| 87% |
With manganese(IV) oxide; In chloroform; at 20℃; |
Boc2O was added in one portion at r.t. to a solution of (4-aminomethyl-phenyl)-methanol Compound 3a (21.2 mmol, 2.9 g) in CH2C12 (100 mL). The resulting solution wasstirred for 48h, then washed with a 10% citric acid solution (50 mL) followed by brine. Theorganic layer was separated, then dried over Na2SC>4 and filtered. The solvent was removed invacua to obtain <strong>[123986-64-1](4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester</strong> Compound 3b as awhite solid (5.2 g, 99% yield), which was used in the next step without further purification.MnO2 (9.6 g) was added to a solution of Compound 3b (21.2 mmol, 5.2 g) inchloroform (60 mL), forming a black suspension that was stirred at r.t. overnight then filteredthrough a pad of celite. The solvent was evaporated in vacua to obtain (4-forinyl-benzyl)-carbamic acid tert-butyl ester Compound 3c as a white solid (4.3 g, 87% yield), which was usedin the next step without purification.; NaB(OAc)3H (2.8 mmol, 0.58 g) was added to a mixture of Compound 3c (2.6 mmol,0.6 g) and tetrahydro-pyran-4-ylamine Compound 3d (2.6 mmol, 0.26 g) in CH2C12 (25 mL)and the resulting suspension was stirred at r.t. An aliquot of the reaction mixture showed theformation of product (MS m/e 321; 100%). An aqueous solution of formaldehyde (37%solution, 8.6 mmol, 0.7 mL) was added to the reaction mixture, followed by NaB(OAc)3H (2.8mmol, 0.58 g) added in one portion under ice cooling. The reaction mixture was stirred at r.t.for about 2h, then made basic with a 2N NaOH solution and extracted with CH2C12. Theorganic layer was washed with brine, then separated and dried over Na2SO4. The drying agentwas filtered and the solvent was removed in vacua to yield (4-[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester Compound 3e as a pale yellow oil.MS m/e 235 (M+H, 100%). The product was purified by column chromatography (4:1CH2Cl2:MeOH) to yield a colorless oil (0.52 g, 59% yield).; Compound 3e was dissolved in CH2Cl2, then HC1 in dioxane was added and themixture was stirred at r.t. for 12 hrs. The solvent was removed and the gummy residue wasmade basic with 2N NaOH and extracted with EtOAc. The organic layer was washed withbrine, then separated and dried over Na2SO4. The drying agent was filtered and the solvent wasremoved in vacua to obtain (4-aminomethyl-benzyl)-methyl-(tetrahydro-pyran-4-yl)-amineCompound 3f as a pale yellow oil (0.3 g, 83% yield). MS m/e 235 (M+H, 100%).; A solution of 3-(3-trifluoromethyl-phenyl)-acryloyl chloride Compound 3g (0.3 mrnol,0.07 g) in THF (2 mL) was added dropwise to a solution of Compound 3f (0.2 mmol, 0.05 g)and Et3N (0.8 mmol, 0.14 mL) in THF (10 mL) at 0C. The resulting suspension was allowedto warm to r.t. overnight. The reaction mixture was made basic with a 2N NaOH solution andextracted with EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2X10 mL) andthe organic layers were washed with brine, then dried over Na2SO4 and filtered. The solventwas removed in vacua to yield a yellow solid (with methane) as the product. The crude productwas purified by preparative TLC (9:1 EtOAc-.MeOH, Rf = 0.2) to yield N-(4-[methyl-(tetrahydro-pyran-4-yi)-amino]-methyl}-benzyi)-3-(3-trifluoromethyl-phenyl)-acrylamideCompound 3h (0.06 g, 49% yield). MS m/e 433 (M+H, 100%).; Mel (0.08 mL, 1.28 mmol) was added dropwise to a solution of Compound 3h (0.07mmol, 0.03 g) in a mixture of acetone:acetonitrile (2 mL). The resulting solution was stirred atr.t. for 24h to provide a residue. The residue was washed with ether (2x 1 mL) and dried undera high vacuum to provide Compound 64 (0.04 g, 93% yield) as an iodide salt. MS m/e 584(M+H, 100%). |
| 87% |
With manganese(IV) oxide; In chloroform; at 20℃; |
MnO2 (9.6 g) was added to a solution of Compound 3b (21.2 mmol, 5.2 g) in chloroform (60 mL), forming a black suspension that was stirred at r.t. overnight then filtered through a pad of celite. The solvent was evaporated in vacuo to obtain (4-formyl-benzyl)-carbamic acid tert-butyl ester Compound 3c as a white solid (4.3 g, 87% yield), which was used in the next step without purification. |
| 80% |
With manganese(IV) oxide; In dichloromethane; at 20℃; for 16h; |
Stage 3 - Alcohol oxidation; Stage 2 product (5.87g, 24.73mmol) was stirred in DCM (20OmL) with MnO2 (16.71g, 192.20mmol) for 16h at RT. The reaction was then filtered through celite and the solvent removed in vacuo to give the product as a yellow oil which was used in the next step without further purification (4.63g, 80%). m/z = 258 [M+Na]+. |
| 80% |
With manganese(IV) oxide; In dichloromethane; at 20℃; for 16h; |
Stage 3 - Preparation of te/t-butyl (4-formylbenzyl)carbamate; Stage 2 product (5.87g, 24.73mmol) was stirred in DCM (20OmL) with MnO2 (16.71g, 192.2mmol) for 16h at RT. The reaction was then filtered through celite and the solvent removed in vacuo to give the product as a yellow oil (4.63g, 80%). m/z = 258 [M+Na] |
| 70% |
With sodium acetate; pyridinium chlorochromate; In dichloromethane; at 25℃; for 1h; |
To a solution of (4-Hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (4.5 g, 18.2 mmol) in dichloromethane (45 ml) were added PCC (4.07 g, 18.2 mmol), sodium acetate (0.26 g, 3.2 mmol) and the mixture was stirred at 25 C over a period of 60 min. The resulting mixture was diluted with ethyl acetate (200 mL) and it was stirred for 30 min. Then the reaction mixture filtered through Buchner funnel, filtrate was washed with water (2X50 mL) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain (4-Formyl-benzyl)-carbamic acid tert-butyl ester as a pale yellow solid(3.0 g, 70 %). |
| 70% |
With sodium acetate; pyridinium chlorochromate; In dichloromethane; at 25℃; for 1h; |
To a solution of (4-Hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (4.5 g, 18.2 mmol) in dichloromethane (45 ml) were added PCC (4.07 g, 18 2 mmol), sodium acetate (0.26 g, 3.2 mmol) and the mixture was stirred at 25 C. over a period of 60 min. The resulting mixture was diluted with ethyl acetate (200 mL) and it was stirred for 30 min. Then the reaction mixture filtered through Buchner funnel, filtrate was washed with water (2*50 mL) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain (4-Formyl-benzyl)-carbamic acid tert-butyl ester as a pale yellow solid (3.0 g, 70%). |
|
manganese(IV) oxide; In chloroform; at 20℃; for 15h; |
The compound (18.0 g) obtained in Example 103-2 was dissolved in chloroform (540 ml) and then added with manganese dioxide (chemically processed product) (118 g), followed by stirring at room temperature for 15 hours. The reaction solution was filtrated through Celite and the filtrate was then concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (17.1 g) as a white solid. |
|
With manganese(IV) oxide; In chloroform; for 1h;Heating / reflux; |
Reference Example 64 tert-Butyl 4-formylbenzylcarbamate Manganese dioxide (1.22 g) was added to a chloroform solution (20 ml) of tert--butyl 4-hydroxymethylbenzylcarbamate (1.22 g), followed by heating under reflux for 1 hour. After celite filtration, the filtrate was concentrated, the thus obtained residue was purified by silica gel column chromatography, and the fraction obtained from the elude of n-hexane:ethyl acetate = 2:1 was concentrated under reduced pressure to obtain the title compound (965 mg) as a colorless oil. 1H-NMR (400 MHz, CDCl3) delta: 1.46 (9H, s), 4.39 (2H, d, J=5.6 Hz), 5.16 (1H, bs), 7.44 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.1 Hz), 9.98 (1H, s). ESI-MS m/z: 236 (M+H)+. |
|
With manganese(IV) oxide; In chloroform; at 20℃; |
The compound (17.6 g) obtained in Example 23-2 was dissolved in chloroform (400 ml) and then added with manganese dioxide (chemically processed product) (88.2 g) and the whole was stirred overnight at room temperature. After completion of the reaction, the resultant was filtrated through Celite. The solvent was distilled off, thereby obtaining the subject compound (20.4 g) as a colorless crystal. |
|
With manganese(IV) oxide; In ethyl acetate; at 20℃; for 1h; |
Example 3 tert-butyl (4-formylbenzyl)carbamate To an ethyl acetate (50 mL) solution of tert-butyl [4-(hydroxymethyl)benzyl]carbamate (3.0 g), manganese dioxide (20.0 g) was added. The reaction solution was stirred at room temperature for one hour. The reaction solution was filtered through celite (trade name). The filtrate was conentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 8: 2 ? 7: 3) to obtain the title compound having the following physical properties (2.3 g). Rf 0.83 (chloroform: methanol = 9: 1); NMR (CDCl3): delta 1.47 (s, 9H), 4.40 (m, 2H), 4.95 (m, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.86 (d, J = 7.8 Hz, 2H), 10.00 (s, 1H). |
|
With Dess-Martin periodane; In dichloromethane; at 20℃; for 2.5h; |
Dess-Martin periodinane (1.25 eq) was added to a flask with a stir bar. Diluted with DCM (0.25 M), and the resulting slurry was stirred vigorously at roomtemperature. Added a solution of alcohol (1.00 eq) in DCM (0.20 M) in dropwise fashion, and the resulting reaction mixture was stirred vigorously under Ar at room temperature. After 2.5 hrs, TLC indicated complete conversion of starting material. The reaction mixture was poured over a 1:1 mixture of saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 (55 mL per mmol alcohol). The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. A solution ofamine (1.00 eq) in DCM (0.12 M) was added to a flask with a stir bar. Added a solution of aldehyde (1.05 eq) in DCM (0.53 M), and the resulting mixture was stirred under Ar at room temperature for 5 mm. After this time, acetic acid (1.00 eq) was added, and the resulting mixture was stirred under Ar at room temperature for 15 mm. After this time, sodium triacetoxyborohydride (3.00 eq) was added, and the resulting reaction mixture was allowed to stir overnight at room temperature under Ar. In the morning, thereaction mixture was diluted with DCM and washed once with 1 M aqueous sodium hydroxide. The resulting aqueous layer was extracted 3 times with DCM. Combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The cmde material was taken up in DCM (40 mL per mmol amine), filtered, and evaporated under reduced pressure. |
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