WO2014108830A1 - A process for preparing pharmaceutically acceptable salt of saxagliptin - Google Patents
A process for preparing pharmaceutically acceptable salt of saxagliptin Download PDFInfo
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- WO2014108830A1 WO2014108830A1 PCT/IB2014/058109 IB2014058109W WO2014108830A1 WO 2014108830 A1 WO2014108830 A1 WO 2014108830A1 IB 2014058109 W IB2014058109 W IB 2014058109W WO 2014108830 A1 WO2014108830 A1 WO 2014108830A1
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- saxagliptin
- pharmaceutically acceptable
- acceptable salt
- boc
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Definitions
- the present invention provides a process for the preparation of intermediate of Saxagliptin, amide compound of Formula II, and its conversion to pharmaceutically acceptable salt of Saxagliptin.
- Saxagliptin of Formula I is chemically known as (IS,3S,5S)-2-[(2S)-2-Amino-2-(3- hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1 .0]hexane-3-carbonitrile, which is an orally-active inhibitor of the DPP4 enzyme.
- Saxagliptin is marketed under the trade name ONGLYZA by Bristol-Myers Squibb for the treatment of type 2 diabetes.
- U.S. Patent No. 6,395,767 discloses Saxagliptin and salts thereof.
- the US '767 provides a process for preparing TFA salt of Saxagliptin from amide compound.
- amide compound involves dissolution of (S)-a-[[(1 ,1 - dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 -acetic acid in dimethylformamide and then reaction with (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide TFA salt in presence of 1 -hydroxybenzotriazole (HOBT), 1 -Ethyl-3-(3-dimethyllaminopropyl)carbodiimide (EDC) and triethylamine. Further, the resultant amide compound is purified by using column chromatography technique. The yield and purity of amide compound is very low and the process involves use of column chromatography technique for purification, which is commercially very difficult.
- U.S. Pat. No. 7,420,079 discloses Saxagliptin and salts thereof.
- the US ⁇ 79 provides a process for preparation of amide compound, which involves treatment of (S)-a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane- 1 -acetic acid with mesyl chloride in presence THF and diisopropylethylamine (DIPEA) to convert acid into mixed anhydride followed by condensation with (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide.HCI salt in presence of HOBT to provide amide compound.
- DIPEA diisopropylethylamine
- PCT application No. 201 1/12501 1 discloses a process for the preparation of amide compound, which involves addition of the reaction mixture consisting (S)- a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 - acetic acid, (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide MSA salt and acetonitrile into the mixture of HOBT and DIPEA at room temperature, which is then added into EDC. HCI at 0°C, followed by DIPEA is added. The resultant reaction mixture is stirred for 12 hours to provide amide compound of Formula II.
- the present invention relates to a process for the preparation of amide compound of formula II, a process for purification thereof, and its conversion to saxagliptin or a pharmaceutically acceptable salt thereof.
- step b) adding additive, coupling reagent and then base to the suspension of step a);
- Formula IV or a salt thereof to react with the mixture of step b) at room temperature to provide amide compound.
- a process for the preparation of amide compound of formula II which comprises reaction of (1 S,3S,5S)-2- azabicyclo [3.1 .0]hexane-3-carboxamide of Formula V or a salt thereof with (S)- a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 - acetic acid using coupling reagent in the presence of additive and base in a mixture of isopropyl acetate and acetonitrile.
- step b) reaction of pure amide compound of step a) with trifluoroacetic anhydride (TFAA) in presence of eth l nicotinate to provide of formula I II :
- step d) converting Boc-saxagliptin of formula IV of step c) to pharmaceutically acceptable salt of Saxagliptin using acid in presence of isopropyl alcohol and water to afford pharmaceutically acceptable salt of saxagliptin.
- the present invention provides a process for the isolation of intermediate of Saxagliptin, boc-saxagliptin of formula IV or a pharmaceutically acceptable salt thereof.
- the process comprises:
- step a) i) providing solution of Boc-saxagliptin in ketone solvent at elevated temperature; ii) adding water to the solution of step a);
- the saxagliptin or a pharmaceutically acceptable salt thereof of the present invention is useful for the treatment of type 2 diabetes.
- substantially free refers to saxagliptin, an intermediate thereof, or a salt thereof that contains total impurities less than 1 %.
- the intermediates and starting materials of the present invention may be used as free bases or its salts.
- Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.
- step b) adding additive, coupling reagent and then base to the suspension of step a);
- the solvent include but are not limited to ester such as ethyl acetate, isopropyl acetate, 2-methoxyethyl acetate and the like; nitrile such as acetonitrile, propionitrile, and the like, chlorinated solvent such as dichloromethane, chlorobenzene and the like; formamides such as dimethyl formamide, dimethyl acetamide and the like; ethers such as diethyl ether, diisopropyl ether, ethyl tert- butyl ether, 1 ,4-dioxane, THF, and the like; dimethyl sulfoxide, N-methyl pyrrolidine, water; or mixture thereof.
- the solvent is selected from acetate and nitrile or mixture thereof.
- the solvent is a mixture of acetonitrile and isopropyl acetate (IPAc).
- the coupling reagent used for the amide formation is selected from carbodiimide such as 1 -Ethyl-3-(3-dimethyllaminopropyl)carbodiimide (EDC), EDC.HCI, Dicyclohexylcarbodiimide (DCC), N-cyclohexyl-N'-isopropylcarbodiimide, N- cyclohexyl-N'-tert-butylcarbodiimide, diisopropylcarbodiimide (DIC) and the like.
- carbodiimide such as 1 -Ethyl-3-(3-dimethyllaminopropyl)carbodiimide (EDC), EDC.HCI, Dicyclohexylcarbodiimide (DCC), N-cyclohexyl-N'-isopropylcarbodiimide, N- cyclohexyl-N'-tert-butylcarbodiimide, diiso
- the additive used is selected from the group of N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1 -hydroxybenzotriazole (HOBt), 6-chloro-1 -hydroxybenzotriazole (6-CI-HOBt), 1 -hydroxy-7- azabenzotriazole (HOAt) and 3-hydroxy-4-oxo-3,4-dihydro-1 ,2,3-benzotriazine (HODhbt) or hydrates thereof
- the base used for the amide formation is selected from N-Methylmorpholine (NMM), di-isopropylethylamine (DIPEA) or Hunig base, triethylamine (TEA) and the like.
- NMM N-Methylmorpholine
- DIPEA di-isopropylethylamine
- TEA triethylamine
- the suitable temperature for the formation of amide compound of formula II is room temperature, for example, is about 20°C to about 35°C.
- the reaction may be maintained at room temperature for a period of 30 minutes to about 4 hours.
- Both of reactants can be in the form of a base or pharmaceutically acceptable salts.
- salt is a hydrochloride salt and methane sulfonic acid (MSA) salt.
- MSA methane sulfonic acid
- (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide (Azabicyclic compound) is in the form of MSA salt and (S)-a-[[(1 ,1 - dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 -acetic acid (Boc-adamantic acid) is in the free form.
- Both reactants may be obtained by any method known in the art, for example, US 6,395,767.
- the reaction mixture is quenched in presence of quenching agent, extracted the amide compound into isopropyl acetate and then washed with base and brine solution to afford pure amide compound free from impurity including additive content.
- the quenching agent is selected from water, acid, alcohol and the like.
- the base is selected from inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
- the resultant amide compound may be prepared in-situ or isolated by using suitable techniques such as recrystallization, slurry in suitable solvent and anti- solvent technique.
- the present invention comprises in-situ formation of amide compound of formula II.
- reaction conditions of the present invention for example, addition of reactants and use of selected solvent or mixture of solvents provides pure amide compound of formula II and reduces by-product formation.
- amide compound of formula II obtained from the present invention is greater than 98% determined by HPLC.
- a process for the preparation of amide compound of formula II which comprises reaction of (1 S,3S,5S)-2- azabicyclo [3.1 .0]hexane-3-carboxamide of Formula V or a salt thereof with (S)- a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 - acetic acid using coupling reagent in the presence of additive and base in a mixture of isopropyl acetate and acetonitrile.
- the quantity of acetonitrile (ACN) used for the amide formation may be in the range of about 2 to 4 times for per gram of boc-adamantic acid.
- the quantity of isopropyl acetate (IPAc) may be in the range of about 1 to about 2 times for per gram of boc-adamantic acid.
- the coupling reagent is EDC.HCI, additive is HOBT hydrate and base is diisopropylethylamine.
- step b) reaction of pure amide compound of step a) with trifluoroacetic anhydride (TFAA) in presence of eth l nicotinate to provide of formula II I :
- step b) deprotecting the compound of formula II I of step b) with base in presence of alcohol to provide Boc-saxagliptin of formula IV:
- step d) converting Boc-saxagliptin of formula IV of step c) to pharmaceutically acceptable salt of Saxagliptin using acid in presence of isopropyl alcohol and water to afford pharmaceutically acceptable salt of saxagliptin.
- the present invention provides in-situ preparation of the compound of formula II and III.
- step a) involves suspension of (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide MSA salt in isopropyl acetate and acetonitrile at room temperature to form reaction mixture. Further, it involves addition of additive, for example, HOBT or its hydrate, coupling agent, for example, EDC HCI and then base, for example, diisopropylethylamine, respectively, to the reaction mixture.
- additive for example, HOBT or its hydrate
- coupling agent for example, EDC HCI
- base for example, diisopropylethylamine
- the reaction mixture is quenched with acid, extracted the amide compound into isopropyl acetate and then washed the isopropyl acetate layer with base and brine solution to afford pure amide compound free from impurity including additive content.
- the acid may be hydrochloric acid and the base may be potassium bicarbonate.
- the resultant solution comprising pure amide compound having purity greater than 98% is subjected for further reaction steps.
- the step b) involves adding trifluoroacetic anhydride (TFAA) into the ester solution comprising pure amide compound, obtained from the step a), at a temperature below 10°C in presence of ethyl nicotinate to provide compound of formula III.
- TFAA trifluoroacetic anhydride
- the reaction may be maintained for a period of 30 minutes to about 1 hour to affect yield of the reaction at 0-10 °C.
- reaction mixture may be subjected for further reaction or may be subjected for quenching with quenching agents and then treated with acid to get reaction mixture into organic layer.
- quenching agent is selected from tetramethylethylenediamine (TMEDA), alcohol, acid, water or in combination thereof.
- the present invention for preparation of the compound of formula III involves use of single solvent, which is used for preparation of amide compound and its extraction form the reaction mixture.
- single solvent for example, isopropyl acetate, affects the yield and purity, and it can be easily handled in large scale preparation also.
- the present process conditions for preparing the compound of Formula III from (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide MSA salt also reduces/controls the formation of impurity of formula A, which converts amide compound of Formula II in further deprotection reaction step, which may be difficult to remove by using simple purification techniques.
- the step c) involves selective deprotection of hydroxyl protecting group of formula III obtained from the step b) using base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like to provide Boc-saxagliptin of formula IV.
- base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like to provide Boc-saxagliptin of formula IV.
- the deprotection reaction is performed in presence of alcohol, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and the like at a temperature of about 35 to about 50°C.
- alcohol such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and the like at a temperature of about 35 to about 50°C.
- the reaction may be maintained for a period of 45 minutes to 4 hours to affect the yield and purity of Boc-saxagliptin of formula IV.
- reaction mixture may be subjected for further reaction step or may be subjected for separation of organic layer and isolation of solid using a solvent mixture of ketone and water.
- the step d) involves preparation of pharmaceutically acceptable salt of Saxagliptin from Boc-saxagliptin of Formula IV using acid in presence of isopropyl alcohol and water at elevated temperature, for example, 60-65 °C, for a period more than 1 hour.
- the reaction may be maintained at least 2 hours or more to affect the precipitation and purity of pharmaceutically acceptable salt of Saxagliptin.
- the quantity of acid is about 1 .5 to about 2 molar equivalents with respect to molar equivalent of Boc-saxagliptin.
- the acid may be selected from hydrochloric acid (HCI), methane sulfonic acid, trifluoroacetic acid, acetic acid and the like.
- the present invention involves use of HCI for formation of Saxagliptin hydrochloride salt.
- the HCI used may be concentrated HCI, HCI gas or source of HCI like alcoholic HCI, acetone. HCI and the like.
- the alcoholic HCI is selected from ethanolic HCI, propanolic HCI, isopropanolic HCI and the like.
- the purity of Saxagliptin hydrochloride prepared by the process of present invention is greater than about 99.5% determined by HPLC.
- the present invention provides a process for the isolation of intermediate of Saxagliptin, boc-saxagliptin of formula IV, which comprises: i) providing solution of Boc-saxagliptin in ketone solvent at elevated temperature;
- step a) adding water to the solution of step a);
- Providing a solution in step a) includes obtaining a solution of boc-saxagliptin in a ketone solvent or its combination with an organic solvent such as ester, alcohol, water and the like as a final step in the preparation of the compound or dissolving Boc-saxagliptin in ketone solvent.
- the ketone is selected from acetone, ethylmethyl ketone, methyl ter-butyl ketone and the like; or mixtures thereof.
- the solution in step a) may be provided at elevated temperature ranging from about room temperature to about boiling point of the solvent.
- the temperature may be at about 35 °C to about 55°C.
- the solution may optionally be treated with activated charcoal and then filtered to remove the carbon.
- the solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite.
- a clarifying agent such as Celite.
- the filtration apparatus may need to be heated or cooled to avoid undesired crystallization.
- Water is added slowly to the solution obtained in step a).
- the addition of water may be performed for a period of 30 minutes to 2 hours.
- the reaction mass obtained in step b) may be cooled to below room temperature or to below 10°C and stirred for 1 hour or more to affect the purity of the solid.
- the reaction mass may be cooled to temperatures about 0°C to about 5°C and stirred for 4 hours or more.
- the solid obtained from step c) may be recovered using known techniques such as filtration.
- the obtained solid may be dried and then subjected for the development of Saxagliptin or its pharmaceutically acceptable salt.
- the drying may be suitably carried out using any of equipment at atmospheric pressure or under reduced pressures, at temperatures less than about 40°C, less than about 30°C, less than about 20°C and any other suitable temperatures.
- the drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
- Example -1 Process for preparing Boc-Saxagliptin
- Azabicyclic salt 75 gm was suspended in isopropyl acetate (150 ml) and Acetonitril (300 ml) then 1 -hydroxybenzotriazole hydrate (45 gm), Ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride (65 gm), Diisopropylethylamine (90 gm) and Boc-adamantic acid (100 gm) were added at room temperature and stirred for 3 hour at 25-35°C.
- Boc-Saxagliptin residue (120 gm) obtained from the reaction was dissolved in the acetone (200 ml) at 40-50 °C. Then water (600 ml) was added slowly over a period of 1 -2 hr at 40-50 °C, then reaction mass was cooled to 5-10 °C, maintained for 4 hr, filtered and dried to get Boc-Saxagliptin.
- Amide Compound of Formula II 0.1 %.
- Example-2 A process for preparing Saxagliptin HCI:
- BOC-Saxagliptin 100 gm was suspended in isopropyl alcohol (100 ml).
Abstract
The present invention relates to a process for the preparation of intermediate of Saxagliptin, amide compound of Formula (II), and its conversion to pharmaceutically acceptable salt Saxagliptin.
Description
A PROCESS FOR PREPARING PHARMACEUTICALLY ACCEPTABLE SALT
OF SAXAGLIPTIN
Field of Invention
The present invention provides a process for the preparation of intermediate of Saxagliptin, amide compound of Formula II, and its conversion to pharmaceutically acceptable salt of Saxagliptin.
Formula II
Background of the invention
Saxagliptin of Formula I is chemically known as (IS,3S,5S)-2-[(2S)-2-Amino-2-(3- hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1 .0]hexane-3-carbonitrile, which is an orally-active inhibitor of the DPP4 enzyme.
Formula I
Saxagliptin is marketed under the trade name ONGLYZA by Bristol-Myers Squibb for the treatment of type 2 diabetes.
U.S. Patent No. 6,395,767 discloses Saxagliptin and salts thereof. The US '767 provides a process for preparing TFA salt of Saxagliptin from amide compound. The process of amide compound involves dissolution of (S)-a-[[(1 ,1 - dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 -acetic acid in dimethylformamide and then reaction with (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide TFA salt in presence of 1 -hydroxybenzotriazole (HOBT), 1 -Ethyl-3-(3-dimethyllaminopropyl)carbodiimide (EDC) and triethylamine. Further, the resultant amide compound is purified by using column chromatography technique. The yield and purity of amide compound is very low and the process involves use of column chromatography technique for purification, which is commercially very difficult.
U.S. Pat. No. 7,420,079 discloses Saxagliptin and salts thereof. The US Ό79 provides a process for preparation of amide compound, which involves treatment of (S)-a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane- 1 -acetic acid with mesyl chloride in presence THF and diisopropylethylamine (DIPEA) to convert acid into mixed anhydride followed by condensation with (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide.HCI salt in presence of HOBT to provide amide compound. The yield is very low due to formation of first mixed anhydride and then reacting with amine compound.
PCT application No. 201 1/12501 1 discloses a process for the preparation of amide compound, which involves addition of the reaction mixture consisting (S)- a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 - acetic acid, (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide MSA salt and acetonitrile into the mixture of HOBT and DIPEA at room temperature, which is then added into EDC. HCI at 0°C, followed by DIPEA is added. The resultant reaction mixture is stirred for 12 hours to provide amide compound of Formula II. The use of longer hours and unfavorable reaction conditions provides lower yield and impure amide compound.
Various other prior art references, for example, US 7,741 ,082, US 7,214,702, David et al., in Journal of Medicinal Chemistry, 2005, 48 (15), pp 5025 Liu et al., in Bioorganic & Medicinal Chemistry Vol. 19 (3), 1 136, S.A. Scott et al., in Organic Process Research & Development 2009, 13, 1 169 discloses a process for preparing amide compound and its conversion to Saxagliptin.
The above prior art processes faces one or the other difficulties like degradation of activated ester, formation of byproducts, which carry over to final product while converting amide compound to pharmaceutically acceptable salt of Saxagliptin. The resultant byproduct may require tedious purification to remove in the final stage. For example, US 6,395,767 discloses purification of intermediates using column chromatography and US 201 1 /275687A1 discloses a process for purification of Boc-saxagliptin using isopropyl alcohol and water, which are not industrially feasible processes and not provides pure compounds.
Therefore, there is a need to develop a process for preparing amide compound and its conversion to pharmaceutically acceptable salt of saxagliptin that is lower cost alternative, simple and industrially applicable, result in high yield and high purity of the intermediate as well as pharmaceutically acceptable salt of Saxagliptin.
Summary of the Invention
The present invention relates to a process for the preparation of amide compound of formula II, a process for purification thereof, and its conversion to saxagliptin or a pharmaceutically acceptable salt thereof.
In an aspect of the present invention provides a process for the preparation of amide compound of formula II:
Formula II
pharmaceutically acceptable salt thereof, which comprises:
a) suspending (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide of formula V:
b) adding additive, coupling reagent and then base to the suspension of step a); and
c) finally adding (S)-a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3- hydroxytricyclo-[3.3.1 .1 ]decane-1 -acetic acid of Formula IV:
Formula IV or a salt thereof to react with the mixture of step b) at room temperature to provide amide compound.
In another aspect of the present invention provides a process for the preparation of amide compound of formula II, which comprises reaction of (1 S,3S,5S)-2- azabicyclo [3.1 .0]hexane-3-carboxamide of Formula V or a salt thereof with (S)- a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 - acetic acid using coupling reagent in the presence of additive and base in a mixture of isopropyl acetate and acetonitrile.
In another aspect of the present invention provides a process for the preparation of pharmaceutically acceptable salt of Saxagliptin thereof comprises:
a) reaction of (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide MSA salt of Formula VA:
Formula V A with (S)-a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-
[3.3.1 .1 ]decane-1 -acetic acid of formula IV:
Formula IV
using coupling agent in the presence of additive and base in a mixture of isopropyl acetate and acetonitrile to provide pure amide of formula II:
or a pharmaceutically acceptable salt thereof; b) reaction of pure amide compound of step a) with trifluoroacetic anhydride (TFAA) in presence of eth l nicotinate to provide of formula I II :
Formula I II
or a pharmaceutically acceptable salt thereof; c) deprotecting the compound of formula II I of step b) with base in presence of alcohol to provide Boc-saxa liptin of formula IV:
Formula IV
or a pharmaceutically acceptable salt thereof; and
d) converting Boc-saxagliptin of formula IV of step c) to pharmaceutically acceptable salt of Saxagliptin using acid in presence of isopropyl alcohol and water to afford pharmaceutically acceptable salt of saxagliptin.
In another aspect, the present invention provides a process for the isolation of intermediate of Saxagliptin, boc-saxagliptin of formula IV or a pharmaceutically acceptable salt thereof. The process comprises:
i) providing solution of Boc-saxagliptin in ketone solvent at elevated temperature;
ii) adding water to the solution of step a);
iii) optionally, cooling to below room temperature; and
iv) recovering pure Boc-saxagliptin having purity greater than 99%.
The saxagliptin or a pharmaceutically acceptable salt thereof of the present invention is useful for the treatment of type 2 diabetes.
Description of the Invention
The term "substantially free" as used herein, unless otherwise defined, refers to saxagliptin, an intermediate thereof, or a salt thereof that contains total impurities less than 1 %.
The intermediates and starting materials of the present invention may be used as free bases or its salts.
The term "pure" as used herein, unless otherwise defined, the compound that has purity of greater than or equal to 99 % or greater than or equal to 99.5 %.
The salt or pharmaceutically acceptable salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.
In an aspect of the present invention provides a process for the preparation of amide compound of formula II:
Formula II
pharmaceutically acceptable salt thereof, which comprises:
a) suspending (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide of formula V:
b) adding additive, coupling reagent and then base to the suspension of step a); and
c) finally adding (S)-a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3- hydroxytricyclo-[3.3.1 .1 ]decane-1 -acetic acid of Formula IV:
Formula IV or a salt thereof to react with the mixture of step b) at room temperature to provide amide compound.
The present inventors found preferred reaction conditions for coupling of (S)-a- [[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 -acetic acid or salt thereof with (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide or salt thereof that provided a faster rate of reaction to achieve higher yield and greater purity of amide compound of formula II.
The solvent include but are not limited to ester such as ethyl acetate, isopropyl acetate, 2-methoxyethyl acetate and the like; nitrile such as acetonitrile, propionitrile, and the like, chlorinated solvent such as dichloromethane, chlorobenzene and the like; formamides such as dimethyl formamide, dimethyl acetamide and the like; ethers such as diethyl ether, diisopropyl ether, ethyl tert- butyl ether, 1 ,4-dioxane, THF, and the like; dimethyl sulfoxide, N-methyl pyrrolidine, water; or mixture thereof. In an embodiment, the solvent is selected from acetate and nitrile or mixture thereof. In another embodiment, the solvent is a mixture of acetonitrile and isopropyl acetate (IPAc).
The coupling reagent used for the amide formation is selected from carbodiimide such as 1 -Ethyl-3-(3-dimethyllaminopropyl)carbodiimide (EDC), EDC.HCI, Dicyclohexylcarbodiimide (DCC), N-cyclohexyl-N'-isopropylcarbodiimide, N- cyclohexyl-N'-tert-butylcarbodiimide, diisopropylcarbodiimide (DIC) and the like.
The additive used is selected from the group of N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1 -hydroxybenzotriazole (HOBt), 6-chloro-1 -hydroxybenzotriazole (6-CI-HOBt), 1 -hydroxy-7- azabenzotriazole (HOAt) and 3-hydroxy-4-oxo-3,4-dihydro-1 ,2,3-benzotriazine (HODhbt) or hydrates thereof
The base used for the amide formation is selected from N-Methylmorpholine (NMM), di-isopropylethylamine (DIPEA) or Hunig base, triethylamine (TEA) and the like.
The suitable temperature for the formation of amide compound of formula II is room temperature, for example, is about 20°C to about 35°C. The reaction may be maintained at room temperature for a period of 30 minutes to about 4 hours.
Both of reactants can be in the form of a base or pharmaceutically acceptable salts. For example, salt is a hydrochloride salt and methane sulfonic acid (MSA) salt. In an embodiment, (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide (Azabicyclic compound) is in the form of MSA salt and (S)-a-[[(1 ,1 - dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 -acetic acid (Boc-adamantic acid) is in the free form. Both reactants may be obtained by any method known in the art, for example, US 6,395,767.
After completion of the reaction, the reaction mixture is quenched in presence of quenching agent, extracted the amide compound into isopropyl acetate and then washed with base and brine solution to afford pure amide compound free from impurity including additive content. The quenching agent is selected from water, acid, alcohol and the like. The base is selected from inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
The resultant amide compound may be prepared in-situ or isolated by using suitable techniques such as recrystallization, slurry in suitable solvent and anti- solvent technique. In an embodiment, the present invention comprises in-situ formation of amide compound of formula II.
The reaction conditions of the present invention, for example, addition of reactants and use of selected solvent or mixture of solvents provides pure amide compound of formula II and reduces by-product formation.
The purity of amide compound of formula II obtained from the present invention is greater than 98% determined by HPLC.
In another aspect of the present invention provides a process for the preparation of amide compound of formula II, which comprises reaction of (1 S,3S,5S)-2- azabicyclo [3.1 .0]hexane-3-carboxamide of Formula V or a salt thereof with (S)- a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 - acetic acid using coupling reagent in the presence of additive and base in a mixture of isopropyl acetate and acetonitrile.
The quantity of acetonitrile (ACN) used for the amide formation may be in the range of about 2 to 4 times for per gram of boc-adamantic acid. The quantity of isopropyl acetate (IPAc) may be in the range of about 1 to about 2 times for per gram of boc-adamantic acid. The coupling reagent is EDC.HCI, additive is HOBT hydrate and base is diisopropylethylamine.
The overall process for preparing amide compound of Formula II is depicted in the following Scheme I:
acid Formula II
In another aspect of the present invention provides a process for the preparation of pharmaceutically acceptable salt of Saxagliptin thereof comprises:
a) reaction of (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide MSA salt of Formula VA:
[3.3.1 .1 ]decane-1 -acetic acid of formula IV:
Formula IV
using coupling agent in the presence of additive and base in a mixture of isopropyl acetate and acetonitrile to rovide pure amide of formula II :
Formula I I
or a pharmaceutically acceptable salt thereof; b) reaction of pure amide compound of step a) with trifluoroacetic anhydride (TFAA) in presence of eth l nicotinate to provide of formula II I :
Formula I II
or a pharmaceutically acceptable salt thereof; c) deprotecting the compound of formula II I of step b) with base in presence of alcohol to provide Boc-saxagliptin of formula IV:
Formula IV
or a pharmaceutically acceptable salt thereof; and
d) converting Boc-saxagliptin of formula IV of step c) to pharmaceutically acceptable salt of Saxagliptin using acid in presence of isopropyl alcohol and water to afford pharmaceutically acceptable salt of saxagliptin.
In an embodiment, the present invention provides in-situ preparation of the compound of formula II and III.
The reaction of step a) involves suspension of (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide MSA salt in isopropyl acetate and acetonitrile at room temperature to form reaction mixture. Further, it involves addition of additive, for example, HOBT or its hydrate, coupling agent, for example, EDC HCI and then base, for example, diisopropylethylamine, respectively, to the reaction mixture. Later, it involves addition of (S)-a-[[(1 ,1 - dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo-[3.3.1 .1 ]decane-1 -acetic to the reaction mixture and then stirring for a period of 30 minutes to about 3 hours or more at room temperature to affect the completion of the reaction.
After completion of the reaction, the reaction mixture is quenched with acid, extracted the amide compound into isopropyl acetate and then washed the isopropyl acetate layer with base and brine solution to afford pure amide compound free from impurity including additive content. The acid may be hydrochloric acid and the base may be potassium bicarbonate.
The resultant solution comprising pure amide compound having purity greater than 98% is subjected for further reaction steps.
The step b) involves adding trifluoroacetic anhydride (TFAA) into the ester solution comprising pure amide compound, obtained from the step a), at a temperature below 10°C in presence of ethyl nicotinate to provide compound of formula III.
The reaction may be maintained for a period of 30 minutes to about 1 hour to affect yield of the reaction at 0-10 °C.
After completion of the reaction, the reaction mixture may be subjected for further reaction or may be subjected for quenching with quenching agents and then treated with acid to get reaction mixture into organic layer. The quenching agent is selected from tetramethylethylenediamine (TMEDA), alcohol, acid, water or in combination thereof.
The present invention for preparation of the compound of formula III involves use of single solvent, which is used for preparation of amide compound and its extraction form the reaction mixture. The use of single solvent, for example, isopropyl acetate, affects the yield and purity, and it can be easily handled in large scale preparation also.
The present process conditions for preparing the compound of Formula III from (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide MSA salt also reduces/controls the formation of impurity of formula A, which converts amide compound of Formula II in further deprotection reaction step, which may be difficult to remove by using simple purification techniques.
The step c) involves selective deprotection of hydroxyl protecting group of formula III obtained from the step b) using base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like to provide Boc-saxagliptin of formula IV.
The deprotection reaction is performed in presence of alcohol, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and the like at a temperature of about 35 to about 50°C. The reaction may be maintained for a period of 45 minutes to 4 hours to affect the yield and purity of Boc-saxagliptin of formula IV.
After completion of the reaction, the reaction mixture may be subjected for further reaction step or may be subjected for separation of organic layer and isolation of solid using a solvent mixture of ketone and water.
The step d) involves preparation of pharmaceutically acceptable salt of Saxagliptin from Boc-saxagliptin of Formula IV using acid in presence of isopropyl alcohol and water at elevated temperature, for example, 60-65 °C, for a period more than 1 hour. In an embodiment, the reaction may be maintained at least 2 hours or more to affect the precipitation and purity of pharmaceutically acceptable salt of Saxagliptin.
The quantity of acid is about 1 .5 to about 2 molar equivalents with respect to molar equivalent of Boc-saxagliptin. The acid may be selected from hydrochloric acid (HCI), methane sulfonic acid, trifluoroacetic acid, acetic acid and the like.
In an embodiment, the present invention involves use of HCI for formation of Saxagliptin hydrochloride salt. The HCI used may be concentrated HCI, HCI gas or source of HCI like alcoholic HCI, acetone. HCI and the like. The alcoholic HCI is selected from ethanolic HCI, propanolic HCI, isopropanolic HCI and the like.
The purity of Saxagliptin hydrochloride prepared by the process of present invention is greater than about 99.5% determined by HPLC.
The overall process for preparing pharmaceutically acceptable salt of Saxagliptin is de icted in the scheme II:
Formula III
Formula IV
In another aspect, the present invention provides a process for the isolation of intermediate of Saxagliptin, boc-saxagliptin of formula IV, which comprises:
i) providing solution of Boc-saxagliptin in ketone solvent at elevated temperature;
ii) adding water to the solution of step a);
iii) optionally, cooling to below room temperature; and
iv) recovering pure Boc-saxaglipitn having purity greater than 99%.
Providing a solution in step a) includes obtaining a solution of boc-saxagliptin in a ketone solvent or its combination with an organic solvent such as ester, alcohol, water and the like as a final step in the preparation of the compound or dissolving Boc-saxagliptin in ketone solvent. The ketone is selected from acetone, ethylmethyl ketone, methyl ter-butyl ketone and the like; or mixtures thereof.
The solution in step a) may be provided at elevated temperature ranging from about room temperature to about boiling point of the solvent. The temperature may be at about 35 °C to about 55°C.
The solution may optionally be treated with activated charcoal and then filtered to remove the carbon.
The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite. Depending upon the equipment used, as well as the concentration and temperature of the solution, the filtration apparatus may need to be heated or cooled to avoid undesired crystallization.
Water is added slowly to the solution obtained in step a). The addition of water may be performed for a period of 30 minutes to 2 hours.
The reaction mass obtained in step b) may be cooled to below room temperature or to below 10°C and stirred for 1 hour or more to affect the purity of the solid. In
embodiments, the reaction mass may be cooled to temperatures about 0°C to about 5°C and stirred for 4 hours or more.
The solid obtained from step c) may be recovered using known techniques such as filtration.
The obtained solid may be dried and then subjected for the development of Saxagliptin or its pharmaceutically acceptable salt. The drying may be suitably carried out using any of equipment at atmospheric pressure or under reduced pressures, at temperatures less than about 40°C, less than about 30°C, less than about 20°C and any other suitable temperatures. The drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.
EXAMPLES
Example -1 : Process for preparing Boc-Saxagliptin
Azabicyclic salt (75 gm) was suspended in isopropyl acetate (150 ml) and Acetonitril (300 ml) then 1 -hydroxybenzotriazole hydrate (45 gm), Ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride (65 gm), Diisopropylethylamine (90 gm) and Boc-adamantic acid (100 gm) were added at room temperature and stirred for 3 hour at 25-35°C. After completion of the reaction, the reaction mixture was quenched with hydrochloric acid (30 ml), extracted with Isopropyl acetate (900 ml) and washed with potassium bicarbonate and brine solution to get condensed product with HPLC purity 98%. This is taken directly next stage.
To the above organic layer Ethyl nicotinate (145 gm) was added. Trifluoroacetic anhydride (120 gm) was added to the reaction mixture at 0-5°C and stirred for 1 hour at 5-10 °C. After completion of the reaction, the reaction mixture was quenched with water and tetramethylethylenediamine (50 gm). Then the organic layer was treated with aqueous Hydrochloric acid to get organic layer of diprotected saxagliptin. This is taken directly into next stage.
To the above organic layer potassium carbonate solution (125 gm/500 ml water) and methanol were added. The reaction mixture was stirred at 40-45°C for 3 hr. After completion of the reaction, the organic layer was separated and concentrated to get Boc-Saxagliptin residue.
Boc-Saxagliptin residue (120 gm) obtained from the reaction was dissolved in the acetone (200 ml) at 40-50 °C. Then water (600 ml) was added slowly over a period of 1 -2 hr at 40-50 °C, then reaction mass was cooled to 5-10 °C, maintained for 4 hr, filtered and dried to get Boc-Saxagliptin.
Yield: 100 gm
Purity: 99.6% determined by HPLC.
Amide Compound of Formula II: 0.1 %.
Example-2: A process for preparing Saxagliptin HCI:
BOC-Saxagliptin (100 gm) was suspended in isopropyl alcohol (100 ml). Water
(100 ml) and Concentrated Hydrochloric acid (30 ml) were added to the reaction suspension and stirred at 60-65 °C for 3 hours. Isopropyl alcohol (800 ml) was added to the reaction mixture, filtered and then dried to get Saxagliptin hydrochloride.
Yield: 75 gm, (89% yield)
Purity: 99.9% determined by HPLC.
Claims
We Claim:
1 . A process for the pre aration of amide compound of formula II:
Formula II
or a pharmaceutically acceptable salt thereof, which comprises:
suspending (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide formula V:
b) adding additive, coupling reagent and then base to the suspension of step a); and
c) finally adding (S)-a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3- hydroxytricyclo-[3.3.1 .1 ]decane-1 -acetic acid of Formula IV:
Formula IV
or a salt thereof to react with the mixture of step b) at room temperature to provide amide compound.
The process of claim 1 , wherein the solvent is selected from ester, nitrile, chlorinated solvent, formamide, ethers, water or combination thereof.
The process of claim 1 , wherein the solvent is a mixture of acetonitrile and isopropyl acetate.
The process of claim 1 , wherein the coupling reagent is carbodiimide compound.
The process of claim 1 , wherein the additive is 1 -hydroxybenzotriazole.
The process of claim 1 , wherein the amide compound of Formula II uses in the preparation of Saxagliptin or its pharmaceutically acceptable salt.
The process of claim 1 , wherein the amide compound of formula II has purity of greater than 98 % by HPLC.
A process for the isolation of intermediate of Saxagliptin, Boc-saxagliptin of formula IV, which comprises:
providing solution of Boc-saxagliptin in ketone solvent at elevated temperature;
adding water to the solution of step a);
optionally, cooling to below room temperature; and
recovering pure Boc-saxagliptin.
9. The process of claim 8, wherein the ketone solvent is acetone.
10. The process of claim 8, wherein the Boc-saxagliptin uses in the preparation of Saxagliptin or pharmaceutically acceptable salt.
1 1 . A process for the preparation of pharmaceutically acceptable salt of Saxagliptin thereof comprises:
a) reaction of (1 S,3S,5S)-2-azabicyclo [3.1 .0]hexane-3-carboxamide MSA salt of Formula VA:
Formula VA with (S)-a-[[(1 ,1 -dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo- [3.3.1 .1 ]decane-1 -acetic acid of formula IV:
Formula IV
using coupling agent in the presence of additive and base in a mixture of isopropyl acetate and acetonitrile to rovide pure amide of formula II:
Formula II
or a pharmaceutically acceptable salt thereof;
b) reaction of pure amide compound of step a) with trifluoroacetic anhydride (TFAA) in presence of ethyl nicotinate to provide of formula I I I:
Formula I II
or a pharmaceutically acceptable salt thereof; c) deprotecting the compound of formula I II of step b) with base in presence of alcohol to rovide Boc-saxagliptin of formula IV:
Formula IV
or a pharmaceutically acceptable salt thereof; and
d) converting Boc-saxagliptin of formula IV of step c) to pharmaceutically acceptable salt of Saxagliptin using acid in presence of isopropyl alcohol and water to afford pharmaceutically acceptable salt of saxagliptin.
12. The process of claim 1 1 , wherein the additive is HOBT or its hydrate and base is diisopropylethylamine.
13. The process of claim 1 1 , wherein the coupling agent is EDC.HCI.
14. The process of claim 1 1 , wherein the step b) is performed in the presence of isopropyl acetate.
15. The process of claim 1 1 , wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
16. The process of claim 1 1 , wherein the acid is selected from hydrochloric acid, methane sulfonic acid, trifluoroacetic acid and acetic acid.
17. The process of claim 1 1 , wherein the pharmaceutically acceptable salt of saxagliptin is saxagliptin hydrochloride.
18. The process of claim 1 1 , wherein the pharmaceutically acceptable salt of saxagliptin is having purity greater than about 99.5%.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
US7214702B2 (en) | 2004-05-25 | 2007-05-08 | Bristol-Myers Squibb Company | Process for producing a dipeptidyl peptidase IV inhibitor |
US7420079B2 (en) | 2002-12-09 | 2008-09-02 | Bristol-Myers Squibb Company | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
US7741082B2 (en) | 2004-04-14 | 2010-06-22 | Bristol-Myers Squibb Company | Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor |
WO2011125011A1 (en) | 2010-04-05 | 2011-10-13 | Cadila Pharmaceuticals Limited | Novel hypoglycemic compounds |
US20110275687A1 (en) | 2010-05-05 | 2011-11-10 | Teva Pharmaceutical Industries Ltd. | Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof |
-
2014
- 2014-01-08 WO PCT/IB2014/058109 patent/WO2014108830A1/en active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
US7420079B2 (en) | 2002-12-09 | 2008-09-02 | Bristol-Myers Squibb Company | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
US7741082B2 (en) | 2004-04-14 | 2010-06-22 | Bristol-Myers Squibb Company | Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor |
US7214702B2 (en) | 2004-05-25 | 2007-05-08 | Bristol-Myers Squibb Company | Process for producing a dipeptidyl peptidase IV inhibitor |
WO2011125011A1 (en) | 2010-04-05 | 2011-10-13 | Cadila Pharmaceuticals Limited | Novel hypoglycemic compounds |
US20110275687A1 (en) | 2010-05-05 | 2011-11-10 | Teva Pharmaceutical Industries Ltd. | Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof |
Non-Patent Citations (4)
Title |
---|
DAVID ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, no. 15, 2005, pages 5025 |
LIU ET AL., BIOORGANIC & MEDICINAL CHEMISTRY, vol. 19, no. 3, pages 1136 |
S.A. SCOTT ET AL., ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 13, 2009, pages 1169 |
SCOTT A SAVAGE ET AL: "Preparation of Saxagliptin, a Novel DPP-IV Inhibitor", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, CAMBRIDGE, GB, vol. 13, no. 6, 1 January 2009 (2009-01-01), pages 1169 - 1176, XP002645166, DOI: 10.1021/OP900226J * |
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