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WO2001002375A1 - Synthese d'oxadiazoles - Google Patents

Synthese d'oxadiazoles Download PDF

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Publication number
WO2001002375A1
WO2001002375A1 PCT/US2000/017577 US0017577W WO0102375A1 WO 2001002375 A1 WO2001002375 A1 WO 2001002375A1 US 0017577 W US0017577 W US 0017577W WO 0102375 A1 WO0102375 A1 WO 0102375A1
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Prior art keywords
phenyl
formula
alkyl
compound
alkylene
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Legal status (The legal status 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 status listed.)
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PCT/US2000/017577
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English (en)
Inventor
Jeffrey Mark Dener
Cuong Quoc Ly
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Axys Pharmaceuticals Inc
ChemRx Advanced Technologies Inc
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Axys Pharmaceuticals Inc
ChemRx Advanced Technologies Inc
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Priority to AU58916/00A priority Critical patent/AU5891600A/en
Publication of WO2001002375A1 publication Critical patent/WO2001002375A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention relates to a process for synthesizing Oxadiazoles.
  • Oxadiazoles are known to exhibit biological/pharmacological activity. Oxaindoles were first proposed as ester biosteres in conjunction with muscarinic agonist activity by Watjen et al., in J. Med. Chem., 1989, 32, 2281-2291 and Showell et al., in J. Med. Chem., 1991, 34, 1086-1094. Orlek et al., in 1991, J. Med. Chem.,
  • the present invention provides a process for the synthesis of a compound or an array of compounds of Formula I Also provided by the present invention is an array of compounds of Formula I synthesized by the process of the present ention
  • the present invention provides a process for the synthesizing compounds represented by Formula T
  • Z represents an aryl group substituted with R 1 , R 5 and R 6 , Q represents CO, SO 2 or C(O)NH,
  • R 2 represents C C ⁇ alkylene, C ⁇ -C ] 4 substituted alkylene, (CH 2 ) 0 6 -Ar, Ar-(CH 2 ) ⁇ 6 , or C 5 ⁇ o cycloalkylene-(CH 2 ) 0 -6;
  • R 3 represents -C 14 alkyl, aryl, substituted aryl, C1- 4 alkylene-aryl, C ⁇ -C,o alkylene-O-aryl, -Cjo alkylene-S-ary], heteroaryl or Cj-Cio alkylene-S-C]-C 6 alkyl;
  • R 4 represents H or C 1-4 alkyl; alternatively R 2 and R 4 along with the nitrogen atom to which they are attached form a 4 to 7 membered heterocyclic ⁇ ng substituted with at least one substituent selected from C1-4 alkyl, Ph, OH, H, OC 1-4 alkyl, NHCO-C alkyl and halogen, and R , R 5 and R 6 independently at each occurance are selected from H, 6 alky], O- 6 alkyl and SO 2 -C 1-4 alkyl; alternatively, when on adjacent carbon atoms, R 5 and R 6 can be taken together to form
  • a preferred embodiment of the present invention provides a procss wherein the dehydrating agent m step (A) is selected from EDC, DIC, DCC and CDI, and the catalyst in step (A) is selected from DBU, Et 3 N, 4-DMAP and HOBt
  • the deprotecting agent in step (B) is selected from HC1, HBr, HF, hydrochromic acid, p-toluene sulfonic acid, formic acid and TFA.
  • Yet another preferred embodiment provides a process wherein the cation scavenger in step (B) is anisole and the base in step (C) is selected from N-methy] morpholme, t ⁇ ethyl amme, py ⁇ dme, N,N-dnsopropyl ethyl amine, N-methyl pipe ⁇ dme, N-ethyl morpholme and 2,6-lut ⁇ dme
  • Z represents a phenyl group substituted with R 1 , R 5 and R 6 ; R 1 , R 5 and R 6 are independently selected from H, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 and SO 2 CH 3 , and R 3 represents 2,3,5,6-tetramethyl-phenyl, 3,4- dimethoxy-phenyl, 2-ethoxy-phen-l-yl, 4- ⁇ sopropyl-phen-l-y], 2-Ethoxy-
  • Z represents an aryl group substituted with R 1 , R 5 and R 6 ,
  • Q represents CO, SO 2 or C(O)NH
  • R 2 represents Ci-C alkylene, C]-C ⁇ substituted alkylene, (CH 2 )o 6-Ar, Ar-(CH 2 )o 6, or C5.10 cycloalkylene-(CH 2 )o 6 ;
  • R 3 represents C ⁇ -Cj alkyl, aryl, substituted aryl, C]-C 1 alkylene-aryl, C1-C10 alkylene-O-aryl, -C 10 alkylene-S-aryl, heteroaryl, or Cj-Cio alkylene-S-C]-C 6 alkyl;
  • R 4 represents H or d alkyl; alternatively R 2 and R 4 along with the nitrogen atom to which they are attached form a 4 to 7 membered heterocyclic ⁇ ng substituted with at least one substituent selected from C alkyl, Ph, OH, H, OC alkyl, NHCO-C, 4 alkyl and halogen; and
  • R 1 , R 5 and R 6 independently at each occurance are selected from H, Cj 6 alkyl, O-C] 6 alkyl and SO 2 -C, 4 alkyl, alternatively when on adjacent carbon atoms, R 5 and R 6 can be taken together to form
  • R 1 , R 5 and R 6 are independently selected from H, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 and SO 2 CH 3 ; and R 3 represents 2,3,5,6-tetramethyl-phenyl, 3,4-dimethoxy-phenyl, 2-ethoxy-phen-l-yl, 4-isopropyl-phen-l-yl, 2-Ethoxy- naphthalen-1-yl, l-phenoxy-propy]-l-yl, phenyl, CH 2 -S-Ph, 4-( l .l-Dimethyl- propyl)-phenyl-l-yl, 4-methoxy-benzyl, 2-nitro-benzyl, 4-chloro-phenyl-l-yl, naphthyl, 2-isopropyl-5-methyl-cyclohexyloxymethyl, 4-methoxy-benzyl, 2,3- dichlor
  • the novel process of the present invention uses reagents and starting mate ⁇ als available from commercial sources including Ald ⁇ ch Chemicals, Advanced ChemTech, Sigma and the like. Starting mate ⁇ als can also be prepared by methods known to one skilled in the art Some such methods are discussed below
  • Compounds of Formula 2 can be prepared by treating a corresponding benzonit ⁇ le with hydroxylamme hydrochlo ⁇ de in the presence of a base with ethanol as the solvent. After stir ⁇ ng the reaction mixture for a few hours, the reaction mixture is concentrated and the resulting residue t ⁇ turated with water to yield a compound of Formula 2 as a precipitate.
  • Method B 2-Methoxybenzamidoxime.
  • a suspension of hydroxylamme hydrochlo ⁇ de (11 5 g, 0.165 mol), Na 2 C0 3 (17.5 g, 0.165 mol) and 2- methoxybenzomt ⁇ le (20.0 g) in a mixture of EtOH (350 mL ) and H 2 O (30 mL) was heated at 80°C for 10 hours, and the filtered residue washed with EtOH The combined filtrate was concentrated in vacuo to give a semi solid product which was t ⁇ turated with a mixture of ether/hexane to yield a white solid, which was isolated and washed with hexane then d ⁇ ed to afford 17 4 g (70%) of the desired product
  • the other starting material utilized in reaction Scheme I is a protected amino acid represented by a compound of Formula 3
  • These compounds comp ⁇ se an amino group and a carboxylic acid group.
  • the amino group is generally protected with a protecting group (e.g., a Boc group).
  • a protecting group e.g., a Boc group.
  • These compounds of Formula 3 can be purchased from commercial sources including Sigma, Nova Biochem and Advanced ChemTech. Specific compounds of Formula 3 were synthesized as outlined by the following procedures.
  • BOC-trans-4-(Aminomethyl)cycIohexanecarboxylic acid This compound was prepared using the general procedure for Boc-protection outlined above ⁇ -NMR (300 MHz, DMSO-d 6 ) ⁇ : 0.75-0 95 (m, 2H), 1.35 (s, 9H), 1.22-1.3 (m, 3H), 1.73 (d, 2H), 1.85 (d, 2H), 2.13 (m, 1H), 2.80 (t, 2H), 6.79 (t, 1H).
  • BOC-DL-3-Aminobutyric acid A solution of NaOH (6.40 g, 0.160 mol) in water (250 mL) was mixed with DL-3-ammobutyric acid (15.0 g, 0.145 mol) and a THF solution of (BOC) 2 O (0.160 mol). The resulting mixture was stirred at ambient temperature for 8-16 hours and then concentrated in vacuo to remove most of the THF. The resulting aqueous layer was acidified to pH 2-3 with solid KHSO 4 . The mixture was extracted with ether and the combined extracts were d ⁇ ed (MgSO 4 ) and concentrated to afford 22.5 g (76%) of the title compound as a white solid.
  • BOC-4-Piperidinoacetic acid A suspension of 4-py ⁇ dylacet ⁇ c acid hydrochlo ⁇ de
  • a solution of NaOH (12.0 g, 0.300 mol) in water (300 mL) was mixed with 4-p ⁇ pe ⁇ d ⁇ neacet ⁇ c acid hydrochlo ⁇ de from above and the resulting mixture was cooled in an ice water bath.
  • the cooled mixture was treated with THF (100 mL) followed by (BOC) 2 O (0.140 mol) in THF.
  • the resulting solution was agitated at ambient temperature for 8-16 hours.
  • the reaction mixture was concentrated under reduced pressure to yield an aqueous solution.
  • the aqueous solution was washed with ether and then acidified to pH 1-2 with 85% H 3 PO 4 .
  • Compounds of Formula 6a are available from commercial sources including Aldrich Chemicals, Lancaster and Acros. These compounds of Formula 6a can also be prepared by procedures known to one skilled in the art.
  • acid chlorides represented by compounds of Formula 6a can be prepared by the mixing a carboxylic acid (1 eq.) with oxalyl chloride (1 to 2 eq.) in an inert medium. This resulting mixture was stirred from about 10 minutes to about an hour at a temperature ranging from about 25°C to about the boiling point of the inert solvent. The mixture was then concentrated to yield the co ⁇ esponding acid chloride, a compound of Formula 6a.
  • the In a reaction vessel was placed an inert solvent mixture of a compound of Formula 3 (1 eq.). This mixture was sequentially treated with an inert solvent (preferably 1,4-dioxane) mixture of a base, preferably 4-DMAP (0.15 to 0.3 eq.), and 0.9 to 1.2 eq. of a dehydrating agent, preferably EDC also in an inert solvent, preferably CHC1 3 . This resulting mixture was then agitated for up to 30 minutes followed by the addition of 1 eq. of an appropriate hydroxy amidine, a compound of Formula 2, as an inert solvent mixture, preferably as a 1,4-dioxane mixture.
  • an inert solvent preferably 1,4-dioxane
  • This reaction mixture was agitated from about 12 to about 36 hours followed by dilution with about 1 eq. of a base, preferably triethyl amine. This diluted mixture was further agitated from about 5 to about 30 minutes and heated to a temperature of about 80°C to about 110°C in an inert atmosphere for about 4 to about 10 hours.
  • a base preferably triethyl amine
  • the workup procedure consists of diluting the reaction mixture with an inert solvent, preferably CHC1 3 , followed by dilution with an aqueous carboxylic acid solution, a preferred carboxylic acid solution being an aqueous 10% citric acid solution, to form a two phase mixture.
  • This mixture was filtered through a pre- activated hydromatrix material, pre-activated with a 10% aqueous citric acid solution.
  • the hydromat ⁇ x mate ⁇ al was ⁇ nsed w th additional amounts of CHCI 3 and the combined filtrate was concentrated to yield a compound of Formula 4.
  • STEP-B The compound of Formula 4 is treated with a deprotecting agent (e.g., TFA), optionally in the presence of a cation scavenger (e.g., anisole), and the resulting mixture is agitated from about 1 to about 3 hours.
  • a deprotecting agent e.g., TFA
  • a cation scavenger e.g., anisole
  • the reaction mixture is then concentrated and the residue is dissolved in a 50% aqueous acetonit ⁇ le solution. This solution is maintained at about -80°C for at least about five hours, preferably up to about 18 hours, and then lyophihzed to yield a compound of Formula 5.
  • the compound of Formula 5 is treated with about 2 to about 5 eq. of a base, preferably a solution of DIPEA in CHCI 3 , followed by the addition of about 0.8 to about 2 eq. of a compound of Formula 6a, i.e., an acid chloride or sulfonyl chloride, which acts as an acylating agent.
  • a compound of Formula 6a i.e., an acid chloride or sulfonyl chloride, which acts as an acylating agent.
  • the compound of Formula 6a preferably is used a solution, typically in an inert solvent and preferably in CHCI 3 .
  • reaction mixture is agitated at ambient temperature for up to 3 hours.
  • About 1 to about 5 eq. of a 10% aqueous solution of Na 2 CO 3 then is added and this resulting mixture is agitated for up to 4 hours.
  • the reaction mixture is then filtered through preactivated hydromatrix mate ⁇ a] (preactivated with 10% Na 2 CO 3 ).
  • the hydromat ⁇ x mate ⁇ al is washed with an inert solvent, preferably CH 2 C1 2 , and the combined filtrate is diluted with about 1 to about 5 eq. HO (as a 2N solution).
  • the acidified mixture is agitated for about 1 to about 4 hours and filtered through preactivated hydromat ⁇ x material (preactivated with 2N HCl).
  • the hydromatrix material is washed with an inert solvent, preferably CH 2 C1 2 , to remove any trapped reaction product.
  • the combined filtrate is passed through silica and evaporated to yield a residue. This residue is lyophihzed to yield a compound of Formula I.
  • the compound of Formula 5 ( 1 eq.) is treated with about 1 to about 3 eq. of base, (e.g., DIPEA) in an inert solvent (e.g., ACN, CHC ⁇ or mixtures thereof)-
  • base e.g., DIPEA
  • an inert solvent e.g., ACN, CHC ⁇ or mixtures thereof
  • the mixture is agitated for up to about 30 minutes and then about 0 8 to about 2 eq of a compound of Formula 6b is added, typically as a solution in an inert solvent, preferably in CHC1 3
  • This resulting mixture is stirred for 12-24 hours and then diluted with a 10% aqueous Na 2 C0 3 solution
  • the solution is mixed and then filtered through pre-activated hydromat ⁇ x mate ⁇ al (preactivated with 10% aqueous Na 2 CO 3 solution)
  • the hydromat ⁇ x mate ⁇ al is ⁇ nsed with CHC1 3 and the combined filtrate is treated with 2N
  • the acidified mixture is agitated for about 1 to about 4 hours and filtered through preactivated hydromat ⁇ x mate ⁇ al (preactivated with 2N HCl)
  • the hydromat ⁇ x mate ⁇ al is washed with an inert solvent, preferably CH2Q 2 , to remove any trapped reaction product
  • the combined filtrate is passed through silica and evaporated to yield a residue This lesidue is lyophihzed to yield a compound of Formula I
  • the present process can also be used to prepare an array or a library of compounds Expe ⁇ mental details to prepare such an array or library are discussed below.
  • the plates were returned to the reciprocal shake, clamped, and shaken on setting 5 for 4-5 minutes
  • the reaction mixtures of each well were concentrated by heating the plate, uncovered, at 100-105°C in a nitrogen-purged oven of 7 hours
  • the plates were removed from the oven and allowed to cool to room temperature
  • a 1:1 mixture (v:v) of TFA in DCM (1 mL) was dispensed into each well of the plates obtained from STEP-A
  • a teflon sheet was secured on top of each plate and was shaken on a reciprocal shaker for 2 hours
  • the contents of each well were concentrated in a Genevac evaporator for 3-4 hours.
  • the residues in each well were redissolved in 50% aqueous ACN (1 mL) and the plates were shaken on an IKA Works microtiter plate shaker (IKA Works Inc , VWR Scientific, catalog number 33994-220) for 30 minutes.
  • the plates were removed from the shaker and 10% aqueous Na 2 C ⁇ solution (300 ⁇ L) was dispensed in to each well
  • the plates were shaken on a reciprocal shaker for 2 hours and the mixtures were transfe ⁇ ed to Polyfiltronics plates (PP, 10 ⁇ m) with wells previously half-filled with hydromat ⁇ x mate ⁇ al and pre-activated with 10% aqueous Na 2 CO 3 (500 ⁇ L)
  • the plates were placed over 2-mL square-well Beckman plates Each source well is ⁇ nsed once with CHCL, (250 ⁇ L) and the ⁇ nse was transfe ⁇ ed to the co ⁇ esponding well of the Polyfiltronics plates
  • Each well of the Polyfiltronics plates was washed with CHC1 3 (2 x 250 ⁇ L) and allowed to drain into the Beckman plates
  • the mixtures were transferred, using the Robbins Hydra fitted with small gauge needles to prevent clogging by the resin, to Polyfiltronics plates (PP, 10 ⁇ m) with wells previously loaded with a th layer of silica gel (30-40 mg; Baxter Scientific Products, 6 ⁇ A, 230-400 mesh; catalog number C4582-85) and filtered in to 2-mL Beckman plates.
  • PP Polyfiltronics plates
  • Each well of the reaction plates were ⁇ nsed with CHQ 3 (2x250 ⁇ L) and the ⁇ nses transferred to the Polyfiltronics plates
  • the filtrate in each well of the Beckman plates was concentrated on a Genevac evaporator for 3-4 hours.
  • ACN (1.25 mL) was dispensed in to each well and the plates were shaken on an orbital shaker for 30 minutes and the solutions were sonicated for 15-20 minutes The plates were cent ⁇ fuged for 30 minutes in either the Savant or Genevac evaporators without applying heat or vacuum. The supernatant solutions were transferred by the Robbins HydraTM to a set of second pre-weighed 2-mL square-well Beckman plates. The plates were placed in a freezer at -80°C for 5-16 hours and the solutions lyophihzed in a tray lyophi zer (tray temperature: 20"C) for 18 hours.
  • the plates were removed from the shaker and 10% aqueous Na 2 C ⁇ 3 solution (300 ⁇ L) was added to each well.
  • the plates were shaken on a reciprocal shaker for 2 hours and then the mixtures were filtered through Polyfiltronics plates (PP, 10 ⁇ m) with wells previously half-filled with hydromat ⁇ x mate ⁇ al and pre-activated with 10% aqueous Na 2 CO (500 ⁇ L) in to 2 mL square-well Beckman plates
  • Each well is rinsed once with CHCI 3 (250 ⁇ L) and ⁇ nse was transfe ⁇ ed in the Polyfiltronics plates was washed with CHC1 3 (2x250 ⁇ L).
  • the wells of the Polyfiltronics plates were drained into the Beckman plates.
  • 2 N aqueous HCl 300 ⁇ L was dispensed in to each well of the Beckman plates and the plates were shaken on a reciprocal shaker for 2 hours.
  • the contents of each well were filtered through Polyfiltronics plates (PP, 10 ⁇ m), compnsmg wells previously half-filled with hydromatrix material and pre-activated with 2 N HCl (500 ⁇ L), in to 2 mL square-well Beckman plates with wells previously loaded with 100- 120 mg of Dowex-1 anion exchange resin.
  • Each source well is ⁇ nsed with CHCI 3 (2x250 ⁇ L) and the rinses transferred to the Polyfiltronics plates.
  • the wells of the Polyfiltronics plates were washed through with CHCI 3 (250 ⁇ L) and allowed to drain in to the Beckman collection plates which were put into a plastic container and shaken on a reciprocal shaker overnight.
  • the contents of the wells were filtered through Polyfiltronics plates (PP, 10 ⁇ m) with wells previously loaded with a thin layer of silica gel (30-40 mg; Baxter Scientific Products, 60A, 230-400 mesh; catalog number C4582-85) in to 2 mL Beckman collection plates.
  • Each well of the reaction plates was ⁇ nsed with CHC1 3 (2x250 ⁇ L) and the ⁇ nses transferred to the Polyfiltronics plates.
  • the solvent contents of the wells in the collection plates were concentrated on a Genevac evaporator for 3- 4 hours.
  • ACN (1.25 mL) was dispensed in to each well and the plates were shaken on an orbital shaker for 30 minutes. The mixtures then were sonicated for another 15-20 minutes. The plates were cent ⁇ fuged for 30 minutes in either the Savant or Genevac evaporators without applying heat or vacuum. The supernatants were transfe ⁇ ed by the Robbins HydraTM to a set of second pre-weighed 2 mL square-well Beckman plates. The plates were placed in the -80°C freezer for 5-16 hours The mixtures then were lyophihzed in a tray lyophihzer (tray temperature- 20°C) for 18 hours
  • Mode Positive ion ESI injection volume 5 DL flow rate 0 3 mL/min, 50% solvent B.
  • Alkyl "Alkyl”, or “alkyl radical” is meant to indicate a hydrocarbon moiety of up to 14 carbon atoms, unless indicated otherwise. This hydrocarbon is generally attached to at least one other atom, and can be straight chain, or branched, or cyclic, or a combination thereof.
  • straight chain alkyl is meant to represent an unbranched hydrocarbon moiety of up to 8 carbon atoms.
  • An example of a straight chain alkyl is a n-pentyl group.
  • alkelene represents an alkyl group, as defined above, except that it has at least one center of unsaturation, i.e., a double bond.
  • Illustrative examples are butene, propene, and pentene.
  • Alkylene represents a straight chain, branched, cyclic or a combination thereof hydrocarbon group which is attached to two other groups Examples are -CH 2 - (methylene), cyclohexylene and -CH -CH 2 - (ethylene)
  • Array of compounds This term indicates a collection of independent (individual) compounds that are synthesized by the process of the present invention Generally the term a ⁇ ay of compounds indicates a collection of individual compounds distinct from one another Also included in the array (library) of compounds is a mixture of the individual compounds.
  • library of compounds can be interchangeably used with the term 'array of compounds"
  • Aryl is intended to represent a stable substituted or unsubstituted (collectively also referred to as 'optionally substituted 5 ) six to fourteen membered mono-, bi- or t ⁇ -cychc hydrocarbon radical compnsmg carbon and hydrogen atoms
  • Illustrative examples are phenyl (Ph), naphthyl, anthracy] groups, and piperanyl
  • the aryl group preferably is substituted with one to three substituents selected from H, C, 8 straight chain or branched alk> l, OCi 4 alkyl halogen and SCi .
  • heteroaryl is intended to represent a stable 5 to 10 membered aryl group ("aryl” as defined above), wherein one or more of the carbon atoms is replaced by a hetero atom selected from N, O, and S
  • the hetero atoms can exist m their chemically allowed oxidation states
  • a Sulfur (S) atom can exist as a sulfide, sulfoxide, or sulfone
  • Preferred heteroaryl groups are six membered ⁇ ng systems compnsmg not more than 2 hetero atoms
  • Illustrative examples of preferred heteroaryl groups are thienyl, N-substituted succi mide, 3-(alkyl am ⁇ no)-5,5-d ⁇ alkyl- 2-cyclohexen-l-one, methyl py ⁇ dyl, alkyl theophylline, furyl, pyrrol yl, indoly], py ⁇ midinyl, iso
  • Catalyst is intended to represent an additive that facilitates the course of a reaction but does not get incorporated in to the final product
  • Illustrative examples of catalysts are N-hydroxybenzot ⁇ azole (HOBt), l-hydroxy-7- azabenzot ⁇ azole (HO At) and N-hydroxysuccinimide
  • solid support (SS) signifies polymenc mate ⁇ al for supported synthesis A detailed desc ⁇ ption of the terms linker molecule, and solid support can be found in The Combinato ⁇ al Index, B A Bunin, 1998, which is incorporated herein by reference
  • Cation Scavenger represents a reagent which can intercept a cation generated du ⁇ ng a reaction, for example under acidic conditions By intercepting the cation the cation scavenger can prevent the cation from reacting with the product formed du ⁇ ng the reaction
  • Illustrative examples of cation scavengers are water, t ⁇ ethylsilane, anisole, thioamsole, dimefhylsulfide, phenol and 1,2-ethaned ⁇ th ⁇ ol.
  • the term “optional” or “optionally” means that the subsequently descnbed event or circumstance may or may not occur, and that the desc ⁇ ption includes instances where the event or circumstance occurs and instances in which it does not
  • the phrase “optionally is substituted with one to three substituents” means that the group referred to may or may not be substituted in order to fall within the scope of the invention
  • the term “optionally substituted” is intended to mean that any one or more hydrogens on a designated atom can be replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
  • inert solvent is intended to represent solvents which do not react with the reagents dissolved therein.
  • inert solvents are tetrahydrofuran (THF), methylene chlo ⁇ de, dichloro methane (DCM), ethyl acetate (EtOAc), dimethyl formamide (DMF), diaoxane, chloroform, and DMSO.
  • Protecting Group (PG) “Protecting group” or “PG”, as used in the present invention, is a group that is attached to, or placed on, an atom so the protected atom does not react with reactants , thereby tempora ⁇ ly rende ⁇ ng the protected atom inactive.
  • protecting groups are tetrahydropyran (THP), tert-butyl-oxy carbonyl (BOC), and fluoromethyloxy carbonyl (FMOC)
  • THP tetrahydropyran
  • BOC tert-butyl-oxy carbonyl
  • FMOC fluoromethyloxy carbonyl
  • deprotecting agent is used to mean an agent which selectively removes a PG from a functional group such as an amine group
  • the deprotecting agent can be an acidic or basic moiety as understood by one skilled in the art
  • protecting group or "PG”, as used herein, indicates a group that protects an amine functional group rendenng the amine inactive
  • a detailed desc ⁇ ption of the terms “deprotecting agent”, and “protecting group” (PG) is available in Protective Groups in Organic Synthesis, 2nd edition, T W Greene and P G M Wuts, 1991, which is incorporated herein by reference
  • dehydrating agent represents an agent which facilitates removal of any water or moisture which may be present in a reaction mixture or formed dunng a reaction
  • Typical dehydrating/drying agents known to one skilled in the art are intended to be included herein
  • Representative examples of dehydrating/drymg agents are magnesium sulfate, sodium sulfate, tnmethyl orthoformate, tnethyl orthoformate, tnmethyl ortho acetate and tnethyl ortho acetate or any moisture which may be present in
  • suitable base as used in step (C) herein represents an ammo compound which can absorb or abstract a proton from a compound of Formula 5
  • a desirable class of the suitable base is tertiary amines
  • suitable base are N-methylmorpholme (NMM), N- ethylmorphohne, N-methylpipe ⁇ dine, N-ethylpipendine, tnethyl amine, pyndine, lutidine and N,N-d ⁇ sopropylethylamme (DIPEA), alkali metal salts of tnmethyl silanol, potassium tnmethylsilanoate, tetrabutylammomum hydroxide, tetramethylammonium hydroxide, lithium hydroxide and aqueous solutions of alkali metal hydroxides, carbonates and bicarbonates.
  • DIPEA N-methylmorpholme
  • DIPEA dimethylpyri metal salts of tnmethyl silanol
  • Halogen or halogen is intended to represent Cl, Br, I and F
  • ACD Available Chemicals Directory
  • ACN Acetonit ⁇ le
  • CDI 1 , 1 ' -Carbon yldnmidazole
  • DCM Dichloromethane
  • DIPEA N,N-D ⁇ sopropylefhylam ⁇ ne
  • EDC l-(3-D ⁇ methylam ⁇ nopropy])-3-ethylcarbodnm ⁇ de hydrochlo ⁇ de
  • HOBt 1 -Hydroxybenzot ⁇ azole

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Abstract

La présente invention concerne la synthèse de composés organiques oxadiazolés où l'oxadiazole est constitué, soit en groupe seul, soit en grands réseaux. Ces composés organiques oxadiazolés sont représentés par la formule (I).
PCT/US2000/017577 1999-07-01 2000-06-26 Synthese d'oxadiazoles Ceased WO2001002375A1 (fr)

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AU58916/00A AU5891600A (en) 1999-07-01 2000-06-26 Process for synthesizing oxadiazoles

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US14220299P 1999-07-01 1999-07-01
US60/142,202 1999-07-01

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WO2005118538A3 (fr) * 2004-04-20 2006-12-21 Amgen Inc Arylsulfonamides et leurs utilisations
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WO2012063933A1 (fr) 2010-11-12 2012-05-18 塩野義製薬株式会社 Dérivé 6,7-insaturaté-7-carbamoyl-morphinane et procédé pour le produire
USRE46365E1 (en) 2005-05-25 2017-04-11 Shionogi & Co., Ltd. 6,7-unsaturated-7-carbamoyl substituted morphinan derivative

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US8163775B2 (en) 2003-11-06 2012-04-24 Addex Pharma Sa Allosteric modulators of metabotropic glutamate receptors
US8030331B2 (en) 2003-11-06 2011-10-04 Addex Pharma Sa Allosteric modulators of metabotropic glutamate receptors
JP2007510713A (ja) * 2003-11-06 2007-04-26 アデックス ファーマシューティカルズ ソシエテ アノニム 代謝型グルタミン酸受容体のアロステリック調節因子
US7834035B2 (en) 2003-11-06 2010-11-16 Addex Pharma Sa Allosteric modulators of metabotropic glutamate receptors
WO2005090298A1 (fr) * 2004-03-19 2005-09-29 Biotie Therapies Corporation Derives sulfonamides
US7834047B2 (en) 2004-04-20 2010-11-16 Amgen Inc. Arylsulfonamides and uses related thereto
US7495012B2 (en) 2004-04-20 2009-02-24 Amgen Inc. Arylsulfonamides and uses related thereto
AU2005250336B2 (en) * 2004-04-20 2011-06-09 Amgen, Inc. Arylsulfonamides and uses as hydroxysteroid dehydrogenase
WO2005118538A3 (fr) * 2004-04-20 2006-12-21 Amgen Inc Arylsulfonamides et leurs utilisations
EA015263B1 (ru) * 2005-05-18 2011-06-30 Аддекс Фарма Са Производные оксадиазола и их применение в качестве положительных аллостерических модуляторов метаботропных глутаматных рецепторов
WO2006123249A3 (fr) * 2005-05-18 2007-02-08 Addex Pharmaceuticals Sa Nouveaux derives d'oxadiazole et leur utilisation comme modulateurs allosteriques positifs des recepteurs metabotropiques du glutamate
USRE46365E1 (en) 2005-05-25 2017-04-11 Shionogi & Co., Ltd. 6,7-unsaturated-7-carbamoyl substituted morphinan derivative
USRE46375E1 (en) 2005-05-25 2017-04-25 Shionogi & Co., Ltd. 6,7-unsaturated-7-carbamoyl substituted morphinan derivative
JP2009541474A (ja) * 2006-07-04 2009-11-26 アンスティトゥー パストゥール ド リール エチオナミド活性の増強効果を有する化合物及びその使用
US9296756B2 (en) 2010-11-12 2016-03-29 Shionogi & Co., Ltd. Crystal of 6,7-unsaturated-7-carbamoyl morphinan derivative and method for producing the same
US9315512B2 (en) 2010-11-12 2016-04-19 Shionogi & Co., Ltd. Crystal of 6,7-unsaturated-7-carbamoyl morphinan derivative and method for producing the same
US9464094B2 (en) 2010-11-12 2016-10-11 Shionogi & Co., Ltd. Crystal of 6,7-unsaturated-7-carbamoyl morphinan derivative and method for producing the same
US9108975B2 (en) 2010-11-12 2015-08-18 Shionogi & Co., Ltd. Crystal of 6,7-unsaturated-7-carbamoyl morphinan derivative and method for producing the same
WO2012063933A1 (fr) 2010-11-12 2012-05-18 塩野義製薬株式会社 Dérivé 6,7-insaturaté-7-carbamoyl-morphinane et procédé pour le produire
RU2643807C1 (ru) * 2010-11-12 2018-02-06 Сионоги Энд Ко., Лтд. Кристаллы производных 6,7-ненасыщенного-7-карбамоилморфинана и способ их получения
US9902732B2 (en) 2010-11-12 2018-02-27 Shionogi & Co., Ltd. Crystal of 6,7-unsaturated-7-carbamoyl morphinan derivative and method for producing the same
US9951082B2 (en) 2010-11-12 2018-04-24 Shionogi & Co., Ltd. Crystal of 6,7-unsaturated-7-carbamoyl morphinan derivative and method for producing the same
EP3560929A2 (fr) 2010-11-12 2019-10-30 Shionogi & Co., Ltd Dérivé 6,7-insaturaté-7-carbamoyl-morphinane et procédé pour le produire

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