DESC:
FIELD OF THE INVENTION:
The present invention relates to an efficient and industrially advantageous process for the preparation of Gemigliptin intermediate (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoic acid of Formula-I.
The present invention also relates to provide a process for the preparation of tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoate of Formula-IV and its use for the preparation of Gemigliptin or salt or hydrate or solvate thereof.
BACKGROUND OF THE INVENTION:
The compound (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoic acid of Formula-I,

[Formula-I]
is a useful intermediate for the preparation of Gemigliptin or salt or hydrate or solvate thereof.
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-V,

[Formula-V]
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) discloses process for preparation of (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoic acid of Formula-I comprising reacting 3S-tert-butoxycarbonylamino-4-oxo-butyric acid tert-butylester with 5-amino-4,4-difluoropentanoic acid methyl ester hydrochloric acid salt in presence of 1,2-dichloroethane and sodium triacetoxyborohydride followed by purification using column chromatography to obtain tert-butyl (3S)-3-[(t-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoate. Resulting compound was deprotected using solution of chloromethane and trifluoroacetic acid (1:1) to obtain (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoic acid having 39% yield.
The major drawback of US ‘848 process is, it requires column chromatography purification which is industrially not viable. Also, the overall process results into lower yield and is silent about purity of the obtained (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoic acid. Therefore, it is not an attractive option for large scale industrial production.
As prior art process requires column chromatography and results into lower yield. Thus, there is a need to develop a novel process for the preparation of (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoic acid which solves the problem of prior art.
Present inventors have developed an efficient and novel process for the preparation of (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxopiperidin-1-yl)-butanoic acid 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 (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoic acid.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide an efficient and industrially advantageous process for the preparation of (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoic acid of Formula-I.
Another object of the present invention is to provide a process for the preparation of tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoate of Formula-IV and its 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 compound of Formula-I,

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

[Formula-II]
“wherein R1 is hydroxy protecting group”
with compound of Formula-III,

[Formula-III]
“wherein R2 is C1-C8 substituted or unsubstituted alkyl”
to obtain compound of Formula-IV; and

[Formula-IV]
b) converting the compound of Formula-IV to obtain compound of Formula-I.

Second aspect of the present invention is to provide a process for preparation of compound of Formula-IV,

[Formula-IV]
comprising reacting compound of Formula-II,

[Formula-II]
“wherein R1 is hydroxy protecting group”
with compound of Formula-III,

[Formula-III]
“wherein R2 is C1-C8 substituted or unsubstituted alkyl”
to obtain compound of Formula-IV.
Third aspect of the present invention is to provide a process for preparation of compound of Formula-I,

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

[Formula-IV]
with acid followed by further reaction with di-tert-butyl dicarbonate to obtain compound of Formula-I.
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 provides a process for preparation of compound of Formula-I,

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

[Formula-II]
“wherein R1 is hydroxy protecting group”
with compound of Formula-III,

[Formula-III]
“wherein R2 is C1-C8 substituted or unsubstituted alkyl”
to obtain compound of Formula-IV; and

[Formula-IV]
b) converting the compound of Formula-IV to obtain compound of Formula-I.
In the first embedment of step a), the compound of Formula-II and compound of Formula-III can be prepared as per process known in the prior art.
In the first embodiment of step a), the reaction of compound of Formula-II with compound of Formula-III can 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, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate potassium carbonate.
The acid can be selected from the group consisting of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as formic acid, acetic acid, tartaric 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 first embodiment of step a), the reaction of compound of Formula-II with compound of Formula-III can be carried at temperature of 20°C to reflux temperature of the solvent used.
After completion of the reaction, acid can be added to resulting mixture. Resulting mixture can be stirred for 2 hours to 10 hours.
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), conversion of compound of Formula-IV to compound of the Formula-I can be carried out by reacting compound of Formula-IV in presence of acid and solvent followed by further reaction using di-tert-butyl dicarbonate.
The acid can be selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid, trifluoroacetic acid (TFA).
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 water or mixture(s) thereof.
In the first embodiment of step b), reaction of compound of Formula-IV with acid can be carried out at temperature of 20°C to reflux temperature of the solvent used.
In the first embodiment of step b), after completion of reaction of compound of Formula-IV with acid further reaction with di-tert-butyl dicarbonate can be carried out at temperature of 20°C to reflux temperature of the solvent used. After completion of reaction, acid can be added to resulting mixture.
Resulting compound of Formula-I can be isolated by isolation methods such as distillation or degassing or crystallization, recrystallization, or solvent-anti solvent methods.
According to second embodiment, the present invention provides a process for preparation of compound of Formula-IV,

[Formula-IV]
comprising reacting compound of Formula-II,

[Formula-II]
“wherein R1 is hydroxy protecting group”
with compound of Formula-III,

[Formula-III]
“wherein R2 is C1-C8 substituted or unsubstituted alkyl”
to obtain compound of Formula-IV.
In the second embodiment, the compound of Formula-II and Formula-III can be prepared as per process known in the prior art.
In the second embodiment, the reaction of compound of Formula-II with compound of Formula-III can 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, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate potassium carbonate.
The acid can be selected from the group consisting of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as formic acid, acetic acid, tartaric 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 second embodiment, the reaction of compound of Formula-II with compound of Formula-III can be carried at temperature of 20°C to reflux temperature of the solvent used.
After completion of the reaction, acid can be added to resulting mixture. Resulting mixture can be stirred for 2 hours to 10 hours.
The compound of Formula-IV can be isolated by isolation methods such as distillation or degassing or crystallization, recrystallization, or solvent-anti solvent methods.
The hydroxy protecting group according to present invention can be any protecting group suitable for a hydroxy functional group. Representative hydroxy protecting groups include, but are not limited to, silanes such as trimethyl silane (TMS), t-butyl dimethyl silane (TBDMS), or t-butyl diphenyl silane (TBDPS), ethers such as methyl-methoxy (MOM), tetrahydropyran (THP), t-butyl, allyl, or benzyl, and esters such as acetyl, pivaloyl, or benzoyl, or mesylate (Ms), or tosyl (Ts) or triflate (Tf).
Third aspect of the present invention is to provide a process for preparation of compound of Formula-I,

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

[Formula-IV]
with acid followed by further reaction with di-tert-butyl dicarbonate to obtain compound of Formula-I.
In the third embodiment, conversion of compound of Formula-IV to compound of the Formula-I can be carried out by reacting compound of Formula-IV in presence of acid and solvent followed by further reaction using di-tert-butyl dicarbonate.
The acid can be selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid, trifluoroacetic acid (TFA).
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 water or mixture(s) thereof.
In the third embodiment, reaction of compound of Formula-IV with acid can be carried out at temperature of 20°C to reflux temperature of the solvent used.
In the third embodiment, after completion of reaction of compound of Formula-IV with acid further reaction with di-tert-butyl dicarbonate can be carried out at temperature of 20°C to reflux temperature of the solvent used. After completion of reaction, acid can be added to resulting mixture.
The compound of Formula-I can be isolated by isolation methods such as distillation or degassing or crystallization, recrystallization, or solvent-anti solvent methods.
The compound of Formula-I obtained according to present invention can be converted to Gemigliptin or salt or hydrate or solvate thereof.

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 tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoate of Formula-IV

[Formula-IV]
To a stirred solution of methylene dichloride (50 mL) and triethylamine (12.72 g), tert-butyl (3S)-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]-butanoate (19.10 g) and methyl 5-amino-4,4-difluoropentanoate (10 g) were added at temperature of 25°C to 35°C. Resulting mixture was stirred for 30 minutes at same temperature. Resulting mixture was then stirred for 21 hours at 40°C to 50°C. Resulting mixture was cooled at 25°C to 35°C and acetic acid was added. Resulting mixture was maintained for 5 hours at same temperature. 0.5 N aqueous hydrochloric acid solution was added to resulting mixture. Resulting mixture was stirred for 30 minutes and allowed to separate organic and aqueous layers. Resulting organic layer was distilled under reduced pressure to obtain title compound.
Yield: 80 %
Example-02: Preparation of (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoic acid of Formula-I

[Formula-I]
To a stirred solution of water (45 mL) and tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butanoate of Formula-IV (5.0 g), concentrated hydrochloric acid (1.25 mL) was added at 25°C to 35°C. Resulting mixture was heated at temperature of 80°C to 90°C for 18 hours. After completion reaction, resulting mixture was cooled at 25°C to 35°C and 5% aqueous sodium carbonate was added to adjust the pH to 8.5. To the resulting mixture, di-tert-butyl dicarbonate (3.3 g) was added and mixture was stirred for 18 hours. Resulting mixture was cooled at 0°C to 10°C and pH was adjusted to 4.5 using 1N aqueous hydrochloric acid. Methylene dichloride 50 (mL) was added to resulting mixture and mixture was allowed to separate organic and aqueous layers. Resulting organic layer-1 kept aside and aqueous layer was washed with methylene dichloride 50 (mL). All the organic layers were combined and distilled to obtain title compound.
Yield: 70 % ,CLAIMS:

I / We Claim:
1. A process for preparation of compound of Formula-I,

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

[Formula-II]
“wherein R1 is hydroxy protecting group”
with compound of Formula-III,

[Formula-III]
“wherein R2 is C1-C8 substituted or unsubstituted alkyl”
to obtain compound of Formula-IV; and

[Formula-IV]
b) converting the compound of Formula-IV to obtain compound of Formula-I.

2. The process as claimed in claim 1, wherein the reaction of compound of Formula-II with compound of Formula-III is carried out in presence of base and solvent at temperature of 20°C to reflux temperature of the solvent used.
3. The process as claimed in claim 2, wherein base is 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, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and solvent is 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.
4. The process as claimed in claim 1, wherein compound of Formula-IV is converted to compound of the Formula-I by reacting compound of Formula-IV in presence of acid and solvent followed by further reaction using di-tert-butyl decarbonate.
5. The process as claimed in claim 4, wherein acid is sulfuric acid, hydrochloric acid, phosphoric acid, or trifluoroacetic acid (TFA) and solvent is 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 water or mixture(s) thereof..
6. A process for preparation of compound of Formula-IV,

[Formula-IV]
comprising reacting compound of Formula-II,

[Formula-II]
“wherein R1 is hydroxy protecting group”
with compound of Formula-III,

[Formula-III]
“wherein R2 is C1-C8 substituted or unsubstituted alkyl”
to obtain compound of Formula-IV.
7. The process as claimed in claim 6, wherein reaction of compound of Formula-II with compound of Formula-III can be carried out in presence of base and solvent at 20°C to reflux temperature of the solvent used.
8. The process as claimed in claim 7, wherein base is 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, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and solvent is 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.
9. A process for preparation of compound of Formula-I,

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

[Formula-IV]
with acid followed by further reaction with di-tert-butyl dicarbonate to obtain compound of Formula-I.
10. The process as claimed in claim 9, wherein acid is sulfuric acid, hydrochloric acid, phosphoric acid, or trifluoroacetic acid (TFA).

Dated this 27th November 2024

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