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14th September 2012 @ 04:06
This experiment aims to conver the free base of JRC 12-6 into the hydrochloride salt.

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50 mg SM was dissolved in 10 mL acetonitrile. HCl gas, from CaCl2 (4.89 g), and hydrochloric acid (8 mL) was bubbled through for 2 hr, then purged with nitrogen over the weekend.

Risk Assessment:
Paper copy signed by C.S.P. McErlean
JRC41-1.pdf
Attached Files
13th July 2012 @ 11:12
The succesful synthesis of the desired compound has been established in JRC 12-4. This experiment uses similar conditions (at reflux and with a nucleophilic catalyst (DMAP)) to hopefully lead to a greater yield of desired product. This experiment is based loosely upon a procedure detailed by Yasuda et al. (2002).

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Reaction start time: 4:30 PM, 13/07/2012
3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (726 mg, 3.04 mmol, 1 equiv.) and DIPEA (1.2 mL, 6.9 mmol, 2.3 equiv.) were dissolved in acetonitrile (10 mL) with stirring. To the stirring solution was added DMAP (40 mg, 0.33 mmol, 0.1 equiv.) and 4-chloro-N-methylaniline (0.42 mL, 3.46 mmol, 1.1 equiv.). This reaction mixture was heated to reflux and stirred for 60 hr. TLC analysis during this time was attempted but the TLC's were generally too complex to be of any use, showing multiple (5) new products in the RM columns. At +60 hr the reaction was allowed to cool to rt before being extracted with ethyl acetate (100 mL) and water (40 mL). The organic layer was washed with water (3 x 30 mL) and brine (30 mL) before being dried over anhydrous magnesium sulfate. The solvent was removed and the product dried in vacuo to yield a brown liquid (904 mg). 1H-NMR indicates this crude mixture contains starting material and desired product, alongside several impurities. The residue was purified by flash chromatography using 5% EtOAc/hexane as the eluent, increasing in polarity to 100% EtOAc once two products had been eluted in the first solvent. Three fractions were collected.

5% EtOAc/hexane:
5% EtOAc/hexane: 296.1 mg. This is the desired material (0.861 mmol, 28%)
100% EtOAc: 311 mg. This is aniline SM (2.56 mmol, 74%)

This product is clean by NMR. The resultant red solid was recrystallised twice from 50% EtOH/water to yield radiating maroon crystals (mg)

m.p. 120.4-121.1
HRMS: 366.03953
Attached Files
21st June 2012 @ 23:46
JRC 12-4 lead to the successful synthesis of the title compound. The aim of this experiment is to investigate the effect of replacing acetonitrile with chloroform.

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Reaction start time: 4:50 pm, 20/06/2012
3-Chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (147.9 mg, 0.620 mmol, 1 equiv.) was dissolved in chloroform and stirred, whilst 4-chloro-N-methylaniline (0.22 mL, 1.81 mmol, 2.91 equiv.) was added dropwise. To this stirring solution was added triethylamine (0.26 mL, 1.86 mmol, 3 equiv.) dropwise. After the addition was complete the stirring solution was heated to reflux and stirred for 22 hr. TLC at + 22hr showed both new products and starting material.

TLC (10% MeOH/DCM): Visualised with UV/potassium permanganate/vanillin
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Reaction solution was heated at reflux with stirring for a further 15 hr. Reaction solution was allowed to cool to rt before being extracted with chloroform (30 mL) and water (30 mL). The aqueous layer was washed with chloroform (30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (30 mL), before being dried over anhydrous magnesium sulfate. The solvent was removed and the product dried in vacuo to yield an orange oil (266.7 mg).
Attached Files
16th June 2012 @ 12:30
3-Chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole was succesfully synthesised in JRC 11-4 in good yield. This experiment is designed to investigate whether this compound can undergo coupling with amines to yield sulfonamides. This ability will be investigated by using varying chemical conditions. In part A, JRC 11-4 will be coupled with 4-chloro-N-methylaniline in conditions identical to those in previous experiments in the JRC 12-x series (see JRC 12-3, JRC 12-2 and JRC 12-1). In part B, benzylamine will be coupled with JRC 11-4, also in identical conditions to previous entries in the JRC 12-x series. In part C, benzylamine will be coupled with JRC 11-4 using triethylamine as a replacement base for potassium carbonate. These experiments are based loosely upon a procedure described by Yasuda et al (2002).

Part A

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Experiment start time: 4:00 pm, 09/06/2012
3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (516.3 mg, 2.162 mmol, 1 equiv.) and potassium carbonate (610 mg, 4.41 mmol, 2 equiv.) were dissolved in acetonitrile (3.0 mL). 4-chloro-N-methylaniline (0.52 mL, 4.29 mmol, 1.9 equiv.) was added dropwise before the mixture was stirred at 28 °C for 48 hr. TLC at this stage indicated that minimal quantities of new product had been formed, and that minimal quantities of starting material had been consumed. The reaction mixture was heated to 50 °C and heated for 96 hr. The reaction was cooled and extracted with ethyl acetate (20 mL). The organic layer was washed with water (3 x 20 mL) and brine (20 mL) before being dried over anhydrous magnesium sulfate. The solvent was removed and the product dried in vacuo to yield an orange liquid which 1H-NMR revealed to be a complex mixture containing some of the desired product (crude: 414.4 mg).

An investigation into appropriate solvent systems revealed 5% ethyl acetate/hexane (with increasing EtOAc conc. with time if neccesary) to be the most appropriate. Flash chromatography was performed using this solvent system, using the crude mixture from the above reaction (414.4 mg) in ~2 mL chloroform. Five fractions were obtained from this column:

Fraction 1 (5% EtOAc/hexane): -
Fraction 2 (5% EtOAc/hexane): -
Fraction 3 (5% EtOAc/hexane): - 129 mg
Fraction 4 (10% EtOAc/hexane): 1.3 mg
Fraction 5 (ethyl acetate wash): 116 mg

The column was flushed with 15% MeOH/DCM. TLC showed no compounds resulting from this wash. 1H-NMR indicated that fraction 5 - the ethyl acetate wash - contained the desired product as a pale orange film (116 mg, 0.34 mmol, 16%).

1H-NMR:
1.zip
JRC12-4(A)EtOAc wash.pdf


To purify this compound so that it could be sent for testing, the film was dissolved in a small amount of DCM and subjected to a flash silica column using 50% EtOAc/petrol increasing to 60% EtOAc/petrol increasing finally to 100% EtOAc. Two fractions were collected.

Fraction 1 (50-60 % EtOAc/petrol): 34 mg
Fraction 2 (60-100 % EtOAc/petrol): 4 mg

1H-NMR revealed that fraction 1 contained a fairly pure sample contaminated by ethyl acetate, hexane, DCM and an unknown compound (8.071 ppm (s), and ~3.3 ppm (s). Sample was blown under nitrogen and sent with Paul's compounds for testing (ON WHAT?)

1H-NMR:
1.zip
JRC12-4(A)pure.pdf


Low Res. Mass Spec.: Want: 343, Found: 366 (M+Na) and 385 (?).
ms/ms (parent ion: 366): Found: 141/143 (C7H7ClN+H); 233 (?); 278 (difference of 233 and 278 = Me2H2N+); 338 (difference of 338 and 366 = CO).

13C-NMR:
TriazCNMR.zip
Triaz.pdf


The aqueous phase was acidified with 2.5M HCl until pH was stable at ~ pH 5. A cloudy white precipitate formed at ~pH 7 which then floated to the top of the liquid at ~ pH 4. Ethyl acetate (50 mL) was added and the precipitate disappeared. The organic layer was washed with water (3 x 20 mL) and brine (40 mL) before being dried over anhydrous magnesium sulfate. The solvent was removed and the product dried in vacuo to yield a solid containing both white and brown particles (153 mg).

Part B

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Experiment start time: 4:00 pm, 09/06/2012
3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (408.9 mg, 1.713 mmol, 1 equiv.) and potassium carbonate (516 mg, 3.73 mmol, 2.1 equiv.) were dissolved in acetonitrile (3.0 mL). Benzylamine (0.40 mL, 3.66 mmol, 2.1 equiv.) was added dropwise before the mixture was stirred at 28 °C for 48 hr. TLC at this stage indicated that minimal quantities of new product had been formed, and that minimal quantities of starting material had been consumed. The reaction mixture was heated to 50 °C and heated for 96 hr. The reaction was cooled and extracted with ethyl acetate (20 mL). The organic layer was washed with water (3 x 20 mL) and brine (20 mL) before being dried over anhydrous magnesium sulfate. The solvent was removed and the product dried in vacuo to yield an orange liquid (crude: 102.6 mg).

This crude liquid was dissolve in DCM and subjected to a flash silica column. Three fractions were eluted. The first came off quickly with 5% EtOAc/pet., the second came off with 100% EtOAc/pet. and the third came off with 10% MeOH/DCM.

Fraction 1:
Fraction 2: 99 mg
NMR reveals shifts expected
Fraction 3:

Part C

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Experiment start time: 4:00 pm, 09/06/2012
3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (401.5 mg, 1.682 mmol, 1 equiv.) and triethylamine (0.40 mL, 2.86 mmol, 1.7 equiv.) were dissolved in acetonitrile (3.0 mL). Benzylamine (0.37 mL, 3.38 mmol, 2.0 equiv.) was added dropwise before the mixture was stirred at 28 °C for 48 hr. TLC at this stage indicated that minimal quantities of new product had been formed, and that minimal quantities of starting material had been consumed. The reaction mixture was heated to 50 °C and heated for 96 hr. The reaction was cooled and extracted with ethyl acetate (20 mL). The organic layer was washed with water (3 x 20 mL) and brine (20 mL) before being dried over anhydrous magnesium sulfate. The solvent was removed and the product dried in vacuo to yield an orange liquid (185.1 mg).

Risk Assessment:
As for JRC 12-1

References:
Yasuda, N.; Nagakura, T.; Yamazaki, K.; Yoshikawa, S.; Okuda, T.; Ikuta, H.; Koyanagi, M. ( Eisai Co., Ltd.). Preparation of N-carbamoylazoles as dipeptidyl peptidase IV inhibitors. European Patent 1 258 480 A1, 2002; SciFinder Scholar AN 2002:886010 (accessed 2/3/2012)
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14th June 2012 @ 11:41
Previous experiments in the JRC 11-x series (see JRC 11-3 and JRC 11-2 have failed to yield the title compound in sizable quantities. The aim of this experiment is to generate sizable quantities of the desired product. The method of this reaction is identical to previous experiments within this series, until the purification steps are reached. At this point, the solvents from this reaction will be removed under high vacuumm, so that the desired product can be isolated. This experiment is adapted from one described by Yasuda et al. (2002), and is described below:

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Reaction start time: 12:30 pm, 06/06/2012
3-benzylthio-1-dimethylcarbamoyl-1H-1,2,4-triazole (2.722 g, 10.37 mmol, 1 equiv.) was dissolved in acetic acid (10 mL, 174.6 mmol, 16.8 equiv.) and water (3.8 mL, 210.9 mmol, 20.3 equiv.) and stirred at -5 °C. To the stirring solution was bubbled chlorine gas (9.101 L, 406.2 mmol, 39.1 equiv.) for 1.5 hr.

Chlorine Gas Generation:

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Total quantities of chlorine gas were generated according to the following schedule.

Generation time: 12:30 pm
To trichloroisocyanuric acid (12.00 g, 43.89 mmol, 1 equiv.) was added 32% hydrochloric acid (15 mL, 153 mmol, 3.48 equiv.) to generate chlorine gas (2.940 L, 131.6 mmol, 3 equiv.) which was bubbled directly into the reaction vessel.

Generation time: 1:00 pm
To trichloroisocyanuric acid (12.85 g, 46.99 mmol, 1 equiv.) was added 32% hydrochloric acid (14 mL, 142.8 mmol, 3.03 equiv.) to generate chlorine gas (3.3978 L, 140.97 mmol, 3 equiv.) which was bubbled directly into the reaction vessel.

Generation time: 1:30 pm
To trichloroisocyanuric acid (12.18 g, 44.55 mmol, 1 equiv.) was added 32% hydrochloric acid (15 mL, 153 mmol, 3.43 equiv.) to generate chlorine gas (2.9937 L, 133.65 mmol, 3 equiv.) which was bubbled directly into the reaction vessel.

At +1.5 hr the reaction vessel was flushed with nitrogen before the solvents were removed in vacuo. At +5 hr the removal of solvent was halted and the reaction mixture was stirred under argon. At +21.5 hr the solvents were removed again in vacuo. At this point, boiling of solvent occured for approx. 10 min. The desired product was obtained as an impure viscous oil (2.690 g, 11.27 mmol, 108% yield) as indicated by 1H-NMR, alongside benzyl chloride and acetic acid.

1H-NMR: NEED NMR

Risk Assessment: As for JRC 11-1

References:
Yasuda, N.; Nagakura, T.; Yamazaki, K.; Yoshikawa, S.; Okuda, T.; Ikuta, H.; Koyanagi, M. ( Eisai Co., Ltd.). Preparation of N-carbamoylazoles as dipeptidyl peptidase IV inhibitors. European Patent 1 258 480 A1, 2002; SciFinder Scholar AN 2002:886010 (accessed 2/3/2012).
Attached Files