S-ethyl N,N-bis(2-methylpropyl)carbamothioate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound obtained in Step A (21.4 mmol) is dissolved in 120 ml of tetrahydrofuran, and potassium tent-butylate (64.2 mmol) is added in small portions. After stirring for 30 minutes at ambient temperature, the reaction mixture is evaporated to dryness. The residue obtained is taken up in 150 ml of water and the aqueous phase is extracted twice with 60 ml of diethyl ether. The organic phase is washed with water, dried over magnesium sulphate, decolourised on vegetable carbon and evaporated. The residue obtained is purified on silica gel (eluant: petroleum ether) to yield the title product in the form of a yellow oil. the reaction mixture is evaporated to dryness The residue obtained the aqueous phase is extracted twice with 60 ml of diethyl ether The organic phase is washed with water dried over magnesium sulphate evaporated The residue obtained is purified on silica gel (eluant: petroleum ether)

反応条件: temp:-35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of oxalyl chloride (1.05 mL, 17.22 mmol) in dry tetrahydrofuran (40 mL) cooled to -78° C., dry dimethyl sulfoxyde (1.3 mL, 18.04 mmol) was added dropwise and then stirred during 35 min at -35° C. The reaction mixture was cooled again to -78° C. and methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (6 g, 16.4 mmol) dissolved in tetrahydrofuran (20 mL) was added and the mixture was stirred during 15 min at -35° C., then triethylamine (11.5 mL, 82.65 mmol) was added and the mixture was stirred during 1 h at -35° C. This aldehyde was used without purification and isolation in a Wittig reaction described as follows. To dried triphenylmethylphosphonium bromide (11.7 g, 32.8 mmol) suspended in tetrahydrofuran (700 mL) was added dropwise at -78° C. a 1.42 M solution of n-butyllithium in hexane (23 mL, 32.66 mmol). The reaction mixture was warmed to room temperature and stirred during 1.5 h. Then the mixture was cooled to 0° C. and potassium tertio-butylate (3.68 g, 32.8 mmol) and dry tertio-butyl alcohol (3mL, 31.8 mmol) were added. The mixture was stirred again at room temperature during 30 min. The reaction mixture was cooled to -78° C. and the tetrahydrofuran solution of the aldehyde prepared above was added dropwise. The reaction mixture was warmed to room temperature and stirred during 2 h. A saturated aqueous solution of ammonium chloride and the solvents were evaporated under reduced pressure. The residue was dissolved in ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a brown oil. Flash chromatography on silica gel and elution with a 4:96 mixture of ethyl acetate and toluene afforded the expected olefine methyl 2,3,4-tri-O-benzyl-6,7-dideoxy-α-D-glucohept-6-enopyranoside (3.26 g, 55%) which crystallized from hexane; m.p. 46°-47° C. The reaction mixture was cooled again to -78° C. was added the mixture was stirred during 15 min at -35° C. the mixture was stirred during 1 h at -35° C This aldehyde was used without purification and isolation in a Wittig reaction The reaction mixture was warmed to room temperature stirred during 1.5 h Then the mixture was cooled to 0° C. were added The mixture was stirred again at room temperature during 30 min The reaction mixture was cooled to -78° C. above was added dropwise The reaction mixture was warmed to room temperature stirred during 2 h A saturated aqueous solution of ammonium chloride and the solvents were evaporated under reduced pressure The residue was dissolved in ether washed with water The organic layer was dried over sodium sulfate filtered concentrated under reduced pressure to afford a brown oil Flash chromatography on silica gel and elution with a 4:96 mixture of ethyl acetate and toluene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of (6-bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) (171.6 mg, 0.5 mmol), commercially available 2-amino-pyrimidine (95.1 mg, 1.0 mmol), tert.-butyl-XPhos (34 mg, 0.08 mmol), Pd2 dba3 (18.3 mg, 0.02 mmol), sodium tet.-butylate (52.9 mg, 0.55 mmol) and dioxane (3 ml) was heated in a sealed tube at 100° C. for 17 h. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification of the crude product by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) yielded the title compound (65 mg, 36%) as a light yellow solid. extracted with ethyl acetate (2×40 ml) The combined organic layers were washed with brine (20 ml) dried (MgSO4) evaporated Further purification of the crude product by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/hexane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a reaction sequence analogous to that described for the preparation of the optically active Building block H, the cyclization of the (RS)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide with potassium tent-butylate, followed by the palladium-catalyzed amination yielded the (RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one. Its reaction with Lawesson's reagent and the following treatment with hydrochloric acid yielded the title compound as a light yellow solid. Mass (calculated) C11H13FN2OS.ClH [276.762]; (found) [M+H]+=241. In a reaction sequence analogous to that described for the preparation of the optically active Building block H

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In analogy to the cyclization reaction described for the preparation of Building block C, the reaction of (2RS)-bromo-N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-propionamide with potassium tent-butylate yielded besides the N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-acrylamide (0.381 g, 30% of theory), (2R,5S)-2-benzyl-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one and (2S,5R)-2-benzyl-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one as the dominant diastereoisomer in form of a white foam (51% of theory). Mass (calculated) C18H17BrFNO2[378.244]; (found) [M+H]+=378, [M+2-H]+=380. In analogy to the cyclization reaction described for the preparation of Building block C

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In close analogy to the reaction sequence described for the preparation of Building block C, the cyclization of the (R)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide with potassium tent-butylate, followed by the palladium-catalyzed amination, and, finally, by the hydrolysis yielded the (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one hydrochloride as a light yellow solid. Mass (calculated) C11H14ClN2O2 [260.698]; (found) [M+H]+=225. In close analogy to the reaction sequence described for the preparation of Building block C

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In close analogy to the reaction sequence described for the preparation of Building block A, the cyclization of the (R)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide with potassium tent-butylate, followed by the palladium-catalyzed amination, and, finally, by the hydrolysis yielded the (R)-5-(3-amino-phenyl)-5-methyl-morpholin-3-one hydrochloride as a light yellow solid. Mass (calculated) C11H15ClN2O2 [242.707]; (found) [M+H]+=207. In close analogy to the reaction sequence described for the preparation of Building block A

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 43.4 g. (0.2 mole) of O-ethyl N,N-diisobutyl-thiocarbamate are introduced into a 100 ml. round-bottomed flask, and 2.5 g. of diethyl sulfate are added. The mixture is refluxed for 90 minutes on an oil bath heated to 160°C, and thereafter the product is isolated by vacuum distillation. 39.8 g. (92 %) of S-ethyl N,N-diisobutyl-thiocarbamate are obtained; b.p.: 137°-138°C/20 Hgmm., nD25 = 1.4689. The mixture is refluxed for 90 minutes on an oil bath the product is isolated by vacuum distillation

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 23.7 g of potassium t.-butylate were added to a solution of 125.3 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(3-fluorophenyl)-cyclohexane (cis/trans 50/47) in 630 ml of dimethyl sulphoxide, the mixture was stirred at 100° C. for 2 hrs., cooled and poured into 2500 ml of 5 percent sodium chloride solution. The reaction mixture was extracted with methylene chloride, the organic phase was dried over sodium sulfate, filtered and the filtrate was evaporated. Crystallization of the residue from isopropanol gave 121.9 g of trans-4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(3-fluorophenyl)cyclohexane as colorless crystals (trans content 99.8%). , cooled The reaction mixture was extracted with methylene chloride the organic phase was dried over sodium sulfate filtered the filtrate was evaporated Crystallization of the residue from isopropanol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of potassium ter.butylate (3.77 g, 33.6 mmols) and 3alpha-hydroxy-7-keto-5beta-cholanic acid (2.5 g, 6.36 mmols) in ter.butyl-alcohol (50 ml), kept at the reflux under nitrogen and under stirring, sodium metal (1.75 g, 0.76 gram-atoms) is added. The reaction mixture is maintained under stirring and reflux for 2 hours and then worked up as disclosed in example 1; 2.5 g of the residue consisting of the CDCA (7%) and the UDCA (93) are thus obtained. reflux under nitrogen The reaction mixture is maintained under stirring reflux for 2 hours