WO2015092805A1 - A process for preparation of trelagliptin succinate - Google Patents
A process for preparation of trelagliptin succinate Download PDFInfo
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- WO2015092805A1 WO2015092805A1 PCT/IN2014/000563 IN2014000563W WO2015092805A1 WO 2015092805 A1 WO2015092805 A1 WO 2015092805A1 IN 2014000563 W IN2014000563 W IN 2014000563W WO 2015092805 A1 WO2015092805 A1 WO 2015092805A1
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- IWYJYHUNXVAVAA-OAHLLOKOSA-N CN(C(C=C(N1Cc2cc(F)ccc2C#N)N(CCC2)C[C@@H]2N)=O)C1=O Chemical compound CN(C(C=C(N1Cc2cc(F)ccc2C#N)N(CCC2)C[C@@H]2N)=O)C1=O IWYJYHUNXVAVAA-OAHLLOKOSA-N 0.000 description 2
- SGLXGFAZAARYJY-UHFFFAOYSA-N CN(C(C=C(N1)Cl)=O)C1=O Chemical compound CN(C(C=C(N1)Cl)=O)C1=O SGLXGFAZAARYJY-UHFFFAOYSA-N 0.000 description 1
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions
- the present invention relates to a novel process for preparation of Trelagliptin succinate.
- Trelagliptin is dipeptidyl peptidase IV (DPP-IV) inhibitor and useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
- DPP-IV dipeptidyl peptidase IV
- Trelagliptin and its pharmaceutical acceptable salts are disclosed in US 8,288,539, US 7,807,689 and US 7,906,523.
- Trelagliptin and its pharmaceutical acceptable salts is disclosed in various patents namely US 8,222,411, US 7,906,523, and US 8,288,539. According to the described processes, 2-bromo-5-fluorotoluene and CuCN in DMF was refluxed for 24 hrs to obtain 4-fluoro-2-methyl benzonitrile(31) which further reacts with NBS and AIBN in CC1 4 at reflux temperature for 2hrs to obtain 2-bromo methyl-4- fluorobenzonitrile(32)which further reacts with 3-methyl-6-chloro uracil in DMSO in presence of K 2 C0 3 at 60°C for 2hrs to give 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro- 2H-pyrimidin-l-yl-methyl)-4-fluoro benzonitrile(33).
- Trelagliptin The prior art processes reported for preparing Trelagliptin involves multi steps and complexity. Isolation and purification of each step make the process more tedious and uneconomical. Therefore, it is required to develop an efficient process to avoid multiple isolations and purifications of intermediate products.
- the present invention aims to provide novel, advantageous and economical process for preparing Trelagliptin succinate with high purity and high yield that remains the objective of the invention, for which protection is sought.
- the present invention discloses a novel process for preparing Trelagliptin succinate (Formula-II).
- the invention provides a process for isolating Trelagliptin hydrochloride from protected Trelagliptin by deprotection which comprises:
- the present invention describes a novel process for preparing(R)-2-[[6-(3- aminopiperidin-l -yl)-3-methyl-2, 4-dioxo-3, 4-dihydropyrimidin- l -(2H)-yl] methyl]-4- '
- the present invention provides insifu condensation process for preparing protected Trelagliptin of forniula-VII
- the reaction is carried out at an elevated temperature of 50- 100°C to obtain protected Trelagliptin.
- the 2-(halomethyl)-4-fluorobenzonitrile is selected from 2-(bromomethyl)-4- fluorobenzonitrile, 2-(chloromethyl)-4-fluorobenzonitrile or 2-(iodomethyl)-4- fluorobenzonitrile.
- 2-(chloro methyl) -4- fluorobenzonitrile is used in presence of catalyst and 2 -(bromo methyl)-4- fluorobenzonitrile is used in the absence of catalyst.
- Catalyst is used to enhance the rate of reaction.
- the solvent used in the said process is selected from the group consisting of polar aprotic solvents such as ⁇ , ⁇ -dimethyl acetamide, ⁇ , ⁇ -dimefhyl formamide, dimethyl sulfoxide; chloride solvents such as dichloromethane; ketones such as acetone, methyl ethyl ketone; ethers such as methyl tertiary butyl ether, diisopropyl ether; other solvents such as ethyl acetate, heptane, or mixtures of two or more solvents.
- polar aprotic solvents such as ⁇ , ⁇ -dimethyl acetamide, ⁇ , ⁇ -dimefhyl formamide, dimethyl sulfoxide
- chloride solvents such as dichloromethane
- ketones such as acetone, methyl ethyl ketone
- ethers such as methyl tertiary butyl ether, diisopropyl
- the base is selected from inorganic base or organic base.
- the inorganic base is selected from carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate &sodium methoxide and the organic base such as trisubstituted amines selected from triethylamine, diisopropyl ethylamine, N-methyl morpholine& N-methyl pyrrolidine.
- the protecting group for (3R)-piperidine-3-amine is selected from Carbobenzyloxy (Cbz), p-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9- Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), Carbamate, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), Tosyl (Ts), Mesyl (Ms) and other Sulfonamides (Nosyl&Nps).
- the suitable catalyst is selected from Potassium iodide, sodium iodide, sodium bromide, potassium bromide.
- the HPLC purity of the protected Trelagliptin thus obtained is in the range of 96-98%.
- the invention provides process for Trelagliptin hydrochloride salt of formula-VIII from protected Trelagliptin of formula-VII by deprotection process
- the deprotection process is carried out by hydrogenolysis, using deprotection agents such as concentrated strong acids like HCl, HBr. H2SO4, CH 3 COOH,CF 3 COOH or mixture thereof or strong acids in solution form; bases such as Piperidine, aqueous or gaseous ammonia or methylamine; aliphatic amides, ammonium cerium(IV) nitrate; strong reducing agents like sodium in liquid ammonia or sodium naphthalenide; samarium iodide, tributyltin hydride or Pd/C, Palladium hydroxide.
- deprotection agents such as concentrated strong acids like HCl, HBr. H2SO4, CH 3 COOH,CF 3 COOH or mixture thereof or strong acids in solution form; bases such as Piperidine, aqueous or gaseous ammonia or methylamine; aliphatic amides, ammonium cerium(IV) nitrate; strong reducing agents like sodium in liquid ammonia
- the deprotecting agent for BOC deprotection is selected from the group consisting of alcoholic hydrochloric acid; 5-25% hydrochloric acid in acetic acid; 5-50% acetic acid in ethyl acetate; aq. Hydrochloric acid ( 1 : 1 ) and trifluoroacetic acid.
- the alcohol may be selected from methanol, ethanol and isopropanol.
- a Further aspect involves process for preparation of Trelagliptin succinate of formula-ll from Trelagliptin hydrochloride of formula-VIII which comprises:
- the HPLC purity of Trelagliptin succinate thus obtained is more than 99.96% preferably in the range of 99.96- 100%.
- the instant invention provides process for preparing Trelagliptin succinate according to scheme-II.
- Trelagliptin hydrochloride salt was added into the mixture of 675cc methylene dichloride and 405 cc water. pH was adjusted to 12- 13 using 10% aqs. Sodiumhydroxide solution. The aqs layer was extracted with 810 cc methylene dichloride. The organic layer was washed with 675 cc, 20% NaClaqs. solution. The organic layer was finally washed with 675 cc water followed by charcolization. The solution was filtered off through Hyflo bed and the filtrate was passed through 0.047 moles sodium sulphate. The solvent from the filtrate was distilled off completely under reduced pressure at35-60°C and degassed for 30-45 min.
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Abstract
The present invention discloses a process for preparing (R)-2-[[6-(3-Aminopiperidin-1-yl)-3-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl] methyl]-4-fluorobenzonitrile succinate known as Trelagliptin succinate of formula-II.
Description
A PROCESS FOR PREPARATION OF TRELAGLIPTIN SUCCINATE"
FIELD OF INVENTION:
The present invention relates to a novel process for preparation of Trelagliptin succinate. BACKGROUND OF INVENTION:
(R)-2-[[6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l-(2H)- yl]methyl]-4-fluorobenzonitrile is known as Trelagliptin (Formula-I). Trelagliptin is dipeptidyl peptidase IV (DPP-IV) inhibitor and useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
Formula-I
Trelagliptin and its pharmaceutical acceptable salts are disclosed in US 8,288,539, US 7,807,689 and US 7,906,523.
Process for preparation of Trelagliptin and its pharmaceutical acceptable salts is disclosed in various patents namely US 8,222,411, US 7,906,523, and US 8,288,539. According to the described processes, 2-bromo-5-fluorotoluene and CuCN in DMF was refluxed for 24 hrs to obtain 4-fluoro-2-methyl benzonitrile(31) which further reacts with NBS and AIBN in CC14 at reflux temperature for 2hrs to obtain 2-bromo methyl-4- fluorobenzonitrile(32)which further reacts with 3-methyl-6-chloro uracil in DMSO in presence of K2C03 at 60°C for 2hrs to give 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro- 2H-pyrimidin-l-yl-methyl)-4-fluoro benzonitrile(33). 2-(6-chloro-3-methyl-2,4-dioxo- 3,4-dihydro-2H-pyrimidin-l -yl-methyl)-4-fluoro benzonitrile thus obtained reacts with
(R)-3-amino- piperidine dihydrochloridein IPA and in presence of sodium bicarbonate at 60°C for 2hrs to give (R)-2-[[6-(3-aminopiperidin- l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin- l -(2H)-ylJmethyl]-4-fluorobenzonitrile (Trelagliptin). (Scheme-I)
33
Scheme-I
US 8,084,605describes succinate salt of Trelagliptin and its various polymorphic forms and also provides novel methods for preparing polymorphic forms.
The prior art processes reported for preparing Trelagliptin involves multi steps and complexity. Isolation and purification of each step make the process more tedious and uneconomical. Therefore, it is required to develop an efficient process to avoid multiple isolations and purifications of intermediate products.
Accordingly, the present invention aims to provide novel, advantageous and economical process for preparing Trelagliptin succinate with high purity and high yield that remains the objective of the invention, for which protection is sought.
SUMMARY OF THE INVENTION:
The present invention discloses a novel process for preparing Trelagliptin succinate (Formula-II).
In a preferred embodiment the present invention provides insitu condensation process for preparing protected Trelagliptin of formula-VII which comprises:
(a) reacting 6-chloro-3-methylpyrimidine-2,4-( l H, 3H)-dione of formula III with 2-(halomethyl)-4-fluorobenzonitrile of formula IV in presence of aprotic solvent, a base, and optionally in presence of suitable catalyst at an elevated temperature to obtain formula-V,
(b) reacting 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidine- 1 (2H)- yl)methyl]-4-fluorobenzonitrile of formula V insitu with protected (3R)- piperidine-3-amine of formula VI at an elevated temperature to obtain protected Trelagliptin of formula VII.
In another embodiment, the invention provides a process for isolating Trelagliptin hydrochloride from protected Trelagliptin by deprotection which comprises:
(a) reacting protected Trelagliptin of formula-VII with deprotecting agent at a temperature of-5 to 25°C and
(b) isolating Trelagliptin hydrochloride of formula-VIII.
In yet another preferred embodiment the invention provides process for manufacturing succinate salt of Trelagliptin which involves:
(a) reacting the compound of formula-VIII in presence of solvent and succinic acid;
(b) adjusting the pH between 5.0-6.0 and
(c) isolating Trelagliptin succinate of formula-II.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention describes a novel process for preparing(R)-2-[[6-(3- aminopiperidin-l -yl)-3-methyl-2, 4-dioxo-3, 4-dihydropyrimidin- l -(2H)-yl] methyl]-4-'
Formula-H
According to one aspect, the present invention provides insifu condensation process for preparing protected Trelagliptin of forniula-VII
Where = BOC
Formula-VII
which comprises:
(a) reacting 6-chIoro-3-methylpyrimidine-2,4-( l H, 3H)-dione of formula
where X= CI, Br, I
Formula-IV
with 2-(halomethyl)-fluorobenzonitrile of formula IV using aprotic solvent in presence of a base and optionally in presence of suitable catalyst at an elevated temperature to obtain formula-V.
Formula-V
(b) reacting 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidine- l -(2H)- yl)methyl]-4-fluorobenzonitrile of formula V insitu
H
Where R = BOC
Formula-VI
with protected (3R)-piperidine-3-amine of formula VI at an elevated temperature to obtain protected Trelagliptin of formula VII.
Formula-VII
According to the above process, the reaction is carried out at an elevated temperature of 50- 100°C to obtain protected Trelagliptin.
The 2-(halomethyl)-4-fluorobenzonitrile is selected from 2-(bromomethyl)-4- fluorobenzonitrile, 2-(chloromethyl)-4-fluorobenzonitrile or 2-(iodomethyl)-4- fluorobenzonitrile. According to the process of the invention,2-(chloro methyl) -4- fluorobenzonitrile is used in presence of catalyst and 2 -(bromo methyl)-4- fluorobenzonitrile is used in the absence of catalyst. Catalyst is used to enhance the rate of reaction.
The solvent used in the said process is selected from the group consisting of polar aprotic solvents such as Ν,Ν-dimethyl acetamide, Ν,Ν-dimefhyl formamide, dimethyl sulfoxide; chloride solvents such as dichloromethane; ketones such as acetone, methyl ethyl ketone; ethers such as methyl tertiary butyl ether, diisopropyl ether; other solvents such as ethyl acetate, heptane, or mixtures of two or more solvents.
The base is selected from inorganic base or organic base. The inorganic base is selected from carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate &sodium methoxide and the organic base such as trisubstituted amines selected from triethylamine, diisopropyl ethylamine, N-methyl morpholine& N-methyl pyrrolidine.
The protecting group for (3R)-piperidine-3-amine is selected from Carbobenzyloxy (Cbz), p-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9- Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), Carbamate, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), Tosyl (Ts), Mesyl (Ms) and other Sulfonamides (Nosyl&Nps).
In accordance with the said process, the suitable catalyst is selected from Potassium iodide, sodium iodide, sodium bromide, potassium bromide. The HPLC purity of the protected Trelagliptin thus obtained is in the range of 96-98%.
In another aspect, the invention provides process for Trelagliptin hydrochloride salt of formula-VIII from protected Trelagliptin of formula-VII by deprotection process
Formula-VIII
which comprises:
(a) reacting protected Trelagliptin of formula-VII with deprotecting agent at a temperature of-5 to 25°C and
(b) isolating Trelagliptin hydrochloride of formula-VIII.
The deprotection process is carried out by hydrogenolysis, using deprotection agents such as concentrated strong acids like HCl, HBr. H2SO4, CH3COOH,CF3COOH or mixture thereof or strong acids in solution form; bases such as Piperidine, aqueous or gaseous ammonia or methylamine; aliphatic amides, ammonium cerium(IV) nitrate; strong reducing agents like sodium in liquid ammonia or sodium naphthalenide; samarium iodide, tributyltin hydride or Pd/C, Palladium hydroxide.
Specifically, the deprotecting agent for BOC deprotection is selected from the group consisting of alcoholic hydrochloric acid; 5-25% hydrochloric acid in acetic acid; 5-50% acetic acid in ethyl acetate; aq. Hydrochloric acid ( 1 : 1 ) and trifluoroacetic acid. The alcohol may be selected from methanol, ethanol and isopropanol.
The HPLC purity of the Trelagliptin hydrochloride thus obtained is 97-99%.
A Further aspect involves process for preparation of Trelagliptin succinate of formula-ll from Trelagliptin hydrochloride of formula-VIII which comprises:
(a) converting Formula-VIII into formula-II by treating with succinic acid in presence of acetone;
(b) adjusting the pH between 5.0-6.0
(c) Isolating Trelagliptin succinate of formula-II.
The HPLC purity of Trelagliptin succinate thus obtained is more than 99.96% preferably in the range of 99.96- 100%.
Formula-Ill Formula-lV Fortnula-V Formula-VII
Formula-II Formula-VIII
Where R = BOC
Scheme-II
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples:
Example: 1 Preparation of protected Trelagliptin
To the 200cc dimethyl acetamide, charged 0.31 1 moles of formula III and 0.342 moles of formula IV (where X= Br). After stirring for 15-30 min at ambient temperature added 0.467 moles potassium carbonate and again stirred the reaction mass for 60-90 min at elevated temperature at around 50-100°C. The insitu reaction carry forwarded by adding 0.342 moles protected (3R)-piperidine-3-amine of formula VI and 0.560 moles potassium carbonate at elevated temperature of about 50-100°C and stirred for 90-180 min. After completion of reaction, the reaction mixture was cooled and slowly added 1250 cc water
at0-30°Cand stirred for 10-30 min, Product was filtered and washed with water. The wet solid was dried at 35-80°C to obtain 98- 100% yield of protected Trelagliptin.
HPLC Purity: 96-98%
Example: 2 Preparation of protected Trelagliptin
To the 200cc dimethyl acetamide, charged 0.31 1 moles of formula III, 0.342 moles of formula IV (where X= CI) and 0.030 moles of potassium iodide .After stirring for 15-30 min at ambient temperature added 0.467 moles potassium carbonate and again stirred the reaction mass for 60-90 min at elevated temperature at around 50-100°C. The insitu reaction cany forwarded by adding 0.342 moles protected (3R)-piperidine-3-amine of formula VI and 0.560 moles potassium carbonate at elevated temperature at about 50- 100°C and stined for 90- 180 min. After completion of reaction, the reaction mixture was cooled and slowly added 1250 cc water at0-30°C and stirred for 10-30 min. Product was filtered and washed with water. The wet solid was dried at 35-80°C to obtain 98- 100% yield of protected Trelagliptin.
HPLC Purity: 96-98%
Example: 3 Preparation of protected Trelagliptin
To the 250cc methylene dichloride, charged 0.31 1 moles of formula III and 0.342 moles of formula IV (where X= Br). After stirring for 15-30 min at ambient temperature added 0.715 moles of triethylamine and again stirred the reaction mass for 90- 120 min at maintained temperature of around35-50°C. The insitu reaction carry forwarded by adding 0.342 moles protected (3R)-piperidine-3-amine of formula VI and again stirred for 120- 150 min at maintained temperature at about35-50°C. After completion of reaction, the organic layer was washed withwater followed by 20% aq. Sodium chloride solution and again washed with water. The solvent was evaporated under reduced pressure to obtain protected Trelagliptin. Inorganic impurities were removed by making slurry in water. The wet solid was dried at 40-60°C to get protected Trelagliptin with yield of 98- 100%.
HPLC Purity: 96-98%
Example: 4 Preparation of protected Trelagliptin
To the 200cc acetone, charged 0.31 1 moles of formula III and 0.342 moles of formula IV
triethyl amine and again stirred the reaction mass for 60-90 min at elevated temperature of about 40-65°C. The insitu reaction carry forwarded by adding 0.342 moles protected (3R)-piperidine-3-amine of formula VI and 0.342 moles triethyl amine at temperature of around30-60°C and stirred for 90-120 min. After completion of reaction, the reaction mixture was cooled and slowly added 1250 cc water at0-30°C and stirred for 10-30 min. Product was filtered and washed with water. The wet solid was dried at 35-80°C to obtain 98-100% yield of protected Trelagliptin.
HPLC Purity: 96-98%
Example 5: Preparation of Trelagliptinhydrochloride
To the 405cc methanol, charged 0.295moles of formula VII(where R= BOC)and stirred below 10°C, preferably at 0±10°C. 540cc 20-25% Methanolichydrochloric acid was slowly added for 30-90 min at 0±10°C and the reaction mass was stirred for 60-90 min. The hydrochloride salt precipitated was filtered and suck dried well to obtain 90-99% yield of Trelagliptin hydrochloride.
HPLC Purity: 97-99%
Example 6: Preparation of Trelagliptinsuccinate
Trelagliptin hydrochloride salt was added into the mixture of 675cc methylene dichloride and 405 cc water. pH was adjusted to 12- 13 using 10% aqs. Sodiumhydroxide solution. The aqs layer was extracted with 810 cc methylene dichloride. The organic layer was washed with 675 cc, 20% NaClaqs. solution. The organic layer was finally washed with 675 cc water followed by charcolization. The solution was filtered off through Hyflo bed and the filtrate was passed through 0.047 moles sodium sulphate. The solvent from the filtrate was distilled off completely under reduced pressure at35-60°C and degassed for 30-45 min. To the degassed mass 1080 cc acetone was added and heated to temperature at 40-60°C. Added 0.206 moles of succinic acid by maintaining pH in between 5.0-6.0 preferably at 5.5-6.0. Stirred the reaction mass for 10-30min and cooled to 10±5°C. The obtained succinate salt was filtered off and washed with 270 cc acetone. Wet material was dried at 40-80°C to afford Trelagliptin succinate with a yield of65-90%.
HPLC Purity: 99.96-100%.
Claims
1. A process for preparing Trelagliptin succinate (formula-II) comprises:
Formula-II
(a) reacting 6-chloro-3-methylpyrimidine-2,4-( l H, 3H)-dione with 2- (halomethyl)-fluorobenzonitrile in presence of solvent, a base at an elevated temperature to obtain 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidine- l (2H)-yl)methyl]-4-fluorobenzonitrile;
(b) reacting 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidine- 1 (2H)- yl)methyl]-4-fluorobenzonitrile insitu with protected (3R)-piperidine-3-amine at an elevated temperature to obtain protected Trelagliptin;
(c) reacting protected Trelagliptin with deprotecting agent to obtain Trelagliptin hydrochloride and
(d) converting Trelagliptin hydrochloride into Trelagliptin succinate in presence of acetone and succinic acid by maintaining pH at 5.0-6.0.
2. The process according to claim 1 , wherein the base in step (a) is inorganic or organic base.
3. The process according to claim 2, wherein the inorganic base is selected from the group consisting of carbonate salts of alkali and alkaline earth metals such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate and sodium methoxide and the organic base is selected from the group consisting of trisubstituted amines like triethylamine, diisopropyl ethylamine, N-methyl morpholine and N-methyl pyrrolidine.
4. The process according to claim 1 , wherein the 2-(halo methyl)-4- fluorobenzonitirle in step (a) is selected from the group consisting of 2-(bromo methyl)-4-fluorobenzonitrile,2-(chloro methyl)-4- fluorobenzonitrile or 2-(iodo methyl)-4-fluorobenzonitrile.
5. The process according to claim 1 , wherein the reaction of 6-chloro-3- methylpyrimidine-2,4-( l H, 3H)-dione with 2-(halomethyl)-fluorobenzonitrile is optionally conducted in presence of a catalyst.
6. The process according to claim 5, wherein, the 2-(chloro methyl) -4- fluorobenzonitrile is used in presence of catalyst and 2-(bromo methyl)-4- fluorobenzonitrile is used in the absence of catalyst.
7. The process according to claim 5, wherein the catalyst is selected from the group consisting of Potassium iodide, sodium iodide, sodium bromide or potassium bromide.
8. The process according to claim 1 , wherein the solvent used in step (a) is selected from the group consisting of polar aprotic solvents such as N,N-dimethyl acetamide, Ν,Ν-dimethyl formamide, dimethyl sulfoxide; chloride solvents such as dichloromethane; ketones such as acetone, methyl ethyl ketone; ethers such as methyl tertiary butyl ether, diisopropyl ether; other solvents such as ethyl acetate, heptane, or mixtures of two or more solvents.
9. The process according to claim 8, wherein the solvent is selected from the group consisting of N, N-dimethylacetamide, N, N-dimethylformamide or dimethylsulfoxide.
10. The process according to claim 1 , wherein the elevated temperature in step (a) and step (b) is in the range of 50- 100°C.
11. The process according to claim 1 , wherein the temperature in step (c) and (d) is in
12. The process according to claim 1 , wherein the amine protecting group in step (b) is selected from the group consisting of Carbobenzyloxy (Cbz), p-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9- Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), Carbamate, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p- methoxyphenyl (PMP), Tosyl (Ts), Mesyl (Ms) or other Sulfonamides (Nosyl & Nps).
13. The process according to claim 1 , wherein the deprotecting agent in step (c) is selected from concentrated strong acids such as HC1, HBr, H2SO4, CH3COOH, CF3COOH or mixture thereof or strong acids in solution form; bases such as Piperidine, aqueous or gaseous ammonia or methylamine; aliphatic amides, ammonium cerium(IV) nitrate, concentrated acids (HBr, H2SO4); strong reducing agents such as sodium in liquid ammonia, sodium naphthalenide; samarium iodide, tributyltin hydride or Pd/C, Palladium hydroxide.
14. The process according to claim 12, wherein the deprotecting agent is selected from the group consisting of alcoholic hydrochloric acid, 5-25% hydrochloric acid in acetic acid, 5-50% acetic acid in ethyl acetate, aq. hydrochloric acid ( 1 : 1 ) or trifluoroacetic acid.
15. The process according to any of the preceding claims, wherein purity of protected Trelagliptin, Trelagliptin hydrochloride and Trelagliptin succinate is 96-98%, 97- 99% and 99.9- 100% respectively.
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105541793A (en) * | 2016-01-04 | 2016-05-04 | 河北国龙制药有限公司 | Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate |
CN105646447A (en) * | 2015-12-25 | 2016-06-08 | 北京康立生医药技术开发有限公司 | Synthesis method of dipeptidyl peptidase inhibitor |
CN107434800A (en) * | 2016-05-27 | 2017-12-05 | 威海迪素制药有限公司 | A kind of amber love song Ge Lieting crystal formations A preparation method |
CN108822080A (en) * | 2018-08-31 | 2018-11-16 | 四川新斯顿制药股份有限公司 | The preparation method of amber love song Ge Lieting |
CN109668988A (en) * | 2019-02-27 | 2019-04-23 | 浙江华贝药业有限责任公司 | A method of 2- (two bromomethyls) -4- fluorobenzonitrile in analysis measurement amber love song Ge Lieting |
CN109734673A (en) * | 2019-02-27 | 2019-05-10 | 浙江华贝药业有限责任公司 | A kind of purification process of compound |
CN110483478A (en) * | 2019-08-15 | 2019-11-22 | 广东工业大学 | A kind of crystalline state song Ge Lieting and its preparation method and application, song Ge Lieting succinate crystal and preparation method thereof |
CN115448887A (en) * | 2022-09-05 | 2022-12-09 | 河北国龙制药有限公司 | Trelagliptin succinate intermediate impurity and preparation method and application thereof |
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105646447A (en) * | 2015-12-25 | 2016-06-08 | 北京康立生医药技术开发有限公司 | Synthesis method of dipeptidyl peptidase inhibitor |
CN105541793A (en) * | 2016-01-04 | 2016-05-04 | 河北国龙制药有限公司 | Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate |
CN105541793B (en) * | 2016-01-04 | 2018-08-10 | 河北国龙制药有限公司 | The synthetic method of bent Ge Lieting |
CN107434800A (en) * | 2016-05-27 | 2017-12-05 | 威海迪素制药有限公司 | A kind of amber love song Ge Lieting crystal formations A preparation method |
CN108822080A (en) * | 2018-08-31 | 2018-11-16 | 四川新斯顿制药股份有限公司 | The preparation method of amber love song Ge Lieting |
CN109668988A (en) * | 2019-02-27 | 2019-04-23 | 浙江华贝药业有限责任公司 | A method of 2- (two bromomethyls) -4- fluorobenzonitrile in analysis measurement amber love song Ge Lieting |
CN109734673A (en) * | 2019-02-27 | 2019-05-10 | 浙江华贝药业有限责任公司 | A kind of purification process of compound |
CN109668988B (en) * | 2019-02-27 | 2021-07-02 | 浙江华贝药业有限责任公司 | Method for analyzing and determining 2- (dibromomethyl) -4-fluorobenzonitrile in trelagliptin succinate |
CN110483478A (en) * | 2019-08-15 | 2019-11-22 | 广东工业大学 | A kind of crystalline state song Ge Lieting and its preparation method and application, song Ge Lieting succinate crystal and preparation method thereof |
CN115448887A (en) * | 2022-09-05 | 2022-12-09 | 河北国龙制药有限公司 | Trelagliptin succinate intermediate impurity and preparation method and application thereof |
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EP3083580A1 (en) | 2016-10-26 |
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