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12th June 2014 @ 11:35

 

Amination of bromochlorothienopyrimidine (AT-6-4) was repeated on 100 mg of substrate in 2ml of IPA and 4ml of ammonia at 120°C in a sealed tube for 3 hours. The solvents were removed in vacuo and the resulting orange solid was sufficiently pure to use as-is (B1, 102 mg, quantitative yield with 1eq ammonium chloride)

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12th June 2014 @ 11:33

 

  Synthesis of 3-bromo-4-methyl-benzenesulfonamide (PT-17) was set up as before. Bromine was added all at once and the reaction allowed to exotherm. After 22 hours the reaction was worked up as before but contained significant starting material. To be repeated with slow addition.

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9th June 2014 @ 16:28


3-bromo-4-methylbenzenesulfonamide (1.12g, 4.488 mmol)[1], bis(pinacolato)diboron (1.710 g, 6.735 mmol), potassium acetate (1.762 g, 17.96 mmol) was dissolved in 1,4-dioxan (22.5 mL) and degassed with argon for ten minutes. Pd(dppf)2.CH2Cl2 (184 mg, 0.226 mmol) was added and the reaction heated to reflux under argon for 22 hours. The reaction was cooled to room temperature, diluted with methanol (40 mL) and dichloromethane (40 mL). Sonication was used to disperse solids and the resulting mixture was filtered through celite and evaporated under reduced pressure to give a black solid B1 (4.01 g), NMR and TLC indicated consumption of starting material and the appearance of a single new product.[1]

 

NMR and mass spec indicated that this was not the desired product. Starting material to be re-purified or re-synthesised in a purer form.

 

Literature NMR (CDCl3): http://www.sciencedirect.com/science/article/pii/S0960894X10014587

 

Literature M/S (ESI): http://worldwide.espacenet.com/publicationDetails/biblio?CC=US&NR=2006199817&KC=&FT=E&locale=en_EP (page 53)

  

  

Notes:

[1] Material contaminated with an unknown (but substantial) quantity of an insoluble impurity thought to be elemental sulfur. Trying this as a test reaction due to material availability.

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9th June 2014 @ 13:31

 

Synthesis of 6-Bromo-4-chlorothieno[3,2-d]pyrimidine (AEW 99-1) was repeated at 0.4x scale.

 

To the commercial starting material (0.84 g, 4.92 mmol, 1.0 equiv.) in THF (50 mL) at -78 C was added n-BuLi (4.6 mL, 7.4 mmol, 1.5 equiv.) dropwise and the reaction mixture stirred at -78 C for 30 minutes. Bromine (0.5 mL, 9.84 mmol, 2.0 equiv.) was added dropwise and the reaction mixture warmed to rt and stirred for 1 h. The reaction mixture was diluted with an aqueous solution of sodium thiosulfate (60 mL) and extracted into ethyl acetate (3 x 40 mL). The combined organic extracts were dried (MgSO4), concentrated under reduced pressure to give an orange solid (1.86 g) which contained the desired product with ca. 20% starting material by NMR. This was purified by dry column vacuum chromatography (10% ethyl acetate in heptane) to give a tan solid C1 (797 mg, 3.19 mmol, 64.8%) in acceptable purity by NMR.

 

NMR: 

PT-19-C1.pdf
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8th April 2014 @ 17:47


Synthesis of Boronic Acid Pinacol Ester - MNR103-1 was repeated at a scale of 0.7067. 3-bromobenzenesulfonamide (1.06 g, 4.488 mmol), bis(pinacolato)diboron (1.710 g, 6.735 mmol), potassium acetate (1.762 g, 17.96 mmol) was dissolved in 1,4-dioxan (22.5 mL) and degassed with argon for ten minutes. Pd(dppf)2.CH2Cl2 [1] (184 mg, 0.226 mmol) was added and the reaction heated to reflux under argon for 22 hours, then cooled and filtered through a plug of celite, followed by washings with methanol (20 ml) and dichloromethane (20 ml). The combined organic layers were concentrated in vacuo and purified using dry column vacuum chromatography (1-10% methanol in dichloromethane, 10 fractions) to give three products:

C1, a tan solid (380 mg)

NMR indicated only one set of aromatic peaks consistent with the desired product and some excess pinacol. This was triturated overnight in hexanes (25 mL) and filtered to give a pale cream solid D1(171 mg). NMR indicated that all residual pinacol had been removed. 

PT-1-18-D1.pdf

C2, a dark oily solid (1.773 g)

NMR indicated only one set of aromatic peaks consistent with the desired product and a large amount of excess pinacol. This was recrystallised from ethanol/water (1:1) to give grey crystals D2 (305 mg). NMR indicated that all residual pinacol had been removed. 

PT-1-18-D2.pdf

C3, a tan solid (49 mg)

NMR indicated only one set of aromatic peaks consistent with the desired product and a small amount of excess pinacol.

 



InChi String:

InChI=1S/C6H6BrNO2S/c7-5-2-1-3-6(4-5)11(8,9)10/h1-4H,(H2,8,9,10)

and

InChI=1S/C12H24B2O4/c1-9(2)10(3,4)16-13(15-9)14-17-11(5,6)12(7,8)18-14/h1-8H3

gives

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)

 

Notes:

1) used instead of Pd(dppf)2Cl2 due to availability of dichloromethane complex;

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