Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to building blocks for the creation of a high degree of structural diversity among compounds within a combinatorial library.
• compounds that may serve as building blocks and methods for generating such compounds.
• Combinatorial chemistry refers to techniques for creating a multiplicity of compounds, referred to as a "library”, and then testing the library or each member of the library for biological activity. In recent years, combinatorial chemistry has become an important tool for the drug discovery efforts of many pharmaceutical companies.
• a "building block” is a reagent or compound which can combine (i.e., react) with one or more other reagents to yield the compounds which, together, form a combinatorial library.
• building block is a reagent or compound which can combine (i.e., react) with one or more other reagents to yield the compounds which, together, form a combinatorial library.
• the present invention provides a compound having the formula:
• R, Ri , R are independently selected from the group consisting of hydrogen, Cj-C ⁇ lower alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkylcarbonyl, C 3 -C 6 cycloalkyl, trifluoromethylcarbonyl, or (CH ) n - ⁇ henyl or -(CH 2 ) n - heteroaryl where n is 0 to 4 and where the phenyl or the heteroaryl is optionally substituted with 1 to 3 halogens, C ⁇ -C 6 lower alkyl, C ⁇ -C 6 alkoxy, C 2 -C 6 alkylcarbonyl, carboxy, or C ⁇ -C 6 carboxyalkyl; aryl or heteroaryl carbonyl which may be optionally substituted with 1 to 3 halogens, C ⁇ -C 6 lower alkyl, C]-C 6 alkoxy, C 2 -C 6 alkyl
• n 1, 2, or 3
• W is N, CH, or O, provided that when W is O, R 3 does not exist;
• R 3 is hydrogen, C ⁇ -C 6 lower alkyl, C 2 -C 6 alkenyl, C -C 6 alkynyl, C -C 6 alkylcarbonyl, C -C 6 cycloalkyl, carboxy, C 2 -C 6 alkoxycarbonyl, aryl or heteroaryl, each of which is optionally mono-, di-, or trisubstituted with straight or branched chain lower alkyl having 1 to 6 carbon atoms, halogen, trifluoromethyl, hydroxy, straight or branched chain lower alkenyl having 2 to 6 carbon atoms, trifluormethoxy, or amino, dialkylamino having 2 to 6 carbon atoms, -CO 2 R where R is alkyl having 1-6 carbon atoms, -(CH ) m -O-R 5 where m is 1-6 and R 5 is hydrogen or lower alkyl having 1-6 carbon atoms.
• the present invention provides building blocks for combinatorial libraries.
• the present invention provides a composition comprising a compound having structural formula I as defined above in combination with a acceptable carrier.
• the present invention relates to building blocks for the synthesis of a collection of compounds as a combinatorial library.
• a "collection of compounds” comprises at least three different compounds, also referred to as the "disclosed building blocks" or the "member compounds".
• the collection comprises at least five different compounds, more preferably at least thirty different compounds.
• the collection comprises at least fifty different compounds.
• Each of the disclosed building blocks is: 1) substantially pure; 2) is substantially free of contamination by the other building herein; and 3) contains at least one reactive group.
• a building block can contain one or more non- reactive functional groups.
• substantially pure means, for example, that the disclosed building block is at least about 80% pure, and preferably at least about 90% pure and more preferably at least about 95% pure.
• substantially free of contamination by other members of the collection means, for example, that the disclosed building block contains less than 5% of the other building blocks in the collection and more preferably less than 1.0% of the other building blocks in the collection, and even more preferably less than 0.1% of the other building blocks in the collection.
• a “reactive functional group” allows the compound in the collection to be reacted directly with other reagents or compounds to form a member of a combinatorial library or a precursor thereof. "Reacted directly” means, for example, that the reactive functional group can react and form covalent bonds with the other compounds without the need of intervening reactions such as a deprotection reaction.
• the reactive functional group determines the interconnection chemistries, i.e., the manner in which the disclosed building block can be reacted with other building blocks of the combinatorial library.
• reactive functional groups include a hydroxyl group, a primary amine group, a secondary amine group, a thiol, a carboxylic acid, an ester, an aldehyde, an azide, a nitrile, an isonitrile, an epoxide, an aziridine, an isocyanate, a thioisocyanate and a halide.
• non-reactive functional group is inert under the reaction conditions employed for interconnecting the disclosed building blocks with other building blocks used to prepare a member of a combinatorial library or a precursor thereof, unless the non-reactive functional group is, for example, first activated or undergoes a deprotection reaction.
• non-reactive functional groups include an ether, a thioether, a tertiary amine, an alkene, an alkyne, an alkoxycarbonyl, a ketal or an acetal.
• a member compound has at least one reactive functional group. More than one reactive functional group can be present in a member compound, provided that the reactivity of each reactive functional group is orthogonal to the reactivities of the other functional groups, i.e., each reactive functional group can selectively react in the presence of the others.
• a reactive functional group can be introduced into the building block or member compound by, for example, formation of a carbon-heteroatom bond between a precursor compound and a reagent. Specific examples are provided in the following paragraphs.
• the formation of a carbon-heteroatom bond between a precursor compound and a reagent can occur by reacting an electrophilic precursor compound and a nucleophilic reagent.
• a reactive functional group which can be introduced by this type of transformation is a secondary amine R'NH-, which is formed from the reaction of an electrophilic precursor compound and R 1 NH 2 , or the anion thereof (or by the reaction of a carbonyl group with a primary amine under reducing conditions).
• RI is an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group.
• R ' is an aliphatic or aromatic group substituted with at least one reactive functional group.
• nucleophilic reagent for this type of transformation is R ⁇ R IV NH, or the anion thereof, wherein R I ⁇ and R IV , together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring or is substituted with a reactive functional group.
• the reaction of this nucleophilic reagent with an electrophilic precursor can introduce R ' R N- into a member compound.
• Examples of other reactive functional groups which can be introduced into a member compound include H 2 N-, HO-, C1-, Br-, I-, CN-, N 3 -, NC-, which are formed by the reaction of a suitable electrophilic precursor compound with NH (or NH 2 " ), H 2 O (or OH “ ), Cl “ , Br “ , T, CN “ , N 3 “ , and trimethylsily cyanide, respectively.
• the nucleophile can also be a part of the elecrophilic precursor, i.e., the reaction is intramolecular, respectively.
• the nucleophile can also be part of the electrophilic precursor, i.e., the reaction is intramolecular.
• Epoxides and aziridines are examples of reactive functional groups formed in this manner.
• suitable electrophilic precursors which can be used to introduce reactive functional groups into a building block by reaction with a nucleophilic reagent include alkyl halies, aryl halides, alkyl sulfates, alkyl sulfonates, epoxides and aziridines.
• a reactive functional group can also be formed by converting a reactive functional group present in a member compound to a different reactive group.
• This type of reaction is the conversion of a primary amine to isocyanate by reaction with phosgene or Cl-COO-C(CL ) or the replacement of a halide with an amine.
• a reactive functional group can be formed by removing a protecting group present in a member compound. Examples include cleaving a tert- butoxycarbonyl group (hereinafter "BOC”) to regenerate a free primary or secondary amine or hydrolyzing an acetal or ketal to liberate an aldehyde or ketone, respectively.
• BOC tert- butoxycarbonyl group
• the formation of a carbon-heteratom bond between a precursor compound and reagent can also occur by reacting a nucleophilic precursor compound, e.g., a compound containing one or more double and/or triple bonds, and an electrophilic reagent.
• a nucleophilic precursor compound e.g., a compound containing one or more double and/or triple bonds
• an electrophilic reagent e.g., -Cl, -Br-, -I, -OH, -O-, -N 3 , and an aziridine
• an aziridine can be formed by reacting a compound containing one or more double and/or triple bonds with, for example, SC1 2 , RSC1, SBr 2 , SI , N-bromosuccinimide, meta-chloroperbenzoic acid, NaN3 or tosyl chloramine.
• a non-reactive functional group can be introduced into a building block or member compound by formation of a carbon-heteroatom bond between a precursor compound and a reagent, for example, by reacting an electrophilic precursor compound and a neucleophilic reagent.
• electrophilic precursor compounds are as described above for introducing reactive functional groups into building blocks.
• suitable nucleophilic reagents for introducing non- reactive functional groups into a building block include R V R V1 NH, R V SH, R v OH, or the anions thereof.
• R and R VI are independently an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group.
• Substituted aliphatic and substituted aromatic groups represented by R v and R VI can contain non- reactive functional groups but no reactive functional groups.
• These nucleophilic reagents, together with a suitable electrophilic precursor compound, can be used to introduce R V R V1 N-, R V S- and R v OH, respectively into a building block.
• Another example of a suitable necleophilic reagent for introducing a non-reactive functional group into the building block is R VI, R VIII NH, or the anion thereof.
• R v " and R v ⁇ together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic group which does not contain -NH- in the non-aromatic heterocyclic ring and is not substituted with a reactive functional group.
• R VII R VII1 NH or its anion and a suitable eletrophilic precursor compound R V1I R VIII N- can be introduced into a building block.
• a suitable nucleophilic reagent for introducing a non-reactive functional group into a building block is R VI NH 2 , or the anion thereof. Use of this reagent and a precursor molecular having at least to electrophilic sites results in the formation of a non-reactive R IV N ⁇ functional group.
• the disclosed building blocks can be formed from virtually any combination of the eletrophilic precursor compounds and the nucleophilic reagents which are disclosed herein or from the nucleophilic precursor compounds (e.g., compounds containing one or more units of unsaturation) and the electrophilic reagents which are disclosed herein, provided that at least one reactive group is present in the building block.
• the collection includes building block.
• the collection includes building blocks which are formed from an electrophilic precursor compound and a nucleophilic reagent disclosed herein or from a nucleophilic precursor compound containing one or more units of unsaturation and an electrophilic reagent disclosed herein.
• the collection consists of building blocks from an electrophilic precursor compound and a nucleophilic reagent disclosed herein or from a nucleophilic precursor compound containing one or more units of unsaturation and an electrophilic reagent disclosed herein.
• the collection includes the building blocks disclosed herein.
• the collection consists of the building blocks disclosed herein.
• novel compounds encompassed by the instant invention can be described by the general Formula I set forth above or the pharmaceutically acceptable non-toxic salts thereof.
• the present invention provides a compound of
• R, Ri, R 2 are independently selected from the group consisting of hydrogen, C ⁇ -C 6 lower alkyl, C -C 6 alkylcarbonyl, trifluoromethylcarbonyl, or
• (CH ) n -phenyl where n is 0 to 4 and where the phenyl is optionally substituted with halogen, C ⁇ -C 6 lower alkyl, C]-C 6 carboxy, C 2 -C 6 alkylcarbonyl; in addition, Ri and R , together with the nitrogen to which each is attached, may form azide or a structure shown below:
• a compound of Formula I has R is selected from CH -phenyl, H, t-butyl,
• a compound of Formula I wherein R is CH 2 -phenyl and wherein Rj, R and the N to which each is attached form azide or a structure selected from:
• R is hydrogen and wherein R 1 ⁇ R 2 and the N to which each is attached form a structure selected from:
• a compound of Formula I where R is t- butyl and where Ri, R and the N to which each is attached form one of the following structures:
• R is
• the most preferred compounds include the following and their pharmaceutically acceptable salts: 2-methoxyphenylpiperazine; l-(2-pyridyl)- piperazine; 1-pyrimidylpiperazine; 1-phenylpiperazine; 1-methylpiperazine; morpholine; piperidine; pyrrolidine; dimethylamine; methylamine; isopropylamine; methallyamine; sodium azide; azetidin-3-ol; 2-methoxyphenlpiperazine; 1(2- hydroxyethyl)-piperazine; piperazine; 1 -tert-butoxycarbonyl perhydrodiazepine; 1- methylpiperazine; 1-phenylpiperazine; 1-pyrimidylpiperazine; 4- fluorophenylpiperazine; 4-methoxyphenylpiperazine; 4-methylphenylpiperazine; 4- trifluoromethoxyphenylpiperazine; 4-trifluoromethylphenylpiperazine; 1 -(2-pyridy
• Alkyl means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms (unless stated otherwise; preferably C]-C 6 ) and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and the like.
• Halo includes fluoro, chloro, bromo, and iodo.
• Alkenyl means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and one double bond and includes ethenyl, 3-buten-l-yl, 2-ethenylbutyl, 3-hexen-l-yl, and the like.
• Alkynyl means straight and branched hydrocarbon radicals having from 2 to
• C 2 -C ⁇ 0 alkynyl groups include propynyl, 2-butyn-l-yl, 3-pentyn-l-yl, and the like.
• Cycloalkyl means a cyclic hydrocarbyl group such as cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl, and the like.
• Alkoxy refers to the alkyl groups mentioned above bound through a single oxygen atom, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.
• Carboalkoxy refers to an organic acid esterified with a lower alcohol or amidated with an amine, respectively. Such groups include, for example,
• Alkanoyl or alkylcarbonyl groups are alkyl as previously defined linked through a carbonyl, i.e., C ⁇ -C ⁇ o-C(O)- or C 2 -C 6 -C(O)-.
• Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
• acyl includes a Ci-Cio alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR'R" or a carboxylic or heterocyclic group.
• Typical acyl groups include acetyl, benzoyl, and the like.
• alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted by N, NR, phenyl, substituted phenyl, thio, Ci-Cio alkyl (preferably
• Ci-Cio alkoxy (preferably C ⁇ -C 6 ), hydroxy, carboxy, -Cio alkoxycarbonyl
• substituted nitrogen means nitrogen bearing Cr o alkyl (preferably C ⁇ -C 6 ) or (CH ) n Ph where n is 1, 2, or 3.
• substituted alkyl groups examples include 2-aminoethyl,
• substituted alkynyl groups examples include 2-methoxyethynyl,
• Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 3 -diethylamino-2-hydroxy-propoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
• substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-l-yl,
• aliphatic groups comprise straight chained, branched or cyclic C ⁇ -C 8 hydrocarbons which are completely saturated or which contain one or more units of unsaturation.
• Suitable substituents for an aliphatic group or an aromatic group comprise reactive functional groups and non-reactive functional groups, as described above.
• Heteroaryl groups are aryls having from 4 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Mono and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl.
• Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, benzofuranyl, indoyl, and the like.
• Aromatic groups may also comprise carbocyclic aromatic groups such as phenyl, 1 -naphthyl, 2-naphthyl, 1-anthracyl and 2-anthacyl, and heterocyclic aromatic groups such as N-imidazolyl, 2-imidazole, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidy, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazole, 4-thiazole, 5-thiazole, 2- oxazolyl, 4-oxazolyl and 5-oxazolyl.
• carbocyclic aromatic groups such as phenyl, 1 -naphthyl, 2-naphthyl, 1-anthracyl and 2-anthacyl
• aromatic groups may comprise fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings.
• Examples include 2-benzothienyl, 3 -benzothienyl, 2- benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2- benzothiazole, 2-benzooxazole, 2-benzimidazole, 2-quinolinyl, 3-quinolinyl, 2- benzothiazole, 2-benzooxazole, 2-benzimidazole, 2-quinolinyl, 3-quinolinyl, 1- isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and acridinyl.
• Preferred Ar groups are phenyl and substituted phenyl.
• the alkyl and alkoxy groups can be substituted as defined herein.
• typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl.
• the compounds of the instant invention may be prepared using the chemical synthesis described below:
• the starting azetidinols may be prepared utilizing a modified procedure of Gaertner (J. Org. Chem., 1967, 32. 2972) according to the following sequence:
• mesylation is carried out at low temperature to minimize side reactions; mesylate is used immediately to prevent decomposition; the displacement reaction is carried out in water; and, by-products are easily removed (a feature of ClickchemTM).
• the product crashes out of solution (particularly in the case of aromatic nucleophiles were a slight excess of the mesylate is employed).
• use of the tert-butyl group leads to a cleaner displacement reaction thus leading to a more easily purifiable product.
• the majority of known studies on substituted azetidines have avoided benzyl as the protecting group, and have instead used benzhydryl (Chatterjee, et al. Synthesis, 1973, 153).
• Acylative dealkylation is also contemplated by the instant invention.
• the procedure using acetic anhydride was developed by Dave (J. Org. Chem., 1996, 61, 5453), though its use was limited to three substrates due probably to difficulty in isolating the products.
• the present invention solves certain difficulties associated with the method of Dave by: using a co-solvent; providing a modified work-up that makes product isolation easier; extend the scope of the process of Dave to a number of new substrates; and, providing an improved method for hydrolysis of the amide bond using hydrogen chloride gas in ethanol.
• the present invention also extends the scope of the acylative dealkylation method, and provides a method that allows the deprotection of acid sensitive compounds. For instance, several of the substrates in the current study contain acid- sensitive functional groups and cannot, therefore, be deprotected by either of the methods described above.
• the instant invention provides a new method for the cleavage of the tert-butyl group in these systems (Nussbaumer, et al., Tetrahedron, 1991, 47, 4591). As with the acetic anhydride method, the instant invention provides a two step method first involving formation of the trifluoroacetamide followed by cleavage under basic conditions.
• the advantages of the instant invention include: the reaction takes place at 0°C; only slightly more than a stoichiometric amount of trifluoroacetic anhydride is required; the reaction is very rapid (with the addition of one equivalent of triethylamine, the reaction is complete within one hour); the work- up is simple; the reaction is very clean, thus simplifying product isolation; amide hydrolysis is also rapid and takes place at room temperature.
• IL acetonitrile
• Triethylamine (303.1 g, 3 mol) was added, and the mixture was refluxed for 3 days (a white solid was observed to precipitate from solution within 24 hrs). After being allowed to cool to room temperature, triethylamine hydrochloride was filtered off, and the solid washed with petroleum ether. Removal of the solvent in vacuo gave a yellow oil, which was distilled (oil bath 75 °C) to give the silyl ether (400 g, 95% pure, 97% yield) as a colorless oil (b.p. 45 °C/2-3 mmHg).
• N-t-butyl-O-trimethylsilylazetidine 400 g, 2 mol was added portionwise to 3 ⁇ Hydrochloric acid solution (733 mL) at room temperature, and the resulting mixture was stirred at ambient temperature. An exothermic reaction took place.
• N-benzyl-3-methylaminoazetidine (6.0g, 22%o) as a slightly yellow liquid. Further purification can be carried out by distillation (75-78°C/ ImmHg) to afford N-benzyl-3-methylaminoazetidine as a colourless liquid.
• the hydrochloride salt (185g, 0.41mol) was dissolved in methanol (IL), and palladium hydroxide (21g, 20% on carbon) was added.
• the bottle was evacuated, and then pressurised under hydrogen (40psi) and shaken whilst being heated to 60°C. On reaching the desired temperature, the pressure was increased to ⁇ Opsi, and shaking continued for a further 48 hours (during this time the hydrogen pressure was recharged twice).
• the heater was then turned off, and the reaction allowed to cool to room temperature under hydrogen. After the hydrogen pressure had been released, the bottle was then opened, and the reaction was filtered through celite washing with hot methanol (8L) followed by water (3L).
• the viscous black residue was poured into a mixture of 50% potassium hydroxide (120ml) and ice water (400ml) ensuring the resulting solution is at basic pH. After being allowed to stir for 30 minutes at 0°C, the aqueous solution was extracted with methylene chloride (3 x 600ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 80 : 10 : 10 ; ethyl acetate : methanol : triethylamine. The product (93g, 70%>) was obtained as a slightly yellow solid.
• the viscous black residue was poured into a mixture of 50% potassium hydroxide (120ml) and ice water (400ml) ensuring the resulting solution is at basic pH. After being allowed to stir for 30 minutes at 0°C, the aqueous solution was extracted with methylene chloride (3 x 400ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 80 : 10 : 10 ; ethyl acetate : methanol : triethylamine. The product (83.5g, 74.5%) was obtained as a slightly yellow solid.
• the viscous black residue was poured into a mixture of 50%> potassium hydroxide (120ml) and ice water (400ml) ensuring the resulting solution is at basic pH. After being allowed to stir for 30 minutes at 0°C, the aqueous solution was extracted with methylene chloride (3 x 600ml). The combined organic extracts were dried over magnesium sulfate, and the solvent removed in vacuo to afford the product as a light brown solid. Purification of the product was carried out by passing it through a pad of silica gel eluting the product with 80 : 10 : 10 ; ethyl acetate : methanol : triethylamine. The product (76g, 83%>) was obtained as a slightly yellow solid.

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Citations (7)

• 1998
  • 1998-10-15 WO PCT/US1998/021786 patent/WO1999019297A1/en active Application Filing
  • 1998-10-15 AU AU10895/99A patent/AU1089599A/en not_active Abandoned

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