Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 55145-45-4 | MDL No. : | MFCD06411307 |
Formula : | C12H24O2Si | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HXKBGMNGSYGPRB-UHFFFAOYSA-N |
M.W : | 228.40 | Pubchem ID : | 10609430 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
82% | In dichloromethane at -78 - 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1H-imidazole; In dichloromethane; | <strong>[13482-22-9]4-hydroxycyclohexanone</strong> (500 mg, 4.38 mmol), TBS-C1 (792 mg, 5.26 mmol),and imidazole (447 mg, 6.57 mmol) were dissolved in DCM (8761 tL) for 3 hours. The reaction mixture was diluted with DCM, washed with water, 1 N HC1, saturated NaHCO3, then brine, dried (Na2504), filtered, and concentrated in vacuo to give Intermediate 140Aas alight yellow oil: ?H NMR (400MHz, CHLOROFORM-cl) 4.09 (if, J=5.1, 2.7 Hz, 1H), 2.69-2.56 (m, 2H), 2.24-2.14 (m, 2H), 1.99-1.77 (m, 4H), 0.88 (s, 9H), 0.06 (s, 6 H). | |
40.4 g | With dmap; triethylamine; In N,N-dimethyl-formamide; at 10 - 35℃; for 16h; | To a solution of the crude <strong>[13482-22-9]4-hydroxycyclohexan-1-one</strong> (21.2 g), 4-dimethylaminopyridine (7.48 g) and triethylamine (22.5 g) in DMF (350 mL) was slowly added tert-butyldimethylsilyl chloride (30.2 g) at room temperature, and the mixture was stirred at room temperature for 16 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was passed through a silica gel pad (ethyl acetate/hexane) to give the crude title compound (40.4 g). 1H NMR (300 MHz, CDCl3) delta 4.13 (tt, J=5.0, 2.5 Hz, 1H), 2.58-2.76 (m, 2H), 2.17-2.31 (m, 2H), 1.81-2.05 (m, 4H), 0.92 (s, 9H), 0.10 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; chiral bis-naphthylethylamine hydrochloride; triethylamine 1.) THF, hexane, -100 deg C, 2 min, 2.) THF, hexane, -100 deg C, 30 min; Yield given. Multistep reaction. Yields of byproduct given. Title compound not separated from byproducts; | ||
With N,N'-bis<(S,S)-2,4-diphenylpent-3-yl>urea dilithium salt In tetrahydrofuran; hexane at -100℃; for 0.833333h; Yield given; Yields of byproduct given. Title compound not separated from byproducts; | ||
With n-butyllithium; N,N'-bis<(2R)-phenyl-1-(R)-phenylethyl>propyl>urea In tetrahydrofuran; hexane at -100℃; for 0.833333h; Yield given; Yields of byproduct given. Title compound not separated from byproducts; |
With n-butyllithium; (R,R)-(+)-bis[alpha-methylbenzyl]amine hydrochloride In tetrahydrofuran; hexane at -100℃; for 3h; Title compound not separated from byproducts; | ||
With n-butyllithium; (+)-bis(α-methylbenzyl)amine hydrochloride In tetrahydrofuran at -100 - -78℃; Title compound not separated from byproducts; | ||
Stage #1: chloro-trimethyl-silane With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; 2C13H14NS(1-)*Mg(2+) In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran at -78℃; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
Stage #1: chloro-trimethyl-silane With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; 2C16H18N(1-)*Mg(2+) In tetrahydrofuran at -78℃; for 16h; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran optical yield given as %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With n-butyllithium; (R,R)-N,N-bis-(1-phenylethyl)amine In tetrahydrofuran at -95℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 4h; | |
92% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 1.16667h; | 32 Intermediate Preparation 32; Trifluoro-methanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxy)-cvclohex-l-enyl ester; To a solution of 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanone (2.63 g, 11.5 mmol) and N-phenylbis(trifluoromethanesulphonimide) (6.26g, 17.3 mmol) in THF (50 mL) at -78 0C is added lithium bis(trimethylsilyl)amide (16.1 mL, 1.0 M) dropwise over 10 minutes. The mixture is stirred and allowed to warm to room temperature over 60 minutes. The reaction is quenched with brine (25 mL) and concentrated under reduced pressure. The residue is extracted with EtOAc (2 x 50 mL). The combined organic layers are dried over Na2SO4, filtered, and concentrated. The crude product is purified by flash chromatography eluting with 10% EtOAc/Hexanes to afford the title compound (3.82 g, 92%). MS m/z 361.0 (M+l). |
88% | With sodium hexamethyldisilazane In tetrahydrofuran at 20℃; |
Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.166667h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; | 188.1 Diisopropylamine (1.7 mL, 12.0 mmol) was taken up in 30 mL of THF and chilled to -78 0C. N-butyllithium, (4.8 mL, 2.5 M in heaxnes) was added. After 5 minutes, 4-((tert- butyl(dimethyl)silyl)oxy)cyclohexanone (2.3 g, 10.0 mmol) was added dropwise in 8 mL of THF. After 10 minutes, n-phenyltriflimide (4.0 g, 11.0 mmol) was added dropwise in 8 mL of THF. After 10 minutes, the mixture was warmed to rt and stirred for 12 hours. The mixture was quenched with 40 mL of aq NH4Cl and extracted twice with 40 mL of EtOAc. The combined organic extracts were washed with 40 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0 to 5% EtO Ac/hexanes) afforded 4-((tert-butyl(dimethyl)silyl)oxy)- 1 -cyclohexen- 1 -yl trifluoromethanesulfonate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With iron(III) chloride hexahydrate; acetaldehyde In dichloromethane at 20℃; for 2h; chemoselective reaction; | |
81% | With cerium(III) chloride; sodium iodide In acetonitrile for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | General procedure: Oxalyl chloride (0.34 mL) was added dropwise to a solution of ion-supported methyl sulfoxide A-1 (C6) (1.60 g, 4.0 mmol) in CH2Cl2 (6 mL) at -70 C and the mixture was stirred for 30 min at the same temperature. Then, a solution of alcohol (2.0 mmol) in CH2Cl2 (3 mL) was added dropwise at -70 C and the obtained mixture was stirred for 30 min. Triethylamine (1.66 mL, 12 mmol) was added dropwise at -70 C and the mixture was stirred for 1 h at the same temperature. The resulting mixture was warmed to -60 C and stirred for 1.5 h at the same temperature. Then, the mixture was warmed to -50 C and stirred for 1 h at the same temperature. Finally, the mixture was warmed to room temperature and stirred for 2 h at the same temperature. The reaction mixture was quenched with water (10 mL), neutralized (pH=6-7) with aq 1 M HCl solution, and extracted with diethyl ether (40 mL×2). The organic layer was washed with water (10 mL), dried over Na2SO4, and filtered. After removal of the solvent, aldehyde or ketone was obtained. The purity was estimated by 1H NMR measurements. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: propynoic acid ethyl ester With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran; hexane at -78 - 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With trimethyl orthoformate In dichloromethane at 60℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: chloro-trimethyl-silane With di-tert-butylmagnesium; lithium chloride In tetrahydrofuran at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | |
With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In hexanes at 70℃; for 3h; | 67.1 Step 1: N'-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylidene]-hydrazinecarboxylic acid tert-butyl ester tert-Butyldimethylsilyloxy-cyclohexanone (3.146 g, 97%, 13.36 mmol, CAS #55145-45-4, purchased from Aldrich) was dissolved in hexanes (24 mL). tert-Butyl carbazate (1.80 g, 98%, 13.35 mmol) was added and the mixture was heated at 70° C. for 3 hours. Upon cooling to room temperature a white solid precipitated out of solution. The solid was collected by filtration, washed with hexanes and dried to give N'-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylidene]-hydrazinecarboxylic acid tert-butyl ester (4.12 g, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Stage #1: 1,4-Cyclohexanediol; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Stage #2: With pyridinium chlorochromate In dichloromethane for 1.5h; Further stages.; | |
Stage #1: 1,4-Cyclohexanediol; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; Stage #2: With pyridinium chlorochromate In dichloromethane at 0℃; for 3h; | 1.3 Step3: 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanone; [00151] To a solution of 1,4-cyclohexanediol (20.0 g, 0.172 mol; Aldrich) and lH-Imidazole (33 g, 0.48 mol; Aldrich) in N,N-dimethylformamide (250 mL, 3.2 mol; Acros) was added a solution of tert-butyldimethylsilyl chloride (20.0 g, 0.133 mol; Aldrich) in N,N- dimethylformamide (100 mL, 1 mol; Acros) via a dropping funnel at 0 °C. The mixture was was allowed to warm to room temperature and stirred overnight. TLC (ethyl acetate/hexane 1 :4) showed almost complete reaction and the mixture was partitioned between water and ether, the organic phase dried over MgSO4 and concentrated in vacuo. [00152] The crude product from above was dissolved in methylene chloride (500 mL, 8 mol; Acros) and mixed with Celite (10Og). Pyridinium chlorochromate (41 g, 0.19 mol; Aldrich) was added in 5 portions at 0 °C. The cooling bath was removed and the mixture stirred for 3 hours. The mixture was filtered thru a short silica gel column and the column washed with methylene chloride. The filtrates were concentrated and further purified on CombiFlash silica gel column with 0-50% ethyl acetate in hexane to give the desired product as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With samarium diiodide In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-iodophenylamine; 4-(tert-butyldimethylsilyloxy)cyclohexanone With acetic acid In dichloromethane at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; Stage #3: With sodium hydrogencarbonate In dichloromethane; water | 39 [4-(tei ^Butyldimethylsilanyloxy)cyclohexyl] -(2-iodophenyl)amine; To a solution of 2- iodoaniline (2.5 g, 10.9 mmol) in dichloromethane (160 mL) was added 4-(tert- butyldimethylsilanyloxy)cyclohexanone (2.39 g, 10.9 mmol) and acetic acid (8 mL). After the reaction was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (3.47 g, 16.4 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic solution was dried (MgSO4) and concentrated to give 4.47 g of the desired amine, which was used without further purification. LC-MS (C18H3OlNOSi calc'd 431) m/z 432 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium tetrahydroborate; In methanol; at -50 - 20℃; | Sodium tetrahydroborate (0.41 g, 0.011 mol) was added in small portions to a solution of 4-[tert-butyl(dimethyl)silyl]oxycyclohexanone (1.0 g, 0.0044 mol) in methanol (10 mL) at -50 C. The mixture was gradually warmed to RT, and was diluted with ethyl acetate. The organic solution was washed with NaHCO3 solution (7.5%), water, and brine, dried over MgSO4, filtered, and concentrated to yield the desired product (0.94 g, 93%) which was directly used in next step reaction without further purification. LCMS: (M+H)+=231.2. |
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 0.5h; | Sodium borohydride (83 mg, 2.19 mmol) was added to a solution of 4-(tert- butyldimethylsilyloxy)cyclohexanone (0.5 mL, 1 .99 mmol) in methanol (4 mL), cooled to 0 C. The reaction mixture was stirred at room temperature for 30 min, and then carefully quenched with a saturated solution of aqueous NH4CI (10 mL). The aqueous layer was extracted with DCM (3 x 10 mL) and the combined organic extracts were filtered over a phase separator, concentrated under reduced pressure to give crude 4-[fe/?-butyl(dimethyl)silyl]oxycyclohexanol (assumed quantitative) which was used directly in the next step. NMR (400 MHz, CDCI3, delta) (2:1 mixture of conformers): 3.82-3.72 (m, 0.6H), 3.69-3.53 (m, 1 .4H), 1 .96-1 .18 (m, 9H), 0.90-0.78 (m, 9H), 0.04-0.03 (m, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.5% | Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone; 3-chloro-aniline In 1,2-dichloro-ethane at 20℃; for 0.5h; Molecular sieve; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Stage #3: With water; sodium hydrogencarbonate In dichloromethane; 1,2-dichloro-ethane | 54.a a) trans- [4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyll -(3-chloro-phenyl)-amine; To a solution of 3-chloroaniline (1.27 g, 10 mmol) in 1,2-dichloroethane (20 ml) were added molecular sieves (4g, size 0.4 nM) and 4-(tert-butyldimethylsilyloxy)- cyclohexanone (4.57 g, 20 mmol). After stirring the mixture for 30 min at room temperature sodium triacetoxyborohydride (8.48 g, 40 mmol) and acetic acid (1.2 g, 20 mmol) were added. The reaction mixture was stirred at room temperature overnight. For workup dichloromethane (100 ml) and IM sodium bicarbonate solution (40 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (heptane/ethyl acetate = 1:1) to yield a colourless liquid (0.80 mg, 23.5%); MS (EI): 339.2; 341.3 (M+-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone With ammonia In methanol at 20℃; for 0.25h; Stage #2: 2-Allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In methanol at 20℃; for 16h; | a a) 1-Allyl-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamineTo a solution of 1.0 g (4.38 mmol) of 4-(terf-butyldimethylsilyloxy)cyclohexanone in 6.2 mL (43.8 mmol) of 7N ammonia in methanol, previously stirred for 15 min at room temperature, were added dropwise 3.5 mL (7.0 mmo.) of a 2M solution of 2-allyl- 4,4,5,5-tetramethyl-1 ,3,2-dioxa-boro.ane in methanol. The reaction mixture was stirred for 16 h at room temperature. The volatiles were removed in vacuo and the residue could be purified by silica gel chromatography using dichloromethane / methanol / NH3 aq. as eluent. Rt = 1.19 min (Method C). Detected mass: 270.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: trimethylsilylacetylene With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1.5h; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran; hexane at -78℃; for 1h; Stage #3: With water; ammonium chloride In tetrahydrofuran; diethyl ether; hexane | 1.4 Step 4: 4-(tert-Butyl-dimethyl-silanyloxy)-l -ethyny 1-cyclohexanol; [00153] To a solution of N,N-diisopropylamine (12 mL, 0.087 mol; Aldrich) in anhydrous tetrahydrofuran (100 mL, 1 mol; Acros) was added dropwise 1.6 M n-Butyllithium in hexane (54 mL; Aldrich) at -78 °C and the mixture stirred for 30 minutes. (Trimethylsilyl)acetylene (12 mL, 0.087 mol; Aldrich) was then added and stirred for Ih before a solution of 4-(tert- Butyl-dimethyl-silanyloxy)-cyclohexanone (16.5 g, 0.0722 mol) in THF (2OmL) was added and stirred for an hour at -78 0C and then warmed to room temperature. TLC showed complete reaction. The mixture was partitioned between saturated ammonium chloride and ether, the organic phase was dried over MgSO4 and concentration in vacuo to give a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran at -78 - 20℃; for 2.5h; | g.32A To a 5.0 L round bottom flask containing 4-(tert-butyldimethylsilyloxy)cyclohexanone (7.03 g, 30.8 mmol) (Aldrich) was added THF (100 mL) and the reaction was cooled to -78° C. To the reaction mixture was added lithium bis(trimethylsilyl)amide (33.9 ml, 33.9 mmol) (Aldrich) and the reaction mixture was stirred for 30 minutes followed by the addition of iodomethane (2.309 ml, 36.9 mmol). The reaction mixture was stirred for 30 minutes at -78° C. and 2 hours at room temperature, quenched with saturated NH4Cl, extracted with EtOAc (200 mL), dried (NaSO4), filtered, and concentrated in vacuo. The residue was purified on SiO2 and eluted with 0-20% ethyl acetate/hexane to give a white solid (6.40 g) in 86% yield. 1H NMR (300 MHz, CDCl3) δ ppm 4.19-4.07 (m, 1H), 2.98-2.72 (m, 1H), 2.50-1.99 (m, 2H), 1.91-1.64 (m, 2H), 1.62-1.44 (m, 1H), 1.15 (dt, J=4.4, 6.8, 1H), 1.07-0.99 (m, 3H), 0.95-0.85 (m, 9H), 0.11 (d, J=1.6, 6H). MS (DCI+) M/Z 243. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 31% 2: 61% | Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone; 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)aniline With sodium triacetoxyborohydride In dichloromethane at 20℃; for 24h; Stage #2: With ammonium chloride In dichloromethane; water | 32 A mixture of 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanone (1.72 ml, 6.85 mml) [C.A.S.55145-45-4], 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylamine (1 g, 4.56 mmol) and sodium triacetoxy-borohydride (1.44 g, 6.85 mmol) in DCM (25 ml) was stirred at r.t. for 1 day. Then, the mixture was washed with NH4Cl (aqueous sat. solution). The organic layer was collected, dried (MgSO4) and evaporated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; heptane/EtOAc up to 5% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D32-a (trans) (0.566 g, 31%) and D32-b (cis) (1.089 g, 61%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.58% | Stage #1: diethyl 1-cyanomethylphosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 30℃; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran at 0 - 30℃; | 212.1 To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (46.0 mL) at 0 0C was added drop wise a solution of diethyl cyanomethylphosphonate (7.80 mL, 0.0482 mol) in tetrahydrofuran (80 mL). The reaction was warmed to room temperature and then cooled at 0 0C again. To the reaction mixture was a solution of 4-(tert-butyl(dimethyl)silyl)oxycyclohexanone (10.0 g, 0.04378 mol) in tetrahydrofuran (40 mL). The reaction was allowed to warm up to room temperature and stirred overnight. After being quenched with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried over MgSθ4 and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 20% EtOAc in hexanes, to give the desired product (8.54 g, 77.58%). LCMS (M+H) 252.4. |
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | (4-Trifluoromethylsulfanyl-phenyl)-amine (386 mg, 2 mmol) and 4-tert-butyl-dimethyl- silyloxy-cyclohexanone (457 mg, 2 mmol) were dissolved in acetonitrile (5 mL), and the resulting solution was refluxed for 1 hr. After cooling the mixture to room temperature, sodium triacetoxyborohydride (848 mg, 4 mmol) was added. The mixture was then stirred at room temperature for 18 hr. Afterward, the mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium hydrogencarbonate (10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. An oily residue was obtained. This residue was purified by column chromatography on silica gel (cyclohexane/diethylether, 98:2). The trans isomer was isolated as a colorless oil (180 mg, 22% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 144h; | 32 (4-Chloro-3-trifluoromethyl-phenyl)-amine (782 mg, 4 mmol) and 4-(tert-butyl-dimethyl- silyloxy)-cyclohexanone (913 mg, 4 mmol) were dissolved in dichloromethane (35 mL). Next, sodium triacetoxyborohydride (1.69 g, 8 mmol) was added, and the mixture was stirred at room temperature for 6 days. The mixture was then diluted with dichloromethane (35 mL), washed with water (25 mL), washed with HCl 1N (25 mL), washed with water (25 mL), and washed with brine (25 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. This afforded an oily residue, which was purified by column chromatography on silica gel (pentane/ether gradient). The desired product was isolated as a yellow oil (1.3 g of 1 : 1 mixtures of cis and trans isomers, 80% yield). ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 144h; | 34 (4-Trifluoromethoxy-3-trifluoromethyl-phenyl)-amine (735 mg, 3 mmol) and 4-(tert- butyl-dimethyl-silyloxy)-cyclohexanone (685 mg, 3 mmol) were dissolved in dichloromethane (25 mL). Next, sodium triacetoxyborohydride (1.27 g, 6 mmol) was added. The resulting mixture was stirred at room temperature for 6 days. Afterward, the mixture was diluted with dichloromethane (25 mL), washed with water (20 mL), washed with HCl 1N (20 mL), washed with water (20 mL), and washed with brine (20 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum to afford an oily residue. The residue was purified by column chromatography on silica gel (pentane/ether gradient). The desired product was isolated as a colorless oil (900 mg of 1 : 1 mixtures of cis and trans isomers, 66% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With phosphomolybdic heteropolyacid monohydrate; dihydrogen peroxide In diethyl ether at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With boron trifluoride diethyl etherate In dichloromethane at -78℃; for 0.5h; Inert atmosphere; optical yield given as %de; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With boron trifluoride diethyl etherate In dichloromethane at -78℃; for 0.5h; Inert atmosphere; optical yield given as %de; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran; hexane at 20℃; for 20h; | Intermediate 92. Tert-butyl(dimethyl)[(4-methylenecyclohexyl)oxy]silane Intermediate 92. Tert-butyl(dimethyl)[(4-methylenecyclohexyl)oxy]silane Butyl lithium (1 .55ml_ of a 1.6M solution in hexanes, 2.48mmol) was added over a suspension of methyltnphenylphosphonium bromide (0.85g, 2.38mmol) in THF (5ml_), at 0 °C and under argon atmosphere. The reaction mixture was allowed to warm up to r.t. and, after 30 min, a solution of 4-(tert-butyldimethylsilylloxy)cyclohexanone (0.50ml_, 1 .99mmol) in THF (5ml_) and stirring was maintained at r.t. for 20 hours. The reaction mixture was then filtered through a 4μ PTFE membrane, washed with hexanes and the filtrate was concentrated to dryness to afford the title compound (412mg, 94%) as a pale yellow oil. 1 H NMR (300 MHz, cd3od) δ 4.59 (s, 2H), 3.88 (ddd, J = 1 1 .2, 7.5, 3.5 Hz, 1 H), 2.45 - 2.24 (m, 2H), 2.05 (ddd, J = 13.4, 9.2, 4.4 Hz, 2H), 1 .75 (ddd, J = 15.4, 7.4, 3.6 Hz, 2H), 1 .58 - 1.38 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H). |
With n-butyllithium In diethyl ether; hexane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone With sodium hexamethyldisilazane In tetrahydrofuran at -20℃; Stage #2: trifluoromethanesulfonic acid anhydride In tetrahydrofuran at -20 - 20℃; for 12.1667h; | 230.1 STEP 1: 4-(TERT-BUTYLDIMETHYLSILYLOXY)CYCLOHEX-1-ENYL TRIFLUOROMETHANESULFONATE To a 500 mL round bottom was added 4-(tert-butyldimethylsilyloxy)cyclohexanone (7.71 g, 33.8 mmol). A 1M solution of NaHMDS (35.4 mL, 35.4 mmol) in THF was added dropwise after cooling the reaction to -20° C. The resulting orange solution was stirred for 1 h before adding trifluoromethanesulfonic anhydride (10.00 mL, 35.4 mmol) dropwise over 10 minutes. The yellow suspension was allowed to warm to room temperature with stirring over 12 h. It was diluted with 60 mL saturated aqueous NaHCO3 before extracted with diethyl ether (2*75 mL), drying over sodium sulfate, filtering, and drying under reduced pressure to an orange oil that was used crude. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (R)-10-camphorsulfonic acid; magnesium sulfate In ISOPROPYLAMIDE at 90℃; for 1h; | 138 A mixture of 3-amino-5- (5-methyl-lH-pyrazol-4- yl) thiophene-2-carboxamide (100 mg, 0.450 mmol), 4-{ [tert- butyl (dimethyl) silyl] oxyjcyclohexanone (0.339 mL, 1.35 mmol), CSA (10.5 mg, 0.0450 mmol), MgSO4 (108 mg, 0.900 mmol) in anhydrous DMA (1.5 mL) was stirred at 900C for 1 h. The mixture was partitioned between EtOAc (20 mL) and aqueous NaHCO3 (10 mL) . The aqueous layer was extracted with EtOAc (5 mL) . The combined organic layers were washed with brine (5 mL) , dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 30:70 hexane/EtOAc to EtOAc) to give 4- { [tert-butyl (dimethyl) silyl] oxy}-6' - (5-methyl-lH-pyrazol-4- yl) -1' H-spiro [cyclohexane-1, 2' -thieno [3, 2-d] pyrimidin] - 4' (3'H)-one as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With boron trifluoride diethyl etherate In dichloromethane at -78℃; for 6h; Inert atmosphere; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: benzyl rel-[(1S,3R,4S,5S)-4-aminoadamantan-1-yl]methyl}carbamate; 4-(tert-butyldimethylsilyloxy)cyclohexanone With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 4h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | 112; 113 Preparation Example 112, 113 To a solution of benzyl rel-[(1S,3R,4S,5S)-4-aminoadamantan-1-yl]methyl}carbamate (760 mg) in dichloromethane (22.8 ml) were added 4-[tert-butyl (dimethyl)silyl]oxy}cyclohexanone (1.22 ml) and sodium triacetoxyborohydride (1.02 g), followed by stirring at room temperature for 4 hours. To the mixed reaction liquid was added saturated aqueous sodium bicarbonate, followed by extraction with EtOAc. The organic layer was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (hexane-EtOAc) to first elute 674.8 mg of benzyl rel-({(1R,3S,4R,5R)-4-[(cis-4-[tert-butyl (dimethyl)silyl]oxy}cyclohexyl)amino]adamantan-1-yl}methyl)carbamate and then elute 435.8 mg of benzyl rel-({(1R,3S,4R,SR)-4-[(trans-4-[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)amino]adamantan-1-yl}methyl)carbamate. The steric configuration of the obtained product was determined by using the compound (benzyl rel-({(1R,3S,4R,5R)-4-[(trans-4-[tert-butyl (dimethyl)silyl]oxy}cyclohexyl)amino]adamantan-1-yl}methyl)carbamate) eluted later in amino silica gel column chromatography as a starting material to provide the rel-trans-4-[(1R,2S,3S,5S)-5-(aminomethyl)adamantan-2-yl]amino}cyclohexanol obtained in Preparation Example 134, which is then used for Example 45, and by confirming that the HPLC retention time (15.1 min) of the obtained product coincided with that in Example 42 (trans-alcohol product). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran at -78℃; for 2h; | 16 Intermediate (16)Trifluoro-methanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxy)- -1 -enyl esterLDA (0.8 M, 32 mL, 25.47 mmol, 1 equiv.) was cooled to -78°C. To this was added a solution of 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanone (5.82 g, 25.47 mmol, 1 equiv.) in THF (30 mL). The solution was stirred at -78°C for 30 min. To this enolate was transferred a solution of Pyr-NTf2 (CAS 145100-51 -2; 10 g, 25.47 mmol, 1 equiv.) in THF (60 mL) and kept stirring at -78°C for 2h. The reaction was diluted with EtOAc (50 mL) and NH CI aq. (50 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2X20 mL). The combined EtOAc extracts were washed with sodium bicarbonate (20 mL), brine (20 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to afford a liquid product. This was purified on a 120 g silica gel column eluted with 10% EtOAc in heptane to obtain 9 g (98% yield) of the title compound as a colorless liquid.TLC: Rf = 0.9 (silica gel, 30% EtOAc in heptane)1H NMR (300MHz, CDCI3) δ: 5.60 (bs, 1 H), 4.01 (m, 1 H), 2.61 -2.10 (m, 4H), 1 .80 (m, 1 H), 0.91 (s, 9H), 0.002 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diazoacetic acid ethyl ester; 4-(tert-butyldimethylsilyloxy)cyclohexanone With lithium diisopropyl amide In tetrahydrofuran; diethyl ether; hexane at -78℃; for 3h; Stage #2: With ammonium chloride In tetrahydrofuran; diethyl ether; hexane; water Saturated solution; | 4.2. Representative procedure for the preparation of starting materials General procedure: To a stirred solution of 4-phenylcyclohexanone (1.5 mmol, 261 mg) and ethyl diazoacetate (1.8 mmol, 205 mg) in THF (2.0 mL) was added lithium diisopropylamide [prepared by the addition of butyllithium in hexane (1.95 mmol, 1.25 mL) to a solution of diisopropylamine (1.95 mmol, 0.27 mL) in Et2O (2.0 mL) at 0 °C] dropwise at -78 °C. After stirring for 3 h at -78 °C, saturated aqueous NH4Cl was added to the solution. The organic layer was extracted with ethyl acetate, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate=20:1 to give cis-2a [40% (173 mg)] and trans-2a [21% (90 mg)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 7-bromo-2-chloro-5-trityl-5H-pyrrolo[3,2-d]pyrimidine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25h; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran; hexane at -78℃; for 3h; | 4; D 4-((tert-Butyldimethylsilyl)oxy)-1-(2-chloro-5-trityl-5H-pyrrolo[3,2-d]pyrimidin-7- yl)cyclohexanol 4-((tert-Butyldimethylsilyl)oxy)-1-(2-chloro-5-trityl-5H-pyrrolo[3,2-d]pyrimidin-7- yl)cyclohexanol A solution of 7-bromo-2-chloro-5-trityl-5H-pyrrolo[3,2-d]pyrimidine (2.00 g, 3.2 mmol) in THF (20 mL) was added a 2.5 N solution of BuLi in hexane (2.82 mL, 7.04 mmol) at -78 °C. Then 4-((tert-butyldimethylsilyl)oxy)cyclohexanone (1.2 mL) was added after 15 min. The reaction was stirred at -78 °C for 3 hour, quenched with brine and extracted with EtOAc (3x). The combined organic layer was dried (MgS04), filtered and concentrated. The residue was purified by ISCO to provide the desired product (1.52 g, 76%). 1H NMR (400 MHz, CDC13, two isomers) δ 7.64-7.56 (m, 1H), 7.44-7.41 (m, 1H), 7.35-7.31 (m, 9H), 7.16-7.10 (m, 6H), 3.73-3.68 (m, 1H), 2.55-2.51 (m, 1H), 2.42-2.30 (m, 1H), 2.28-2.19 (m, 1H), 2.07-1.94 (m, 2H), 1.91-1.82 (m, 2H), 1.76-1.62 (m, 2H), 0.82 (s, 9H), 0.01 (s, 6H). 7-(4-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)-2-chloro-5-trityl-5H-pyrrolo[3,2- d]pyrimidine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25 % ee | With C27H31N2O2(1+)*C7H7O2(1-) In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; Overall yield = 70 %Chromat.; enantioselective reaction; | 4.3 Organocatalytic enantioselective deprotonation of prochiral cyclohexanones 4.3.1 General procedure II General procedure: To a solution of cyclohexanone 2a-f (0.25mmol) and QN+1, 4-MeOC6H4O- (0.0125mmol, 7mg) in THF (0.25mL) at -78°C was added BSA (0.375mmol, 92μL) as a solution in THF (0.25mL). The reaction mixture was stirred at the same temperature for 2h. The conversion was measured by GC-FID. Next, 100μL of a saturated solution of NaHCO3 was added at -78°C. The reaction mixture was dried over Na2SO4, filtered and concentrated. The crude product 3a-f was purified on silica gel by using petroleum ether/Et2O (95:5) as eluent and then subjected to GC-FID analysis using chiral column in order to determine the enantiomeric excess. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 57% 2: 14% | Stage #1: tert-butyl (2S)-2-(2'-oxopropyl)pyrrolidine-1-carboxylate With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone With 2,2,2-trifluoroethyl trifluoromethanesulphonate In tetrahydrofuran at 20℃; for 72h; Inert atmosphere; Stage #3: With sodium tetrahydroborate In tetrahydrofuran; methanol at 0 - 20℃; for 3h; Inert atmosphere; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: (methoxymethyl)triphenylphosphonium chloride With lithium diisopropyl amide In tetrahydrofuran at 0℃; for 0.583333h; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran at 20℃; for 2h; | 1 Step 1:tert--(methoxymethylidene)cyclohexyl]oxy}dimethylsilane Prepared in analogy to intermediate A.1 (step 1): (Methoxymethyl)triphenylphosphonium chloride (22.5 g, 65.7 mmol), LDA (32.8 ml of a 2 M solution in THF, 65.7 mmol) and 4-[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (CAS-No. [55145-45-4];10.0 g, 43.8 mmol) were reacted in THF (150 ml) at 0°C for 35 min and at rt for 2 h. The crude product was purified by flash chromatography (SiO2[KP-NH]-hexane/ethyl acetate) to give the desired enol ether (8.89 g, 79%) as a colourless oil. 1H-NMR (300MHz, DMSO-d6): Shift [ppm]= 0.02 - 0.04 (m, 6H), 0.85 - 0.86 (m, 9H), 1.17 - 1.34 (m, 2H), 1.60 - 1.71 (m, 2H), 1.77 - 1.89 (m, 2H), 2.04 - 2.12 (m, 1 H), 2.33 - 2.42 (m, 1 H), 3.45 (s, 3H), 3.74 - 3.83 (m, 1 H), 5.82 (s, 1 H) UPLC-MS (ESI+): [M + H]+ = 257; Rt in min 1.75 |
79% | Stage #1: (methoxymethyl)triphenylphosphonium chloride With lithium diisopropyl amide In tetrahydrofuran at -4 - 0℃; for 0.333333h; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran at 0 - 20℃; for 2.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone; N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide With acetic acid In dichloromethane at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 1.5h; | 72.1 Step 1: N-{1-[1-(4-[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide Step 1: N-{1-[1-(4-[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide To the solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (Example 58, Step 4: 20. mg, 0.049 mmol) in methylene chloride (2 mL) was added 4-[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (Aldrich, catNo.638153: 62 μL 0.25 mmol), followed by acetic acid (8.4 μL, 0.15 mmol). The resulting mixture was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (31 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h, then neutralized with saturated NaHCO3 solution and extracted with DCM. The combined extracts were dried over Na2SO4 then concentrated. The residue was used in the next step without further purification. LC-MS calculated for C33H50F3N4O2Si (M+H)+: m/z=619.4; found 619.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; di-tert-butylmagnesium In tetrahydrofuran at 20℃; for 1h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.2% | Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone With N-Bromosuccinimide; magnesium chloride In 1,4-dioxane at 70℃; for 1h; Stage #2: 2-methoxy-7-methylquinoxaline-5-carbothioamide In 1,4-dioxane at 110℃; for 22h; | 140 Intermediate 1 40B:2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5 ,6,7-tetrahydrobenzo [djthiazol-6-ol Intermediate 140A (9.79 mg, 0.043 mmol), magnesium chloride (4.08 mg, 0.043 mmol), and NBS (7.63 mg, 0.043 mmol) were dissolved in dioxane (429 tL) and heated to 70 °C for 1 hour. Intermediate 1-12 (10 mg, 0.043 mmol) was added and the reactionmixture was stirred for 18 hours. The reaction mixture was heated to 110 °C for 4 hours. The reaction mixture was diluted with EtOAc, washed with water, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. The cmde material was dissolved in 90:10:0.1 MeOH:H20:TFA (ca 1 mL) and allowed to stir overnight. The reaction mixture was concentrated in vacuo. The cmde material was dissolved in DMF, filtered,and purified by preparative HPLC (Method D, 20 to 60% B in 10 minutes) to giveIntermediate 140B (2.7 mg, 0.00825 mmol, 19.2%): ‘H NMR (500MHz,METHANOL-d4) 8.48 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 7.68 (d, J0.8 Hz, 1H),4.26-4.19 (m, 1H), 4.11 (s, 3H), 3.18 (dd, J16.1, 4.8 Hz, 1H), 3.09-3.00 (m, 1H),2.95-2.87 (m, 1H), 2.83 (dd,J=16.2, 7.2 Hz, 1H), 2.61 (s, 3H), 2.17-2.09(m, 1H),2.04-1.95 (m, 1H); LC-MS: Method H, RT = 0.95 mm, MS (ESI) m/z: 328.3 (M+H) Analytical HPLC Method B: 100% purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C19H17F3IN3 With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; isopropylmagnesium bromide In tetrahydrofuran at -20℃; Inert atmosphere; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; | Experimental procedure for the synthesis of A-16b and A-16c The reaction is performed under inert atmosphere. A-14o (160.0 mg, 0.35 mmol, 1 .0 equiv.) is dissolved in dry THF (2 mL) and 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone (79.5 μΙ_, 0.7 mmol, 2.0 equiv.) and cooled to -20 °C. Then isopropylmagnesium bromid (0.4 mL, 1.2 mmol, 3.5 equiv.) is added dropwise and the reaction mixture stirred for 1 h at -20 °C. 4-(7e f-butyldimethylsilyloxy)cyclohexanone (1 16.3 mg, 0.5 mmol, 1.5 equiv.) is added and the reaction mixture stirred for 12 h at rt. The reaction is quenched with NH4CI (sat.) and extracted with DCM. The solvent is removed under reduced pressure and the residue dissolved in DMF. The crude product is purified by chromatography using acetonitrile/water giving the desired products A-16b and A-16C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C18H14F4IN3 With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; isopropylmagnesium bromide In tetrahydrofuran at -20℃; Inert atmosphere; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; | Experimental procedure for the synthesis of A-16b and A-16c General procedure: The reaction is performed under inert atmosphere. A-14o (160.0 mg, 0.35 mmol, 1 .0 equiv.) is dissolved in dry THF (2 mL) and 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone (79.5 μΙ_, 0.7 mmol, 2.0 equiv.) and cooled to -20 °C. Then isopropylmagnesium bromid (0.4 mL, 1.2 mmol, 3.5 equiv.) is added dropwise and the reaction mixture stirred for 1 h at -20 °C. 4-(7e f-butyldimethylsilyloxy)cyclohexanone (1 16.3 mg, 0.5 mmol, 1.5 equiv.) is added and the reaction mixture stirred for 12 h at rt. The reaction is quenched with NH4CI (sat.) and extracted with DCM. The solvent is removed under reduced pressure and the residue dissolved in DMF. The crude product is purified by chromatography using acetonitrile/water giving the desired products A-16b and A-16C. The following compounds A-16 (table 28) are available in an analogous manner starting from different quinazolines A-14 initially obtained (table 18). The crude product A-16 is purified by chromatography if necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 53% 2: 34% | With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 4h; | 5.1.10. Benzyl ({(1s,3R,4s,5S,7s)-4-[(cis-4-[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)amino]adamantan-1-yl}methyl)carbamate (18) andbenzyl ({(1s,3R,4s,5S,7s)-4-[(trans-4-[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)amino]adamantan-1-yl}methyl)carbamate (19) To a solution of 17 (760 mg, 2.4 mmol) and 4-(tert-butyldimethylsilyloxy)cyclohexanone (1.1 g, 4.8 mmol) in CH2Cl2 (23 mL),sodium triacetoxyborohydride (1.0 g, 4.8 mmol) was added and thenstirred at room temperature for 4 h. The reaction mixture was extractedwith EtOAc and saturated aqueous NaHCO3. The organic layer waswashed with H2O, brine, dried over MgSO4 and concentrated in vacuo.The residue was chromatographed on amino silica gel with elutionusing (n-hexane-EtOAc) (10:1 to 1:1) to give 18 (670 mg, 53%, lesspolar) as a colorless oil and 19 (440 mg, 34%, high polar) as a colorlessoil. 18 1H NMR (DMSO-d6) δ ppm 0.02 (6H, s), 0.87 (9H, s), 1.08-1.29(3H, m), 1.33-1.64 (14H, m), 1.70-1.82 (3H, m), 1.91-2.00 (2H, m),2.42-2.54 (1H, m), 2.62-2.69 (1H, m), 2.70 (2H, d, J=6.3 Hz),3.79-3.86 (1H, m, α-position of the oxygen atom), 5.00 (2H, s), 7.18(1H, t, J=6.3 Hz), 7.27-7.41 (5H, m); MS (ESI) m/z 527 [M+H]+. 191H NMR (DMSO-d6) δ ppm 0.02 (6H, s), 0.85 (9H, s), 0.92-1.29 (7H,m), 1.32-1.48 (6H, m), 1.68-1.85 (7H, m), 1.89-1.98 (2H, m),2.31-2.44 (1H, m), 2.61-2.67 (1H, m), 2.70 (2H, d, J=6.3 Hz),3.50-3.61 (1H, m, α-position of the oxygen atom)), 5.00 (2H, s), 7.18(1H, t, J=6.3 Hz), 7.27-7.41 (5H, m); MS (ESI) m/z 527 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With ethene; 5%-palladium/activated carbon; ammonium acetate; potassium carbonate In acetonitrile at 90℃; for 15h; Schlenk technique; | |
42% | With styrene; ammonium hydroxide In 1-methyl-pyrrolidin-2-one at 130℃; for 20h; Sealed tube; Inert atmosphere; | |
50 %Chromat. | Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone With hydrazine hydrate In N,N-dimethyl acetamide at 20℃; for 0.5h; Schlenk technique; Stage #2: In N,N-dimethyl acetamide at 160℃; for 3h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium 10% on activated carbon; hydrogen; acetic acid In methanol at 10 - 35℃; for 16h; | 517.C C) 4-(cis-2,6-dimethylmorpholino)cyclohexan-1-ol (A Mixture of Cis and Trans) A mixture of 4-((tert-butyldimethylsilyl)oxy)cyclohexan-1-one (36.2 g), cis-2,6-dimethylmorpholine (18.3 g), AcOH (9.51 g) and 10% palladium-carbon (8.60 g) in MeOH (700 mL) was stirred under normal pressure of hydrogen atmosphere at room temperature for 16 hr. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 2 M hydrochloric acid (280 mL) and MeOH (200 mL), and the solution was stirred at room temperature for 90 min. Ethyl acetate and saturated brine were added to the mixture, and the mixture was partitioned. The aqueous layer was washed with ethyl acetate, adjusted to pH 9 with carefully adding potassium carbonate and extracted with ethyl acetate. The extracts were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dried by azeotroped with toluene to give the title compound (25.3 g, cis:trans=87:13, determined by 1H NMR). MS m/z 214.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 48% 2: 18% | Stage #1: 2-methyl-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]thieno[3,2-d]pyrimidin-4-amine With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 4-(tert-butyldimethylsilyloxy)cyclohexanone With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; | 5.2 Step 2. To a solution of (i?)-2-methyl-N-(l-(3-(trifluoromethyl)phenyl)ethyl)thieno[3,2- d]pyrimidin-4-amine (100 mg, 296 pmol) in THF (10 mL) was added LiHMDS (1 M, 1.19 mL, 1.19 mmol) at 0 °C. The resulting solution was stirred for 30 min at 0 °C. To the resulting mixture was then added /i-BuLi (2.5 M, 1.19 mL, 3 mmol) at -78 °C. A solution of 4-((/6T/-butyldimethylsilyl)oxy (cyclohexanone (744 pL. 2.96 mmol) in THF (5 mL) was added and the mixture was left to stir at -78 °C for 30 min and then poured into water. (0603) After extraction with EtOAc the combined organic phases were washed with brine and dried over Na2S04. The solvent was removed under reduced pressure and the crude residue was purified by prep-HPLC to give cA-4-((/er/-butyldimethylsilyl)oxy)-l-(2-methyl-4- (((i?)-l-(3-(trifluoromethyl)phenyl)ethyl)amino)thieno[3,2-d]pyrimidin-6-yl)cyclohexanol (80 mg, 48% yield) and /ra/i.v-4-((/c /-butyldimethylsilyl)oxy)- 1 -(2-methyl-4-(((//)- 1 -(3- (trifluoromethyl)phenyl)ethyl)amino)thieno[3,2-d]pyrimidin-6-yl)cyclohexanol (30 mg, 18% yield). LCMS (ESI): m/z: [M+H] calculated for C28H39F3N3O2SS1: 566.2; found 566.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With n-butyllithium In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; | 7.1 Step 1. A solution of 6-bromo-4-chloro-thieno[2,3-d]pyrimidine (300 mg, 1.20 mmol) in dry THF (3 mL) was cooled to -78 °C under N2. A solution of ft-BuLi (2.5 M, 960 pL, 2.4 mmol) was then added, followed by a solution of 4 -[tert- butyl(dimethyl)silyl]oxycyclohexanone (453 pL, 1.80 mmol) in dry THF (3 mL). This mixture was stirred at -78 °C for 2 h and then quenched by the addition of H20. The phases were separated and the solvent was removed under reduced pressure. The crude residue was purified by prep-HPLC to give 4-[/er/-butyl(dimethyl)silyl]oxy-l-(4-chlorothieno[2,3- d]pyrimidin-6-yl)cyclohexanol (100 mg, 21% yield) ' H NMR (400 MHz, METHANOL- ri4) d ppm 8.76 (s, 1 H) 7.35 (d, .7=0.61 Hz, 1 H) 3.82 (tt, .7=9.61, 4.81 Hz, 1 H) 1.95 - 2.09 (m, 4 H) 1.75 - 1.91 (m, 4 H) 0.93 (s, 9 H) 0.11 (d, .7=0.61 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone With n-butyllithium; (1S,1'S)-bis(1-phenylethyl)amine In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: methyl cyanoformate In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; |
Tags: 55145-45-4 synthesis path| 55145-45-4 SDS| 55145-45-4 COA| 55145-45-4 purity| 55145-45-4 application| 55145-45-4 NMR| 55145-45-4 COA| 55145-45-4 structure
[ 126931-29-1 ]
4-((tert-Butyldimethylsilyl)oxy)cyclohexanol
Similarity: 0.86
[ 87184-80-3 ]
5-((tert-Butyldimethylsilyl)oxy)pentanal
Similarity: 0.86
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :