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22nd July 2013 @ 06:41

 Coupling of MJT 16-1 with ortho-sulfonamide boronic acid ester, MNR 103-1. Following methods used by Althea: 90oC for 30 minutes in a microwave reactor (200 W). This is the final stage of the synthesis of one of the aminothienopyrimidine analogues decided upon in the May 2013 Open Consultation.

***

MJT 18-1 was synthesised in 56 % yield.

This is a novel compound; data to be collected: IR, Mpt, LRMS, HRMS

Procedure

 A solution of MJT 16-1 (29.5 mg, 0.0976 mmol, 1 equiv.), MNR 103-1 (34.0 mg,  0.119 mmol, 1.2 equiv.) and PdCl2dppf (27.0 mg, 0.0199 mmol, 0.20 equiv.) in isopropanol (2.0 mL) and K2CO3 (1 M,  0.20 mL, 0.20 mmol, 2.0 equiv.) was degassed with argon for 10 minutes. The reaction mixture was heated at 90oC for 30 minutes in a microwave reactor (200 W). It is now a black solution.

The reaction mixture was diluted with MeOH (50 mL) and filtered through celite. The resulting solution was concentrated to a black solid (0.090 g, >100 %). TLC showed no SM remained and several new products had formed.

Column chromatography (2.5 % MeOH, 0.5 % NH3, 97 % DCM) was used to purify the product and gave one pure fraction as a brown solid (0.021 g, 0.055 mmol, 56 %).

Hazard and Risk Assessment


HIRAC MJT 18-1.pdf

Data

TLC

TLC MJT 18-1 crude

Characterisation Data

1H NMR

MJT 18-1 proton.pdf
MJT 18-1 H NMR raw data

13C NMR

MJT 18-1 carbon.pdf
MJT 18-1 C NMR raw data
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22nd July 2013 @ 06:35

Coupling of Synthesis of 6-bromo-N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (MJT 10-1) with ortho-sulfonamide boronic acid ester, MNR 103-1. Following methods used by Althea: 90oC for 30 minutes in a microwave reactor (200 W). This is the final stage of the synthesis of one of the aminothienopyrimidine analogues discussed in the May 2013 Open Consultation (see 1b).

***

MJT 17-1 was synthesised in 47 % yield.

This is a novel compound, data to be collected: Carbon NMR in DMSO, IR, LRMS, HRMS

Procedure

 A solution of MJT 10-1 (29.5 mg, 0.114 mmol, 1 equiv.), MNR 103-1 (43.0 mg,  0.152 mmol, 1.3 equiv.) and PdCl2dppf (17.0 mg, 0.0232 mmol, 0.20 equiv.) in isopropanol (2.3 mL) and K2CO3 (1 M,  0.23 mL, 0.23 mmol, 2.0 equiv.) was degassed with argon for 10 minutes (see photo MJT17-1A). The reaction mixture was heated at 90oC for 30 minutes in a microwave reactor (200 W). It is now a black solution (see photo MJT17-1B)

The reaction mixture was diluted with MeOH (50 mL) and filtered through celite. The resulting solution was concentrated to a brown solid (0.116 g, 0.347 mmol, >100 %). TLC showed no SM remained and several new products had formed. NMR of this crude product was taken though it was incorrectly calibrated to CDCl3 solvent, and so the peaks occur at the wrong chemical shift values. Correct aromatic peak pattern can be interpreted inferring correct product was made.

Column chromatography (4.5 % MeOH, 0.5 % NH3, 95 % DCM) was used to purify the product and gave one mixed fraction as a brown solid (0.0346 g, 0.10 mmol, 91 %) and one pure fraction as a brown solid (0.005 g, 0.01 mmol, 13 %). It was decided to purify by column again in an attempt to obtain the pure product.

Column chromatography (2.5 % MeOH, 0.5 % NH3, 97 % DCM) was used to purify the combined pure and mixed fractions from the previous column and gave one fraction as a brown solid (0.018 mg, 0.054 mmol, 47 %)

 

Hazard and Risk Assessment

HIRAC MJT 17-1.pdf

Data

TLC

TLC MJT 17-1.JPG

NMR

Crude

MJT_17-1_crude.pdf

Comparable to AT 11-4 NMR - the signals in aromatic region match up


Photos


MJT17-1A

IMG_2161.JPG
 

MJT 17-1B

 

MJT 17-1 post reaction.JPG

Characterisation Data

1H NMR

MJT17-1 pure.pdf
MJT 17-1 raw data H NMR

Mpt. decomposition to black solid at 245-250 ˚C

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17th July 2013 @ 23:41

Bromination of MJT 7-2, using same process as MJT 9-2 but with fewer (2.0) equivalents of n-BuLi. This reduced number of equivalents of n-BuLi was used to attempt deprotonation more selectively at the N-6 position (cf MJT 9-2 which used 2.5 eq and yielded a mixture of 2 regioisomeric products that were brominated at N-6 and N-7). This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

***

A mixture (27 % yield; 54 % considering amount SM recovered) of the desired product and the product brominated at the other carbon of the thiene bond was isolated but these two compounds were not separated. 50 % of SM was recovered.


Procedure

MJT 7-2 (0.148 g, 0.900 mmol, 1.0 equiv.) was dissolved in THF (18 mL) under an atmosphere of argon and cooled to -78 °C over 10 minutes. To the stirring solution was added n-BuLi (2.5 M in hexane, 0.72 mL, 1.8 mmol, 2.0 equiv.) and the stirring was continued for 30 minutes. Bromine (0.10 mL, 1.8 mmol, 2.0 equiv.) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 3.5 hours, it is now an orange solution. TLC  at 1h shows some SM remains and some new product spots. TLC at 3.25 hours again shows SM remains and new product spots. The reaction mixture was quenched after 3.5 hours stirring with a saturated sodium thiosulphate solution (50 mL). From this, product was extracted with ethyl acetate (3 x 25 mL). The combined organic extract was washed with brine (25 mL), dried with MgSO4and concentrated to a brown oil (0.170 g, 0.70 mmol, "78%"). NMR analysis of this crude product showed that it contained SM as well as both monobrominated product isomers.

TLC shows that the aqueous washings contain SM and no product; TLC of aqueous extract basified to pH 12 shows it contains SM and a spot on the baseline.

Column chromatography (50 %, 80 % EtOAc in hexane; 40 - 60 micron silica particles) was conducted to give mixed monobrominated products (0.067 g, 0.27 mmol, 27 %) and recovered SM (0.075 g, 0.45 mmol, 50 % recovery).

Hazard and Risk Assessment

HIRAC MJT 9-2.pdf

Data

TLC


TLC after 1 h and after 3.25 h

TLC 1h and 3.25 h.JPG

TLC of organic extract and aqueous layer

TLC of organic extract and aqueous layer.JPG

NMR

crude product:


MJT 9-3 crude.pdf


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11th July 2013 @ 23:29

Repeat of See Bromination of MNR113-1 to give MNR115-2

Procedure:

Crude AEW 53-1 (740 mg, 1.13 mmol, 1 equiv.) was dissolved in THF (46 mL) and cooled to -78 °C.  To the stirring solution was added n-BuLi (2.5 M in hexanes, 1.35 mL, 3.38 mmol, 1.5 equiv.) and the stirring was continued for 30 minutes.  Bromine (0.23 mL, 4.51 mmol, 2 equiv.) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 2 hours. (Stirred for 6 hours in total as seminars and meetings happened). Quenched with a saturated aqueous soln. of sodium thiosulfate and extracted into EtOAc, washed with brine, dried (MgSO4), filtered and evaporated to give an orange solid. Aqueous basified and extraction procedure repeated to give an orange oil. Proton NMR ran on both fractions - quite messy but looks product like. 

Flash column chromatography over silica (40% EtOAc in Hexane to 100% EtOAc) gives single spot of orange oil. [N.B. Columned too slow, product came out in neat EtOAc]. Contains product plus impurity. Requires further purification for characterisation.


Crude 1H NMR:

AEW 70-1-A.zip
AEW 70-1-B.zip


TLC Crude (100% EtOAc):

AEW 70-1 100% EtOAc.jpg

 

1H NMR first column:

AEW 70-1 first column.pdf
 
AEW 70-1 column.zip


Hazard and Risk Assessment:

See Bromination of MNR113-1 to give MNR115-2

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11th July 2013 @ 23:18

Bromination of MJT 14-1. This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

***

Reaction proceeded to give product in 45 % yield, some of which was taken forward in suzuki coupling with MNR 103-1 to give MJT 18-1, a target compound.

This is a novel compound; data to be collected:IR, LRMS, HRMS


Procedure

 MJT 14-1 (0.360 g, 1.61 mmol, 1.0 equiv.) was dissolved in THF (32 mL) under an atmosphere of argon and cooled to -78 °C over ten minutes. To the stirring solution was added n-BuLi (2.5 M in hexane, 1.0 mL, 2.4 mmol, 1.5 equiv.) and the stirring was continued for 30 minutes to give a yellow solution. Bromine (0.2 mL, 3.2 mmol, 2.0 equiv.) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 2 hours, it is now an orange solution. TLC shows some SM remains and several new products have formed. To the reaction saturated sodium thiosulfate solution on ice (75 mL) was added and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with brine and dried over MgSO4. After concentration crude product was obtained as a brown sludge (0.113 g, 0.37 mmol, 23%). NMR analysis indicated that this extraction isolated a dimer of the desired product and was contaminated with grease.

A TLC of the aqueous wash showed it still contained SM and / or products; it had a pH of 4 and so it was basified with sodium hydrogen carbonate to pH 10 before a further extraction using ethyl acetate (3 x 40 mL), brine wash and drying over MgSOto give crude product / SM (0.29 g, 0.96 mmol, 60 %; total yield now 83 %) as a yellow oil. TLC showed aqueous washings no longer contained SM or product. NMR analysis of this second crude extract shows that it consists mainly of the desired product, with a small amount of SM. This second extraction was purified by column chromatography (10% MeOH in DCM, 40-60 micron silica particles) to give three fractions. In order of elution these were: one fraction as a white solid (0.020 g) shown to be byproduct by NMR, one with a single spot by TLC as a white solid (0.088 g, 0.29 mmol, 18 %) which NMR showed was pure and one with two spots by TLC as a light brown solid (0.129 g, 4.27 mmol, 27 %), again fairly clean by NMR. Both of the later fractions will be taken forward in suzuki couplings.

Hazard and Risk Assessment

HIRAC MJT 16-1.pdf

Data


TLC

 TLC after workup

TLC after workup.JPG

Stained TLC after workup

stained tlc after workup.JPG

H NMR

Of first extraction: dimer of desired product

MJT 16-1 crude first extraction pdf

Of second (basified) extraction: desired product

MJT 16-1 crude second extraction pdf

From column:

byproduct

MJT 16-1 column frac 40- 60.pdf

single product spot fraction

MJT 16-1 column single spot.pdf

mix product fraction

MJT 16-1 mix spot fraction.pdf

H NMR of SM, MJT 14-1

Characterisation Data

1H NMR


MJT 16-1 proton.pdf
MJT 16-1 H NMR raw data

13C NMR


MJT 16-1 carbon.pdf
MJT 16-1 C NMR raw data

Mpt. 49-50 ˚C

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