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CAS No. : | 594-45-6 | MDL No. : | MFCD00007529 |
Formula : | C2H6O3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CCIVGXIOQKPBKL-UHFFFAOYSA-N |
M.W : | 110.13 | Pubchem ID : | 11668 |
Synonyms : |
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Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P280-P303+P361+P353-P304+P340+P310-P305+P351+P338 | UN#: | 2586 |
Hazard Statements: | H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
100% | for 4 h; Reflux | Three 25ml flask were added successively 2.0g Trinidad Technip, 7.5g ethanesulfonic acid, 10ml methanol was heated to reflux, stirred at reflux for 4h, heating was stopped, the solvent was evaporated to dryness, the resulting solid was slurried add 15ml of acetone, suction filtered to give a pale yellow solid 2.4g, yield: 100percent.Purity by HPLC: 99.75percent |
97.3% | at 60℃; | Example 8: Synthesis of the 3-Z-[1 -(4-(N-((4-methyl-piperazin-1 -yl)- methylcarbonyl)-N-methyl-amino)-anilino)-1 -phenyl-methylene]-6- <n="27"/>methoxycarbonyl-2-indolinone, monoethanesulfonate"ANILINO" 3-Z-[1-(4-(N-((4-methyl-pιperazιn-1-yl)-methylcarbonyl)-N-me thyl-amιno)-anιlιno)-1-phenyl-methylene]-6-methoxycarbonyl- 2-ιndolιnone, monoethanesulfonateA suspension of 3-Z-[1 -(4-(N-((4-methyl-piperazin-1 -yl)-methylcarbonyl)-N- nnethyl-annino)-anilino)-1 -phenyl-nnethylene]-6-nnethoxycarbonyl-2-indolinone (30,0 g; 0,055 mol) in methanol (200 ml) and water (2,4 ml) is heated to 60 0C. Aqueous ethanesulfonic acid (70percent (w/w); 8,75 g; 0,056 mol) is added to the reaction mixture. The resulting solution is cooled to 50 0C, seeded and then diluted with isopropanol (200 ml). The mixture is further cooled to 0 0C and stirred for 2 h at this temperature. The precipitate is isolated, washed with isopropanol (120 ml) and dried to furnish 35,1 g (97,3 percent) of the monoethanesulfonate salt of the compound as yellow crystals. 1H-NMR (400 MHz, DMSO-de) δ: 12,26 (s, 11-H); 10,79 (s, 1 H, 1 -H); 9,44 (s, 1 H, 24-H); 7,64 (m, 1 H, 32-H); 7,59 (m, 2 H, 31 -H + 33-H); 7,52 (m, 2 H, 30-H + 34-H); 7,45 (d, J = 1 ,6 Hz, 1 H, 7-H); 7,20 (dd, J = 8,2; 1 ,6 Hz, 1 H, 5-H); 7,16 (m, 2 H, 14-H + 16-H); 6,90 (m, 2 H, 13-H + 17-H); 5,85 (d, J = 8,2 Hz, 1 H, 4-H); 3,78 (s, 3 H, 37-H3); 3,45 - 2,80 (broad m, 4 H, 23-H2 + 25-H2); 3,08 (s, 3 H, 28-H3); 2,88 (s, 2 H, 20-H2); 2,85 - 2,30 (broad m, 4 H, 22-H2 + 26-H2); 2,75 (s, 3 H, 27-H3); 2,44 (q, J = 7,4 Hz, 2 H, 39-H2); 1 ,09 (t, J = 7,4 Hz, 3 H, 38-H3). 13C-NMR (126 MHz, DMSO-de) δ: 9,8 (C-38); 36,6 (C-28); 42,3 (C-27); 45,1 (C-39); 51 ,7 (C- 37); 48,9 (C-22 + C-26); 52,6 (C-23 + C-25); 57,5 (C-20); 97,7 (C-3); 109,5 (C- 7); 1 17,3 (C-4); 121 ,4 (C-5); 123,8 (C-13 + C-17); 124,1 (C-6); 127,7 (C-14 + C- 16); 128,4 (C-30 + C-34); 128,8 (C-9); 129,5 (C-31 + C-33); 130,5 (C-32); 132,0 (C-29); 168,5 (C-9); 136,3 (C-8); 137,3 (C-12); 139,5 (C-15); 158,1 (C-10); 166,3 (C-35); 168,0 (C-19); 170,1 (C-2). MS (m/z): 540 (M(base) + H)+. Anal. <n="28"/>calcd. for C33H39N5O7S: C, 60.17; H, 6.12; N, 10.63; S, 4.87. Found: C, 60.40; H, 6.15; N, 10.70; S, 4.84. |
95% | at 0 - 65℃; for 1 h; | To a Suspension of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl) acetami- de)-phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate 6 (36 g, 0.066 mol) in methanol (237 mL) and water (2.88 mL) ethanesulfonic acid (7.92 g 0.0719 mol) in water (2.88 mL) was added at 60-65°C. The resulting suspension was cooled to 50C, and was diluted with isopropanol (237 mL). The reaction mixture was cooled to 0C and stirred for 1h. The precipitate obtained was filtered and washed with mixture of methanol and isopropanol (50percent) (50 ml), product was dried to obtain crude Nintedanib monoethane sulfonate (36.6 g) which was crystallized from methanol (5 Vol) to obtain pure Nintedanib monoethane sulfonate salt as yellow crystals (33 g) (HPLC purity >99percent). DSC: 298C; IR (KBr, cm-1): 3321, 3273, 1710, 1652, 1615, 1515, 1435, 1378, 1289, 1209, 1161, 1087; 1H-NMR (400 MHz, DMSO): δ 1.08 (t, 3H, J = 7.31 Hz), 2.41-2.47 (q, 2H), 2.50-3.16 (broad m, 13H), 3.37 (s, 3H), 3.76 (s, 3H), 5.82 (d, 1H, J = 7.88Hz), 6.87 (d, 2H, J = 7.36 Hz), 7.14-7.20 (m, 3H), 7.49 (s, 1H), 7.49 (d, 2H, J = 6.68 Hz), 7.56-7.63 (m, 3H), 9.45 (s, 1H), 10.99 (s, 1H), 12.25 (s, 1H), 13C-NMR (100 MHz, DMSO): δ 37.15, 42.79, 45.65, 49.40, 52.26, 53.10, 58.04, 98.25, 110.01, 117.78, 121.97, 124.32, 124.59, 128.27, 128.90, 129.36, 130.00, 131.00, 132.52, 136.79, 137.93, 140.00, 158.66, 166.85, 168.47 and 170.65; MS: m/z 540 [M]+1. |
89.7% | at 50℃; | 500 grams of the crystalline compound of Example 5 is suspended in 10 liters of ethanol, heated to 50 ° C and 180 grams of 70percent aqueous ethanesulfonic acid are added. The resulting solution was cooled to 40 ° C,An additional 4.5 liters of t-butyl ether was added. Crystallize after a few minutes. To achieve complete precipitation, the mixture was stirred for a further 16 hours at room temperature. After cooling to 10 ° C, suction filtration, washing with 2 t-butyl ether and drying under vacuum at 40 ° C,Ethanesulfonate compounds are obtained.Yield: 538 g (89.7percent yield). |
87.6% | at 50℃; | 605 [G] (1.12 mol) of [3-Z- [1- (4- (N- ( (4-METHYL-PIPERAZIN-1-YL)-METHYLCARBONYL)-N-METHYL-] [AMINO)-ANILINO)-1-PHENYL-METHYLENE]-6-METHOXYCARBONYL-2-INDOLINONE] are suspended in 9 litres of methanol and heated to [50°C.] 183.7 [G] (1.121 mol) of 70percent aqueous [ETHANESULPHONIC] acid are added. The solution obtained is cooled to [40°C] and 4. 5 litres of [TERT.-BUTYLMETHYLETHER] are added. After a few minutes crystallisation sets in. To achieve total precipitation the mixture is stirred for another 16 hours at ambient temperature. After cooling to [10°C] it is suction filtered, washed with 2 litres of tert.- butylmethylether and dried [AT 40°C IN VACUO.] Yield : 638 g (87.6percent of theory) Tm. [P.] = 305 [5°C] (DSC 1 OK/min) Purity according to HPLC: 99.4percent Water content: 1.0 to 2.0percent (KF) |
80% | at 60 - 65℃; | Suspension of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamide)phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (36 gm, 0.066 mol) in methanol (237 ml) and water (2.88 ml)was heated to 60-65°C and aq. ethane sulfonic acid was added to the reaction mixture. The resulting solution was cooled to 50°C, seeds diluted with isopropanol (237 ml) was added. The reaction mixture was cooled at 0°C for lhr. Filtered the precipitate, washed with mixture of methanol and isopropanol (50 ml), dried to obtain crude Nintedanib monoethane sulfonate (36.6 gm) and crystallized from methanol (5 Vol) to obtained pure Nintedanib monoethane sulfonate salt as yellow crystals (33 gm) (80percent) (HPLC purity >99percent). DSC: 298°C; IR (KBr, cm-1): 3321, 3273, 1710, 1652, 1615, 1515, 1435, 1378, 1289, 1209, 1161, 1087; 1H-NMR (400 MHz, DMSO): δ 1.08 (t, 3H, J = 7.31 Hz), 2.41-2.47 (q, 2H), 2.50-3.16 (broad m, 13H), 3.37 (s, 3H), 3.76 (s, 3H), 5.82 (d, 1H, J = 7.88Hz), 6.87 (d, 2H, J = 7.36 Hz), 7.14-7.20 (m, 3H), 7.49 (s, 1H), 7.49 (d, 2H, J = 6.68 Hz), 7.56-7.63 (m, 3H), 9.45 (s, 1H), 10.99 (s, 1H), 12.25 (s, 1H), 13C-NMR (100 MHz, DMSO): δ 37.15, 42.79, 45.65, 49.40, 52.26, 53.10, 58.04, 98.25, 110.01, 117.78, 121.97, 124.32, 124.59, 128.27, 128.90, 129.36, 130.00, 131.00, 132.52, 136.79, 137.93, 140.00, 158.66, 166.85, 168.47 and 170.65; MS: m/z 540[M]+1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; ethanol; for 48h; | Esylate Salts of the Compound of Formula IAn esylate salt of the compound of Formula I is prepared by dissolving a mixture of one equivalent of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)- ethoxy}-methyl]-8-phenyl-1 ,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) and one equivalent of ethyl sulfonic acid in anhydrous ethanol, adding sufficient anhydrous diethyl ether to the mixture to induce a cloudy appearance, titrating additional ethanol into the mixture until the solution returned to a clear condition, and leaving the solution sit quiescent for 48 hours until crystals of esylate form I salt form of the compound of Formula I are precipitated. The crystals of the esylate form I salt are collected by vacuum filtration and air dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.6% | Stage #1: 3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-4-yl}-4-methyl-N-(1,3-thiazol-2-yl)benzamide In acetone at 50℃; Stage #2: ethanesulfonic acid In tetrahydrofuran; acetone | 79.79j Acetone (200 uL) was added to free-base version of 3- {8-(2,6-difluorophenyl)-2-[(lH-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-(i]pyrimidin-4-yl}-4-methyl- JV-l,3-thiazol-2-ylbenzamide (25.1 mg), and the resulting mixture was heated to 5O0C. Ethanesulfonic acid was added (1.0 equivalent; IN in TηF), and the mixture stirred for several days. The product was filtered, washed with acetone, and dried overnight in a vacuum oven at 5O0C with a slow nitrogen bleed. The yield was 70.6 % (9.1 mg) of title compound with a melting onset at 2960C (determined by DSC). Alternatively, acetone (501 uL) was added to free-base version of 3-{8-(2,6- difluorophenyl)-2-[(lH-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-4-yl}-4-methyl-λM,3-thiazol-2-ylbenzamide (25.1 mg), and the resulting mixture was heated to 5O0C. Ethanesulfonic acid was added (1.0 equivalent; IN in TηF). Seed crystals were added, and the mixture stirred for several days. The product was filtered, washed with acetone, and dried overnight in a vacuum oven at 5O0C with a slow nitrogen bleed. The yield was 78.1 % (23.3 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20℃; for 2h; | Esylate:; Two equivalents of ethanesulfonic acid were slowly added to 3g of API in 20 mL of THF at room temperature. The resulting suspension was equilibrated for two hours before solids were collected by filtration. Solids were dried under vacuum at 500C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In 4-methyl-2-pentanone at 20 - 30℃; for 1h; | 5; 6; 7 Examples 5 to 7: Reaction Crystallisations (without Anti-solvent); Example 5 Compound A (277 mg; see Preparation A above) was dissolved in methyl iso- butyl ketone (3.1 mL). Ethanesulfonic acid was added (1 eq. , 95%, 48 [UL).] Precipitation of amorphous ethanesulfonate salt occurred immediately. More methyl iso-butyl ketone (6 mL) was added and the slurry was treated with ultrasound. Finally, a third portion of methyl iso-butyl ketone (3.6 mL) was added and then the slurry was left overnight with stirring (magnetic stirrer). The next day, the substance had transformed into crystalline needles. The slurry was filtered off, washed with methyl iso-butyl ketone (0.5 mL) and air dried.; Compound A (236 mg; see Preparation A above) was dissolved at room temperature in methyl iso-butyl ketone (7 mL). Ethanesulfonic acid [(1] eq. , 41 [I1L)] was mixed with 2 mL of methyl iso-butyl ketone in a vial. The solution of Compound A was seeded with crystalline Compound A, ethanesulfonic acid salt (see Examples 4 and 5 above). Then, 250 [GEL] of the methyl iso-butyl ketone solution of ethanesulfonic acid was added in portions over 45 minutes. The solution was seeded again, and the temperature was increased to [30°C.] Then, 500 [U. L] of the methyl iso-butyl ketone solution was added over approximately 1 hour. The resulting slurry was left overnight before a final amount of the methyl iso- butyl ketone/acid solution was added over 20 minutes. The vial was rinsed with 1.5 mL of methyl iso-butyl ketone, which was added to the slurry. After a further 6 hours, the crystals were filtered off, washed with methyl iso-butyl ketone (2 mL) and dried under reduced pressure at 40°C. A total of 258 mg of crystalline salt was obtained which corresponds to a yield of approximately 87%.; Compound A (2.36 g; see Preparation A above) was dissolved in methyl iso-butyl ketone (90 mL). Seed crystals (10 mg) of Compound A, ethanesulfonic acid salt (see Examples 4 to 6 above) were added to the solution, and then ethanesulfonic acid (40 [U. L)] was added in two portions. Further seed crystals (12 mg) and two portions of ethanesulfonic acid (2 x 20 u. L) were then added. The slurry was diluted with methyl iso-butyl ketone (15 [ML)] before the addition of ethanesulfonic acid was continued. A total amount of [330 U. L] ethanesulfonic acid was added, in portions, over 1 hour. A small amount of seed crystals was added and, finally, the slurry was left overnight with stirring. The next day, the crystals were filtered off, washed with methyl iso-butyl ketone (2 x 6 mL) and dried under reduced pressure at [40°C.] After drying, a total of 2.57 g of white, crystalline product was obtained corresponding to a yield of 89%. |
82% | In ethyl acetate; isopropyl alcohol at 21 - 40℃; for 3.33333 - 6.16667h; | 8; 9 Examples 8 and 9: Reaction [CRYSTALLIZATIONS] (with Anti-solvent) Example 8 Compound A (163 mg; see Preparation A above) was dissolved in iso-propanol (1.2 mL). The solution was heated to [35°C.] Ethanesulfonic acid was added (28 [GEL).] Then, ethyl acetate (4.8 [ML)] was added and the solution was seeded with crystalline Compound A, ethanesulphonic acid salt (see Examples 4 to 7 above). Crystallization started almost immediately. The slurry was left for about 80 minutes at [35°C] before being allowed to cool to ambient temperature [(21°C).] Two hours later, the crystals were filtered off, washed three times with ethyl acetate (3 x 0.4 mL), and dried under reduced pressure at [40°C.] A total of 170 mg of crystalline title product was obtained which corresponds to a yield of approximately 82%.; Compound A (20.0 g; see Preparation A above) was dissolved in iso-propanol (146.6 [ML)] at [40°C] and ethanesulfonic acid (3.46 mL, 95%, 1 eq. ) was added to the solution. To the resulting clear solution, seed crystals of Compound A, ethanesulfonic acid salt were added (50 mg; see Examples 4 to [8] above). Then, ethyl acetate (234 mL) was added over 10 minutes. The resulting slightly opaque solution was seeded once more (70 mg) and left for one hour at [40°C] with stirring to allow for crystallization to start. After this, a total of 352 mL of ethyl acetate was added at a constant rate over one hour. When all of the ethyl acetate had been added, the slurry was left for 1 hour, before being cooled to 21°C over 2 hours. The crystallization was allowed to continue for 1 hour at 21°C before the crystals were filtered off, washed twice with ethyl acetate (50 mL + 60 mL) and finally, dried under reduced pressure at [40°C] overnight. A total of 21.6 g of a white, crystalline salt was obtained, corresponding to a yield of approximately 90%. |
In ethanol | 2; 3 Examples 1 and 2 : Preparation of Salts of Compound A; Example 2 Compound A (203 mg; see Preparation A above) was dissolved in ethanol (3 mL) and ethanesulfonic acid [(1] eq. , 95%, 35 [UL)] was added to the solution. The mixture was stirred for a few minutes, and then the solvent was evaporated. The resulting oil was slurried in iso-octane and evaporated to dryness until a solid material was obtained. Finally, the substance was re-slurried in iso-octane and the solvent evaporated again resulting in a white, dry, amorphous. solid. The substance was vacuum dried at [40°C] overnight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; dichloromethane; ethyl acetate; | E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN- 6-yl}-allyl)-acetamide free base, prepared according to the method of either Example 1,2 or 3 (3.00 grams) was dissolved in 40mL ethanol and 6mL methylene chloride. 2.05 molar equivalents of ethanesulfonic acid, dissolved in 10ML ethanol, was added to the solution of free base. The solution was concentrated and taken up in a minimal volume of ethanol, then ethyl acetate was added as an nonsolvent until precipitation occurred. The slurry was stirred at ambient temperature over 48 hours and isolated as E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6- methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide diesylate. The diesylate complex was crystalline by PXRD. DSC showed a clean melting onset at 146C and a peak at 149. 5C. Hygroscopicity: 45% (by weight) at 90% relative humidity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In water; acetone at 20 - 50℃; for 6.5h; | 16 Example 16; [ (LR, 2S, 4R, SR, 6R)-2- (2'S-AMINO-PROPIONYL) AMINO-4-FLUOROBICYCLO [3. L. 0] HEXANE-2, 6-] dicarboxylic acid esylate [A SLURRY OF (1R,] 2S, 4R, 5R, 6R)-2- [2'S- (tert-butoxycarbonylamino) propionyl] - [AMINO-4-FLUOROBICYCLO] [3.1. 0] hexane-2,6-dicarboxylic acid (0.2 g, 0.534 mmol, Preparation 18) in 1.8 mL of acetone is allowed to stir at [50 °C] for 5 minutes. The hazy solution is filtered to clarify the solution followed by rinsing with acetone [(I] x 0.4 mL). The clear filtrate is diluted with 0.1 mL of water, placed in a heating bath at [50 °C,] and treated with 0.124 mL [(1.] 07 mmol) of ethanesulfonic acid dropwise (gas evolution observed). A white slurry is produced after 90 minutes. After stirring a total of 2 hours, another 1.8 mL of acetone is added over 5 min. The heat is turned off and the slurry is allowed to cool gradually to room temperature over 1 hours followed by stirring an additional 2 hours. Filtration, washing with acetone (2 x 1 mL), and vacuum drying at 45 [°C] for 4 hours and at room temperature for 60 hours afforded 0.173 g (84%) of the title compound as a white solid. mp (DSC) [210 °C] (decomp). 'H NMR (500 MHz, CD30D) [8] 5. [58-5.] 42 (m, 1H), 3.92 [(Q,] 1H, J = 7. 0Hz), 2.96 (dd, 1H, J = 14,8. 0 Hz), 2.80 [(Q,] [2H,] 7.3 Hz), 2.42-2. 37 [(M,] 1H), 2.35-2. 30 [(M, 1H),] 2.09 (t, [IH,] J = 3.0 Hz), 1.52 (d, 3H, J = 7.5 Hz), 1.51-1. 40 [(M,] [1H),] 1.30 (t, 3H, J = 7.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In methanol for 4h; Reflux; | 1.5 (5) Preparation of acetic acid Trinidad Neeb (formula (A)) of Three 25ml flask were added successively 2.0g Trinidad Technip, 7.5g ethanesulfonic acid, 10ml methanol was heated to reflux, stirred at reflux for 4h, heating was stopped, the solvent was evaporated to dryness, the resulting solid was slurried add 15ml of acetone, suction filtered to give a pale yellow solid 2.4g, yield: 100%.Purity by HPLC: 99.75% |
97.3% | In methanol; water at 60℃; | 8 Example 8: Synthesis of the 3-Z-[1 -(4-(N-((4-methyl-piperazin-1 -yl)- methylcarbonyl)-N-methyl-amino)-anilino)-1 -phenyl-methylene]-6- methoxycarbonyl-2-indolinone, monoethanesulfonate"ANILINO" 3-Z-[1-(4-(N-((4-methyl-pιperazιn-1-yl)-methylcarbonyl)-N-me thyl-amιno)-anιlιno)-1-phenyl-methylene]-6-methoxycarbonyl- 2-ιndolιnone, monoethanesulfonateA suspension of 3-Z-[1 -(4-(N-((4-methyl-piperazin-1 -yl)-methylcarbonyl)-N- nnethyl-annino)-anilino)-1 -phenyl-nnethylene]-6-nnethoxycarbonyl-2-indolinone (30,0 g; 0,055 mol) in methanol (200 ml) and water (2,4 ml) is heated to 60 0C. Aqueous ethanesulfonic acid (70% (w/w); 8,75 g; 0,056 mol) is added to the reaction mixture. The resulting solution is cooled to 50 0C, seeded and then diluted with isopropanol (200 ml). The mixture is further cooled to 0 0C and stirred for 2 h at this temperature. The precipitate is isolated, washed with isopropanol (120 ml) and dried to furnish 35,1 g (97,3 %) of the monoethanesulfonate salt of the compound as yellow crystals. 1H-NMR (400 MHz, DMSO-de) δ: 12,26 (s, 11-H); 10,79 (s, 1 H, 1 -H); 9,44 (s, 1 H, 24-H); 7,64 (m, 1 H, 32-H); 7,59 (m, 2 H, 31 -H + 33-H); 7,52 (m, 2 H, 30-H + 34-H); 7,45 (d, J = 1 ,6 Hz, 1 H, 7-H); 7,20 (dd, J = 8,2; 1 ,6 Hz, 1 H, 5-H); 7,16 (m, 2 H, 14-H + 16-H); 6,90 (m, 2 H, 13-H + 17-H); 5,85 (d, J = 8,2 Hz, 1 H, 4-H); 3,78 (s, 3 H, 37-H3); 3,45 - 2,80 (broad m, 4 H, 23-H2 + 25-H2); 3,08 (s, 3 H, 28-H3); 2,88 (s, 2 H, 20-H2); 2,85 - 2,30 (broad m, 4 H, 22-H2 + 26-H2); 2,75 (s, 3 H, 27-H3); 2,44 (q, J = 7,4 Hz, 2 H, 39-H2); 1 ,09 (t, J = 7,4 Hz, 3 H, 38-H3). 13C-NMR (126 MHz, DMSO-de) δ: 9,8 (C-38); 36,6 (C-28); 42,3 (C-27); 45,1 (C-39); 51 ,7 (C- 37); 48,9 (C-22 + C-26); 52,6 (C-23 + C-25); 57,5 (C-20); 97,7 (C-3); 109,5 (C- 7); 1 17,3 (C-4); 121 ,4 (C-5); 123,8 (C-13 + C-17); 124,1 (C-6); 127,7 (C-14 + C- 16); 128,4 (C-30 + C-34); 128,8 (C-9); 129,5 (C-31 + C-33); 130,5 (C-32); 132,0 (C-29); 168,5 (C-9); 136,3 (C-8); 137,3 (C-12); 139,5 (C-15); 158,1 (C-10); 166,3 (C-35); 168,0 (C-19); 170,1 (C-2). MS (m/z): 540 (M(base) + H)+. Anal. calcd. for C33H39N5O7S: C, 60.17; H, 6.12; N, 10.63; S, 4.87. Found: C, 60.40; H, 6.15; N, 10.70; S, 4.84. |
96.22% | In methanol; water at 25 - 65℃; | 4 Example-4: Preparation of Nintedanib Esylate Nintedanib free base [I] (200gm), methanol (1134 ml) and purified water (16 ml) were charged into glass assembly at room temperature. Then, the reaction mixture was stirred at 25-30°C for 10-15 and the temperature was raised to 60-65°C. Ethane sulfonic acid (41.22gm) was added into the reaction mass at 60-65°C in 30 minutes. The reaction mass was stirred at 60-65°C for 1.0 hr. The reaction mixture was fine filtered using whatmann filter paper at 60-65 °C and washed with hot methanol (200ml). Remaining filtrate ML was transferred to another clean and dried glass assembly and set temperature of reaction mass to 50-55°C. Isopropyl alcohol (534ml) was added slowly to reaction mass at 50-55°C in 20- 30 minutes. Reaction mass was seeded with Nintedanib Esylate (200mg) (Crystalline API) at 50-55°C. Again isopropyl alcohol (800ml) was added into reaction mixture at 50-55°C. Then, reaction mixture was maintained at 50-55°C for 30 minutes. Gradually, the reaction mixture was cooled to 0-5°C and stirred for 3 hr at same temperature. The precipitated solid was filtered and washed with isopropyl alcohol (200 ml) to get wet material (260.2gm). Followed by drying of the wet cake under vacuum at 45-50 C to get Nintedamb Esylate [II] (232. Igm) as bright yellow solid. Total yield of pure Nintedanib Esylate [II] was 96.22% and purity was 99.85%. |
95% | In methanol; water; isopropyl alcohol at 0 - 65℃; for 1h; | Preparation of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-1yl)acetamide)ph- enyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate ethane sulfonate salt (1): To a Suspension of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl) acetami- de)-phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate 6 (36 g, 0.066 mol) in methanol (237 mL) and water (2.88 mL) ethanesulfonic acid (7.92 g 0.0719 mol) in water (2.88 mL) was added at 60-65°C. The resulting suspension was cooled to 50C, and was diluted with isopropanol (237 mL). The reaction mixture was cooled to 0C and stirred for 1h. The precipitate obtained was filtered and washed with mixture of methanol and isopropanol (50%) (50 ml), product was dried to obtain crude Nintedanib monoethane sulfonate (36.6 g) which was crystallized from methanol (5 Vol) to obtain pure Nintedanib monoethane sulfonate salt as yellow crystals (33 g) (HPLC purity >99%). DSC: 298C; IR (KBr, cm-1): 3321, 3273, 1710, 1652, 1615, 1515, 1435, 1378, 1289, 1209, 1161, 1087; 1H-NMR (400 MHz, DMSO): δ 1.08 (t, 3H, J = 7.31 Hz), 2.41-2.47 (q, 2H), 2.50-3.16 (broad m, 13H), 3.37 (s, 3H), 3.76 (s, 3H), 5.82 (d, 1H, J = 7.88Hz), 6.87 (d, 2H, J = 7.36 Hz), 7.14-7.20 (m, 3H), 7.49 (s, 1H), 7.49 (d, 2H, J = 6.68 Hz), 7.56-7.63 (m, 3H), 9.45 (s, 1H), 10.99 (s, 1H), 12.25 (s, 1H), 13C-NMR (100 MHz, DMSO): δ 37.15, 42.79, 45.65, 49.40, 52.26, 53.10, 58.04, 98.25, 110.01, 117.78, 121.97, 124.32, 124.59, 128.27, 128.90, 129.36, 130.00, 131.00, 132.52, 136.79, 137.93, 140.00, 158.66, 166.85, 168.47 and 170.65; MS: m/z 540 [M]+1. |
95.2% | In methanol; water at 60 - 70℃; for 0.5h; Large scale; | 1.4; 2.4; 3.4 (4) Synthesis of nintedanib ethanesulfonic acid Add 37.06L of methanol and 370.6ml of purified water into a 100L reactor, add 5kg of nintedanib under stirring, warm up to 60-70, add ethanesulfonic acid aqueous solution (1.12kg ethanesulfonic acid, 0.48L water) dropwise, continue to stir for 30min after dropping, measure pH=5.0, add 37.06L isopropanol dropwise, solids will precipitate when half of isopropanol is added dropwise, after the addition is complete, cool to room temperature, then to 0-10°C, continue stirring for 2h to crystallize, after suction filtration, the filter cake was washed with 10 L of isopropanol and dried to obtain 5.73 kg of product with a yield of 95.2% and a purity of 100%. |
91.27% | In methanol at 50 - 55℃; for 0.5h; | 1 The 2L glass bottle was charged with anhydrous methanol 1.2L. Addition 100.0g Example 1 of (3Z) -3 - [ (4 - {methyl)}-[(methylpiperaz 4 -yl) acetyl] amino} phenyl} amino}-(phenyl) methylene} -1 - oxo -2 -2-dihydroindole 3 - methyl formate (compound C) dripped unitedly , 50 - 55 °C and reacted 70% -6 - and the reaction 50 - 55 °C was completed, followed by addition of 3.6L 0.5h isopropyl alcohol 58.3g, and the like. The residue was stirred 25 - 30 °C 4h, filtered through suction filtration, filtered, washed, dried, yellow crystalline powder ethanesulfonate (compound D) was obtained 109.9g, and unitant , Scott and 91.27% unitz . 99.96% were obtained. |
89.7% | In ethanol; water at 50℃; | 6 Example 6: Synthesis of Nidanubile Ethanesulfonate 500 grams of the crystalline compound of Example 5 is suspended in 10 liters of ethanol, heated to 50 ° C and 180 grams of 70% aqueous ethanesulfonic acid are added. The resulting solution was cooled to 40 ° C,An additional 4.5 liters of t-butyl ether was added. Crystallize after a few minutes. To achieve complete precipitation, the mixture was stirred for a further 16 hours at room temperature. After cooling to 10 ° C, suction filtration, washing with 2 t-butyl ether and drying under vacuum at 40 ° C,Ethanesulfonate compounds are obtained.Yield: 538 g (89.7% yield). |
89% | In methanol; water at 60℃; | 4 Example 4. Nintedanib esylate A suspension of (Z)-3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (75 g) in methanol (500 ml) and water (6 ml) was heated to 60 °C and ethanesulfonic acid (70 w-% aq., 18.3 ml) was added to the mixture. A clear solution was obtained. The solution was cooled to 50 °C, seeded and 2-propanol (500 ml) was added while maintaining the temperature at 50 °C. The resulting suspension was cooled to 0 °C and stirred for 1-2 h, then isolated by filtration and washed with 2-propanol (300 ml). The solids were dried in a vacuum oven at 40 °C overnight to obtain Nintedanib esylate (84.5 g, 89 %, 99.8 a-%) as a bright yellow solid. |
87.6% | In methanol; water at 50℃; | 2 Example 2; 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone monoethanesulphonate 605 [G] (1.12 mol) of [3-Z- [1- (4- (N- ( (4-METHYL-PIPERAZIN-1-YL)-METHYLCARBONYL)-N-METHYL-] [AMINO)-ANILINO)-1-PHENYL-METHYLENE]-6-METHOXYCARBONYL-2-INDOLINONE] are suspended in 9 litres of methanol and heated to [50°C.] 183.7 [G] (1.121 mol) of 70% aqueous [ETHANESULPHONIC] acid are added. The solution obtained is cooled to [40°C] and 4. 5 litres of [TERT.-BUTYLMETHYLETHER] are added. After a few minutes crystallisation sets in. To achieve total precipitation the mixture is stirred for another 16 hours at ambient temperature. After cooling to [10°C] it is suction filtered, washed with 2 litres of tert.- butylmethylether and dried [AT 40°C IN VACUO.] Yield : 638 g (87.6% of theory) Tm. [P.] = 305 [5°C] (DSC 1 OK/min) Purity according to HPLC: 99.4% Water content: 1.0 to 2.0% (KF) |
80% | In methanol; water at 60 - 65℃; | 1.5 Step-5: Preparation of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-lyl)acetamide) phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate ethane sulfonate salt: Suspension of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamide)phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (36 gm, 0.066 mol) in methanol (237 ml) and water (2.88 ml)was heated to 60-65°C and aq. ethane sulfonic acid was added to the reaction mixture. The resulting solution was cooled to 50°C, seeds diluted with isopropanol (237 ml) was added. The reaction mixture was cooled at 0°C for lhr. Filtered the precipitate, washed with mixture of methanol and isopropanol (50 ml), dried to obtain crude Nintedanib monoethane sulfonate (36.6 gm) and crystallized from methanol (5 Vol) to obtained pure Nintedanib monoethane sulfonate salt as yellow crystals (33 gm) (80%) (HPLC purity >99%). DSC: 298°C; IR (KBr, cm-1): 3321, 3273, 1710, 1652, 1615, 1515, 1435, 1378, 1289, 1209, 1161, 1087; 1H-NMR (400 MHz, DMSO): δ 1.08 (t, 3H, J = 7.31 Hz), 2.41-2.47 (q, 2H), 2.50-3.16 (broad m, 13H), 3.37 (s, 3H), 3.76 (s, 3H), 5.82 (d, 1H, J = 7.88Hz), 6.87 (d, 2H, J = 7.36 Hz), 7.14-7.20 (m, 3H), 7.49 (s, 1H), 7.49 (d, 2H, J = 6.68 Hz), 7.56-7.63 (m, 3H), 9.45 (s, 1H), 10.99 (s, 1H), 12.25 (s, 1H), 13C-NMR (100 MHz, DMSO): δ 37.15, 42.79, 45.65, 49.40, 52.26, 53.10, 58.04, 98.25, 110.01, 117.78, 121.97, 124.32, 124.59, 128.27, 128.90, 129.36, 130.00, 131.00, 132.52, 136.79, 137.93, 140.00, 158.66, 166.85, 168.47 and 170.65; MS: m/z 540[M]+1. |
In methanol; water at 50℃; | 605 g (1.12 mol) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone are suspended in 9 litres methanol and heated to 50°C. 183.7 g (1.121 mol) of a 70% aqueous solution of ethanesulfonate is added. The resulting solution is cooled to 40°C and mixed with 4.5 litres ter-butylmethylether. Cristallisation occurs after a few minutes. In order to achieve a complete precipitation, the whole is mixed for 16 hours at room temperature. After cooling to a temperature of 10°C, the liquid is sucked up, the precipitate is washed with 2 litres ter-butylmethylether and vacuum dried at 40°C. [] Recovered product:638 g (87.6% of theoretical value)Tsmp. =305 +/- 5°C (DSC 10K/min)Purity (measured by HPLC):99.4%Water content:1.0 bis 2.0% (KF) | |
In dichloromethane at 10℃; for 5h; Large scale; | 1 Example 1 Preparation of nidanibu ethanesulfonate crude 100L5.92kg88.8kg1.27kg(10)5h3012h5.7kg79.9 | |
In methanol at 40 - 50℃; | 1.S4; 2.S4; 3.S4; 4.S4; 5.S4; 6.S4; 7.S4; 1.S4; 5.S4; 6.S4 S4: Preparation of nintedanib ethanesulfonate Add INT04 and methanol to the reaction kettle at room temperature, stir and raise the temperature to 50°C, add 70% ethanesulfonic acid solution dropwise, keep the reaction warm, cool the refrigerant water to 40°C, add methyl tert-butyl ether dropwise, and slowly drop to room temperature. Add isopropyl ether, then reduce to 0-10°C, keep the crystals incubated for 1 h, filter with suction, wash the filter cake with methyl tert-butyl ether, and dry the wet product under vacuum to obtain yellow solid nintedanib ethanesulfonate.In step S4, the mass ratio of INT04, ethanesulfonic acid solution, methanol, methyl tert-butyl ether, and isopropyl ether is 1:0.3:8:7:4, and the solvent is methanol and the reaction time is 2h;In step S4, after the methyl tert-butyl ether is added dropwise, the temperature of the reaction solution is first cooled to 25-30°C, and the crystal is incubated for 1 hour; then isopropyl ether is added dropwise, and then the temperature is reduced to 0-5°C, and the crystal is incubated for 1 hour for filtration; | |
7 g | In methanol; water; isopropyl alcohol at 0 - 60℃; for 2h; | 13 Example 13: Preparation of nintedanib ethanesulfonate Add 6 g of nintedanib prepared in Example 7 to 40 ml of methanol and 0.5 ml of water, and heat to 60°C. Add 1.75 g of ethanesulfonic acid aqueous solution to the reaction solution,During the process of adding 40ml of isopropanol, the temperature is controlled at 55-60°C. After the addition, the temperature is lowered to 0-5°C, the temperature is kept and stirred for 2 hours, filtered, and dried to obtain 7.0 g of nintedanib ethanesulfonate with a purity of 99.5% |
In methanol; dichloromethane at 20 - 30℃; for 16h; | 1 Example 1 Take a certain volume of methanol and dichloromethane mixed solution in a 500ml jacketed crystallizer, keep the temperature at 20-30°C, dissolve intedanib free base in the methanol and dichloromethane mixed solution, methanol The volume ratio with dichloromethane is 1:1-1:10, preferably 1:2-1:5. Fully dissolve intedanib free base in the mixed solution and pass through a 0.45μm organic filter membrane to remove impurities. For the filtrate, keeping the temperature constant at 20°C-30°C, slowly add ethanesulfonic acid, and the molar ratio of intedanib free base to ethanesulfonic acid is 1:1.02.The yellow solid precipitates out slowly, keep stirring at this temperature for 16 hours, then separate the precipitated crystals at room temperature, and then place it at 25°C-60°C and dry for 24 hours, preferably at 40°C-60°C, and dry for 1-48 hours, preferably 12-36 hours, get crystal form I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; ethyl acetate; at 20℃; | To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea free base in MeOH-EtOAc was added 1 equivalent of ethanesulfonic acid. The mixture was stirred at ambient temperature and then reduced in vacuo. The residue was taken up in MeOH and to the solution was added Et2O. Mixture left to stand for 72 h and the solid formed collected by filtration and dried to give l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea ethanesulfonate salt. | |
In methanol; ethyl acetate; at 20℃; | To a solution of 1 -cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H- pyrazol-4-yl]-urea free base in MeOH-EtOAc was added 1 equivalent of ethanesulfonic acid. The mixture was stirred at ambient temperature and then reduced in vacuo. The residue was taken up in MeOH and to the solution was added Et2O. Mixture left to stand for 72 h and the solid formed collected by filtration and dried to give 1-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-urea ethanesulfonate salt. | |
In methanol; ethyl acetate; at 20℃;Product distribution / selectivity; | D. Preparation of l-Cvclopropyl-B-rS-rS-Mophiholin^-ylmethyl-lH-Benzoimidazol^-vD-lH- Pyrazol-4-yli-Urea ethanesulfonate salt; To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-yhnethyl-lH-benzoimidazol-2-yl)-lH- pyrazol-4-yl]-urea free base in MeOH-EtOAc was added 1 equivalent of ethanesulfonic acid. The mixture was stirred at ambient temperature and then reduced in vacuo. The residue was taken up in MeOH and to the solution was added Et2O. Mixture left to stand for 72 h and the solid formed collected by filtration and dried to give l-cyclopropyl-3-[3-(5-morpholin-4- ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea ethanesulfonate salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 0 - 80℃; for 1.83333h; | Example 13. A crystalline form of the dimethyl sulfoxide solvate of the ethanesulfonate of <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> Dimethyl sulfoxide (4 mL) was added at room temperature to <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (400 mg, 0.937 mmol), and the mixture was then dissolved at 60 C. To the reaction mixture were added ethanesulfonic acid (92 muL, 1.124 mmol), ethyl acetate (2.4 mL) and a crystalline form of the ethanesulfonate of <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (Form beta) obtained in (Preparation method 1) of Example 12 in this order, and the mixture was then stirred at 60 C for 20 min. After a further addition of ethyl acetate (1.6 mL), the reaction mixture was once heated to 80 C, and then cooled to 0 C over 1.5 hours. Precipitated crystals were filtered off and dried at 60 C to give the titled crystals (523 mg). The 1H-NMR chemical shift values for the ethanesulfonate are as follows: 1H-NMR Spectrum (DMSO-d6) delta(ppm): 0.43 (2H, m), 0.66 (2H, m), 1.05 (3H, t, J=7.4 Hz), 2.38 (2H, q, J=7.4 Hz), 2.58 (1H, m), 4.08 (3H, s), 6.88 (1H, s), 7.24 (1H, s), 7.34 (1H, d, J=9.0 Hz), 7.60 (1H, s), 7.61 (1H, s), 7.88 (1H, s), 7.94 (1H, s), 8.05 (1H, s), 8.36 (1H, d, J=9.0 Hz), 8.72 (1H, s), 8.92(1H,s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; ethyl acetate; at 20 - 60℃; for 10.5h;Product distribution / selectivity; | Example 11. A crystalline form of the ethanesulfonate of <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (Form alpha) (Preparation method 1) Dimethyl sulfoxide (1.5 mL) and ethanesulfonic acid (34 muL, 0.422 mmol) were added to <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (150 mg, 0.351 mmol) and the mixture was dissolved at room temperature. Ethyl acetate (1.5 mL) was added dropwise to the reaction mixture at 60 C over 1.5 hours. 30 min after the addition of ethyl acetate was completed, the reaction mixture was cooled to room temperature over 1.5 hours, and then stirred at room temperature for a further 7 hours. Precipitated crystals were filtered off and dried at 60 C to give the titled crystals (176 mg). | |
In water; acetic acid; isopropyl alcohol; at 0 - 60℃; for 3h;Product distribution / selectivity; | (Preparation method 2) Acetic acid (0.75 mL) and ethanesulfonic acid (34 muL, 0.422 mmol) were added at room temperature to <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (150 mg, 0.351 mmol), and the mixture was then dissolved at 60 C. To the reaction mixture were added water (0.225 mL), 2-propanol (2 mL), a crystalline form of the ethanesulfonate of <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (Form beta) obtained in (Preparation method 1) of Example 12, and 2-propanol (2.5 mL) in this order, and the mixture was then cooled to 0 C over 2.5 hours, and stirred for 30 min. Precipitated crystals were filtered off and dried at 60 C to give the titled crystals (139 mg). | |
In ethanol; at 20 - 65℃; for 7h;Product distribution / selectivity; | (Preparation method 2) Ethanol (40 mL) and ethanesulfonic acid (459 muL, 5.622 mmol) were added to <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (150 mg, 0.351 mmol) at room temperature and the mixture was dissolved at 65 C. The reaction mixture was cooled with a bath at a temperature of 22 C, and seed crystals of a crystalline form of the ethanesulfonate of <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (Form alpha) was added. The mixture was stirred for further 7 hours. Precipitated crystals were filtered off and dried at 70 C to give the titled crystals (1.55g). |
In dimethyl sulfoxide; ethyl acetate; at 20 - 60℃; for 10.5h;Product distribution / selectivity; | Reference Example 14 A crystalline form of the ethanesulfonate of <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (Form alpha) (Preparation method 1) To 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy -6-quinolinecarboxamide (150 mg, 0.351 mmol) were added dimethylsulfoxide (1.5 mL) and ethanesulfonic acid (34 muL, 0.422 mmol) at room temperature for dissolution. Ethyl acetate (1.5 mL) was added dropwise to the reaction mixture at 60 C. over a period of 1.5 hours. 30 min after completion of the dropwise addition of ethyl acetate, the reaction mixture was allowed to cool down to room temperature over a period of 1.5 hours, followed by further stirring at room temperature for 7 hours. Precipitated crystals were collected by filtration and dried at 60 C. to give the titled crystals (176 mg). | |
In dimethyl sulfoxide; ethyl acetate; at 0 - 80℃; for 1.83333h; | Reference Example 16 A crystalline form of the dimethylsulfoxide solvate of the ethanesulfonate of <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> To 4-3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy -6-quinolinecarboxamide (400 mg, 0.937 mmol) was added dimethylsulfoxide (4 mL) at room temperature, followed by dissolution at 60 C. To the reaction mixture were added ethanesulfonic acid (92 muL, 1.124 mmol), ethyl acetate (2.4 mL) and a crystalline form of the ethanesulfonate of <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (Form beta) obtained in Reference Example 15 (Preparation method 1) in that order, and the mixture was then stirred at 60 C. for 20 min. After a further addition of ethyl acetate (1.6 mL), the reaction mixture was once heated to 80 C., and then cooled to 0 C. over a period of 1.5 hours. Precipitated crystals were collected by filtration and dried at 60 C. to give the titled crystals (523 mg). The 1H-NMR chemical shift values for the ethanesulfonate are as follows: 1H-NMR Spectrum (DMSO-d6) delta(ppm): 0.43 (2H, m), 0.66 (2H, m), 1.05 (3H, t, J=7.4 Hz), 2.38 (2H, q, J=7.4 Hz), 2.58 (1H, m), 4.08 (3H, s), 6.88 (1H, s), 7.24 (1H, s), 7.34 (1H, d, J-9.0 Hz), 7.60 (1H, s), 7.61 (1H, s), 7.88 (1H, s), 7.94 (1H, s), 8.05 (1H, s), 8.36 (1H, d, J=9.0 Hz), 8.72 (1H, s), 8.92 (1H, s) | |
With acetic acid; In water; isopropyl alcohol; at 0 - 60℃; for 3h;Product distribution / selectivity; | (Preparation method 2) To 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy -6-quinolinecarboxamide (150 mg, 0.351 mmol) were added acetic acid (0.75 mL) and ethanesulfonic acid (34 muL, 0.422 mmol) at room temperature, followed by dissolution at 60 C. To the reaction mixture were added water (0.225 mL), 2-propanol (2 mL), a crystalline form of the ethanesulfonate of <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (Form beta) obtained in Reference Example 15 (Preparation method 1), and 2-propanol (2.5 mL) in that order, and the mixture was then cooled to 0 C. over a period of 2.5 hours, and stirred for 30 min. | |
In ethanol; at 22 - 65℃; for 7h;Product distribution / selectivity; | (Preparation method 2) To 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy -6-quinolinecarboxamide (150 mg, 0.351 mmol) were added ethanol (40 mL) and ethanesulfonic acid (459 muL, 5.622 mmol) at room temperature, followed by dissolution at 65 C. The reaction mixture was cooled with a bath at a temperature of 22 C., and seed crystals of a crystalline form of the ethanesulfonate of <strong>[417716-92-8]4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide</strong> (Form alpha) was added. The mixture was further stirred for 7 hours. Precipitated crystals were collected by filtration and dried at 70 C. to give the titled crystals (1.55 g). |
Yield | Reaction Conditions | Operation in experiment |
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94% | In 4-methyl-2-pentanone at 50℃; | (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1 ,2,3,4,4a, 10b-hexahydro- phenanthridin-2-ol ethansulfonate(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1 ,2,3,4,4a, 10b-hexahydro- phenanthridin-2-ol (1.5 g; 3.64 mmol) is dissolved in 9 ml of 4-methyl-2-pentanone. The solution is heated up to 50 0C. 312 μl (3.82 mmol) of ethansulfonic acid are added. After crystallisation 3 ml 4- methyl-2-pentanon is added and the suspension is stirred over night. The crystals are filtered off and dried to obtain 1.78 g (94 %) of the title compound (m.p.: 216°C). |
Yield | Reaction Conditions | Operation in experiment |
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19% | In hydrogenchloride; methanol; N,N-dimethyl-formamide | 26 (+-)-cis-4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol EXAMPLE 26 (+-)-cis-4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol The title compound of Example 25 (0.91 g, 2.79 mmol) was dissolved in dry DMF (1 mL). Triethylorthoformate (10 mL) and ethane sulfonic acid (0.29 mL, 3.4 mmol) were added and the solution heated at 65° C. for 24 hours. The solution was evaporated to a syrup. The syrup was dissolved in 1N HCl (15 mL) and stirred for three hours. The pH was adjusted to 7 with 5N sodium hydroxide and the resulting mixture (oil formed) was extracted with i-propanol:chloroform/1:3 (3*100 mL). The combined organic layers were dried (MgSO4) and evaporated to a red glass (0.93 g). A solution of this glass in methanol (20 mL) was heated with cyclopropylamine (2 mL) in a Parr bomb at 70° C. for 18 hours. The resulting solution was evaporated to a dark glass which was adsorbed on silica gel. Elution with 7% methanol-ethylacetate gave title compound (148 mg, 19%) as white powder, after trituration with acetonitrile; 1 H-NMR (DMSO-d6) identical with that of the title compound of Example 5. |
Yield | Reaction Conditions | Operation in experiment |
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86% | In ethyl acetate; acetonitrile | 2 Preparation of 1-(4-chloro-phenyl)-1-hydroxy-1,2-dihydro-as-triazino[6,1-a]isoquinolinium-ethanesulfonate EXAMPLE 2 Preparation of 1-(4-chloro-phenyl)-1-hydroxy-1,2-dihydro-as-triazino[6,1-a]isoquinolinium-ethanesulfonate 3.55 g (0.0091 mole) of 1-(4-chloro-phenyl)-1-hydroxy-1,2-dihydro-as-triazino[6,1-a]isoquinolinium-bromide are reacted with 2.22 g (0.0022 mole) of ethane sulfonic acid in 50 ml of acetonitrile. The reaction mixture is evaporated to dryness and the residue dissolved in ethyl acetate. On cooling 3.3 g of the aimed compound precipitate in the form of prismatic crystals. Yield 86%. Mp.: 187-188 C.°. |
Yield | Reaction Conditions | Operation in experiment |
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In acetone; at 50℃;Product distribution / selectivity; | Example 7[0042] About 50-60 mg of form A of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base was suspended in 0.75 mL of a listed solvent. The stoichiometric amount of a noted acid was subsequently added to the suspension. For inorganic acids, the mixture was stirred at ambient temperature for about 5 hours, and for sulfonic acids, it was stirred at 500C overnight. Solids were collected by filtration and analyzed by XRPD and NMR. | |
In tetrahydrofuran; at 50℃;Product distribution / selectivity; | Example 7[0042] About 50-60 mg of form A of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base was suspended in 0.75 mL of a listed solvent. The stoichiometric amount of a noted acid was subsequently added to the suspension. For inorganic acids, the mixture was stirred at ambient temperature for about 5 hours, and for sulfonic acids, it was stirred at 500C overnight. Solids were collected by filtration and analyzed by XRPD and NMR. | |
In acetone; at 50℃;Product distribution / selectivity; | Example 8[0044] About 300-310 mg of form B of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base was suspended in 9 mL of 2-propanol for HCl and 15 mL acetone for the sulfonic acids. The stoichiometric amount of the noted acid was subsequently added to the suspension. For HCl, the mixture was stirred at ambient temperature for 5 hours, and for sulfonic acids, it was stirred at 50C overnight. Then, the mixture was cooled to ambient temperature, collected by filtration and analyzed by XRPD and NMR. |
Yield | Reaction Conditions | Operation in experiment |
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83% | In carbonic acid dimethyl ester at 3 - 90℃; for 96h; | 40 Ethanesulfonic acid (0.38 mL, 4.6 mmol, 2 eq) is slowly added to a solution of(R)-δ^-chloiOphenyl)-1-(2,4-dichlorophenyl)-N^piperidin-i-ylH.S-dihydrO-IH- pyrazole-3-carboxamide (1.00 g, 2.2 mmol, 1 eq.) in 10 mL of dimethyl carbonate at 9O0C. The resulting solution is cooled to room temperature and kept at 30C for4 days. The crystals formed are filtered off, washed with cold dimethyl carbonate, and dried under vacuum (10 mm Hg) at 5O0C for 4 hours to give the salt as a white solid (1.03 g, 83 % yield). DSC analysis: Broad melting point at 180-1880C.TG analysis: Weight loss due to decomposition, at temperatures higher than2590C.FTIR (ATR) υmax: 2957, 2514, 1686, 1549, 1473, 1292, 1219, 1147, 1088, 1040,834, 815 and 739 cm1 EPO 1H NMR (400 MHz1 (CD3)2CNOD) δ: 1.20 (t, J = 7 Hz, 3H), 1.51-1.60 (m, 2H), 1.85-1.96 (m, 4H), 2.71 (q, J = 7 Hz, 2H)1 3.21 (dd, J = 6 Hz, J = 18 Hz, 1 H), 3.44-3.61 (m, 4H), 3.80 (dd, J = 12 Hz, J = 18 Hz1 1 H), 6.02 (dd, J = 6 Hz, J = 12 Hz, 1 H), 7.27-7.50 (m, 7H), 7.65 (d, 9 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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95.6% | In acetone at 25 - 50℃; for 20h; | 25 Example 25 esylate [Show Image] A suspension of 3.01 g base (10 mmoles) in 36 ml acetone is heated to 50°C. 1.16 g ethanesulfonic acid (10.5 mmoles) are added. The resulting clear solution is allowed to cool. Crystallization takes spontaneously place at ca. 45 °C. The suspension is stirred at 25°C for 20 h and filtered. The solid is washed with 15 ml acetone and dried first for 2 h at 50°C / ca. 10 mbar and then for 20 h at 80°C and ca. 10 mbar. Yield: 3.93 g whitish powder (95.6 %) Elemental analysis: Calc.: 52.54 % C; 7.10 % H; 17.02 % N; 7.79 % S; 15.55 % OFound: 52.65 % C; 7.01 % H; 17.07 % N; 7.70 % S; 15.59 % O |
Yield | Reaction Conditions | Operation in experiment |
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86% | In ethanol at 20℃; for 1h; | 1 Example 1 : Preparation of N- hydroxy-4-{5-[4-(5-isopropyl-2-methyl-l,3-thiazol-4-yl)phenoxy]pentoxy}benzami dine 2 ethansulfonic acid salt; [51] 3 g (6.614 mmol) of N- hydroxy-4-{5-[4-(5-isopropyl-2-methyl-l,3-thiazol-4-yl)phenoxy]pentoxy}benzamidin e was dissolved in 30 ml of ethanol, and was mixed with 1.14 ml (2.2 equivalents) of ethanesulfonic acid with agitation at room temperature for 1 hr. The solution was then mixed with 30 ml of acetone and 60 ml of hexane with agitation for 1 hr. The produced solid was recovered by filtration, washed with acetone, and dried under vacuum. As a result, 4.17 g (yield: 86%) of N-Hydroxy-4-{5-[4-(5-isopropyl-2-methyl-l,3-thiazol-4-yl)phenoxy]pentoxy} benzamidine 2 ethansulfonic acid salt was obtained as a white solid.[52] The obtained N-Hydroxy-4-{5-[4-(5-isopropyl-2-methyl-l,3-thiazol-4-yl)phenoxy] pentoxyl benzamidine 2 ethansulfonic acid salt was analyzed for the content of ethanesulfonic acid and melting point, and the results are as follows.[53] -Content of ethanesulfonic acid (Theoretical value: 32.7%, Measured value: 33.0%), [54] -Melting point: 1410C |
Yield | Reaction Conditions | Operation in experiment |
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93.27% | In butanone at 0 - 50℃; | 2 Example 2: 5-Amino-3-(2',3'-di-O-acetyl-beta-D-ribofuranosyl)-3H-thiazolo[4,5-d]pyrimidin-2-one Esylate 5.0 g 5-Amino-3-(2',3'-di-O-acetyl-beta-D-ribofuranosyl)-3H-thiazolo[4,5-d]pyrimidin-2-one base (13.01 mmoles) are dissolved in 15 ml methyl-ethylketone (MEK) and the solution is heated to 50°C. A solution of 1.43 g ethansulfonic acid (12.36 mmoles) in 3 ml MEK is added dropwise over ca. 5 min. The dropping funnel is rinsed with 2 ml MEK. The solution is clarified via filtration at 50 °C over a glasfiber filter. The filter is rinsed with 5 ml MEK of 50°C. The filtrate is allowed to cool. Some seeds are added at 30°C and crystallization takes place. The suspension is stirred at room temperature over night and then further stirred at 0°C for two hours. The solid is collected after filtration and washing with 6 ml MEK of 0°C. The salt is dried at 60°C and 8 mbar for ca. 20 h. Yield: 5.70 g white powder (93.27%) |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine In dichloromethane at 20 - 40℃; | 140 Compound 140; Ethanesulfonic acid [4-(2-bromo-3-oxo-3,3a,4,5,6,6a-hexahydro-pentalen-l-yl)-phenyl]-amide; 3-(4-Amino-phenyl)-2-bromo-4,5,6,6a-tetrahydro-3aH-pentalen-l-one (25mg, 0.09 mmol) and N,N- diisopropylethylamine (33mg, 0.26mmol) were mixed in CH2Cb (0.5ml, dry) at RT. To this suspension, the sulphonyl chloride (0.26mmol) in CH2Cl2 (0.5ml, dry) was added. The mixture was stirred at 40 0C over night. The mixture was washed with HCl IM and the organic phase separated using a phase separator. Concentration and purification by preparative HPLC afforded 1 lmg of the title compound. ES/MS m/z: 385.97 (pos. M + H), 381.99 (neg. M - H); 1H NMR (d6-Acetone, 500MHz): d 8.00 (m, 2H), 7.50 (m, 2H), 4.02 (m, IH), 3.25 (m, 2H), 3.02 (m, IH), 1.85 (m, 3H), 1.62 (m, IH) 1.51 (m, IH), 1.32 (m, 3H) and 1.28 (m, IH). |
Yield | Reaction Conditions | Operation in experiment |
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96% | Stage #1: ethanesulfonic acid With trichloroisocyanuric acid; triphenylphosphine In tetrahydrofuran at 0 - 5℃; Stage #2: With sodium azide In tetrahydrofuran at 5 - 20℃; | General procedure: To a solution of CCA(0.1548 g, 0.6 mmol) in tetrahydrofuran (3-5 mL), PPh3 (0.5246 g, 2 mmol)was added at 0-5°C with stirring. A white suspension was formed to which p-toluenesulfonic acid (0.1720 g, 1 mmol) was added and stirring continued for 15 min. NaN3 (0.065 g, 1 mmol) was added and the temperature was raised up to room temperature. Stirring was continued for 1 min at room temperature. After completion of the reaction (TLC), the reaction mixture was concentrated, washed with EtOAc (4-6 mL), and cold distilled water (5 mL). The organic layer was dried with anhydrous Na2SO4, passed through a short silica-gel column using n-hexane/ethylacetate (10/1) as eluent. p-Toluenesulfonyl azide was obtained with 98% yield after removing the solvent under reduced pressure. |
83% | With sodium azide; trichloroacetonitrile; triphenylphosphine In acetonitrile at 20℃; for 2h; | |
With sodium azide; trichloroisocyanuric acid; triphenylphosphine In tetrahydrofuran at 20℃; | General procedure for the synthesis of sulfonyl-1H-1,2,3-triazolyl-thiomorpholine 1,1-dioxide derivatives (5a-5l) General procedure: To a 50mL round bottom flask, trichloroisocyanuric acid(TCCA) (1.5 mmol) and PPh3 (4 mmol) in THF (15 mL)were added and allowed to stir at 0-5 C for 15 min. Then,the sulfonic acid (4) (2 mmol), and NaN3 (2.5 mmol) wereintroduced into the resulting solution and stirring was continuedat room temperature for 30-45 min. Later, the 4-(prop-2-yn-1-yl)thiomorpholine 1,1-dioxide (3) (2 mmol)and CuI (10 mmol%) and the resulting reaction mixture wasstirred at room temperature for further 8 to 10 h. After thecompletion as shown by TLC, the reaction mixture wascarefully poured into ice water (30 mL). The resulting solidwas filtered, washed with excess of water and dried underreduced pressure. Finally, the crude product obtained waspurified by column chromatography (eluent ethylacetate-hexane, 2:3) to afford the pure desired 1,2,3-triazolederivatives in good yields. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol | 9 250 mg prasugrel (free base) were dissolved in 5 ml of metha- nol and the solution was stirred at room temperature. An equimolar amount of ethane sulfonic acid dissolved in 2 ml methanol was added. The solvent was evaporated in a rotatory evaporator and dried over night in vacuum.13C NMR ([D6]DMSO; standard: tetramethylsilane; equipment:Bruker DTX 200, 50.3 MHz) : δ = 10.34 (s) , 13.41 (s) , 13.87(s), 20.53 (s), 21.28 (s) , 22.47(s), 46.09(s), 50.42 (broad),69.91 (s), 112.78 (s) , 116.20 (d; 14.1 Hz), 117.73 (d; 21.2Hz), 124.48 (s ), 125.05 (s), 126.76 (s), 133.3 (s) , 134.65 (d; 8.5Hz), 150.74 (s) , 161.87 (d; 250.1Hz), 168.51 (s) , 202.65 (s) ppm.The 13C-NMR spectrum of prasugrel ethanesulfonate is shown in Fig. 3, the 1H-NMR spectrum in Fig. 4. |
Yield | Reaction Conditions | Operation in experiment |
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In water;Product distribution / selectivity; | 1.05 g (4 mmol) of desvenlafaxine was suspended in 15 ml of water and 0.47 ml (4 mmol) of ethanesulphonic acid was added. After the addition of acid the solution was formed. This solution was filtered and filtrate was evaporated. The residue was dried by addition and evaporation of isopropanol. After that, to the residue 5 ml of diethyl ether was added and the formed suspension was stirred for 1h at room temperature. Then the suspension was filtered and dried to isolate solid desvenlafaxine ethanesulphonate (0.69 g). IR: 2936, 1616, 1595, 1517, 1451, 1243, 1136, 1040, 967, 960, 841, 744, 622, 576 |
Yield | Reaction Conditions | Operation in experiment |
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70% | In methanol at 20 - 30℃; | 121 Compound 65 (202mg) was suspended in methanol (1mL) and ethanesulfonic acid (58.8mg) was added to the suspension at room temperature (20 to 30°C). After the compound was dissolved, the mixture was concentrated under reduced pressure. Then, ethanol (2.0mL) was added to the resulting residue and the mixture was stirred under reflux. Water (100μL) was then added portionwise. Once the residue was dissolved, the mixture was stirred overnight as it was allowed to cool. Subsequently, the mixture was stirred and cooled with ice for 1 hour, and was suction-filtered. The resulting solid was washed with ethanol and dried to give 181mg (70% yield) of the desired product as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
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80% | In methanol at 20℃; | 5 Examples 2 - 5 (general procedure) To a solution/suspension of the acid (1.1 equiv.) in solvent (0.5 ml) was added a solution of Intermediate 11 a (100 mg, 0.11 mmol) in the same solvent (1 ml) with stirring. The mixtures were stirred at RT overnight. The salt was filtered, washed with a small amount of cold solvent and dried in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
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71% | In methanol; isopropyl alcohol at 20℃; | 6 In a 50 ml flask sitagliptin free base (303 mg) was dissolved in methanol (1.5 ml) and iPrOH (10 ml). Then 0.2M solution of ethanesulfonic acid (3.72 ml) was added dropwise and left to stir for 2 hours at room temperature. Formed crystals were collected using suction filtration through a porous ceramic filter to yield a white powder (272 mg, 71 %). Melting point 199 -202°C. |
Yield | Reaction Conditions | Operation in experiment |
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91% | In ethanol; at 25 - 35℃; for 4h; | Example 1 : Preparation of Sorafenib Ethane SulphonateEthanol (20 mL) was added to a reaction vessel containing <strong>[284461-73-0]sorafenib</strong> free base (4.0 g). Ethane sulphonic acid (1.62 mL) was added drop wise to the above reaction mixture. The reaction mixture was stirred at about 25C to 35C for about 4 hours. The solid was filtered, washed with ethanol (2 x 10 mL) and dried under reduced pressure at about 60C for about 5 hours to obtain <strong>[284461-73-0]sorafenib</strong> ethane sulphonate.Yield: 91%HPLC Purity: 99.46% |
Yield | Reaction Conditions | Operation in experiment |
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88.9% | In butanone; at 26℃; for 3h; | Example 4: Preparation of Sorafenib ethane-sulphonate3 g Sorafenib and 0.71 g ethane-suiphonic acid were added to 45 ml MEK and stirred at 26C for 3 hours. The resulting solid was isolated by filtration and dried under vacuum at 60C for 13 hours. (Yield: 88.9 %) |
Yield | Reaction Conditions | Operation in experiment |
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97% | In methanol for 1h; Reflux; | 1. General procedure for preparation of pyrylium sulfanates General procedure: 0.03 mole of sulfonic acid was dissolved in 50 mL methanol and equimolar amount of 4-pyrone soluble in methanol was added. The mixture was stirring and heating at boiling point of methanol using reflexive condenser for 1h. Methanol was removed under reduced pressure (60 °C, 30×102 Pa). The obtained liquid product was shaken with 20 mL diethyl ether and dried out under vacuum for 3 hours or obtained solid product was crystallized from the mixture of methanol/toluene, 1:5. |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; at 45℃; | Ethanesulfonic acid 95% (104 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and was then added dropwise to a stirred solution of <strong>[500287-72-9]Rilpivirine</strong> base form II (0.30 g, 0.82 mmol) in THF (6 mL, 20V) at 45C. Precipitation was observed. The reaction mixture was cooled to room temperature for 30 min and stirring was continued at the same temperature for 17 h. The reaction mixture was then filtered to give the title compound. The filter cake was dried in a vacuum oven at 50C for 17 h. A white solid was obtained. XRD analysis of the solid indicated the same polymorphic form as was identified in the wet material. |
Yield | Reaction Conditions | Operation in experiment |
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89.3% | In methanol at 21 - 60℃; for 26.5h; | 5 Preparation of Lapatinib diesylateEthanesulfonic acid (1.90 g, 17.3 mmol) was added to a stirred suspension of GW572016X (5.0 g, 8.6 mmol) in methanol (100 ml) at 21 °C. An additional amount of methanol (50 ml) was added. The reaction was heated at 600C for 30 minutes, then cooled to 210C and left for 26 hours. The bright yellow solid was collected by filtration and washed with methanol (50 ml) then dried under vacuum for 2 hours 50 minutes at 45°C to give the title salt. (6.16 g, 89.3% yield) An X-ray powder diffraction pattern and an infrared spectrum were obtained and are depicted in Figure 5(a) and Figure 5(b) respectively. |
Yield | Reaction Conditions | Operation in experiment |
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84.7% | In water; acetone at 21℃; for 18.5h; Reflux; | 6 Preparation of Lapatinib monoesylateEthanesulfonic acid (947.6 mg, 8.6 mmol) was added to a stirred suspension of GW572016X (5.0 g, 8.6 mmol) in a mixture of acetone (75 ml) and water (5 ml) at 210C. The reaction was heated at reflux for 30 minutes then cooled to 210C and stirred for 18 hours to give the title salt. The yellow solid was collected by filtration, washed with acetone (75 ml) then dried under vacuum at 400C for 64 hours. (5.04 g, 84.7% yield). An X-ray powder diffraction pattern and infrared spectrum were obtained and are depicted in Figure 6(a) and Figure 6(b) respectively. |
Yield | Reaction Conditions | Operation in experiment |
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75% | With 2,2,4,4,6,6-hexachloro-1,3,5-triaza-2,4,6-triphosphorine; triethylamine In dichloromethane at 20℃; | General procedure General procedure: Phosphonitrilic chloride (3) (0.5 mmol) was added to a solution of the sulfonic acid (1.5 mmol), the imine (1.0 mmol) and Et3N (5.0 mmol) in dry CH2Cl2 (15 ml) at room temperature and the mixture was stirred for 8-10 h. The mixture was washed successively with saturated NaHCO3 (15 ml) and brine (15 ml). The organic layer was dried (Na2SO4), filtered and the solvent was removed to give the crude product. Pure b-sultams 6a-n were obtained by purification via short column chromatography on silica-gel (EtOAc/hexane, 3:7). 4-Methyl-2-(p-ethoxyphenyl)-3-(pchlorophenyl)- 1,2-thiazetidine 1,1-dioxide (6h). White solid mp: 116-118 C. IR (KBr) cm 1: 1138, 1309 (SO2); 1H NMR (300 MHz, CDCl3) d 1.14 (Me, d, 3H, J = 7.1 Hz), 1.33 (Me, t, 3H, J = 6.8 Hz), 4.06 (OCH2, q, 2H, J = 6.8 Hz), 4.37 (H-4, dq, 1H, J = 7.1, 8.7 Hz), 4.87 (H-3, d, 1H, J = 8.7 Hz), 6.81-8.11 (ArH, m, 8H); 13C NMR (75 MHz, CDCl3) d 12.7, 15.1 (2Me), 56.2 (C-4), 57.0 (C-3), 61.4 (OCH2), 115.2, 117.7, 123.1, 125.9, 126.5, 129.3, 143.1, 155.8 (aromatic carbons); Anal. Calcd for C17H18ClNO3S: C, 58.03; H, 5.16; N, 3.98; S, 9.11. Found: C, 58.16; H, 5.31; N, 4.07; S, 9.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With Vilsmeier reagent; triethylamine In dichloromethane at 0 - 20℃; diastereoselective reaction; | |
66% | With 2,2,4,4,6,6-hexachloro-1,3,5-triaza-2,4,6-triphosphorine; triethylamine In dichloromethane at 20℃; | General procedure General procedure: Phosphonitrilic chloride (3) (0.5 mmol) was added to a solution of the sulfonic acid (1.5 mmol), the imine (1.0 mmol) and Et3N (5.0 mmol) in dry CH2Cl2 (15 ml) at room temperature and the mixture was stirred for 8-10 h. The mixture was washed successively with saturated NaHCO3 (15 ml) and brine (15 ml). The organic layer was dried (Na2SO4), filtered and the solvent was removed to give the crude product. Pure b-sultams 6a-n were obtained by purification via short column chromatography on silica-gel (EtOAc/hexane, 3:7). |
Yield | Reaction Conditions | Operation in experiment |
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69% | With 2,2,4,4,6,6-hexachloro-1,3,5-triaza-2,4,6-triphosphorine; triethylamine In dichloromethane at 20℃; | General procedure General procedure: Phosphonitrilic chloride (3) (0.5 mmol) was added to a solution of the sulfonic acid (1.5 mmol), the imine (1.0 mmol) and Et3N (5.0 mmol) in dry CH2Cl2 (15 ml) at room temperature and the mixture was stirred for 8-10 h. The mixture was washed successively with saturated NaHCO3 (15 ml) and brine (15 ml). The organic layer was dried (Na2SO4), filtered and the solvent was removed to give the crude product. Pure b-sultams 6a-n were obtained by purification via short column chromatography on silica-gel (EtOAc/hexane, 3:7). |
65% | With Vilsmeier reagent; triethylamine In dichloromethane at 0 - 20℃; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
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37% | With 2,2,4,4,6,6-hexachloro-1,3,5-triaza-2,4,6-triphosphorine; triethylamine In dichloromethane at 20℃; | General procedure General procedure: Phosphonitrilic chloride (3) (0.5 mmol) was added to a solution of the sulfonic acid (1.5 mmol), the imine (1.0 mmol) and Et3N (5.0 mmol) in dry CH2Cl2 (15 ml) at room temperature and the mixture was stirred for 8-10 h. The mixture was washed successively with saturated NaHCO3 (15 ml) and brine (15 ml). The organic layer was dried (Na2SO4), filtered and the solvent was removed to give the crude product. Pure b-sultams 6a-n were obtained by purification via short column chromatography on silica-gel (EtOAc/hexane, 3:7). |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; at 50℃; | General procedure: [00416] Formula I free base (ca. 30 mg) was suspended in selected solvents (THF, nitromethane, acetonitrile and MEK; 50 volumes, 1.5 mL) at 50C with stirring. The corresponding acid (1 equivalent) was added and the samples were stirred for 30 minutes, prior to ramping at l C -min_1 to 25C. The samples were placed in a shaker and subjected to heating/cooling cycles, between room temperature and 50C, with four hours at each condition. Details about the acids used for these experiments, including input materials and amounts, are summarized in Table 3 below.Table 3. Input materials used for the salt screensolution in THF)[00417] After 16 hours, an aliquot was taken, isolated by vacuum filtration, dried by suction and analyzed by XRPD. Further solvent (25 volumes) was added, and the suspensions were allowed to cycle for four more days. An aliquot was taken, isolated by vacuum filtration, dried by suction and analyzed by XRPD. Further acid (0.2 equivalents, 17 ??) and solvent (25 volumes) were added to those samples showing the presence of free base in the XRPD pattern, suggesting incomplete salt formation. The samples were stored in a shaker and subjected to heating/cooling cycles, between room temperature and 50C, with four hours at each condition for one week. An aliquot was taken, isolated by vacuum filtration, dried by suction and analyzed by XRPD. Water (10% for MeCN, and 5% for THF, MEK and nitromethane, based on ca. 1.5 mL solvent) was added and the samples were cycled for a further 5 days. An aliquot was taken, isolated by vacuum filtration, dried by suction and analyzed by XRPD.[00418] For samples exhibiting new XRPD patterns, the remaining solid was isolated by vacuum filtration, dried by suction and further characterization was undertaken as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In 2-methyltetrahydrofuran at 1 - 49℃; for 0.5h; Cooling with ice; | 1 Said solution was heated to internal temperature of 49 °C and ethane sulfonic acid (1.737 ml, 20.23 mmol) in 2-methyltetrahydrofuran (20.00 ml) was added dropwise over 15 min (massive crystals formation was observed when 8.25 ml of acid solution had been added). The RM was then allowed to cool to room temperature, immersed in an ice bath until internal temperature reached 1 °C, and was stirred at that temperature for 15 min. The solids were filtered off, washed with cold 2-methyltetrahydrofuran (60.0 ml), and then vacuum dried at 40 °C for 1 hour affording abiraterone-3-acetate esylate (1A) (8.21 g, 16.30 mmol, 85 % yield, assay 99.6% HPLC-ES) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
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98.4% | In ethyl acetate at 0 - 20℃; for 12h; | 10 Synthesis of Dodecyl 2-(dimethylamino)propanoate ethane sulfonate Salt (21, Nex-30) Synthesis of Dodecyl 2-(dimethylamino)propanoate ethane sulfonate Salt (21, Nex-30) A stirred solution of DDAIP base 4 (85 g, 298 mmol) in ethyl acetate (600 mL) was cooled to 0° C., then ethane sulfonic acid 20 (32.79 g, 298 mmol) was added in one lot. After addition, the temperature of the reaction mixture was slowly raised to RT, stirred at RT for 12 h and the reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum and flushed with hexane. The obtained residue was taken in n-hexane (200 mL) and stirred at RT for 2 h (No solid). The obtained sticky solid kept in deep freezer for 12 h to afford dodecyl 2-(dimethylamino)propanoate ethane sulfonate salt (21, Nex-30) (116 g, yield: 98.4%) as a hygroscopic solid, Mp: 45-50° C. 1H-NMR (400 MHz, CDCl3): δ 0.9 (t, 31H), 1.3 (m, 18H), 1.35 (t, 3H), 1.7 (d, 31H), 1.8 (q, 21H), 2.9 (q, 2H), 3 (m, 6H), 4.2 (m, 2H), 4.2 (m, 1H); LCMS: 286 (M++1); HPLC: 99.47%. is a 1H-NMR spectrum (400 MHz, CDCl3) of dodecyl 2-(dimethylamino)propanoate ethane sulfonate salt (Nex-30). is a LCMS spectrum: 286 (M++1) of dodecyl 2-(dimethylamino)propanoate ethane sulfonate salt. is a HPLC chromatogram of dodecyl 2-(dimethylamino)propanoate ethane sulfonate salt showing a peak area of 99.5%. Methods as in . |
Yield | Reaction Conditions | Operation in experiment |
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71% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 25℃; Green chemistry; stereoselective reaction; | General procedure for the synthesis of β-sultams 3a-l. General procedure: The T3P (1.5 mmol, 50% solution in DMF) was added to a solution of sulfonic acid (1.5 mmol), imine (1 mmol) and triethylamine (5.0 mmol) in dry CH2Cl2 (20 ml) at 0 °C and the mixture was stirred overnight at room temperature. The reaction mixture was washed successively with saturated NaHCO3 (20 ml) and brine (20 ml). The organic layer was dried (Na2SO4), filtered and the solvent was removed to give the crude product, which was purified by short column chromatography on silica gel (EtOAc-hexane, 3 : 7) to give pure β-sultams 3a-l. Spectral data for known compounds 3b and 3d-l have been previously reported. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 25℃; Green chemistry; stereoselective reaction; | General procedure for the synthesis of β-sultams 3a-l. General procedure: The T3P (1.5 mmol, 50% solution in DMF) was added to a solution of sulfonic acid (1.5 mmol), imine (1 mmol) and triethylamine (5.0 mmol) in dry CH2Cl2 (20 ml) at 0 °C and the mixture was stirred overnight at room temperature. The reaction mixture was washed successively with saturated NaHCO3 (20 ml) and brine (20 ml). The organic layer was dried (Na2SO4), filtered and the solvent was removed to give the crude product, which was purified by short column chromatography on silica gel (EtOAc-hexane, 3 : 7) to give pure β-sultams 3a-l. Spectral data for known compounds 3b and 3d-l have been previously reported. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 25℃; Green chemistry; stereoselective reaction; | General procedure for the synthesis of β-sultams 3a-l. General procedure: The T3P (1.5 mmol, 50% solution in DMF) was added to a solution of sulfonic acid (1.5 mmol), imine (1 mmol) and triethylamine (5.0 mmol) in dry CH2Cl2 (20 ml) at 0 °C and the mixture was stirred overnight at room temperature. The reaction mixture was washed successively with saturated NaHCO3 (20 ml) and brine (20 ml). The organic layer was dried (Na2SO4), filtered and the solvent was removed to give the crude product, which was purified by short column chromatography on silica gel (EtOAc-hexane, 3 : 7) to give pure β-sultams 3a-l. Spectral data for known compounds 3b and 3d-l have been previously reported. |
Yield | Reaction Conditions | Operation in experiment |
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49% | In isopropyl alcohol at 20℃; for 23h; | 5 Example 5 (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide ethanesulfonate hydrate crystal Example 5 (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide ethanesulfonate hydrate crystal [0076] Ethanesulfonic acid (0.032 ml, 0.39 mmol) was added to a 2-propanol (3 ml) solution of the compound (221 mg, 0.36 mmol) obtained in Example 1 and then the resulting mixture was stirred at room temperature for 23 hours. The precipitate was collected by filtration to give 128 mg (49%) of the title crystal. 1H-NMR (400 MHz, DMSO-d6) δ: 0.62 (3H, s), 0.92 (3H, s), 1.05 (3H, t, J=7.4 Hz), 1.09-1.59 (6H, m), 1.62-2.06 (5H, m), 2.38 (2H, q, J=7.4 Hz), 2.59-3.07 (1H, m), 3.27-3.79 (5H, m), 4.53-4.76 (1H, m), 4.78-5.16 (1H, m), 6.79 (1H, s), 7.00-7.23 (3H, m), 7.51-7.75 (2H, m), 8.21-8.41 (1H, m), 8.48-9.07 (1H, m), 10.35 (1H, br s), 11.19 (1H, br s). Anal. Calcd for C30H34Cl2FN5O4·C2H5SO3H·4H2O: C, 48.00; H, 6.04; N, 8.75. Found: C, 47.97; H, 5.93; N, 8.56. [0077] The X-ray powder diffraction pattern of the title crystal is shown in Figure 7, the adsorption-desorption isotherms thereof are shown in Figure 14, and the thermal analysis data (TG/DTA) thereof are shown in Figure 22. [Table 6] Peak of X-ray powder diffraction pattern (relative intensity of 23 or more) Peak number 2θ d value Relative intensity Peak number 2θ d value Relative intensity 1 6.28 14.06 100 6 16.62 5.33 28 2 7.72 11.44 39 7 16.96 5.22 32 3 12.62 7.01 39 8 19.68 4.51 36 4 14.06 6.29 36 9 21.18 4.19 38 5 15.50 5.71 23 10 25.82 3.45 24 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: ethanesulfonic acid With N-chlorobenzotriazole; triphenylphosphine In dichloromethane at 0 - 20℃; for 0.25h; Stage #2: aniline With triethylamine at 20℃; for 1.16667h; | Typical Procedure for Conversion of Sulfonic Acids to Sulfonamides.N-benzyl-4-methylbenzenesulfonamide (Table 6, Entry 6) General procedure: To a cold solution of PPh3 (0.327 g, 1.25 mmol) in CH2Cl2 (3 mL), freshly preparedNCBT (0.188 g, 1.25 mmol) was added with continuous stirring. p-Toluenesulfonic acid(0.172 g, 1 mmol)was then added and stirringwas continued for 15min at room temperature.Benzylamine (0.267 g, 2.5 mmol) was added. The white suspension was neutralized by triethylamine (0.139 mL). Stirring was continued for 80 min at room temperature. Theprogress of the reaction was followed by TLC. Upon completion of the reaction, theconcentrated residue was passed through a short silica-gel column using n-hexane-ethylacetate (3:1) as eluent. N-Benzyl-4-methylbenzenesulfonamide was obtained with 90%(0.236 g) yield after removing the solvent under reduced pressure |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; tert-butyl methyl ether; di-isopropyl ether; at 40℃; | 10274] Compound 1(56.9mg, 0.137 mmole) was dissolved in 1.0 ml of t-butyl methyl ether:isopropyl ether 1:1 at 40 C. with stirring. A measured amount of ethanesulfonic acid (11.5 jtL, 0.137 mmole) was diluted in 50 pL of in tetrahydrothran:isopropyl ether 1:3. The acid solution was added to Compound I solution at 40C. resulting in milky solution that oiled out. Additionally, aliquots of tetrahydrothran:isopropyl ether 1:3 mixture (2x0.5 mL) and isopropyl ether (2x0.5 mL) were added at 40 C. without any effect on the system. The sample was crash cooled by placing it a freezet Off-white precipitation occurred within approximately 0.5 hout The solids were isolated by vacuum filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: ethanesulfonic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In dichloromethane for 0.5h; Stage #2: methyl (S)-4-(2-amino-3-(1H-indol-3-yl)propanamido)benzoate hydrochloride With triethylamine In dichloromethane | 17 4.1.5. Methyl (S)-4-(2-acetamido-3-(1H-indol-3-yl)propanamido)benzoate (7b) General procedure: To a solution of acetic acid (0.12 g, 2 mmol) in anhydrous CH2Cl2, was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 0.71 g, 2.2 mmol), followed by Et3N (0.3 g, 3 mmol). 30 min later, compound 6 (0.82 g, 2.2 mmol) was added followed by Et3N (0.3 g, 3 mmol). After the reaction finished, the solution was washed with 1 N HCl (2 * 30 mL), saturated NaHCO3 (2 * 30 mL) and brine (2 * 30 mL), dried over Na2SO4 overnight, and the solvent was evaporated under vacuum. The crude product was recrystallized by EtOAc and petroleum ether to achieve a white pure solid (0.38 g, 50%). 4.1.17 Methyl (S)-4-(2-(ethylsulfonamido)-3-(1H-indol-3-yl)propanamido)benzoate (7n) Using the synthetic method for 7b, compound 6 and ethanesulfonic acid gave 7n as a white pure solid (52% yield). Mp: 180-182 °C 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 10.47 (s, 1H), 7.92 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.71-7.65 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 4.32-4.26 (m, 1H), 3.83 (s, 3H), 3.20-2.99 (m, 2H), 2.73-2.54 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). ESI-MS m/z: 430.5 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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In acetone; at 20 - 55℃; for 18.5h; | The esylate salt of SRi can be prepared as follows: 4-(2- (2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol free base (0.60 gram; 1.40 mmoles) are dissolved in 12 ml acetone at 50 C. Ethanesulfonic acid (0.155 gram; 1.40 mmoles) is added drop wise. The crystallization takes place quickly. The resulting white suspension is allowed to cool over about 30 minutes to room temperature. The suspension is stirred for about 18 hours at room temperature and filtered. The solid is washed with 6 ml acetone inthree portions and dried first for about 3 hours at 50 C./about5210 mbar and then for about 16 hours at 80 C./about 10 mbar.The material has a melting point at about 231 C. with amelting enthalpy of 76 g/J.In another embodiment, the i esylate salt of SRi comprisesthe following powder X-ray diffraction peaks (Angle 2-0):6.3, 9.9, 18.4, 25.3, 26.1; and which in an additional embodiment comprises the following powder X-ray diffraction peaks(Angle 2-0): 6.3, 9.9, 17.1, 17.9, 18.4, 19.0,22.0,25.3,26.1,27.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With silver nitrate; sodium hydroxide In water at 5 - 10℃; | Compound 5 lodonium, di-2-thienyl-, salt with with ethanesulfonic acid (1:1) Silver ethanesulfonate [0086] To a solution of silver nitrate (13.7 g, 80.6 mmol) in deionized water (25.0 mL) was added a solution of sodium hydroxide (3.30 g, 80.8 mmol) in deionized water (100 mL). The precipitated silver oxide was collected by suction filtration and washed with deionized water until the washes were -pH 7. The silver oxide was used “as is” without further purification. To a cold (5-10°C), stuffing suspension of silver oxide (7.48 g, 32.3 mmol) in deionized water (8.00 mL) was added ethanesulfonic acid (7.18 g, 65.2 mmol). The mixture was stirred until a clear solution was obtained (15-30 minutes), and then suction filtered. The filtrate was concentrated to dryness and the residue was suspended in acetone (50 mL). The suspension was suction filtered and the filter cake was washed with acetone (200 mL), then dried in vacuo at room temperature to give silver ethanesulfonate (4.5 g, 64%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In methanol; at 50℃; for 1h; | 200 mg (0.653 mmol) of {3R)-3-cyclopentyl-3-[4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of methanol by heating to 50C applying a continuous agitation. 76.1 mu (0.653 mmol) of ethanesulphonic acid was diluted with 2 mL of methanol at room temperature. The methanol solution of ethanesulphonic acid was drop-wise added to the solution of (3R)- 3-cyclopentyl-3-[4-(7H-pyrrolo[2i3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50eC, agitated for additional 60 minutes at 50C and then cooled back to room temperature. The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction. Product: 204 mg; yield: 75% HPLC purity: 98.9% The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy. Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 5. |
Yield | Reaction Conditions | Operation in experiment |
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In water; ethyl acetate; at 50℃; for 2h; | 1.0gof <strong>[755037-03-7]Regorafenib</strong> added into 10mL of ethyl acetate and 1ml water and after heated up to reflux for clear solution added 0.23g of ethanesulfonic acid. Cooled to room temperature and stirring was continued for 2 hours after precipitation. filtered, the filter cake was wash with 1mL of ethanesulfonicacid, collected the filter cake at 50~80 C dried to constant weight for giving <strong>[755037-03-7]Regorafenib</strong> Ethanesulfonic acid salt crystal form alpha . |
Yield | Reaction Conditions | Operation in experiment |
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49% | In isopropyl alcohol at 20℃; for 23h; | 5 Example 5(3’R,4’S,5’R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl] -6”-chloro-4’-(2-chloro-3-fluoropyridin-4-yl)-4,4-dim-ethyl-2”-oxo-l “,2”-dihydrodispiro[cyclohexane- 1 ,2’-pyrro-lidine-3’,3 “-indole] -5’-carboxamide ethanesulfonate hydrate crystal Ethanesulfonic acid (0.032 ml, 0.39 mmol) was added to a 2-propanol (3 ml) solution of the compound (221 mg, 0.36 mmol) obtained in Example 1 and then the resulting mixturewas stirred at room temperature for 23 hours. The precipitate was collected by filtration to give 128 mg (49%) of the title crystal.‘H-NMR (400 MHz, DMSO-d5) ö: 0.62 (3H, s), 0.92 (3H, s), 1.05 (3H, t, J=7.4 Hz), 1.09-1.59 (6H, m), 1.62-2.06 (5H,m), 2.38 (2H, q, J=7.4 Hz), 2.59-3.07 (1H, m), 3.27-3.79 (5H,m), 4.53-4.76 (1H, m), 4.78-5.16 (1H, m), 6.79 (1H, s), 7.00-7.23 (3H, m), 7.51-7.75 (2H, m), 8.21-8.41 (1H, m), 8.48-9.07 (1H, m), 10.35 (1H, br s), 11.19 (1H, br s).Anal. Calcd for C30H34C12FN504.C2H5SO3H.4H20: C,48.00; H, 6.04; N, 8.75. Found: C, 47.97; H, 5.93; N, 8.56.The X-ray powder diffraction pattern of the title crystal is shown in FIG. 7, the adsorption-desorption isotherms thereof are shown in FIG. 14, and the thermal analysis data (TG/ DTA) thereof are shown in FIG. 22. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; ethyl acetate; at 20℃; | Example 8: Preparation and Characterization of tenofovir alafenamide ethanesulfonate Tenofovir alafenamide free base was dissolved in 50 volumes of ethyl acetate (EtOAc) at room temperature, 1.1 eq. of 1M ethane sulfonic acid in THF was added. Precipitation was observed immediately. Filtration gave crystalline tenofovir alafenamide ethanesulfonate. Crystals with the same XRPD pattern were obtained similarly in IPA and THF. NMR spectrum indicated 1 equivalent of ethane sulfonic acid. The XRPD is shown in Figure 14. Material exposed to stress condition (40 °C 75percent RH for 14 days) showed no XRPD change. Prominent peaks were selected from observed peaks by identifying substantially non- overlapping, low-angle peaks with strong intensity. The prominent peaks of tenofovir alafenamide ethanesulfonate include: 9.0, 9.9, 17.0, and 21.4 ± 0.2° 2 Theta. The observed peaks of tenofovir alafenamide ethanesulfonate are shown in Table 8. Table 8. Observed peaks in the XRPD pattern of tenofovir alafenamide ethanesulfonate Presented in Figure 28 is the experimental differential scanning calorimetry (DSC) and Thermo-gravimetric Analysis (TGA) of TAF ethanesulfonate. DSC showed a sharp endotherm with onset of 177 °C. TGA showed 0.8percent weight loss upon heating from RT to 100 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; at 20℃; for 24.0h; | (R)-N-(4-(3-aminopiperidin-1 -yl)-5-bromo- 1 H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidemono-ethanesulfonic acid salt: Approximately 10 g of (R)-N-(4-(3-aminopiperidin- 1 -yl)-5-bromo-1 H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was weighed into a XRPD500 mL round-bottom flask, andthen approximately 500 mLof acetone was added. 1.0 equivalents of ethanesulfonic acid DSCwas slowly titrated into the sample. The suspension was keptTGAstirnng on a magnetic stirrer at room temperature. Afier 24hrs, the remaining solid was isolated by vacuum filtering.After that, the wet cake was suspended with 180 mL acetone 10234]purification. The purified solid samples were isolated by vatedvacuum filtering and dried under reduced pressure at roomtemperature. The physical properties of the non-solvatedmono-esylate salt of (R)-N-(4-(3-aminopiperidin- l-yl)-5-bromo-1 H-pyrrolo[2 3-b]pyridin-3-yl)cyclopropanecar-boxamide are summarized in Table 44 below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; for 24.0h; | Method A: (R)-N-(4-(3-aminopipedin-1 -yl)-5- bromo-1 H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecar- boxamide (40mg, 0.11 mmol) was dissolved in about 1 mL of tetrahydroffiran. Ethanesulfonic acid (0.22 mmol, 24.5 mg) was added and the resulting suspension stirred for one day. The solids were isolated by centrifugation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In 1,4-dioxane; at 80℃; for 1.66667h; | 2.0 g (4.7 mmol) filgotinib base were dissolved in 200 ml 1,4-dioxane and heated to 80C. 1.14 g (10.3 mmol) ethanesulfonic acid were added dropwise over 40 min. After completion, the reaction mixture was stirred for another 60 min at 80C, then slowly cooled down to 23C and stirred over night. The product was filtered off, washed with 80 ml 1,4-dioxane and dried for 3 weeks at 35C / 7 mbar. Name Filgotinib diesylate, Form DE2 Yield: 2.87 g (95 % of theory) purity (HPLC/UV, method B, 99.0 % tr= 2.2 min, lambda=230 nm: 1H NMR (400 MHz, DMSO-rf6) 0.81 - 0.87 (m, 4 H) 1.08 (t, 7=7.43 Hz, 6 H) 2.00 [5 ppm] (br. s? 1 H) 2.46 - 2.52 (m, 6 H) 3.55 (s, 1 H (dioxane)) 3.57 (br. s., 4 H) 3.65 (br. s., 4 H) 4.54 (br. s., 2 H) 7.41 (dd, 7=7.04, 1.56 Hz, 1 H) 7.71 - 7.77 (m, 3 H) 7.79 - 7.83 (m, 1 H) 8.11 (d, 7=8.21 Hz, 2 H) 11.35 (br. s., 1 H) FT-IR (ATR) [cm"1] : 2983, 2933, 1713, 1647, 1597, 1570, 1527, 1504, 1458, 1419, 1398, 1346, 1311 , 1275, 1246, 1190, 1176, 1128, 1066, 1026, 978, 955, 910, 866, 839, 822, 796, 783, 766, 737, 714, 675, 650, 633, 625, 607 XRPD 1st priority reflections 7.9, 9.5, 19.5, 21.3, 23.2 2nd priority reflections 11.3, 15.9, 18.3, 20.8, 22.4 DSC endotherms: 140-180C (br. with peak at 172C),210-230C (br. with peak at 218), 20- 400C (br. with peak at 341 C) exotherms: 175-210C (br. with peak at 180C) |
Yield | Reaction Conditions | Operation in experiment |
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92.3% | In methanol at 20℃; for 16h; | 2 Preparation of cephalosporin ester ethanesulfonate(IVa) 100.0 g (0.15 mol) of Boc cephalosporin (II), 1 L of methanol and 38.6 mL (0.30 mol) of ethanesulfonic acid were added in a 3 L reaction flask, followed by stirring at 20 ° C for 16 hours. Add 1 L of Riga petroleum ether to 20 ° C for 60 min. Filtered, washed and dried in vacuo to give 93.8 g of a white solid, the molar yield was 92.3%, HPLC purity 99.3%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In acetonitrile at 20 - 66℃; for 1h; Inert atmosphere; | 35 Example 35 Preparation of the Ethanesulfonic acid adduct of (S)-7-(3,4-difluorobenzyl)-6- (methoxymethyl)-2-(5-methyl-2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimidin-4-yl)- 6,7-dihydroimidazo [ 1 ,2-a] pyrazin-8(5H)-one (5)-2-(2-chloro-5 -methylpyrim ^ dihydroimidazo[l,2-a]pyrazin-8(5H)-one (Intermediate 35a; 2.2 g, 5.07 mmol), 1-methyl- lH-pyrazol-5-amine (0.754 g, 7.61 mmol) and cesium carbonate (3.30 g, 10.14 mmol) were dissolved in 2-MeTHF (25 mL) and water (2.5 mL) and degassed with nitrogen. 2'- (dicyclohexylphosphanyl)-N,N-dimethyl-[l,l'-biphenyl]-2-amine (0.160 g, 0.41 mmol) and Pd2dba3 (0.186 g, 0.20 mmol) were added and the mixture further degassed with nitrogen. The reaction was then heated at 80 °C for 24 hours. The reaction was cooled to ambient temperature and further 2'-(dicyclohexylphosphanyl)-N,N-dimethyl-[l,l'-biphenyl]-2- amine (0.160 g, 0.41 mmol) and Pd2dba3 (0.186 g, 0.20 mmol) were added and the reaction degassed with nitrogen. The reaction was then stirred at 80 °C for 16 hours. Silicycle (1.2 g, SiliaMetS Thiol) was added and the reaction cooled to ambient temperature. The reaction mixture was filtered through celite washing with EtOAc. The reaction was extracted with ethyl acetate, washed with aqueous citric acid (0.5 M) and saturated sodium bicarbonate. The volatiles were then removed under reduced pressure. Purification by preparative supercritical fluid chromatography (Kromasil DIOL column, 250 mm x 50 mm, 10 urn, mobile phase 25% EtOH/NH3 100/0.5 in C02, 140 bar) afforded (5)-7-(3,4- difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((l -methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[l,2-a]pyrazin-8(5H)-one (1.38 g) which was used without further purification in the next stage. (5)-7-(3,4-difluorobenzyl)-6- (methoxymethyl)-2-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7- dihydroimidazo[l,2-a]pyrazin-8(5H)-one (1.3 g, 1.93 mmol) from the previous step was dissolved in acetonitrile (2 mL) and heated to 66 °C. Ethanesulfonic acid (0.22 mL, 2.63 mmol) in acetonitrile (2 mL) was then added. The reaction was then stirred at ambient temperature for 1 hour. A precipitiate was observed. Further acetonitrile (3 mL) was added and the precipitate filered, washed with acetonitrile (3 mL) and dried under vacuum for 66 hours to afford the ethanesulfonic adduct of (5)-7-(3,4-difluorobenzyl)-6- (methoxymethyl)-2-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7- dihydroimidazo[l,2-a]pyrazin-8(5H)-one (0.41 g). The filtrate was evaporated under reduced pressure and acetonitrile (3 mL) and MTBE (2 mL) were added. The resulting precipitate was filtered and dried under vacuum to afford further ethanesulfonic adduct of (5)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((l -methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[l,2-a]pyrazin-8(5H)-one (0.73 g). The 2 batches were combined to afford the ethanesulfonic acid adduct of (5)-7-(3,4- difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((l -methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[l ,2-a]pyrazin-8(5H)-one (Example 35; 1.14 g, 72%) in a 1 :2 molar ratio of ethane suflonic acid:(5)-7-(3,4-difluorobenzyl)-6- (methoxymethyl)-2-(5-methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7- dihydroimidazo[l ,2-a]pyrazin-8(5H)-one as determined by H NMR. H NMR (500 MHz, DMSO, 27 °C) 1.08 (1.5H, t), 2.42 (1H, q), 2.52 (3H, m), 3.18 (3H, s), 3.32 (1H, dd), 3.41 (1H, dd), 3.73 (3H, s), 4.05 (1H, dtd), 4.39 (1H, d), 4.43 - 4.56 (2H, m), 5.09 (1H, d), 6.38 (1H, d), 7.19 - 7.32 (1H, m), 7.38 - 7.45 (2H, m), 7.48 (1H, ddd), 7.98 (1H, s), 8.36 (1H, d), 9.38 (1H, s). m/z (ES+) [M+H]+ 495 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In acetonitrile at 5 - 55℃; for 24h; Inert atmosphere; | 18a Example 18a Preparation of (R)-7-(3,4-Difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((l- methyl-lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[l,2-a]pyrazin- 8(5H)-one Ethanesulfonic acid adduct Form 1 To a hot solution of (i?)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((l- methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[ 1 ,2-a]pyrazin-8(5H)- one (Example 18; 1 14 g, 200.56 mmol) in MeCN (500 mL) at 55 °C was added a solution of ethanesulfonic acid (17.02 mL, 210.59 mmol) in acetonitrile (100 mL). The reaction mixture was slowly cooled to 5 °C over 24 hours, the resulting solid was filtered and washed with cold MeCN (200 mL) to afford the ethanesulfonic acid adduct Form 1 of (R)-7-(3,4- difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((l -methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[l ,2-a]pyrazin-8(5H)-one Form 1 (Example 18a; 1 19 g, 98%) as a solid. The adduct was determined by H NMR to be a 1 : 1 molar ratio of ethanesulfonic acid: (R)-7-(3 ,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-(( 1 - methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[ 1 ,2-a]pyrazin-8(5H)- one. H NMR (400 MHz, DMSO, 24 °C) δ 1.08 (3H, t), 2.44 - 2.49 (2H, m), 2.51 (3H, s), 3.16 (3H, s), 3.32 (1H, dd), 3.41 (1H, dd), 3.76 (3H, s), 3.97 - 4.12 (1H, m), 4.32 - 4.62 (3H, m), 5.08 (1H, d), 6.48 (1H, d), 7.17 - 7.30 (1H, m), 7.34 - 7.52 (2H, m), 7.55 (1H, d), 8.04 (1H, s), 8.39 (1H, s), 9.67 (1H, s). (i?)-7-(3,4-difiuorobenzyl)-6-(methoxymethyl)-2-(5- methyl-2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo[l , 2- a]pyrazin-8(5H)-one ethanesulfonic acid adduct Form 1 was determined to be crystalline by XRPD (Figure 1) and had a melting point of 203.8 °C (onset) (Figure 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.8% | In methanol; water at 40℃; for 21h; | 135 (Example 135) N-[4-(2-Amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)phenyl]-5-(4-methylphenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydropyridine-3-carboxamide ethanesulfonate hydrate (Example 135) N-[4-(2-Amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)phenyl]-5-(4-methylphenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydropyridine-3-carboxamide ethanesulfonate hydrate To N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)phenyl]-5-(4-methylphenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydropyridine-3-carboxamide (251 mg, 350 μmol), methanol (1.00 ml) and water (3.65 ml) were added. Then, a 1.00 mol/L aqueous ethanesulfonic acid solution (368 μl, 368 μmol) was added thereto. A small amount of seed crystal obtained by the method given below was added to the mixture. The mixture was stirred at 40° C. for approximately 21 hours and subsequently at room temperature for approximately 30 minutes and suction-filtered with a Kiriyama funnel, and the deposited solid was collected by filtration. Then, the solid was dried in air to obtain the title compound (265 mg, yield: 81.8%) as a crystalline solid. 1H-NMR (DMSO-D6) δ: 13.22 (1H, s), 8.72 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=2.0 Hz), 8.20 (2H, dd, J=8.5, 2.0 Hz), 7.90 (2H, d, J=8.5 Hz), 7.61-7.49 (6H, m), 7.32 (1H, d, J=2.0 Hz), 7.29-7.24 (3H, m), 7.06 (1H, d, J=8.5 Hz), 4.11 (2H, d, J=7.5 Hz), 4.01-3.93 (2H, m), 3.87-3.24 (14H, m), 2.41-2.31 (5H, m), 2.16-2.04 (1H, m), 1.46 (2H, d, J=11.5 Hz), 1.37-1.25 (2H, m), 1.06 (3H, t, J=7.5 Hz). Elemental analysis values for C42H44N4O7.1.0C2H5SO3H.5.5H2O Calcd: C, 57.07; H, 6.64; N, 6.05; S, 3.46. Found: C, 57.13; H, 6.78; N, 6.08; S, 3.60. The powder X-ray diffraction (CuKα, λ=1.54 angstroms, scanning rate=20°/min) pattern is shown in FIG. 6, and peaks having a relative intensity of 5 or more with the maximum peak intensity defined as 100 are shown in Table 31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.8% | In ethyl acetate; at 20 - 22℃; for 2h; | 1.00 g (2.69 mmol) of { 1 -(ethylsulphonyl)-3 - [4-(7H-pyrrolo [2,3 -djpirimidin-4-yl)- 1H-pyrazol-1-yljazetidin-3-yl}acetonitrile (baricitinib) is suspended in 15 ml of ethyl acetate at20-22 C, then while stirring a solution of 326.2 mg (2.96 mmol; 1.1 equiv.) ofethanesulfonic acid made with 5 ml of ethyl acetate is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 C, then the precipitated solid material is filtered, washed on the filter with ethyl acetate, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.28 g (98.8%) of a white coloured solid product is obtained.The sample is spectroscopically and morphologically identical to the substance produced withmethod ?A?. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dipotassium peroxodisulfate; palladium diacetate In dichloromethane at 60℃; for 24h; Inert atmosphere; Sealed tube; stereoselective reaction; | Alkenyl Sulfonates 3a-x; General Procedure General procedure: To a pressure-affordable thick-wall glass tube containing aryl/alkylsulfonic acid 1 (0.15 mmol), alkyne 2 (0.90 mmol), Pd(OAc)2 (1.7 mg, 0.0075 mmol), and K2S2O8 (122 mg, 0.45 mmol) were added anhyd CH2Cl2 (5 mL). The tube was sealed with an O-ring and a teflon cap. The mixture was then stirred at 60 °C for 24 h. Upon completion of the reaction, CH2Cl2 was removed under reduced pressure. Elution with CH2Cl2/hexanes (2:1) gave the desired product (Z)-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dipotassium peroxodisulfate; palladium diacetate In dichloromethane at 60℃; for 24h; Inert atmosphere; Sealed tube; stereoselective reaction; | Dialkyl (2Z,4E)-3-(Aryl/Alkylsulfonyloxy)hexa-2,4-dienedioates 3y,z and 3aa-ad General procedure: To a pressure-affordable thick-wall glass tube containing aryl/alkylsulfonic acid 1 (0.25 mmol), enyndioate 2i (168 mg, 1.00 mmol), Pd(OAc)2 (6 mg, 0.025 mmol), and K2S2O8 (68 mg, 0.25 mmol) were added anhyd CH2Cl2 (4 mL) under N2. The tube was sealed with an O-ring and a teflon cap. The mixture was then stirred at 60 °C for 24 h. Upon completion of the reaction, CH2Cl2 was removed under reduced pressure. Elution with hexanes/EtOAc (4:1) gave the respective desired products 3y,z and 3aa-ad. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; at 70 - 75℃; | General procedure: Stage I (0144) Table 11 illustrates the selected counter ions for the salt screening of beta-GPA. Salt screening experiments were designed in 1:1.1 equivalence (eq) for beta-GPA to counter ion. [table-us-00011-en] TABLE 11 List of selected counterions beta- Counterion Counterion GPA sequence molecular Sample ID (mg) Counterion wt 2162-42-1 to 4 30 Hydrochloric 1 36.46 acid (36-38%)* 2162-42-5 to 8 30 Hydrobromic 2 80.91 acid (48%)* 2162-42-9 to 12 30 Sulfuric acid 3 98.08 (95-98%)* 2162-42-13 to 16 30 Phosphoric acid 4 98.00 (85%)* 2162-42-17 to 20 30 Methane sulfonic 5 96.11 acid (98%)* 2162-42-21 to 24 30 Maleic acid 6 116.07 2162-42-25 to 28 30 Fumaric acid 7 116.07 2162-42-29 to 32 30 Tartaric acid 8 150.09 2162-42-33 to 36 30 Ethanesulfonic 9 110.13 acid 2162-42-37 to 40 30 Ethanedisulfonic 10 190.20 acid 2162-42-41 to 44 30 Citric acid 11 192.12 2162-42-45 to 48 30 Malic acid 12 134.09 2162-42-49 to 52 30 Lactic acid 13 90.08 2162-42-53 to 56 30 Aspartic acid 14 133.1 2162-42-57 to 60 30 Succinic acid 15 118.09 2162-42-61 to 64 30 Sodium 16 40.00 hydroxide 2162-42-65 to 68 30 Potassium 17 56.11 hydroxide 2162-42-69 to 72 30 Oxalic acid 18 90.03 2162-45-1 to 4 30 Magnesium 19 58.32 hydroxide 76 salt screening experiments of beta-GPA with 19 different counter ions were set up with 30 mg of beta-GPA. Sets of four vials for each counterion were set up with four different solvents (0.3 mL): ethanol:water (9:1), isopropanol, acetone:water (9:1) and acetonitrile. (0146) Appropriate amounts of beta-GPA and the counterion were dissolved in the respective solvents and heated to 70-75 C. until dissolved. An additional 0.1 mL of water was added to the samples containing isopropanol, acetone:water (9:1) and acetonitrile. To samples containing L-aspartic acid, around 1.5 mL of water was required to dissolve the solids. After a clear solution was obtained, the samples were left for stirring at room temperature. Solids were observed in the following samples: 2163-42-4, 25, 26, 27, 28, 45 and 53 through 75. The solids were filtered and analyzed by XRPD immediately as wet sample. The samples that did not yield solids were placed in the oven at 50 C. for drying. The following samples resulted in solids after overnight drying: 2162-42-2, 1, 2, 3 and 21 through 24. The experiments with L-aspartic acid, sodium hydroxide, potassium hydroxide, and magnesium hydroxide resulted in the precipitation of either beta-GPA or the counterion. All the experimental observations were recorded after every step and are listed in Table 12. [table-us-00012-en] TABLE 12 Results of Salt screening Sample ID Counterion Solvent After 24 hours After Drying XRPD 2162-42-1 Hydrochloric EtOH:H2O (9:1) Clear Solution White Solid Pattern 1A 2162-42-2 Acid IPA Clear Solution White Solid 2162-42-3 Acetone:H2O (9:1) Clear Solution White Solid 2162-42-4 MeCN White Solid N/A 2162-42-5 Hydrobromic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-6 Acid IPA Clear Solution Gel N/A 2162-42-7 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-8 MeCN Clear Solution Gel N/A 2162-42-9 Sulfuric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-10 IPA Clear Solution Gel N/A 2162-42-11 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-12 MeCN Clear Solution Gel N/A 2162-42-13 Phosphoric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-14 IPA Clear Solution Gel N/A 2162-42-15 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-16 MeCN Clear Solution Gel N/A 2162-42-17 Methanesulfonic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-18 Acid IPA Clear Solution Gel N/A 2162-42-19 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-20 MeCN Clear Solution Gel N/A 2162-42-21 Maleic Acid EtOH:H2O (9:1) Clear Solution White Solid Pattern 6A 2162-42-22 IPA Clear Solution White Solid 2162-42-23 Acetone:H2O (9:1) Clear Solution White Solid 2162-42-24 MeCN Clear Solution White Solid 2162-42-25 Fumaric Acid EtOH:H2O (9:1) White Solid N/A Pattern 7A 2162-42-26 IPA White Solid N/A 2162-42-27 Acetone:H2O (9:1) White Solid N/A 2162-42-28 MeCN White Solid N/A 2162-42-29 L-Tartaric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-30 IPA Clear Solution Gel N/A 2162-42-31 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-32 MeCN Clear Solution Gel N/A 2162-42-33 Ethanesulfonic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-34 Acid IPA Clear Solution Gel N/A 2162-42-35 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-36 MeCN Clear Solution Gel N/A 2162-42-37 Ethanedisulfonic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-38 Acid IPA Clear Solution Gel N/A 2162-42-39 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-40 MeCN Clear Solution Gel N/A 2162-42-41 Citric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-42 IPA Clear Solution Gel N/A 2162-42-43 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-44 MeCN Clear Solution Gel N/A 2162-42-45 L-Malic Acid EtOH:H2O (9:1) White Solid N/A Pattern 12A 2162-42-46 IPA Clear Solution Gel N/A 2162-42-47 Acetone:H2O (9:1) Clear Solution Gel N/... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In acetonitrile at 20℃; for 1h; | 2 Example 2:Preparation of 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5- tetrahydro- 1 H- 1 -benzazepine Ethanesulfonate Manufacturing of 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H-1-benzazepine (5.0 g)And acetonitrile (250 ml) were placed in a reactor, ethanesulfonic acid (1.67 g) was added thereto,And the mixture was stirred at room temperature for 1 hour.The reaction mixture was further stirred for 2 hours at 0 ° C. and filtered.The obtained filtrate was washed with acetonitrile,And dried at 60 ° C. or lower for 14 hours to give ethanesulfonic acid of 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro- A salt was obtained (84%, 5.60 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In water; acetonitrile at 40℃; for 0.5h; | 233A Example 233 A - Preparation of crystalline form 1 of 4-(((3S,4S)-4-(aminomethyl)- 1-((5-chloropyridin-2-yl)sulfonyl)-4-hydroxypyrrolidin-3-yl)oxy)-2- fluorobenzonitrile, esylate anhydrate To a solution of 4-(((3S,4S)-4-(aminomethyl)-1-((5-chloropyridin-2-yl)sulfonyl)-4- hydroxypyrrolidin-3-yl)oxy)-2-fluorobenzonitrile (500 mg, 1.2 mmol) in acetonitrile (5 mL) at 40oC was added ethanesulfonic acid (70% wt. soluiton in water) in three equal poritions. The resulting reaction mixture was stirred at 40oC for 30 minutes and then cooled to room temperature. Diethyl ether was added dropwise until the solution became cloudy and the resulting mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with diethyl ether to provide crystalline 4-(((3S,4S)-4-(aminomethyl)-1-((5-chloropyridin-2-yl)sulfonyl)-4-hydroxypyrrolidin-3- yl)oxy)-2-fluorobenzonitrile, esyalte salt (550 mg, Form 1; 83% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid In water at 40℃; for 24h; | 24 Example 24 - Preparation and characterization of Compound 1 ethanesulfonic acid salt A stock solution of ethane sulfonic acid was prepared in water (47 μL of sulfuric acid in 953 μL H2O). 400 μL of the appropriate solvent was added to the vial containing the weighed compound 1, 100 μL of the ethane sulfonic acid stock solution was then added to the solvent/compound 1 slurry (1.05 eq. of acid to free base). The samples were then temperature cycled between ambient and 40 °C in 4 hour cycles over 24 hrs. | |
In acetone at 20 - 40℃; for 24h; | 24 Example 24 - Preparation and characterization of Compound 1 ethanesulfonic acid salt A stock solution of ethane sulfonic acid was prepared in water (47 μΙ_, of sulfuric acid in 953 μ^ H20). 400 μ^ of the appropriate solvent was added to the vial containing the weighed compound 1, 100 μ^ of the ethane sulfonic acid stock solution was then added to the solvent/compound 1 slurry (1.05 eq. of acid to free base). The samples were then temperature cycled between ambient and 40 °C in 4 hour cycles over 24 hrs. (1612) Observations from the treatment of Compound 1 with ethanesulfonic acid are shown Table 49 below: (1613) Table 49 (1614) (1615) To the samples which were recovered as clear solutions, 2-3 mg of Compound 1 was added to produce a mobile slurry and the sample temperature cycled for a further 2-3 hours. XRPD analysis of ethanesulfonic acid experiments recovered 4 crystalline hits, free base (Form I) recovered from acetone, THF and TBME. Insufficient solids were recovered from methanol, ethanol and 2-propanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.79 g | In ethanol; at 20 - 80℃; | 1 g (0.309 mmol) of <strong>[283173-50-2]Rucaparib</strong> free base was suspended at room temperature in 40 mL of 96percent EtOH. Reaction mixture was then heated to 75-80°C and clear yellow solution was obtained. 0.74 mL (0.927 mmol) of Ethanesulfonic acid was added dropwise. The reaction mixture was then slowly cooled down to 0-5°C. Solvent was partly removed under reduced pressure and crystallization occurred. Suspension was stirred at 0-5°C for 1.5 hour at 20- 25°C. Crystals were filtered off and dried in vacuum oven at 50°C/10 mbar for 3 hours to obtain 0.79 g of <strong>[283173-50-2]Rucaparib</strong> Esylate Form I. XRPD pattern is given in Figure 29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | In tetrahydrofuran; acetone at 20 - 25℃; Reflux; | 4 Comparative Example 4: Preparation of esilate salt of N(5-(4-(4-((dimethylamino)methyl)-3-phenyl- 1 H-pyrazol- 1 -yl)pyrimidine-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide A reactor was charged with N(5-(4-(4-((dimethylamino)methyl)-3-phenyl- 1 H-pyrazol- 1 -yl)pyrimidine-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (15.00 g, 27.0 mmol) prepared by the same process as disclosed in WO 2016-060443 and tetrahydrofuran (300 mL), which were stirred. Ethanesulfonic acid (2.98 g, 27.1 mmol) was diluted in tetrahydrofuran (45 mL), which was added dropwise thereto while kept at 20 to 25 °C. Then, the reaction mixture was stirred at room temperature for 11 hours or more. The reaction mixture was filtered under a reduced pressure, and the solid thus obtained was vacuum dried to obtain 16.20 g of esilate salt of N(5-(4-(4-((dimethylamino)methyl)-3-phenyl- 1 H-pyrazol- 1 -yl)pyrimidine-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (yield: 90.1%) as the title compound.The title compound of N(5-(4-(4-((dimethylamino)methyl)-3-phenyl- 1 H-pyrazol- 1 -yl)pyrimidine-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide esilate was measured under the same conditions as in Example 1. The results of measurement with 1H-NMR (400 MHz, DMSO-d6) are as follows:1H-NMR (400 MHz, DMSO-d6) ö 9.69(s, 1H), 9.34(s, 1H), 9.22(s, 1H), 8.75(s, 1H),8.58(d, 1H), 8.36(s, 1H), 7.77(d, 2H), 7.52-7.58(q, 3H), 7.33(d, 1H), 6.94(s, 1H),6.69-6.76(q, 1H), 6.26(d, 1H), 5.80(d, 1H), 4.46(s, 2H), 3.89(s, 3H), 3.82(s, 4H),2.87(s, 4H), 2.65(s, 6H), 2.34-2.39(q, 2H), 1.03-1.06(t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 20℃; for 0.5h; | To a stirred solution of Larotrectinib free base (30 mg, 1 eq) in methanol (0.5 mL) a solution of ethansulfonic acid (6.0 muEpsilon, 1.07 eq) in methanol (0.6 mL) was added. The obtained clear solution was stirred at RT for 0.5 hour and then concentrated by vacuum oven at 40 C overnight to produce oil. The residue was slurried with ethyl acetate (0.3 mL) at 50 C for 17 hours and then cooled to RT and stirred for 1 hour. The solid was filtered and characterized by X-ray powder diffraction to give Larotrectinib ethanesulfonate salt form El as depicted in Figure 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.91% | In ethyl acetate at 20℃; for 3h; | 19 Example 19(2R,3S,5R,6S)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine ethanesulfonate (compound 19) (2R,3S,5R,6S)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine (0.70 g, 1.5 mmol) and ethyl acetate (7 mL) The solution was lyophilized; a solution of ethanesulfonic acid (0.17 g, 1.5 mmol) in ethyl acetate (1 mL) was added dropwise to obtain a clear solution; a large amount of white solid was gradually precipitated under stirring at room temperature, stirring was continued for 3 hours; filtered under reduced pressure, and the filter cake was reduced at 40 ° C. Dry for 30min,(2R,3S,5R,6S)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c Pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine ethanesulfonate (Compound 19),White solid 0.67g,Yield: 77.91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.4% | In methanol; dichloromethane; isopropyl alcohol at 20 - 50℃; for 2.5h; | 10 Example 10 Preparation of the Ethanesulfonic Acid Salt Ethanesulfonic acid (95%, 0.063 mL, 1.2 equiv) was added to a solution of Compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL). The reaction was heated to 50 °C, distilling off the dichloromethane. Isopropyl alcohol (3 mL) was added. The mixture was stirred at 50 °C for about 1 h. The mixture was cooled to room temperature and stirred for another 1.5 h. The reaction was filtered and the solids were washed with methyl t-butyl ether (1.5 mL). The solid was dried at 40 °C under vacuum overnight to provide Compound 1 ethanesulfonic acid salt (0.27 g, 73.4% yield). Figure 32 shows the 'H NMR of Compound 1 ethanesulfonic acid salt. Figure 33 shows the XRPD pattern of Compound 1 ethanesulfonic acid salt. Figure 34 shows the DSC thermogram of a solid form of Compound 1 ethanesulfonic acid salt. Figure 35 shows the TGA thermogram of a solid form of Compound 1 ethanesulfonic acid salt. Analytical data collected on the product, including characterization by XRPD, DSC, and TGA were performed as described in Example 1. The ethanesulfonic acid salt exhibits a DSC thermogram having an endothermic peak at a temperature of about 227 °C. Table 9: XRPD of the Ethanesulfonic Acid Salt |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; dimethyl sulfoxide; at 70℃; | About 200 mg of Compound I (free base) in DMSO (about 0.5M, about 0.9 mL) was charged to a hot (about 70 C) tube comprising toluene or IPA (about 15 vols.). About 1 equivalent of an ethane sulfonic acid was added as a 1M solution in THF to the Compound I (free base) solution. The resulting solution/suspension was held isothermal for about 4 hours and cooled overnight prior to filtration, drying, and analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; acetone; | Ethane Sulfonate crystalline salt: was prepared in a primary salt screen. A 2 ml_ aliquot of acetone was added to ~40 mg of free base. 1.05 equivalents of ethane sulfonate as a 1 M solution in THF were added and the sample was temperature cycled for 3-5 days. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | at 110℃; for 12h; Sealed tube; | General procedure for the synthesis of phosphonium salts 3 General procedure: As shown in Tables 1 and 2, phosphine, acid and orthoformate in a mol ratio of 1:1:5 were added to the reaction tube. The reaction mixture was stirred at 110 °C. After the completion of the reaction, the reaction mixture was cooled to room temperature, and the excessed orthoformate was evaporated under reduced pressure. The obtained residue was recrystallized with dichloromethane andethyl acetate, and washed with ethyl acetate and petroleum ether .The product was dried in a vacuum oven at 60 °C overnight to obtain desired pure phosphonium salts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | Stage #1: methyl 1-acetyl-3-[ethoxy(phenyl)methylidene]-2-oxo-2,3-dihydro-7H-indole-6-carboxylate; C22H30N6O2 at 70℃; for 8h; Stage #2: ethanesulfonic acid In ethanol; water Reflux; | 1.3 3. Preparation of the nidanib compound of formula I The compound of formula II (10 g, 24.4 mmol) and methyl 1-(acetyl)-3-[ethoxy (phenyl)methylene]-2-oxoindoline-6-carboxylate (18.0 g , 49.1mmol) was added to N, N-diethylacetamide 300mL, heated to 70 °C , stirring reaction for 8h, the reaction was completed, the temperature was reduced to 25 °C , potassium hydroxide (0.68g, 12.2mmol) methanol solution was added, stirring 4-5h, Filter, wash with methanol, add the solid to absolute ethanol (240mL), add 36mL of water, heat to reflux, add 80% ethanesulfonic acid (3.5, 25.6mmol), dissolve first, then gradually precipitate the solid, filter, anhydrous Methanol was washed and blow dried at 50 °C for 8 hours to obtain 24.0 g of the compound of formula I.Molar yield 91.5% (calculated as compound of formula II), HPLC: 99.97%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.6% | Stage #1: 3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylic acid methyl ester; C22H30N6O2 In N,N-dimethyl acetamide at 80℃; for 9h; Stage #2: ethanesulfonic acid In ethanol; water Reflux; | 2.3 3. Preparation of the nidanib compound of formula I The compound of formula II (10 g, 24.4 mmol) and methyl 3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (15.1 g, 48.8 mmol) were added to N , N-dimethylacetamide 240mL,Heated to 80 °C , stirred for 9 hours,After the reaction was completed, the temperature was lowered to 25 °C, kept under stirring for 5 hours, filtered and washed with methanol. The solid was added to absolute ethanol (210 mL), 30 mL of water was added, heated to reflux, and pure ethanesulfonic acid (2.8 g, 25.6 mmol) was added. , Dissolve first,Then, a solid was gradually precipitated, filtered, washed with anhydrous methanol, and dried by air blowing at 50 ° C for 8 hours to obtain 22.3 g of the compound of formula I. Molar yield 80.6% (based on compound of formula II), HPLC: 94.89%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.7% | In ethyl acetate at 20℃; | 19a Preparation of 4-Cyclopropy1-N-[(S)-(4,4-difluorocyclohexy1)-[7-[[(4S)-2-oxo-4- (trifluoromethy1)imidazolidin- 1 -y1]methy1]imidazo[ 1 ,2-b]pyridazin-2-y1]methy1]- 1 ,2,5 - oxadiazole-3 -carboxamide; ethanesulfonic acid The esy1ate salt of 4-cyclopropy1-N-[(S)-(4,4-difluorocyclohexy1)-[7-[[(4S)-2-oxo-4- (trifluoromethy1)imidazolidin- 1 -y1]methy1]imidazo[ 1 ,2-b]pyridazin-2-y1]methy1]- 1 ,2,5 - oxadiazole-3 -carboxamide is prepared by dissolving 4-cyclopropy1-N-[(S)-(4,4- difluorocyclohexy1)-[7-[[(4S)-2-oxo-4-(trifluoromethy1)imidazolidin-1- y1]methy1]imidazo[l,2-b]pyridazin-2-y1]methy1]-l,2,5-oxadiazole-3-carboxamide (1.8 g, (0523) 3.166 mmol) (Example 19) in EtOAc (10 mL) while stirring at 800 rpm at amdient temperature to a clear yellowish solution. This solution is filtered through a 0.45 pm syringe filter into a new clean vial. To this solution is added of 95% ethanesulfonic acid (300 mL, 3.473 mmol) and the clear solution persists. The solution begins to cloud within minutes. After an hour, a thick slurry of white solid forms, and another 10 mL of EtOAc is added to thin the slurry slightly. This slurry is allowed to stir at 800 rpm overnight. A thick slurry of bright white solid results. The white solid is isolated on a Whatman paper filter under vacuum. The cake of bright white solid is dried in place for 15 minutes under nitrogen stream, then kept overnight in a 70 °C vacuum oven to give the title compound (1.283 g, 59.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.4% | In ethanol at 80℃; for 1h; | 22 Example 22. Example 22. preparation process and structure identification data of compound 43 8-Dichloromethylene dihydroberberine (200 mg, 0.478 mmol) was weighed and placed into the reaction bottle, and 5 ml 95% ethanol was added in the reaction bottle and the mixture was well-mixed. Then, ethanesulfonic acid (117 μl, 1.434 mmol) was added in batchwise and, after finishing, the reaction mixture was reacted for 1 h under stiring and refluxing on 80°C oil bath under heating. The reaction mixture was cooled to room temperature. 10 ml diethyl ether anhydrous was added in the reaction mixture to make the product precipitated. Filtration was conducted under reduced pressure. The filter cake was washed using diethyl ether anhydrous and tetrahydrofuran until the filtrate was colourless. The filter cake was dried under vacuum to yield 8-dichloromethyl-berberine ethanesulfonate red solid 193 mg in yield 76.4%. 1H NMR (400 MHz, DMSO-d6) δ: 9.21 (s, 1H, ArCH=C), 9.19 (s, 1H, CHCl2), 8.33 (d, J = 9.2 Hz, 1H, ArH), 8.14 (d, J = 9.2 Hz, 1H, ArH), 7.85 (s, 1H, ArH), 7.16 (s, 1H, ArH), 6.21 (s, 2H, OCH2O), 5.26 (t, J = 6.0 Hz, 2H, NCH2CH2), 4.12 (s, 3H, ArOCH3), 4.05 (s, 3H, ArOCH3), 3.30 (t, J = 6.0 Hz, 2H, NCH2CH2), 2.37 (q, J = 7.6 Hz, 2H, ), 1.05 (t, J = 7.6 Hz, 3H, ); 13C NMR (100 MHz, DMSO-d6) δ: 153.37, 150.34, 147.66, 147.03, 142.62, 140.74, 134.86, 131.59, 126.67, 125.34, 124.50, 120.60, 119.85, 107.81, 106.01, 102.17, 62.83, 62.37, 57.24, 52.96, 45.05, 25.79, 9.79. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.1% | In ethanol at 80℃; for 1h; | 21 Example 21. Example 21. preparation process and structure identification data of compound 41 8-Dichloromethylene dihydrocoptisine (200 mg, 0.497 mmol) was weighed and placed into the reaction bottle, and 5 ml 95% ethanol was added in the reaction bottle and the mixture was well-mixed. Then, ethanesulfonic acid (122 μl, 1.492 mmol) was added in batchwise and, after finishing, the reaction mixture was reacted for 1 h under stiring and refluxing on 80°C oil bath under heating. The reaction mixture was cooled to room temperature. Filtration was conducted under reduced pressure. The filter cake was washed using tetrahydrofuran and diethyl ether anhydrous and until the filtrate was colourless. The filter cake was dried under vacuum to yield 8-dichloromethyl-coptisine ethanesulfonate red solid 171 mg in yield 67.1%. 1H NMR (400 MHz, DMSO-d6) δ: 9.21 (s, 1H, ArCH=C), 8.68 (s, 1H, CHCl2), 8.16 (d, J = 8.8 Hz, 1H, ArH), 7.98 (d, J = 8.8 Hz, 1H, ArH), 7.84 (s, 1H, ArH), 7.16 (s, 1H, ArH), 6.57 (s, 2H, OCH2O), 6.21 (s, 2H, OCH2O), 5.22 (t, 2H, J = 5.6 Hz, NCH2CH2), 3.29 (t, 2H, J = 6.0 Hz, NCH2CH2), 2.35 (q, 2H, J = 7.2 Hz, ), 1.03 (t, J = 7.2 Hz, 3H, ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In acetic acid methyl ester at 0 - 40℃; | 3 Example 3: Preparation of Aprocitentan:ethanesulfonic acid Aprocitentan (600 mg) was dissolved in methyl acetate (10 mL) at 52 °C. To the stirred solution ethanesulfonic acid (89.6 pL, 1 eq.) was added. The obtained solution was cooled to 0 °C in an ice water bath, precipitation started around 40 °C. The obtained solid was isolated by vacuum filtration and dried in air for 20 minutes. The obtained solid was analyzed by XRPD. Crystalline Aprocitentamethanesulfonic acid was obtained (yield: 79%). XRPD pattern is given in Figure 3. |
Tags: 594-45-6 synthesis path| 594-45-6 SDS| 594-45-6 COA| 594-45-6 purity| 594-45-6 application| 594-45-6 NMR| 594-45-6 COA| 594-45-6 structure
[ 1092929-45-7 ]
1,2-Ethanedisulfonic Acid hydrate
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[ 1092929-45-7 ]
1,2-Ethanedisulfonic Acid hydrate
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[ 1092929-45-7 ]
1,2-Ethanedisulfonic Acid hydrate
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[ 5982-56-9 ]
Ethane-1,2-disulfonic acid dihydrate
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[ 1092929-45-7 ]
1,2-Ethanedisulfonic Acid hydrate
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Ethane-1,2-disulfonic acid dihydrate
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