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26th November 2010 @ 00:29
Scale-up of the racemic resolution of rac-PZQamine under (semi) optimized conditions of former experiments

See related experiments:
Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 - MW49-11)
Racemic resolution of praziquanamine with (+)-Dibenzoyl-D-tartaric acid (MW49)
Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30) -> S-(+)-PZQamine
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)


scheme MW49-5.png



Start time: 12:10 PM 26/11/2010
End time: 1:40 PM 26/11/2010

Procedure:
rac-Praziquanamine (1.27 g, 6.27 mmol, M.W. 202.1 g/mol) and (-)-dibenzoyl-L-tartaric acid* 2 i-PrOH (3.00 g, 6.27 mmol, M.W. 478.5 g/mol) were dissolved in a mixture of i-PrOH (60 mL) and water (12 mL) by heating the stirred mixture.

After 90 min at room temperature the crystals were filtered off:
diastereomeric salt: Yield 1.55 g (2.76 mmol, 44%)
m.p. 145.5-147.5°C
[α]D20 = -123° (c = 1, DMSO)
liberated amine: [α]D20 = -242° (c = 1, DCM) -> 82% ee

- After further 3 h the formed crystals were filtered off: 267 mg (8%)
m.p. 145-147°C
- salt [α]D20 = -110° (c = 1, DMSO)
- liberated amine: [α]D20 = -220° (c = 1, DCM) -> 74% ee


mother liquor:
diastereomeric salt: 2.76 g
liberated amine 501 mg (2.48 mmol, 40%)
[α]D20 = +247° (c = 1, DCM) -> 83% ee
1H NMR: Data: 1H NMR MW49-12 remain 1. crystallization.pdf

- M.W. diastereomeric salt = 560.6 g/mol)


2. Crystallization
Start time: 2:40 PM 2/12/2010
End time: 3:30 PM 2/12/2010

The salt (1.33 g, 2.37 mmol) was dissolved in a mixture of i-PrOH (20 mL) and water (10 mL) by heating. After 50 min the precipitate was filtered off.
diastereomeric salt: Yield: 1.20 g (90%, overall: 40%)
m.p. 147-148.5°C
- liberated amine: [α]D20 = -279° (c = 1, DCM) -> 94% ee!!! (100 mg salt for liberation)


3. Crystallization
Start time: 1:20 PM 3/12/2010
End time: 2:30 PM 3/12/2010

The salt (1.08 g, 1.93 mmol) was dissolved in a mixture of i-PrOH (20 mL) and water (10 mL) by heating. After 50 min the precipitate was filtered off.
Yield: 927 mg (86%)
m.p. 147-148.5°C
- liberated amine (865 mg salt): 271 mg (1.34 mmol, 21%)
[α]D20 = -303° (c = 1, DCM) -> 100% ee !!!

Recovering of the resolving agent:
The basic aq. solution (after PZQamine was extracted) was made acidic to pH ~1 by adding 2 N HCl solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under reduced pressure.

Yield 873 g (7.16 mmol, 57%, M.W. 122.1 g/mol) colorless solid benzoic acid -> hydrolysis of the (-)-Dibenzoyl-L-tartaric acid (under basic conditions)
1H NMR: Data: 1H NMR MW49-12 recovered resolving agent.pdf
13C NMR: Data: 13C NMR MW49-12 recovered resolving agent.pdf
-> too basic conditions / change order of extraction first acidic, then basic


remain 2./3. crystallization, liberated amine 71 mg
Attached Files
17th November 2010 @ 04:18
Testing (-)-dibenzoyl-L-tartaric acid as a resolving agent for the racemic resolution or PZQamine via diastereomeric salt formation to obtain R-(-)-PZQamine

See related experiments:
Racemic resolution of praziquanamine with (+)-Dibenzoyl-D-tartaric acid (MW49)
Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30) -> S-(+)-PZQamine
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)


scheme MW49-5.png



Start time: 13:45 PM 17/11/2010
End time: 13:45 PM 17/11/2010

Procedure:
rac-Praziquanamine (101 mg, 500 µmol) and (-)-dibenzoyl-L-tartaric acid* 2 i-PrOH(239 mg, 0.5 mmol) were dissolved in a various solvents (mixtures) by heating the stirred mixture.

- M.W. diastereomeric salt = 560.6 g/mol)

MW49-5:
Solvent: EtOH/water 9:1, 3 mL
- formation of crystals after 5 min
- after 1 h: 185 mg (66%)
- salt: [α]D20 = -100° (c = 1, DMSO)

MW49-6:
Solvent: EtOH/water 9:1, 4 mL
- formation of crystals after 5 min
- after 1 h: 159 mg (57%)
- salt: [α]D20 = -103° (c = 1, DMSO)

MW49-7:
Solvent: EtOH/water 9:1, 5 mL
- formation of crystals after 15 min
- after 1 h: 128 mg (46%)
- salt: [α]D20 = -110° (c = 1, DMSO)
- 118 mg recrystallized from EtOH/water (2 mL, 9:1), after 50 min: 90 mg (76%, 32% over-all)
Diastereomeric salt: [α]D20 = -117° (c = 1, DMSO)
m.p. = 149-150.5°C

PZQamine: 24 mg
[α]D20 = -257° (c = 1.71, DCM) -> 87% ee (calculation error -> c=1 ?)


-> crystallization too fast, lower concentration should slow down the crystallization



Further experiments:

Start time: 6:15 PM 17/11/2010
End time: 7:40 PM 17/11/2010

MW49-8:
Solvent: EtOH/water 9:1, 6 mL
(former MW49-6, - 10.4 mg for optical rotation)
- after 90 min: 127 mg (45%)
Diastereomeric salt: [α]D20 = -118° (c = 1, DMSO) [not consistent ???]
m.p. = 144-145°C

PZQamine: 36 mg
[α]D20 = -198° (c = 1, DCM) 67% ee

MW49-9:
Solvent: EtOH/water 9:1, 7 mL
(former MW49-5, - 12.3 mg for optical rotation)
- after 90 min: 72 mg (26%)
Diastereomeric salt: [α]D20 = -115° (c = 1, DMSO)
m.p. = 147-148°C

PZQamine: 16 mg
[α]D20 = -210° (c = 1, DCM) -> 71% ee

Results:
- rising melting point of the diastereomeric salt
- deviations of the optical rotation (not consistent)
- crystallisation with another solvent / solvent mixture (higher content of water or i-PrOH/water)


MW49-10:
Start time: 10:30 PM 24/11/2010
End time: 13:00 PM 24/11/2010

Solvent: EtOH/water 9:1, 5 mL
- at first no crystals, stirring -> precipitate
- heated again - formation of crystals after 30 min
- after 3 h: 155 mg (55%)
m.p. = 136-138°-c
- salt: [α]D20 = -103° (c = 1, DMSO)

2. Crystallization: Solvent: EtOH/water 2:1, 3 mL
Start time: 9:00 PM 24/11/2010
End time: 9:30 PM 24/11/2010

after 1 h: 110 mg (39%)
- salt: [α]D20 = -115° (c = 1, DMSO)
- PZA: [α]D20 = -246° (c = 0.90, DCM) -> 83% ee



MW49-11:
Start time: 10:30 PM 24/11/2010
End time: 11:00 PM 24/11/2010

Solvent: i-PrOH/water 5:1, 3 mL
- crystallization too fast

Solvent: i-PrOH/water 5:1, 4 mL
- crystallization after 5 min, after 30 min separated: 172 mg (61%)
- salt: m.p. = 135-137°C, [α]D20 = -115° (c = 1, DMSO)

2. Crystallization:
Start time: 9:00 PM 24/11/2010
End time: 9:20 PM 24/11/2010

Solvent: i-PrOH/water 2:1, 3 mL
- complete precipitation

Solvent: i-PrOH/water 2:1, 4 mL
- after 1 h: yield: 99mg (35%)
- salt: [α]D20 = -121° (c = 1, DMSO)
[α]D20 = -262° (c = 1.09, DCM) -> 89% ee
Attached Files
8th November 2010 @ 13:36
Testing (+)-dibenzoyl-D-tartaric acid as a resolving agent for the racemic resolution or PZQamine via diastereomeric salt formation

See related experiments:
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)
Synthesis of (+)-Dibenzoyl-D-tartaric acid - alternative route (MW10-6)

and subsequent experiments:
Optimizing the racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-14)
Multigram-scale racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-13)
Scale-up: Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-12)
Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 - MW49-11)

Scheme


Start time: 7:30 PM 8/11/2010
End time: 12:30 PM 9/11/2010

Procedure:
rac-Praziquanamine (101 mg, 500 µmol) and (+)-dibenzoyl-D-tartaric acid* 2 i-PrOH(239 mg, 0.5 mmol) were dissolved in a various solvents (mixtures) by heating the stirred mixture.

- M.W. diastereomeric salt = 560.6 g/mol)

MW49-1: (previous experiment*)
Solvent: i-PrOH/water 5:1,
*) wrong stoichiometry due to a wrong molecular weight of (+)-dibenzoyl-D-tartaric acid (2 molecules of iPrOH in the crystal weren't considered)

2 mL: no precipitate after 1 day at room temperature and 2 days in the fridge, evaporated solvents in a stream of nitrogen
added 3 mL of solvent - crystallization
- After 15 h at room temperature: 140 mg (250 mmol, 50%) colorless crystals
- salt: [α]D20 = 109° (c = 1, DMSO)
- basic liberation of the amine: 39 mg pale brown solid
- PZQamine: [α]D20 = + 212° (c = 1, DCM) -> 72% ee
[α]D20 = 296° (c=1, DCM) )


MW49-2:
Solvent: EtOH/water 9:1
1 mL: rapid precipitation of a crystals when the mixture cooled down -> added 1 mL and heated to reflux
2 mL: slow crystallization, began after ~10 min standing at room temperature
- After 15 h at room temperature: 213 mg (373 mmol, 75%) colorless precipitate -> added 1 mL of solvent and dissolve the solid by heating
3 mL: crystals after ~15 min, after 4 h solvent was removed: 186 mg (332 mmol, 66%) of a crystalline colorless solid
4 mL: crystals, after 4 h solvent was removed: 163 mg (291 mmol, 58%)
- salt: [α]D20 = 111° (c = 1, DMSO)
- basic liberation of the amine: 48 mg pale brown solid
- PZQamine: [α]D20 = + 183° (c = 1, DCM) -> 62% ee
- mother liquor: [α]D20 = - 33° (c = 1, DMSO)

MW49-3:
Solvent: i-PrOH/water 5:1
1 mL: rapid precipitation of a colorless solid
2 mL: residue couldn't get dissolved by heating
3 mL: slow crystallization, began after ~10 min standing at room temperature
- After 15 h at room temperature: 209 mg (380 mmol, 76%) colorless precipitate -> added 1 mL of solvent and dissolve the solid by heating
4 mL: crystals after ~20 min, after 4 h solvent was removed: 177 mg (316 mmol, 63%) of a crystalline colorless solid
5 mL: crystals, after 4 h solvent was removed: 154 mg (275 mmol, 55%)
- salt: [α]D20 = 110° (c = 1, DMSO)
- basic liberation of the amine: 41 mg pale brown solid
- PZQamine: [α]D20 = + 190° (c = 1, DCM) -> 64% ee
- mother liquor: [α]D20 = - 23° (c = 1, DMSO)

MW49-4:
Solvent: EtOH/water 9:1
3 mL: after 2 h 157 mg

3 mL: after 1 h
- 1. precipitate (106 mg, 38%): [α]D20 = + 112° (c = 1, DMSO),
liberated salt: 92 mg
PZQamine: 30 mg
[α]D20 = 157° (c = 1, DCM)

2. precipitate (73 mg, 26%): [α]D20 = + 83.7° (c = 1, DMSO)
PZQamine: 22 mg
[α]D20 = 79.0° (c = 1, DCM)

mother liquor (113 mg, 40%):: [α]D20 = - 31.8° (c = 1, DMSO)
PZQamine: 33 mg
[α]D20 = -203° (c = 1, DCM)

-> solution is too concentrated (?)

Racemate:
rac-Praziquanamine (32 mg) and (+)-dibenzoyl-D-tartaric acid* 2 i-PrOH were dissolved in a mixture of EtOH and water 9:1 and the solvent was evaporated.
Remain: 102 mg pale yellow solid
[α]D20 = 37.5° (c = 1, DMSO)

Results:
(+)-dibenzoyl-D-tartaric acid shows excellent resolving abilities for PZQamine
(+)-PZQamine can be obtained from (+)-dibenzoyl-D-tartaric acid -> can (-)-PZQamine obtained from (-)-dibenzoyl-L-tartaric acid???
crystallization process is much faster - nice crystals can be obtained after a few minutes when the solution cools down to room temperature (seed crystals?)
Resolving agent (-)-dibenzoyl-L-tartaric acid is cheaper than (+)-di-p-anisoyl-D-tartaric acid! -> naturally occuring L-tartaric acid and more common resolving agent (syntheis costs are lower)
Attached Files
3rd November 2010 @ 10:07
Preparation of a resolving agent for the racemic resolution of PZQ via diastereomeric salt formation

Repetition of the experiment: Scale-Up: Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-5)

See also:
Synthesis of (-)-Di-p-anisoyl-L-tartaric acid (MW46-4)
Repetition of the Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-3)
Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-2)
Synthesis of (-)-Di-p-anisoyl-L-tartaric acid (MW46-1)

Scheme


Hazard and Risk Assessment:
HIRAC MW46-5 corrected


Start time: 8:30 PM 3/11/2010

Procedure: [1]
A mixture of p-methoxy benzoic acid (33.6 g, 253 mmol, M.W. 152.1 g/mol) and SOCl2 (82 g, 691 mmol 50 mL, 2.72 eq., d=1.64 g/mL, M.W. 119.0 g/mol) was stirred for 13 h at room temperature -> still unreacted starting material (no clear solution)
Heat it to reflux for 3 h and evaporate excess of SOCl2 (high vac condensing with liquid nitrogen to remove trace of SOCl2)
- added 2S,3S-D(-)-tartaric acid (12.5 g, 83.0 mmol, M.W. 150.1 g/mol) and heated to 140°C for 1 h till a pale yellow solid was formed, then the mixture was heated to 160°C for 1 h. When the mixture was cooled to 100°C toluene (100 mL) was added and another time toluene (50 mL) was added when it was cooled to room temperature. The colorless solid was filtered off and rinsed with a small amount of toluene.

The dried solid was dissolved in a mixture acetone (150 mL) and water (10 mL) and heated to reflux for 2 h. After addition of water (100 mL) acetone was evaporated and another time water (100 mL) was added. The colorless precipitate was filtered off and dried in an air stream.

65.3 g (156 mmol, 94%) colorless solid, wet (M.W. 418.4 g/mol)
1H NMR: (+)-Di-p-anisoyl-D-tartaric acid and p-methoxybenzoic acid 1:08.5 : Data: 1H NMR MW46-6 after hydrolysis.pdf

1. heating with toluene (100 mL)
31.5 g (75.3 mmol, 91%) colorless solid
1H NMR: Data: 1H NMR MW46-6 1. heating with toluene.pdf - remaining p-methoxybenzoic acid

2. heating with toluene (100 mL)
27.3 g (65.2 mmol, 79%) colorless solid
1H NMR: Data: 1H NMR MW46-6 2. heating with toluene.pdf - remaining p-methoxybenzoic acid

3. heating with toluene (100 mL)
21.5 g (51.4 mmol, 62%) colorless solid
m.p. 187-189 °C
1H NMR:Data: 1H NMR MW46-6 3. heating with toluene.pdf - remaining p-methoxybenzoic acid (~ 10 mol%)

4. heating with toluene (100 mL)
19.9 g (47.6 mmol, 57%) colorless solid
m.p. 195-197 °C
1H NMR: Data: 1H NMR MW46-6 4. heating with toluene.pdf no more remaining p-methoxybenzoic acid!!!
Data: 1H NMR MW46-6 JCAMP-DX.dx

Analytical data:
[α]D20 = 169° (c=1, MeOH) (lit. [2] 167° (c=1, MeOH))
see: Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-2)

Procedure from reference: [1]
EXAMPLE 53 (p. 42)
[0327] Add p-anisic acid (77 g, 0.55 mol) to 100 mL SOCl2 and stir overnight at room temperature. Evaporate the excess SOCl2 to give p-anisoyl chloride. Add (2R,3R)-(+)-tartaric acid (25 g, 166 mmol) and stir the mixture and heat at 170.deg.C for an hour. Allow the mixture to cool to 100.deg.C and add 200 mL toluene. Cool the mixture to room temperature and add another 100 mL toluene. Collect the precipitate, rinse with toluene and dry. Reflux the crude product in a mixture of 300 mL acetone and 20 mL water for two hours. Then add 200 mL water and evaporate the acetone. Add another 200 mL water and collect the precipitate, rinse with water and dry. Reflux the product in 200 mL toluene for 15 minutes and collect the precipitate while the mixture is hot. Rinse the precipitate with 50 mL warm toluene and dry to give (2R,3R)-(-)-di-(p-anisoyl)tartaric acid.



References:
[1] "Novel processes for the preparation or (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol", Daugs et al. US Patent Application (2002), US 2002/0151717A1. [Example 20, p. 27-28]

[2] „Über die Reduktion der China-Ketone zu China-Alkoholen und über die sterische Umlagerung von China-Alkaloiden. Stereochemische Forschungen. II.“, P. Rabe, Justus Liebigs Annalen der Chemie, 1932, 492, 242–266. doi: 10.1002/jlac.19324920112.
Linked Posts
Attached Files
3rd November 2010 @ 05:48
Preparation of starting material for a scaled-up racemic resolution of PZQamine

Following the optimized conditions for rac-PZQ: see Optimizing the acid cleavage conditions II

MW2-13.png


Hazard and Risk Assessment:
Data: HIRAC MW2

Start time: 3:30 PM 3/11/2010
End time: 9:15 AM 4/11/2010


Procedure:
rac-PZQ (20.0 g, 64.0 mmol) was dissolved in a mixture of EtOH (150 mL) and 1N HCl (600 mL, 53.0 mL of 11.3 N HCl solution (35%) in 547 mL water) and heated to reflux for 18 h. Reaction monitored by TLC showed a complete consumption of PZQ (TLC, EA/hexane 1:1, Rf = 0.15 for PZQ)

work-up: cooled solution basified NaOH solution (5 N) to ph 13, extracted with DCM (4 x 30 mL), washed with brine, dried over NaSO4, evaporated.
Crude Yield: 16.2 g (80.1 mmol, 125%) pale yellow liquid - dry it in high vac.

Notes:
Reaction time can be reduced to 8-10 h under reflux conditions. TLC spot which has a similar Rf value as the starting material comes from a side product.
The main side product is ethyl cyclohexanecarboxylate with has an odor of pineapple and can be removed by an extraction (with EtOAc or DCM) of the acidic aq. solution, also most of the yellow stain can be removed in this extraction step.
Colorless PZQamine stains yellow after standing a while in the light at room temperature.
Attached Files