DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL PROCESS FOR THE PREPARATION OF DPP-IV INHIBITORS

We, GRANULES INDIA LIMITED,
a company incorporated under the companies act, 1956 having address at
My Home Hub; 2nd Floor; 3rd Block; Madhapur; Hyderabad – 500081, India

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of DPP-IV inhibitors. In particular, the present invention relates to an improved process for the preparation of Teneligliptin.

More particularly, the present invention relates to an improved process for the preparation of Teneligliptin which is commercially feasible.

BACKGROUND OF THE INVENTION
DPP-IV inhibitors (Dipeptidyl peptidase-IV) have recently emerged as a new class of antidiabetic that show favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. Teneligliptin, a novel DPP-IV inhibitor, exhibits a unique structure characterized by five consecutive rings, which produce a potent and long-lasting effect. Teneligliptin is currently used in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea- or thiazolidine-class drugs. Teneligliptin was originally synthesized by Mitsubishi Tanabe Pharma Corporation (Osaka, Japan) and was the first drug of its kind to be synthesized in Japan. Mitsubishi Tanabe Pharma Corporation and Daiichi Sankyo Co, Ltd, (Tokyo, Japan) jointly sell the drug under the brand name TENERIA®.

The chemical name of Teneligliptin is 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine and the molecular formula is C22H30N6OS. The structural formula of Teneligliptin is:

Teneligliptin is disclosed for the first time in US 7,074,794 B2. This patent also discloses process for preparing Teneligliptin which comprises reaction of 1-tert-butoxycarbonylpiperazine with diketene in DMF to give l-acetoacetyl-4-tert-butoxycarbonylpiperazine which is further reacted with phenylhydrazine in ethanol in the presence of methanesulfonic acid; followed by cyclization with phosphorous oxychloride in pyridine to obtain 1-tert-butoxycarbonyl-4-(3-methyl-1-phenyl-5-pyrazolyl)piperazine; deprotection of tert-butoxycarbonyl group with trifluoroacetic acid and finally reacting the obtained compound with tert-butyl (2S)-4-oxo-2-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidine-l-carboxylate to give Teneligliptin or salts . The process is shown in the scheme given below:

Scheme I

PCT Publication No. WO 2014/041560 A2 discloses a process for the preparation of Teneligliptin which comprises converting trans-4-hydroxy-l-proline into an hydroxy ester compound; converting the hydroxy ester compound to keto compound; reacting the keto compound with 1-(3-methyl-1-phenyl-lH-pyrazol-5-yl)piperazine or salt thereof to obtain protected 1-(3-methyl-1-phenyl-lH-pyrazol-5-yl)piperazin-1-yl)pyrrolidine-2-carboxylate; and reacting the compound thus obtained with 1, 3-thiazolidine to obtain Teneligliptin. The process is shown in the scheme given below:
Scheme II

In view of the importance of Teneligliptin as a pharmaceutical product it is therefore, desirable to provide an efficient process for the preparation of Teneligliptin.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an alternative approach for the preparation of Teneligliptin which avoids use of standard intermediates and which provides at least a useful alternative approach over the one disclosed in the art.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of Teneligliptin of Formula I

which comprises:
i) converting trans-4-hydroxy-1-proline of Formula II

to compound of Formula III

wherein Pg represents amino protecting group,
ii) oxidation of compound of Formula III to compound of Formula IV

wherein Pg is as defined above using an oxidizing agent in a solvent,
iii) reaction of compound of Formula IV with compound of Formula V

in a solvent in the presence of a reducing agent to obtain compound of Formula VI

wherein Pg is as defined above,
iv) reaction of compound of Formula VI with 1,3-thiazolidine

in the presence of a condensing reagent to obtain a compound of Formula VII

wherein Pg is as defined above,
v) converting the compound of Formula VII to Teneligliptin of Formula I and its salts or hydrates thereof.

In yet another aspect, the present invention provides a process for the preparation of compound of Formula VI

wherein Pg represents amino protecting group; which comprises
i) converting trans-4-hydroxy-1-proline of Formula II

to compound of Formula III

wherein Pg is as defined above,
ii) oxidation of compound of Formula III to compound of Formula IV

wherein Pg is as defined above using an oxidizing agent in a solvent,
iii) reaction of compound of Formula IV with compound of Formula V

in a solvent in the presence of a reducing agent to obtain compound of Formula VI.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine (Teneligliptin) of Formula I.

According to the present invention amino protecting groups Pg may be used to prevent unwanted reactions of an amino group while performing a desired transformation. Amino protecting groups allow easy covalent attachment to a nitrogen atom as well as selective cleavage from the nitrogen atom. Suitable "amino protecting groups" are selected from alkoxycarbonyl such as ethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), and the like; or acyl such as acetyl (Ac), benzoyl (Bz), and the like; or sulfonyl such as methanesulfonyl, trifluoromethanesulfonyl, and the like; or arylalkyl such as benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl (trityl), and the like; or alkenylalkyl such as allyl, prenyl, and the like; or diarylmethyleneyl such as (C6H5)2C=N and the like or and silyl such as tert-butyldimethylsilyl, triisopropylsilyl, and the like are known to one skilled in the art. The chemistry of amino protecting groups can be found in Wuts and Greene, Greene's Protective Groups in Organic Synthesis, 4th Ed., pp 696-926, John Wiley & Sons: New York, 2006.

In another embodiment suitable solvent used in step (i) for amino protection of trans-4-hydroxy-1-proline is selected from water, methylene chloride, dichloroethane, chloroform, ethyl acetate, butyl acetate, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetonitrile, acetone, dimethylsulfoxide, N,N-dimethylformamide, benzene, toluene or mixtures thereof.

In another embodiment suitable oxidizing agent used in the present invention is selected from MnO2, 2-iodoxybenzoic acid, Dess-Martin oxidation, Potassium dichromate, Pyridinium chlorochromate (PCC), pyridine sulphur trioxide, Swern oxidation, TEMPO, Ruthenium oxide mono hydrate and the like.

In another embodiment suitable solvent used in the oxidation reaction in step (ii) is selected from water, alcohols like methanol, ethanol, isopropanol; esters like ethyl acetate, tertiary butyl acetate; hydrocarbons like toluene; ethers like ethyl ether, methyl ether, dioxane, tetrahydrofuran; dimethylformamide; dimethylsulfoxide; acetonitrile; ketones like acetone, methyl ethyl ketone or mixtures thereof.

In yet another embodiment suitable reducing agent used in step (iii) of the present invention may be selected from borohydrides such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, alkyl and dialkyl cyanoborohydrides, potassium borohydride, zinc borohydride, and lithium tri-sec-butyl borohydride; hydride such as lithium hydride and lithium aluminium hydride or mixtures thereof. If necessary, they can be used in the presence of an acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, sulphuric acid or hydrochloric acid or a base such as triethylamine. Preferably mixture of sodium triacetoxyborohydride and acetic acid is used.

In yet another embodiment suitable solvent used in step (iii) of the present invention are inert solvents selected from ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like or; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane and the like; or hydrocarbons such as toluene, xylene and the like; or alcohols such as methanol and ethanol, propanol, butanol and the like; or nitriles such as acetonitrile. These solvents can be used either alone or in the form of a mixture of two or more of them.

In yet another embodiment suitable condensing reagent used in step (iv) of the present invention is selected from the group consisting of phenylsilane; 1,1'-carbonyldiimidazole (CDI); benzotriazol-1-yloxytris (dimethylamino) phophonium hexafluorophosphate (BOP); 1-hydroxybenzotriazole hydrate (HOBt); PyBOP (Analog of the BOP); 1,3-dicyclohexylcarbodiimide (DCC); 1,3-diisopropylcarbodiimide (DIC); N,N-diisopropylethylamine (DIEA); 4-dimethylaminopyridine (DMAP); 1,4-dithio-L-threitol (DTT); N-ethyl-N'-(3-dimethylaminopropyl) carbodidimide hydrochloride (EDC HCl); 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU); 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU); 2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl aminiumhexafluorophosphate (HCTU); O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU); tetramethylfluoroformamidiniunhexafluorophosphate (TFFH).

In yet another embodiment suitable solvent used in step (iv) of the present invention is selected from the group consisting of halogenated solvent or a polar solvent such as chloroform, dichloromethane and the like or dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, sulfolane, diglyme, 1,4-dioxane, tetrahydrofuran, acetonitrile, acetone or mixtures thereof. Preferably dimethylformamide is used.

According to the present invention when Pg is an amino group protecting group, the protecting group must be removed from the compound of Formula VII to obtain Teneliglitpin. The deprotection may occur in situ in the reaction mixture for the coupling reaction, or it may be accomplished in a separate step.

In yet another embodiment deprotection or conversion of the compound of Formula VII to Teneligliptin is carried out using suitable acid selected from hydrochloric acid, hydrobromic acid, triflouroacetic acid, sulfuric acid, pivalic acid, acetic acid, formic acid and the like. In particular hydrobromic acid may be used. The embodiments of the process comprises use of hydrobromic acid in form of its isopropanolic solution, hydrobromic acid gas or its solution in suitable solvent like acetone, ethyl acetate etc. More particularly, the isopropanolic hydrobromide solution may be used.

In yet another embodiment suitable solvent used in the present invention in step v) is selected from alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like; or ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; or chloro solvents such as MDC, chloroform, ethylene dichloride and chlorobenzene and the like; or hydrocarbons such as toluene, xylene, ethylbenzene and the like; or esters such as ethyl acetate, isopropyl acetate, n-butyl acetate and the like; or ethers like tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether and the like; or polar solvents like water, DMF, DMAc, DMSO, NMP and the like or mixtures thereof. Preferably mixture of isopropanol and methanol is used.
According to the present invention, one or more sequential steps are carried out with or without isolating intermediate compounds.

The reactions in any of the steps of the present invention are carried out in the absence or presence of a solvent.

In a preferred embodiment, the present invention provides an improved process for the preparation of Teneligliptin which comprises:
i) converting trans-4-hydroxy-1-proline of Formula II

to compound of Formula IIIa

ii) oxidation of compound of Formula IIIa to compound of Formula IVa

iii) reaction of compound of Formula IVa with compound of Formula V

in a solvent in the presence of a reducing agent to obtain compound of Formula VIa

iv) reaction of compound of Formula VIa with 1,3-thiazolidine

in the presence of a condensing reagent to obtain a compound of Formula VIIa

v) converting the compound of Formula VIIa to Teneligliptin of Formula I and its salts or hydrates thereof.

In a most preferred embodiment, the present invention provides an improved process for the preparation of Teneligliptin hydrobromide which comprises:
i) converting trans-4-hydroxy-1-proline of Formula II

to compound of Formula IIIa

ii) oxidation of compound of Formula IIIa to compound of Formula IVa using ruthenium oxide monohydrate in the presence of sodium meta periodate.

iii) reaction of compound of Formula IVa with compound of Formula V

in toluene in the presence of sodium triacetoxyborohydride and acetic acid to obtain compound of Formula VIa

iv) reaction of compound of Formula VIa with 1,3-thiazolidine

in the presence of HOBT and EDC to obtain a compound of Formula VIIa

v) converting the compound of Formula VIIa to Teneligliptin hydrobromide and its hydrate.

In yet another preferred embodiment, the present invention provides a process for the preparation of compound of Formula VIa

which comprises:
i) converting trans-4-hydroxy-1-proline of Formula II

to compound of Formula IIIa

ii) oxidation of compound of Formula IIIa to compound of Formula IVa

iii) reaction of compound of Formula IVa with compound of Formula V

in a solvent in the presence of a reducing agent to obtain compound of Formula VIa.

In yet another most preferred embodiment, the present invention provides a process for the preparation of compound of Formula VIa

which comprises:
i) converting trans-4-hydroxy-1-proline of Formula II

to compound of Formula IIIa

ii) oxidation of compound of Formula IIIa to compound of Formula IVa

iii) reaction of compound of Formula IVa with compound of Formula V

in toluene in the presence of sodium triacetoxyborohydride and acetic acid to obtain compound of Formula VIa

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.

EXAMPLES
Example 1
Preparation of Formula IIIa:
Trans L-hydroxy proline (1 mol) was charged in to water (5 V) at RT, pH was adjusted to 10 to 11 with sodium hydroxide. Then BOC anhydride (0.0399 mol) solution (dissolved in acetone) was added and maintained for 5hrs at RT. Upon completion of reaction, pH was adjusted to 2.5-3.0 with aq. acid. Charged MIBK and heated the reaction mass to 40°C, separated the layers. Aqueous layer was re-extracted with MIBK. MIBK was distilled completely under vacuum and isolated in MIBK and n-hexane at 0-5°C. The obtained compound was confirmed by 1H-NMR, Mass, IR.

Preparation of Formula IVa:
Mixture of compound IIIa (1 mol) and ruthenium oxide monohydrate was added into water and cooled to 0-5°C. Sodium meta periodate solution was added at 0-5°C. The reaction mass was maintained at RT for 5-6 hrs. The mass was filtered and the filter MLs were extracted into ethyl acetate and concentrated under vacuum. The obtained compound was confirmed by 1H-NMR & Mass.
1H NMR (400 MHz, DMSO-d6): 12.88 (br s, 1H), 4.51-4.55 (m, 1H), 3.86-3.77 (m, 1H), 3.69-3.63 (m, 1H), 3.16 - 3.06 (m, 1H), -2.49 (m, 1H, overlapped with DMSO), 1.40 and 1.3 (2 s, 9H). ESI-MS (m/z): 227.9 [M-H]-

Preparation of Formula VIa:
Compound of Formula V (1 mol) and IVa (1 mol) were charged into toluene at RT. Stirred the reaction mass for 30 min and mixture of acetic acid and sodium triacetoxyborohydride were added. Maintained the reaction mass at RT for 24 hrs. Then charged water and layers were separated. Organic layer was concentrated. The isolated product was characterized by 1H-NMR, Mass, IR.
1H NMR (400 MHz, DMSO): d 1.33-1.38 (m, 9H), 1.54- 1.59 (m, 1H), 2.14 (s, 3H), 2.2 -2.2 (s, 1H), 2.47 - 2.76 (m, 9H), 2.92 -3.01 (m, 1H), 3.65-3.68 (m, 1H), 4.03-4.05 (t, 1H), 5.78 (s, 1H), 7.25-7.29 (t, 1H, J = 15.2Hz), 7.43-7.47 (t, 2H, J–15.8Hz), 7.72-7.74 (d, 2H, J-7.3Hz), 12.556 (brs, 1H); ESI-MS (m/z): 456 [M+H]+

Preparation of Formula VIIa:
Compound of formula VIa (1 mol) and 1,3-thiazolidine (1 mol) were charged in to DMF at RT. Then HOBt hydrate (1 mol) and EDC HCl (2 mol) were charged at RT. Stirred the mass for 6- 8 hrs at RT. After completion of reaction water and toluene were charged. Separated the layers and organic layer was washed with sodium bicarbonate solution. Organic layer was concentrated and charged isopropyl alcohol & Aq. HBr. Stirred the reaction mass to 3-4 hrs. The obtained compound was purified in methanol to yield the title compound. The isolated product was characterized by 1H-NMR, 13C-NMR, Mass, IR and XRPD. ,CLAIMS:We Claim:
1. An improved process for the preparation of Teneligliptin of Formula I

which comprises:
i) converting trans-4-hydroxy-1-proline of Formula II

to compound of Formula III

wherein Pg represents amino protecting group,
ii) oxidation of compound of Formula III to compound of Formula IV

wherein Pg is as defined above using an oxidizing agent in a solvent,
iii) reaction of compound of Formula IV with compound of Formula V

in a solvent in the presence of a reducing agent to obtain compound of Formula VI

wherein Pg is as defined above,
iv) reaction of compound of Formula VI with 1,3-thiazolidine

in the presence of a condensing reagent to obtain a compound of Formula VII

wherein Pg is as defined above,
v) converting the compound of Formula VII to Teneligliptin of Formula I and its salts or
hydrates thereof.

2. An improved process for the preparation of compound of Formula VI

wherein Pg represents amino protecting group; which comprises
i) converting trans-4-hydroxy-1-proline of Formula II

to compound of Formula III

wherein Pg is as defined above,
ii) oxidation of compound of Formula III to compound of Formula IV

wherein Pg is as defined above using an oxidizing agent in a solvent,
iii) reaction of compound of Formula IV with compound of Formula V

in a solvent in the presence of a reducing agent to obtain compound of Formula VI.

3. The process as claimed in any of the preceding claims, wherein the oxidation of compound of Formula III is carried out in the presence of a suitable oxidizing agent selected from MnO2, 2-iodoxybenzoic acid, Dess-Martin oxidation, Potassium dichromate, Pyridinium chlorochromate (PCC), pyridine sulphur trioxide, Swern oxidation, TEMPO, Ruthenium oxide mono hydrate and the like.

4. The process as claimed in claim 3, wherein the oxidizing agent is preferably ruthenium oxide monohydrate.

5. The process as claimed in any of the preceding claims, wherein the compound of Formula IV is reacted with compound of Formula V in the presence of a reducing agent selected from borohydrides such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, alkyl and dialkyl cyanoborohydrides, potassium borohydride, zinc borohydride, and lithium tri-sec-butyl borohydride; hydride such as lithium hydride and lithium aluminium hydride or mixtures thereof. If necessary, they can be used in the presence of an acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, sulphuric acid or hydrochloric acid or a base such as triethylamine. Preferably mixture of sodium triacetoxyborohydride and acetic acid is used.

6. The process as claimed in claim 5, wherein the reaction of compound of Formula IV with compound of Formula V is preferably carried out in the presence of acetic acid and sodium triacetoxyborohydride.

7. The process as claimed in any of the preceding claims, wherein the condensation of compound of Formula VI with 1,3-thiazolidine is carried out in the presence of suitable condensing reagent selected from phenylsilane; 1,1'-carbonyldiimidazole (CDI); benzotriazol-1-yloxytris (dimethylamino) phophonium hexafluorophosphate (BOP); 1-hydroxybenzotriazole hydrate (HOBt); PyBOP (Analog of the BOP); 1,3-dicyclohexylcarbodiimide (DCC); 1,3-diisopropylcarbodiimide (DIC); N,N-diisopropylethylamine (DIEA); 4-dimethylaminopyridine (DMAP); 1,4-dithio-L-threitol (DTT); N-ethyl-N'-(3-dimethylaminopropyl) carbodidimide hydrochloride (EDC HCl); 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU); 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU); 2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl aminiumhexafluorophosphate (HCTU); O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU); tetramethylfluoroformamidiniunhexafluorophosphate (TFFH).

8. The process as claimed in claim 7, wherein the condensation of compound of Formula VI with 1,3-thiazolidine is preferably carried out in the presence of HOBt hydrate (1 mol) and EDC HCl.

9. The process as claimed in any of the preceding claims, wherein the solvent is selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, tertiary butyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

Dated this Eighth (08th) day of August 2016.

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883