All Notebooks | Help | Support | About
31st May 2010 @ 09:03
Preparation of the "Ugi intermediate" of PZQ as starting material for the Pictet-Spengler cyclisation

See also: N-Cyclohexanoyl-protection of the amine intermediate MW7-2-27 of PZQ: Upscale (MW29-4)

N-(2,2-dimethoxyethyl)-N-(2-oxo-2-(phenethylamino)ethyl)cyclohexanecarboxamide

Reaction Scheme



Table1



Hazard and Risk Assessment:
Reaction Class: 2
Hazards: X Irritant, C Corrosive
Risk rating: U = Unlikely

Start time: 5:00 pm
End time: 10:15 am 1/06/2010

To a suspension of MW7-2-27 (100 mg, 330 µmol) and Na2CO3 (87.5 mg, 826 µmol) in DCM (5 mL) was added cyclohexanecarboxylic acid chloride (53.3 mg, 363 µmol) at 0°C and warmed to room temperature.

- after 2 h / 4 h: TLC (EA:MeOH:TEA = 1:1:0.02) --> slow reaction, starting material left
- after 17 h: yellow solution, work-up: quenched with water, extracted with DCM, dried over sodium sulfate, concentrated

Yellow oil, crude yield: 151 mg
TLC (EA:MeOH:TEA = 1:1:0.02, stain: ninhydrin): still some starting material left + other impurities

- base to weak to liberate amine effectively from the hydrochloride?


MW29-2/MW29-3

Reaction Scheme2


Table2



Start time: 6:15 pm 1/06/2010
End time: 8:30 pm

MW29-2:
To a solution of MW7-2-27 (100 mg, 330 µmol) and Et3N (83.6 mg, 826 µmol) in DCM (5 mL) was added cyclohexanecarboxylic acid chloride (53.3 mg, 363 µmol) at 0°C, warmed to room temperature and stirred for 2 h.
- pale yellow solution: TLC (EA:MeOH:TEA = 1:1:0.02) [better eluent: EA = 100%] --> complete conversion, no starting material or side products
Work-up: quenched with water, extracted with DCM, washed with aq. ammonium chloride, dried over sodium sulfate.

Crude yield: 119 mg (344 µmol, 104%) pale yellow oil, impurities of cyclohexanecarboxylic acid chloride?
Rf (TLC EA, 100%; stain: Ceric ammonium molybdate) = 0.50.
1H NMR: quite pure, 2 rotamers ~ 1:1
MW29 (345.5).


MW29-3:
MW7-2-27 (100 mg, 330 µmol) was dissolved in a mixture of DCM (5 mL) and 2 N NaOH (1 mL) and cyclohexanecarboxylic acid chloride (53.3 mg, 363 µmol) was added at 0°C. The cooled solution was stirred for 2 h.
- pale yellow solution: TLC (EA:MeOH:TEA = 1:1:0.02) --> complete conversion, no starting material but one side product (? Similar Rf, faintly visible)
Work-up: quenched with water, extracted with DCM, washed with aq. ammonium chloride, dried over sodium sulfate.

Crude yield: 112 mg (324 µmol, 98%) yellow oil
TLC (EA = 100%, stain: Ceric ammonium molybdate)
1H NMR: product + impurities, 2 rotamers

--> upscale the conditions of MW29-2: see MW29-4
Linked Posts
This post is linked by:
Attached Files
24th May 2010 @ 11:53
Creation date: 25/05/2010 19:45

Reaction Scheme


Table1


Hazard and Risk Assessment:
Reaction Class: 2
Hazards: X Irritant, C Corrosive, F Flammable
Risk rating: U = Unlikely

Start time (Trial 1-3): 18:35
Start time (Trial 4): 19:00
Start time (Trial 5-7): 19:30

End time: 10:00 26/05/2010

Trial 1-3:
MW14-3-79 (50.0 mg, 194 µmol) was dissolved in toluene (2 mL), phenylphosphinic acid (1, 2, 5 eq., see table) was added and stirred at rt
- 1,2 clear pale yellow solution; 3 cloudy pale yellow solution
- after 16 h: 1 and 3 cloudy solutions, get clear after heating, work-up
TLC (EA:MeOH:TEA = 1:1:0.02) --> no conversion, starting material

Trial 4:
MW14-3-79 (50.0 mg, 194 µmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at rt --> clear orange solution
- after 16 h: brown solution, work-up
TLC (EA:MeOH:TEA = 1:1:0.02) --> nearly complete conversion, less starting material
1H NMR: broad signals, unselective conversion, no starting material monitored

Trial 5-7:
MW14-3-79 (50.0 mg, 194 µmol) was dissolved in toluene (2 mL), p-TsOH (1, 2, 5 eq., see table) was added and stirred at rt
First cloudy solutions, then brown precipitate
- after 16 h: brown precipitate on the bottom of the vials, colorless precipitate on the wall, not soluble by heating
TLC (EA:MeOH:TEA = 1:1:0.02) --> nearly complete conversion, less starting material, heterocyclic product ? Same Rf / stain color like cyclized amine
1H NMR: product with impurities, good conversion
1H NMR T5
1H NMR T6
1H NMR T7


Work-up:
- Basic work-up, 2 N NaOH solution, extraction with chloroform, dried over sodium sulfate

TLC (EA:MeOH:TEA = 1:1:0.02) from the chloroform solutions, stain: Ceric ammonium molybdate
TLC1
TLC2
Linked Posts
This post is linked by:
Attached Files
21st May 2010 @ 10:36
Preparing starting material for the Pictet-Spengler cyclisation, Repeated experiment, see here:(www.thesynapticleap.org/node/301)


9,10-dimethoxy-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a] isoquinoline

Reaction.png


Ordered starting materials arrived:
  • Aminoacetaldehyde dimethyl acetal (Alfa Aesar, 99%)
  • 3,4-Dimethoxyphenetylamine (Alfa Aesar, 99%)


Table1.jpg



Procedure:
MW9-3-77 (2.39 g, 9.29 mmol) and aminoacetaldehyde dimethyl acetal (2.00 g, 19.0 mmol) were dissolved in toluene (10 mL) and heated to reflux. After 30 min the starting material was completely consumed, as monitored by TLC (hexane/EA = 1:1).
The solution was cooled to 0°C, the resulting precipitate was filtered off and washed with cold toluene. The filtrate was quenched with 2 N NaOH solution and the aqueous layer was extracted five times with ethyl acetate. The combined organic layers were washed brine, dried over sodium sulfate and concentrated under reduced pressure.
  • Purification by column chromatography (silica gel, EA/MeOH/TEA = 20:1:0.1)

    - TLC (EA:MeOH:TEA, 10:1:0.1; stain: Ceric ammonium molybdate):
DSC09862.JPG




Results:
Product MW14-3-79: 2.25 g (6.89 mmol, 74%) yellow oil (small impurities of aminoacetaldehyde dimethyl acetal).


Analytical data:
Rf (EA:MeOH:TEA, 10:1:0.1) = 0.41.
1H NMR (CDCl3, 200 MHz): δ = 1.78 (bs, 1H), 2.65 (d, J = 5.3 Hz, 2 H), 2.78 (t, J = 7.0 Hz, 2 H), 3.25 (s, 2H), 3.35 (s, 6 H), 3.53 (td, J = 7.0, 6.3 Hz, 2 H), 3.86 (s, 3H), 3.87(s, 3H), 4.31 (t, J = 5.3 Hz, 1 H), 6.72-6.84 (m, 3H), 7.31 (bs, 1H). [Data: 1H NMR]
13C NMR (CDCl3, 50.3 MHz): δ = 35.4, 40.2, 51.1, 52.4, 54.0 (2 C), 55.9, 56.0, 103.4, 111.4, 112.0, 120.7, 131.5, 147.4, 149.1, 171.5. [Data: 13C MW14-3]
IR (neat): nu = 3325 cm-1, 2935, 2834, 1660, 1652, 1514, 1260, 1234, 1127, 1056, 1025. [Data: IR]
MS (ESI (+)) m/z (%): 653 (100, [M2H]+), 548 (29), 327 (56, [MH]+), 295 (35).
HRMS (ESI (+)) Calcd. for [C16H26N2O5H]+: 327.1914, found: 327.1910.
C16H26N2O5 (326.4).

-> starting material for MW28 (Pictet-Spengler cyclisation) and MW32 (N-cyclohexanoly protection)


References:
[1] “Formation of Pyrazinoisoquinoline Ring System by the Tandem Amidoalkylation and N-Acyliminium Ion Cyclization: An Efficient Synthesis of Praziquantel”, J. H. Kim, Y. S. Lee, H. Park and C. S. Kim, Tetrahedron, 1998, 54, 7395-7400.
Linked Posts
This post is linked by:
Attached Files