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Synthesis of 2-(4-chlorophenyl)-3-oxo-3-phenylpropanenitrile (JSLT 4-1)

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

 

Synthesis of  2-4-(chlorophenyl)-3-oxopentaneitrile (JSLT 1-1)

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

Synthesis of [COMPOUND NAME]

Synthesis of 2-((3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazin-5-yl)oxy)-1-(3,4-difluorophenyl)-N,N-dimethylethan-1-amine (AEW 323-1)

Synthesis of blah from blah

Procedure

irfgiwef

Risk assessment

sample.pdf

 

Data

ndus

 

Compound Strings

InChI=1S/C4H2Cl2N2/c5-3-1-7-2-4(6)8-3/h1-2H
AuxInfo=1/0/N:3,5,2,6,7,8,4,1/E:(1,2)(3,4)(5,6)/rA:8NCCNCCClCl/rB:s1;d2;s3;d4;d1s5;s2;s6;/rC:-7.625,2.8734,0;-8.9587,2.1034,0;-8.9587,.5633,0;-7.625,-.2067,0;-6.2913,.5633,0;-6.2913,2.1034,0;-10.2924,2.8733,0;-4.9576,2.8733,0;

to

InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)
AuxInfo=1/1/N:4,6,3,7,8,1,5,2,9/rA:9NNCCNCCClN/rB:;s2;d3;s4;d5;d2s6;s3;s1s7;/rC:9.2719,1.9733,0;5.2708,2.7434,0;3.9372,1.9733,0;3.9372,.4333,0;5.2708,-.3367,0;6.6045,.4333,0;6.6045,1.9733,0;2.6035,2.7433,0;7.9382,2.7433,0;

 

ClC1=CN=CC(Cl)=N1

to

NNC1=NC(Cl)=CN=C1

Synthesis of [COMPOUND NAME]

Summary

First step in synthesis towards compound XX, described in [link to GitHub Issue]


References

Synthesis of 2-Chloro-6-hydrazinylpyrazine (AEW 85-x)


Reaction scheme

Procedure

A cooled (–T ºC) solution of COMPOUND XX (XX mg, XX mmol) in SOLVENT1 (XX mL) was treated with REAGENT1 (XX mL, XX mmol, X.X equiv.), followed by REAGENT2 (XX mL, XX mmol, X.X equiv.). After stirring at –T ºC for 2 h the reaction was quenched by the addition of AQREAGENT1 (XX mL), SOLVENT2 (XX mL) was added and the layers were separated. The aqueous phase was extracted with SOLVENT2 (X x XX mL), the combined organic extracts were washed with brine (XX mL), dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography (XX:XX EtOAc/hexanes) to yield COMPOUND XX (XX mg, XX%) as a colourless oil.


Risk assessment

attach file (PDF) or link to previous risk assessment


Data

insert TLC images (PNG)

attach NMRs, IR, MS (PDF and compressed raw files)


Characterisation Data (for new compounds)

m. pt. XXX-XXX °C (lit. XXX °C); b. pt. XXX-XXX °C (lit. XXX °C); Rf 0.XX (XX:XX EtOAc/hexane); HPLC Tr XX min. (XX:XX EtOAc/hexane); IR (thin film) XXXX, XXXX cm-1; 1H NMR (XXX MHz, CDCl3) d X.XX (XH, X, J = X.X Hz, XX), X.XX (XH, X, J = X.X Hz, XX); 13C NMR (XXX MHz, CDCl3) d XXX.X (X); HRMS (+CI, NH3) Calc. for XX [MH]+: XXX.XXXX, found: XXX.XXXX; m/z (+CI, NH3) XXX ([M + NH4]+, XX), XX ([MH]+, XX), XXX (XX), XXX (100); Anal. Calcd for CXXHXXNXXOXXSiXX: C, XX.XX; H, XX.XX; N, XX.XX. Found: C, XX.XX, H, XX.XX, N, XX.XX.

 

Compound Strings

InChi

to

InChi

 

SMILES

to

SMILES

Benzylic amine compounds

In order to support Github issue #504, I used my previously described Matched Molecular Pairs (MMP), coupled with ECFP regression, to create and prioritize benzylic amine substitutes. MMP approach has been described here

In this case, the lead compound had the smiles '

FC(F)OC1=CC=C(C=C1)C1=NN=C2C=NC=C(COC(=O)C3=CC=CC=C3)N12

'

When fed to the MMP program, this generated 285,618 compounds. I then filtered out all the compounds which had the amine at the desired spot, which then reduced the pool to 47 compounds. All of the compounds can be found here

These compounds then had their EC50 predicted after training a MLP on the 125 compounds taken from the Master List which were designated 'series 4' and had appropriate EC50 values.