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9th April 2013 @ 01:40
Mnr: MNR111-120

Starting material - Bromination of MNR89 at the 7 position - MNR118-1

As for Chlorination of MNR89 To Give MNR99-3

NMR reference  WO2011093684  (A2) ― 2011-08-04 - page 19 step 3

 

Hazard Assessment

HIRAC MNR99.pdf

Procedure

To MNR118-1 (0.180 g, 0.78 mmol) at room temperature was added POCl3 (0.73 mL, 7.79 mmol) under argon and the mixture was heated to reflux for 3 hours during which time the reaction turned a dark brown colour.  The the reaction was then allowed to reach room temperature and was slowly added dropwise to ice (20 mL) in a beaker.  The mixture was then slowly neutralised with sodium bicarbonate.  Once the reaction was fully quenched it was filtered and washed with water to give a pale brown soild (0.086g) 

NMR

 

mnr119-2_filter_1H.pdf
mnr119-2_filter_13C.pdf
mnr119-2_filter.zip

Conclusion

NMR showed mainly starting material with less than 5% product.  The reaction has therefore started to go but has not had long enough.  Reaction needs repeated possibly at a higher temperature and for a longer period of time.

 

The new peaks in the 1H NMR at 9.17 and 8.80 are of different shifts to that of AT-5-6 (9.02 and 8.06) therefore suggesting that the Br substitution has occurred at the 7 position.


AT-5-6-DMSO.pdf

Strings

Starting material

InChI=1S/C6H3BrN2OS/c7-3-1-11-5-4(3)8-2-9-6(5)10/h1-2H,(H,8,9,10)

Product

InChI=1S/C6H2BrClN2S/c7-3-1-11-5-4(3)9-2-10-6(5)8/h1-2H

 

 

Attached Files
8th April 2013 @ 05:24
Mnr: MNR111-120

Starting material from Bromination of MNR113-1 to give MNR115-2

as for - Arylation of MNR101-2 with MNR103-1 to give MNR106-1

repeat of Suzuki Coupling of MNR115 to give MNR116-1 but using clean starting material  

Hazard Assessment

HIRAC MNR103.pdf

Procedure

To a degassed solution of IPA (2 mL) and aqueous potassium carbonate (1 M, 0.34 mL) was added MNR115-2 (0.07 g, 0.17 mmol) and  phenylboronic acid (0.025 g, 0.21 mmol) and the reaction mixture further degassed for 5 minutes. Pd(dppf)Cl2 (0.025 g, 0.03 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 MeOH (3 x 15 mL).  

column - 40-100% EtOAc/Hex

Fracs 17-53       0.040 g as a sticky gum with some solid.

The product was then triturated with 50% Et2O/Hexane to give an off white solid (0.016 g, 0.04 mmol, 23%)

NMR


mnr116-2_1H.pdf
mnr116-2.zip

Conclusion

 NMR not 100% clear/clean.  Reaction needs repeated before being sent for testing.

Strings 

Starting material

InChI=1S/C17H16BrFN4S/c18-15-9-14-16(24-15)17(21-11-20-14)23-7-5-22(6-8-23)10-12-1-3-13(19)4-2-12/h1-4,9,11H,5-8,10H2

InChI=1S/C6H7BO2/c8-7(9)6-4-2-1-3-5-6/h1-5,8-9H

 

Product

InChI=1S/C23H21FN4S/c24-19-8-6-17(7-9-19)15-27-10-12-28(13-11-27)23-22-20(25-16-26-23)14-21(29-22)18-4-2-1-3-5-18/h1-9,14,16H,10-13,15H2

Attached Files
4th April 2013 @ 06:09
Mnr: MNR111-120

Microwave Assisted Arylation of MNR115-2 using MNR103-1 to give MNR120-1

Starting material from Bromination of MNR113-1 to give MNR115-2

and Synthesis of Boronic Acid Pinacol Ester - MNR103-1

as for Arylation of aminobromothienopyrimidine (AT-17-1)

Hazard Assessment

 

 

 

Procedure

MNR115-2 (0.07 g, 0.17 mmol), MNR103-1 (0.058 g, 0.21 mmol) and PdCl2(dppf) (0.025 g, 0.03 mmol) were added to a microwave tube and added was IPA (2 ml) and potasisium carbonate solution (1M) (0.34 ml, 0.34 mmol).  The mixture was degassed with argon for 5 mniutes then sealed and heated to 90 °C in the microwave reactor (200 W) for 30 minutes. 

 

NMR

 

mnr120-1_1H.pdf
mnr120-1.zip

Conclusion

good 1H NMR, sample can be sent for testing

Strings

Starting material

InChI=1S/C12H18BNO4S/c1-11(2)12(3,4)18-13(17-11)9-6-5-7-10(8-9)19(14,15)16/h5-8H,1-4H3,(H2,14,15,16)

InChI=1S/C17H16BrFN4S/c18-15-9-14-16(24-15)17(21-11-20-14)23-7-5-22(6-8-23)10-12-1-3-13(19)4-2-12/h1-4,9,11H,5-8,10H2

Product

InChI=1S/C23H22FN5O2S2/c24-18-6-4-16(5-7-18)14-28-8-10-29(11-9-28)23-22-20(26-15-27-23)13-21(32-22)17-2-1-3-19(12-17)33(25,30)31/h1-7,12-13,15H,8-11,14H2,(H2,25,30,31)

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Attached Files
4th April 2013 @ 00:34
Mnr: MNR111-120

Attempted bromination of MNR99 at the 7 position rather than the 6 position. 

As for WO2011093684  (A2) ― 2011-08-04 - page 19 step 2

Starting material - Chlorination of MNR89 To Give MNR99-3

As for Bromination of MNR89 at the 7 position - MNR118-1

 

Hazard Assessment

 

 

 

Procedure

MNR99-3 (0.30 g, 1.76 mmol) was dissolved in acetic acid (2 ml) (*2 mL was used to make up volume in the reaction tube).  Bromine (0.27 mL, 5.27 mmol) was added and the reaction was stirred in a sealed tube at 120 °C for 14 hours.  The reaction mixture was cooled to room temperature, no precipitate had formed in the black reaction mixture.  The reaction mixture was transfered to a round bottomed flask ans rinsed with DCM (10 mL).  The mixture was distilled to remove the DCM then under reduced pressure to remove the acetic acid.  Ice was added to the resulting mixture and the solid was filtered off washing with water.


Column

Frac  6-26   - product?  not sure why this was not taken further (14/5/2013)

Frac 27-40

 

NMR

 

 

mnr119-1_frac6-26_1H.pdf
mnr119-1_frac27-40_1H.pdf

 

Strings

Starting material

 InChI=1S/C6H3ClN2S/c7-6-5-4(1-2-10-5)8-3-9-6/h1-3H

Product

InChI=1S/C6H2BrClN2S/c7-3-1-11-5-4(3)9-2-10-6(5)8/h1-2H

 

Attached Files
4th April 2013 @ 00:08
Mnr: MNR111-120

Attempted bromination of MNR89 at the 7 position rather than the 6 position. 

As for WO2011093684  (A2) ― 2011-08-04 - page 19 step 2

Starting material - Synthesis of thienopyrimidine MNR89-2

 

Hazard Assessment

 

 

 

Procedure

MNR89-2 (0.30 g, 1.97 mmol) was dissolved in acetic acid (2 ml) (*2 mL was used to make up volume in the reaction tube).  Bromine (0.3 mL, 5.91 mmol) was added and the reaction was stirred in a sealed tube at 120 °C for 14 hours.  The reaction mixture was cooled to room temperature and a precipitate had formed in the brown reaction mixture.  The reaction mixture was transfered to a round bottomed flask ans rinsed with EtOAc (10 mL).  The mixture was distilled to remove the EtOAc then under reduced pressure to remove the acetic acid. 

** During the distillation, the reaction mixture bumped across the apparatus.  It was decided at this stage to rinse and filter everything.  The glassware was washed with EtOAc and water to give a pale brown solid which was dried under vacuum (0.205 g, 1.35 mmol, 68%) 

NMR

 

mnr118-1_filter_1H.pdf
mnr118-1_filter.zip

 

1H NMR consistent with literature

 

Conclusion

Title product produced in reasonable yield, taken on to the next step to prove substituion at the correct position.

Strings

Starting material

InChI=1S/C6H4N2OS/c9-6-5-4(1-2-10-5)7-3-8-6/h1-3H,(H,7,8,9) 

Product

InChI=1S/C6H3BrN2OS/c7-3-1-11-5-4(3)8-2-9-6(5)10/h1-2H,(H,8,9,10) 

 


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