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10. (WO2013138200) GREEN CHEMISTRY SYNTHESIS OF THE MALARIA DRUG AMODIAQUINE AND ANALOGS THEREOF
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

Green Chemistry Synthesis of the Malaria Drug Amodiaquine and

Analogs thereof

RELATED APPLICATION

[0001] This PCT application claims priority from U.S. Provisional Application 61/610,267, filed March 13, 2012, and the complete disclosure thereof is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The inventions generally relate to novel methods for synthesizing a compound useful in treating malaria. More particularly, the present inventions relate to the synthesis of amodiaquine and amodiaquine-analogs.

BACKGROUND

[0003] Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. This is a parasitic disease that involves high fevers, shaking chills, flu-like symptoms, and anemia. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, and in severe cases progressing to coma or death. Approximately 50% of the world's population is exposed to the threat of malaria, where this disease kills millions directly or indirectly through respiratory infections and anemia. Approximately 50% of the disease related deaths are to children. Malaria is widespread in tropical and subtropical regions, including much of Sub-Saharan Africa, Asia, and the Americas. Deaths from malaria in sub-Saharan Africa occur predominately (over 90%) in infants, children, and pregnant women.

[0004] The treatment of malaria depends on the severity of the disease. When properly treated, a patient with malaria can expect a complete recovery. Uncomplicated malaria is treated with oral drugs. Amodiaquine (AQ) is an older drug that was first disclosed in 1948 (J.Amer.Chem.Soc, 1948, 70: 1363-1373). AQ became an important drug with the approval of artesunate: amodiaquine (ASAQ) as an "artemisinin

combination therapy" (ACT) recommended by the World Health Organization (WHO) for the treatment of uncomplicated malaria. Amodiaquine acquired a renewed value with the advent of the approval of the ASAQ combination as an effective ACT. ACT is the most effective strategy for treating Plasmodium. ƒalciparum infection, in order to avoid the development of drugresistance against artemisinin-based therapies. ASAQ is heavily used in Nigeria and other nations of West Africa. The National authorities in many African countries have adopted the recommended standard for the combination, artemisinin combination therapies (ACTs), for the treatment of malaria. An adult course of treatment (ACTs) uses 100 mg of artesunate combined with 270 mg of amodiaquine in a fixed-dose combination tablet taken twice-daily for three days.

[0005] ASAQ is of high priority in Nigeria because (1) the malaria vector has not acquired significant resistance to this ACT in the Economic Community of West Arican States (ECOWAS) area; and (2) amodiaquine is less expensive and/or less toxic than alternatives such as lumefantrine or halofantrine.

[0006] Despite these advantages, many subtropical regions, including much of sub-Saharan Africa lack adequate access to medicines in general and specifically ACTs. Additionally, a high percentage of ACTs in Africa have been shown to be counterfeit. There has been a long-standing, unmet need for improved technology in the manufacturing of such drugs, which would be most advantageously met by utilizing a smaller manufacturing footprint, lower environmental impact and lower investment cost for manufacturing startup. There has also been an unmet need for green chemistry technology for drug synthesis that is economically sustainable for producing critical drugs, especially in the sub-Saharan region of Africa.

[0007] Despite considerable efforts, these challenges have not been met by current synthesis methods for amodiaquine and its analogs (derivatives).

SUMMARY OF THE INVENTION

[0008] The present one pot methods for the synthesis of amodiaquine and its analogs are simple and can occur in a single reaction vessel. In one of its aspects, a one -pot synthesis can consist of two steps, wherein the entire synthesis of the amodiaquine, its analogs, and salts thereof can occur in a single reaction vessel. The one pot methods additionally eliminate expensive and environmentally-objectionable solvents from the synthesis. The yield is increased and the purity of material prepared is acceptable for human use.

[0009] In an aspect, a general method described herein advantageously utilizes a one-pot synthesis for preparing a compound or its pharmaceutically acceptable salts, in which the compound is represented by the general formula:


wherein X represents a suitable functional substitutent, and R1 and R2 are independently alkyl, aryl or hetero-aryl, as examples. Exemplary functional substitutents for X include halide, alkyl, alkoxyalkyl, halo-alkyl, or halo-alkoxy by way of example.

[0009] In one of its aspects, a one-pot method involves combining a heated mixture formed in situ comprised of an aminophenol, a suitable substituted-quinoline, such as a di-substituted quinoline, in a polar solvent with acid present with an aldehyde and a secondary amine, without isolating intermediates or precursors, to obtain the compound or its pharmaceutically acceptable salt. In one of its further aspects, the one-pot method involves (a) heating a mixture comprising aminophenol, a substituted-quinoline, such as a suitable di-halogen-substituted quinoline, in a polar solvent with an acid present; and (b) combining the reaction mixture with an aldehyde and secondary amine, without isolating intermediates or precursors (such as after (a)), to obtain the compound or its pharmaceutically acceptable salt.

[0010] In another of its aspects, a general method described herein advantageously utilizes a one-pot process for preparing a compound or its pharmaceutical salts, in which the compound is represented by the formula:


wherein X is as described above, and R1 and R2 are as described above. X is preferably halogen. R1 and R2 are preferably alkyl.

[0011] In one of its aspects, a one pot synthesis for producing the compound or its pharmaceutically acceptable salts comprises:

(a) heating a mixture comprising aminophenol, 4,7 di-halogen substituted-quinoline in a polar solvent with acid present; and

(b) combining the reaction mixture with an aldehyde and secondary amine, without isolating intermediates or precursors, to obtain the compound or its pharmaceutically acceptable salt.

[0012] Amodiaquine is an exemplary compound obtainable by the methods described herein. An exemplary method for producing amodiaquine is:


[0013] In an aspect, analogs can be suitably prepared, such as by using a different secondary diamine. For example, an exemplary di-alkyl analog of amodiquine is a di-isopropyl analog that can be prepared using di-isopropyl amine instead of di-ethylamine, and such di-isopropyl analog is represented by the formula:


.

[0014] A di-aryl substituted analog can be prepared in a similar fashion using an aryl-substituted secondary amine instead of a secondary di-alkylamine. An exemplary di-aryl analog of amodiquine can be prepared using a di-aryl amine, such as diphenyl amine instead of diethylamine, and such diphenyl analog is represented by the formula:


It will be appreciated that different alkyl-substituted or aryl-substituted analogs of amodiaquine can be prepared by selecting a suitable secondary amine.

[0015] Another illustrative synthesis involves using a 3-aminophenol. For example, such a synthesis can be illustrated as follows:


[0016] In a similar fashion, an analog having a di-aryl phenyl group is obtainable as follows:

[0017] In one of its aspects, an illustrative one-pot synthesis is described in Example 3.

DETAILED DESCRIPTION OF THE INVENTION

[0018] In one of its aspects a method described herein advantageously utilizes a one-pot process for preparing a compound, or its pharmaceutical salts, and preferably the compound is represented by the formula:


wherein X is a halogen, and R1 and R2 are independently alkyl, aryl or hetero-aryl, and the method comprises the steps of:

(a) heating a mixture comprising aminophenol, 4,7 di-halogen substituted- quinoline in a polar solvent with acid present; and

(b) combining the reaction mixture with an aldehyde and secondary amine, without isolating intermediates or precursors, to obtain the compound or its pharmaceutically acceptable salt.

[0019] The one-pot synthesis methods described are conducted in one reaction vessel. This avoids the need for each step being conducted as a batch followed by recovery and isolation of the desired intermediate before proceeding to the next step in the batch synthesis. The present one-pot synthesis methods are therefore more facile and less labor intensive since isolation of intermediates after each step in a multi-step synthesis is no longer required.

[0020] Illustrative "secondary amines" for this invention therefore include dialkyl amines (such as dimethyl amine, diethyl amine, etc.); arylamines (such as diphenylamine, dinaphthyl amine, etc.), akyl-aryl amines (such as N-methylaniline, N-isopropylaniline, etc.), Alkyl, halo, nitro, suitably-protected phenolic derivatives, and cyano substituents as disclosed above for aryl groups, and heteroaryl amines (e.g., nitrogen-containing heterocycles, oxygen-containing heterocycles, and sulfur-containing heterocycles).

[0021] In an aspect for preparing a compound, such as amodiaquine or an amodiaquine analog, R1 and R2 are alkyl. R1 and R2 can be different or identical, and also can be C1 -C6 alkyl in which case the secondary amine used in the synthesis is a di-(C1-C6) alkylamine. When R1 and R2 are C1-C6 alkyl, exemplary alkyls include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, pentyl and hexyl, as examples. In principle, R1 and R2 can form a cyclic alkyl group, such as cyclopentyl or cyclohexyl.

[0022] In an aspect for preparing a compound, such as amodiaquine or an amodiaquine-analog (or derivative), R1 and R2 are ethyl and the secondary amine used in the synthesis is diethylamine.

[0023] In an aspect for preparing a compound, such as an amodiaquine-analog or derivative, R1 and R2 are both isopropyl and the secondary amine used in the synthesis is di-isopropy lamine .

[0024] In an aspect for preparing a compound, such as an aryl-analog or derivative of amodiaquine, R1 and R2 can be the same or different, and can be an aryl group, by using a suitable aryl-substituted amine. Aryl groups include unsubstituted phenyl ring, naphthalene ring, anthracene ring, phenanthrene ring, as examples. Di-phenyl amine is an example. A phenyl ring can be alkylated at ortho-, meta-, and para-positions (e. g. 2-methylphenyl, 3-ethylphenyl, 4-isopropylphenyl, 2,4-dimethylphenyl, etc.). Similarly, alkylated naphthyl, anthracene, and phenanthrene-rings (e.g. 2-methylnapthyl, 3-ethylnapthyl, 1-methyl-2-ethylnaphthyl, 4-isopropylanthracenyl, 5-tert-butylphenanthryl, 2-isopropyl-6-tert-butylphenanthryl, etc.) are suitable. The aforementioned aromatic rings can have halogen substitution(s) (such as fluoro, chloro, bromo, and iodo groups, trifluoromethyl groups, pentafluoroethyl groups, hexafluoro-isopropyl groups etc.) at

various positions. The aforementioned aromatic rings can have nitro substitution(s). The aforementioned aromatic rings can be protected phenol and/or bis-phenol substitution(s). The aforementioned aromatic rings can have cyano substitution(s).

[0025] In an aspect of the invention, R1 and R2 can, independent of one another, represent a heteroaryl group. Illustrative heteroaryl groups for this invention include nitrogen-containing heterocycles, oxygen-containing heterocycles, and sulfur-containing heterocycles. Nitrogen-containing heterocycles include substituted pyridines, protected piperidines, protected piperazine, etc., substituted indoles, substituted quinolines and isoquinolines, substituted benzo[g] quinolines, acridines, etc., protected pyrroles, dihydropyrroles, and imidazoles, as examples. Oxygen-containing heterocycles include substituted furans, 2,3- and 2,5-dihydrofurans, benzofurans, etc., substituted dihydro-2H-pyrans, substituted 9H-xanthenes, and substituted Dibenzo[b,e][1,4]dioxins, as examples. Sulfur-containing heterocycles include substituted thiophene derivatives, 2,3- and 2,5-dihydrothiophenes, etc., substituted 9H-thioxanthenes, substituted dihydro-2H-thiopyrans, and substituted 4H-1-benzothiopyrans, as examples.

[0026] In an aspect of the invention, R1 and R2 can form a ring containing a hetero atom, such as a pyrrolidone-based moiety.

[0027] In an aspect of a present method, such as amodiaquine or an amodiaquine-analog, in step (a) the halogen of 4,7 di-halo substituted quinoline is selected from fluorine, chlorine bromine, and iodine. It is preferably chlorine or bromine, and is most preferably chlorine.

[0028] In an aspect of a present method, X will be determined based on the halogen selected when the substituted quinoline is 4,7 di-halo substituted quinoline. X is accordingly fluorine, chlorine bromine, or iodine. X is preferably chlorine or bromine, and most preferably chlorine.

[0029] In an aspect of a present method, the compound produced is an amodiaquine-analog having the hydroxyl group in the ortho- or para-position relative to the R1R2-amine substituent (di-alkyl amine substituent or the like).

[0030] In an aspect of a present method, a compound, such as an amodiaquine analog, can be prepared using a substituted quinoline that has a leaving group at the 4-position other than a halogen. Suitable such alternative leaving groups at the 4-position include toluenesufonate (tosylate) and trifluoromethane sulfonate (triflate), just to mention examples.

[0031] In an aspect of a present method, such as for preparing amodiaquine analogs, the X-group can be lower alkyl, such as C1 - C6 alkyl, halo-alkyl such as tri-fluoromethyl or the like, halo-alkoxy such as trifluoromethoxy or the like, lower-alkoxy such as methoxy, or other similarly alkylated oxygen-containing substituent, an acetyl or a similarly acylated oxygen-containing derivative.

[0032] As will be appreciated, in an aspect of the method for preparing a compound represented by the general formula or an analog thereof, the X-group can be at the 5, 6, 7 or 8 position of the quinoline ring.

[0033] As evident from the present description, in various aspects of a present method, a suitable substituted quinoline compound is allowed to react with a selected aminophenol. Suitable substituted quinolines include those having a leaving group (LG) at the 4-position represented by the formula:


wherein LG designates a suitable leaving group, such as halogen or another exemplary group such as toluenesufonate (tosylate) and trifluoromethane sulfonate (triflate), just to mention examples. X can be at the 5, 6, 7 or 8-position of the quinoline ring. A wide variety of functionality can be tolerated for an X substitutent, and halide, alkyl, alkyloxy, ahalo-alkoxy, halo-alkyl, and halo-alkoxy are examples. It will be appreciated that the substituted quinolones with a LG in the 4-position can have more than one X substituent. Exemplary 4-LG-subsituted quinolines that have at least one X and how they are prepared include those described in Madrid et al., Bioorganic & Medicinal Chemistry Letters 15: 1015-1018 (2005), the complete disclosure of which is incorporated herein by reference. A 4,7 di-chloro quinoline is useful in the synthesis of amodiaquine as disclosed elsewhere herein. Exemplary substituted 4-halo,7-haloalkyl-quinolines, where X represents halo-alkyl include, for example, 4-chloro-7-trifluoromethylquinoline. Accordingly, various 4-aminoquinolines can be prepared wherein the X-group (substituent) can include such substituents is a 5 -alkyl, 5-phenoxy, 6-alkyl, 6-alkoxy, 6-halo-alkyl, 6-halo-alkoxy, 6-cyano, 6-halo, 6-thioalkyl, 6-morpholino, 7-alkyl, 7-alkoxy, 7-halogen, 7-haloalkyl, 7-halo-alkoxy, 8-cyano, 8-phenoxy, 8-halo, 8-halo-alkyl, 8-halo alkoxy, or 8-morpholino, just to mention examples. Halogen includes bromo, chloro, fluoro and iodo.

[0033] Compounds revealed to inhibit Endothelial Growth Factor Receptor (EGFR) Tyrosine Kinase are described in the Journal of American Science 6(10), 73-84 (2010), the complete disclosure of which is incorporated herein by reference. Various substituted analogs of amodiaqine for the treatment of malaria are revealed in various publications such as, for instance, Heindel et al., J.Med.Chem. 13, 156-157. (1970); O'Neill et al., O'Neill et al., J. Med. Chem. 37, 1362-1370 (1994); De et al., Am. J. Trap Med. Hyg., 55(6), 579-583 (Dec. 1996), O'Neill et al., J. Med. Chem. 40, 437-448 (1997); Raynes, et al., J. Med. Chem, 42, 2747-2752 (1999); J. Med. Chem., 45, 4975-4983 (2002); O'Neill et al., J. Med. Chem. 46, 4933-4945 (2003); Lawrence et al., Organic Process R&D

Journal, 12, 294-297 (2008); and O'Neill et al., J. Med. Chem., 52, 1828-1844 (2009), the complete disclosures of which are incorporated herein by reference.

[0034] In an aspect for preparing a compound, such as amodiaquine or an amodiaquine -analog, in step (a) an aminophenol can be, for example, a 4-aminophenol or a 3-aminophenol, or a 2-aminophenol. It will be appreciated that an aminophenol may optionally be substituted. Optional substituent(s) can include, for example, halogen.

[0035] In a further aspect for preparing an amodiaquine or amodiaquine-analog, in step (a) the molar ratio of aminophenol to the suitable substituted quinoline, such as a 4,7-dichloroquinoline, can be varied to maximize the yield of the desired compound obtained in step (b), while minimizing the production of impurities and byproducts. For example, the molar ratio of aminophenol, such as 4-aminophenol, to 4,7-di-halo substituted quinoline is about 0.80 to about 1.20; preferably about 0.85 to about 1.10; more preferably about 0.95 to about 1.10; and most preferably 1.00 to about 1.10. Additionally, a slight molar excess of aminophenol can be tolerated without materially adversely affecting the chemical reaction in step (a) and the subsequent step (b) in the one-pot synthesis.

[0036] In one aspect of the invention, in step (a), the polar solvent with an acid is a polar acidic solvent. A polar acidic solvent can comprise a lower carboxylic acid, such as a C1-C6 carboxylic acid, including acetic acid, propionic acid, butyric acid and/or isobutyric acid by way of example, preferably acetic acid, preferably in a concentration of starting dihaloquinoline of about 0.5 Molar to about 6 Molar. Alternatively, in step (a), in addition to the polar acidic solvent, a small amount of an alcohol may be present, wherein the alcohol comprises at least one of methanol, ethanol, propanol, and isopropanol, butanol (1-butanol, or isomers such as 2-butanol or iso-butanol) preferably in an amount of about 50% by volume or concentration in the mixture of about 0.5 Molar to about 6 Molar. The amount of alcohol, if used, is preferably small, if not minimal, to avoid promoting side reactions and esterification of the acid solvent. A small amount of alcohol can be 5% to about 50% by volume, particularly about 10% to about 20% by volume. By present preference, however, step (a) can be conducted without an alcohol.

[0037] In another aspect for preparing a compound, such as amodiaquine or an amodiaquine-analog, in step (a) the mixture of aminophenol, such as a 3-aminophenol or a 4-aminophenol, and a 4,7-di-halogen substituted quinoline, such as 4,7-dichloroquinoline, or another suitable substituted quinoline, is heated to reflux the reaction solvent. Preferably the temperature is about 60°C to about 145°C, and most preferably, is a temperature of about 110°C. Temperatures in step (a) above 110°C may lead to an increase in byproducts and impurities.

[0038] In an aspect for preparing a compound, such as amodiaquine or an amodiaquine-analog, the compound produced generally has not more than about 10% impurities, preferably, not more than 8%, most preferably, not more than 5% impurities. In principle, impurity levels as low as 0.5% or less can be obtained with the present processes. Depending on the compound being produced, some of the exemplary impurities that may be generated may, for example, be represented as:

[0039] In one aspect for preparing a compound, such as amodiaquine or an amodiaquine-analog, the yield of the compound is generally at least about 80%, preferably about 85% or more.

[0040] In another aspect for preparing a compound such as amodiaquine or an amodiaquine analog, the yield of the compound is generally about 90% or more, preferably as high as 95%-98%.

[0041] In another aspect for preparing a compound, such as amodiaquine or an amodiaquine-analog, step (b) is heated, preferably at a temperature in about 40°C to about 140°C, most preferably, at a temperature of about 110°C. It should be noted that higher temperatures in step (a), such as above 110°C, may lead to an increase in byproducts and impurities.

[0042] In a further aspect for preparing a compound, such as amodiaquine or an amodiaquine-analog, step (b) is performed in an acidic solution, and preferably an aqueous acidic solution. The aqueous acidic solution can be a hydrochloric acid solution, preferably at a concentration of about 5% to about 50%. Alternatively, the aqueous acidic solution can be an acetic acid solution, such as, preferably at a concentration of about 5% to about 50%. The process in step (b) can be performed in a strong organic acid solution. The strong organic acid solution can be a trifluoroacetic acid solution, such as of at a concentration of about 5% to about 33%.

[0043] In one aspect for preparing a compound, such as amodiaquine or an amodiaquine-analog, the aldehyde comprises formaldehyde.

[0044] In one aspect for preparing a compound, such as amodiaquine or an amodiaquine-analog, there is a substantial reduction in the waste generated when compared to the current conventional synthesis methods. There can be as little as 3-5 kilograms of waste generated per kilogram of drug produced, preferably 1-3 kilograms of waste generated per kilogram of drug produced.

[0045] In an aspect for preparing a compound, such as amodiaquine or an amodiaquine-analog, step (a) is conducted for about one hour to about five hours, preferably, for about three hours, most preferably, for about one hour.

[0046] In an aspect for preparing a compound, such as amodiaquine or an amodiaquine-analog, step (b) is conducted for about three hours to about twenty hours, preferably, for about fourteen hours, most preferably, for about four hours.

[0047] It will be appreciated that in an aspect of the present method for preparing a compound according to the general formula or analogs thereof, the one-pot method can be conducted in a suitable reactor, such as in a flow reactor. It will be appreciated that the method can be conducted as a continuous process. In principle, suitable reactors include reactors from Microfluidics (so-called "asia flow reactor"), Vapourtec (so-called "Vaportec" flow reactor), and flow reactors from Uniqsis.

[0048] A current reported conventional synthesis method of manufacturing amodiaquine, which typically results in only a 65% yield with a significant quantity of impurities and byproducts far greater than 10%, is depicted below. The reported conventional method requires four to five steps in which intermediates are isolated and/or purified after each step before being able to conduct the next step in the synthesis, with the consequent economic and labor penalties compounded by undesired reduction in yield. Typically, significantly amounts of byproducts and impurities are produced in each step. The final product typically contains impurities in amounts that exceed 10 wt. %.


[0049] A four-five step conventional process for preparing analogs is shown below, with purification of intermediates required after each step or most steps, with consequent of reduction in yield and the other disadvantages associated with such a cumbersome and inefficient multistep process. Typically significant amounts of byproducts and impurities are produced in each step.


[0050] The current conventional synthesis methods are not "one-pot" [0051] The current conventional synthesis methods for preparing amodiaquine and its analogs result substantial amounts of impurities, and depending on the product, such impurities may include:





[0052] Advantageously, the present one pot methods dramatically reduce the amount of undesired byproducts and impurities and consequently, additionally make isolating (working up) the active pharmaceutical ingredient (API) more facile. The one-pot method includes in one of its aspects a method having two-steps conducted in the one pot.

[0053] The methods described herein advantageously provide a two step synthesis of the compound, including as amodiaquine or an amodiaquine-analog, compared to the previous and current conventional four to five-step syntheses of amodiaquine or an analog thereof, which usually require at least five days to complete. In one aspect of the present synthesis, the desired product is obtainable within one day, as compared to the five days typically required by the four to five step current conventional syntheses. [0054] In an aspect of the present synthesis, the inventions enable reduced capital investment in plant, equipment and the like since the desired compound is synthesized in only two steps, in one pot, compared to the multi-pot five-step synthesis. The reduced number of steps can also reduce labor cost.

[0055] The present two-step synthesis in one pot results in (a) reduction in the number of steps of the synthesis, without requiring intermediate(s) to be isolated after each step, thereby simplifying production and reducing costs and capital investment; and (b) reduction in the number of solvents and reagents used in production, reducing the waste generated in the synthesis by about 80% (or even more) to achieve a 'greener' synthesis; and (c) an improved overall yield from 60-65% to greater than about 90%, preferably at least about 92%.

[0056] In another embodiment, the present invention provides pharmaceutical composition comprising a compound, such as amodiaquine or an amodiaquine-analog, or a pharmaceutically acceptable salt thereof obtained in accordance with the present methods and a pharmaceutically acceptable carrier.

[0057] The dosing contemplates administration of a therapeutically effective amount of the compound, such as amodiaquine or an analog thereof, or pharmaceutically acceptable salt form thereof to the patient.

[0058] Dosage forms of compositions suitable for administration contain from about 67.5 mg to about 270 mg of active ingredient as amodiaquine.

[0059] A pharmaceutical drug, also referred to as a finished pharmaceutical product (FPP) medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, mitigation, or prevention of disease.

[0060] The pharmaceutical compound amodiaquine synthesized by the disclosed method can be used in the finished pharmaceutical product artesunate: amodiaquine (ASAQ) as the "artemisinin combination therapy" (ACT).

[0061] Salt forms of the amodiaquine or amodiaquine-analog product

[0062] Salt forms of the active pharmaceutical ingredient, such as amodiaquine or an analog thereof, are useful. The salts can have inorganic or organic character. Salts of hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, citric acid, oxalic acid, benzoic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, tartaric acid, fumaric acid, maleic acid, malic acid, lactic acid, and methanesulfonic acid, as examples, are useful, although this list is not intended to be limiting as far as this description is concerned.

[0063] The finished pharmaceutical products (FPPs) containing the active pharmaceutical ingredient(s), which can include amodiaquine, an analog thereof or their pharmaceutically acceptable salts, can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions.

[0064] Producing the phamaceutically acceptable salts:

[0065] The methods herein can be modified to produce various pharmaceutically acceptable salt forms a compound, such as of AQ and AQ analogs thereof, by changing (selecting) the acid added to the reaction mixture at the end of Step 2, and by doing so induce crystallization of such different salt forms as may be required for use, directly from the reaction mixture.

[0066] Recovery of the end product in this invention is accomplished by direct crystallization from the reaction mixture of the one-pot synthesis. The composition of the solvent mixture for isolation can be adjusted by addition of additional acetic acid or other cosolvents including water or alcoholic solvents such as methanol, ethanol, 1-propanol, or isopropanol, as examples crystallization of the desired product is accomplished by addition of the acid required to produce the desired salt form, followed by direct crystallization of the product from the reaction mixture. In one aspect of this invention, the end product is amodiaquine obtained as its dihyrochloride, dihydrate crystalline form, which is the form used in preparing Finished Pharmaceutical Products of the Artemisinin Combination Therapy ASAQ (Artesunate : Amodiaquine).

[0067] The methods described provide unexpected advantages, including an unexpected shortening and simplification of the synthesis of the compound, such as AQ and AQ analogs, and a direct, uncomplicated method for isolation of the desired product and various salt forms thereof by crystallization from the reaction mixtures.

[0068] Seminal advantages with respect to AQ and its analogs include:

1. an improved yield of an AQ analog from 74% to over 90% and an improved yield of AQ from about 60-65% to greater than 90%;

2. a reduction of about 80% or even greater in the amount of the waste generated versus the current reported conventional synthesis method for AQ and AQ-analogs,

3. synthetic convenience (the reaction is done in "one-pot" fashion and isolation is accomplished in very high recovery by direct precipitation of the product from the reaction mixture),

4. less capital investment is needed since less equipment is used to perform the more facile synthesis in one-pot, and

5. the use of inexpensive, environmentally-benign solvents, such as acetic acid (instead of Ν,Ν-dimethylformamide, used in the current conventional synthesis method), which makes the synthesis more ideally suited for practice, especially in resource-poor settings.

[0069] Additionally, the unexpected simplification from the current conventional synthesis having four-five steps to the present novel two step synthesis process (a so- called "one pot" synthesis) means isolating intermediates after each step is no longer required.

[0070] The complete disclosures of Burckhalter et al. J.Amer.Chem.Soc, 1948, 70: 1363-1373; Burckhalter et al. US. Patent No. 2,474,819; Burckhalter et al. US. Patent No. 2,474,821; World Malaria Report, 2011; and Saha et al. International J. Chem Research., 2009, l(2):322-328 are incorporated herein by reference.

[0071] EXAMPLES

[0072] The following non-limiting examples further describe aspects of the present inventions.

[0073] EXAMPLE 1

[0074] To a mixture of 4-aminophenol (11.4 grams, 0.104 mol) and 4,7-dichloroquinoline (19.8 grams, 0.10 mol), acetic acid was added (60 ml, 3.0 volumes w/v relative to 4,7-dichloroquinoline) with stirring at room temperature and the resulting mixture was heated with stirring at 110°C for about one hour. The mixture was cooled to 20°C and formaldehyde (14.06 grams of a 32% aqueous solution, 0.150 mol, 1.5 mol eq) and diethylamine (10.95 grams, 0.150 mol, 1.5 mol eq were sequentially added to the same reaction vessel). The reaction mixture was then heated and reaction occurred at 50°C for four hours. The mixture was cooled in an ice water bath and 22 mL of 37% aqueous hydrochloric acid solution (containing 0.264 mol of HCl) was added at a rate so that the internal temperature did not exceed 40°C. Stirring was continued for an additional 2 hours to complete the precipitation of the desired product as yellow crystals The precipitated crystals were collected by filtration and dried at room temperature to a constant weight to obtain 42.7 grams of amodiaquine dihydrochloride dihydrate (92% yield) in a purity of greater than 99% as determined by HPLC analysis.

[0075] EXAMPLE 2

[0076] A suitable reaction vessel was charged with 4,7-dichloroquinoline (3.96 g, 0.020 mol, 1.0 eq) and m-aminophenol (2.29 g, 0.021 mol, 1.05 mol equiv). Acetic acid (12 mL) was added. The reaction mixture was heated to reflux and maintained at reflux for 4 h. At t = 4 h, the reaction mixture was cooled to room temperature and formaldehyde (37% w/v solution, 2.45 mL, 30 mmol, 1.5 mol eq) and diisopropylamine (4.2 mL, 0.030 mol, 1.5 mol eq) were added. The reaction mixture was stirred at room temperature for ca. 10 minutes and then heated and maintained at 50°C for 8 hours. At the end of the reaction, acetic acid was removed under reduced pressure and water (100 mL) was added. The resultant orange precipitate was filtered and washed with 2 X 100 mL water. The solid was air dried to a constant weight to obtain 7.1 grams of the desired product (93 % yield) as orange powder.

[0077] EXAMPLE 3

[0078] A suitable reaction vessel was charged with 4,7-dichloroquinoline (3.96 g, 0.020 mol, 1.0 eq) and m-aminophenol (2.29 g, 0.021 mol, 1.05 mol equiv). Acetic acid (12 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. At 4 hours, the reaction mixture was cooled to room temperature and formaldehyde (37% w/v solution, 2.45 mL, 30 mmol, 1.5 mol eq) and diphenylamine (5.08 g, 0.030 mol, 1.5 mol eq) were added. The reaction mixture was stirred at room temperature for ca. 10 minutes and then heated and maintained at 50°C for 8 hours. At the end of the reaction, acetic acid was removed under reduced pressure and water (100 mL) was added. The resultant orange precipitate was filtered and washed with 2 X 100 mL water. The solid was air dried to a constant weight to obtain the desired aryl analog.

[0079] The complete disclosure of U.S. Provisional Application 61/610,267, filed March 13, 2012, is incorporated herein by reference.

[0080] While the invention has been described in terms of preferred embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims.