4-bromopiperidine

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: In Scheme 1, above, isopropylideneadenosine 1 is used to synthesize toluenesulfonyl isopropylideneadenosine, 2 (2′,3′-O-isopropylidene-5′-O-toluene-p-sulfonyl adenosine). An anhydrous pyridine solution of commercially available 2′,3′-isopropylideneadenosine 1 is shaken with p-toluenesulfonyl chloride. In a separate reaction, the synthon 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester 4 was synthesized using the method of Plettenburg in which potassium thioacetate and 4-bromo-piperidine 3 are heated in DMF. According to modified procedures based on an existing protocol (Isakovic et al., Bioorg. & Med. Chem. Lett. (2009) 19: 2742-2746), synthon 4 is reacted with sodium methoxide to form the thiol, followed by the reaction with 2 to give 4-[6-(6-Amino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester 5. Under the TFA/DCM condition, cleavage of the BOC protection group and subsequent reaction of 6 with (2-bromo-ethyl)-carbamic acid tert-butyl ester provides intermediate 7. The deprotection of 7 yields 8, which contains an amino group used to link 8 to the pterin moiety. In a separate reaction

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

Procedure: In Scheme 1, above, isopropylideneadenosine 1 is used to synthesize toluenesulfonyl isopropylideneadenosine, 2 (2′,3′-O-isopropylidene-5′-O-toluene-p-sulfonyl adenosine). An anhydrous pyridine solution of commercially available 2′,3′-isopropylideneadenosine 1 is shaken with p-toluenesulfonyl chloride. In a separate reaction, the synthon 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester 4 was synthesized using the method of Plettenburg in which potassium thioacetate and 4-bromo-piperidine 3 are heated in DMF. According to modified procedures based on an existing protocol (Isakovic et al., Bioorg. & Med. Chem. Lett. (2009) 19: 2742-2746), synthon 4 is reacted with sodium methoxide to form the thiol, followed by the reaction with 2 to give 4-[6-(6-Amino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester 5. Under the TFA/DCM condition, cleavage of the BOC protection group and subsequent reaction of 6 with (2-bromo-ethyl)-carbamic acid tert-butyl ester provides intermediate 7. The deprotection of 7 yields 8, which contains an amino group used to link 8 to the pterin moiety. In a separate reaction

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

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

Procedure: 4-Bromopiperidine (5.75 g, 23.5 mmol) was dissolved in pyridine (50 mL) and treated with tosyl chloride (5.8 g, 30.5 mmol). The reaction mixture was stirred for 12 h at r.t. and then diluted with dichloromethane (150 mL) and HCl (1 M aqueous solution, 50 mL). The organic layer was washed with brine (80 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (40% EtOAc/hexane) to give 4-bromo-1-tosylpiperidine as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.27-4.24 (m, 1H), 3.20-3.17 (m, 2H), 3.13-3.11 (m, 2H), 2.46 (s, 3H), 2.23-2.17 (m, 2H), 2.08-2.05 (m, 2H); MS (ESI) 318.0 (M+H)+. The organic layer was washed with brine (80 mL) dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography (40% EtOAc/hexane)

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

Procedure: In Scheme 1, above, isopropylideneadenosine 1 is used to synthesize toluenesulfonyl isopropylideneadenosine, 2 (2′,3′-O-isopropylidene-5′-O-toluene-p-sulfonyl adenosine). An anhydrous pyridine solution of commercially available 2′,3′-isopropylideneadenosine 1 is shaken with p-toluenesulfonyl chloride. In a separate reaction, the synthon 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester 4 was synthesized using the method of Plettenburg in which potassium thioacetate and 4-bromo-piperidine 3 are heated in DMF. According to modified procedures based on an existing protocol (Isakovic et al., Bioorg. & Med. Chem. Lett. (2009) 19: 2742-2746), synthon 4 is reacted with sodium methoxide to form the thiol, followed by the reaction with 2 to give 4-[6-(6-Amino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester 5. Under the TFA/DCM condition, cleavage of the BOC protection group and subsequent reaction of 6 with (2-bromo-ethyl)-carbamic acid tert-butyl ester provides intermediate 7. The deprotection of 7 yields 8, which contains an amino group used to link 8 to the pterin moiety. In a separate reaction