DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

PROCESS FOR PREPARATION OF SUPRAMOLECULAR COMPLEX OF SACUBUTRIL & VALSARTAN

FIELD OF INVENTION
The present application relates to a process for the preparation of hemicalcium salt of sacubitril. Specifically the present application relates to triethylamine salt of Sacubitril and its use for the preparation of a supra-molecular complex of sacubitril and valsartan. Further the present application relates to a convenient process for the preparation of supra-molecular complex of sacubitril and valsartan.

BACKGROUND
US Patent No. 8877938 (hereinafter the US’938 patent) discloses a crystalline form of supra-molecular complex of valsartan and sacubitril. It is known in the literature as LCZ-696 (Tetrahedron Letters 53, 2012, 275–276). The chemical name of the supra-molecular complex is trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3´-methyl-2´-(pentanoyl{2´´-(tetrazol-5-ylate)-biphenyl-4´-ylmethyl}amino)butyrate] hemipentahydrate (CAS # 936623-90-4). The US’938 patent discloses two processes for the preparation of supra-molecular complex of valsartan and sacubitril. One of the processes involves the use of mixture of acetone-water as solvent and the other process involves the use of a mixture isopropyl acetate-acetone-water as solvent.

SUMMARY
One aspect of the present application relates to a process for the preparation of hemicalcium salt of sacubitril comprising the step of converting triethylamine salt of sacubitril to hemicalcium salt without using sodium hydroxide.

Another aspect of the present application relates to a process for the preparation of hemicalcium salt of sacubitril comprising the steps of:
(a) reacting compound of formula (I) with succinic anhydride and triethylamine in a suitable solvent and

(b) treating the product of step (a) with a source of calcium ion without using sodium hydroxide.

Yet another aspect of the present application relates to use of triethylamine salt of sacubitril for the preparation of supra-molecular complex of valsartan and sacubitril without using sodium hydroxide.

Another aspect of the present application relates to process for preparation of compound of formula (I) comprising
(a) reacting of triethyl orthoformate and hydrogen chloride gas to provide ethanolic HCl;
(b) treating compound of formula (II) with ethanolic HCl
.

Still another aspect of the present application relates to a process for preparation of supra-molecular complex of valsartan and sacubitril comprising reacting sacubitril and valsartan in presence of ethyl acetate-acetone-water as solvent combination.

DESCRIPTION OF FIGURES
Figure 1 is an illustration of a PXRD pattern of sacubitril hemicalcium as obtained from
example 3.
Figure 2 is an illustration of a PXRD pattern of sacubitril hemicalcium as obtained from
example 5.
Figure 3 is an illustration of a PXRD pattern of sacubitril hemicalcium as obtained from
example 6.

DETAILED DESCRIPTION
One aspect of the present application relates to a process for the preparation of hemicalcium salt of sacubitril comprising the step of converting triethylamine salt of Sacubitril to hemicalcium salt.

Another aspect of the present application relates to a process for the preparation of hemicalcium salt of sacubitril comprising the steps of:
(a) reacting compound of formula (I) with succinic anhydride and triethylamine in a suitable solvent and

(b) treating the product of step (a) with a source of calcium ion without using sodium hydroxide.

The present application relates to a process which further provides pure sacubitril hemicalcium in terms of chemical purity. Specifically, the content of diacid impurity, compound of formula (III)

is lower in sacubitril hemicalcium when compared to known processes in the literature.
The compound of formula (I) and succinic anhydride may be taken in a suitable solvent. The suitable solvent may include but not limited to nitrile solvent such as acetonitrile and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide and the like. Specifically, the solvent is an ester solvent such as ethyl acetate, isopropyl acetate and the like. More specifically, the solvent is ethyl acetate.
Triethylamine may be added drop-wise or at once to the above reaction mass. Alternatively, the reaction mass may be added to triethylamine either drop-wise or at once. The temperature of the reaction mass may be maintained at about 0 °C to the boiling point of the solvent for about 1 hour to 15 hours. Specifically, the temperature of the reaction mass may be maintained at about 20-30 °C for about 4 hours. The reaction may be quenched by the addition of water. The triethylamine salt of sacubitril may be found in the aqueous layer which may be taken up directly for the next reaction without any isolation. Alternatively, triethylamine salt of sacubitril may be isolated from the reaction mass by a process known to a person skilled in the art. The isolated triethylamine salt of sacubitril may be crystallized, if required from a suitable solvent.
The aqueous solution comprising triethylamine salt of sacubitril may be heated to a temperature from about 50 °C to the boiling point of the solvent. Specifically, a solution containing triethylamine salt of sacubitril may be heated to a temperature of about 70 °C to about 80 °C and an aqueous solution of a source of calcium ion may be added to the reaction mass drop-wise. Alternatively, the reaction mass may be added to an aqueous solution of a source of calcium ion drop-wise. The reaction mass may be cooled to a temperature of about 0 °C to about 40 °C. Specifically, the reaction mass may be cooled to a temperature of about 20 °C to about 35 °C. The precipitated hemicalcium salt of sacubitril may be isolated by any technique known in the art such as filtration. The hemicalcium salt of sacubitril may be optionally dried in a hot-air oven or vacuum oven.
The source of calcium ion may include but not limited to calcium acetate, calcium chloride, calcium hydroxide and the like. Specifically, the source of calcium ion may be calcium chloride.

Another aspect of the present application relates to crystalline form of sacubitril hemicalcium. The major 2? peaks of crystalline form of sacubitril hemicalcium, isolated from different batches have been tabulated in Table 1.
Experiment No.
Example 3 Example 5 Example 6
3.6 3.2 3.6
4.0 3.6 6.0
6.0 6.0 6.4
6.4 6.4 7.6
7.6 7.4 8.4
8.4 7.6 10.8
10.8 8.4 11.3
11.3 10.8 12.8
12.2 11.3 14.6
12.8 11.5
14.6 12.0
12.8
14.6

Another aspect of the present application relates to process for preparation of compound of formula (I) comprising
(a) reacting a mixture of triethyl orthoformate and water with hydrogen chloride gas to provide ethanolic HCl;
(b) treating compound of formula (II) with ethanolic HCl
.
The PCT application, WO2008/083967 discloses a process for the preparation of compound of formula (I) from a compound of formula (II) by treating the compound of formula (II) with thionyl chloride or thionyl bromide in presence of ethanol. The process is not suitable for commercial preparation of sacubitril because thionyl chloride is known to be a toxic raw-material.
Hydrogen chloride gas may be purged into triethyl orthoformate for a period of about 30 minutes to about 5 hours at a temperature about 0 °C to about boiling point of the solvent to provide ethanolic HCl. Specifically, hydrogen chloride gas may be purged into triethyl orthoformate for a period of about 45 minutes to about 2 hours at a temperature about 0 °C to about 10 °C to provide ethanolic HCl. Thus generated, ethanolic HCl, may be reacted with compound of formula (II) at a temperature of about 0 °C to about boiling point of the solvent for a period of about 1 hour to about 10 hours. Specifically, the reaction may be performed at a temperature of about 20 °C to about boiling point of the solvent for a period of about 2 hours to about 5 hours. More specifically, the reaction may be performed at a temperature of about 50 °C to about 60 °C for a period of about 1 hour. The compound of formula (I) may be isolated by any known methods in the art. Specifically, the compound of formula (I) may be isolated by distillation of the solvent under vacuum. Alternatively, the compound of formula (I) may be isolated by filtration. Optionally, the compound of formula (I) may be dried.

One aspect of the present application relates to a process for preparation of supra-molecular complex of valsartan and sacubitril comprising reacting sacubitril and valsartan in presence of ethyl acetate-acetone-water as solvent combination.

The US’938 patent discloses a process for the preparation of supra-molecular complex of valsartan and sacubitril in a solvent mixture of isopropyl acetate-acetone-water. The inventors of the present application found out that the same supra-molecular complex of valsartan and sacubitril, as reported in US’938 patent, may be obtained from a solvent mixture of ethyl acetate-acetone-water. As ethyl acetate is readily available and cheaper solvent in comparison to isopropyl acetate, the present application relates to an economically viable process for the preparation of supra-molecular complex of valsartan and sacubitril.
Hemicalcium salt of sacubitril may be treated with dilute hydrochloric acid in ethyl acetate at about 10 °C to about 30 °C. The organic layer containing sacubitril free acid may be taken as such from the reaction mass. Alternatively, sacubitril free acid may be isolated and optionally crystallized and carried forward to the next step.
To a solution of sacubitril free acid and valsartan in a combination of ethyl acetate and acetone, aqueous sodium hydroxide may be added at a temperature from about 10 °C to about 50 °C. Specifically, aqueous sodium hydroxide may be added at a temperature of about 25 °C. The reaction mass may be maintained at about 25 °C for about 1 hour. The supra-molecular complex of valsartan and sacubitril may be isolated from the reaction mass by any known technique in the art such as filtration. Optionally, the supra-molecular complex of valsartan and sacubitril may be dried at a suitable temperature.
One aspect of the present application relates to supra-molecular complex of valsartan and sacubitril, prepared by the process of the present application, having more than 95% purity and having similar PXRD pattern as reported in the US’938 patent. Specifically, the present application relates to supra-molecular complex of valsartan and sacubitril, prepared by the process of the present application, having more than 97% purity and having similar PXRD pattern as reported in the US’938 patent. More specifically, the present application relates to supra-molecular complex of valsartan and sacubitril, prepared by the process of the present application, having more than 99% purity and having similar PXRD pattern as reported in the US’938 patent.

Certain specific aspects and embodiments are further described by the following examples, being provided only for purposes of illustration, and the scope of the disclosure is not intended to be limited by the examples.

EXAMPLES
Example 1: Preparation of ethyl (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl-pentanoate hydrochloride (I)
A mixture of (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (II) (5 g) and ethanolic HCl (100 mL) was heated to reflux at 75-77 °C for about 3 hours. After the completion of the reaction, the solvent was distilled off under vacuum and heptane (50 mL) was added at 29 °C. The heterogenous mass was stirred for 1 hour. The solid was filtered and dried to afford the title compound.
Yield: 4.3 g
Purity (by HPLC): 98.20%

Example 2: Preparation of ethyl (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl-pentanoate hydrochloride (I)
Hydrogen chloride gas was purged for about 2 hours to the mixture of triethyl orthoformate (150 mL) and water (18 mL) at 10 °C. The compound, (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid (II) (5 g) was added to the reaction mass and heated to 55 °C for about 1 hour and the solvent was distilled off under vacuum. Heptane (50 mL) was added to flask and stirred for about 20 minutes. The solid was collected by filtration and washed further with heptane (50 mL). The solid was dried at 55 °C to afford the title compound.
Yield: 4.54 g
Purity (by HPLC): 98.93%

Example 3: Preparation of hemicalcium salt of sacubitril
Compound of formula (I) (5 g), succinic anhydride (2.16 g) and ethyl acetate (50 mL) were charged in a reaction vessel. Triethylamine (5.8 g) was added drop-wise to the above mixture keeping the temperature below 30 °C. The reaction mass was stirred for approximately 5 hours keeping the temperature constant. The reaction mass was left overnight. Water (50 mL) was added to the reaction mass and the aqueous layer was separated. The aqueous layer was washed with ethyl acetate (50 mL). The aqueous layer was taken in a separate reaction vessel and heated to a temperature of about 70-80 °C. An aqueous solution of calcium chloride (1.6 g in 25 mL water) was added to the reaction vessel. The reaction mass was stirred at the same temperature for about 1 hour. The reaction mass was cooled to 24 °C and stirred for about 1 hour. The solid was filtered and washed with water (75 mL). The collected solid was dried at 65 °C for about 4 hours to afford the title compound.
Yield: 4.7 g
Purity (by HPLC): 99.70%

Example 4: Preparation of sacubitril
To a mixture of compound of formula (I) (50 g), succinic anhydride (21.57 g) and isopropyl acetate (500 mL), triethylamine (58.2 g) was added slowly over a period of about 2 hours maintaining the temperature at 22-25 °C. The reaction mass was stirred for about 2 hours. Water (250 mL) was added to the reaction mass for quenching. The organic layer was separated from the aqueous layer. The aqueous layer was further washed twice with isopropyl acetate (1 X 250 mL; 1 X 500 mL). The pH of the aqueous layer was adjusted to 2-3 by adding hydrochloric acid (1N, 100 mL). The aqueous layer was extracted with isopropyl acetate twice (2 X 250 mL). The organic layer was combined and washed with brine (1 X 100 mL). The organic layer was used in the next step as such.

Example 5: Preparation of hemicalcium salt of sacubitril
A mixture of the organic layer (375 mL), as obtained in Example 4, and water (300 mL) was cooled to 20-25 °C. The pH of the reaction mass was adjusted to 9 by the addition of aqueous solution of sodium hydroxide (1N, 80 mL). The aqueous layer was separated and heated to about 78-79 °C. An aqueous solution of calcium chloride (9.7 g in 150 mL water) was added to the reaction mixture over a period of 30 minutes. The reaction mass was stirred for about 15 minutes at 78-79 °C and then it was allowed to cool down slowly over a period of about 3 hours. The precipitated solid was filtered at 33 °C and washed with water (150 mL). The solid was dried in a vacuum drier at 45-55 °C for about 4 hours.
Yield: 26.7 g
Purity (by HPLC): 99.67%

Example 6: Preparation of hemicalcium salt of sacubitril
To a mixture of compound of formula (I) (5 g), ethyl acetate (50 mL) and succinic anhydride (2.16 g), triethylamine (5.82 g) was added slowly over a period of 15 minutes at 22 °C. The reaction mass was stirred at 22 °C for about 6 hours and quenched with water (50 mL). The aqueous layer was separated and washed with ethyl acetate (2 X 50 mL). The pH of the aqueous layer was made acidic by the addition of hydrochloric acid (5 mL). The aqueous layer was extracted with ethyl acetate (2 X 50 mL) and dried over sodium sulfate. Water (50 mL) was added to ethyl acetate layer and the pH of the reaction mass was adjusted to 7.5-8.5 by the addition of aqueous solution of sodium hydroxide (1N). The aqueous layer was separated and heated to 85 °C. An aqueous solution of calcium chloride (1.72 g in 50 mL water) was added to the above solution slowly over a period of 10 minutes and the reaction mass was stirred for 20 minutes. The reaction mass was allowed to cool down slowly and the precipitated solid was isolated by filtration at 33 °C. The solid was washed with water (10 mL) and dried in an oven at 45-60 °C for 3 hours to afford the desired compound.
Yield: 3.2 g
Purity (by HPLC): 99.78%

Example 7: Preparation of supra-molecular complex of valsartan and sacubitril
To a mixture of hemicalcium salt of sacubitril (10 g) in ethyl acetate (100 mL), hydrochloric acid (2N, 22.80 mL) was added drop-wise at 20 °C. The reaction mass was stirred for about 30 minutes and the organic layer was separated. The organic layer was washed with water (3 x 20 mL) and the distilled up to 17.5 mL of the mass. A solution of valsartan (9.02 g) in acetone (200 mL) was charged to the concentrated mass containing sacubitril free acid. Aqueous solution of sodium hydroxide (2.48 g in 5 mL water) was added slowly to the reaction mass and the reaction mass was stirred for about 30 minutes. Ethyl acetate (100 mL) was added to the reaction mass and the reaction mass was distilled under vacuum up to 170 mL of the mass left in the reaction vessel. Ethyl acetate (20 mL) was charged and distilled until the volume reached 170 mL. The reaction mass was stirred for about 90 minutes at 25 °C. The precipitated solid was filtered and washed with ethyl acetate (2 x 20 mL). The solid was kept for aerial drying at 24 °C for about 24 hours to afford the desired compound.
Yield: 18 g
Purity (by HPLC): 98.5%
,CLAIMS:We Claim:
1. A process for the preparation of hemicalcium salt of sacubitril comprising the step of converting triethylamine salt of sacubitril to hemicalcium salt.
2. The process of claim 1, further comprising treating compound of formula (I)

with triethylamine and succinic anhydride.
3. The process of claim 2, wherein treating compound of formula (I) with triethylamine and succinic anhydride is performed in presence of a solvent.
4. The process of claim 3, wherein the solvent is an ester solvent.
5. The process of claim 1, wherein triethylamine salt is treated with a source of calcium.
6. The process of claim 5, wherein the source of calcium is calcium chloride.
7. The process of claim 1, further comprising converting sacubitril hemicalcium to supra-molecular complex of sacubitril and valsartan.