GLYCINE TERT-BUTYL ESTER AND ITS SALT THEREOF”

RELATED APPLICATION

This application claims the benefit to Indian Provisional Application No. IN202121017102, filed on April 11, 2021, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a scalable and efficient process for the preparation of substantially pureGlycine tert-butyl ester.The invention further relates to preparation of substantially pureGlycine tert-butyl esterand its salt of formula (I) using commercially available metal phthalimide in presence of inorganic base and solvent.

BACKGROUND OF THE INVENTION

Glycine tert-butyl ester[CAS No. 6456-74-2] is an important raw material in peptide synthesis.lt is also used widely in the preparation of various intermediates and APIs. For example, Glycine tert-butyl ester is used for a synthesis of Rosuvastatin tert-butyl glycinate salt to manufacture Rosuvastatin calcium and in preparation of (R)-2-benzyloxy carbonylamino-2-phenyl-acetic acid tert-butyl ester to prepare Elobixibat. It is essential to remove any impurities during preparation of Glycine tert-butyl ester to avoid further creation of additional impurities, or cascading impurities which may be difficult to remove in final APIs. Thus, preparationof substantially pureGlycine tert-butyl ester and its salts is extremely important.

Several publications such as CN 104263795; CN 103214383; KR 2012108225; e-EROS Encyclopedia of Reagents for Organic Synthesis, 2001, 1-2; Organic & Biomolecular Chemistry, 10 (30) 5787-5790; Bioorganic & Medicinal Chemistry, 22 (14) 4854-4858; Tetrahedron Letters, 53 (6), 641-645, 2012;Jr. Justus Liebigs Annalen der Chemise, Vol 660, 54-59, 1962, and the like disclosed the preparation of Glycine tert-butyl ester. The known processes however, have one or the other disadvantages, for example:(i) use of toxicor expensive reagents such as pyridine, phosphorus oxychloride, perchloro acid, sulfuric acid, sodium azide, phenyl hydrazine; (ii) use of expensive catalysts such as triethyl benzyl ammonium chloride, hexadecyltributyl phosphonium bromide; (iii) more number of step; (iv) tedious and troublesome operations such as higher reaction temperature, extraction; distillation, purification; (v) low chemical purity. Thus, these processes are not an industrially scalable.

To overcome the limitations of the prior processes known in the art, the inventors of the present invention have developed a robust, cost-effective, and scalable process for preparation of substantially pureGlycine tert-butyl ester and its salt with purity more than96%.

SUMMARY OF THE INVENTION

In one aspect, the invention provides an improved process of substantially pureGlycine tert- butyl ester and its saltof formula (I)where X is Cl, Br, I

In another aspect, the present invention provides a cost-effective process by avoiding toxic, expensive reagents, catalysts, multiple operations(s) in an environment friendly and industrially scalable manner.

In another aspect, the present invention provides a process for the preparation of substantially pure Glycine tert-butyl ester and its salts thereof formula (I) with or without involving purification.

In another aspect, the present invention relates to a processfor the preparation of substantially pure Glycine tert-butyl ester and its salts (I)where aprocess comprises the steps: a) reacting a compound of formula (II) where M is Potassium or Calcium, with tert-butyl halo acetate of formula (III) to obtain compound of formula (IV) in presence of an inorganic base and solvent; b) reacting compound of formula (IV) with base in presence of chlorinated solvent; c) treating with acid.

In another aspect, the present invention relates to a processfor the preparation of substantially pureGlycine tert-butyl ester and its salts (I) where a process comprises the steps: a) reacting a compound of formula (II) where M is Potassium or Calcium, with tert-butyl halo acetate of formula (III) to obtain compound of formula (IV) in presence of an inorganic base and solvent; b) optionally purifying in hydrocarbon solvent; c) reacting compound of formula (IV) with base in presence of chlorinatedsolvent; d) treating with acid; e) optionally purifying in ketonic solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is described more in details hereinafter. The invention is embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

In one embodiment, the instant invention provides the preparation of substantially pureGlycine tert-butyl ester and its salts which involve only two steps, starting from commercially availablepotassium or sodiumphthalimide and tert-butyl halo acetate, thus the process is economically viable.

The term solvent used herein, refers to the single solvent or mixture of solvents.

In another embodiment of the present invention, wherein substantially pureGlycine tert-butyl ester and its salt of formula (I) is prepared by reacting potassium or sodium phthalimideof formula (II) and tert-butyl halo acetate of formula (III) in mild reaction conditions to obtain compound of formula (IV), which on further treatment with base resulted into desired substantially pureGlycine tert-butyl ester.

In another embodiment of the present invention, wherein the preparation of compound of formula (IV) is carried out under self-exotherm, minimum volume of solvent and, isolated by quenching in water and avoiding distillation process. The resulting compound of formula (IV) is optionallypurified by simple crystallization in hydrocarbon solvent.

In one embodiment, the substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 90%.

In one embodiment, the substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 96%.

In one embodiment, the substantially pure Glycine tert-butyl ester and its saltof formula (I) having purity more than 99%.

In another embodiment, the process for preparation of substantially pure Glycine tert-butyl ester and its salts does not involve purification step and generates less effluent, thus process is environment friendly and thereby industriallyscalable.

In an embodiment, the present invention provides a process for the preparation of substantially pureGlycine tert-butyl ester and its salt of formula (I) is illustrated in the following synthetic scheme.

(II) (III) (IV) (I) The term “substantially pure” Glycine tert-butyl ester and its saltof formula (I) mentioned herein contains purity more than 96%; preferably more than 99%.

In another embodiment, the present invention provides an improved process for preparation of compound (IV) by reacting commercially available reagents such as potassium or sodium phthalimide and tert-butyl halo acetate in presence of inorganic base and without use of costly catalyst.

In another embodiment of the present invention, wherein the tert-butyl halo acetate is selected from tert-butyl chloro acetate, tert-butyl bromoacetate and tert-butyl iodoacetate; more preferably tert-butyl chloroacetate.

In another embodiment of the present invention, wherein the inorganic base in step (a) is selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (CS2CO3), potassium carbonate (K2CO3), and sodium carbonate (Na ₂ C0 ₃ ).

In another embodiment of present invention, wherein solvent in step (a) is selected from N,N- dimethylformamide (DMF), toluene, eye lo hexane, 77-hcptanc, mo no-halo benzenes such as monochlorobenzene, dihalobenzenes such as dichlorobenzene, dialkyl (CfCi2) ethers, and the like; more preferably N,N-dimethylformamide.

In another embodiment of present invention, wherein hydrocarbon solvent is selected from toluene, cyclohexane, 77-heptane, pentane and the like; more preferably 77-heptane.

In another embodiment of the present invention, wherein the preparation of compound (IV) is carried out at a temperature20°C to 80°C.

In another embodiment of the present invention, wherein the purification of compound (IV) is carried out at a temperature 20°C to 100°C.

In another embodiment of the present invention, wherein the base used inthe preparation of compound (I) isselected from hydrazine hydrate, hydrazine mono hydrate, and triethyl amine; preferably hydrazine mono-hydrate.

In another embodiment of the present invention, wherein the chlorinated solvent is selected from chloroform, dichloromethane, dichloroethane and the like. In another embodiment of the present invention, wherein an acidis selected from hydrochloric acid in 1,4-dioxane, hydrochloric acid in hexane, hydrochloric acid in methanol, hydrochloric acid in toluene, hydrochloric acid in isopropyl alcohol; preferably in hydrochloric acid in 1,4- dioxane.

In another embodiment of the present invention, wherein aketonic solvent is selected from acetone, methyl ethyl ketone, acetophenone, cyclopentanone, 2-pentanone, preferablyacetone.

In another embodiment of the present invention, wherein preparation ofsubstantially pure compound (I) is carried out at a temperature between 20°C to 30°C.

In another embodiment of the present invention, wherein the purification of substantially purecompound (I) is carried out at a temperature 0°C to 30°C.

The preparation of the starting material used in the present invention is well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXAMPLES:

1) Preparation of compound (IV).

In a solution of compound (II) (1.3Kg) in DMF (2.0L), a powder potassium carbonate (4.58 g) was added at 20°C to 30°C. A tert-butyl chloroacetate (1.0 Kg) was added dropwise at 20°C to 80°C for 1-2 hrs. The reaction mixture was allowed to cool to 20°C to 30°C and stirred for 4-8 hrs. The reaction completion was ensured by HPLC. After completion, the reaction mixture was quenched by adding water at 0°C to 10°C and stirred for 2-3 hrs. The reaction mixture was filtered and dried to obtain compound (IV) (yield: 2.14-2.2 Kg, 95-98%, HPLC purity 96-97%).

2) Purification of Compound (IV)

A compound of formula (IV) was charged into n-heptane(3-5V) at 20°C to 30°C. The mixture was heated at 90°C to 100 °C for 2 hrsand cooled to 20°C to 30°C and stirred for 2 hrs. The solution was filtered, washed with n-hcptanc (IV), dried to obtain pure compound formula (IV; yield: 1.9-2.14 Kg, 85-95%; HPLC purity 99.5%). Ή NMR (DMSO-d6): d 1.45 (s, 9H, (CH ₃ ) ₃ ), 4.32 (s, 2H, CH ₂ ), 7.72 (dd, J = 5.6, 3.2 Hz,2H, Ar-H), 7.86 (dd, J = 5.6, 3.2 Hz, 2H, Ar-H); LCMS-279 [M + H ₂ 0] ⁺ .

3) Preparation of compound (I).

In a solution ofcompound (IV) (1.0 Kg) in dichloromethane (8.0 L), hydrazine mono hydrate (2.0 L) (95-99%)was added at 20°C to 30°C. The reaction mixture was stirred at 20°C to 30°C for 18-26 hrs. The reaction completion was ensured by HPLC. After completion, reaction mixture was quenched by adding water (8-10V)and organic layer separated. Aqueous layer extracted with dichloromethane (2V). Combined organic layer was washed with water (2V). The solvent was removedup to -2.5V. To above reaction mass, toluene (3V) was added at 40-45 °C and further distilled up to3V at 40°C to 45°C under vacuum.To this organic mass a solution of 4MHC1 in 1, 4-dioxane (0.7 to 1.0V) was added at 0°C to 10°C and stirred for 0.5 to lhr.The reaction mass was filtered, washed with tolueneand dried to obtain compound of formula (I) (yield: 417-482 g, 65-75% yield, 90-96% HPLC purity)

4) Purification of Compound (I)

A compound of formula (I) was charged into an acetone (2-3V) at 20°C to 30°C stirred for 2 hrs. The solution was cooled to 0°C to 5°C for 2 hrs. and precipitated compound was filtered, and dried to obtain pure compound formula (1)352-417 g, 55-60%; HPLC purity 99.8%)

Ή NMR (CDCL) -Ή NMR (DMSO-d6): d 1.44 (s, 9H, (CH ₃ ) ₃ ), 3.64 (s, 2H, CH ₂ ), 8.42 (bs, 3H, NH ₃ C1), MS- 173 [M free amine + ACN] ⁺ .