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CAS No. : | 120-18-3 | MDL No. : | MFCD00004089 |
Formula : | C10H8O3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KVBGVZZKJNLNJU-UHFFFAOYSA-N |
M.W : | 208.23 | Pubchem ID : | 8420 |
Synonyms : |
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Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P234-P260-P264-P280-P301+P330+P331+P310-P303+P361+P353+P310+P363-P304+P340+P310-P305+P351+P338+P310-P390-P405-P406-P501 | UN#: | 2585 |
Hazard Statements: | H290-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 |
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99% | In isopropyl alcohol for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; for 0.5h;Heating / reflux; | 1 g (2 mmol) of telmisartan is suspended in 10 mL of methanol and then 0.46 g (2 mmol) of naphthalene-2-sulphonic acid is added. The suspension is heated under reflux temperature for 0.5 h and then cooled to room temperature, filtered, washed with water and dried at 35C in a vacuum drier. 1.39 g telmisartan 2-naphthalenesulphonate is isolated.T: 258-264CIR: 1697, 1461, 1269, 1264, 1189, 863, 758, 741 XRD: crystalline, figure 21 |
Yield | Reaction Conditions | Operation in experiment |
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With Ion exchange resin (Amberlite) (H+ form); In methanol; | Compound C-8 Ion exchange resin (Amberlite) (H+ form) was added to a solution of sodium 2-naphthalenesulfonate in methanol. The mixture was stirred overnight and filtered and the solvent was evaporated. The residue was lyophilized yielding 2-naphthalenesulfonic acid. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; dichloromethane; | A. Preparation of (IA) where R1 and R2 are hydrogen, and R3 is 4-chloro A mixture of 4-chloroisoindoline (700 mg), 2-methylthio-2-thiazoline (600 mg), and beta-naphthylsulfonic acid (35 mg) was heated at 150 C. for 30 minutes. The product was cooled, dissolved in methylene chloride, washed with water, the organic layer dried over anhydrous potassium carbonate, filtered, and solvent removed from the filtrate under reduced pressure. The residue was chromatographed on silica gel packed in methylene chloride/2% methanol/ammonia, eluding with methylene chloride/2% methanol, to give 4-chloro-2-(thiazolin-2-yl)isoindoline, a compound of Formula (IA), m.p. 167-169 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tert-butyl methyl ether; acetone for 1h; | 500 mg of the compound, which is obtained according to the procedure b described in Example 10, is suspended in 2.5 ml_ acetone and 2.5 ml_ TBME. 521 mg naphthalene-2-sulfonic acid in 1.0 ml_ acetone is added and the suspension is stirred for 1 h. The suspension is filtered and dried. Violet crystals (580 mg) are obtained. The compound contains 1.0 eq naphthalene-2-sulfonic acid/mol. 1 H-NMR (200 MHz, d6-DMSO): δ = 2.72 (s, 3 H, CH3), 2.74 (s, 3 H, CH3), 4.38 (d, 2 H, J = 4.5 Hz, CH2), 6.17 (d, 1 H, J = 16.2 Hz, CH=CH), 6.60 (bs, 1 H, Ar-H), 7.29 (d, 1 H, J = 15.0 Hz, CH=CH), 7.40 (m, 1 H, Ar-H), 7.52 (m, 2 H, Ar-H), 7.67 - 8.00 (m, 7 H, Ar-H), 8.05 - 8.17 (m, 3 H, Ar-H), 9.72 (bs, 1 H, exchangeable-H), 10.61 (bs, 1 H, exchangeable-H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In dichloromethane; at 20℃; for 4.0h; | EXAMPLE 2; 5-Amino-4-oxopentanoic acid 2-naphtylsulfonate (ALA-napsylate, also referred to herein as ?AN-302?) A solution of N-Boc-5-aminolevulinic acid (1 eq) and 2-naphthylsulfonic acid (1 eq) in dry CH2Cl2 under N2 was stirred for 4 h in rt. Water (20 mL) was then added, and the aqueous layer was washed with CH2Cl2 and evaporated to give 5-amino-4-oxopentanoic acid 2-napthylsulfonate as a white solid (68% yield), mp 172-175 C. 1H-NMR (300 MHz, MeOD) ppm delta2.61 (t, J=6.3 Hz, 2H, CH2CO2), 2.74 (t, J=6.1 Hz, 2H, CH2CO), 4.01 (s, 2H, CH2NH2), 7.56 (m, 2H, H6, H7), 7.9 (m, 4H, H3, H4, H5, H8), 8.63 (m, 1H, H1). 13C-NMR (300 MHz, MeOD)ppm 28.3 (CH2CO2),35.3 (CH2CO), 48.1 (CH2NH2), 124.0 (C3), 126.4 (C4), 127.9 (C1), 128.5 (C7), 128.8 (C6), 129.3 (C8), 128.8 (C5), 132.2 (C2), 133.8 (C9), 135.3 (C10), 175.8 (CO2), 203.1 (CO). MS (ES+): m/z 114 (MH+-H2O, 100). MS (ES-): m/z 207 (M-, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In ethyl acetate; at 2 - 25℃; for 97h; | To a solution of 4.66 g (8.00 mmol) of 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester in 32 ml of ethyl acetate was added dropwise a solution of 5.97 g (26.4 mmol) of 2-naphthalenesulfonic acid monohydrate in 120 ml of ethyl acetate at 25C over 30 minutes. After completion of the dropwise addition, the reaction solution was further stirred for 30 minutes. The reaction solution was allowed to stand at 2C for four days to precipitate the solid. The precipitated crude solid was collected by filtration and then washed with 100 ml of ethyl acetate and dried under reduced pressure at 45C for three hours to give 7.72 g (97%) of the title compound as a white powder. 1H-NMR spectrum (DMSO-d6, deltappm): 1.00(d;J=6Hz,3H), 1.18(dd;J=6Hz,2Hz,3H), 2.28(s,3H), 4.06-4.42(m,4H), 4.74-4.90(m,2H), 4.96-5.18(m,1H), 5.73-6.00(m,1H), 6.84(brs,2H), 7.37-7.57(m,15H), 7.60-7.66(m,1H), 7.70-7.76(m,2H), 7.85-8.04(m,8H), 8.14-8.18(m,2H), 8.92(brs,1H), 10.88-11.37(m,1H). The powder X-ray diffraction pattern of this compound is shown in Figure 7. This compound had specific peaks in the X-ray diffraction pattern and was a crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol for 21h; | Crystalline polymorph A+B 2.00 g (E)-N-(2-Amino-phenyl)-3-{1-[4-(1-methyl-1H-pyrazol-4-yl)-benzene sulfonyl]-1H-pyrrol-3-yl}-acrylamide was suspended in 40 mL isopropanol. 1.46 g naphthalene-2-sulfonic acid (70%) was added and the suspension was stirred for 24 h. The suspension was filtered, the filter cake was washed with 20 mL isopropanol and dried. An off-white solid (2.72 g) was obtained. The characteristic peaks of the X-ray powder diffraction pattern of this salt are substantially summarized in Table 18 and substantially shown in Figure 18. Table 18: XRPD pattern of crystalline (E)-N-(2-amino-phenyl)-3-{1-(4- (1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide naphthalene-2-sulfonate polymorph A+B comprising the following peaks (relative intensities > 10) | |
In methanol for 1h; | Crystalline polymorph C 1.00 g (E)-N-(2-Amino-phenyl)-3-{1-[4-(1-methyl-1H-pyrazol-4-yl)-benzene sulfonyl]-1H-pyrrol-3-yl}-acrylamide was suspended in 15 mL methanol. 1.46 g naphthalene-2-sulfonic acid (70%) was added and the solution was filtered. Seeding crystals were added to the filtrate and the suspension was stirred for 1 h. The suspension was filtered and dried. An off-white solid (1.28 g) was obtained. The characteristic peaks of the X-ray powder diffraction pattern of this salt are substantially summarized in Table 20 and substantially shown in Figure 20. Table 20: XRPD pattern of crystalline (E)-N-(2-amino-phenyl)-3-{1-[4-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide naphthalene-2-sulfonate polymorph C comprising the following peaks (relative intensities > 10) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In acetone at 20℃; for 0.75h; | 3 30 ml dry acetone was added to 3.0 g Prasugrel and stirred for 15 min to get a clear solution. A solution of 1.635 g of 2-naphtahlene sulfonic acid in 12 ml acetone (dried over 3A Molecular sieve) was added slowly to the clear solution of Prasugrel in acetone at room temperature in 30 min. The reaction mixture was stirred at room temperature for 15 min. The acetone was completely evaporated resulting in an oily layer in the flask. 90 ml toluene was added to the oil and stirred slowly for 2 hours at ambient temperature. The reaction mass was kept in a freezer overnight, was filtered under nitrogen atmosphere at room temperature and dried under high vaccum for approximately two days. Yield: 69%; DSC: 1570C; Melting range = 152-156°C; IR: 1755, 1711 , 1617, 1593, 1496, 1376 cm"1; HPLC: Prasugrel = 99.17% |
In methanol | 8 250 mg prasugrel (free base) were dissolved in 5 ml of methanol and the solution was stirred at room temperature. An equimolar amount of 2-naphthalene 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 = 13.44 (s) , 13.89 (s) , 20.55(s), 21.33 (s), 22.63 (s) , 50.5 (broad), 70.1 (s) , 112.78(s), 116.01 (d; 14.1 Hz), 117.73 (d; 21.2 Hz), 124.63 (s),124.79 (s), 124.99 (s), 125.07 (s), 126.73 (s) , 127.18 (s),127.35 (s), 128.25, 128.36, 129.29 (s) , 133.01 (s) , 133.16 (s), 133.64 (s), 134.59 (d; 8.5 Hz), 146.27 (s) , 150.74 (s) ,161.87 (d; 250.1Hz), 168.51 (s) , 202.84 (s) ppm.The 13C-NMR spectrum of prasugrel-2-napsylate is shown in Fig. 1, the 1H-NMR spectrum in Fig. 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; at 25 - 55℃; for 0.5h; | 10 g of (R)-(+)-<strong>[136236-51-6]rasagiline</strong> base and 100 mL acetone were taken in round bottom flask at 25C. 12.14 g of naphthalene-2-sulphonic acid was added and heated at 55C with stirring for 30 mins. The reaction mixture was cooled to 25C-35C and stirred for 1 hour. The product was filtered and washed with acetone. The product was dried for 12 hours at 45C under vacuum to obtain crystalline (R)-<strong>[136236-51-6]rasagiline</strong> 2-napsylate. The product is characterized by XRD (FIG.l 1 ) and DSC (FIG.12). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water at 20℃; for 48h; | 2-Naphthalenesulfonate (napsylate)A/-[5-[4-(5-[(2 ,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1 ,3-oxazol-2-yl)-1 H-indazol-6-yl]- 2-(methyloxy)-3-pyridinyl]methanesulfonamide (0.200g, 0.390mmol) was dissolved in tetrahydrofuran (3.2ml) and water (0.8ml). Separately, 2-naphthalenesulfonic acid (0.081 mg, 0.390mmol, 1.0eq) was dissolved in tetrahydrofuran (0.8ml) and added to the A/-[5-[4-(5-[(2 ,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1 ,3-oxazol-2-yl)-1 H-indazol-6-yl]- 2-(methyloxy)-3-pyridinyl]methanesulfonamide solution. This was seeded with a previous napsylate salt, however these seeds dissolved. The solution was allowed to evaporate at ambient temperature for 2 days. The white solid formed was triturated in water and sonicated before being filtered and washed with water. The damp solids were dried further in vacuo at 40-50°C for 5 days to give the napsylate salt (254.8mg, 91 %th).NMR: consistent with salt formationNMR (400MHz, DMSO d6) d = 13.56 (s, 1 H), 10.38 (bs, 1 H), 9.42 (s, 1 H), 8.69 (s, 1 H), 8.43 (d, J = 2.2Hz, 1 H), 8.15 (s, 1 H), 8.03 (s, 1 H), 8.00 (d, J = 2.0Hz, 1 H), 7.96 (m, 2H), 7.86 (m, 2H), 7.71 (m, 2H), 7.53 (m, 2H), 4.68 (bs, 2H), 4.01 (s, 3H), 3.79 (bs, 2H), 3.50 (bs, 2H), 3.1 1 (s, 3H), 2.78 (bs, 2H), 1.14 (d, J = 6.1 Hz, 6H).NMR also shows some unidentified low level impurities and residual tetrahydrofuran (0.1 molar equivalents). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Example 35. Synthesis, Purification and Characterization of Doxorubicin Naphthalene-2-SulfonateA 250-mL round-bottom flask equipped with a magnetic bar and athermocouple was charged with doxorubicin»HCl (NetQem, 1.47 g, 2.53 mmol) and anhydrous THF (150 mL, 100 vol). The suspension was evacuated for 15 seconds with stirring and filled up with nitrogen (1 atm). 1 M (KOtBu)/THF solution (2.7 mL, 2.70 mmol) was added dropwise with stirring over 10 min. The mixture turned a purple color and a slight exotherm was observed, causing the reaction temperature to rise from 20.2 C to 21.4 C within 15 min. The solution was stirred at 21.1 C for one hour and 2-naphthalenesulfonic acid (0.63 g, 3.04 mmol) was added in one portion. The mixture immediately turned to a red color and the precipitation of fine particles was observed. The solution was stirred for an hour at ambient temperature and then filtered under nitrogen. The filtration was slow and took about 1 h. The filter cake was washed with THF (3 x 10 mL) and dried under vacuum at 25 C for 16 h to afford 2.1 g of doxorubicin naphthalene-2-sulfonate as a dark red solid [yield:>100%]. HPLC analysis indicated a 98% purity (AUC, 480 nm). The H NMR analysis showed that the ratio of 2-naphthalenesulfonic acid to doxorubicin was -1.08.To remove residual 2-naphthalenesulfonic acid, the doxorubicin naphthalene- 2-sulfonate was slurried in 5:1 MTBE/MeOH (60 mL) for 3 h. The suspension was filtered and the filter cake was dried under vacuum at 25 C for 24 h to afford 1.90 g1of the product as a fine red powder [yield: 100%]. The H NMR analysis indicated a clean product with a 1 : 1 ratio of doxorubicin to 2-naphthalenesulfonic acid. HPLC analysis showed >98% purity (AUC, 480 nm). The physical appearance of the product was similar to doxorubicin»HCl. DSC analysis of doxorubicin naphthalene-2- sulfonate showed a sharp peak with a melting range of 203.1 - 207.4 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; | For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; | For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.4% | In acetonitrile Reflux; | 12.2 Example 12 Lapatinib naphtalene 2 sulfonic acid (1 : 1) salt Form I and Form II 2) Form II Example 12 Lapatinib naphtalene 2 sulfonic acid (1 : 1) salt Form I and Form II 1) Form I Into an apparatus 80 cm3 ethanol is weighed in whereupon 0.800 g (1.38 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.312 g (1.38 mmol) naphtalene-2-sulfonic acid monohydrate is added. Immediately precipitate starts to appear, to the reaction mixture further 30 cm3 ethanol is added then it is stirred and allowed to cool to room temperature, the it is stirred for a further 20 hours. The precipitated crystalline product is filtered and washed with a little cold ethanol and tert-butyl methyl ether. The product is dried on 25 °C for 24 hours under 6.1 mbar pressure. Yield: 1.023 g (93.9 %). The obtained salt is recrystallized according to the following: 0.400 g material is recrystallized from 22 cm3 acetonitrile/water 9:1 mixture. After cooling to room temperature the mixture is further stirred for one hour, then for 30 minutes on a temperature of 0-5 °C. The precipitated product is filtered then washed with a little cold solution then with tert-buthyl methyl ether. The product is dried on 50 °C for 4 days under 3.9 mbar pressure. Yield: 0.337 g (84.3 %). Melting point: 194.8-199.0 °C Analysis calculated for C29H26ClFN4O4S-C10H8O3S (789.31): Calculated: C: 59.35 H: 4.34 N: 7.10 CI: 4.49 S: 8.12 Measured: C: 58.94 H: 4.36 N: 7.00 CI: 4.46 S: 7.96 IR (KBr, cm"1): 3416, 3017, 2771, 1592, 1567, 1526, 1503, 1448, 1420, 1386, 1297, 1271, 1248, 1139, 1092, 1059, 1032, 966, 922, 868, 836, 787, 749, 676, 623, 567, 523, 503. 1H- MR (DMSO-ffc, 400 MHz): 10.00 (b, 1H), 9.12 (b, 1H), 8.86 (s, 1H), 8.61 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.15 (s, 1H), 8.00 (d, J=1.6, Hz, 1H), 7.95 (m, 1H), 7.89 (m, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.72 (m, 2H), 7.52 (m, 2H), 7.47 (m, 1H), 7.34 (m, 1H), 7.32 (m, 1H), 7.28 (d, J=9.0 Hz, 1H), 7.19 (m, 1H), 7.16 (d, J=3.4 Hz, 1H), 6.84 (d, J=3.2 Hz, 1H), 5.27 (s, 2H), 4.41 (s, 2H), 3.55 (m, 2H), 3.45 (m, 2H), 3.14 (s, 3H). 2) Form II Into an apparatusl5 cm3 acetonitrile is weighed in whereupon 0.600 g (1.03 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.234 g (1.03 mmol) naphtalene-2-sulfonic acid monohydrate in 5 cm3 acetonitrile is added. Precipitate starts to appear the reaction mixture is stirred for a further 20 hours. The precipitated crystalline product is filtered and washed with a little cold acetonitrile and tert-butyl methyl ether. The product is dried on 50 °C for 48 hours under 2.8 mbar pressure. Yield: 0.694 g (85.4 %) Melting point: 200-205 °C IR (KBr, cm"1): 3379, 2764, 1602, 1567, 1541, 1525, 1496, 1450, 1421, 1296, 1246, 1139, 1089, 1028, 958, 922, 904, 839, 783, 747, 676, 623, 565, 518, 504, 477. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at -10 - 20℃; for 25h; | Example 5Preparation of anhydrous <strong>[284461-73-0]sorafenib</strong> naphthalene-2-sulfonic acid (1 :1) salt form III(<strong>[284461-73-0]sorafenib</strong> napsylate)Into an apparatus equipped with thermostat, 10 cm3of acetonitrile is weighed in, whereupon 0.200 g (0.43 mmol) <strong>[284461-73-0]sorafenib</strong> base is suspended under intensive stirring. The suspension is cooled to (-10) C and 0.090 g (0.43 mmol) of naphthalene-2-sulfonic acid dissolved in 1 cm3of acetonitrile is added at this temperature. The reaction mixture is stirred for one hour at (-10) C and subsequently for 24 hours at room temperature. The precipitated crystalline product is filtered, washed with a little amount of acetonitrile and dried at 45 C under vacuum to constant weight.Yield: 0.225 g (77.7 %)Mp.: 198-206 C |
Yield | Reaction Conditions | Operation in experiment |
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83% | In tetrahydrofuran at 20℃; for 0.5h; | 14 Large Scale Preparation of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide Dinapsylate To a solution of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide free base (15 g, 0.062 mol) dissolved in anhydrous tetrahydrofuran (300 mL, 20 vol) was added 2-naphthalene sulfonic acid hydrate (25.7 g, 0.123 mol, 2 eq) in one portion. Solids rapidly precipitate from the initially cloudy mixture. The mixture was stirred at ambient temperature for about 30 min, and then the solids were collected by vacuum filtration. The wet cake was dried in a 40° C. vacuum oven to afford 33.9 g (83% yield) of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide Dinapsylate as a white solid. 1H NMR confirmed the identity and XRD pattern matches the small scale screen sample pattern. |
Yield | Reaction Conditions | Operation in experiment |
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96% | In acetonitrile at 60℃; for 1h; | 2 EXAMPLE 2: Method for producing the crystalline form of the naph halene-2- sulfonate of 3-l(dimethy inino)raerJiylI--V-{2-[4-(hydroxy carbamoyl)phenoxy]ethyl}-l-benzofuran-2-carboxamide In a 50 mL flask, an equivalent of 3-[(dimemylainmo)mefhyl]-N-{2-[4- (hydroxycarbamoyl)phenoxy]ethyl}-l-benzofuran-2-carboxamide (free base) (1115.5 mg; 2.807 mmol) was added, followed by an equivalent of naphthalene-2-sulfonic acid monohydrate (635.9 mg; 2.806 mmol). Then 25 mL of acetonitrile were added and the reaction mixture was subjected to sustained magnetic stirring at 60 °C for 1 hour. Next the reaction mixture was cooled under sustained magnetic stirring to 10 °C at a speed between 1 and 1.5 °C/min, then maintained for approximately 1 day at 10 °C. After filtration on a porosity 3 glass frit, the solid was dried in a desiccator in vacuo (100 mbar) in order to give the compound of the title with an output of 96 %. The solid was characterized by the powder X-ray diffraction diagram and the NMR spectrum detailed in the following Examples 7 and 9. |
Yield | Reaction Conditions | Operation in experiment |
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73% | 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. 182.9 mg (0.653 mmol) of 2-naphthalenesulphonic acid was dissolved in 2 mL of methanol at room temperature. The methanol solution of 2-naphthalenesulphonic acid was drop-wise added to the solution of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2/3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50C, 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: 278 mg; yield: 73% HPLC purity: 99.0% 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 9. |
Yield | Reaction Conditions | Operation in experiment |
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254.8 mg | In tetrahydrofuran; water | 2-Naphthalenesulfonate (napsylate) 2-Naphthalenesulfonate (napsylate) N-[5-[4-(5-[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (0.200 g, 0.390 mmol) was dissolved in tetrahydrofuran (3.2 ml) and water (0.8 ml). Separately, 2-naphthalenesulfonic acid (0.081 mg, 0.390 mmol, 1.0 eq) was dissolved in tetrahydrofuran (0.8 ml) and added to the N-[5-[4-(5-[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide solution. This was seeded with a previous napsylate salt, however these seeds dissolved. The solution was allowed to evaporate at ambient temperature for 2 days. The white solid formed was triturated in water and sonicated before being filtered and washed with water. The damp solids were dried further in vacuo at 40-50° C. for 5 days to give the napsylate salt (254.8 mg, 91% th). NMR: consistent with salt formation NMR (400 MHz, DMSO d6) d=13.56 (s, 1H), 10.38 (bs, 1H), 9.42 (s, 1H), 8.69 (s, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.96 (m, 2H), 7.86 (m, 2H), 7.71 (m, 2H), 7.53 (m, 2H), 4.68 (bs, 2H), 4.01 (s, 3H), 3.79 (bs, 2H), 3.50 (bs, 2H), 3.11 (s, 3H), 2.78 (bs, 2H), 1.14 (d, J=6.1 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
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33% | With sodium hydroxide In ethanol; water for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
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58% | With sodium hydroxide In ethanol; water at 20℃; | 2 2.2. Synthesis of the copper(II) synergist complex CuSO4 · 5H2O (1.248 g, 5 mmol) was dissolved in deionized water(ca. 30 mL) before a solution of the ligand L (4.145 g, 20 mmol) inethanol (ca. 5 mL) was added and the mixture stirred at ambienttemperature. To this was added drop-wise a solution of HNS(2.082 g, 10 mmol) in ethanol (ca. 5 mL) and a suitable amount ofNaOH solution to keep the equilibrium pH value of about 2. Afterthe addition was completed, it was stirred for another 1.5 h. Theresulting solution was separated into two phases after standing.The organic fraction was dried over anhydrous MgSO4, filtered, andreduced to dryness on the rotary evaporator. Subsequently, thedried solid was dissolved in methanol (ca. 5 mL) and extracted withn-hexane (5 5 mL). Finally, the lower solution (methanol) wascollected. The removal of the solvent on the rotary evaporator gavea dark blue solid (the copper(II) synergist complex). Blue crystalwas obtained by slow evaporation of a methanol/water (20:1, v/v)solution of the copper(II) synergist complex at ambient temperaturewithin 20 days. Yield: 2.685 g (58%). Anal. Calc. forC44H52N2Cu1O12S2 (%): C, 56.91; H, 5.64; N, 3.02; S, 6.91; Found (%):C, 56.86; H, 5.60; N, 2.97; S, 7.14. |
Yield | Reaction Conditions | Operation in experiment |
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90.3% | In acetone; at 20℃; for 48h;Reflux; | 1.0 g (2.23 mmol) palbociclib base and 25 ml acetone are measured into a device providingintensive stirring, then during heating at reflux 505.44 mg (2.23 mmol) naphthalene-2-sulfonic acid monohydrate is added. The solution is cooled to room temperature, stirred for 48hours, then the crystalline product is filtered, washed with a small amount of cold acetone and then dried in a vacuum drying cabinet (55 °C, 6 mbar, 18 h). Yield: 1.32 g (90.3percent). Mp.: no characteristic value, thermal decomposition takes place above 280 °C. Analysis with respect to the chemical formula C34H37N705S (655.77):Calculated C: 62.27 percent H: 5.69 percent N: 14.95 percent S: 4.89 percent Measured C: 61.83 percent H: 5.67 percent N: 14.90 percent S: 4.85 percent. 1H-NMR (DMSO-d6, 500 MHz): 10.17 (bs, 1H), 8.96 (s, 1H), 8.62 (b, 2H), 8.14 (s, 1H), 8.12(d, 1=2.8 Hz, 1H), 7.96 (m, 1H), 7.90 (m, 2H), 7.85 (d, 1=8.6 Hz, 1H), 7.72 (dd, 11=1.5 Hz,12=8.6 Hz, 1H), 7.54 (dd, 11=2.8 Hz, 12=9.0 Hz, 1H), 7.52 (m, 2H), 5.83 (m, 1H), 3.38 (m,4H), 3.27 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H), 2.25 (m, 2H), 1.89 (m, 2H), 1.78 (m, 2H), 1.59(m, 2H). 13C-NMR (DMSO-d6, 125 MHz): 202.50, 160.86, 158.62, 158.34, 154.90, 154.86, 145.83,145.47, 142.42, 142.14, 132.84, 132.29, 129.57, 128.56, 127.56, 127.38, 126.50, 126.38,125.85, 124.14, 115.18, 106.90, 53.10, 45.86, 42.85, 31.42, 27.69, 25.24, 13.76. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.32 g | In dichloromethane for 0.5h; | 4 Preparation of ticagrelor naphthalene sulfonic acid salt ticagrelor in 4.0 g40 mL of dichloromethane is injected1.73 g of 2-naphthalene sulfonic acid hydrate was added.This mixed solution was added to isopropyl etherSlowly injected into 400 mL, and stirred for 30 minutes. After all of the solid was precipitated, it was obtained by filtration under nitrogen,The obtained solid was vacuum-dried at 40°C for 16 hours to obtain 5.32 g of ticagrelor naphthalene sulfonate. |
Yield | Reaction Conditions | Operation in experiment |
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at 40℃; for 24h; | 19 Example 19 - Preparation and characterization of Compound 1 naphthalene-2-sulfonic acid salt 250 μL of the appropriate solvent was added to the vials containing 20 mg of compound 1. In a separate vial, 250 μL of the appropriate solvent was added to the vial containing naphthalene-2-sulfonic acid (14.14 mg). The solutions/slurries were then added to the solvent/compound 1 solution (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 tert-butyl methyl ether at 20 - 40℃; for 24h; | 19 Example 19 - Preparation and characterization of Compound 1 naphthalene- 2-sulfonic acid salt 250 [iL of the appropriate solvent was added to the vials containing 20 mg of compound 1. In a separate vial, 250 μΙ_, of the appropriate solvent was added to the vial containing naphthalene-2-sulfonic acid (14.14 mg). The solutions/slurries were then added to the solvent/compound 1 solution (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. (1584) Observations from the treatment of Compound 1 with naphthalene-2-sulfonic acid are shown in Table 44 below. (1585) Table 44 (1586) (1587) 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 naphthalene-2-sulfonic acid experiments recovered 3 crystalline hits, free base (Form I) recovered from ethanol, THF and TBME. Insufficient solids were recovered from acetone, methanol and 2-propanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; | Tenofovir Alafenamide (about 1 g) was mixed with 2-naphthalenesulfonic acid (about 0.4 g) and acetone (about 10 mL). The solution was put in a glass vial with an open lid and allowed to evaporate. Tenofovir Alafenamide Napsylate Form I was isolated and characterized as discussed below. |
Yield | Reaction Conditions | Operation in experiment |
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1.2 g | In methanol at 20 - 60℃; for 28h; | 13 Example 13 Preparation of the solid form of elagolix with 2-naphtalenesulfonic acid The free form of elagolix (900 mg) was stirred in 20 ml of methanol together with 2-naphtalenesulfonic acid (303 mg). The resulting mixture was heated at 60 °C for 4 h, then allowed to cool and stirred at room temperature for 24 h. After evaporation of the solvent, 1.2 g of amorphous solid form of elagolix with 2- naphtalenesulfonic acid was obtained. (0282) The differential scanning calorimetry curve of the solid form of elagolix with 2-naphtalenesulfonic acid exhibits the glass transition temperature of 101 °C to 113 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.6% | Stage #1: nickel(II) sulfate hexahydrate; naphthalene-2-sulfonate In hexane at 40℃; for 0.5h; Stage #2: methyl 3-pyridinecarboxylate; water In methanol; ethanol at 40℃; for 2h; | 5 Preparation method of naphthalenesulfonic acid(short carbon chain acidic ligand) and methyl nicotinate (short carbon chain containing N ligand) two ligands and nickel ion synthesis multi-ligand nickel complex Weigh 2.082g, 10mmol of naphthalenesulfonic acid was added to 100mL of agitated flask to dissolve in 30mL of n-hexane, add 1.314g, 5mmol NiSO4·6H2O, and stir the reaction in a constant temperature water bath at 40 °C for 30min, the reaction After completion The mixture was transferred to a 500 mL round bottom flask, and an appropriate amount of absolute ethanol was added to cyclone to remove ethanol and water. The ethanol and water were azeotroped, and the obtained blue solid was dissolved in anhydrous methanol. Filtration removes inorganic salt impurities such as undissolved Na2SO4 and NiSO4. The filtrate is rotary evaporated to remove methanol to obtain green naphthalenesulfonic acid nickel; Dissolving nickel naphthalene sulfonate in 30 mL of a solvent of methanol:ethanol:water in a volume ratio of 10:10:2, then adding 2.057 g, 15 mmol of methyl nicotinate in a constant temperature water bath at 40 ° C for 120 min, the reaction is completed. After that, the single crystal was cultured by a slow solvent evaporation method at room temperature, and 4.132 g of a green needle-shaped single crystal was grown for eight days. The yield of the two ligand nickel complexes of naphthalenesulfonic acid and methyl nicotinate is as high as 96.6%. The pH value was constant at 2.0 during the whole reaction, and was adjusted with dilute sulfuric acid and 5% NaOH solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.9% | Stage #1: copper(ll) sulfate pentahydrate; naphthalene-2-sulfonate In hexane at 41℃; for 0.416667h; Stage #2: hexyl nicotinate; water In methanol; ethanol at 41℃; for 1.83333h; | 4 Preparation method of naphthalenesulfonic acid(short carbon chain acidic ligand) and hexyl nicotinate (short carbon chain containing N ligand) two ligands and copper ion synthesis multi-ligand copper complex 2.082g, 10 mmol naphthalenesulfonic acid was added to a 100 mL Erlenmeyer flask [or erlenmeyer flask with Ground Joint and stopper] and dissolved in 30 mL of n-hexane, then 1.248g, 5mmol CuSO4 5H2O , and Magnetically stirred the reaction for 25min in a constant temperature water bath at 41 °C. After the reaction was completed, the mixture was transferred to a 500 mL round bottom flask, an appropriate amount of absolute ethanol was added for rotary evaporation to remove ethanol and water, then ethanol and water were azeotroped, the obtained blue solid was dissolved in absolute methanol, the inorganic salt impurities such as undissolved Na2SO4 and CuSO4 are removed by filtration, and the filtrate is rotary evaporated to remove ethanol to obtain blue copper naphthalene sulfonic acid ; copper naphthalenesulfonic acid was dissolved in 30 mL of a solvent of methanol: ethanol: water in a volume ratio of 10:10:2, then 3.109 g, 15 mmol of hexyl nicotinate was added and stirred the reaction in a constant temperature water bath at 41 ° C for 110 min. After completion of the reaction, the sample was allowed to stand at room temperature, the single crystal was cultured by a slow solvent evaporation method, and 4.362 g of a blue needle-shaped single crystal was grown in seven days ,and yield of the obtained naphthalenesulfonic acid and hexyl nicotinate two ligands copper complex is as high as 93.9%. The pH value of the whole reaction process was constant at 2.0, which was adjusted with dilute sulfuric acid and 5% NaOH solution |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In tetrahydrofuran at 25 - 50℃; for 17.5h; | 27; 28 Preparation of crystalline napsylate of roxadustat of form I 0.50 g of roxadustat of form A and 0.47 g of 2-naphtalenesulfonic acid (1.1 equivalents) were dosed into a flask. Subsequently, THF (15 ml) was added and the mixture was stirred for 0.5 h at the temperature of 50°C and the mixture was further stirred for another 17 h at the temperature of 25°C. Then, the suspension was filtered, washed with a minimal quantity of THF and the product was dried in vacuum at the temperature of 40°C for at least 0.5 h. The product was obtained in the form of white powder in the yield of 0.56 g (70%). An IR measurement confirmed formation of a salt. Ratio of roxadustat:2-naphtalenesulfonic acid = 1:1, contents of solvents: 0.45 molar equivalents ofTHF, determined by means ofNMR. (0369) lH-NMR (500 MHz, DMSO-d6): 9.15 (1H, t, J= 6.1 Hz, NH), 8.32 (1H, d, J= 9.1 Hz, AiH), 8.15 (1H, s, ArH), 7.98 (1Η, m, ArH), 7.91 (1Η, m, ArH), 7.87 (1Η, d, J= 8.6 Hz, ArH), 7.72 (1H, dd, J = 8.5, 1.6 Hz, ArH), 7.64 (1Η, d, J = 2.3 Hz, ArH), 7.56 (1Η, dd, J = 9.1, 2.3 Hz, ArH), 7.53 (2Η, m, ArH), 7.49 (2Η, t, J = 8.0 Hz, ArH), 111 (1H, t, J = 7.5 Hz, ArH), 7.20 (2Η, d, J= 8.0 Hz, ArH), 4.06 (2Η, d, J= 6.1 Hz, CH2), 2.72 (3Η, s, CH3). (0370) 13C NMR (125 MHz, DMSO-d6): 170.76, 169.85, 157.80, 155.51, 152.91, 146.83, 145.62, 132.67, 132.12, 131.41, 130.38, 128.43, 127.42, 127.26, 126.38, 126.25, 125.28, 124.55, 123.98, 123.97, 123.57, 122.56, 119.48, 119.41, 112.17, 40.61, 21.44. (0371) The X-ray powder pattern is shown in Fig. 50, the DSC record is shown in Fig. 51, Tt = 147°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water at 20 - 40℃; for 24h; | 4.C C. Primary salt screen General procedure: The samples were then temperature cycled between ambient (RT) and 40C in 4-hour cycles over 24 hours. Each mixture was filtered and isolated solids were analyzed (wet) by XRPD to determine crystallinity and form. Samples in which solid was not observed were stored uncapped to allow solvent evaporation. The remaining samples were placed in an oven at 40C and 75% RH overnight. The samples were then reanalyzed by XRPD to determine any changes in form or crystallinity. The observations and results, including the different diffractogram patterns observed during the screen, are shown in Tables 29-53, below, and Figures 24A-24B through 47A- 47B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In acetone; at 20℃;Inert atmosphere; | 1.5 g (3.81 mmol) of the formula (I) lumateperone base according to example 9 is dissolved in 12 ml acetone. The acetone solution of naphthalene-2-sulfonic acid monohydrate (1.726 g, 7.62 mmol) is prepared separately using 2 ml acetone. The acetone solution of naphthalene-2- sulfonic acid monohydrate is added drop by drop at room temperature to the lumateperone base solution in an argon atmosphere. A white crystalline substance precipitates. The suspension is stirred for 1 day at room temperature, then cooled in a ice and water bath, then the crystalline substance is filtered out. The product is then washed on the filter with a little cold acetone. The filtered lumateperone dinapsylate salt is dried until constant weight at 40 C, 2.5 g (83%). The raw product can be further purified using acetonitrile recrystallization (250 ml). 1.8 g (60%) white crystals, mp: 188-192 C. [OI]D25 = 4.4 (c = 1.00, DMF). HPLC purity: 99.628% (figure 8) IR (KBr): 3006, 2621, 2400, 1678, 1599, 1482, 1237, 1167, 1086, 1026, 676 cm 1. 1H-NMR (DMSO-i/e, 400 MHz): 9.10 (b, 1H), 8.14 (bs, 2* lH), 8.04 (~dd, 7i = 5.6 Hz, 72 = 8.8 Hz, 2H), 7.97 (m, 2* 1H), 7.90 (m, 2* lH), 7.86 (d, 7 = 8.5 Hz, 2* lH), 7.71 (dd, 7i =1.7 Hz, J2 = 8.5 Hz, 2* lH), 7.53 (m, 2* lH), 7.51 (m, 2* lH), 7.37 (~t, J = 8.8 Hz, 2H), 6.61 (m, 1H), 6.53 (m, 1H), 6.44 (m, 1H), 3.60 (m, 1H), 3.46 (m, 1H), 3.45 (m, 1H), 3.45 (m, 1H), 3.41 (m, 1H), 3.35 (m, 1H), 3.33 (m, 1H), 3.23 (m, 1H), 3.13 (m, 2H), 3.11 (m, 1H), 3.08 (m, 1H), 3.03 (m, 1H), 2.81 (m, 3H), 2.70 (m, 1H), 2.57 (m, 1H), 2.26 (m, 1H), 2.06 (m, 1H), 2.03 (m, 1H), 2.00 (m, 1H) ppm. 13C-NMR (DMSO- , 100 MHz): 197.37; 165,25 (d, J = 251.6 Hz); 145.74; l37.67w; l35.46w; 133.27 (d, J = 2.9 Hz); 132,90; 132.32; 131.06 (d, J = 9.5 Hz); 128.63; 127.63; 127.49; 127. l2w; 126.61; 126.47; 124.21; 124.14; l20.87w; 115 92 (d, J = 22.0 Hz); H3.42w; 1 l0.07w; 62.30; 55.72; 52.66; 50.07; 47.93; 43.74; 37.56w; 35.02; 21.88; 18.20 (w: weak) ppm. COSY: 8.14-7.71-7.86, 8.04-7.37, 7.97-7.51-7.53-7.90, 6.53-6.61-6.44, (3.60, 2.57)-3.33- 3.23-(2.26, 2.06)-(3.45, 3.03), (3.46, 3.35)-(3.4l, 2.70), 3.l3-(2.03, 2.00)-(3.l l, 3.08). HSQC (140 Hz): 8.14-124.21, 8.04-131.06, 7.97-128.63, 7.90-127.63, 7.86-127.49, 7.71- 124.14, 7.53-126.61, 7.51-126.47, 7.37-115.92, 6.61-120.87, 6.53-113.42, 6.44-110.07, 3.60- 52.66, 3.46-50.07, 3.45-47.93, 3.41-43.74,3.35-50.07, 3.33-38.81, 3.23-62.30, 3.13-35.02, 3.11-55.72, 3.08-55.72, 2.81-37.56, 2.70-43.74, 2.57-52.66, 2.26-21.88, 3.03-47.93, 2.06- 21.88, 2.03-18.20, 2.00-18.20. HMBC (140 Hz, 8 Hz): 8.14-(132.90, 128.63, 124.14), 8.04-Q97.37, 165.25, 131.06), 7.97- (132.90, 126.61), 7.90-(l32.32, 126.47), 7.86-Q45.74, 132.32), 7.71-Q32.90, 124.21), 7.53- (132.90, 128.63), 7.5l-(l32.32, 127.63), 7.37-Q65.25, 133.27, 115.92), 6.61-135.46, 6.53- 110.07, 6.44-137.67, 3.13-(197.37, 18.20), (3.11, 3.08)-l8.20. X-ray powder diffractogram: figure 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.92 g | In acetone; at 20℃; for 24h;Inert atmosphere; Cooling with ice; | 1.00 g (2.54 mmol) formula (I) lumateperone base according to example 9 is dissolved in 6 ml acetone and in an argon atmosphere 0.575 g (2.54 mmol) naphthalene-2-sulfonic acid monohydrate is added to this in a single portion. The salt precipitates almost immediately after the acid has been dissolved. The suspension is stirred at room temperature for 24 hours, then cooled for 30 minutes in an ice and water bath. The salt is filtered using a glass filter, then washed with about 0.5 ml cold acetone. 1.10 g mononapsylate is obtained, which is purified further by recrystallization from 60 ml isopropanol. 0.92 g white crystalline product is obtained, mp: 165-172 C. lHNMR (DMSO- e, 400 MHz): 8.14 (d, J= 0.6 Hz, 1H), 8.04 (~dd, J = 5.5 Hz, j2 = 9.0 Hz, 2H), 7.97 (m, 1H), 7.90 (m, 1H), 7.86 (d, j= 8.6 Hz, 1H), 7.71 (dd, L = 1.6 Hz, j2 = 8.5 Hz, 1H), 7.52 (m, 2H), 7.37 (~t, J= 8.9 Hz, 2H), 6.60 (m, 1H), 6.52 (m, 1H), 6.43 (m, 1H), 3.60 (m, 1H), 3.46 (m, 1H), 3.45 (m, 1H), 3.41 (m, 1H), 3.32 (m, 1H), 3.31 (m, 1H), 3.23 (m, 1H), 3.12 (m, 2H), 3.10 (m, 1H), 3.08 (m, 1H), 3.03 (m, 1H), 2.81 (s, 3H), 2.71 (m, 1H), 2.57 (m, 1H), 2.25 (m, lH), 2.06 (m, 1H), 2.02 (m, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 20 - 60℃; | Tenofovir alafenamide free base (3 g) was added to the reaction portion, followed by suspension with ethyl acetate (60 mL). 2-naphthalenesulfonic acid (1.87 g) was added thereto, followed by stirring at room temperature for 10 minutes. It heated up to 60 degreeC and stirred overnight, and cooled to room temperature. After crystals were formed, they were further stirred for 2 hours. The resulting crystals were filtered and dried in vacuo overnight at room temperature to obtain the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In ethanol; water at 0 - 20℃; for 5h; | 9 Example 9-Synthesis of Edoxaban Napsylate Add 100 ml of EtOH and 40 ml of H2O to 5.0 g of Edoxaban free base and heat up to 60 to 70 °C to dissolve completely. After adding 1.90 g of Naphthalene-2-sulfonic acid, the mixture is stirred for 2 hours at room temperature, cooled to 0° C., stirred for 3 hours, and dehydrated. Wash with 20 ml EtOH. After washing and drying with nitrogen, 3.5 g of Edoxaban Napsylate was obtained. (Yield 82%, purity 99.89%) |
81% | In ethanol; water at 70℃; for 5h; | 10 <Example 10> Preparation of edoxaban naphthalene-2-sulfonate of the present invention To 1.0 g of edoxaban free base, 40 mL of methylene chloride was added and suspended. Naphthalene-2-sulfonic acid solution (1.82 mL, 1.0M ethanol solution) was added, stirred for 1 hour, and then concentrated. After adding 20 mL of 85% ethanol to the concentrate, the concentrated residue was released, the temperature was raised to 70°C, and the mixture was stirred for 1 hour. It was cooled to room temperature and stirred for 3 hours. The resulting solid was filtered and dried under vacuum at an internal temperature of 50° C. overnight to obtain 1.12 g (81%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In methanol; isopropyl alcohol at 0℃; for 1.5h; | 2.2. Synthesis of 4-vinyl benzylamine salts General procedure: In round-bottom flask (100 mL), 4-vinyl benzylamine (0.80 g,6.3 mmol) was dissolved in 20 mL of methanol, and then 15 mL of isopropanolsolution containing β-naphthalene sulfonic acid 1a (1.31 g,6.3 mmol) was added dropwise (about 1.5 h) at 0 °C. The precipitatewas filtered and dried to afford white 4-vinyl benzylamine naphthalenesulfonate 1a (2.0 g, 95 %). 1H NMR (600.0 MHz, DMSO-d6): δ 8.17 (s,4 H), 7.97 (dd, J=5.8, 3.4 Hz, 1 H), 7.91 (dd, J=5.8, 3.4 Hz, 1 H),7.88 (d, J =6Hz, 1 H), 7.74 (d, J =6 Hz, 1 H), 7.54-7.52 (m, 2 H),7.50 (d, J =12 Hz, 2 H), 6.76-6.71 (m, 1 H), 5.87(d, J=18 Hz, 1 H),5.29 (d, J=12 Hz, 1 H), 4.03 (s, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In water; acetonitrile at 20 - 75℃; for 4.08333h; | 5 Example 5 A Napsylate Salt of Compound 1 (Form I) A 5-L three neck flask equipped with an overhead stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1, 263.3 g, 452.7 mmol) and MeCN (2 L, 8 vol). The resulting mixture was stirred and heated to 75° C. (inner temperature) for 15 min to form a clear solution, filtered through polyethylene frit filter and rinsed with MeCN (200 mL). To this solution at 70° C. (internal temperature) was added slowly a pre-filtered solution of 2-naphthalenesulfonic acid hydrate (108 g, 466.2 mmol (based on 1.3 hydrate, KF), 1.03 eq) in deionized H2O (54 mL, 0.5 vol) and MeCN (300 mL) over 25 min and rinsed with MeCN (100 mL) (internal temperature dopped to 64° C.). The resulting solution was stirred at 65° C. for 40 min. The resulting mixture was slowly cooled to RT and stirred over 3 h. The solid was collected by filtration, washed with MeCN (250 mL*2), air-dried (1 h) and then dried in an oven under vacuum at 50° C. overnight (24 h) to afford N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)-carbamoyl)piperidin-2-yl)benzenaminium naphthalene-2-sulfonate as off-white crystals, with a recovery yield of 330.3 g (92%). 1H NMR (400 MHz, DMSO-d6) (RT) δ 10.44 (s, 1H), 8.12 (s, 1H), 8.00-7.80 (m, 4H), 7.70-7.28 (m, 8H), 7.19-7.00 (m, 3H), 6.43-6.34 (m, 1H), 4.80-4.10 (br, 2H), 3.70-3.68 (m, 1H), 3.40-2.99 (m, 3H), 2.38-2.00 (m, 5H), 1.90-1.40 (m, 14H); (65° C.) δ 10.21 (d, J=8.8 Hz, 1H), 8.13 (s, 1H), 7.99-7.78 (m, 4H), 7.75-7.20 (m, 8H), 7.18-6.64 (m, 4H), 6.42-6.36 (m, 1H), 5.80-5.20 (br, 1H), 3.25-2.98 (m, 3H), 2.40-2.00 (m, 6H), 1.96-1.40 (m, 13H). MS: (ES) m/z calculated for C33H36F4N3O2 [M+H]+ 582.3, found 582.2. A plot of the XRPD is shown in , and Table 6, below, summarizes significant peaks observed in the XRPD plot. HPLC (both achiral analytical and chiral): >99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 5 - 40℃; | 6.3.d Preparation of Form A of the 2-Naphthalenesulfonate Salt 2-Propanol (15 vol; 3.4 mL) was added to starting material of Compound 1 (225 mg). One equivalent of solid 2-naphthalenesulfonic acid hydrate (110 mg) and seed crystals of Form A of the 2-naphthalenesulfonate salt were added. The mixture mostly dissolved then observed an increased precipitation. The mixture was temperature-cycled with stirring from 40-5° C. overnight. The solids were isolated by filtration under vacuum and air-dried for about 20 minutes. The yield was about 80.7% (263 mg), and the solids were consistent with Form A of the 2-naphthalenesulfonate salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67 mg | In tert-butyl methyl ether; water monomer; ethyl acetate at 5 - 50℃; for 16h; Sealed tube; | 1 Example 1 : Preparation of Remdesivir Napsylate Form APO-I In a sealed vial, remdesivir free base (54 mg) and naphthalene-2-sulfonic acid hydrate (23 mg) were dissolved in ethyl acetate (5.0 ml_), followed by addition of tert- butyl methyl ether (10.0 ml_). The resulting suspension was temperature cycled for 16 hours, after which the precipitated solid was collected by filtration, washed with tert- butyl methyl ether (2 ml_) and dried in vacuo at room temperature for approximately 24 hours to afford remdesivir naphthalene-2 -sulfonate Form APO-I (67 mg) as a white solid. 1H NMR analysis of the solid (DMSO-cfe, 400 MHz) indicated a molar ratio of remdesivir:naphthalene-2-sulfonic acid of approximately 1 :1. The PXRD diffractogram and DSC thermogram of a sample prepared by this method are shown in Figure 1 and Figure 8, respectively. 1H NMR (DMSO-de, 400 MHz): 9.11 (br s, 1 H), 8.65 (br s, 1 H), 8.14 (s, 1 H), 8.13 (s, 1 H), 7.95-8.00 (m, 1 H), 7.88-7.92 (m, 1 H), 7.86 (d, J=8.5 Hz, 1 H), 7.71 (d, J= 8.3 Hz, 1 H), 7.51 -7.54 (m, 2H), 7.35 (t, J= 7.8 Hz, 2H) 7.16-7.20 (m, 4H), 6.94 (d, J= 4.5 Hz, 1 H), 6.04 (dd, J=12.6, 10.4 Hz, 1 H), 4.59 (d, J=4.6 Hz, 1 H), 4.21-4.28 (m, 2H), 4.09 (quint, J= 5.9 Hz, 1 H), 3.92-3.99 (m, 2H), 3.88 (dd, J= 11 .0, 5.8 Hz, 1 H), 3.76-3.85 (m, 1 H), 1 .42 (sep, J=6.1 Hz, 1 H), 1.20-1.29 (m, 7H), 0.80 (t, J=7A Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 2 - 8℃; for 24h; | 18.C C. Compound (1) Napsylate salt A mixture of Compound (1) Free Base (500mg) in THF (5 mL) was heated at 40 °C with agitation until dissolution was complete. Naphthalene-2-sulfonic acid (251.71 mg, 1.05 eq) was added resulting in the clear solution turning pale pink. The solution was placed at 2- 8 °C for ca. 24 hours during which the solution darkened though no solids had formed. Heptane (500 pL) was added dropwise at ambient temperature (22 °C) until precipitation was observed and the solids isolated by filtration. (0674) XRPD analysis identified a new diffraction pattern different from both the free base pattern 1 and the diffraction pattern for 2-naphthalenesulfonic acid. PLM showed small, birefringent particles with no clearly defined morphology. 1 H-NMR showed evidence of salt formation from shifting peaks and a broadened water peak with 1 equivalent of naphthalene-2- sulfonic acid present. (0675) FT-IR analysis showed peak shifting indicating formation of a salt. (0676) 1691cm'1 - C=O stretching vibration (carbonyl and ester functionality) 3057cm'1 - R-OH stretching vibration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile at 20℃; | 24 Example 24: Preparation of Amcenestrant napsylate Form N1 Amcenestrant (200 mg) was suspended in acetonitrile (2 mL) at room temperature. Naphthalene-2-sulfonic acid was added to the suspension (90.12 mg, 1.2eq.). It was left to stir for 4 days at room temperature. Then it was filtered off over blue ribbon filter paper and dried for 4 hours at 80°C. Obtained powder was analyzed by XRPD. Amcenestrant napsylate Form N1 was obtained. |
Tags: 120-18-3 synthesis path| 120-18-3 SDS| 120-18-3 COA| 120-18-3 purity| 120-18-3 application| 120-18-3 NMR| 120-18-3 COA| 120-18-3 structure
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Code | Phrase |
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H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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