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

PROCESS FOR PREPARATION OF SACUBUTRIL INTERMEDIATE
FIELD OF INVENTION
The present application relates to a process for the preparation of sacubitril and salt thereof. Specifically, the present application relates to a process for the preparation of an intermediate of sacubitril and salt thereof, tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate (IA). Specifically, the present application relates to a process for the preparation of sacubitril and salt thereof. The application also relates to a compound of formula (III)

wherein P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999 and P2 and P3 is independently selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.
BACKGROUND
US Patent No. US5217996 A (hereinafter the US’996 patent) discloses sacubitril and its use in the treatment of cardiovascular disorders. US Patent No. US8877938 B2 (hereinafter the US’938 patent) teaches a supra-molecular complex of sacubitril and valsartan. 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).
Many patent literatures disclose processes for preparation of sacubitril and intermediates thereof e.g. US Patent Nos. US8115016B2, US8580974B2, US8703990B2, US8835668B2, US8946481B2, US9067883B2 and US9085529B2. The disclosed processes involve many steps and use of expensive raw materials which make the process commercially unviable.
US Patent Application No. US20150210632A1 (hereinafter the US’632 application) teaches a process for preparing ethyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoate involving reaction between (S)-epicholorohydrin with biphenyl bromide. However, there is a need in the art for an alternate cost-effective process for preparation of sacubitril.
SUMMARY
First aspect of the present application relates to a compound of formula (III)

wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999 and P2 and P3 is independently selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Second aspect of the present application relates to a process for preparation of compound of formula (III)

comprising the steps of:
(a) treating compound of formula (II) with a suitable hydroxy protecting group to provide a compound of formula (A)
;
and
(b) treating the compound of formula (A) with 4-biphenyl magnesium halide;
wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999 and P2 and P3 is independently selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Third aspect of the present application relates to use of compound of formula (III) for the preparation of sacubitril and salt thereof.
Fourth aspect of the present application relates to use of compound of formula (III) for the preparation of LCZ-696.

Fifth aspect of the present application relates to a compound of formula (IIIA)

wherein, P2 and P3, independently, is selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Sixth aspect of the present application relates to a process for preparation of compound of formula (IIIA)

comprising the steps of:
(a) treating compound of formula (II) with tert-butyl dimethyl silyl chloride to provide a compound of formula (B)
;
and
(b) treating the compound of formula (B) with 4-biphenyl magnesium halide;
wherein, P2 and P3, independently, is selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Seventh aspect of the present application relates to use of compound of formula (IIIA) for the preparation of sacubitril and salt thereof.
Eighth aspect of the present application relates to use of compound of formula (IIIA) for the preparation of LCZ-696.

Ninth aspect of the present application relates to a compound of formula (IIIB)

wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Tenth aspect of the present application relates to a process for preparation of compound of formula (IIIB)

comprising the steps of:
(a) treating compound of formula (IIA) with a suitable hydroxy protecting group to provide a compound of formula (C)
;
and
(b) treating the compound of formula (C) with 4-biphenyl magnesium halide.

Eleventh aspect of the present application relates to use of compound of formula (IIIB) for the preparation of sacubitril and salt thereof.
Twelfth aspect of the present application relates to use of compound of formula (IIIB) for the preparation of LCZ-696.

Thirteenth aspect of the present application relates to a compound of formula (IIIC)
.
Fourteenth aspect of the present application relates to a process for preparation of compound of formula (IIIC)

comprising the steps of:
(a) treating compound of formula (IIA) with tert-butyl dimethyl silyl chloride to provide a compound of formula (D)
;
and
(b) treating the compound of formula (D) with 4-biphenyl magnesium halide.

Fifteenth aspect of the present application relates to use of compound of formula (IIIC) for the preparation of sacubitril and salt thereof.
Sixteenth aspect of the present application relates to use of compound of formula (IIIC) for the preparation of LCZ-696.

Seventeenth aspect of the present application relates to a process for the preparation of compound of formula (I)

comprising the steps of:
(a) treating a compound of formula (II) with a suitable hydroxy protecting group to provide a compound of formula (A)
;
(b) treating the compound of formula (A) with 4-biphenyl magnesium halide to provide compound of formula (III)
;
(c) optionally, treating compound of formula (III) with a suitable reagent to provide compound of formula (IIID)
;
and
(d) reducing the compound of formula (III) or compound of formula (IIID);
wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999 and P2 and P3 is independently selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Eighteenth aspect of the present application relates to a process for the preparation of tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate (IA)

comprising the steps of:
(a) treating compound of formula (IIA) with a suitable hydroxy protecting group to provide a compound of formula (C)
;
(b) treating the compound of formula (C) with 4-biphenyl magnesium halide to provide compound of formula (IIIB)
;
(c) optionally, treating compound of formula (IIIB) with a suitable reagent to provide compound of formula (IIIE)
;

and
(d) reducing the compound of formula (IIIB) or compound of formula (IIIE);
wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Nineteenth aspect of the present application relates to a process for the preparation of sacubitril and salt thereof comprising converting compound of formula (I) or compound of formula (IA), as prepared by the process of the present application, to sacubitril and salt thereof.
Twentieth aspect of the present application relates to a process for the preparation of LCZ-696 comprising converting compound of formula (I) or compound of formula (IA), as prepared by the process of the present application, to LCZ-696.

Twenty first aspect of the present application relates to a process for preparation of compound of formula (IV)

comprising the steps of:
(a) reacting compound of formula (V) with alkyl chloroformate to provide compound of formula (VI)

OR
(a1) reacting compound of formula (V) with N-hydroxysuccinamide to provide compound of formula (VIII)

(b) reacting compound of formula (VI) or compound of formula (VIII) with sodium borohydride to provide compound of formula (VII)


(c) cyclizing compound of formula (VII),
wherein P4 is an amino protecting group, P5 is a hydroxyl protecting group and R is an C1-C6 alkyl.
DETAILED DESCRIPTION
First aspect of the present application relates to a compound of formula (III)

wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999 and P2 and P3 is independently selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Second aspect of the present application relates to a process for preparation of compound of formula (III)

comprising the steps of:
(a) treating compound of formula (II) with a suitable hydroxy protecting group to provide a compound of formula (A)
;
and
(b) treating the compound of formula (A) with 4-biphenyl magnesium halide;
wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999 and P2 and P3 is independently selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.
The suitable hydroxy protecting group of step (a) may be any protecting group known in the art. Specifically, the suitable hydroxy protecting group of step (a) may be any protecting group known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999. More specifically, the suitable hydroxy protecting group of step (a) may be a silyl group. Most specifically, the suitable hydroxy protecting group of step (a) may be tert-butyl dimethyl silyl. The compound of formula (II) may be treated with suitable hydroxyl protecting group in a solvent including but not limited to polar aprotic solvent such as dimethyl formamide, dimethyl sulfoxide and the like; alcohol solvent such as methanol, ethanol and the like; ether solvent such as tetrahydrofuran, acetone and the like; chlorinated solvent such as dichloromethane, chloroform and the like; hydrocarbon solvent such as toluene, xylene and the like and mixtures thereof. Specifically, the solvent may be a polar aprotic solvent. The compound of formula (II) may be treated with suitable hydroxyl protecting group in presence of a base such as imidazole, morpholine, triethylamine, diisopropyl ethylamine and the like. Specifically, the base may be imidazole.
The compound of formula (A) may be treated with 4-biphenyl magnesium halide to provide compound of formula (III). Specifically, the compound of formula (A) may be treated with 4-biphenyl magnesium bromide to provide compound of formula (III). The suitable solvent may include but not limited to an alcohol solvent such as methanol, ethanol and the like; ether solvent such as tetrahydrofuran, 1,4-dioxane and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; aliphatic hydrocarbon solvent such as n-hexane, cyclopentane and the like; chlorinated hydrocarbon solvent such as dichloromethane, chloroform and the like. More specifically, the solvent may be an ether solvent. More specifically, the solvent may be tetrahydrofuran. The reaction may be performed for about 15 minutes to about 3 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction may be performed for about 30 minutes to about 1 hour at about 20 °C to about 30 °C. The product, compound of formula (III), may be isolated from the reaction mass by methods known in the art.

Third aspect of the present application relates to use of compound of formula (III) for the preparation of sacubitril and salt thereof.
Fourth aspect of the present application relates to use of compound of formula (III) for the preparation of LCZ-696.

Fifth aspect of the present application relates to a compound of formula (IIIA)

wherein, P2 and P3, independently, is selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Sixth aspect of the present application relates to a process for preparation of compound of formula (IIIA)

comprising the steps of:
(a) treating compound of formula (II) with tert-butyl dimethyl silyl chloride to provide a compound of formula (B)
;
and
(b) treating the compound of formula (B) with 4-biphenyl magnesium halide;
wherein, P2 and P3, independently, is selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Seventh aspect of the present application relates to use of compound of formula (IIIA) for the preparation of sacubitril and salt thereof.
Eighth aspect of the present application relates to use of compound of formula (IIIA) for the preparation of LCZ-696.

Ninth aspect of the present application relates to a compound of formula (IIIB)

wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Tenth aspect of the present application relates to a process for preparation of compound of formula (IIIB)

comprising the steps of:
(a) treating compound of formula (IIA) with a suitable hydroxy protecting group to provide a compound of formula (C)
;
and
(b) treating the compound of formula (C) with 4-biphenyl magnesium halide.

Eleventh aspect of the present application relates to use of compound of formula (IIIB) for the preparation of sacubitril and salt thereof.
Twelfth aspect of the present application relates to use of compound of formula (IIIB) for the preparation of LCZ-696.

Thirteenth aspect of the present application relates to a compound of formula (IIIC)
.

Fourteenth aspect of the present application relates to a process for preparation of compound of formula (IIIC)

comprising the steps of:
(a) treating compound of formula (IIA) with tert-butyl dimethyl silyl chloride to provide a compound of formula (D)
;
and
(b) treating the compound of formula (D) with 4-biphenyl magnesium halide.

Fifteenth aspect of the present application relates to use of compound of formula (IIIC) for the preparation of sacubitril and salt thereof.
Sixteenth aspect of the present application relates to use of compound of formula (IIIC) for the preparation of LCZ-696.
Seventeenth aspect of the present application relates to a process for the preparation of compound of formula (I)

comprising the steps of:
(a) treating a compound of formula (II) with a suitable hydroxy protecting group to provide a compound of formula (A)
;
(b) treating the compound of formula (A) with 4-biphenyl magnesium halide to provide compound of formula (III)
;
(c) optionally, treating compound of formula (III) with a suitable reagent to provide compound of formula (IIID)
;
and
(d) reducing the compound of formula (III) or compound of formula (IIID);
wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999 and P2 and P3 is independently selected from a group of hydrogen, and any amino protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.

Reduction of compound of formula (III) or compound of formula (IIID) in step (d) to provide compound of formula (I) may be performed by catalytic hydrogenation. Specifically, reduction of compound of formula (III) or compound of formula (IIID) in step (d) to provide compound of formula (I) may be performed in presence of a heterogeneous catalyst. More specifically, reduction of compound of formula (III) or compound of formula (IIID) in step (d) to provide compound of formula (I) may be performed in presence of palladium/charcoal. Optionally, the reduction of compound of formula (III) or compound of formula (IIID) in step (d) to provide compound of formula (I) may be performed in presence of an acid. The solvent for reduction includes but not limited to an alcohol solvent such as methanol, ethanol and the like; ether solvent such as tetrahydrofuran, 1,4-dioxane and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; an ester solvent such as ethyl ester, n-butyl ester and the like. More specifically, the solvent may be an alcohol solvent. More specifically, the solvent may be methanol. The product, compound of formula (I), may be isolated from the reaction mass by a process known in the art.
One aspect of the present application relates to a compound of formula (IIIF)
,
which may be formed as an intermediate during the reduction of compound of formula (III) or compound of formula (IIID).
Another aspect of the present application relates to isolation of compound of formula (IIIF) from the reaction mixture and optional purification by a process known in the art, e.g. crystallization and then further reduction of compound of formula (IIIF) to provide compound of formula (I). Alternatively, the compound of formula (IIIF) may be directly reduced, without isolation, to provide compound of formula (I), wherein compound of formula (IIIF) may be produced as an intermediate.

Eighteenth aspect of the present application relates to a process for the preparation of tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate (IA)

comprising the steps of:
(a) treating compound of formula (IIA) with a suitable hydroxy protecting group to provide a compound of formula (C)
;
(b) treating the compound of formula (C) with 4-biphenyl magnesium halide to provide compound of formula (IIIB)
;
(c) optionally, treating compound of formula (IIIB) with a suitable reagent to provide compound of formula (IIIE)
;

and
(d) reducing the compound of formula (IIIB) or compound of formula (IIIE);
wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group as known in Greene et al., “Protective Groups in Organic Synthesis”, 3rd edition, 1999.
One aspect of the present application relates to a compound of formula (IIIG)
,
which may be formed as an intermediate during the reduction of compound of formula (IIIB) or compound of formula (IIIE).
Another aspect of the present application relates to isolation of compound of formula (IIIG) from the reaction mixture and optional purification by a process known in the art, e.g. crystallization and then further reduction of compound of formula (IIIG) to provide compound of formula (IA). Alternatively, the compound of formula (IIIG) may be directly reduced, without isolation, to provide compound of formula (IA), wherein compound of formula (IIIG) may be produced as an intermediate.

Nineteenth aspect of the present application relates to a process for the preparation of sacubitril and salt thereof comprising converting compound of formula (I) or compound of formula (IA), as prepared by the process of the present application, to sacubitril and salt thereof.
Twentieth aspect of the present application relates to a process for the preparation of LCZ-696 comprising converting compound of formula (I) or compound of formula (IA), as prepared by the process of the present application, to LCZ-696.
The compound of formula (I) or compound of formula (IA) may be converted to sacubitril and salt thereof by a process known in the art. Specifically, the compound of formula (I) or compound of formula (IA) may be converted to sacubitril by a process as known in the PCT application, WO2008/031567A1. Sacubitril and salt thereof, as produced by the process of the present application, may be converted to LCZ-696 as known in the US’938 patent.

Twenty first aspect of the present application relates to a process for preparation of compound of formula (IV)

comprising the steps of:
(a) reacting compound of formula (V) with alkyl chloroformate to provide compound of formula (VI)

OR
(a1) reacting compound of formula (V) with N-hydroxysuccinamide to provide compound of formula (VIII)

(b) reacting compound of formula (VI) or compound of formula (VIII) with sodium borohydride to provide compound of formula (VII)


(c) cyclizing compound of formula (VII),
wherein P4 is an amino protecting group, P5 is a hydroxyl protecting group and R is an C1-C6 alkyl.

One specific aspect of the present application relates to a process for the preparation of compound of formula (IVA)

comprising the steps of:
(a) reacting compound of formula (VA) with ethyl chloroformate to provide compound of formula (VIA)

OR
(a1) reacting compound of formula (VA) with N-hydroxysuccinamide to provide compound of formula (VIIIA)

(b) reacting compound of formula (VIA) or (VIIIA) with sodium borohydride to provide compound of formula (VIIA)


(c) cyclizing compound of formula (VIIA),
wherein TBS is tert-butyl dimethylsilyl and Boc is tert-butyloxycarbonyl.

Step (a) may be performed in a suitable solvent including but not limited to alcohol solvent such as methanol, ethanol and the like; ether solvent such as tetrahydrofuran, 1,4-dioxane and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; an ester solvent such as ethyl ester, n-butyl ester and the like. Specifically, the solvent may be an ether solvent. More specifically, the solvent may be tetrahydrofuran. Step (a) may be performed from about 0 °C to about boiling point of the solvent for about 15 minutes to about 5 hours. Specifically, step (a) may be performed from about 5 °C to about 10 °C for about 30 minutes to about 2 hours. The product, compound of formula (VI), may be isolated by any known methods in the art. Alternatively, the product may be carried forward to the next step as such.
Step (a1) may be performed in a suitable solvent including but not limited to ether solvent such as tetrahydrofuran, 1,4-dioxane and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; an ester solvent such as ethyl ester, n-butyl ester and the like. Specifically, the solvent may be an ester solvent. More specifically, the solvent may be ethyl acetate. Step (a1) may be performed from about 0 °C to about boiling point of the solvent for about 15 minutes to about 15 hours. Specifically, step (a1) may be performed from about 0 °C to about 40 °C for about 1 hour to about 8 hours. In one specific embodiment of step (a1), the reaction of compound of formula (V) and N-hydroxysuccinimide may be performed in presence of N,N'-dicyclohexylcarbodiimide. The product, compound of formula (VIII), may be isolated by any known methods in the art. Alternatively, the product may be carried forward to the next step as such.
Step (b) may be performed in a suitable solvent including but not limited to alcohol solvent such as methanol, ethanol and the like; ether solvent such as tetrahydrofuran, 1,4-dioxane and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; an ester solvent such as ethyl ester, n-butyl ester and the like; mixtures thereof. Specifically, step (b) may be performed in a mixture of an alcohol solvent and an ether solvent. More specifically, step (b) may be performed in a mixture of methanol and tetrahydrofuran. Alternatively, step (b) may be performed in a mixture of an ester solvent and an ether solvent. Specificallly, step (b) may be performed in a mixture of ethyl acetate and tetrahydrofuran. Step (b) may be performed from about 0 °C to about boiling point of the solvent for about 1 hour to about 25 hours. Specifically, step (b) may be performed from about 20 °C to about 50 °C for about 5 hours to about 15 hours. Alternatively, step (b) may be performed at about 0 °C to about 20 °C for about 15 minutes to about 2 hours. The product, compound of formula (VII), may be isolated by any known methods in the art. Alternatively, the product may be carried forward to the next step as such.

The cyclization of compound of formula (VII) to provide compound of formula (IV) in step (c) may be carried out by a process as known in the art. Specifically, the step (c) may be carried out by a process as known in Tetrahedron Letters, 1998, 39(51), 9389. The compound of formula (V) may be prepared by a process known in the art. Specifically, the compound of formula (V) may be prepared by a process as known in Tetrahedron Letters, 1984, 25(9), 911. The compound of formula (IV) may be converted into compound of formula (I) by a process known in the art. Specifically, the compound of formula (IVA) may be converted into compound of formula (IA) by a process known in CN105237560A.
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 N-Boc-L-Serine
To a solution of L-serine (30 g) in water (140 mL), a solution of sodium hydroxide (17.13 g) in water (80 mL) was added and the reaction mass was cooled to 0 °C. A solution of di-tert-butyl carbonate (74.6 g) in acetone (100 mL) was added drop wise to the reaction mass. After the addition was over, the reaction mass was stirred at 29 °C for about 3 hours and distilled under vacuum at 55 °C. The reaction mass was cooled to 28 °C and n-hexane (150 mL) was added to the reaction mass. The reaction mass was stirred for about 1 hour and the precipitated solid was filtered, washed with n-hexane (75 mL) and dried under vacuum at about 35-40 °C for 10 hours to provide the title compound.
Yield: 55.5 g
Example 2: Preparation of (S)-tert-butyl-(3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (IIA)
To a cold solution of N-Boc-L-Serine (30 g) in dichloromethane (600 mL), N-methyl morpholine (15.53 g) and N,O-dimethylhydroxylammonium chloride (15.69 g) were added at about 5 °C. After stirring the reaction mass for about 5 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (28.9 g) was added. The reaction mass was stirred further for 2 hours at about 10-28 °C. The reaction mass was quenched by 1M hydrochloric acid (150 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 300 mL). The combined organic layer was washed with sodium bicarbonate solution (10 %, 150 mL), distilled under vacuum to provide solid desired compound.
Yield: 28.5 g
Example 3: Preparation of tert-butyl (S)-(3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-yl)carbamate (D)
To a solution of (S)-tert-butyl-(3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (IIA) (10 g) in dimethyl formamide (80 mL), imidazole (5.48 g) was added at 0 °C and stirred for 5 minutes. Tert-butyl dimethyl silyl chloride (6.37 g) was added to the reaction mass and the reaction mass was stirred at about 0-5 °C for about 1 hour. The reaction was quenched with water (100 mL) and extracted with dichloromethane (100 mL). The combined organic layer was distilled under vacuum to provide the title compound.
Yield: 13.5 g
Example 4: Preparation of (S)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-((tert-butyldimethyl-silyl)oxy)-1-oxopropan-2-yl)carbamate (IIIC)
To a solution of magnesium turnings (1.8 g) in tetrahydrofuran (15 mL), a pinch of iodine was added and the reaction mass was heated to 40-50 °C. A solution of biphenyl bromide (17.36 g) in tetrahydrofuran (50 mL) was added drop wise keeping the temperature constant. The reaction mass was stirred for about 30 minutes and then cooled to 10-15 °C. A solution of tert-butyl (S)-(3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-yl)carbamate (D) (9 g) in tetrahydrofuran (50 mL) was added to the reaction mass drop wise. The reaction mass was quenched with ammonium chloride solution (5 g in 50 mL water) and then extracted with ethyl acetate (300 mL). The organic layer was distilled to provide the crude compound. The crude compound was purified by column chromatography over silica gel using 3% ethyl acetate in n-hexane to provide the desired compound.
Yield: 1 g
Example 5: Preparation of tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate (IA)
To a solution of (S)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-((tert-butyldimethyl-silyl)oxy)-1-oxopropan-2-yl)carbamate (IIIC) (1 g) in methanol (30 mL), sulfuric acid (0.2 g) and palladium/charcoal (100 mg) was added. The reaction mass was maintained under hydrogen atmosphere (7 atm pressure) at 40 °C for 4 hours. The reaction mass was filtered through celite and the celite bed was washed with methanol (6 mL). The organic layer was distilled under vacuum to provide the crude compound. The crude compound was purified by column chromatography using 20% ethyl acetate in n-hexane to provide the title compound.
Yield: 0.3 g
Example 6: Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)-oxy)propanoic propionic anhydride (VIA)
A cold solution of N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-serine (10 g) in tetrahydrofuran (100 mL), triethylamine (3.8 g) was added at about 9-10 °C. Ethyl chloroformate (3.74 g) was added slowly to the reaction mass keeping the temperature constant. The reaction mass was stirred for about 90 minutes at about 5-10 °C. The precipitated solid was filtered and the filtrate containing the desired compound has been used directly in the next step.
Example 7: Preparation of tert-butyl (R)-(1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate (VIIA)
Sodium borohydride (1.18 g) was added to the filtrate of Example 6 slowly and the reaction mass was allowed to heat up to 40-45 °C. Methanol (10 mL) was added to the reaction mass. The reaction mass was stirred for about 15 hours and then quenched by the addition of ammonium chloride solution (2 g in 20 mL water). The reaction mass was extracted with ethyl acetate (150 mL), the organic layer was washed with brine (40 mL) and dried over sodium sulfate. The organic layer was distilled under vacuum to provide crude desired compound, which was purified by column chromatography over silica gel using 20% ethyl actetate/n-hexane as eluant.
Yield: 3.3 g
Example 8: Preparation of tert-butyl (R)-2-(((tert-butyldimethylsilyl)oxy)-methyl)aziridine-1-carboxylate (IVA)
In a solution of triphenyl phosphine (6.44 g) in tetrahydrofuran (20 mL) and acetonitrile (2 mL), diidopropyl azodicarboxylate (4.96 g) was added at about 5 °C. The reaction mass was stirred for about 45 minutes and a solution of tert-butyl (R)-(1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate (VIIA) (5 g) in tetrahydrofuran (5 mL) was added to the reaction mass. The reaction mass was stirred for 15 hours and then the organic solvent was concentrated under vacuum. The crude product was purified by column chromatography over silica gel using 10% ethyl actetate/n-hexane as eluant.
Yield: 2.5 g
Example 9: Preparation of tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate (IA)
To a cold mixture of copper (I) iodide (49.7 mg) in tetrahydrofuran (20 mL), biphenyl magnesium bromide (672 mg) was added at about 5 °C. A solution of tert-butyl (R)-2-(((tert-butyldimethylsilyl)oxy)-methyl)aziridine-1-carboxylate (IVA) (500 mg) in tetrahydrofuran (5 mL) was also added to the reaction mass. The reaction mass was stirred for 3 hours and then the reaction was quenched by the addition of aqueous solution of ammonium chloride (1 g in 10 mL water). The reaction mass was extracted with ethyl acetate (50 mL) and concentrated under vacuum to provide the crude compound, which was purified by column chromatography over silica gel using 5% ethyl actetate/n-hexane as eluant.
Yield: 0.6 g
Example 10: Preparation of 2,5-dioxopyrrolidin-1-yl N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-serinate (VIIIA)
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-propanoic acid (20 g) in ethyl acetate (100 mL), N-hydroxy succinamide (7.93 g) was added at about 0 °C, followed by addition of a solution of N,N'-dicyclohexylcarbodiimide (13.56 g) in ethyl acetate (60 mL). The reaction mass was allowed to warm up to 28 °C and stirred for about 6 hours. The precipitated solid was filtered and washed with ethyl acetate (60 mL). The filtrate was washed with an aqueous solution of sodium bicarbonate (10 %) and further by brine solution. Organic layer was evaporated under vacuum to provide the crude title compound.
Example 11: Preparation of tert-butyl (R)-(1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate (VIIA)
A solution of tetrahydrofuran and water was cooled to 0 °C and sodium borohydride (2.36 g) was added. The crude compound obtained from Example 10, was dissolved in ethyl acetate and the solution was added to sodium borohydride containing reaction mass keeping the temperature constant. The reaction mass was stirred for about 1 hour at 0-15 °C and quenched by the addition of an aqueous solution of ammonium chloride. The organic layer was separated and washed with water. The crude desired compound was obtained by vacuum distillation of the organic layer, which was purified by column chromatography over silica gel using ethyl acetate/n-hexane as eluant.
Yield: 7 g
,CLAIMS:WE CLAIM:
1. A process for preparation of compound of formula (IV)

comprising the steps of:
(a) reacting compound of formula (V) with alkyl chloroformate to provide compound of formula (VI)

OR
(a1) reacting compound of formula (V) with N-hydroxysuccinamide to provide compound of formula (VIII)

(b) reacting compound of formula (VI) or compound of formula (VIII) with sodium borohydride to provide compound of formula (VII)


(c) cyclizing compound of formula (VII),
wherein P4 is an amino protecting group, P5 is a hydroxyl protecting group and R is an C1-C6 alkyl.
2. The process of claim 1, wherein P4 is Boc and P5 is TBS.
3. The process of claim 2, further comprising converting compound of formula (IV) to tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate (IA).
4. The process of claim 1, wherein alkyl chloroformate is ethyl chloroformate.
5. The process of claim 1, wherein step (a1) is performed in presence of N,N'-dicyclohexylcarbodiimide.
6. A compound of formula (III)

wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group and P2 and P3 is independently selected from a group of hydrogen, and any amino protecting group.
7. The compound of claim 6, wherein P1 is selected from a group of hydrogen, and any hydroxy protecting group and P2 is hydrogen and P3 is Boc.
8. A process for the preparation of compound of formula (I)

comprising the steps of:
(a) treating a compound of formula (II) with a suitable hydroxy protecting group to provide a compound of formula (A)
;
(b) treating the compound of formula (A) with 4-biphenyl magnesium halide to provide compound of formula (III)
;
(c) optionally, treating compound of formula (III) with a suitable reagent to provide compound of formula (IIID)
;
and
(d) reducing the compound of formula (III) or compound of formula (IIID);
wherein, P1 is selected from a group of hydrogen, and any hydroxy protecting group and P2 and P3 is independently selected from a group of hydrogen, and any amino protecting group.
9. The process of claim 8, wherein P1 is tert-butyl dimthylsilyl, P2 is hydrogen and P3 is Boc.
10. The process of claim 8, further comprising conversion of compound of formula (I) to sacubitril or salt thereof.