DESC:FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLET SPECIFICATION
(Section 10; rule 13)

“CRYSTALLINE SOLID FORM OF SACUBITRIL SODIUM, SACUBITRIL AND PROCESS FOR THE PREPARATION THEREOF”

UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT ESTATE OFF. S. V. ROAD, JOGESHWARI (W) MUMBAI 400102
MAHARASHTRA, INDIA

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

CRYSTALLINE SOLID FORM OF SACUBITRIL SODIUM, SACUBITRIL AND PROCESS FOR THE PREPARATION THEREOF

FILED OF THE INVENTION:

The present invention relates to crystalline solid form of sacubitril, sacubitril sodium and process for the preparation thereof.

BACKGROUND OF THE INVENTION:

US 5,217,996 described sacubitril compound of formula (I) which is chemically described as (2R, 4S)-5- (biphenyl-4-yl)-4-[(3-carboxypropionyl) amino]-2-methylpentanoic acid ethyl ester. Sacubitril is an antihypertensive drug and used in combination with valsartan for the treatment of hypertension and heart failure. The combination of sacubitril and valsartan formed a complex, which is marketed as ENTRESTO®.

ENTRESTO® contains a complex comprised of anionic forms of sacubitril and valsartan, sodium cations and water molecules. It was approved on Jul 7, 2015 under priority review process of USFDA. The complex is chemically described as Octadecasodiumhexakis(4-{[(1S,3R)-1-([1,1´-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4oxobutanoate)hexakis(N-pentanoyl-N-{[2´-(1H-tetrazol-1-id-5-yl)[1,1´-biphenyl]-4-yl]methyl}-L-valinate)—water (1/15). Alternate name 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 having following structural formula.

ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Prior art process such as in US 5,217,996 discloses preparation of compound of formula (I) is in free carboxylic acid form which does not crystallizes and the product as an oil. Whereas present invention involve preparation of crystalline sacubitril and crystalline sacubitril sodium salt which is easy for isolation and purification with good yield. US’996 and J. Med. Chem. 1995 (38) page no. 1689-1700 discloses reduction of N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester compound of formula (VI) to gives N-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester as a 80: 20 mixture of diastereomers.

Sacubitril is chiraly pure isomer. Disadvantages of using 80: 20 mixture of N-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester diastereomers eventually will lead to 80: 20 mixture of diastereomers of Sacubitril. US’996 described method for purification 80: 20 mixture of diastereomers of Sacubitril by derivatization followed by chromatographic separation and de protection to get chiraly pure sacubitril. This process is not preferable for use on an industrial scale.
The aim of the present invention is to provide purification process for N-t-butoxycarbonyl (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester compound of formula (VII) to obtain pure compound.

WO 2016150337, WO 2016135751, WO 2017003483, WO 2017009784, CN 106278933 and CN 105753733A discloses various polymorphic form of sacubitril or its salts and process to prepared it.

Most of the available literature involves the presence of sacubitril as glassy oil compound. Generally, an oil is difficult to handle and contains impurities. Further, in some cases chromatography is not preferable for use on an industrial scale.

The aim of the present invention is to provide an alternative method of preparing sacubitril, which can be used on a large scale and allows sacubitril to be easily purified and isolated.

The aim of the present invention is therefore to provide an alternative method of preparing sacubitril sodium salt, which can be used on a large scale and allows sacubitril sodium to be easily worked up, purified, and isolated.
New solid state forms of a compound can improve the performance characteristics of a pharmaceutical product. e.g., better processing or improved shelf-life or improved solubility. For at least these reasons, there is a need for solid state forms of sacubitril and sacubitril sodium compound.

OBJECT OF THE INVENTION:
One object of the invention provides a crystalline form of sacubitril sodium.

Another object of the invention is to provide a process for preparing the above crystalline sacubitril sodium.
Yet another object of the invention provides a crystalline form of sacubitril.

Yet another object of the invention is to provide a process for preparing the above crystalline form of sacubitril.

SUMMARY OF THE INVENTION:
In one aspect object of the invention provides a crystalline form of sacubitril sodium characterized by an X- ray powder diffraction pattern with characteristic peaks at about 3.5, 5.2, 6.4, 8.7, 10.5, 11.4, 12.2, 15.8, 17.4, 19.3, 20.7, 26.8, and 29.6 ± 0.2 degrees two-theta.

Another aspect object of the invention provides a process for preparing crystalline form of sacubitril sodium comprising:
a) crystallizing sacubitril sodium from a solution of sacubitril sodium in a solvent system selected from the group consisting of ester, ether, aromatic solvent or mixture thereof;
Wherein the crystallization of step a) is carried out by cooling the solution to crystallize out sacubitril sodium;
b) isolating the crystalline form of sacubitril sodium that appears in the prior step; and
c) Removing the solvent from the crystalline form of sacubitril sodium thus obtained.
Another aspect object of the invention provides a crystalline form of sacubitril compound of formula (I) characterized by an X- ray powder diffraction pattern with characteristic peaks at about 4.0,4.3, 5.4, 9.8, 12.3, 13.0, 13.8, 14.1, 16.3, 17.2, 17.8, 19.2, 20.7, 21.4, 22.5, 23.2 and 25.8 ± 0.2 degrees 2?.

Another aspect object of the invention provides a process for preparing crystalline form of sacubitril compound of formula (I) comprising:
a) providing a solution of sacubitril sodium compound of formula (II) in water and ethyl acetate;
b) adding acid to solution of step a) to get sacubitril solution;
c) adding non polar anti solvent;
d) precipitating the solid sacubitril compound of formula (I); and
e) Recovering the sacubitril compound of formula (I) in crystalline form.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 shows an X-Ray powder diffraction pattern of crystalline form of sacubitril sodium.
Figure 2 shows DSC thermogram of crystalline form of sacubitril sodium.
Figure 3 shows an X-Ray powder diffraction pattern of crystalline form of sacubitril.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a crystalline form of sacubitril sodium and a process for its preparation which is simple, ecofriendly, inexpensive, reproducible, robust and well suited on commercial scale.

The present invention provides a crystalline form of sacubitril sodium characterized by an X- ray powder diffraction pattern with characteristic peaks at about 3.5, 5.2, 6.4, 8.7, 10.5, 11.4, 12.2, 15.8, 17.4, 19.3, 20.7, 26.8, and 29.6 ± 0.2 degrees two-theta.

The present invention further provides the crystalline form of sacubitril sodium as characterized by differential scanning calorimetry with an endotherm curve at about 58 °C, with an onset at about 73 °C and an end set at about 99 °C.

As mentioned above, the crystalline form of sacubitril sodium of the present invention can be prepared by a process comprising following steps;
a) crystallizing sacubitril sodium from a solution of sacubitril sodium in a solvent system selected from the group consisting of ester, ether, aromatic solvent or mixture thereof;
wherein the crystallization of step a) is carried out by cooling the solution to crystallized out sacubitril sodium;
b) isolating the crystalline form of sacubitril sodium that appears in the prior step; and
c) removing the solvent from the crystalline form of sacubitril sodium thus obtained.

In the preferred embodiment of the present invention, the solvent system is selected from ester solvent such as isopropyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl acetate, ether solvent such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, aromatic solvent such as toluene, xylenes and mixture(s) thereof.

The sacubitril sodium is dissolved in a solvent system at a temperature range from 30?-85? C, more preferably 60?-65?C for the time period of 20-60 minutes. Then the hot solution is cool to 20?-40?C and stirred for about 5-15 hours. Filter and dry the obtained solid to get crystalline form of sacubitril sodium characterized by an X- ray powder diffraction pattern with characteristic peaks at about 3.5, 5.2, 6.4, 8.7, 10.5, 11.4, 12.2, 15.8, 17.4, 19.3, 20.7, 26.8, and 29.6 ± 0.2 degrees two-theta.

The present invention relates to a crystalline form of sacubitril compound of formula (I) and a process for its preparation which is simple, ecofriendly, inexpensive, reproducible, robust and well suited on commercial scale.

The present invention provides a crystalline form of sacubitril characterized by an X- ray powder diffraction pattern with characteristic peaks at about 4.0,4.3, 5.4, 9.8, 12.3, 13.0, 13.8, 14.1, 16.3, 17.2, 17.8, 19.2, 20.7, 21.4, 22.5, 23.2 and 25.8 ± 0.2 degrees 2?.

In another embodiment of the present invention is to provide process for the preparation of crystalline sacubitril comprises following steps;
a) providing a solution of sacubitril sodium compound of formula (II) in water and ethyl acetate;
b) adding acid to solution of step a) to get sacubitril solution;
c) adding non polar anti solvent;
d) precipitating the solid sacubitril compound of formula (I); and
e) recovering the sacubitril compound of formula (I) in crystalline form.
The solution of sacubitril sodium can be obtained by dissolving sacubitril sodium salt in a solvent system such as water, ethyl acetate or their aqueous mixtures at temperature at about 20-40?C. The obtained solution is preferably allowed to cool, such to a temperature about 15-20?C. To the cool solution of sacubitril sodium, citric acid solution was added at temperature about 15-20?C and stirred for 10-20 minutes. Separate the organic layer and concentrate under reduced pressure to get thick gummy oil of sacubitril.

To the thick gummy oil, ethyl acetate was added and heat the solution about 40-60?C, adding anti solvent to the solution and stirred at the solution at temperature 40-60?C for 20-45 minutes. Cool the mixture and again add anti solvent at temperature about 20-40?C and stirred for 2-6 hours. Filter the obtained solid to get crystalline form of sacubitril characterized by an X- ray powder diffraction pattern with characteristic peaks at about 4.0,4.3, 5.4, 9.8, 12.3, 13.0, 13.8, 14.1, 16.3, 17.2, 17.8, 19.2, 20.7, 21.4, 22.5, 23.2 and 25.8 ± 0.2 degrees 2?.

Crystallization include adding an anti-solvent to facilitate the precipitation of compound. The term “anti-solvent” refers to liquid that, when added to a solution of compound in a solvent, includes precipitation of compound. The anti-solvent may also be in a binary mixture with the solvent when the solution prepared.

Anti-solvent for the above crystallization is selected from hexanes, heptanes cyclic and acyclic saturated hydrocarbons from C5 to C10 and the like.

Acid used for step (b) is selected from citric acid, formic acid, acetic acid, phosphoric acid.

Sacubitril compound of formula (I) can be prepared by following manner as shown in scheme 1.

In another embodiment of the present invention is to provide purification process of compound of formula (VII) in the presence of the solvent system is selected from ester solvent such as isopropyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl acetate, ether solvent such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, aromatic solvent such as toluene, xylenes, alcoholic solvents such as methanol, ethanol, IPA, n-butanol, sec-butanol and mixture(s) thereof. Purification of obtained diasteromeric product is carried by heating at about 60-80 °C in the solvent system, further product is cooled and filtered at 25-30?C.

X-Ray Powder Diffraction Method: Explain--The X-ray powder diffraction pattern was measured with X’Pert PRO X-ray powder diffractometer, equipped with copper IR radiation source = 1.54184 A°, X’celerator (2.022° 2?) detector.
Scanning parameter- Angle range-3-40 deg. Step size- 0.0167, time per step- 50.165 sec, continuous scan.

DSC Method: Explain DSC analysis was performed on Perkin-Elmer Pyris bU with heating rate of 10 °C/min, under nitrogen flow of 30 ml/min. A hermetic aluminium closed pan without hole was used and sample mass was about 2-5 mg.
In the following examples, the preferred embodiment of the present invention are described only by the way if illustrating the process of the present invention. However, these are not intended to limit the scope of the present invention in any way.

Examples:
Example 1: Preparation of (R)-tert-butyl 1-(biphenyl-4-yl)-3-oxopropan-2-ylcarbamate of formula (III)
In a 500 ml round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 25 gm (R)-tert-butyl 1-(biphenyl-4-yl)-3-hydroxypropan-2-ylcarbamate formula (II) and 300 ml of ethyl acetate and 150 ml water. Added 9.5 gm of sodium bromide, 9.6 gm of sodium bicarbonate. Cool reaction mixture to 0-5 ° C. Added 0.12 g TEMPO and 6.8 gm of sodium hypochlorite. To the reaction mixture, 400 ml water is added and ethyl acetate layer is separated. The ethyl acetate layer is concentrated at 50-55?C under vacuum. The white solid product obtained 23.1 gm, (93 %) titled compound having 89% purity.

Example 2: Preparation of (R)-5-(biphenyl-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpent-2-enoic acid of formula (VI)

In a 500 ml round bottom flask, equipped with a mechanical stirrer, thermometer and an additional funnel, 25 gm of (R)-tert-butyl 1-(biphenyl-4-yl)-3-oxopropan-2-ylcarbamate and 200 ml THF was added. To the reaction mixture 32.5 gm of ethyl-2-(triphenyl-5-phosphanylidene) propionate and 50 ml THF was added. The reaction was stirred for 2.0 hours at 50-55°C. The reaction mixture was concentrated and the residue was dissolved in 100 methanol and 25 ml water, to which 4.6gm sodium hydroxide was added. The reaction was stirred at 55-60?C for 2.0 hours. The pH of the reaction mixture was adjusted to 4-5 with citric acid solution. The solid obtained was filtered and washed with water to get of (R)-5-(biphenyl-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpent-2-enoic acid (30 gm) having 79% purity.

Example 3: Preparation of (2R, 4S)-5-(biphenyl-4-yl)-4-(tert-butoxycarbonylamino)-2-methyl pentanoic acid formula (VII)
In a 700 ml autoclave equipped with H2 and N2 gas cylinder. 12 gm of (R)-5-(biphenyl-4-yl)-4-(tert-butoxycarbonylamino)-2-methylpent-2-enoic acid and 100 ml of isopropyl acetate was added. 1.2 gm 10% palladium on carbon (50 % wet) was added to which hydrogen gas was purged with a pressure of 4-5 kg/cm2. The reaction mixture was stirred at 25-30°C for 4-6 hours. After completion the reaction mixture was filtered through bed of celite. Filtrate was collected and washed with 50 ml 10% citric acid solution. Separated organic layer and distilled under vacuum at 40-45°C to get 11.5g threo- erythro mixture (4:1). Obtained compound was re suspended in 35 ml 2- butanol. Warmed this reaction mixture to 65-70°C, allowed cool to 25-30°C and filtered obtained solids to get (2R,4S)-5-(biphenyl-4-yl)-4-(tert-butoxycarbonylamino)-2-methyl pentanoic acid 7gm having 99.5% purity. [Other diastereomers less 0.1%]

Example 4: Preparation of (2R, 4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride of formula (VIII)

In a three litre four neck flask add 250 gm (2R,4S)-5-(biphenyl-4-yl)-4-(tert-butoxycarbonylamino)-2-methyl pentanoic acid and 1.0 lit toluene and 250 ml ethanol 25-30oC. Added drop wise 47.30 ml thionyl chloride at 25-30oC (below 40-45°C). Gradually raise the temperature 65-70oC. Stir the reaction mixture for 4-5 hours at 65-70oC. Concentrate reaction mixture under vacuum at 45-50°C. Charge ethyl acetate (1.0 lit.) at 45-50°C. Gradually raise the temperature to 65-70oC and stir the reaction mass for 30-60 min. gradually cool the reaction mixture to 25-30°C and stir for 60-90 min. Filter the product and wash the bed with ethyl acetate (250ml). Dry the product at 55-60oC to get (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride 215 gm (95%) with 98% HPLC purity.

Example 5: Preparation N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-(2R)-methylbutanoic acid ethyl ester sodium salt formula (IX) i.e. sacubitril sodium

In 10.0 lit four neck flask provided with overhead stirrer, thermometer pocket, fitted with condenser, add 400 gm of (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride in 2.8 lit MDC and 138.3 gm of succinic anhydride at 25-30oC. Cool the reaction mixture to 5-10oC and maintain for 15-20 min. Add 320 ml of triethylamine at 5-10oC. Gradually raise the temperature 25-30oC. Stir the reaction mass 2-3 hours at 25-30oC. After completion, add 1.37 liters of water and 20% aq. Citric acid (v/v) (1.2 lit.). Stired for 15-20 min. at 25-30 °C. Separate the organic layer and wash with water (1.4 lit). Collect the organic layer and distill under vacuum at 40-45°C. Thick oily mass obtained. Add 2.0 liters methanol to the obtained oily mass and add sodium acetate solution (103.91 gm in 200 ml water) at 25-30°C. Stir the reaction mixture at 25-30°C for 30-60 min. Distil the reaction mixture under vacuum at 40-45°C. To the thick oily mass add 800 ml of isopropyl acetate and stirring for 30-40 min at 40-45°C. Distil isopropyl acetate under vacuum at 40-45°C. Thick foamy solid is formed. Recrystallization is done by adding 3.60 liters of isopropyl acetate and stirring for 30-40 min at 60-65°C. Allow to cool to 30-35 °C. Stir at 30-35 °C for 8-10 hours. Filter the solid and wash with 400 ml isopropyl acetate. Compound is slightly hygroscopic. Dry in vacuum oven 35-40oC for 10 to 12 hours to get 360 gm (72%) of Sacubitril sodium with 99.5 % HPLC purity.

Example 5: Preparation N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-(2R)-methylbutanoic acid ethyl ester formula (I) i.e. sacubitril

In a 500 ml four neck flask provided with overhead stirrer, thermometer pocket, water condenser, etc, suspend 50.0 gm of sacubitril sodium salt in 150 ml water and 150 ml ethyl acetate at 25-30oC. Cool the reaction mixture to 15-20oC. Add 10% aq. Citric acid solution (15 gm citric acid in 150 ml water) at 15-20 oC and stir for 10-15 min. Separate organic layer and extract aqueous layer with 100 ml ethyl acetate. Wash combined organic layers with water (150 ml) and brine (150 ml). Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Re dissolve thick gummy oil in 50 ml ethyl acetate. Heat reaction mixture to 50- 55 °C. Add 200 ml hexanes at 50-55 °C. Stir for 30-35 min at 50-55 °C. Allow to cool reaction mixture to 30-35 °C. Add 250 ml hexanes and stir for 3-4 hours at 30-35 °C. Filter the solid and wash with 100 ml hexanes. Dry in vacuum oven at 35-40?C to get 41 gm (87%) of Sacubitril with 99.9 % HPLC purity.
,CLAIMS:We claim:
1. A process for preparation of crystalline form of sacubitril sodium comprising dissolving sacubitril sodium in a solvent system at temperature range from 30?C to 85?C to form a solution;
cooling the solution about 20?C-40?C; and
isolating crystalline form of sacubitril sodium having X- ray powder diffraction pattern with characteristic peaks at 3.5, 5.2, 6.4, 8.7, 10.5, 11.4, 12.2, 15.8, 17.4, 19.3, 20.7, 26.8, and 29.6 ± 0.2 degrees two-theta.

2. The process as claimed in claim 1, wherein solvent system is selected from ester solvent such as isopropyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl acetate, ether solvent such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, aromatic solvent such as toluene, xylenes and mixture(s) thereof.

3. The process as claimed in claim 2, wherein solvent is isopropyl acetate.

4. A crystalline form of sacubitril sodium characterized by an X- ray powder diffraction pattern with characteristic peaks at about 3.5, 5.2, 6.4, 8.7, 10.5, 11.4, 12.2, 15.8, 17.4, 19.3, 20.7, 26.8, and 29.6 ± 0.2 degrees two-theta.

5. A process for preparation of crystalline form of sacubitril comprising steps of;
a. providing a solution of sacubitril sodium salt in water and ethyl acetate;
b. adding acid to solution of step a) to get sacubitril solution;
c. adding non polar anti solvent;
d. precipitating the solid sacubitril compound of formula (I); and
e. recovering the sacubitril compound of formula (I) in crystalline form having X- ray powder diffraction pattern with characteristic peaks at 4.0,4.3, 5.4, 9.8, 12.3, 13.0, 13.8, 14.1, 16.3, 17.2, 17.8, 19.2, 20.7, 21.4, 22.5, 23.2 and 25.8 ± 0.2 degrees 2?.

6. The process as claimed in claim 5, wherein anti-solvent is selected from hexane, heptane, C5 to C10 cyclic and acyclic saturated hydrocarbons.

7. The process as claimed in claim 5, wherein solution of sacubitril sodium is obtained by dissolving sacubitril sodium salt in a solvent system selected from water, ethyl acetate or aqueous mixture thereof at temperature 20?C-40?C.

8. The process as claimed in claim 5, wherein acid is selected from citric acid, formic acid, acetic acid, phosphoric acid.

9. A process for purification of 80% :20% mixture of compound of formula (VII) is carried out in a solvent system selected from ester solvent such as isopropyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl acetate, ether solvent such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, aromatic solvent such as toluene, xylenes, alcoholic solvents such as methanol, ethanol, IPA, n-butanol, sec-butanol and mixture(s) thereof to get compound of formula (VII).

10. The process as claimed in claim 9, wherein purification is carried out at temperature 60?C-80?C in the solvent system.

Dated this 16th Day of January 2019
For UNICHEM LABORATORIES LTD.,

Gautam Bakshi
Head – IPM
IN/PA 1069