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7th May 2013 @ 01:26
Mnr: MNR101-110

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

 

HIRAC MNR107.pdf

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

mnr107-2_crude_1H.pdf
mnr107-2_crude.zip
- contains traces of DCM and EtOAc

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

Attached Files
14th March 2013 @ 07:09
Mnr: MNR101-110

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

 

HIRAC MNR108.pdf

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

 
mnr108-2_crude_1H.pdf
mnr108-2_crude.zip
 
Conclusion


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

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Attached Files
13th March 2013 @ 06:37
Mnr: MNR101-110

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

HIRAC MNR103.pdf

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)

Attached Files
13th March 2013 @ 02:07
Mnr: MNR101-110

Following a prep from US7235576  (B1)  -  Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - page 16 column 26

Hazard Assessment

 

HIRAC MNR108.pdf

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

 
 
Conclusion

 

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

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Attached Files
13th March 2013 @ 01:56
Mnr: MNR101-110

Following a prep from US7235576  (B1)  -  Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - page 16 column 26

Hazard Assessment

 

HIRAC MNR108.pdf

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

 
mnr108-1_crude_1H.pdf
mnr108-1_crude.zip
 
Conclusion

 This reaction has not worked, but it should be assumed that the methlamine  used was of a poor quality and the reaction should be repeated using another source of methlamine

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

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Attached Files