Synthesis and Structure-Affinity Relationships of Receptor Ligands with 1,3-Dioxane Structure methods
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2.3. Lipophilicity and Metabolic Stability (In Vitro) of Selected σ 1 Receptor Ligands
reagent used in the protocol.
- Use
- A balanced lipophilicity is crucial for the pharmacokinetics and pharmacodynamics of drugs. As measure for the lipophilicity, the logD 7.4 value of selected compounds was recorded using the recently developed micro-shake flask method. In this method, a compound was distributed between a MOPS buffer pH 7.4 and n -oct...
3. Materials and Materials
reagent used in the protocol.
- Use
- Pentane-1,3,5-triol ( 6, 1.69 g, 14 mmol), benzaldehyde ( 7a, 3.5 mL, 35 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in CH 2 Cl 2 abs. (60 mL) and heated to reflux for 16 h, using an inverse Dean-Stark apparatus. For workup, the reaction mixture was washed with saturated aqueous solution of NaHCO 3 (3...
3. Materials and Materials
reagent used in the protocol.
- Use
- Pentane-1,3,5-triol ( 6, 2.01 g, 16.6 mmol), propiophenone ( 7b 4.4 mL, 33.2 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in toluene (90 mL) and heated to reflux for 1.5 h, using a Dean-Stark apparatus filled with molecular sieves 4 Å. For workup, the reaction mixture was washed with saturated aque...
3. Materials and Materials
reagent used in the protocol.
- Use
- Under N 2 atmosphere, oxalyl chloride (0.51 mL, 6 mmol) was dissolved in CH 2 Cl 2 abs. (25 mL) and cooled down to -78 °C. At this temperature, a solution of DMSO (0.85 mL, 12 mmol) in CH 2 Cl 2 abs. (7.5 mL) was added very slowly (using a syringe pump, 7 mL/h) and the mixture was stirred for 15 min at &#...
3. Materials and Materials
reagent used in the protocol.
- Use
- Under N 2 atmosphere, oxalyl chloride (0.87 mL, 10.15 mmol) was dissolved in CH 2 Cl 2 abs. (26 mL) and cooled down to -78 °C. At this temperature, a solution of DMSO (1.44 mL, 20.30 mmol) in CH 2 Cl 2 abs. (12 mL) was added very slowly (using a syringe pump, 9 mL/h) and the mixture was stirred for 15 min...
3. Materials and Materials
reagent used in the protocol.
- Use
- Under N 2 atmosphere the commercially available P-ylide Ph 3 P=CH-CO 2 Et (1.23 g, 4.5 mmol) was dissolved in THF abs. (20 mL). A solution of the aldehyde 9a (619 mg, 3 mmol) in THF abs. (8 mL) was added, and the solution was diluted with THF to a total volume of 40 mL. The mixture was stirred for 24 h at rt and the...
3. Materials and Materials
reagent used in the protocol.
- Use
- Under N 2 atmosphere the commercially available P-ylide Ph 3 P=CH-CO 2 CH 3 (2.10 g, 6.27 mmol) was dissolved in THF abs. (20 mL). A solution of the aldehyde 9b (983 mg, 4.18 mmol) in THF abs. (10 mL) was added, and the solution was diluted with THF to a total volume of 65 mL. The mixture was stirred for 21 h at rt....
3. Materials and Materials
reagent used in the protocol.
- Use
- Under N 2 atmosphere, a solution of the saturated ester 11a (650 mg, 2.33 mmol) in THF abs. (40 mL) was cooled down to 0 °C. LiBH 4 (4 M solution in THF, 2.3 mL, 9.2 mmol) was added slowly. The mixture was stirred at rt for 17 h and then heated to reflux for 2 h. For workup, the mixture was cooled down to rt an...
3. Materials and Materials
Pentane-1,3,5-triol ( 6, 1.69 g, 14 mmol), benzaldehyde ( 7a, 3.5 mL, 35 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in CH 2 Cl 2 abs. (60 mL) and heated to reflux for 16 h, using an inverse Dean-Stark apparatus. For workup, the reaction mixture was washed with saturated aqueous solution of NaHCO 3 (3...
- Use
- Pentane-1,3,5-triol ( 6, 1.69 g, 14 mmol), benzaldehyde ( 7a, 3.5 mL, 35 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in CH 2 Cl 2 abs. (60 mL) and heated to reflux for 16 h, using an inverse Dean-Stark apparatus. For workup, the reaction mixture was washed with saturated aqueous solution of NaHCO 3 (3...
3. Materials and Materials
Pentane-1,3,5-triol ( 6, 2.01 g, 16.6 mmol), propiophenone ( 7b 4.4 mL, 33.2 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in toluene (90 mL) and heated to reflux for 1.5 h, using a Dean-Stark apparatus filled with molecular sieves 4 Å. For workup, the reaction mixture was washed with saturated aque...
- Use
- Pentane-1,3,5-triol ( 6, 2.01 g, 16.6 mmol), propiophenone ( 7b 4.4 mL, 33.2 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in toluene (90 mL) and heated to reflux for 1.5 h, using a Dean-Stark apparatus filled with molecular sieves 4 Å. For workup, the reaction mixture was washed with saturated aque...
3. Materials and Materials
Mesylate 15a (86 mg, 0.27 mmol) was dissolved in a solution of methylamine in ethanol (33% m / m, 8 mL). The mixture was heated to reflux for 3 h, using a reflux apparatus equipped with a rubber balloon to avoid loss of gaseous amine. Ethanol was removed under reduced pressure. The residue was dissolved in CH 2 Cl...
- Use
- Mesylate 15a (86 mg, 0.27 mmol) was dissolved in a solution of methylamine in ethanol (33% m / m, 8 mL). The mixture was heated to reflux for 3 h, using a reflux apparatus equipped with a rubber balloon to avoid loss of gaseous amine. Ethanol was removed under reduced pressure. The residue was dissolved in CH 2 Cl...
3. Materials and Materials
Mesylate 15b (58 mg, 0.17 mmol) was dissolved in a solution of methylamine in ethanol (33% m / m, 5 mL). The mixture was heated to reflux for 5 h, using a reflux apparatus equipped with a rubber balloon to avoid loss of gaseous amine. Ethanol was removed under reduced pressure. The residue was dissolved in CH 2 Cl...
- Use
- Mesylate 15b (58 mg, 0.17 mmol) was dissolved in a solution of methylamine in ethanol (33% m / m, 5 mL). The mixture was heated to reflux for 5 h, using a reflux apparatus equipped with a rubber balloon to avoid loss of gaseous amine. Ethanol was removed under reduced pressure. The residue was dissolved in CH 2 Cl...
3. Materials and Materials
The saturated ketone 22b (100 mg, 0.30 mmol) and NH 4 OAc (347 mg, 4.5 mmol) were dissolved in methanol abs. (20 mL) using ultrasound. NaBH 3 CN (95%, 64 mg, 0.97 mmol) was added, and the mixture was heated to reflux for 24 h, using a reflux apparatus equipped with a rubber balloon. Water (30 mL) was added, and the...
- Use
- The saturated ketone 22b (100 mg, 0.30 mmol) and NH 4 OAc (347 mg, 4.5 mmol) were dissolved in methanol abs. (20 mL) using ultrasound. NaBH 3 CN (95%, 64 mg, 0.97 mmol) was added, and the mixture was heated to reflux for 24 h, using a reflux apparatus equipped with a rubber balloon. Water (30 mL) was added, and the...
3. Materials and Materials
The saturated ketone 22a (100 mg, 0.32 mmol) was dissolved in CH 2 Cl 2 abs. (7 mL). Methylamine (2 M solution in THF, 0.24 mL, 0.48 mmol) and NaBH(OAc) 3 (95%, 214 mg, 0.96 mmol) were added. The mixture was heated to reflux, using a reflux apparatus equipped with a rubber balloon to avoid loss of gaseous amine. Add...
- Use
- The saturated ketone 22a (100 mg, 0.32 mmol) was dissolved in CH 2 Cl 2 abs. (7 mL). Methylamine (2 M solution in THF, 0.24 mL, 0.48 mmol) and NaBH(OAc) 3 (95%, 214 mg, 0.96 mmol) were added. The mixture was heated to reflux, using a reflux apparatus equipped with a rubber balloon to avoid loss of gaseous amine. Add...
3. Materials and Materials
The saturated ketone 22b (80 mg, 0.24 mmol) was dissolved in CH 2 Cl 2 abs. (7 mL). Methylamine (2 M solution in THF, 0.36 mL, 0.72 mmol) and NaBH(OAc) 3 (95%, 161 mg, 0.72 mmol) were added. The mixture was heated to reflux, using a reflux apparatus equipped with a rubber balloon to avoid loss of gaseous amine. Addi...
- Use
- The saturated ketone 22b (80 mg, 0.24 mmol) was dissolved in CH 2 Cl 2 abs. (7 mL). Methylamine (2 M solution in THF, 0.36 mL, 0.72 mmol) and NaBH(OAc) 3 (95%, 161 mg, 0.72 mmol) were added. The mixture was heated to reflux, using a reflux apparatus equipped with a rubber balloon to avoid loss of gaseous amine. Addi...
3.2.5. Protein Determination
The protein concentration was determined by the method of Bradford, modified by Stoscheck. Om brief, the Bradford solution was prepared by dissolving 5 mg of Coomassie Brilliant Blue G 250 in 2.5 mL of EtOH (95%, v / v ). 10 mL deionized H 2 O and 5 mL phosphoric acid (85%, m / v ) were added to this solution, the m...
- Use
- The protein concentration was determined by the method of Bradford, modified by Stoscheck. Om brief, the Bradford solution was prepared by dissolving 5 mg of Coomassie Brilliant Blue G 250 in 2.5 mL of EtOH (95%, v / v ). 10 mL deionized H 2 O and 5 mL phosphoric acid (85%, m / v ) were added to this solution, the m...
3.2.6. General Procedures for the Binding Assays
Software used for acquisition, scoring, statistics, or reporting.
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- The test compound solutions were prepared by dissolving approximately 10 µmol (usually 2-4 mg) of test compound in DMSO so that a 10 mM stock solution was obtained. To obtain the required test solutions for the assay, the DMSO stock solution was diluted with the respective assay buffer. The filtermats wer...
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2.3. Lipophilicity and Metabolic Stability (In Vitro) of Selected σ 1 Receptor Ligands
A balanced lipophilicity is crucial for the pharmacokinetics and pharmacodynamics of drugs. As measure for the lipophilicity, the logD 7.4 value of selected compounds was recorded using the recently developed micro-shake flask method. In this method, a compound was distributed between a MOPS buffer pH 7.4 and n -octanol and the amount of compound in the buffer layer was determined by MS analysis [ ] ( ).
3. Materials and Materials
Pentane-1,3,5-triol ( 6, 1.69 g, 14 mmol), benzaldehyde ( 7a, 3.5 mL, 35 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in CH 2 Cl 2 abs. (60 mL) and heated to reflux for 16 h, using an inverse Dean-Stark apparatus. For workup, the reaction mixture was washed with saturated aqueous solution of NaHCO 3 (3 × 20 mL), dried (K 2 CO 3 ) and the solvent was removed in vacuo. The residue was purified by flash column chromatography (Ø 6 cm, cyclohexane:thyl acetate = 1:1, length 20 cm, fraction 65 mL, R f = 0.28). Colorless oil, yield 2.27 g (78%). C 12 H 16 O 3, M r = 208.3. MS (EI): m / z [%] = 208 (M, 33), 207 (M-H, 100), 177 (M-CH 2 OH, 13), 105 (PhCO, 47), 77 (Ph, 42). IR (neat): ν ˜ [cm -1 ] = 3420 (O-H), 3066, 3034 (Ar-H), 2947, 2857 (C-H), 1098 (C-O-C), 749, 697 (arom. monosubst.). 1 H NMR (CDCl 3 ): δ [ppm] = 1.54 (dtd, J = 13.1/2.5/1.4 Hz,...
3. Materials and Materials
( Z )- 10a (R f = 0.15): Colorless oil, yield 76 mg (9.1%). C 16 H 20 O 4, M r = 276.3. IR (neat): ν ˜ [cm -1 ] = 2977, 2922, 2851 (C-H), 1714 (CO 2 R), 1646 (C=C), 1098 (C-O), 750, 697 (arom. monosubst). 1 H NMR (CDCl 3 ): δ [ppm] = 1.29 (t, J = 7.1 Hz, 3 H, CO 2 CH 2 C H 3 ), 1.56 (dtd, J = 13.3/3.8/1.4 Hz, 1 H, 5-H eq ), 1.89 (dddd, J = 13.1/12.3/11.4/5.1 Hz, 1 H, 5-H ax ), 2.87-2.95 (m, 1 H, diox-C H 2 -CH=CH), 3.10 (dddd, J = 15.7/7.6/4.5/1.7 Hz, 1 H, diox-C H 2 -CH=CH), 3.97 (ddd, J = 12.3/11.6/2.6 Hz, 1 H, 6-H ax ), 3.96-4.02 (m, 1 H, 4-H ax ), 4.18 (q, J = 7.1 Hz, 2 H, CO 2 C H 2 CH 3 ), 4.27 (ddd, J = 11.3/4.9/1.1 Hz, 1 H, 6-H eq ), 5.52 (s, 1 H, 2-H ax ), 5.88 (dt, J = 11.6/1.8 Hz, 1 H, CH=C H -CO 2 R), 6.45 (ddd, J = 11.6/7.7/6.9 Hz, 1 H, C H =CH-CO 2 R), 7.31-7.39 (m, 3 H, Ar-H), 7.48-7.50 (m, 2 H, Ar-H). HPLC (method ACN): pur...
3. Materials and Materials
Pentane-1,3,5-triol ( 6, 2.01 g, 16.6 mmol), propiophenone ( 7b 4.4 mL, 33.2 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in toluene (90 mL) and heated to reflux for 1.5 h, using a Dean-Stark apparatus filled with molecular sieves 4 Å. For workup, the reaction mixture was washed with saturated aqueous solution of NaHCO 3 (3 × 30 mL) and with brine (1 × 30 mL) and dried (K 2 CO 3 ). The solvent was removed in vacuo, and the residue was purified by flash column chromatography (Ø 8 cm, cyclohexane:ethyl acetate = 7:3, length 17 cm, fraction 65 mL, R f = 0.24). Colorless oil, yield 3.51 g (90%). C 14 H 20 O 3, M r = 236.3. MS (EI): m / z [%] = 237 (M + H, 24), 207 (M-CH 3 -CH 2, 100), 105 (Ph-CO, 67). IR (neat): ν ˜ [cm -1 ] = 3420 (O-H), 2926, 2875 (C-H), 756, 703 (arom. monosubst.). 1 H NMR (CDCl 3 ): δ [ppm] = 0.80 (t, J = 7.5 Hz,...
3. Materials and Materials
Under N 2 atmosphere, oxalyl chloride (0.51 mL, 6 mmol) was dissolved in CH 2 Cl 2 abs. (25 mL) and cooled down to -78 °C. At this temperature, a solution of DMSO (0.85 mL, 12 mmol) in CH 2 Cl 2 abs. (7.5 mL) was added very slowly (using a syringe pump, 7 mL/h) and the mixture was stirred for 15 min at -78 °C. Then, a solution of the alcohol 8a (1.043 g, 5 mmol) in CH 2 Cl 2 abs. (7.5 mL) was added (using a syringe pump, 12 mL/h). The mixture was stirred for additional 45 min at -78 °C before NEt 3 (3.5 mL, 25 mmol) was added. After warming to rt, n -hexane (40 mL) was added. The precipitate was filtered off using a glass suction filter and washed several times with Et 2 O. The filtrate was concentrated (600 mbar, 40 °C) and the filtration procedure was repeated once. The solvent was removed in vacuo, and the residue was purified by flash column c...
3. Materials and Materials
Under N 2 atmosphere, oxalyl chloride (0.87 mL, 10.15 mmol) was dissolved in CH 2 Cl 2 abs. (26 mL) and cooled down to -78 °C. At this temperature, a solution of DMSO (1.44 mL, 20.30 mmol) in CH 2 Cl 2 abs. (12 mL) was added very slowly (using a syringe pump, 9 mL/h) and the mixture was stirred for 15 min at -78 °C. Then a solution of the alcohol 8b (2.00 g, 8.46 mmol) in CH 2 Cl 2 abs. (12 mL) was added (using a syringe pump, 18 mL/h). The mixture was stirred for additional 45 min at -78 °C before NEt 3 (6.6 mL, 42.30 mmol) was added. After warming to rt, n -hexane (40 mL) was added. The precipitate was filtered off using a glass suction filter and washed several times with Et 2 O. The filtrate was concentrated (600 mbar, 40 °C) and the filtration procedure was repeated once. The solvent was removed in vacuo, and the residue was purified by flash...
3. Materials and Materials
Under N 2 atmosphere the commercially available P-ylide Ph 3 P=CH-CO 2 Et (1.23 g, 4.5 mmol) was dissolved in THF abs. (20 mL). A solution of the aldehyde 9a (619 mg, 3 mmol) in THF abs. (8 mL) was added, and the solution was diluted with THF to a total volume of 40 mL. The mixture was stirred for 24 h at rt and then heated to reflux for 2 h. Water (30 mL) and brine (15 mL) were added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (1 × 40 mL) and dried (K 2 CO 3 ). The solvent was removed in vacuo, and the residue was adsorbed on silica gel and loaded on the column (Ø 5.5 cm, cyclohexane:ethyl acetate = 9:1, length 18 cm, fraction 65 mL).
3. Materials and Materials
( E )- 10a (R f = 0.12: Colorless oil, yield 712 mg (86%). C 16 H 20 O 4, M r = 276.3. MS (ESI): m / z [%] = 277 (M + H, 10), 294 (M + NH 4, 22), 299 (M + Na, 26), 575 (2 × M + Na, 20), 577 (M + Ph 3 P = O + Na, 100). IR (neat): ν ˜ [cm -1 ] = 2979, 2853 (C-H), 1715 (CO 2 R), 1656 (C=C), 1099 (C-O), 751, 697 (arom. monosubst). 1H NMR (CDCl 3 ): δ [ppm] = 1.29 (t, J = 7.1 Hz, 3 H, CO 2 CH 2 -C H 3 ), 1.53-1.58 (m, 1 H, 5-H eq ), 1.85 (dddd, J = 13.1/12.3/11.4/5.0 Hz, 1 H, 5-H ax ), 2.46 (dddd, J = 14.7/7.4/5.7/1.4 Hz, 1 H, diox-C H 2 -CH=CH), 1.60 (dtd, J = 14.8/6.9/1.5 Hz, 1 H, diox-C H 2 -CH=CH), 3.96 (td, J = 12.0/2.6 Hz, 1 H, 6-H ax ), 3.95-4.02 (m, 1 H, 4-H ax ), 4.19 (q, J = 7.1 Hz, 2 H, CO 2 C H 2 -CH 3 ), 4.28 (ddd, J = 11.4/5.0/1.2 Hz, 1 H, 6-H eq ), 5.52 (s, 1 H, 2-H ax ), 5.93 (dt, J = 15.7/1.4 Hz, 1 H, CH=C H -CO 2 R), 7.01 (dt, J = 1...
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A balanced lipophilicity is crucial for the pharmacokinetics and pharmacodynamics of drugs. As measure for the lipophilicity, the logD 7.4 value of selected compounds was record...
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- Per-sample or per-animal endpoint measurements collected during the experiment
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- Summary statistics and between-group or across-timepoint comparisons
The test compound solutions were prepared by dissolving approximately 10 µmol (usually 2-4 mg) of test compound in DMSO so that a 10 mM stock solution was obtained. T...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
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inferred from protocolPreprocessing / cleaning
Under N 2 atmosphere the commercially available P-ylide Ph 3 P=CH-CO 2 Et (1.23 g, 4.5 mmol) was dissolved in THF abs.
from paperScoring or quantification
Quantify the primary readouts for this experiment: A balanced lipophilicity is crucial for the pharmacokinetics and pharmacodynamics of drugs. As measure for the lipophilicity, the logD 7.4 value of selected compounds was record...; The test compound solutions were prepared by dissolving approximately 10 µmol (usually 2-4 mg) of test compound in DMSO so that a 10 mM stock solution was obtained. T....
from paperStatistical comparison
Under N 2 atmosphere the commercially available P-ylide Ph 3 P=CH-CO 2 Et (1.23 g, 4.5 mmol) was dissolved in THF abs. (20 mL). A solution of the aldehyde 9a (619 mg, 3 mmol) in...; Under N 2 atmosphere the commercially available P-ylide Ph 3 P=CH-CO 2 CH 3 (2.10 g, 6.27 mmol) was dissolved in THF abs. (20 mL). A solution of the aldehyde 9b (983 mg, 4.18 mm...; The test compound solutions were prepared by dissolving approximately 10 µmol (usually 2-4 mg) of test compound in DMSO so that a 10 mM stock solution was obtained. T...
from paperReporting output
Report representative outputs alongside summary comparisons for A balanced lipophilicity is crucial for the pharmacokinetics and pharmacodynamics of drugs. As measure for the lipophilicity, the logD 7.4 value of selected compounds was record..., The test compound solutions were prepared by dissolving approximately 10 µmol (usually 2-4 mg) of test compound in DMSO so that a 10 mM stock solution was obtained. T....
inferred from protocolStructured statistical methods
Under N 2 atmosphere the commercially available P-ylide Ph 3 P=CH-CO 2 Et (1.23 g, 4.5 mmol) was dissolved in THF abs. (20 mL). A solution of the aldehyde 9a (619 mg, 3 mmol) in...; Under N 2 atmosphere the commercially available P-ylide Ph 3 P=CH-CO 2 CH 3 (2.10 g, 6.27 mmol) was dissolved in THF abs. (20 mL). A solution of the aldehyde 9b (983 mg, 4.18 mm...; The test compound solutions were prepared by dissolving approximately 10 µmol (usually 2-4 mg) of test compound in DMSO so that a 10 mM stock solution was obtained. T...
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Evidence quotes (8)
A balanced lipophilicity is crucial for the pharmacokinetics and pharmacodynamics of drugs. As measure for the lipophilicity, the logD 7.4 value of selected compounds was recorded using the recently developed micro-shake flask method. In this method, a compound was distributed between a MOPS buffer pH 7.4 and n -octanol and the amount of compound in the buffer layer was determined by MS analysis [ ] ( ).
Pentane-1,3,5-triol ( 6, 1.69 g, 14 mmol), benzaldehyde ( 7a, 3.5 mL, 35 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in CH 2 Cl 2 abs. (60 mL) and heated to reflux for 16 h, using an inverse Dean-Stark apparatus. For workup, the reaction mixture was washed with saturated aqueous solution of NaHCO 3 (3 × 20 mL), dried (K 2 CO 3 ) and the solvent was removed in vacuo. The residue was purified by flash column chromatography (Ø 6 cm, cyclohexane:thyl acetate = 1:1, length 20 cm, fraction 65 mL, R f = 0.28). Colorless oil, yield 2.27 g (78%). C 12 H 16 O 3, M r = 208.3. MS (EI): m / z [%] = 208 (M, 33), 207 (M-H, 100), 177 (M-CH 2 OH, 13), 105 (PhCO, 47), 77 (Ph, 42). IR (neat): ν ˜ [cm -1 ] = 3420 (O-H), 3066, 3034 (Ar-H), 2947, 2857 (C-H), 1098 (C-O-C), 749, 697 (arom. monosubst.). 1 H NMR (CDCl 3 ): δ [ppm] = 1.54 (dtd, J = 13.1/2.5/1.4 Hz, 1H, 5-H eq ), 1.79-1.99 (m, 3H, C H 2 -CH 2 -OH and 5-H ax ), 2.11 (dd, J = 6.1/4.7 Hz, 1H, CH 2 -O H ), 3.79-3.90 (m, 2H, C H 2 -OH), 3.99 (td, J = 11.7/2.6 Hz, 1H, 6-H ax ), 4.09-4.16 (m, 1H, 4-H ax ), 4.28 (ddd, J = 11.4/5.0/1.1 Hz, 1H, 6-H eq ), 5.54 (s, 1H, 2-H ax ), 7.30R...
( Z )- 10a (R f = 0.15): Colorless oil, yield 76 mg (9.1%). C 16 H 20 O 4, M r = 276.3. IR (neat): ν ˜ [cm -1 ] = 2977, 2922, 2851 (C-H), 1714 (CO 2 R), 1646 (C=C), 1098 (C-O), 750, 697 (arom. monosubst). 1 H NMR (CDCl 3 ): δ [ppm] = 1.29 (t, J = 7.1 Hz, 3 H, CO 2 CH 2 C H 3 ), 1.56 (dtd, J = 13.3/3.8/1.4 Hz, 1 H, 5-H eq ), 1.89 (dddd, J = 13.1/12.3/11.4/5.1 Hz, 1 H, 5-H ax ), 2.87-2.95 (m, 1 H, diox-C H 2 -CH=CH), 3.10 (dddd, J = 15.7/7.6/4.5/1.7 Hz, 1 H, diox-C H 2 -CH=CH), 3.97 (ddd, J = 12.3/11.6/2.6 Hz, 1 H, 6-H ax ), 3.96-4.02 (m, 1 H, 4-H ax ), 4.18 (q, J = 7.1 Hz, 2 H, CO 2 C H 2 CH 3 ), 4.27 (ddd, J = 11.3/4.9/1.1 Hz, 1 H, 6-H eq ), 5.52 (s, 1 H, 2-H ax ), 5.88 (dt, J = 11.6/1.8 Hz, 1 H, CH=C H -CO 2 R), 6.45 (ddd, J = 11.6/7.7/6.9 Hz, 1 H, C H =CH-CO 2 R), 7.31-7.39 (m, 3 H, Ar-H), 7.48-7.50 (m, 2 H, Ar-H). HPLC (method ACN): purity 93.0%, t R = 20.90 min. Contamination with 2.9% of ( E )- 10a (t R = 20.35 min) was observed.
Pentane-1,3,5-triol ( 6, 2.01 g, 16.6 mmol), propiophenone ( 7b 4.4 mL, 33.2 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in toluene (90 mL) and heated to reflux for 1.5 h, using a Dean-Stark apparatus filled with molecular sieves 4 Å. For workup, the reaction mixture was washed with saturated aqueous solution of NaHCO 3 (3 × 30 mL) and with brine (1 × 30 mL) and dried (K 2 CO 3 ). The solvent was removed in vacuo, and the residue was purified by flash column chromatography (Ø 8 cm, cyclohexane:ethyl acetate = 7:3, length 17 cm, fraction 65 mL, R f = 0.24). Colorless oil, yield 3.51 g (90%). C 14 H 20 O 3, M r = 236.3. MS (EI): m / z [%] = 237 (M + H, 24), 207 (M-CH 3 -CH 2, 100), 105 (Ph-CO, 67). IR (neat): ν ˜ [cm -1 ] = 3420 (O-H), 2926, 2875 (C-H), 756, 703 (arom. monosubst.). 1 H NMR (CDCl 3 ): δ [ppm] = 0.80 (t, J = 7.5 Hz, 3 H, diox-CH 2 -C H 3 ), 1.25-1.30 (m, 1 H, 5-H eq ), 1.69-1.89 (m, 3 H, 5-H ax, C H 2 -CH 2 -OH), 1.75 (q, J = 7.5 Hz, 2 H, diox-C H 2 -CH 3 ), 2.58 (s, 1 H, O- H ), 3.81 (td, J = 12.0/2.5 Hz, 1 H, 6-H ax ), 3.87-3.91 (m, 3 H, 6-H eq, C H 2 -OH), 3.93-4.00 (m, 1 H, 4-H ax...
Under N 2 atmosphere, oxalyl chloride (0.51 mL, 6 mmol) was dissolved in CH 2 Cl 2 abs. (25 mL) and cooled down to -78 °C. At this temperature, a solution of DMSO (0.85 mL, 12 mmol) in CH 2 Cl 2 abs. (7.5 mL) was added very slowly (using a syringe pump, 7 mL/h) and the mixture was stirred for 15 min at -78 °C. Then, a solution of the alcohol 8a (1.043 g, 5 mmol) in CH 2 Cl 2 abs. (7.5 mL) was added (using a syringe pump, 12 mL/h). The mixture was stirred for additional 45 min at -78 °C before NEt 3 (3.5 mL, 25 mmol) was added. After warming to rt, n -hexane (40 mL) was added. The precipitate was filtered off using a glass suction filter and washed several times with Et 2 O. The filtrate was concentrated (600 mbar, 40 °C) and the filtration procedure was repeated once. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (Ø 5.5 cm, cyclohexane:ethyl acetate = 8:2, length 20 cm, fraction 65 mL, R f = 0.16). Colorless oil with sweet smell, yield 0.994 g (91%). C 12 H 14 O 3, M r = 206.3. MS (EI): m / z = 207 (M + H, 53), 205 (M-H, 76), 177 (M-CHO, 6), 105 (PhCO, 100), 77 (Ph, 81). IR (neat): ν...
Under N 2 atmosphere, oxalyl chloride (0.87 mL, 10.15 mmol) was dissolved in CH 2 Cl 2 abs. (26 mL) and cooled down to -78 °C. At this temperature, a solution of DMSO (1.44 mL, 20.30 mmol) in CH 2 Cl 2 abs. (12 mL) was added very slowly (using a syringe pump, 9 mL/h) and the mixture was stirred for 15 min at -78 °C. Then a solution of the alcohol 8b (2.00 g, 8.46 mmol) in CH 2 Cl 2 abs. (12 mL) was added (using a syringe pump, 18 mL/h). The mixture was stirred for additional 45 min at -78 °C before NEt 3 (6.6 mL, 42.30 mmol) was added. After warming to rt, n -hexane (40 mL) was added. The precipitate was filtered off using a glass suction filter and washed several times with Et 2 O. The filtrate was concentrated (600 mbar, 40 °C) and the filtration procedure was repeated once. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (6 cm, cyclohexane:ethyl acetate = 9.25:0.75, length 18 cm, fraction 65 mL, R f = 0.09). Colorless solid, mp 55.8 °C, yield 1.76 g (89%). C 14 H 18 O 3, M r = 234.3. MS (EI): m / z [%] = 235 (M + H, 41), 205 (M-CH 3 -CH 2, 100), 105 (Ph-CO, 52). IR (neat): ν ˜...
Under N 2 atmosphere the commercially available P-ylide Ph 3 P=CH-CO 2 Et (1.23 g, 4.5 mmol) was dissolved in THF abs. (20 mL). A solution of the aldehyde 9a (619 mg, 3 mmol) in THF abs. (8 mL) was added, and the solution was diluted with THF to a total volume of 40 mL. The mixture was stirred for 24 h at rt and then heated to reflux for 2 h. Water (30 mL) and brine (15 mL) were added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (1 × 40 mL) and dried (K 2 CO 3 ). The solvent was removed in vacuo, and the residue was adsorbed on silica gel and loaded on the column (Ø 5.5 cm, cyclohexane:ethyl acetate = 9:1, length 18 cm, fraction 65 mL).
( E )- 10a (R f = 0.12: Colorless oil, yield 712 mg (86%). C 16 H 20 O 4, M r = 276.3. MS (ESI): m / z [%] = 277 (M + H, 10), 294 (M + NH 4, 22), 299 (M + Na, 26), 575 (2 × M + Na, 20), 577 (M + Ph 3 P = O + Na, 100). IR (neat): ν ˜ [cm -1 ] = 2979, 2853 (C-H), 1715 (CO 2 R), 1656 (C=C), 1099 (C-O), 751, 697 (arom. monosubst). 1H NMR (CDCl 3 ): δ [ppm] = 1.29 (t, J = 7.1 Hz, 3 H, CO 2 CH 2 -C H 3 ), 1.53-1.58 (m, 1 H, 5-H eq ), 1.85 (dddd, J = 13.1/12.3/11.4/5.0 Hz, 1 H, 5-H ax ), 2.46 (dddd, J = 14.7/7.4/5.7/1.4 Hz, 1 H, diox-C H 2 -CH=CH), 1.60 (dtd, J = 14.8/6.9/1.5 Hz, 1 H, diox-C H 2 -CH=CH), 3.96 (td, J = 12.0/2.6 Hz, 1 H, 6-H ax ), 3.95-4.02 (m, 1 H, 4-H ax ), 4.19 (q, J = 7.1 Hz, 2 H, CO 2 C H 2 -CH 3 ), 4.28 (ddd, J = 11.4/5.0/1.2 Hz, 1 H, 6-H eq ), 5.52 (s, 1 H, 2-H ax ), 5.93 (dt, J = 15.7/1.4 Hz, 1 H, CH=C H -CO 2 R), 7.01 (dt, J = 15.6/7.3 Hz, 1 H, C H =CH-CO 2 R), 7.33-7.39 (m, 3 H, Ar-H), 7.48-7.50 (m, 2 H, Ar-H). HPLC (method ACN): purity 93.4%, t R = 20.34 min. Contamination with 1.7% of ( Z )- 10a (t R = 20.35 min) was observed.
Machine-readable layer
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"name": "2.3. Lipophilicity and Metabolic Stability (In Vitro) of Selected σ 1 Receptor Ligands",
"text": "A balanced lipophilicity is crucial for the pharmacokinetics and pharmacodynamics of drugs. As measure for the lipophilicity, the logD 7.4 value of selected compounds was recorded using the recently developed micro-shake flask method. In this method, a compound was distributed between a MOPS buffer pH 7.4 and n -octanol and the amount of compound in the buffer layer was determined by MS analysis [ ] ( )."
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"text": "Pentane-1,3,5-triol ( 6, 1.69 g, 14 mmol), benzaldehyde ( 7a, 3.5 mL, 35 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in CH 2 Cl 2 abs. (60 mL) and heated to reflux for 16 h, using an inverse Dean-Stark apparatus. For workup, the reaction mixture was washed with saturated aqueous solution of NaHCO 3 (3 × 20 mL), dried (K 2 CO 3 ) and the solvent was removed in vacuo. The residue was purified by flash column chromatography (Ø 6 cm, cyclohexane:thyl acetate = 1:1, length 20 cm, fraction 65 mL, R f = 0.28). Colorless oil, yield 2.27 g (78%). C 12 H 16 O 3, M r = 208.3. MS (EI): m / z [%] = 208 (M, 33), 207 (M-H, 100), 177 (M-CH 2 OH, 13), 105 (PhCO, 47), 77 (Ph, 42). IR (neat): ν ˜ [cm -1 ] = 3420 (O-H), 3066, 3034 (Ar-H), 2947, 2857 (C-H), 1098 (C-O-C), 749, 697 (arom. monosubst.). 1 H NMR (CDCl 3 ): δ [ppm] = 1.54 (dtd, J = 13.1/2.5/1.4 Hz,..."
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"name": "3. Materials and Materials",
"text": "( Z )- 10a (R f = 0.15): Colorless oil, yield 76 mg (9.1%). C 16 H 20 O 4, M r = 276.3. IR (neat): ν ˜ [cm -1 ] = 2977, 2922, 2851 (C-H), 1714 (CO 2 R), 1646 (C=C), 1098 (C-O), 750, 697 (arom. monosubst). 1 H NMR (CDCl 3 ): δ [ppm] = 1.29 (t, J = 7.1 Hz, 3 H, CO 2 CH 2 C H 3 ), 1.56 (dtd, J = 13.3/3.8/1.4 Hz, 1 H, 5-H eq ), 1.89 (dddd, J = 13.1/12.3/11.4/5.1 Hz, 1 H, 5-H ax ), 2.87-2.95 (m, 1 H, diox-C H 2 -CH=CH), 3.10 (dddd, J = 15.7/7.6/4.5/1.7 Hz, 1 H, diox-C H 2 -CH=CH), 3.97 (ddd, J = 12.3/11.6/2.6 Hz, 1 H, 6-H ax ), 3.96-4.02 (m, 1 H, 4-H ax ), 4.18 (q, J = 7.1 Hz, 2 H, CO 2 C H 2 CH 3 ), 4.27 (ddd, J = 11.3/4.9/1.1 Hz, 1 H, 6-H eq ), 5.52 (s, 1 H, 2-H ax ), 5.88 (dt, J = 11.6/1.8 Hz, 1 H, CH=C H -CO 2 R), 6.45 (ddd, J = 11.6/7.7/6.9 Hz, 1 H, C H =CH-CO 2 R), 7.31-7.39 (m, 3 H, Ar-H), 7.48-7.50 (m, 2 H, Ar-H). HPLC (method ACN): pur..."
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"name": "3. Materials and Materials",
"text": "Pentane-1,3,5-triol ( 6, 2.01 g, 16.6 mmol), propiophenone ( 7b 4.4 mL, 33.2 mmol) and p -toluenesulfonic acid (75 mg) were dissolved in toluene (90 mL) and heated to reflux for 1.5 h, using a Dean-Stark apparatus filled with molecular sieves 4 Å. For workup, the reaction mixture was washed with saturated aqueous solution of NaHCO 3 (3 × 30 mL) and with brine (1 × 30 mL) and dried (K 2 CO 3 ). The solvent was removed in vacuo, and the residue was purified by flash column chromatography (Ø 8 cm, cyclohexane:ethyl acetate = 7:3, length 17 cm, fraction 65 mL, R f = 0.24). Colorless oil, yield 3.51 g (90%). C 14 H 20 O 3, M r = 236.3. MS (EI): m / z [%] = 237 (M + H, 24), 207 (M-CH 3 -CH 2, 100), 105 (Ph-CO, 67). IR (neat): ν ˜ [cm -1 ] = 3420 (O-H), 2926, 2875 (C-H), 756, 703 (arom. monosubst.). 1 H NMR (CDCl 3 ): δ [ppm] = 0.80 (t, J = 7.5 Hz,..."
},
{
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"name": "3. Materials and Materials",
"text": "Under N 2 atmosphere, oxalyl chloride (0.51 mL, 6 mmol) was dissolved in CH 2 Cl 2 abs. (25 mL) and cooled down to -78 °C. At this temperature, a solution of DMSO (0.85 mL, 12 mmol) in CH 2 Cl 2 abs. (7.5 mL) was added very slowly (using a syringe pump, 7 mL/h) and the mixture was stirred for 15 min at -78 °C. Then, a solution of the alcohol 8a (1.043 g, 5 mmol) in CH 2 Cl 2 abs. (7.5 mL) was added (using a syringe pump, 12 mL/h). The mixture was stirred for additional 45 min at -78 °C before NEt 3 (3.5 mL, 25 mmol) was added. After warming to rt, n -hexane (40 mL) was added. The precipitate was filtered off using a glass suction filter and washed several times with Et 2 O. The filtrate was concentrated (600 mbar, 40 °C) and the filtration procedure was repeated once. The solvent was removed in vacuo, and the residue was purified by flash column c..."
},
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"name": "3. Materials and Materials",
"text": "Under N 2 atmosphere, oxalyl chloride (0.87 mL, 10.15 mmol) was dissolved in CH 2 Cl 2 abs. (26 mL) and cooled down to -78 °C. At this temperature, a solution of DMSO (1.44 mL, 20.30 mmol) in CH 2 Cl 2 abs. (12 mL) was added very slowly (using a syringe pump, 9 mL/h) and the mixture was stirred for 15 min at -78 °C. Then a solution of the alcohol 8b (2.00 g, 8.46 mmol) in CH 2 Cl 2 abs. (12 mL) was added (using a syringe pump, 18 mL/h). The mixture was stirred for additional 45 min at -78 °C before NEt 3 (6.6 mL, 42.30 mmol) was added. After warming to rt, n -hexane (40 mL) was added. The precipitate was filtered off using a glass suction filter and washed several times with Et 2 O. The filtrate was concentrated (600 mbar, 40 °C) and the filtration procedure was repeated once. The solvent was removed in vacuo, and the residue was purified by flash..."
},
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"@type": "HowToStep",
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"name": "3. Materials and Materials",
"text": "Under N 2 atmosphere the commercially available P-ylide Ph 3 P=CH-CO 2 Et (1.23 g, 4.5 mmol) was dissolved in THF abs. (20 mL). A solution of the aldehyde 9a (619 mg, 3 mmol) in THF abs. (8 mL) was added, and the solution was diluted with THF to a total volume of 40 mL. The mixture was stirred for 24 h at rt and then heated to reflux for 2 h. Water (30 mL) and brine (15 mL) were added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (1 × 40 mL) and dried (K 2 CO 3 ). The solvent was removed in vacuo, and the residue was adsorbed on silica gel and loaded on the column (Ø 5.5 cm, cyclohexane:ethyl acetate = 9:1, length 18 cm, fraction 65 mL)."
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"text": "( E )- 10a (R f = 0.12: Colorless oil, yield 712 mg (86%). C 16 H 20 O 4, M r = 276.3. MS (ESI): m / z [%] = 277 (M + H, 10), 294 (M + NH 4, 22), 299 (M + Na, 26), 575 (2 × M + Na, 20), 577 (M + Ph 3 P = O + Na, 100). IR (neat): ν ˜ [cm -1 ] = 2979, 2853 (C-H), 1715 (CO 2 R), 1656 (C=C), 1099 (C-O), 751, 697 (arom. monosubst). 1H NMR (CDCl 3 ): δ [ppm] = 1.29 (t, J = 7.1 Hz, 3 H, CO 2 CH 2 -C H 3 ), 1.53-1.58 (m, 1 H, 5-H eq ), 1.85 (dddd, J = 13.1/12.3/11.4/5.0 Hz, 1 H, 5-H ax ), 2.46 (dddd, J = 14.7/7.4/5.7/1.4 Hz, 1 H, diox-C H 2 -CH=CH), 1.60 (dtd, J = 14.8/6.9/1.5 Hz, 1 H, diox-C H 2 -CH=CH), 3.96 (td, J = 12.0/2.6 Hz, 1 H, 6-H ax ), 3.95-4.02 (m, 1 H, 4-H ax ), 4.19 (q, J = 7.1 Hz, 2 H, CO 2 C H 2 -CH 3 ), 4.28 (ddd, J = 11.4/5.0/1.2 Hz, 1 H, 6-H eq ), 5.52 (s, 1 H, 2-H ax ), 5.93 (dt, J = 15.7/1.4 Hz, 1 H, CH=C H -CO 2 R), 7.01 (dt, J = 1..."
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