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31st October 2010 @ 23:59
Preparation of a resolving agent for the racemic resolution of PZQ via diastereomeric salt formation
- patent procedure from Aventis Pharmaceuticals [1] suggested and mailed by Jean Paul Seerden (Syncom) on 22/10/2010

See also:
Repetition: Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-6)
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


Table1


Hazard and Risk Assessment:
HIRAC MW46-5 corrected


Start time: 10:30 PM 1/11/2010


Procedure: [1]
A mixture of p-methoxy benzoic acid (77 g, 506 mmol) and SOCl2 (164 g, 1.38 mol 100 mL, 2.72 eq.) was placed in a 500 mL flask and stirred for 1 h at room temperature. The mixture was heated to reflux for 5 h. The excess SOCl2 was distilled off, 2S,3S-D(-)-tartaric acid (25 g, 166 mmol) was added and the mixture was heated to 170°C. The mixture was cooled to 100 °C and toluene (200 mL) was added.

1. Precipitate from toluene at room temperature: 37.3 g brown solid
1H NMR: lots of unreacted starting material left () (p-methoxybenzoic acid) Data: 1H NMR MW46-5 Anhydride 1. precipitation.pdf
2. Precipitate from toluene after 1 day in the fridge: 15.9 g brown solid
1H NMR: starting material (~40%) Data: 1H NMR MW46-5 Anhydride 2. precipitation.pdf

-> no complete conversion of the p-methoxybenzoic acid to p-methoxybenzoyl chloride ?
Repetition of the experiment, see Repetition: Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-6)

Hydrolysis of the Anhydride:
- 1. Precipitate was dissolved in a mixture of acetone (150 mL) and water (10 mL) and heated to reflux for 2 h. Water (100 mL) was added and aceton was evaporated and another time water was added (100 mL). The brown precipitate was filtered and dried.
- 2. Precipitate was dissolved in a mixture of acetone (75 mL) and water (5 mL) and heated to reflux for 2 h. Water (50 mL) was added and aceton was evaporated and another time water was added (50 mL). The brown precipitate was filtered and dried.

Heating to reflux with toluene:
1. Precipitate: heating to reflux with toluene (100 mL) for 15 min, filtered off the hot solution and rinsed with warm toluene (25 mL) to give a pale brown solid (20.3 g).
1H NMR: large amount of p-methoxybenzoic acid Data: 1H NMR MW46-5-1 after heating with toluene.pdf

2. Precipitate: heating to reflux with toluene (50 mL) for 15 min, filtered off the hot solution and rinsed with warm toluene (13 mL) to give a pale brown solid (12.2 g)
Data: 1H NMR MW46-5-2 after heating with toluene.pdf



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.
Attached Files
29th October 2010 @ 02:14
Preparation of a resolving agent for the racemic resolution of PZQ via diastereomeric salt formation

See also:
Repetition: Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-6)
Scale-Up: Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-5)
Repetition of the Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-3)
Synthesis of (+)-Di-p-anisoyl-L-tartaric acid (MW46-2)
Synthesis of (-)-Di-p-anisoyl-L-tartaric acid (MW46-1)

Reaction Scheme


Table1


Hazard and Risk Assessment:
HIRAC MW46


Start time: 5:15 PM 06/10/2010
End time: 10:00 AM 08/09/2010

Procedure: [1]
A mixture of L-(+)-tartaric acid (4.50 g, 30.0 mmol) and FeCl3 (100 mg, 600 µmol, 2 mol%) in xylene (15 mL) was heated to 95°C and p-methoxybenzoyl chloride (10.2 g, 60.0 mmol, 8.12 mL, 1.0 eq.) was added dropwise over a period of 1 h. After stirring for additional 2 h thionyl chloride (4.28 g, 36.0 mmo, 2.62 mL, 1.2 eq.) was added over a period of 1h. The mixture was heated to 110° for 2 h and then cooled to room temperature while stirring for 11 h. The ice cooled reaction mixture was filtered off and the brown precipitate was washed with cold toluene aobtaining the tartaric acid anhydride as a pale brown solid.

Yield: 6.12 g (14.6 mmol, 49%) of a pale brown solid
1H NMR: Data: 1H NMR MW46-4.pdf
[alpha]D20 = -163° (c=1, EtOH), (lit: 163° (c=1, EtOH) [3])

References:
[1] "Process for preparation of chiral tartaric acid derivatives" Z. Zhou, Y. Hu, Yu; X. Sun, Y. Guo, H. Yao, H. Chen, Faming Zhuanli Shenqing Gongkai Shuomingshu (2008), CN 101239913 A 20080813, Language: Chinese.

[2] "Novel processes for the preparation of (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol", W. Laux, G. Guillamot, F. Laskovics, C.-H. King, J. Hitt, S. Stolz-Dunn, I. Tomlinson and J. N. Koek, U.S. Pat. Appl. Publ. (2005), US 20050261341 A1 20051124.

[3] TCI America, Chemical Supplier for (+)-Di-p-anisoyl-D-tartaric Acid
Attached Files
28th October 2010 @ 07:35
Testing a resolution method for (+)-PZQamine with (-)-di-p-anisoyl-L-tartaric acid following a resolution method for (+)-PZQamine with (-)-di-p-anisoyl-L-tartaric acid developed by Syncom B.V.

See: Diastereomeric salt resolution of praziquanamine with (+)-di-p-anisoyl-D-tartaric acid (MW47-1)
Upscale: Diastereomeric salt resolution of praziquanamine with (+)-di-p-anisoyl-D-tartaric acid (MW47-2)
and Synthesis of (-)-Di-p-anisoyl-L-tartaric acid (MW46-4)

Reaction Scheme


Start time: 4:10 PM 27/10/2010
End time: 10:00 AM 28/10/2010

Procedure:
rac-Praziquanamine (505 mg, 2.50 mmol) and (-)-di-p-anisoyl-L-tartaric acid (1.07 g, 2.50 mmol) [link to the procedure for purified resolving agent...] was dissolved in a mixture of isopropanol (10 mL) and water (2.0 mL) by heating. The solution was allowed to cool to room temperature and stand over night.

After 18 h the mother liquor was pipetted off and the remaining pale yellow solid was dried in a gentle stream of nitrogen.


Diasteromeric salt (1. precipitation):
656 mg (1.08 mmol, 43%) of a pale yellow amorphous solid (M.W. diastereomeric salt = 606.6 g/mol)
[α]D20 (diasteromeric salt) = - 1.4° (c = 1, DMSO)

- Liberation of the diasteromeric salt:
The salt (101 mg, 167 µmol) was dissolved in 2 N NaOH and extracted with DCM (3 x 5 mL), dried over sodium sulfate, evaporated:
Yield of S-(+)-PZQamine: 22 mg (117 mmol, 30% overall yield) of a colorless solid.
[α]D20 = 260° (c = 1, DCM) -> 85% ee (for [α]D20 = 296° (c=1, DCM) )

Recrystallization of the diastereomeric salt (1. precipitation):
The salt (504 mg, 830 µmol) was dissolved in a mixture of i-propanol and water 2:1 (8 mL) by heating to reflux and stirring the solution until all solid got dissolved.
2. crystallization from i-PrOH_water 2 to 1.JPG


Salt: [α]D20 = 15.3° (c = 1, DMSO)
Liberated salt (361 mg) yield: 101 mg colorless solid
[α]D20 = 274° (c = 1, DCM) -> 90% ee
1H NMR: Data: MW47-3 recrystallized from i-PrOH_water 2_1.pdf

Recrystallization of the diastereomeric salt (2. precipitate) after 3 d in the fridge: 245 mg colorless solid

Mother liquor after 10 h at room temperature (after 1. precipitation): 491 mg (809 µmol, 32%) yellow crystalline precipitate
Mother liquor i-PrOH_water 4 to 1b.JPG
2. precipitate from the mother liquor.JPG


Salt: [α]D20 = -140° (c = 1, DMSO)
Liberated salt (460 mg): 184 mg yellow oil
[α]D20 = -191° (c = 1, DCM) -> 65% ee

Mother liquor (2. precipitate) after 3 d in the fridge: 310 mg pale yellow solid
Attached Files
20th October 2010 @ 04:07
Synthesis of a chiral acid as a potential resolving agent for Praziquanamine following a previous procedure for the Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30)

See also:
Synthesis of (+)-Dibenzoyl-D-tartaric acid (MW10-5)
Scale-up: Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-7)

Scheme MW10-6.png


Table MW10-6.JPG


Hazard and Risk Assessment:
HRAF MW10.pdf


Start time: 6:00 PM 19/10/2010
End time: 10:00 PM 19/10/2010

A mixture D-(-)-tartaric acid (4.50 g, 30 mmol) and benzoyl chloride (14.8 g, 12.2 mL, 105 mmol) was heated to 130°C for 4 h. After which time a pale yellow solid was formed and the mixture was cooled to room temperature. The solid was washed with cold Et2O and recrystallized from toluene (100 mL) affording a fine crystalline colorless solid. The solid was dried in a air stream.
The solvent of resulting mother liquor was evaporated: remaining solid 5.4 g (crude 15.1 mmol) -> recrystallizing a 2. time from toluene: 1.40 g of a colorless solid: benzoic acid
1H NMR: Data: 1H NMR MW 10-6 remain.pdf


Yield: 8.40 g (23.4 mmol, 78%) of a fine crystalline colorless solid, small impurity/trace (signal at 6.70 ppm - anhydride?), broad water / OH-peak.
1H NMR:Data: 1H NMR MW 10-6.pdf
IR:Data: IR MW10-6.pdf no OH/COOH bands!? -> compare with MW10-5
[α]D20 = -104° (c=1, EtOH)
Correction: Yield for the anhydride: 8.40 g (24.7 mmol, 82%)

m.p. = 191-192°C (lit. XX)
154-156 °C (Sigma-Aldrich - monohydrate?)
Scifinder: range from 86-88°C to 183-184°C

-> anhydride??
Anhydride


Hydrolysis of the anhydride:
1. Trial:
The anhydride (1.00 g, 2.93 mmol) was dissolved in a mixture of Aceton (10 mL) and water (0.5 mL) and heated to reflux. After 2 h the solvent was evaporated and the water was removed by azeotropic distillation with toluene -> no solid was obtained
-recrystallized from chloroform: no crystals, but a colorless solid
Yield: 1.05 g (2.93 mmol, 100%) colorless solid
1H NMR: Data: 1H NMR MW 10-6a.pdf
IR: Data: IR MW10-6a.pdf: IR matches with literature [xx]
m.p. 112-116°C

2. Trial: [1]
The anhydride (1.00 g, 2.93 mmol) dissolved in a minimum of a mixture of acetone and water 20:1 (~ 5 mL) and heated to reflux. After 10 min the mixture was allowed to cool to room temperature - no precipitate; slowly remove of the solvent in a gentle stream of nitrogen -> oil

3. Trial:
The anhydride (1.00 g, 2.93 mmol) was dissolved in a minimum amount of hot toluene (~25 mL), water (500 µL) was added and stirred for 30 min
IR: Data: IR MW10-6c: no OH/acid bands in IR
-> anhydride

4. Trial:
The anhydride (1.00 g, 2.93 mmol) was dissolved in a minimum amount of hot ethanol(~ 8 mL), water (500 µL) was added and heated to reflux for 10 min -> oil

5. Bulk:
The anhydride (6.74 g, 19.8 mmol) was dissolved in a mixture of Aceton (20 mL) and water (1.0 mL) and heated to reflux. After 2 h the solvent was evaporated, dissolved in Et2O, dried over sodium sulfate and evaporated while heating to 50°C. The solid residue was obtained with impurities of the solvent (no crystallization).

Yield: 7.37 g (20.6 mmol, 104%) colorless solid

Recrystallization:

ethyl acetate -
ethyl acetate/ hexane -
CHCl3 -
toluene -
toluene / CHCl3 -
isopropanol ?

See: Sucessful recrystallization (MW10-5)

Recrystallization from i-PrOH/hexane 1:2 (~ 9.0 g in 75 mL solvent)
Yield: 5.14 g colorless crystaline solid
remain in mother liquor: 3.80 g pale yellow oil

Analytical data:
m.p. 98-101°C.
[α]D20 = -85.1° (c=1, EtOH).
Data: 13C NMR MW10-6


References:
[1] “The Reduction of Various Sugar Acids to Glycitols with Lithium Aluminum Hydride”, R. K. Ness, H. G. Fletcher and C. S. Hudson, J. Am. Chem Soc. 1951, 73, 10, 4759-4761.

[2] “Relative Stereoselectivity of the Reactions of (2R,3R)- and (2R,3S)-Dibenzoyloxysuccinic Anhydrides with Chiral Amines and Alcohols”, K. H. Bell, Aust. J. Chem. 1987, 40, 399-404. doi:10.1071/CH9870399.
Linked Entries
Attached Files
20th October 2010 @ 02:05
Synthesis of a chiral acid as a potential resolving agent for Praziquanamine following a patent procedure for the Synthesis of (-)-Di-p-anisoyl-L-tartaric acid (MW46-1)

See also:
Synthesis of (+)-Dibenzoyl-D-tartaric acid - alternative route (MW10-6)
Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30) and previous experiments MW10-2-32, MW10-3-33, MW10-4-37 (lab notebook #1)

Scheme MW10-5


Table MW10-5.JPG


Hazard and Risk Assessment:
HRAF MW10.pdf


Start time: 5:15 PM 06/10/2010
End time: 10:00 AM 08/09/2010

Procedure: [1]
A mixture of D-(-)-tartaric acid (6.0 g, 40.0 mmol) and FeCl3 (130 mg, 800 µmol, 0.02 eq.) in xylene (20 mL) was heated to 95°C and benzoyl chloride (11.3 g, 80.0 mmol, 9.3 mL, 2.0 eq.) was added dropwise over a period of 1.0 h. After stirring for additional 1 h at the same temperature thionyl chloride (5.71 g, 48.0 mmol, 3.49 mL, 1.2 eq.) was added over a period of 1h and the mixture was stirred for another 1 h. The mixture was heated to 110° for 2 h and then cooled down to room temperature while stirring for 11 h.
The ice cooled reaction mixture was filtered off and the brown precipitate was washed with cold toluene and hexane obtaining the tartaric acid anhydride as a pale grey solid.

- remain from the mother liquor: 590 mg benzoic acid -> remaining starting material, reaction not completed
- no NMR possible: impurities of iron (paramagnetic)

Hydrolysis of the anyhdride:
Test reaction with 1 g anhydride: Data: 1H NMR 10-5 test.pdf

3.80 g (10.6 mmol) of a pale green solid, solvent impurities (Et2O), no benzoic acid
1H NMR: Data: 1H NMR 10-5 hydrolysis of the anhydride.pdf

IR (neat): nu = 3065 cm-1, 1719, 1239, 1178, 1092, 704. Data: IR MW10-5.pdf:
-data matches with IR spectrum from AIST database (search for CAS # 2743-38-6)
[α]D20 = -104° (c=1, EtOH)

Recrystallization
Recrystallized from DCM/i-PrOH: residue was dissolved in a minimum of hot DCM and stored in the fridge for 1 d. The obtained spicular crystals were filtered off and washed with cold DCM.
yield: 320 mg, remain: 1.48 g oil -> lots of remaining substanz in the mother liquor, slow crystallization - useful as seed crystals...
-drying crystals over 2 days

m.p. = 97-99°C [lit: XX]
1H NMR:Data: 1H NMR 10-5 recryrstallized from i-PrOH DCM.pdf: remaining i-PrOH in the crystal (2 molecules)
-> (+)-Dibenzoyl-D-tartaric acid * 2 i-PrOH: M.W. = 478.5 g/mol

Recrystallization from:
- i-PrOH/CHCl3 (1:1, 216 mg in 0.4 mL): fridge/seed crystals- no crystallization
- i-PrOH/CHCl3 (1:10, 215 mg in 2 mL): fridge/seed crystals- no crystallization
- i-PrOH/hexane (1:1, 226 mg in 1.2 mL): fridge, then seed crystal from previous crystals -> crystallization!!!

Yield: 185 mg (82%)
-> test for optimizing solvent/conditions
1H NMR: Data: 1H NMR 10-5 recryrstallized from i-PrOH hexane.pdf: 2 molecules of i-PrOH in the crystal

Recrystallization from i-PrOH/hexane 1:2 (~ 1.5 g in 20 mL solvent)
Yield: 964 mg colorless - pale brown crystalline solid
remain in mother liquor: 483 mg pale brown solid

See alternative procedure to (+)-Dibenzoyl-D-tartaric acid (MW10-6)

Analytical data:
m.p. 97-100°C.
[α]D20 = +84.5° (c=1, EtOH).
MS (ESI (-)) m/z (%): 357 (100) [M-H]-.
HRMS (ESI (-)) Calcd. for [ C18H13O8]-: 357.0616, found: 357.0616.
HRMS (ESI (+)) Calcd. for [C18H14O8+Na]+: 381.0581, found: 381.0579.

References:
[1] "Process for preparation of chiral tartaric acid derivatives" Z. Zhou, Y. Hu, Yu; X. Sun, Y. Guo, H. Yao, H. Chen, Faming Zhuanli Shenqing Gongkai Shuomingshu (2008), CN 101239913 A 20080813, Language: Chinese.

[2] "Novel processes for the preparation of (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol", W. Laux, G. Guillamot, F. Laskovics, C.-H. King, J. Hitt, S. Stolz-Dunn, I. Tomlinson and J. N. Koek, U.S. Pat. Appl. Publ. (2005), US 20050261341 A1 20051124.
Attached Files