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3rd July 2014 @ 09:38

 

 

Conditions from Synthesis of 3-(7-aminothiazolo[4,5-d]pyrimidin-2-yl)-4-methyl-benzenesulfonamide (PT-22) were used on a 2x scale, to synthesise OSM-S-106.

 

PT-21-B1 (56.7 mg, 0.2 mmol) was dissolved in isopropyl alcohol (4 mL) and to this was added PT-18-D1 (68 mg, 0.24 mmol, 1.2 eq) followed by potassium carbonate solution (1M, 0.4 mL, 2 equivalents). The solution was degassed with nitrogen for 5 minutes and Pd(dppf)2.CH2Cl2 (32 mg, 40 umol, 20 mol%) was added. The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel, then evaporated to dryness. NMR (B1) indicated peaks consistent with a single major product, the title compound, plus misc. impurities (Reference spectrum):

PT-23-B1 1H NMR detail.png

The crude mixture was purified by dry flash column chromatography (gradient: 100% chloroform to 80% chloroform, 18% methanol, 2% sat. aq. ammonia) to give the title compound in two batches: 

C1, pale tan solid, 32.3 mg, 0.105 mmol, 52.8%

C2, tan solid, 23.1 mg, 0.075 mmol, 37.7%

Combined yield: 90.5%


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2nd July 2014 @ 18:11

 

 

The procedure was used from Synthesis of 3-(4-(2-(dimethylamino)ethoxy)thieno[3,2-d]pyrimidin-6-yl)benzenesulfonamide (MJT 18-1).

 

PT-21-B1 (28.3 mg, 0.1 mmol) was dissolved in isopropyl alcohol (2 mL) and to this was added PT-20-3-C1 (47 mg, 0.12 mmol, 1.2 eq) followed by potassium carbonate solution (1M, 0.2 mL, 2 equivalents). The solution was degassed with nitrogen for 5 minutes and Pd(dppf)2.CH2Cl2 (16 mg, 20 umol, 20 mol%) was added. The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel, then dry-loaded onto silica and purified using dry column vacuum chromatography (0-10% methanol in chloroform, 20 fractions, then 1% sat. aq. ammonia, 9% methanol, 90% chloroform for 5 tubes) to give the title compound as the most beautiful tan solid I've ever seen (16.8 mg, 52 umol, 52%), which was only sparingly soluble in chloroform. 



NMR:

Consistent with desired product. (Note: earlier data was taken when spectrometer was accidentally set to +45°C by a previous user, and is present in the tarball)

1H 13C interpreted.pdf


Mass Spectroscopy (Nominal):

Consistent. [M+H] and [2M+H] visible.

PT-22-C1 ESI Nominal.jpg


Mass Spectroscopy (Accurate):

Main peak consistent to within 2ppm: Observed: 321.0474 Calculated: 321.04801

13C peak consistent to within 4ppm: Observed: 322.0499 Calculated: 322.05137

13C * 2 peak consistent to within 3ppm: Observed: 323.0447 Calculated: 323.04381

PT-22-C1 ESI Accurate.jpg
IMG_20140707_115156.jpg


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1st July 2014 @ 16:01


The previous reaction Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-methylbenzenesulfonamide (PT-1-20-2) was repeated on a 1/3 scale with the purified product from Resynthesis of 3-bromo-4-methyl-benzenesulfonamide (PT-17-3).

3-bromo-4-methylbenzenesulfonamide (93 mg, 0.372 mmol), bis(pinacolato)diboron (142 mg, 0.559 mmol, 1.5 eq), potassium acetate (147 mg, 1.5 mmol, 4eq) was dissolved in 1,4-dioxan (2 mL) and degassed with argon for ten minutes. Pd(dppf)2.CH2Cl2 (15 mg, 17 umol, 5 mol%) was added and the reaction heated to 100°C in a sealed tube for 16 hours. TLC and NMR indicated one major product consistent with reported literature for the title compound. The reaction was diluted with methanol/dichloromethane (20 mL, 1:1), filtered through celite, and evaporated directly onto silica, then purified by dry column vacuum chromatography (0-50% ethyl acetate in heptane, 10 fractions)[1] to give the title compound as a waxy white solid (93 mg, 76% pure, MW 297, 0.238 mmol, 64%). 1H NMR consistent with literature. Taken on as-is due to time constraints.



 

 Notes:

[1] The product co-elutes closely with starting material and the last few fractions that eluted were discarded.

 

NMR:

PT-20-3-C1 1H NMR CDCL3.pdf

Compound integrated 12.5:10 for boronate to pinacol, corresponding to a molar purity of 55% and a mass purity of 76%

 

Literature: 

http://www.sciencedirect.com/science/article/pii/S0960894X10014587

 

 

InChI:

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19th June 2014 @ 11:25

 

Synthesis of 3-bromo-4-methyl-benzenesulfonamide (PT-17) was repeated on a 0.5x scale (2g sulfonamide (11.7 mmol), 0.4g iron, 6mL bromine). Bromine was added dropwise with cooling in an ice-water bath, and the reaction stirred at room temperature for 16 hours. NMR indicated the reaction was not complete, so stirring was continued at room temperature for a further 48 hours. NMR indicated a trace of starting material but otherwise a very clean conversion so stirring was continued for a further 48 hours until no starting material was observed by NMR. The reaction mixture was purged of excess bromine under a stream of nitrogen, and then diluted with dichloromethane (200 mL) and washed with sodium thiosulfate (2M, 2 x 150 mL), saturated sodium carbonate solution, and brine. The organic layers were combined and treated with activated carbon and magnesium sulfate, and filtered through celite to yield a white solid B1 (ca. 560 mg, 19% [1]). The product was purified by dry column vacuum chromatography (ethyl acetate in heptane gradient: 0-25% in 4 fractions, 25% for 2 fractions, 25-50% in 10 fractions) to give the title compound as a white solid C1 (456 mg, 15%)[2,3]

 

NMR:

PT-17-3-C1 1H NMR DMSO.pdf
PT-17-3-C1 1H NMR CDCL3.pdf

Consistent with literature values (below)


Literature:

US2006199817 (page 53)


 InChI:

Reactant: InChI=1S/C7H9NO2S/c1-6-2-4-7(5-3-6)11(8,9)10/h2-5H,1H3,(H2,8,9,10)

Product: InChI=1S/C7H8BrNO2S/c1-5-2-3-6(4-7(5)8)12(9,10)11/h2-4H,1H3,(H2,9,10,11)

 

 

Notes:

[1] Low yield is due to losses in workup. Previous attempts to minimises these losses have also lead to impurity problems.

[2] I strongly suspect the sulfur problem has been solved, as this is the first batch that has passed the (highly scientific) "sniff test".

[3] The lower than expected mass recovery from the chromatography could, again, be due to the removal of elemental sulfur or other non-organic but organic-soluble impurities.

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16th June 2014 @ 15:54


The previous reaction Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-methylbenzenesulfonamide (PT-1-20) was repeated on 0.25x scale with the semi-purified (but hopefully sulfur-free product from Resynthesis of 3-bromo-4-methyl-benzenesulfonamide (PT-17-2).

3-bromo-4-methylbenzenesulfonamide (280 mg), bis(pinacolato)diboron (427 mg), potassium acetate (440 mg) was dissolved in 1,4-dioxan (6 mL) and degassed with argon for ten minutes. Pd(dppf)2.CH2Cl2 (46 mg) was added and the reaction heated to 100°C in a sealed tube for 16 hours. The reaction mixture was diluted with methanol (20 mL) and dichloromethane (20 mL) and treated with activated carbon then filtered through celite and evaporated to give a dark solid. NMR indicated the same material as previous, with signals corresponding to pinacol but no arylboronate. Could be the dimer?

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