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22nd July 2013 @ 07:41

 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 @ 07:35

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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18th July 2013 @ 00:41

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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12th July 2013 @ 00:18

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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9th July 2013 @ 23:40

Bromination of MJT 7-2, using same process as MJT 9-1 but with more (2.5) equivalents of n-BuLi to account for deprotonation on the amine hydrogen as well as deprotonation at the N-6 position to improve the yield compared to MJT 9-1. This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

***

Reaction proceeded to give a mixture of the desired product and one other product brominated at the other carbon of the thiene bond. It was discovered that column chromatography is able to separate these products.

The reaction was repeated in an attempt to synthesise just the desired product - see MJT 9-3.


Procedure

11AM 11-07-2013

MJT 7-2 (0.200 g, 1.21 mmol, 1.0 equiv.) was dissolved in THF (25 mL) under an atmosphere of argon and cooled to -78 °C. To the stirring solution was added n-BuLi (2.5 M in hexane, 1.2 mL, 3.0 mmol, 2.5 equiv.) and the stirring was continued for 30 minutes. Bromine (0.12 mL, 2.4 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 shows some SM remains and two new product spots of which one is feint and one is sharp. The reaction mixture was quenched with a saturated sodium thiosulphate solution on ice (70 mL). From this the product was extracted with ethyl acetate (3 x 50 mL). The combined organic extract was washed with brine, dried with MgSO4 and concentrated to a brown sludge (0.200 g, 0.82 mmol, "68%"). NMR analysis of this crude product showed the desired product (major) was formed along with a byproduct (minor) and that some SM remained and that there is grease contaminant in this crude product.

In future the aqueous wash would be basified during extraction to ensure all SM and products are collected and don't remain in aqueous phase as a salt (see MJT 16-1 first vs second extraction NMR). This was completed on a small scale and analysis of the resulting organic layer revealed that the duplicate peaks were not caused by the presence of a salt; rather they were more likely caused by the two possible monobrominated products.

Flash column chromatography (50% ethyl acetate in hexane; 40-60 micron silica particles) was used to isolate a single spot fraction (0.060 g after concentration) which NMR showed  contained a mix of isomers of the monobrominated product. A further fraction containing a mixture of spots (0.030 g) was also isolated but NMR showed that it contained one of the monobrominated species along with a small amount of product dimer. Salt remained on the column and was washed off with 10% methanol in DCM to give 0.020 g of brown sludge which was discarded.

 

 

 

Hazard and Risk Assessment

HIRAC MJT 9-1.pdf

Data


TLC

MJT 9-2 post workup

H NMR

crude produt:

MJT 9-2 crude.pdf

single product spot from column:

MJT 9-2 pure from column.pdf

two spot mix from column:

MJT 9-2 column mix.pdf

after basic workup:

MJT 9-2 after basic workup.pdf

H NMR of SM, MJT 7-2

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