DESC:RELATED APPLICATION
This application claims the benefit of priority of Indian patent application number IN 201921009976 filed on Mar. 14, 2019, which is incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to novel process of preparation of Ivosidenib. Further, present invention also provides novel intermediates for process of preparation of Ivosidenib.
BACKGROUND OF THE INVENTION
Ivosidenib, has a chemical name (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluoro-cyclobutyl)-amino]-2¬-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoro pyridine-3-yl)-5-oxo pyrrolidine-2-carboxamide. Ivosidenib is represented by the following chemical structure according to Formula 1.

Ivosidenib is an orally-available, small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro. Inhibition of the mutant IDH1 enzyme by Ivosidenib led to decreased 2¬ HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, Ivosidenib decreased 2-HG levels ex-vivo, reduced blast counts, and increased percentages of mature myeloid cells.
U.S. Patent No. 9,474,779 discloses the preparation of Ivosidenib by the process as depicted in Scheme I:

Scheme 1
Since the process disclosed in U.S. Patent No. 9,474,779 gives no specific example for the seperation of diastereomers and the patent applies standard method for the said seperation.
ACS Medicinal Chemistry Letters (4), 300-305, Journal 2018 also discloses similar process as U.S. Patent No. 9,474,779 where chiral separation step was carried out in the last stage of the synthetic process to obtain Ivosidenib.
However, carrying out the chiral separation at last step is difficult, costly, and not suitable for an industrial scale preparation due to use of column chromatography; Further, carrying out the chiral separation at last step affects the overall yield and cost of the manufacturing process.
Thus, there exists a need in the art for the development of an easy, cost-effective, and industrially advantageous process for the preparation of Ivosidenib which overcomes the difficulties of the prior art process.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide novel process of preparation of Ivosidenib comprising converting chiral compound of Formula (A) to Ivosidenib.

Formula A
Wherein, R is –OH, -OR’;wherein R’ is an leaving group such as, but not limited to, alkyl, aryl or alkylaryl, alkylheteroaryl, hetroaryl which is substituted or non-substituted;.
Yet another aspect of the present invention relates to novel compounds of Formula (V) and Formula (VI).

Still another aspect of the present invention relates to use of a compound selected form the group consisting of compound of Formula II, Formula V, Formula VI or Formula VII for preparing Ivosidenib or a pharmaceutical composition of Ivosidenib.

DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention is to provide novel process of preparation of Ivosidenib comprising converting chiral compound of Formula (A) to Ivosidenib.

Formula A
An embodiment of the present invention is scheme 2 which illustrates the synthesis of compounds of the present invention.

Scheme 2
Scheme 2 illustrates the synthesis of Ivosidenib of the present invention.
An embodiment of the present invention is to get novel compound of Formula VII.

Compound of Formula (VII) can be prepared in two ways as illustrated in scheme 2; by following Step A and step C or by following Step B and step D.
In step A, compound of Formula (II) or its reactive derivative is condensed with compound of Formula (III) or its reactive derivative to get compound of Formula (V) using standard amide coupling conditions. The reactive dertivative of compound of Formula (II) and (III) includes but not limited to silyl dertivative, mixed anhydride or use of leaving groups etc. The reaction is preferably conducted in the presence of solvent that does not affect the course of the reaction and optionally in the presence of base like pyridine, DBU, TEA and the like. The condensation reaction can also be conducted in the presence of Lewis Acid like B(OCH2CF3)3, Ti(OiPr)4, ZrCl4, 3,4,5-F3C6H2B(OH)2, dimethyl silyl chloride etc and solvent selected from acetonitrile or CPME or tert-Amyl methyl ether etc, without protecting the amino group.
In step C, compound of Formula (V) condensed with compound of Formula (IV) to get compound of Formula (VII) using standard conditions such as use of one or more below mentioned conditions:
• Pd(OAC)2, sodium tertiary butoxide, Toluene ;
• sodium tertiary butylate,1,N-bis(diphenyl phosphine)ferrocene palladium (II)chloride [Pd2(dba)3], sodium tertiary butoxide, Toluene, 100 c;
• Microwave irridation, cesium carbonate, DMF;
• Pd2(dba)3, sodium tertiary butoxide, Toluene, BINAP
• cesium carbonate,1,4-dioxane, Pd2(dba)3 ;
• N,N –dimethyl-1,2 –cyclohexyldiamine,K3PO4,CuI;
• CS2CO3, CuBr;
• Fe(acetylacetonate)3, cesium carbonate
• K2CO3, L-proline, DMSO, Copper (I) Iodide.
In step B, compound of Formula (II) is condensed with compound of Formula (IV) to get compound of Formula (VI) using standard conditions similar as disclosed in step C.
In step D, compound of Formula (VI) condensed with compound of Formula (III) to get compound of Formula (VII) using standard conditions such as use of one or more reagents or their combinations such as DCC/DMAP; HATU/DIEA; HBTU/ DIEA; EDC/HOBT; EDC /DMAP; T3P/ DIEA; BOP/TEA; PYBOP/TEA; SOCl2 (acid chloride to amide); CDI/THF or Mixed Anhydride.
In embodiment of the present invention, Ivosidenib of Formula (I) is prepared from compound of Formula (VII) by two ways: condensing with compound of Formula (VIII) by following route E or step wise condensation with compound of Formula (IX) and (XI) by following step F and step G.
In step E, compound of Formula (VII) condensed with compound of Formula (VIII) to get Ivosidenib of Formula (I) using standard conditions similar as disclosed in step D.
In step F, compound of Formula (VII) condensed with compound of Formula (IX) to get compound of Formula (X) standard conditions similar as disclosed in step D.
In step G, compound of Formula (X) condensed with compound of Formula (XI) to get Ivosidenib of Formula (I) using standard conditions similar as disclosed in step C.
In another embodiment the present invention relates to the preparation of compound of Formula (VIII) which is shown in Scheme 3 given below:
Scheme 3
In scheme 3, compound of Formula (IX) is first protected with any protecting group such as but not limited to leaving group such as, but not limited to, alkyl, aryl, silyl or alkylaryl which is substituted or non-substituted. Representative leaving groups includes but not limited p-methoxy benzyl (PMBZ), p-nitrobenzyl, silyl, TMS, TBDMS, methyl, iso-propyl and the like. The protected compound of formula (IX) condensed with compound of Formula (XI) which on deprotection gives compound of Formula (VIII). Deprotection can be performed in presence of reagents such as montmorillonite/ MDC; AlCl3/ anisole; TFA/anisole or Lithium hydroxide/THF/water.
In an embodiment, the protected compound of formula (IX) condensed with compound of Formula (XI) in Buchwald condition; wherein reaction is carried out in presence of the transition metal catalyst which is a palladium compound selected from the group consisting of tetrakis(triphenylphosphine)palladium [(Ph3P)4Pd], tris(dibenzylideneacetone)dipalladium[Pd2(dba)3], bis(dibenzylidene acetone) palladium (0) [(dba)2Pd], palladium acetate [Pd(OAc)2], palladium chloride (PdCl2), bis(benzonitrile)dichloropalladium [(C6H5CN)2PdCl2] and (Bis-(diphenyl phosphinoferrocene)palladium dichloride dichloromethane complex (Pd(dppf)2Cl2), and the ligand compound which is selected from Xant-phos, 2,2'-bis (diphenylphosphino)-1,1'-binaphthalene (BINAP), (S)-(-)-(1,1-bi-naphthalene-2,2'-diyl)bis(diphenylphosphine) [S(-)BINAP], (R)-(-)-(1,1-bi-naphthalene-2,2'-diyl)bis(diphenylphosphine) [R(-)BINAP], 1,3 bis(diphenylphosphino) propane, triphenylphosphine (Ph3P), triorthotolylphosphine [(o-CH3Ph)3P], Bis[(2-diphenyl phosphino)phenyl] ether and tri-t-butylphosphine, 2-dicyclohexyl phosphino-2',6'-di-methoxybiphenyl [S-Phos], (R) or (S)-(+)-5,5'-bis(diphenyl phosphino)-4,4'-bi-l,3-benzodioxole [SEGPHOS] and (4-(N,N-dimethylamino) phenyl)di-tert-butyl phosphine [A-Phos].
An illustration of the preparation of compounds of the present invention is shown in Schemes 4-6.

Scheme 4
Scheme 5
Scheme 6
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples:
Example 1: Preparation of (2S)-(2-chlorophenyl)[(5-fluoropyridin-3-yl) amino]acetic acid (compound of formula VI)
To a mixture of (2S)-amino-(2-chlorophenyl)aceticacid (3.0 g) and 3-iodo-5-fluoropyridine (2.52 g) in DMSO (30ml), copper iodide (216 mg), L-proline (216 mg) and potassium carbonate (3.12 g) were added. The obtained reaction mass was stirred at 70°C. After completion of reaction, DMSO was distilled out from reaction mass under vacuum and residue was separated by column chromatography. (Yield: 5.0 g).
Example 2: Preparation of (2S)-2-(2-chlorophenyl)-N-(3,3-difluoro-cyclo butyl)-2-[(5-fluoropyridin-3-yl)amino]acetamide (compound of formula VII)
To a mixture of ((2S)-(2-chlorophenyl)[(5-fluoropyridin-3-yl)amino]aceticacid (5.0 g) in DMF (25ml), EDC.HCl was added and stirred at 30°C for 15 min and followed by addition of 4-methyl-morpholine (1.78 g), HOBT (2.38 g) and 3,3-difluorocyclobutanamine hydrochloride (2.0 g). The obtained reaction mass was stirred at 30°C till completion of reaction and then followed by addition of water and extracted with ethyl acetate and separated. The obtained organic layer was distilled out and separated by column chromatography. (Yield: 4.0 g).
Example 3: Preparation of Benzyl-(2S)-5-oxopyrrolidine-2-carboxylate:
To a mixture of (2S)-5-oxopyrrolidine-2-carboxylic acid (50.0 g) in acetone (500 ml), benzyl chloride (50 ml) and TEA (61 ml) were added. The obtained reaction mass was heated to 55ºC for 20 hrs till completion of reaction and then cooled to 30°C. To the obtained reaction mass dichloromethane was added and washed with brine solution at 25-30°C. The obtained reaction mass was concentrated and then obtained oil was triturates with hexane. (Yield: 50.0 g).
Example 4: Preparation of benzyl-(2S)-1-(4-cyanopyridin-2-yl)-5-oxo pyrrolidine-2-carboxylate
To a mixture of benzyl (2S)-5-oxopyrrolidine-2-carboxylate (20g) and 2-bromo-4-cyano pyridine (24.92 g) in 1,4-dioxane (300ml), CS2CO3 (42.32 g), Xantphos (3.8 g) and Pd2(dba)3 (8.92 g) were added. The reaction mass was heated to 80ºC till completion of reaction and then cooled to 30°C. The obtained reaction mass was concentrated and then separated by column chromatography. (Yield: 5.0 g).
Example 5: Preparation of (2S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxylic acid (compound of formula VIII)
To a mixture of benzyl-(2S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (10g) in methanol (300ml), Pd/C (1.0 g) and methanol (100ml) at were added in autoclave and hydrogen applied at 30°C for till complies reaction. The obtained reaction mass was filtered and filtrate was concentrated. The obtained residue was separated by column chromatography. (Yield: 3.0 g).
Example 6: Preparation of (S)-N-((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide.
To a mixture (2S)-2-(2-chlorophenyl)-N-(3,3-difluoro-cyclobutyl)-2-[(5-fluoropyridin-3-yl)amino]acetamide (5.0 g) in dichloromethane (25ml), tetramethylfluoroformamidinium hexafluoro phosphate (5.71g) and diisopropylamine (4.38 g) were added and stirred at 0-5°C for 1-2 hrs,. To the obtained reaction mass (S)-5-oxomorpholine-2-carboxylic acid was added and heated up to 80-90°C in sealed tube till completion of reaction. The reaction mass was cooled to 25-30°C and washed with water and both layer were separated. The organic layer was concentrated under reduced pressure. The residue was separated by column chromatography.
Example 7: Preparation of Ivosidenib
To a mixture (2S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxylic acid (5.0 g) in dichloromethane (25ml), tetramethylfluoroformamidinium hexafluoro phosphate (5.71g) and diisopropylamine (4.38 g) were added and stirred at 0-5°C for 1-2 hrs,. To the obtained reaction mass (2S)-2-(2-chlorophenyl)-N-(3,3-difluorocyclo-butyl)-2-[(5-fluoropyridin-3-yl)amino]acetamide (8.0 g) was added and heated up to 80-90°C in sealed tube till completion of reaction. The reaction mass was cooled to 25-30°C and washed with water and both layer were separated. The organic layer was concentrated under reduced pressure. The residue was separated by column chromatography. (Yield: 3.2 g).
,CLAIMS:1. A process of preparation of Ivosidenib compound of Formula 1 comprising ;

converting compound of Formula II or Formula V or Formula VI or Formula VII to compound of Formula 1.

2. A process of preparation of a compound of Formula VIII comprising ;

a) protecting compound of Formula IX;

b) condensation of protected compound of Formula IX and Formula XI to obtain Formula XII;

c) deprotection of Formula XII.
3. A process of preparation of a compound of Formula VIII comprising ;

condensation of compound of Formula IX and Formula XI.

4. Use of a compound selected form the group consisting of compound of Formula A, Formula V, Formula VI or Formula VII or Formula VIII for preparing Ivosidenib or a pharmaceutical composition of Ivosidenib.
5. The compound of Formula V:

6. The compound of Formula VI: