A process for the preparation of diamino intermediates for the production of chloroquine, hydroxychloroquine and mepacrine thereof

Abstract

The present invention relates to a process for preparation of novoldiamine of formula 1, hydroxynovol diamine of formula 2 and their utility for the production of chloroquine of formula 3, hydroxychloroquine of formula 4 and mepacrine of formula 5. O A-^Y0" —— , novoldiamine hydroxynovoldiamine o N mepacrine CI' ^ ^N" chloroquine CI' ^ ^N' hydroxychloroquine levulinic acid.

Description

FIELD OF THE INVENTIONThe present invention relates to a process for the preparation of diamino intermediate compound of formula I [novoldiamine (1) and hydroxynovoldiamine (2)]. Particularly, present invention relates to compound of formula I useful for the preparation of drug API's such as chloroquine (3),hydroxychloroquine (4) and mepacrine (5).NH2 Rwhen R=H, novoldiamine (1) when R=OH, hydroxynovoldiamine (2)Formula IMore particularly, present invention relates to a process for the preparation of key intermediates such as novoldiamine of formula 1 and hydroxynovoldiamine of formula 2 involving minimal chemical transformations starting from levulinic acid and their utilization for synthesizing drug APIs such as chloroquine of formula 3, hydroxychloroquine of formula 4 and mepacrine of formula 5.BACK GROUND OF THE INVENTIONChloroquine (CQ) an aminoquinolone derivative discovered in 1934 by Hans Andersag was the first developed drug in the 1940s for the treatment of malaria. It was granted FDA Approval on 31 October 1949. Hydroxychloroquine (HCQ) with an additional hydroxyl moiety on chloroquine was granted FDA approval on 18 April 1955. Hydroxychloroquine, is used widely in autoimmune disease, but has also been employed for the treatment of malaria, where it is reported as being half as toxic as the closely related- chloroquine (CQ) and active against Plasmodium falciparum. Chloroquine and hydroxychloroquine are on the World Health Organization's List of Essential Medicines. HCQ was developed during World War II as a derivative of quinacrine with less severe side effects. HCQ was also used for the prophylaxis of malaria in regions where chloroquine resistance is unlikely. CQ and its derivative HCQ have since been repurposed for the treatment of a number of other conditions including HIV, systemic lupus erythematosus, and rheumatoid arthritis. It is also used to treat extraintestinal amoebiasis as well as treatment and prophylaxis of Zika virus. During the beginning of pandemic covid-19, HCQ was once again used as prophylaxis. Mepacrine, also called quinacrine or by the trade name Atabrine, is a medication with several uses. The main uses of mepacrine are as an antiprotozoal, antirheumatic and an intrapleural sclerosing agent. Mepacrine is also used off-label for the treatment of systemic lupus erythematosus. As an intrapleural sclerosing agent, it is used as pneumothorax prophylaxis in patients at high risk of recurrence, e.g., cystic fibrosis patients. In addition to medical applications, mepacrine is an effective in vitro research tool for the epifluorescent visualization of cells, especially platelets. Mepacrine is a green fluorescent dye taken up by most cells.The general commercial synthetic route for novoldiamine / hydroxynovoldiamine include the utility of 5-chloro-2-pentanone as the key raw material which is coupled with diethyl amine or N-ethylethanolamine and then treated with methanolic ammonia and further reduced with Raney Nickel to yield novoldiamine / hydroxynovoldiamine respectively. (WO 2005 / 062,723, US 2,546,658).There are also other routes in the prior art for ex. ethylacetoacetate is alkylated using N, diethylchloroethylamine followed by hydrolysis and decarboxylation with NaOH and later treatment of resulting ketone with ammonia followed by Raney Nickel reduction to get novoldiamine. The reported procedures however involve either larger no. of steps and or suffer from low yields (GB 1157637; US 4,421,920; Current Science, (1943) , 12(3) , PP-82-83). Moreover, we depend on other countries for raw materials such as either 5-chloropentanone or ethylacetoacetate. Thus, to overcome the dependency, it is always in demand to utilize raw materials that can be produced indigeneously or available readily from nature.Levulinic acid (LA) also known as 4-oxopentanoic acid or gamma ketovaleric acid is a C-5 chemical and is identified as one of the key platform chemicals. It is considered as one of the 12 'building blocks' of the green chemical industry of the future. It is a short chain fatty acid and possesses a ketone carbonyl group and an acidic carboxyl group which imparts it an ability to react with different functional groups to form a wide range of derivatives, thereby, making LA an ideal platform chemical. LA can be synthesized from several different raw materials for instance, monosaccharides (like glucose and fructose), precursors such as 5-hydroxymethyl furfural (HMF) and furfural, polysaccharides (like starch, cellulose and hemicelluloses and chitin) and renewable resources such as starch-rich waste and lignocellulosic biomass. In our present process, levulinic acid has been utilized as starting material to synthesize the key intermediates novoldiamine and hydroxynovoldiamine.OBJECTIVE OF THE INVENTIONMain objective of the present invention is to provide a cost-effective, atom-economy and scalable process for the synthesis of diamino intermediate of formula I. Another object of the present invention is to provide novoldiamine of formula 1 and hydroxynovoldiamine of formula 2 which serve as key intermediates leading to the production of chloroquine of formula 3, hydroxychloroquine of formula 4 and mepacrine of formula 5.SUMMARY OF THE INVENTIONAccordingly, present invention provides a process for the preparation of compounds of formula I comprising the steps of:wherein R=H or OH;a) activating levulinic acid of formula (a) with agent to get the imidazolide of formula (b);Formula aFormula bb) treating the imidazolide of formula (b) as activated in step (a) with secondary amine of formula (c) to get the amide of formula (d);Formula (c) when R=H, 6when R=OH, 8 Formula (d)c) treating the amide as obtained in step (b) with hydroxylamine hydrochloride to get the corresponding oxime of formula (e);NOH Rwhen R=H,7 when R=OH, 9Formula (e)d) treating the oxime as obtained in step (c) with reducing agent to yield compound of formula I. NH2 RWherein,R=H (1) or R=OH (2)In an embodiment of the present invention, compound of formula I is selected from NH2 fnovoldiamineNH, OHhydroxynovoldiamineIn yet another embodiment of the present invention, secondary amine used is selected from diethyl amine and 2-(ethylamino)ethan-1-ol.In yet another embodiment of the present invention, agent used is selected from dicyclohexylcarbodiimide (DCC), p-toluenesulfonyl chloride (TosCl) or 1,1'-carbonyldiimidazole (CDI).In yet another embodiment of the present invention, reducing agent used is selected from the group consisting of LiAlH4, BH3DMS or BH3.THF.BRIEF DESCRIPTION OF THE FIGURESFig. 1 represents process steps for the preparation of novoldiamine 1 and hydroxynovoldiamine 2 of formula I.Fig. 2 represents the process step for the preparation of chloroquine 3, hydroxychloroquine 4 and mepacrine 5 following prior art procedures.DETAILED DESCRIPTION OF THE INVENTIONPresent invention provides a new and easily scalable, effective process for the preparation of formula I and their utility for production of chloroquine, hydroxychloroquine and mepacrine thereof.This process is an efficient and convenient method involving easily accessible starting material and reaction procedures.Present invention provide a process wherein the intermediates V,V-diethyl-4-oxopentanamide 6 / V-ethyl-V-(2-hydroxyethyl)-4-oxopentanamide (8) and V,V-diethyl-4-(hydroxyimino) pentanamide 7 / V-ethyl-V-(2-hydroxyethyl)-4-(hydroxyimino) pentanamide (9), could be obtained by simple reaction protocol employing activating agents such as CDI, or by conversion of levulinic acid to the corresponding acid chloride by thionyl chloride or oxalyl chloride and treatment with diethyl amine or V-ethyl ethanolamine. Further derivatization of the keto moiety in 6 or 8 to the corresponding oxime 7 and 9 using hydroxylamine hydrochloride in presence of sodium acetate and finally one pot reduction of oxime and amide to the corresponding amine employing reducing agents such as LiAlH4 or BH3.THF or BH3.DMS respectively as reagents to produce the corresponding diamines novoldiamine and hydroxynovoldiamine.The present invention provides a process for the preparation of V,V-diethyl-4-oxopentanamide (6). Activation of levulinic acid with agents like dicyclohexylcarbodiimide (DCC), p-toluenesulfonyl chloride (TosCl), in particularly with 1,1' -carbonyldiimidazole (CDI) to form imidazolide and then treatment with secondary amine such as diethyl amine or #-ethylethanolamine to get the corresponding amides 6 or 8 respectively.The present invention also describes the process of preparation of levulinoyl chloride by treating levulinic acid with acid chloride forming reagents such oxalyl chloride or in particularly with thionyl chloride following prior art and then treating the resulted acid chloride with secondary amine where R=H or R=OH. In particular, levulinic acid is treated with carbonyldiimidazole (CDI) to get the imidazolide and then further treated with secondary amine (R=H, or R=OH) to give the corresponding amide of levulinic acid. The process also relates to the conversion of amide 6 to the corresponding oxime #,#-diethyl-4-(hydroxyimino) pentanamide (7) by treatment of 6 with hydroxylamine hydrochloride in presence of sodium acetate.The process also relates to the conversion of amide 8 to the corresponding oxime #-ethyl-#-(2-hydroxyethyl)-4-(hydroxyimino) pentanamide (9) by treatment of 8 with hydroxylamine hydrochloride in presence of sodium acetate.The process also relates to the one pot reduction of oxime and amide to the corresponding diamine by reducing agents such as LiAlH4 or BH3DMS in particularly with BH3.THF. Thus, the oxime amide 7 is treated with BH3.THF and after workup provides novoldiamine 1. The oxime amide 9 is treated with BH3.THF and after workup provides hydroxynovoldiamine 2 (Fig. 1). The process also relates to the utility of these compounds 1 and 2 as key intermediates for the production of chloroquine 3, hydroxychloroquine 4 and mepacrine 5 (Fig. 2) following prior art procedures.Example 1Synthesis of N,N-diethyl-4-oxopentanamide (6)The reaction flask was loaded with carbonyldiimidazole (1.01eq.) and tetrahydrofuran under nitrogen environment. Levulinic acid (1.00eq.) diluted in THF, was added slowly into the reaction pot and held at room temperature for 20min. V, V-diethylamine (1.01eq.) diluted in THF was added into the reaction pot. The reaction mixture was allowed to stir at room temperature for 8 h. 5 Thereafter, THF was removed under reduced pressure, cooled to 0°C and diluted with 6 N HCl to maintain the pH ~ 6. The aqueous layer was extracted twice with ethyl acetate, organic layers were combined, dried (Na2SO4), concentrated on rotary evaporator to afford compound 6 as a clear, pale yellow liquid. (Yield > 96.5%). 1H NMR (400 MHz, CDCl3) : δ 3.33 (m, 4H), 2.77 (t, J = 6.5 Hz, 2H), 2.56 (t, J = 6.5 Hz, 2H), 2.19 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) : δ 208.2, 170.8, 41.9, 40.4, 38.3, 30.2, 26.9, 14.1, 13.0(major peaks). 13C NMR (101 MHz, CDCl3) : δ 206.8, 175.8, 37.9, 29.9, 27.7 (minor peaks).Example 2Synthesis of N, N-diethyl-4-(hydroxyimino) pentanamide (7)Under a nitrogen atmosphere, to a solution of compound 6 (1.00 eq.) in EtOH: Water (2:1) at room temperature was added hydroxylamine hydrochloride (1.20 eq.) and sodium acetate (1.30 eq.) The resulting reaction mixture was stirred at a temperature of about 70°C for 8 h. Thereafter, ethanol was distilled off under reduced pressure, and then extracted twice with DCM. The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to provide compound 7 as a dark yellow liquid (Yield > 95 %). 1H NMR (400 MHz, CDCl3) : δ 8.32 (s, 1H), 3.36 (q, J = 7.1 Hz, 2H), 3.30 (q, J = 7.2 Hz, 2H), 2.59 - 2.48 (m, 4H), 1.91 (m, 3H), 1.16 (t, J = 7.2 Hz, 3H), 1.12 - 1.06 (m, 3H).Example 3Synthesis of N,N-diethylpentane-1,4-diamine / Novoldiamine (1)Compound 7 (1.00eq.) was taken into RBF under a nitrogen atmosphere. BH3-THF solution (1 M, 10.00eq.) was added drop wise over the period of 1h. The mixture was allowed to stir for 18h, then cooled, acidified with 2 M hydrochloric acid, and stirred for 18h at room temperature. It was then concentrated under vacuum, alkalized with 20% aqueous sodium hydroxide solution filtered and distilled off to get compound 1 as a clear, transparent liquid (yield > 90.00%). 1H NMR (400 MHz, CDCl3) : δ 2.94 - 2.85 (m, 1H), 2.56 - 2.49 (m, 4H), 2.44 - 2.39 (m, 2H), 1.56 - 1.44 (m, 2H), 1.34 - 1.28 (m, 2H), 1.07 (d, J = 6.3 Hz, 3H), 1.05 - 0.99 (m, 6H). 13C NMR (101 MHz, CDCb) 5 53.0, 46.9, 46.8, 38.2, 24.0, 11.6.Example 4Synthesis of N-ethyl-N-(2-hydroxyethyl)-4-oxopentanamide (8)The reaction flask was loaded with carbonyldiimidazole (1.01eq.) and tetrahydrofuran under nitrogen environment. Levulinic acid (1.00eq.) diluted in THF, was added slowly into the reaction pot and held at room temperature for 20 minutes. 2-(Ethylamino)ethanol (1.01eq.) diluted in THF was added into the reaction pot. The reaction mixture was allowed to stir at room temperature for 8h. Thereafter, THF was removed under reduced pressure, cooled to 0°C and diluted with 6 N HCl to maintain the pH ~ 6. The aqueous layer was extracted twice with ethyl acetate, organic layers were combined, dried (Na2SO4), concentrated on rotary evaporator to afford compound 6 as a clear, pale yellow liquid. (Yield > 95 %). 1H NMR (400 MHz, CDCl3) : δ 3.80 (t, J = 5.4 Hz, 0.6H), 3.75 (t, J = 5.1 Hz, 1.4H), 3.54 - 3.47 (m, 2H), 3.46 - 3.36 (m, 2H), 2.86 - 2.78 (m, 2H), 2.68 -2.60 (m, 2H), 2.24 - 2.17 (m, 3H), 1.23 (t, J = 7.2 Hz, 2H), 1.11 (t, J = 7.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) : δ 207.9, 173.5, 62.5, 49.6, 44.1, 38.2, 30.1, 26.9, 13.9(major peaks). 13C NMR (101 MHz, CDCl3) : δ 209.1, 171.8, 60.8, 49.5, 41.0, 38.6, 30.0, 26.9, 12.8(minor peaks).Example 5Synthesis of N-ethyl-N-(2-hydroxyethyl)-4-(hydroxyimino)pentanamide (9)Under a nitrogen atmosphere, to a solution of compound 8 (1.00eq.) in EtOH: Water (2:1) at room temperature was added hydroxylamine hydrochloride (1.20eq.) and sodium acetate (1.30eq.) The resulting reaction mixture was stirred at a temperature of about 70°C for 8 h. Thereafter, ethanol was distilled off under reduced pressure, and then extracted twice with DCM. The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to provide Compound 9 as a dark yellow liquid (Yield > 92 %). 1H NMR (400 MHz, CDCl3) 3.75 (m, 2H), 3.55 - 3.46 (m, 2H), 3.44 - 3.36 (m, 2H), 2.64 (m, 2H), 2.60 - 2.51 (m, 2H), 1.90 (m, 3H), 1.16 (m, 3H).Example 6Synthesis of 2-((4-aminopentyl)(ethyl)amino)ethan-1-ol / Hydroxynovoldiamine (2)Compound 9 (1.00eq.) was taken into RBF under a nitrogen atmosphere. BH3-THF solution (1 M, 10.00eq.) was added drop wise over the period of 1h. The mixture was allowed to stir for 18h, then cooled, acidified with 2 M hydrochloric acid, and stirred for 18h at room temperature. It was then concentrated under vacuum, alkalized with 20% aqueous sodium hydroxide solution filtered and distilled off to get compound 2 as a clear, transparent liquid (yield > 88.00%). 1H NMR (400 MHz, CDCl3) : δ 3.53 (t, 2H), 2.95 - 2.85 (m, 1H), 2.60-2.53 (m, 2H), 2.45 (t, 2H), 1.57 - 1.41 (m, 2H), 1.36 - 1.27 (m, 2H), 1.09 - 1.05 (d, 3H), 1.02 (t, J = 9.0, 5.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) : δ 58.41, 54.99, 53.34, 47.27, 46.92, 37.88, 24.23, 24.15, 11.85.Procedure for coupling chlorinated arenes with diamines: In an RBF (50 ml), 1 equiv. of substituted quinoline, 1.20 equiv. of diamino compound (novoldiamine. Or novoldiamine) and 3.00 equiv. of phenol were charged. Reaction was allowed to heat at 120 °C with continuous stirring for 18 h. After 18 h, reaction mixture was cooled to room temperature and diluted with dichloromethane. The resulting mixture was washed with 1.5 M NaOH solution and the wash was back-extracted with dichloromethane. The combined organic layer was extracted with 1 M hydrochloric acid. The aqueous extract was basified to pH 12 with potassium carbonate solution and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography. Chloroquine, The above procedure was used to synthesize chloroquine 3, with 4,7-dichloroquinoline and novoldiamine as reaction substrates to yield 3 as a pale yellow solid; (Yield= 69.5%), 1HNMR (400 MHz, CDCl3) : δ 8.47 (d, J = 5.6 Hz, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.95 (d, J =2.0 Hz, 1H), 7.39-7.33 (m, 1H), 6.37 (d, J = 5.7 Hz, 1H), 3.77-3.69 (m, 1H), 2.90-2.83 (m, 4H), 2.80-2.74 (m, 2H), 1.98-1.85 (m, 2H), 1.79-1.67 (m, 2H), 1.32 (d, J = 6.4 Hz, 3H), 1.17 (t, J = 7.3 Hz, 6H), 0.89-0.81 (m, 1H). 13C NMR (101 MHz, CDCl3) : δ 177.0, 150.6, 150.3, 147.9, 135.5, 127.2, 125.4, 122.7, 117.3, 98.7, 51.9, 48.5, 46.3, 33.5, 29.7, 23.4, 22.1, 20.3, 9.2. ESI MS calcd for C18H2ClN3 [M+H]+: m / z 320; found: 320.Hydroxychloroquine, The above procedure was used to synthesize hydroxchloroquine 4, with 4,7-dichloroquinoline and hydroxynovoldiamine as reaction substrates to yield 4 as a pale yellow solid (Yield = 62.7%), 1H NMR (400 MHz, DMSO) : δ 8.51(d, J = 5.4Hz, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.70 (d, J=9.0 Hz 1H), 7.37-7.33 (m, 1H), 6.40 (d, J= 5.4 Hz, 1H), 4.94 (d, J = 7.5 Hz, 1H), 3.7630 3.65 (m, 1H), 3.55 (t, J = 5.4 Hz, 2H), 2.64-2.46 (m, 8H), 1.77-1.52 (m, 4H), 1.32 (d, J = 65.3 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) : δ 152.0, 149.3, 148.9, 134.9, 128.8, 125.2, 120.9, 117.2, 99.2, 58.4, 54.8, 52.9, 48.3, 47.4, 34.4, 24.0, 20.4, 11.7. ESI MS calcd for C18H27QN3O [M+H]+: m / z 336; found: 336.Mepacrine, 5: The above procedure was used to synthesize mepacrine 5, with dechlorinated arene 5 and novoldiamine as reaction substrates to yield as yellow solid; (Yield = 70.00 %), 1H NMR (250 MHz, CDCl3) : δ = 8.12 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 9.4 Hz, 2H), 7.46 (dd, J = 9.4, 2.7 Hz, 1H), 7.37 (dd, J = 9.3, 2.1 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 4.49 (br d, J=1 0.7 Hz,1H), 4.114.00 (m, 1H), 4.01 (s, 3H), 2.55-2.40 (m, 6 H), 1.74-1.62 (m, 4 H), 1.30 (d, J = 6.4 Hz, 3 H), 1.00 (t, J = 7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3) : δ 156.6, 149.7,148.6, 147.4, 135.2, 132.0, 128.8,125.4, 125.1, 124.3, 119.8,117.8, 99.7, 56.4, 56.0, 53.1, 47.2 (2 C), 37.3, 24.3, 22.7, 11.8. ESI MS calcd for C23H2OCM3O [M+H]+: m / z 400.21; found: 400.19.ADVANTAGES OF THE INVENTIONThe various advantages of the present process are given below.. The main advantage of the present invention is that it provides an efficient process for the preparation of novoldiamine, hydroxynovoldiamine which are in turn used for the production of chloroquine, hydroxychloroquine and mepacrine.. Further the present invention employ simpler reaction parameters amenable for large scale to achieve the production of novoldiamine and hydroxynovoldiamine.. Isolation and / or purification of these key intermediate products novoldiamine and hydroxynovoldiamine is done efficiently by distillation.. The process is cost-effective, and scalable method for the production of chloroquine, hydroxychloroquine and mepacrine.. The process starts with levulinic acid which is easily accessible from feed stock indigenously. One need not depend on abroad countries for this starting material.

Claims

1. A process for the preparation of compounds of formula I comprising the steps of: wherein R=H or OH; a) activating levulinic acid of formula (a) with agent to get the imidazolide of formula (b); Formula a Formula b b) treating the imidazolide of formula (b) as activated in step (a) with secondary amine of formula (c) to get the amide of formula (d); Formula (d) c) treating the amide as obtained in step (b) with hydroxylamine hydrochloride to get the corresponding oxime of formula (e); Formula (e) d) treating the oxime as obtained in step (c) with reducing agent to yield compound of formula I. Wherein, R=H (1) or R=OH (2)2. The process as claimed in claim 1, wherein compound of formula I is selected from novoldiamine NH2 r OH hydroxynovoldiamine3. The process as claimed in claim 1, wherein secondary amine used is selected from diethyl amine and 2-(ethylamino)ethan-1-ol.

4. The process as claimed in claim 1, wherein agent used is selected from dicyclohexylcarbodiimide (DCC), p-toluenesulfonyl chloride (TosCl) or 1,1'-carbonyldiimidazole (CDI).

5. The process as claimed in claim 1, wherein reducing agent used is selected from the group consisting of LiAlH4, BH3DMS or BH3.THF.