CN111793026A - Hydroxychloroquine sulfate, crystal form of enantiomer thereof and preparation method of crystal form - Google Patents
Hydroxychloroquine sulfate, crystal form of enantiomer thereof and preparation method of crystal form Download PDFInfo
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- CN111793026A CN111793026A CN202010715431.1A CN202010715431A CN111793026A CN 111793026 A CN111793026 A CN 111793026A CN 202010715431 A CN202010715431 A CN 202010715431A CN 111793026 A CN111793026 A CN 111793026A
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- hydroxychloroquine
- hydroxychloroquine sulfate
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- 229960002927 hydroxychloroquine sulfate Drugs 0.000 title claims abstract description 95
- ZAVJTSLIGAGALR-UHFFFAOYSA-N 2-(2,2,2-trifluoroacetyl)cyclooctan-1-one Chemical compound FC(F)(F)C(=O)C1CCCCCCC1=O ZAVJTSLIGAGALR-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 239000013078 crystal Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 43
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims abstract description 86
- 229960004171 hydroxychloroquine Drugs 0.000 claims abstract description 45
- XXSMGPRMXLTPCZ-AWEZNQCLSA-N 2-[[(4s)-4-[(7-chloroquinolin-4-yl)amino]pentyl]-ethylamino]ethanol Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-AWEZNQCLSA-N 0.000 claims abstract description 35
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 19
- FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims description 44
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 36
- 238000001035 drying Methods 0.000 claims description 33
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 30
- 239000003960 organic solvent Substances 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 22
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 16
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- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 9
- 230000003287 optical effect Effects 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000000243 solution Substances 0.000 description 28
- HXEWMTXDBOQQKO-UHFFFAOYSA-N 4,7-dichloroquinoline Chemical compound ClC1=CC=NC2=CC(Cl)=CC=C21 HXEWMTXDBOQQKO-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 238000001816 cooling Methods 0.000 description 19
- XUVXSSOPXQRCGL-VIFPVBQESA-N 2-[[(4s)-4-aminopentyl]-ethylamino]ethanol Chemical compound OCCN(CC)CCC[C@H](C)N XUVXSSOPXQRCGL-VIFPVBQESA-N 0.000 description 18
- XUVXSSOPXQRCGL-SECBINFHSA-N 2-[[(4r)-4-aminopentyl]-ethylamino]ethanol Chemical compound OCCN(CC)CCC[C@@H](C)N XUVXSSOPXQRCGL-SECBINFHSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 235000019441 ethanol Nutrition 0.000 description 15
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- 238000004321 preservation Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000006482 condensation reaction Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- XUVXSSOPXQRCGL-UHFFFAOYSA-N 2-[4-aminopentyl(ethyl)amino]ethanol Chemical compound OCCN(CC)CCCC(C)N XUVXSSOPXQRCGL-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 125000003158 alcohol group Chemical group 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
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- 239000012230 colorless oil Substances 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000006266 etherification reaction Methods 0.000 description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- BFKVXNPJXXJUGQ-UHFFFAOYSA-N [CH2]CCCC Chemical compound [CH2]CCCC BFKVXNPJXXJUGQ-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
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- 238000012360 testing method Methods 0.000 description 2
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
A hydroxychloroquine sulfate and crystal forms of enantiomers thereof and a preparation method. The invention provides a crystal form A hydroxychloroquine sulfate, wherein the X-ray powder diffraction pattern of the crystal form A hydroxychloroquine sulfate is 10.8o、13.0o、13.3o、16.9o、17.2o、17.5o、19.9o、21.3o、23.5o、24.0oAnd 26.7o±0.2oHas a characteristic peak and does not contain hydroxychloroquine oxynitride; the invention provides a hydroxychloroquine crystal, wherein the X-ray powder diffraction pattern is 7.5o、14.9o、16.5o、19.2o、19.6o、22.8o、23.6oAnd 26.7o±0.2oHas a characteristic peak; the invention provides S-hydroxychloroquine sulfate monohydrate, and the X-ray powder diffraction pattern is 12.2o、13.0o、14.9o、17.8o、22.7o、23.3o、25.0oAnd 26.2o±0.2oHas a characteristic peak; the invention also provides an R-hydroxychloroquine sulfate with an X-ray powder diffraction pattern of 12.2o、13.0o、14.9o、17.8o、22.7o、23.3o、25.0oAnd 26.2o±0.2oHas characteristic peaks.
Description
Technical Field
The invention relates to a hydroxychloroquine sulfate crystal and a preparation method thereof, in particular to S-hydroxychloroquine sulfate, R-hydroxychloroquine sulfate and a hydroxychloroquine sulfate crystal.
Background
Hydroxychloroquine sulfate (Hydroxychloroquine sulfate), chemically named 2- [ [4- [ (7-chloro-4-quinolyl) amino group]Pentyl radical]Ethylamino group]-ethanol sulfate, chemical structure is shown as formula I, hydroxychloroquine is its free alkali,
clinically, it is used for rheumatoid arthritis, juvenile chronic arthritis, discoid lupus erythematosus and systemic lupus erythematosus, and skin lesions caused or aggravated by sunlight.
S-hydroxychloroquine sulfate, chemically named (S) - (+) -2- [ [4- [ (7-chloro-4-quinolyl) amino group]Pentyl radical]Ethylamino group]-ethanol sulfate, chemical structure as shown in formula II, S-hydroxychloroquine as its free alkali,
r-hydroxychloroquine sulfate, chemically named (R) - (-) -2- [ [4- [ (7-chloro-4-quinolinyl) amino]Pentyl radical]Ethylamino group]-ethanol sulfate, chemical structure is shown as formula III, R-hydroxychloroquine is its free alkali,
in the case of hydroxychloroquine sulfate disclosed in patent CN102050781B, concentrated sulfuric acid is added under the condition of an organic solvent of esters and alcohols to obtain hydroxychloroquine sulfate.
Patent CN103724261B discloses adding concentrated sulfuric acid into an organic solvent, and then slowly dropping hydroxychloroquine organic solvent to prepare hydroxychloroquine sulfate.
Patents CN104230803A and CN109456266A both disclose that hydroxychloroquine sulfate is prepared by adding concentrated sulfuric acid into organic solvent containing water and alcohols.
Patent CN108727263A discloses a hydroxychloroquine sulfate of crystal form A, according to the disclosure, the disclosed hydroxychloroquine sulfate of crystal form A is more stable than hydroxychloroquine sulfate in the prior art, the key technical characteristics of the preparation method are that a sulfuric acid aqueous solution with a mass fraction of 40% -60% is adopted, and the preparation method is characterized by adopting means of XRPD, DSC and IR.
Although the stability of the hydroxychloroquine sulfate in the crystal form a prepared by the method disclosed in patent CN108727263A is good, the preparation method has certain defects, and in the preparation method, after the addition of the sulfuric acid solution is finished, the temperature needs to be raised for reaction, so that the risk of generating hydroxychloroquine oxynitride (CAS: 1449223-88-4) and etherification products exists, and further the hydroxychloroquine oxynitride and the etherification products remain in the product, and therefore, the method needs to be improved.
The patent CN105693606 discloses an asymmetric synthesis method of optically pure R/S-hydroxychloroquine, and because S-hydroxychloroquine and R-hydroxychloroquine have different biological properties, the deep research on the two isomers has important significance for the application of the medicine in new fields, and the acquisition of a stable crystal form is an important link of research and development.
S-hydroxychloroquine or R-hydroxychloroquine is generally prepared by condensation reaction of (S) -2- [ (4-aminopentyl) ethylamino ] ethanol or (R) -2- [ (4-aminopentyl) ethylamino ] ethanol and 4, 7-dichloroquinoline, and the prior art can adopt (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol and chiral resolution reagent L- (+) -mandelic acid (namely S- (+) -mandelic acid) or D- (-) -mandelic acid (namely R- (-) -mandelic acid) to be prepared by resolution, the resolution method disclosed needs repeated resolution and crystallization, and has the disadvantages of complex operation and low yield.
In view of the above problems, the inventors have conducted intensive research work to reduce the risk of production of hydroxychloroquine nitroxide (CAS: 1449223-88-4) and etherification products while maintaining the hydroxychloroquine sulfate crystal form a; on the other hand, the method is to study the resolution of the hydroxychloroquine side chain, simplify the operation and prepare the optically pure hydroxychloroquine sulfate crystal by adopting the optically pure hydroxychloroquine side chain obtained by the resolution.
Disclosure of Invention
The inventor carries out intensive research on the risks existing in the preparation of the hydroxychloroquine sulfate in the crystal form A by the existing method, and unexpectedly finds that the hydroxychloroquine sulfate in the crystal form A can be obtained when the reaction is carried out at low temperature, the production of hydroxychloroquine oxynitride can be avoided, the yield is over 80%, and the purity is more than 99.6%, preferably more than 99.8%, and more preferably more than 99.9%.
The invention provides a preparation method of A crystal form hydroxychloroquine sulfate, wherein the hydroxychloroquine sulfate does not contain hydroxychloroquine nitrogen oxide, and the preparation method is characterized in that in the step of salifying, the reaction temperature is not more than 25 ℃.
Preferably, the preparation method of the hydroxychloroquine sulfate crystal form A is characterized by dissolving hydroxychloroquine in an organic solvent, slowly adding a sulfuric acid solution at 15-25 ℃ to adjust the pH, keeping the temperature for 1, stirring and crystallizing, cooling to 10-15 ℃, keeping the temperature for 2, stirring and crystallizing, filtering and drying to obtain the hydroxychloroquine sulfate crystal form A;
wherein the organic solvent is an alcohol solvent, preferably monohydric alcohol of C1-C4;
wherein the weight ratio of the hydroxychloroquine to the organic solvent is 1: 3.5-4.5;
wherein the mass fraction concentration of the sulfuric acid solution is 40-60%, preferably 50-55%;
wherein the pH value is adjusted to 2-3;
wherein the temperature of the heat preservation 1 is 15-25 ℃;
wherein the stirring time of the heat preservation 1 is 3-5 h;
wherein the temperature of the heat preservation 2 is 10-15 ℃;
wherein the stirring time of the heat preservation 2 is 5-8 h;
wherein the drying temperature is 50-65 ℃, and preferably 60 ℃;
wherein the drying time is 6-10 h;
wherein the drying adopts a vacuum drying mode.
The hydroxychloroquine sulfate prepared by the method provided by the invention has the following X-ray diffraction pattern data:
the XPRD test conditions of the invention are as follows:
the instrument comprises the following steps: panalytical X' Pert3 powder X-ray diffractometer; target: cu, Ka; wavelength K alpha 1: 1.54060A, K alpha 2: 1.54443A; pipe pressure: 40 kV; pipe flow: 40 mA; step length [ 2 ]o2θ]: 0.0260; time of scanning per step s]：37.9440。
Further, the invention provides a preparation method of the A crystal form hydroxychloroquine sulfate, which is characterized by comprising the following steps:
1) condensation reaction: reacting 4, 7-dichloroquinoline with a hydroxychloroquine side chain in the presence of an alcohol organic solvent, adjusting the pH value after the reaction is finished, extracting by adopting halogenated alkane, concentrating, and recrystallizing to obtain hydroxychloroquine;
2) salt forming reaction: dissolving the hydroxychloroquine obtained in the step 1) in an organic solvent, slowly adding a sulfuric acid solution at 15-25 ℃ to adjust the pH value, keeping the temperature for 1, stirring and crystallizing, cooling to 10-15 ℃, keeping the temperature for 2, stirring and crystallizing, filtering, and drying to obtain the hydroxychloroquine sulfate with the crystal form A.
The hydroxychloroquine crystal prepared by the method provided by the invention has the following X-ray diffraction pattern data:
the A crystal form hydroxychloroquine sulfate has an X-ray powder diffraction pattern expressed by a 2 theta angle of 10.8o、13.0o、13.3o、16.9o、17.2o、17.5o、19.9o、21.3o、23.5o、24.0oAnd 26.7o±0.2oHas a characteristic peak; the hydroxychloroquine crystal has an X-ray powder diffraction pattern expressed by a 2 theta angle of 7.5o、14.9o、16.5o、19.2o、19.6o、22.8o、23.6oAnd 26.7o±0.2oHas characteristic peaks.
The preparation and the crystal form of the S-hydroxychloroquine sulfate monohydrate are researched, a splitting method is adopted, high-yield (S) -2- [ (4-amino pentyl) ethylamino ] ethanol is adopted, the (S) -2- [ (4-amino pentyl) ethylamino ] ethanol and 4, 7-dichloroquinoline are subjected to condensation reaction to prepare S-hydroxychloroquine, sulfate is formed at low temperature, and S-hydroxychloroquine sulfate monohydrate is obtained and does not contain S-hydroxychloroquine oxynitride impurities.
The invention provides a preparation method of S-hydroxychloroquine sulfate monohydrate, which is characterized in that in the salifying step, the reaction temperature is not more than 30 ℃.
Preferably, the preparation method of the S-hydroxychloroquine sulfate monohydrate is characterized by dissolving S-hydroxychloroquine in an organic solvent, slowly adding a sulfuric acid solution at 15-25 ℃ to adjust the pH, keeping the temperature for 1, stirring, crystallizing, cooling to 10-15 ℃, keeping the temperature for 2, stirring, crystallizing, filtering and drying to obtain the S-hydroxychloroquine sulfate monohydrate;
wherein the organic solvent is an alcohol solvent, preferably monohydric alcohol of C1-C4;
wherein the weight ratio of the hydroxychloroquine to the organic solvent is 1: 3.5-4.5;
wherein the mass fraction concentration of the sulfuric acid solution is 40-60%, preferably 50-55%;
wherein the pH value is adjusted to 2-3;
wherein the temperature of the heat preservation 1 is 15-25 ℃;
wherein the stirring time of the heat preservation 1 is 0.5-2 h;
wherein the temperature of the heat preservation 2 is 10-15 ℃;
wherein the stirring time of the heat preservation 2 is 5-8 h;
wherein the drying temperature is 50-65 ℃, and preferably 60 ℃;
wherein the drying time is 6-10 h;
wherein the drying adopts a vacuum drying mode.
The S-hydroxychloroquine sulfate monohydrate prepared by the method provided by the invention has the following X-ray diffraction pattern data:
further, the preparation method of the S-hydroxychloroquine sulfate monohydrate provided by the invention is characterized by comprising the following steps:
1) condensation reaction: reacting 4, 7-dichloroquinoline with an S-hydroxychloroquine side chain in the presence of an alcohol organic solvent, adjusting the pH value after the reaction is finished, extracting by adopting halogenated alkane, and concentrating to obtain hydroxychloroquine;
2) salt forming reaction: dissolving the hydroxychloroquine obtained in the step 1) in an organic solvent, slowly adding a sulfuric acid solution at 15-25 ℃ to adjust the pH value, keeping the temperature for 1, stirring and crystallizing, cooling to 10-15 ℃, keeping the temperature for 2, stirring and crystallizing, filtering, and drying to obtain the S-hydroxychloroquine sulfate monohydrate.
The invention also provides a preparation method of (S) -2- [ (4-amino pentyl) ethylamino ] ethanol S- (+) -mandelate, which is characterized in that (+/-) -2- [ (4-amino pentyl) ethylamino ] ethanol is dissolved in an organic solvent, and L- (+) -mandelic acid is added for salification;
wherein the molar ratio of the L- (+) -mandelic acid to the (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol is 1: 1.9-2.3, preferably 1: 2;
wherein the weight ratio of the (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol to the organic solvent is 1: 2.5-4.5, preferably 1: 3;
wherein the organic solvent is C1-C4 monohydric alcohol, preferably isopropanol;
preferably, the method further comprises filtering and drying.
The (S) -2- [ (4-amino pentyl) ethylamino ] ethanol S- (+) -mandelate prepared by the method provided by the invention is neutralized in alkaline aqueous solution, extracted by dichloromethane, dried and concentrated to obtain the (S) -2- [ (4-amino pentyl) ethylamino ] ethanol.
The S-hydroxychloroquine sulfate monohydrate provided by the invention has an X-ray powder diffraction pattern expressed by a 2 theta angle of 12.2o、13.0o、14.9o、17.8o、22.7o、23.3o、25.0oAnd 26.2o±0.2oHas characteristic peaks.
The preparation and the crystal form of the R-hydroxychloroquine sulfate are researched, a resolution method is adopted, high-yield (R) -2- [ (4-amino pentyl) ethylamino ] ethanol is adopted, the (R) -2- [ (4-amino pentyl) ethylamino ] ethanol and 4, 7-dichloroquinoline are subjected to condensation reaction to prepare the R-hydroxychloroquine, the R-hydroxychloroquine sulfate is formed into sulfate under the low-temperature condition, and the R-hydroxychloroquine sulfate does not contain R-hydroxychloroquine oxynitride impurities.
The invention provides a preparation method of R-hydroxychloroquine sulfate, wherein the R-hydroxychloroquine sulfate does not contain hydroxychloroquine nitrogen oxide, and is characterized in that in the step of salifying, the reaction temperature is not more than 35 ℃.
Preferably, the preparation method of the R-hydroxychloroquine sulfate is characterized in that the R-hydroxychloroquine is dissolved in an organic solvent, a sulfuric acid solution is slowly added at the temperature of 15-25 ℃ to adjust the pH value, the temperature is kept 1, stirring and crystallization are carried out, the temperature is reduced to 10-15 ℃, the temperature is kept 2, stirring and crystallization are carried out, and the R-hydroxychloroquine sulfate is obtained after filtration and drying;
wherein the organic solvent is an alcohol solvent, preferably monohydric alcohol of C1-C4;
wherein the weight ratio of the hydroxychloroquine to the organic solvent is 1: 3.5-4.5;
wherein the mass fraction concentration of the sulfuric acid solution is 40-60%, preferably 50-55%;
wherein the pH value is adjusted to 2-3;
wherein the temperature of the heat preservation 1 is 15-25 ℃;
wherein the stirring time of the heat preservation 1 is 0.5-2 h;
wherein the temperature of the heat preservation 2 is 10-15 ℃;
wherein the stirring time of the heat preservation 2 is 5-8 h;
wherein the drying temperature is 50-65 ℃, and preferably 60 ℃;
wherein the drying time is 6-10 h;
wherein the drying adopts a vacuum drying mode.
The R-hydroxychloroquine sulfate prepared by the method provided by the invention has the following X-ray diffraction pattern data:
further, the preparation method of the R-hydroxychloroquine sulfate provided by the invention is characterized by comprising the following steps:
1) condensation reaction: reacting 4, 7-dichloroquinoline with an R-hydroxychloroquine side chain in the presence of an alcohol organic solvent, adjusting the pH value after the reaction is finished, extracting by adopting halogenated alkane, and concentrating to obtain hydroxychloroquine;
2) salt forming reaction: dissolving the hydroxychloroquine obtained in the step 1) in an organic solvent, slowly adding a sulfuric acid solution at 15-25 ℃ to adjust the pH value, keeping the temperature for 1, stirring and crystallizing, cooling to 10-15 ℃, keeping the temperature for 2, stirring and crystallizing, filtering, and drying to obtain the R-hydroxychloroquine sulfate.
The invention also provides a preparation method of (R) -2- [ (4-aminopentyl) ethylamino ] ethanol R- (-) -mandelate, which is characterized in that (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol is dissolved in an organic solvent, and D- (-) -mandelic acid is added for salification;
wherein the molar ratio of the D- (-) -mandelic acid to the (+ -) -2- [ (4-aminopentyl) ethylamino ] ethanol is 1: 1.9-2.3, preferably 1: 2;
wherein the weight ratio of the (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol to the organic solvent is 1: 2.5-4.5, preferably 1: 3;
wherein the organic solvent is C1-C4 monohydric alcohol, preferably isopropanol;
preferably, the method further comprises filtering and drying.
The (R) -2- [ (4-amino pentyl) ethylamino ] ethanol R- (-) -mandelate prepared by the method provided by the invention is neutralized in alkaline aqueous solution, extracted by dichloromethane, dried and concentrated to obtain the (R) -2- [ (4-amino pentyl) ethylamino ] ethanol.
The R-hydroxychloroquine sulfate provided by the invention has an X-ray powder diffraction pattern expressed by a 2 theta angle of 12.2o、13.0o、14.9o、17.8o、22.7o、23.3o、25.0oAnd 26.2o±0.2oHas characteristic peaks.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention: the term "XRPD" refers to powder X-ray diffraction;
the term "HPLC" refers to high performance liquid chromatography;
the hydroxychloroquine side chain is 5- (N-ethyl-N-2-hydroxyethyl amino) -2-pentylamine;
the S-hydroxychloroquine side chain is (S) -2- [ (4-amino pentyl) ethylamino ] ethanol;
the R-hydroxychloroquine side chain is (R) -2- [ (4-amino pentyl) ethylamino ] ethanol;
the optically pure hydroxychloroquine sulfate is S-hydroxychloroquine sulfate or R-hydroxychloroquine sulfate;
the optically pure hydroxychloroquine side chain is (S) -2- [ (4-aminopentyl) ethylamino ] ethanol (the structural formula is shown in a formula VI) or (R) -2- [ (4-aminopentyl) ethylamino ] ethanol (the structural formula is shown in a formula VII);
the optically pure hydroxychloroquine side chain mandelate is (R) -2- [ (4-aminopentyl) ethylamino ] ethanol R- (-) -mandelate (the structural formula is shown in the formula V) or (S) -2- [ (4-aminopentyl) ethylamino ] ethanol S- (+) -mandelate (the structural formula is shown in the formula IV);
the hydroxychloroquine sulfate and the hydroxychloroquine sulfate are different names of the same substance;
the invention has the beneficial effects that: (1) the hydroxychloroquine sulfate crystal form A with high chemical stability is prepared by using a simple and feasible preparation method, the method avoids high-temperature reaction, reduces the risk of production of hydroxychloroquine nitrogen oxides, is easy for industrial production, and has stable and reliable quality; (2) for the optically pure hydroxychloroquine sulfate, specific reaction conditions are adopted, and the optically pure hydroxychloroquine side chain mandelate is obtained by high-yield resolution; the preparation method is simple and feasible, the optically pure hydroxychloroquine sulfate is prepared, the method avoids high-temperature reaction, reduces the risk of generating corresponding hydroxychloroquine nitrogen oxides, is easy for industrial production, and has stable and reliable quality.
Drawings
FIG. 1 example 1 Hydroxychloroquine XRPD spectrum
FIG. 2 example 2 Hydroxychloroquine sulfate XRPD spectrum
FIG. 3 example 2 hydroxychloroquine sulfate HPLC chemical purity profile
FIG. 4 XRPD spectrum of example 9S-hydroxychloroquine sulfate monohydrate
FIG. 5 HPLC optical purity spectrum of example 9S-hydroxychloroquine sulfate monohydrate
FIG. 6 XRPD spectrum of example 15R-hydroxychloroquine sulfate
FIG. 7 HPLC optical purity spectrum of example 15R-hydroxychloroquine sulfate
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions.
The method for detecting the purity of the hydroxychloroquine and the salt thereof comprises the following steps:
the instrument comprises the following steps: preparing an ultraviolet detector and an electronic analytical balance by using a high performance liquid chromatograph;
a chromatographic column: octadecylsilane chemically bonded silica is used as a packed column;
flow rate: 1.0 ml/min; detection wavelength: 242 nm; sample introduction amount: 20 mu l of the mixture; column temperature: 35 ℃;
mobile phase A: acetonitrile: water: phosphoric acid (100: 900:2, V/V/V);
mobile phase B: acetonitrile: water: phosphoric acid (800: 200:1, V/V/V);
elution was performed with the following gradient:
the instrument related to the XPRD test of the invention is a PANALYTICAL X' Pert3 powder X-ray diffractometer, and the conditions are as follows: the instrument comprises the following steps: (ii) a Target: cu, Ka; wavelength K alpha 1: 1.54060A, K alpha 2: 1.54443A; pipe pressure: 40 kV; pipe flow: 40 mA; step size [ o2 θ ]: 0.0260; scanning time [ s ] per step: 37.9440.
EXAMPLE 1 Hydroxychloroquine preparation
Weighing 100g of 4, 7-dichloroquinoline, 105.6g of hydroxychloroquine side chain and 25g of isopropanol in a 500ml three-necked bottle, heating to 90 ℃, preserving heat for 30min, and heating to 95 ℃ for reaction for 24 h; cooling to 70 ℃, dropwise adding a 5% sodium hydroxide solution (prepared from 13g of sodium hydroxide and 247g of water), adding 350g of dichloromethane, stirring for 5min, standing for liquid separation, and concentrating a dichloromethane layer under reduced pressure; adding 450g of ethyl acetate and 50g of isopropanol into the concentrate, stirring for dissolving, crystallizing at 20-30 ℃ for 6h, performing suction filtration, drying a filter cake at 55-65 ℃ for 6h, and collecting 118g of hydroxychloroquine with the purity of 99.5%.
EXAMPLE 2 preparation of Hydroxychloroquine sulfate
Adding 118g of hydroxychloroquine obtained in example 1 into a 1000ml three-necked bottle, adding 4 times of anhydrous ethanol by weight, stirring for dissolving, dropwise adding a sulfuric acid solution (mass fraction concentration is 47%) at 15-25 ℃, adjusting pH =2, stirring for 3h, slowly cooling to 10-15 ℃ for crystallization for 6h, filtering, and drying wet products in a vacuum drying oven at 60 ℃ for 8h to obtain 122g of hydroxychloroquine sulfate, wherein the purity is 99.81%, and hydroxychloroquine nitrogen oxides are not detected.
EXAMPLE 3 Hydroxychloroquine preparation
Weighing 100g of 4, 7-dichloroquinoline, 110 g of hydroxychloroquine side chain and 30g of isopropanol in a 500ml three-necked bottle, heating to 90 ℃, preserving heat for 30min, and heating to 100 ℃ for reaction for 24 h; cooling to 80 ℃, dropwise adding a 5% sodium hydroxide solution (prepared from 13g of sodium hydroxide and 247g of water), adding 350g of dichloromethane, stirring for 5min, standing for liquid separation, and concentrating a dichloromethane layer under reduced pressure; adding 500g of ethyl acetate and 50g of isopropanol into the concentrate, stirring for dissolving, crystallizing at 20-30 ℃ for 6h, performing suction filtration, drying a filter cake at 55-65 ℃ for 6h, and collecting to obtain 123g of hydroxychloroquine with the purity of 99.7%.
EXAMPLE 4 preparation of Hydroxychloroquine sulfate
Adding 123g of hydroxychloroquine obtained in example 3 into a 1000ml three-necked bottle, adding anhydrous ethanol in an amount which is 4.5 times the weight of the hydroxychloroquine, stirring to dissolve the hydroxychloroquine, dropwise adding a sulfuric acid solution (mass fraction concentration is 55%) at 20 ℃, adjusting the pH =2, stirring for 3h at 15-20 ℃, slowly cooling to 10 ℃ for crystallization for 6h, filtering, and drying wet products in a vacuum drying oven at 60 ℃ for 8h to obtain 128g of hydroxychloroquine sulfate with the purity of 99.81%, wherein hydroxychloroquine nitrogen oxides are not detected.
EXAMPLE 5 preparation of Hydroxychloroquine
Weighing 100g of 4, 7-dichloroquinoline, 98g of hydroxychloroquine side chain and 25g of isopropanol in a 500ml three-necked bottle, and heating to 90 ℃ for reaction for 24 hours; cooling to 70-80 deg.C, adding 5% sodium hydroxide solution (prepared from 13g sodium hydroxide and 247g water) dropwise, adding 350g dichloromethane, stirring for 5min, standing, separating, and concentrating dichloromethane layer under reduced pressure; adding 450g of ethyl acetate and 60g of isopropanol into the concentrate, stirring and dissolving, crystallizing at 30 ℃ for 6h, performing suction filtration, drying a filter cake at 65 ℃ for 6h, and collecting to obtain 120g of hydroxychloroquine with the purity of 99.6%.
EXAMPLE 6 preparation of Hydroxychloroquine sulfate
Adding 120g of hydroxychloroquine obtained in example 5 into a 1000ml three-necked bottle, adding 3.5 times of absolute ethyl alcohol by weight, stirring for dissolution, dropwise adding a sulfuric acid solution (mass fraction concentration is 40%) at 15-25 ℃, adjusting pH =3, stirring for 3h at 20-25 ℃, slowly cooling to 15 ℃ for crystallization for 8h, filtering, and placing a wet product in a vacuum drying oven for drying for 8h at 60 ℃ to obtain 130g of hydroxychloroquine sulfate with the purity of 99.8%, wherein hydroxychloroquine nitrogen oxides are not detected.
EXAMPLE 7 preparation of (S) -2- [ (4-Aminopentyl) ethylamino ] ethanol S- (+) -mandelate
100g (0.574 mol) (+ -) -2- [ (4-aminopentyl) ethylamino ] ethanol was weighed into a round-bottomed flask, and 300 g of isopropyl alcohol was added thereto and dissolved by stirring; adding 43.65 g (0.287 mol) L- (+) -mandelic acid (S- (+) -mandelic acid) into the reaction bottle, stirring for 15min to separate out a large amount of white solid; and (5) carrying out suction filtration, and drying the obtained white solid in a vacuum drying oven at 60 ℃ for 8 h. 84.0g of white solid is obtained, which is (S) -2- [ (4-amino pentyl) ethylamino ] ethanol S- (+) -mandelate, with a yield of 90.0%.
The measured specific photometric values were as follows, (S) -2- [ (4-aminopentyl) ethylamino]Ethanol S- (+) -mandelate:
EXAMPLE 8 preparation of S-Hydroxychloroquine side chain
84.0g of (S) -2- [ (4-aminopentyl) ethylamino ] ethanol S- (+) -mandelate prepared in example 7 was dissolved in 200g of water, NaOH was added to adjust pH =8-9, an appropriate amount of sodium chloride was added to the aqueous phase, and anhydrous sodium sulfate was extracted with dichloromethane, dried and concentrated to obtain 44.8 g (0.257 mol) of a colorless oily substance as a free base form of (S) -2- [ (4-aminopentyl) ethylamino ] ethanol (i.e., S-hydroxychloroquine side chain).
Example 9 preparation of S-Hydroxychloroquine sulfate monohydrate
Transferring all S-hydroxychloroquine side chains prepared in example 7 to a three-necked flask, adding 40g (0.202 mol) of 4, 7-dichloroquinoline and 10g of isopropanol, heating at 100 ℃, stirring, reacting for 24h, stopping the reaction, and naturally cooling; adding HCl solution to adjust the pH to be =2, adding 10% NaOH solution to the water phase to adjust the pH to be more than 12, extracting with dichloromethane, and washing the organic phase with water until the pH of the water phase is = 7-8. The organic phase is rotated and evaporated until the brown oily matter is not changed, 67.84g is weighed, 271g of absolute ethyl alcohol (4 times of the mass) is added, and the mixture is stirred and dissolved; dropwise adding a sulfuric acid solution (mass fraction concentration is 51%) until the pH is = 2-3, and reacting at 30 ℃ for 1 hour; stopping heating, cooling, crystallizing, filtering and drying to obtain a white solid which is S- (+) -hydroxychloroquine sulfate monohydrate, the yield is 70.0%, the chemical purity is 99.7% (HPLC), the optical purity is 99.64%, no S-hydroxychloroquine nitrogen oxide impurity is detected, and the water content is 3.98%.
Specific optical rotation of S- (+) -hydroxychloroquine sulfate:
EXAMPLE 10 preparation of (S) -2- [ (4-Aminopentyl) ethylamino ] ethanol S- (+) -mandelate
Weighing 100g of (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol, adding 450g of isopropanol into a round-bottom flask, and stirring to dissolve the ethanol; adding 45g L- (+) -mandelic acid into the reaction bottle, stirring for 15min, and separating out a large amount of white solid; and (5) carrying out suction filtration, and drying the obtained white solid in a vacuum drying oven at 60 ℃ for 8 h. 80.0g of white solid was obtained as (S) -2- [ (4-aminopentyl) ethylamino ] ethanol S- (+) -mandelate salt.
EXAMPLE 11 preparation of S-Hydroxychloroquine side chain
80.0g of (S) -2- [ (4-aminopentyl) ethylamino ] ethanol S- (+) -mandelate obtained in example 10 was dissolved in 200g of water, NaOH was added to adjust pH =8-9, and an appropriate amount of sodium chloride was added to the aqueous phase, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration to obtain 43.2g of a colorless oil as a free base form of (S) -2- [ (4-aminopentyl) ethylamino ] ethanol (i.e., S-hydroxychloroquine side chain).
EXAMPLE 12 preparation of S-Hydroxychloroquine sulfate monohydrate
Transferring all S-hydroxychloroquine side chains prepared in example 11 to a three-necked flask, adding 40g of 4, 7-dichloroquinoline and 10g of isopropanol, heating at 100 ℃, stirring, reacting for 24 hours, stopping the reaction, and naturally cooling; adding HCl solution to adjust the pH to be =2, adding 10% NaOH solution to the water phase to adjust the pH to be more than 12, extracting with dichloromethane, and washing the organic phase with water until the pH of the water phase is = 7-8. The organic phase is rotated and evaporated until brown oily matter is not changed, 65g of the organic phase is weighed, 230g of absolute ethyl alcohol is added, and the mixture is stirred and dissolved; dropwise adding a sulfuric acid solution (mass fraction concentration is 45%) until the pH is = 2-3, and reacting at 30 ℃ for 1 hour; stopping heating, cooling, crystallizing, filtering and drying to obtain a white solid which is S- (+) -hydroxychloroquine sulfate monohydrate, the yield is 75.2%, the chemical purity is 99.8%, the optical purity is 99.71%, no S-hydroxychloroquine nitrogen oxide impurity is detected, and the water content is 4.01%.
EXAMPLE 13 preparation of R- (-) -mandelate salt of (R) -2- [ (4-aminopentyl) ethylamino ] ethanol
100g (0.574 mol) (+ -) -2- [ (4-aminopentyl) ethylamino ] ethanol was weighed into a round-bottomed flask, and 300 g of isopropyl alcohol was added thereto and dissolved by stirring; adding 43.65 g (0.287 mol) D- (-) -mandelic acid (namely R- (-) -mandelic acid) into the reaction bottle, stirring for 15min, and separating out a large amount of white solid; and (5) carrying out suction filtration, and putting the obtained white solid into a vacuum drying oven for drying for 8 h. 84.0g of a white solid was obtained as (R) -2- [ (4-aminopentyl) ethylamino ] ethanol R- (-) -mandelate salt in a yield of 90.0%.
The measured specific photometric values were as follows, (R) -2- [ (4-aminopentyl) ethylamino]Ethanol R- (-) -mandelate:
EXAMPLE 14 preparation of the R-Hydroxychloroquine side chain
84.0g of (R) -2- [ (4-aminopentyl) ethylamino ] ethanol R- (-) -mandelate obtained in example 13 was dissolved in 200g of water, NaOH was added to adjust pH =8-9, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated to obtain 44.8 g (0.257 mol) of a colorless oil as a free base form of (R) -2- [ (4-aminopentyl) ethylamino ] ethanol (i.e., R-hydroxychloroquine side chain).
EXAMPLE 15 preparation of R-Hydroxychloroquine sulfate
All the R-hydroxychloroquine side chains prepared in example 14 were transferred to a three-necked flask, and 40g (0.202 mol) of 4, 7-dichloroquinoline and 10g of isopropanol were added thereto at 100oC, heating, stirring, reacting for 24 hours, stopping the reaction, and naturally cooling; adjusting pH =3-4 by adding HCl solution, and adjusting pH by adding 10% NaOH solution to the above aqueous phase>And 12, extracting with dichloromethane, and washing an organic phase with water until the pH of an aqueous phase is = 7-8 to remove residual chiral side chains. The organic phase is rotated and evaporated until the brown oily matter is not changed, 67.84g is weighed, 271g of absolute ethyl alcohol (4 times of the mass) is added, and the mixture is stirred and dissolved; dropwise adding a sulfuric acid solution (mass fraction concentration is 51%) until the pH is = 2-3, and reacting at 35 ℃ for 1 hour; stopping heating, cooling, crystallizing, filtering and drying to obtain a white solid which is R- (-) -hydroxychloroquine sulfate, wherein the yield is 70.0%, the chemical purity is 99.7% (HPLC), the optical purity is 99.64%, and no R-hydroxychloroquine nitrogen oxide impurity is detected.
Specific optical rotation of S- (+) -hydroxychloroquine sulfate:
EXAMPLE 16 preparation of R- (-) -mandelate salt of (R) -2- [ (4-aminopentyl) ethylamino ] ethanol
Weighing 100g of (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol, adding 450g of isopropanol into a round-bottom flask, and stirring to dissolve the ethanol; adding 45g of D- (-) -mandelic acid into the reaction bottle, stirring for 15min, and separating out a large amount of white solid; and (5) carrying out suction filtration, and drying the obtained white solid in a vacuum drying oven at 60 ℃ for 8 h. 80.0g of a white solid was obtained as (R) -2- [ (4-aminopentyl) ethylamino ] ethanol R- (-) -mandelate salt.
EXAMPLE 17 preparation of the R-Hydroxychloroquine side chain
80.0g of (R) -2- [ (4-aminopentyl) ethylamino ] ethanol R- (-) -mandelate obtained in example 16 was dissolved in 200g of water, NaOH was added to adjust pH =8-9, an appropriate amount of sodium chloride was added to the aqueous phase, and anhydrous sodium sulfate was extracted with methylene chloride, dried and concentrated to obtain 43.2g of a colorless oil as a free base form of (R) -2- [ (4-aminopentyl) ethylamino ] ethanol (i.e., R-hydroxychloroquine side chain).
EXAMPLE 18 preparation of R-Hydroxychloroquine sulfate
Transferring all the R-hydroxychloroquine side chains prepared in example 17 to a three-necked flask, adding 40g of 4, 7-dichloroquinoline and 10g of isopropanol, heating at 100 ℃, stirring, reacting for 24 hours, stopping the reaction, and naturally cooling; adding HCl solution to adjust the pH to be =2, adding 10% NaOH solution to the water phase to adjust the pH to be more than 12, extracting with dichloromethane, and washing the organic phase with water until the pH of the water phase is = 7-8. The organic phase is rotated and evaporated until brown oily matter is not changed, 65g of the organic phase is weighed, 230g of absolute ethyl alcohol is added, and the mixture is stirred and dissolved; dropwise adding a sulfuric acid solution (mass fraction concentration is 45%) until the pH is = 2-3, and reacting at 30 ℃ for 1 hour; stopping heating, cooling, crystallizing, filtering and drying to obtain a white solid which is R- (-) -hydroxychloroquine sulfate, wherein the yield is 73.5%, the chemical purity is 99.8%, the optical purity is 99.71%, and no R-hydroxychloroquine nitrogen oxide impurity is detected.
Claims (10)
1. The A crystal form hydroxychloroquine sulfate is characterized in that an X-ray powder diffraction pattern expressed by a 2 theta angle is 10.8o、13.0o、13.3o、16.9o、17.2o、17.5o、19.9o、21.3o、23.5o、24.0oAnd 26.7o±0.2oHas a characteristic peak;
the A crystal form hydroxychloroquine sulfate does not contain hydroxychloroquine oxynitride.
2. The hydroxychloroquine crystal is characterized in that an X-ray powder diffraction pattern expressed by a 2 theta angle is 7.5o、14.9o、16.5o、19.2o、19.6o、22.8o、23.6oAnd 26.7o±0.2oHas characteristic peaks.
3. The S-hydroxychloroquine sulfate monohydrate is characterized in that an X-ray powder diffraction pattern expressed by a 2 theta angle is 12.2o、13.0o、14.9o、17.8o、22.7o、23.3o、25.0oAnd 26.2o±0.2oHas characteristic peaks.
4. The R-hydroxychloroquine sulfate is characterized in that the X-ray powder diffraction pattern expressed by the 2 theta angle is 12.2o、13.0o、14.9o、17.8o、22.7o、23.3o、25.0oAnd 26.2o±0.2oHas characteristic peaks.
5. A process for preparing hydroxychloroquine sulfate crystalline form a as claimed in claim 1, wherein, in the step of salification, the reaction temperature is not greater than 25 ℃.
6. The method of claim 5, wherein hydroxychloroquine is dissolved in an organic solvent, a sulfuric acid solution is slowly added at 15-25 ℃ to adjust the pH, the temperature is kept at 1 for stirring crystallization, the temperature is reduced to 10-15 ℃, the temperature is kept at 2 for stirring crystallization, and the hydroxychloroquine sulfate of the crystal form A is obtained through filtration and drying.
7. A process for preparing S-hydroxychloroquine sulfate monohydrate as claimed in claim 3, wherein, in the step of salification, the reaction temperature is not more than 30 ℃;
the S-hydroxychloroquine sulfate monohydrate does not contain hydroxychloroquine oxynitride.
8. A process for preparing the R-hydroxychloroquine sulfate of claim 4, wherein, in the salt formation step, the reaction temperature is not greater than 35 ℃;
the R-hydroxychloroquine sulfate does not contain hydroxychloroquine nitrogen oxides.
9. A method for preparing optical pure hydroxychloroquine side chain mandelate is characterized in that (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol is dissolved in an organic solvent, and L- (+) -mandelic acid is added for salification or D- (-) -mandelic acid is added for salification;
the molar ratio of the salified L- (+) -mandelic acid or salified D- (-) -mandelic acid to (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol is 1: 1.9-2.3;
the weight ratio of the (+/-) -2- [ (4-amino pentyl) ethylamino ] ethanol to the organic solvent is 1: 2.5-4.5, wherein the organic solvent is C1-C4 monohydric alcohol.
10. The method of claim 9, wherein the organic solvent is isopropanol.
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| CN113603642A (en) * | 2020-11-16 | 2021-11-05 | 上海中西三维药业有限公司 | Hydroxychloroquine sulfate hydrate, crystal form thereof, preparation method and application thereof |
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