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CAS No. : | 133-37-9 | MDL No. : | MFCD00071626 |
Formula : | C4H6O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FEWJPZIEWOKRBE-JCYAYHJZSA-N |
M.W : | 150.09 | Pubchem ID : | 444305 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 4.0 |
Molar Refractivity : | 27.21 |
TPSA : | 115.06 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.55 cm/s |
Log Po/w (iLOGP) : | -0.29 |
Log Po/w (XLOGP3) : | -1.88 |
Log Po/w (WLOGP) : | -2.12 |
Log Po/w (MLOGP) : | -2.18 |
Log Po/w (SILICOS-IT) : | -1.88 |
Consensus Log Po/w : | -1.67 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | 0.61 |
Solubility : | 614.0 mg/ml ; 4.09 mol/l |
Class : | Highly soluble |
Log S (Ali) : | -0.02 |
Solubility : | 144.0 mg/ml ; 0.963 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 2.44 |
Solubility : | 41700.0 mg/ml ; 278.0 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.57 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With Dowex 50W-X8 (H+) In benzene Heating; | |
With hydrogenchloride | ||
With hydrogenchloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroquinone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide | ||
With potassium hydroxide | ||
With sodium hydroxide Racemisierung; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
bei der trocknen Destillation; | ||
With hydrogenchloride at 180℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Spaltung mit Cinchonin; | ||
With sodium ammoniumracemat durch Krystallisation; | ||
With sodium ammoniumracemat; water durch Krystallisation; hierbei scheidet sich ein mechanisch trennbares Gemisch gleicher Teile der enantiostereomeren Natriumammoniumtartrate aus; |
Durch Impfen der uebersaettigten Loesung des Racemats mit einer der Komponenten; | ||
durch biochemische Spaltung mittels Aspergillus niger und griseus; | ||
Durch Kombination mit optisch aktiven Alkaloiden, z.B.Chinicin,Cinchonicin; | ||
With water; (+)-N-methylamphetamine | ||
With ethanol; 2-<D-glycero-D-gulo-hexahydroxyhexyl>-benzimidazole | ||
fraktionierte Krystallisation des sauren l-Menthylesters; | ||
fraktionierte Krystallisation des sauren l-Bornylesters; | ||
Spaltung mit Benzyl-<d-α-phenaethyl>-amin; | ||
Spaltung mit d-1-Oxy-hydrindamin-(2); | ||
With Cinchonin | ||
mit Hilfe von Aspergillus fumigatus; | ||
mit Hilfe von Penicillum lilacinum; | ||
durch biochemische Spaltung mittels Penicillium glaucum; | ||
With water; Cinchonin beim Erkalten krystallisiert reines l-weinsaures Cinchonin; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water at 165℃; | ||
With hydrogenchloride | ||
With alkaline solution ueber den Verlauf dieser Reaktion; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acidic l-bornyl ester | ||
With acidic l-menthyl ester durch fraktionierte Krystallisation; | ||
With N-benzyl-1-phenylethylamine |
With d-1-oxy-hydrindamine; Cinchonin |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium permanganate at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; dihydrogen peroxide at 70 - 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminium salt | ||
With water at 175℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; lead dioxide bei der elektrolytischen Oxydation; | ||
With dihydrogen peroxide; tungsten(VI) oxide | ||
With dihydrogen peroxide; tungsten(VI) oxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chlorate; osmium(VIII) oxide; water | ||
With sodium chlorate; osmium(VIII) oxide; water at 50℃; | ||
With osmium(VIII) oxide; potassium chlorate; water at 50℃; |
With sodium chlorate; osmium(VIII) oxide; water | ||
With potassium permanganate | ||
With sodium chlorate; osmium(VIII) oxide; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With osmium(VIII) oxide; dihydrogen peroxide; <i>tert</i>-butyl alcohol at 0℃; | ||
With osmium(VIII) oxide; dihydrogen peroxide; <i>tert</i>-butyl alcohol at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; dihydrogen peroxide | ||
With sodium hydroxide; dihydrogen peroxide at 70 - 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With bis(cyclopentadienyl)-titanium(III) chloride In tetrahydrofuran at -78 - 20℃; | |
With acetic acid; zinc | ||
elektrolytische Reduktion; |
With alkali elektrolytische Reduktion; | ||
Electrolysis; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; dihydrogen peroxide | ||
With sodium hydroxide; dihydrogen peroxide at 70 - 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water bei der Spaltung scheidet sich ChinotoxinLg-tartrat aus; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With acidic ion exchange resin In chloroform for 40h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitric acid at 56℃; | ||
With silver(I) acetate und Oxydation der entstandenen (+-)-Threonsaeure mit HNO3; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitric acid at 56℃; | ||
With silver(l) oxide und Oxydation der entstandenen (+-)-Threonsaeure mit HNO3; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With permanganate(VII) ion |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; chlorine; potassium bromide In water at 0 - 5℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogenchloride for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4 A molecular sieve In xylene for 19h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.1% | In water; isopropyl alcohol at 20℃; for 4h; | 8 Example 8: l-ethoxy-5-fluoro-4,4-dimethoxy-l-oxopentan-3-aminium tartarate (10, R1= ethyl, R2= methyl, R6=H); A solution of ethyl 3-amino-5-fluoro-44-dimethoxypentanoate (1, R1= ethyl, R2= methyl, 4.33 g, 19.4 mmol) in isopropanol (40 mL) was heated to 50 0C, and treated with a solution of D,L-tartaric acid (2.91 g, 19.4 mmol) in water (6.6 mL). The oil bath was removed and the mixture was stirred at ambient mixture for 2 h. The resulting suspension was diluted with a mixture of isopropanol (47 mL) and water (2 mL), and stirring was continued for further 2 h. The precipitate was filtered, washed with isopropanol (18 mL) and dried over N2 purge to give the title compound (10, R1= ethyl, R2= methyl, R6=H, 6.31 g, 87.1%). 1H NMR (500 MHz, CDCl3) δ 4.58 (dd, J = 11.0 and 46.5 Hz, IH), 4.40 (dd, J = 11.0 and 46.5 Hz, IH), 4.09 (s, 2H), 4.04 (q, J = 6.8 Hz, 2H), 3.44 (dd, J = 3.1 and 10.4 Hz, IH), 3.18 (s, 3H), 3.17 (s, 3H), 2.58 (dd, J = 3.5 and 15.9 Hz, IH), 2.29 (ddd, J = 1.9, 9.8 and 15.9 Hz, IH), 1.16 (t, 2.58, J = 7.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 50℃; | 10 (S)-tolterodine D-tartrate D-tartaric acid (34.5 mg; 0.23 MMOL) was added to a solution of (S)- tolterodine (75 mg; 0.23 MMOL), prepared according to the preceding Example 9, in EtOH (5 ML). The mixture thus obtained was heated to about 50°C, filtered while hot to remove a slight turbidity, and then concentrated to dryness at reduced pressure to give a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Detailed Process Description for (S)-Amlodipine Hemi-D-Tartrate DMAC solvate: The following is a typical batch description for the process using the racemic besylate salt as an input. 1. N, N-Dimethylacetamide (DMAC) (152.7 kg) was charged to a 100 gal reactor (T- 110A). 2. D-Tartaric acid (13. 88 kg) was charged slowly to T-110A. 3. The solution in T-11 OA was mixed and held for use later in the batch. 4. (R -<strong>[111470-99-6]Amlodipine besylate</strong> (49.81 kg) was charged to a 200 gal reactor (R-120), followed by methyl t-butyl ether (MTBE) (239.3 kg). 5. Aqueous sodium hydroxide (IN) (137. 2kg) was added to R-120. 6. The contents of R-120 were agitated for 20-30 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 7. The bottom aqueous layer was removed and USP water (66.0 kg) was charged to R- 120. 8. The contents of R-120 were agitated for a minimum of 20 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 9. The bottom aqueous layer was removed and USP water (66.0 kg) was charged to R- 120. 10. The contents of R-120 were agitated for a minimum of 20 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 11. The bottom aqueous layer was removed from R-120. 12. The contents of R-120 were polish filtered through a 3am cartridge filter to R- 110A, followed by a reactor and line rinse with MTBE (49.9 kg). 13. The contents of R-110A were concentrated under vacuum (maximum 50C) to a calculated volume (109 L). 14. DMAC (152. 8 kg) was charged to the contents ofR-110A. 15. The contents of R-11 OA were again concentrated under vacuum, this time until the batch temperature reached 45-55 C. The final volume was 208L. 16. R-110A contents were cooled to 20 to 25 C, followed by the addition of the previously prepared D-tartaric acid solution (166. 0kg) at 20-25 C over 20 to 30 minutes. 17. The mixture was heated to 68-72 C over 55 to 65 minutes, and held at this temperature for 55 to 65 minutes. 18. The reaction mixture was cooled to 21 to 23 C over 2 to 3 hours using a linear cooling profile and agitated at this temperature for 30 to 40 minutes. 19. The slurry was filtered on a centrifuge (CE-102) in one load and washed with DMAC (75.7 kg) and MTBE (59.9 kg). 20. The wet cake was discharged (20.33 kg) and dried in vacuum tray dryer (D-401) for a minimum of 6 hours at 45-50C to yield 20.086 kg of (S)-Amlodipine Hemi-D- Tartrate DMAC solvate. | ||
With sodium hydroxide; In tert-butyl methyl ether; ISOPROPYLAMIDE; water; at 20 - 72℃; for 5.66667 - 6.41667h;Resolution of racemate; | The following is a typical batch description for the process using the racemic besylate salt as an input. 1. NN-Dimethylacetamide (DMAC) (152.7 kg) was charged to a 100 gal reactor (T-110A). 2. D-Tartaric acid (13.88 kg) was charged slowly to T-110A. 3. The solution in T-11OA was mixed and held for use later in the batch. 4. (RS)-<strong>[111470-99-6]Amlodipine besylate</strong> (49.81kg) was charged to a 200 gal reactor (R-120), followed by methyl t-butyl ether (MTBE) (239.3 kg). 5. Aqueous sodium hydroxide (1 N) (137.2 kg) was added to R-120. 6. The contents of R-120 were agitated for 20-30 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 7. The bottom aqueous layer was removed and USP water (66.0 kg) was charged to R-120. 8. The contents of R-120 were agitated for a minimum of 20 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 9. The bottom aqueous layer was removed and USP water (66.0 kg) was charged to R-120. 10. The contents of R-120 were agitated for a minimum of 20 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 11. The bottom aqueous layer was removed from R-120. 12. The contents of R-120 were polish filtered through a 3 " m cartridge filter to R- 110A, followed by a reactor and line rinse with MTBE (49.9 kg). 13. The contents of R-110A were concentrated under vacuum (maximum 50No.C) to a calculated volume (109 L). 14. DMAC (152.8 kg) was charged to the contents of R-110A. 15. The contents of R-110A were again concentrated under vacuum, this time until the batch temperature reached 45-55No.C. The final volume was 208 L. 16. R-110A contents were cooled to 20 to 25No.C, followed by the addition of the previously prepared D-tartaric acid solution (166.0 kg) at 20-25No.C over 20 to 30 minutes. 17. The mixture was heated to 68-72No.C over 55 to 65 minutes, and held at this temperature for 55 to 65 minutes. 18. The reaction mixture was cooled to 21 to 23No.C over 2 to 3 hours using a linear cooling profile and agitated at this temperature for 30 to 40 minutes. 19. The slurry was filtered on a centrifuge (CE-102) in one load and washed with DMAC (75.7 kg) and MTBE (59.9 kg). 20. The wet cake was discharged (20.33 kg) and dried in vacuum tray dryer (D-401) for a minimum of 6 hours at 45-50No.C to yield 20.086 kg of (S)-Amlodipine Hemi-D-Tartrate DMAC solvate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water In ethanol at 50℃; | 5.1; 5.4 EXAMPLE 5; TARTARIC ACID SALTS OF COMPOUND I; EXAMPLE 5.1; HIGH THROUGHPUT CRYSTALLIZATION SCREENING; [00326] The following crystalline forms of tartaric acid salts were prepared by high throughput crystallization, according to the general procedure described in Example 1.1:[00327] Larger quantities of the tartaric acid salts were prepared according to the following procedures:; EXAMPLE 5.4; FORM V.3; [00330] A mixture was prepared by combining 0.225 g of racemic tartaric acid in 15 mL of ethanol followed by the addition of 1.0 g of Compound I. The mixture was heated to 5O0C and stirred overnight. The slurry was then cooled to ambient temperature and the resulting solid material was isolated and dried to afford 0.86 g of crystalline material that was found to contain 1 eq. of racemic tartaric acid and 0.5 eq. of ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol soln. of tartaric acid in ethanol added NH3 (neutral react.), resulted white ppt., then pptd. crystallic powder; filtrated, washed with alc. and ether; | ||
tartaric acid oversatd. with NH3; | ||
tartaric acid oversatd. with NH3; |
In ethanol soln. of tartaric acid in ethanol added NH3 (neutral react.), resulted white ppt., then pptd. crystallic powder; filtrated, washed with alc. and ether; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium bicarbonate In water neutralization of tartaric acid with sodium bicarbonate, addn. of soln. of Co-complex; crystn. on standing (several days); elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water In water addn. of tartaric acid soln. to a diluted solution of Cu(CH3COO)2;; | ||
With H2O In water addn. of tartaric acid soln. to a diluted solution of Cu(CH3COO)2;; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
>99 | With water In water ppt.;; | |
With water In water hot concd. solns.;; | ||
With H2O In water hot concd. solns.;; |
>99 | With H2O In water ppt.;; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In not given | ||
In not given |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In diethyl ether byproducts: H2, cyclopentadiene; Ar atmosphere; 20 h, 95°C; ppt. was filtered off, washed with ether, and dried; elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With air In tetrahydrofuran bubbling air through cobaltocene soln. in presence of of tartaric acid (1 equiv.); filtration, recrystn. (H2O); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With air In tetrahydrofuran bubbling air through cobaltocene soln. in presence of of tartaric acid (2 equiv.); filtration, recrystn. (H2O); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In water High Pressure; reaction of In(OH)3, organic ligand and H2O at 110°C for 2 days; elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With KOH In water High Pressure; hydrothermally with KOH in H2O at 140°C for 2 d; XRD; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.7% | In water at 20℃; for 4 - 5h; | 14 EXAMPLE 14 Preparation of (R)-Amlodipine-D-Hemitartrate DMF Solvate D-tartaric acid (1.47 gms; 0.01 moles) was added to the mother liquor obtained from Example 1. and stirred at ambient temperature for 240-300 minutes, till complete precipitation of the product. The title compound was then filtered and dried. Yield: 6.4 gms. % Yield; 67.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.38% | In water; at 20℃; for 4.5h;Product distribution / selectivity; | EXAMPLE-9 (R)-<strong>[88150-42-9]Amlodipine</strong>-D-hemitartrate Dimethyl Formamide Solvate (RS)-<strong>[88150-42-9]Amlodipine</strong> (16 gm, 0.04 moles) was dissolved in 140 ml dimethyl formamide water mixture (15% water in DMF). To this mixture, a solution of D-tartaric acid, prepared by dissolving tartaric acid (1.47 g, 0.01 moles) in 20 ml DMF+water mixture (proportion as referred above) was added drop wise in 30 min. The mixture was stirred for 4 hr at room temperature after addition. The slurry was filtered and the residual solid was washed with acetone (10 ml) and dried to give the title product: Yield=7.4 gm. % Yield: 78.38%. Melting point; 137 C. Optical Purity by Chiral HPLC: 99.50% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In tetrahydrofuran for 17h; | 7 [00110] A 250 mL reactor was charged with 1.5 g (^-zopiclone, 90 mL tetrahydrofuran and heated to 40 0C to dissolve. A 125 mL reactor was charged with 630 mg d-tartartic acid and 60 mL tetrahydrofuran, and was heated to 40 0C to dissolve. The acid solution was transferred to the zopiclone solution, seeded and mixed for 17 hours. The reactor slurry was filtered and washed with tetrahydrofuran in a filter. The wet cake was dried under vacuum to provide the titled compound in 77% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1. N, N-Dimethylacetamide (DMAC) (152.7 kg) was charged to a 100 gal reactor (T-110A). 2. D-Tartaric acid (13.88 kg) was charged slowly to T-110A. 3. The solution in T-110A was mixed and held for use later in the batch. 4. (RS)-<strong>[111470-99-6]Amlodipine besylate</strong> (49.81kg) was charged to a 200 gal reactor (R-120), followed by methyl t-butyl ether (MTBE) (239.3 kg). 5. Aqueous sodium hydroxide (1 N) (137.2 kg) was added to R-120. 6. The contents of R-120 were agitated for 20-30 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 7. The bottom aqueous layer was removed and USP water (66.0 kg) was charged to R-120. 8. The contents of R-120 were agitated for a minimum of 20 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 9. The bottom aqueous layer was removed and USP water (66.0 kg) was charged to R-120. 10. The contents of R-120 were agitated for a minimum of 20 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 11. The bottom aqueous layer was removed from R-120. 12. The contents of R-120 were polish filtered through a 3 mum cartridge filter to R- 110A, followed by a reactor and line rinse with MTBE (49.9 kg). 13. The contents of R-110A were concentrated under vacuum (maximum 50C) to a calculated volume (109 L). 14. DMAC (152.8 kg) was charged to the contents of R-110A. 15. The contents of R-110A were again concentrated under vacuum, this time until the batch temperature reached 45-55C. The final volume was 208 L. 16. R-110A contents were cooled to 20 to 25C, followed by the addition of the previously prepared D-tartaric acid solution (166.0 kg) at 20-25C over 20 to 30 minutes. 17. The mixture was heated to 68-72C over 55 to 65 minutes, and held at this temperature for 55 to 65 minutes. 18. The reaction mixture was cooled to 21 to 23C over 2 to 3 hours using a linear cooling profile and agitated at this temperature for 30 to 40 minutes. 19. The slurry was filtered on a centrifuge (CE-102) in one load and washed with DMAC (75.7 kg) and MTBE (59.9 kg). 20. The wet cake was discharged (20.33 kg) and dried in vacuum tray dryer (D-401) for a minimum of 6 hours at 45-50C to yield 20.086 kg of (S(at)-Amlodipine Hemi-D-Tartrate DMAC solvate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methylated spirit industrial 74 O.P. Reflux; | 3b Example 3b(5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol D-Tartrate; (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (1.50 g (96% w/w, 3.1 mmoles), D-tartaric Acid (0.51 g, 3.4 mmoles) and methylated spirit industrial 74 O.P. (15.0 ml) were charged to a 100 ml reactor and heated to reflux. Product began to precipitate. On cooling more product precipitated. Product was isolated, washed with methylated spirit industrial 74 O.P. and dried in vacuum oven at 50 C for 4 h to yield 1.98 g of (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol D-Tartrate as a yellow solid.NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22-1.26 (3H, d), 1.34-1.39 (3H, d), 3.14-4.00 (19H, overlapping m), 4.30 (2H, s), 4.40 (1H, d), 4.57 (2H, s), 4.72-4.80 (1H, broad), 5.11-5.23 (1H, broad), 7.09 (1H, d), 7.60 (1H, d), 8.05 (1H, dd), 8.16 (1H, d), 8.31 (1H, s).M.pt: Begins to decompose from about 128° C. onwards forming a resin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With calcium acetate In water at 60℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With strontium(II) acetate In water at 100℃; for 48h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With barium(II) acetate In water at 60℃; for 48h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.3% | In ethanol; for 0.08333330000000001h;Reflux; | The racemic base 2b, prepared in Example 3, optionally purified as described in Example 4, 5 or 6, in the quantity of 17.2 g is dissolved in 172 ml of warm wine spirit. A solution of 6.24 g of D-tartaric acid in 62 ml of wine spirit is added to this solution and the resulting solution is carefully heated to slight reflux for 5 minutes. During spontaneous cooling the required lasofoxifene D-tartrate precipitates in the yield of 11.8 g, i.e. 50.3percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: tiotropium bromide With Dowex 1x8-200, bicarbonate loaded In water at 25℃; for 0.25h; Stage #2: D-tartaric acid In water | 19 Example 19 Crystalline Anhydrous Tiotropium Tartrate (Form I) 1.00 g of tiotropium bromide monohydrate (according to WO 02/30928) was dissolved in 50 ml of demineralised water at 25° C. 10 ml of bicarbonate loaded IER slurry was added to this solution and stirred for 5 minutes before a second equivalent of 5 ml bicarbonate loaded IER slurry was added. The mixture was stirred for additional 5 minutes. A silver nitrate test as described above indicated the completion of the exchange. After stirring for an additional 5 minutes the slurry was filtered with PTFE filters with a pore size of 10 μm. The collector vial was previously charged with 1.1 equivalents of D-tartaric acid in 10 ml of water. From the resulting solution water was evaporated under vacuum over a water bath which was kept below 35° C. The obtained solid was further dried under vacuum yielding an amorphous oil of the tartrate of tiotropium. Approx. 500 mg of the amorphous tiotropium tartrate are dissolved in 4 ml of a water. In two steps 75 μl (40+35 μl) of this stock solution is transferred into one of the small vials of a 96 well plate. The plate containing the stock solution was placed in a vacuum chamber (1 kPa) at room temperature for 24 h for each dosing step. After the stock solvent was evaporated 30 μl of a mixture of acetonitrile/water=50:50 was added to this vial. The whole 96 well plate is sealed afterwards and heated up with a heating rate of 5° C./min to 50° C. at which the plate stays for an additional 30 minutes. Afterwards the plate is cooled with a cooling rate of 5° C./h to a final temperature of 5° C. At this temperature the plate remained for a hold time of 24 h. The plates are opened afterwards the solid is obtained by evaporation of the solvent at room temperature in a vacuum chamber (13 kPa). Melting point: 180+/-3° C. (DSC); table 19 summarizes the X-ray powder reflections obtained for this form. TABLE 19 2 Θ [°] d []I/Io [%] 4.38 20.16 100 8.74 10.11 24 10.78 8.20 27 12.18 7.25 15 12.82 6.90 38 13.90 6.36 6 14.46 6.12 16 16.22 5.46 58 17.42 5.08 66 17.98 4.93 38 18.86 4.70 14 20.10 4.41 99 21.58 4.11 20 22.14 4.02 11 23.66 3.76 7 24.38 3.65 11 25.90 3.44 4 26.46 3.36 9 | |
Stage #1: tiotropium bromide With Dowex 1x8-200, bicarbonate loaded In water at 25℃; for 0.25h; Stage #2: D-tartaric acid In water | 20 Example 20 Crystalline Anhydrous Tiotropium Tartrate (Form II) 1.00 g of tiotropium bromide monohydrate (according to WO 02/30928) was dissolved in 50 ml of demineralised water at 25° C. 10 ml of bicarbonate loaded IER slurry was added to this solution and stirred for 5 minutes before a second equivalent of 5 ml bicarbonate loaded IER slurry was added. The mixture was stirred for additional 5 minutes. A silver nitrate test as described above indicated the completion of the exchange. After stirring for an additional 5 minutes the slurry was filtered with PTFE filters with a pore size of 10 μm. The collector vial was previously charged with 1.1 equivalents of D-tartaric acid in 10 ml of water. From the resulting solution water was evaporated under vacuum over a water bath which was kept below 35° C. The obtained solid was further dried under vacuum yielding an amorphous oil of the tartrate of tiotropium. Approx. 500 mg of the amorphous tiotropium tartrate are dissolved in 4 ml of a water. In two steps 75 μl (40+35 μl) of this stock solution is transferred into one of the small vials of a 96 well plate. The plate containing the stock solution was placed in a vacuum chamber (1 kPa) at room temperature for 24 h for each dosing step. After the stock solvent was evaporated 30 μl of ethanol was added to this vial. The whole 96 well plate is sealed afterwards and heated up with a heating rate of 5° C./min to 50° C. at which the plate stays for an additional 30 minutes. Afterwards the plate is cooled with a cooling rate of 5° C./h to a final temperature of 25° C. At this temperature the plate remained for a hold time of 24 h. The plates are opened afterwards the solid is obtained by evaporation of the solvent at room temperature in a vacuum chamber (13 kPa). Melting point: 190+/-3° C. (DSC); table 20 summarizes the X-ray powder reflections obtained for this form. TABLE 20 2 Θ [°] d []I/Io [%] 5.62 15.71 61 9.42 9.38 93 11.22 7.88 28 12.82 6.90 23 14.82 5.97 47 15.78 5.61 17 16.02 5.53 21 16.82 5.26 76 18.14 4.88 100 19.02 4.66 21 20.26 4.38 45 21.58 4.11 70 22.26 3.99 45 22.82 3.89 36 24.18 3.68 39 24.78 3.59 14 25.54 3.48 18 26.78 3.33 18 27.22 3.28 8 28.58 3.12 14 29.30 3.04 22 29.94 2.98 14 | |
Stage #1: tiotropium bromide With Dowex 1x8-200, bicarbonate loaded In water at 25℃; for 0.25h; Stage #2: D-tartaric acid In water | 21 Example 21 Crystalline Anhydrous Tiotropium Tartrate (Form III) 1.00 g of tiotropium bromide monohydrate (according to WO 02/30928) was dissolved in 50 ml of demineralised water at 25° C. 10 ml of bicarbonate loaded IER slurry was added to this solution and stirred for 5 minutes before a second equivalent of 5 ml bicarbonate loaded IER slurry was added. The mixture was stirred for additional 5 minutes. A silver nitrate test as described above indicated the completion of the exchange. After stirring for an additional 5 minutes the slurry was filtered with PTFE filters with a pore size of 10 μm. The collector vial was previously charged with 1.1 equivalents of D-tartaric acid in 10 ml of water. From the resulting solution water was evaporated under vacuum over a water bath which was kept below 35° C. The obtained solid was further dried under vacuum yielding an amorphous oil of the tartrate of tiotropium. Approx. 500 mg of the amorphous tiotropium tartrate are dissolved in 4 ml of a water. In two steps 75 μl (40+35 μl) of this stock solution is transferred into one of the small vials of a 96 well plate. The plate containing the stock solution was placed in a vacuum chamber (1 kPa) at room temperature for 24 h for each dosing step. After the stock solvent was evaporated 30 μl of a mixture of 1-methyl-2-pyrrolidinon (=NMP) was added to this vial. The whole 96 well plate is sealed afterwards and heated up with a heating rate of 5° C./min to 50° C. at which the plate stays for an additional 30 minutes. Afterwards the plate is cooled with a cooling rate of 5° C./h to a final temperature of 5° C. At this temperature the plate remained for a hold time of 24 h. The plates are opened afterwards the solid is obtained by evaporation of the solvent at room temperature in a vacuum chamber (13 kPa). Table 21 summarizes the X-ray powder reflections obtained for this form. TABLE 21 2 Θ [°] d []I/Io [%] 8.54 10.34 35 12.42 7.12 24 13.14 6.73 35 13.90 6.36 49 14.46 6.12 47 15.82 5.60 37 16.22 5.46 25 17.06 5.19 62 17.58 5.04 100 18.30 4.84 30 19.06 4.65 31 20.22 4.39 16 21.90 4.05 54 22.66 3.92 11 23.70 3.76 14 24.86 3.58 28 25.66 3.49 14 27.42 3.25 26 27.98 3.19 14 28.82 3.09 7 29.46 3.03 11 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0% | With NH3*H2O In methanol; ammonia aq. NH3; addn. of methanolic soln. of copper compd. to soln. of dihydroxysuccinicacid in methanol/aq. ammonia with pH 9.1-9.5, stirring for 5 min, addn. of water with stirring, heating for 5 min; cooling to room temp., slow evapn. for 1 wk, isolation of crystals, elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.64% | In methanol for 5h; Reflux; | 6.6 g (0,0087 mol) of telmisartan te/t-butylester, obtained as described in step6.1., was dissolved in methanol (25 ml) and 1,31 g (0,0087 mol) DL-tartaric acid was added. The reaction mass was heated under reflux for 5 h. Afterwards, the solvent was distilled under vacuum. 52 ml of acetone was added to the obtained residue and the suspension was stirred for 10 min. The solvent was distilled under vacuum completely. 30 ml of tert-Butylmethylether was added to the obtained residue and the suspension was heated to reflux for 1 h. Distill out the solvent completely under vacuum. Again, 30 ml of te/t-Butylmethylether was added to the obtained residue and the suspension was heated to reflux for 1 h. Afterwards, the reaction mass was cooled down to 25-30 C, filtered and the resulted solid was dried under vacuum at 5O0C until constant weight.Yield: 4.3 gYield (molar): 68.64%HPLC: 97.72%M.P.: 174°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 5 - 50℃; for 3h; | 1 Example 12-Methyl-5-vinylpyridinium DL-hydrogentartrate; DL-Tartaric acid (53.66 g, 357 mmol) was dissolved in hot (50 °C) ethanol (600 ml). The solution was added to a solution of crude 2-methyl-5-vinylpyridine (70.8 wt% MVP, 22.2 wt% MEP; 40.07 g, 238 mmol) in ethanol (20 ml) at 20-25 °C over a period of 1 h. The resulting suspension was aged at 20 °C for 30 min, cooled to 5 °C over a period of 60 min, and aged at 5 °C for another 30 min. The precipitated product was filtered and washed with cold (5 °C) ethanol (40 ml). After drying over night (35 °C, 20-100 mbar), 2-methyl-5-vinylpyridinium DL-hydrogentartrate was obtained as a white solid.Yield: 68.90 g (92%).GC: 85.4 area% MVP, 14.1 area% MEP.The molar ratio tartrate/pyridines was assessed by 1H NMR to be 1.0:1.0.The product was further purified by recrystallization from ethanol: 60.0 g MVP DL-tar- trate obtained as described above were dissolved in ethanol (330 ml) at 60 °C. After cooling to 25 °C over a period of 30 min, followed by cooling to 0 °C over a period of90 min, the mixture was aged at 0 °C for another 60 min. The recrystallized product was filtered off, washed with cold (5 °C) ethanol (30 ml) and dried.Yield: 48.7 g (86%) white solid.GC: 90.8 area% MVP, 9.0 area% MEP.The molar ratio tartrate/pyridines was assessed by 1H NMR to be 1.0:1.0.Onset temperature of decomposition (DSC): 147 °C.Enthalpy of decomposition (DSC): 192 J/g.W NMR (DMSO-de, 400 MHz): δ 8.50 (d, 1 H), 7.82 (dd, 1 H), 7.24 (d, 1 H), 6.73 (dd, 1 H), 5.90 (dd, 1 H), 5.33 (d, 1 H), 4.34 (s, 2H), 2.46 (s, 3H).13C NMR (DMSO-de, 126 MHz): δ 173.0, 157.2, 147.1 , 133.3, 132.9, 129.8, 123.0, 1 15.4, 72.1 , 23.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water; | The tartrate salt of brimonidine can be synthesized by adding (L)-(+)-tartaric acid to a solution of brimonidine in aqueous methanol. The brimonidine tartrate will separate out of solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 mg | In n-heptane; 2,2,2-trifluoroethanol; water; ethyl acetate at 20℃; for 24h; | 7 Example 7 - Preparation of a DL-Tartaric Acid Cocrystal of Lenalidomide Example 7 - Preparation of a DL-Tartaric Acid Cocrystal of Lenalidomide [00129] In a 4ml vial lOOmg of 3-(4-amino-l-oxo-l,3-dihydroisoindol-2-yl)piperidine-2,6- dione and 65 mg of DL-tartaric acid was taken and 3 ml of ethyl acetate: 2,2,2-trifhioro ethanol:heptanes:water (10: 10:20: 1) was added. It formed slurry at room temperature (RT). The slurry was stirred for approximately 24 hours, at which time approximately 3 to 10 mg of the solid present was isolated by vacuum filtration and air dried. XRPD data from this solid sample was examined and compared to XRPD data from known solid phases of 3-(4-amino-l-oxo-l,3- dihydroisoindol-2-yl)piperidine-2,6-dione and DL-tartaric acid in order to determine if, in addition to a novel solid phase, identified as the 3-(4-amino-l-oxo-l,3-dihydroisoindol-2- yl)piperidine-2,6-dione-DL-tartaric acid cocrystal, excess 3-(4-amino-l-oxo-l,3- dihydroisoindol-2-yl)piperidine-2,6-dione or DL-tartaric acid was present in the solid isolated from the reaction. Additional 3-(4-amino-l-oxo-l,3-dihydroisoindol-2-yl)piperidine-2,6-dione or DL-tartaric acid was added in 1 to 10 mg amounts to drive the product towards pure cocrystal. The process of isolating a 3 to 10 mg sample, obtaining and analyzing the XRPD data, and adding additional 3-(4-amino-l-oxo-l,3-dihydroisoindol-2-yl)piperidine-2,6-dione or DL-tartaric acid in 1 to 10 mg amounts and stirring for approximately 24 hours was repeated until the product obtained was only cocrystal based on XRPD data. The isolated solid was analyzed by XRPD, Raman spectroscopy, and 1H-NMR. The XRPD pattern of the material isolated at the end of the reaction is substantially the same as that shown in FIG 30. The Raman spectrum is substantially the same as that shown in FIG. 31. The 1H-NMR spectrum is substantially the same as that shown in FIGS. 32A, 32B, 32C, and 32D. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide In water for 168h; |
Yield | Reaction Conditions | Operation in experiment |
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With cesium hydroxide In water for 168h; |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide In water for 190h; Reflux; | 4b Preparation of a Non-Caking Additive Via DL-Tartaric Acid In a 30-liter steam-heated jacketed vessel 15.41 kg of 50 wt % of sodium hydroxide (in water) solution (ex Sigma) were mixed with 1.815 kg of demineralized water and 10.592 kg of racemic DL-tartaric acid (ex Jinzhan, Ninghai organic chemical factory, China). The mixture was boiled under reflux at atmospheric pressure and stirred for 190 hours in total. During this period samples were taken of the reaction mixture and the conversion of DL-tartaric acid to meso-tartaric acid was determined by 1H-NMR (see Table 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 25℃; for 24h; | 2.2. Synthesis of Lu2(C4H4O6)3·6H2O and Lu2O3:Ln (Ln = Eu3+,Tb3+) General procedure: In a typical experiment, 3 mmol D, L-tartaric acid was dissolved in ethanol-water solution (15 mL ethanol and 5 mL H2O). Subsequently, 2 mmol Lu(NO3)3 (1 M) was added into the above solution. After vigorous stirring for 30 min, the obtained solution was transferred into a thermostat water bath and maintained at 25 C for 24 h. The obtained precipitation was separated by centrifugation, washed with distilled water and ethanol several times, and dried at 60 C in air. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 25℃; for 24h; | 2.2. Synthesis of Lu2(C4H4O6)3·6H2O and Lu2O3:Ln (Ln = Eu3+,Tb3+) General procedure: In a typical experiment, 3 mmol D, L-tartaric acid was dissolved in ethanol-water solution (15 mL ethanol and 5 mL H2O). Subsequently, 2 mmol Lu(NO3)3 (1 M) was added into the above solution. After vigorous stirring for 30 min, the obtained solution was transferred into a thermostat water bath and maintained at 25 C for 24 h. The obtained precipitation was separated by centrifugation, washed with distilled water and ethanol several times, and dried at 60 C in air. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 25℃; for 24h; | 2.2. Synthesis of Lu2(C4H4O6)3·6H2O and Lu2O3:Ln (Ln = Eu3+,Tb3+) General procedure: In a typical experiment, 3 mmol D, L-tartaric acid was dissolved in ethanol-water solution (15 mL ethanol and 5 mL H2O). Subsequently, 2 mmol Lu(NO3)3 (1 M) was added into the above solution. After vigorous stirring for 30 min, the obtained solution was transferred into a thermostat water bath and maintained at 25 C for 24 h. The obtained precipitation was separated by centrifugation, washed with distilled water and ethanol several times, and dried at 60 C in air. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | In water at 19 - 30℃; for 3h; | S3, split, racemic: A, added in the reaction bottle 620g purified water, 22.1gD-(-)-tartaric acid, stirring temperature controlling 19-21 °C dissolves clear, crushing to the hydride 80g, stirring dissolution cleaning, temperature control 19-21 °C joins in 11.3gD-(-)-tartaric acid dissolved in 20g solution purification of water, the temperature of the solution 25-30°C, is omitted, the stirring 30 seconds, still clarification system, such as, by adding a small amount of crystal seeds, stirring 3 times, devitrifying 3 hours, the crystallization finishes, slow stirring crystallization, 2-3 hours cooling to 8 °C, maintain 7-9 °C slow stirring 2 hours, filtration, using 20gx3 dichloromethane rinsing 3 times, oil or tartrate;B, merging the above-mentioned the filtrate and wash solution, is added under stirring 26.8g solid sodium bicarbonate for free, 7-8 adjusting the pH value, the accent finishes, static hierarchical, dichloromethane is used for water 40gx3 extraction, combined with the organic layer, anhydrous sodium sulfate for 8g drying 5 hours, filtering, the filtrate to dryness under reduced pressure, to obtain 48g recovering solid, percent recovery is 60%, purity ≥ 99%, is used for the racemization;C, in the above-mentioned tartrate 50g in water, stirring, add 14.5g saturated sodium bicarbonate aqueous solution to free, 7-8 adjusting the pH value, the accent finishes, dichloromethane is used for 40gx4 extraction, combined with the organic layer, anhydrous sodium sulfate 5.5g drying 5 hours, filtering, the filtrate to dryness under reduced pressure, to obtain resolution 26.5-28g, yield 33-35%, ≥ 98% purity; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | In water; acetone at 20℃; for 1h; | 3 Preparation of (-)-huperzine A-D-tartaric acid salt Example 3: Preparation of (-)-huperzine A-D-tartaric acid salt, 6 g of (+-)-huperzine A was suspended in acetone-water with a ratio of 1:1 (v:v). 3.1 g of D-tartaric acid was added at 20° C. After stirring for 1 h, the resulting salt was filtered to obtain a solid which was then recrystallized from anhydrous ethanol to give 4 g of (-)-huperzine A-D-tartaric acid salt. Yield: 51%, HPLC purity: 98% (310 nm), optical purity: 95%, m.p.: 182-185° C. 1H NMR (400 MHz, D20) ö 7.87 (d, J=9.6 Hz, 1H),6.63 (d, J=9.6 Hz, 1H), 5.63-5.64 (m, 1H), 5.51-5.56 (m, 1H),4.51 (s, 2H), 3.88 (s, 1H), 3.04-3.10 (m, 1H), 2.79-2.84 (m,1H), 2.68-2.72 (m, 1H), 2.53-2.57 (m, 1H), 1.82 (d, J=6.4 Hz,3H), 1.65 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; dichloromethane; at 50℃; for 1h; | Filgotinib free base (0.5 g) was dissolved in dichloromethane (13 ml) and methanol (2 ml), D-tartaric acid (0.19 g) was dissolved in dichloromethane (17 ml) and methanol (3 ml). The acid solution was dropped into the solution of filgotinib at 50C. The reaction mixture was stirred for 1 hour and then slowly cooled to 23C. The reaction mixture was stirred for 3 days, no salt formation could be observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With toluene-4-sulfonic acid In toluene for 12h; Dean-Stark; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol at 60℃; | 14.a Example 14: Preparation processes for novel tartrate salt form a) Tartrate salt Tartrate-NF1 preparation: i) Experiment from 2-PrOH Example 14: Preparation processes for novel tartrate salt form a) Tartrate salt Tartrate-NF1 preparation: i) Experiment from 2-PrOH: Approx. 147 mg of N-(4,5-bis-methanesulfonyl-2-methyl-benzoyl)-guanidine free base are dissolved in 3 mL of 2-propanol at 60 °C. Approx. 67.9 mg DL-tartaric acid is added to the clear solution, and the solution was subjected to 3 repetitive cooling/heating cycles from 60-5 °C with 0.1 K/min, followed by a post-slurry step at the end of the 3rd cooling segment at 5 °C. Obtained solid-state residue after the repetitive cooling/heating cycle is separated by centrifugation, and dried under nitrogen purge gas at ambient temperature for few hours to give a powder sample. 1 H NMR (500 MHz, DMSO-d6) δ = 8.44 (s, 1H), 8.37 - 7.61 (m, 3H), 6.95 (s br, 2H), 4.03 (s, 2H), 3.45 (s, 3H), 3.43 (s, 3H), 2.63 (s, 3H). Chemical purity >98% (NMR analysis). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.3% | In di-isopropyl ether; isopropyl alcohol at 15 - 45℃; | 9 Preparation of Tenofovir disoproxil D-tartrate and Form A thereof In 3 5 ~ 45 ° C, Tenofovir disoproxil 10.0g (19.3mmol) and D-tartaric acid 3.lg (20.6mmol), was dissolved in 300mL isopropanol, dissolved completely,Controlling the inner temperature 35 ~ 45 ° C dropping diisopropyl ether 100mL, dropping was stirred and cooled to 15 ~ 20 ° C, continue stirring crystallization; suction filtration; cake was dried under reduced pressure at 20 ~ 30 ° C, 9.7 g of tenofovir disoproxil D-tartrate was obtained in a yield of 75.3% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.07 g | In tetrahydrofuran; water; at 40 - 50℃; | lg of <strong>[283173-50-2]Rucaparib</strong> base (3.09 mmol), prepared according to the process described in Example 5, was dissolved in 15 mL of THF/H2O mixture (2: 1) while heating at 40-50°C. To the clear solution of <strong>[283173-50-2]Rucaparib</strong> base, 0.93 g (2 eq) of D-(-)- tartaric acid dissolved in 5 mL of water, was added while stirring at 40-50°C. Clear reaction mixture was then cooled down and crystallization occurred while stirring in ice bath. Obtained suspension was stirred for 1 hour at 0-5°C. Crystals were filtered off under vacuum and analyzed by XRPD as Form I of <strong>[283173-50-2]Rucaparib</strong> D-(-)-Tartrate. Wet crystals were dried in vacuum oven at 50°C for 4 hours to obtain 1.07 g of material, that was analyzed by XRPD as Form II of <strong>[283173-50-2]Rucaparib</strong> D-(-)-Tartrate. XRPD of <strong>[283173-50-2]Rucaparib</strong> D-(-)-Tartrate Form I is given in Figure 14. XRPD of <strong>[283173-50-2]Rucaparib</strong> D-(-)-Tartrate Form II is given in Figure 15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In ethanol; for 0.08333330000000001h;Reflux; | Purified lasofoxifene (2 g) from step d was dissolved in 20 mL of 95ethanol, and mixed together with 0.78 g D-tartaric acid, which is dissolved in 7.8 mL of 95ethanol. The mixed solution was carefully heated to slight reflux for 5 minutes, and then cooled to room temperature. About 1.4 g precipitation of lasofoxifene D-tartrate salt was obtained (Yield 50) .[0163]Lasofoxifene D-tartrate was dissolved in DMSO-d6(50 mg/mL) for NMR analysis.1H NMR (600 MHz, DMSO-d6) delta 1.711.85 (m, 5H) , 2.08 (s, 1H) , 2.902.99 (m, 6H) , 3.17 (br, 2H) , 3.295 (m, 1H) , 4.024.06 (m, 4H) , 4.17 (d, J 3.6 Hz, lH) 4.43 (br, 2H) , 6.6 (m, 5H) , 6.81 (d, J 6.4 Hz, 2H) , 7.11 (s, 1H) , 7.13 (s, 2H) .13C NMR (150 MHz, DMSO-d6) delta 174.26, 155.74, 155.36, 144.12, 137.08, 135.37, 131.09, 130.97, 130.04, 127.83, 127.61, 125.87, 114.35, 113.58, 112.91, 71.90, 64.07, 53.59, 53.100, 49.40, 44.41, 29.244, 22.56, 22.41. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With arsenic(III) trioxide In water at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: DL-tartaric acid With lithium hydroxide monohydrate In water for 0.166667h; Darkness; Stage #2: Pt(2,2':6',2''-terpyridine)Cl for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.5 g | In acetic acid butyl ester; water at 60℃; for 1h; | 1; 2 A high-content tilmicosin preparation method comprising the following steps: (1) Put 43.5g of tilmicosin into a three-necked bottle, add 450mL of mixed solvent (butyl acetate: water = 95:5), stir and dissolve, add D-tartaric acid 15g. The mixture was heated to 60 °C with stirring, and the mixture was kept at room temperature for 1 hour, and then the mixture was cooled to room temperature to precipitate a large amount of solid. After suction filtration, it was dried at 55 °C for 8 hours to obtain 49.5 g of tilmicosin tartrate. (2) 49.5 g of tilmicosin tartrate was dissolved in 200 mL of water, and once with 150 mL of butyl acetate, the aqueous layer was adjusted to pH 9-10 with sodium hydroxide having a mass fraction of 20%. A large amount of solid was precipitated, and after suction filtration, it was dried at 50 °C for 12 hours to obtain a high content of 40.9 g of tilmicosin, and the purification yield was 94%. The high content of tilmicosin is white, and the clarity of the solution is lighter than that of the yellow standard colorimetric solution No. 4, with a content of 96.3% and a total impurity of 5.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methoxybenzene; In ethanol; at 70℃; | The reprocessing procedure included dissolving 1C in a chloroform and ethanol mixture and activated charcoal was added. The resulting slurry was stirred at room temperature for 1 hour and filtered. The filtered solid was washed, combined with filtrate and the solvents were removed by distillation. Then ethanol was added, and distillation repeated to remove chloroform. After the distillation, resulting slurry was cooled and filtered to give purified 1C. The obtained material was dissolved with mixture of anisole and ethanol at 70C. Ethanol solution of tartaric acid was then added to this solution and subsequently seeded with Form A. The resulting slurry is cooled to 20C and filtered, washed with ethanol, dried to afford the polymorph of a tartaric acid salt of a compound of structure (I). The purity of the desired product was assessed to be 99.5% by HPLC. 1H NMR (400 MHz, DMSO-d 1H), 8.29 (s, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 7.71 (td, J = 7.2, 1.4 Hz), 7.57 (d, J = 8.4 Hz, 2H), 7.38 (td, J = 7.2 Hz, J = 1.0 Hz), 7.18 (d, J = 8.4 Hz, 2H), 4.19 (s, 4H), 3.51 (s, 2H), 2.86 (bs, 3H),2.65 (s, 6H), 2.60-2.50 (m, 8H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In methanol; dichloromethane at 20 - 50℃; | 2 Example 2 Preparation of the D-(-)-Tartaric Acid Salt -(-)-tartaric acid (32.55 mg, 0.217 mmol, 1.12 eq.) was added to a solution of Compound 1 (94.55 mg, 0.194 mmol) in a 1 :1 v/v mixture of methanol and dichloromethane (2.4 mL). The reaction mixture was stirred to give a thick slurry. The slurry was stirred for 1.5 h at 50 °C for 65 min, and then cooled to room temperature and stirred overnight. The slurry was filtered, and the solids were dried under vacuum at 36-40 °C overnight (16 h) to provide Compound 1 //-(-)-tartaric acid salt (104.6 mg, 84% yield). The stoichiometric ratio between Compound 1 and //-(-)-tartaric acid was determined as 1 :1 by NMR (Figure 1). The crystallinity of the Compound 1 D-(-)- tartrate was confirmed by XRPD (Figure 2) and further supported by DSC (Figure 3) and TGA (Figure 4). Analytical data collected on the product, including characterization by XRPD, DSC, and TGA were performed as described in Example 1. The //-(-(-tartaric acid salt exhibits a DSC thermogram having an endothermic peak at a temperature of about 276 °C. Table 1. XRPD Peak Data for the D-(-)-Tartaric Acid Salt |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.4 g | In water; acetonitrile at 25 - 30℃; | 2; 7-8 Example 2. Preparation of (-)-cybenzoline-D-tartrate 15 g of the (±)-cybenzoline free base prepared according to Example 1 was dissolved in 250 ml of acetonitrile and then stirred at a temperature of 25 to 30 °C for 15 minutes, D dissolved in 30 ml of water A solution of -(-)-tartaric acid (1.0 m.eq.) was added at a temperature of 25 to 30 °C for 20 minutes to obtain a mixture.After stirring the mixture for 30 minutes, 250 ml of methyl tertiary butyl ether (MTBE) was added to the mixture for 20 minutes, and stirred at room temperature for 2 hours and 30 minutes to prepare a mixture.The mixture was heated to a temperature of 50 to 55 °C, stirred for 1 hour, then cooled to 25 to 30 °C and stirred for 1 hour.The obtained solid was filtered and washed with 23 ml of acetonitrile to obtain 6.4 g of (-)-cibenzoline-D-tartrate salt having a chiral purity of 99.0% as determined by chiral HPLC (yield: 41( w/w)%). |
41 % | In water; acetonitrile at 25 - 30℃; | 1-2 Preparation Example 1-2: Preparation of (-)-Cibenzoline-D-Tartrate Preparation Example 1-2: Preparation of (-)-Cibenzoline-D-Tartrate 15 g of the (+-)-cibenzoline free base prepared according to Preparation Example 1-1 was dissolved in 250 ml of acetonitrile and then stirred at a temperature of 25 to 30° C. for 15 min, and D-(-)-tartaric acid (1.0 m. eq.) solution in water (30 ml) was added thereto 20 min at a temperature of 25 to 30° C. to obtain a mixture. The mixture was stirred for 30 min, and 250 ml of methyl tert butyl ether (MTBE) was added to the mixture over 20 min, followed by stirring for 2.5 hours at room temperature, thereby preparing a mixture. The mixture was heated to a temperature of 50 to 55° C., stirred for 1 hour, and then allowed to cool at 25 to 30° C. and stirred for 1 hour. The obtained solid was filtered and washed with 23 ml of acetonitrile to afford (-)-cibenzoline-D-tartrate (6.4 g) having 99.0% chiral purity measured by chiral HPLC (yield: 41 (w/w) %). 1H-NMR (400 MHz, CD3OD): 7.38 (m, 6H); 7.29 (m, 3H); 7.20 (m, 1H); 4.40 (s, 2H); 3.71 (m, 2H); 3.52 (m, 2H); 2.83 (t, 1H); 2.34 (t, 1H); 1.90 (t, 1H) ppm. 13C-NMR (100 MHz, CD3OD): 177.01, 170.68, 144.71, 139.88, 130.73, 129.82, 129.72, 128.90, 128.77, 128.19, 74.21, 45.52, 42.54, 23.02, 20.11. IR (cm-1): 1731.23, 3531.63. |
41 % | In water; acetonitrile at 25 - 30℃; | 1-2 Preparation Example 1-2: Preparation of (-)-Cibenzoline-D-Tartrate Preparation Example 1-2: Preparation of (-)-Cibenzoline-D-Tartrate 15 g of the (+-)-cibenzoline free base prepared according to Preparation Example 1-1 was dissolved in 250 ml of acetonitrile and then stirred at a temperature of 25 to 30° C. for 15 min, and D-(-)-tartaric acid (1.0 m. eq.) solution in water (30 ml) was added thereto 20 min at a temperature of 25 to 30° C. to obtain a mixture. The mixture was stirred for 30 min, and 250 ml of methyl tert butyl ether (MTBE) was added to the mixture over 20 min, followed by stirring for 2.5 hours at room temperature, thereby preparing a mixture. The mixture was heated to a temperature of 50 to 55° C., stirred for 1 hour, and then allowed to cool at 25 to 30° C. and stirred for 1 hour. The obtained solid was filtered and washed with 23 ml of acetonitrile to afford (-)-cibenzoline-D-tartrate (6.4 g) having 99.0% chiral purity measured by chiral HPLC (yield: 41 (w/w) %). 1H-NMR (400 MHz, CD3OD): 7.38 (m, 6H); 7.29 (m, 3H); 7.20 (m, 1H); 4.40 (s, 2H); 3.71 (m, 2H); 3.52 (m, 2H); 2.83 (t, 1H); 2.34 (t, 1H); 1.90 (t, 1H) ppm. 13C-NMR (100 MHz, CD3OD): 177.01, 170.68, 144.71, 139.88, 130.73, 129.82, 129.72, 128.90, 128.77, 128.19, 74.21, 45.52, 42.54, 23.02, 20.11. IR (cm-1): 1731.23, 3531.63. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In water at 60℃; |
Tags: 133-37-9 synthesis path| 133-37-9 SDS| 133-37-9 COA| 133-37-9 purity| 133-37-9 application| 133-37-9 NMR| 133-37-9 COA| 133-37-9 structure
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