WO2013138200A1 - Synthèse de chimie verte du médicament contre le paludisme, l'amodiaquine et ses analogues - Google Patents

Synthèse de chimie verte du médicament contre le paludisme, l'amodiaquine et ses analogues Download PDF

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WO2013138200A1
WO2013138200A1 PCT/US2013/030005 US2013030005W WO2013138200A1 WO 2013138200 A1 WO2013138200 A1 WO 2013138200A1 US 2013030005 W US2013030005 W US 2013030005W WO 2013138200 A1 WO2013138200 A1 WO 2013138200A1
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acid
amodiaquine
aminophenol
compound
synthesis
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PCT/US2013/030005
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English (en)
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Joseph Marian Fortunak
Amol Anant KULKARNI
Christopher King
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Howard University
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Priority to ZA2014/08356A priority Critical patent/ZA201408356B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • C07D215/18—Halogen atoms or nitro radicals
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • 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.
  • ACT is the most effective strategy for treating Plasmodium, falciparum infection, in order to avoid the development of drugresistance against artemisinin-based therapies.
  • ASAQ is heavily used in Nigeria and other countries 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 uses 100 mg of artesunate combined with 270 mg of amodiaquine in a fixed-dose combination tablet taken twice-daily for three days.
  • 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.
  • ECOWAS Economic Community of West Arican States
  • the present one pot methods for the synthesis of amodiaquine and its analogs are simple and can occur in a single reaction vessel.
  • 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.
  • 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:
  • X represents a suitable functional substitutent
  • Ri and R 2 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.
  • 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.
  • 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.
  • a substituted-quinoline such as a suitable di-halogen-substituted quinoline
  • 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:
  • Ri and R 2 are as described above.
  • X is preferably halogen.
  • Ri and R 2 are preferably alkyl.
  • a one pot synthesis for producing the compound or its pharmaceutically acceptable salts comprises:
  • Amodiaquine is an exemplary compound obtainable by the methods described herein.
  • An exemplary method for producing amodiaquine is:
  • analogs can be suitably prepared, such as by using a different secondary diamine.
  • 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:
  • 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:
  • alkyl-substituted or aryl-substituted analogs of amodiaquine can be prepared by selecting a suitable secondary amine.
  • 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:
  • X is a halogen
  • Ri and R 2 are independently alkyl, aryl or hetero-aryl, and the method comprises the steps of:
  • 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.
  • 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).
  • 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,
  • Ri and R 2 are alkyl.
  • Ri and R 2 can be different or identical, and also can be Ci - C 6 alkyl in which case the secondary amine used in the synthesis is a di-(Ci-C 6 ) alkylamine.
  • exemplary alkyls include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, pentyl and hexyl, as examples.
  • Ri and R 2 can form a cyclic alkyl group, such as cyclopentyl or cyclohexyl.
  • Ri and R 2 are ethyl and the secondary amine used in the synthesis is diethylamine.
  • Ri and R 2 are both isopropyl and the secondary amine used in the synthesis is di-isopropy lamine .
  • Ri and R 2 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 /?ara-positions (e. g.
  • alkylated naphthyl, anthracene, and phenanthrene -rings e.g. 2-methylnapthyl, 3- ethylnapthyl, l-methyl-2-ethylnaphthyl, 4-isopropylanthracenyl, 5-tert-butylphenanthryl, 2-isopropyl-6-tert-butylphenanthryl, etc.
  • 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 fo ' s-phenol substitution(s).
  • the aforementioned aromatic rings can have cyano substitution(s).
  • Ri and R 2 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[£,e][l,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-l-benzothiopyrans, as examples.
  • Ri and R 2 can form a ring containing a hetero atom, such as a pyrrolidone-based moiety.
  • 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.
  • 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.
  • the compound produced is an amodiaquine- analog having the hydroxyl group in the ortho- or para-position relative to the RiR 2 - amine substituent (di-alkyl amine substituent or the like).
  • a compound such as an amodiaquine analog
  • 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.
  • the X-group can be lower alkyl, such as Ci - C 6 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.
  • 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.
  • the X-group can be at the 5, 6, 7 or 8 position of the quinoline ring.
  • 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:
  • LG 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.
  • X-group 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.
  • an aminophenol in step (a) 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.
  • step (a) 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.
  • 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.
  • 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.
  • the polar solvent with an acid is a polar acidic solvent.
  • a polar acidic solvent can comprise a lower carboxylic acid, such as a Ci-C 6 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.
  • a small amount of an alcohol 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.
  • step (a) can be conducted without an alcohol.
  • step (a) 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.
  • 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.
  • the compound produced 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:
  • the yield of the compound is generally at least about 80%, preferably about 85% or more.
  • the yield of the compound is generally about 90%> or more, preferably as high as 95%-98%.
  • 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.
  • 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%.
  • 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%.
  • the aldehyde comprises formaldehyde.
  • step (a) is conducted for about one hour to about five hours, preferably, for about three hours, most preferably, for about one hour.
  • step (b) is conducted for about three hours to about twenty hours, preferably, for about fourteen hours, most preferably, for about four hours.
  • 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.
  • suitable reactors include reactors from Microfluidics (so-called “asia flow reactor”), Vapourtec (so-called “Vaportec” flow reactor), and flow reactors from Uniqsis.
  • 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.
  • significantly amounts of byproducts and impurities are produced in each step.
  • the final product typically contains impurities in amounts that exceed 10 wt. %.
  • 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.
  • the current conventional synthesis methods are not “one-pot”
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%>.
  • the present invention provides pharmaceutical composition
  • 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.
  • 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.
  • compositions suitable for administration contain from about 67.5 mg to about 270 mg of active ingredient as amodiaquine.
  • a pharmaceutical drug also referred to as a finished pharmaceutical product (FPP) medicine, medication or medicament
  • FPP finished pharmaceutical product
  • 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).
  • ASAQ amodiaquine
  • ACT artificialemisinin combination therapy
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • the unexpected simplification from the current conventional synthesis having four-five steps to the present novel two step synthesis process means isolating intermediates after each step is no longer required.
  • 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.

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Abstract

L'invention concerne des procédés pour une synthèse de chimie verte en un seul contenant d'amodiaquine et des analogues d'amodiaquine. Les procédés ont un plus faible impact environnemental, un plus faible coût d'investissement, des quantités réduites de sous-produits et d'impuretés et un temps de synthèse plus court, par comparaison avec les procédés de synthèse classiques actuels. Les procédés réduisent le nombre total d'étapes de la synthèse de quatre ou cinq à deux, simplifiant ainsi la production, et permettent à un nombre réduit de solvants et de réactifs d'être utilisés dans la production, réduisant ainsi les déchets générés dans la synthèse. Les procédés peuvent réduire les déchets à environ 3 à 5 kilogrammes de déchets générés par kilogramme de produit fabriqué et améliorent étonnamment le rendement global de 60 à 65 % à plus de 90 % par comparaison avec les procédés de synthèse classiques actuels pour l'amodiaquine et ses analogues.
PCT/US2013/030005 2012-03-13 2013-03-08 Synthèse de chimie verte du médicament contre le paludisme, l'amodiaquine et ses analogues WO2013138200A1 (fr)

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