DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
INTRODUCTION
Aspects of the present application relates to intermediates of evocalcet, processes for the preparation of intermediates of evocalcet and processes for the preparation of evocalcet.
Evocalcet is useful for the treatment of hyperparathyroidism. The chemical name of evocalcet is 2-{4-[(3S)-3-{[(1R)-1-(Naphthalen-1-yl)ethyl]amino} pyrrolidin-1-yl] phenyl} acetic acid, the structural formula is shown below.

US8362274B2 describes evocalcet and its pharmaceutical composition. US9643920B2 describes two crystalline forms of evocalcet (Form A and Form B) and process for the preparation thereof.
The prior art process for the preparation of evocalcet have major drawbacks such as slow reaction rate for the 2-nitrobenzenesulfonate ester formation step; the need to employ toxic, extremely hygroscopic and difficult to store trimethylamine hydrochloride, late stage palladium mediated buchwald coupling, and difficulties with respect to removal of process related metal impurities. Therefore, there remains a need for additional processes for the preparation of evocalcet in an environmentally-friendly, cost-effective, and industrially applicable manner.
SUMMARY OF THE INVENTION
In an aspect, the present application provides compound of formula (IG), formula (II) and formula (III)

wherein R1, R2 and R3 is alkyl, aryl or arylalkyl group.
wherein P is , ,
In an aspect, the present application provides a process for the preparation of compound of formula (IG), which comprises reacting a compound of formula (IAG)

wherein R1, R2 and R3 is alkyl, aryl or arylalkyl group.
with a compound of formula (IB)

to provide the compound of formula (IG).
In an aspect, the present application provides a process for the preparation of compound of formula (I),

which comprises reacting a compound of formula (IA)

with a compound of formula (IB)

to provide the compound of formula (I).

In an aspect, the present application provides a process for the preparation of compound of formula (II), which comprises reacting a compound of formula (IG) with appropriate fluoride reagent, such as a tetra-n-butylammonium fluoride (TBAF) to provide the compound of formula (II).
In an aspect, the present application provides a process for the preparation of compound of formula (II), which comprises reacting a compound of formula (I) with a tetra-n-butylammonium fluoride (TBAF) to provide the compound of formula (II).
In an aspect, the present application provides process for the preparation of compound of formula (III), which comprises reacting a compound of formula (II) with methanesulfonyl chloride (mesyl chloride), p-toluenesulfonyl chloride (tosyl chloride) or 4-nitrobenzenesulfonyl chloride to provide the compound of formula (III).

In an aspect, the present application provides a process for the preparation of compound of formula (IV),

which comprises reacting a compound of formula (III) with a compound of formula (IVA) to provide the compound of formula (IV).

In an aspect, the present application provides a process for the preparation of compound of formula (IV), which comprises reacting a compound of formula (F)

with a compound of formula (IB) to provide the compound of formula (IV).

In an aspect, the present application provides a process for the preparation of compound of formula (E),

which comprises reacting a compound of formula (C) with a compound of formula (IVA) to provide the compound of formula (E)

In an aspect, the present application provides a process for the preparation of compound of formula (C),

wherein PG is Boc, Cbz and Fmoc.
which comprises reacting a compound of formula (A) with a compound of formula (B) to provide the compound of formula (C)

In an aspect, the present application provides a process for the preparation of evocalcet comprising the steps of:
(a) reacting a compound of formula (A)

wherein PG is Boc, Cbz and Fmoc.
with a compound of formula (B)

to provide the compound of formula (C);

(b) reacting a compound of formula (C) with a compound of formula (IVA)

to provide the compound of formula (E);

(c) reacting a compound of formula (E) with deprotecting reagent to provide the compound of formula (F);

(d) reacting a compound of formula (F) with a compound of formula (IB)

to provide the compound of formula (IV);

(e) reacting a compound of formula (IV) with acid to provide evocalcet.
In an aspect, the present application provides a process for the preparation of evocalcet comprising the steps of:
(a) reacting a compound of formula (A) with suitable silyl chloride in the presence of imidazole to provide the compound of formula (AAG);

wherein PG is Boc, Cbz and Fmoc.
wherein R1, R2 and R3 is alkyl, aryl or arylalkyl group.
(b) reacting a compound of formula (AAG) with a trifluoroacetic acid (TFA) to provide the compound of formula (IAG);
(c) reacting a compound of formula (IAG) with a compound of formula (IB) to provide the compound of formula (IG);
(d) reacting a compound of formula (IG) with appropriate fluoride reagent, such as a tetra-n-butylammonium fluoride (TBAF) to provide the compound of formula (II);
(e) reacting a compound of formula (II) with a compound of formula (B) to provide the compound of formula (IIIA);

(f) reacting a compound of formula (IIIA) with a compound of formula (IVA) to provide the compound of formula (IV);
(g) reacting a compound of formula (IV) with acid to provide evocalcet.
In an aspect, the present application provides a process for the preparation of evocalcet comprises:
(a) reacting a compound of formula (A) with a tert-butyldimethylsilyl chloride (TBSCl) in the presence of imidazole to provide the compound of formula (AA);
(b) reacting a compound of formula (AA) with a trifluoroacetic acid (TFA) to provide the compound of formula (IA);
(c) reacting a compound of formula (IA) with a compound of formula (IB) to provide the compound of formula (I);
(d) reacting a compound of formula (I) with tetra-n-butylammonium fluoride (TBAF) to provide the compound of formula (II);
(e) reacting a compound of formula (II) with a compound of formula (B) to provide the compound of formula (IIIA);
(f) reacting a compound of formula (IIIA) with a compound of formula (IVA) to provide the compound of formula (IV);
(g) reacting a compound of formula (IV) with acid to provide evocalcet.

DETAILED DESCRIPTION OF THE INVENTION

In an aspect, the present application provides compound of formula (IG), formula (II) and formula (III)

wherein R1, R2 and R3 is alkyl, aryl or arylalkyl group.
wherein P is , ,
In an aspect, the present application provides a process for the preparation of compound of formula (IV),

which comprises reacting a compound of formula (F)

with a compound of formula (IB)

to provide the compound of formula (IV).
In one embodiment, compound of formula (F) can be converted into its free base prior to its reaction with compound of formula (IB). Free base formation of compound of formula (F) can be performed in presence of a suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, alkoxides, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, lithium carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide, magnesium oxide, or the like; and organic bases such as, primary, secondary, or tertiary amines, such as ammonia, aqueous ammonia, triethylamine, diisopropylethylamine, N-methylmorpholine.
In another embodiment, free base formation can be carried out in a suitable solvent that is not limited to: halogenated hydrocarbon, C1-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
In another embodiment, the preparation of compound of formula (IV) can be performed in presence of suitable reagent that are known in the art. Specifically, the suitable reagents refer to palladium (II) acetate [Pd(OAc)2], Cesium carbonate (Cs2CO3) and XPhos.

In another embodiment, the preparation of compound of formula (IV) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; C1-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
In another embodiment, the preparation of compound of formula (IV) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula (IV) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
In an aspect, the present application provides a process for the preparation of compound of formula (E),

wherein PG is Boc, Cbz and Fmoc.
which comprises reacting a compound of formula (C)

with a compound of formula (IVA)

to provide the compound of formula (E)
In one embodiment, the preparation of compound of formula (E) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula (E) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
In an aspect, the present application provides a process for the preparation of compound of formula (C),

wherein PG is Boc, Cbz and Fmoc.
which comprises reacting a compound of formula (A)

with a compound of formula (B) in presence of base

to provide the compound of formula (C)
In one embodiment, the preparation of compound of formula (C) can be performed in presence of suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, carboxylates, e.g., potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, lithium carbonate, lithium acetate, or the like; and organic bases such as, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine.
In another embodiment, the preparation of compound of formula (C) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; C3-6 ketones; C2-6 ethers; polar aprotic solvents; or any mixtures thereof.
In another embodiment, the preparation of compound of formula (C) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula (C) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
In an aspect, the present application provides a process for the preparation of evocalcet comprising the steps of:
(a) reacting a compound of formula (A)

wherein PG is Boc, Cbz and Fmoc.
with a compound of formula (B)

to provide the compound of formula (C);

(b) reacting a compound of formula (C) with a compound of formula (IVA)

to provide the compound of formula (E);

(c) reacting a compound of formula (E) with acetyl chloride to provide the compound of formula (F);

(d) reacting a compound of formula (F) with a compound of formula (IB)

to provide the compound of formula (IV);

(e) reacting a compound of formula (IV) with acid to provide evocalcet.
In one embodiment, the step a) can be performed in presence of suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, carboxylates e.g., potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, lithium carbonate, lithium acetate, or the like; and organic bases such as, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine.
In another embodiment, the preparation of compound of formula (C) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; C3-6 ketones; C2-6 ethers; polar aprotic solvents; or any mixtures thereof.
In another embodiment, the step a) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula (C) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
In another embodiment, the step b) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula E) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
In another embodiment, the step c) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; C1-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
In another embodiment, the step c) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula F) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent. In embodiments, solvent as described above may be added and stirred for sufficient time after evaporation before isolation of the product.
In another embodiment, compound of formula F) can be converted into its free base. Free base formation of compound of formula F) can be performed in presence of a suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, alkoxides, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, lithium carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide, magnesium oxide, or the like; and organic bases such as, primary, secondary, or tertiary amines, such as ammonia, aqueous ammonia, triethylamine, diisopropylethylamine, N-methylmorpholine.
In another embodiment, free base formation of compound of formula F) can be carried out in a suitable solvent that is not limited to: halogenated hydrocarbon, C1-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
In another embodiment, the step d) can be performed in presence of suitable reagents that are known in the art. Specifically, the suitable reagents refer to palladium (II) acetate [Pd(OAc)2], Cesium carbonate (Cs2CO3) and XPhos.
In another embodiment, the step d) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; C1-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
In another embodiment, the step d) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula (IV) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent. In embodiments, solvent as described above may be added and stirred for sufficient time after evaporation before isolation of the product.
In another embodiment, the step e) can be performed in presence of suitable acid that is not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like.
In another embodiment, the step e) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; C1-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
In another embodiment, the step e) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment of step e), the purification of the evocalcet can be carried out in a suitable solvent to produce purified compound. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Solvents that are useful in the reaction include, but are not limited to: C1-6 alcohols; C3-6 ketones; C2-6 ethers; C3-6 esters; C2-6 nitriles; halogenated hydrocarbons; aliphatic or aromatic hydrocarbons; aprotic polar solvents; any mixtures of two or more thereof; or their combinations with water in various proportions. Examples of such solvents include ethers, such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, dioxane, or dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketones, such as acetone or methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone; esters, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate or butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; alcohols such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, ethylene glycol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin; nitriles, such as acetonitrile, propionitrile; polar aprotic solvents, such as for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide; nitromethane; water or mixtures thereof.
In another embodiment of step e), the purification of product can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment of step e), evocalcet can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
In another embodiment, the present application provides chemical purity of evocalcet may be more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
In another embodiment, the present application provides particle size (D90) of evocalcet may be less than 100 microns or less than 50 microns or less than 20 microns.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
DEFINITIONS
The following definitions are used in connection with the compounds of the present invention unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
The term "reacting" is intended to represent bringing the chemical reactants together under conditions such to cause the chemical reaction indicated to take place.
An “aliphatic or aromatic hydrocarbon” is a liquid hydrocarbon, which may be linear, branched, or cyclic and may be saturated, unsaturated, or aromatic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of “C5-C8 aliphatic or aromatic hydrocarbons”, include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or mixtures thereof.
“Alcohols” are organic solvents containing a carbon bound to a hydroxyl group. “C1-C6 Alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
A “ketone” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-6 Ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
An “ether” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “C2-6 Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbons” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

Examples
Example-1: Preparation of tert-butyl (S)-3-(((R)-1-(naphthalen-1-yl)ethyl)amino)pyrrolidine-1-carboxylate.
Compound of Formula A1 (500 mg) and dichloromethane (5 mL) were charged into a reactor at 25°C. Triethylamine (0.81 g) was added to the reaction mixture at 25°C. 4-nitrobenzenesulfonyl chloride (Compound of Formula B1, 0.71 mg) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 2 hours. The reaction mixture was added to ice-cold aq. NaHCO3 solution (10 mL) and extracted with MTBE (15 mL X 4). The MTBE extracts was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the compound of Formula C1.
Compound of Formula C1 (1 g) and (R)-1-(naphthalen-1-yl)ethan-1-amine (Compound of Formula Iva, 1.6 g) were charged into a reactor at 25 °C. The reaction mixture was heated to 90°C and stirred for 16 hrs. After completion of the reaction, the obtained product was purified by column chromatography using 15-20% EtOAc-hexane. The fractions, containing the desired product, were concentrated under reduced pressure to obtain the title compound as colorless gummy liquid. Yield: 68.9%; Purity by chiral HPLC: 98.1%
Example-2: Preparation of (S)-N-((R)-1-(naphthalen-1-yl)ethyl)pyrrolidin-3-amine•dihydrochloride•mono isopropyl alcohol solvate
Isopropyl alcohol (1.7 L) was charged into a reactor at 25oC. Acetyl chloride (319.1 g) was added to isopropyl alcohol at 5oC and stirred for 30 minutes. A solution of compound of Formula E1 (213 g), dissolved in isopropyl alcohol (1 L), was added to the reaction mixture at 5oC. The reaction mixture was heated to 60 oC and stirred for 2 hrs. The reaction mixture was cooled to 10oC and stirred for 30 minutes. The reaction mixture was filtered and washed with isopropyl alcohol (639 mL). The resultant solid was dried under reduced pressure at 45oC for 30 minutes to obtain the title compound. Yield: 87.19%; HPLC purity: 99.77%
Example-3: Preparation of tert-butyl 2-(4-((S)-3-(((R)-1-(naphthalen-1-yl)ethyl) amino)pyrrolidin-1-yl)phenyl)acetate.
Compound of Formula F (203 g) and water (609 mL) were charged into a reactor at 25 oC. 10% aqueous sodium hydroxide solution (1.21 L) was slowly added to the reaction mixture at 10 oC. The reaction mixture was stirred at 10 oC for 10 minutes, and then extracted with toluene (1 L X 3). The toluene extracts were combined, washed with water and brine, and finally dried over anhydrous sodium sulfate. The organic layer was concentrated at 45oC under reduced pressure to obtain the free base of compound of Formula F. The free base and toluene (2.03 L) were charged into a reactor at 25°C under nitrogen atmosphere. Cesium carbonate (531.4 g), Compound of Formula 1B (162.17 g) and water (0.87 mL) were added to the reaction mixture at 25oC. The reaction mixture was de-gassed with nitrogen under stirring for 30 minutes at 25oC. Xphos (5.18 g) and palladium(II) acetate (2.43 g) were added to the reaction mixture at 25oC under nitrogen atmosphere. The reaction mixture was heated to 95oC and stirred for 22 hrs under nitrogen atmosphere. Water (2.03 L) was added to the reaction mixture at 25 oC and stirred for 10 minutes. The organic layer was separated from the aqueous layer which was then extracted with toluene (1 L X 2). The separated organic layers were combined, washed sequentially with 10% thiourea solution (1 L X 2), water (1 L X 2) and brine (1 L), and finally dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure at 45oC to obtain a brown colored syrup (HPLC purity: 90.86%).
The crude material was purified by column chromatography using 15% EtOAc-hexane. The fractions, containing the desired product, were concentrated at 40 oC under reduced pressure to obtain the title compound as a light brown colored syrup. Yield: 83.5%; HPLC purity: 95.39%
Example-4: Preparation of evocalcet
Compound of Formula IV (195 g) and dichloromethane (975 mL) were charged into a reactor at 25 oC. A 4M solution of HCl in dioxane (975 mL) was slowly added to the reaction mixture at 10oC. The reaction mixture was warmed to 25oC and stirred for 24 hrs. The reaction mixture was concentrated under reduced pressure at 45oC. Water (975 mL) and 10% aq. NaOH solution (585 mL) were added to the residue at 25°C. The resultant mixture was washed with ethyl acetate (975 mL X 2). The aqueous layer was charged into a reactor at 25oC. 10% citric acid solution (195 mL) was slowly added to the reaction mixture at 15oC and stirred for 1 hr. The reaction mixture was filtered and washed with water (975 mL) and ethanol (975 mL). The obtained crude solid was dried in a hot-air oven at 45oC for 22 hrs. Yield: 79.6%; HPLC purity: 96.40%; Purity by chiral HPLC: 98.4%
The crude solid (135 g) and dimethylacetamide (675 mL) were charged into a reactor at 25oC. The reaction mixture was heated to 65oC and stirred for 45 minutes. Ethanol (2 L) was slowly added to the reaction mixture at 65oC over 2 hrs. The reaction mixture was cooled to 10oC and stirred for 45 minutes. The resultant suspension was filtered and washed with ethanol (675 mL). The obtained solid was dried at 48oC under vacuum for 3 hrs. to obtain the title compound as an off-white solid. Yield: 69.0%; HPLC purity: 99.40%; Purity by chiral HPLC: 99.7%
Example-5: Preparation of tert-butyl (R)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate (AA1)
Compound of Formula A1 (20 g), imidazole (18.17 g) and dichloromethane (150 mL) were charged into a reactor at 25oC under nitrogen atmosphere. A solution of tert-butyldimethylsilyl chloride (TBSCl, 16.1 g), dissolved in 50 mL of dichloromethane, was added to the reaction mixture at 0 °C over 30 minutes. The reaction mixture was heated to 25 oC and stirred for 16 hrs. Water (200 mL) was added to the reaction mixture at 25 oC. The organic layer was separated from aqueous layer, which was then extracted with DCM (40 mL X 4). The separated organic layers were combined, washed sequentially with water (150 mL) and brine (150 mL), and finally dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography using 10-15% EtOAc-hexane. The fractions, containing the product, were concentrated under reduced pressure to obtain the title compound as a pale yellow oil. Yield: 90%
Example-6: Preparation of (R)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (IA)
Compound of Formula AA1 (10 g) and dichloromethane (60 mL) were charged into a reactor at 25 oC under nitrogen atmosphere. Trifluoroacetic acid (TFA) (28.5 mL) was added to the reaction mixture at 0°C over 30 minutes. The reaction mixture was stirred at 0 °C for 2 hrs. The pH of the reaction mixture was adjusted to ~8 using aq. NaHCO3 at 0 °C. The volatiles were removed from the reaction mixture by concentration under reduced pressure. The remaining mixture was extracted with ethyl acetate (200 mL X 3). The ethyl acetate extracts were combined, washed with and brine (100 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure to obtain the title compound as a light brown oil, which was taken forward to the next step without any further purification. Yield: 6.70 g.
Example-7: Preparation of tert-butyl (R)-2-(4-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)phenyl)acetate.
Compound of Formula IA (6.7 g), tert-butyl 2-(4-bromophenyl)acetate (Compound of Formula IB, 9.02 g), cesium carbonate (43.3 g) and toluene (70 mL) were charged into a reactor at 25oC and under nitrogen atmosphere. The reaction mixture was de-gassed at 25oC with argon for 10 minutes. Pd(OAc)2 (0.372 g) and Xphos (0.762 g) were added to the reaction mixture at 25oC. The reaction mixture was de-gassed again with argon for 10 minutes and then heated to 95 oC and stirred for 20 hrs. The reaction mixture was cooled to 25oC and filtered through a pad of celite. The celite pad was washed with MTBE (200 mL). The filtrate and washings were concentrated under reduced pressure to obtain the title compound as a brown oil, which was taken forward to the next step without any further purification. Yield: 13.0 g
Example-8: Preparation of tert-butyl (R)-2-(4-(3-hydroxypyrrolidin-1-yl)phenyl) acetate.
Compound of Formula I (13.0 g) and THF (100 mL) were charged into a reactor at 25oC under nitrogen atmosphere. Tetrabutylammonium fluoride (TBAF, 50 mL) was added to the reaction mixture at 0oC over 20 minutes under nitrogen atmosphere. The reaction mixture was warmed to 25 °C and stirred for 2 hrs. Aqueous NH4Cl solution (100 mL) was added to the reaction mixture at 0oC. The organic layer was separated from the aqueous layer, which was then extracted with ethyl acetate (75 mL X 3). The separated organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure to obtain a brown residue. The obtained residue was dissolved in 1:1 hexane-MTBE (500 mL). The obtained solution was washed with water (300 mL X 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product as a brown residue. The obtained crude product was purified by column chromatography using 15-20% EtOAc-hexane. The fractions, containing the product, was concentrated under reduced pressure to obtain the title compound as a pale brown solid. Yield: 5.3 g (57.6% over 3 steps, i.e. from Compound of Formula AA)
Example-9: Preparation of tert-butyl 2-(4-((S)-3-(((R)-1-(naphthalen-1-yl)ethyl) amino)pyrrolidin-1-yl)phenyl)acetate.
Compound of Formula II (500 mg) and dichloromethane (5 mL) were charged into a reactor at 25oC under nitrogen atmosphere. Triethylamine (0.92 mL) was added to the reaction mixture at 25°C. 4-nitrobenzenesulfonyl chloride (Compound of Formula B, 600 mg) added to the reaction mixture at 0 °C. The reaction mixture was warmed to 25°C and stirred for 2 hrs. The reaction mixture was added to ice-cold 1.0% aqueous NaHCO3 solution (50 mL) and the resulting mixture was extracted with MTBE (20 mL X 2). The MTBE extracts were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure to obtain a brown oil.
Compound IIIA (850 mg) and (R)-1-(naphthalen-1-yl)ethanamine (1.0 mL) were charged into a reactor at 25 oC under nitrogen atmosphere. The reaction mixture was heated to 95 oC and stirred for 16 hrs. The reaction mixture was purified by column chromatography using 15-20% EtOAc-hexane. The fractions, containing the product, were concentrated under reduced pressure to obtain the title compound as a pale brown oil. Yield: 470 mg.
Example-10: Preparation of evocalcet
Compound of Formula IV (100 mg), obtained in Example-9, and dichloromethane (0.5 mL) were charged into a reactor at 25oC under nitrogen atmosphere. A 4M HCl solution in 1,4-dioxane (0.5 mL) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to 25°C and stirred for 6 hrs. The reaction mixture was concentrated under reduced pressure. Toluene (2 mL) was added to the obtained residue and the mixture concentrated under reduced pressure. The preceding operation was repeated twice. The obtained solid was washed twice with 1:1 hexane-MTBE (2 mL), and dissolved in water (2.0 mL) and 10% aqueous NaOH (3.0 mL). The solution obtained was washed with ethyl acetate (2 mL X 2). 10% aqueous citric acid solution (1.0 mL) was added to the reaction mixture at 0oC. The resultant suspension was filtered and the solid obtained dried under reduced pressure to obtain the title compound. Yield: 65 mg; HPLC purity: 97.82%; Purity by chiral HPLC: 96.5%
Example-11: Preparation of tert-butyl 2-(4-((S)-3-(((R)-1-(naphthalen-1-yl)ethyl)amino)pyrrolidin-1-yl)phenyl)acetate.
Compound of Formula II (500 mg) and dichloromethane (5 mL) were charged into a reactor at 25 oC under nitrogen atmosphere. Triethylamine (0.76 mL) was added to the reaction mixture at 0 °C. A solution of methanesulfonyl chloride (310 mg) in dichloromethane (2.5 mL) was added to the reaction mixture at 0 °C over 5 minutes. The reaction mixture was warmed to 25 °C and stirred for 2 hrs. The reaction mixture was added to ice-cold 1.0% aqueous NaHCO3 solution (50 mL) and the resulting mixture was extracted with MTBE (20 mL X 2). The MTBE extracts were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure to obtain the compound of formula IIIB as a brown oil.
Compound of Formula IIIB (680 mg) and (R)-1-(naphthalen-1-yl)ethanamine (1.0 mL) were charged into a reactor at 25 oC under nitrogen atmosphere. The reaction mixture was heated to 95 oC and stirred for 16 hrs. The reaction mixture was purified by column chromatography using 15-20% EtOAc-hexane. The fractions, containing the product, was concentrated under reduced pressure to obtain the title compound as a pale yellow oil. Yield: 527 mg
Example-12: Preparation of evocalcet.
Compound of Formula IV (100 mg), obtained by Example-11, and dichloromethane (0.5 mL) were charged into a reactor at 25oC under nitrogen atmosphere. 4M HCl solution in 1,4-dioxane (0.5 mL) was added the reaction mixture at 0 °C. The reaction mixture was warmed to 25°C and stirred for 6 hrs. The reaction mixture was concentrated under reduced pressure. Toluene (2 mL) was added to the obtained residue and the mixture concentrated under reduced pressure. The preceding operation was repeated twice. The obtained solid was washed twice with 1:1 hexane-MTBE (2 mL) and then dissolved in water (2.0 mL) and 10% aqueous NaOH (2.0 mL The solution obtained was washed with ethyl acetate (2 mL X 2). 10% aqueous citric acid solution (1.0 mL) was added to the mixture at 0oC. The resultant suspension was filtered and the solid obtained dried under reduced pressure for 16 hrs. to obtain the title compound. Yield: 68 mg; Purity by chiral HPLC: 94.5%.

,CLAIMS:We claim
1. A process for the preparation of evocalcet comprising the steps of:
(a) reacting a compound of formula (A) with a compound of formula (B) to provide the compound of formula (C);
, ,
wherein PG is Boc, Cbz and Fmoc.
(b) reacting a compound of formula (C) with a compound of formula (IVA) to provide the compound of formula (E);
,
(c) reacting a compound of formula (E) with deprotecting reagent to provide the compound of formula (F);

(d) reacting a compound of formula (F) with a compound of formula (IB) to provide the compound of formula (IV);
,
(e) reacting a compound of formula (IV) with acid to provide evocalcet.
2. The process of claim 1, wherein the deprotecting reagent is selected from acid, base (or) Pd-C/H2.
3. A process for the preparation of compound of formula (IV),

which comprises reacting a compound of formula (F) with a compound of formula (IB) to provide the compound of formula (IV).
,
4. A process for the preparation of compound of formula (E),

which comprises reacting a compound of formula (C) with a compound of formula (IVA) to provide the compound of formula (E)
,
5. A process for the preparation of compound of formula (C),

wherein PG is Boc, Cbz and Fmoc.
which comprises reacting a compound of formula (A) with a compound of formula (B) in presence of base to provide the compound of formula (C)

,
6. A process for the preparation of compound of formula (IV),

which comprises reacting a compound of formula (III) with a compound of formula (IVA)
to provide the compound of formula (IV).
,
wherein P is , ,
7. A compound of formula (IG), formula (II) and formula (III)

wherein R1, R2 and R3 is alkyl, aryl or arylalkyl group.
wherein P is , ,
8. A process for the preparation of compound of formula (III),

wherein P is , ,
which comprises reacting a compound of formula (II) with sulfonyl chloride.

9. The process of claim 8, wherein the sulfonyl chloride is selected from methanesulfonyl chloride (mesyl chloride), p-toluenesulfonyl chloride (tosyl chloride) or 4-nitrobenzenesulfonyl chloride.