(R,R)-Di-p-anisoyltartaric acid

white to light yellow crystal powde

Stir the (R)-α-(2, 3-dimethoxyphenyl)-4-piperidinemethanol, (2R, 3R)-(-)-di-(p-anisoyl)tartaric acid (7g) with 10 mL concentrated ammonia and 20 mL MeOH. After 2 hours, add 30 mL HAdd 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°C for an hour. Allow the mixture to cool to 100°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.To a stirred solution of intermediate 1 (102 g, 439.7 mmol) in 5percent water in methanol (1236 ml, 12V), D-di-p-anisoyltartaric acid (92.86 g, 219.8 mmol) was added at RT and refluxed for 30 min.In first instance all the material was dissolved and then salt was precipitated as a white solid.The mixture was stirred at RT overnight before the solid was collected by filtration and washedtwice with 5percent of water in methanol (2 x 1.0 L). The optical purities of the solid was 87percent ee. Thesolid was refluxed in methanol containing 5percent of water 12 V (1.2 L). The mixture was allowed to cool to RT and stirred overnight before the solid was collected by filtration and washed twice with5percent of water in methanol (2 x 1.0 L). The optical purity of the solid was 94percent ee. The solid wasagain dissolved in refluxing methanol containing 5percent of water (1.2 L). The mixture was allowed tocool to RT and stirred overnight before the solid was collected by filtration and washed with 5percentof water in methanol (1.2 L). The optical purity of the solid was 97.94percent ee (enantiomeric purity 98.9percent). The latter was dried in vacuum to furnish the title compound as D-di-p-anisoyltartaricacid salt (1-( 1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazine hemi( (2R, 3R)-2, 3-bis( (4-methoxybenzoyl)oxy)succinate)). Yield: 33percent (65 g, off-white solid). The above solid wasdissolved in water (100 ml) and the resulting solution was basified (pH = 14) using 5 N NaOH solution (200 ml). The compound was extracted with EtOAc (2 x 500 ml). The combined organic layer was washed with brine solution (500 ml), dried over anhydrous Na2S04 . It wasevaporated under vacuum to give the title compound. Yield: 59percent (30.5 g, pale brown gummysolid). 1H NMR (300 MHz, DMSO-d6): o 7.12 (d, J = 7.2 Hz, 1 H), 6.72 (d, J = 7.8 Hz, 1 H), 6.66(s, 1 H), 4.49 (t, J = 8.7 Hz, 2H), 3.30 (q, J = 6.6 Hz, 1 H), 3.12 (t, J = 8.6 Hz, 2H), 2.65-2.62 (m, 4H), 2.20-2.17 (m, 4H), 1.20 (d, J = 6.6 Hz, 3H). LCMS: (Method A) 233.0 (M+H), Rt. 1.6 min, 84.2percent (Max). HPLC: (Method A) Rt. 1.6 min, 85.8percent (Max). Chiral HPLC: (Method A) Rt. 3.0min, 97.8percent (Max).EXAMPLE 226 Synthesis of (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-//-(thiazol-4- yl)benzenesulfonamide formate Step 1. Preparation of (S)-/V-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide {2R, 3R)-2, 3- bis((4-methoxybenzoyl)oxy)succinate To a solution of (-)-0, 0'-di-p-toluoyl- .-tartaric acid (1 1.5 g, 27.7 mmol) in ehtnaol (200 ml) was added A/-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide (9.0 g, 38.7 mmol). The mixture was stirred at 10 °C for 15 minutes, and then heated to 70 °C for 10 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred for 48 h. The resultant solid was filtered off, the filter cake washed with ethanol (100 ml) and dried under reduced pressure to provide a colorless solid. The solid was dissolved in ethanol (100 ml_), heated to reflux for 30 minutes, and allowed to cool to ambient temperature. The obtained precipitate was filtered off and to give a colorless solid. The recrystallization step was repeated twice to provide the title compound as a colorless solid (20.9 g, 33percent yield): H NMR (400 MHz, DMSO-d6) 8.07 (s, 1 H), 7.94 (d, J = 8.8 Hz, 4H), 7.44-7.38 (m, 2H), 7.36-7.25 (m, 3H), 7.06 (d, J = 8.8 Hz, 4H), 5.69 (s, 2H), 4.12-4.02 (m, 2H), 3.83 (s, 6H), 3.24 (d, J = 11.4 Hz, 1 H), 3.10 (d, J = 6.4 Hz, 2H), 2.97 (d, J = 11.4 Hz, 1 H), 2.14 (td, J = 12.8, 6.4 Hz, 1 H), 1.88-1.77 (m, 1 H), 1.74 (s, 3H), 1.29 (s, 3H), two COOH not observed.Weigh 0.147g Ondansetron racemate and0.219 g O, O'-di-p-anisal-L-tartaric acid resolving agentInto a 50ml round bottom flask, 18 ml of dichloromethane and 5 ml of methanol were added, Ultrasound assisted heating reflux for 1 hour, Solids dissolve quickly, the solution is clear, Standing or stirring for three hours cooling, suction filtration, 0.163 g of O, O'-di-p-anisalyl-L-tartrate as a white powdery solid levododeoxytron, The optical purity was 90.5percent ee and the yield was 44.5percent.The above oil was cast in 180 mL of isopropanol, To this was added 15.09 g (39.05 mmol)L - (-) - p-methyl dibenzoyl tartaric acid and 140 mL of water, Heated to 80 ° C, The solution becomes clear, Slowly cool down to 30 ° C, Add seed, Slowly cool down to 5 ° C, Keep stirring for 12h, There are a lot of white crystal precipitation, filter, Collecting filter cake, Washed with isopropanol / water (1.3: 1)Vacuum was dried under reduced pressure to give white crystals 15.38 (1.6. & Gt; 99percent), Yield: 32.0percent, (S)-1(S, S)-DMTA (81.8percent yield) was obtained from 1 and (S, S)-DMTA by using the above mentioned method. The colorless solid(6.97 g, 0.01 mol) was stirred in a solution of Na2CO3 (1.6 g, 0.015 mol) and then extracted with ethyl acetate (100 mL 3).The extracts were washed with water (100 mL 2), dried over (anhydrous Na2SO4), and evaporated. The residue (S)-1 (2.68 g, 96.1percent yield and 99.1percent ee) was obtained as a colorless solid.Equimolar quantities of (S)-1 and 4 were dissolve in ethyl acetate.After the organic phases concentrated in vacuum, the resultingcrystals were collected by filtration. Mp: 90 C; IR (KBr):m = 3431, 2961, 2872, 2834, 2730, 2024, 1913, 1722, 1608, 1512, 1468, 1405, 1265, 1170, 1106, 1024, 839, 769, 693 and515 cm1; 1H NMR (400 MHz, CDCl3, d): 8.02 (d, J = 8.8 Hz, 4H), 7.34 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 4H), 5.91 (s, 2H), 3.82 (s, 6H), 3.47'3.45 (m, 1H), 2.69'2.14 (m, 10H), 1.84'1.80 (m, 1H), 1.75'1.65 (m, 2H), 1.43'1.35 (m, 1H), 1.28'1.20 (m, 1H), 1.00'0.96 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3, d): 169.4, 164.3, 162.4, 138.6, 132.4, 131.1, 128.9, 127.7, 121.3, 112.5, 70.9, 70.4, 54.4, 48.4, 34.2, 33.6, 32.6, 24.5, 22.1, 20.9, 14.9 ppm.Sibutramine 1 (31.0 g, 0.11 mol) was added to a solution of 4(41.7 g, 0.1 mol) in ethanol (530 mL). While stirring, n-hexane(500 mL) was added to the solution. The mixture was heated atreflux for 1 h and then cooled to room temperature. The resultingcolorless crystals were collected by filtration and recrystallized inisopropanol. 32.6 g (84.5percent yield and 98.6percent ee) of the salt of (R)-14 was obtained. Mp: 161 C; IR (KBr): m = 3431, 2955, 2879, 2847, 2040, 1919, 1716, 1614, 1506, 1347, 1252, 1176, 1099, 1024, 846, 769, 699 and 521 cm1; 1H NMR (400 MHz, CDCl3, d):8.03 (d, J = 8.8 Hz, 4H), 7.35 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 4H), 5.92 (s, 2H), 3.82 (s, 6H), 3.48'3.45(m, 1H), 2.58'2.19 (m, 10H), 1.74'1.69 (m, 2H), 1.63'1.58 (m, 1H), 1.44'1.36 (m, 1H), 1.28'1.22 (m, 1H), 1.01'0.96 (m, 6H)ppm; 13C NMR (100 MHz, CDCl3, d): 169.4, 164.3, 162.4, 138.7, 132.4, 131.1, 128.9, 127.7, 121.3, 112.5, 70.8, 70.5, 54.4, 48.3, 34.3, 33.6, 32.5, 24.5, 22.0, 20.9, 14.8 ppm.General procedure: To a 250 mL flask were added rac-3 (6.857 g, 9.5 mmol) and CHCl3 (27 mL). Then thesolution was heated to 40 °C. A solution of (+)-Di-p-methoxybenzoyl-D-tartaric acid (4.568 g, 9.5mmol) in EtOAc (41 mL) was added dropwise to the reaction mixture. After stirring for 30 min at 40 °C, the solution was cooled to room temperature and stirred for another 1 h. The combined filtrate was filtered and washed with a mixtured solution of CHCl3/EtOAc (1/3) (10 mLx3). The solid was transferred to a flask and dried under vacuum to give complex [(S)-4/(D)-DMTA] as a white solid (4.447 g, 78 percent yield).Then DCM (30 mL) and 2 mol/L NaOH (10 mL) was added to the flask and the mixture was stirred for 30 min at room temperature. The organic layer was separated, washed with 2 mol/L NaOH and brine, then dried over anhydrous Na2SO4, filtered and concentrated under vacuum togive (S)-4 as a white solid (2.940 g, >99percent ee).

Molecular Weight:418.3
XLogP3:2.5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:11
Exact Mass:418.08999677
Monoisotopic Mass:418.08999677
Topological Polar Surface Area:146
Heavy Atom Count:30
Complexity:563
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes