DESC:RELATED PATENT APPLICATION(S)
This application claims the priority to and benefit of Indian Provisional Patent Application No. 201741015680 filed on May 03, 2017; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION
The present invention describes an improved process for the preparation of substantially pure 6-aminohexanoic acid (6-aminocaproic acid) having purity greater than 99.5% as determined by HPLC.

BACKGROUND OF THE INVENTION
6-Aminohexanoic acid (I), also known as 6-aminocaproic acid, is a derivative and analogue of the amino acid lysine, which makes it an effective inhibitor for enzymes that binds to the residue. 6-Aminocaproic acid (Amicar) is FDA-approved for the use in the treatment of acute bleeding due to elevated fibrinolytic activity. It is used as antihemorrhagic, and antifibrinolytic agent.

The synthesis of 6-aminohexanoic acid (I) has been reported in many patents and non-patent literature, the contents of which are hereby incorporated as reference in their entirety.

The German Patent GB826243 discloses the preparation for e-6-aminocaproic acid from e-caprolactam. The e-caprolactam is dissolved in water, heated and treated with concentrated sulfuric acid. The pH of the solution is neutralized with ammonia gas and washed with dehydrated methanol, precipitate removed by filtration and the filtrate treated with 30% hydrogen peroxide, centrifuged and evaporated to obtain e-6-aminocaproic acid (I). Ammonia forms water soluble ammonium sulphate salt which is difficult to separate from the water soluble 6-aminocaproic acid.
The US Patent No. 3655748 discloses the synthesis for e-6-aminocaproic acid wherein e-caprolactam is treated with barium hydroxide octahydrate and the product obtained is hydrolysed to form e-6-aminocaproic acid. Addition of carbon-dioxide precipitates barium carbonate, which is a toxic by-product and not suitable for active pharmaceutical ingredient application.

The US Patent No. 4950429 discloses the synthesis for 6-aminocaproic acid from 5-formylvaleric acid using Raney nickel, excess ammonia and hydrogen at high temperature and pressure, wherein the product is obtained with low yield.

The US Patent No. 6372939 discloses the synthesis of 6-aminocaproic acid from 5-cyanovaleric acid in the presence of 1-methyl-2-pyrrolidinone, ammonium hydroxide and 5% ruthenium /titanium dioxide (Ru/TiO2) under hydrogen pressure to provide 6-aminocaproic acid and caprolactam.

The US Patent No. 8809581 discloses preparation of 6-aminocaproic acid from different derivatives of amino-hexanoic acid using palladium hydroxide, water and ethanol and recrystallizing it from acetone to obtain the product with high purity and moderate yield.

The Organic Syntheses, Coll. Vol. 4, p.39 (1963); Vol. 32, p.13 (1952) discloses the synthesis of 6-aminohexanoic acid from e-caprolactam using acid hydrolysis and purified by column chromatography using Amberlite resin.

Most of the above prior art processes uses tedious, complicated processes, stringent reaction conditions, expensive reagents and catalysts (palladium salts, Raney-nickel, ruthenium, zirconium, and titanium dioxide catalysts), toxic by-products (barium carbonate), risky chemicals (hydrogen-peroxide) which is explosive in nature and restricts the application of the above process in industrial scale.

Hence, the present inventors herein provide an improved process which is cost-effective and safe for the preparation of 6-aminohexanoic acid in significantly high yield and purity which is applicable at industrial scale.

SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide an improved process for the preparation of 6-aminohexanoic acid (I).

In yet another object, the invention provides a method of purification of 6-aminohexanoic acid (I) to obtain a pure compound, with purity greater than 99.5% as determined by high-performance liquid chromatography (HPLC).

In one aspect of the invention, there is provided a process for the preparation of 6-aminohexanoic acid (I), the said process comprising the steps of:

a) reacting cyclohexanone (IV)

with hydroxylamine hydrochloride in the presence of base and protic solvent to obtain cyclohexanone oxime (III);

b) reacting cyclohexanone oxime (III) in the presence of acid to form azepan-2-one (II);

c) reacting azepan-2-one (caprolactam) (II) with a suitable acid to obtain crude 6-aminohexanoic acid (I); and

d) purifying crude 6-aminohexanoic acid (I) in protic solvent to obtain to 6- aminohexanoic acid (I) with purity greater than 99.5% as determined by HPLC.

In some embodiment of the invention, the base employed in step a) of the above described process for the preparation of 6-aminohexanoic acid is selected from the group comprising of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, potassium acetate, aqueous ammonia, methanolic ammonia, triethylamine, pyridine or the like.

In some other embodiment of the invention, the acid employed in step b) and step c) of the above described process for the preparation of 6-aminohexanoic acid is selected from the group comprising of sulphuric acid, hydrochloric acid, nitric acid, p-toluene sulfonic acid, phosphoric acid, polyphosphoric acid or the like.

In some embodiment of the invention, the protic solvent employed in step a) and d) of the above described process for the preparation of 6-aminohexanoic acid are selected from a group comprising of methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, water or the like or the mixture thereof.

In another aspect of the invention, there is provided a process for the purification of 6-aminohexanoic acid (I), comprising steps of:
(i). providing a solution of 6-aminohexanoic acid (I), in a protic solvent;
(ii). treating with decolorizing agent;
(iii). adding protic solvent and heating to 70-80°C; and
(iv). isolating pure 6-aminohexanoic acid (I).

In some embodiment of the invention, the protic solvent employed in the above described process for the purification of 6-aminohexanoic acid (I) is selected from the group comprising of water, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol or mixture thereof.

In some embodiment of the invention, the decolorizing agent used in the above described process for the purification of 6-aminohexanoic acid (I) is neutral charcoal (Norit CN1).

In some other embodiment of the invention, there is provided a process for the preparation of 6-aminohexanoic acid (I) having purity greater than 99.5% as determined by HPLC.

In some embodiment of the invention, there is provided a process for the purification of 6-aminohexanoic acid (I), wherein the impurity level of 6-aminohexanoic acid obtained is less than 0.5% (w/w), preferably less than 0.2% (w/w).

In another aspect of the invention, there is provided a process for the preparation of crystalline form of 6-aminohexanoic acid (I), characterized by X-ray diffraction spectrum having peaks expressed as 2? values at about10.54, 11.88, 21.58, 23.93, 28.29 ± 0.2 degrees, said process comprising the steps of:


a) reacting cyclohexanone (IV)

with hydroxylamine hydrochloride in the presence of base and protic solvent to obtain cyclohexanone oxime (III);

b) reacting cyclohexanone oxime (III) in the presence of acid to form azepan-2-one (II);

c) reacting azepan-2-one(caprolactam) (II) with a suitable acid to obtain crude 6-aminohexanoic acid (I);
d) providing a solution of 6-aminohexanoic acid (I), in a protic solvent;
e) treating with decolorizing agent;
f) adding protic solvent and heating to 70-80°C; and
g) isolating crystalline form of 6-aminohexanoic acid (I).

Furthermore, in another object of the invention, residue on ignition of the 6-aminohexanoic acid (I) is less than 0.5%; and heavy metals content is less than 10 ppm.

BRIEF DESCRIPTION OF DRAWINGS
Figure-1: X-ray powder diffractogram (XRD) of 6-aminohexanoic acid (I)
Figure-2: Thermogravimetric analysis (TGA) thermogram of 6-aminohexanoic acid (I)

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of 6-aminohexanoic acid (I) in substantially pure form.

The present invention is schematically represented in Scheme-I below:
Scheme-I

In one aspect of the invention, there is provided a process for the preparation of 6-aminohexanoic acid (I), the said process comprising the steps of:

a) reacting cyclohexanone (IV)

with hydroxylamine hydrochloride in the presence of base and protic solvent to obtain cyclohexanone oxime (III);

b) reacting cyclohexanone oxime (III) in the presence of acid to form azepan-2-one (II);

c) reacting azepan-2-one (caprolactam) (II) with a suitable acid to obtain crude 6-aminohexanoic acid (I); and

d) purifying crude 6-aminohexanoic acid (I) in protic solvents to obtain to 6- aminohexanoic acid (I) with purity greater than 99.5% as determined by HPLC.

In one embodiment, this invention provides an improved method for the synthesis of substantially pure 6-aminohexanoic acid (I) having purity greater than 99.5% as determined by HPLC.

In another embodiment, the present invention provides an improved method of purification of 6-aminohexanoic acid (I) crude using commonly available solvents and simple filtration technique to obtain 6-aminohexanoic acid which is having purity greater than 99.5% as determined by HPLC and has enhanced yield.

The step a) of the above described reaction scheme for the preparation of 6-aminohexanoic acid proceeds with the formation of cyclohexanone oxime (III) by reacting cyclohexanone (IV) with hydroxylamine hydrochloride in presence of a base and a protic solvent. In some embodiment of the invention, the base employed in step a) for the preparation of cyclohexanone (IV) is selected from the group comprising sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, potassium acetate, aqueous ammonia, methanolic ammonia, triethylamine, pyridine or the like. In some embodiment, the protic solvent used in step a) is selected from a group comprising of isopropyl alcohol, methanol, ethanol, n-propanol, n-butanol, water or a mixture thereof. In some embodiment of the invention, step a) is carried out in presence of a suitable buffering solution selected from sodium acetate, potassium acetate, acetic acid or the like.
The step b) follows Beckmann rearrangement reaction which involves the acid-catalyzed rearrangement of cyclohexanone oxime (III) in the presence of suitable mineral acid, followed by the treatment with suitable base to obtain azepan-2-one (II). In some embodiment, the suitable mineral acid used in step b) is selected from the group comprising of sulphuric acid, hydrochloric acid, nitric acid, p-toluene sulfonic acid, phosphoric acid, polyphosphoric acid or the like. In some embodiment of the invention, the suitable base employed in the preparation of azepane-2-one (II) is selected from sodium hydroxide, potassium hydroxide, aqueous ammonia or the like. In some embodiment, azepan-2-one (II) obtained in step b) is further purifiied by using suitable aprotic solvent selected from a group comprising of hexane, cyclohexane, petroleum ether or the like.

The step c) involves acid-hydrolysis of azepan-2-one (II) in the presence of a suitable acid to obtain crude 6-aminohexanoic acid (I). The product (I) is soluble only in suitable alcohols hence isolation is difficult, more over use of any inorganic bases makes the isolation of 6-aminohexanoic acid from salts difficult and tedious; hence, the use of basic resin is advantageous as it helps the easy isolation of 6-aminohexanoic acid in free form and decreases the residual on ignition. The suitable acid used in this step c) is selected from the group comprising of sulphuric acid, hydrochloric acid, nitric acid, hydrobromic acid, p-toluene sulfonic acid, phosphoric acid, polyphosphoric acid or the like. In some embodiment, the hydrolysis reaction of step c) is carried out in presence of a suitable resin. In some other embodiment, the hydrolysis reaction of step c) is carried in the presence of basic resin preferably Indion 810(OH) resin.

The step d) involves the further purification of crude 6-aminohexanoic acid (I) obtained in step c). The crude 6-aminohexanoic acid (I) obtained in step c) is dissolved in water and treated with neutral charcoal to remove traces of colored impurities, then passed through Hyflo and micron filter and subsequently suitable protic solvent is added and then heated at 70-80°C. In some embodiment, the protic solvent used in step d) is selected from a group comprising of isopropyl alcohol, methanol, ethanol, n-propanol, n-butanol, water or a mixture thereof to obtain pure 6-aminohexanoic acid (I) having purity greater than 99.5% as determined by HPLC.

The protic solvents used in step a), step b), step c) and step d) were selected from a group comprising of water, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, or the like or a mixture thereof. Preferably water and isopropyl alcohol were used in the present invention.

In another aspect of the invention, there is provided a process for the purification of 6-aminohexanoic acid (I), comprising steps of:
(i). providing a solution of 6-aminohexanoic acid (I), in a protic solvent;
(ii). treating with decolorizing agent;
(iii). adding protic solvent and heating to 70-80°C; and
(iv). isolating pure 6-aminohexanoic acid (I).

In some embodiment of the invention, the protic solvent employed in the above described process for the purification of 6-aminohexanoic acid (I) is selected from the group comprising of water, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol or mixture thereof.

In some embodiment of the invention, the decolorizing agent used in the above described process for the purification of 6-aminohexanoic acid (I) is neutral charcoal. In some other embodiments, the neutral charcoal used as decolorizing agent is Norit CN1.

In some other embodiment of the invention, there is provided a process for the preparation of 6-aminohexanoic acid (I) having purity greater than 99.5% as determined by HPLC.

In some embodiment of the invention, there is provided a process for the purification of 6-aminohexanoic acid (I), wherein the impurity level of 6-aminohexanoic acid obtained is less than 0.5% (w/w), preferably less than 0.2% (w/w).

In another aspect of the invention, there is provided a process for the preparation of crystalline form of 6-aminohexanoic acid (I), characterized by X-ray diffraction spectrum having peaks expressed as 2? values at about 10.54, 11.88, 21.58, 23.93, 28.29 ± 0.2 degrees, said process comprising the steps of:


a) reacting cyclohexanone (IV)

with hydroxylamine hydrochloride in the presence of base and protic solvent to obtain cyclohexanone oxime (III);

b) reacting cyclohexanone oxime (III) in the presence of acid to form azepan-2-one (II);

c) reacting azepan-2-one(caprolactam) (II) with a suitable acid to obtain crude 6-aminohexanoic acid (I);
d) providing a solution of 6-aminohexanoic acid (I), in a protic solvent;
e) treating with decolorizing agent;
f) adding protic solvent and heating to 70-80°C; and
g) isolating crystalline form of 6-aminohexanoic acid (I).

In another aspect, 6-aminohexanoic acid produced in the above method is having total impurities less than 0.5%. More specifically the caprolactam impurity, the dimer and trimer impurity level were found to be less than 0.02%.

In another aspect, 6-aminohexanoic acid produced in the above method is having residue on ignition less than 0.1 % w/w; preferably less than 0.05% and heavy metal less than 10 ppm.

The X-Ray powder diffractogram shows characteristic peaks of 6-aminohexanoic acid obtained by the process of the invention that may have 2(?) values as shown in Figure 1 and Table 1 below.
Table 1: X-Ray diffraction data of 6-aminohexanoic acid (I)
S. No. 2 Theta (2?) Relative intensity %
1. 10.54 36.1
2. 11.88 10.5
3. 17.62 3.1
4. 18.39 4.1
5. 18.58 3.2
6. 19.14 2.3
7. 20.09 2.3
8. 20.55 2.4
9. 21.58 5
10. 23.22 2.5
11. 23.93 100
12. 26.66 2.4
13. 28.29 6.2
14. 32.2 3.1

The 6-aminohexanoic acid (I) obtained by the process of the present invention is characterized by TGA as illustrated in Figure-2.

The following examples further illustrate the present invention but should not be construed in any way as to limit its scope.

EXAMPLES
EXAMPLE 1
Preparation of Cyclohexanone Oxime (III):
99.1 g (1.42 mol) of hydroxyl amine hydrochloride was dissolved in 500 mL of demineralized water (DM water) at 25-30°C. 400 mL of sodium acetate solution and 100 g of cyclohexanone (IV) were added to the reaction mass and stirred for 3-4 hrs at 40-45°C. The reaction mass was cooled to 25-30°C and the solid so obtained was filtered under vacuum, washed with chilled water and dried to yield cyclohexanone oxime (III).
Yield %: 98
Purity by GC%: 99.5

EXAMPLE 2
Preparation of Azepan-2-One (II):
100 g (0.88 mol) of cyclohexanone oxime (III) was added lot wise to a preheated solution of 85% sulphuric acid at 115-120°C and stirred for 30-60 minutes. The reaction mass was cooled to 0-5°C and treated with 24% potassium hydroxide solution to maintain pH of 8 - 8.5. The solid formed was filtered and washed with dichloromethane. After separation of the layers, the aqueous layer was extracted with different volumes of dichloromethane. The organic layers were collected and dried over sodium sulphate and filtered. The filtrate was then distilled under vacuum. The crude so obtained was washed with n-hexane and dried to obtain azepan-2-one (caprolactam) (II).
Yield %: 55
Purity by GC %: 99.7

EXAMPLE 3
Alternative method for the preparation of Azepan-2-one (II):
100 g (0.88 mol) of cyclohexanone oxime (III) was added lot wise to a preheated solution of 85% sulphuric acid at 115-120 °C and stirred for 30-60 minutes. The reaction mass was then cooled to -10 - 0°C with addition of 20-25% of aqueous ammonia solution. The temperature of the reaction mass was raised to 25-30°C and filtered. The solid obtained was washed with dichloromethane and then dried. The filtrate was treated with 250 mL of dichloromethane, stirred and the layers were separated. 10 g of neutral charcoal was added to the total organic layer at 25-30°C and filtered through Hyflo. The filtrate was dried over sodium sulphate and distilled under vacuum below 45°C. The crude was washed with methanol and acetone. The crude so obtained was further washed with n-hexane at 25-30°C. The reaction mass was cooled to 10-15°C and stirred for 60 minutes at 10-15°C. The solid formed was filtered under vacuum in nitrogen atmosphere, washed with n-hexane and dried to get azepan-2-one (caprolactam) (II).
Yield %: 60
Purity by GC%: 99.69

EXAMPLE 4
Preparation of crude 6-Aminohexanoic acid (I):
100 g (0.88 mol) of azepan-2-one (II) was dissolved in 300 mL of DM water, stirred with addition of 92.5 mL of hydrochloric acid at 25-30°C. The reaction mass was heated and stirred for 3-4 hrs at 95-100°C. On completion of reaction, the reaction mass was gradually cooled to 0-5°C to obtain crude 6-aminohexanoic acid. To the crude 650 mL basic resin (Indion 810(OH) resin) washed with DM water was added to the reaction mass and stirred for 60 to 90 minutes at 25-30°C. The reaction mixture was then filtered and washed with DM water. Another lot of basic resin was similarly processed, and the reaction filtrate passed over the resin below 30 °C. The chloride content of the total reaction filtrate was checked. The chloride free reaction mass was collected, and vacuum distilled below 50°C to prevent the impurity formation. The crude so obtained was mixed with 250 mL isopropyl alcohol, and stirred for 1 hr at 25-30°C. The solid so formed was filtered under vacuum, washed with 50 mL of isopropyl alcohol and dried at 25-30°C to obtain crude 6-aminohexanoic acid (I).
Yield %: 52
Purity as determined by HPLC (%): 99.85

EXAMPLE 5
Purification of crude 6-aminohexanoic acid (I):
100 g (0.88 mol) of crude 6-aminohexanoic acid (I) was dissolved in 150 mL of DM water. 5.0 g of neutral charcoal (Norit CN1) was added to the reaction mass and stirred for 20-30 min at 25-30°C. The reaction mass was filtered through Hyflo and passed through 0.22-micron filter. 1000 mL of isopropyl alcohol was added to the filtrate and stirred for 1-2 hrs at 75-80 °C. The reaction mixture was cooled to 15-20°C with stirring. The solid formed was filtered under vacuum, washed with isopropyl alcohol and dried to obtain pure 6-aminohexanoic acid (I).
Yield %: 90
Purity as determined by HPLC (%): 99.90
,CLAIMS:
1. A process for the preparation of 6-aminohexanoic acid (I), the said process comprising the steps of:


a) reacting cyclohexanone (IV)

with hydroxylamine hydrochloride in the presence of base and protic solvent to obtain cyclohexanone oxime (III);

b) reacting cyclohexanone oxime (III) in the presence of acid to form azepan-2-one (II);

c) reacting azepan-2-one (caprolactam) (II) with a suitable acid to obtain crude 6-aminohexanoic acid (I); and

d) purifying crude 6-aminohexanoic acid (I) in protic solvent to obtain to 6- aminohexanoic acid (I) with purity greater than 99.5% as determined by HPLC.

2. The process as claimed in claim 1, wherein the base employed in step a) is selected from the group comprising of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, potassium acetate, aqueous ammonia, methanolic ammonia, triethylamine, pyridine or the like.

3. The process as claimed in claim 1, wherein the acid employed in step b) and step c) is selected from the group comprising of sulphuric acid, hydrochloric acid, nitric acid, p-toluene sulfonic acid, phosphoric acid, polyphosphoric acid or the like.

4. The process as claimed in claim 1, wherein the protic solvent employed in step a) and d) are selected from a group comprising of methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, water or the like.

5. A process for the purification of 6-aminohexanoic acid (I), comprising steps of:
(i). providing a solution of 6-aminohexanoic acid (I), in a protic solvent;
(ii). treating with decolorizing agent;
(iii). adding protic solvent and heating to 70-80°C; and
(iv). isolating pure 6-aminohexanoic acid (I).

6. The process as claimed in claim 5, wherein the protic solvent employed is selected from the group comprising of water, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol or mixture thereof.

7. The process as claimed in claim 5, wherein the decolorizing agent used is neutral charcoal.

8. The process as claimed in claim 5, wherein purity of 6-aminohexanoic acid product is greater than 99.5% as determined by HPLC.
9. The process as claimed in claim 5, wherein the impurity level of 6-aminohexanoic acid is less than 0.5% (w/w), preferably less than 0.2% (w/w).

10. A process for the preparation of crystalline form of 6-aminohexanoic acid (I), characterized by X-ray diffraction spectrum having peaks expressed as 2? values at about10.54, 11.88, 21.58, 23.93, 28.29 ± 0.2 degrees, said process comprising the steps of:


a) reacting cyclohexanone (IV)

with hydroxylamine hydrochloride in the presence of base and protic solvent to obtain cyclohexanone oxime (III);

b) reacting cyclohexanone oxime (III) in the presence of acid to form azepan-2-one (II);

c) reacting azepan-2-one (caprolactam) (II) with a suitable acid to obtain crude 6-aminohexanoic acid (I);
d) providing a solution of 6-aminohexanoic acid (I), in a protic solvent;
e) treating with decolorizing agent;
f) adding protic solvent and heating to 70-80°C; and
g) isolating crystalline form of 6-aminohexanoic acid (I).