(2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate

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: MsCl (4.4 mL, 56 mmol) was added slowly to a solution of Et3N (9.8 mL, 71 mmol) and (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (6.87 g, 47.0 mmol) in CH2Cl2 (100 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The mixture was extracted with CH2Cl2 and the organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a colorless liquid: yield 10.02 g (95%). quenched with H2O (100 mL) The mixture was extracted with CH2Cl2 the organic fractions were dried (MgSO4) concentrated in vacuo

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

Procedure: 4-Hydroxybenzophenone is treated with equimolar quantity of sodium hydride in dry dimethylformamide at 0° C. under an inert atmosphere. After stirring at ambient temperature for 2 hours, a bright yellow clear solution is obtained. To this solution is added equimolar quantity of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (its synthesis in two steps from commercially available 2-hydroxymethyl-1,3-propanediol is described in European Patent EP2103611). After stirring at ambient temperature for 16 hours, the reaction mixture is diluted with water and extracted with dichloromethane. The organic phase is evaporated to dryness and the crude product is purified by column chromatography. This provide the intermediate {4-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]phenyl}(phenyl)methanone. This intermediate is then dissolved in acetone, excess of 1M hydrochloric acid is added and the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is evaporated to dryness under reduced pressure, and the residue is purified by column chromatography to provide the desired {4-[3-hydroxy-2-(hydroxymethyl)propoxy]phenyl}(phenyl)methanone. a bright yellow clear solution is obtained After stirring at ambient temperature for 16 hours extracted with dichloromethane The organic phase is evaporated to dryness the crude product is purified by column chromatography

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methylamine solution (3 mL, 34.8 mmol) was added to a solution of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (0.9 g, 4.01 mmol, prepared as per B. Xu et al. J. Med. Chem. 2002, 45, 5694) in DMSO (7 mL) and stirred at 75° C. overnight. The reaction was diluted with CHCl3 and the CHCl3 washed with water (×2), dried and concentrated in vacuo to afford approximately 670 mg of crude product. The crude material was columned on silica eluting with DCM, 20% MeOH/DCM, and 20% 7N NH3 in MeOH/DCM to afford (2,2-dimethyl-1,3-dioxan-5-yl)-N-methylmethanamine (330 mg, 52% yield) as an oily residue. 13C NMR (CD3OD) δ 99.7, 64.4 (2×CH2), 52.3, 36.9, 36.0, 26.0, 23.5. the CHCl3 washed with water (×2) dried concentrated in vacuo to afford approximately 670 mg of crude product

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

Procedure: A solution of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (1.70 g, 7.58 mmol) in benzylamine (10 mL, 92 mmol) was stirred at 80° C. and monitored by TLC. After 2 h the reaction was complete therefore concentrated in vacuo. The residue was diluted with toluene (containing a small amount of ethyl acetate) and washed with water, dried and concentrate in vacuo. Column chromatography on silica eluting with ethyl acetate afforded N-benzyl(2,2-dimethyl-1,3-dioxan-5-yl)methanamine (1.51 g, 85% yield) as a yellow oil. 13C NMR (CD3OD) δ 140.8, 129.4 (2XCH), 128.1, 99.3, 64.0 (2XCH2), 54.7, 33.7, 25.6, 23.0 After 2 h the reaction was complete therefore concentrated in vacuo The residue was diluted with toluene ( containing a small amount of ethyl acetate) and washed with water dried concentrate in vacuo

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

Procedure: MsCl (4.4 mL, 56 mmol) was added slowly to a solution of Et3N (9.8 mL, 71 mmol) and (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (6.87 g, 47.0 mmol) in CH2Cl2 (100 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The mixture was extracted with CH2Cl2 and the organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a colorless liquid: yield 10.02 g (95%). quenched with H2O (100 mL) The mixture was extracted with CH2Cl2 the organic fractions were dried (MgSO4) concentrated in vacuo

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 solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (28.8 mg, 0.08 mmol, Example 5 step b) in isopropanol (3.5 mL) and 2 N aq. NaOH (0.6 mL) is added a catalytic amount of NaI followed by methanesulfonic acid 2,2-dimethyl-[1,3]dioxan-5-ylmethyl ester (90 mg, 0.40 mmol, B. Xu, G. Kirschenheuter, A. F. Greslin, X. Cheng, J. Sennelo, M. Cattaneo, M. L. Zighetti, A. Chen, S.-A, Kim, H. S. Kim, N. Bischofberger, G. Cook, K. A. Jacobson, J. Med. Chem. 45 (2002) 5694-5709). The reaction mixture is shaken at rt for 8 h, diluted with 1 N aq. NaOH, and extracted twice with DCM. The organic extracts are dried over MgSO4, filtered and evaporated. The residue is purified by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-benzylamide (28 mg) as a colourless solid. LC-MS: tR=1.13 min, [M+1]+=484.34. extracted twice with DCM The organic extracts are dried over MgSO4 filtered evaporated The residue is purified by prep

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

Procedure: To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (28.8 mg, 0.08 mmol, Example 5 step b) in isopropanol (3.5 mL) and 2 N aq. NaOH (0.6 mL) is added a catalytic amount of NaI followed by methanesulfonic acid 2,2-dimethyl-[1,3]dioxan-5-ylmethyl ester (90 mg, 0.40 mmol, B. Xu, G. Kirschenheuter, A. F. Greslin, X. Cheng, J. Sennelo, M. Cattaneo, M. L. Zighetti, A. Chen, S.-A, Kim, H. S. Kim, N. Bischofberger, G. Cook, K. A. Jacobson, J. Med. Chem. 45 (2002) 5694-5709). The reaction mixture is shaken at rt for 8 h, diluted with 1 N aq. NaOH, and extracted twice with DCM. The organic extracts are dried over MgSO4, filtered and evaporated. The residue is purified by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-benzylamide (28 mg) as a colourless solid. LC-MS: tR=1.13 min, [M+1]+=484.34. extracted twice with DCM The organic extracts are dried over MgSO4 filtered evaporated The residue is purified by prep

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (200 mg, 0.569 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), methanesulfonic acid 2,2-dimethyl-[1,3]dioxan-5-ylmethyl ester (290 mg, 1.71 mmol) is added. The mixture is stirred at 60° C. for 24 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with heptane:EA 3:1 to give 4-{3-[4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-2-isobutyl-6-methyl-pyridine which is dissolved in THF (5 mL), water (0.5 mL) and TFA (0.25 mL). The solution is stirred at rt for 1 h before the solvent is evaporated. The remaining residue is separated by chromatography on prep. TLC plates with DCM containing 10% of MeOH to give 2-{2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxymethyl}-propane-1,3-diol (20 mg) as a colourless oil; LC-MS: tR=0.86 min, [M+1]+=440.12. washed with sat. aq. NaHCO3 solution extract is dried over MgSO4 filtered evaporated The crude product is purified by chromatography on prep