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27th October 2016 @ 07:00

# Note: This reaction was conducted 10/05-10/07. We maintain a paper notebook with correct date recorded. 

Reaction: 

 

Table of Reagents:

 

Setup: 

1. RB flask (250 mL) w/stir bar; stirring plate;

2. Septum + Ar balloon.

Procedure:

Synthesis: 10/05/16-10/07/16

1. Dissolved 1.1169 g RXCG 2-2 (3.74 mmol, 1 eqv) in 40 mL of DCM, resulting in a yellow suspension.

2. Added 2.6011 g PhI(OAc)2 (8.08 mmol, 2 eqv) in the solution mixture, resulting in an orange/red suspension. After 1 min, it became a clear orange/brownish solution.

3. Stirred the solution at r.t. for 49 hrs to yield a clear yellow solution (TLC tested after 24 hrs and after 49 hrs, the reaction was complete but close enough). Solvent was removed under reduced pressure.

reaction mixture after 24 hrs

**solution was a little orange

reaction mixture after 49 hrs

**yellow solution

 

Workup: 10/07/16

4. Added saturate aqueous solution of sodium hydrogen carbonate (15 mL), and diluted with DCM (5 mL). White solid formed in the aqueous layer.

5. Drained organic layers, and washed aqueous layers with 10 mL DCM three times.

6. Combined the organic layers, washed with 15 mL of saturate aqueous sodium hydrogen carbonate 5 times, until no light brown solid formed in the aqueous layer when more saturated NaHCO3 was added. 

7. The organic layer was washed with 30 mL of brine; then dried with Na2SO4.

8. Removed Na2SO4 from the solution.

9. Removed solvents under reduced pressure to yield a pale yellow solid.

10. Performed TLC for the crude. TLC indicated impurities/dragging for the product (30 % HEX; 70 % EtOAc; UV; silica. RF:(4) 0.768; (5) 0.304).

11. Added diethyl ether (~8 mL) to the mixture. Sonicated to yield a pale yellow solid precipitate; filtered the solid and washed with cold diethyl ether; dried the solid over the vaccuum for ~1 hr.

12. Put the product through biotage; combined the fractions where the product was present.

13. Performed TLC for purified product. TLC indicated pure product (30 % HEX; 70 % EtOAc; UV; silica. RF:(4) 0.782; (5) 0.327).

14. Removed the solvent under reduced pressure. A white/pale yellow solid formed.

15. Dried the solid overnight in high vac; collected as RXCG 3-3 (yield: 0.6566 g; 70.1 %). 

16. NMR indicated that the post-column product was pure. 

TLC

 

Product 

NMR 

RXCG_3_3_post_column.pdf

 

SMILES:

ClC1=CN=CC(N/N=C/C2=CC=C(OC(F)F)C=C2)=N1 --> ClC1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21

lnChi Strings:

InChI=1S/C12H9ClF2N4O/c13-10-6-16-7-11(18-10)19-17-5-8-1-3-9(4-2-8)20-12(14)15/h1-7,12H,(H,18,19)/b17-5+

-->

InChI=1S/C12H7ClF2N4O/c13-9-5-16-6-10-17-18-11(19(9)10)7-1-3-8(4-2-7)20-12(14)15/h1-6,12H 

Reference:

Synthesis of 5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (AEW 205-6)

5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (JU 19-1)

Attached Files
27th October 2016 @ 04:53

# Note: This reaction was conducted 09/29-10/03. We maintain a paper notebook with correct date recorded. 

Reaction: 

 

Table of Reagents:

 

Setup: 

1. RB flask (100 mL) w/stir bar; stirring plate;

2. Septum + Ar balloon.

Procedure:

Synthesis: 09/29/16-10/02/16

1. Dissolved 226 mg RXCG 2-2 (0.76 mmol, 1 eqv) in 8 mL of DCM. The solution was yellow.

2. Added 0.5154 g PhI(OAc)2 (1.60 mmol, 2.1 eqv) in the solution mixture. The mixture became orange/yellow, but turned yellow after 1 minute.

3. Stirred the resulting clear yellow solution at r.t. for 108 hrs.

Workup: 10/02/16-10/03/16

4. Added saturate aqueous solution of sodium hydrogen carbonate (15 mL), and diluted with DCM (5 mL).

5. Drained organic layers, and washed aqueous layers with 10 mL DCM three times.

6. Combined the organic layers, wash with saturate aqueous sodium hydrogen carbonate (15 mL), brine (15 mL), and dry with sodium sulfate.

7. Removed Na2SO4 from the solution.

8. Removed solvents under reduced pressure to yield a yellow solid.

9. Performed TLC for the crude. TLC indicated minor impurities for the product (30 % HEX; 70 % EtOAc; UV; silica. RF:(4) 0.76; (5) 0.37; (5) 0.57).

10. Added diethyl ether (~8 mL) to the mixture. Sonicated to yield a pale yellow solid precipitate; filtered the solid and washed with cold diethyl ether; dried overnight.

11. Filtrate was collected; removed solvent under reduced pressure; and dried overnight.

12. NMR indicated that the precipitate and the solid left in the filtrate were identical, but not pure. 

13. Combined the soid and purified the product through biotage (yield: 0.0859 g; 34 %). 

14. The product was dried overnight in high vac.

15. NMR indicated that the post-column product was pure. 

Product before sonication

TLC

NMR:

 

RXCG_3_2_post_column.pdf

SMILES:

ClC1=CN=CC(N/N=C/C2=CC=C(OC(F)F)C=C2)=N1 --> ClC1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21

lnChi Strings:

InChI=1S/C12H9ClF2N4O/c13-10-6-16-7-11(18-10)19-17-5-8-1-3-9(4-2-8)20-12(14)15/h1-7,12H,(H,18,19)/b17-5+

-->

InChI=1S/C12H7ClF2N4O/c13-9-5-16-6-10-17-18-11(19(9)10)7-1-3-8(4-2-7)20-12(14)15/h1-6,12H 

Reference:

Synthesis of 5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (AEW 205-6)

5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (JU 19-1)

 
Attached Files
26th October 2016 @ 00:01

# Note: This reaction was conducted 10/20. We maintain a paper notebook with correct date recorded. 

Reaction: 

Table of Reagents:

Procedure: 10/20

1. Dissolved RXCG 3-3 (0.100 g, 0.337 mmol), KOH (0.0875 g, 1.56 mmol), and 18-crown-6 (0.0219 g, 0.0820 mmol) in toluene: yellow solution.

2. Added tropic acid (0.0448 g, 0.270 mmol) to the mixture: did not completely dissolve. 

3. Stirred at 40-50 oC. Reaction started to turn orange; the initially white precipitate gradually turned black-brown. Reaction time: 2.5 h. 

TLC on black-brown precipitate during rxn: 

70 % EtOAc, 30 % HEX, UV, silica; (RF: (5): 0.35; (6): 0.19; (7???): 0.035)

Workup: 10/20

4. Added 6 mL water to reaction mixture; diluted with 6 mL EtOAc.

5. Adjusted pH to 1-2 using 1M HCl. 

6. Separated organic layer; extracted aqueous layer with EtOAc (6 mL).

7. Washed combined organic layer with water (4 mL).

8. Re-extracted last wash with ether (4 mL).

9. Washed combined org. layer with brine (4 mL) and dried with MgSO4. Removed solvent under reduced pressure.

9. Yield: 0.1024 g; 89.0 %.  

TLC pre-rotavap: 

90 % EtOAc, 10 % HEX, UV, silica. (RF: (5): 0.59; (6): 0.45; (7???): 0.034)

 

 

Analysis:

We took 1H NMR on the product, which appeared to be a mixture of predominantly precursors (5) and (6). No reaction happened. 

RXCG 6-1 1H NMR

 

SMILES:

ClC1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21 + OCC(C1=CC=CC=C1)C(O)=O --> FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C4=CC=CC=C4)C(O)=O)N32

InChl:

InChI=1S/C12H7ClF2N4O/c13-9-5-16-6-10-17-18-11(19(9)10)7-1-3-8(4-2-7)20-12(14)15/h1-6,12H + InChI=1S/C9H10O3/c10-6-8(9(11)12)7-4-2-1-3-5-7/h1-5,8,10H,6H2,(H,11,12) --> InChI=1S/C21H16F2N4O4/c22-21(23)31-15-8-6-14(7-9-15)19-26-25-17-10-24-11-18(27(17)19)30-12-16(20(28)29)13-4-2-1-3-5-13/h1-11,16,21H,12H2,(H,28,29)

Reference: 

1. Williamson, A. E. “Synthesis of 3-(4-(difluoromethoxy)phenyl)-5-(2-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)-[1,2,4]triazolo[4,3-a]pyrazine (AEW 289-1).” Open Source Malaria (OSM), Triazopyrazine series. Updated on Apr 20, 2016. Available 



Attached Files
22nd October 2016 @ 00:44

# Note: This reaction was conducted 09/20-09/22. We maintain a paper notebook with correct date recorded. 

Reaction: 

 

Table of Reagents:

 

Setup: 

1. RB flask (250 mL) w/stir bar; stirring plate;

2. Septum + Ar balloon.

Procedure:

Synthesis: 09/20/16-09/22/16

  1. Dissolved 0.9692 g RXCG 2-1 (3.24 mmol, 1 eqv) in 35 mL of DCM. The solution was yellow/orange.
  2. Added 2.4989 g PhI(OAc)2 (7.76 mmol, 2.4 eqv) in the solution mixture. The mixture became dark brown.
  3. Stirred the resulting orange/brown suspension at r.t. for 45.5 hrs to yield a red/orange solution.

When PhI(OAc)2 was first added to the solution mixture (left) and after 30 min:

 

 

Workup: 09/22/16

4. Added saturate aqueous solution of sodium hydrogen carbonate (16 mL), and diluted with DCM (5 mL).

5. Drained organic layers, and washed aqueous layers with 10 mL DCM three times.

6. Combined the organic layers, wash with saturate aqueous sodium hydrogen carbonate (15 mL), brine (15 mL), and dry with MgSO4.

7. Removed MgSO4 from the solution.

8. Removed solvents under reduced pressure to yield a orange/yellow syrup.

9. Performed TLC for the crude. TLC indicated two spots for the product (30 % HEX; 70 % EtOAc; UV; silica. RF:(4) 0.76; (5) 0.36; (5) 0.04); NMR confirmed the presence of impurity.

10. The product was purified through biotage; fraction 11-19 were combined (yield: 0.4796 g; 46.6 %). 

11. NMR indicated that impurity still presented in the product. 

TLC before column

Sonication: 09/23/16

12. Added diethyl ether (~8 mL) to the mixture. Sonicated to yield a pale yellow solid precipitate, present in a deep orange/red solution.

13. Filtered the solid and washed with cold diethyl ether.

14. Dried at high vac to yield as a yellow solid (yield:0.0220 g; 2.3 %)

15. Performed NMR, and NMR indicated pure product. 

NMR post-sonication:

RXCG_3_1_post_sonications_PROTON_cdcl3_01.pdf

SMILES:

ClC1=CN=CC(N/N=C/C2=CC=C(OC(F)F)C=C2)=N1 --> ClC1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21

lnChi Strings:

InChI=1S/C12H9ClF2N4O/c13-10-6-16-7-11(18-10)19-17-5-8-1-3-9(4-2-8)20-12(14)15/h1-7,12H,(H,18,19)/b17-5+

-->

InChI=1S/C12H7ClF2N4O/c13-9-5-16-6-10-17-18-11(19(9)10)7-1-3-8(4-2-7)20-12(14)15/h1-6,12H 

Reference:

Synthesis of 5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (AEW 205-6)

5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (JU 19-1)

Attached Files
20th October 2016 @ 22:13

# Note: This reaction was conducted 09/08-09/14. We maintain a paper notebook with correct date recorded. 

Reaction: 

R:2,6-dichloropyrazine; R:hydrzine hydrate; S:EtOH; reflux; P: 2-chloro-6-hydrazinylpyrazine

Table of Reagents:

 

Setup: 

1. Heat bath;

2. RB flask (250 mL) w/stir bar; stirring plate;

3. Septum + Ar balloon.

Procedure:

Synthesis: 09/08/16-09/13/16

(1)  Dissolved 4.2043 g of 2,6-dichloropyrazine (28.2 mmol, 1 eq) in 56 mL of EtOH. A clear solution was resulted.

(2)  Added 2.7 mL hydrazine hydrate (54.0 mmol, 2 eq, excess) in the mixture. The mixture turned white and murky. 

(3)  Refluxed for 117 hours while stirring, in a closed system with Ar balloon. A yellow solution was resulted at first, then turned orangish yellow.

(4)  Removed solvent under reduced pressure. A yellow solid was resulted.

Workup: 09/13/16-09/14/16

(5)  Added ~20 mL of water and ~60 mL EtOAc to transfer all solid. Shook to dissolve all solid. Yellow solution resulted with brown/red emulsion.

(6)  Added NaHCO3 (aq) until the organic layer had pH ~7;

(7) Removed the organic layer.

(8)  Extracted the aqueous layer with 30 mL EtOAc 2 times.

(9)  Combined the organic layers, and washed with ~20 mL of brine, 20 mL of NaHCO3, and 20 mL of brine. Emulsion was drained into the aqueous portion. The organic layer had a redish orange color but looks yellow after dilution.

(10)  Added MgSO4 to dry the water in the organic layer, then filtered. Concentrated under reduced pressure. Yellow solid resulted.

(11) The solid was dried under high vaccuum for 24 hrs. Collected solid as RXCG 1-2 (yield 2.5135 g; 61.6 %)

(12) Performed TLC for the crude. TLC indicated that product formed was pure; (70 % HEX; 30 % EtOAc; UV; silica. RF:(1) 0.56; (2) 0.046;

(13) NMR indicated that the product was pure. 

TLC: 

NMR:

RXCG_1_2.pdf
 

SMILES:

ClC1=NC(Cl)=CN=C1 + NN.[H]O[H] --> ClC1=CN=CC(NN)=N1

lnChi Strings:

InChI=1S/C4H2Cl2N2/c5-3-1-7-2-4(6)8-3/h1-2H

and InChI=1S/H4N2.H2O/c1-2;/h1-2H2;1H2

to InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)

Reference:

Synthesis of 2-Chloro-6-hydrazinylpyrazine (AEW 85-9)

Attached Files