WO2004087650A2 - Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv - Google Patents

Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv Download PDF

Info

Publication number
WO2004087650A2
WO2004087650A2 PCT/US2004/008826 US2004008826W WO2004087650A2 WO 2004087650 A2 WO2004087650 A2 WO 2004087650A2 US 2004008826 W US2004008826 W US 2004008826W WO 2004087650 A2 WO2004087650 A2 WO 2004087650A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
structural formula
producing
treating
organic solvent
Prior art date
Application number
PCT/US2004/008826
Other languages
English (en)
Other versions
WO2004087650A3 (fr
Inventor
Remy Angelaud
Joseph D. Armstrong, Iii
David Askin
Jaume Balsells
Karl Hansen
Jaemoon Lee
Peter E. Maligres
Nelo R. Rivera
Yi Xiao
Yong-Li Zhong
Original Assignee
Merck & Co. Inc.
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 Merck & Co. Inc. filed Critical Merck & Co. Inc.
Publication of WO2004087650A2 publication Critical patent/WO2004087650A2/fr
Publication of WO2004087650A3 publication Critical patent/WO2004087650A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/20—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • 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 relates to a process for the preparation of chiral beta-amino acid amide inhibitors of dipeptidyl peptidase-IV which are useful for the treatment of Type 2 diabetes.
  • the present invention also provides structurally novel intermediates useful in the disclosed process.
  • WO 03/004498 also described a process for preparing compounds of formula I.
  • a large number of synthetic transformations was required with a low overall chemical and optical yield.
  • the present invention there are produced more efficiently compounds of structural formula I with an optical purity in excess of 95% in considerably fewer chemical steps with an overall chemical yield of about 45-47% starting from commercially available substituted phenylacetic acids.
  • a smaller number of chromatographic purification steps is necessary throughout the synthetic sequence.
  • This invention is concerned with a modular approach for preparing substituted beta- amino acid amide derivatives of structural formula I and certain useful intermediates obtained during that process.
  • the process involves the chiral reduction of a beta-keto ester intermediate to generate a chiral beta-hydroxy ester which is hydrolyzed, converted into a benzyloxyamide and then cyclized to an N- benzyloxyazetidinone intermediate.
  • the final steps in the sequence entail saponification of the N- benzyloxyazetidinone, amide coupling with a tetrahydrotriazolopyrazine and cleavage of the benzyloxy amine protecting group by hydrogenolysis.
  • compounds of structural formula I are inhibitors of the enzyme dipeptidyl peptidase-IV (DP-IV) 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;
  • Rl is hydrogen or Ci _4 alkyl unsubstituted or substituted with one to five fluorines; comprising the steps of:
  • R2 is C ⁇ _6 alkyl; by treating a compound of structural formula II with a C ⁇ -6 alkanol;
  • 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 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
  • l, -carbonyldiimidazole or 1,1'- 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 p-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 DCM, DCE, THF, dimethoxymethane, DME, DMF, DMAc, NMP, DMSO, rPAc, EtOAc, MTBE, toluene, MeCN, and propionitrile.
  • the reaction is carried out in the presence of base, such as triethylamine, N,N- diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, N,N- dimethylaniline, DMAP, DABCO, and DBU.
  • base such as triethylamine, N,N- diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, N,N- dimethylaniline, DMAP, DABCO, and DBU.
  • base such as triethylamine, N,N- diisopropylethylamine, diisopropylamine, 2,4,6-collidine, imidazole, pyridine, lutidine, N,N- dimethylaniline, DMAP, DABCO, and DBU.
  • the Meldrum's acid adduct is prepared using
  • the second step in the process of the present invention concerns conversion of a Meldrum' s acid adduct of formula II into a beta-keto ester of structural formula V. This is accomplished by alcoholysis with a C ⁇ . alkanol.
  • Preferred alkanols include methanol and ethanol.
  • the reaction is preferably conducted in refluxing methanol.
  • the third step in the process of the present invention involves asymmetric reduction of the beta-keto group in a compound of structural formula V with a chiral reducing agent in a suitable organic solvent to afford a chiral beta-hydroxy ester of structural formula VI.
  • the chiral reduction is effected by Noyori-type asymmetric hydrogenation using [(5)-(BINAP-RuCl2)]Et3N or (5)-BINAP-RuCl2 in MeOH as the chiral catalyst [see R. Noyori et al., Angew. Chem. Int. Ed.. 40: 40- 73 (2001)].
  • the asymmetric hydrogenation is typically carried out using elevated pressures of hydrogen gas.
  • the chiral beta-hydroxy ester of formula VI is typically obtained in greater than 90% yield and 90% ee.
  • Other chiral catalysts that can also be employed for the asymmetric hydrogenation include (5)- [2,2]Phanephos, Duphos, as well as other chiral bisphosphines.
  • the fourth step in the process of the present invention entails hydrolysis of a chiral beta- hydroxy ester of structural formula VI to afford a chiral beta-hydroxy acid of structural formula VII.
  • the hydrolysis is effected under aqueous base conditions with an alkali metal hydroxide, such as lithium, sodium, and potassium hydroxide; an alkaline earth metal hydroxide, such as barium, calcium, and magnesium hydroxide; or an alkali metal carbonate, such as lithium, sodium, potassium, and cesium carbonate.
  • Solvents that are compatible for the saponification reaction include THF, DME, dioxane, DCE, and toluene all in the presence of water.
  • the organic solvent is aqueous THF.
  • the fifth step in the process of the present invention is conversion of a chiral beta- hydroxy acid of formula VII into a beta-hydroxy benzyloxyamide of structural formula VITI. This is achieved by amide coupling with 0-benzylhydroxylamine in the presence of a coupling reagent in a suitable solvent.
  • Embodiments of coupling reagents include l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC), l-cyclohexyl-3-(2- morpholmoethyl)carbodiimide, 1,3-di-tert-butylcarbodiimide, l-(dimethylaminopropyl)-3- ethylcarbodiimide methiodide, l-tert-butyl-3-(1 ⁇ iphenylmethyl)-carbodiimide, 1,3- diisopropylcarbodiimide, bis-(diphenylmethyl)-carbodiimide, l-tert-butyl-3-ethylcarbodiimide, 1-methyl- 2-chloropyridinium iodide, 2-ethoxy-l-ethoxycarbonyl-
  • Suitable solvents for the amide coupling reaction include water, THF, MeCN, DMF, DMAc, DCM, ethyl acetate, DCE, JPAc, chloroform, propiontrile, and mixtures thereof.
  • a preferred solvent is water.
  • the sixth step in the process of the present invention concerns cyclocondensation of a beta-hydroxy benzyloxyamide of structural formula VITI to generate a beta-lactam or azetidinone of structural formula LX using Mitsunobu reaction conditions.
  • the azodicarboxylate is a di-(Ci-4 alkyl) azodicarboxylate, dibenzyl azodicarboxylate, or bis(2,2,2-trichloroethyl) azodicarboxylate.
  • the reaction is performed in the presence of a phosphine ligand, such as a trialkyl- and a triarylphosphine, in a suitable organic solvent.
  • trialkylphosphines include tributylphosphine and trioctylphosphine.
  • triarylphosphine include triphenylphosphine and tri(o-tolyl)phosphine.
  • Suitable organic solvents for the Mitsunobu reaction include DCM, chloroform, DCE, toluene, MTBE, THF, EtOAc, D?Ac, dimethoxyethane, diethoxyethane, acetonitrile, DMF, xylene, 1,4-dioxane, propionitrile, and mixtures thereof.
  • DCM diisopropyl azodicarboxylate
  • triphenylphosphine in toluene.
  • the seventh step in the process of the present invention is hydrolysis of a beta-lactam of structural formula LX to afford a beta-amino acid of structural formula X.
  • the hydrolysis can be effected under either aqueous acid or aqueous base conditions.
  • an alkali metal hydroxide such as lithium, sodium, and potassium hydroxide
  • an alkaline earth metal hydroxide such as barium, calcium, and magnesium hydroxide
  • an alkali metal carbonate such as lithium, sodium, potassium, and cesium carbonate
  • Solvents that are compatible for the saponification reaction include THF, DME, dioxane, DCE, and toluene, all in the presence of water.
  • the organic solvent is miscible with water.
  • the hydrolysis can also be performed by heating a beta-lactam of formula LX with aqueous acid in methanol, such as aqueous hydrochloric acid and aqueous sulfuric acid.
  • the penultimate step in the process of the present invention is amide coupling of a beta- amino acid of structural formula X with a tetrahydro[l,2,4]triazolo[4,3- ]pyrazine of structural formula XII or an amine salt thereof in the presence of a coupling reagent in a suitable organic solvent to afford a beta-amino acid amide of structural formula XL
  • a coupling reagent in a suitable organic solvent to afford a beta-amino acid amide of structural formula XL
  • the scope and ranges of conditions that can be employed for the amide coupling reaction are similar to those for the conversion of VII into Vffl.
  • the coupling reaction is performed using EDC in the presence of N-methylmorpholme in acetonitrile or DMF or an aqueous mixture thereof.
  • the final step in the process of the present invention is removal of the benzyloxy protecting group on the amine functionality of a compound of structural formula XI.
  • This is accomplished under hydrogenolytic conditions in the presence of a metal catalyst in an organic solvent.
  • Suitable organic solvents for the hydrogenolysis include, but are not limited to, a lower alkanol, such as methanol, ethanol, and isopropyl alcohol; THF, DME, diethoxyethane, and IPAc, and aqueous mixtures thereof.
  • JPAc can also be used with an additive, such as HCl, HBr, acetic acid, and formic acid.
  • Transfer hydrogenation conditions can also be employed wherein the hydrogen is generated in situ.
  • Sources of hydrogen for the transfer hydrogenation include ammonium formate, formic acid, cyclohexene, and isopropyl alcohol.
  • Metal catalysts include Pd/C, PCI/AI2O3, Pd/CaC03, and Pd(OH)2/C.
  • Other catalysts can also be used such as Pt, Rh, and Ni based catalysts, or oxides thereof, alone or on supports such as carbon, silica, and alumina.
  • the hydrogenolysis is carried out with 10% Pd/C as catalyst in methanol as the solvent.
  • 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.
  • 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.
  • 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 1-4 alkyl unsubstituted or substituted with one to five fluorines.
  • Rl is hydrogen or C 1-4 alkyl unsubstituted or substituted with one to five fluorines.
  • Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl and Rl is trifluoromethyl. Representative experimental procedures utilizing the novel process are detailed below.
  • DABCO is l,4-diazabicyclo[2.2.2]octane
  • DBU is 1,8- diazabicyclo[5.4.0]undec-5-ene
  • DCE is 1,2-dichloroethane
  • DCM is dichloromethane
  • DMAc is N,N- dimethylacetamide
  • DMAP is 4-(dimethylamino)pyridine
  • DME is 1,2-dimethoxyethane
  • DMF is N,N- dimethylformamide
  • EtOAc is ethyl acetate
  • EtOH is ethanol
  • HPLC high-performance liquid chromatography
  • IPAc is isopropyl acetate
  • MeCN is acetonitrile
  • MeOH is methanol
  • MTBE is methyl t- butyl ether
  • NMM is
  • 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.
  • Hydrazine (20.1 g, 35 wt% in water, 0.22 mol) was mixed with 310 mL of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) was added over 60 min. The internal temperature was increased to 25 °C from 14 °C. The resulting solution was aged at 22 - 25 °C for 60 min. The solution was cooled to 7 °C. 17.9 g of 50 wt% aqueous NaOH (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously over 130 min at a temperature below 16 °C.
  • Step D Preparation of 3-(trifluoromethyl)-5.6,7,8-tetrahydrorL2,41triazolor4.3- ⁇ 1pyrazine.
  • hydrochloride salt (1-4) A suspension of amidine L3 (27.3 g, 0.13 mol) in 110 mL of methanol was warmed to
  • Step A Preparation of 5-ri-hvdroxy-2-(2.5-difluorophenyl)ethylidene1-2.2-dimethyl- 3- dioxane-4,6-dione (2-2)
  • Oxalyl chloride (2.54 Kg, 1.72 L, 20.1 mol) was slowly added to a slurry of 2,5- difluorophenylacetic acid (3.00 Kg, 17.4 mol) and DMF (9 mL) in dichloromethane (11 L) at 25-30 °C over 1.5 h. The mixture was stirred for 2 h at room temperature until the end of HCl gas evolution.
  • Dichloromethane and excess (COCl) 2 were distilled off (20-25 °C, 28" Hg).
  • Step B Preparation of methyl 4-(2,5-difluorophenyl)-3-oxobutanoate (2-3)
  • ketoester 7_ _ ⁇ as a crystalline solid: mp 37- 39 °C. lH NMR (CDCI 3 ): ⁇ 3.50 (s, 2H), 3.69 (s, 3H), 3.83 (d, 2H), 6.86-6.94 (m, 2H), 6.94-7.00 (m, 1H). enol form: 3.48 (s), 3.67 (s), 12.04 (s).
  • Step B The solution from Step B was divided into 2 batches (approx. 12 L each) and degassed by bubbling in N 2 for 15 min. 2N HCl (70 mL) and then (S)-BfNAP-RuCl 2 (22.3 g, 0.4 mol%) were added to each batch which was then submitted to hydrogenation (H 2 , 150 psi, 5 gal autoclave) at 60 °C for 4-5 h. Both batches were then combined and further processed as described in Step D.
  • the methanol solution of ⁇ -hydroxyester from Step C was solvent switched to THF (17 L final volume) using 35 L of THF with a minimal residual volume of 5 L (20-25 °C, 28 " Hg).
  • a solution of LiOH.H 2 0 (2.37 kg, 56.5 mol) in water (12 L) was added at 20-25 °C to the preceding mixture.
  • the solution was stirred for 30 min, MTBE (8 L) was then added and the layers separated.
  • the aqueous layer was extracted with MTBE (2 x 8 L) then the combined organic layers were back-extracted with water (8 L).
  • the combined aqueous layers were used directly in Step E below.
  • Step F Preparation of (4R)4-(benzyloxy)-4-(2,5-difluorobenzyl)azetidin-2-one (2-7)
  • Triphenylphosphine (3.64 kg, 13.9 mol) was slowly added to a solution of diisopropyl azodicarboxylate (2.80 kg, 2.73 L, 13.9 mol) in toluene (43 L) at such a rate that the temperature did not rise above 25 °C over 30 min.
  • the ⁇ -hydroxamate from Step E (4.05 kg, 12.6 mol) was then added portionwise at 20-30 °C over 30 min. After 2 h at 20-22 °C, 12-15 A% of starting hydroxamate remained (HPLC).
  • a solution was prepared from triphenylphosphine (364 g) and DIAD (280 g) in toluene (4.3 L) as described above.
  • Step H Preparation of 7-r(3R)-3-r(benzyloxy)amino1-4-(2.5-difluorophenyl)butanovn-3-
  • Step I Preparation of (2R)-4-oxo-4-r3-(trifluoromethyl)-5,6-dihydrori.2,41triazolor4.3- ⁇ lpyrazin-7(8H)-vn-l-(2.5-difluorophenyl)butan-2-amine (2-10)
  • the methanol solution of free amine (26 L) was added to the tartaric acid solution dropwise keeping temperature at about 60-65 °C.
  • the precipitated crystalline salt was aged for 30 min at this temperature and cooled gradually to 0°C with efficient stirring. After aging for 1 h at 0 °C, the crude salt was filtered off and rinsed with 3 L of 2: 1 iPA-MeOH (pre-cooled to 0°C). The cake was dried in a filter pot under reduced pressure with a nitrogen sweep for 16 h to give the crude tartrate as a white crystalline solid (3.97 Kg).
  • the crude (L)-tartaric acid salt (2.0 Kg) was dissolved in 50 L of MeOH at reflux temperature (about 59°C). The homogenous solution was cooled to 45 °C and transferred to a 100 L round-bottom flask through an in-line filter. About 5 L of methanol was distilled off. The solution was heated to about 50-55°C and JPA (43 L) was charged (in-line filter) slowly over 30 min keeping the temperature at about 55-65°C. After aging the slurry for 1 h at about 60-65°C, the slurry was gradually cooled to 0 °C with efficient stirring.
  • This compound was prepared in a similar fashion as Example 1, but using commercially available 2,4,5-trifluorophenylacetic acid in place of 2,5-difluorophenylacetic acid in Step A. Melting point 114.1 - 115.7 °C. l ⁇ NMR (300 MHz, CD3CN): ⁇ 7.26 (m), 7.08 (m), 4.90 (s), 4.89 (s), 4.14 (m), 3.95 (m), 3.40 (m), 2.68

Abstract

L'invention concerne un nouveau procédé pour la préparation d'inhibiteurs d'amide d'acide béta-amino chiral de dipeptidyle peptidase-IV, et les intermédiaires utiles obtenus par ce procédé. Les produits obtenus à partir de ce procédé instantané sont des inhibiteurs de dipeptidyle peptidase-IV et par conséquent, ils sont utiles pour le traitement de diabètes de type 2.
PCT/US2004/008826 2003-03-27 2004-03-23 Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv WO2004087650A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45797603P 2003-03-27 2003-03-27
US60/457,976 2003-03-27

Publications (2)

Publication Number Publication Date
WO2004087650A2 true WO2004087650A2 (fr) 2004-10-14
WO2004087650A3 WO2004087650A3 (fr) 2005-01-13

Family

ID=33131737

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/008826 WO2004087650A2 (fr) 2003-03-27 2004-03-23 Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv

Country Status (1)

Country Link
WO (1) WO2004087650A2 (fr)

Cited By (69)

* 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
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
WO2008110308A2 (fr) * 2007-03-09 2008-09-18 Syngenta Participations Ag Nouveaux herbicides
JP2009504599A (ja) * 2005-08-11 2009-02-05 エフ．ホフマン−ラ ロシュ アーゲー Ｄｐｐ−ｉｖ阻害剤を含有する医薬組成物
WO2009045507A2 (fr) * 2007-10-03 2009-04-09 Teva Pharmaceutical Industries Ltd. Procédés d'élaboration d'intermédiaire de sitagliptine via une réduction enzymatique
WO2009064476A1 (fr) * 2007-11-13 2009-05-22 Teva Pharmaceutical Industries Ltd. Préparation d'un intermédiaire de sitagliptine
WO2009084024A2 (fr) * 2007-11-02 2009-07-09 Glenmark Generics Limited Procédé pour la préparation de r-sitagliptine et de ses sels pharmaceutiquement acceptables
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
WO2010000469A2 (fr) * 2008-07-03 2010-01-07 Ratiopharm Gmbh Sels cristallins de sitagliptine
EP2223923A1 (fr) 2009-02-25 2010-09-01 Esteve Química, S.A. Procédé pour la préparation d'un dérivé d'acide aminé chiral bêta et intermédiaires correspondants
WO2010114292A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré de fabrication d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2010114291A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré d'élaboration d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
US7820666B2 (en) 2007-05-08 2010-10-26 Concert Pharmaceuticals, Inc. Tetrahydrotriazolopyrazine derivatives and uses thereof
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
WO2011035725A1 (fr) 2009-09-27 2011-03-31 浙江九洲药业股份有限公司 Intermédiaires de la sitaglipine, leurs procédés de préparation et leurs utilisations
WO2011040717A2 (fr) * 2009-10-01 2011-04-07 Hanmi Holdings Co., Ltd. Procédé pour préparer un intermédiaire de sitagliptine en utilisant de l'oxirane chirale
CN101570538B (zh) * 2008-04-29 2011-04-20 上海博康精细化工有限公司 一种西他列汀中间体的制备方法
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
CN102093245A (zh) * 2009-12-14 2011-06-15 浙江海翔药业股份有限公司 一种西他列汀中间体、西他列汀或其盐的制备方法
WO2011123641A1 (fr) 2010-03-31 2011-10-06 Teva Pharmaceutical Industries Ltd. Formes à l'état solide de sels de sitagliptine
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
WO2011049344A3 (fr) * 2009-10-21 2011-10-13 Hanmi Holdings Co., Ltd. Procédé de préparation de sitagliptine et intermédiaires utilisés dans celui-ci
EP2392575A1 (fr) 2010-06-04 2011-12-07 LEK Pharmaceuticals d.d. Nouvelle approche synthétique pour composés à substitution ß-aminobutyryle
WO2011151443A1 (fr) 2010-06-04 2011-12-08 Lek Pharmaceuticals D.D. Nouvelle approche synthétique de ss-aminobutyryles substitués
EP2397141A1 (fr) 2010-06-16 2011-12-21 LEK Pharmaceuticals d.d. Procédé pour la synthèse d'acides aminés beta et leurs dérivés
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
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
WO2012025944A2 (fr) 2010-08-27 2012-03-01 Usv Limited Sitagliptine, sels et polymorphes de celle-ci
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
WO2012042534A2 (fr) * 2010-09-28 2012-04-05 Glenmark Generics Limited Procédés de préparation de r-sitagliptine et de ses intermédiaires
WO2012072036A1 (fr) 2010-12-03 2012-06-07 浙江海翔药业股份有限公司 Intermédiaires de sitagliptine et leur procédé de préparation
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8278486B2 (en) 2008-12-31 2012-10-02 Chiral Quest, Inc. Process and intermediates for the preparation of N-acylated-4-aryl beta-amino acid derivatives
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
EP2508506A1 (fr) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Préparation d'intermédiaires de la sitagliptine
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
US8309724B2 (en) 2007-12-20 2012-11-13 Dr. Reddy's Laboratories Limited Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof
EP2527320A1 (fr) 2011-05-27 2012-11-28 LEK Pharmaceuticals d.d. Préparation d'intermédiaires de la sitagliptine
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US8329696B2 (en) 2009-03-30 2012-12-11 Teva Pharmaceuticals Industries Ltd. Solid state forms of sitagliptin salts
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
CN102838511A (zh) * 2011-06-24 2012-12-26 浙江海翔药业股份有限公司 一种西他列汀的中间体及其制备方法和应用
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
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2013065066A1 (fr) 2011-11-02 2013-05-10 Cadila Healthcare Limited Procédés de préparation de 4-oxo-4-[3-(trifluorométhyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-1-(2,4,5-trifluorophényl)- butan-2-amine
WO2013084210A1 (fr) 2011-12-08 2013-06-13 Ranbaxy Laboratories Limited Forme amorphe de sels de sitagliptine
EP2674432A1 (fr) 2012-06-14 2013-12-18 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation de composés à substitution ß-aminobutyryle 5,6,7,8-tétrahydro[1,4]diazolo[4,3-alpha]pyrazines-7-yl
WO2014023930A1 (fr) 2012-08-08 2014-02-13 Cipla Limited Procédé pour la préparation de sitagliptine et composés intermédiaires
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
TWI453182B (zh) * 2009-06-26 2014-09-21 Jiangsu Hengrui Medicine Co Ｒ－β－胺基苯丁酸衍生物的製備方法
US8846916B2 (en) 2009-05-11 2014-09-30 Generics [Uk] Limited Sitagliptin synthesis
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8946224B2 (en) 2010-11-11 2015-02-03 Redx Pharma Limited Substituted [1,2,4]triazolo[4,3-A]pyrazines for medicaments and pharmaceutical compositions
CN105017260A (zh) * 2015-07-30 2015-11-04 新发药业有限公司 一种西他列汀中间体三唑并吡嗪衍生物的制备方法
CN105315286A (zh) * 2014-07-30 2016-02-10 连云港润众制药有限公司 西格列汀的制备
WO2016112880A1 (fr) 2015-01-13 2016-07-21 Zentiva, K.S Modification cristalline 3 de (3r)-3-amino-l-[3-(trifluorométhyl)-6,8-dihydro-5h-[l1,2,4]triazolol[4,3-]pyrazin-7-yl]-4-(2,4,5-trifluorophényl)butan-1-one l-tartrate
WO2016112879A1 (fr) 2015-01-13 2016-07-21 Zentiva, K.S. Modification cristalline 2 de (3/?)-3-amino-l-[3-(trifluorométhyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-alpha]pyrazin-7-yl]-4-(2,4,5-trifluorophényl)butan-1-one l-tartrate
KR20160146124A (ko) 2015-06-11 2016-12-21 동방에프티엘(주) 시타글립틴의 개선된 제조방법
KR20160148371A (ko) 2015-06-16 2016-12-26 경동제약 주식회사 Dpp-iv 억제제의 제조를 위한 신규 중간체, 이의 제조방법 및 이를 이용한 dpp-iv 억제제의 제조방법
CN109608348A (zh) * 2018-12-28 2019-04-12 凯瑞斯德生化(苏州)有限公司 一种(r)-3-叔丁氧羰基氨基-4-(2,4,5-三氟苯基)丁酸的合成方法
US10450315B2 (en) 2015-01-08 2019-10-22 Lee Pharma Limited Process for the preparation of dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
CN111087400A (zh) * 2020-01-13 2020-05-01 天津民祥生物医药股份有限公司 一种西他列汀的合成方法
CN111349098A (zh) * 2020-03-19 2020-06-30 湖南复瑞生物医药技术有限责任公司 一种西他列汀中间体的制备方法
CN113461691A (zh) * 2020-12-31 2021-10-01 浙江美诺华药物化学有限公司 一种的西他列汀杂质及其制备方法与其检测方法
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008507541A (ja) 2004-07-23 2008-03-13 ロイヤルティ，スーザン・マリー ペプチダーゼ阻害剤
EP2146210A1 (fr) 2008-04-07 2010-01-20 Arena Pharmaceuticals, Inc. Procédés d'utilisation du récepteur couplé aux protéines A G pour identifier les secrétagogues de peptide YY (PYY) et composés utiles dans le traitement d'états modulés par PYY

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Cited By (109)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
JP2009504599A (ja) * 2005-08-11 2009-02-05 エフ．ホフマン−ラ ロシュ アーゲー Ｄｐｐ−ｉｖ阻害剤を含有する医薬組成物
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
EP2253311A2 (fr) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Utilisation d'agonistes du récepteur de GPR119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose, et thérapie de combinaison associée
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
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
WO2008110308A3 (fr) * 2007-03-09 2008-12-11 Syngenta Participations Ag Nouveaux herbicides
WO2008110308A2 (fr) * 2007-03-09 2008-09-18 Syngenta Participations Ag Nouveaux herbicides
US8084649B2 (en) 2007-03-09 2011-12-27 Syngenta Crop Protection, Inc. Herbicides
JP2010520867A (ja) * 2007-03-09 2010-06-17 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト 新規除草剤
AU2008226027B2 (en) * 2007-03-09 2014-01-30 Syngenta Limited Novel herbicides
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
US7820666B2 (en) 2007-05-08 2010-10-26 Concert Pharmaceuticals, Inc. Tetrahydrotriazolopyrazine derivatives and uses thereof
WO2009045507A3 (fr) * 2007-10-03 2009-06-04 Teva Pharma Procédés d'élaboration d'intermédiaire de sitagliptine via une réduction enzymatique
WO2009045507A2 (fr) * 2007-10-03 2009-04-09 Teva Pharmaceutical Industries Ltd. Procédés d'élaboration d'intermédiaire de sitagliptine via une réduction enzymatique
US8334385B2 (en) 2007-11-02 2012-12-18 Glenmark Generics Limited Process for the preparation of R-sitagliptin and its pharmaceutically acceptable salts thereof
WO2009084024A3 (fr) * 2007-11-02 2009-10-29 Glenmark Generics Limited Procédé pour la préparation de r-sitagliptine et de ses sels pharmaceutiquement acceptables
WO2009084024A2 (fr) * 2007-11-02 2009-07-09 Glenmark Generics Limited Procédé pour la préparation de r-sitagliptine et de ses sels pharmaceutiquement acceptables
WO2009064476A1 (fr) * 2007-11-13 2009-05-22 Teva Pharmaceutical Industries Ltd. Préparation d'un intermédiaire de sitagliptine
US8309724B2 (en) 2007-12-20 2012-11-13 Dr. Reddy's Laboratories Limited Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof
EP2599781A1 (fr) 2007-12-20 2013-06-05 Dr. Reddy's Laboratories Ltd. Procédés pour la préparation de la sitagliptine et de ses sels pharmaceutiquement acceptables
US8969558B2 (en) 2007-12-20 2015-03-03 Dr. Reddy's Laboratories Limited Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof
EP2679590A1 (fr) 2007-12-20 2014-01-01 Dr. Reddy's Laboratories Ltd. Procédés pour la préparation de la sitagliptine et de ses sels pharmaceutiquement acceptables
CN101570538B (zh) * 2008-04-29 2011-04-20 上海博康精细化工有限公司 一种西他列汀中间体的制备方法
EP2586782B2 (fr) † 2008-07-03 2017-10-04 ratiopharm GmbH Sels cristallins de sitagliptine
WO2010000469A3 (fr) * 2008-07-03 2010-11-18 Ratiopharm Gmbh Sels cristallins de sitagliptine
WO2010000469A2 (fr) * 2008-07-03 2010-01-07 Ratiopharm Gmbh Sels cristallins de sitagliptine
US8278486B2 (en) 2008-12-31 2012-10-02 Chiral Quest, Inc. Process and intermediates for the preparation of N-acylated-4-aryl beta-amino acid derivatives
WO2010097420A1 (fr) 2009-02-25 2010-09-02 Esteve Química, S.A. Procédé de préparation d'un dérivé béta aminoacide chiral et intermédiaires utilisés dans ledit procédé
EP2223923A1 (fr) 2009-02-25 2010-09-01 Esteve Química, S.A. Procédé pour la préparation d'un dérivé d'acide aminé chiral bêta et intermédiaires correspondants
CN103922971A (zh) * 2009-03-30 2014-07-16 东亚制药株式会社 用于制备二肽基肽酶-iv抑制剂的中间体的改进方法
EP2669265A2 (fr) 2009-03-30 2013-12-04 Dong-A Pharmaceutical Co., Ltd. Procédé amélioré de préparation d'inhibiteur de dipeptidyl peptidase-IV et d'intermédiaire
EP2669266A1 (fr) 2009-03-30 2013-12-04 Dong-A Pharmaceutical Co., Ltd. Procédé amélioré de préparation d'inhibiteur de dipeptidyl peptidase-IV et d'intermédiaire
CN103922971B (zh) * 2009-03-30 2016-05-11 东亚St株式会社 用于制备二肽基肽酶-iv抑制剂的中间体的改进方法
WO2010114291A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré d'élaboration d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2010114292A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré de fabrication d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
US8329696B2 (en) 2009-03-30 2012-12-11 Teva Pharmaceuticals Industries Ltd. Solid state forms of sitagliptin salts
US8846916B2 (en) 2009-05-11 2014-09-30 Generics [Uk] Limited Sitagliptin synthesis
TWI453182B (zh) * 2009-06-26 2014-09-21 Jiangsu Hengrui Medicine Co Ｒ－β－胺基苯丁酸衍生物的製備方法
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
US8471057B2 (en) 2009-09-27 2013-06-25 Zhejiang Jiuzhou Pharmaceutical Co., Ltd. Sitagliptin intermediates, preparation methods and uses thereof
WO2011035725A1 (fr) 2009-09-27 2011-03-31 浙江九洲药业股份有限公司 Intermédiaires de la sitaglipine, leurs procédés de préparation et leurs utilisations
WO2011040717A3 (fr) * 2009-10-01 2011-10-13 Hanmi Holdings Co., Ltd. Procédé pour préparer un intermédiaire de sitagliptine en utilisant de l'oxirane chirale
WO2011040717A2 (fr) * 2009-10-01 2011-04-07 Hanmi Holdings Co., Ltd. Procédé pour préparer un intermédiaire de sitagliptine en utilisant de l'oxirane chirale
CN102574862A (zh) * 2009-10-21 2012-07-11 韩美控股株式会社 西他列汀的制备方法及其中使用的中间体
JP2013508355A (ja) * 2009-10-21 2013-03-07 ハンミ・サイエンス・カンパニー・リミテッド シタグリプチンの製造方法、およびこれに用いられる中間体
US8624026B2 (en) 2009-10-21 2014-01-07 Hanmi Science Co., Ltd Method of preparing sitagliptin and intermediates used therein
WO2011049344A3 (fr) * 2009-10-21 2011-10-13 Hanmi Holdings Co., Ltd. Procédé de préparation de sitagliptine et intermédiaires utilisés dans celui-ci
TWI421253B (zh) * 2009-10-21 2014-01-01 Hanmi Holdings Co Ltd 製備西他列汀（ｓｉｔａｇｌｉｐｔｉｎ）的方法以及其中所使用的中間產物
KR101222679B1 (ko) 2009-10-21 2013-01-16 한미사이언스 주식회사 시타글립틴의 제조 방법 및 이에 사용되는 중간체
CN102093245A (zh) * 2009-12-14 2011-06-15 浙江海翔药业股份有限公司 一种西他列汀中间体、西他列汀或其盐的制备方法
CN102093245B (zh) * 2009-12-14 2015-04-15 浙江海翔药业股份有限公司 一种西他列汀中间体、西他列汀或其盐的制备方法
WO2011123641A1 (fr) 2010-03-31 2011-10-06 Teva Pharmaceutical Industries Ltd. Formes à l'état solide de sels de sitagliptine
US8183373B2 (en) 2010-03-31 2012-05-22 Teva Pharmaceutical Industries Ltd. Solid state forms of sitagliptin salts
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
WO2011151443A1 (fr) 2010-06-04 2011-12-08 Lek Pharmaceuticals D.D. Nouvelle approche synthétique de ss-aminobutyryles substitués
EP2392575A1 (fr) 2010-06-04 2011-12-07 LEK Pharmaceuticals d.d. Nouvelle approche synthétique pour composés à substitution ß-aminobutyryle
EP2397141A1 (fr) 2010-06-16 2011-12-21 LEK Pharmaceuticals d.d. Procédé pour la synthèse d'acides aminés beta et leurs dérivés
WO2012025944A2 (fr) 2010-08-27 2012-03-01 Usv Limited Sitagliptine, sels et polymorphes de celle-ci
US20130158265A1 (en) * 2010-08-27 2013-06-20 Dhananjay Govind Sathe Sitagliptin, salts and polymorphs thereof
WO2012025944A3 (fr) * 2010-08-27 2013-03-14 Usv Limited Sitagliptine, sels et polymorphes de celle-ci
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
EP3323818A1 (fr) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2012042534A2 (fr) * 2010-09-28 2012-04-05 Glenmark Generics Limited Procédés de préparation de r-sitagliptine et de ses intermédiaires
WO2012042534A3 (fr) * 2010-09-28 2012-06-07 Glenmark Generics Limited Procédés de préparation de r-sitagliptine et de ses intermédiaires
US8946224B2 (en) 2010-11-11 2015-02-03 Redx Pharma Limited Substituted [1,2,4]triazolo[4,3-A]pyrazines for medicaments and pharmaceutical compositions
WO2012072036A1 (fr) 2010-12-03 2012-06-07 浙江海翔药业股份有限公司 Intermédiaires de sitagliptine et leur procédé de préparation
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
US9174930B2 (en) 2011-04-08 2015-11-03 Lek Pharmaceuticals D.D. Preparation of sitagliptin intermediates
WO2012136383A2 (fr) 2011-04-08 2012-10-11 Lek Pharmaceuticals D.D. Préparation d'intermédiaires de sitagliptine
EP2508506A1 (fr) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Préparation d'intermédiaires de la sitagliptine
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
EP2527320A1 (fr) 2011-05-27 2012-11-28 LEK Pharmaceuticals d.d. Préparation d'intermédiaires de la sitagliptine
WO2012163815A1 (fr) 2011-05-27 2012-12-06 Lek Pharmaceuticals D.D. Préparation d'intermédiaires de sitagliptine
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
CN102838511A (zh) * 2011-06-24 2012-12-26 浙江海翔药业股份有限公司 一种西他列汀的中间体及其制备方法和应用
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
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2013065066A1 (fr) 2011-11-02 2013-05-10 Cadila Healthcare Limited Procédés de préparation de 4-oxo-4-[3-(trifluorométhyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-1-(2,4,5-trifluorophényl)- butan-2-amine
WO2013084210A1 (fr) 2011-12-08 2013-06-13 Ranbaxy Laboratories Limited Forme amorphe de sels de sitagliptine
WO2013186326A1 (fr) 2012-06-14 2013-12-19 Lek Pharmaceuticals D.D. Nouvelle voie de synthèse pour la préparation de composés de 5,6,7,8-tétrahydro[1,4]diazolo [4,3-alpha]pyrazin-7-yle substitués par ss-aminobutyryle
EP2674432A1 (fr) 2012-06-14 2013-12-18 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation de composés à substitution ß-aminobutyryle 5,6,7,8-tétrahydro[1,4]diazolo[4,3-alpha]pyrazines-7-yl
US9388188B2 (en) 2012-06-14 2016-07-12 Lek Pharmaceuticals D.D. Synthetic route for the preparation of β-aminobutyryl substituted 5,6,7,8-tetrahydro[1,4]diazolo[4,3-alpha ]pyrazin-7-yl compounds
WO2014023930A1 (fr) 2012-08-08 2014-02-13 Cipla Limited Procédé pour la préparation de sitagliptine et composés intermédiaires
US9233967B2 (en) 2012-08-08 2016-01-12 Cipla Limited Process for the preparation of sitagliptin and intermediate compounds
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
CN105315286A (zh) * 2014-07-30 2016-02-10 连云港润众制药有限公司 西格列汀的制备
US10450315B2 (en) 2015-01-08 2019-10-22 Lee Pharma Limited Process for the preparation of dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor
WO2016112879A1 (fr) 2015-01-13 2016-07-21 Zentiva, K.S. Modification cristalline 2 de (3/?)-3-amino-l-[3-(trifluorométhyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-alpha]pyrazin-7-yl]-4-(2,4,5-trifluorophényl)butan-1-one l-tartrate
WO2016112880A1 (fr) 2015-01-13 2016-07-21 Zentiva, K.S Modification cristalline 3 de (3r)-3-amino-l-[3-(trifluorométhyl)-6,8-dihydro-5h-[l1,2,4]triazolol[4,3-]pyrazin-7-yl]-4-(2,4,5-trifluorophényl)butan-1-one l-tartrate
US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11400072B2 (en) 2015-03-09 2022-08-02 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
KR20160146124A (ko) 2015-06-11 2016-12-21 동방에프티엘(주) 시타글립틴의 개선된 제조방법
KR20160148371A (ko) 2015-06-16 2016-12-26 경동제약 주식회사 Dpp-iv 억제제의 제조를 위한 신규 중간체, 이의 제조방법 및 이를 이용한 dpp-iv 억제제의 제조방법
JP2018519290A (ja) * 2015-06-16 2018-07-19 キュン ドン ファーム． カンパニー リミテッド Ｄｐｐ−ｉｖ阻害剤の製造のための新規中間体、その製造方法、及びそれを用いたｄｐｐ−ｉｖ阻害剤の製造方法
CN105017260A (zh) * 2015-07-30 2015-11-04 新发药业有限公司 一种西他列汀中间体三唑并吡嗪衍生物的制备方法
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
CN109608348A (zh) * 2018-12-28 2019-04-12 凯瑞斯德生化(苏州)有限公司 一种(r)-3-叔丁氧羰基氨基-4-(2,4,5-三氟苯基)丁酸的合成方法
CN111087400A (zh) * 2020-01-13 2020-05-01 天津民祥生物医药股份有限公司 一种西他列汀的合成方法
CN111349098A (zh) * 2020-03-19 2020-06-30 湖南复瑞生物医药技术有限责任公司 一种西他列汀中间体的制备方法
CN113461691A (zh) * 2020-12-31 2021-10-01 浙江美诺华药物化学有限公司 一种的西他列汀杂质及其制备方法与其检测方法

Also Published As

Publication number Publication date
WO2004087650A3 (fr) 2005-01-13

Similar Documents

Publication Publication Date Title
WO2004087650A2 (fr) Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv
WO2004085661A2 (fr) Procede de synthese de derives d'acides amines beta chiraux
US6103901A (en) Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative
EP2451786B1 (fr) Procédé amélioré de préparation d'ambrisentan et nouveaux intermédiaires associés
AU2004212435A1 (en) Process for preparing pyrrolotriazine kinase inhibitors
WO2004080958A2 (fr) Procede pour preparer des tetrahydrotriazolopyrazines et leurs produits intermediaires
JP3488155B2 (ja) 成長ホルモン分泌促進物質の製造及び中間体
EP2566843B1 (fr) Procédé de préparation de dérivés chiraux de bêta-amino carboxamide
WO2012150328A1 (fr) Procédé de production de sitagliptine
WO2004083212A1 (fr) Procede de preparation d'intermediaires de beta-cetoamide utilises dans la preparation d'inhibiteurs de dipeptidyle peptidase
KR102068754B1 (ko) 의약품 합성용 중간체 화합물의 제조 방법
KR100766578B1 (ko) 레바미피드의 제조방법
KR100205767B1 (ko) 아제티디논의 입체 선택적인 제조방법
JP2002179658A (ja) Ｎ−［１−（ｓ）−エトキシカルボニル−３−フェニルプロピル］−ｌ−アラニンｎ−カルボキシアンハイドライドの製造方法及びその製造方法で使用する化合物
JP2022535112A (ja) ４－フェニル－５－アルコキシカルボニル－２－チアゾール－２－イル－１，４－ジヒドロピリミジン－６－イル］メチル］－３－オキソ－５，６，８，８ａ－テトラヒドロ－１Ｈ－イミダゾ［１，５－ａ］ピラジン－２－イル］－カルボン酸を調製するための代替方法
JP4181233B2 (ja) ピロリジン−２，４−ジオン誘導体の製法
US20130197229A1 (en) Method of making azaindazole derivatives
CN114315800B (zh) 一种托匹司他的制备方法
EP0947505B1 (fr) Procédé de préparation de dérivés optiquement actifs de 4-hydroxy-2-pyrrolidone
CN113773323B (zh) 3r-氨基取代丁酰胺衍生物的制备方法
JP3518627B2 (ja) 光学活性５−ヒドロキシメチルオキサゾリジノン誘導体の製造法
TW202208377A (zh) 製備烷基7-胺基-5-甲基-[1,2,5]噁二唑并[3,4-b]吡啶羧酸酯之方法
CN117015542A (zh) 吡咯并吡啶衍生物的制备方法
JPH07267950A (ja) ５−クロロ−ｎ−（４，５−ジヒドロ−１ｈ−イミダゾール−２−イル）−２，１，３−ベンゾチアジアゾール−４−アミン又はその酸付加塩の製造方法
JPH1192450A (ja) ３−アミノ−３−アルコキシアクリル酸エステル及びその製造法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase