Production process for hydroxychloroquine under concentrated conditions

Abstract

The present invention discloses an improved, practical and solvent-accelareted process for the synthesis of hydroxychloroquine by the reaction of 4,7- dichloroquinoline and 2-[(4-aminopentyl)(ethyl)amino]ethanol under concentrated conditions.

Description

[0001] DESCRIPTION PRODUCTION PROCESS FOR HYDROXYCHLOROQUINE UNDER CONCENTRATED CONDITIONS

[0002] Technical Field of the Invention

[0003] The present invention relates to an improved production process for hydroxychloroquine (HCQ) (I) under concentrated conditions. HCQ (I) has been used as an anti-malarial drug as well as a non-steroidal anti-inflammatory drug in the treatment of rheumatoid arthritis in patients with cardiovascular diseases. The invention discloses an advanced process for the production of hydroxychloroquine (I) that offers ease of application and efficiency.

[0004] Prior Art

[0005] Hydroxychloroquine (I) (2-[4-[[7-chloro-4-quinolinylamino]pentyl]-ethylamino]ethanol; CAS No. 118-42-3) was discovered in 1950 (Surrey and Hammmer, J. Am. Chem. Soc. 1950, Vol. 72(4), pp. 1814-1815). US Patent No. 2,546,658 in 1951 discloses isolation of its diphosphate salt. It is usedas a non-steroidal anti-inflammatory drug in the treatment of malaria and rheumatoid arthritis in patients with cardiovascular diseases. It is administered orally in the form of its sulfate salt, hydroxychloroquine sulfate (II).

[0006] In the state of the art, the synthesis of hydroxychloroquine (I) is generally carried out by heating of 4,7-dichloroquinoline (DCQ, III) and hydroxynovaldiamine (HNDA, IV, 2- [(4-aminopentyl)(ethyl)amino]ethanol) in different stoichiometric ratios at high temperatures (>125 °C) in a solvent-free environment for a long time period (18-36 hours).

[0007] Surrey and Hammmer, J. Am. Chem. Soc. 1950, Vol. 72(4), pp. 1814-1815, disclosed in 1950 the first synthesis of hydroxychloroquine (I) by heating 4,7-dichloroquinoline (III) with hydroxynovaldiamine (IV) at 130 °C for 18 hours in the presence of overstoichiometric amount of phenol (2.10 molar equivalents relativeto DCQ). Thus, hydroxychloroquine (I) was isolated with a 71 % yield.

[0008] Further, the following articles and patents have been published for the synthesis of hydroxychloroquine (I) in the state of the art.

[0009] In the United Kingdom patent document GB 680255 dated 1952 it was shown that adding a catalytic amount of potassium iodide (1 .3 mol%) to the reaction mixture, along with an excess stoichiometric amount of phenol (2.10 molar equivalents), in the synthesis of hydroxychloroquine (I) from 4,7-dichloroquinoline (III) and hydroxyethylaminoethylamine (IV) was beneficial for the reaction yield; hydroxychloroquine was obtained with a 73% yield after 18 hours at 130 °C.

[0010] Herbert et al., Tetrahedron: Asymmetry 1994, Vol. 5(9), pp. 1815-1822, disclose the use of N,N-diisopropylethylamine (1.16 mol equivalents) for the synthesis of enantiopure (S)-hydroxychloroquine ((S)-l) and (R)-hydroxychloroquine ((R)-l) from DCQ (III) and (S)-HNDA or (R)-HNDA, respectively. After 96 hours at 125 °C, (S)-l or (R)-l is obtained in 78% yield.

[0011] Patent document WO 2005 / 062723 dated 2005 discloses that hydroxychloroquine (I) can be produced in 77% yield at lower temperatures (such as 110 °C) in the presence of catalytic amounts of potassium iodide (5 mol%) and sodium hydroxide (40 mol%).

[0012] Canada patent document CA 2561987 dated 2008 discloses that hydroxychloroquine (I) is obtained in 80% yield from the reaction of DCQ (III) and HNDA (IV) at 130 °C for 24 h, in methanol (MeOH), ethanol (EtOH) or 2-propanol ( / -PrOH) as solvent. The purpose of using the solvent is claimed to be to create a homogeneous mixture of 4,7- DCQ (III) and HNDA (IV), which are not homogeneously miscible by themselves, making large-scale applications more efficient and safer. In a given example, an homogeneous mixture consisting of DCQ (0.5 mol), HNDA (0.75 mol) and the solvent (i.e. , / -PrOH) is heated and the solvent is practically completely removed by distillation; the resulting mixture is then heated to 130 °C and stirred for 24 hours. In the present invention, however, the solvent effect as well as the effect of the amount of the solvent on the yield of HCQ (I) have been disclosed; by employing a certain amount of dimethyl sulfoxide (e.g., 1.00 mol equivalent relative to DCQ), HCQ is obtained with a higher yield compared to the solvent free condition.

[0013] China patent document CN 202111599460 dated 2021 discloses the synthesis of HCQ from DCQ (III) and HNDA (IV) at 110 °C using a catalytic amount of phenol together with an alcohol (propanol, 2-propanol, n-butanol, 2-butanol). In a given example, HCQ (I) is prepared in 69% yield from DCQ (1.00 mol equiv) and HNDA (1.13 mol equiv) at 110 °C for 7 hours in the presence of 2-propanol (1 .30 mol equiv) and fenol (0.40 mol equiv).

[0014] Patent document WO 2010 / 027150 dated 2010 teaches DCQ (1.00 mol equiv) and HNDA (1.10 mol equiv) can undergo reaction at 110 °C to 120 °C for 4-6 hours under high pressure (10-20 bar) provided by nitrogen gas to give HCQ. It is claimed that HCQ (I) can be synthesized in 76% yield at 110 °C which is the lowest reaction temperature reported so far. Although the technique is remarkable in terms of the low temperature applied, it requires a special pressure-resistant reactor.

[0015] The method presented in the present invention does not require the use of a pressure- resistant reactor.

[0016] The Chinese patent document CN 103724261 dated 2013 discloses that HCQ (I) can be synthesized in high yield (88%) from DCQ (III) and HNDA (IV) by increasing the reaction temperature gradually. The reaction temperature is first increased to 100 °C from the rom temperature, held at this temperature for a period of 1 hour, then increased to 130 °C and stirred at this temperature for 20 hours. Remarkable yields are attained by employing almost stoichiometrically equivalent amounts of DCQ (III) and HNDA (IV) (1 :1.1 mol equivalent ratio).

[0017] The Chinese patent document CN 104230803 dated 2014 discloses that the use of catalytic amount of sodium ethoxide (NaOC2H5, 20 mol%) can accelerate the formation of HCQ (I) from DCQ (III) and HNDA (IV), thus providing 88% yield in 13 hours at 120 °C.

[0018] Patent document WO 2019 / 165337 dated 2019 discloses an integrated continuous flow process for the synthesis of hydroxychloroquine (I). DCQ (III) and HNDA (IV) are reacted in ethanol in the presence of triethylamine (0.55 mol equiv) and potassium carbonate (0.50 mol equiv). It was reported that hydroxychloroquine (I) was obtained with 78% yield using silica gel flash chromatography after stirring the reaction mixture at 125°C for 6 hours.

[0019] The Chinese patent document CN 109456266 dated 2018 discloses that the reaction between DCQ (III) and HNDA (IV) to give HCQ can be catalyzed by alumina loaded with potassium fluoride.

[0020] In the present invention, it is disclosed that, unlike the prior arts discussed above, HCQ (I) and its sulfate salt (II) can be obtained with high yields (88% yield) without using special equipments such as high-pressure reactors.

[0021] Technical Problem That the Invention Aims to Solve

[0022] The present invention is intended to overcome the disadvantages of the existing methods for the synthesis of hydroxychloroquine in the state of the art.

[0023] The main disadvantages of the above-mentioned methods are as follows.

[0024] (i) DCQ (III) is a solid and HNDA (IV) is a viscous liquid and they do not mix homogeneously with each other. On the other hand, DCQ (III) sublimes easily at high temperatures (>90 °C). These two conditions lead to reproducibility problems in the methods of synthesizing hydroxychloroquine (I) from DCQ (III) and HNDA (IV) by heating under solvent-free conditions, thus requiring the design of special reactors.

[0025] (ii) In methods requiring pressure (e.g. WO 2010 / 027150), special pressure-resistant reactors must be used.

[0026] (iii) Some methods in the state of the art require the use of catalysts or promoters, such as phenol (US 2546658), potassium iodide (GB 680255 and WO 2005 / 062723), sodium ethoxide (CN 104230803), triethylamine (WO 2019 / 165337). The use of these catalysts in the reaction results in an increase in purification steps and production costs.

[0027] (iv) New methods that provide satisfactory results in terms of reaction efficiency, product selectivity and ease of application are needed.

[0028] The present invention discloses a method with higher efficiency and higher product selectivity that exploits the accelerating effect of a certain amount of certain organic solvents (such as dimethyl sulfoxide, acetonitrile, 2-propanol) on the formation of HCQ (I) from DCQ (III) and HNDA (IV) using standard reactors. Thus, the need for special catalysts or special reactors reported in the methods of the state of the art has been eliminatedand the reaction efficiency has increased.

[0029] Figure 1. Hydroxychloroquine (I) process flow diagram

[0030] Figure 2. Hydroxychloroquine sulfate (II) process flow diagram

[0031] Chemicals

[0032] Hydroxychloroquine (HCQ)

[0033] II. Hydroxychloroquine sulfate (HCQS)

[0034] III. 4,7-Dichloroquinoline (DCQ)

[0035] IV. Hydroxynovaldiamine (HNDA)

[0036] V. Organic solvent

[0037] VI. Dichloromethane (DCM)

[0038] VII. Distilled water

[0039] VIII. Waste water

[0040] IX. 1 N aqueous NaOH solution

[0041] X. 8 N aqueous HCI solution

[0042] XI. Absolute ethanol (EtOH)

[0043] XII. Solution of 0.4 M H2SO4 in ethanol

[0044] XIII. Filtrate ethanol (EtOH) Operations (Figure 1)

[0045] Ai. The reactor is first evacuated (10 mBar) and backfilled with nitrogen,

[0046] A2. Heating and mixing operations carried out under nitrogen atmosphere in the reactor (at 110-135 °C for 12-40 hour),

[0047] B. Dissolving and cooling done in the reactor (at 20-25 °C for 15-30 minutes),

[0048] C. pH adjustment and washing (pH 11-13, 25 °C),

[0049] D. Phase separation in the decanter

[0050] E. pH adjustment and washing are done (pH 3.4-4.0, 20-25 °C, 15-30 minutes),

[0051] F. Phase separation in the decanter

[0052] G. pH adjustment and washing (pH 12-14, 25 °C),

[0053] H. Phase separation

[0054] J. Washing (1 time)

[0055] K. Evaporation (600-800 mBar, 25-35 °C),

[0056] L. Drying (0.1-0.5 mBar, 10-12 hour, 25-30 °C),

[0057] Operations (Figure 2)

[0058] M. Cooling in the reactor (15-25 °C),

[0059] N. Heating in the reactor (60-80 °C, 30-60 minutes),

[0060] P. Filtration and washing (with absolute ethanol),

[0061] R. Drying (50-100 mBar, 40-50 °C, 10-12 hours)

[0062] Disclosure of the Invention

[0063] In order to improve the state of the art, the present invention offers a high-yield synthesis method of hydroxychloroquine (HCQ, I) from 4,7-dichloroquinoline (DCQ, III) and hydroxynovaldiamine (HNDA, IV) by using certain amounts of some ordinary organic solvents. The HCQ production process disclosed by the invention comprises the following steps as shown in the process flow diagram in Figure 1 :

[0064] (A1 ) DCQ (1 .00 mol equiv) and HNDA (1 .40-1 .50 mol equiv) are weighed and loaded into a reactor. The reactor is evacuated for 15 minutes using vacuum manifold and filled back with nitrogen, (A2) The organic solvent (V) (0.20-5.00 mol equiv) is added to the reactor under a positive pressure of nitrogen atmosphere and the reactor is heated to 110-135 °C using a thermocirculator and the resulting mixture is stirred for 12-40 hours,

[0065] (B) The cooled reaction mixture is dissolved in dichloromethane (VI).

[0066] (C) Distilled water (VII) is added to the mixture, the pH value of the aqueous phase of the resulting two-phase mixture is adjusted to 11.0-13.0 using 1.0 N aqueous sodium hydroxide (IX) solution,

[0067] (D) The phases are separated,

[0068] (E) Distilled water (VII) is added to the organic phase, the pH value of the aqueous phase of the resulting mixture is adjusted to 3.4-4.0 using 8.0 N hydrochloric acid (X) and the mixture is stirred for phase separation at 20-25 °C for 15-30 minutes,

[0069] (F) The phases are separated,

[0070] (G) Dichloromethane (VI) is added to the aqueous phase, the pH value of the aqueous phase of the two-phase mixture is adjusted to 12.0-14.0 using 1.0 N aqueous sodium hydroxide (IX),

[0071] (H) The phases are separated,

[0072] (J) The organic phase is washed with water,

[0073] (K) Volatile components of the organic phase are evaporated (600-800 mbar, 25-35 °C),

[0074] (L) Hydroxychloroquine (I) obtained after evaporation is dried in vacuum (0.1 -0.5 mbar) at 25-30 °C for 12 hours.

[0075] HCQ synthesis method of the invention involves the reaction of DCQ (III) and HNDA (IV) in the presence of a certain amount of a certain organic solvent and / or additive.

[0076] In a preferred embodiment of the present invention, the organic solvent added to the system in step A2 of the process flow diagram shown in Figure 1 , which provides increased yield in the synthesis of HCQ (I) from DCQ (III) and HNDA (IV), is dimethyl sulfoxide, / so-propanol or acetonitrile. In a more preferred application, the solvent used is dimethyl sulfoxide (DMSO). In a more preferred application, the amount of solvent to be used is in the range of 0.50-1.50 molar equivalents relative to DCQ (III). The preferred temperature in step A2 is 130 °C and the duration time is 24 hours.

[0077] In the present invention, it has been observed that the reaction necessary for the synthesis of HCQ (I) proceeds with higher yield in the presence of some of the above- mentioned organic solvents and / or additives compared to neat (solvent-free) reaction conditions.

[0078] The present invention offers advantages such as increasing the reaction yield, reducing impurities in the reaction mixture, and enabling easier purification of HCQ (I) by using 0.2-5.0 mol equivalent amounts of the preferred solvents (e.g. DMSO).

[0079] In addition, the use of 0.2-5.0 molar equivalents amount of the solvent in the present invention ensures that the reaction mixture is completely homogeneous and practically prevents the sublimation of DCQ. Thus, HCQ (I) can be synthesized in common reactors without the need for special reactors.

[0080] The formation reaction of HCQ (I) from DCQ (III) and HNDA (IV) is a nucleophilic aromatic substitution (SuAr) reaction. It is widely known that in SuAr reactions, the choice of solvent is crucial for reaction results by affecting the reaction mechanism, reaction rate and selectivity (C. Reichardt, Solvent and Solvent Effects in Organic Chemistry 3rd edition, Weinheim: Wiley-VCH, 2003).

[0081] During the development of the present invention, the solvent effect on the formation of HCQ (I) from DCQ (III) and HNDA (IV) was investigated (Tablel ). The test reactions in Table 1 and the determination of conversions and yields are carried out as follows: An oven-dried 10 mL Schlenk tube equipped with a magnetic stirring bar and capped with a glass stopper is charged with DCQ (2.0 mmol, 1 .00 molar equivalent) and HNDA (3.0 mmol, 1 .50 equivalent). The tube was closed and connected to a vacuum-nitrogen system. After evacuating the tube for 15 min, the system is backfilled with dry nitrogen. If the test reaction will be carried out in the presence of a solvent, the amount of solvent specified in Table 1 is added to the test tube under positive pressure nitrogen atmosphere. The closed test tube is immersed in an oil bath at the temperature specified in Table 1 and the reaction mixture is stirred for the duration specified in Table 1 . After the time specified in Table 1 , the reaction mixture is removed from the oil bath and allowed to cool to room temperature. After the reaction mixture is cooled to room temperature, it is dissolved in dichloromethane (ca. 50 mL) and transferred into a beaker. 50 mL of distilled water are added to the beaker. The pH value of the aqueous phase was adjusted to 12 with 1.0 N aqueous solution of NaOH. The two-phase mixture is transferred into a separatory funnel. The phases are separated, the organic phase (dichloromethane phase) washed twice with distilled water (2 x 50 mL). The organic phase is transferred into a round bottom flask, volatile components in the flask are removed under vacuum (0.1 mbar, 30 °C, 1 hour) by rotary evaporatorion. The remaining viscous residue is dissolved in dichloromethane (10 mL). To the homogeneous solution in the flask, 1 ,3,5-trimethylbenzene (240.2 mg, 2.0 mmol, 1.00 molar equivalents) is added as an internal standard. 0.2 mL of the resulting homogenous solution is mixed with 0.3 mL deuterochloroform (CDCh) in an NMR tube. The1H NMR spectrum is recorded and the conversion of DCQ (III) and the yield of HCQ (I) are calculated from the spectrum.

[0082] In the present invention, the formation of hydroxychloroquine (I) from DCQ (III) and HNDA (IV) was first tested at different temperatures (110, 120 and 130 °C) under solvent-free conditions, to determine the effect of temperature on the reaction (See Table 1 , entries 1-3). The effect of different types of organic solvents on conversion and yield was tested at 110 °C in order to compare with the results obtained under solvent-free conditions. Preferably at least one of the following solvents was used in the screening reactions for the synthesis of hydroxychloroquine (I): Xylenes, p-xylene, toluene, ethyl acetate (EtOAc), / so-propyl acetate ( / -PrOAc), tetrahydrofuran (THF), 2- methyltetrahydrofuran (2-MeTHF), ethanol (EtOH), / so-propanol ( / -PrOH), n-butanol (n-BuOH), 2-butanol (sec-butanol), / so-butanol ( / -BuOH), fe / Y-butanol (f-BuOH), 2,2,2- trifluoroethanol (TFE), 1 ,1 ,1 ,3,3,3-hexafluoro-2-propanol (HFIP), dimethyl formamide (DMF), dimethyl acetamide (DMA), ZV-methyl-2-pyrrolidine (NMP), dimethyl carbonate (Me2CO3), ethylene carbonate, acetonitrile (CH3CN), dimethyl sulfoxide (DMSO). Among these, those that provide higher yield are reflected in Table 1 , while the others are not included. No transformation was observed when solvents not listed in Table 1 were used. The best solvents that provide the best progress in terms of conversion and selectivity in the reactions carried out at 110 °C are, in a decreasing order, dimethyl sulfoxide (DMSO), / so-propanol and acetonitrile (See Table 1 , entries 4-9). In experiments conducted with these three solvents at 130 °C, DMSO was superior in terms of conversion and yield (See Table 1 , entries 10-12). In experiments conducted at 130 °C, even better results were achieved in terms of conversion and yield if 1.00 molar equivalent of DMSO or / so-propanol relative to DCQ was used. It was observed that DMSO afforded the highest yield (See Table 1 , entry 13 and 14). Table 1. Synthesis of hydroxychloroquine (I) from 4,7-dichloroquinoline (III) and hydroxynovaldiamine (IV).a a Reactions were carried out under nitrogen atmosphere. b Conversions and yields were determined with aid of 1 H qNMR spectroscopy by adding 1 ,3,5- trimethylbenzene (mesitylene) into the combined organic phases after aqueous extractive work-up of the reaction mixtures

[0083] Additionally, it was observed that the amount of DMSO used is crucial to attain high conversion and yield (Table 1 , entries 15-20). 20 experiments whose results explicitly demonstrate the effect of the amount and the type of the solvent are shown in Table 1.

[0084] The present invention also provides a process flowchart diagram for the production of hydroxychloroquine sulfate (II) using hydroxychloroquine (I) produced by the method set forth in the present invention (Figure 2). The process flow diagram shown in Figure 2 comprises the following process steps:

[0085] (M) HCQ (1.00 molar equivalent) is weighed and placed into a double-jacketed glass reactor equipped with a mechanical stirrer and absolute ethanol (4.0-5.0 L absolute ethanol relative to 1 .00 mol of HCQ) is added to the reactor to dissolve HCQ. A 0.4 M sulfuric acid-ethanol solution (1.00 molar equivalent H2SO4 relative to HCQ) is added dropwise. The addition rate is adjusted so that the temperature of the mixture does not exceed 25 °C.

[0086] (N) The mixture is heated to 60-80 °C and stirred at this temperature for 30-60 minutes.

[0087] (O) Heating is stopped, and it is left to cool down (15-25 °C) with stirring at approximately 50 rotation per minute for 6-12 hours and allowed to crystallization.

[0088] (P) The white crystals formed are filtered and washed with absolute ethanol.

[0089] (R) The white crystalline product is dried first in air and then under vacuum (50-100 mbar) at 40-50 °C for 10-12 hours.

[0090] The present invention is described below in more detail and specifically with an example. The claims presented for the invention are not limited to the examples given in this description but include Example 1 for the production of hydroxychloroquine (I) and Example 2 for the production of hydroxychloroquine sulfate (II).

[0091] Example 1 : Synthesis of Hydroxychloroquine (I)

[0092] A 50 mL double-jacketed glass reactor that is equipped with a magnetic stirring bar is charged with DCQ (III) (9.90 g, 50.0 mmol, 1 .00 molar equiv) and HNDA (IV) (13.07 g, 75.0 mmol). The reactor was capped with a glass stopper, evacuated for 15 min and back-filled with dry nitrogen (A1). Dimethyl sulfoxide (V) (3.91 g, approximately 3.55 mL, 50.0 mmol) is added to the reactor under positive pressure nitrogen atmosphere. The reactor is heated to 130 °C with the help of a thermocirculator and stirred at 130 °C for 24 hours (A2). After cooling the reaction mixture is cooled down to room temperature, it is dissoved in 200 mL dichloromethane (B) and transferred to another reactor then 3 x 200 = 600 mL distilled water (VII) is added. While stirring the two- phase mixture by a mechanic stirrer, the pH value of the aqueous phase is adjusted to 12 using 1.0 N aqueous NaOH (C). During this process, 50 mL NaOH(aq) (1.0 N) is consumed. After separation of the phases, the aqueous phase is discarded (D). 100 mL distilled water is added to the organic phase. While the resulting two-phase mixture is stirred, the pH value of the aqueous phase is adjusted to 3.4 using 8.0 N aqueous HCI (E). The phases are then separated (F); unreacted DCQ remains in the dichloromethane phase, and the product hydroxychloroquine hydrochloride in the aqueous phase. 3 x 200 = 600 mL DCM (VI) is aded to the aqueous phase. With stirring, the pH value of the aqueous phase of the two-phase mixture is adjusted to 12.0 by adding 1.0 N aqueous NaOH (G). 50 mL aqueous NaOH (1.0 N) is consumed for this process. The phases are separated (H), and the organic phase is washed once with 200 mL water (J). The solvent and other volatile components are removed by evaporation under 800 mBar vacuum (K). The resulting residue is crude hydroxychloroquine (HCQ) which is then dried in vacuum (0.1 mbar) at 25 °C for 12 hours (L). The purity of the product (HCQ) is checked by 1 H NMR. NMR-pure hydroxychloroquine (14.74 g, 43.9 mmol, 88% yield) (I) is obtained as a colorless viscous liquid with the following properties:1H NMR (600 MHz, CDCIs): 5 = 8,48 (d, J = 5,4 Hz, 1 H), 7,92 (d, J = 2,0 Hz, 1 H), 7,71 (d, J = 9,0 Hz, 1 H), 7,31 (dd, J = 8,9, 1 ,6 Hz, 1 H), 6,38 (d, J = 5,4 Hz, 1 H), 5,06 (d, J = 6,9 Hz, 1 H), 3,70-3,66 (m, 1 H), 3,55 (td, J = 5,3, 1 ,9 Hz, 2H), 3,08 (br s, 1 H), 2,59-2,52 (m, 4H), 2,50-2,45 (m, 2H), 1 ,73-1 ,67 (m, 1 H), 1 ,63-1 ,51 (m, 3H), 1 ,29 (d, J = 6,4 Hz, 3H), 0,99 (t, J = 7,1 Hz, 3H).13C{1H} NMR (150 MHz, CDCI3): 5 = 152,0, 149,3, 149,1 , 134,9, 128,8, 125,2, 121 ,2, 117,3, 99,2, 58,5, 54,8, 53,0, 48,4, 47,5, 34,4, 24,1 , 20,5, 11 ,8.13C{1H} NMR (APT, 100 MHz, CDCI3): 5 = 152,0 (CH), 149,3 (C), 149, 1 (C), 134,9 (C), 128,8 (CH), 125,2 (CH), 121 ,2 (CH), 117,3 (C), 99,2 (CH), 58,5 (CH2), 54,8 (CH2), 53,0 (CH2), 48,4 (CH), 47,5 (CH2), 34,4 (CH2), 24,1 (CH2), 20,5 (CH3), 11 ,8 (CH3). HRMS (ESI-TOF): m / z [M + H]+calculated for C18H27CINO3: 336,1837; found: 336,1871.

[0093] Example 2: Synthesis of Hydroxychloroquine Sulfate (II)

[0094] A 2 L double-jacketed glass reactor that is equipped with a mechanical stirrer and connected to a thermocirculating cooler is charged with hydroxychloroquine (33.6 g, 100 mmol). HCQ is dissolved upon addition of 450 mL of absolute EtOH to obtain a homogeneous solution. The resulting homogeneous mixture is cooled to 15 °C with the aid of the circulating cooler. While stirring the mixture by the mechanical stirrer (100-200 rpm), 250 mL of 0.4 M sulfuric acid solution (100 mmol H2SO4) in ethanol is added dropwise keeping the temperature below 25 °C (M). After the addition of ethanolic H2SO4, the mixture is stirred for 30 minutes at approximately 60 °C (N). Heating is stopped, and the reaction mixture is left to cool down (15-25 °C) and crystallize for 6-12 hours with stirring at a rate of approximately 50 rpm (O). The resulting white solid crystals are filtered through a 20 pm filter and washed with 100 mL absolute ethanol (P). The product is first dried in air and then under vacuum (50 mbar) at 50 °C for 12 hours (R). Thus, hydroxychloroquine sulfate (II) (40.4 g, 93 mmol, 93% yield) is obtained. Melting point: 246-247 °C. UV-Vis (HCI(aq)): Amax (Abs.) = 343 nm (0,4447), 329 nm (0,4051 ), 256 nm (0,3673), 236 (0,4225), 221 nm (0,7312). FTIR (KBr): i / max (crrr1) = 3400 (m, v(O-H)), 3222 (m, v(N-H)), 3089 (m, v(Carom-H)), 2970 (m, v(Caiiph-H)), 2930 (m, v(Caiiph-H)), 1632 (s, v(C=C)), 1614, 1552, 1458, 1342, 1248, 1215, 1115, 823, 619.1H NMR (400 MHz, D2O): 5 = 8,16-8,14 (m, 1 H), 7,96-7,91 (m, 1 H), 7,45-7,42 (m, 1 H), 7,33-7,28 (m, 1 H), 6,73-6,71 (m, 1 H), 4,02 (br s, 1 H), 3,82 (t, J = 5,1 Hz, 2H), 3,26-3,20 (m, 6H), 1 ,81-1 ,73 (m, 4H), 1 ,37 (d, J = 6,4 Hz, 3H), 1 ,23 (t, J = 7,3 Hz, 3H).13C{1H} NMR (APT, 100 MHz, D2O): 5 = 154,8 (C), 142,0 (CH), 138,8 (C), 137,5 (C), 126,9 (CH), 123,9 (CH), 118,5 (CH), 114,6 (C), 98,5 (CH), 55,2 (CH2), 53,6 (CH2), 52,0 (CH2), 49,4 (CH), 48,2 (CH2), 48,1 (CH2), 31 ,7 (CH2), 20,0 (CH2), 18,6 (CH3), 7,8 (CH3).

[0095] Application of the Invention to Industry

[0096] Hydroxychloroquine (I), obtained as a result of the production method of the present invention, is used in the treatment of malaria and rheumatoid arthritis diseases.

Claims

CLAIMS1. A method for synthesizing hydroxychloroquine (I), characterized by the steps of: a) reacting 4,7-dichloroquinoline (III) and hydroxynovaldiamine (IV) in the presence of an organic solvent in an amount ranging from 0.20 - 5.00 molar equivalents relative to 4,7-dichloroquinoline (III) under nitrogen atmosphere (A1 ), b) stirring and heating the resulting mixture at a temperature between 110-135 °C for 12-40 hours (A2),(c) adding dichloromethane (VI) to the cooled mixture to dissolve (B),(d) adding distilled water (VII) to the mixture followed by adjusting the pH value of the aqueous phase to 11 .0-13.0 using 1 .0 N aqueous NaOH (IX) solution (C),(e) separating the resulting two phases (D),(f) adding distilled water (VII) to the separated organic phase followed by adjusting the pH value of the aqueous phase to 3.4-4.0 using 8.0 N aqueous HCI (X) solution and stirring the mixture at 20-25 °C for 15-30 minutes to allow phase separation(E),(g) separating the resulting two phases (F),(h) adding dichloromethane to the separated aqueous phase followed by adjusting the pH value of the aqueous phase to 12.0-14.0 using 1 .0 N aqueous NaOH (IX) solution (G),(i) separating the resulting two phases (H),(j) washing the separated organic phase with distilled water (VII) (J),(k) evaporating the volatile components of the organic phase (K),(l) drying the product (hydroxychloroquine) in vacuum.

2. The method as in claim 1 , wherein the organic solvent (V) used in step (A1 ) is preferably one or more selected from / so-propanol ( / -PrOH), acetonitrile or dimethyl sulfoxide.

3. The method as in claim 2, wherein the organic solvent (V) is dimethyl sulfoxide (DMSO).

4. The method as in claim 1 , wherein the amount of the organic solvent (V) used is preferably in the range of 0.20-5.00 molar equivalents relative to the amount of 4,7- dichloroquinoline (III).

5. The method as in claim 4, wherein the amount of the organic solvent (V) used is preferably in the range of 0.50-1.50 molar equivalents relative to the amount of 4,7- dichloroquinoline (III).

6. The method as in claim 1 , wherein the temperature in step (b) (A2) is preferably 130 °C.

7. The method as in claim 1 , wherein the duration in step (b) (A2) is preferably 24 hours.

8. A method for synthesizing hydroxychloroquine sulfate (II), characterized by the steps of: i. dissolving hydroxychloroquine (I) in absolute ethanol (XI) to obtain a homogeneous solution and adding 0.4 M ethanolic sulfuric acid (XII) dropwise while maintaining the solution temperature below 25 °C (M), ii. heating the mixture for 30-60 minutes (N), iii. allowing the mixture to cool and crystallize for 6-12 hours (O), iv. filtering the resulting crystals and subsequently washing the crystals with absolute ethanol (XI) (P), v. drying the obtained crystalline product first in air and then under vacuum (R).

9. The method for synthesizing hydroxychloroquine sulfate (II) as in claim 8, wherein the amount of absolute ethanol (XI) used in step (M) is in the range of 4.0-5.0 liters per 1 .0 mol of hydroxychloroquine (I).

10. The method for synthesizing hydroxychloroquine sulfate (II) as in claim 8, wherein the heating step (N) is conducted at a temperature in the range of 60 °C to 80 °C.

11. The method for synthesizing hydroxychloroquine sulfate (II) as in claim 8, wherein the crystallization step (0) is carried out at a temperature in the range of 15 °C to 25 °C.

12. The method for synthesizing hydroxychloroquine sulfate (II) as in claim 8, wherein the vacuum drying step (R) is conducted at a vacuum level in the range of 50 to 100 mbar and a temperature in the range of 40 to 50 °C.

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