DESC:FIELD OF THE INVENTION:
The present invention relates to an efficient and industrially advantageous process for the preparation of Gemigliptin of Formula-I or salt or hydrate or solvate thereof.
The present invention also relates to provides Gemigliptin intermediates of Formula-IV, Formula-V, Formula-VI, Formula-VII, and their use for the preparation of Gemigliptin or salt or hydrate or solvate thereof.
BACKGROUND OF THE INVENTION:
Gemigliptin is chemically known as 1-{(2S)-2-amino-4-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-4-oxo-butyl}-5,5-difluoropiperidin-2-one, having the structure of Formula-I,

[Formula-I]
Gemigliptin has been developed by LG Life Sciences Ltd. and approved by Korean Food and Drug Administration (KFDA) on June 27th, 2012 under proprietary name Zemiglo®. Gemigliptin exhibits superior inhibitory activity against dipeptidyl peptidase-IV (DPP-IV) and thus Gemigliptin is useful as an agent for treating diabetes. Gemigliptin particularly useful for the treatment and prevention of type II diabetes. Particularly, Zemiglo® tablet contain Gemigliptin tartrate sesquihydrate as an active substance.
The US patent number US 7879848 (herein after US ‘848) first discloses Gemigliptin. The process to prepare Gemigliptin has been also disclosed in US ‘848 by reacting (3S)-3-[(t-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxopiperidin-1-yl)-butanoic acid with hydrochloric acid salt of 2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine in presence of condensing agent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), catalyst 1-hydroxybenzotriazole (HOBT), dimethylformamide and diisopropylethylamine to obtain t-butyl{(1S)-3-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-1-[(5,5-difluoro-2-oxopiperidin-1-yl)methyl]-3-oxpropyl}carbamate having 51% yield. Resulting compound was then deprotected using ethyl acetate and hydrochloric acid to obtain Gemigliptin having 56% yield.
The major drawback of US ‘848 process is, it requires prep-TLC for the purification which is industrially not viable. Also, the overall process results into lower yield and is silent about purity of the obtained intermediates and final Gemigliptin. Therefore, it is not an attractive option for large scale industrial production.
As Prior art process requires prep-TLC and results into lower yield. Thus, there is a need to develop a novel process for the preparation of Gemigliptin and its intermediates which solves the problem of prior art.
Present inventors have developed an efficient and novel process for the preparation of Gemigliptin or salt or hydrate or solvate thereof and its intermediates which offer advantages over the prior-art processes in terms of high yield, high purity and less effluents and simple scalable procedure suitable for large scale industrial production of Gemigliptin of Formula-I or salt or hydrate or solvate thereof.
OBJECT OF THE INVENTION:
The main object of the present invention is to provides an efficient and industrially advantageous process for the preparation of Gemigliptin of Formula-I or salt or hydrate or solvate thereof.
Another object of the present invention is to provides Gemigliptin intermediates of Formula-IV, Formula-V, Formula-VI, Formula-VII, and their use for the preparation of Gemigliptin or salt or hydrate thereof.
Another one object of the present invention is to provides an efficient and industrially advantageous process for the preparation of Gemigliptin intermediates of Formula-IV, Formula-V, Formula-VI, Formula-VII, and their use for the preparation of Gemigliptin or salt or hydrate or solvate thereof.

SUMMARY OF INVENTION:
First aspect of the present invention is to provide a process for preparation of Gemigliptin of Formula-I or salt or hydrate or solvate thereof,

[Formula-I]
comprising the steps of:
a) reacting compound of Formula-II or salt thereof,

[Formula-II]
with compound of Formula-III,

[Formula-III]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
to obtain compound of Formula-IV,

[Formula-IV]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
b) converting the compound of Formula-IV to compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
c) converting the compound of Formula-V to compound of Formula-VI; and

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
d) reacting compound of Formula-VI with compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C1-C5¬ substituted or unsubstituted alkyl group”
to obtain Gemigliptin of Formula-I or salt or hydrate or solvate thereof.
Second aspect of the present invention is to provide a process for preparation of compound of Formula-IV,

[Formula-IV]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
comprising reacting compound of Formula-II or salt thereof,

[Formula-II]
with compound of Formula-III,

[Formula-III]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
to obtain compound of Formula-IV.
Third aspect of present invention is to provide a process for preparation of compound of Formula-IVa,

[Formula-IVa]
comprising converting the compound of Formula-IVb,

[Formula-IVb]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group, provided that R1 and R2 together are not hydrogen”
to compound of Formula-IVa.
Fourth aspect of the present invention is to provide a process for preparation of compound of Formula-IVc,

[Formula-IVc]
comprising reacting compound of Formula-IVa,

[Formula-IVa]
with amino protecting agent to obtain compound of Formula-IVc.
Fifth aspect of the present invention is to provide a process for preparation of compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
comprising converting the compound of Formula-IV,

[Formula-IV]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
to compound of Formula-V.
Sixth aspect of the present invention is to provide a process for preparation of compound of Formula-VI,

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
comprising converting the compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
to compound of Formula-VI.
Seventh aspect of the present invention is to provide a process for preparation of Gemigliptin of Formula-I or salt or hydrate or solvate thereof,

[Formula-I]
comprising reacting compound of Formula-VI,

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
with compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C1-C5¬ substituted or unsubstituted alkyl group”
to obtain Gemigliptin of Formula-I or salt or hydrate or solvate thereof.
Eighth aspect of the present invention is to provide a process for preparation of compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C2-C5¬ substituted or unsubstituted alkyl”
comprising reducing compound of Formula-VIII,

[Formula-VIII]
“wherein R3 is C2-C5¬ substituted or unsubstituted alkyl group”
to obtain compound of Formula-VII or salt thereof.
Ninth aspect of the present invention is to provide a compound of Formula-IV,

[Formula-IV]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
Tenth aspect of the present invention is to provide compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
Eleventh aspect of the present invention is to provide compound of compound of Formula-VI,

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
Twelfth aspect of present invention is to provide compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C2-C5¬ substituted or unsubstituted alkyl group”.
DETAILED DESCRIPTION OF INVENTION:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used in this specification, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
According to first embodiment, the present invention is to provide a process for preparation of Gemigliptin of Formula-I or salt or hydrate or solvate thereof,

[Formula-I]
comprising the steps of:
a) reacting compound of Formula-II or salt thereof,

[Formula-II]
with compound of Formula-III,

[Formula-III]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
to obtain compound of Formula-IV,

[Formula-IV]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
b) converting the compound of Formula-IV to compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
c) converting the compound of Formula-V to compound of Formula-VI; and

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
d) reacting compound of Formula-VI with compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C1-C5¬ substituted or unsubstituted alkyl group”
to obtain Gemigliptin of Formula-I or salt or hydrate or solvate thereof.
In the first embodiment of step a), the compound of Formula-II or salt thereof and compound of Formula-III can be prepared as per process known in the prior-art.
In the first embodiment of step a), reaction of compound of Formula-II or salt thereof with compound of Formula-III can be carried out in presence of coupling agent and solvent.
The coupling agent can be selected from the group consisting of 1,3-dicyclohexylcarbodiimide (DCC), isobutyl chloroformate, pivaloyl chloride, isovaleryl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), 1-cyclohexyl-3-morpholinoethylcarbodiimide, 1-hydroxybenzotriazole (HOBT), 2-Hydroxypyridine-N-oxide (HOPO), 1-cyclohexyl-3-(4-diethylaminocyclohexyl)carbodiimide, N,N'-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolinium chloride, isobutyl chloroformate and phase-transfer catalyst such as benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tributylhexylphosphonium bromide, tetraethylphosphonium tetrafluoroborate.
The solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.
In the first embodiment of step a), the reaction of compound of Formula-II or salt thereof with compound of Formula-III can be carried out at temperature of 0°C to reflux temperature of solvent used.
After completion of the reaction, the compound of Formula-IV can be isolated by isolation methods such as distillation or degassing or crystallization, recrystallization, or solvent-anti solvent methods.
In the first embodiment of step b), the compound of Formula-IV can be converted to compound of Formula-V in single step or in multiple steps. The compound of Formula-IV can also be deprotected completely followed by further conversion by amino protection and reduction to obtain compound of Formula-V.
The reducing agent for the reduction can be selected from group consisting of metal catalyst, such as sodium borohydride, lithium borohydride sodium borohydride or in combination with boron trifluoride etherate or in combination with sulfuric acid, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, platinum oxide and palladium on carbon.
The solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.
In the first embodiment of step b), the converting compound of Formula-IV to compound of Formula-V can be carried out temperature of 0°C to reflux temperature of the solvent used.
After completion of the reaction, the compound of Formula-V can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing or compound of Formula-V can be isolated by processes known in the prior-art such as crystallization, recrystallization, or solvent-anti solvent methods.
In the first embodiment of step c), the compound of Formula-V can be converting to compound of Formula-VI by oxidising the compound of Formula-V by using oxidising agent to obtain compound of Formula-VI.
In the first embodiment of step c), the oxidising agent can be selected from the group consisting of pyridinium chlorochromate (PCC), Dess–Martin periodinane, pyridinium dichromate (PDC), 2,2,6,6-Tetramethylpiperidinyloxy (TEMPO), Sodium hypochlorite and swern oxidation using oxalyl chloride, dimethyl sulfoxide, triethylamine.
In the first embodiment of step c), the converting compound of Formula-V to compound of Formula-VI can be carried out at temperature up to reflux temperature of the solvent used
After completion of the reaction, the compound of Formula-VI can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing or compound of Formula-VI can be isolated by processes known in the prior-art such as crystallization, recrystallization, or solvent-anti solvent methods.
In the first embodiment of step d), the reaction compound of Formula-VI with compound of Formula-VII or salt thereof can be carried out in presence of reducing agent, solvent and acid.
The reducing agent can be selected from group consisting of suitable metal catalyst, such as sodium borohydride, lithium borohydride sodium borohydride or in combination with boron trifluoride etherate or in combination with sulfuric acid, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, platinum oxide and palladium on carbon.
The solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.
The acid can be selected from the group consisting of organic acid or inorganic acid; wherein organic acid can be selected from acetic acid, trifluoroacetic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid and propionic acid; inorganic acid can be selected from hydrochloric acid, conc. sulfuric acid, nitric acid, phosphoric acid.
In the first embodiment of step d), the reaction of compound of Formula-VI with compound of Formula-VII or salt thereof can be carried out up to reflux temperature of the solvent used.
After completion of the reaction, the Gemigliptin of Formula-I can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing or Gemigliptin of Formula-I can be isolated by processes known in the prior-art such as crystallization, recrystallization, or solvent-anti solvent methods.
According to second embodiment of the present invention is to provide a process for preparation of compound of Formula-IV,

[Formula-IV]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
comprising reacting compound of Formula-II or salt thereof,

[Formula-II]
with compound of Formula-III,

[Formula-III]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
to obtain compound of Formula-IV.
In the second embodiment, the compound of Formula-II or salt thereof and compound of Formula-III can be prepared process known in the prior-art.
In the second embodiment, the reaction of compound of Formula-II or salt thereof with compound of Formula-III can be carried out in presence of coupling agent and solvent.
The coupling agent can be selected from the group consisting of 1,3-dicyclohexylcarbodiimide (DCC), isobutyl chloroformate, pivaloyl chloride, isovaleryl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), 1-cyclohexyl-3-morpholinoethylcarbodiimide, 1-hydroxybenzotriazole (HOBT), 2-Hydroxypyridine-N-oxide (HOPO), 1-cyclohexyl-3-(4-diethylaminocyclohexyl)carbodiimide, N,N'-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolinium chloride, isobutyl chloroformate and phase-transfer catalyst such as benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tributylhexylphosphonium bromide, tetraethylphosphonium tetrafluoroborate.
The solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.
In the second embodiment, the reaction of compound of Formula-II or salt thereof with compound of Formula-III can be carried out up to reflux temperature of solvent used.
After completion of the reaction, the compound of Formula-IV can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing or compound of Formula-IV can be isolated by processes known in the prior-art such as crystallization, recrystallization, or solvent-anti solvent methods.
According to third embodiment of the present invention is to provide a process for preparation of compound of Formula-IVa,

[Formula-IVa]
comprising converting the compound of Formula-IVb,

[Formula-IVb]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group, provided that R1 and R2 together are not hydrogen”
to compound of Formula-IVa.
In the third embodiment, the converting compound of Formula-IVb to compound of Formula-IVa can be carried in presence of acid and solvent.
The acid can be selected from the group consisting of organic acid or inorganic acid; wherein organic acid can be selected from acetic acid, trifluoroacetic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid and propionic acid; inorganic acid can be selected from hydrochloric acid, conc. sulfuric acid, nitric acid and phosphoric acid.
The solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane, water or mixture(s) thereof.
In the third embodiment, the converting compound of Formula-IVb to compound of Formula-IVa can be carried up to the reflux temperature of solvent used.
After completion of the reaction, the compound of Formula-IVa can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing or compound of Formula-IVa can be isolated by processes known in the prior-art such as crystallization, recrystallization, or solvent-anti solvent methods.
According to fourth embodiment of the present invention is to provide a process for preparation of compound of Formula-IVc,

[Formula-IVc]
comprising reacting compound of Formula-IVa,

[Formula-IVa]
with amino protecting agent to obtain compound of Formula-IVc.
In the fourth embodiment, the amino protecting agent can be selected from group consisting of tert-butyl carbamate, 1-(tert-butoxycarbonyl)imidazole, [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile], 2-(tert-butoxycarbonylthio)-4,6-dimethylpyrimidine, 1-tert-butoxycarbonyl-1,2,4-triazole, tert-butyl phenyl carbonate, tert-butyl carbazate, N-(tert-butoxycarbonyloxy)-phthalimide.
In the fourth embodiment, the reaction of compound of Formula-IVa with amino protecting agent can also be carried out in presence of base and solvent.
The base can be selected from the group consisting of organic base such as triethyl amine, tert-butyl amine, pyridine, imidazole; inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
The solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.
In the fourth embodiment, the reaction of compound of Formula-IVa with amino protecting agent can be carried out up to reflux temperature of the solvent used.
After completion of the reaction, the compound of Formula-IVc can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing or compound of Formula-IVc can be isolated by processes known in the prior-art such as crystallization, recrystallization, or solvent-anti solvent methods.
According to fifth embodiment of the present invention is to provide a process for preparation of compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
comprising converting the compound of Formula-IV,

[Formula-IV]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
to compound of Formula-V.
In the fifth embodiment, the converting the compound of Formula-IV to compound of Formula-V can be carried out in presence of reducing agent and solvent.
The reducing agent can be selected from group consisting of suitable metal catalyst, such as sodium borohydride, lithium borohydride sodium borohydride or in combination with boron trifluoride etherate or in combination with sulfuric acid, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, platinum oxide and palladium on carbon.
The solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.
In the fifth embodiment, converting the compound of Formula-IV to compound of Formula-V can be carried out up to reflux temperature of the solvent used.
After completion of the reaction, the compound of Formula-V can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing or compound of Formula-V can be isolated by processes known in the prior-art such as crystallization, recrystallization, or solvent-anti solvent methods.
According to sixth embodiment of the present invention is to provide a process for preparation of compound of Formula-VI,

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
comprising converting the compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
to compound of Formula-VI.
In the sixth embodiment, the compound of Formula-V can be converting to compound of Formula-VI by oxidising the compound of Formula-V by using oxidising agent to obtain compound of Formula-VI.
The oxidising agent can be selected from the group consisting of pyridinium chlorochromate (PCC), Dess–Martin periodinane, pyridinium dichromate (PDC), 2,2,6,6-Tetramethylpiperidinyloxy (TEMPO), Sodium hypochlorite and swern oxidation using oxalyl chloride, dimethyl sulfoxide, triethylamine.
In the sixth embodiment, the converting compound of Formula-V to compound of Formula-VI can be carried out up to reflux temperature of solvent used.
After completion of the reaction, the compound of Formula-VI can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing or compound of Formula-VI can be isolated by processes known in the prior-art such as crystallization, recrystallization, or solvent-anti solvent methods.
According to seventh embodiment of the present invention is to provide a process for preparation of Gemigliptin of Formula-I or salt or hydrate or solvate thereof,

[Formula-I]
comprising reacting compound of Formula-VI,

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
with compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C1-C5¬ substituted or unsubstituted alkyl group”
to obtain Gemigliptin of Formula-I or salt or hydrate or solvate thereof.
In the seventh embodiment, the reaction compound of Formula-VI with compound of Formula-VII or salt thereof can be carried out in presence of reducing agent, solvent and acid.
The reducing agent can be selected from group consisting of suitable metal catalyst, such as sodium borohydride, lithium borohydride sodium borohydride or in combination with boron trifluoride etherate or in combination with sulfuric acid, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, platinum oxide and palladium on carbon.
The solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.
The acid can be selected from the group consisting of organic acid or inorganic acid; wherein organic acid can be selected from acetic acid, trifluoroacetic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid and propionic acid; inorganic acid can be selected from hydrochloric acid, conc. sulfuric acid, nitric acid and phosphoric acid.
In the seventh embodiment, the reaction of compound of Formula-VI with compound of Formula-VII or salt thereof can be carried out up to the reflux temperature of the solvent used.
After completion of the reaction, the Gemigliptin of Formula-I can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing or Gemigliptin of Formula-I can be isolated by processes known in the prior-art such as crystallization, recrystallization, or solvent-anti solvent methods.
According to eighth embodiment of the present invention is to provide a process for preparation of compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C2-C5¬ substituted or unsubstituted alkyl”
comprising reducing compound of Formula-VIII,

[Formula-VIII]
“wherein R3 is C2-C5¬ substituted or unsubstituted alkyl group”
to obtain compound of Formula-VII or salt thereof.
In the eighth embodiment, the compound of Formula-VIII can be commercially available or can be prepared process known in the prior-art.
In the eighth embodiment, the reducing compound of Formula-VIII by using reducing agent to obtain compound of Formula-VII or salt thereof.
The reducing agent can be selected from group consisting of suitable metal catalyst, such as sodium borohydride, lithium borohydride sodium borohydride or in combination with boron trifluoride etherate or in combination with sulfuric acid, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, platinum oxide and palladium on carbon.
In the eighth embodiment, the reducing compound of Formula-VIII by using reducing agent to obtain compound of Formula-VII can be carried out in presence of acid and solvent.
The acid can be selected from the group consisting of organic acid or inorganic acid; wherein organic acid can be selected from acetic acid, trifluoroacetic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid and propionic acid; inorganic acid can be selected from hydrochloric acid, conc. sulfuric acid, nitric acid and phosphoric acid.
The solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.
In the eighth embodiment, the reducing compound of Formula-VIII using suitable reducing agent to obtain compound of Formula-VII can be carried out up to reflux temperature of the solvent used.
After completion of the reaction, the compound Formula-VII can be isolated by removing the solvent followed by drying. Generally, solvent can be removed by distillation or degassing or compound Formula-VII can be isolated by processes known in the prior-art such as crystallization, recrystallization, or solvent-anti solvent methods.
According to nineth embodiment of the present invention is to provide a compound of Formula-IV,

[Formula-IV]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
According to tenth embodiment of the present invention is to provide compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
According to eleventh embodiment of the present invention is to provide compound of compound of Formula-VI,

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
According to twelfth embodiment of present invention is to provide compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C2-C5¬ substituted or unsubstituted alkyl group”
EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example-01: Preparation of compound of Formula-IVd

[Formula-IVd]
To a stirred solution of methylene dichloride (50 mL) and (3S)-4-tert-butoxy-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoic acid of Formula-IIIa (10.8 g), dicyclohexyl carbodiimide (8.92 g) was added at 25°C to 35°C. Resulting mixture was stirred for 90 minutes and 2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride of Formula-II (10 g) was added slowly. The obtained mixture was stirred for 120 minutes. After completion of reaction, the mixture was filtered and resulting filtrate was distilled to remove solvent completely. Resulting mass was purified by methyl tert-butyl ether to obtain title compound.
Example-02: Preparation of compound of Formula-IVa

[Formula-IVa]
To a stirred solution of water (45 mL) and compound of Formula-IVd (10.0 g) obtained in Example-01, concentrated hydrochloric acid (1.1 g) was added slowly at 25°C to 35°C. Resulting mixture was heated at 80°C to 90° for 10 hours. After completion of reaction, the resulting mixture was cooled at room temperature and pH of the mixture was adjusted to 7 to 8. Methylene dichloride (50 mL) was added to resulting mixture and stirred for 5 minutes. Resulting mixture was allowed to separate organic and aqueous layer. The organic layer-1 was kept aside and aqueous layer was extracted using methylene dichloride (2 x 50 mL). All the organic layers were combined together and distilled to remove solvent. Resulting distilled mass was treated with n-Heptane to obtain title compound.
Example-03: Preparation of compound of Formula-IVc

[Formula-IVc]
To a stirred solution of tetrahydrofuran (25 mL) and compound of Formula-IVa (5.0 g) obtained in Example-02, triethyl amine (1.57 g) was added at 25°C to 35°C. Resulting mixture was cooled at 0°C to 10°C and di-tert-butyl decarbonate (3.39 g) was added at same temperature. Resulting mixture was stirred for 2 hours. After completion of reaction, water was added to the mixture and pH is adjusted to 4 to 5. Resulting mixture was allowed to separate organic and aqueous layer. Methylene dichloride (250 mL) was added to resulting mixture and stirred for 5 minutes. Resulting mixture was allowed to separate organic and aqueous layer. The organic layer-1 was kept aside and aqueous layer was extracted using methylene dichloride (2 x 25 mL). All the organic layers were combined together and distilled to remove solvent. Resulting distilled mass was treated with isopropyl alcohol to obtain title compound.
Example-04: Preparation of compound of Formula-Va

[Formula-Va]
To a stirred solution of tetrahydrofuran (25 mL) and compound of Formula-IVc (5.0 g) obtained in Example-03, ethyl orthoformate (1.83 g) was added slowly at 0°C to 10°C. Resulting mixture was stirred for 1 hours and sodium borohydride (0.58 g) was added slowly at 0°C to 10°C, temperature of mixture slowly raised up to 25°C to 35°C. After completion reaction, ethyl acetate and water were added to the resulting mixture at 25°C to 35°C. pH of the mixture was adjusted to 8 to 9 using triethylamine. Resulting mixture was allowed to separate organic and aqueous layer. The organic layer-1 was kept aside and aqueous layer was extracted using ethyl acetate. All the organic layers were combined together and distilled to remove solvent. Resulting distilled mass was treated with isopropyl alcohol to obtain title compound.
Example-05: Preparation of compound of Formula-VIa

[Formula-VIa]
To a stirred solution of dimethyl sulfoxide (25 mL) and compound of Formula-Va (5.0 g) obtained in Example-04, triethyl amine (1.60 g) was added at 0°C to 10°C. To the resulting mixture oxalyl chloride (1.35 gm) was slowly added at 0°C to 10°C and stirred for 1 hour, slowly temperature of the mixture raised up to 25°C to 35°C. After completion of reaction, ethyl acetate and water was added at same temperature. Resulting mixture was allowed to separate organic and aqueous layer. The organic layer-1 was kept aside and aqueous layer was extracted using ethyl acetate. All the organic layers were combined together and distilled to remove solvent. Resulting distilled mass was treated with isopropyl alcohol to obtain title compound.
Example-06: Preparation of compound of Formula-VIIa

[Formula-VIIa]
To a stirred solution of tetrahydrofuran (25 mL) and ethyl 5-amino-4,4-difluoro-5-oxopentanoate of Formula-VIIIa (5.0 g), sodium borohydride (3.38 g) was added at 25°C to 35°C. The temperature of the mixture was raised to 50°C, sulfuric acid (4.4 g) was slowly added and resulting mixture was stirred for 2 hours. After completion of reaction, resulting mixture was cooled at 0°C to 10°C, water was added and pH of the mixture was adjusted to 8 to 9. Methylene dichloride was added to resulting mixture and allowed to separate organic and aqueous layers. Resulting organic layer-1 kept aside and aqueous layer was extracted with Methylene dichloride. All the combined organic layer were distilled to obtain title compound.
Example-07: Preparation of Gemigliptin of Formula-I

[Formula-I]
To a stirred solution of methylene dichloride (25 mL) and compound of Formula-VIa (5.0 g) obtained in Example-05 and compound of Formula-VIIa (5.0 g) obtained in Example-06 was added at 0°C to 10°C. To the resulting mixture sodium triacetoxyborohydride (1.92 g) was added at 0°C to 10°C and stirred the mixture to reflux temperature for 6 hours. After completion reaction dilute hydrochloric acid was added stirred the mixture for 2 hours. Resulting mixture was allowed to separate organic and aqueous layer. The organic layer-1 was kept aside and aqueous layer was extracted using methylene dichloride. All the organic layers were combined together and distilled to remove solvent. Resulting distilled mass was treated with isopropyl alcohol to obtain title compound.

,CLAIMS:
I / We Claim:
1. A process for preparation of Gemigliptin of Formula-I or salt or hydrate or solvate thereof,

[Formula-I]
comprising the steps of:
a) reacting compound of Formula-II or salt thereof,

[Formula-II]
with compound of Formula-III,

[Formula-III]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
to obtain compound of Formula-IV;

[Formula-IV]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
b) converting the compound of Formula-IV to compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
c) converting the compound of Formula-V to compound of Formula-VI; and

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
d) reacting compound of Formula-VI with compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C1-C5¬ substituted or unsubstituted alkyl group”
to obtain Gemigliptin of Formula-I or salt or hydrate or solvate thereof.
2. The process as claimed in claim 1, wherein reaction of compound of Formula-II or salt thereof with compound of Formula-III can be carried out in presence of coupling agent selected from the group consisting of 1,3-dicyclohexylcarbodiimide (DCC), pivaloyl chloride, isovaleryl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), 1-cyclohexyl-3-morpholinoethylcarbodiimide, 1-hydroxybenzotriazole (HOBT), 2-Hydroxypyridine-N-oxide (HOPO), 1-cyclohexyl-3-(4-diethylaminocyclohexyl)carbodiimide, N,N'-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolinium chloride, isobutyl chloroformate and phase-transfer catalyst such as benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tributylhexylphosphonium bromide, tetraethylphosphonium tetrafluoroborate; and solvent selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof.
3. The process as claimed in claim-1, wherein compound of Formula-V can be converted to compound of Formula-VI using oxidising agent selected from the group consisting of pyridinium chlorochromate (PCC), Dess–Martin periodinane, pyridinium dichromate (PDC), 2,2,6,6-Tetramethylpiperidinyloxy (TEMPO), Sodium hypochlorite or agent of Swern oxidation reaction namely oxalyl chloride, dimethyl sulfoxide and triethylamine.
4. The process as claimed in claim-1, wherein the reaction compound of Formula-VI with compound of Formula-VII or salt thereof can be carried out in presence of reducing agent, solvent and acid.
5. The process as claimed in claim-4, wherein reducing agent can be selected from group consisting of suitable metal catalyst, such as sodium borohydride, lithium borohydride, or in combination with boron trifluoride etherate or in combination with sulfuric acid, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, aluminium hydrides, platinum oxide and palladium on carbon; solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; alkane such as n-hexane, heptane or cyclohexane or mixture(s) thereof; and acid can be selected from the group consisting of organic acid or inorganic acid wherein organic acid can be selected from acetic acid, trifluoroacetic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid and propionic acid; inorganic acid can be selected from hydrochloric acid, conc. sulfuric acid, nitric acid, phosphoric acid.
6. A process for preparation of compound of Formula-IVa,

[Formula-IVa]
comprising the steps of:
a) reacting compound of Formula-II or salt thereof,

[Formula-II]
with compound of Formula-III,

[Formula-III]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
to obtain compound of Formula-IVb; and

[Formula-IVb]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group, provided that R1 and R2 together are not hydrogen”
b) converting the compound of Formula-IVb to compound of Formula-IVa.
7. A process for preparation of compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
comprising converting the compound of Formula-IV,

[Formula-IV]
“wherein R1 is hydrogen or amino protecting group; and
R2 is hydrogen or hydroxy protecting group”
to compound of Formula-V.
8. A process for preparation of compound of Formula-VI,

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
comprising converting the compound of Formula-V,

[Formula-V]
“wherein R1 is hydrogen or amino protecting group”
to compound of Formula-VI.
9. A process for preparation of Gemigliptin of Formula-I or salt or hydrate or solvate thereof,

[Formula-I]
comprising reacting compound of Formula-VI,

[Formula-VI]
“wherein R1 is hydrogen or amino protecting group”
with compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C1-C5¬ substituted or unsubstituted alkyl group”
to obtain Gemigliptin of Formula-I or salt or hydrate or solvate thereof.
10. A process for preparation of compound of Formula-VII or salt thereof,

[Formula-VII]
“wherein R3 is C2-C5¬ substituted or unsubstituted alkyl”
comprising reducing compound of Formula-VIII,

[Formula-VIII]
“wherein R3 is C2-C5¬ substituted or unsubstituted alkyl group”
to obtain compound of Formula-VII or salt thereof.
Dated this 01st October 2024

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.