Title of Invention	A PROCESS FOR THE SYNTHESIS OF 5-(N-ETHYL-N-2-HYDROXY ETHYLAMINO)-2-PENTYL AMINE (HYDROXY NOVOLDAMINE), 5-N,N-DIETHYLAMINO)-2-PENTYLAMINE(NOVOLDAMINE)
Abstract	A process for the synthesis of 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (Hydroxy Novoldamine), 5-(N,N-diethylamino)-2-pentylamine(Novoldamine) wherein the said process comprises a) ketalization of 1-chloro-4-pentanone carried out by treating it with glycol selected from ethylene glycol or neopentyl glycol in a molar ratio of 1:2 in presence of non polar organic solvent selected from toluene, cyclohexane, xylene, heptane and hexane and catalyst selected from para-toluene sulphonic acid, methane sulphonic acid, perchloric acid at temperature range of 80-140°C for 20-25 hours to obtain compound of formula (I) 2(3'-chloropropyl)2-methyl-1,3-dioxalane, 2-(3 '-chloropropyl) -2,5,5-Trimethyl 1,3-dioxane; 0) b) condensation of said compound of formula (I) 2(3'-chloropropyl)2-methyl- 1,3-dioxalane, 2-(3'-chIoropropyl) -2,5,5-Trimethyl 1,3-dioxane with substituted amine derivatives of formula (V) N-ethyl-N-2-hydroxy ethyl amine, N,N-diethylamine in a molar ratio of 2:5 in presence of non-polar solvents selected from toluene, xylene and cyclohexane at temperature ranging from 90°C-140°C for 18 hours to obtain compound of formula (II) 2-(3' -N-ethy 1- N-2-hydroxyethylaminopropyl)-2-methyl-1,3 -dioxalane (HNK Ketal); 3 H< 1 NR2 R1=R2=Ethyl or R1R2=Ethyl Rl=Ethyl; R1 =Ethyl R2=Hydroxy ethyl (11) (V) c) deprotection of the ketal group of compound of formula (II), 2-(3,-N-ethyI-N-2-hydroxyethylaminopropyl)-2-methyl-l,3-dioxalane (HNK Ketal) under acidic conditions at temperature range of 10- 50°C for 6-7 hours to obtain compound of formula (III) 5-(N-ethyl-N-2-hyd^xyethylamino)-4-pentanone or 5-(N.N-diethylamino)-4-pentanone; and 0 NT Ri = R2 = Ethyl (or) R1=Ethyl; R2=Hydroxy ethyl d) reductive amination of compound of formula (III), 5-(N-ethyl-N-2-hydroxyethylamino)-4-pentanone or 5-(N,N-diethylamino)-4-pentanone is carried out by treating it with alcoholic ammonia in presence of catalyst such as Raney Nickel under mild hydrogenation conditions such as 10-30 kg/cm2 and temperature ranging from 40-130°C for 2-5 hours to yield compound of formula (IV) namely 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine and 5-(N,N'diethyIamino)-2-pentylamine. 10 (IV) i)Ri ,R2= Ethyl—>- 5-[N,N-diethylamino]-2-pentylamine] ii) R, = Ethyl, R2 = hydroxy ethyl —*■ 5-[N-ethyl-N-2-hydroxyethylamino]-2-pent

Title of Invention

A PROCESS FOR THE SYNTHESIS OF 5-(N-ETHYL-N-2-HYDROXY ETHYLAMINO)-2-PENTYL AMINE (HYDROXY NOVOLDAMINE), 5-N,N-DIETHYLAMINO)-2-PENTYLAMINE(NOVOLDAMINE)

Abstract

A process for the synthesis of 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (Hydroxy Novoldamine), 5-(N,N-diethylamino)-2-pentylamine(Novoldamine) wherein the said process comprises a) ketalization of 1-chloro-4-pentanone carried out by treating it with glycol selected from ethylene glycol or neopentyl glycol in a molar ratio of 1:2 in presence of non polar organic solvent selected from toluene, cyclohexane, xylene, heptane and hexane and catalyst selected from para-toluene sulphonic acid, methane sulphonic acid, perchloric acid at temperature range of 80-140°C for 20-25 hours to obtain compound of formula (I) 2(3'-chloropropyl)2-methyl-1,3-dioxalane, 2-(3 '-chloropropyl) -2,5,5-Trimethyl 1,3-dioxane; 0) b) condensation of said compound of formula (I) 2(3'-chloropropyl)2-methyl- 1,3-dioxalane, 2-(3'-chIoropropyl) -2,5,5-Trimethyl 1,3-dioxane with substituted amine derivatives of formula (V) N-ethyl-N-2-hydroxy ethyl amine, N,N-diethylamine in a molar ratio of 2:5 in presence of non-polar solvents selected from toluene, xylene and cyclohexane at temperature ranging from 90°C-140°C for 18 hours to obtain compound of formula (II) 2-(3' -N-ethy 1- N-2-hydroxyethylaminopropyl)-2-methyl-1,3 -dioxalane (HNK Ketal); 3 H< 1 NR2 R1=R2=Ethyl or R1R2=Ethyl Rl=Ethyl; R1 =Ethyl R2=Hydroxy ethyl (11) (V) c) deprotection of the ketal group of compound of formula (II), 2-(3,-N-ethyI-N-2-hydroxyethylaminopropyl)-2-methyl-l,3-dioxalane (HNK Ketal) under acidic conditions at temperature range of 10- 50°C for 6-7 hours to obtain compound of formula (III) 5-(N-ethyl-N-2-hyd^xyethylamino)-4-pentanone or 5-(N.N-diethylamino)-4-pentanone; and 0 NT Ri = R2 = Ethyl (or) R1=Ethyl; R2=Hydroxy ethyl d) reductive amination of compound of formula (III), 5-(N-ethyl-N-2-hydroxyethylamino)-4-pentanone or 5-(N,N-diethylamino)-4-pentanone is carried out by treating it with alcoholic ammonia in presence of catalyst such as Raney Nickel under mild hydrogenation conditions such as 10-30 kg/cm2 and temperature ranging from 40-130°C for 2-5 hours to yield compound of formula (IV) namely 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine and 5-(N,N'diethyIamino)-2-pentylamine. 10 (IV) i)Ri ,R2= Ethyl—>- 5-[N,N-diethylamino]-2-pentylamine] ii) R, = Ethyl, R2 = hydroxy ethyl —*■ 5-[N-ethyl-N-2-hydroxyethylamino]-2-pent

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "A process for the synthesis of 5-(N-ethyl-N-2-hydroxy ethylamino)-2-pentyl amine (Hydroxy Novoldamine), 5-N,N-diethylamino)-2-pentylamine(Novoldamine)" (a) IPCA LABORATORIES LIMITED (b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed; Technical Field of Invention This invention relates to a process for preparation of substituted aminopentylamines, key intermediates in the preparation of anti-malarial, anti-rheumatic agents such as chloroquine sulphate, chloroquine phosphate, chloroquine and hydroxy chloroquine base, or theif acid addition salts starting from l-chloro-4-pentanone. Background and prior art Hydroxy novoldamine, chemically known as 5-(N-ethyI-N-2-hydroxy ethylamino)-2-pentyl)amine and novoldamine, chemically known as 5-(N,N-diethylamino)-2-pentylamine are the intermediates of anti-malarial drugs viz; hydroxychloroquine and chloroquine. US patent 2,365,825 discloses a method for preparation of N,N-diethylamino alcohols, particularly N,N-diethyl-l-amino-4-pentanol which comprises reacting 1,4-pentanediol with diethylamine in the presence of a metal hydrogenation catalyst more specifically Ni /tfeat temperature range within 120-250° C. US patent 2,442,854 discusses an improved process for preparing the oxime of 1-diethylamino-4-pentanone, an intermediate used in the synthesis of novaldamine. This reported process comprises acidic decarboxylation of [(diethylami no ethyl) ethyl acetoacetate] to obtain 1 -diethylamino-4-pentanone in presence of sulfuric acid. 2. US patent 2,546,658 describes a process for preparation of hydroxy novoldamine, wherein the condensation of l-halo-4-pentanone with N-ethyl-N-2-hydroxyethylamine to yield l-(N-ethyl-N-2-hydroxyethylamine)-4-pentanone and its further reductive animation to give 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine, is disclosed. Hydroxy novoldamine was used as a primary starting material for the preparation of 2-{[4-(7-benz[c] acridinylamino)pentyl]ethylamino}ethanol, which was used as an amebicidal agent was described in US patent no 2,915,523. Starting from 5-chloro-2-pentanone, 2-ethylaminoethanol, sodium chloride and xylene, for 5-(N-ethyl-2-hydroxyehylamino)-2-pentanone was obtained which was reductively hydrogenated to give 2-[(4-amino pentyl)ethyl amino]ethanol, as per this patent. GB patent 1,157,637 describes a process for the preparation of novoldamine and related amines which comprises of catalytic hydrogenation of methyl glutaronitrile, reductive alkylation of 2-methyl glutaronitrile, hydrolyzing valeronitrile, treating valeramide with an aqueous alkaline solution of an akali metal hypohalite. US patent 4,910,343 describes a simple and economical method of producing the novel nitro amine compounds which are enamine compound, l-diethylamino-4-nitropenetene-l and its partially reduced counterpart, l-diethylamino-4-nitropentane. These compounds further provide a new synthetic route to the formation of novaldamine. RO 62684 describes the preparation of N-ethyl-N-hydroxyethyl-l,4-pentanediamine by reacting 5-[N-(2-hydroxyethy) ethylamino]-2-pentanone with ammonia and hydrogen over Raney Nickel. Novoldamine and hydroxy novoldamine are prepared by various synthetic routes in prior art as described above. But, most of the methods are not practiced due to the complexity of synthesis. The drawback of the processes described in the prior art is that the isolation of the required compound is very difficult because of the higher concentrations of impurities in the product and therefore gives very poor yields of the pure compound. The major drawback of the reported processes starting from 1- chloro-4-pentanone is their high reactivity with the amines, leading to uncontrollable exotherm at large scale, formation of impurities which are very difficult to remove, as stated above. In a nutshell, the process mentioned in prior art are not plant friendly and require repeated purification by high vacuum fractional distillation for getting the product of desired quality, which ultimately leads to increased cost of manufacture. Hence there is a need for development of economically as well as plant friendly process for the title products. Objectives • The main objective of the present invention is to provide a simple plant friendly and economical process for the manufacture of aminopentylamines having desired quality for transferring the latter in to the corresponding quinolines of high purity. • A further objective of the present invention is to reduce the reactivity of 1-chloro-4-pentanone to control high exotherm at large scale operations, by protecting the keto group to provide a better quality and yield of the title product. • A further objective of the present invention is to provide better reaction condition for reductive amination at lower hydrogen pressure and stoichiometric amounts of catalyst such as Raney Nickel. Summary of the invention This invention relates to a novel process for the preparation of substituted aminopentylamines, more particularly 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine and 5-(N,N-diethylamino)-2-pentylamine which are the key intermediates in the synthesis of hydroxy chloroquine & chloroquine and their acid addition salts. Detailed description In accordance with the above basic objective of the present invention, there is provided a protection of carbonyl group of 1- chloro-4-pentanone with protecting groups like monoethylene glycol, neopentyl glycol etc. to provide a 2-(3'-chloropropyl)-2-methyl 1,3-dioxalane, 2-(3,-chloropropyl)-2,5,5-trimethyl-l,3-diOxalane of formula(I) The reaction is carried out between l-chloro-4-pentanone with monoethylene glycol, neopenthy glycol; in the molar ratio of 1.0 to2.0 preferably 1.1 in non-polar solvents like toluene, xylene, cyclohexane, heptane, hexane using acid catalyst like para-toluene sulphonic acid, methane sulphonic acid, perchloric acid etc. at a temperature ranging from 80 to 140°C preferably between 80 to 90°C for a period of 15 to 30 hours. The product of formula (I) is then condensed with amines (v) such as N-ethyl-N-2-hydroxyethyl amine, N,N-diethylamine to give the condensed product of formula(II). Ketalization 1 -chloro-4-pentanone (I) HN: ■R2 (S) [Ri = R2 = As described earlier] (II) Rt, R2 = Ethyl Ri = Ethyl R2 = Hydroxy ethyl Further reaction is carried out between formula(I) with substituted amines of formula (V) such as N-ethyl-N-2-hydroxy ethyl amine, N,N-diethylamine in the molar ratio of 2.0 to5.0 preferably 2.2 in non- polar solvents like toluene, xylene, cyclohexane at a 5 temperature ranging from 90 to 140°C, preferably 120 to 130°C, for a period of 18 to20 hours. The product of formula (II) is then hydrolyzed in acidic condition to give desired ketone of the formula (III). ^2 Ri = R2 = As described earlier ] on) The product of the formula (II) is hydrolyzed in acidic conditions using acids like hydrochloric acid, sulphuric acid, perchloric acid, phosphoric acid, para-toluene sulphonic acid, methane sulphonic acid, trifluro aectic acid etc. in the molar ratio of 1.1 to5.0 preferably 1.5 in aqueous condition at a temperature ranging from 10 to 50°C preferably 25 to 35° C for a period of 6 to7 hours, which is then reductively animated, yields the desired title compound of formula (IV). 5-[N,N-diethylamino]-2-pentylamine] ii) R1 = Ethyl, R2 = Hydroxy ethyl —- 5-[N-ethyl-N-2-hydroxyethylamino]-2-pentylamine The reaction is carried out between condensed ketone of formula (III) in presence of ammonical alcoholic solvents like methanol, ethanol, isopropanol and catalyst Raney Nickel under hydrogen pressure ranging from 10 to 30 kg/cm preferably 20 to 22 kg/cm at a temperature ranging from 40 to 130° C preferably 80 to 85° C for a period of 2 to5 hours. 6 The following examples illustrate the process of the invention in greater details and are in no way limiting the scope of the invention. Experimental Example 1 1 -chloro-4-pentanone: Acetyl butyrolactone (lOOgm) is added dropwise in a mixture of water (lOOgm), hydrochloric acid (120gm) and sodium chloride (20gm) at 100 tol05°C. After completing the reaction, the resulting product is collected by distillation. The yield of the product is 80gms. Example 2 2-(3,-chloropropvO-2-methyl-l,3-dioxalane: Ethylene glycol (40gms), cyclohexane (160ml) & para-toluene sulphonic acid (lgm) are added to 1-chloro-4-pentanone (80gm). The reaction mixture is heated to 80 to 90° C for 20 to25 hours and removes the water azeotropically from the reaction mixture. The reaction mass is cooled. Water (40 ml) is added to the reaction mass and separated the aqueous layer. Organic layer is distilled under vacuum to isolate the oily product. The yield of the product is lOOgms. Example 3 2-f3,-N-ethvl-N-2-hvdroxvethvlaminopropvn-2-methvl-1.3-dioxalane(HNKKetal) Toluene (200ml) and ethylamino ethanol (130gm) are added to product of formula (I) (lOOgm). The reaction mass is heated tol25 to 130°C for 15 to 18 hours. The reaction is cooled. Water (10ml) added and the aqueous layer is separated. The organic layer is distilled out to isolate the product. The yield of the product is 1 lOgms. Example 4 l-(N-ethyl-N-2-hydroxyethyl amino)-4 -pentanone Water (100ml) and cone, hydrochloric acid (10ml) is added to the HNK Ketal (HOgm). The reaction mass is stirred for 4 to 5hours at 30° C - 40° C. Then the reaction mixture is neutralized with caustic lye solution. Aqueous layer is separated to isolate the product layer. The yield of the product is lOOgm. Example 5 5-(N-ethvl-N-2-hvdroxvethylamino)-2-pentvlamine: The l-(N-ethyl-N-2hydroxyethylamino)-4-pentanone (lOOgm) was diluted with ammonical methanol (400ml) and reduced catalytically with Raney Nickel (5gm) at 40°C to 80°C using 15 to 20 kg hydrogen pressure in 4 to 5 hours. After completion of the reaction, catalyst was filtered. Methanol was distilled out at atmospheric pressure to give the crude product. The crude product was subjected to high vacuum fractional distillation to get the product of better quality in very high yield. The yield of the product is 80gms. 8 ^mended We claim 1. A process for the synthesis of 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (Hydroxy Novoldamine), 5-(N,N-diethylamino)-2-pentylamine(Novoldamine) wherein the said process comprises a) ketalization of 1-chloro-4-pentanone carried out by treating it with glycol selected from ethylene glycol or neopentyl glycol in a molar ratio of 1:2 in presence of non polar organic solvent selected from toluene, cyclohexane, xylene, heptane and hexane and catalyst selected from para-toluene sulphonic acid, methane sulphonic acid, perchloric acid at temperature range of 80-140°C for 20-25 hours to obtain compound of formula (I) 2(3'-chloropropyl)2-methyl-1,3-dioxalane, 2-(3 '-chloropropyl) -2,5,5-Trimethyl 1,3-dioxane; 0) b) condensation of said compound of formula (I) 2(3'-chloropropyl)2-methyl- 1,3-dioxalane, 2-(3'-chIoropropyl) -2,5,5-Trimethyl 1,3-dioxane with substituted amine derivatives of formula (V) N-ethyl-N-2-hydroxy ethyl amine, N,N-diethylamine in a molar ratio of 2:5 in presence of non-polar solvents selected from toluene, xylene and cyclohexane at temperature ranging from 90°C-140°C for 18 hours to obtain compound of formula (II) 2-(3' -N-ethy 1- N-2-hydroxyethylaminopropyl)-2-methyl-1,3 -dioxalane (HNK Ketal); 3 H NR2 R1=R2=Ethyl or R1R2=Ethyl Rl=Ethyl; R1 =Ethyl R2=Hydroxy ethyl (11) (V) c) deprotection of the ketal group of compound of formula (II), 2-(3,-N-ethyI-N-2-hydroxyethylaminopropyl)-2-methyl-l,3-dioxalane (HNK Ketal) under acidic conditions at temperature range of 10- 50°C for 6-7 hours to obtain compound of formula (III) 5-(N-ethyl-N-2-hyd^xyethylamino)-4-pentanone or 5-(N.N-diethylamino)-4-pentanone; and 0 NT Ri = R2 = Ethyl (or) R1=Ethyl; R2=Hydroxy ethyl d) reductive amination of compound of formula (III), 5-(N-ethyl-N-2-hydroxyethylamino)-4-pentanone or 5-(N,N-diethylamino)-4-pentanone is carried out by treating it with alcoholic ammonia in presence of catalyst such as Raney Nickel under mild hydrogenation conditions such as 10-30 kg/cm2 and temperature ranging from 40-130°C for 2-5 hours to yield compound of formula (IV) namely 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine and 5-(N,N'diethyIamino)-2-pentylamine. 10 (IV) i)Ri ,R2= Ethyl—>- 5-[N,N-diethylamino]-2-pentylamine] ii) R, = Ethyl, R2 = hydroxy ethyl —■ 5-[N-ethyl-N-2-hydroxyethylamino]-2-pent 2. The process as claimed in claiml wherein, said catalyst for ketalization of 1-chloro-4-pentanone is preferably p-toluene sulphonic acid. 3. The process as claimed in claiml and 2 wherein, said non polar organic solvent for ketalization of l-chloro-4-pentanone is preferably cyclohexane. 4. The process as claimed in claiml to 3 wherein ketalization reaction is carried out at temperature range 80-90°C. 5. The process as claimed in claim 1 wherein said non-polar solvent for condensation of ketal (I) with substituted amine (V) is preferably toluene. 6. The process as claimed in claim 1, and 5, wherein said condensation of ketal (I) with substituted amine (V) is carried out at temperature range 125 to 130°C for 15-18 hours. 7. The process as claimed in claim 1, wherein said acid for deprotection of ketal (II) is selected from hydrochloric acid, sulphuric acid, perchloric acid, phosphoric acid, para-toluene sulphonic acid, methane sulphonic acid, trifluro acetic acids. 8. The process as claimed in claim 1 and 7 wherein said acid for deprotection of ketal (II) is preferably hydrochloric acid. The process as claimed in claim 1, 7 and 8 wherein said deprotection of ketal group of formula II is carried out in acidic conditions at temperature between 30-40°C for 4 to 5 hours. 10. The process as claimed in claim 1 wherein said reductive amination of compound of formula (III), 5- (N-ethyl-N-2-ydroxyethylamino)-4-pentanone or 5-(N,N-diethylamino)-4-pentanone is carried out at temperature between 80-85°C for 4-5 hours. 11. A process for the synthesis of 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (Hydroxy Novoldamine), 5-(N,N-diethylamino)-2-pentylamine(Novoldamine) as substantially described herein with reference to the foregoing examples 1 to 5. DR. GOPAKUMAR G. NAIR Agent for the Applicant Dated this 24th Day of November 2003 vO-

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; rule 13]

"A process for the synthesis of 5-(N-ethyl-N-2-hydroxy ethylamino)-2-pentyl amine (Hydroxy Novoldamine), 5-N,N-diethylamino)-2-pentylamine(Novoldamine)"
(a) IPCA LABORATORIES LIMITED
(b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of this invention and the manner in which it is to be performed;

Technical Field of Invention
This invention relates to a process for preparation of substituted aminopentylamines, key intermediates in the preparation of anti-malarial, anti-rheumatic agents such as chloroquine sulphate, chloroquine phosphate, chloroquine and hydroxy chloroquine base, or theif acid addition salts starting from l-chloro-4-pentanone.
Background and prior art
Hydroxy novoldamine, chemically known as 5-(N-ethyI-N-2-hydroxy ethylamino)-2-pentyl)amine and novoldamine, chemically known as 5-(N,N-diethylamino)-2-pentylamine are the intermediates of anti-malarial drugs viz; hydroxychloroquine and chloroquine.
US patent 2,365,825 discloses a method for preparation of N,N-diethylamino alcohols, particularly N,N-diethyl-l-amino-4-pentanol which comprises reacting 1,4-pentanediol with diethylamine in the presence of a metal hydrogenation catalyst more specifically Ni /tfeat temperature range within 120-250° C.
US patent 2,442,854 discusses an improved process for preparing the oxime of 1-diethylamino-4-pentanone, an intermediate used in the synthesis of novaldamine. This reported process comprises acidic decarboxylation of [(diethylami no ethyl) ethyl acetoacetate] to obtain 1 -diethylamino-4-pentanone in presence of sulfuric acid.
2.

US patent 2,546,658 describes a process for preparation of hydroxy novoldamine, wherein the condensation of l-halo-4-pentanone with N-ethyl-N-2-hydroxyethylamine to yield l-(N-ethyl-N-2-hydroxyethylamine)-4-pentanone and its further reductive animation to give 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine, is disclosed.
Hydroxy novoldamine was used as a primary starting material for the preparation of 2-{[4-(7-benz[c] acridinylamino)pentyl]ethylamino}ethanol, which was used as an amebicidal agent was described in US patent no 2,915,523. Starting from 5-chloro-2-pentanone, 2-ethylaminoethanol, sodium chloride and xylene, for 5-(N-ethyl-2-hydroxyehylamino)-2-pentanone was obtained which was reductively hydrogenated to give 2-[(4-amino pentyl)ethyl amino]ethanol, as per this patent.
GB patent 1,157,637 describes a process for the preparation of novoldamine and related amines which comprises of catalytic hydrogenation of methyl glutaronitrile, reductive alkylation of 2-methyl glutaronitrile, hydrolyzing valeronitrile, treating valeramide with an aqueous alkaline solution of an akali metal hypohalite.
US patent 4,910,343 describes a simple and economical method of producing the novel nitro amine compounds which are enamine compound, l-diethylamino-4-nitropenetene-l and its partially reduced counterpart, l-diethylamino-4-nitropentane. These compounds further provide a new synthetic route to the formation of novaldamine.
RO 62684 describes the preparation of N-ethyl-N-hydroxyethyl-l,4-pentanediamine by reacting 5-[N-(2-hydroxyethy) ethylamino]-2-pentanone with ammonia and hydrogen over Raney Nickel.
Novoldamine and hydroxy novoldamine are prepared by various synthetic routes in prior art as described above. But, most of the methods are not practiced due to the complexity of synthesis. The drawback of the processes described in the prior art is that the isolation of the required compound is very difficult because of the higher concentrations of impurities in the product and therefore gives very poor yields of the pure compound.

The major drawback of the reported processes starting from 1- chloro-4-pentanone is their high reactivity with the amines, leading to uncontrollable exotherm at large scale, formation of impurities which are very difficult to remove, as stated above.
In a nutshell, the process mentioned in prior art are not plant friendly and require repeated purification by high vacuum fractional distillation for getting the product of desired quality, which ultimately leads to increased cost of manufacture. Hence there is a need for development of economically as well as plant friendly process for the title products.
Objectives
• The main objective of the present invention is to provide a simple plant friendly and economical process for the manufacture of aminopentylamines having desired quality for transferring the latter in to the corresponding quinolines of high purity.
• A further objective of the present invention is to reduce the reactivity of 1-chloro-4-pentanone to control high exotherm at large scale operations, by protecting the keto group to provide a better quality and yield of the title product.
• A further objective of the present invention is to provide better reaction condition for reductive amination at lower hydrogen pressure and stoichiometric amounts of catalyst such as Raney Nickel.
Summary of the invention
This invention relates to a novel process for the preparation of substituted aminopentylamines, more particularly 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine and 5-(N,N-diethylamino)-2-pentylamine which are the key intermediates in the synthesis of hydroxy chloroquine & chloroquine and their acid addition salts.

Detailed description
In accordance with the above basic objective of the present invention, there is provided a protection of carbonyl group of 1- chloro-4-pentanone with protecting groups like monoethylene glycol, neopentyl glycol etc. to provide a 2-(3'-chloropropyl)-2-methyl 1,3-dioxalane, 2-(3,-chloropropyl)-2,5,5-trimethyl-l,3-diOxalane of formula(I)
The reaction is carried out between l-chloro-4-pentanone with monoethylene glycol, neopenthy glycol; in the molar ratio of 1.0 to2.0 preferably 1.1 in non-polar solvents like toluene, xylene, cyclohexane, heptane, hexane using acid catalyst like para-toluene sulphonic acid, methane sulphonic acid, perchloric acid etc. at a temperature ranging from 80 to 140°C preferably between 80 to 90°C for a period of 15 to 30 hours. The product of formula (I) is then condensed with amines (v) such as N-ethyl-N-2-hydroxyethyl amine, N,N-diethylamine to give the condensed product of formula(II).

Ketalization

1 -chloro-4-pentanone

(I)

HN:

■R2

(S)

[Ri = R2 = As described earlier] (II)

Rt, R2 = Ethyl
Ri = Ethyl
R2 = Hydroxy ethyl

Further reaction is carried out between formula(I) with substituted amines of formula (V) such as N-ethyl-N-2-hydroxy ethyl amine, N,N-diethylamine in the molar ratio of 2.0 to5.0 preferably 2.2 in non- polar solvents like toluene, xylene, cyclohexane at a
5

temperature ranging from 90 to 140°C, preferably 120 to 130°C, for a period of 18 to20 hours.
The product of formula (II) is then hydrolyzed in acidic condition to give desired ketone of the formula (III).

^2 Ri = R2 = As described earlier ]
on)
The product of the formula (II) is hydrolyzed in acidic conditions using acids like hydrochloric acid, sulphuric acid, perchloric acid, phosphoric acid, para-toluene sulphonic acid, methane sulphonic acid, trifluro aectic acid etc. in the molar ratio of 1.1 to5.0 preferably 1.5 in aqueous condition at a temperature ranging from 10 to 50°C preferably 25 to 35° C for a period of 6 to7 hours, which is then reductively animated, yields the desired title compound of formula (IV).

5-[N,N-diethylamino]-2-pentylamine] ii) R1 = Ethyl, R2 = Hydroxy ethyl —*- 5-[N-ethyl-N-2-hydroxyethylamino]-2-pentylamine
The reaction is carried out between condensed ketone of formula (III) in presence of ammonical alcoholic solvents like methanol, ethanol, isopropanol and catalyst Raney Nickel under hydrogen pressure ranging from 10 to 30 kg/cm preferably 20 to 22 kg/cm at a temperature ranging from 40 to 130° C preferably 80 to 85° C for a period of 2 to5 hours.
6

The following examples illustrate the process of the invention in greater details and are in no way limiting the scope of the invention.
Experimental Example 1
1 -chloro-4-pentanone:
Acetyl butyrolactone (lOOgm) is added dropwise in a mixture of water (lOOgm), hydrochloric acid (120gm) and sodium chloride (20gm) at 100 tol05°C. After completing the reaction, the resulting product is collected by distillation. The yield of the product is 80gms.
Example 2
2-(3,-chloropropvO-2-methyl-l,3-dioxalane:
Ethylene glycol (40gms), cyclohexane (160ml) & para-toluene sulphonic acid (lgm) are added to 1-chloro-4-pentanone (80gm). The reaction mixture is heated to 80 to 90° C for 20 to25 hours and removes the water azeotropically from the reaction mixture. The reaction mass is cooled. Water (40 ml) is added to the reaction mass and separated the aqueous layer. Organic layer is distilled under vacuum to isolate the oily product. The yield of the product is lOOgms.
Example 3
2-f3,-N-ethvl-N-2-hvdroxvethvlaminopropvn-2-methvl-1.3-dioxalane(HNKKetal) Toluene (200ml) and ethylamino ethanol (130gm) are added to product of formula (I) (lOOgm). The reaction mass is heated tol25 to 130°C for 15 to 18 hours. The reaction is cooled. Water (10ml) added and the aqueous layer is separated. The organic layer is distilled out to isolate the product. The yield of the product is 1 lOgms.
Example 4
l-(N-ethyl-N-2-hydroxyethyl amino)-4 -pentanone

Water (100ml) and cone, hydrochloric acid (10ml) is added to the HNK Ketal (HOgm). The reaction mass is stirred for 4 to 5hours at 30° C - 40° C. Then the reaction mixture is neutralized with caustic lye solution. Aqueous layer is separated to isolate the product layer. The yield of the product is lOOgm.
Example 5
5-(N-ethvl-N-2-hvdroxvethylamino)-2-pentvlamine:
The l-(N-ethyl-N-2hydroxyethylamino)-4-pentanone (lOOgm) was diluted with ammonical methanol (400ml) and reduced catalytically with Raney Nickel (5gm) at 40°C to 80°C using 15 to 20 kg hydrogen pressure in 4 to 5 hours.
After completion of the reaction, catalyst was filtered. Methanol was distilled out at atmospheric pressure to give the crude product. The crude product was subjected to high vacuum fractional distillation to get the product of better quality in very high yield. The yield of the product is 80gms.
8

^mended

We claim
1. A process for the synthesis of 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (Hydroxy Novoldamine), 5-(N,N-diethylamino)-2-pentylamine(Novoldamine) wherein the said process comprises
a) ketalization of 1-chloro-4-pentanone carried out by treating it with glycol selected from ethylene glycol or neopentyl glycol in a molar ratio of 1:2 in presence of non polar organic solvent selected from toluene, cyclohexane, xylene, heptane and hexane and catalyst selected from para-toluene sulphonic acid, methane sulphonic acid, perchloric acid at temperature range of 80-140°C for 20-25 hours to obtain compound of formula (I) 2(3'-chloropropyl)2-methyl-1,3-dioxalane, 2-(3 '-chloropropyl) -2,5,5-Trimethyl 1,3-dioxane;

0)
b) condensation of said compound of formula (I) 2(3'-chloropropyl)2-methyl-
1,3-dioxalane, 2-(3'-chIoropropyl) -2,5,5-Trimethyl 1,3-dioxane with
substituted amine derivatives of formula (V) N-ethyl-N-2-hydroxy ethyl
amine, N,N-diethylamine in a molar ratio of 2:5 in presence of non-polar
solvents selected from toluene, xylene and cyclohexane at temperature
ranging from 90°C-140°C for 18 hours to obtain compound of formula (II)
2-(3' -N-ethy 1- N-2-hydroxyethylaminopropyl)-2-methyl-1,3 -dioxalane
(HNK Ketal);
3

H NR2
R1=R2=Ethyl or R1R2=Ethyl
Rl=Ethyl; R1 =Ethyl
R2=Hydroxy ethyl
(11) (V)
c) deprotection of the ketal group of compound of formula (II), 2-(3,-N-ethyI-N-2-hydroxyethylaminopropyl)-2-methyl-l,3-dioxalane (HNK Ketal) under acidic conditions at temperature range of 10- 50°C for 6-7 hours to obtain compound of formula (III) 5-(N-ethyl-N-2-hyd^xyethylamino)-4-pentanone or 5-(N.N-diethylamino)-4-pentanone; and

0
NT

Ri = R2 = Ethyl (or)
R1=Ethyl; R2=Hydroxy ethyl
d) reductive amination of compound of formula (III), 5-(N-ethyl-N-2-hydroxyethylamino)-4-pentanone or 5-(N,N-diethylamino)-4-pentanone is carried out by treating it with alcoholic ammonia in presence of catalyst such as Raney Nickel under mild hydrogenation conditions such as 10-30 kg/cm2 and temperature ranging from 40-130°C for 2-5 hours to yield compound of formula (IV) namely 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine and 5-(N,N'diethyIamino)-2-pentylamine.
10

(IV)
i)Ri ,R2= Ethyl—>- 5-[N,N-diethylamino]-2-pentylamine]
ii) R, = Ethyl, R2 = hydroxy ethyl —*■ 5-[N-ethyl-N-2-hydroxyethylamino]-2-pent
2. The process as claimed in claiml wherein, said catalyst for ketalization of 1-chloro-4-pentanone is preferably p-toluene sulphonic acid.
3. The process as claimed in claiml and 2 wherein, said non polar organic solvent for ketalization of l-chloro-4-pentanone is preferably cyclohexane.
4. The process as claimed in claiml to 3 wherein ketalization reaction is carried out at temperature range 80-90°C.
5. The process as claimed in claim 1 wherein said non-polar solvent for condensation of ketal (I) with substituted amine (V) is preferably toluene.
6. The process as claimed in claim 1, and 5, wherein said condensation of ketal (I) with substituted amine (V) is carried out at temperature range 125 to 130°C for 15-18 hours.
7. The process as claimed in claim 1, wherein said acid for deprotection of ketal (II) is selected from hydrochloric acid, sulphuric acid, perchloric acid, phosphoric acid, para-toluene sulphonic acid, methane sulphonic acid, trifluro acetic acids.
8. The process as claimed in claim 1 and 7 wherein said acid for deprotection of ketal (II) is preferably hydrochloric acid.

The process as claimed in claim 1, 7 and 8 wherein said deprotection of ketal group of formula II is carried out in acidic conditions at temperature between 30-40°C for 4 to 5 hours.
10. The process as claimed in claim 1 wherein said reductive amination of compound of formula (III), 5- (N-ethyl-N-2-ydroxyethylamino)-4-pentanone or 5-(N,N-diethylamino)-4-pentanone is carried out at temperature between 80-85°C for 4-5 hours.
11. A process for the synthesis of 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (Hydroxy Novoldamine), 5-(N,N-diethylamino)-2-pentylamine(Novoldamine) as substantially described herein with reference to the foregoing examples 1 to 5.

DR. GOPAKUMAR G. NAIR
Agent for the Applicant
Dated this 24th Day of November 2003
vO-

Documents:

1215-mum-2003 claims.pdf

1215-mum-2003 correspondence(ipo).pdf

1215-mum-2003 correspondence.pdf

1215-mum-2003 description(granted).pdf

1215-mum-2003 form 1.pdf

1215-mum-2003 form 19.pdf

1215-mum-2003 form 2(granted).pdf

1215-mum-2003 form 2(title page).pdf

1215-mum-2003 form 26.pdf

1215-mum-2003 form 3.pdf

1215-mum-2003 power of attorney.pdf

1215-mum-2003-cancelled pages(12-05-2004).pdf

1215-mum-2003-claims.doc

1215-mum-2003-description(granted).doc

1215-mum-2003-form 2(granted).doc

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Patent Number

207076

Indian Patent Application Number

1215/MUM/2003

PG Journal Number

30/2008

Publication Date

25-Jul-2008

Grant Date

21-May-2007

Date of Filing

24-Nov-2003

Name of Patentee

M/S. IPCA LABORATORIES LIMITED

Applicant Address

48, KANDIVALI INDUSTRIAL ESTATE, MUMBAI - 400 067

Inventors:

#	Inventor's Name	Inventor's Address
1	KUMAR, ASHOK	B/203,204, STERLING CO. HSG. SOC., A2-A3, SUNDARBAN COMPLEX, ANDHERI (WEST), MUMBAI - 400 053

PCT International Classification Number

A61K 31/01

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA