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CAS No. : | 54-05-7 | MDL No. : | MFCD00024009 |
Formula : | C18H26ClN3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WHTVZRBIWZFKQO-UHFFFAOYSA-N |
M.W : | 319.87 | Pubchem ID : | 2719 |
Synonyms : |
NSC-187208;CHQ;CQ
|
Num. heavy atoms : | 22 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 8 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 97.41 |
TPSA : | 28.16 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -4.96 cm/s |
Log Po/w (iLOGP) : | 3.95 |
Log Po/w (XLOGP3) : | 4.63 |
Log Po/w (WLOGP) : | 4.62 |
Log Po/w (MLOGP) : | 3.2 |
Log Po/w (SILICOS-IT) : | 4.32 |
Consensus Log Po/w : | 4.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.55 |
Solubility : | 0.00905 mg/ml ; 0.0000283 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.95 |
Solubility : | 0.00361 mg/ml ; 0.0000113 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -6.92 |
Solubility : | 0.0000386 mg/ml ; 0.000000121 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.76 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
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Using this method the following compounds were prepared. 1. Verapamil 2. Isoniazid 3. Chloroquine 4. Tamoxifen 5. Ibuprofen 6. Propranolol 7. Glyburide |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; In water; | All materials were purchased from Sigma-Aldrich, with the exception of hemin (Cl-Fe(III)PPIX, Fluka) and D2O (Merck). Reagents were of analytical grade and were used without further purification. Unless otherwise stated, the CQ used was the diphosphate salt. The free base form of CQ was prepared from the diphosphate salt by adding 2 M NaOH to an aqueous CQ solution (0.2 M) and extracting the resultant free base into dichloromethane. The organic layer was separated, dried over MgSO4 and removed under vacuum. The resulting oil was dried over phosphorous pentoxide, washed with a small quantity of diethyl ether and dried once more under vacuum. This afforded CQ free base as a white solid. All Fe(III)PPIX solutions were freshly prepared and stored in the dark until use. To avoid buildup of adsorbed Fe(III)PPIX, all apparatus that came into contact with Fe(III)PPIX were scrupulously washed as previously described [28]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In aq. buffer; at 25℃;pH 7.4; | Job plots were conducted in triplicate by varying the mole fraction of Fe(III)PPIX and CQ in the same aqueous solvent system used for spectrophotometric titrations, subject to the constraint that the total additive concentration of Fe(III)PPIX and CQ remained 0.2 mM. The stock Fe(III)PPIX solution (2 mM in 0.015 M NaOH) and CQ solution (2 mM in 0.2 M HEPES) were used to make fifteen working solutions with Fe(III)PPIX mole fractions of 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.50, 0.40, 0.30, 0.20, 0.10 and 0.00. The working solutions consisted of (i) a combined volume of CQ and Fe(III)PPIX solutions of 0.1 mL (individual volumes based on the mole fraction required); (ii) an aliquot of HEPES buffer (0.2 M, pH 7.4) equal to the difference in volume between 0.1 mL and the volume of CQ solution added; (iii) an aliquot of NaOH (0.015 M) equal to the difference in volume between 0.1 mL and the volume of Fe(III)PPIX solution added; and (iv) 0.8 mL water. Solutions gave a measured pH in the range 7.5-7.6. The UV-visible spectrum of each solution was recorded in a 0.1 cm pathlength quartz cuvette at 25.0 or 30.0 ± 0.2 C and analyzed at 370 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: A solution of the precursor (0.25 mmol) with an excess of NH4PF6 (0.50 mmol) in methanol (25 mL) was stirred for 1 h. CQ (0.50mmol), also dissolved in methanol (10 mL), was added to this solution, and the mixture was stirred under reflux for 24 h. The orange-red solutionthat was obtained was dried under vacuum, dissolved in dichloromethane, and the precipitate filtered off. The orange-red solution was dried under vacuum to obtain an orange-red solid, which was washed with diethyl ether (3 × 30 mL) and dichloromethane and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | General procedure: A solution of the precursor (0.25 mmol) with an excess of NH4PF6 (0.50 mmol) in methanol (25 mL) was stirred for 1 h. CQ (0.50mmol), also dissolved in methanol (10 mL), was added to this solution, and the mixture was stirred under reflux for 24 h. The orange-red solutionthat was obtained was dried under vacuum, dissolved in dichloromethane, and the precipitate filtered off. The orange-red solution was dried under vacuum to obtain an orange-red solid, which was washed with diethyl ether (3 × 30 mL) and dichloromethane and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | General procedure: A solution of the precursor (0.25 mmol) with an excess of NH4PF6 (0.50 mmol) in methanol (25 mL) was stirred for 1 h. CQ (0.50mmol), also dissolved in methanol (10 mL), was added to this solution, and the mixture was stirred under reflux for 24 h. The orange-red solutionthat was obtained was dried under vacuum, dissolved in dichloromethane, and the precipitate filtered off. The orange-red solution was dried under vacuum to obtain an orange-red solid, which was washed with diethyl ether (3 × 30 mL) and dichloromethane and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: A solution of the precursor (0.25 mmol) with an excess of NH4PF6 (0.50 mmol) in methanol (25 mL) was stirred for 1 h. CQ (0.50mmol), also dissolved in methanol (10 mL), was added to this solution, and the mixture was stirred under reflux for 24 h. The orange-red solutionthat was obtained was dried under vacuum, dissolved in dichloromethane, and the precipitate filtered off. The orange-red solution was dried under vacuum to obtain an orange-red solid, which was washed with diethyl ether (3 × 30 mL) and dichloromethane and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With D-tartaric acid; trimethylamine-borane; In dichloromethane; at 20 - 60℃; for 21.5h; | The reaction product of the process and is similar to the processing described in Example 1, except that: the solvent, the reducing agent and chiral reagents were: 240 mL of dichloromethane (140mL flask with three, constant pressure funnel with 100mL), 10.2g (0.14 mol) of borane trimethylamine complex and 2.1g (0.014mol) (D) - tartaric acid. After 4-amino-7-chloro-quinoline and <strong>[105-14-6]5-diethylamino-2-pentanone</strong> was slowly added dropwise to a mixture of reducing agent and by a constant pressure funnel chiral agent is continued at room temperature for 1.5h, the reaction temperature insulationIs 60 , incubation time 20h. The product is (+) - (S) - chloroquine 16.2g, 50% yield; HPLC analysis handled enantioselectivity, ee% = 85%, [alpha] 20.5D = + 90.3 (c = 1.00, EtOH) . | |
With L-Tartaric acid; tetrabutylammonium (cyano)trihydroborate; In N,N-dimethyl-formamide; at 20 - 60℃; for 15.5h; | The reaction product of the process and is similar to the processing described in Example 1, except that: the solvent, the reducing agent and the chiral agent are:160mL dimethylformamide (three-neck flask with 100mL, constant pressure funnel with 60mL),45.1g (0.16mol) tetrabutyl ammonium borane cyanoAnd 2.4g (0.016mol) (L) - tartaric acid. 4-amino-7-chloro-quinoline and5- diethylamino-2-pentanone was slowly dropped from the constant pressure funnelAfter a mixture of a reducing agent and a chiral agent continued at room temperature for 1.5h, the reaction temperature insulation is 60 , incubation time 14h. The product as a brown solid (-) - (R) - chloroquine (Formula 2) 11.8g, yield 36.5%; enantioselective chiral HPLC analysis, ee% = 68% To 500mL with constant pressure funnel and reflux condenser, three-necked flask200mL of tetrahydrofuran (solvent), 2.64g (0.12mol) of lithium borohydride (reducing agent) and 4.18g (0.012mol) (+) - BINOL phosphate (chiral agent), stirred at room temperature 10min, a mixed solution, to the constant pressure funnel was added 17.8g (0.1mol) 4- amino-7-chloroquinoline, 15.7g (0.12mol) 5- diethylamino-2-pentanone and 100mL of tetrahydrofuran was slowly added dropwise by a constant pressure funnel mixed solution (about 30min), after the dropping, the reaction continued at room temperature for 1h, then warmed to 50 deg.] C the reaction was kept. The reaction monitored by TLC, the reaction was completed (the present embodiment requires 16h), cooled to room temperature, the reaction system was added 400mL saturated brine, and then extracted with ethyl acetate, each 150 mL, and extracted 3 times. Obtained by extraction of the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation and dried (vacuum degree 10KPa, the operating temperature of 40 deg.] C), was added containing 200g of silica gel (200-300 mesh) column chromatography, eluting with agent of (acetone: methanol: triethylamine volume ratio = 50:: 501) and other elution, TLC detection, the same as the combined effluent solvent was removed by rotary evaporation (vacuum degree 10KPa, operating temperature of 40 ) to give a brown solid, acetone was then added and methanol mixed solvent (acetone: methanol volume ratio = 70: 30, where methanol can be replaced with ethanol or isopropyl alcohol), at reflux, a mixed solvent is gradually added to just dissolve the solid product, reflux was continued for 30min after standing, cooling, filtration, 40 dried. As a yellow solid (+) - (S) - chloroquine (Formula 1) 21.7g, 68% yield. Melting point: 65 ~ 67 , product enantioselective chiral HPLC analysis, ee% = 92%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The light yellow oily chloroformate (92 mg, -0.2 mmol) was dissolved in 0.3 mL CH2C12and added to a mixture of K2C03(138.2 mg, 1 mmol) and chloroquine (CQ) (63.8 mg, 0.2 mmol) in dry CH2C12(0.8 mL) at 0C under Ar. After obeing stirred for 1.5 hr at 0 C, the reaction mixture was filtered and the solids washed with 3 mL dry CH2CI2. The filtrate was transferred to a dry 25 mL round bottom flask under Ar at 0 C followed by dropwise addition of TMS-Br (122.5 mg, 0.8 mmol). After 20 min, the reaction was allowed to warm to rt for 24 hr. The volatiles were evaporated in vacuo. The residue was dissolved in CH OH (8 mL) and then concentrated in vacuo. This procedure was repeated 4 additional times to obtain dark brown oil. The resulting oil was dissolved in EtOH (1 mL) followed by addition to 10 mL of Et20 resulting in formation of a brownish-white precipitate. The solid was isolated by filtration and dried under high vacuum overnight affording 148 mg (90- 100%) of 3 (BTCQ 1) (CH3OH-H2O solvate) a white solid havinglNMR (500 MHz, D20) 5 8.25 (s, 1H), 8.18 (d, J = 5 Hz, 1H), 7.79 (1H), 7.59 (d, J= 10 Hz, 1H), 6.80 (s, 1H), 4.44-4.40 (m, 1H), 4.09 (m, 1H), 3.72 (t, J= 5 Hz, 2H), 3.15 (m, 6H), 2.40 (m, 2H), 2.01 (t, J = 5 Hz, 2H), 1.81 (m, 4H), 1.36 (d, J = 5 Hz, 3H), 1.20 (m, 6H);1C NMR (400 MHz, D20) delta 177.67, 174.86, 155.36, 142.07, 139.17, 138.11, 127.18, 124.01, 119.02, 115.18, 98.39, 60.74, 51.06, 47.23, 32.27, 31.81, 30.26, 27.53, 20.15, 18.68, 17.38, 8.09;1P NMR (400 MHz, D20) delta -1.85; MS (ESI) m/z (M+H+) 623.0, 625.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | An oven dried round bottom flask was charged with the solution of rac- chloroquine in anhydrous dichloromethane (0.15 g, 0.47 mmol in 2 mL). Potassium carbonate (0.347 g, 2.24 mmol) was added and the white suspension was cooled to 0C. A solution of chloroformate in anhydrous dichloromethane (0.265 g, 0.47 mmol in 0.3 mL) was added and the contents were stirred at 0 C for 2 h. The reaction mixture was diluted with dichloromethane (10 mL) and the contents were filtered. The filtrate was concentrated under reduced pressure and the crude mixture was taken to the next step without purification. An oven dried round bottom flask was charged with a solution of crude mixture from previous step in anhydrous dichloromethane (0.3 g, 0.379 mmol in 2 mL). After cooling to 0 C, neat trimethylsilyl bromide (0.25 mL) was added and the contents were gradually warmed to room temperature and stirred for 24 h. Thereaction mixture was concentrated under reduced pressure and the crude mixture was dissolved in anhydrous methanol (10 mL). After stirring at room temperature for 10 min, the reaction mixture was concentrated under reduced pressure. The above process was repeated twice and the crude mixture was washed with diethyl ether (3 times) to yield rac-(13-(7-chloroquinolin-4-yl)-18-ethyl-14-methyl-3,12-dioxo-l l-oxa- 2,13,18-triazaicosane-l,l-diyl)diphosphonic acid (0.285 g, 93 %) as lemon yellow powder.Thermo-MS (ESI)m/z(M+ H)Cald forC28H45CIN4O9P2: 680.08, found:680.08delta 8.63 (d, J= 5 Hz, 1H), 8.51-8.39 (m, 1H), 7.84 (s, 1H),17.63 (d, J= 5 Hz, 1H), 6.98-6.91 (m, 1H), 4.61-4.54 (m,H-NMR (400 MHz, CDC13)1H)4 23-4.11 (m, 2H), 3.32-3.11 (m, 7H), 2.31-2.22 (m,2H), 1.99-1.74 (m, 6H), 1.63-1.53 (m, 2H), 1.43-1.33(m, 4H), 1.31-1.18 (m, 12H).delta 177.63, 174.82, 155.21, 143.11, 138.71, 138.57,13C-NMR (100 MHz, CDCl3) 127.11, 126.10, 119.21, 115.51, 99.07, 69.05, 52.17,48.07, 46.53, 43.01, 35.95, 35.71, 34.31, 32.43, 28.84,25.51, 23.71, 20.01, 16.13, 11.15.1P-NMR (400 MHz, CD3OD)delta 1557^ 15 45 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
An oven dried round bottom flask was charged with a solution of tetraethyl (2-(4-hydroxyphenyl)ethane-l,l-diyl)bis(phosphonate) in anhydrous dichloromethane (0.15 g, 0.38 mmol in 1 mL). Neat N-ethyl-N-isopropylpropan-2- amine (0.13 mL, 0.76 mmol) was added and the contents were cooled to 0C. Neat diphosgene (0.09 mL, 0.76 mmol) was added drop wise and the contents were stirred at 0C for 2 h. The reaction mixture was concentrated under reduced pressure and dried under high vacuum for 2h.An oven dried round bottom flask was charged with a solution of rac- N4-(7-chloroquinolin-4-yl)-N1^V1-diethylpentane-l,4-diamine in anhydrous dichloromethane (0.097 g, 0.304 mmol in 1 mL). Preactivated potassium carbonate (0.262 g, 1.9 mmol) was added and the contents were cooled to 0 C. A solution of chloroformate in anhydrous dichloromethane (0.17g, 0.38 mmol in 0.3 mL) was added drop wise and the contents were stirred at 0C for 3 h. The reaction mixture was diluted with anhydrous dichloromethane (10 mL) and filtered. The filtrate was concentrated under reduced pressure and redissolved in anhydrous dichloromethane (1 mL). Neat trimethylsilyl bromide (1 mL) was added and the contents were stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and the crude mixture was dissolved in 10 mL methanol and stirred at room temperature for 5 min. The organic layer was concentrated under reduced pressure and this procedure was repeated three times to yield colored solid. The solids were washed with cold diethyl ether and cold dichloromethane to yield rao(2-(4-(((7- chloroquinolin-4-yl)(4-(diethylamino)butyl)carbamoyl)oxy)phenyl)-ethane-l,l- diyl)diphos-phonic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
An oven dried round bottom flask was charged with a solution of rac- N4-(7-chloroquinolin-4-yl)-N1^V1-diethylpentane-l,4-diamine in anhydrous dichloromethane (57 mg, 0.18 mmol in 1 mL). Preactivated potassium carbonate (0.124 g, 0.9 mmol) was added in one portion and the contents were cooled to 0C. A solution of chloromethyl formate in anhydrous dichloromethane (90 mg, 0.18 mmol in 0.5 mL) was added drop wise and the contents were stirred at 0C for 1 h. The reaction mixture was diluted with anhydrous dichloromethane and filtered. The filtrate was concentrated under reduced pressure to yield colorless oil which was dried under reduced pressure for 2 h.An oven dried round bottom flask was charged with a solution of crude mixture (from previous step) in anhydrous dichloromethane (1 mL). Neattrimethylsily bromide (1 mL) was added and the contents were stirred at room temperature for 24 h. After concentrating under reduced pressure, the reaction mixture was dissolved in methanol and stirred for 5 min. The organic layer was concentrated under reduced pressure and this procedure was repeated three times to yield colored solid. The solids were washed with cold diethyl ether and cold dichloromethane to yield rac-((4-((((7-chloroquinolin-4-yl)(5-(diethylamino)pentan-2- yl)carbamoyl)oxy)methyl)benzamido)meth-ylene)diphosphonic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.32% | With phosphoric acid In ethanol | 1.3; 1.4; 2.3; 2.4; 33; 3.4; 5.3; 5.4; 1.3; 1.4; 2.3; 2.4; 3.3; 3.4 (3) Preparation of chloroquine phosphate 338.5 g of chloroquine (1.06 mol) and 90 mL of ethanol were mixed, 150 mL of phosphoric acid (85%, 1.30 mol) was added dropwise, and the reaction was incubated. After the reaction was completed, 502.3 g of crude chloroquine phosphate was obtained by filtration. (4) Refining of chloroquine phosphate 502.3 g of crude chloroquine phosphate was heated to dissolve in 200 ml of ethanol, stirred in an ice-water bath to crystallize, filtered and dried to obtain 458.2 g of chloroquine phosphate with a yield of 80.32% and a liquid chromatography purity (HPLC): 98.44%. |
66.11% | With phosphoric acid In ethanol at 60 - 65℃; | 1-3; 1-2 Salt formation: Add 65.3 g of crude chloroquine to 196 g of 80% ethanol, stir and raise the temperature to 60°C,Add 46g of phosphoric acid dropwise, keep it at 6065 for 23h after dropping, and then precipitate a yellowish solid, Cooled to 25-30°C, suction filtered, washed with an appropriate amount of 95% ethanol to obtain an off-white solid with a wet weight of 208g.Refining: Add 208g of crude chloroquine phosphate to 312g of water, stir, and heat to about 80 to completely dissolve.Add 5g of charcoal for needles, keep it at 8085 for 1h, and filter. After the filtrate is evaporated to remove 232g of water in a 70 water bath under reduced pressureAdd 312g of 95% ethanol, keep it at reflux for 2h to precipitate a white solid, cool to 2530, filter with suction,Wash with an appropriate amount of 95% ethanol to obtain a white solid with a wet weight of 106g.Dry to constant weight at 80°C to obtain 86.1 g of dry product. The yield is 66.11%,The purity is 99.41%, the maximum single impurity is 0.39% (standard≤0.5%), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | In methanol at 55℃; for 8h; Inert atmosphere; | 1 Specific embodiment one Add 0.01 mol of chloroquine to the reactor, and then add 25 mL of methanol solution, stir and mix well. Then 0.01 mol glycyrrhizic acid was dissolved in 15 mL methanol solution. Add dropwise to the reaction vessel. Set the temperature to 55°C and reflux for 8 hours. Pass in inert gas to protect the reaction. After the reaction is over, it is concentrated by rotary evaporation under vacuum to 1/5 of the original reaction solution, filtered and washed, and frozen and crystallized at 5°C. Dry for 24h in a vacuum oven at 55°C. 10.45 g of pure chloroquine glycyrrhizic acid product is obtained, and the yield is about 91.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.4% | In methanol at 60℃; for 12h; Inert atmosphere; | 3 Specific embodiment three 0.02molGlycyrrhetinic acid added to the reaction vessel,Then add 40 mL of methanol solution.Stir to mix well. Pass argon protection, then mix 0.01 mol of chloroquine and 20 mL of methanol solution thoroughly, and add them dropwise to the reaction vessel. The reaction temperature was set to 60°C, and the reaction was refluxed for 12 hours.After the reaction is over, we post-process the reaction. In a vacuum system, the reaction solution was concentrated to saturation, and frozen and crystallized at about 5°C. After the crystals are precipitated, they are subjected to suction filtration, washing, recrystallization, etc., and dried in a vacuum oven at 55° C. for 24 hours to obtain 11.53 g of pure chloroquine diglycyrrhetinic acid salt, with a yield of about 91.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | In methanol Inert atmosphere; Cooling with ice; | 1 Specific embodiment one Specific embodiment oneAdd 0.01 mol of glycyrrhetinic acid into the reaction vessel, place it in an ice-water bath, and then add 20 mL of methanol solution. Stir to mix well. Pass argon protection, then mix 0.01 mol of chloroquine and 20 mL of methanol solution thoroughly and mix them evenly, and add them dropwise to the reaction vessel.After the reaction is over, we post-process the reaction. In a vacuum system, the reaction solution was concentrated to saturation, and frozen and crystallized at about 5°C. After the crystals are precipitated, they are subjected to suction filtration, washing, recrystallization, etc., and dried in a vacuum oven at 50° C. for 24 hours to obtain 7.233 g of pure chloroquine glycyrrhetinic acid salt, with a yield of about 91.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 56% 2: 12% | With potassium pyrosulfite; palladium 10% on activated carbon; water; ammonium formate at 120℃; for 16h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
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1: 2.56 g 2: 2.48 g | With diethylamine In hexane; isopropyl alcohol at 35℃; Resolution of racemate; | 1 Dissolve 5.03 g of chloroquine in an equal volume of n-hexane/isopropanol/diethylamine in a ratio of 85:15:0.1 (v/v/v). The obtained solution was loaded into CHIRALPAKAY-H (AYH0CE-VC001) chiral column, and eluted with the same solvent system. The preparation conditions are: the flow rate is 1.0 mL/min, the detection wavelength is UV 254 nm, and the temperature is 35°C. The first compound to elute at 4.86 minutes is S-chloroquine, and the second compound to elute at 5.33 minutes is R-chloroquine. The components of each enantiomer are collected and combined. Using a rotary evaporator to remove the solvent under reduced pressure, pure optical isomers were obtained. The mass of S-chloroquine was 2.56g, ee>95%; the mass of R-chloroquine was 2.48g, ee>95% |
1: 2.56 g 2: 2.48 g | With diethylamine In hexane; isopropyl alcohol at 35℃; Resolution of racemate; | Dissolve 5.03 g of chloroquine in an equal volume of n-hexane/isopropanol/diethylamine in a ratio of 85:15:0.1 (v/v/v). The obtained solution was loaded into CHIRALPAKAY-H (AYH0CE-VC001) chiral column, and eluted with the same solvent system. The preparation conditions are: the flow rate is 1.0 mL/min, the detection wavelength is UV 254 nm, and the temperature is 35°C. The first compound to elute at 4.86 minutes is S-chloroquine, and the second compound to elute at 5.33 minutes is R-chloroquine. The components of each enantiomer are collected and combined. Using a rotary evaporator to remove the solvent under reduced pressure, pure optical isomers were obtained. The mass of S-chloroquine was 2.56g, ee>95%; the mass of R-chloroquine was 2.48g, ee>95%, and the results were shown in Figure 1 |
2.7 g | Stage #1: Chloroquine With (R)-1,1'-binaphthyl-2,2'-phosphoric acid In isopropyl alcohol; acetone at 80℃; for 1h; Stage #2: With sodium hydroxide In methanol for 1h; enantioselective reaction; | 2.1-2.2; 2.4; 4.3; 5.2 (1) Preparation of R- (-) -chloroquine binaphthol phosphate Taking 7.2g chloroquine racemate, adding 8.4g of (R)-(-)-binaphthol phosphate, adding 75g of isopropanol and 20g of acetone, heating to dissolve at 80°C , keeping the temperature for 1h, stirring and cooling to room temperature, cooling to 0-4°C , standing for 24h, separating out crystals, filtering, draining, storing filtrate as S-enriched mother liquor, obtaining a filter cake which is light yellow solid, and drying at 60°C to obtain 7.5g of the solid which is R-(-)-chloroquine binaphthol phosphate.(2) Preparation of R-(-)-chloroquine and recovery of (R)-(-)-binaphthol phosphate Adding 15g of methanol and 10g of sodium hydroxide solution with the concentration of 20 percent by mass into 7.5g (11mmol) of the solid obtained in the step (1), stirring for 1h, adding 50ml of dichloromethane and 50ml of water, stirring, separating out a large amount of solid with good crystal form, filtering to obtain a wet weight of 8.5g of white crystalline solid which is released (R)-(-)-binaphthol phosphate sodium salt, carrying out phase separation on the filtrate, carrying out back extraction on the water phase by using 50ml of dichloromethane, washing the organic phase by using 50ml of x 3 water, combining the organic phases, adding anhydrous sodium sulfate, stirring and drying for 1h, filtering, distilling the filtrate at normal pressure to recover the solvent, evaporating to dryness under reduced pressure at 90°C and 10kPa until no bubbling exists, obtaining 2.7g of light yellow oily matter which is R- (-) -chloroquine, and analyzing the enantioselectivity by chiral HPLC, wherein the ee value is 81%; |
With EnantioPak AD chiral column In ethanol; diethylamine; acetonitrile at 34.84℃; Resolution of racemate; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: Chloroquine With (S)-Malic acid In ethanol; ethyl acetate at 0 - 5℃; for 0.5h; Stage #2: With sodium ethanolate In methanol at 0 - 20℃; for 0.5h; | 13-15 Example 13: Preparation of (R)-chloroquine L-malate The racemic chloroquine (5g, 15.67mol) was dissolved in ethanol/ethyl acetate (v/v=1:2, 30mL), and L-malic acid (6.7g, 50.16mol) was dissolved in ethanol/ethyl acetate Ester (v/v=1:2, 15 mL), 0°C, slowly drop the ethanol/ethyl acetate solution of L-malic acid into the ethanol/ethyl acetate solution of the racemate. When the temperature is raised to 5°C, the reaction is carried out for 30 minutes. When the reaction is complete, most of the (S)-chloroquine L-malic acid salt is dissolved in the ethanol/ethyl acetate mixed solution, and the (R)-chloroquine L-malic acid salt After precipitation, the crude L-malate salt of (R)-chloroquine (5.0 g) was obtained by suction filtration.Example 14: L-malate recrystallization purification of (R)-chloroquineWeigh (R)-chloroquine L-malate crude product (5.0g) suspended in 10mL ethanol/ethyl acetate (v/v=1:2), heated to reflux until completely dissolved, slowly cooled to room temperature, and kept warm Stir for 1 to 2 hours, and continue to lower the temperature to 5 to 10° C., stir for 30 min, and filter with suction to obtain (R)-chloroquine L-malate (4.4 g) with an optical purity of 87.8% ee. Then, according to the above recrystallization method, the L-malate of (R)-chloroquine obtained above was recrystallized once to obtain the L-malate of (R)-chloroquine with an optical purity of 98.8% ee. (3.9 g).Example 15: Preparation of (R)-chloroquineSodium ethoxide (1.5g, 21.64mol) was added to 10ml of anhydrous methanol in batches. After stirring for about 10min at 0, the system became clear. Slowly add (R)-chloroquine L-malate (3.9g , 5.41mmol), stirred at room temperature for 30min, concentrated under reduced pressure to remove methanol. Add 20ml of ethyl acetate, stir at room temperature for 1 hour, filter with suction to remove the salt, and concentrate the ethyl acetate mother liquor under reduced pressure to obtain (R)-chloroquine (1.7g), purity>99%, chiral purity>99.92%, yield 68 %. |
2.1 g | Stage #1: Chloroquine With (R)-1,1'-binaphthyl-2,2'-phosphoric acid In isopropyl alcohol; acetone at 60℃; for 1h; Stage #2: With sodium hydroxide In methanol for 1h; enantioselective reaction; | 1.1-1.3; 3.1-3.2; 3.5-3.6; 4.2; 5.1 (1) Preparation of R-(-)-chloroquine binaphthol phosphate Taking 4.6g chloroquine racemate (CAS No.54-05-7), adding 5.4g of (R)-(-)-binaphthol phosphate, adding 50g of isopropanol and 16g of acetone, heating and dissolving at 60°C , keeping the temperature for 1h, stirring and cooling to room temperature, cooling to 0-4°C , standing for 12h, precipitating crystals (shown in a figure 1A), filtering, draining, storing filtrate as S-rich mother liquor, wherein a filter cake is light yellow solid (shown in a figure 1B), and drying at 60°C to obtain 6.2g of solid, wherein the solid is R-(-)-chloroquine binaphthol phosphate.(2) Recrystallization Adding 30g of isopropanol and 9g of acetone into 6.2g of the solid obtained in the step (1), heating and dissolving at 60°C , slowly stirring to room temperature, cooling to 0-4°C , standing for 6h, separating out large-particle crystals, filtering, draining to obtain a glossy loose solid (shown in figure 1C), and drying at 60 to obtain 4.7g of solid. (3) Preparation of R-(-)-chloroquine and recovery of (R)-(-)-binaphthol phosphate 4.7g (7mmol) of the solid obtained in the step (2) is added with 10g of methanol and 7g of sodium hydroxide solution with the concentration of 20 percent by mass, the mixture is stirred for 1h, then 50ml of dichloromethane and 50ml of water are added, the mixture is stirred, a large amount of solid with good crystal form is separated out, the mixture is filtered, the wet weight is 5.31g of white crystalline solid which is the released (R)-(-)-binaphthol phosphate sodium salt, the filtrate is subjected to phase separation, the water phase is back extracted by 40ml of dichloromethane, the organic phase is washed by 40ml of x 3 water, the organic phases are combined, anhydrous sodium sulfate is added, the mixture is stirred and dried for 1h, the filtrate is filtered, the solvent is recovered by normal pressure distillation, the filtrate is evaporated to dryness under 10kPa under reduced pressure at 90°C until no bubbling is realized, 2.1g of light yellow oily matter is obtained, the solid is cooled and is R(-)-chloroquine, the enantioselectivity of the product is analyzed by chiral HPLC, ee value is 99%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: Chloroquine With D-Malic acid In ethanol; ethyl acetate at 0 - 5℃; for 0.5h; Stage #2: With sodium ethanolate In methanol at 0 - 20℃; for 0.5h; | 16-18 Example 16: Preparation of (S)-chloroquine D-malate The racemic chloroquine (5g, 15.67mol) was dissolved in ethanol/ethyl acetate (v/v=1:2, 30mL), and D-malic acid (6.7g, 50.16mol) was dissolved in ethanol/ethyl acetate Ester (v/v=1:2, 15mL), 0°C, slowly drop the ethanol/ethyl acetate solution of D-malic acid into the ethanol/ethyl acetate solution of the racemate. When the temperature is raised to 5°C, the reaction is carried out for 30 minutes. When the reaction is complete, most of the D-malic acid salt of (R)-chloroquine is dissolved in the ethanol/ethyl acetate mixed solution, and the D-malic acid salt of (S)-chloroquine After precipitation, the crude product of (S)-chloroquine D-malate (4.8 g) was obtained by suction filtration.Example 17: D-malate recrystallization purification of (S)-chloroquineWeigh (S)-chloroquine D-malate crude product (4.8g) suspended in 10mL ethanol/ethyl acetate (v/v=1:2), heated to reflux until completely dissolved, slowly cooled to room temperature, and kept warm Stir for 1 to 2 hours, and continue to lower the temperature to 5 to 10°C, stir for 30 min, and filter with suction to obtain (S)-chloroquine D-malate (4.3 g) with an optical purity of 88.3% ee. Then, according to the above recrystallization method, the D-malate of (S)-chloroquine obtained above was recrystallized once to obtain the D-malate of (S)-chloroquine with an optical purity of 97.4% ee. (3.6 g).Example 18: Preparation of (S)-chloroquineSodium ethoxide (1.36g, 20.0mol) was added to 10ml of anhydrous methanol in batches. After stirring for about 10min at 0, the system became clear. Slowly add (S)-chloroquine D-malate (3.6g) , 5.0mmol), stirred at room temperature for 30min, concentrated under reduced pressure to remove methanol. Add 20ml of ethyl acetate, stir at room temperature for 1 hour, filter with suction to remove the salt, and concentrate the ethyl acetate mother liquor under reduced pressure to obtain (S)-hydroxychloroquine (1.4g), purity>99%, chiral purity>99.92%, yield 56% |
3.9 g | Stage #1: Chloroquine With (R)-1,1'-binaphthyl-2,2'-phosphoric acid In isopropyl alcohol; acetone at 70℃; for 1h; Stage #2: With sodium hydroxide In methanol for 1h; enantioselective reaction; | 1.1-1.2; 1.5-1.6; 3.1-3.3 (1) Preparation of S-(+)-chloroquine binaphthol phosphate Taking 8.3g chloroquine racemate, adding 9.7g of (S)-(+)-binaphthol phosphate, adding 90g of isopropanol and 30g of acetone, heating and dissolving at 70°C , keeping the temperature for 1h, stirring and cooling to room temperature, cooling to 0-4°C , standing for 18h, separating out crystals, filtering, draining, storing filtrate as R-rich mother liquor, obtaining a light yellow solid filter cake, and drying at 60°C to obtain 11.8g of S-(+)-chloroquine binaphthol phosphate. (2) Recrystallization Adding 11.8g (17.7mmol) of the solid obtained in the step (1) into 75g of isopropanol and 25g of acetone, heating to dissolve at 70°C , slowly stirring to room temperature, cooling to 0-4°C , standing for 6 hours, separating out large-particle crystals, filtering, draining to obtain a loose solid with luster, and drying at 60°C to obtain 11.8g of the solid.(2) Recrystallization Adding 11.8g (17.7mmol) of the solid obtained in the step (1) into 75g of isopropanol and 25g of acetone, heating to dissolve at 70°C , slowly stirring to room temperature, cooling to 0-4°C , standing for 6 hours, separating out large-particle crystals, filtering, draining to obtain a loose solid with luster, and drying at 60°C to obtain 8.6g of the solid.(3) Preparation of S-(+)-chloroquine and recovery of (S)-(+)-binaphthol phosphate Adding 8.6g (12.9mmol) of solid obtained in the step (2) into 15g of methanol and 10g of sodium hydroxide solution with the concentration of 30 percent by mass, stirring for 1h, adding 80ml of dichloromethane and 80ml of water, stirring, separating out a large amount of solid with good crystal form, filtering to obtain wet 10.2g of white crystalline solid which is released (S)-(+)-binaphthol phosphate sodium salt, separating the filtrate, back-extracting the aqueous phase with 60ml of dichloromethane, washing the organic phase with 60ml of 3 water, combining the organic phases, adding anhydrous sodium sulfate, stirring and drying for 1h, filtering, distilling the filtrate at normal pressure to recover the solvent, evaporating to dryness at 90°C under 10kPa under reduced pressure until no bubbling is achieved, obtaining 3.9g of light yellow oily matter, cooling to obtain a yellow solid, and drying the yellow oily matter. The solid is S-(+)-chloroquine, the enantioselectivity of the product is analyzed by chiral HPLC, and the ee value is 99.6 %; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.2% | With phosphoric acid In ethanol at 45 - 50℃; for 4h; | 1-3 Acidification to salt:Add 135.6 g of dry chloroquine and 300.0 g of 80% ethanol into the crystallization flask, and stir until the chloroquine is completely dissolved at the temperature; add phosphoric acid to pH=5.4.The internal temperature was controlled at 45.050.0; after a large amount of crystals were precipitated, the temperature was kept and crystallized for 4h; cooled to 10.0, and filtered to obtain wet chloroquine phosphate.80.090.0 vacuum drying for 7h to obtain 209.8g white finished product, total yield 78.2%,Purity≥99.5%, maximum single impurity≤0.1% (HPLC area normalization method). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With [Rh(OMe)(cod)]2; deuterium gas In tetrahydrofuran at 55℃; for 24h; | |
100% | With [Rh(OMe)(cod)]2; deuterium gas In tetrahydrofuran at 55℃; for 24h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.7% | With potassium borohydrate at 20 - 25℃; for 2h; | Preferred embodiment: 4-Amino-7-chloroquinoline (20g, 0.11mol), triethylamine (12.4g, 0.12mol), 200mL of toluene and 40mL of dimethyl sulfoxide, stirred and cooled to 0-5°C, and added dropwise trifluoromethanesulfonic acid Acyl chloride (20.4g, 0.12mol) was dripped in about 30min, then raised to 20-25°C for reaction for 4h, TLC detected that the raw material point basically disappeared, and the reaction was stopped.After washing the above reaction solution with water (100 mL*2), set up a reflux condensation water separator, dehydrate at 110C for 1 h, add 5-diethylamino-2-pentanol (21 g, 0.13 mol), (2-hydroxy-4 -tert-butylbenzyl)diphenylphosphine oxide (P-3, 3.5g, 11mmol), the dehydration reaction under reflux was continued for 30h, and the spot of intermediate 10 detected by TLC basically disappeared.After the reaction, the solvent was evaporated to dryness, 100 mL of anhydrous ethanol and sodium ethoxide (8.2 g, 0.12 mol) were added, and the reaction was carried out at 20-25 ° C for 8 h. The point of TLC detection of intermediate 11 basically disappeared.Potassium borohydride (g, 40mmol) was added to the reaction solution, and the reaction was continued for 2h at 20-25°C,TLC detected that the point of intermediate 12 basically disappeared, the reaction was stopped, the solvent was evaporated under reduced pressure, 100 mL of dichloromethane and 100 mL of water were added, the layers were separated, the aqueous layer was extracted once with 100 mL of dichloromethane, the organic layers were combined, and washed with 150 mL of water After 1 time, the organic layer was mixed with 200 mL of water, and concentrated hydrochloric acid was slowly added to pH=4.5 under stirring, fully stirred, and the chloroquine was salified into the acid water layer, and the organic layer was spin-dried to recover 3.3 g (2-hydroxyl- 4-tert-butylbenzyl)diphenylphosphine oxide (94.3% recovery);Add 200 mL of DCM to the aqueous layer, add 20% aqueous sodium hydroxide solution to pH=10, stir well, separate the layers, discard the aqueous layer, and spin dry the organic layer to obtain 2.37 g of off-white chloroquine crude product, which is recrystallized from ethyl acetate to obtain 2.20 g White solid, yield: 62.7% (calculated as 4-amino-7-chloroquinoline), purity 99.5%. |
Tags: 54-05-7 synthesis path| 54-05-7 SDS| 54-05-7 COA| 54-05-7 purity| 54-05-7 application| 54-05-7 NMR| 54-05-7 COA| 54-05-7 structure
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