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17th July 2017 @ 19:03

Scheme: 

DaraprimS3Scheme.png

SM/P

3-(4-chlorophenyl)-4-methoxyhexanenitrile

Guanidine chloride

Sodium methoxide

product

mw

221.68

95.53

54.02

248.71

Equiv

1.00

3.00

3.00

1.00

mmol

0.50

1.45

1.49

0.50

g

0.11

0.143

0.080

0.124

mL

 

 

 

 

g/mL

 

 

1.059

 

Procedure: 

7/7/17 Guanidine hydrochloride (0.143 g, 1.45 mmol, 3 eq) and sodium methoxide (0.080 g, 1.49 mmol, 3 eq) were dissolved in ethanol (1.13 mL) and stirred for 5 minutes. A solution of 3-(4-chlorophenyl)-4-methoxyhexanenitrile (o.11 g, 0.50 mmol, 1 eq) in ethanol (0.37 mL) was added. The reaction mixture was heated under reflux for 18 h.

7/8/17 Reaction removed from reflux at 2:30 pm.

TLC in 30:70 EtOAc in Hexanes. Spots are UV active.

SM (left)= 3-(4-chlorophenyl)-4-methoxyhexanenitrile

Cospot (Middle)

Product (Right) 

DaraprimS3_TLC.jpg

7/10/17 The reaction mixture was diluted with dichloromethane. Saturated NaCl was added and the mixture was extracted three times with dichloromethane. Organic extracts were combined and dried over MgSO4. Solvent was removed under reduced pressure. NMR obtained. 

JSLT_Daraprim_NMRcrude_CDCl3.png

7/11/17 Product was crystallized from methanol. Too much methanol was added the first time and no crystals formed.

7/12/17 Solvent was removed under reduced pressure. Product was crystallized from methanol and placed in the freezer overnight.

7/13/17 Solvent was removed carefully with a pipette, and crystals were washed with cold methanol. NMR obtained. 

JSLT_DaraprimS3_NMR_CDCl3.jpg

7/20/17 Crystals were derivitized in order to run GC-MS. A small sample of the crystals (1 mg) was placed in a microcentrifuge tube and a 40 mg/mL solution of methoxyamine hydrochloride in pyridine (10 μL) was added. The tube was heated to 30°C for 90 minutes in a standard heatblock. After 90 minutes, N-methyl-N-trimethylsilyltrifluoroacetamide (90 μL) was added and the samples were heated at 37°C for 30 minutes. (Fiehn, O.; Kind, T. Metabolomics 2009, 3–18.

This added TMS groups as shown:

 

Derivatization.png

 The GC-MS showed an mpeak at 392 and an [m-15]peak at 377


pyrimethamineGCMS2.png
pyrimethamineGCMS.png
Attached Files
17th July 2017 @ 18:37

Scheme: 

DaraprimS2Scheme.png

Compound

MW(m)

Mol(Mmol)

Mol(M)

Mass

Density

Volume(mL)

Equiv

Trimethylsilyl)diazomethane

114.2230

20.78

2.10

 

 

1.1

1.20

methanol, anhydrous

32.04

 

 

 

0.791

8

 

2-(4-chlorophenyl)-3-oxopentanenitrile

207.6570

1.75

 

363mg

 

 

1

(Z)-2-(4-chlorophenyl)-3-methoxypent-2-enenitrile

221.6840

1.75

 

388mg

 

 

1

Procedure: 

6/25/17.  To a 1-neck 24/40 x 250 mL RB with stir bar and septum were added 40 mL anhydrous toluene and 8 mL anhydrous methanol with stirring under a balloon of Ar.  To this stirring, clear, colorless solution was added 1.2 mL of a 2.0 M solution of TMS-diazomethane dropwise at about 1 drop/second to give a clear, light yellow/brown solution which was stirred at RT for 5 hours.

The Ar balloon was removed, and mineral oil bubbler line was connected via needle through the septum.  A clear, colorless solution of 2-(4-chlorophenyl)-3-oxopentanenitrile in 2 mL of anhydrous methanol was then added dropwise at about 1 drop/second.  N2 gas generation was evident by bubbling of the bubbler.  The resulting solution was allowed to stir at RT for 30 mins.

The reaction mixture was diluted with 4 mL Et2O and 20 mL 10% ac AcOH.  The aqueous phase was extracted 3x Et2O, and the combined organic layer was washed with saturated aqueous K2CO3, dried over MgSO4.

DaraprimS2_TLC.jpg

6/26/17 The crude product (0.807 g, 3.64 mmol, 208 %yield) was purified by column chromatography, using 10:90 EtOAc: Hexanes as the starting eluent, and then increasing to 20:80 EtOAc: Hexanes. Fractions 44-52 were collected, and the solvent was removed under reduced pressure to yield an amber-colored oil (0.110 g, 0.50 mmol, 28% yield). 

JSLT_DaraprimS2_NMR_CDCl3.pdf
Attached Files
17th July 2017 @ 18:24

Scheme:

Scheme

Compound 

MW(m) 

Mol(Mmol 

Mol(M) 

Mass 

Density 

Volume(mL) 

Equiv  

LDA, 2.0 M in THF/heptane/ethylbenzene 

+ 20 ML dry THF 

 

 

20.78 

2 

 

 

10.4 

1.05 

4-chlorobenzeneacetonitrile 

in 30mL dry THF 

151.59 

19.79 

 

3000 mg 

 

 

1 

Benzoyl chloride 

in 5mL dry THF 

140.566 

19.79 

 

 

1.21 

2.30 

1 

2-(4-chlorophenyl)-3-oxopentanenitrile 

 

207.66 

19.79 

 

1.55g 

1.104 

1.41mL 

1 

Procedure:

6/1/17 – A dry 1-neck 250 mL 24/40 round bottom flask with septum was put under an Argon environment while the 20 mL dry THF was added and 10.4 mL 2.0 M LDA to give a light-med brown-orange solution, which was cooled to ~ -80 ˚C with dry ice/acetone.  A clear, colorless solution of 4-chlorobenzeneacetonitrile in 30 mL dry THF was then added to the solution at about 4 drops/sec down the cooled side of the 250 mL RB flask to give a clear light-med brown-orange solution, which was stirred for approximately 10 minutes at ~ -80 ˚C.  With dry ice/acetone bath still in place, a clear, colorless solution of propionyl chloride in 5 mL dry THF was added dropwise at about ~ 2 drops/second to give a cloudy light-medium tan suspension, which was allowed to stir overnight and warm to room temperature slowly as the cooling bath warmed. 

6/2/17 -  In the morning a light-medium tan suspension was present.  The reaction was quenched at RT with saturated aqueous ammonium chloride which afforded a clear, light-medium red-orange solution with a white/colorless solid in the bottom. 

 The reaction was transferred to a separatory funnel, and the organic layer was washed with H2O (the NH4Cl solid dissolved with addition of H2O), brine, dried over MgSO4, and concentrated to a dark red-brown color.  

To the resulting crude product was added a minimal amount of CH2Cl2, followed by a minimal amount of dry silica.  The volatiles were removed and the dry silica was stored in the fridge overnight.  

The resulting silica was dry transferred onto a silica column. 

The column was eluted with 10:90 EtOAc/Hexanes and 20:80 EtoOAc/Hexanes until the last product began to come off column, followed by EtOAc to completely remove it. Fractions 14-19 showed one of the products with the highly concentrated top spot; Fractions 27-38 showed another product near the bottom of the baseline. 


TLC Results:

  • SM = 4-chlorobenzeneacetonitrile 

  • Cospot 

  • P = Reaction solution post work up.  

  • Spots are UV active.  

  • 10:90 EtOAc in Hexanes  

    JSLT_BenzoylTLC
     
    JSLT_BenzoylTLC
    JSLT_BenzoylTLC
    JSLT_BenzoylTLC


    The starting eluent for column was 30:70 EtOAc:Hexanes. Fractions 63-80 were collected and the solvent was removed under educed pressure.  6/6/17 NMR is still malfunctioning so there is no identification on the multiple products. Products were weighed. 

      • Fractions 14-19: 1.43g 

      • Fractions 27-38: 0.50g 

      • Fractions 63-80: 0.335g

 

6/6/2017 NMR is still malfunctioning so there is no identification on the mutiple products.

6/8/17 NMR for the collected fractions indicated that one of the products was in fractions 14-19 and the other product was in fractions 63-80. Fractions 27-38 appeared to contained starting material (4-chlorobenzeneacetonitrile).

 

JSLT_BEnzoyl4_13.png
JSLT_Benzoyl44_1.png
JS_LTBEnzoyl444_1.png

 

Attached Files
17th July 2017 @ 18:10

Screen Shot 2017-07-17 at 1.33.40 PM.png

Compound 

MW(m) 

Mol(Mmol 

Mol(M) 

Mass 

Density 

Volume(mL) 

Equiv  

LDA, 2.0 M in 20 ML dry THF 

 

 

20.78 

2 

 

 

10.4 

1.05 

4-chlorobenzeneacetonitrile 

 

151.59 

19.79 

 

3000 mg 

1.059 

1.73 

1 

propionyl chloride 

92.52 

 

 

 

 

 

1 

Product  

 

207.66 

19.79 

 

4110 mg 

 

 

1 

 

 

 5/22/17 – A dry 1-neck 250 mL 24/40 round bottom flask with septum was used. Once under Argon the 20 mL dry THF and 10.4 mL 2.0 M LDA gave a light-med brown-orange solution, which was cooled to ~ -80 ˚C with dry ice/acetone.  A clear, colorless solution of 4-chlorobenzeneacetonitrile in 30 mL dry THF was then added to the aforementioned solution at about 4 drops/sec down the cooled side of the 250 mL RB flask to give a clear light-med brown-orange solution, which was stirred for approximately 10 minutes at ~ -80 ˚C.  With dry ice/acetone bath still in place, a clear, colorless solution of propionyl chloride in 5 mL dry THF was added dropwise at about ~ 2 drops/second to give a cloudy light-medium tan suspension, which was allowed to stir overnight and warm to room temperature slowly as the cooling bath warmed. 

5/23/17 -  In the morning a concentrated darkish yellow suspension was present.  The reaction was quenched at RT with saturated aqueous ammonium chloride which afforded a clear, light-medium red-orange solution with a white/colorless solid in the bottom. 

The reaction mixture was transferred to a separatory funnel, and the organic layer was washed with H2O (the NH4Cl solid dissolved with addition of H2O), brine, dried over MgSO4, and concentrated to a brown liquid.   

To the resulting crude product was added a minimal amount of CH2Cl2, followed by a minimal amount of dry silica.  The volatiles were removed and the dry silica was stored in the fridge overnight.  

5/24/17 - The resulting silica was dry transferred onto a silica column. 

The column was eluted with 10:90 EtOAc/Hexanes until the last product began to come off column, followed by EtOAc to completely remove it. 

Fractions 26-50 and small Erlenmeyer’s A-E were collected and concentrated on high vacuum, and NMR was obtained -- labeled spot “3” -- (1.4g, 6.74 mmol, 34% yield)  

JSLT_DaraprimS1_TLC.pdf

 

JSLT_daraprim_step1_spot3_PROTON_cdcl3_01.pdf
 

JSLT_DaraprimS1_GCMS.pdf
JSLT_Daraprim_S1_GCMS2.pdf
JSLT_DaraprimS1_GCMS3.pdf
Attached Files