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6th December 2016 @ 09:29

MOD-1-030 MOD-1-034

Re-Synthesis of 4-(4-((2-(6-chloropyrazin-2-yl)hydrazineylidene)methyl)phenyl)morpholine (isomer isolation)

Reaction Scheme for resynthesis

Reaction 1-MOD-1-034

Reagent

Equivalent

Molecular weight

mmol

Quant.

2-chloro-6-hydraziynlpyrazine

1.00

144.56

0.35

50 mg

4-morpholinobenzaldehyde

1.00

191.23

0.35

62 mg

Ethanol

 

46.07

-

4 mL

 

 

 

 

 





Procedure

2-chloro-6-hydrazinylpyrazine (50 mg) was stirred into ethanol (4 mL). 4-morpholinobenzaldehyde (62  mg) was then added and stirred at ambient temperature for 8 hours.

 

MOD-1-034 reaction T=8.png

The reaction mixture changed colour from yellow to orange after 8 hours.

Upon completion (as detemrined by TLC analysis (Pet. Ether/ EtOAc 7:3) the solvent was removed under reduced pressure to give the product MOD-1-034 as a orange solid (0.0995 g, 0.31 mmol, 90.17%).

TLC 1.png

1H NMR of the product MOD-1-034 was taken in different solvents to compare which was the best solvent and the see isomer seperation. MeOD was determined as the best solvent. The NMR showed that many isomers of the product were afforded.

 

Reaction 2-MOD-1-030

Reagent

Equivalent

Molecular weight

mmol

Quant.

2-chloro-6-hydraziynlpyrazine

1.00

144.56

0.35

50 mg

4-morpholinobenzaldehyde

1.00

191.23

0.35

62 mg

MeCN

 

60.05

-

0.045 mL

AcOH

 

41.01

-

1 mL

 

Procedure

2-chloro-6-hydrazinylpyrazine (50 mg) was stirred into MeCN (1 mL). 4-morpholinobenzaldehyde (62  mg) and AcOH (0.045 mL) was then added and stirred at ambient temperature for 8 hours.

The reaction mixture changed colour from yellow to red after 8 hours.

MOD-1-030 reaction T=8.png

Upon completion (as detemrined by TLC analysis (Pet. Ether/ EtOAc 7:3) the solvent was removed under reduced pressure to give the product MOD-1-030 as a red solid (0.1048g, 0.33 mmol, 92.23%).

TLC 1.png

1H NMR of the product MOD-1-034 was taken in different solvents to compare which was the best solvent and the see isomer seperation. MeOD was determined as the best solvent. The NMR showed that many isomers of the product were afforded.

Isomer Seperation

Due to both MOD-1-030 and MOD-1-034 containing isomers the products were combied. The best solvent system was determined as (Toluene/Acetone 19:1).

Solvent system analysis 1.png

Solvent system analysis 2.png

The crude mixture was purified via flash chromatography on silica gel (Toluene/Acetone 19:1). Forming fractions MOD-1-034-3-4, MOD-1-034-5-42, MOD-1-034-43-54. The fractions all contained isomers and therfore were not successfully seperated. 

References

1.T. York, Open Source Malaria, Malaria.ourexperiment.org, 2016.

2.C. Xia, Open Source Malaria, Malaria.ourexperiment.org, 2016.

3.B. Xie, Open Source Malaria, Malaria.ourexperiment.org, 2016.

 

Attached Files
20th November 2016 @ 16:57

MOD-1-026

Synthesis of 4-(4-(5-chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)phenyl)morpholine

Synthesis of 4-(4-(5-chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)phenyl)morpholine

 

Reagent

Equivalent

Molecular weight

mmol

Quant.

4-(4-((2-(6-chloropyrazin-2-yl)hydrazineylidene)methyl)phenyl)morpholine

1.00

317.10

0.99

313 mg

PIDA

1.00

322.1

0.99

318 mg

DCM

-

84.93

-

18 mL





Procedure

4-(4-((2-(6-chloropyrazin-2-yl)hydrazineylidene)methyl)phenyl)morpholine (313 mg, 0.99 mmol) was stirred into a flask with  CH2Cl(18 mL) at room temperature. PhI(OAc)(318 mg, 0.99 mmol)  was added and stirred for 2 hrs. A yellow colour was formed.  

Reaction T=0.5.png

TLC analysis showed the reaction was incomplete (Pet. Ether/EtOAc 7:3).

TLC T=2.png

PhI(OAc)2 (0.031 g) and DCM (4.0 mL) were added to the mixture and the reaction was left stirring for 18 hrs. An orange solution was formed.

Reaction T=4.png

TLC analysis (Pet. Ether/EtOAc 1:1) showed the presence of many products.

TLC T=30.png

The organic layer was washed with saturated NaHCO3 solution (30 mL). The inorganic layer was extracted with DCM (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and the solvent removed in vacuo. Yielding crude product MOD-1-026.

The crude product was purified by flash column chromatography on silica (EtOAc/pet.ether 1:1) yielding several frctions MOD-1-026-A (7.1 mg), MOD-1-026-B (55 mg), MOD-1-026-C (37 mg), MOD-1-026-D (3.6 mg), MOD-1-026-E (66 mg) and MOD-1-026-F (62 mg).

Column.png

TLC of fractions

MOD-1-026-A.pdf

MOD-1-026-B.pdf

MOD-1-026-C.pdf

MOD-1-026-D.pdf

MOD-1-026-E.pdf

MOD-1-026-F.pdf

Upon analysis of NMR each fraction contained many isomers as shown in the TLC's of the fractions. Efforts for the last few weeks of project will turn to seperation of the isomers through the use of different solvents for the column and reaction for the condensation step ref. MOD-1-022 (See this link for previous experiment Synthesis of 4-(4-((2-(6-chloropyrazin-2-yl)hydrazineylidene)methyl)phenyl)morpholine)

Attached Files
10th November 2016 @ 14:32

MOD-1-022

Synthesis of 4-(4-((2-(6-chloropyrazin-2-yl)hydrazineylidene)methyl)phenyl)morpholine

Reaction Scheme- Synthesis of 4-(4-((2-(6-chloropyrazin-2-yl)hydrazineylidene)methyl)phenyl)morpholine

Reagent

Equivalent

Molecular weight

mmol

Quant.

2-chloro-6-hydraziynlpyrazine

1.00

144.56

1.38

200 mg

4-morpholinobenzaldehyde

1.00

191.23

1.38

265 mg

Ethanol

 

46.07

-

10 mL

 

 

 

 

 

 

 

 

Procedure

2-chloro-6-hydrazinylpyrazine (0.2 g) was stirred into ethanol (10 mL). 4-morpholinobenzaldehyde (0.265 g) was then added and stirred at ambient temperature for 8 hours.

Reaction at T=0.png

The reaction mixture changed colour from yellow to orange/red after 2 hours.

 

Reaction at T=8.png

Upon completion (as detemrined by TLC analysis (Pet. Ether/ EtOAc 1:1) the solvent was removed under reduced pressure to give the product MOD-1-022 as a red solid (0.4043g, 1.27 mmol, 92.16%).

TLC.png
 

1H NMR of the product MOD-1-022 was taken in DMSO as the product did not dissolve well in CDCl3. The NMR showed that many isomers of the product were afforded.

MOD-1-022-CDCL3.pdf

MOD-1-022-DMSO.pdf

References

1.T. York, Open Source Malaria, Malaria.ourexperiment.org, 2016.

2.C. Xia, Open Source Malaria, Malaria.ourexperiment.org, 2016.

3.B. Xie, Open Source Malaria, Malaria.ourexperiment.org, 2016.

 

 

Linked Entries
Attached Files
10th November 2016 @ 13:47

MOD-1-016

Nucleophilic aromatic substitution- Synthesis of 4-morpholinobenzaldehyde (N15) (Scale up)

 Reaction Scheme- Synthesis of 4-morpholinobenzaldehyde using Nucleophilic aromatic substitution

 

 

Reagent

Equivalent

Molecular weight

mmol

Quant.

4-Flourobenzaldehyde

1.00

185.02

8.0

0.87 mL

Morpholine

1.30

87.12

10.4

0.152 mL

K2CO3

2.23

138.21

20.26

2.23 g

DMF

-

73.10

-

15 mL

 

 

 

 

 

 

 



 

Procedure

P-fluorobenzaldehyde (1.00 g, 0.87 mL, 8.0 mmol) was added to DMF (15 mL). Morpholine (0.905 mg, 0.89 ml, 10.4 mmol) and then potassium carbonate (2.23 g, 20.16 mmol) were then added sequentially and the reaction stirred at ambient temperature for 0.5 hours.

 

 
Reaction at T=0.png

The reaction mixture was then heated for 24 hours to 100oC. 

 

Reaction at T=24h.jpg
 

 

TLC 1.png

Upon completion (as determined by TLC analysis (Pet. Ether/ EtOAc 5:3)). The reaction mixture was cooled to room temperature, and diluted with water and then extracted into EtOAc. The organic layer was then dried with MgSO4 and the solvent was removed under reduced pressure.

The crude product was purified by flash chromatography on silica gel (Pet. Ether/Diethyl Ether 4:1) to give the product MOD-1-016 as a colourless solid (1.2924 g, 0.81mmol, 84%)

 

 
Column.png

TLC analysis of the fractions showed good separation of the products.

 

 
TLC of fractions.png

1H NMR (MOD-1-016-A) fractions 5-6, (MOD-1-016-B) fractions 8-11 and (MOD-1-016-C) fractions 14-35 showed that MOD-1-016-C was the product. 

MOD-1-016-C PROTON 1.pdf

 

Analysis of MOD-1-016-C (Product)

Yield 84% yellow solid m.p: 65-69oC. R.f=0.24 (Pet. Ether/ EtOAc 5:3).  1H NMR (400 MHz CDCl3) δ 9.80 (1H, s, CHO), 7.77 (2H, d, J=9.2 Hz CHAr) 6.92 (2H, d, J 8.9 Hz, CHAr), 3.87−3.85(4H, m, CH2), 3.37−3.34 (4H, m, CH2)

References

1. C. Tintori, A. Brai, M. Dasso Lang, D. Deodato, A. Greco, B. Bizzarri, L. Cascone, A. Casian, C. Zamperini, E. Dreassi, E. Crespan, G. Maga, G. Vanham, E. Ceresola, F. Canducci, K. Ariën and M. Botta, J. Med. Chem., 2016, 59, 2747-2759.

2. M. Abdel-Atty, N. Farag, S. Kassab, R. Serya and K. Abouzid, Bioorg. Chem., 2014, 57, 65-82.

Attached Files
21st October 2016 @ 13:05

 MOD-1-011

Nucleophilic aromatic substitution- Synthesis of 4-morpholinobenzaldehyde (N15)

 Reaction Scheme- Synthesis of 4-morpholinobenzaldehyde using Nucleophilic aromatic substitution

 

 

Reagent

Equivalent

Molecular weight

mmol

Quant.

4-Flourobenzaldehyde

1.00

185.02

1.6

0.173 mL

Morpholine

1.00

87.12

1.6

0.152 mL

K2CO3

0.03

138.21

4.12

445 mg

DMF

-

73.10

-

3 mL

 

 

 

 

 

 

 



 

Procedure

P-fluorobenzaldehyde (200 mg, 0.173 mL, 1.6 mmol) was added to DMF (3 mL). Morpholine (0.150mg g, 0.152 ml, 1.6 mmol) and then potassium carbonate (445 mg, 4.12 mmol) were then added sequentially and the reaction sired at ambient temperature for 0.5 hours.

Reaction T=0 SnAr.png

The reaction mixture was then heated for 24 hours to 100oC. 

TLC-1.png

Upon completion (as detemrined by TLC analysis (Pet. Ether/ EtOAc 5:3)). The reaction mixture was cooled to room temperature, and diluted with water and then extracted into dichloromethane. The organic layer was then dried with MgSO4 and the solvent was removed under reduced pressure.

The crude product was purified by flash chromatography on silica gel (Pet. Ether/Diethyl Ether 4:1) to give the product MOD-1-011 as a colourless solid (0.1562g, 0.81mmol, 51%)

 

Silica Column.png

TLC analysis of the fractions showed good separation of the products.

TLC-Fractions SnAr.png

1H NMR (MOD-1-011-A) fractions 3-4, (MOD-1-011-B) fractions 5-9 and (MOD-1-011-C) fractions 15-25 showed that MOD-1-011-C was the product. 

MOD-1-011-C 1H.png

Analysis of MOD-1-011-C (Product)

Yield 51% white solid m.p: 65-69oC. R.f=0.24 (Pet. Ether/ EtOAc 5:3).  1H NMR (400 MHz CDCl3) δ 9.80 (1H, s, CHO), 7.77 (2H, d, J=9.2 Hz CHAr) 6.92 (2H, d, J 8.8 Hz, CHAr), 3.87−3.85(4H, m, CH2), 3.37−3.34 (4H, m, CH2). 13C  NMR (100 Mhz CDCl3) δ 190.50 (CHO), 155.14 (CAr), 131.81(CHAr), 127.66(CAr), 113.45 (CHAr), 66.50 (CQuat), 47.29 (CQuat) νmax (ATR) /cm-1 2964, 2851, 1667, 1596, 1222, 1170, 820, cm-1. HRMS (ESI+) C11H14NO2 [M+H]+ Requires:

mass spec compound required

found 192.1019.

MOD-1-011-C 1H.png

MOD-1-011-C CARBON.png

MOD-1-011-C COSY.png

MOD-1-011-C DEPT135.png

MOD-1-011-C HSQC.png

MOD-1-011 MS.png

References

1. C. Tintori, A. Brai, M. Dasso Lang, D. Deodato, A. Greco, B. Bizzarri, L. Cascone, A. Casian, C. Zamperini, E. Dreassi, E. Crespan, G. Maga, G. Vanham, E. Ceresola, F. Canducci, K. Ariën and M. Botta, J. Med. Chem., 2016, 59, 2747-2759.

2. M. Abdel-Atty, N. Farag, S. Kassab, R. Serya and K. Abouzid, Bioorganic Chemistry, 2014, 57, 65-82.

Attached Files