.3 g of 5% palladium-carbon catalyst, After 3 times of nitrogen replacement, Hydrogen pressure to 0.2-0.3MPa, 30-35 catalytic hydrogenation reaction for 4 hours, The palladium carbon was separated by filtration, The obtained filtrate was added to 80 g of water, 20% sodium hydroxide solution to adjust the pH to 7-8 (methanesulfonic acid produced by neutralization), Layered, The aqueous layer was extracted 3 times with dichloromethane, 20 grams of dichloromethane each time, Combine the dichloromethane layers, 3.0 grams of anhydrous sodium sulfate was dried for 3 hours, filter, Distilling the filtrate to recover the solvent, 20.6 g of 4-methylpiperidin-3-one were obtained as a pale yellow liquid, Yield 91.2%, Gas phase purity was 99.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.5% | With sulfuric acid In methanol at 20℃; for 16h; Inert atmosphere; | 1 Step 1: Preparation of methyl 4-methoxy-2-methylbutanoate 3-methyldihydrofuran-2(3H)-one (4.0 g, 40 mmol) was dissolved in methanol (40 mL), and triethyl orthoformate (8.48 g, 80 mmol) and concentrated sulfuric acid (100 mg) were added at room temperature. The reaction solution was stirred at room temperature for 16 hrs, then poured into water (200 mL), and then extracted with ethyl acetate (100 mL*2). Organic phases were combined and washed once with brine (100 mL), dried over sodium sulfate and filtered, and concentrated to obtain a crude product of methyl 4-methoxy-2-methylbutanoate (4.0 g, yield 68.5%). MS m/z (ESI): 147 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With 2-methyl-1,10-phenanthroline; (1,5-cyclooctadiene)(methoxy)iridium(I) dimer In Cyclooctan at 100℃; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-methyltetrahydro-2-furanone; methyl iodide With potassium hydroxide In tetrahydrofuran at 20℃; for 24h; Darkness; Stage #2: With water In tetrahydrofuran for 5h; Stage #3: With hydrogenchloride In water | 64.A Step A: 4-methoxy-2-methylbutyric acid (Compound 64.1) The compound α-methyl-γ-butyrolactone (5g, 50mmol) was dissolved in 40mL of dry tetrahydrofuran, and potassium hydroxide (15.4g, 275mmol) and methyl iodide (24.14g, 170mmol) were added to the reaction flask, Stir for 24 hours at room temperature and protected from light. After that, the reaction solution was added to water (100 mL) and stirring was continued for at least 5 hours. The aqueous solution was washed three times with dichloromethane (35 mL), then the aqueous phase was acidified with hydrochloric acid (pH=4), extracted with dichloromethane (30 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration and spin-drying, the crude compound was obtained (5 g, yield: 75.8%, yellow oil) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dibutyltin diacetate In tetrahydrofuran at 65℃; for 4h; | General procedure for ring-opening processes General procedure: An oven-dried reaction flask (20 mL) was charged with amine(1, 4.38 mmol), lactone (2, 2.19 mmol, 1.0 equiv), dibutyltin acetate(20 mol%) and THF (5 mL). The resulting mixture was stirred at65 C for 4 h. The crude products were purified by flash columnchromatography on silica gel to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | With aluminum (III) chloride at 40 - 82℃; for 17h; | 1-2 Example 1: Preparation of 2-methyl-3,4-dihydro-1(2H)-naphthone (III) Add 400 grams of benzene and 60.0 grams (0.6 mol) of α-methyl-γ-butyrolactone to a 1000 ml four-necked flask connected with a stirring, thermometer, reflux condenser, and air duct. The temperature is within the range of 40-50°C. Add 300 grams (2.25 moles) of anhydrous aluminum trichloride (30 grams per batch) in 10 batches, and the addition is complete in 2 hours. Afterwards, it was refluxed and stirred at 80-82°C for 15 hours, cooled to 20-25°C, and added to a mixture of 250ml of 35wt% concentrated hydrochloric acid and 1500g of ice water. The layers were separated. The aqueous layer was extracted with dichloromethane three times each 200 grams, combined the organic phases, distilled to recover dichloromethane and benzene, and distilled under reduced pressure (115-125/1mm mercury column) to obtain 89.8 grams of 2-methyl-3,4-dihydro-1(2H)-naphthone (III) The yield is 93.5%, and the gas purity is 99.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-methyltetrahydro-2-furanone With sodium hydroxide In water at 70℃; for 24h; Stage #2: benzyl bromide With tetrabutylammomium bromide In acetone at 60℃; for 24h; | The crude product(153.7 mg) was dissolved in 3.0 mL of an aqueous solution containing NaOH (52.0 mg, 1.30 mmol). Themixture was treated at 70 oC for 24 h. After that, the solvent was removed azeotropically with toluene, and3.0 mL of acetone was added to the residue. After the addition of tetrabutylammonium bromide (21.6 mg,0.067 mmol) and BnBr (187.1 μL, 1.58 mmol), the mixture was again stirred at 60 oC for 24 h. The mixturewas washed with several milliliters of EtOAc, and which was washed with 1 M aqueous NaHSO4, saturatedaqueous NaHCO3 and water. The organic layer was dried over anhydrous Na2SO4 and purified by silicagel CC after evaporation (EtOAc/hexane, 1:2) to afford 4 (120.6 mg, 29% in 3 steps). 1H NMR (270 MHz,CDCl3) d: 1.21 (3H, d, J = 6.9 Hz, CH3), 1.63-1.75 (1H, m, H-3a), 1.86-2.01 (1H, m, H-3b), 2.69 (1H,sext, J = 7.0 Hz, H-2), 3.65 (2H, br d, H-4), 5.12 (2H, s, benzyl), 7.33 (5H, m, Ph); 13C NMR (67.5 MHz,CDCl3) d:16.9 (CH3), 36.1 (C-3), 36.3 (C-2), 60.2 (C-4), 66.1 (benzyl), 127.9 (aromatic), 128.0 (aromatic),128.4 (aromatic), 135.9 (aromatic), 176.5 (C-1); FI-MS: m/z =208.1 [M]+. |
Tags: 1679-47-6 synthesis path| 1679-47-6 SDS| 1679-47-6 COA| 1679-47-6 purity| 1679-47-6 application| 1679-47-6 NMR| 1679-47-6 COA| 1679-47-6 structure
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