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9th January 2013 @ 06:58
Mnr: MNR61-70
Scaled up synthesis of (Z)-2-((3-hydroxyphenyl)imino)thiazolidin-4-one (MNR70-2) from MNR69-1.

Prep from ZYH14-1
As for MNR70-1

MNR70_scheme.png
MNR70-2_table.PNG

Hazard Assessment
HIRAC MNR70.pdf


Procedure

Reaction on at 1800, 09/01/13

To a mixture of MNR69-1 (3.10 g, 18.4 mmol) and sodium acetate trihydrate (2.51 g, 18.43 mmol) in ethanol (20 mL) was added ethyl bromoacetate (2.0 ml, 18.4 mmol) dropwise and the mixture was heated to 60 °C for 16 hours.

The reaction was allowed to cool to room temperature then ice was added. Nothing significant precipitated out, only what looked like an oily side product. The Reaction mixture was then extracted with EtOAC (25 ml x 2). The organic fractions were combined, dried over MgSO4, filtered and concentrated to give a dark orange oil ( g).

TLC

NMR

Conclusion

Strings
Starting materials
InChI=1S/C7H8N2OS/c8-7(11)9-5-2-1-3-6(10)4-5/h1-4,10H,(H3,8,9,11)

Product
InChI=1S/C9H8N2O2S/c12-7-3-1-2-6(4-7)10-9-11-8(13)5-14-9/h1-4,12H,5H2,(H,10,11,13)
Attached Files
4th January 2013 @ 00:53
Mnr: MNR61-70
Synthesis of (Z)-2-((3-hydroxyphenyl)imino)thiazolidin-4-one (MNR70-1) from MNR69-1.

Prep from ZYH14-1

MNR70_scheme.png
MNR70-1_table.PNG

Hazard Assessment
HIRAC MNR70.pdf


Procedure

Reaction on at 1720, 06/01/13

To a mixture of MNR69-1 ( 0.15 g, 0.89 mmol) and sodium acetate trihydrate (0.121 g, 0.89 mmol) in ethanol (2 mL) was added ethyl bromoacetate (0.1 mL, 0.89 mmol) dropwise and the mixture was heated to 60 °C for 16 hours. The reaction was allowed to cool to room temperature then ice was added. Nothing significant precipitated out, only what looked like an oily side product. The Reaction mixture was then extracted with EtOAC (25 ml x 2). The organic fractions were combined, dried over MgSO4, filtered and concentrated to give a dark orange oil (0.305 g).

The crude was purified by FCC using 50-100% EtOAc/HEx. Major spot (bottom spot) collected between fractions 19 and 40.

Fracs 19-40 0.124 g as a brown film stuck to the walls of the flask.


TLC
Reaction mixture after 16 hours, ran in 75% EtOAc/Hex. TLC inconclusive.
TLC Direct from RXN

After workup, ran in 75% EtOAc/Hex. Complete consumption of starting materail.
TLC after WU

NMR
mnr70-1_frac19-40_1H.pdf
mnr70-1_frac19-40_13C.pdf
mnr70-1_frac19-40.zip


The original NMR's look like a mess and not very promising at all. However on standing the NMR sample, in MeOD, slowly crystallised to give white crystals. The remaining crude was taken up in methanol in an attempt to obtain more crystals but no crystals formed after standing overnight. The mixture was then concentrated and taken up in EtOAc, after standing for 24 hours crystals had formed, these were washed with Et2O and dried to give pale brown crystals (0.075 g, 0.35 mmol, 40%)

NMR of Crystals
mnr70-1_crystals.zip
mnr70-1_crystals_13C.pdf
mnr70-1_crystals_1H.pdf


Conclusion
Product was probably lost on the column and during work up. On repeating this reaction attempts should be made to purify by crystallisation.

Strings
Starting materials
InChI=1S/C7H8N2OS/c8-7(11)9-5-2-1-3-6(10)4-5/h1-4,10H,(H3,8,9,11)

Product
InChI=1S/C9H8N2O2S/c12-7-3-1-2-6(4-7)10-9-11-8(13)5-14-9/h1-4,12H,5H2,(H,10,11,13)
Attached Files
3rd January 2013 @ 05:55
Mnr: MNR61-70
Synthesis of 1-(3-hydroxyphenyl)thiourea (MNR69-1) from MNR68-1.

Ref
From Step 4 page 63 of -WO2011119894 (A2) ― 2011-09-29

MNR69_scheme.png
MNR69-1_table.PNG

Hazard Assessment
HIRAC MNR69.pdf


Procedure
To a stirred solution of MNR68-1 (3.8 g, 25.1 mmol) in MeOH (50 mL) was added ammonium hydroxide solution (28%) (35 mL, 251 mmol) dropwise at 5 C. After addition the reaction was allowed to warm to room temperature and was left to stir overnight (although prep said only 2 hours, reaction had to be left due to time constraints). TLC in the morning showed complete consumption of starting material. The reaction mixture was concentrated to remove the MeOH, water was added and the mixture was extracted with EtOAc (30 mL x 3). The organic fractions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give a dark yellow solid (3.318 g, 19.7 mmol, 78%)

TLC
Reaction mixture after 16 hours, ran in 50% EtOAc/Hex
SANY0032.JPG

NMR
Sample not soluble in CDCl3
mnr69-1_crude_1H.pdf
mnr69-1_crude_13C.pdf
mnr69-1_crude.zip

Conclusion
Crude clean by NMR and taken on to the next step without future purification.

Strings
Starting materials
InChI=1S/C7H5NOS/c9-7-3-1-2-6(4-7)8-5-10/h1-4,9H

Product
InChI=1S/C7H8N2OS/c8-7(11)9-5-2-1-3-6(10)4-5/h1-4,10H,(H3,8,9,11)
Attached Files
3rd January 2013 @ 00:09
Mnr: MNR61-70
Synthesis of 3-isothiocyanatophenol (MNR68-1) from 3-aminophenol.

Ref
From Step 3 page 62 of -WO2011119894 (A2) ― 2011-09-29

MNR68_scheme.png
MNR68-1_table.PNG

Hazard Assessment
HIRAC MNR68-1.pdf


Procedure
To a stirring suspension of 3-aminophenol (5.0 g, 45.8 mmol) in DCM (25 mL) cool in a ice/water bath was added thiophosgene (5.27 mL, 68.7 mmol) and the mixture was allowed to stir at room temperature for 2 hours at which time TLC only showed faint traces of the starting material. The reaction was diluted with DCM (25 mL) and slowly quenched with NaHCO3 solution and the organic phase separated. At this stage approximately 50% of the organic phase was split due to pressure build up in the separating funnel, in future the reaction should be left to quench longer in a large flask. The Orangic layer was then washed with brine, dried over MgSO4, filtered and concentrated to give a brown oil (3.9 g, 25.8 mmol, 56%)

TLC
TLC of reaction mixture after 2 hours ran in 25% EtOAc/Hex
SANY0031.JPG


NMR
NMR showed product with slight traces of impurites
mnr68-1_crude_1H.pdf
mnr68-1_crude_13C.pdf
mnr68-1_crude.zip


Conclusion
Crude product taken onto the next step without further purification.

Strings
Starting materials
InChI=1S/C6H7NO/c7-5-2-1-3-6(8)4-5/h1-4,8H,7H2
InChI=1S/CCl2S/c2-1(3)4

Product
InChI=1S/C7H5NOS/c9-7-3-1-2-6(4-7)8-5-10/h1-4,9H
Attached Files