DESC:PROCESS FOR PREPARATION OF HYDROXY NOVALDIAMINE
TECHNICAL FIELD
[0001] The present invention generally relates to process for preparation of hydroxy novaldiamine or 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine or 5-[N,N-diethylamino]2-pentylamine. The present invention is additionally related to synthesis of hydroxy novaldiamine from commercially available petroleum product thiophene. The present invention also relates to synthesis of hydroxychloroquine (HCQ) using hydroxy novaldiamine (HNDA). The present invention specifically relates to a process for preparation of Novaldiamine or 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine or 5-[N,N-diethylamino]2-pentylamine from thiophene derivatives wherein the hydroxy novaldiamine (HNDA) is further used for synthesis of hydroxychloroquine (HCQ).
BACKGROUND OF THE INVENTION
[0002] Hydroxychloroquine (HCQ) is a family anti-malarial class of drugs that have a wide range of applications and uses as therapeutic systemic anti-inflammatory agents for a variety of serious inflammatory and auto-immune diseases such as, but not limited to, rheumatoid arthritis and lupus erythematosus for much of the last half century.
[0003] HCQ has a remarkably wide range of actions including antagonist activity to histamine and antigen-induced bronchospasm and reduction of antibody responses, particularly those involving production of allergic antibody. Other actions relevant to the anti-asthmatic anti-allergic actions contained in this application include alterations in cell-mediated immunity, alterations in mediator effects and pathways, including evidence for inhibition of the arachidonic pathway cascade which results in the production of potent spasmogenic and inflammatory mediators such as leukotrienes, some novel and potentially important antiviral actions as well as other significant miscellaneous anti-inflammatory effects. In recent past, with the outburst of the pandemic COVID 19, HCQ is considered as an effective drug for treating the patients affected with COVID 19.
[0004] Methods for synthesis of Hydroxychloroquine (HCQ) are well known in the art. In one embodiment of prior art, WO2005062723A2 proposes a process for synthesis of Hydroxychloroquine (HCQ) using hydroxy novaldiamine (HNDA). It is therefore production of hydroxy novaldiamine with high purity and higher yield rate has become predominantly important for effective synthesis of Hydroxychloroquine (HCQ). Majority of prior art approaches for production of hydroxy novaldiamine are costly and obtained poor yields. Furthermore, the prior art methods for production of hydroxy novaldiamine (HNDA) are unable to produce high quality hydroxy novaldiamine thereby making them inefficient for production of high quality hydroxy novaldiamine. Furthermore, the prior art approaches for production of hydroxy novaldiamine do not teach a process for production of high quality hydroxy novaldiamine or hydroxy novaldiamine or 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine or 5-[N,N-diethylamino]2-pentylamine from thiophene derivatives with simple isolation techniques.
[0005] Based on the foregoing a need therefore exists for an improved process for preparation of high purity and high yield hydroxy novaldiamine for use in synthesis of Hydroxychloroquine (HCQ). Also, a need exists for an improved process for preparation of Hydroxy Novaldiamine or 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine or 5-[N,N-diethylamino]2-pentylamine from thiophene derivatives wherein the hydroxy novaldiamine is further used for synthesis of hydroxychloroquine (HCQ), as discussed in greater detail herein.
SUMMARY OF THE INVENTION
[0006] The following summary is provided to facilitate an understanding of some of the innovative features unique to the disclosed embodiment and is not intended to be a full description. A full appreciation of the various aspects of the embodiments disclosed herein can be gained by taking the entire specification, claims, drawings, and abstract as a whole.
[0007] Therefore, one aspect of the disclosed embodiment is to provide for an improved high yield and high purity hydroxy novaldiamine for synthesis of Hydroxychloroquine (HCQ).
[0008] It is another aspect of the disclosed embodiment to provide for an improved process for preparation of high purity and high yield hydroxy novaldiamine for use in synthesis of Hydroxychloroquine (HCQ).
[0009] It is further aspect of the disclosed embodiment to provide for an improved process for preparation of hydroxy novaldiamine or 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine or 5-[N,N-diethylamino]2-pentylamine from thiophene derivatives wherein the hydroxy novaldiamine is further used for synthesis of hydroxychloroquine (HCQ).
[00010] The aforementioned aspects and other objectives and advantages can now be achieved as described herein. A process for preparation of hydroxy novaldiamine (or) 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (or) 5-[N,N-diethylamino]2-pentylamine from thiophene derivatives wherein the hydroxy novaldiamine is further used for synthesis of hydroxychloroquine (HCQ), is disclosed herein. Thiophene (C4H4S) is functionalized with a formyl group (-CH=O, formylation reaction) in order to obtain Thiophene-2-carboxaldehyde (III). Thiophene-2-carboxaldehyde (III) is treated with sulfuric acid and nitric acid (Nitration process) at a temperature ranging from -15 oC to 0 oC for a period of 1 to 2 hour to obtain compound (IV). The compound (IV) is subjected to reductive amination with appropriate secondary amine 2-Ethyl Ethanolamine in the presence of reducing reagent at refluxing temperature (preferably 90-120 oC) for a period of 10 hours. When the reaction is carried out and product was neutralized with based and extracted with organic solvent to get the third step of the product (V). The reductive desulfurization of thiophene derivative (V) in the presence of Raney Ni results in a ring opening product that is subject to nitro group reduction in order to obtain pentylamine or Hydroxy Novaldiamine (II). Absorption of thiophene on the Ni surface results in geometric distortion of the adsorbed molecule and the loss of aromaticity of the thiophene ring further ring opening results in the formation of pentylamine or Hydroxy Novaldiamine (II).
[00011] In one embodiment of the present invention, the reductive desulfurization of compound of formula (V) is performed in alcoholic solvents selected from methanol, ethanol, isopropanol and the like wherein the reductive amination process is carried out at a temperature ranging between about 40oC to 130oC under a hydrogen pressure ranging from about 5 to 35 kg/cm2. In another embodiment of the present invention, the compound (IV) is subject to reduction in order to obtain compound (IVa) and is subjected to halogenation in order to obtain the compound (IVb). The compound (IVb) is subjected to N-alkylation to obtain the compound (V). The reductive desulfurization of thiophene derivative (V) in the presence of Raney Ni results in a ring opening product that is subject to nitro group reduction in order to obtain pentylamine or Hydroxy Novaldiamine (II). Absorption of thiophene on the Ni surface results in geometric distortion of the adsorbed molecule and the loss of aromaticity of the thiophene ring further ring opening results in the formation of pentylamine or Hydroxy Novaldiamine (II).
DETAILED DESCRIPTION
[00012] The particular values and configurations discussed in these non-limiting examples can be varied and are cited merely to illustrate at least one embodiment and are not intended to limit the scope thereof.
[00013] A process for preparation of hydroxy novaldiamine (II) (or) 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (or) 5-[N,N-diethylamino]2-pentylamine from thiophene derivatives wherein the hydroxy novaldiamine is further used for synthesis of hydroxychloroquine (HCQ). The hydroxy novaldiamine is key intermediate for synthesis of hydroxychloroquine (HCQ).

[00014] Thiophene (C4H4S) is functionalized with a formyl group (-CH=O, formylation reaction) in order to obtain Thiophene-2-carboxaldehyde (III). Thiophene is a heterocyclic compound with the chemical formula C4H4S that has a planar five-membered ring, it is aromatic as indicated by its extensive substitution reactions. It is a colorless liquid with a benzene-like odor. In most of its reactions, it resembles benzene. Compounds analogous to thiophene include furan (C4H4O) and pyrrole (C4H4NH), which each vary by the heteroatom in the ring. A person skilled in the art can appreciate the use of the petroleum compound, Thiophane for production of hydroxy novaldiamine (or) 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (or) 5-[N,N-diethylamino]2-pentylamine from thiophane and its derivates within the scope of the proposed invention.

[00015] Thiophene-2-carboxaldehyde (III) is treated with sulfuric acid and nitric acid (Nitration process) at a temperature ranging from -15 oC to 0 oC for a period of 1 to 2 hour to obtain 4-nitrothiophene-2-carbaldehyde (IV). The compound (IV) is subjected to reductive amination with appropriate secondary amine 2-Ethyl Ethanolamine in the presence of reducing reagent at refluxing temperature (preferably 90-120oC) for a period of 10 hours. When the reaction is carried out and product was neutralized with based and extracted with organic solvent to get the third step of the product 2-(ethyl((4-nitrothiophen-2-yl)methyl)amino)ethanol (V). The reductive desulfurization of thiophene derivative (V) in the presence of Raney Ni results in a ring opening product that is subject to nitro group reduction in order to obtain pentylamine or Hydroxy Novaldiamine (II). Absorption of thiophene on the Ni surface results in geometric distortion of the adsorbed molecule and the loss of aromaticity of the thiophene ring further ring opening results in the formation of pentylamine or Hydroxy Novaldiamine (II).
[00016] The non-polar solvents used in the condensation step is selected from toluene, xylene, cyclohexane, hexane, THF and heptane. The process according to claim 3, wherein the condensation of compound of formula (V) and formula are conducted at a temperature ranging from about 0oC to 120oC. The substituted amines of formula (V) are N-Ethyl-N-2-hydroxy ethylamine or N,N-diethylamine.
[00017] The substituted groups on compound of formula (V) is selected to form new derivatives:

[00018] In one embodiment of the present invention, the reductive desulfurization of compound of formula (V) is performed in alcoholic solvents selected from methanol, ethanol, isopropanol and the like wherein the reductive amination process is carried out at a temperature ranging between about 40oC to 130oC under a hydrogen pressure ranging from about 5 to 35 kg/cm2. In another embodiment of the present invention, the compound (IV) is subject to reduction in order to obtain compound (IVa) and is subjected to halogenation in order to obtain the compound (IVb). The compound (IVb) is subjected to N-alkylation to obtain the compound (V). The preparation of reductive amination compound (V) prepared via reduction of aldehyde group compound (IVa) followed by halogenation (IVb) and N-alkylation.
[00019] The reductive desulfurization of thiophene derivative (V) in the presence of Raney Ni results in a ring opening product that is subject to nitro group reduction in order to obtain pentylamine or Hydroxy Novaldiamine (II). Absorption of thiophene on the Ni surface results in geometric distortion of the adsorbed molecule and the loss of aromaticity of the thiophene ring further ring opening results in the formation of pentylamine or Hydroxy Novaldiamine (II).
[00020] It will be appreciated that variations of the above-disclosed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Also, that various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.
,CLAIMS:I/We CLAIM:
1. A process for preparation of hydroxy novaldiamine from thiophene derivatives, comprising:
functionalizing Thiophene (C4H4S) with a formyl group (-CH=O, formylation reaction) in order to obtain Thiophene-2-carboxaldehyde (III);
treating Thiophene-2-carboxaldehyde (III) with sulfuric acid and nitric acid (Nitration process) at a temperature ranging from -15-0 oC for a period of 1 to 2 hour to obtain compound (IV);
reductive amination of compound (IV) with secondary amine 2-Ethyl Ethanolamine in the presence of reducing reagent at refluxing temperature (preferably 90-120oC) for a period of 10 hours;
neutralizing compound (IV) with base and extracting with organic solvent to get the third step of the product (V);
reductive desulfurization of thiophene derivative (V) in the presence of Raney Ni to obtain a ring opening product that is subject to nitro group reduction in order to obtain pentylamine or Hydroxy Novaldiamine (II);
absorption of thiophene on the Ni surface to result in geometric distortion of the adsorbed molecule and the loss of aromaticity of the thiophene ring further ring opening resulting in the formation of pentylamine/Hydroxy Novaldiamine (II).
2. The process as claimed in claim 1 wherein the hydroxy novaldiamine (II) comprises of 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine.
3. The process as claimed in claim 1 wherein the hydroxy novaldiamine (II) comprises of 5-[N,N-diethylamino]2-pentylamine.
4. The process as claimed in claim 1 wherein the hydroxy novaldiamine (II) is used for synthesis of hydroxychloroquine (HCQ).
5. The process as claimed in claim 1 wherein the reductive desulfurization of compound of formula (V) is performed in alcoholic solvents wherein the reductive amination process is carried out at a temperature ranging between about 40oC to 130oC under a hydrogen pressure ranging from about 5 to 35 kg/cm2.
6. The process as claimed in claim 1 wherein the compound (IV) is subject to reduction in order to obtain compound (IVa) and is subjected to halogenation in order to obtain the compound (IVb) wherein the compound (IVb) is subjected to N-alkylation to obtain thiophene derivative (V).