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29th January 2013 @ 00:29

This reaction will be carried out with two reaction vessels, each containing 1.00g of the starting material (AB2-1/JRC13-6) to allow for large-scale synthesis of the desired material. 

 

Experiment start time: 11.30am 29/01/2013

Under argon gas, 4-chlorothieno[3,2-d]pyrimidine (1.000 g, 5.861 mmol, 1 equiv.) was dissolved in dried THF (50 mL) at -78 °C for 10 min before n-butyllithium solution (2.086 M in hexane, 2.809 mL, 5.861 mmol, 1 equiv.) was added dropwise. The solution was dark yellow in colour. After 40 min with occassional stirring at  -78 °C, elemental bromine (0.304 mL, 5.920 mmol, 1.01 equiv.) was added dropwise. The reaction vessels were not the same in colour. Possible contamination from the suba-seal may explain the colour difference as the other reaction vessel was dark with a green tinge. For both mixtures, a distinct colour change occured as the solution turned a dark red. The solution was left to cool to rt. After 1 hr, the solution was quenched with water and extracted with chloroform. The mixture was washed with aqueous Na2S2O3 until it became light orange and the colour no longer faded upon further addition. The organic layer was washed with brine (100 mL) and was dried over MgSO4 before removing CHCl3 in vacuo. The crude product was retrieved and was separated by column.

Two separate columns were done simultaneously due to a large amount of product to be dry-loaded. From one column, the product formed one spot on TLC, whereas the other showed an additional shadow beneath the spot of interest. The products were kept separate and dried in vacuo. Analysis by NMR showed that the reaction had not gone to completion as a large amount of starting material was recovered. 227 mg pure product was retrieved (12.3 %). The low yield is possibly due to the contaminated suba-seal and lack of stirring. 

 

Fraction

Spot

NMR

Weight

 Observation

Column A:

1-3
(5% EtOAc/ hexane)

 

None

-

-

 

4
(5% EtOAc/ hexane)

Supposed product plus top impurity

 -

-

 

5-8

(5% EtOAc/ hexane)

Co-spot (supposed product)

 

 Y - product

 115 mg

White (with orange-yellow tinge) fluffy crystals, finer than column B crystals

9 -22
(5% EtOAc/ hexane)

Co-spot plus starting material

 Y – SM

171 mg

 

22- 30
EtOAc

Starting material

 Y – SM

184 mg

 Dark orange liquid

Column B:

1-6
(5% EtOAc/ hexane)

None

 -

-

-

7 -9
(5% EtOAc/ hexane) 

Top impurity plus cospot

 

 

 

10-17
(5% EtOAc/ hexane)

Supposed product

 Y – product

112 mg

White (with orange-yellow tinge) fluffy crystals

18-40
(5% EtOAc/ hexane, 10%, 100%)

None

 Y – SM

381 mg

 Dark orange

Attached Files
24th January 2013 @ 03:46
Mnr: MNR81-90

Synthesis of thienopyrimidine (MNR89-1) from methyl-3-aminothiophene-2-carboxylate

As for compound 22, Method B

Hazard Assessment

HIRAC MNR89.pdf

Procedure

To methyl-3-aminothiophene-2-carboxylate (9.89 g, 62.9 mmol) and ammonium formate (4.36 g, 69.2 mmol) was added formic acid (2.61 mL, 69.21 mmol) and formamide (13.7 mL, 346 mmol) and the mixture was heated to 140 °C.  After 19 hours, the reaction was cooled to room temperature, filtered and washed with water to give an off white solid that was dried under vacuum (7.5 g).  NMR of this showed desired product with slight traces of impurities.  The crude was recrystalised with EtOH (230 ml) to give fine white crystals.

 

1st crop - 3.075 g, 20.21 mmol, 32 %

2nd crop 3.94 g, 25.89 mmol, 41 %

Total recovered - 7.015 g, 46.1 mmol, 73 %

 

NMR

crude filter

 

mnr89-1_filter_1H.pdf
mnr89-1_filter.zip

1st crop

mnr89-1_1stcrop_1H.pdf
MNR89-1_1stCrop.zip


Strings


Starting Material

InChI=1S/C6H7NO2S/c1-9-6(8)5-4(7)2-3-10-5/h2-3H,7H2,1H3

InChI=1S/CH3NO/c2-1-3/h1H,(H2,2,3)

Product

InChI=1S/C6H4N2OS/c9-6-5-4(1-2-10-5)7-3-8-6/h1-3H,(H,7,8,9)

Linked Posts
Attached Files
23rd January 2013 @ 23:49

Experiment start time: 5.30 pm, 23/01/2013

6-bromothieno[3,2-d]pyrimidin-4-amine (40 mg, 0.17 mmol, 1 equiv.) and 4-sulfamoylphenylboronic acid, pinacol ester (54 mg, 0.19 mmol, 1.1 equiv.) were combined with potassium acetate (68 mg, 0.7 mmol, 4 equiv.) and dissolved in 20% 1,4-dioxane/H2O (2.5 mL). The mixture was degassed (under argon gas) and PdCl2 (dppf) (13 mg, 10 mol % was added). The resultant solution was heated at reflux (101 °C).

After 15 hours, a TLC was taken of the reaction mixture, using an ethyl acetate work up. 100% ethyl acetate was used as the eluent. The plate showed that some conversion had occured but the reaction was not complete. A further 10 mg of PdCl2 was added and the reaction was left to continue at reflux with stirring. After 6 hrs, another TLC was taken. Again, the reaction had not gone to completion and was left to continue heating at reflux with stirring overnight. After a further 21 hours, the reaction was left to cool to rt. The product was extracted with EtOAc (100 mL), water (2 x 50 mL) and brine (50 mL). It was noted that the aqueous layers contained brown impurities which sunk to the bottom of the layer. The resultant organic layer was dried with MgSO4 and concentrated in vacuo to yield 16.9 mg of crude product. It is suspected that more of the product has been left in the separating funnel due to its orange tinge. Sodium hydrogen carbonate was added to the collected aqueous layers and DCM was added to dissolve the component stuck to the sides. No layers were extracted. The product was analysed by NMR, which showed there was some aromatic species, but the spectrum did not correspond to the desired product. 

Attached Files
23rd January 2013 @ 07:05
Mnr: MNR81-90

Repeat of conditions and substrates used in JRC50-2 to form the 4-substituted product - MNR86-1

 

Hazard Assessment

HIRAC MNR86.pdf

Procedure

JRC40-2 (0.040 g, 0.17 mmol), 4-sulfamoylphenylboronic acid, pinacol ester (0.054 g, 0.19 mmol), potassium acetate (0.068 g, 0.70 mmol) and PdCl2(dppf) (0.013 g, 0.02 mmol) were dissolved in degassed 20% 1,4-dioxane/H2O (2 mL) (degassed by passing N2 through the solution for about 15 mniutes).  The resulting mixture was heated at reflux for 24 hours at which time TLC still showed starting JRC40-2.  4-sulfamoylphenylboronic acid, pinacol ester (0.054 g, 0.19 mmol) and PdCl2(dppf) (0.013 g, 0.02 mmol) was added to the reaction and refluxing was contiuned overnight.  In the morning the reaction had run dry, ground joint on the condenser wasn't tight.  The reaction was allowed to cool to room temperature, water (2mL) was added and extracted with EtOAc (5 ml x 3), the organics were combined and washed with brine (5 mL) then dried over anhydrous MgSO4, filtered and concentrated to give the crude (0.126 g) as ayellow/red solid.  Recrystallisation was attempted in 50% EtOH/H20 (2.5 mL) as per JRC50-2

TLC

After 15 hours the first TLC was taken.  Cataylst, boronic acid and JRC40-2 were all co-spotted with the reaction mixure (which was given a mini workup with water and EtOAc).  TLC ran in 100% EtOAc and showed both starting materials were still in the reaction mixture and a new lower running spot.

SANY0056.JPG

The reaction was left to stir at reflux.  TLC after 24 hours very similar to this one at 15 hours.

Attached Files
18th January 2013 @ 03:06

AB6-1

Experiment start time: 3.05 pm

Phenylboronic acid (500 mg, 4.1 mmol, 1 eq) and pinacol (484 mg, 4.1 mmol, 1 eq) were dissolved in anhydrous diethyl ether (~10 mL). Under nitrogen gas, the solution was left to stir at room temperature (on a hot day however) for 1hr before being concentrated under reduced pressure on rotavapor. The retrieved product was a viscous solution with small white crystals apparent. An NMR spectrum for the crude product was obtained. 2.5% ethanol in hexane (2.5 mL) was added to the mixture which was then heated and placed in an ice bath to allow recrystallisation of the desired product. Significant recrystallisation was not observed. The sample was placed in the refrigerator and after 14 hours many crystals were observed. The sample has been left to continue being cooled in the refrigerator (~320 mg). After refrigeration for 3 days, the light yellow oil was still present. TLC on silica with hexane showed a spot (impurity) as well as the product. This impurity was removed by flushing the crude mixture through silica with hexane to yield 122.693 mg of the title product as a fine white crystal. 

Attached Files