Tag Archives: Malaria

The first step to synthesis of 2-chloro-6-hydrazinylpyrazine

Synthesis of 2-chloro-6-hydrazinylpyrazinesynthesis of blah from blah

Procedure:

 

2,6-dichloropyrazine(2.1g) was dissolved in EtOH (28 mL, 0.50 M 3 %), and hydrazine (1.35 mL, 2 eq) added. The reaction mixture was stirred at reflux for 16 hours.

 

The solvent was removed under reduced pressure. Water (20 mL) and EtOAc (~55mL) were added, and the mixture was shaken in an attempt to dissolve all solid. The organic layer was removed and the aqueous layer was washed 3 times with EtOAc.

 

An insoluble brown solid was filtered off and aqueous layer was washed 3 times with EtOAc.

Risk assesment

Risk Assesment YANG.pdf

 

DATA

 

Because of some reasons , this lab do not have any TLC's picture 

NMR: 

email_DK-1_1_1.pdf

 

Compound strings

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<MDocument><MChemicalStruct><molecule molID="m1"><atomArray atomID="a1 a2 a3 a4 a5 a6 a7 a8" elementType="Cl Cl C C N C C N" x2="-15.2493126776983 -20.584019384069276 -16.582996689835532 -16.582996689835532 -17.91666603088379 -19.250335371932046 -19.250335371932046 -17.91666603088379" y2="3.206675097163168 3.206675097163168 2.4366835674892773 0.8966496863711964 0.1266327458121559 0.8966496863711964 2.4366835674892773 3.2067005080483177"></atomArray><bondArray><bond id="b1" atomRefs2="a3 a1" order="1"></bond><bond id="b2" atomRefs2="a4 a3" order="1"></bond><bond id="b3" atomRefs2="a5 a4" order="2"></bond><bond id="b4" atomRefs2="a6 a5" order="1"></bond><bond id="b5" atomRefs2="a7 a2" order="1"></bond><bond id="b6" atomRefs2="a7 a6" order="2"></bond><bond id="b7" atomRefs2="a8 a3" order="2"></bond><bond id="b8" atomRefs2="a8 a7" order="1"></bond></bondArray></molecule></MChemicalStruct></MDocument>
</cml>

to

<?xml version="1.0" encoding="GBK"?><cml xmlns="http://www.chemaxon.com" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.chemaxon.com/marvin/schema/mrvSchema_16_02_15.xsd" version="ChemAxon file format v16.02.15, generated by v17.14.0">
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</cml>

 

ClC1=CN=CC(Cl)=N1

to

NNC1=NC(Cl)=CN=C1



Synthesis of 5-(4-chlorophenyl)-6-methylpyrimidine-2,4-diamine

Scheme:

AcetylScheme.png

SM/P 

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

Guanidine chloride 

Sodium methoxide 

5-(4-chlorophenyl)-6-methylpyrimidine-2-diamine 

 

mw 

207.66 

95.53 

54.02 

234.69 
 

Equiv 

1.00 

3.00 

3.00 

1.00 

 

mmol 

2.72 

8.16 

8.16 

2.72 

 

g 

0.565 

0.78 

0.44 

0.6 
 

mL 

 
 

 

 
 

 

g/mL 

 

 

1.059 

 

Procedure:

7/17/17 Guanidine hydrochloride (0.78 g, 8.16 mmol, 3 eq) and sodium methoxide (0.44 g, 8.16 mmol, eq) were dissolved in ethanol (5.8 mL) and stirred for 5 min. A solution of (Z)-2-(4-chlorophenyl)-3-methoxy-3-phenylacrylonitrile (0.565 g, 2.72 mmol, 1 eq) in ethanol (1.9 mL) was added to the cloudy, white solution. The reaction mixture was heated under reflux for 6 hours. Some starting material was lost from syringe during transfer.  

AcetylTLC.jpg

30:70 EtOAc: Hexanes, silica gel plate. Starting material gone after 6 hours of reflux.

7/18/17 The reaction mixture was diluted with dichloromethane. Saturated NaCl was added and the mixture was extracted with dichloromethane and then washed with saturated NaCl. Organic extracts were dried over MgSO4. Solvent was removed under reduced pressure to yield a white/yellow solid (0.157 g,0.67 mmol26 % yield).  

Product was crystallized from methanol and placed in the freezer overnight to yield white crystals (0.0845 g, 0.36 mmol, 14% yield).  

JS_LTDaraprimAcetylS3Crystals_PROTON_cdcl3_01.jpeg


Synthesis of 2-chloro-6-hydrazinylpyrazine

Summary

This is the first step, synthesising 2-Chloro-6-hydrazinylpyrazine. There will be another 3 reactions after this, to create the brominated "Jasper 3" compund to test its functionalities. 

References

 Synthesis of 2-Chloro-6-hydrazinylpyrazine


Reaction scheme Reaction Scheme

Procedure

2.020g of 2,6-dichloropyrazine (modified from 2.3g in the risk assessment) an placed in an RB flask. Aproxiametly 10ml of EtOH was added to the flask. 1.4ml of Hydrazine was then added using a syringe. The flask was then attached to the reflux apparatus and refluxed at 100 for 3 hours. TLC was done at 1 hour and 3 hours to monitor the reaction. The TLC at 3 hours indicated the reaction was complete. The sample was then cooled down to room temperature, the solvent evaporated and the sample was dried using high vacuum.  

Risk Assessment

Risk Assessment
 

Data

Unfortuately there were no photos taken of the TLC for this experiment. 

The NMR output will be added soon.  

 

Compound strings

Synthesis 2-(4-chlorophenyl)-3-oxopentanenitrile (JSLT 7-1)

Scheme:

Screen Shot 2017-07-17 at 2.58.36 PM.png

Compound

MW(m)

Mol(Mmol)

Mol(M)

Mass

Density

Volume(mL)

Equiv

LDA, 2.0 M in THF

 

20.78

2

 

 

10.4

1.05

4-chlorobenzeneacetonitrile

in 30mL dry THF

151.59

19.79

 

3000 mg

 

 

1

Acetyl chloride

in 5mL dry THF

77.99

19.79

 

 

 

 

1

2-(4-chlorophenyl)-3-oxopentanenitrile

 

193.63

19.79

 

3.83 g

1.104

1.41mL

1

5/26/17 – A dry 1-neck 250 mL 24/40 round bottom flask with septum was put under Argon while 10.4 mL 2.0 M LDA in 20 mL dry THF was added 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.

5/30/17 -  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.

5/30/17.  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. The aqueous layer was extracted 2 x EtOAc, and the combined organic layers were dried over MgSO4 and concentrated to a dark red-brown liquid. TLC taken.

AcetylS1.png

5/31/17 -   To the resulting crude product was added a minimal amount of CH2Cl2, followed by a minimal amount of dry silica.  The volatiles were removed. The resulting silica was dry transferred onto a silica column. The product was purified with a column with the starting eluent 50:50 EtOAc/Hexanes until the last product began to come off column, followed by EtOAc to completely remove it.

6/1/17 - Fractions 45-60 and Erlenmeyer’s 1-4 were collected and concentrated on high vacuum. NMR was obtained. 

AcetylNMRCDCl3.png

Synthesis of (Z)-2-(4-chlorophenyl)-3-methoxybut-2-enenitrile( JS_LT 8-1)

Reaction Scheme:

Screen Shot 2017-07-17 at 2.58.36 PM.png

Reactants and Products

SM/P 

(Trimethylsilyl)diazomethane 

methanol, anhydrous 

2-(4-chlorophenyl)-3-oxobutanenitrile 

(Z)-2-(4-chlorophenyl)-

3-methoxybut-2-enenitrile 

mw 

114.2230 

32.04 

193.63 

207.66 

Equiv 

1.20 

  

1.00 

1.00 

mmol 

7.46 

  

6.21 

6.21 

mg 

  

  

1203 

1290 

mL 

3.73 

28 

  

  

g/mL 

  

0.791 

  

  

M 

2.0 

  

  

  

  

in Et2O 

  

  

  

bp ˚C 

  

64.7 

  

  

Procedure:

7/12/17  To a 1-neck 24/40 x 250 mL RB with stir bar and septum were added 140 mL anhydrous toluene and 28 mL anhydrous methanol with stirring under a balloon of Ar.  To this stirring, clear, colorless solution was added 3.73 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 in 7 mL of anhydrous methanol was then added dropwise at about 1 drop/second.  N2 gas generation was  evident by bubbling of the bubbler.  

7/13/17 The reaction mixture was diluted with 14 mL Et2O and 70 mL 10% ac AcOH.  The aqueous phase was extracted 3x Et2O, and the combined organic layer was washed with saturated aqueous K2CO3, dried over MgSO4placed on the high vac and concentrated to yield an amber/brown oil (1.41g, 6.79 mmol, 109% yield).  

7/14/17 The crude product was purified by column chromatography, using 30:70 EtOAc: Hexanes as the starting eluent. Fraction 12-26 were collected, and the solvent was removed under reduced pressure to yield an amber/brown-colored oil (0.565 g, 2.72 mmol, 44% yield). 

7/13/2017 TLC Results  

  • SM= 2-(4-chlorophenyl)-3-oxobutanenitrile 

  • Cospot 

  • P= Fractions 12-26 

    Screen Shot 2017-07-17 at 3.05.08 PM.png

7/14/2017 After the column, msot impurities disappeared from the NMR. Only one small impurity( on the left) remained present.

Screen Shot 2017-07-17 at 3.07.56 PM.png


 

Synthesis of 5-(4-chlorophenyl)-6-phenylpyrimidine-2,4-diamine(JSLT_6-1)

Scheme:

Screen Shot 2017-07-17 at 2.34.05 PM.png

Products and Reactants:

SM/P 

(Z)-2-(4-chlorophenyl)-3-methoxy

-3-phenylacrylonitrile 

Guanidine chloride 

Sodium methoxide 

5-(4-chlorophenyl)-

6-phenylpyrimidine-2,4-diamine 

 

mw 

269.73 

95.53 

54.02 

296.76 
 

Equiv 

1.00 

3.00 

3.00 

1.00 

mmol 

0.489 

1.47 

1.47 

0.489 

g 

0.132 

0.140 

0.079 

0.145

mL 

 

 

 
 

 

g/mL 

 

 

1.059 

 

 

Procedure:

7/12/17 Guanidine hydrochloride (0.140g,eq) and sodium methoxide (0.084g,eq) were dissolved in ethanol (1.05 mL) and stirred for 5 min. A solution of (Z)-2-(4-chlorophenyl)-3-methoxy-3-phenylacrylonitrile (1 eqand ethanol (0.35 mL) was added to the cloudy, white solution. Threaction mixture was then  heated under reflux for 18 h. 

7/13/17 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 to yield a red/orange solid (0.064 g, 0.216 mmol, 44% yield).  

7/14/17 Product was crystallized from methanol and placed in the freezer overnight.  

7/17/2017 Recrystallization was reattempted.  Methanol was removed carefully with a pipette. Crystals were rinsed with ice-cold methanol and placed on high vac overnight (0.014g, .047 mmol, 10% yield).

TLC:

7/13/2017 

  • SM =2-(4-chlorophenyl)-3-methoxy-3-phenylacrylonitrile 

  • Co 

  • P = 5-(4-chlorophenyl)-6-phenylpyrimidine-2,4-diamine 

  • 10:90 EtOAc: Hexanes  

    Screen Shot 2017-07-17 at 2.39.14 PM.png


NMR Spectra:

JS_LT_DaraprimBenzoylCrystals_PROTON_cdcl3_01.jpeg

Synthesis of (Z)-2-(4-chlorophenyl)-3-methoxy-3-phenylacrylonitrile (JSLT 5-1)

Scheme: 

Screen Shot 2017-07-17 at 2.25.04 PM.png

SM/P

(Trimethylsilyl)diazomethane

methanol, anhydrous

2-(4-chlorophenyl)-3-oxo-3-phenylpropanenitrile

(Z)-2-(4-chlorophenyl)-3-methoxy-3-phenylacrylonitrile

mw

114.2230

32.04

255.05

269.73

Equiv

1.20

 

1.00

1.00

mmol

8.33

 

6.94

6.94

mg

 

 

1770

1872

mL

4.16

31.7

 

 

g/mL

 

0.791

 

 

M

2.0

 

 

 

 

in Et2O

 

 

 

bp ˚C

 

64.7

 

 

7/6/17.  To a 1-neck 24/40 x 250 mL RB with stir bar and septum were added 150 mL anhydrous toluene and 32 mL anhydrous methanol with stirring under a balloon of Ar.  To this stirring, clear, colorless solution was added 4.16 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-oxo-3-phenylpropanenitrile and (Z)-2-(4-chlorophenyl)-3-hydroxy-3-phenylacrylonitrile (both products from step 1) in 8 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 clear, colorless solution was allowed to stir at RT for 30 mins.

7/7/17 The reaction mixture was diluted with 15 mL Et2O and 80 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, and concentrated to give oil (1.01 g, 3.74 mmol, 54% yield). It appeared from the TLC that fractions 63-80 from the previous step reacted, while fractions 14-19 did not.

20:80 EtOAc:Hexanes

TLCDaraprimBenzoyl.jpg

7/11/17 The crude product was purified by column chromatography, using 10:90 EtOAc: Hexanes as the starting eluent, and then increasing to 20:80 EtOAc: Hexanes. Fraction 23-35 were collected, and the solvent was removed under reduced pressure to yield an amber/brown-colored oil (0.132 g, 0.489 mmol, 7% yield). 

TLCDaraprimBenzoyl2.jpg

Screen Shot 2017-07-17 at 2.25.04 PM.png

Synthesis of Pyrimethamine (Daraprim) (JSLT 3-1)

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

Synthesis of  (Z)-2-(4-chlorophenyl)-3-methoxypent-2-enenitrile (JSLT 2-1)

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 prop. Intermediate 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

Synthesis of  (Z)-2-(4-chlorophenyl)-3-methoxypent-2-enenitrile (JSLT 2-1)

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