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- February 2012 (4)
- - New section - (1)
- Completed Experiments (158)
- Experiments (174)
- MNR101-110 (13)
- MNR111-120 (13)
- MNR51-60 (3)
- MNR61-70 (1)
- MNR81-90 (4)
- MNR91-100 (5)
- mnr121-130 (7)
Synthesis of 1-(4-fluorobenzyl)piperazine as a coupling partner to make TCMDC-132385
Following procedure from DOI: 10.1021/jm900722z - General Procedure for 1-Benzylpiperazines 35-36
As for Synthesis of 1-(4-fluorobenzyl)piperazine - MNR107-1
Hazard Assessment
Procedure
Anhydrous piperazine (4.32 g 50.2 mmol) was added to THF (17 mL) and the mixture was heated to reflux until the piperazine was fully dissolved. To the solution was added 4-fluorobenzyl chloride (1.0 mL, 8.37 mmol) dropwise. A white precipitate was formed immediately. The reaction mixture was refluxed for 1 hour and then allowed to cool to room temperature. The excess piperazine was filtered off and washed with EtOAc (30 mL). The organic layer was concentrated. The crude white sollid was washed with KOH solution (pH >12) (40 mL) and the the aqueous layer was extracted with DCM (3 x 50mL). The organic layers were combined, dried, filtered concentrated to give a cloudy white oil (1.759 g, >8.37 mmol, >100%)
NMR
Conclusion
Reaction proceeded as before and crude 1H NMR was consistent as before. Crude product was dried further under hi-vac before being taken on to the next step without further purification.
Strings
Starting Material
InChI=1S/C7H6ClF/c8-5-6-1-3-7(9)4-2-6/h1-4H,5H2
InChI=1S/C4H10N2/c1-2-6-4-3-5-1/h5-6H,1-4H2
Product
InChI=1S/C11H15FN2/c12-11-3-1-10(2-4-11)9-14-7-5-13-6-8-14/h1-4,13H,5-9H2
Repeat of Synthesis of N-methyl-3-bromobenzenesulfonamide - MNR108-1 but using methylamine (33% in EtOH)
Following a prep from US7235576 (B1) - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - page 16 column 26
Hazard Assessment
Procedure
To a solution of 3-bromobenzenesulfonyl chloride (recovered from MNR108-1)(1.37 mmol) in THF (2mL) at 0 °C was added methylamine (33% in EtOH, 2 mL). The resulting solution was allowed to warm to room temperature and stirred overnight. In the morning, HCl (1M, 5 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The organic fractions were combined, dried, filtered and concentrated to give the crude (0.307 g). Crude NMR showed a mess with little sign of product. The reaction was not taken any further.
NMR
The reaction has not yeiled any product but this could be due to the fact that the starting material was recovered from the previous attempt. This reaction needs repeated again using fresh starting material.
Strings
Starting material
InChI=1S/C6H4BrClO2S/c7-5-2-1-3-6(4-5)11(8,9)10/h1-4H
Product
InChI=1S/C7H8BrNO2S/c1-9-12(10,11)7-4-2-3-6(8)5-7/h2-5,9H,1H3
Starting material from Bromination of MNR100-2 to give MNR101-3 and Bromination of MNR100-2 to give MNR101-2
as for - Arylation of MNR101-2 with MNR103-1 to give MNR106-1
Hazard Assessment
Procedure
To a degassed solution of IPA (2 mL) and aqueous potassium carbonate (1 M, 0.4 mL) was added MNR101-2 (0.06 g, 0.20 mmol) and 4-sulfamoylphenylboronic acid, pinacol ester (0.068g, 0.24 mmol) and the reaction mixture further degassed for 5 minutes. Pd(dppf)Cl2 (0.029 g, 0.04 mmol) was added and the reaction mixture stirred at 80 °C overnight (15 hours). The reaction was allowed to cool to room temperature and was filtered through celite and rinsed with EtOAc (3 x 15 mL).
TLC
Column 75-100% EtOAc/Hex
NMR
Conclusion
Strings
Starting material
InChI=1S/C10H10BrN3OS/c11-8-5-7-9(16-8)10(13-6-12-7)14-1-3-15-4-2-14/h5-6H,1-4H2
InChI=1S/C12H18BNO4S/c1-11(2)12(3,4)18-13(17-11)9-5-7-10(8-6-9)19(14,15)16/h5-8H,14H2,1-4H3/q+1
Product
InChI=1S/C16H16N4O3S2/c17-25(21,22)12-3-1-11(2-4-12)14-9-13-15(24-14)16(19-10-18-13)20-5-7-23-8-6-20/h1-4,9-10H,5-8H2,(H2,17,21,22)
Following a prep from US7235576 (B1) - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - page 16 column 26
Hazard Assessment
Procedure
To a solution of 3-bromobenzenesulfonyl chloride (0.20 mL, 1.37 mmol) in THF (2mL) at 0 °C was added dimethylamine (33% in EtOH, 2 mL). The resulting solution was allowed to warm to room temperature and stirred overnight. In the morning, HCl (1M, 5 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The organic fractions were combined, dried, filtered and concentrated to give the crude at a off white solid (0.397 g, 110%)
NMR
Strings
Starting material
InChI=1S/C6H4BrClO2S/c7-5-2-1-3-6(4-5)11(8,9)10/h1-4H
Product
InChI=1S/C8H10BrNO2S/c1-10(2)13(11,12)8-5-3-4-7(9)6-8/h3-6H,1-2H3
Following a prep from US7235576 (B1) - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - page 16 column 26
Hazard Assessment
Procedure
To a solution of 3-bromobenzenesulfonyl chloride (0.20 mL, 1.37 mmol) in THF (2mL) at 0 °C was added methylamine (2.0 M in THF, 3.42 mL, 6.85 mmol). The resulting solution was allowed to warm to room temperature and stirred overnight.
** Note - the methlamine came out of an old bottle and the sureseal was broken. I took the last 3 mL out of the bottle and it wasn't a clear solution as expected.
In the morning TLC showed littel to no reaction. In the morning, HCl (1M, 5 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The organic fractions were combined, dried, filtered and concentrated to give the crude (0.347 g). Crude NMR showed mainly starting material and other impurities.
NMR
Strings
Starting material
InChI=1S/C6H4BrClO2S/c7-5-2-1-3-6(4-5)11(8,9)10/h1-4H
Product
InChI=1S/C7H8BrNO2S/c1-9-12(10,11)7-4-2-3-6(8)5-7/h2-5,9H,1H3