DESC:FIELD OF THE INVENTION
Provided herein a process for the preparation of amino keto-epoxide, particularly (2S)-2-amino-4-methyl-1-[(2R)-2-methyl-2-oxiranyl]-1-pentanone of Formula (II) or its salt and use of compound of formula (II) obtained by the present invention in the synthesis of Carfilzomib.

(II)
BACKGROUND OF THE INVENTION
Carfilzomib (KYPROLIS®), an epoxomicin derivative, is a selective proteasome inhibitor. Carfilzomib is used to treat patients with multiple myeloma who have already been treated with at least two other medications.
Carfilzomib has the chemical name (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide and has the following structural Formula (I).

(I)
US 7232818 B2 discloses a process for the preparation of Carfilzomib. The last step in this synthesis is coupling of keto-epoxide formula (II).

Formula (II)
with a peptide compound of formula

to obtain Carfilzomib (Formula-I).
The process for the preparation of compound of Formula (II) comprises the epoxidation of the corresponding N-protected amino keto-alkene with H2O2 as described in N. Sin, et al. "Total synthesis of the potent proteasome-inhibitor epoxomicin: a useful tool for understanding proteasome biology", Bio org. Med. Chem. Lett. 1999, Vol. 9, pp. 2283- 2288. However, the reaction occurs with a low diastereoselectivity of 1 .7:1.


US 2005/256324A1 (WO2005/111009A2) discloses the stereoselective preparation of N-protected amino keto- epoxides from the corresponding allylic alcohols. However, the method involves two additional steps and the diastereoselectivity is also poor.
US 8367617 B2 (WO2009/045497A1) discloses a method of synthesis of N-protected amino keto-epoxides by stereo selective epoxidation of the corresponding N-protected amino keto-alkene with an aqueous solution of sodium hypochlorite or calcium hypochlorite in the presence of a co-solvent. The obtained N- protected amino keto-epoxide is subsequently deprotected to obtain a salt of the compound of Formula (II).
Zhang et al. "Spirodiepoxides: Synthesis of Epoxomicinoids", J. Org. Chem. 2009, Vol. 74, pp. 7707-7714 disclose the preparation of N-protected amino keto-epoxides from the corresponding allene compound.
US 2017/088582A1 (WO2015/179441A2) discloses the preparation of N-protected amino keto-epoxides by reacting corresponding N-protected amino keto-alkene with NaOCl in pyridine. A mixture of diastereomers is obtained, separated by flash chromatography and further treated with TFA to prepare corresponding TFA salts.
The diastereoselectivity of the epoxidation processes disclosed in the prior art literatures as mentioned above is low. The deprotection of the obtained N-protected amino keto-epoxide is usually carried out by the use of trifluoroacetic acid. However, in order to obtain the corresponding trifluoroacetic acid salt with relatively good diasteromeric purity, the N- protected amino keto-epoxide must be previously purified by chromatography.
Therefore, from what is known in the art, it is evident that the provision of an efficient and industrially scalable process for the preparation of compound of formula (II) or its salt would be of great interest and very useful for the preparation of some pharmaceutically active compounds such as Carfilzomib.

SUMMARY OF THE INVENTION
In one aspect relates to process for the preparation of (2S)-2-amino-4-methyl-1-[(2R)-2-methyl-2-oxiranyl]-1-pentanone of Formula (II) or its salt, comprising the steps of:

(II)
a) epoxidation of N-protected amino keto compound of formula (III)

with Corey–Chaykovsky reagent to obtain compound of formula (IV);

b) oxidation of formula (IV) to obtain compound of formula (V) ;

c) resolving the compound of formula (V) to obtain desired isomer of formula (V’);

d) deprotecting the protecting group in compound of formula (V’) to obtain compound of formula (II); and
e) optionally isolating salt of compound of formula (II).
In another aspect of the present invention provides use of compound of formula (II) or its salt obtained by the process of present invention in the preparation of Carfilzomib.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly the process for the preparation of (2S)-2-amino-4-methyl-1-[(2R)-2-methyl-2-oxiranyl]-1-pentanone of Formula (II)

(II)
or its salt, which is depicted in the following Scheme-1:

Scheme-1
The salt of compound of formula (II) can be selected from inorganic salts such as hydro chloric acid, hydro bromic acid, trifluoro acetic acid, formic acid, trichloro acetic acid, methane sulfonic acid, ethanedioic acid and the like.
The group PG as shown in the compound of Formula (III), (IV), (V) and (V’) represents a protecting group and selected from group tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), p-methoxyphenyl (PMP), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl (trityl), trichloroethoxycarbonyl (Troc).
The present invention Corey–Chaykovsky reagent is selected from dimethyloxosulfonium methylide and dimethylsulfonium methylide, the later can be generated in situ by reaction of trimethylsulfoxonium iodide with DMSO in the presence of base such as NaH and tert-BuOH.
The said epoxidation reaction of the present invention is carried out in the temperature range of 20 to 70 oC, preferable 20 to 50 oC, more preferable 25 to 40 oC.

The oxidation of formula (IV) to obtain compound of formula (V) is done using an oxidising agent selected from pyridiniumchlorochromate (PCC), pyridinium dichromate (PDC - Cornforth reagent), DMSO-Sulfurtrioxidepyridine complex (Parikh–doering oxidation reagent), oxalyl chloride-DMSO (Swern oxidation reagent), corey kim oxidation reagent and dess martin oxidation reagent. The oxidation may be carried out in a solvent that does not affect the course of the reaction and includes acetonitrile, dichloro methane, DMSO and toluene.
Resolution of the compound of formula (V) to obtained desired isomer of the present invention may be carried out by column chromatography, chiral column chromatography or preparative HPLC techniques or crystallization technique optionally using chiral resolving agent.
The de-protection of compound of formula (V’) is carried out using a de-protecting reagent. Depending on the nature of protecting group the de-protecting agent particularly selected from CAN (Ceric ammonium nitrate), Pd/C, trichloroisocyanuric acid, [bis(acetoxy)iodo]benzene, trifluoroacetic acid (TFA), HCl in dioxane, boron tris(trifluoroacetate), cyanogen bromide and like, more preferable is CAN (Ceric ammonium nitrate).
The starting material N-protected amino compound of formula (III) is prepared according to the procedure described in Adv. Synth. Catal. 2004, 346, 1131 – 1140 (Table-2). Particularly it is obtained by direct proline-catalyzed asymmetric addition of ketones to imines.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope of the invention. The progresses of the reaction were monitored using HPLC or TLC.

EXAMPLES
Example-1: Preparation of compound (III) (PG = PMP or PMB)
To a reaction mixture of anhydrous DMSO (600 mL) and 1-hydroxypropan-2-one (36.07 mL), P-anisidine (20 g), isovaleraldehyde (19.18 mL) followed by L-proline (3.7 g) were added and the resulting homogeneous reaction mixture was stirred at room temperature till completion of reaction. After completion of reaction, the reaction mass was quenched with aqueous NH4Cl solution. The product was extracted with ethyl acetate and the ethyl acetate layer was dried. The pH of organic phase was adjusted pH 1 with HCl in ethyl acetate at 0-5 oC. The solid precipitated was filtered to obtain desired compound (III) (21 g).
Example-2: Preparation of compound (IV) (PG = PMP or PMB)
To a reaction mixture of anhydrous DMSO (150 mL), trimethylsulfoxonium iodide (13.27 g) and potassium tert-butoxide (6.73 g), compound (III) (8 g) was added. Resulting homogeneous reaction mixture was stirred at room temperature till completion of reaction. The reaction mass was quenched with water and ethyl acetate, layers were separated and aqueous phase was extracted thoroughly with ethyl acetate. Combined organic phases were dried (MgSO4), and concentrated under reduced pressure to obtain compound (IV) (8.7 g).
Example-3: Preparation of compounds (V’) (PG = PMP or PMB)
To the solution of compound (IV) (5.0 g) in acetonitrile (25 ml) at 25-30 oC Dess-Martin Per iodine (15.2 g) solution in acetonitrile (30 ml) was added over a period of 60 min at 0 oC and reaction mass was stirred at room temperature till completion of the reaction. After completion of the reaction, reaction mass was quenched with sodium bicarbonate solution and extracted with ethyl acetate and organic layer was dried with Na2SO4, concentrated under reduced pressure.
The mixture of isomers as obtained above is subjected to a HPLC purification using YMC C18 column, phase (eluent 0.1-0.2% trifluoroacetic acid (mobile phase A) and acetonitrile (mobile phase B) to obtain desired isomer compound of formula (V’).
Example-4: Preparation of compound (II)
To the solution of compound (V’) (5.0 g) in acetonitrile: water (3:1, 20 ml) at 25-30 oC, cesium ammonium nitrate (40.0 g) was added at 0 oC and reaction mass was stirred at room temperature for 2h. After completion of the reaction, reaction mass was quenched with sodium bicarbonate solution and extracted with ethyl acetate and organic layer was dried with Na2SO4, concentrated under reduced pressure to get the compound of formula (II).

Example-5: Preparation hydrochloride salt of compound (II)
To 10g compound (II) in 50ml dichloromethane, add 20 ml concentrated hydrochloric acid between 0oC to 10oC. Allow the reaction mixture to reach room temperature and stir for about 4 hours. Concentrate the reaction mixture under reduced pressure removes solvent and excessive hydrochloric acid, adds the mixed solvent 50ml of ethyl acetate and heptane, filter and dried under vacuum to obtain the titled compound.

Example-6: Preparation TFA salt of compound (II)
To 5g compound (II) was added 20 ml trifluoro acetic acid between 0oC to 10oC. Allow the reaction mixture to stir for about 2 hours. Concentrate the reaction mixture under reduced pressure removes solvent, filter and dried under vacuum to obtain the titled compound.

Dated this 20th day of May, 2020

Dr. S. Ganesan
,CLAIMS:We claim:
1. A process for the preparation of (2S)-2-amino-4-methyl-1-[(2R)-2-methyl-2-oxiranyl]-1-pentanone of Formula (II) or its salt, comprising the steps of:

(II)
a) epoxidation of N-protected amino keto compound of formula (III)

with Corey–chaykovsky reagent to obtain compound of formula (IV);

b) oxidation of formula (IV) in the presence of oxidising agent and suitable solvent to obtain compound of formula (V) ;

c) resolving the compound of formula (V) to obtain desired isomer of formula (V’);

d) deprotecting compound of formula (V’) in the presence of deprotecting agent and solvent to obtain compound of formula (II); and
e) optionally isolating salt of compound of formula (II).
2. The process as claimed in claim 1, where in PG is selected from tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), p-methoxyphenyl (PMP), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl (trityl) and trichloroethoxycarbonyl (Troc).
3. The process as claimed in claim 1, wherein Corey–chaykovsky reagent in step (a) is selected from dimethyloxosulfonium methylide and dimethylsulfonium methylide.
4. The process as claimed in claim 1, wherein oxidising agent in step (b) selected from pyridiniumchlorochromate (PCC), pyridinium dichromate (PDC - Cornforth reagent), DMSO-sulfurtrioxidepyridine complex (Parikh–doering oxidation reagent), oxalyl chloride-DMSO (Swern oxidation reagent), Corey kim oxidation reagent and Dess martin oxidation reagent.
5. The process as claimed in claim 1,wherein de-protecting agent in step (d) is selected from CAN (Ceric ammonium nitrate), Pd/C, trichloroisocyanuric acid, [bis(acetoxy)iodo]benzene, trifluoroacetic acid (TFA), HCl in dioxane, boron tris(trifluoroacetate and cyanogen bromide.

6. The process as claimed in claim1, wherein suitable solvent is selected from acetonitrile, water, dichloro methane, DMSO and toluene.

7. The process as claimed in claim 1, wherein optionally isolating salt of compound of formula (II) is selected from hydro chloric acid, hydro bromic acid, trifluoro acetic acid, formic acid, trichloro acetic acid, methane sulfonic acid and ethanedioic acid.

8. Use of compound of formula (II) or its salt obtained by the process as claimed in claim 1 in the preparation of Carfilzomib.

Dated this 20th day of May, 2020

Dr. S. Ganesan