4-phenylmethoxybut-2-yn-1-ol

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

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

Procedure: The crude alkyne I1 (81.9 g, 560 mmol) was dissolved in 500 ml of THF and cooled to −78° C. A 2.5M solution of n-hexyl lithium (250 ml, 625 mmol) was added dropwise over a period of 2 hours, so that the temperature did not exceed −70° C. Stirring was continued for 3 hours at −78° C. and then solid paraformaldehyde (20.18 g, 672 mmol) was added. The dry ice-bath was removed and the reaction allowed to warm up to room temperature over night (approx. 20 hours). The mixture was diluted with 600 ml of TBME and extracted with 400 ml of an ammonium chloride solution (20%). The aqueous layer was extracted once more with 200 ml of TBME and the combined organic fractions were washed three times with 400 ml of a brine, dried over anhydrous sodium sulfate and evaporated to give an orange liquid. Yield: 87.9 g (89%). did not exceed −70° C The dry ice-bath was removed to warm up to room temperature over night (approx. 20 hours) The mixture was diluted with 600 ml of TBME extracted with 400 ml of an ammonium chloride solution (20%) The aqueous layer was extracted once more with 200 ml of TBME the combined organic fractions were washed three times with 400 ml of a brine dried over anhydrous sodium sulfate evaporated to give an orange liquid

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

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

Procedure: According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 0.345 g (1.0 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 0.211 g (1.2 mmol) of 4-(benzyloxy)-2-butyn-1-ol provided 0.211 g (42%) of methyl 4-[(4-{[4-(benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylate as a pale yellow oil.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 390 mg of 4-benzyloxy-2-butyn-1-ol (prepared starting from 2-butyn-1,4-diol and benzylbromide in analogy to a procedure reported in Tetrahedron Left. 38 (1997), 7887-7890) in 5 ml DMF:THF 1:1 was added 97 mg of 55% NaH in mineral oil. After the evolution of gas had ceased, 250 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)4-pyrimidinyl]benzene sulfonamide (Example 5a) was added and the mixture was stirred at 50° C. for 20 h before it was diluted with 75 ml of ethyl acetate. The mixture was washed with 75 ml of 10% aqueous citric acid and 75 ml of water, and evaporated. The crude product was purified by chromatography on prep. tlc-plates with ethyl acetate:methanol:sat. aqueous ammonia 10:2:1 to give 125 mg of 4-tert.-butyl-N-[6-(4-benzyloxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide as a yellow foam. LC-MS: tR=5.93 min, [M+1]+=666.47, [M−1]−=664.63. Left The mixture was washed with 75 ml of 10% aqueous citric acid and 75 ml of water evaporated The crude product was purified by chromatography on prep

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

Procedure: According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 0.345 g (1.0 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 0.211 g (1.2 mmol) of 4-(benzyloxy)-2-butyn-1-ol provided 3.211 g (42%) of methyl 4-[(4-{[4-(benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylate as a pale yellow oil. Electrospray Mass Spec: 504.2 (M+H)+.

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

Procedure: The crude alkyne I1 (81.9 g, 560 mmol) was dissolved in 500 ml of THF and cooled to −78° C. A 2.5M solution of n-hexyl lithium (250 ml, 625 mmol) was added dropwise over a period of 2 hours, so that the temperature did not exceed −70° C. Stirring was continued for 3 hours at −78° C. and then solid paraformaldehyde (20.18 g, 672 mmol) was added. The dry ice-bath was removed and the reaction allowed to warm up to room temperature over night (approx. 20 hours). The mixture was diluted with 600 ml of TBME and extracted with 400 ml of an ammonium chloride solution (20%). The aqueous layer was extracted once more with 200 ml of TBME and the combined organic fractions were washed three times with 400 ml of a brine, dried over anhydrous sodium sulfate and evaporated to give an orange liquid. Yield: 87.9 g (89%). did not exceed −70° C The dry ice-bath was removed to warm up to room temperature over night (approx. 20 hours) The mixture was diluted with 600 ml of TBME extracted with 400 ml of an ammonium chloride solution (20%) The aqueous layer was extracted once more with 200 ml of TBME the combined organic fractions were washed three times with 400 ml of a brine dried over anhydrous sodium sulfate evaporated to give an orange liquid