WO2001002375A1 - Process for synthesizing oxadiazoles - Google Patents

Process for synthesizing 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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phenyl
formula
alkyl
compound
alkylene
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PCT/US2000/017577
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French (fr)
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Jeffrey Mark Dener
Cuong Quoc Ly
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Chemrx Advanced Technologies, Inc.
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Priority to AU58916/00A priority Critical patent/AU5891600A/en
Publication of WO2001002375A1 publication Critical patent/WO2001002375A1/en

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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

The present invention relates to a process for the synthesis of a single as well as large array of oxadiazole based organic compounds. These oxadiazole based organic compounds are represented by compounds of formula (I).

Description

PROCESS FOR SYNTHESIZING OXADIAZOLES
FIELD OF INVENTION
The present invention relates to a process for synthesizing Oxadiazoles.
BACKGROUND OF THE INVENTION
Obtaining a better understanding of the important factors in molecular recognition in conjunction with developing new therapeutic agents has been a major focus of research in the pharmaceutical industry. This process generally begins with screening a large number of compounds against a specific receptor or enzyme. Methods are being developed which permit the synthesis of a large array of compounds, or of mixtures of compounds, that can be screened for their biological activity.
There are however only a few methods that facilitate the quick synthesis of small organic molecules. For this reason, small organic molecules of potential therapeutic interest are still synthesized and evaluated one at a time, thus reducing the number of potential therapeutic agents that could be evaluated for their biological activity.
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.,
1991, 2726-2735, proposed a benzodiazepine receptor partial activity for Oxadiazoles.
Diana et al., in 1991 reported evaluating oxadiazoles for their antirhinovirus activity (J. Med. Chem., 1994, 37, 2421-2436). Oxadiazoles are thus gaining acceptance and attention as organic molecules having potential therapeutic value.
Procedures to synthesize oxadiazoles are known. One such procedure is reported in
Synthetic Communications, 12 (6), 457-461 (1992.
Given the potential therapeutic utility of oxadiazoles, it is important to be able to synthesize oxadiazoles in a rapid fashion. There is thus a need for synthetic methodology which will facilitate synthesis of a single as well as a array of oxadiazole based organic compounds. SUMMARY OF THE INVENTION
Keeping the above discussed need m mind, 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
Figure imgf000003_0001
ention
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the synthesizing compounds represented by Formula T
Figure imgf000003_0002
Formula I
wherein:
Z represents an aryl group substituted with R1, R5 and R6, Q represents CO, SO2 or C(O)NH,
R2 represents C Cι alkylene, Cι-C] 4 substituted alkylene, (CH2)0 6-Ar, Ar-(CH2)ι 6, or C5 ιo cycloalkylene-(CH2)0-6;
R3 represents -C14 alkyl, aryl, substituted aryl, C1- 4 alkylene-aryl, Cι-C,o alkylene-O-aryl, -Cjo alkylene-S-ary], heteroaryl or Cj-Cio alkylene-S-C]-C6 alkyl;
R4 represents H or C1-4 alkyl; alternatively R2 and R4 along with the nitrogen atom to which they are attached form a 4 to 7 membered heterocyclic πng substituted with at least one substituent selected from C1-4 alkyl, Ph, OH, H, OC1-4 alkyl, NHCO-C alkyl and halogen, and R , R5 and R6 independently at each occurance are selected from H, 6 alky], O- 6 alkyl and SO2-C1-4 alkyl; alternatively, when on adjacent carbon atoms, R5 and R6 can be taken together to form
Figure imgf000004_0001
said process comprising
(A) treating a compound of Formula 2
Z-C(=NOH)NH2 .Formula 2
with a compound of Formula 3
HOOC-R -NH-PG .Formula 3
in the presence of a dehydrating agent and optionally in the presence of a catalyst, at a temperature of from about 25°C to about 85°C, to yield a compound of Formula 4
Figure imgf000004_0002
.Formula 4
where Z and R are as defined above, and PG represents a protecting group;
(B) treating a compound of Formula 4 with a deprotecting agent, optionally in the presence of a cation scavenger, to yield a compound of Formula 5
Figure imgf000005_0001
Formula 5
where Z and R are as defined above.
(C) treating a compound of Formula 5 with (0 a compound of Formula 6a
R3-Q-X Formula 6a
in the presence of a base, and where R3 is as defined above, Q represents CO or SO2, and X represents a halogen, to form a compound of Formula I, where Q represents CO or SO2; or
(π) a compound of Formula 6b
R3-N=C=O Formula 6b in the presence of a base, and where R3 is as defined above, to form a compound of Formula I, wherein Q represents C(O)-NH.
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, Et3N, 4-DMAP and HOBt Another preferred embodiment provides a process wherein 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, tπethyl amme, pyπdme, N,N-dnsopropyl ethyl amine, N-methyl pipeπdme, N-ethyl morpholme and 2,6-lutιdme Also provided in yet another preferred embodiment is a process wherein Z represents a phenyl group substituted with R1, R5 and R6; R1, R5 and R6 are independently selected from H, CH3, C2H5, OCH3, OC2H5 and SO2CH3, and R3 represents 2,3,5,6-tetramethyl-phenyl, 3,4- dimethoxy-phenyl, 2-ethoxy-phen-l-yl, 4-ιsopropyl-phen-l-y], 2-Ethoxy- naphthalen-1-yl, 1-phenoxy-propyl-l-yl, phenyl, CH2-S-Ph, 4-(l.l-Dιmethyl- propyl)-pheny]-l-yl, 4-methoxy-benzyl, 2-nιtro-benzyl, 4-chloro-phenyl-l-yl, naphthyl, 2-ιsopropyl-5-methyl-cyclohexyloxymethyl, 4-methoxy-benzyl, 2,3- dιchloro-phenyl-1-yl, 1-p-tolyl-cyclopentyl, 6-chloro-pyπdιn-3-yl, 2.5-dιmethyl- phenyl-1-yl, 2-methylsulfanyl-ethyl, 2,6-dιchloro-phenyl-l-yl, 1-phenyl-propyl-l- yl, 4-methyl-3-nιtro-pheny]-l-yl, 2,3,6-tπfluoro-phenyl-l-yl, 3-methyl-butane-l-y], 4-pentyloxy-pheny]-l-yl, 4-methyl-phenyl-l-yl, 2,4-dιmethoxy-phenyl-l-yl, or benzo[ 1 ,3]dιoxol-5-yl Another aspect of the present invention provides an array of compounds of
Formula I
Figure imgf000006_0001
Formula I
wherein:
Z represents an aryl group substituted with R1, R5 and R6,
Q represents CO, SO2 or C(O)NH;
R2 represents Ci-C alkylene, C]-Cι substituted alkylene, (CH2)o 6-Ar, Ar-(CH2)o 6, or C5.10 cycloalkylene-(CH2)o 6; R3 represents Cι-Cj alkyl, aryl, substituted aryl, C]-C1 alkylene-aryl, C1-C10 alkylene-O-aryl, -C10 alkylene-S-aryl, heteroaryl, or Cj-Cio alkylene-S-C]-C6 alkyl;
R4 represents H or d alkyl; alternatively R2 and R4 along with the nitrogen atom to which they are attached form a 4 to 7 membered heterocyclic πng substituted with at least one substituent selected from C alkyl, Ph, OH, H, OC alkyl, NHCO-C, 4 alkyl and halogen; and
R1, R5 and R6 independently at each occurance are selected from H, Cj 6 alkyl, O-C] 6 alkyl and SO2-C, 4 alkyl, alternatively when on adjacent carbon atoms, R5 and R6 can be taken together to form
Figure imgf000007_0001
A preferred embodiment of this aspect of the present invention provides an array of compounds wherein, R1, R5 and R6 are independently selected from H, CH3, C2H5, OCH3, OC2H5 and SO2CH3; and R3 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, CH2-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- dichloro-phenyl-1-yl, 1-p-tolyl-cyclopentyl, 6-chloro-pyridin-3-yl, 2,5-dimethyl- phenyl-1-yl, 2-methylsulfanyl-ethyl, 2,6-dichloro-phenyl-l-yl, 1-phenyl-propyl-l- yl, 4-methy]-3-nitro-phenyl-l-yl, 2,3,6-trifluoro-phenyl-l-yl, 3-methyl-butane-l-yl, 4-pentyloxy-phenyl-l-yl, 4-methyl-pheny]-l-yl, 2,4-dimethoxy-phenyl-l-yl, or benzo[l,3]dioxol-5-yl.
The novel process of the present invention is summarized in Scheme-I below.
SCHEME-I
Figure imgf000007_0002
Figure imgf000008_0001
Formula I
Expeπmental details of each step of the process are discussed below
Expeπmental Details
General Comments
The novel process of the present invention uses reagents and starting mateπals available from commercial sources including Aldπch Chemicals, Advanced ChemTech, Sigma and the like. Starting mateπals can also be prepared by methods known to one skilled in the art Some such methods are discussed below
Starting Matenals
Compounds of Formula 2: General Procedure
Compounds of Formula 2 can be prepared by treating a corresponding benzonitπle with hydroxylamme hydrochloπde in the presence of a base with ethanol as the solvent. After stirπng the reaction mixture for a few hours, the reaction mixture is concentrated and the resulting residue tπturated with water to yield a compound of Formula 2 as a precipitate.
Specific compounds of Formula 2 were prepared by procedures discussed below. Method A: 4-Methoxybenzamidoxime: A mixture of hydroxylamme hydrochloπde
(12.0 g 0.172 mol) and DIPEA (22.2 g, 0.172 mol) in ethanol (350 mL) was stirred while 4-methoxybenzonιtπle (19.2 g, 0.144 mol) was added The resulting mixture was stirred at ambient temperature for about 12 to 24 hours and then concentrated in vacuo to yield an oily residue. The oily residue was tπturated with water (300 mL) and the resulting precipitate was isolated, washed with H2O, and dπed in vacuo to afford the desired product (17.5 g, 73%) .
MS (ESI) m/z 167 (M+H, 100%)
1H-NMR (DMSO- ) δ: 3.75 (s, 3H), 5.75 (s, 2H), 6.90 (d, 2H), 7.65 (d, 2H), 9.45 (s, 1H).
The following compounds of Formula 2 were prepared using the procedure in Method A above. 4-Methylbenzamidoxime
MS (ESI) m/z 150 (100%).
1H-NMR (DMSO-dβ) δ: 2.28 (s, 3H), 5.77 (s, 2H), 7.2 (d, 2H), 7.6 (d, 2H), 9.57 (s,
1H).
Piperonylamidoxime
MS (ESI) m/z 180 (100%)
1H-NMR (DMSO-d6) δ 5.75 (s, 2H), 6.03 (s, 2H), 6.88 (d, 1H), 7.23 (d, 2H), 9.51 (s,
1H).
3,4-Dimethylbenzamidoxime
MS (ESI) m/z 165 (M+H, 100%)
1H-NMR (DMSO- ) δ: 2.23 (s, 6H), 5.75 (s, 2H), 7.2 (d, 1H), 7.36-7.48 (m, 2H), 9.5 (s, 1H).
4-Methylsulfonylbenzamidoxime
MS (ESI) m/z 215 (M+H, 100%)
1H-NMR (DMSO- ) δ: 3.23 (s, 3H), 6.0 (s, 2H), 7.87 (s, 4H), 9.98 (s, 1H). 3-Methoxybenzamidoxime
MS (ESI) m/z 167 (M+H, 100%)
1H-NMR (DMSO- ) δ: 3.77 (s, 3H), 5.85 (s, 2H), 6.9-7.35 (m, 4H), 9.7 (s, 1H). 3-Methylbenzamidoxime
MS (ESI) m z 151 (M+H, 100%)
1H-NMR (DMSO-cfe) δ 2 33 (s, 3H), 5 75 (s, 2H), 7 2-7 5 (m, 4H), 9 6 (s, 1H) 4-«-Butoxybenzamidoxime
MS (ESI) m/z 209 (M+H, 100%)
1H-NMR (DMSO- 6) 5 0.85 (s, 3H), 1 35-1 74 (m, 4H), 3 95 (m, 2H), 5 8 (s, 2H), 6 90 (d, 2H), 7 64 (d, 2H), 9 50 (s, 1H)
Method B: 2-Methoxybenzamidoxime. A suspension of hydroxylamme hydrochloπde (11 5 g, 0.165 mol), Na2C03 (17.5 g, 0.165 mol) and 2- methoxybenzomtπle (20.0 g) in a mixture of EtOH (350 mL ) and H2O (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 tπturated with a mixture of ether/hexane to yield a white solid, which was isolated and washed with hexane then dπed to afford 17 4 g (70%) of the desired product
MS (ESI) m/z 167 (M+H, 100%)
Η-NMR (300 MHz, OMSO-d6) δ. 3 81 (s, 3H), 5 6 (s, 2H), 6.90 (t, 1H), 7.10 (d, 1H),
7.35 (t, 2H), 9 40 (s, 1H).
Compounds of Formula 3
The other starting material utilized in reaction Scheme I is a protected amino acid represented by a compound of Formula 3 These compounds compπse an amino group and a carboxylic acid group. The amino group is generally protected with 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.
4-(BOC-aminomethyl)benzoic acid: A solution of NaOH (5.80 g, 0 145 mol) in H2O (250 mL) was mixed with 4-(amιnomethyl)benzoιc acid (20.0 g, 0.132 mol) . After the acid had dissolved, a solution of di-t-butyl-dicarbonate (31 8 g, 0 145 mol) in THF (100 mL) was added The mixture was stiπed at room 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 KHSO4 The mixture was extracted with ether and the combined extracts were dπed (MgSO4) and concentrated to yield 32.7 g (99%) of the title compound as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ: 1.39 (s, 9H), 4 20 (d, 2H), 7.36 (d, 2H), 7.48 (t, 1H), 7.88 (d, 2H).
BOC-trans-4-(Aminomethyl)cycIohexanecarboxylic acid: This compound was prepared using the general procedure for Boc-protection outlined above Η-NMR (300 MHz, DMSO-d6) δ: 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-Aminocyclohexanecarboxylic acid: This compound was prepared using the general procedure for Boc-protection outlined above
BOC-4-AminocyclohexanecarboxyIic acid. This compound was prepared using the general procedure for Boc-protection outlined above.
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)2O (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 KHSO4. The mixture was extracted with ether and the combined extracts were dπed (MgSO4) and concentrated to afford 22.5 g (76%) of the title compound as a white solid.
BOC-DL-β-Aminoisobutyric acid: This compound was prepared using the general procedure for Boc-protection outlined above.
1H-NMR (300 MHz, DMSO- 6) δ: 0.17 (d, 3H), 0.54 (s, 9H), 1.60-1.70 (m, 1H), 2.02-2.12 (m, 1H), 2.25-2.35 (m, 1H), 6.00 (t, 1H), 11.35 (s.lH)
BOC-DL-3-Amino-3-phenylpropionic acid: This compound was prepared using the general procedure for Boc-protection outlined above.
1H-NMR (300 MHz, DMSO- ) δ: 0.50 (s, 9H), 1.71-1.80 (m, 2H), 4.05 (t, 1H), 6.35- 6.45 (m, 5H), 6.70 (d, 1H), 11.37 (s, 1H). BOC-DL-Nipecotic acid: This compound was prepared using the procedure outlined for the preparation of Boc-DL-3-Amιnobutyπc acid above
Η-NMR (300 MHz, DMSO-d6) δ- 1.38 (s, 9H), 1.42-1 63 (m, 2H), 1.86-1 91 (m. 2H), 2 24-2 32 (m, 1H), 2.81 (dt, 1H), 3 66 (br d, 1H), 3 89 (br s, 2H), 12 3 (s, 1H)
BOC-4-Piperidinoacetic acid: A suspension of 4-pyπdylacetιc acid hydrochloπde
(24.3 g, 0 140 mol) and PtO2 (2.07 g ) m AcOH (150 mL ) was hydrogenated at 50 psi This hydrogenated mixture was filtered and the filtrate was concentrated to yield a colorless semi solid mixture The semi solid mixture was tπturated with diethyl ether (250 mL) to yield a suspension and this suspension was stiπed for up to 12 hours leading to the formation of a solid. The resulting solid was isolated, washed with ether and hexane and dπed in vacuo to give of 4-pιpeπdιneacetιc acid hydrochloπde (25 4 g, 100%) as a white powder.
A solution of NaOH (12.0 g, 0.300 mol) in water (300 mL) was mixed with 4-pιpeπdιneacetιc acid hydrochloπde 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)2O (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% H3PO4. The acidic solution was extracted with ethyl acetate, the combined ethyl acetate extracts were washed with bπne, dπed (Na2SO4) and concentrated in vacuo to yield the title compound (29.1 g,
86%) as a white solid.
1H-NMR (300 MHz, DMSO- 6) δ: 1.01 (dq, 2H), 1.37 (s, 9H), 1.60 (br d, 2H), 1.73- 1.82 (m, 1H), 2.12 (d, 2H), 2.67 (br s, 2H), 3.88 (br d, 2H), 12.1 (s, 1H).
BOC-DL-3-(3-piperidino)propionic acid. This compound was prepared by the procedure outlined above.
1H-NMR (300 MHz, DMSO- 6) δ: 1.00-1.44 (m, with s at 1.37 ppm, 13H), 1.52-1.57 (m, 1H), 1.70-1.75 (m, 1H), 2.23 (t, 2H), 2.78 (br t, 2H), 3.68 (br s, 2H), 12.1 (s, 1H).
Compounds of Formula 6a
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. For example, 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 coπesponding acid chloride, a compound of Formula 6a.
Compounds of Formula 6b Compounds of Formula 6b, which are isocyanates, are available from commercial sources such as Aldrich chemicals and Lancaster.
Scheme-I General Procedures
STEP- A
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 CHC13. 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. 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.
The workup procedure consists of diluting the reaction mixture with an inert solvent, preferably CHC13, 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 hydromatπx mateπal was πnsed w th additional amounts of CHCI3 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. The reaction mixture is then concentrated and the residue is dissolved in a 50% aqueous acetonitπle 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.
STEP-C(i)
The compound of Formula 5 is treated with about 2 to about 5 eq. of a base, preferably a solution of DIPEA in CHCI3, 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. The compound of Formula 6a preferably is used a solution, typically in an inert solvent and preferably in CHCI3.
The above reaction mixture is agitated at ambient temperature for up to 3 hours. About 1 to about 5 eq. of a 10% aqueous solution of Na2CO3 then is added and this resulting mixture is agitated for up to 4 hours. The reaction mixture is then filtered through preactivated hydromatrix mateπa] (preactivated with 10% Na2CO3). The hydromatπx mateπal is washed with an inert solvent, preferably CH2C12, 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 hydromatπx material (preactivated with 2N HCl). The hydromatrix material is washed with an inert solvent, preferably CH2C12, 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.
STEP-C(ii)
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)- 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 CHC13 This resulting mixture is stirred for 12-24 hours and then diluted with a 10% aqueous Na2C03 solution The solution is mixed and then filtered through pre-activated hydromatπx mateπal (preactivated with 10% aqueous Na2CO3 solution) The hydromatπx mateπal is πnsed with CHC13 and the combined filtrate is treated with 2N aqueous HCl
The acidified mixture is agitated for about 1 to about 4 hours and filtered through preactivated hydromatπx mateπal (preactivated with 2N HCl) The hydromatπx mateπal is washed with an inert solvent, preferably CH2Q2, 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
Library Synthesis
The present process can also be used to prepare an array or a library of compounds Expeπmental details to prepare such an array or library are discussed below.
STEP-A
Solutions of compounds of Formula 3 in 1,4-dioxane (700 mL, 0 14 mmol) was dispensed into arranged wells of square well Beckman plate using Robbms Hydra™ 96 well dispenser (Robbins Scientific, catalog number 1029-80-1) Solutions of DMAP in 1,4-dioxane (80 μL, 0.04 mmol) and EDC in CHC13 (140 μL, 0.14 mmol) were dispensed sequentially to each well The plates were shaken on rmcrotiter plate shaker (IKA works; VWR Scientific, Catalog No. 33994-228) for 5- 10 minutes and then solutions of compounds of Formula 2 in 1,4-dioxane 9700 μL, 0.14 mmol) were dispensed in to assigned wells The plates were covered with a teflon sheet, clamped and shaken on a reciprocal shaker number 57008-195) at setting 6 for 18 hours. The plates were removed from the shaker and undamped and then tπethyl amine (20 μL, 0.14 mmol) was dispensed into each well. 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
The residue in each well was dissolved in CHC13 (1 mL) and 10% aqueous citπc acid solution (300 mL) dispensed in to each well The plates were shaken on a reciprocal shaker for 2 h The two-phase mixtures were transferred to Polyfiltronics plates (type PP, 10 μm) with wells previously half-filled with hydromatπx mateπal and pre-activated of 10% aq citric acid (500 μL) and the plates were placed over 2- mL square-well Beckman collection plates Each source well is πnsed once with CHC13 (250 μL) and the πnse transferred to corresponding well of the Polyfiltronics plate Each well of the Polyfiltronics plate was washed with CHC13 (2x250 mL) and allowed to drain The solution in the collection plates was concentrated in a Genevac evaporator for 3-4 h (Atlas, catalog number HT-12-CDOP), to yield a library of compounds of Formula 4.
STEP-B
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. Alternatively the well contents were agitated in parallel using a modified Chiron Mimetopes "PIN" holder fitted with 96 pegs The solutions then were frozen and stored in a -80°C freezer (Revco, catalog ULT-2586-7 A) for 5- 16 hours. The well contents (or solutions) then were lyophihzed in a tray lyophihzer (Virtis Umtop, catalog number 800L; tray temperature. 20°C) for 18 hours to yield a library of compounds of Formula 5
STEP-C(i)
A solution of DIPEA in CHCI3 (500 μL; 0.322 mmol) was dispensed in to each well of the plates obtained from STEP-B and the plates were shaken for 5-10 min Solutions of compounds of Formula 6a in CHC13 (840 μL, 0 126 mmol) were added in to each well The plates were co\ ered with a teflon sheet, clamped, and shaken on a reciprocal shaker for 18 hours
The plates were removed from the shaker and 10% aqueous Na2Cθ solution (300 μL) was dispensed in to each well The plates were shaken on a reciprocal shaker for 2 hours and the mixtures were transfeπed to Polyfiltronics plates (PP, 10 μm) with wells previously half-filled with hydromatπx mateπal and pre-activated with 10% aqueous Na2CO3 (500 μL) The plates were placed over 2-mL square-well Beckman plates Each source well is πnsed once with CHCL, (250 μL) and the πnse was transfeπed to the coπesponding well of the Polyfiltronics plates Each well of the Polyfiltronics plates was washed with CHC13 (2 x 250 μL) and allowed to drain into the Beckman plates
2 N aqueous HCl was dispensed in to each well and the plates were shaken on a reciprocal shaker for 2 hours. The mixtures were filtered through Polyfiltronics plates (PP, 10 μm) with wells previously half-filled with hydromatπx mateπal and pre-activated with 2N HCl (500 μL) in to 2-mL square-well Beckman plates with wells loaded with 100-120 mg of Dowex-1 amon exchange resin Each source well was πnsed with CHCI3 (2x250 μL) and the πnses drained into Beckman collection plates which in turn were put into a plastic container The plastic container was tightly-capped and shaken on a reciprocal shaker for 8-16 hours.
The mixtures were transferred, using the Robbins Hydra fitted with small gauge needles to prevent clogging by the resin, to Polyfiltronics plates (PP, 10 μm) with wells previously loaded with a th layer of silica gel (30-40 mg; Baxter Scientific Products, 6θA, 230-400 mesh; catalog number C4582-85) and filtered in to 2-mL Beckman plates. Each well of the reaction plates were πnsed with CHQ3 (2x250 μL) and the πnses 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 centπfuged for 30 minutes in either the Savant or Genevac evaporators without applying heat or vacuum. The supernatant solutions were transferred by the Robbins Hydra™ 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.
STEP-C(ii)
A 0.4 M solution of DIPEA in CHCI3 (450 μL; 0.182 mmol) was suspended in to each well of the plates obtained in STEP-B and the plates were shaken tor 5-10 min. Solutions of compounds of Formula 6b in CHCI3 (840 μL; 0.126 mmol) were dispensed in to each well and the plates were covered with a Teflon sheet, clamped, and shaken on a reciprocal shaker for 18 h.
The plates were removed from the shaker and 10% aqueous Na2Cθ3 solution (300 μL) 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 μm) with wells previously half-filled with hydromatπx mateπal and pre-activated with 10% aqueous Na2CO (500 μL) in to 2 mL square-well Beckman plates Each well is rinsed once with CHCI3 (250 μL) and πnse was transfeπed in the Polyfiltronics plates was washed with CHC13 (2x250 μL). The wells of the Polyfiltronics plates were drained into the Beckman plates.
2 N aqueous HCl (300 μL) 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 μm), compnsmg wells previously half-filled with hydromatrix material and pre-activated with 2 N HCl (500 μL), 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 πnsed with CHCI3 (2x250 μL) and the rinses transferred to the Polyfiltronics plates. The wells of the Polyfiltronics plates were washed through with CHCI3 (250 μL) 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 μm) 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 πnsed with CHC13 (2x250 μL) and the πnses 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 centπfuged for 30 minutes in either the Savant or Genevac evaporators without applying heat or vacuum. The supernatants were transfeπed by the Robbins Hydra™ 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
The following standards were prepared using the novel process of the present invention. Standard-1
Figure imgf000019_0001
Molecular formula: C23H21N3O4S
1H-NMR (300 MHz, CDCI3) δ 2.41 (s, 3H), 3.87 (s, 3H), 4.23 (d, 2H), 4 78 (t, 1H), 7.00 (d, 2H), 7.30 (d, 2H), 7.38 (d, 2H), 7.75 (d, 2H), 8.11 (m, 4H).
Analysis: %C %H %N
Calcd: 63.43 4.89 9.65
Found: 63.40 4.96 9.72 Standard-2
Figure imgf000020_0001
Molecular formula: C,4H15N3θ4
'H-NMR (300 MHz, CDC13) δ 1.15 (t, 3H), 2.21 (q, 2H), 3.23 (t, 2H), 3.76 (q, 2H). 6.05 (s, 2H), 6.15, (br s, IH), 6.90 (d, IH), 7.50 (s, IH), 7.64 (d, IH).
Elemental Analysis: %C %H %N Calcd: 58.13 5.23 14.53 Found: 58.29 5.41 14.61
Standard-3
Figure imgf000020_0002
Molecular formula: C23H27N3O5S
1H-NMR (300 MHz, CDC13) δ 1.09-2.24 (m, 9H), 2.8-2.91 (m, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 4.50 (br s, IH), 6.93 (d, IH), 7.31 (s, IH), 7.41 (m, 4H), 8.05 (d, 2H).
Analysis: %C %H %N
Calcd: 60.38 5.95 9.18
Found: 60.33 6.03 9.31 Standard-4
Figure imgf000021_0001
Molecular formula: C23H25CIR1O3
1H-NMR (300 MHz, CDC13) δ 0.91 (t, 3H), 1.40-2.20 (m, 7H), 2.35 (br s, IH), 3.15- 3.75 (m, 4H), 3.76-4.35 (m, with t at 3.99, 3H), 6.90 (d, 2H), 7.40 (d, IH), 7.70 (d, IH), 8.94 (br s, 2H), 8.45 (s, IH).
Elemental Analysis: %C %H %N Calcd: 62.65 5.71 12.71
Found: 62.85 5.76 12.74
Standard-5
Structure:
Figure imgf000021_0002
Molecular formula: C22H25N3O4
1H-NMR (300 MHz, CDC13) δ 1.72 (m, 2H), 1.95 (m, 2H), 2.38 (s, 3H), 2.97 (t, 2H), 3.49 (q, 2H), 3.81 (s, 3H), 3.88 (s, 3H), 6.44 (d, IH), 6.59 (q, IH), 7.25 (d, 2H), 7.77 (br s, IH), 7.9 (d, 2H), 8.14 (d, IH).
Elemental Analysis: %C %H %N
Calcd: 66.82 6.37 10.63
Found: 66.93 6.42 10.52 Standard-6
Figure imgf000022_0001
Molecular formula: C26H33N3O3S
Η-NMR (300 MHz, CDC13) δ 0.67 (t, 3H), 1.29 (s, 6H), 1.61 - 1.70 (m, 4H), 2.20-2.45 (m, with s at 2.32, 9H), 2.69 (t, IH), 3.28-3.39 (m, IH), 3.81 (br d, IH), 4.15 (br d, IH), 7.26 (d, IH), 7.51 (d, 2H), 7.71 (d, 2H), 7.75-7.82, ( , 2H).
Elemental Analysis: %C %H %N Calcd: 66.78 7.11 8.99 Found: 66.59 7.11 8.70
Standard -7
Figure imgf000022_0002
Molecular formula: C]4Hι6N4O4
H-NMR (300 MHz, CD3OD) δ: 1.06 (t, 3H), 3.05-3.25 (m, with t at 3.11, 4H), 3.30 (s, IH), 3.59 (t, 3H), 4.89 (s, 2H), 6.04 (s, 2H), 6.94 (d, IH), 7.47 (s, IH), 7.62 (d, IH)
13C-NMR (270 MHz, CD3OD/CDCl3) δ: 14.6, 27.5, 34.7, 36.8, 101.7, 108.4, 122.0, 148.1, 150.3, 159.3, 167.9, 178.5
MS m/z 305 (M+H, 100%). Elemental Analysis: %C %H %N
Calcd: 55.26 5.30 18.41
Found: 55.50 5.46 18.60
Standard-8
Figure imgf000023_0001
Molecular formula: C23H26N4O3
Η-NMR (300 MHz, CDC13) δ: 1.00-1.10 (m, 2H), 1.49-1.70 (m, 4H), 1.85-1.90 (m, 2H), 2.15-2.21 (m, 2H), 3.90 (br t, IH), 3.12 (t, 2H), 3.74 (s, 3H), 5.71 (t, IH), 6.70 (d, IH), 6.85 (d, IH), 7.03 (s, IH), 7.17 (t, IH), 7.45 (d, 2H), 7.57 (s, IH), 8.05 (d, 2H)
13C-NMR (67.5 MHz, CDC13) δ: 29.8, 36.5, 37.6, 46.0, 55.2, 106.3, 108.7, 112.5, 127.4, 128.9, 130.0, 131.1, 140.3, 156.6, 160.4, 168.2, 182.6
MS m/z 407 (M+H, 100%).
Elemental Analysis: %C %H %N Calcd: 67.96 6.45 13.78 Found: 67.73 6.29 13.75
Standard-9
Figure imgf000023_0002
Molecular formula: C24H28N4O3
1H-NMR (300 MHz, CDC13) δ: 0.99 (t, 3H), 1.40-1.95 (m, 7H), 2.10-2.20 (m, 2H), 3.23-2.26 (m, IH), 3.45-3.50 (m, IH), 3.52-3.61 ( , IH), 3.90-4.04 (m, 4H), 6.95 (d. 2H), 7.20-7.42 (m, 5H), 7.96 (d, 2H)
13C-NMR (67.5 MHz, CDC13) δ: 13.9, 19.3, 23.5, 27.9, 31.3, 34.5, 44.4, 47.7, 67.9, 114.8, 118.6, 1 19.8, 122.9, 128.9, 129.2, 139.4, 155.3, 161.7, 168.0, 179.8 MS m/z 421 (M+H, 100%).
Elemental Analysis: %C %H %N Calcd: 68.55 6.71 13.32 Found: 68.38 6.73 13.29
Standard-10
Figure imgf000024_0001
Molecular formula: C22H26N4O4
1H-NMR (300 MHz, CDCI3) δ: 1.60-1.65 (m, 2H), 1.92-1.97 (m, 2H), 2.42 (s, 3H), 2.98 (t, 2H), 2.40 (q, 2H), 3.79 (s, 3H), 3.81 (s, 3H), 4.66 (br t, IH), 6.30 (s, IH), 6.47 (d, 2H), 7.30 (d, 2H), 7.65 (d, IH), 7.94 (d, IH)
13C-NMR (67.5 MHz, CDCI3) δ: 21.6, 23.9, 26.3, 29.6, 39.7, 55.6, 55.7, 99.1, 104.1, 121.2, 122.8, 124.0, 127.3, 129.6, 141.5, 151.1, 156.4, 156.8, 168.3, 179.5
MS m/z 411 (M+H, 100%).
Elemental Analysis: %C %H %N
Calcd: 64.37 6.38 13.65
Found: 64.12 6.48 13.43 Standard- 11
Figure imgf000025_0001
Molecular formula: C23H26N4O2S
1H-NMR (300 MHz, CDC13) δ: 1.55-1.70 (m, 4H), 2.10-2.30 (m, 3H), 2.28 (s, 3H), 2.33 (s, 3H), 2.43 (s, 3H), 3.20-3.27 (m, 2H), 3.75-3.90 (m, 2H), 4.07-4.15 (dd, IH), 6.90 (d, IH), 7.07 (d, IH), 7.15 (t, IH), 7.23 (d, IH), 7.35 (s, IH), 7.52 (s, IH), 7.78 (d, IH)
13C-NMR (67.5 MHz, CDC13) δ: 15.7, 19.7, 20.0, 23.4, 27.8, 34.4, 44.3, 47.8, 1 16.4, 117.4, 120.9, 123.9, 125.0, 128.6, 129.1, 130.3, 137.5, 139.3, 140.0, 140.6, 155.4, 168.4, 179.9
MS m/z 423 (M+H, 100%). ital Analysis: %C %H %C
Calcd: 65.38 6.20 13.26
Found: 65.18 6.16 13.08
Standard-12
Figure imgf000025_0002
Molecular formula: C22H23BrN4O2 Η-NMR (300 MHz, CDC13) δ: 1.55-1.75 (m, 4H), 2.11-2.28 (m, 3H), 2.24 (s, 3H), 2.30 (s, 3H), 3.25-3.40 (m, 2H), 3.80-3.90 (m, 2H), 4.10-4.15 (dd, IH). 7.25 (d, 2H), 7.37 (d, 2H), 7.60 (s, IH), 7.78 (d, 2H) 13C-NMR (67.5 MHz, CDC13) δ: 19.7, 20.0, 23.3, 27.6, 34.4, 44.2, 47.9. 115.1 , 121.2, 123.8, 125.1, 128.5, 130.3, 131.8, 137.5, 138.7, 140.7, 155.2, 168.3, 179.9
MS: m/z 455 (M+H, 100%). Elemental Analysis: %C %H %N
Calcd: 58.03 5.09 12.30
Found: 57.98 5.30 12.36
Analysis Procedure
A. Chromatography: All standards were analyzed on a Hewlett Packard HPI IOO HPLC employing a Zorbax 4.6 mm x 7.5 cm SP-C18 column with a guard column. Standards were monitored at UV settings of 214 and 254 nm. The column was heated at 40°C and the flow rate was 0.800 mL per minute for all runs. Gradient elution was performed using water with 0.05% TFA (solvent A) and acetonitrile containing 0.05% TFA (solvent B) as mobile phases. Most samples were prepared as dilute solutions in acetonitrile, methanol or mixtures thereof.
HPLC Gradient:
Time (minutes) % Solvent B 0.00 0.00
5.00 100
8.00 100.0 9.50 0.00
B. Mass Spectrometry: Identity of peaks observed by HPLC were determined by electrospray (ESI) LC/MS analysis on a Finnigan TSQ 7000 mass spectrometer with a Hewlett Packard HP 1050 HPLC. Alternatively, purified compounds or relatively pure mixtures were analyzed with a Hewlett Packard 5989 particle beam mass spectrometer and Hewlett Packard 59980 LC/MS interface in either CI or El mode, with a Hewlett Packard HP1050 HPLC using methanol as mobile phase for direct injection of samples. Most samples were prepared as dilute solutions in acetonitrile or methanol. For analysis of both the test library and production library, direct injection MS analysis was performed on the Sciex 150 MCA, Shimadzu LC-10 HPLC, according to the following conditions
LC/MS Assay
Mobile A Water (containing 0 05% AcOH and 1 0% MeOH)
Mobile B Methanol (containing 0 05% AcOH and 1.0% water)
Figure imgf000027_0001
Sample volume- 10.0 μL Column Zorbax 3 0 x 50.0 mm column with inline filter
Temp . 40 °C
Gradient 0 to 100% B in 6 0 min, 100% B for 1 0 min, 0% B for
Figure imgf000027_0002
Detection UV monitoπng at 214, 254, 280, and 320 nm
MS Assay
Mode Positive ion ESI injection volume 5 DL flow rate 0 3 mL/min, 50% solvent B.
DEFINITIONS
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 The term "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- The term "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: The term "alkylene" represents a straight chain, branched, cyclic or a combination thereof hydrocarbon group which is attached to two other groups Examples are -CH2- (methylene), cyclohexylene and -CH -CH2- (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 aπay 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 The term "library of compounds" can be interchangeably used with the term 'array of compounds"
Aryl The terms "Ar" and "aryl", as used herein, are intended to represent a stable substituted or unsubstituted (collectively also referred to as 'optionally substituted5) six to fourteen membered mono-, bi- or tπ-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. 4 alkyl Heteroaryl The term "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 Thus a Sulfur (S) atom can exist as a sulfide, sulfoxide, or sulfone Preferred heteroaryl groups are six membered πng systems compnsmg not more than 2 hetero atoms Illustrative examples of preferred heteroaryl groups are thienyl, N-substituted succi mide, 3-(alkyl amιno)-5,5-dιalkyl- 2-cyclohexen-l-one, methyl pyπdyl, alkyl theophylline, furyl, pyrrol yl, indoly], pyπmidinyl, isoxazolyl, puπnyl, lmidazolyl, pyπdyl, pyrazolyl, quinolyl, and pyrazinyl A hetero aryl group is preferably substituted with one to three substituents selected from H, d 8 straight chain or branched alkyl, OCi 4 alkyl, halogen and SC] 4 alkyl
Catalyst The term "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-hydroxybenzotπazole (HOBt), l-hydroxy-7- azabenzotπazole (HO At) and N-hydroxysuccinimide The term solid support (SS), as used in the present invention, signifies polymenc mateπal for supported synthesis A detailed descπption of the terms linker molecule, and solid support can be found in The Combinatoπal Index, B A Bunin, 1998, which is incorporated herein by reference
Cation Scavenger The term "cation scavenger" as used herein represents a reagent which can intercept a cation generated duπng a reaction, for example under acidic conditions By intercepting the cation the cation scavenger can prevent the cation from reacting with the product formed duπng the reaction Illustrative examples of cation scavengers are water, tπethylsilane, anisole, thioamsole, dimefhylsulfide, phenol and 1,2-ethanedιthιol. Optional or Optionally The term "optional" or "optionally" means that the subsequently descnbed event or circumstance may or may not occur, and that the descπption includes instances where the event or circumstance occurs and instances in which it does not For example, 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 Thus 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. When the substituent is keto (=O) then 2 hydrogens on the atom are replaced. Inert Solvent: The term "inert solvent" is intended to represent solvents which do not react with the reagents dissolved therein. Illustrative examples of inert solvents are tetrahydrofuran (THF), methylene chloπde, 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 temporaπly rendeπng the protected atom inactive. Illustrative examples of protecting groups are tetrahydropyran (THP), tert-butyl-oxy carbonyl (BOC), and fluoromethyloxy carbonyl (FMOC) A comprehensive list and descπption of protecting groups can be found in Protective groups in Organic Synthesis, second edition, T.W. Greene and P.G.M Wuts, 1991, which are incorporated herein by reference. Deprotecting Agent: The term "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 The term "protecting group" or "PG", as used herein, indicates a group that protects an amine functional group rendenng the amine inactive A detailed descπption 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 As used herein the term "dehydrating agent" (also some times refeπed to as "drying 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
Base (as used m step (Q) The term "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 Illustrative examples of the suitable base are N-methylmorpholme (NMM), N- ethylmorphohne, N-methylpipeπdine, N-ethylpipendine, tnethyl amine, pyndine, lutidine and N,N-dπsopropylethylamme (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. As used in the present invention, the illustration:
generally indicates a point of attachment of the group, compnsmg the illustration, to another group or atom
Halogen The term "halo" or "halogen" is intended to represent Cl, Br, I and F
Abbreviations
ACD = Available Chemicals Directory ACN = Acetonitπle
AcOH = Acetic Acid
AUC = Area under curve
BAM = Benzamidoxime BOC = t-Butoxycarbonyl
CI = Chemical Ionization
CDI = 1 , 1 ' -Carbon yldnmidazole
1 ,2-DCE = 1 ,2-Dιchloroethane
DCM = Dichloromethane DIPEA = N,N-Dιιsopropylefhylamιne
DIC = 1 ,3-Dιιsopropylcarbodιιmιde
DMAP = 4-(Dιmethy]amιno)pyπdme
EDC = l-(3-Dιmethylamιnopropy])-3-ethylcarbodnmιde hydrochloπde
El = Electron Impact ESI = Electrospray ionization
HCl = Hydrochloπc Acid
HOBt = 1 -Hydroxybenzotπazole
HPLC = High Performance Liquid Chromatography
LLE = Liquid Liquid Extraction

Claims

A process for synthesizing a compound or an array of compounds of Formula
Figure imgf000032_0001
Formula I
wherein Z represents an aryl group substituted with R1, R and R ,
Q represents CO, SO2 or C(O)NH,
R2 represents CpC alkylene, -CM substituted alkylene, (CH2)o 6-Ar, Ar-(CH2)i 6, or C5 10 cycloalkylene-(CH2)o β,
R3 represents C1.-C1.4 alky], aryl, substituted aryl, C1-C14 alkylene-aryl, Ci-Cio alkylene-O-aryl, C1-C10 alkylene-S-aryl, heteroaryl or Cι-C]0 alkylene-S-Cι-C6 alkyl,
R represents H or 4 alkyl, alternatively R2 and R4 along with the nitrogen atom to which they are attached form a 4 to 7 membered heterocyclic πng substituted with at least one substituent selected from Ci 4 alkyl, Ph, OH, H, O 4 alkyl, NHCO-Ci 4 alkyl and halogen, and
R1, R5 and R6 independently at each occurance are selected from H, 6 alkyl, O- 6 alkyl and SO2-d 4 alkyl, alternatively, when on adjacent carbon atoms, R and R can be taken together to form
Figure imgf000032_0002
said process compnsmg (A) treating a compound of Formula 2
Z-C(=NOH)NH2 Formula 2
with a compound of Formula 3
HOOC-R2-NH-PG Formula 3
in the presence of a dehydrating agent and optionally in the presence of a catalyst, at a temperature of from about 25°C to about 85°C, to yield a compound of Formula 4
Figure imgf000033_0001
Formula 4
where Z and R2 are as defined above, and PG represents a protecting group;
(B) treating a compound of Formula 4 with a deprotecting agent, optionally in the presence of a cation scavenger, to yield a compound of Formula 5
Figure imgf000033_0002
Formula 5
where Z and R are as defined above;
(C) treating a compound of Formula 5 with: (i) a compound of Formula 6a R3-Q-X Formula 6a
in the presence of a base, and where R3 is as defined above, Q represents CO or SO2, and X represents a halogen, to yield a compound of Formula I, or (11) a compound of Formula 6b
R3-N=C=0 Formula 6b in the presence of a base, and where R3 is as defined above, to yield a compound of Formula I, wherein Q represents C(O)-NH
2. A process of Claim 1 wherein the dehydrating agent in step (A) is selected from EDC, DIC, DCC and CDI.
3. A process of claim 2 wherein step (A) is earned out in the presence of a catalyst selected from DBU, Et3N, 4-DMAP and HOBt.
4. A process of claim 3 wherein the deprotecting agent in step (B) is selected from HCl, HBr, HF, hydrochromic acid, p-toluene sulfonic acid, formic acid and TFA.
5. A process of claim 4 wherein the cation scavenger in step (B) is anisole.
6. A process of Claim 5 wherein the base m step (C) is selected from N-methy] morpholme, tnethyl amine, pyridine, N,N-diιsopropyl ethyl amine, N-methyl piperidme, N-ethyl morpholine and 2,6-lutidine.
7. A process of claim 6 wherein Z represents a phenyl group substituted with R1
R5 and R τ>'6
8. A process of claim 7 wherein R1, R and R are independently selected from
H, CH3, C2H5, OCH3, OC2H5 and SO2CH3. 9 A process of claim 8 wherein R represents 2,3,5,6-tetramethyl-phenyl, 3,4- dimethoxy-phenyl, 2-ethoxy-phen-l-yl, 4-ιsopropyl-phen-l-yl, 2-Ethoxy- naphthalen-1-yl, 1-phenoxy-propyl-l-yl, phenyl, CH2-S-Ph, 4-(l ,l-Dιmethyl- propyl)-phenyl-l-yl, 4-methoxy-benzyl, 2-nιtro-benzyl, 4-chloro-phenyl-l-yl, naphthyl, 2-ιsopropyl-5-methyl-cyclohexyloxymethyl, 4-methoxy-benzyl, 2,3- dιchloro-phenyl-1-yl, 1-p-tolyl-cyclopentyl, 6-chloro-pyπdιn-3-yl, 2,5-dιmethyl phenyl-1-yl, 2-methylsulfanyl-ethyl, 2,6-dιchloro-phenyl-l -yl, 1-phenyl-propyl-l- yl, 4-methyl-3-nιtro-phenyl-l-yl, 2,3,6-tπfluoro-phenyl-l-yl, 3-methyl-butane-l-yl, 4-pentyloxy-phenyl-l-yl, 4-methyl-phenyl-l-yl, 2,4-dimethoxy-phenyl-l-yl, or benzo[l,3]dιoxol-5-yl
10 An aπay of compounds of Formula I
Figure imgf000035_0001
Formula I
wherein
Z represents an aryl group substituted with R1, R and R ,
Q represents CO, SO2 or C(O)NH, R2 represents C1-C14 alkylene, C1-C14 substituted alkylene, (CH )o 6-Ar, Ar-(CH2)o 6, or C5 10 cycloalkylene-(CH2)0 6,
R3 represents Cι-Cι4 alkyl, aryl, substituted aryl, C1-C14 alkylene-aryl, Cι-Cι0 alkylene-O-aryl, C1-C10 alkylene-S-aryl, heteroaryl, or C1-C10 alkylene-S-Cι-C6 alkyl, R4 represents H or Ci 4 alkyl; alternatively R2 and R4 along with the nitrogen atom to which they are attached form a 4 to 7 membered heterocyclic πng substituted with at least one substituent selected from Ci 4 alkyl, Ph, OH, H, OCi 4 alkyl, NHCO-Ci 4 alkyl and halogen, and R1, R5 and R6 independently at each occurance are selected from H, C,. alkyl, O-Cι-6 alkyl and SO2-C ι-4 alkyl; alternatively when on adjacent carbon atoms, R5 and R6 can be taken together to form
Figure imgf000036_0001
1 1. The array of compounds of claim 10 wherein
R1, R5 and R6 are independently selected from H, CH3, C2H5, OCH3, OC2H5 and
Figure imgf000036_0002
R3 represents 2,3,5,6-tetramethyl-phenyl, 3,4-dimethoxy-phenyl, 2-ethoxy-phen-l- yl, 4-isopropyl-phen-l-yl, 2-Ethoxy-naphthalen-l-yl, 1-phenoxy-propyl-l-yl, phenyl, CH2-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-dichloro-phenyl-l -yl, 1-p-tolyl- cyclopentyl, 6-chloro-pyridin-3-yl, 2,5-dimethyl-phenyl-l-yl, 2-methylsulfanyl- ethyl, 2,6-dichloro-phenyl-l-yl, 1-phenyl-propyl-l-yl, 4-methyl-3-nitro-phenyl-l-yl, 2,3,6-trifluoro-phenyl-l-yl, 3-methyl-butane-l-yl, 4-pentyloxy-phenyl-l-yl, 4- methyl-phenyl-1-yl, 2,4-dimethoxy-phenyl-l-yl, or benzo[l ,3]dioxol-5-yl.
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