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30th September 2010 @ 09:54
Testing a resolution method for (-)-PZQamine with (+)-di-p-anisoyl-D-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)
and Synthesis of the resolving agent (+)-di-p-anisoyl-D-tartaric acid

Reaction Scheme


Start time: 6:30 PM 30/09/2010
End time: 10:00 AM 5/10/2010

Procedure:
rac-Praziquanamine (505 mg, 2.50 mmol) and (+)-di-p-anisoyl-D-tartaric acid (1.07 g, 2.50 mmol) 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 over night.

- after 20 h at room temperature: little precipitate was formed
-> fridge at +5°C over 4 days: liquid was separated from the solid by pipetting off, precipitate was dried by a gentle stream of nitrogen: 1.72 g of a pale brown solid

113 mg of the salt liberated with 2 N NaOH, aq. solution extracted with DCM, dried over sodium sulfate, evaporated: 32 mg of a colorless solid
[a]D20 = -9° (c = 1, DCM).

Recrystallisation of the diastereomeric salt of
- 100 mg from 3.0 mL iPrOH/water (5:1)
- 103 mg from 2.5 mL iPrOH/water (2:1)
30th September 2010 @ 02:11
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)
Synthesis of (-)-Di-p-anisoyl-L-tartaric acid (MW46-4)
Synthesis of (+)-Di-p-anisoyl-D-tartaric acid (MW46-2)
Synthesis of (-)-Di-p-anisoyl-L-tartaric acid (MW46-1)

Reaction Scheme


Table MW46-2


Hazard and Risk Assessment:
HIRAC MW46


Start time: 4:35 PM 23/09/2010
End time: 10:10 AM 24/09/2010

Procedure: [1]
A mixture of D-(-)-tartaric acid (4.62 g, 30.8 mmol) and FeCl3 (100 mg, 617 µmol) in xylene (20 mL) was heated to 95°C and p-methoxybenzoyl chloride (12.0 g, 70.3 mmol, 9.52 mL) was added dropwise over a period of 1.5 h. After stirring for additional 2 h thionyl chloride was added over a period of 1h and the mixture was stirred for another 2 h. The mixture was heated to 110° for 2 h and then cooled to room temperature while stirring for 4 h.
The reaction mixture was filtered off and the brown precipitate was washed with cold toluene.

- 1 g of the crude precipitate (wet cake) were used for a test reaction for the hydrolysis of the anhydride

The solid was recrystallized from hot toluene. The precipitate was filtered off from various states of the cryistallization process:
  1. from hot toluene (~ 50°C): 3.23 g
Data: 1H MW46-3 (anhydride 1st precipitation from toluene hot)
from toluene at room temperature: 1.35 g
Data: 1H MW46-3 (anhydride 2nd precipitation from toluene)
from the ice coold mixture: 5.50 g

- 1 g of the 1. precipitate were used for another test reaction for the hydrolysis of the anhydride

Hydrolysis of the anhydride: [2]
-> see procedure: Synthesis of (+)-Di-p-anisoyl-L-tartaric acid (MW46-2)

  • A: 1 g of the crude precipitate (see above) dissolved in acetone (10 mL) and water (2 mL); after heating for 2 h added water (10 mL), evaporated aceton, cooled with an ice bath, filtered off.
    - 423 mg pale orange precipitate (dry)
Data: 1H MW46-3 (1. hydrolysis of anhydride)

B: A: 1 g of the 1. precipitate from toluene (see above) dissolved in acetone (10 mL) and water (2 mL); after heating for 2 h added water (10 mL), evaporated aceton, cooled with an ice bath, filtered off.
- 621 mg pale orange precipitate (dry)Data: 1H MW46-3 (2. hydrolysis of anhydride)

C: 1. and 2. precipitation combined (3.58 g) dissolved in acetone (40 mL) and water (10 mL); after heating for 2 h added water (40 mL), evaporated aceton, cooled with an ice bath, filtered off.
- 4.19 g pale orange precipitate (wet cake) Data: 1H MW46-3c (3. hydrolysis of anhydride)

D: 3. precipitation (5.50 g) dissolved in acetone (40 mL) and water (10 mL); after heating for 2 h added water (40 mL), evaporated aceton, cooled with an ice bath, filtered off.
- 6.33 g pale orange precipitate (wet cake)Data: 1H MW46-3d (4. hydrolysis of anhydride)

-> all obtained hydrolysed still containing a small amount of p-methoxy benzoic acid

Combined precipitates were recrystallized from water:
  1. The crude (+)-Di-p-anisoyl-D-tartaric acid (~11 g) was placed in a 1 L round-bottom flask, water (800 mL) was added and heated to reflux. The orange solid was filtered of and the mother liquor was cooled in an ice-bath. The colorless precipitate was filtered off and the aq. layer was reused for the recrystallization of the remaining solid.
    Yield: 1.86 g mircocrystalline solid, p-methoxy benzoic acid impurity 29 mol%
Data: 1H MW46-3c_d (1. precipitation from water)

The remain orange solid and water (800 mL) was heated another time to reflux. The orange solid was filtered of and the mother liquor was cooled in an ice-bath for 3 h. The colorless precipitate was filtered off and the aq. layer was reused for the recrystallization of the remaining solid.
Yield: 5.56 g mircocrystalline solid, p-methoxy benzoic acid impurity 20 mol% Data: 1H MW46-3c_d (2. precipitation from water)

The remain solid was dissolved in acetone (30 mL) and water (300 mL) and heated to reflux, then water (200 mL) was added and heated to reflux a 2. time. The solution was cooled to room temperature over night, then cooled to 0°C and the solid was filtered off
Yield: 2.40 g small crystals, no impurities !!!Data: 1H MW46-3c_d (precipitation from acetone_water)

[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
27th September 2010 @ 02:42
Testing a resolution method for (-)-PZQamine with (+)-di-p-anisoyl-D-tartaric acid following a resolution method for (+)-PZQamine with (-)-di-p-anisoyl-L-tartaric acid developed by Syncom B.V.

See also:
Synthesis of the resolving agent (+)-di-p-anisoyl-D-tartaric acid
Upscale: Diastereomeric salt resolution of praziquanamine with (+)-di-p-anisoyl-D-tartaric acid (MW47-2)
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)

Reaction Scheme


Start time: 4:35 PM 25/09/2010
End time: 10:10 AM 27/09/2010

Procedure:
rac-Praziquanamine (101 mg, 500 µmol) and (+)-di-p-anisoyl-D-tartaric acid (214 mg, 0.5 mmol) was dissolved in a mixture of isopropanol (2.0 mL) and water (0.4 mL) by heating. The pale yellow solution was allowed to cool to room temperature and stand for 40 h.
The solution was removed with a pipette and the remaining solid was dried in a gentle stream of nitrogen.

Yield: 134 mg (43%) of a colorless amorphous solid
- solid is sparingly soluble in water and MeOH, good soluble in 2 N NaOH
- 11.3 mg used for recrystallisation in MeOH, solid couldn't be completely solved in MeOH (2 mL). Small crystals obtained when mixture cooled to room temperature.

Liberation of the salt with 2 N NaOH, extraction of the aq. layer with DCM (3 x 5 mL), concentrated.
Yield: 25 mg (124 µmol, 25%) PZQamine as a colorless solid
Data: 1H NMR MW47-1 ((-)-PZQamine liberated from the salt)
[a]D20 = -244° (c=1, DCM)

Mother liquor concentrated, solid liberated with 2 N NaOH (see above)
Yield: 30 mg (30%) yellow oil
[a]D20 = +160° (c=1.30, DCM)

loss of PZQamine during work-up (hydrolysis of the compound by NaOH?)
Attached Files
20th September 2010 @ 16:58
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)
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-L-tartaric acid (MW46-1)


Reaction Scheme


Table MW46-2


Hazard and Risk Assessment:
HIRAC MW46


Start time: 11:45 AM 16/09/2010
End time: 2:10 PM 17/09/2010

Procedure: [1]
A mixture of D-(-)-tartaric acid (4.62 g, 30.8 mmol) and FeCl3 (100 mg, 617 µmol) in xylene (20 mL) was heated to 95°C and p-methoxybenzoyl chloride (12.0 g, 70.3 mmol, 9.52 mL) was added dropwise over a period of 1.5 h. After stirring for additional 2 h thionyl chloride was added over a period of 1h and the mixture was stirred for another 2 h. The mixture was heated to 110° for 2 h and then cooled to room temperature while stirring for 4 h.
The ice cooled reaction mixture was filtered off and the brown precipitate was washed with cold toluene and hexane obtaining the di-p-anisoyl-D-tartaric acid anhydride as a pale brown solid.

Hydrolysis of the anhydride: [2]

The remaining solid was solved in a mixture of acetone (30 mL) and water (10 mL) and heated to reflux for 2 h. To the solution was added water (60 mL) causing a precipitation of a colorless solid. Acetone was removed by distillation till the reaction mixture reached a temperature of about 80°C. The mixture was cooled to 0°C and the pale brown precipitate was isolated by filtration.

crude product: pale brown solid
1H NMR MW46-2 (crude product)


- drying residue
- recrystallization from EtOH: only p-methoxybenzoic acid (935 mg) obtained as colorless solid
1H NMR MW46-2 (1st recrystallization from EtOH)
1H NMR MW46-2 (remain recrystallisation from EtOH)


- recrystallization from EtOH/water -> no crystals

- 1st recrystallization from water: 1.30g amorphous colorless solid, 1:1 ratio of Di-p-anisoyl-D-tartaric acid and p-methoxybenzoic acid, remaining pale yellow/orange solid almost pure di-p-anisoyl-D-tartaric acid(NMR) -> recrystallizing ?
1H NMR MW46-2 (2nd bulk precipitate from water)
1H NMR MW46-2 (remain recrystallization from water).jpg



other solvents tested for crystallization: toluene (sparingly soluble), ethyl acetate (2 layers), MeOH (no crystals)

side product: p-methoxybenzoic acid
1H NMR, 13C NMR: p-methoxybenzoic acid
m.p. 182-184°C (lit: 182-185°C [Sigma-Aldrich])

- 2rd cyrstallization from water: 1.28 g (3.06 mmol, 10%) colorless solid (freeze dried) - impurities of p-methoxybenzoic

- 3rd cyrstallization from water: 525 mg (1.26 mmol, 5%) colorless solid (freeze dried) - still impurities of p-methoxybenzoic acid
1H NMR MW46-2 (3rd precipitation from water)


- 4th cyrstallization from water: 969 mg (2.32 mmol, 8%) colorless solid (freeze dried) - traces of p-methoxybenzoic acid
1H NMR MW46-2 (4th precipitation from water)



Results:
- method produces large impurities of p-methoxybenzoic acid
- most of the impurities of p-methoxybenzoic acid can be removed by crystallization from EtOH
- recrystallized precipitat from water contains product and p-methoxybenzoic acid

Analytical data:
m.p. 186-188.5°C (lit: 186 [3])
1H NMR (DMSO-d6, 200 MHz) : δ = 3.50 (bs, 2H), 3.86 (s, 6H), 5.80 (s, 2H), 7.13 (d, J=8 Hz, 4H), 7.97 (d, J=8 Hz, 4H).
Data: 1H NMR MW46-2 (+)-p-dianisoly-D-tartaric acid in DMSO
13C NMR (DMSO-d6, 50.3 MHz) : δ = 55.7 (2C), 71.2 (2C), 114.4 (4C), 120.7 (2C),131.6 (4C), 163.8 (2C), 164.3 (2C),167.4 (2C).
Data: 13C NMR MW46-2 (+)-p-dianisoly-D-tartaric acid in DMSO
IR (neat): nu = 2943 cm-1, 1720, 1662, 1601, 1243, 1170, 1103, 1012, 847, 762, 691.
Data: IR MW46-2
MS (ESI (+)) m/z (%): 875 (35) [2M+K]+, 859 (85) [2M+Na]+, 441 (53) [M+Na]+, 435 (85), 329 (100).
HRMS (ESI (+)) Calcd. for [C20H18O10+Na]+: 441.07922, found: 441.0790.
[alpha]D20 = +157° (c=1, EtOH), [alpha]D20 = +167° (c=1, MeOH). (lit: 163° (c=1, EtOH) [4])
[α]D20 = 169° (c=1, MeOH) -> see: MW46-6
C20H18O10 (418.4).

[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] „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.

[4] TCI America, Chemical Supplier for (+)-Di-p-anisoyl-D-tartaric Acid
Attached Files
16th September 2010 @ 03:28
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)
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)

Reaction Scheme correction


Table MW46-1


Hazard and Risk Assessment:
HIRAC MW46


Start time: 11:31 AM 15/09/2010
End time: 9:10 PM 15/09/2010

Procedure: [1]
A mixture of L-(+)-tartaric acid (2.31 g, 15.4 mmol) and FeCl3 (100 mg, 617 µmol) in xylene (10 mL) was heated to 95°C and p-methoxybenzoyl chloride (6.00 g, 35.3 mmol, 4.76 mL) was added dropwise over a period of 1 h. After stirring for additional 2 h thionyl chloride was added over a period of 30 min 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 4 h.
The ice cooled reaction mixture was filtered off and the brown precipitate was washed with cold toluene and hexane obtaining the Di-p-anisoyl-L-tartaric acid anhydride as a pale brown solid.

1H NMR: di-p-anisoyl-L-tartaric acid anhydride with remaining solvents (toluene, hexane), no remaining p-methoxybenzoyl chloride (?)

Hydrolysis of the anhydride: [2]

Start time: 11:00 AM 16/09/2010
End time: 13:40 PM 16/09/2010

The remaining solid was solved in a mixture of acetone (15 mL) and water (5 mL) and heated to reflux for 2 h. To the solution was added water (20 mL) causing a precipitation of a colorless solid. Acetone was removed by distillation till the reaction mixture reached a temperature of about 80°C. The mixture was cooled to 0°C and the pale brown precipitate was isolated by filtration.

1H NMR: di-p-anisoyl-L-tartaric acid and an excess p-methoxybenzoic acid as side product (?)

- Drying of the crude product by heating to about 80°C in vacuo -> problems with the heating mantle (too hot!)
- Residue was dissolved in acetone, a colorless (sparingly soluble) residue was identified as p-methoxybenzoic acid

side product: p-methoxybenzoic acid
1H NMR, 13C NMR: p-methoxybenzoic acid
m.p. 182-184°C (lit: 182-185°C [Sigma-Aldrich])

Procedure from reference: [1]
(translated from Chinese)
To a 1000 mL 3-necked round-bottom flask (condenser, gas-catcher, thermometer, dropping funnel) xylene (300 mL) and L-tartaric acid were added. A catalytic amount of FeCl3 was added while stirring. The reaction mixture was heated to 90-95°C. Then p-methoxybenzoyl chloride (260 g) in toluene was added dropwise in 3 h (90-95°C). SOCl2 (96 g) was added dropwise in ca. 3 h. The reaction mixture was heated to 110-115°C and stirred for 2 h, then cooled down to room temperature while stirring for 4 h. The pressure was reduced to remove HCl gas. The reaction mixture was filtered. The solid was washed with tiny amount of toluene, dried give a white solid.


Procedure from reference: [2]
EXAMPLE 20
Scheme B, step a and step b, and Scheme C, step a: (R)-.alpha.-(2,3-Dimeth- oxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, (2S,3S)-(+)-di-(p-anisoyl)tartaric acid salt (3a')

[0193] In a suitable reactor, maintained under an argon atmosphere, is slurried p-anisic acid (39.5 kg, 260 mol) with about 51 kg of xylenes..sup.1 Oxalyl chloride (27.7 kg) is added while maintaining the temperature below about 60.degree. C. The mixture is heated between 50-60.degree. C. for about 1 hour until a homogeneous solution is formed. The mixture is heated to about 100.degree. C. and any remaining oxalyl chloride is removed by distillation. The mixture is then cooled to 60-70.degree. C.

[0194] In a second suitable reactor, (2S,3S)-(-)-tartaric acid (12.7 kg, 85 mol) is slurried with about 45 kg of xylenes.sup.2. The warm (above 70.degree. C.) solution of p-anisoyl chloride is added and the mixture is heated to about 135.degree. C. for about 3 hours. The mixture is then cooled to about 60.degree. C. About 13 kg of oxalyl chloride is added and the mixture is heated to about 65.degree. C. for at least 1 hour. The reaction mixture may be heated to about 70.degree. C. to partially dissolve the anhydride.sup.3. The mixture is then maintained at this temperature for about 1 hour. The crystallization is completed by cooling the mixture to about -10.degree. C. for approximately 1 hour prior to isolating the anhydride by filtration. The wet cake is washed with about 38 kg of cold xylenes to typically afford 22-36 kg (13-20% xylenes) of anhydride (70-91% yield).sup.4.

[0195] A suitable reactor is charged with anhydride (28 kg, 60 mol) as a xylenes wet cake, acetone (78 kg) and 26 kg of water. The mixture is heated at reflux (60.degree. C.) for about 2 hours. To the mixture (at about 60.degree. C.) is added about 190 kg of water, causing precipitation of (2S,3S)-(+)-di-(p-anisoyl)tartaric acid. Acetone is removed by distillation until the temperature of the mixture reaches about 80.degree. C. The mixture is cooled to about 5.degree. C. and the product is isolated by filtration. The reactor and transfer lines are rinsed with about 38 kg of water. The wet cake is washed with about 170 kg of water to typically afford 23-33 kg (with 5-30% solvent) of (2S,3S)-(+)-di-(p-anisoyl)tartaric acid (64-104% yield)..sup.5 The product is dried at about 70-80.degree. C. (under vacuum)..sup.6


[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