WO2021242806A1 - Intermédiaires et procédés de préparation d'un agoniste du récepteur glp-1 - Google Patents

Intermédiaires et procédés de préparation d'un agoniste du récepteur glp-1 Download PDF

Info

Publication number
WO2021242806A1
WO2021242806A1 PCT/US2021/034154 US2021034154W WO2021242806A1 WO 2021242806 A1 WO2021242806 A1 WO 2021242806A1 US 2021034154 W US2021034154 W US 2021034154W WO 2021242806 A1 WO2021242806 A1 WO 2021242806A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
reaction
salt
solvent
Prior art date
Application number
PCT/US2021/034154
Other languages
English (en)
Inventor
Dharma Rao Polisetti
Thomas Scott Yokum
Yuanqiang SUN
Original Assignee
Vtv Therapeutics 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 Vtv Therapeutics Llc filed Critical Vtv Therapeutics Llc
Publication of WO2021242806A1 publication Critical patent/WO2021242806A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the invention belongs to the field of drug synthesis, and particularly relates to a intermediates and methods for preparing (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)- 1-pheny I propyl)- 2,3,6,7,8,9-hexahydro-[l,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4- (2,3-dimethylpyridin-4-yl) phenyl) propanoic acid dihydrochloride.
  • OAD2 dihydrochloride is an oral, non-peptide glucagon-like peptide 1 (GLP-1) receptor agonist.
  • OAD2 dihydrochloride has a molecular formula of C50H49CI4N3O6, a molecular weight of 929.76, and the following chemical structure:
  • a patent for invention CN102378574B discloses a method for preparing OAD2 (summarized in Scheme 1), which utilizes 4-hydroxyacetophenone as the starting material and comprises 14 steps including nucleophilic substitution, bromination, asymmetric reduction, condensation, hydrolysis, etc.
  • the present invention provides a method for preparing OAD2 dihydrochloride. Compared with the prior art, the method has less steps and increased yield, and adopts multi-step continuous feeding reaction, which does not require column chromatographic separation and is suitable for industrial production. Further, the method installs a chiral center using a different route than previously disclosed. In a first aspect, the present invention provides a process for preparing a compound of
  • the present invention provides a process for preparing a compound of Formula 14, or a salt thereof: wherein the process comprises treating a compound of Formula 13, or salt thereof, to hydrolysis conditions to give a compound of Formula 14, or salt thereof, wherein R 1 is C 1-6 alkyl and R 2 is a C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or an arylmethoxy group.
  • the present invention provides a process for preparing a compound of Formula 15, or a salt thereof: wherein the process comprises (a) reacting a compound of Formula 14, or salt thereof, with (S)-phenylpropyl amine and a reducing agent to give a compound of Formula 15, and (b) optionally forming a salt of the compound of Formula 15.
  • the present invention provides a process for preparing a compound of Formula 8, or salt thereof: wherein the process comprises (a) reacting a compound of Formula 15, or salt thereof, with a formaldehyde equivalent to give a compound of Formula 8 and (b) optionally forming an alkali metal or an earth alkali metal salt of compound of Formula 8.
  • the present invention provides a process for preparing a compound of Formula 10, or salt thereof: wherein the process comprises reacting a compound of Formula 8-M: , wherein M is an alkali metal or earth alkali metal, with the compound of Formula 9 to give the compound of Formula 10, or salt thereof
  • the present invention provides a process for preparing the mono HCI salt of OAD2 (compound of Formula 11), wherein the process comprises a first step of hydrolyzing the methyl ester of the compound of Formula 10 acid so as to produce the mono HCI salt of OAD2 (compound of Formula 11):
  • the present invention provides a process for preparing the di-HCI salt of
  • the process comprises reacting the mono HCI salt of OAD2 (compound 11) with HCl, so as to produce the di-HCl salt of OAD2.
  • the specific preparation method may comprise one or more of the steps in Aspects 1 to 7 as shown below in Scheme 2.
  • the present invention provides compounds of Formula 13 and 14. Detailed Description of the Invention Definitions
  • alkyl as used herein means a monovalent saturated hydrocarbon group which may be linear or branched or combinations thereof. Unless otherwise defined, such alkyl groups typically contain from 1 to 12 carbon atoms.
  • alkyl groups include, by way of example, methyl (Me), ethyl (Et), n-propyl (n-Pr) or (nPr), isopropyl (i-Pr) or (iPr), n-butyl (n-Bu) or (nBu), sec-butyl, isobutyl, tert-butyl (t-Bu) or (tBu), n-pentyl, n-hexyl, 2,2-dimethylpropyl, 2- methylbutyl, 3-methylbutyl, 2-ethylbutyl, 2,2-dimethylpentyl, 2-propylpentyl, and the like.
  • C 1-3 alkyl means an alkyl group having from 1 to 3 carbon atoms wherein the carbon atoms are in any chemically-acceptable configuration, including linear or branched configurations.
  • haloalkyl refers to straight-chain or branched alkyl groups having 1 to 12 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms.
  • C 1-2 -haloalkyl groups include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, 1-chloroethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl groups.
  • alkoxy refers to an alkyl group attached via an oxygen atom.
  • C 1-2 -alkoxy is a C 1-2 -alkyl group, as defined above, attached via an oxygen atom.
  • C 1-3 -Alkoxy examples include methoxy, ethoxy, n-propoxy and 1-methylethoxy (isopropoxy).
  • haloalkoxy refers to a haloalkyl group attached via an oxygen atom.
  • C 1-3 haloalkoxy groups include OCH 2 F, OCHF 2 , OCF 3 , OCH 2 Cl, OCHCl 2 , OCCl 3 , 2- fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2,2-trichloroethoxy, and 2-fluoropropoxy.
  • aryl refers to an aryl group with 6 to 14 carbon atoms as ring members.
  • Aryl is a mono-, bi- or polycyclic carbocyclic (i.e.
  • ring system where one or more rings are aromatic.
  • One example for a monocyclic aryl radical is phenyl.
  • bicyclic rings two rings maybe condensed, i.e. they share two vicinal C atoms as ring members.
  • One example for a bicyclic aryl group is naphthyl.
  • polycyclic aryl rings three or more rings may be condensed. Examples for polycyclic aryl radicals are fluorenyl (9H-fluorenyl), phenanthrenyl and anthracenyl.
  • One or more of the hydrogens of the aryl group may be independently substituted with a substituent independently selected from the group consisting of halogen, nitro, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.
  • arylmethoxy is aryl as defined above bound by a methoxy group to the remainder of the molecule. Examples of arylmethoxy groups include benzyloxy, 9- fluorenylmethoxy, p-nitrobenzyloxy, 2,4-dichlorobenzyloxy, and 5-benzisoxazolylmethoxy.
  • a suitable "coupling agent" for the formation of an amide bond between a compound of Formula 14 with a compound of Formula 9 may be selected from the group consisting of N,N'- carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI), 1-hydroxy-1,2,3-benzotriazole (HOBT), benzotriazole-1- yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazole-1-yloxy- tripyrrolidino-phosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethylamino)-methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxi-de hexafluorophosphate (
  • non-polar organic solvent includes aliphatic hydrocarbons, such as alkanes, e.g. pentane, hexane, heptane, octane, mixtures thereof and technical mixtures, such as petrol ether; cycloaliphatic hydrocarbons, such as cycloalkanes, e.g.
  • chlorinated aliphatic hydrocarbons such as halogenalkanes, e.g. dichloromethane, trichloromethane, tetrachloromethane, dichloroethane or tetrachloroethane, aromatic hydrocarbons, such as benzene, toluene, the xylenes, ethylbenzene, cumene (isopropylbenzene), chlorobenzene, o-dichlorobenzene or nitrobenzene, or open-chained ethers, such as diethylether, dipropylether, methyl-tert-butylether or methyl-isobutylether.
  • chlorinated aliphatic hydrocarbons such as halogenalkanes, e.g. dichloromethane, trichloromethane, tetrachloromethane, dichloroethane or tetrachloroethane, aromatic hydrocarbon
  • a non-polar organic solvent is selected from the group consisting of benzene, toluene, the xylenes, ethylbenzene, cumene (isopropylbenzene), chlorobenzene, o- dichlorobenzene and nitrobenzene.
  • a non-polar organic solvent is selected from the group consisting of toluene, xylenes, and chlorobenzene.
  • polar aprotic solvent as used herein includes solvents which are water-miscible in a desired ratio of water/polar aprotic solvent to be used in a reaction.
  • a polar aprotic solvent are solvents without a functional group from which a proton can dissociate. "Miscible” means that a homogenous solution is formed.
  • suitable polar aprotic solvents are amides, such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; sulfoxides, such as dimethylsulfoxide (DMSO); lactams, such as N-methylpyrrolidone (NMP); cyclic ethers, such as tetrahydrofuran, 1,3-dioxane and 1,4-dioxane; ketones, such as acetone and methylethylketone; nitriles, such as acetonitrile; lactones, such as gamma-butyrolactone; nitro compounds, such as nitromethane; ureas, such as tetramethyl urea or dimethylpropylene urea (DMPU); s
  • the polar aprotic co-solvent is a cyclic ether, such as tetrahydrofuran, or 1,4- dioxane.
  • polar protic solvent includes solvents such as water, acetic acid, formic acid, methanol, ethanol, n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert- butanol, n-propanol, isopropanol, 1,2 propan-diol, and glycerol.
  • base refers to inorganic and organic bases.
  • Suitable inorganic bases may include for example alkali metal carbonates, e.g. Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 , earth alkaline metal carbonates, e.g. MgCC or CaCC , alkali metal phosphates, e.g. U 3 PO 4 , Na 3 P0 4 , K 3 PO 4 or CS 3 PO 4 , earth alkaline metal phosphates, e.g. Mg 3 (P0 4 or CasiPC , alkali metal hydrogenphosphates, e.g. Li 2 HPO 4 , Na 2 HPO 4 , K 2 HPO 4 or CS 2 HPO 4 , earth alkaline metal hydrogenphosphates, e.g.
  • alkali metal carbonates e.g. Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3
  • earth alkaline metal carbonates e.g. MgCC or CaCC
  • Suitable organic bases may include open-chained amines, e.g. trimethylamine, triethylamine, tripropylamine, ethyldiisopropylamine and the like, or basic N-heterocycles, such as morpholine, pyridine, lutidine, DMAP, DABCO, DBU or DBN.
  • the present invention provides a process for preparing a compound of Formula 13, or salt thereof: wherein the process comprises reacting a compound of Formula 1: with a compound of Formula 12: to give a compound of Formula 13, or salt thereof, wherein R a and R b are independently selected from C 1-6 a Ikyl, R 1 is C 1-6 alkyl, and R 2 is a C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or an arylmethoxy group.
  • the reaction is conducted in a solvent comprising one or more solvents selected from the group consisting of dichloromethane, toluene, tetrahydrofuran, and 2- methyltetrahydrofuran.
  • the reaction is conducted in a non-polar organic solvent.
  • the reaction is conducted in toluene.
  • the reaction is conducted in 2-methyltetrahydrofuran.
  • R 1 , R 2 , R a and R b are methyl or ethyl
  • the reaction is carried out under alkaline conditions.
  • a base is added to the reaction to create alkaline conditions.
  • the base is an organic base.
  • the organic base is one, two or more bases selected from the group consisting of DBU, DMAP, triethylamine, isopropylamine, dibutylamine, piperazine, piperidine, and morpholine.
  • the base is dimethylaminopyridine (DMAP).
  • the compounds of Formula 1 and Formula 12 and the alkaline reagent (base) are fed at a molar ratio in the range of 1:1.05:1.5 to 1:2:3.
  • Compound 1 and acetylamino-(dimethoxy-phosphoryl)-acetic acid ethyl ester may be suspended in dry dichloromethane (DCM).
  • DCM dry dichloromethane
  • DBU 2 eq
  • the internal temperature may be raised to BO- 34 °C and progress of the reaction monitored by TLC (50:50 hexanes:EtOAc).
  • 4 angstrom molecular sieves may be added, and mixture was stirred overnight at room temperature. The solvent is evaporated, and the residue suspended in MeOFI and water added while stirring.
  • the workup mode of is as follows: after the completion of the reaction, an aqueous solution of ammonium chloride is added to the reaction, and the reaction mixture is stirred and washed; the aqueous layer is separated and removed out, and the organic layer is washed with saturated brine and then concentrated; methanol/water is added to the concentrated solution and stirred to crystalize, and the precipitated crystals are filtered and dried to give the compound of Formula 13.
  • the present invention provides a process for preparing a compound of Formula 14, or a salt thereof: wherein the process comprises treating a compound of Formula 13, or salt thereof, to hydrolysis conditions to give a compound of Formula 14, or salt thereof, wherein R 1 is C 1-6 alkyl and R 2 is a C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or an arylmethoxy group.
  • the reaction is conducted in a solvent.
  • the solvent is a polar aprotic solvent.
  • the solvent is one, two or more selected from the group consisting of 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, dimethylacetamide, and dimethylformamide.
  • the solvent is N-methylpyrrolidone.
  • the reaction is carried out under acidic condition.
  • an acid is added to the reaction to create acidic conditions.
  • the acid is an aqueous solution, wherein the acid is one, two or more selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid.
  • the acid is an aqueous solution of hydrochloric acid.
  • the compound of Formula 13 and the acidic aqueous solution are fed at a molar ratio in the range of 1:10 to 1:13, and the concentration of the acidic aqueous solution is between 2 mol/L and 6 mol/L.
  • the workup mode is as follows: afterthe completion ofthe reaction, the temperature is lowered and water is added and stirred to crystalize; wet product is obtained after filtration, and then the wet product is slurried with methanol/dichloromethane; and compound 14 is obtained after filtration and drying.
  • the present invention provides a process for preparing a compound of Formula 15, or a salt thereof: wherein the process comprises (a) reacting a compound of Formula 14, or salt thereof, with (S)-phenylpropyl amine and a reducing agent to give a compound of Formula 15, and (b) optionally forming a salt of the compound of Formula 15.
  • the reaction is conducted in a solvent, wherein the solvent is one, two or more solvents selected from the group consisting of dioxane, N-methylpyrrolidone, dimethyl sulfoxide, toluene, dimethylformamide, and dimethylacetamide.
  • the solvent is a mixture of toluene and dimethylacetamide.
  • the solvent is a mixture of a polar aprotic solvent and a non-polar organic solvent.
  • the reaction is carried out under alkaline condition.
  • the alkaline reaction condition is created by adding an organic base.
  • the organic base is one, two or more selected from the group consisting of triethylamine, isopropylamine, diethylamine, n-butylamine, DBU, DMAP, and N,N- diisopropylethylamine.
  • the organic base is isopropylamine.
  • the reducing agent used in this reaction may be any reducing agent suitable to reduce an imine formed between the compound of Formula 14 and (S)-phenylpropyl amine without substantially reacting with the other portions of the compound.
  • the reducing agent may be a borohydride reagent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium tris[2-(ethylhexanoic)]borohydride, and the like can be used.
  • the reducing agent may be formed in situ.
  • the reducing agent is sodium tris[2-(ethylhexanoic)]borohydride.
  • the reducing agent is NaBFI(OCOR c ) 3 , with R c being C 1 -C 12 alkyl, and preferably C 7 -C 9 alkyl.
  • the molar amount of the reducing agent may be between 1 to 3 times to that of compound 14, and preferably 1.5 to 2 times.
  • the reaction is worked up as follows: after the completion of the reaction, partial solvent is removed out by concentration, and then methanol is added and stirred to crystalize.
  • the present invention provides a process for preparing a compound of Formula 8, or salt thereof: wherein the process comprises (a) reacting a compound of Formula 15, or salt thereof, with a formaldehyde equivalent to give a compound of Formula 8 and (b) optionally forming an alkali metal or an earth alkali metal salt of compound of Formula 8.
  • reaction forms a sodium salt of the compound of Formula 8.
  • the reaction solvent is a mixture of a polar aprotic solvent and a non polar organic solvent.
  • the solvent is one, two or more selected from the group consisting of toluene, xylene, chlorobenzene, ethyl acetate, isopropyl acetate, propyl acetate, and butyl acetate.
  • the solvent is a mixture of chlorobenzene and isopropyl acetate.
  • an acid catalyst is added to the reaction.
  • the acid catalyst is one, two or more selected from the group consisting of trifluoroacetic acid, concentrated sulfuric acid, hydrochloric acid, and trifluoromethanesulfonic acid.
  • the acid catalyst is trifluoromethanesulfonic acid.
  • the reaction is carried out at a temperature in the range of 20 to 50°C, and preferably in the range of 30 to 40°C.
  • the workup mode of the reaction is as follows: the temperature is lowered, and a sodium hydroxide solution of 1 to 4 mol/L is added at a weight amount of 8 to 11 times to that of compound 15; after stirring and extraction, organic layer is separated and then washed with saturated brine; a high boiling solvent is added, and then low boiling solvent is removed out by stirring and concentration; the concentrating is stopped till the remaining concentrated solution is approximately 4 times to that of compound 15 by weight; and the remaining concentrated solution is directly used in the next step of the reaction.
  • the high boiling solvent is one, two or more selected from the group consisting of N,N-dimethylformamide, N,N- dimethylacetamide, and dimethyl sulfoxide, and preferably N,N-dimethylacetamide.
  • the present invention provides a process for preparing a compound of Formula 10, or salt thereof: wherein the process comprises reacting a compound of Formula 8-M: , wherein M is an alkali metal or earth alkali metal, with the compound of Formula 9 to give the compound of Formula 10, or salt thereof
  • the reaction solvent is a polar aprotic solvent.
  • the reaction solvent is one, two or more selected from the group consisting of N,N- dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.
  • the reaction solvent is N,N-dimethylacetamide.
  • M is an alkali metal. In a further embodiment, M is sodium.
  • the reaction is carried out at a temperature in the range of 10 to 40°C, and preferably in the range of 20 to 30°C.
  • a coupling agent is added to the reaction.
  • the coupling agent is selected from the group consisting of HATU, HBTU, HCTU, PyBOP, and TBTU.
  • the coupling agent is PyBOP.
  • the reaction is conduction under alkaline conditions.
  • the alkaline condition is achieved by adding a base is added to the reaction.
  • the base is an organic base.
  • the base is selected from the group consisting of triethylamine, N-methylmorpholine, diisopropylethylamine, and 4- methylaminopyridine.
  • the base is N-methylmorpholine.
  • compound 8-M and coupling agent are fed at a molar ratio in the range of 1:1.1 to 1:3.
  • compound 8-M, compound 9 and an organic base are fed at a molar ratio in the range of 1:1.05:1 to 1:1.1:3.
  • the workup mode of the reaction is as follows: after the completion of the reaction, ethyl acetate and water are added under stirring to extract, aqueous layer is separated and removed out, and the organic layer is poured into the reaction solvent that is used in the next step and then concentrated till the remaining concentrated solution is approximated 2 times to that of compound 8-M by weight; and the remaining concentrated solution is directly used in the next step of the reaction without separation.
  • the present invention provides a process for preparing the mono HCI salt of OAD2 (compound of Formula 11), wherein the process comprises a first step of hydrolyzing the methyl ester of the compound of Formula 10
  • the reaction solvent is a polar aprotic solvent.
  • the reaction solvent is selected from the group consisting of 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, acetone, and acetonitrile, and preferably tetrahydrofuran.
  • the weight amount of the solvent is 4 to 8 times to that of OAD2.
  • the reaction is carried out at a temperature in the range of 10 to 40°C, and preferably in the range of 15 to 25°C.
  • an alkaline solution is added to the reaction.
  • the alkaline solution is a sodium hydroxide solution of 2 to 4 mol/L, and compound 10 and sodium hydroxide are fed at a molar ratio in the range of 1:4 to 1:6.
  • the process of adding a hydrochloric acid solution of 1 to 2 mol/L; and the pH is adjusted to the range of 1 to 4, and preferably to the range of 2 to 3.
  • the workup mode of the reaction is as follows: after adjusting the pH to between 1 to 4, the reaction mixture is stirred to crystalize or stood to crystalize, and preferably stood to crystalize. Seventh Aspect
  • the present invention provides a process for preparing the di-HCI salt of OAD2, wherein the process comprises reacting the mono HCI salt of OAD2 (compound 11) with HCI, so as to produce the di-HCI salt of OAD2.
  • the reaction is conducted in a solvent mixture comprising water and a polar aprotic solvent. In another embodiment, the reaction is conducted in a solvent mixture comprising water and a solvent selected from the group consisting of acetic acid, tetrahydrofuran, and acetone. In another embodiment, the reaction is conducted in a solvent mixture comprising water and tetrahydrofuran, and the weight amount of the reaction solvent is 15 to 20 times to that of mono HCI salt of OAD2.
  • a hydrochloric acid solution A is first added and stirred, and subsequently water is added and further stirred, and then a hydrochloric acid solution B is added and stirred to crystalize.
  • the weight amount of hydrochloric acid solution A is 2 to 3 times to that of the mono HCI salt of OAD2, and the weight amount of hydrochloric acid solution B is 6 to 8 times to that of compound mono HCI salt of OAD2.
  • the concentrations of hydrochloric acid solutions A and B are 3 to 6 mol/L, and preferably 4 to 5 mol/L.
  • the specific preparation method may comprise one or more of the steps in Aspects 1 to 7 as shown below in Scheme 2.
  • the present invention provides intermediate compounds of Formula 13 and 14.
  • the present invention provides a compound of Formula 13, or salt thereof: , wherein R 1 is Ci-6 alkyl, and R 2 is a Ci-6 alkyl or arylmethoxy group.
  • R 1 is methyl.
  • R 2 is methyl.
  • R 1 is methyl and R 2 is methyl.
  • the present invention provides a compound of Formula 14, or a salt thereof:
  • the invention may achieve the following beneficial effects: compared with the prior art methods, the method of the invention for preparing OAD2 dihydrochloride has fewer steps, does not require separation and purification by column chromatography, and is suitable for industrial scale production. Moreover, in the method of the invention, the steps for preparing the mono HCI salt of OAD2 from compound 15 can be carried out in a continuous feeding mode, may not require purification process; the workup is simplified and the loss of the product is minimized; solid product may be precipitated from a certain solvent by the salt forming mode of acid and alkaline, to achieve purification effect and meanwhile obtain mono HCI salt of OAD2 having high purity, and then target compound OAD2 di HCI is obtained via further salt forming step.
  • the preparation method of the invention may have a total yield of more than 35% from compound 1 to the final product compound OAD2 dihydrochloride, and the purity of the final product may be more than 98%.
  • the method of the invention may have a significantly improved yield and is suitable for large-scale industrial production.
  • the certain embodiments of the current method have reached a batch size of 50 kg and showed good process stability and controllable product quality.
  • Example 1 Process for preparation of compound 13 (where R 1 is -ethyl and R 2 is -methyl)
  • the temperature of the mixture was adjusted to 20.4°C, and the resulting mixture was agitated at 20.4-21.1°C for 10 min.
  • the layers were separated, and the organic layer was washed with brine (2 x 14.6 kg).
  • the organic layer was diluted with DMF (10.8 kg), and the mixture was concentrated under reduced pressure to 12 L volume. DMF (10.8 kg) was added, and the mixture stirred at 22.4-25.0 °C for 10 min.
  • the DMF solution of 8-M was used as starting material in Example 5B.
  • the mixture was stirred at 5.7-8.8 °C for 2.5 h which resulted in formation of a slurry.
  • the slurry was warmed to 16.5°C and stirred at 16.5-18.7°C for 1 h.
  • the solids were collected by filtration and then washed with water (5.8 kg) and 2-methyltetrahydrofuran (5.1 kg).
  • the solid product was dried at 39 °C under reduced pressure to afford 6.4 kg of crude OAD2-HCI as a white solid.
  • the crude OAD2-HCI (6.4 kg), 2-methyltetrahydrofuran (110.2 kg) and water (12.8 kg) were combined. The mixture was heated to 55.0 °C and agitated at 55.0-65.0°C for 2 h. The mixture was cooled to 25.0 °C over 1 h and stirred at 19.8-25.0°C for 1 h. The solids were filtered, washed with 2-methyltetrahydrofuran (4.1 kg) and dried at 39 °C under reduced pressure to afford 4.2 kg OAD2-HCI as white solid.
  • OAD2-HCI (4.1 kg) was treated with AcOH (8.9 kg), the temperature of the mixture was adjusted to 19.7 °C, and the mixture was stirred at 19.4-19.7 °C for 30 min.
  • 5N HCI (prepared from water 5.0 kg, 37% HCI 4.2 kg) was added over 10 min while maintaining a temperature below 25 °C. The mixture was stirred at 19.1 - 21.2 °C for 1 h. Water (84.0 kg) was added over 1 h while maintaining a temperature below 25 °C. The mixture was stirred at 19.7-22.4 °C for 1.5 h to provide a clear solution which was transferred to a second reaction vessel along with AcOH (4.1 kg) and water (8.5 kg). 5N HCI (prepared from water 14.6 kg, HCI 37% 12.6 kg) was added while maintaining a temperature below 25 °C. The mixture was stirred at 19.4 -

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés et des intermédiaires clés utiles pour préparer un agoniste du récepteur GLP-1, dichlorhydrate (" OAD2 dichlorhydrate ") de l'acide (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phényl-7-((S)-1-phénylpropyl)- 2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-diméthylpyridin-4-yl)phényl)propanoïque. Les procédés peuvent être exécutés à l'échelle industrielle et à un rendement plus élevé que les procédés précédemment décrits.
PCT/US2021/034154 2020-05-28 2021-05-26 Intermédiaires et procédés de préparation d'un agoniste du récepteur glp-1 WO2021242806A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063030942P 2020-05-28 2020-05-28
US63/030,942 2020-05-28

Publications (1)

Publication Number Publication Date
WO2021242806A1 true WO2021242806A1 (fr) 2021-12-02

Family

ID=76601715

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/034154 WO2021242806A1 (fr) 2020-05-28 2021-05-26 Intermédiaires et procédés de préparation d'un agoniste du récepteur glp-1

Country Status (2)

Country Link
TW (1) TW202206420A (fr)
WO (1) WO2021242806A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023029979A1 (fr) * 2021-09-03 2023-03-09 杭州中美华东制药有限公司 Procédé de préparation d'un intermédiaire agoniste du récepteur de glp-1

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007093013A1 (fr) 2006-02-17 2007-08-23 Monash University Procédé de synthèse de ponts dicarba dans des composés organiques
WO2010114824A1 (fr) 2009-03-30 2010-10-07 Transtech Pharma Inc Dérivés d'azoanthracène substitués, compositions pharmaceutiques et leurs procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007093013A1 (fr) 2006-02-17 2007-08-23 Monash University Procédé de synthèse de ponts dicarba dans des composés organiques
WO2010114824A1 (fr) 2009-03-30 2010-10-07 Transtech Pharma Inc Dérivés d'azoanthracène substitués, compositions pharmaceutiques et leurs procédés d'utilisation
CN102378574A (zh) 2009-03-30 2012-03-14 转化技术制药公司 取代的偶氮蒽衍生物、药物组合物及其使用方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THEODORA W GREENE ET AL: "Protection for the Amino Group", 9 April 1999, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3RD EDITION, JOHN WILEY & SONS, INC, NEW YORK, PAGE(S) 494 - 653, ISBN: 978-0-471-16019-9, XP009527465 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023029979A1 (fr) * 2021-09-03 2023-03-09 杭州中美华东制药有限公司 Procédé de préparation d'un intermédiaire agoniste du récepteur de glp-1

Also Published As

Publication number Publication date
TW202206420A (zh) 2022-02-16

Similar Documents

Publication Publication Date Title
JP6061158B2 (ja) ６−（７−（（１−アミノシクロプロピル）メトキシ）−６−メトキシキノリン−４−イルオキシ）−ｎ−メチル−１−ナフトアミド、またはそれの薬学的に許容される塩の合成中間体およびその使用
CA2988594C (fr) Procedes de fabrication d'inhibiteurs de proteine desacetylase
JP2013532164A (ja) トロンビン特異的インヒビターを調製する方法
CN114805314B (zh) 一种恩赛特韦的合成方法
US10927095B2 (en) Processes for the preparation of Niraparib and intermediates thereof
WO2021242806A1 (fr) Intermédiaires et procédés de préparation d'un agoniste du récepteur glp-1
JP2008531642A (ja) 薬学活性化合物イルベサルタンおよびその合成中間体を得る方法
CN115667222B (zh) 一种制备glp-1受体激动剂的方法
EP1904481B1 (fr) Procede d'elaboration de composes benzimidazole
JP5279449B2 (ja) ５−｛４−［２−（５−エチル−２−ピリジル）エトキシ］ベンジル｝−２，４−チアゾリジンジオン塩酸塩の製造方法
CN111763198B (zh) 一种5-取代环丙基甲酰氨基吲哚衍生物的制备方法
CN110577520B (zh) 一种6-硝基-4-取代氨基喹唑啉衍生物的制备方法
KR102201609B1 (ko) 날데메딘의 제조방법
JP2022529000A (ja) 置換２－［２－（フェニル）エチルアミノ］アルカンアミド誘導体の製造方法
EP1698611A1 (fr) Procede de production d'un derive de l'acide phenylacetique
WO2022034427A1 (fr) Processus amélioré de préparation de 4-oxoisotrétinoïne
JP4416111B2 (ja) ２，３−ジアミノピリジン誘導体の製造方法
EP2305650A1 (fr) Nouveau procédé de préparation de Telmisartan
KR20220107602A (ko) 5-치환된 테트라졸의 신규 제조방법
CA3227445A1 (fr) Procede de production d'intermediaire synthetique de derive de pyridine monocyclique
JP6169721B2 (ja) パピローマウイルスの治療で用いることができるヒドラジンの合成方法
KR101152607B1 (ko) ６-[４-(２-피페리딘-1-일-에톡시)-페닐]-３-피리딘-４-일-피라졸로[１,５-ａ]피리미딘의 제조방법
CN111410650A (zh) 制备磺胺类药物的方法
CN116997544A (zh) 用于合成5-{5-氯-2-[(3s)-3-[(吗啉-4-基)甲基]-3,4-二氢异喹啉-2(1h)-羰基]苯基}-1,2-二甲基-1h-吡咯-3-甲酸衍生物的新方法及其在生产药物化合物中的应用
CN110621652A (zh) 二氨基苯化合物的制造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21734595

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21734595

Country of ref document: EP

Kind code of ref document: A1