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31st January 2013 @ 16:37

 

 

 

Crude product Resynthesis of MD 6-3 (PT-1-4) (31 mg, 62% purity, 54 umol) was dissolved in neat thionyl chloride (3 ml) and stirred overnight at 60°C under a dry nitrogen atmosphere, when TLC (10% MeOH/CHCl3) indicated consumption of starting material. The thionyl chloride was removed in vacuo and replaced by a pyridine solution of H-Sar-OMe•HCl (5eq in 3 ml, 34 mg). The reaction was stirred at room temperature for a further 3 hours, then diluted with EtOAc (20 mL) and washed with 20 ml portions of 2M HCl, sat. Na2CO3 * 2, more HCl, and brine. The organic phase was dried over MgSO4 and evaporated to give a beige solid (PT-1-7A, 14 mg).

 Risks as in Chlorination of PT-1-4A (PT-1-6)

NMR analysis: PT-1-7a was found to consist of silicone grease. Conclusion: All reaction products were water soluble - time-course and mass spectroscopy studies are required.

30th January 2013 @ 15:01

 

Crude product Resynthesis of MD 6-3 (PT-1-4) (31 mg, 62% purity, 54 umol) was dissolved in neat thionyl chloride (3 ml) and stirred overnight at room temperature under a dry nitrogen atmosphere. The thionyl chloride was removed in vacuo and replaced by a pyridine solution of H-Sar-OMe•HCl (5eq in 3 ml, 34 mg). The reaction was stirred at room temperature for a further 3 hours, whereupon TLC indicated recovery of unreacted starting acid only (1:9 MeOH:CHCl3, Rf ca. 0.5); for future experiments, progress should be tested during the chlorination step.

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30th January 2013 @ 14:35

 

Crude pt-6-4 (68.3 mg, 131 umol) was dissolved in MeOH (20 ml) and to this was added concentrated aqueous ammonia (10 ml). The resulting suspension was stirred vigorously overnight, when TLC and mass spec (PT-1-5RM, ESI+, [M+Na]+ = 512) indicated complete conversion to desired product. The solvents were removed in vacuo; 1H NMR (PT-1-5A) indicated complete conversion to the primary amide, with impurities. The product was purified by vacuum filtration through a plug of SiO2 (15-40 um) in a pasteur pippette (0-10% MeOH/CHCl3) to give the title compound as a tan foam (PT-1-5B, 30.1 mg, 61 umol, 46%) which still contained some impurities. The product was purified by dry column vacuum chromatography (50-100% ethyl acetate/heptane, then 0-5% methanol in ethyl acetate) to give the title compound as a tan oil (16.8 mg, 35 umol, 26%).

 

Analysis: 1H and 13C NMR consistent with title compound plus traces of residual solvent. Mass spec consistent (observed: M+Na, 512). Note: samples submitted under incorrect sample code (112b1) due to operator error.

 

ESI-Acc (Finnegan MAT-900 ESI-Positive HRMS): Expected 489.11466 (C13H24O6FS2) found 489.11439 (0.26 ppm)

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24th January 2013 @ 15:34

 

1-(4-Fluoro-phenyl)-2,5-dimethyl-1H-pyrrole (PT 1-1) (750 mg, 4 mmol) and sulfur trioxide•pyridine (600 mg, 4 mmol) were dissolved in toluene (6 mL) and heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, then diluted with distilled water (20 mL) and extracted with dichloromethane (3 x 20 mL). The aqueous phase was evaporated to dryness to give a brown-white solid A (977 mg, NMR = pt-1-4A). The organic phase was evaporated to dryness to give only pure unreacted starting material (424 mg, 2.25 mmol, 56% recovery. NMR = PT-1-4B).

Analysis:

PT-1-4A NMR.png
 Sample A contained only mono-sulfonated pyrrole ring as evidenced by the desymmetrised pyrrole methyl groups and 3:3:1:4 distribution of integrals. The sample also contained 1.8 pyridiniums per product, indicating the product is present as a pyridinium salt and is probably also contaminated with pyridinium sulfate or unreacted Py•SO3. Lack of a third methyl peak at 2.3 indicated absence of toluene, which would otherwise complicate the aromatic region.

ESI-MS negative found m/z 268 indicating mono-substitution.

See also: Upscaled synthesis of sodium 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-sulfonate (MD 6-3)

Conclusion: Further purification pending. Assuming no loss of material, PT-1-4A is 62% pure.

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17th January 2013 @ 18:13

Reaction Scheme

Solid PT 1-1 (567 mg, 3mmol) was dissolved in dry dichloromethane (3 mL). The reaction was split into three equal parts A, B, and C. To each portion was added 1, 2, and 4 equivalents of chlorosulfonic acid respectively (1eq = 1mmol, 116.5 mg, 66.5 uL). The reactions were stirred at RT under nitrogen for 16h. Sarcosine methyl ester hydrochloride (1.88g, 15 mmol) was suspended in dichloromethane and washed with 10% NaOH solution. After drying over MgSO4, most of the dichloromethane was carefully evaporated and the residue taken up in pyridine (6 ml). The solution was split into three equal parts and added dropwise  to reactions A, B, and C with cooling in an ice-bath (5 eq. per reaction). The reactions were then stirred at room temperature for 4 hours, whereupon TLC indicated the formation of a new spot and consumption of starting material in C only (with highly polar species also present in every case). The reactions were then worked up as follows:

The reaction mixture was diluted with EtOAc (40 mL) and washed with 50mL each of saturated aqueous sodium carbonate, 2M HCl and brine. The organic phase was dried over MgSO4 and concentrated in vacuo to yield a solid.

A: 51.0mg, Starting material (by 1H NMR)

B: 53.4mg, Starting material (by 1H NMR)

C: 86.5mg brown-red oil.

 

68.3mg of the crude product C was purified by dissolving in ethyl acetate and passing through a plug of silica with 88% recovery to give a pale green oil D, subjected to further analysis. NMR indicated double substitution. MS-ESI+ [M+Na]+ = 542

 

NMR:

PT-1-3D.pdf
PT-1-3D 13C.pdf

 

 

 

 

MS:

PT-1-3C mass spec.jpg

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