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CAS No. : | 3144-16-9 | MDL No. : | MFCD00064157 |
Formula : | C10H16O4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 232.30 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.9 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 56.17 |
TPSA : | 79.82 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.33 cm/s |
Log Po/w (iLOGP) : | 0.62 |
Log Po/w (XLOGP3) : | 0.54 |
Log Po/w (WLOGP) : | 2.35 |
Log Po/w (MLOGP) : | 1.06 |
Log Po/w (SILICOS-IT) : | 1.07 |
Consensus Log Po/w : | 1.13 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.49 |
Solubility : | 7.54 mg/ml ; 0.0325 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.79 |
Solubility : | 3.79 mg/ml ; 0.0163 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.99 |
Solubility : | 2.37 mg/ml ; 0.0102 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.69 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P234-P260-P280-P303+P361+P353-P304+P340+P310-P305+P351+P338 | UN#: | 3261 |
Hazard Statements: | H314-H290 | Packing Group: | Ⅱ |
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 |
---|---|---|
With brucine man zerlegt das ausscheideten Brucinsalz der <d-Campher>-β-sulfonsaeure mit Barytwasser; | ||
With brucine |
Yield | Reaction Conditions | Operation in experiment |
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89% | With thionyl chloride; at 20 - 40℃; | Thionyl chloride (37.7 mL, 516 mmol) was added to (+)-camphor-10-sulfonic acid (40 g, 172 mmol) in a 1L flask. The mixture was stirred at room temperature for 1 h, warmed at 40 oC for a further 6 h and then cooled back to room temperature and left stirring overnight. The mixture was diluted with ether (400 mL) and quenched over ice/water. The aqueous layer was extracted with ether (400 mL). The combined organic extracts were washed with water (200 mL) and satd. sodium hydrogen carbonate soln. (4 100 mL) until the evolution of CO2 had ceased, and then dried and evaporated to afford the title compound as a white solid (38 g, 89 %). m.p.: 62-63 oC (from ether); Lit.1: 67-68 oC. [alpha]D (c 1.29, CHCl3, 27 oC) +30.9; Lit.2: (c 4.2, CHCl3) +28.8. IR: max (N) 2921, 1741 (C=O), 1459, 1368, 1279, 1171, 1132, 1102, 1045 (SO2), 854, 768 cm-1. 1H NMR (400.1 MHz; CDCl3, Me4Si): 0.94 (3H, s, 7-CH3), 1.16 (3H, s, 7-CH3), 1.47-1.54 (1H, m), 1.76-1.83 (1H, m), 2.01 (1H, d, 2J = 18.4, 3-CH2 endo), 2.08-2.16 (1H, m), 2.18 (1H, t, 3J = 4.7, 4-CH), 2.42-2.52 (2H, m), 3.74 (1H, d, 2J = 14.3, CH2SO2Cl), 4.32 (1H, d, 2J = 14.3, CH2SO2Cl) ppm. 13C NMR (100.6 MHz; CDCl3; Me4Si): delta 19.2 (7-CH3), 19.3 (7-CH3), 24.8 (C-5), 26.4 (C-6), 41.8 (C-3), 42.3 (C-4), 47.7 (C-7), 59.2 (C-1), 63.7 (CH2SO2Cl), 212.3 (C-2) ppm. |
With thionyl chloride; for 12h;Reflux; | (1S)-(+)-Camphor-10-sulfonic acid (1.16 g, 5 mmol) was refluxed in thionyl chloride (8 mL) for 12 h. Then, the excess thionyl chloride was removed under reduced pressure to afford (1S)-(+)-10-camphorsulfonyl chloride, which was used in the next step without purification. | |
With thionyl chloride; for 2h;Reflux; | (i) Synthesis of Compound 2 With reference to the scheme 5a, compound 1 (10.02 g, 43.1 mmol) and SOCl2 (10 mL, 137 mmol) were refluxed for 2 hours in a 50-mL round-bottom flask, and then recrystallized in iced n-hexane (100-mL) after being cooled to room temperature. Posterior to filtration, bright white slice solids were obtained. The solids were dissolved in dichloromethane (10 mL), and then slowly dropped into a 100-mL round-bottom flask containing 4-(N,N-dimethylamino)pyridine (DMAP, 0.53 g, 4.3 mmol), dichloromethane (20 mL), morpholine (5.6 mL, 64.7 mmol), and NEt3 (4.4 mL, 43.1 mmol), followed by being stirred at 0 C. for 17 hours then warm to room temperature for additional 3 hours. 1 N HCl aqueous solution was added for neutralization to stop reaction. Water phase was further extracted with dichloromethane (3×20 mL) and then organic phase was collected, dried with anhydrous sodium sulfate, filtrated, and concentrated. The crude extract was purified by column chromatography (gradient elution, ethyl acetate:n-hexane:dichloromethane=1:1:1 to 1:0.25:1 as an eluent) to afford white solid compound 2 (9.77 g, 72%), (7,7-dimethyl-1-(morpholine-4-sulfonylmethyl)-bicyclo[2.2.1]heptan-2-one). The related properties of the compound 2 are listed as follows:Specific rotation: [alpha]D24+33.6 (c 1.0, CHCl3).1H NMR (400 MHz, CDCl3): delta 3.75 (t, J=4.6 Hz, 4H), 3.32 (d, J=14.4 Hz, 1H), 3.30-3.24 (m, 4H), 2.72 (d, J=14.4 Hz, 1H), 2.54-2.46 (m, 1H), 2.37 (dt, J=18.4 Hz, 4.4 Hz, 1H), 2.09 (t, J=4.4 Hz, 1H), 2.07-1.98 (m, 1H), 1.93 (d, J=18.4 Hz, 1H), 1.66-1.59 (m, 1H), 1.45-1.38 (m, 1H), 1.11 (s, 3H), 0.86 (s, 3H).13C NMR (100 MHz, CDCl3): delta 214.9 (CO), 66.3 (CH2×2), 57.9 (C), 47.7 (C), 45.6 (CH2×2), 44.2 (CH2), 42.5 (CH), 42.3 (CH2), 26.7 (CH2), 24.9 (CH2), 19.7 (CH3), 19.5 (CH3).IR: (neat) 2953, 2890, 2855, 1746, 1343, 1330, 1261, 1151, 1110.HRMS: calculated for C14H23NO4S 301.1348. found 301.1335. |
With thionyl chloride; for 2h;Reflux; | (i) Synthesis of Compound 1; With reference to Scheme la illustrated above, compound 19 (10.02 g, 43.1 mmol) and SOCl2 (10 ml, 137 mmol) were added in a 50-ml round-bottomed flask, refluxed for 2 hours, cooled to room temperature, and then poured into iced hexane (100 ml) for recrystalization. The resultant mixture was filtrated to give a bright white sheet solid. The solid was dissolved in dichloromethane (10 ml) and slowly dropwise added to a mixture containing 4-N,N-dimethylaminopyridine (0.53 g, 4.3 mmol), dichloromethane (20 ml), diisopropylamine (9.1 ml, 64.7 mmol), and triethylamine (4.4 ml, 43.1 mmol) in a 100-ml round-bottomed flask. The resultant mixture was refluxed at 50 C. for 2 hours, neutralized to be neutral by 3 N HCl aqueous solution, and then extracted with dichloromethane (20 ml×3). The resultant organic phase was dried with anhydrous sodium sulfate, filtrated, and then condensed. The crude extract was purified by chromatography (eluent:ethyl acetate:n-hexane=1:8) to give a white solid 31 (11.1 g, 74%), i.e. 7,7-Dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl-N,N-diisopropyl-methanesulfonamide). The data of the compound are listed as follows: 1H-NMR (400 MHz, CDCl3): delta 3.72 (septet, J=6.8 Hz, 2H), 3.26 (d, J=14.4 Hz, 1H), 2.72 (d, J=14.4 Hz, 1H), 2.56-2.49 (m, 1H), 2.30 (dt, J=4.0, 18.4 Hz, 1H), 2.02-1.92 (m, 2H), 1.85 (d, J=18.4 Hz, 1H), 1.58-1.51 (m, 1H), 1.34-1.25 (m, 13H), 1.10 (s, 3H), 0.82 (s, 3H). 13C-NMR (100 MHz, CDCl3): delta 215.4 (C), 58.7 (C), 51.1 (CH2), 48.2 (CH), 47.4 (C), 42.8 (CH), 42.5 (CH2), 26.7 (CH2), 25.1 (CH2), 22.4 (CH3), 22.0 (CH3), 20.1 (CH3), 19.7 (CH3). | |
With thionyl chloride; In chloroform; for 15h;Reflux; | Freshly distilled thionyl chloride (22.0 ml,0.3 mol) was added dropwise to a boiling solution of (1S)-(+)-10-camphorsulfonicacid (58.0 g, 0.25 mol) in 500 ml of dry chloroform. The reactionmixture was refluxed for 15 h; the solvent was evaporated in a vacuum,and the residue was dried in a vacuum desiccator with NaOH to constantweight. The product was dissolved in 400 ml of dry dichloromethane, anda mixture of 42.0 ml (~0.3 mol) of triethylamine and 32.0 ml (0.35 mol)of butan-1-ol was added dropwise. The mixture was stirred at room temperaturefor 48 h and washed with 1 n aqueous HCl (2×200 ml), saturatedNaHCO3 solution (3×200 ml) and water to neutral pH. Organic phasewas dried over anhydrous Na2SO4, and the solvent was removed. 64.2 g(89%) of butyl (S)-camphorsulfonate was obtained.N-Methylimidazole (17.2 g, 0.21 mol) was added to a solution of butyl(S)-camphorsulfonate (60.0 g, 0.21 mol) in 300 ml of anhydrous toluene,and the reaction mixture was refluxed for 30 h. Solvent was removed in avacuum, and 200 ml of toluene was added to the residue. Solvent wasagain removed in a vacuum, and the residue was dried for 6 h in a vacuumat 80 C and 0.2 Torr to give 70.0 g (99%) of the product | |
With thionyl chloride; at 120℃; for 1.5h; | General procedure: (S)-Camphor-10-sulfonic acid (500 mg, 2.15 mmol) was treated with SOCl2 (0.625 mL, 8.61 mmol) for 1.5 h at 120 C to get (S)-camphor-10-sulfonyl chloride. Excess SOCl2 was evaporated twice with toluene (5 mL) at reduced pressure. The solution of (S)-camphor-10-sulfonyl chloride (215 mg, 0.85 mmol) in acetonitrile (20 mL) was added dropwise into a solution of (R,R)-1,2-diphenylethylene-1,2-diamine (DPEN; 200 mg, 1.1 eq) and triethylamine (TEA; 240 muL, 4 eq) in acetonitrile (40 mL) at 0 C for 30 min. After further 60 min of the reaction, the white precipitate of TEA?HCl was filtered off and the reaction mixture was diluted with dichloromethane and evaporated at 40 C at reduced pressure. The product was dissolved in 0.1 M solution of NaOH (30 mL) and extracted with dichloromethane (3 * 10 mL). Combined extracts were dried over anhydrous Na2SO4 and evaporated. The crude product was purified by flash column chromatography using Silicagel 60 and mobile phase consisting of ethyl acetate/hexane/TEA (1/1/0.02) yielding ochre crystals of pure (1R,2R)-N-((S)-camphor-10-sulfonyl)-1,2-diphenylethylene-1,2-diamine. Yield: 280 mg, 77%; purity: 98%. | |
With thionyl chloride; In 1,4-dioxane; at 110℃; for 2h; | (11 mmol) of D (+) - 10-camphorsulfonic acid and 1.84 g (15 mmol) of thionyl chloride were added to 40 mL of 1,4-dioxane as a solvent in a 50 mL round bottom flask,The mixture was refluxed at 110 C for 2 h to give D (+) - 10-camphorsulfonyl chloride. 20mL of toluene as a solvent in an ice bath was added 1.02g (10mmol) (±) - tetrahydrofuran-3-methanol and 2.02g (20mmol) of triethylamine were mixed,The resulting D (+) - 10- camphorsulfonic chloride was slowly added dropwise using a dropping funnel (in 20 minutes), to recover at 25 was stirred 12h, was added 1.29g (15mmol) of sodium hydrogen carbonate saturated solution, stirred for 10 minutes, Extracted with 20 x 3 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The solvent was evaporated under reduced pressure to give 2.68 g (yield: 84.8%) of tetrahydrofuran-3-methyl camphorsulfonic acid ester, which was obtained as a colorless oil, which was purified by chromatography (ethyl acetate = 0 to 0.5)After leaving for 72 h, 2.47 g of a clear crystal was obtained (yield: 92.1%). In 3mL tetrahydrofuran was added 25mL round bottom flask was added the solvent 0.08g (2mmol) of 60% sodium hydride and 0.218g (2mmol) uniformly mixing benzyl alcohol, stirred for 10 minutes, was added 0.632g (2mmol) transparent crystal, stirred 24h at 25 , Filtered and washed with 50 mL of methylene chloride. The solvent was distilled off under reduced pressure and the residue was purified by chromatography (ethyl acetate: 0 to 1) to give 0.121 g of S (+) - -3-tetrahydrofuran methanol, yield 59%, purity> 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 120℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Versuche zur Zerlegung in Enantiomere; |
Yield | Reaction Conditions | Operation in experiment |
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88% | With water In isopropyl alcohol at 20℃; for 1h; | 1 Example 1 : Preparation of S-(-)-amlodipine (lS)-(+)-10-camsylate hydrate; 30O g of (S)-amlodipine free base obtained in Preparation 2 was added to a mixture of 900 mi of isopropanol and 900 mi of distilled water, and 170.4g of (lS)-(+)-10-camphor sulfonic acid was added thereto, and the resulting mixture was warmed to obtain a homogeneous solution. To this solution, 30.0g of activated carbon was added and stirred at room temperature for 1 hour. The mixture was then filtered through celite and washed with 300 mi of isopropanol and 300 mi of distilled water. 6.3 Z of distilled water was slowely added to the filtrate, stirred at 20 °C for 3 hours, and the precipitated solid was filtered. The solid was washed with 600 ml of an isopropanol-water mixture (1:5, v/v), dried under a warm air flow at 40°C, to obtain 414 g (yield: 88.0%) of the title compound in the form of a white solid.Optical purity: > 99.9% ee Moisture content: 4.4~4.6% M.P.: 146.3-150.50C1H-NMR (300 MHz, CDCl3) δ (ppm) : 7.75(s, 4H), 7.45~6.09(m5 4H, ArH)5 5.39(s5 IH), 4.77(q, 2H)5 4.03(m, 2H), 3.85(m, 2H), 3.58(s, 3H), 3.35(m, 2H)5 3.05(q, 2H)5 2.50~2.20(m, 2H)52.38(s, 3H)5 2.10~1.80(m, 3H)5 1.75(m5 IH)5 1.38(m, IH), 1.15(t, 3H), 1.00(s5 3H)5 0.80(s5 3H)The crystalline state of the S-(-)-amlodipine (lS)-(+)-10-camsylate hydrate obtained was analyzed by X-ray diffraction spectroscopy (FIG. 1). The observed main peaks at characteristic diffraction angles are listed in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In water; isopropyl alcohol at 40℃; | 12 Example 12: Preparation of (lS)-(+)-camphorsulfonate of S-(-)-amIodipine10 g of S-(-)-amlodipine obtained in Example 11 was suspended in a mixed solvent of 30 ml of 2-propanol and 30 ml of water, and 5.7 g of (lS)-(+)- camphorsulfonate was added thereto, and the mixture was heated to 40 °C to obtain a homogenous solution. The resulting solution was cooled to room temperature, insoluble materials formed were removed by filtering, and 120 ml of water was added dropwise to the filtrate, and stirred for 4 hours. The precipitate formed was filtered, washed with a mixed solvent of 2-propanol and water (1/5, v/v) and dried at 40 °C , to obtain a hydrate form of the title compound as a white crystalline powder (14.5 g; yield: 88%). m.p.: 146 to 149 °C ; water content: 4.5 %; [ α ]D25: -7.2° (c=l .0, MeOH);S-(-)-amlodipine optical purity (chiral HPLC): 99.9 % ee;1H-NMR (CDCl3, ppm): δ 7.75 (s, 4H), 7.45-6.09 (m, 4H, ArH), 5.39 (s, IH), 4.77 (q, 2H), 4.03 (m, 2H), 3.85 (m, 2H), 3.58 (s, 3H), 3.35 (m, 2H), 3.05 (q, 2H), 2.50-2.20 (m, 2H)52.38 (s, 3H)52.10-1.80 (m, 3H)51.75 (m. IH)51.38 (m, IH)51.15 (t, 3H)51.00 (s, 3H)50.80 (s, 3H).IR(KBr, cm-1): 343I53395, 3077, 2953, 1748, 1691, 1643, 161I51438, 1289, 1206, 1099, 1041. |
84% | In tert-butyl methyl ether; isopropyl alcohol at 25℃; for 2h; | 3 16.8 g of an anhydrate of S-(-)-amlodipine (lS)-(+)-10-camsylate, which is a white crystalline solid, was produced using the same method as in Example 1, except that (lS)-(+)-10-camphorsulfonic acid was used instead of (lR)-(-)-10-camphorsulfonic acid (yield: 84%, water content: 0.20%).[73] The X-ray diffraction spectrum of the anhydrate of crystalline S-(-)-amlodipine(lS)-(+)-10-camsylate is shown in FIG. 2, and its elemental analysis data and melting point are given as follows.[74] - Elemental Analysis for C H ClN O S [found(%) (C: 56.11, H: 6.59, N: 4.36,J 30 42 2 9O: 22.42), calculated(%) (C: 56.21, H: 6.58, N: 4.40, O: 22.45)],[75] - m.p.: 94-990C. |
83% | In water at 25℃; for 2h; | 4 .63 g of an anhydrate of S-(-)-amlodipine (lS)-(+)-10-camsylate, which is a white crystalline solid, was produced using the same method as in Example 2, except that (lS)-(+)-10-camphorsulfonic acid was used instead of (lR)-(-)-10-camphorsulfonic acid (yield: 83%, water content: 0.25%).[80] The elemental analysis data and melting point of the anhydrate of crystalline S- (-)-amlodipine (lS)-(+)-10-camsylate are given as follows. [81] - Elemental Analysis for C3 H42ClN2O S [found(%) (C: 56.11, H: 6.59, N: 4.36, O: 22.42), calculated(%) (C: 56.46, H: 6.68, N: 4.42, O: 22.54)],[82] - m.p.: 94-990C |
81.5% | In hexane; tert-butyl methyl ether; isopropyl alcohol at 20℃; for 2h; | 2 Example 2: Preparation of S-f-Vamlodipine H S)-(V)- 10-camsylate anhydride; 5 g of (S)-amlodipine free base obtained in Preparation 2 was added to 25 ml of isopropanol, in which 2.85g of (lS)-(+)-10-camphor sulfonic acid was dissolved. To the resulting solution, 99 mi of methyl ?-butyl ether (MTBE) and 2 mi ofhexane were added and stirred at room temperature for 2 hours. The resulting solid was filtered under a nitrogen atmosphere and dried in vacuo, to obtain 6.4 g (yield: 81.5%) of the title compound in the form of a white solid.Optical purity: > 99.9% eeMoisture content: 0.3%M.P.: 145.5-149.4 °C1H-NMR data was the same as that in Example 1.The crystalline state of the S-(-)-amlodipine (lS)-(+)-10-camsylate anhydride obtained was analyzed by X-ray diffraction spectroscopy (FIG. 2). The observed main peaks at characteristic diffraction angles are listed in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 40 - 80℃; for 0.166667 - 1h;Resolution of racemate;Purification / work up; | Example 5Resolution of dl-alpha-m-HydroxyphenylethylmethylamineRacemic dl-alpha-m-Hydroxyphenylethylmethylamine (20 g) dissolved in Ethanol (300 ml) was added d-camphorsulphonic acid (33 g), and the reaction mixture was heated to 40-80 C. for 10-60 mins, and then Ethanol was distilled out completely under vacuum, the same operation was repeated twice with Ethanol (100 ml×2). Residual mass was added Ethyl acetate (250 ml) and distilled out. The residual mass was added i-Propanol (60 ml) and stirred for 2-3 days at 0-25 C. The precipitated solid was filtered (10-20 g).The camphorsulfonate thus obtained was dissolved in Sod. Carbonate soln and then extracted with Ethyl acetate (2×25 ml). Combined organic layer was distilled out and Cyclohexane (50 ml) was added to the residual mass and stirred for 10-30 mins. The solid material was then filtered and dried under vacuum at 40-80 C. (5-10 g) (m.p. 171 C. [alpha]D -68.0; c=5.0 in C5H5N) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 99 percent / thionyl chloride / DMF / 3 h / 20 °C 2: 100 percent / ammonium hydroxide / dioxane / 6 h / 20 - 95 °C 3: 66 percent / sodium borohydride / methanol; H2O / 1 h / 5 °C | ||
Multi-step reaction with 3 steps 1: SOCl2 2: NH3 / dioxane; H2O 3: 93 percent / NaBH4 / methanol; H2O | ||
Multi-step reaction with 2 steps 1: 1.) SOCl2, DMF, 2.) conc. NH3 / 1.) 115 deg C, 2.) 1,4-dioxane, a) RT, 2 h, b) 90 deg C, 4 h 2: 74 percent / NaBH4 / methanol; H2O / 5 °C |
Multi-step reaction with 4 steps 1: SOCl2 / 3 h / Heating 2: NH3 / CHCl3 / 7 h / 0 °C 3: 100 percent / 4 h / 170 °C 4: 85 percent / LiAlH4 / tetrahydrofuran / 12 h / 20 °C | ||
Multi-step reaction with 2 steps 1: SOCl2; aqueous NH3; concentrated aqueous HCl / aufeinanderfolgendes Behandeln 2: Raney nickel; ethanol / Hydrogenation | ||
Multi-step reaction with 2 steps 1.1: thionyl chloride / chloroform / 16.75 h / 80 °C 1.2: 3 h / 0 - 20 °C 1.3: Amberlyst 15 / 4 h / 100 °C / Dean-Stark 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 6 h / 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: SOCl2 2: NH3 / dioxane; H2O 3: 93 percent / NaBH4 / methanol; H2O 4: 85 percent / NaH / toluene; various solvent(s) / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In methanol; acetone; at 30 - 50℃; for 1.33333h;Heating / reflux; | 2.5 kg of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1 H- 1 ,2,4-triazol-1 yl)butan-2-ol was charged into a reactor containing 25 L of acetone. 1.65 kg of R-(-)-10-camphor sulphonic acid was added and heated to about 50 C. 12.5 L of methanol was added to the reaction mass to make a clear solution. It was then heated to reflux and maintained for 20 minutes. The reaction mass was then cooled to about 30 C and maintained for about 1 hour. The separated solid was centrifuged and washed with 2.5 L of chilled acetone. The obtained solid was dried at about 55-60 C under a vacuum of about 650 mm Hg for about 8 hours to yield 1.35 kg of the title compound as a crystalline solid. (Yield: 65.0%) |
Yield | Reaction Conditions | Operation in experiment |
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89% | In ethanol; ethyl acetate; at 30 - 50℃; for 0.916667h;Product distribution / selectivity; | Example 28: (S)-3-methyIamino-l-thiophen-2-yl-propan-l-ol l-(S)-(7,7-dimethyl-2- oxobicyclo[2.2.1]hept-l-yl)-methane sulfonate; A mixture of (5)-3-methylammo-l-thiophen-2-yl-propan-l-ol (34.2 g, 200 mmol) and ethyl acetate (400 mL) is heated to 30 C, then a mixture of (+)-camphor-10-sulfonic acid (46.4 g, 200 mmol), ethyl acetate (100 mL) and ethanol (100 mL) is added dropwise at 30 0C in 40 minutes. At the end of the addition, the resulting solution is heated to 50 0C, stirred for 15 minutes at that temperature, then cooled to 25 C. Once cold, the reaction mixture is concentrated to dryness and ethyl acetate (500 mL) is added to the residue. The resulting mixture is then heated to reflux, kept at that temperature for 15 minutes, then cooled to 25 C in 30 minutes while seeding the reaction mixture when the temperature reaches about 40 C. Once cold, the resulting suspension is stirred for 30 additional minutes. Afterwards, the precipitate is filtrated, washed with ethyl acetate (2*50 mL) and dried at 40 C under vacuum (20 mbar) for 15 h affording a white solid (71.5 g, 89%); 1H-NMR (CDCl3, 400 MHz) : 7.2 (1 H, dm), 7.0 (1 H, m), 6.9 (1 H, m), 5.21 (1 H, t), 3.3 (3 H, m), 2.82 (1 H, d), 2.75 (3 H, s), 2.50 (1 H, m, symm.), 2.3 (3 H, m), 2.1 (1 H, m), 2.0 (1 H, m), 1.85 (1 H, d), 1.74 (1 H, m, symm.), 1.4 (1 H, m), 1.04 (3 H, s), 0.82 (3 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 60 - 65℃; | EXAMPLE 1; Preparation of <strong>[122883-93-6]Ziprasidone</strong> Camphorsulfonate; A 2 liters round-bottom four necked flask, equipped with mechanical stirrer, reflux condenser and thermometer, is loaded with 61 g of ziprasidone free base and 1110 ml of methanol. The suspension is heated to a temperature of 60-65 C. and a solution of 36.03 g of (S) camphorsulfonic acid in 90 ml of methanol is added thereto, under stirring. The resulting suspension is cooled to a temperature of approx. 5-20 C., filtered on a Buckner funnel, the solid is washed with methanol (2×30 ml) on the filter and dried in a static dryer at a temperature of 50 C. to constant weight. 85 g (S) of ziprasidone camphorsulfonate are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.4% | In ethanol at 70℃; Heating / reflux; | 4 Into an apparatus equipped with an intensive stirrer 20 ml of anhydrous ethanol is added then it is heated to boiling. During reflux and intensive stirring Ig (2.2 mmoles) of aripiprazole is added and dissolved, then 0.55 g (2,2 mmoles) of l(S)-(+)- camphorsulfonic acid monohydrate is added at 70 0C. The mixture EPO is heated to its boiling point, then left to cool to room temperature. The precipitated crystalline product is filtered off, and washed with ethanol.Thus, 1.33 g (86.4%) of white crystals are obtained. Melting point: 190-192 °CAnalysis based on the chemical formula of C23H27Cl2N3O2 . C10H16O4S (680.70)Calculated: C: 58.23 H: 6 .37 Cl: 10.42 N: 6 .17Measured: C: 58.28 H: 6 .33 Cl: 10.32 N: 6 .26IR (KBr): 3252, 1739, 1700, 1186, 1030 cm -1HNMR (CDCl3, i500): 10.98 (b, IH), 8.73 (bs, IH), 7.23 (dd, J1=IJ Hz, J2=7.9 Hz, IH), 7.18 (~t, J=8.0 Hz, IH), 7.11 (dd, J1=IJ Hz, J2=7.9 Hz, IH), 7.01 (d, J=8.3 Hz, IH), 6.53 (d, J=2.3 Hz, IH), 6.48 (dd, h=2.5 Hz, J2=8.3 Hz, IH), 4.01 (t, J=6.0 Hz, 2H), 3.77 (m, 2H), 3.58 (m, 2H), 3.38 (m, 2H), 3.33 (d, J=14.5 Hz, IH), 3.25 (m, 2H), 3.09 (m, 2H), 2.89 (d, J=14.7 Hz, IH), 2.86 (t, J=7.7 Hz, 2H), 2.70 (m, IH), 2.58 (t, J=7.5 Hz, 2H), 2.32 (m, IH), 2.05 (m, 4H, 1.88 (m, 3H), 1.77 (m, IH), 1.37 (m, IH), 1.10 (s, 3H), 0.83 (s, 3H) ppm.CNMR: 217.03, 171.54, 158.10, 149.07, 138.53, 133.99, 128.49, 127.89, 127.57, 126.02, 119.59, 115.98, 108.75, 102.48, 67.17, EPO 58.44, 57.17, 52.38, 48.06, 47.94, 47.60, 42.93, 42.58, 31.04, 26.98, 26.25, 24.57, 20.82, 19.88, 19.79 ppm. |
Yield | Reaction Conditions | Operation in experiment |
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65.2% | Stage #1: (1S)-10-camphorsulfonic acid; imatinib In methanol at 20℃; for 1h; Activated carbon; Stage #2: In isopropyl alcohol at 20℃; for 1h; | 2 Example 2 : Preparation of imatinib D-(+)-camphorsulphonic acid salt[39] 5 g of4-[(4-methyl-l-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amin o]phenyl]-benzamide was added to 20 ml of methanol. While stirring, 2.4 g of D- (+)-camphorsulphonic acid and 0.1 g of activated carbon were slowly added thereto, and further stirred at room temperature for 1 hr. The solution was filtered, washed with 5 ml of methanol, and then distilled off under reduced pressure. Then, 50 ml of isopropanol was added thereto, and stirred at room temperature for 1 hr. The solid mixture was filtered and washed with 10 ml of isopropanol, and then dried under reduced pressure to give 4.8 g of solid (65.2%).[40] Melting point (m.p.): 130- 1320C |
Yield | Reaction Conditions | Operation in experiment |
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84% | In ethanol; at 20.0℃; for 1.0h; | Example 25 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide(1S)-(+)-10-camphorsulfonic acid salt A solution of <strong>[1142363-52-7]4-cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide</strong> (52.4 mg, 0.113 mmol, as prepared in Example 15, step (h)) in EtOH (2 mL) was treated with (1S)-(+)-10-camphorsulfonic acid (26.4 mg, 0.113 mmol) at room temperature for 1 h. The solvents were evaporated in vacuo, and the residue was dried under high vacuum overnight. The solid was dissolved in a minimum amount of EtOH (1 mL) with sonication and heating. While warm, the solution was slowly treated with hexanes until first precipitate was seen at the surface of the solution. The mixture was allowed to stir 30 min at room temperature while material continued to precipitate. The solid was filtered and air-dried to afford the title compound (66.2 mg, 84%) as white crystals. 1H-NMR (CD3OD; 400 MHz): delta 9.17 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.95 (d, 1H, J=8.4 Hz), 6.39-6.32 (m, 1H), 3.76-3.64 (m, 1H), 3.38-3.34 (m, 2H), 2.80-2.75 (m, 1H), 2.75-2.65 (m, 1H), 2.54-2.45 (m, 2H), 2.40-2.30 (m, 1H), 2.25-2.18 (m, 2H), 2.10-2.00 (m, 2H), 1.98-1.86 (m, 3H), 1.76-1.66 (m, 4H), 1.65-1.56 (m, 1H), 1.47-1.38 (m, 7H), 1.30 (s, 6H), 1.15 (m, 9H), 0.87 (s, 3H). Mass spectrum (APCI, m/z): Calcd. for C27H35N5O2, 462.3 (M+H), found 462.3. |
Yield | Reaction Conditions | Operation in experiment |
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In ethanol Heating; | 51 Example 51Preparation of (+)-(lS,3'R)-quinuclidin-3'-yl l-phenyl-l,2,3,4-tetrahydro- isoquinoline-2-carboxylate gentisic acid salt In a dry 25 mL round bottom flask ethanol (45 mL), (+)-(lS,3'R)-quinuclidin-3'- yl 1 -phenyl- 1, 2,3 ,4-tetrahydro-isoquinoline-2-carboxylate (5.0 g, % chiral purity > 97.5 % ) were taken. To the clear solution gentisic acid (2.13 g) was added. It was warmed and stirred for 60-120 min. The solvent was distilled out at reduced pressure to obtain the semi-solid mass.Toluene was added and distilled out. The above steps were repeated till solid salt was obtained (Wt.- 6.8 g)Similarly Solifenacin acid salt with following acids were prepared. Some of the salts of Solifenacin were obtained as liquid and some of the salts were obtained as solid. Results are summarized in the table as below:Table 8: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With [bis(acetoxy)iodo]benzene In tetrahydrofuran for 0.0333333h; ultrasound irradiation; | |
76% | With [bis(acetoxy)iodo]benzene; 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 24h; | |
38% | With ammonium iodide; 3-chloro-benzenecarboperoxoic acid In 2,2,2-trifluoroethanol; acetonitrile at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In water; isopropyl alcohol at 40℃; | 12 Example 12; Preparation of (1S)-(+)-camphorsulfonate of S-(-)-amlodipine10 g of S-(-)-amlodipine obtained in Example 11 was suspended in a mixed solvent of 30 ml of 2-propanol and 30 ml of water, and 5.7 g of (1S)-(+)-camphorsulfonate was added thereto, and the mixture was heated to 40° C. to obtain a homogenous solution. The resulting solution was cooled to room temperature, insoluble materials formed were removed by filtering, and 120 ml of water was added dropwise to the filtrate, and stirred for 4 hours. The precipitate formed was filtered, washed with a mixed solvent of 2-propanol and water (1/5, v/v) and dried at 40° C., to obtain a hydrate form of the title compound as a white crystalline powder (14.5 g; yield: 88%).m.p.: 146 to 149° C.;water content: 4.5%;[α]D25: -7.2° (c=1.0, MeOH);S-(-)-amlodipine optical purity (chiral HPLC): 99.9% ee;1H-NMR (CDCl3, ppm): δ 7.75 (s, 4H), 7.45-6.09 (m, 4H, ArH), 5.39 (s, 1H), 4.77 (q, 2H), 4.03 (m, 2H), 3.85 (m, 2H), 3.58 (s, 3H), 3.35 (m, 2H), 3.05 (q, 2H), 2.50-2.20 (m, 2H), 2.38 (s, 3H), 2.10-1.80 (m, 3H), 1.75 (m, 1H), 1.38 (m, 1H), 1.15 (t, 3H), 1.00 (s, 3H), 0.80 (s, 3H).IR (KBr, cm-1): 3431, 3395, 3077, 2953, 1748, 1691, 1643, 1611, 1438, 1289, 1206, 1099, 1041. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 5: Preparation of the d-camphorsulfonate salt of the hydroquinone of 17- AAGTheta ate[0077] <strong>[75747-14-7]17-AAG</strong> (0.30 g, 0.5 mmol, 1.0 equiv) is dissolved in DCM (6 mL) and stirred with a 10% aqueous solution of sodium hydrosulfite (3.5 mL). The solution is stirred for 60 minutes. The organic layer was collected, washed with brine, and 1.2 mL (calc 0.1 mmol of hydroquinone) transferred to a round bottom flask. This solution was put under nitrogen. To this solution was added a solution of d-camphorsulonic acid in denatured IPA (0.100 mmol of d-camphorsulonic acid in 0.25 mL of IPA) dropwise. The resulting mixture was allowed to stir under nitrogen for 1 hour, at which point the mixture was concentrated and the crude mass was reslurried from EtOAc/MTBE. The solid was collected by filtration and dried under reduced pressure to yield 0.051 g of the desired product 6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | In n-heptane; isopropyl alcohol at 20℃; Reflux; | 4 Example 4; (Rasagiline (+)-camphor-10-sulfonate) Racemic N-propargyl-1-aminoindane (25.65 g) was dissolved in 2-propanol (100 ml), and solution was heated to reflux temperature. To reaction mixture, a solution of (+)-camphor-10-sulfonic acid (17.4 g) in 2-propanol (20 ml) was slowly added. Reaction mixture was cooled to r.t., seeded with rasagiline (+)-camphor-10-sulfonate from example 3, and then 160 ml of heptane was slowly added and stirred at r.t. overnight to give rasagiline (+)-camphor-10-sulfonate (16.14 g, yield 27%, 97.00% R(+) enantiomer, melting point: 167 - 170°C) |
27% | In isopropyl alcohol Reflux; | 4 Racemic N-propargyl-1 -aminoindane (25.65 g) was dissolved in 2-propanol (100 ml), and solution was heated to reflux temperature. To reaction mixture, a solution of (+)- camphor-10-sulfonic acid (17.4 g) in 2-propanol (20 ml) was slowly added. Reaction mixture was cooled to r.t., seeded with rasagiline (+)-camphor-10-sulfonate from example 3, and then 160 ml of heptane was slowly added and stirred at r.t. overnight to give rasagiline (+)-camphor-10-sulfonate (16.14 g, yield 27%, 97.00% R(+) enantiomer, melting point: 167 - 170°C) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In methanol; at 20℃; for 1h; | (<strong>[136236-51-6]rasagiline</strong> (S)-camsylate, compound of the Formula VI) 500 mg (2.920 mmoles) of <strong>[136236-51-6]rasagiline</strong> base and 677 mg (2.915 mmoles) of (1 £)-(+)- 10-camphorsulfonic acid are dissolved in 1.0 ml of methanol at room temperature. The solution is stirred for an hour, then evaporated in vacuo and the residue is treated with diisopropyl ether. The solid product is filtered and washed with diisopropyl ether. Thus 1.094 g of a light yellow beige crude salt is obtained which is crystallized from 4.5 ml of hot isopropyl alcohol. The suspension thus obtained is cooled in an icecold water-bath. The precipitated crystals are filtered and finally washed with cold diisopropyl ether.Yield: 932 mg (79 %), off-white crystalsMelting point: 168.5-170.0 CElementary analysis for the Formula: C22H29N04S (403..54):Calculated [%] C: 65.48 H: 7.24 N: 3.47 S: 7.95 0: 15.86 Found [%] C: 65.33 H: 7.06 N: 3.36 S: 8.17IR (KBr): 3455, 3302, 2959, 2656, 1736, 1479, 1220, 1169,1038 cm"1.1H-NMR (DMS0-< 400 MHz) delta 9.46 (s, 2H), 7.61 (d, 1H, J = 7.5 Hz), 7.38 (m, 1H), 7.37 (m, 1H), 7.31 (m, 1H), 4.82 (dd, 1H, J - 7.7, 4.3 Hz), 4.02 (dd, 1H, J = 17.0, 2.5 Hz), 3.98 (dd, 1H, J - 17.0, 2.5 Hz), 3.76 (t, 1H, J = 2.5 Hz), 3.1 1 (m, 1H), 2.90 (m, 1H), 2.89 (d, 1H, J = 14.8 Hz), 2.68 (m, 1H), 2.44 (m, 1H), 2.39 (d, 1H, J = 14.8 Hz), 2.23 (m, 1H), 2.21 (m, 1H), 1.94 (t, 1H, J = 4.5 Hz), 1.86 (m, 1H), 1.79 (d, 1H, J = 18.5 Hz), 1.29 (m, 1H), 1.27 (m, 1H), 1.05 (s, 3H), 0.74 (s, 3H) ppm.HPLC purity: >99.8%[a] 22D =+36.7 (c=l; EtOH) |
In n-heptane; isopropyl alcohol; | Example 3; (Rasagiline (+)-camphor-1 0-sulfonate) Rasagiline base (0.50g) was dissolved in 2-propanol (10 ml) and was combined with solution of (+)-camphor-10-sulfonic acid (0.68 g) in 2-propanol (5 ml). To this combined solution 20 ml of heptane was slowly added, and left to evaporate slowly. After several hours crystals of <strong>[136236-51-6]rasagiline</strong> (+)-camphor-1 0-sulfonate formed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; for 0.833333h;Reflux;Product distribution / selectivity; | Example 4: Preparation of an S-camsylate Salt of Compound 1., S-camsylate Polymorph Form A, Using Tetrahydrofuran.Compound (20 g) was slurried at reflux in tetrahydrofuran (42 ml.) and water (40 ml.) in a jacketed reaction vessel with overhead stirring, and remained as a free base slurry. S-camphor sulfonic acid solution (17.25 g in 20 ml. of water) was added slowly over approximately 10 minutes, to form a clear yellow solution, which was held at reflux for 30 minutes. Water (135 ml.) was then added, over approximately 20 minutes, maintaining reflux. The resulting yellowish slurry was cooled to 10 C and granulated at this temperature to improve crystallinity and yield for a suitable amount of time. Suitable granulation times can be chosen by one of skill in the art. Typical granulation times can range, for example, from about 1 hour to about 48 hours. Filtered solids were washed with chilled water (20 ml.) and dried under vacuum at 50 C to give the final product. | |
for 2.5h; | 56 mg of <strong>[283173-50-2]Rucaparib</strong> Form II and 44 mg of 1 S-(+)-camphor-10- sulphonic acid are placed in an agate jar with 4 agate balls and milled on a rotation ball mill for 2.5 hours. The prepared sample was analyzed by XRD. The XRD pattern is given in Figure 47. | |
In 1,4-dioxane; water; at 30℃; for 12h; | Example 5 Preparation of <strong>[283173-50-2]Rucaparib</strong> Camsylate Form Alpha <strong>[283173-50-2]Rucaparib</strong> base (0.2 g) and S-camphorsulfonic acid (0.14 g) were dissolved in a 1,4-dioxane-water (1:1; 6 mL) mixture at 30 C. The clear solution was stirred at 30 C. for 12 h. The resulting product was filtered and dried at 50 C. under vacuum for 2 h. The resulting product was identified as crystalline (S)-<strong>[283173-50-2]rucaparib</strong> camsylate salt Form alpha. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2,2,2-trifluoroethanol; at 40℃; for 4h;Product distribution / selectivity; | [00224] <strong>[641571-10-0]Nilotinib</strong> base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40C to obtain a mixture. The mixture was stirred and added to a solution of (S)-camphor- sulfonic acid (0.132g, 0.57mmol) in TFE (1 mL) at 40C. The resulting clear solution was stirred for about 4 h at 40C and it was subsequently cooled to 5C. The mixture was kept at 5C overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered and the filter cake was dried at 40C in a vacuum oven overnight to give <strong>[641571-10-0]Nilotinib</strong> camphorsulfonate form I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetone; at 20 - 58℃;Industry scale; Resolution of racemate; | (S)-Nipecotic acid-(S)-Camphorsulfonate saltChiral resolution of (S) Nipecotic acid from commercial racemic mixtureTo a solution of (S)-camphorsulfonic acid (18kg, 77mol) in acetone (127kg) at 55- 58 C, a solution of (R,S)-<strong>[498-95-3]nipecotic acid</strong> (10kg, 77mol) in water (20kg) was quickly charged. The mixture was maintained at 55-58 C until all solids were dissolved. The solution was slowly cooled to 20-25 C to precipitate the salt, then stirred overnight, and isolated. To further increase the diastereomeric purity, the resulting salt was re- crystallized from acetone (16kg) and water (4kg) at 55-58 C. Again, the hot solution was cooled to 20-25 C, stirred overnight, and isolated to give the purified (S)-<strong>[498-95-3]nipecotic acid</strong>-(S)-camphorsulfonate salt (14kg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | General procedure: Crystals of (I) suitable for X-ray diffraction were obtained by disssolving <strong>[139264-17-8]zolmitriptan</strong> (SMS Pharma Research Centre, Hyderabad) and oxalic acid (1:1 v/v) in methanol-water (85:15 v/v, 20 ml) and allowing the solution to evaporate slowly. Crystals of (II) were obtained by slow evaporation of a solution of <strong>[139264-17-8]zolmitriptan</strong> and (S)-camphorsulfonic acid (1:1 v/v) in methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With barium(II) perchlorate In methanol Resolution of racemate; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In dichloromethane; for 1.0h;Inert atmosphere; | General procedure: A round-bottomed flask equipped with a stir bar was charged with (R,R)-(-)-N,N?-Bis(3,5-di-tertbutylsalicylidene)-1,2-cyclohexanediaminocobalt(II) (S19) (500 mg, 0.828 mmol). CH2Cl2 (10mL) was added, and the mixture stirred until complete dissolution had been achieved. (1S)-(+)-10-camphorsulfonic acid (202 mg, 0.870 mmol) was added, and the resulting black solution was stirred vigorously open to the air for 1 h. Solvent was removed via rotary evaporation followedby high vacuum. The solid product was washed with n-pentane (500 mL) on a Buechner funnel.Residual solvent was removed under high vacuum. Isolated 436 mg (62%) of a brown powder. The catalyst was used without further characterization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.8% | In acetone at 20℃; for 24h; | 3 Example 3 Lapatinib (l,SV(+ -camphorsulfonic acid salt (1 :1) Example 3 Lapatinib (l,SV(+ -camphorsulfonic acid salt (1 :1) Into an apparatus 30 cm3 acetone is weighed in whereupon 0.885 g (1.52 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the hot solution under stirring 0.381 g (1.52 mmol) (15)-(+)-camphorsulfonic acid monohydrate in 10 cm3 acetone is added. The reaction mixture is allowed to cool to room temperature under stirring, then 15 cm3 tert- butyl methyl ether is added thereto and further stirred. Slowly crystals start to appear then it is stirred for 24 hours under room temperature then for a further one hour under external ice/water cooling. The precipitated crystalline product is filtered and washed with a little cold acetone and tert-butyl methyl ether. Yield: 1.110 g (89.8 %). Melting point: 123.0-130.8 °C 1H-NMR (DMSO-d6, 500 MHz): 10.07 (b, 1H), 9.40 (b), 8.88 (d, J=1.5 Hz, 1H), 8.61 (s, 1H), 8.25 (dd, Ji=1.7 Hz, J2=8.6 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.75 (dd, Ji=2.6 Hz, J2=9.0 Hz, 1H), 7.48 (m, 1H), 7.34 (m, 1H), 7.33 (m, 1H), 7.30 (d, J=9.0 Hz, 1H), 7.18 (m, 2H), 6.85 (d, J=3.5 Hz, 1H), 5.28 (s, 2H), 4.43 (s, 2H), 3.61 (m, 2H), 3.45 (m, 2H), 3.14 (s, 3H), 2.99 (d, J=14.6 Hz, 1H), 2.62 (m, 1H), 2.48 (d J=14.1 Hz, 1H), 2.24 (m, 1H), 1.93 (m, 1H), 1.82 (m, 2H), 1.35 (m, 1H), 1.25 (m, 1H), 0.99 (s, 3H), 0.72 (s, 3H). 13C-NMR (DMSO-t, 125 MHz): 216.20, 162.36 (d, J=243.7 Hz), 158.3, 154.33, 153.55, 150.24, 148.21, 146.60, 139.78 (d, J=7.3 Hz), 132.88, 130.70 (d, J=8.3 Hz), 129.18, 128.00, 127.86, 124.82, 123.43 (d, J=2.4 Hz), 123.05, 121.29, 117.73, 115.33, 114.83 (d, J=21.0 Hz), 114.70, 1 14.47, 114.13 (d, J=22.0 Hz), 108.27, 72.19, 69.59, 58.27, 50.02, 48.85, 47.25, 47.02, 43.09, 42.37, 42.23, 40.95, 26.97, 26.53. |
Yield | Reaction Conditions | Operation in experiment |
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75 g | In isopropyl alcohol; at 20℃; for 1h; | 1000ml three bottles, a solution of D-CSA (58 g, 0.25 mol) in 116 ml of isopropanol was added dropwise to 478 ml of isopropanol, and the mixture was stirred at room temperature for 1 hour to precipitate a solid. 0 C for 2 hours, filtered, washed with cold isopropanol (30 ml) and dried to give 75 g of (R) -<strong>[14813-01-5]1-benzyl-<strong>[14813-01-5]3-hydroxypiperidine</strong></strong> camphorsulfonate. (Ee: 95%) (theory: 105.9 g). (R) -<strong>[14813-01-5]1-benzyl-<strong>[14813-01-5]3-hydroxypiperidine</strong></strong> camphorsulfonate having a 95% ee value was recrystallized from 3-fold amounts of isopropanol to give (R) -1-benzyl- Camphorsulfonate (99% ee). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane;Heating; Resolution of racemate; | 10 mg of the racemic amine of formula 2a is weighed into a reaction vial, 100 al of the respective (methanol, ethanol, acetone, acetonitrile, ethyl acetate, toluene, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane, or their mixtures with water) solvent is added and the mixture is moderately heated up until all the amine of formula 2a is dissolved. Then, 0.5, or 1.0 molar equivalent of the respective resolution agent is added and the mixture is reheated to produce a clear solution. The reaction vial is closed and left to cool down to the room temperature. The formation of possible crystalline salts is monitored after 2,4, 6, 24 and after 48 hours. Possible crystalline material and mother liquors are analyzed by means of HPLC. |
Yield | Reaction Conditions | Operation in experiment |
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In isopropyl alcohol; | General procedure: To lOg of Ledipasvir in 50mL of ethyl acetate; 4.2g of p-toluene sulfonic acid was added and the reaction mixture was stirred. The generated solid was isolated byfiltration and washed with ethyl acetate to obtain 10.5g of ditosylate salt of ledipasvir? |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; tert-butyl methyl ether;Reflux; Inert atmosphere; | A mixture of <strong>[1223403-58-4](S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide</strong> (0.500 g, 1.17 mmol) and S-(+)-camphorsulfonic acid (0.271 g, 1.17 mmol) in EtOH (3 mL, 200 proof) and MTBE (5 mL) was heated to reflux while stirring to obtain a solution. Upon cooled to ambient temperature, precipitation appeared. The suspension was stirred at room temperature for overnight, then vacuum-filtered, with the filter cake rinsed with MTBE and dried under vacuum at 55 C. to constant weight, yielding crystalline <strong>[1223403-58-4](S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide</strong> ((1 S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.72 g | In hexane at 20℃; for 20h; Inert atmosphere; | 2 Preparation of ticagrelor camphorsulfonic acid salt 10.0 g of ticagrelor and 4.45 g of (+)-10-camphorsulfonic acid were added to 200 mL of heptane under nitrogen,And the mixture was stirred at room temperature for 20 hours.After salt formation, by filtration under nitrogen,The resulting solid was vacuum-dried at 30°C for 16 hours to give 13.72 g of ticagrella camphor sulfonate. |
Yield | Reaction Conditions | Operation in experiment |
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In ethanol at 5 - 50℃; for 20h; | 9 Example 9 - Preparation of Forms A and B of Compound 8 Form A of compound 8 was prepared as follows. [00516] Compound A was dissolved in EtOH (10 vol, 500 μ) at ambient conditions. The solution was heated to 50° C, then treated with camphorsulfonic acid (1.0 mol eq. added as a stock solution, 1M). A cooling ramp was applied from 50° C to 5° C at 0.1° C/min. After 20 hours, the solution was treated with antisolvent (TBME, 4 ml) at ambient conditions. If no solid was obtained post cooling, then antisolvent solutions were filtered, air dried and the attained solid was further analyzed by the appropriate techniques. [00517] Characterization of the resulting material demonstrated a crystalline, anhydrous Form A. [00518] Table 12, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form A of compound 8. [00519] Figure 22 depicts an XRPD pattern of Form A of compound 8. [00520] Figure 23 depicts a DSC thermogram and TGA trace of Form A of compound 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | In acetone; at 20℃; for 1h;Cooling with ice; | <strong>[14252-80-3]Bupivacaine</strong> (1g, 3.46mmol)And D-camphorsulfonic acid (850mg, 3.66mmol)Soluble in 30ml acetone,Heat to dissolve,Slowly drop to room temperature and crystallize in ice water bath for 1h,Filter, the filter cake is dried in vacuum at 60 760mg solid is bupivacaine camphorsulfonate,The yield was 41%.Nuclear magnetic resonance (NMR) analysis confirmed that the molar ratio of bupivacaine to camphorsulfonic acid was 1: 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.4% | In tert-butyl methyl ether; at 15 - 50℃; | <strong>[284461-73-0]4-{4-[([4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide</strong> (10.0 g, 21.51 mmol ) and 2-methoxy-2-methylpropane (200 mL) was added to the reactor. (+)-10-Camposulfonic acid (5.25 g, 22.59 mmol) was added, followed by stirring at room temperature for 30 minutes. The reaction solution was stirred at 50 C for 30 minutes or more, cooled to 15 to 25 C and stirred for 2 hours or more. After filtering the reaction mixture under reduced pressure, the wet cake was washed with 2-methoxy-2-methylpropane (30 mL), and the obtained solid was vacuum dried at 50 to 60 C to prepare in Example 3. 49.80 g of compound was obtained (yield: 99.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; n-heptane at 20℃; for 48h; | 1 General procedure: Base on the solubility test results shown in Table 1, five solvent systems, each a two-solvent mixture, were used in this study. See Table 2 below. Each of twelve chiral organic acids, listed in Table 2, was screened for in-situ precipitation of a (S)-(+)-hydroxychloroquine salt by dissolving the salt-free form of (±)-hydroxychloroquine in each of the five solvent systems to form a solution at a concentration of 40 mg/mL and then adding an equimolar chiral organic acid, in solid form, to 0.5 mL of the solution. The reaction solution was stirred at room temperature for 2 days. |
Tags: 3144-16-9 synthesis path| 3144-16-9 SDS| 3144-16-9 COA| 3144-16-9 purity| 3144-16-9 application| 3144-16-9 NMR| 3144-16-9 COA| 3144-16-9 structure
A108406[ 35963-20-3 ]
((1R,4S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
Reason: Optical isomers
[ 5872-08-2 ]
(7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
Similarity: 1.00
[ 98673-87-1 ]
((1S,4R)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid hydrate
Similarity: 1.00
[ 35963-20-3 ]
((1R,4S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
Similarity: 1.00
[ 21791-94-6 ]
Sodium ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate
Similarity: 0.98
[ 5872-08-2 ]
(7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
Similarity: 1.00
[ 98673-87-1 ]
((1S,4R)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid hydrate
Similarity: 1.00
[ 35963-20-3 ]
((1R,4S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
Similarity: 1.00
[ 73413-79-3 ]
((1S,4S)-7,7-Dimethyl-2,3-dioxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
Similarity: 0.95
[ 5872-08-2 ]
(7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
Similarity: 1.00
[ 98673-87-1 ]
((1S,4R)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid hydrate
Similarity: 1.00
[ 35963-20-3 ]
((1R,4S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid
Similarity: 1.00
[ 21791-94-6 ]
Sodium ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate
Similarity: 0.98
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