WO2015031595A1 - A process for preparation of saxagliptin and its hydrochloride salt - Google Patents

A process for preparation of saxagliptin and its hydrochloride salt Download PDF

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Publication number
WO2015031595A1
WO2015031595A1 PCT/US2014/053123 US2014053123W WO2015031595A1 WO 2015031595 A1 WO2015031595 A1 WO 2015031595A1 US 2014053123 W US2014053123 W US 2014053123W WO 2015031595 A1 WO2015031595 A1 WO 2015031595A1
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WO
WIPO (PCT)
Prior art keywords
hexane
azabicyclo
hydroxyadamantan
tritylamino
carboxamide
Prior art date
Application number
PCT/US2014/053123
Other languages
English (en)
French (fr)
Inventor
Agarwal Virendra KUMAR
Siddiqui Arif BADRULHUSAN
Kataria Lalit KESHAV
Maheta Abhay SUBODHBHAI
Butani Pankaj CHANGANBHAI
Patil Shashikant PRABHAKARRAO
Patil Tushar YASHWANT
Deore Ganesh SURYAKANT
Pansuriya Ketan JAHYANTIBHAI
Patel Hitesh SURESHBHAI
Sondharava Lalit BADHABHAI
Original Assignee
Amneal Pharmaceuticals Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amneal Pharmaceuticals Llc filed Critical Amneal Pharmaceuticals Llc
Priority to US14/911,918 priority Critical patent/US9416105B2/en
Publication of WO2015031595A1 publication Critical patent/WO2015031595A1/en

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to processes for the preparation of saxagliptin and its hydrochloride salt.
  • the present invention also relates to intermediate compounds and their use in processes for preparing saxagliptin.
  • Dipepeptidyl peptidase IV inhibitors are a class of oral hypoglycemic agents that block the enzyme DPP-rV and have been used to treat diabetes mellitus type 2.
  • Saxagliptin has the chemical names (l l S',3 l S , ,5 l S , )-2-[2( l S , )-2-amino-2-(3-hydroxy- adamantan- l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile or (lS,3S,5S)-2-[(2S)-2-[(2S)-2-
  • U.S. Patent 6,395,767 discloses a process for the preparation of saxagliptin, its hydrochloride salt, trifluoroacetate, and benzoate salts, and saxagliptin monohydrate.
  • U.S. Patent 7,705,033 discloses a process for the preparation of saxagliptin monohydrate.
  • U.S. Patent 7,214,702 discloses a process for the preparation of saxagliptin or its hydrochloride salt.
  • the present invention provides a process for the preparation of saxagliptin or its hydrochloride salt, comprising:
  • (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [IV] is prepared by:
  • lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l- :tyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [IV] is prepared by a process, comprising: reacting 3-hydroxyadamantan-l-yl-tert-butoxycarbonylamino acetic acid [II]
  • saxagliptin hydrochloride is in the form of saxagliptin hydrochloride dihydrate.
  • the present invention provides a process for the preparation of saxagliptin or its hydrochloride salt, comprising:
  • the present invention provides intermediate compounds: 3- hydroxyadamantan-l-yl-tritylamino acetic acid [IIA]; (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3- hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [IV]; and (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile [V], and their pharmaceutically acceptable salts, solvates and hydrates thereof; processes for their preparation; and their uses for the preparation of saxagliptin or hydrochloride salt thereof.
  • a triphenylmethyl (trityl) group is superior to other protecting groups in reducing the formation of the cyclic amidine impurity.
  • the trityl group is less expensive, easily available, and easy to handle by being in a solid state, thus making it industrially feasible.
  • it is easier to monitor the reaction using TLC or high performance liquid chromatography ("HPLC"), since it absorbs UV light.
  • HPLC high performance liquid chromatography
  • removing a trityl protecting group can directly yield saxagliptin hydrochloride salt and does not involve formation of saxagliptin which is highly unstable and prone to intramolecular cyclization.
  • the methanesulfonic acid salt of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide [III] used in the present process can be obtained by reacting tert-butyl (lS,3S,5S)-3-carbamoyl- 2-azabicyclo[3.1.0]hexane-2-carboxylate with methanesulfonic acid in the presence of an organic solvent.
  • Organic solvents that may be used include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, iso-butanol, tert-butanol, and the like.
  • Useful temperatures for conducting the reaction are above about 50°C, such as about 60-70°C, or other temperatures.
  • the present invention provides a process for the preparation of saxagliptin or its hydrochloride salt, comprising:
  • (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan- :tyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [IV] is prepared by:
  • the compound [IIA] can be prepared by reacting (lS)-a-amino-3-hydroxyadamantane- acetic acid with triphenylmethyl chloride in the presence of a suitable solvent such as dichloromethane and base such as triethylamine at a temperature of about 25-35°C.
  • reaction of compound [IIA] and compound [III] can be carried out in the presence of one or more halogenated solvents, such as dichloromethane, 1,2-dichloroethane, 1,1- dichloroethane, chloroform, carbon tetrachloride, and the like, at temperatures about 20-40°C or about 25-35°C.
  • halogenated solvents such as dichloromethane, 1,2-dichloroethane, 1,1- dichloroethane, chloroform, carbon tetrachloride, and the like
  • the amide formation can be carried out in the presence of a carbodimide coupling agent, such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), ⁇ , ⁇ '- dicyclohexylcarbodiimide (DCC), or ⁇ , ⁇ '-diisopropylcarbodiimide (DIC).
  • a carbodimide coupling agent such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), ⁇ , ⁇ '- dicyclohexylcarbodiimide (DCC), or ⁇ , ⁇ '-diisopropylcarbodiimide (DIC).
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DCC dicyclohexylcarbodiimide
  • DIC ⁇ , ⁇ '-diisopropylcarbodi
  • the amide bond formation can be carried out in the presence of a tertiary amine base such as N-methylmorpholine (NMM), ⁇ , ⁇ -diisopropylethylamine (DIPEA or Hiinig' s base), and triethylamine (TEA).
  • NMM N-methylmorpholine
  • DIPEA ⁇ , ⁇ -diisopropylethylamine
  • TAA triethylamine
  • (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l- yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide [ ⁇ ] is prepared by:
  • reaction of compound [II] and compound [III] can be carried out in the presence of one or more halogenated solvents, such as dichloromethane, 1,2-dichloroethane, 1,1- dichloroethane, chloroform, carbon tetrachloride, and the like, at temperatures about 20-40°C or about 25-35°C.
  • halogenated solvents such as dichloromethane, 1,2-dichloroethane, 1,1- dichloroethane, chloroform, carbon tetrachloride, and the like
  • the amide formation can be carried out in the presence of a carbodimide coupling agent, such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), ⁇ , ⁇ '- dicyclohexylcarbodiimide (DCC), or ⁇ , ⁇ '-diisopropylcarbodiimide (DIC).
  • a carbodimide coupling agent such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), ⁇ , ⁇ '- dicyclohexylcarbodiimide (DCC), or ⁇ , ⁇ '-diisopropylcarbodiimide (DIC).
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DCC dicyclohexylcarbodiimide
  • DIC ⁇ , ⁇ '-diisopropylcarbodi
  • the amide bond formation can be carried out in the presence of a tertiary amine base such as N-methylmorpholine (NMM), ⁇ , ⁇ -diisopropylethylamine (DIPEA or Hiinig's base), and triethylamine (TEA).
  • NMM N-methylmorpholine
  • DIPEA ⁇ , ⁇ -diisopropylethylamine
  • TAA triethylamine
  • organic solvents include, but are not limited to, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, hexanol, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate, and mixtures of two or more thereof.
  • the base is an organic or inorganic base.
  • exemplary organic bases include, without limitation, triethyl amine, tributyl amine, ammonia, diisopropyl amine, dimethyl amine, diisopropyl ethyl amine, pyridine, and the like.
  • [V] can be scavenged using an aqueous solution of alkali metal carbonates or bicarbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like.
  • alkali metal carbonates or bicarbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like.
  • trifluoroacetic acid generated during the reaction can be scavenged using a 20% aqueous potassium carbonate solution. Completion of scavenging can be confirmed by TLC.
  • the compound (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]- 2-azabicyclo[3.1.0]hexane-3-carbonitrile [V] can optionally be further purified using an alcohol, such as methanol.
  • the removal of the trityl protecting group from compound [V] can be carried out with a solution of hydrochloric acid, such as an aqueous solution having a concentration of HC1 about 34-36% by weight.
  • a solution of hydrochloric acid such as an aqueous solution having a concentration of HC1 about 34-36% by weight.
  • solvents that can be used in the deprotection step include methanol, ethanol, isopropanol, n-butanol, and iso-butanol.
  • the deprotection step can be carried out at temperatures about 20-35°C, or about 25-30°C.
  • Saxagliptin hydrochloride obtained as a residue after distilling the solvent in the deprotection step, can be further purified using an ester, such as methyl acetate, ethyl acetate, and isopropyl acetate as antisolvents.
  • saxagliptin hydrochloride is recovered as saxagliptin hydrochloride dihydrate.
  • the recovered saxagliptin hydrochloride can optionally be converted to saxagliptin using methods known in the art.
  • the present invention provides a process for preparation of saxagliptin hydrochloride as depicted in the scheme-I below.
  • the present invention provides a process for preparation of saxagliptin hydrochloride as depicted in the scheme-II below.
  • Example 1 is provided only for the purpose of illustrating certain specific aspects and embodiments of the present invention and should not be considered as limiting the scope or spirit of the invention in any manner.
  • Example 1 is provided only for the purpose of illustrating certain specific aspects and embodiments of the present invention and should not be considered as limiting the scope or spirit of the invention in any manner.
  • EDC.HC1 l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • the organic layer was washed with dilute hydrochloric acid solution (500 ml, prepared by adding concentrated hydrochloric acid (60 ml) to water (440 ml)), and further washed with sodium bicarbonate solution (3 times), followed by washing with sodium chloride solution.
  • Hydrogen chloride in isopropanol 14.2% w/w, 315.6 g was added over 60 minutes, and the mixture was stirred for 4 hours. Completion of the reaction was confirmed by HPLC.
  • the mixture was distilled under vacuum to remove dichloromethane. Toluene was added to the residue and distilled under vacuum. Acetonitrile (400 ml) was added to the residue followed by addition of triethylamine (79.2 g) over 15 minutes with stirring.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/US2014/053123 2013-08-28 2014-08-28 A process for preparation of saxagliptin and its hydrochloride salt WO2015031595A1 (en)

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IN2813/MUM/2013 2013-08-28
IN2813MU2013 IN2013MU02813A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2013-08-28 2014-08-28

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IN (1) IN2013MU02813A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO2015031595A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106349185A (zh) * 2016-08-26 2017-01-25 河北科技大学 一种氨基保护的3‑羟基金刚烷甘氨酸苯并噻唑‑2‑硫醇活性酯、其制备方法及应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068603A2 (en) * 2000-03-10 2001-09-20 Bristol-Myers Squibb Co. Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use
US20050090539A1 (en) * 2002-12-09 2005-04-28 Vu Truc C. Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof
US20050267191A1 (en) * 2004-05-25 2005-12-01 Sharma Padam N Process for producing a dipeptidyl peptidase IV inhibitor
WO2008131149A2 (en) * 2007-04-20 2008-10-30 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same
WO2011140328A1 (en) * 2010-05-05 2011-11-10 Teva Pharmaceutical Industries Ltd. Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof
US20130023671A1 (en) * 2011-05-24 2013-01-24 Apicore, Llc Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
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TW200538122A (en) 2004-03-31 2005-12-01 Bristol Myers Squibb Co Process for preparing a dipeptidyl peptidase Ⅳ inhibitor and intermediates employed therein

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068603A2 (en) * 2000-03-10 2001-09-20 Bristol-Myers Squibb Co. Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use
US20050090539A1 (en) * 2002-12-09 2005-04-28 Vu Truc C. Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof
US20050267191A1 (en) * 2004-05-25 2005-12-01 Sharma Padam N Process for producing a dipeptidyl peptidase IV inhibitor
WO2008131149A2 (en) * 2007-04-20 2008-10-30 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same
WO2011140328A1 (en) * 2010-05-05 2011-11-10 Teva Pharmaceutical Industries Ltd. Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof
US20130023671A1 (en) * 2011-05-24 2013-01-24 Apicore, Llc Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof

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SAVAGE, SCOTT A. ET AL.: "Preparation of Saxagliptin, a Novel DPP-IV Inhibitor", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 13, 2009, pages 1169 - 1176 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106349185A (zh) * 2016-08-26 2017-01-25 河北科技大学 一种氨基保护的3‑羟基金刚烷甘氨酸苯并噻唑‑2‑硫醇活性酯、其制备方法及应用

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US9416105B2 (en) 2016-08-16
IN2013MU02813A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2015-07-03

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