Related applications

This patent application claims the benefit of priority of Indian patent application number 201841029394 filed on 04 ^th August 2018 which is incorporated herein by reference

Field of the invention

The present invention relates to highly pure 6-aminohexanoic acid of formula- 1 and process for its preparation thereof.

(Formula- 1)

The present invention also relates to an improved process for the preparation of caprolactam of formula-2 which is used for the preparation of 6-aminohexanoic acid of formula- 1.

Background of the invention

6-Aminohexanoic acid is also known as aminocaproic acid, epsilon-aminocaproic acid or e-aminocaproic acid. 6-Aminohexanoic acid is acts as an inhibitor of fibrinolysis which is approved with the brand name of AMICAR ^® with different dosage forms such as 500mg and lgm as a tablet, l.25gm/5ml as a syrup and 250mg/ml as an injectable injection. It is useful in enhancing hemostasis when fibrinolysis contributes to bleeding. Fibrinolytic bleeding may frequently be associated with surgical complications following heart surgery (with or without cardiac bypass procedures) and portacaval shunt, hematological disorders and neoplastic diseases.

US patent document 7491520 B2 discloses a biochemical synthesis of 6- aminohexanoic acid from 6-aminohex-2-enoic acid using an enzymes having a,b-enoate reductase activity such as Acremonium strictum, Clostridium tyrobutyricum, Moorella thermoacetica, Ochrobactrum anthropi, or Clostridium kluyveri.

US patent document 8404465 B2 discloses a process for the preparation of 6- aminohexanoic acid from Lysine using a microoganisam includes at least one nucleic acid encoding a polypeptide by catalyzation and the said process is schematically shown as follows:

Lysine beta-lysine 6-amino-3-oxohexanoic acid 6-amino-3-hydroxyhexanoic acid 6-aminohex-2-enoic acid 6-aminohexanoic acid.

US patent document 9663805 B2 discloses a process for the preparation of 6- aminohexanoic acid from a-ketopimelic acid using a bio-catalyst comprising of two enzymes.

The main drawback of above disclosed prior art processes are involving the use of enzymes, microorganisms and biocatalysts which are highly expensive and also readily not available. Hence, these prior art processes are not viable for the industrial scale-up.

US patent document 8809581 B2 discloses a process for the preparation of 6- aminohexanoic acid comprising reaction of caprolactam with sodium hydroxide or potassium hydroxide and a solubility regulating agent to form an intermediate compound which is hydrogenated in presence of Pd(OH) ₂ catalyst to produce 6-aminohexanoic acid.

The main drawback of above disclosed prior art process is the additional chemical reaction with solubility regulating agent and its hydrogenation reaction in the presence of Pd(OH) ₂ catalyst which is expensive and causes for higher cost of the production of API. Hence, this prior art process is not eco-friendly and not suitable for industrial scale-up.

US patent document 9776953 B2 discloses a process for the preparation of 6- aminohexanoic acid comprising hydrolysis of caprolactam with hydrochloride and then tedious work up/azeotropic distillation with toluene followed by isolation/purification from isopropanol to get pure protic acid salts of 6-aminohexanoic acid which is further treating with an organic base in methanol followed by final purification from methanol, acetone in presence of seeds of 6-aminohexanoic acid.

The drawbacks of the above prior art process:

Consumption of multiple organic solvents in the synthesis and purification of 6- aminohexanoic acid from caprolactam which is not eco-friendly in industrial scale preparations.

Additional steps like isolation and purification of hydrochloride salt 6-aminohexanoic acid as intermediate lengthen the process and also requires additional analytical tests. 6-Aminohexanoic acid has a maximum daily dose of about 24 gm. In view of this US FDA, EMA and other regulatory agencies issues guidelines to limit the chemical impurities, inorganic impurities, organic volatile solvents and other impurities in 6-aminohexanoic acid drug substance as much as possible.

In view of the above facts, there is still need to provide an improved process for the synthesis of highly pure 6-aminohexanoic acid of formula- 1.

Advantages of the present invention:

> Highly pure 6-aminohexanoic acid of formula- 1 obtained according to the present invention free of organic volatile impurities like n-pentane, cyclohexane, n-heptane, isopropanol, pentanol, benzene.

> Highly pure 6-aminohexanoic acid of formula- 1 obtained according to the present invention contains less than 1100 ppm of organic volatile impurities.

> Highly pure 6-aminohexanoic acid of formula- 1 obtained according to the present invention is substantially free of caprolactam impurity.

> Highly pure 6-aminohexanoic acid of formula- 1 obtained according to the present invention is free of chloride content.

Consumption of single organic solvent in the synthesis from caprolactam and until isolation/purification of 6-aminohexanoic acid which is eco-friendly in industrial scale preparations.

Less number of synthetic steps to prepare pure 6-aminohexanoic acid, which leads to the consumption of less number of solvents, reagents, intermediates thereby reducing the formation of lesser pollutants making it eco-friendly and economically viable.

Brief description of the invention

In first embodiment, the present invention provides highly pure 6-aminohexanoic acid of formula- 1 which is free of organic volatile impurities like n-pentane, cyclohexane, n- heptane, isopropanol, pentanol, benzene..

In second embodiment, the present invention provides highly pure 6-aminohexanoic acid of formula- 1 substantially free of caprolactam impurity.

In third embodiment, the present invention provides highly pure 6-aminohexanoic acid of formula- 1 which is free of chloride impurity.

In fourth embodiment, the present invention provides an improved process for the preparation of 6-aminohexanoic acid of formula- 1.

In fifth embodiment, the present invention provides an improved process for the preparation of highly pure 6-aminohexanoic acid of formula- 1.

In sixth embodiment, the present invention provides an improved a process for the preparation of caprolactam of formula-2.

Brief description of the drawings

Figure- 1 : Illustrates the Powdered X-Ray Diffraction (PXRD) Pattern of crystalline form of 6-aminohexanoic acid obtained according to example-3.

Figure-2: Illustrates the Powdered X-Ray Diffraction (PXRD) Pattern of crystalline form of 6-aminohexanoic acid obtained according to example-6.

Detailed description of the invention

As used herein the term“suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o-, or p-xylene, or naphthalene and the like;“ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3- dioxane, l,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1 ,2-dimethoxy ethane and the like;“ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like;“ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2- trifluoroethanol, ethylene glycol, 1 ,2-propanediol (propylene glycol), 2-methoxyethanol, 1, 2- ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like;“polar solvents” such as water or mixtures thereof.

As used herein the term“suitable base” refers to inorganic bases like“alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide or mixtures thereof.

As used herein the term“suitable acid” refers to acid such as formic acid, acetic acid, oxalic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, / oluenesulfonic acid and the like.

As used herein the term“highly pure” refers to 6-aminohexanoic acid contains purity greater than about 99.90% by high performance liquid chromatography (HPLC) or greater than about 99.95% by HPLC or greater than about 99.98% by HPLC or greater than about 99.99% by HPLC.

As used herein the term“substantially free” in related to chemical compound as impurity refers to a content of less than about 0.05% or less than about 0.04% or less than about 0.03% or less than about 0.02% or less than about 0.01% or absent.

Free of chloride content herein refers to less than about 0.05% or absent.

As used herein the term“free” refers to 6-aminohexanoic acid contains less than 2000 ppm or 1000 ppm or 500 ppm or 100 ppm or 50 ppm or absent of organic volatile impurities such as n-pentane, cyclohexane, n-heptane, isopropanol, pentanol, benzene and the like.

The chemical compound as impurity is measured by high performance liquid chromatography (HPLC), organic volatile impurity is measured by gas chromatography (GC) and chloride content is measured by ion chromatography (IC).

In first embodiment, the present invention provides highly pure 6-aminohexanoic acid of formula- 1 which is free of organic volatile impurities.

In one aspect of first embodiment provides highly pure 6-aminohexanoic acid of formula- 1 contains isopropanol organic volatile impurity less than about 1100 ppm.

In second embodiment, the present invention provides highly pure 6-aminohexanoic acid of formula- 1 substantially free of caprolactam impurity.

In third embodiment, the present invention provides highly pure 6-aminohexanoic acid of formula- 1 free of chloride content.

In fourth embodiment, the present invention provides an improved process for the preparation of 6-aminohexanoic acid of formula-l, comprising:

a) reacting the caprolactam with inorganic base in a solvent,

b) neutralizing the product obtained in step-a) with acid optionally in a organic solvent, c) isolating 6-aminohexanoic acid of formula-l

In step-a) the inorganic base is selected form“alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like;“alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; prefarebly alkali metal hydroxides; in step-a) the solvent is polar protic solvent selected from water or alcohol solvents such as methanol, ethanol, n-propanol or isopropanol or mixtures thereof; prefarebly water; in step-b) the acid is selected from acetic acid, formic acid, propanoic acid, oxalic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and the like; prefarebly acetic acid; in step-b) the suitable organic solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, chloro solvents, ketone solvents, nitrile solvents, polar solvents or mixtures thereof; prefarebly alcohol solvents; more prefarebly isopropanol; in step-c) the isolation is carried out by using crystallization, recrystallization or solvent and anti-solvent method using the solvent wherein, the solvent is water, polar protic solvent, anti solvent is isopropanol and /or the isolation also carried out by the methods like distillation, decantation, filtration and then drying any other methods known in the art.

In the second aspect of fourth embodiment, the present invention provides an improved process for the preparation of 6-aminohexanoic acid of formula-l, comprising: a) reacting the caprolactam with aqueous potassium hydroxide solution,

b) adding isopropyl alcohol and charcoal to the product obtained in step-a),

c) filtering the mixture obtained in step-b), d) neutralizing the filtrate obtained in step-c) with acetic acid to provide 6- aminohexanoic acid.

In fifth embodiment, the present invention provides an improved process for the preparation of highly pure 6-aminohexanoic acid, comprising:

a) dissolving crude 6-aminohexanoic acid in water, organic solvent or mixtures thereof, b) optionally filtering the mixture,

c) combining the filtrate obtained in step-a) or step-b) with anti-solvent to provide highly pure 6-aminohexanoic acid.

In step-a), the suitable organic solvent is same as defined hereinbefore; in step-a) the temperature is ranging from 25 °C to reflux temperature of the solvent used; in step-c), the anti-solvent is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, chloroform and the like.

In the first aspect of fifth embodiment, the present invention provides 6- aminohexanoic acid of formula- 1 having purity greater than about 99.90% by high performance liquid chromatography (HPLC). Prefarebly, about 99.98% by HPLC.

In sixth embodiment, the present invention provides a process for the preparation of caprolactam of formula-2, comprising:

a) reacting the cyclohexanone with hydroxylamine or its salt in a suitable solvent, b) in-situ treating the product obtained in step-a) with suitable acid to provide caprolactam of formula-2.

wherein in step-a) the hydroxylamine salt is selected from sulfate, hydrochloride, hydrobromide, hydroiodide and the like; the suitable solvent is selected from hydrocarbon solvents, ether solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or mixtures thereof; in step-b) the acid is mineral acid such as sulfuric acid, nitric acid and the like or organic acid such as formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, camphor sulfonic acid and the like.

In an aspect of the sixth embodiment, the caprolactam obtained by the present invention can be isolated by crystallization or recrystallization from the solvent wherein, the solvent is selected from hydrocarbon solvents, ether solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or mixtures thereof, and/or the isolation also carried out by the methods like distillation, decantation, filtration and then drying any other methods known in the art.

The process of the present invention can be represented schematically as follow:

1. Hydroxylamine (or) its salts /

suitable solvent

2. Suitable acid 1. Inorganic base, water O

3. Isolation from suitable solvent 2. Suitable acid

Formula- 1

Formula-3 Formula-2

Scheme- 1

In another embodiment, the present invention provides pharmaceutical compositions comprising highly pure aminohexanoic acid of formula (1) and pharmaceutically acceptable excipient.

In yet another embodiment, composition comprising highly pure aminohexanoic acid of formula (1) and pharmaceutically acceptable excipient is formulated in a manner suitable for the route of administration to be used.

As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

6- Amino hexanoic acid obtained by the process of the present invention is analyzed by High Performance Liquid Chromatography (HPLC) by following conditions:

Apparatus: A liquid chromatographic system is equipped with variable wavelength UV detector; Column: Inertsil ODS-3V 250*4.6 mm, 5pm (or) equivalent; Column temperature: 40°C; Wave length: 210 nm; Injection volume: 20.0 pL; Elution: isocratic; Diluent: Milli-Q- water; Solution-A: weigh accurately about 0.55gr of sodium l-heptanesulfonate and transfer into 600 mL of diluent. Mobile phase: Dissolve lOgr of monobasic potassium phosphate in 300 ml of solution-A and added 250 mL of methanol. H3PO4 was added to the mixture to adjust to a pH of 2.2 and diluted with Solution-A.

Caprolactam obtained by the process of the present invention is analyzed by Gas Chromatography (GC) under the following conditions:

Apparatus: A gas chromatographic system is equipped with FID; Column: DB-5 Capillary column (or) equivalent; Length: 30 mts; ID: 0.53 mm; film thickness: 3.0mih; Injector temperature: l80°C; split ratio: 1 :7; Injection volume: 0.0 pL; Diluent: methanol; Carrier gas: helium; hydrogen flow: 40 ml/min; air flow: 400 ml/min.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example- 1: Process for the preparation of caprolactam

A mixture of cyclohexanone (50 gms), methanol (100 ml) and hydroxylamine sulfate (40 gms) were stirred for 10 hrs at 25-30°C. Distilled off the solvent completely from the reaction mixture. Sulfuric acid (127 gms) was slowly added to the above obtained compound and stirred for 2 hours at 45-50°C. Heated the reaction mixture to 65-70°C and stirred for 12 hrs. Cooled the reaction mixture to 0-5°C and basified with aqueous sodium hydroxide solution. n-Butanol (150 ml) was added to the reaction mixture at 25-30°C and stirred for 15 min. Separated the both organic and aqueous layers and extracted the aqueous layer with n- butanol. Combined the total organic layers and distilled off the solvent completely under reduced pressure followed by co-distillation with n-heptane. n-Heptane (100 ml) was added to the above obtained compound at 25-30°C and cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and washed with n- heptane and then dried to afford the title compound. (Yield: 60.7 gms)

Example-2: Process for the preparation of caprolactam

A mixture of cyclohexanone (100 gms), cyclohexane (100 ml) and hydroxylamine sulfate (100.35 gms) were stirred for 2 hrs at 25-30°C. Heated the reaction mixture to 45- 50°C and added sulfuric acid (254 gms) and then stirred for 2 hours at same temperature. Heated the reaction mixture to 75-80°C and stirred for 12 hrs at same temperature. Basified the reaction mixture with aqueous sodium hydroxide solution at l0-l5°C. n-Butanol (300 ml) was added to the above reaction mixture at 25-30°C and stirred for 15 min. Separated the both organic and aqueous layers and extracted the aqueous layer with n-butanol. Combined the total organic layers and dried over sodium sulfate. Distilled off the solvent completely from the organic layer and then co-distilled with cyclohexane. Cyclohexane (200 ml) was added to the above obtained compound at 25-30°C and cooled the reaction mixture to 10- l5°C and stirred for 2 hrs at the same temperature. Filtered the compound and washed with cyclohexane and then dried to afford the title compound.

(Yield: 81 gm, M R: 69-72°C, Purity by GC: 99.96%)

Example-3: Process for the preparation of pure 6-aminohexanoic acid

Caprolactam (100 gms) was added to freshly prepared aqueous potassium hydroxide solution (56.5 gms of potassium hydroxide dissolved in 90 ml of water) at 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 10 hrs at same temperature. Isopropanol (600 ml) and charcoal (5 gms) were added to the reaction mixture at 25-30°C and stirred for 30 min at same temperature. Filtered the reaction mixture through hy-flow bed and washed with isopropanol. The obtained filtrate again filtered through filter paper and washed with isopropanol. Acetic acid (85 ml) was added to the above obtained filtrate to neutralized the pH at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 3 hrs. Filtered the precipitated solid and then dried under reduced pressure.

The above obtained solid compound was added to water (94.5 ml) and isopropanol (220.5 ml) at 25-30°C and stirred for 10 min at same temperature. Heated the reaction mixture to 65-70°C and stirred for 30 min. Filtered the obtained solution through filter paper and washed with isopropanol. Isopropanol (504 ml) was added to the above filtrate at 25- 30°C and stirred for 8 hrs at same temperature. Filtered the precipitated solid, washed with isopropanol and then dried to afford the title compound.

(Yield: 50 gms, M R: 202-203°C, Purity by HPLC: 99.93%)

The PXRD pattern of the obtained compound is illustrated in figure- 1.

Example-4: Process for the preparation of highly pure 6-aminohexanoic acid

Caprolactam (110 gms) was added to freshly prepared aqueous potassium hydroxide solution (62 gms of potassium hydroxide dissolved in 100 ml of water) at 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 10 hrs at same temperature. Isopropanol (550 ml) and charcoal (5.5 gms) were added to the reaction mixture at 25-30°C and stirred for 30 min at same temperature. Filtered the reaction mixture through hy-flow bed and washed with isopropanol. Charcoal (5.5 gms) was added to the above obtained filtrate at 25-30°C and filtered for particle free solution, washed with isopropanol. Mixture of acetic acid (95 ml) and isopropanol (110 ml) solution was added to the obtained filtrate to neutralized the pH at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 3 hrs. Filtered the reaction mixture and then dried under reduced pressure.

Water (95 ml) and isopropanol (220 ml) were added to above obtained compound at 25-30°C and stirred for 10 min at same temperature. Heated the reaction mixture to 65-70°C and stirred for 30 min. Filtered the obtained solution through filter paper and washed with isopropanol. Isopropanol (500 ml) was added to the obtained filtrate at 25-30°C and stirred for 8 hrs at same temperature. Filtered the precipitated solid, washed with isopropanol and then dried to afford the title compound.

(Yield: 66 gms, M.R: 202-203°C, Purity by HPLC: 99.98%; Caprolactam impurity: Not detected; 6-(6-aminohexanamido)hexanoic acid (also known as“Dimer impurity”): 0.02%). Example-5: Process for the preparation of pure 6-aminohexanoic acid

Caprolactam (500 gms) was added to freshly prepared aqueous potassium hydroxide solution (280 gms of potassium hydroxide dissolved in 450 ml of water) at 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 10 hrs at same temperature. Isopropanol (2.5 Lt) and charcoal (25 gms) were added to the reaction mixture at 25-30°C and stirred for 30 min at same temperature. Filtered the reaction mixture through hy-flow bed and washed with isopropanol. Mixture of acetic acid (425 ml) and isopropanol (500 ml) solution was added to the obtained filtrate to neutralized the pH. Cooled the reaction mixture to 0-5°C and stirred for 3 hrs. Filtered the precipitated solid, washed with isopropanol and then dried under reduced pressure for 6 hrs. Water (525 ml) and isopropanol (1255 ml) were added to the obtained material at 25-30°C and stirred for 10 min. Heated the reaction mixture to 65-70°C and stirred for 30 min. Filtered the reaction mixture and washed with pre-heated isopropanol. Cooled the filtrate to 25-30°C and slowly added isopropanol and stirred for 8 hrs. Filtered the precipitated solid, washed with isopropanol and then dried to afford title compound.

(Yield: 277 gms, caprolactam impurity: not detected, dimer impurity: 0.02%, purity: 99.98% by HPLC).

Example-6: Process for the preparation of highly pure 6-aminohexanoic acid

6-Aminohexanoic acid (250 gms) of example-5 was added to water (375 ml) and isopropanol (875 ml) at 25-30°C and stirred for 10 min. Heated the mixture to 65-70°C and stirred for 30 min. Filtered the obtained mixture and washed with isopropanol. Isopropanol (2000 ml) was added to obtained material and stirred for 8 hrs, filtered the compound and washed with isopropanol. The obtained wet compound was dried at 60-65°C under vacuum for 18 hrs and cooled to 25-30°C and then milled to afford the title compound.

(Yield: 248.2 gms, caprolactam impurity: not detected, dimer impurity: 0.02%, acetic acid: less than 250 ppm; isopropyl alcohol: 1059 ppm, n-pentane: not detected; cyclohexane: below detection limit; n-heptane: less than LOQ; pentanol: not detected; benzene: not detected; purity: 99.98% by HPLC).

The PXRD pattern of obtained compound was illustrated in figure-2.