WO2010027150A2 - New preparation of hydroxychloroquine - Google Patents
New preparation of hydroxychloroquine Download PDFInfo
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- WO2010027150A2 WO2010027150A2 PCT/KR2009/004660 KR2009004660W WO2010027150A2 WO 2010027150 A2 WO2010027150 A2 WO 2010027150A2 KR 2009004660 W KR2009004660 W KR 2009004660W WO 2010027150 A2 WO2010027150 A2 WO 2010027150A2
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- WIPO (PCT)
- Prior art keywords
- hydroxychloroquine
- high pressure
- process according
- bars
- reaction
- Prior art date
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- 229960004171 hydroxychloroquine Drugs 0.000 title claims abstract description 27
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title abstract description 11
- HXEWMTXDBOQQKO-UHFFFAOYSA-N 4,7-dichloroquinoline Chemical compound ClC1=CC=NC2=CC(Cl)=CC=C21 HXEWMTXDBOQQKO-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 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 claims description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- 229960002927 hydroxychloroquine sulfate Drugs 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- CRCWPKGKPRVXAP-UHFFFAOYSA-N 2-[4-[(7-chloroquinolin-4-yl)amino]pentyl-ethylamino]ethanol;phosphoric acid Chemical compound OP(O)(O)=O.OP(O)(O)=O.ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 CRCWPKGKPRVXAP-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
- 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
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
Definitions
- the present invention relates to a process for the preparation of hydroxychloroquine which is therapeutically effective as an anti-malarial drug.
- Hydroxychloroquine which is 2-[[4-[7-chloro-4-quinolinyl]amino]pentyl]-ethylamino]ethanol and has a structure of the following formula (1), was first disclosed in US Patent No. 2,546,658.
- This US patent teaches a process for preparing hydroxychloroquine diphosphate, which involves reacting 4,7-dichloroquinoline of the following formula 2 with N'-ethyl-N'- ⁇ -hydroxyethyl-1,4-pentadiamine of the following formula 3 in the presence of potassium iodide (KI) and phenol at a temperature of 125 to 130°C for 18 hours or more to thereby prepare crude hydroxychloroquine to which diphosphate is then attached to obtain hydroxychloroquine diphosphate with a yield of 35% (see Reaction Scheme 1 below).
- KI potassium iodide
- US Patent No. 5,314,894 discloses a process for preparing (S)-(+)-hydroxychloroquine wherein 4,7-dichloroquinoline and (S)-N'-ethyl-N'- ⁇ -hydroxyethyl-1,4-pentadiamine with N,N-diisopropylethylamine (b.p 127°C were heated at reflux for 48 hours to obtain (S)-(+)-hydroxychloroquine with a yield of 46%.
- CA Patent No. 2,561,987 teaches a process for preparing hydroxychloroquine, which involves reacting 4,7-dichloroquinoline (2) with N'-ethyl-N'- ⁇ -hydroxyethyl-1,4-pentadiamine (3) at a temperature of 120 to 130°C for 20 to 24 hours, and introducing a protective group, as illustrated below, to the reaction product so as to facilitate the removal of impurities, followed by hydrolysis of the protective group to obtain a desired product hydroxychloroquine.
- each PG represents a protective group.
- the present invention is intended to provide a novel method for preparing hydroxychloroquine, which is capable of inhibiting the formation of byproducts and decreasing production costs by significantly decreasing a reaction temperature and a reaction time using a certain pressure, without a catalyst and a reaction solvent.
- the present invention provides a novel method for preparing hydroxychloroquine using a pressure, which comprises reacting 4,7-dichloroquinoline with N'-ethyl-N'- ⁇ -hydroxyethyl-1,4-pentadiamine under high pressure to obtain hydroxychloroquine of the formula:
- the method of the present invention provides the preparation of hydroxychloroquine by the reaction of 4,7-dichloroquinoline with N'-ethyl-N'- ⁇ -hydroxyethyl-1,4-pentadiamine without use of a catalyst and a solvent.
- high pressure refers to a more greater pressure than atmospheric pressure(1 atm, about 1 bar), which is preferably in the range of 5 to 30 bars and more preferably 10 to 20 bars.
- the high pressure is exerted by an inert gas such as nitrogen (N 2 ) or argon (Ar) gas or by moisture-free air.
- an inert gas such as nitrogen (N 2 ) or argon (Ar) gas or by moisture-free air.
- the reaction time is preferably within 10 hours and more preferably 6 hours.
- the reaction temperature is preferably in the range of 100 to 120°C, although it may vary.
- a reaction molar ratio of 4,7-dichloroquinoline and N'-ethyl-N'- ⁇ -hydroxyethyl-1,4-pentadiamine is preferably in the range of 1:1.05 to 1.5 and more preferably 1:1.05 to 1.1, although it may vary.
- the present invention provides a process for preparing hydroxychloroquine sulfate, comprising:
- Step (b) reacting the hydroxychloroquine of Step (a) with sulfuric acid (H 2 SO 4 ) to obtain hydroxychloroquine sulfate.
- reaction conditions for Step (a) are as defined above.
- the process is carried out as follows. First, 4,7-dichloroquinoline and N'-ethyl-N'- ⁇ -hydroxyethyl-1,4-pentadiamine in a molar ratio of 1:1.1 were placed into a high pressure reactor. Internal pressure of the reactor is then adjusted to the range of 5 to 20 bars and preferably 10 to 15 bars by nitrogen pressure. The reactor is stirred at 80°C for 30 min until 4,7-dichloroquinoline is completely dissolved, followed by further stirring at a temperature of 100 to 120°C for 4 to 6 hours.
- the present invention enables the production of hydroxychloroquine with high purity and high yield while providing various advantages in that the formation of byproducts is inhibited by decreasing a reaction temperature and significantly decreasing a reaction time using a pressure without use of a catalyst and a reaction solvent, and production costs are reduced.
- Reagents used in following examples are directly available from Dae He Chemical Co., Ltd. (Korea) or otherwise is purchased from Aldrich. All solvents are commercially available from Samsung Fine Chemical Co., Ltd. (Korea).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention provides a process for the preparation of hydroxychloroquine by the reaction of 4,7-dichloroquinoline with N'-ethyl-N'-ß-hydroxyethyl-1,4-pentadiamine under high pressure.
Description
The present invention relates to a process for the preparation of hydroxychloroquine which is therapeutically effective as an anti-malarial drug.
Hydroxychloroquine, which is 2-[[4-[7-chloro-4-quinolinyl]amino]pentyl]-ethylamino]ethanol and has a structure of the following formula (1), was first disclosed in US Patent No. 2,546,658. This US patent teaches a process for preparing hydroxychloroquine diphosphate, which involves reacting 4,7-dichloroquinoline of the following formula 2 with N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine of the following formula 3 in the presence of potassium iodide (KI) and phenol at a temperature of 125 to 130℃ for 18 hours or more to thereby prepare crude hydroxychloroquine to which diphosphate is then attached to obtain hydroxychloroquine diphosphate with a yield of 35% (see Reaction Scheme 1 below).
[Reaction Scheme 1]
US Patent No. 5,314,894 discloses a process for preparing (S)-(+)-hydroxychloroquine wherein 4,7-dichloroquinoline and (S)-N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine with N,N-diisopropylethylamine (b.p 127℃ were heated at reflux for 48 hours to obtain (S)-(+)-hydroxychloroquine with a yield of 46%.
Further, CA Patent No. 2,561,987 teaches a process for preparing hydroxychloroquine, which involves reacting 4,7-dichloroquinoline (2) with N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine (3) at a temperature of 120 to 130℃ for 20 to 24 hours, and introducing a protective group, as illustrated below, to the reaction product so as to facilitate the removal of impurities, followed by hydrolysis of the protective group to obtain a desired product hydroxychloroquine.
In formulae A, B, C, each PG represents a protective group.
However, with currently known methods of preparing hydroxychloroquine and its acid addition salts, there is a difficulty in elimination of undesirable byproducts upon the preparation of acid addition salts, due to using a toxic solvent such as phenol or a reagent such as N,N-diisopropylethylamine, which has a high boiling point and a structure similar to that of the final product. Particularly, a long reaction time at high temperatures may result in increased production costs and buildup of byproducts, for which a higher-efficiency synthesis method of hydroxychloroquine and disulfate is required in related industrial fields.
To this end, there is a need for the development of a novel method of synthesizing hydroxychloroquine, which is capable of overcoming a variety of problems and disadvantages as discussed above and is capable of providing a desired product with higher purity and yield.
The present invention is intended to provide a novel method for preparing hydroxychloroquine, which is capable of inhibiting the formation of byproducts and decreasing production costs by significantly decreasing a reaction temperature and a reaction time using a certain pressure, without a catalyst and a reaction solvent.
The present invention provides a novel method for preparing hydroxychloroquine using a pressure, which comprises reacting 4,7-dichloroquinoline with N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine under high pressure to obtain hydroxychloroquine of the formula:
That is, the method of the present invention provides the preparation of hydroxychloroquine by the reaction of 4,7-dichloroquinoline with N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine without use of a catalyst and a solvent.
As used herein, the term "high pressure" refers to a more greater pressure than atmospheric pressure(1 atm, about 1 bar), which is preferably in the range of 5 to 30 bars and more preferably 10 to 20 bars.
In the context of the present invention, the high pressure is exerted by an inert gas such as nitrogen (N2) or argon (Ar) gas or by moisture-free air.
The reaction time is preferably within 10 hours and more preferably 6 hours.
The reaction temperature is preferably in the range of 100 to 120℃, although it may vary.
A reaction molar ratio of 4,7-dichloroquinoline and N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine is preferably in the range of 1:1.05 to 1.5 and more preferably 1:1.05 to 1.1, although it may vary.
Further, the present invention provides a process for preparing hydroxychloroquine sulfate, comprising:
(a) reacting 4,7-dichloroquinoline with N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine under high pressure to obtain hydroxychloroquine of the formula:
(b) reacting the hydroxychloroquine of Step (a) with sulfuric acid (H2SO4) to obtain hydroxychloroquine sulfate.
Here, reaction conditions for Step (a) are as defined above.
The preparation process of hydroxychloroquine according to the present invention will be described in greater detail hereinafter.
The process is carried out as follows. First, 4,7-dichloroquinoline and N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine in a molar ratio of 1:1.1 were placed into a high pressure reactor. Internal pressure of the reactor is then adjusted to the range of 5 to 20 bars and preferably 10 to 15 bars by nitrogen pressure. The reactor is stirred at 80℃ for 30 min until 4,7-dichloroquinoline is completely dissolved, followed by further stirring at a temperature of 100 to 120℃ for 4 to 6 hours.
The present invention enables the production of hydroxychloroquine with high purity and high yield while providing various advantages in that the formation of byproducts is inhibited by decreasing a reaction temperature and significantly decreasing a reaction time using a pressure without use of a catalyst and a reaction solvent, and production costs are reduced.
Now, the present invention will be described in more detail with reference to the following Examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention.
Reagents used in following examples are directly available from Dae He Chemical Co., Ltd. (Korea) or otherwise is purchased from Aldrich. All solvents are commercially available from Samsung Fine Chemical Co., Ltd. (Korea).
Example 1: Preparation of hydroxychloroquine using pressure of 20 bars
10 kg of 4,7-dichloroquinoline and 11.4 kg (1.0 eq) of N'-ethyl-N'-β -hydroxyethyl-1,4-pentadiamine were introduced into a high pressure reactor which was then filled with nitrogen gas to a pressure of 20 bars and stirred at 80℃ for 30 min, followed by further stirring at 100 to 110℃ for 4 hours. The reactor was cooled to a temperature of about 70 to 80℃. And then 30 kg of a 3N HCl aqueous solution and 20 kg of chloroform were added thereto, and the mixture was cooled to room temperature, stirred for 1 hour, and allowed to stand such that a desired product was transferred to the aqueous layer while the remaining byproducts were transferred to the chloroform layer(This procedure was repeated three times). The aqueous layer containing a desired compound was collected. The thus-collected aqueous layer was extracted again with 40 kg of a 2N NaOH aqueous solution and chloroform to remove the aqueous layer, and 5 kg of activated carbon and 5 kg of alumina was added thereto, followed by stirring at 40℃ for 6 hours and filtration. The filtrate was concentrated under reduced pressure and 60 kg of ethylene dichloride (EDC) was added thereto to result in crystallization. The resulting residue was were filtered and dried under vacuum at 40℃ to afford 14 kg (yield: 78.2%) of the title compound.
1H NMR (500 MHz): δ(CDCl3) 7.47(d), 7.92(d), 7.72(d), 7.33(dd), 6.38(d), 5.09(d), 3.50-3.80(m), 2.40-2.70(m), 1.50-1.80(m), 1.30(d), 1.00(t)
Example 2: Preparation of hydroxychloroquine (formula 1) using pressure of 10 bars
10 kg of 4,7-dichloroquinoline and 11.4 kg (1.0 eq) of N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine were introduced into a high pressure reactor which was then filled with nitrogen gas to a pressure of 10 bars, and stirred at 80℃ for 30 min, followed by further stirring at 100 to 110℃ for 6 hours. The reactor was cooled to a temperature of about 70 to 80℃. And then 30 kg of a 3N HCl aqueous solution and 20 kg of chloroform were added thereto, and the mixture was cooled to room temperature, stirred, and allowed to stand such that a desired product was transferred to the aqueous layer while the remaining byproducts were transferred to the chloroform layer(This procedure was repeated three times). The aqueous layer containing a desired compound was collected. The thus-collected aqueous layer was extracted again with 40 kg of a 2N NaOH aqueous solution and 20 kg of chloroform to remove the aqueous layer, and 5 kg of activated carbon and 5 kg of alumina was added thereto, followed by stirring at 40℃ for 6 hours and filtration. The filtrate was concentrated under reduced pressure and 60 kg of EDC was added thereto to result in crystallization. The resulting residue was filtered and dried under vacuum at 40℃ to afford 14.5 g (yield: 75.5%) of the title compound.
1H NMR (500 MHz) values of the obtained compound were identical with those as in Example 1.
Example 3: Preparation of hydroxychloroquine sulfate
10 kg of hydroxychloroquine prepared in Example 1 was dissolved in 100 kg of ethanol, and the solution was cooled to 10℃. A solution of concentrated sulfuric acid (1.58 kg, 1.0 eq) in 50 kg of ethanol was slowly added thereto with stirring for 12 hours. The reaction solution was filtered to afford 11.0 kg (85.2%) of the title compound as a white material.
1H NMR (300 MHz): δ(D2O) 8.08(d), 7.95(d), 7.53(d), 7.35(dd) 6.64(d), 3.94(d), 3.60-3.70(m), 2.90-3.30(m), 1.50-1.80(m), 1.23(d), 1.09(t)
Example 4: Preparation of hydroxychloroquine sulfate
10 kg of hydroxychloroquine prepared in Example 1 was dissolved in 100 kg of ethyl acetate, and a solution of concentrated sulfuric acid (1.58 kg, 1.0 eq) in 50 kg of ethyl acetate was slowly added thereto with stirring at 30℃. Thereafter, the reaction solution was stirred at 0℃ for 12 hours and filtered to afford 10.0 kg (77.5%) of the title compound as a white material.
1H NMR (500 MHz) values of the obtained compound were identical with those as in Example 3.
Claims (11)
- A process for preparing hydroxychloroquine, comprising reacting 4,7-dichloroquinoline with N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine under high pressure to obtain hydroxychloroquine of the formula:
- The process according to claim 1, wherein the reaction is carried out in the absence of catalyst and solvent.
- The process according to claim 1, wherein the high pressure is 5 bars or higher.
- The process according to claim 3, wherein the high pressure is in the range of 10 to 20 bars.
- The process according to any one of claims 1 to 4, wherein the high pressure is applied by an inert gas such as nitrogen (N2) or argon (Ar) gas or by moisture-free air.
- The process according to any one of claims 1 to 4, wherein the reaction time is within 6 hours.
- The process according to any one of claims 1 to 4, wherein the reaction temperature is in the range of 100 to 120℃.
- A process for preparing hydroxychloroquine sulfate, comprising:(a) reacting 4,7-dichloroquinoline with N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine under high pressure of nitrogen (N2) gas to obtain hydroxychloroquine of the formula:; and
(b) reacting the hydroxychloroquine of Step (a) with sulfuric acid (H2SO4) to obtain hydroxychloroquine sulfate. - The process according to claim 8, wherein the high pressure is 5 bars or higher.
- The process according to claim 9, wherein the high pressure is in the range of 10 to 20 bars.
- The process according to any one of claims 8 to 10, wherein the high pressure is applied by an inert gas such as nitrogen (N2) or argon (Ar) gas or by moisture-free air.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2008-0088070 | 2008-09-08 | ||
| KR1020080088070A KR101115412B1 (en) | 2008-09-08 | 2008-09-08 | New preparation of hydroxychloroquine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2010027150A2 true WO2010027150A2 (en) | 2010-03-11 |
| WO2010027150A3 WO2010027150A3 (en) | 2010-06-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2009/004660 WO2010027150A2 (en) | 2008-09-08 | 2009-08-21 | New preparation of hydroxychloroquine |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR101115412B1 (en) |
| WO (1) | WO2010027150A2 (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102050781A (en) * | 2010-12-21 | 2011-05-11 | 重庆康乐制药有限公司 | Industrial preparation method of hydroxychloroquine sulfate |
| CN103724261A (en) * | 2013-12-13 | 2014-04-16 | 武汉武药制药有限公司 | Novel industrial production method for hydroxychloroquine sulfate |
| CN104230803A (en) * | 2014-08-28 | 2014-12-24 | 重庆康乐制药有限公司 | Preparation method of hydroxychloroquine sulfate |
| CN108727263A (en) * | 2018-07-05 | 2018-11-02 | 上海中西三维药业有限公司 | Hydroxychloroquine sulfate crystal form A and preparation method thereof |
| CN109280029A (en) * | 2018-12-11 | 2019-01-29 | 上海应用技术大学 | A kind of preparation method of hydroxychloroquine sulfate |
| CN109456266A (en) * | 2018-11-12 | 2019-03-12 | 南京天际联盟医药科技有限公司 | The novel preparation method of hydroxychloroquine sulfate |
| WO2019165337A1 (en) * | 2018-02-26 | 2019-08-29 | Virginia Commonwealth University | High-yielding continuous flow synthesis of antimalarial drug hydroxychloroquine |
| CN111551645A (en) * | 2020-04-30 | 2020-08-18 | 上海中西三维药业有限公司 | Method for detecting hydroxychloroquine sulfate related substances and application thereof |
| CN112300071A (en) * | 2020-11-25 | 2021-02-02 | 张家港威胜生物医药有限公司 | Synthetic method of high-purity chloroquine phosphate |
| CN113072491A (en) * | 2020-01-06 | 2021-07-06 | 欣凯医药化工中间体（上海）有限公司 | Preparation method of hydroxychloroquine sulfate |
| CN113149904A (en) * | 2021-03-02 | 2021-07-23 | 南京海纳医药科技股份有限公司 | Refining method of hydroxychloroquine crude product |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2546658A (en) * | 1949-07-23 | 1951-03-27 | Sterling Drug Inc | 7-chloro-4-[5-(n-ethyl-n-2-hydroxyethylamino)-2-pentyl] aminoquinoline, its acid addition salts, and method of preparation |
| US5314894A (en) | 1992-09-15 | 1994-05-24 | Sterling Winthrop Inc. | (S)-(+)-hydroxychloroquine |
| WO2005062723A2 (en) | 2003-11-24 | 2005-07-14 | Ipca Laboratories Limited | An improved process for the preparation of 7-chloro-4-(5-n-ehtyl-n-2-hydroxyethylamine)-2-pentyl] aminoquinoline and its intermediates |
| CA2561987A1 (en) * | 2006-10-02 | 2008-04-02 | Apotex Pharmachem Inc. | Process for the preparation of highly pure hydroxychloroquine or a salt thereof |
-
2008
- 2008-09-08 KR KR1020080088070A patent/KR101115412B1/en not_active IP Right Cessation
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2009
- 2009-08-21 WO PCT/KR2009/004660 patent/WO2010027150A2/en active Application Filing
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102050781A (en) * | 2010-12-21 | 2011-05-11 | 重庆康乐制药有限公司 | Industrial preparation method of hydroxychloroquine sulfate |
| CN103724261A (en) * | 2013-12-13 | 2014-04-16 | 武汉武药制药有限公司 | Novel industrial production method for hydroxychloroquine sulfate |
| CN104230803A (en) * | 2014-08-28 | 2014-12-24 | 重庆康乐制药有限公司 | Preparation method of hydroxychloroquine sulfate |
| WO2019165337A1 (en) * | 2018-02-26 | 2019-08-29 | Virginia Commonwealth University | High-yielding continuous flow synthesis of antimalarial drug hydroxychloroquine |
| US12071410B2 (en) | 2018-02-26 | 2024-08-27 | Virginia Commonwealth University | High-yielding continuous flow synthesis of antimalarial drug hydroxychloroquine |
| CN108727263A (en) * | 2018-07-05 | 2018-11-02 | 上海中西三维药业有限公司 | Hydroxychloroquine sulfate crystal form A and preparation method thereof |
| CN109456266A (en) * | 2018-11-12 | 2019-03-12 | 南京天际联盟医药科技有限公司 | The novel preparation method of hydroxychloroquine sulfate |
| CN109280029A (en) * | 2018-12-11 | 2019-01-29 | 上海应用技术大学 | A kind of preparation method of hydroxychloroquine sulfate |
| CN113072491A (en) * | 2020-01-06 | 2021-07-06 | 欣凯医药化工中间体（上海）有限公司 | Preparation method of hydroxychloroquine sulfate |
| CN111551645A (en) * | 2020-04-30 | 2020-08-18 | 上海中西三维药业有限公司 | Method for detecting hydroxychloroquine sulfate related substances and application thereof |
| CN112300071A (en) * | 2020-11-25 | 2021-02-02 | 张家港威胜生物医药有限公司 | Synthetic method of high-purity chloroquine phosphate |
| CN113149904A (en) * | 2021-03-02 | 2021-07-23 | 南京海纳医药科技股份有限公司 | Refining method of hydroxychloroquine crude product |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010027150A3 (en) | 2010-06-17 |
| KR20100029332A (en) | 2010-03-17 |
| KR101115412B1 (en) | 2012-06-12 |
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