trimethyl(trimethylsilyloxy)silane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,3,4-Trifluorobenzoic acid (70 Kg, 398 Mol) in sulphuric acid (96 wt %; 194 L) and hexamethyldisiloxane (6.5 Kg, 40 Mol), at 23° C., was added a 1:1 mixture of sulphuric acid (96 wt %) and nitric acid (98 wt %) (total 70.1 Kg), over 75 min. The temperature of the reaction mixture was maintained between 15 and 25° C. during the addition. The mixture was stirred for a further 5 hours and then run onto ice (700 Kg), keeping the temperature of the ice mixture below 0° C. Water (35 L) was used to rinse the nitration reactor into the quench reactor and the obtained mixture was stirred for 2 hours at 0° C., then isolated on a centrifuge. The resultant wet cake was washed with cold water (350 L), and the solid was then suspended in water (280 L) and stirred for 2 hours at 0° C. This suspension was then centrifuged and the cake was washed with cold water (210 L), then dried in a vacuum oven at 45° C. for 2 days, to provide 2,3,4-Trifluoro-5-nitro benzoic acid (69.4 Kg, 74.3% yield). 1H NMR (400 MHz, d6 DMSO) δ 8.44 (1H, apparent dt, J 2, 7, Ar—H). 19F NMR (376 MHz, d6 DMSO) δ−153.9, −131.5, −120.9. 13C NMR (100 MHz, d6 DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C—F, dt, J 251, 10), 148 (C—F, dd, J 265, 13), 154 (C—F, dd, J 265, 10), 163 (COOH). IR vmax/cm−1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (−) m/z 220 (M−1) detected. The temperature of the reaction mixture was maintained between 15 and 25° C. during the addition to rinse the nitration reactor into the quench reactor the obtained mixture was stirred for 2 hours at 0° C. isolated on a centrifuge The resultant wet cake was washed with cold water (350 L) stirred for 2 hours at 0° C the cake was washed with cold water (210 L) dried in a vacuum oven at 45° C. for 2 days

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound of Example 10E (200 mg, 0.61 mmol) was dissolved in 2 mL of dichloromethane; 100 mg of 4 Å molecular sieves were added, followed by 15 mg of tetrapropylammonium perruthenate and 75 mg of 4-methylmorpholine N-oxide. The mixture was stirred for 2 hours at ambient temperature, and then filtered through diatomaceous earth to removed solids. The crude product was purified by silica gel chromatography using an Analogix IntelliFlash™ 40, eluting with a gradient of 5% to 30% ethyl acetate in hexanes. The compound of Example 10C (200 mg, 0.63 mmol) was combined with this aldehyde according to the coupling procedure described by Kutner et al. in J. Org. Chem. 1988, 53, 3450-3457. The named product was isolated as a mixture of trimethylsilyl ether (Fraction A) and hydroxyl (Fraction B) after chromatographic purification using an Analogix IntelliFlash 280™, eluting with a gradient of 0% to 50% ethyl acetate in hexanes. These products were combined and carried forward to the next step. 100 mg of 4 Å molecular sieves were added filtered through diatomaceous earth to removed solids The crude product was purified by silica gel chromatography eluting with a gradient of 5% to 30% ethyl acetate in hexanes

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A dry 500 mL round-bottomed flask was charged with lithium chloride (4.24 g, 100 mmol, 10.0 equiv), diisopropylamine (3.1 mL, 22.1 mmol, 2.21 equiv), and tetrahydrofuran (35 mL). The suspension was cooled to -78° C., and n-butyllithium (2.04M in hexanes, 10.20 mL, 20.8 mmol, 2.08 equiv) was added via cannula, and the mixture was briefly warmed to 0° C. and then recooled to -78° C. [1S-[1R*, 2R*]]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl benzeneacetamide (2.83 g, 10.0 mmol, 1.0 equiv) was added as a solution in tetrahydrofuran (50 mL), and the mixture was stirred at -78° C. for 1 hour, 0° C. for 10 minutes, and 23° C. for 4 minutes, then cooled to 0° C. Ethyl iodide (3.2 mL, 40 mmol, 4.0 equiv) was added, and the reaction was quenched after 40 minutes with saturated ammonium chloride. The amide was extracted from saturated ammonium chloride (800 mL) with ethyl acetate (3×100 mL), and the combined organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, flash column chromatography (50% ethyl acetate/hexanes) of the oily residue afforded a colorless oil which slowly solidified (2.85 g, 92 % yield). GC analysis of the TMS ether indicated a diastereomeric purity of the amide of greater than 98% de: mp 65°-66° C.; 1H NMR (300 MHz, C6D6) δ6.9-7.4 (m, 5H), 4.95 (br, 1H), 4.51 (t, 1H, J=6.9 Hz), 4.03 (m, 1H), 3.82 (m, 1H), 3.11 (dd, 1H, J=7.5 Hz, 7.0 Hz), 2.78 (s, 3H), 2.48 (m, 2H), 2.25 (m, 1H), 2.12 (s, 3H), 1.90 (m, 1H), 1.73 (m, 2H), 0.98 (d, 3H, J=6.8 Hz), 0.97 (m, 3H), 0.82 (t, 3H, J =7.3 Hz), 0.30 (d, 3H, J=6.5 Hz); 13C NMR (75.5 MHz, CDCl3) δ 175.4, 174.2, 142.3, 141.3, 140.5, 139.6, 128.8, 128.7, 128.7, 128.3, 128.2, 127.8, 127.7, 127.4, 126.9, 126.7, 126.6, 126.3; FTIR (neat film) cm-1: 3384 (br, m), 3027 (m), 2966 (m), 2922 (m), 2873 (m), 1620 (s), 1491 (m), 1453 (m), 1406 (m), 761 (m), 701 (m); HRMS (FAB) Calcd for C20H26NO2 (MH+): 312. 1965. Found: 312. 1962. the mixture was briefly warmed to 0° C. recooled to -78° C. 23° C. for 4 minutes cooled to 0° C the reaction was quenched after 40 minutes with saturated ammonium chloride The amide was extracted from saturated ammonium chloride (800 mL) with ethyl acetate (3×100 mL) the combined organic extracts were dried over sodium sulfate After removal of the solvent under reduced pressure, flash column chromatography (50% ethyl acetate/hexanes) of the oily residue afforded a colorless oil which

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This material was dissolved in THF (0.1 mL), cooled to at 0° C. and treated with 0.5 M CF3TMS in THF (30 μL, 15 mmol) followed by 0.05 M TBAF in THF (5 mL, 0.025 mmol). After stirring for 30 min, the reaction mixture was diluted with saturated aqueous NaHCO3 (2 mL) and H2O (1 mL), extracted with EtOAc (6×), dried over Na2SO4, filtered and concentrated to give the crude bis-TMS ether. extracted with EtOAc (6×) dried over Na2SO4 filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This reaction proceeds slowly without diethylether but reacts faster at reflux temperatures. Trimethylsilanol is condensed during the HMDS distillation step to give HMDSO, which reacts as shown above. reacts faster at reflux temperatures condensed during the HMDS distillation step

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By product hexamethyldisiloxane in ethyl ether reacts with sodium amide to form sodium trimethylsilanolate and HMDS as follows: ##STR5##

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: About 1.9 ml of a 25% solution of phosphonitrile chloride in methylene chloride are added at room temperature with stirring to a mixture containing 486 g (3.0 mol) of hexamethyldisiloxane and 170 g (1.0 mol) of tetrachlorosilane. After the mixture has been stirred at room temperature for 8 hours, the catalyst is deactivated by adding 2.2 ml of tri-n-butylamine. Distillation of the reaction mixture at 18° to 34° C. and at 2 mbar gives 55 g of 3,3-dichlorohexamethyltrisiloxane, but no 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane. Likewise the desired 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane is neither found in the distillation residue (12 g) nor in the cold trap (583 g of a mixture of trimethylchlorosilane and 1,1,1-trichloro-3,3,3-trimethyldisiloxane). After the mixture has been stirred at room temperature for 8 hours Distillation of the reaction mixture at 18° to 34° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: About 1.9 ml of a 25% solution of phosphonitrile chloride in methylene chloride are added at room temperature with stirring to a mixture containing 486 g (3.0 mol) of hexamethyldisiloxane and 170 g (1.0 mol) of tetrachlorosilane. After the mixture has been stirred at room temperature for 8 hours, the catalyst is deactivated by adding 2.2 ml of tri-n-butylamine. Distillation of the reaction mixture at 18° to 34° C. and at 2 mbar gives 55 g of 3,3-dichlorohexamethyltrisiloxane, but no 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane. Likewise the desired 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane is neither found in the distillation residue (12 g) nor in the cold trap (583 g of a mixture of trimethylchlorosilane and 1,1,1-trichloro-3,3,3-trimethyldisiloxane). After the mixture has been stirred at room temperature for 8 hours Distillation of the reaction mixture at 18° to 34° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: About 4.6 g (0.2% by weight) of tetramethylurea and 183.4 g of a 25% solution of phosphonitrile chloride in methylene chloride are added to a mixture containing 1707 g (10.5 mol) of hexamethyldisiloxane and 595 g (3.5 mol) of tetrachlorosilane with stirring in a 4 liter multineck flask fitted with internal thermometer, stirrer and a reflux condenser. The reaction temperature is kept at 45° C. by cooling. After 21 hours, the volatile components of the reaction mixture are removed by distillation at 200 mbar and 100° C. The crude distillate contains 56% of 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane, 29% of 3,3-dichlorohexamethyltrisiloxane and 16% of 3,3-bis(trimethylsiloxy)hexamethyltrisiloxane. The crude distillate is fractionally distilled, and gives, at 20 mbar and 83° to 87° C., 313 g (27% of theory) of 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane in a purity, determined by gas chromatography, of 97%. fitted with internal thermometer, stirrer and a reflux condenser is kept at 45° C. by cooling the volatile components of the reaction mixture are removed by distillation at 200 mbar and 100° C The crude distillate is fractionally distilled