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18th March 2013 @ 03:42
Mnr: MNR111-120

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

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

** Due to time constraints and a compound submission deadline this reaction was put on using MNR115-1.  NMR did show the desired MNR115 but it also contained a lot of BuLi side prodcuts.  

 

Hazard Assessment

HIRAC MNR103.pdf

Procedure

To a degassed solution of IPA (1 mL) and aqueous potassium carbonate (1 M, 0.29 mL) was added MNR115-1 (0.06 g, 0.15 mmol) and  4-methoxyphenylboronic acid (0.027g, 0.18 mmol) and the reaction mixture further degassed for 5 minutes. Pd(dppf)Cl2 (0.022 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).  

TLC 

showed little if no reaction.

 

Reaction not taken any firther due to the result of Suzuki Coupling of MNR115 to give MNR116-1

Conclusion

Crude reaction not purified due to the failure of MNR115.  The reason for is most likely the purity of the starting material.  These reactions need repeated once the bromination is reapeated under the correct conditions. 

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/C7H9BO3/c1-11-7-4-2-6(3-5-7)8(9)10/h2-5,9-10H,1H3

 

Product

InChI=1S/C24H23FN4OS/c1-30-20-8-4-18(5-9-20)22-14-21-23(31-22)24(27-16-26-21)29-12-10-28(11-13-29)15-17-2-6-19(25)7-3-17/h2-9,14,16H,10-13,15H2,1H3

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18th March 2013 @ 03:24
Mnr: MNR111-120

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

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

** Due to time constraints and a compound submission deadline this reaction was put on using MNR115-1.  NMR did show the desired MNR115 but it also contained a lot of BuLi side prodcuts.  

Hazard Assessment

HIRAC MNR103.pdf

Procedure

To a degassed solution of IPA (1 mL) and aqueous potassium carbonate (1 M, 0.25 mL) was added MNR115-1 (0.05 g, 0.12 mmol) and  phenylboronic acid (0.018g, 0.15 mmol) and the reaction mixture further degassed for 5 minutes. Pd(dppf)Cl2 (0.018 g, 0.02 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).  

TLC 

 showed little reaction and mainly starting material

column - 60-80% EtOAc/Hex

Fracs 36-60  0.015 g - dirty starting material similar to what went into the reaction.

NMR

mnr116-1_frac36-60_1H.pdf
mnr116-1_frac36-60.zip

Conclusion

No product recovered.  The reason for this is most likely the purity of the starting material.  This reaction needs repeated once the bromination is reapeated under the correct conditions

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

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17th March 2013 @ 03:24

From J. Org. Chem. 201176, 3571 - 3575.

Hydrolysis of pinacol boronate ester to the corresponding boronic acid, using diethanolamine and hydrochloric acid. 

To 4-sulfamoylphenyl boronic acid pinacol ester (0.050 g, 0.18 mmol, 1.0 equiv.) in ether (1 mL) was added diethanolamine (0.019 mL, 0.20 mmol, 1.1 equiv.) and the reaction mixture stirred at rt until starting material was consumed. The resultant white precipitate was filtered, washed with ether and dried. 

The precipitate was suspended in ether (1 mL) and an aqueous solution of hydrochloric acid (0.1 M, 2 mL) was added and the reaction mixture stirred at room temperature for 20 minutes. The reaction mixture was extracted into ethyl acetate (3 x 10 mL), the combined organic extracts washed with water (10 mL), dried (MgSO4) and concentrated under reduced pressure to give the boronic acid. 

 

HIRAC

AT-16-1.pdf
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17th March 2013 @ 02:19
Mnr: MNR111-120

Starting material from Nucleophilic Displacement of 4-chlorothienopyrimidine with Piperazine MNR107-1 to give MNR113-1

As for Bromination of MNR100-2 to give MNR101-3

Hazard Assessment

HIRAC MNR101-1.pdf

Procedure

Crude MNR113-1 (0.370 g, 1.13 mmol) was dissolved in THF (23 mL) and cooled to -78 °C.  To the stirring solution was added n-BuLi (2.5 M in hexanes, 4.51 mL, 11.3 mmol) and the stirring was continued for 30 minutes.  Bromine (0.23 mL, 4.51 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 2 hours.

** I've used the wrong excel sheet and added way to much BuLi.  Error only noticed after the bromine was added.

 

Sodium thiosulfate solution (30 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL).  The organic layers were commbined, dried, filtered then concentrated in vacuo to yield the crude as a dark brown oil (0.735 g).  

 

TLC - 100% EtOAC - showed two new spots.  Most likely the the mono and di-bromo units.

SANY0069.JPG


Column

40-100% EtOAc/Hex


Fracs 9-30 - 0.102 g - not the di-bromo compound as expected.  Looks like product but not clean.

Fracs 31-43 - 0.112 g product but contained a lot of BuLi by-products

 

 

NMR

 
 
Conclusion

Traces of prodcut isolatted but very messy due the the wrong ammount of BuLi being used. The fractions containing product were taken onto the next step - Suzuki Coupling of MNR115 to give MNR116-1 and Suzuki Coupling of MNR115 to give MNR117-1 due to the submission deadline for the next round of screening.  The chances of these reactions working are small but worth the shot and it's the only material available.  

The reaction needs repeated using less BuLi as previously found and demonstrated.   

Strings

 Starting material

InChI=1S/C17H17FN4S/c18-14-3-1-13(2-4-14)11-21-6-8-22(9-7-21)17-16-15(5-10-23-16)19-12-20-17/h1-5,10,12H,6-9,11H2

Product

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

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17th March 2013 @ 02:11
Mnr: MNR111-120

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-Methoxyphenylboronic acid (0.036g, 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 

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/C7H9BO3/c1-11-7-4-2-6(3-5-7)8(9)10/h2-5,9-10H,1H3

 

Product

InChI=1S/C17H17N3O2S/c1-21-13-4-2-12(3-5-13)15-10-14-16(23-15)17(19-11-18-14)20-6-8-22-9-7-20/h2-5,10-11H,6-9H2,1H3

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