WO2004083212A1 - Procede de preparation d'intermediaires de beta-cetoamide utilises dans la preparation d'inhibiteurs de dipeptidyle peptidase - Google Patents

Procede de preparation d'intermediaires de beta-cetoamide utilises dans la preparation d'inhibiteurs de dipeptidyle peptidase Download PDF

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Publication number
WO2004083212A1
WO2004083212A1 PCT/US2004/007834 US2004007834W WO2004083212A1 WO 2004083212 A1 WO2004083212 A1 WO 2004083212A1 US 2004007834 W US2004007834 W US 2004007834W WO 2004083212 A1 WO2004083212 A1 WO 2004083212A1
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WIPO (PCT)
Prior art keywords
acid
structural formula
compound
substituted
trifluoromethyl
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PCT/US2004/007834
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English (en)
Inventor
Norihiro Ikemoto
Bryon L. Simmons
J. Michael Williams
Feng Xu
Chunhua Yang
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Merck & Co., Inc.
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Publication of WO2004083212A1 publication Critical patent/WO2004083212A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention discloses a novel process and novel intermediates toward the preparation of beta-ketoamide intermediates which are useful in the synthesis of dipeptidyl peptidase-IV (DP-TV) inhibitors for the treatment of type 2 diabetes.
  • DP-TV dipeptidyl peptidase-IV
  • the present invention provides a process for the preparation of beta-ketoamides of structural formula I:
  • Ar is phenyl which is unsubstituted or substituted with one to five substituents independently selected from the group consisting of halogen, trifluoromethyl, and trifluoromethoxy; and Rl is hydrogen or Ci-4 alkyl unsubstituted or substituted with one to five fluorines.
  • the present invention also provides structurally novel intermediates useful in the disclosed process and in the preparation of DP-IV inhibitors.
  • compounds of structural formula I are produced in an efficient manner in two chemical steps starting with an appropriately substituted phenylacetic acid and Meldrum's acid.
  • This invention is concerned with a process for preparing substituted beta- ketoamides of structural formula I and certain useful intermediates obtained during that process.
  • the process involves the reaction of an activated optionally substituted phenylacetic acid with 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid) to generate an intermediate Meldrum's acid adduct which is then reacted with an optionally substituted 5,6,7, 8-tetrahydro[l, 2,4]- triazol[4,3- ⁇ ]pyrazine to afford the desired product.
  • Compounds of structural formula I represent key intermediates in the synthesis of dipeptidyl peptidase-IV (DP-IV) inhibitors disclosed in WO 03/004498 (published 16 January 2003) which are useful for the treatment of type 2 diabetes.
  • Ar is phenyl which is unsubstituted or substituted with one to five substituents independently selected from the group consisting of halogen, trifluoromethyl, and trifluoromethoxy; and Rl is hydrogen or C ⁇ _4 alkyl unsubstituted or substituted with one to five fluorines; comprising the steps of:
  • Rl is CF3 and Ar is phenyl substituted with one to three substituents independently selected from the group consisting of fluorine, bromine, and trifluoromethyl.
  • Ar is 2,5- difluorophenyl or 2,4,5-trifluorophenyl.
  • the final product of the reaction sequence of structural formula I is isolated from the reaction mixture.
  • the final product can be used without isolation for further chemical modification into later-stage compounds.
  • the first step in the process of the present invention entails the preparation of a Meldrum's acid adduct of structural formula II:
  • an appropriately substituted phenylacetic acid with a carboxyl group activating agent to generate an active carboxylic acid species, such as an acyl halide; an active ester, such as an aryl ester; a mixed carboxylic acid anhydride; an acyl imidazole; a mixed carboxylic acid carbonic acid anhydride; and a phosphoric or phosphinic acid mixed anhydride.
  • a carboxyl group activating agent to generate an active carboxylic acid species, such as an acyl halide; an active ester, such as an aryl ester; a mixed carboxylic acid anhydride; an acyl imidazole; a mixed carboxylic acid carbonic acid anhydride; and a phosphoric or phosphinic acid mixed anhydride.
  • the activated phenylacetic acid is allowed to react with 2,2-dimethyl-l,3- dioxane-4,6-dione (Meldrum's acid) in the presence of base
  • Ll'-carbonyldiimidazole or l,l'-thiocarbonyldiimidazole may be used to generate an acyl imidazole; trimethylacetyl (pivaloyl) chloride or isovaleryl chloride to generate a pivalic or isovaleric acid mixed anhydride; oxalyl chloride (in the presence of a catalytic amount of DMF) or phosphorus pentachloride to generate an acid chloride; isobutyl chloroformate to generate an isobutylcarbonic acid mixed anhydride; and diethylcyanophosphate or diethylchlorophosphate to generate a diethylphosphoric acid mixed anhydride.
  • active aryl esters examples include -nitrophenyl esters, 2,4-dinitrophenyl esters, and pentafluorophenyl esters.
  • Meldrum's acid may be initially present in the reaction mixture during the formation of the activated acid species or added subsequently after generation of the activated acid species.
  • the reaction is carried out in a suitable organic solvent, such as THF, dimethoxymethane, DME, DMF, DMAc, NMP, DMSO, IP Ac, EtOAc, MTBE, toluene, and MeCN.
  • the reaction is carried out in the presence of base, such as triethylamine, N,N-diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, NN-dimethylaniline, DMAP, DABCO, and DBU.
  • base such as triethylamine, N,N-diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, NN-dimethylaniline, DMAP, DABCO, and DBU.
  • base such as triethylamine, N,N-diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, NN-dimethylaniline, DMAP, DABCO, and DBU.
  • the Meldrum's acid adduct
  • the subsequent and final step in the process of the present invention entails reaction of the Meldrum's acid adduct of structural formula II with a 5,6,7, 8-tetrahydro[l,2,4]- triazolo[4,3- ⁇ ]pyrazine of structural formula V:
  • a base or an acid salt thereof can be added to the reaction mixture.
  • bases that can be used in this reaction include triethylamine, N,N-diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, DMAP, DABCO, and DBU.
  • Embodiments of acids that can be used in this reaction include trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, -toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, acetic acid, and pivalic acid.
  • a preferred acid is trifluoroacetic acid.
  • the reaction is carried out in a suitable reaction solvent, such as THF, dimethoxymethane, DME, EtOAc, IP Ac, MeCN, DMF, DMAc, NMP, DMSO, MTBE, and toluene.
  • the ketoamide formation is carried out in acidic reaction media to achieve high conversion and high yield. Otherwise, the accuracy of the base charge in the formation of the Meldrum's acid adduct is critical in order to ensure that the ketoamide formation step proceeds in high yield and conversion. Introducing an acid into the reaction system is advantageous, in that it neutralizes the excess base used in formation of the Meldrum's acid adduct if a through-process is applied and results in high conversion allowing for lowering the reaction temperature and suppressing formation of impurities.
  • the Meldrum's acid adduct is not isolated from the reaction mixture but is reacted with a triazole species of formula V, preferably in the form of an acid salt, such as the hydrochloride salt.
  • the reaction is carried out optionally in the presence of acid in a suitable organic solvent. This embodiment is referred to as a "through-process.”
  • the compound of structural formula I need not be isolated, but can be further modified to obtain the DP-IV inhibitors disclosed in WO 03/004498.
  • a further embodiment of the present invention comprises the following novel compounds of structural formula II which are intermediates in the preparation of the compounds of structural formula I: (II)
  • Ar is phenyl which is unsubstituted or substituted with one to five substituents independently selected from the group consisting of halogen, trifluoromethyl, and trifluoromethoxy.
  • Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl.
  • a further embodiment of this invention comprises the following novel compounds of structural formula I which are useful intermediates in the preparation of the dipeptidyl peptidase (DP-IV) inhibitors disclosed in WO 03/004498:
  • Ar is phenyl which is unsubstituted or substituted with one to five substituents independently selected from the group consisting of halogen, trifluoromethyl, and trifluoromethoxy; and Rl is hydrogen or Ci-4 alkyl unsubstituted or substituted with one to five fluorines.
  • Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl and Rl is trifluoromethyl.
  • DABCO is l,4-diazabicyclo[2.2.2]octane
  • DBU is 1,8- diazabicyclo[5.4.0]undec-7-ene
  • DMAc is _V,.V-dimethylacetamide
  • DMAP is 4- (dimethylamino)pyridine
  • DME is 1,2-dimethoxyethane
  • DMF is iV,_V-dimethylformamide
  • DMSO is dimethylsulfoxide
  • EtOAc is ethyl acetate
  • EtOH is ethanol
  • HPLC high- performance liquid chromatography
  • IP Ac is isopropyl acetate
  • MeCN is acetonitrile
  • MeOH is methanol
  • MTBE is methyl t-butyl ether
  • NMP is N-methylpyrrolidinone
  • THF is tetrahydrofuran.
  • halogen is meant fluorine, chlorine, bromine, or iodine.
  • the starting materials are either commercially available or known in the chemical scientific or patent literature. Purification procedures include e.g., distillation, crystallization and normal or reverse phase liquid chromatography.
  • Step D Preparation of 3-(trifluoromethyl)-5,6,7,8-tetrahvdrori ,2,4 Itriazolo.4 ,3- ⁇ lpyrazine, hydrochloride salt (1-4)
  • Example 1 Use of Acetonitrile as Solvent and Pivaloyl Chloride as Acid Activating Agent
  • 2,4,5-Trifluorophenylacetic acid (2-1) (available from several commercial suppliers) (0.25 kg, 1.32 mol), Meldrum's acid (0.21 kg, 1.45 mol), and DMAP (12.9 g, 0.11 mol) were charged into a 5 L three-neck flask.
  • Acetonitrile (750 mL) was added in one portion at room temperature.
  • ⁇ N-diisopropylethylamine (492 mL, 2.83 mol) was added in one portion at room temperature while maintaining the temperature below 40 °C.
  • Pivaloyl chloride (178 mL, 1.45 mol) was added dropwise over 1 to 2 h while maintaining the temperature below 50 °C. The reaction was aged at 45-50 °C for 2-3 h.
  • Triazole hydrochloride L4 (0.30 kg, 1.32 mol) was added in one portion at 40-50 °C. Trifluoroacetic acid (30.3 mL, 0.39 mol) was added dropwise, and the reaction solution aged at 50-55 °C for 6 h. Without further work-up, the crude reaction mixture containing 2X3 can be used directly for conversion into DP-IV inhibitors. The isolated solution yield was 88-90%.
  • Triazole hydrochloride L4 (180 g, 0.789 mol) was added in one portion at 40-50 °C. The reaction solution was aged at 70 °C for several h. 5% Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20 - 45 °C. The batch was seeded and aged at 20 - 30 °C for 1-2 h. Then an additional 525 mL of 5% aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was further cooled to 0 - 5 °C and aged 1 h before filtering the solid.
  • the wet cake was displacement- washed with 20% aqueous DMAc (300 mL), followed by an additional two batches of 20% aqueous DMAc (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. The isolated yield of final product was 89%.
  • 2,4,5-Trifluorophenylacetic acid (2-1) (available from several commercial suppliers) (25 g, 0.132 mol), Meldrum's acid (21 g, 0.145 mol), and DMAP (1.29 g, 0.011 mol) were charged into a 1000 mL three-neck flask. Acetonitrile (75 mL) was added in one portion at room temperature. N,N-diisopropylethylamine (49.2 mL, 0.283 mol) was added in one portion at room temperature while maintaining the temperature below 40 °C. Pivaloyl chloride (17.8 mL, 0.145 mol) was added dropwise over 1 to 2 h while maintaining the temperature below 50 °C.
  • 2,4,5-Trifluorophenylacetic acid (2-1) (11.4 g, 60 mmol) was dissolved in THF (60 mL) and l,l'-carbonyldiimidazole (10.7 g, 66 mmol) was added over 5 min. The mixture was warmed to 51 °C, Meldrum's acid (9.51 g, 66 mmol) was added, and the mixture was aged for 3 h. The reaction mixture was diluted with IP Ac (60 mL) and water (60 mL), and the pH was adjusted to 2.4 with concentrated hydrochloric acid (11.5 mL). The aqueous layer was separated, and the organic layer was washed at 36 °C with 0.1 N HCI (60 mL).
  • n-Heptane (30 mL) was added at room temperature, followed by seed crystals of ketoamide. Additional heptane (20 mL) was added dropwise, and the mixture was stirred overnight. Additional heptane (50 mL) was added slowly and after aging for 2 h, the solids were filtered and washed with 2.2:1 heptane/IP Ac (30 mL). After drying, the ketoamide 2X3 was obtained in 92% yield (26.3 g).

Abstract

L'invention concerne un nouveau procédé permettant de préparer des intermédiaires de bêta-cétoamide s'utilisant dans la synthèse d'inhibiteurs de dipeptidyle peptidase IV, dans le traitement de diabètes de type 2. L'invention concerne également des intermédiaires utiles obtenus selon ledit procédé.
PCT/US2004/007834 2003-03-18 2004-03-12 Procede de preparation d'intermediaires de beta-cetoamide utilises dans la preparation d'inhibiteurs de dipeptidyle peptidase WO2004083212A1 (fr)

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US60/455,458 2003-03-18

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007077508A2 (fr) 2005-12-30 2007-07-12 Ranbaxy Laboratories Limited Dérivés de bêta-aminoacides comme inhibiteurs de la dipeptidylpeptidase iv
US7842707B2 (en) 2004-07-23 2010-11-30 Nuada, Llc Peptidase inhibitors
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2013001457A1 (fr) 2011-06-30 2013-01-03 Ranbaxy Laboratories Limited Nouveaux sels de sitagliptine
WO2013001514A1 (fr) 2011-06-29 2013-01-03 Ranbaxy Laboratories Limited Dispersions solides de sitagliptine et leurs procédés de préparation
WO2013084210A1 (fr) 2011-12-08 2013-06-13 Ranbaxy Laboratories Limited Forme amorphe de sels de sitagliptine
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors

Citations (1)

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WO2003004498A1 (fr) * 2001-07-06 2003-01-16 Merck & Co., Inc. Pyrazines beta-amino tetrahydroimidazo (1, 2-a) et pyrazines tetrahydrotrioazolo (4, 3-a) utilisees en tant qu'inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7842707B2 (en) 2004-07-23 2010-11-30 Nuada, Llc Peptidase inhibitors
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2007077508A2 (fr) 2005-12-30 2007-07-12 Ranbaxy Laboratories Limited Dérivés de bêta-aminoacides comme inhibiteurs de la dipeptidylpeptidase iv
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
WO2013001514A1 (fr) 2011-06-29 2013-01-03 Ranbaxy Laboratories Limited Dispersions solides de sitagliptine et leurs procédés de préparation
WO2013001457A1 (fr) 2011-06-30 2013-01-03 Ranbaxy Laboratories Limited Nouveaux sels de sitagliptine
WO2013084210A1 (fr) 2011-12-08 2013-06-13 Ranbaxy Laboratories Limited Forme amorphe de sels de sitagliptine

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TW200505923A (en) 2005-02-16

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