WO2001074792A2 - Procede de preparation d'inhibiteurs de metalloproteinases matricielles - Google Patents

Procede de preparation d'inhibiteurs de metalloproteinases matricielles Download PDF

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WO2001074792A2
WO2001074792A2 PCT/US2001/010276 US0110276W WO0174792A2 WO 2001074792 A2 WO2001074792 A2 WO 2001074792A2 US 0110276 W US0110276 W US 0110276W WO 0174792 A2 WO0174792 A2 WO 0174792A2
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formula
compound
product
reacting
base
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PCT/US2001/010276
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WO2001074792A3 (fr
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Anne E. Bailey
David R. Hill
Chi-Nung Hsiao
Ravi Kurukulasuriya
Steve Wittenberger
Todd Mcdermott
Maureen Mclaughlin
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms

Definitions

  • This invention relates to a process for the preparation of matrix metalloproteinase inhibitors and to intermediates useful in the process.
  • Matrix metalloproteinases are a class of extracellular enzymes such as collagenase, stromelysin, and gelatinase which are believed to be involved in tissue destruction which accompanies a number of diseases including arthritis and cancer. There is, therefore, a continuing need for compounds which are inhibitors of matrix matalloproteinase.
  • the instant invention discloses a synthesis of metalloproteinase inhibitors from ((4S)-
  • R is selected from the group consisting of hydrogen, an amino protecting group, and -OR ;
  • R is hydrogen or a hydroxy protecting group
  • L 1 is -O- or -N(R 3 )-, wherein R 3 is hydrogen or an ammo protecting group; and X is O or S, the process comprising: (a) reacting a compound of formula (2)
  • R is a carboxyl protecting group, with a reducing agent to provide a first reaction mixture
  • the compound of formula (3) is (4R)-4-(hydroxymethyl)- 1 ,3-oxazolidin-2-one.
  • Another embodiment of the instant invention comprises reacting a compound of formula (1)
  • a base a base
  • a reagent selected from the group consisting of phosgene, thiophosgene, triphosgene, carbonyldiimidazole, thiocarbonyldiimidazole, and a dialkyl carbonate.
  • Another embodiment of the instant invention comprises a process for preparing a compound of formula (5-a)
  • Q is selected from the group consisting of halide, methanesulfonate, and trifluoromethanesulfonate;
  • Y is nitrogen or C(H);
  • R is selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, aminosulfonyl, aminosulfonylalkyl, aryl, arylalkyl, cyano, cyanoalkyl, halo, haloalkyl, (heterocycle)oxy, (heterocycle)oxyalkyl, hydroxy, hydroxyalkyl, phenylalkoxy, phenylalkoxyalkyl phenoxy, phenoxyalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl, perfluorothioalkoxy, perfluorothioalkoxyalkyl, sulfinyl, sulfinylalkylsulfonyl, sulfonylalkyl, thioalkoxy, and thioalkoxyalkyl; and
  • L is -O- or -S-, the process comprising: (a) activating the hydroxyl of the compound of formula (3)
  • step (b) reacting the product of step (a), a compound of formula (4)
  • step (c) optionally oxidizing the product of step (b);
  • step (d) optionally reacting the product of step (b) or step (c) and a compound of formula (6)
  • Q is selected from the group consisting of trialkylstannanes, boronic acid, boronic esters, magnesium halides, zinc halides, and silyl(alkyl)cyclobutanes, and a coupling catalyst.
  • the compound of formula (5-a) is (4R)-4-((4-bromophenoxy)methyl)- 1 ,3 -oxazolidin-2-one and the compound of formula (5-b) is
  • Another embodiment of the instant invention comprises a process for preparing a compound of formula (5-c)
  • step (b) optionally reacting the product from step (a) and an oxidant;
  • step (c) reacting the product of step (a) or step (b), hydrogen, and a hydrogenation catalyst to provide a compound of formula (9)
  • step (e) reacting the product from step (d) and a compound of formula H 2 OR , or a salt thereof, wherein
  • R is a hydroxyl protecting group, under dehydrating conditions to provide a compound of formula (11)
  • step (f) reacting the product of step (e) under Mitsunobu conditions to provide a compound of formula (12)
  • step (h) reacting the product from step (g) and azide under dehydrating conditions.
  • the compound of formula (5-c) is (5R)-l-(benzyloxy)-5-((4-bromophenoxy)methyl)-2-imidazolidinone.
  • Another embodiment of the instant invention comprises a process for preparing a compound of formula (15)
  • Another embodiment of the instant invention comprises a process for preparing of a compound of formula (20),
  • R and R together with the atoms to which they are attached, form a heterocycle selected from the group consisting of 5,5-dimethyl- l,3-oxazolidine-2,4-dionyl; l-methyl-2,4-imidazolidinedionyl; l,5,5-trimethyl-2,4-imidazolidinedionyl; 2,4-imidazolidinedionyl;
  • step (b) reacting the product of step (a) and a compound of formula (17) under Mitsunobu conditions
  • step (b) reacting the product of step (b) and an oxaziridine forming agent to provide a compound of formula (19)
  • step (d) reacting the product of step (c) and a compound of formula H 2 NOR , or a salt thereof, and base;
  • step (e) optionally deprotecting the product of step (d).
  • the compound of formula (20) is selected from the group consisting of 3-((2S)-2-(hydroxyamino)-3-((4'-(trifluoromethoxy)(l , 1 '-biphenyl)-4-yl)oxy)propyl)-5,5- dimethyl-2,4-imidazolidinedione and 3-((2S)-3-(4-bromophenoxy)-2-(hydroxyamino)propyl)-5,5-dimethyl-2,4-imidazolidinedione.
  • Another embodiment of the instant invention comprises a process for preparing of a compound of formula (20-b)
  • the compound of formula (20-b) is 3-((2S)-2-(hydroxyamino)-3-((4'-(trifluoromethoxy)(l 5 r-bi ⁇ henyl)-4-yl)oxy)propyl)-5 3 5- dimethyl-2,4-imidazolidinedione.
  • Another embodiment of the instant invention comprises a process for preparing of a compound of formula (20-c)
  • the compound of formula (20-c) is 3-((2R)-2-((benzyloxy)amino)-3-(4-bromophenoxy)propyl)-5,5-dimethyl-2,4- imidazolidinedione .
  • Another embodiment of the instant invention comprises a process for preparing a compound of formula (23)
  • step (b) optionally deprotecting the product of step (a).
  • the compound of formula (23) is selected from the group consisting of
  • Another embodiment of the instant invention comprises a process for preparing a compound of formula (23-b)
  • step (a) optionally deprotecting the product of step (a).
  • the compound of formula (23-b) is selected from the group consisting of
  • Another embodiment of the instant invention comprises a process for preparing a compound of formula (23-b)
  • step (b) reacting the product of step (a) with a reducing agent to provide a compound of formula
  • step (c) activating the hydroxyl of the product of step (b);
  • step (d) reacting the product of step (c) with base and a compound of formula (4)
  • step (e) optionally oxidizing the product of step (d);
  • step (f) reacting the product of step (d) or step (e), a coupling catalyst, and a compound of formula (6)
  • step (h) reacting the product of step (g) with a compound of formula R -CHO, to provide a compound of formula (16),
  • step (j) reacting the product of step (i) and an oxaziridine forming agent to provide a compound of formula (19)
  • Another embodiment of the instant invention comprises a process for the preparation of a compound of formula (23-b)
  • a base a reagent selected from the group consisting of phosgene, thiophosgene, triphosgene, carbonyldiimidazole, thiocarbonyldiimidazole, and a dialkyl carbonate, to provide a compound of formula (2);
  • step (b) reacting the product of step (a) with a reducing agent to provide a compound of formula
  • step (c) activating the hydroxyl of the product of step (b);
  • step (d) reacting the product of step (c) with base and a compound of formula (4)
  • step (e) optionally oxidizing the product of step (d);
  • step (f) reacting the product of step (e) with base to provide a compound of formula (15),
  • R 5 is Q 1 ;
  • step (g) reacting the product of step (f) with a compound of formula R -CHO to provide a compound of formula (16),
  • R 5 is Q 1 ;
  • step (h) reacting the product of step (g) with a compound of formula (17)
  • step (i) reacting the product of step (h) with an oxaziridine forming agent to provide a compound of formula (19)
  • R 5 is Q 1 ;
  • step (j) reacting the product of step (i) with H 2 NOR , or a salt thereof, and base to provide a compound of formula (20);
  • R 5 is Q 1 ; (k) reacting the product of step (j) with a coupling catalyst and a compound of formula (6)
  • Another embodiment of the instant invention comprises a process for the preparation of a compound of formula (23)
  • R I is hydrogen
  • step (b) optionally oxidizing the product from step (a);
  • step (c) hydrogenating the product of step (a) or step (b) to provide a compound of formula (9)
  • step (e) reacting the product from step (d) with H 2 NOR or a salt thereof, wherein R is a a hydroxyl protecting group, under dehydrating conditions to provide a compound of formula
  • R is a hydroxyl protecting group
  • step (h) activating the product from step (g) with azide to provide a compound of formula (5-c);
  • R is a hydroxyl protecting group
  • R ! is -OR 2 ;
  • R is a hydroxyl protecting group
  • L is -NH-
  • R is a hydroxyl protecting group
  • R is a hydroxyl protecting group
  • R is a hydroxyl protecting group
  • This invention relates to processes for the preparation of matrix metalloproteinase inhibitors and to intermediates which are ueful in these processes of preparation.
  • the following terms have the meanings specified.
  • alkoxy refers to an alkyl group connected to the parent group through an oxygen atom.
  • alkoxyalkyl refers to an alkyl group to which is attached at least one alkoxy group.
  • alkyl refers to a monovalent straight or branched chain saturated hydrocarbon having one to six carbons.
  • alkylsulfinyl refers to an alkyl group connected to the parent group through a sulfinyl group.
  • alkylsulfonyl refers to an alkyl group connected to the parent group through a sulfonyl group.
  • amino refers to -NH 2 or a derivative thereof formed by independent replacement of one or both hydrogens thereon by a substituent selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and an amino protecting group.
  • amino protecting group refers to selectively removable groups which protect amino groups against undesirable side reactions during synthetic procedures and includes all conventional amino protecting groups.
  • amino groups include optionally substituted acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl, ortho- bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, para- methoxybenzyloxycarbonyl, 3 ,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl,
  • aryl refers to a mono or bicyclic carbocyclic ring system having at least one aromatic ring.
  • Aryl groups are exemplified by phenyl, naphthyl, 1 ,2- dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, and indenyl.
  • aryl also includes compounds of formula wherein Y* is -C(O)- or -(CH 2 ) V -, wherein v is 1 or 2; and Z* is -CH 2 - or -O-.
  • the aryl groups of this invention can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, halo, and thioalkoxy.
  • arylalkyl refers to an alkyl group to which is attached at least one aryl group.
  • bases refers to a reagent capable of accepting protons during the course of a reaction.
  • bases include carbonates such as potassium carbonate, potassium bicarbonate sodium carbonate, sodium bicarbonate, and cesium carbonate; halides such as cesium fluoride; phosphates such as potassium phosphate, potassium dihydrogen phosphate, and potassium hydrogen phosphate; hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; trialkylamines such as triethylamine and diisopropylamine; heterocyclic amines such as imidazole, pyridine, pyridazine, pyrimidine, and pyrazine; bicyclic amines such as DBN and DBU; and hydrides such as lithium hydride, sodium hydride, and potassium hydride.
  • the base chosen for a particular conversion depends on the nature of the starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
  • carboxydehyde refers to -CHO.
  • carboxy refers to -CO 2 H.
  • carboxyl protecting group refers to selectively removable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures and includes all conventional carboxyl protecting groups.
  • carboxyl groups include optionally substituted alkyl groups such as methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, and tert-butyl; aryl groups such as phenyl, and naphthyl; optionally substituted arylalkyl groups such as benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, and bis(para-methoxyphenyl)methyl; optionally substituted acylalkyl groups such as acetylmethyl, benzoylmethyl, para- nitrobenzoylmethyl, para-bromobenzoylmethyl, and para-methanesulfonylbenzoylmethyl; optionally
  • Coupled catalyst refers to palladium complexes which enhance the rate of biaryl couplings.
  • catalysts include palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), Pd 2 Cl 2 (dba), and PdCk-C ⁇ C ⁇ .
  • Each of these catalysts can be used with an additive such as triphenylphosphine, triphenylarsine, or a trialkylphosphine such as tributylphosphine optionally present.
  • cyano refers to -CN.
  • cyanoalkyl refers to an alkyl group to which is attached at least one cyano group.
  • cycloalkyl refers to a saturated cyclic alkyl group having three to six carbons.
  • cycloalkylalkoxy refers to an alkoxy group to which is attached at least one cycloalkyl group.
  • cycloalkylalkyl refers to an alkyl group to which is attached at least one cycloalkyl group.
  • halo or halide, as used herein, refer to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl group to which is attached at least one halide.
  • heterocycle refers to five- or six-membered saturated or unsaturated rings having one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatoms can be optionally quaternized.
  • the heterocycles of the instant invention are attached through a carbon atom in the ring.
  • heterocycles include pyrrolidinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl morpholinyl, piperazinyl, thiomorpholinyl, pyridyl, pyrimidinyl, quinolyl, furyl, benzofuryl, thienyl, thiazolyl, pyrimidyl, indolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, 1,2,3-oxadiazolyl, thienyl, triazolyl, 1,3,4-thiadiazolyl, and tetrazolyl.
  • (heterocycle)oxy refers to a heterocycle attached to the parent group through an oxygen atom.
  • (heterocycle)oxyalkyl refers to an alkyl group to which is attached at least one (heterocycle)oxy group.
  • hydroxy refers to -OH.
  • hydroxy protecting group refers to selectively introducible and movable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures.
  • hydroxyl protecting groups include optionally substituted acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
  • hydroxyalkyl refers to an alkyl group to which is attached at least one hydroxy group.
  • Mitsunobu conditions refers to treatment of an alcohol with a diazo compound such as DIAD or DEAD and a triarylphosphine such as triphenylphosphine or a trialkylphosphine such as tributylphosphine.
  • salts refers to salts which are suitable for use in contact with tissue without undue toxicity, irritation, or allergic response and are commensurate with a reasonable benefit/risk ratio.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting a basic group with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, sulfate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, para-toluenesulfonate and undecanoate.
  • Basic nitrogen-containing groups can also be quatemized with alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and arylalkyl halides such as benzyl and phenethyl bromides.
  • alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl, and ste
  • acids employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfiiric, and phosphoric and organic acids as oxalic, maleic succinic, and citric.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxylic acid-containing group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • Pharmaceutically acceptable salts include cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts and nontoxic quaternary ammonia and amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, and ethylamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • prodrugs refers to prodrugs and zwitterionic forms of the compounds which are suitable for contact with tissue without undue toxicity, irritation, allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • phenoxy refers to a phenyl group connected to the parent group through an oxygen atom.
  • phenoxyalkyl refers to an alkyl group to which is attached at least one phenoxy group.
  • phenylalkoxy refers to to an alkoxy group to which is attached at least one phenyl group.
  • phenylalkoxy alkyl refers to an alkyl group to which is attached at least one phenylalkoxy group.
  • perfluoroalkoxy refers to a perfluoroalkyl group attached to the parent group through an oxygen atom.
  • perfluoroalkyl refers to an alkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
  • perfluoroalkoxy alkyl refers to an alkyl group to which is attached at least one perfluoroalkoxy group.
  • perfluorothioalkoxy refers to a perfluoroalkyl group attached to the parent group through a sulfur atom.
  • perfluorothioalkoxyalkyl refers to an alkyl group to which is attached at least one perfluorothioalkoxy group.
  • prodrug refers to compounds which are rapidly transformed in vivo to parent compounds such as, for example, by hydrolysis in blood.
  • reducing agent refers to reagents capable of converting protected carboxy lie acids to alcohols.
  • reducing agents include borane-dimethylsulfide, borane-tetrahydrofuran, and sodium borohydride.
  • sulfonyl refers to -SO 2 -.
  • thioalkoxy refers to an alkyl group attached to the parent ' molecular group through a sulfur atom.
  • thioalkoxyalkyl refers to an alkyl group to which is attached at least one thioalkoxy group.
  • the invention contemplates stereoisomers and mixtures thereof. Individual stereoisomers of compounds are prepared by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the processes described herein and resolved by techniques well-known in the art. Chiral purity (percent enantiomeric excess (ee)) was determined by chiral HPLC
  • Example IN The formylation process used in the synthesis of Example IN is that described in pending U. S. Application Ser. No. , filed on the same day herewith, incorporated herein by reference.
  • R , L , L , X, and Q are defined previously. It will be readily apparent to one skilled in the art that the selective protection and deprotection steps, as well as the order of the steps
  • compounds of formula (1) can be converted to compounds of formula (2) (X is O or S) by treatment of the former with an acylating agent and base.
  • Representative acylating agents include phosgene, triphosgene, carbonyldiimidazole, dialkyl carbonates (for X is O), thiophosgene and thiocarbonyldiimidazole (for X is S).
  • Representative bases include triethylamine, diisopropylethylamine, pyridine, and imidazole.
  • Solvents used in these reactions include dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and chloroform, although dialkyl carbonates can themselves be used as solvents.
  • the reaction temperature is about -10 °C to about 100 °C and depends on the method chosen. Reaction times are typically about 0.5 to about 24 hours.
  • compounds of formula (1) in dichloromethane at 0 °C are treated with triphosgene and triethylamine and stirred for 7 hours to provide compounds of formula (2).
  • Conversion of compounds of formula (2) to compounds of formula (3) can be accomplished by treatment of the former with a reducing agent such as sodium borohydride, lithium aluminum hydride, sodium triacetoxy-borohydride, and lithium tri-tert- butoxyaluminum hydride.
  • Solvents used in these reactions include ethanol, methanol, THF, and diethyl ether.
  • the reaction temperature is about -78 °C to about 35 °C and depends on the process chosen. Reaction times are typically 1 to 24 hours.
  • compounds of formula (2) in ethanol at 0 °C are treated with sodium borohydride and stirred for 5 hours. The reaction is quenched to a pH of between to provide compounds of formula (3).
  • compounds of formula (3) can be converted to compounds of formula (5-a) by activation of the hydroxyl group of the former followed by treatment with compounds of formula (4) and base.
  • Activation of the hydroxyl group can be accomplished by treatment with an acylating or sulfonating agent and base.
  • Representative acylating and sulfonating agents include para-toluenesulfonyl chloride, benzenesulfonyl chloride, trifluoroacetic anhydride, and methanesulfonyl chloride.
  • bases include pyridine, imidazole, diisopropylethylamine, and triethylamine.
  • Solvents used in these reactions include dichloromethane, chloroform, THF, and methyl tert-butyl ether.
  • the reaction temperature is about -10 °C to about 50 °C and depends on the process chosen. Reaction times are typically about 1 to about 24 hours. The products can then be treated with
  • 2 1 compounds of formula (4) (L is O or S; Q is halide, methanesulfonate, or para- toluenesulfonate) and base to provide compounds of formula (5-a).
  • Representative bases include potassium carbonate, sodium carbonate, lithium hexamethyldisilazide, and lithium diisopropylamide.
  • solvents used in these reactions include acetonitrile, water, THF, diethyl ether, and mixtures thereof.
  • the reaction temperature is about 25 °C to about 100 °C and depends on the process chosen. Reaction times are typically about 2 to about 36 hours.
  • compounds of formula (3) in pyridine at 5 °C are treated with para-toluenesulfonyl chloride, warmed to room temperature, and stirred for 16 hours.
  • the products in acetonitrile at 70 °C are treated with compounds of formula (4) and potassium carbonate to provide compounds of formula (5-a).
  • Conversion of compounds of formula (5-a) to compounds of formula (5-b) can be accomplished by treatment of the former with a compound of formula (6) (Y is nitrogen or 2 methine; Q is trialkylstannane, boronic acid, boronic ester, magnesium halide, zinc halide, or silyl(alkyl)cyclobutane) and a coupling catalyst.
  • Representative coupling catalysts include Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 23 Pd(dppf)Cl 2 , Ni(PPh 3 ) 4 , and Pd(OAc) 2 .
  • solvents used in these reactions include THF, water, acetonitrile, dichloromethane, DMF, DME, and mixtures thereof.
  • the reaction temperature is about 25 °C to about 120 °C and depends on the process chosen. Reaction times are typically about 0.5 to about 36 hours.
  • compounds of formula (5-a) in THF and water are treated with potassium phosphate and a compound of formula (6) (Y is CH; Q is boronic acid), heated to 65 °C, and stirred for 1 hour to provide compounds of formula (5-b).
  • compounds of formula (7) can be treated with compounds of formula (4) and base to provide compounds of formula (8).
  • Representative bases include sodium hydroxide, sodium carbonate, potassium carbonate, and lithium hexamethyldisilazide.
  • solvents used in these reactions include DMSO, water, acetonitrile, THF, and mixtures thereof.
  • the reaction temperature is about -10 °C to 50 °C and depends on the process chosen. Reaction times are typically 0.5 to 12 hours.
  • compounds of formula (7) (Q is Cl, R is alkyl) in DMSO and water at room temperature are treated with a compound of formula (4) (L is O and
  • Conversion of compounds of formula (8) to compounds of formula (9) can be accomplished by hydrogenation and (Ru 2 Cl 5 (R)BINAP 2 ) ⁇ t 2 NH 2 .
  • solvents used in this reaction include ethanol, methanol, propanol, and tert-butanol.
  • the reaction temperature is about 50 °C to 150 °C and depends on the process chosen. Reaction times are about 1-24 hours.
  • compounds of formula (8) in ethanol are treated with (Ru 2 Cl 5 (R)BINAP 2 ) " Et 2 NH 2 + and 2M HC1 and heated to 100 °C under hydrogen for 8 hours to provide compounds of formula (9).
  • Compounds of formula (9) (R is alkyl) can be converted to compounds of formula (10) (R is H) by treatment with aqueous base, followed by treatment with aqueous acid.
  • Representative bases include sodium hydroxide, potassiym hydroxide, and lithium hydroxide.
  • acids used in these reactions are hydrochloric acid, acetic acid, nitric acid, and sulfuric acid.
  • Solvents used in these reactions include isopropanol, isopropanol acetate, ethyl acetate, ethanol, methanol, and mixtures thereof.
  • the reaction temperature is about 0 °C to 25 °C and depends on the process chosen. Reaction times are typically 10 minutes to 24 hours.
  • compounds of formula (9) in ethanol at 5 °C are treated with aqueous potassium hydroxide over 10 minutes, warmed to room temperature, treated with water and isopropyl acetate, cooled to 5 °C, and treated with 6M hydrochloric acid to provide compounds of formula (10).
  • Conversion of compounds of formula (10) to compounds of formula (11) can be accomplished by coupling with an appropriately substituted hydroxylamine and a carbonyl activating group such as DCC, DIC, HOBT, EDCI, and PyBOP, and base.
  • Representative bases include NMM, diisopropylethylamine, and DBU.
  • solvents used in these reactions include dichloromethane, chloroform, DMF, THF, and NMP.
  • reaction temperature is about -10 °C to 60 °C and depends on the process chosen. Reaction times are typically 0.5-24 hours.
  • compounds of formula (10) in DMF at 5 °C are treated with EDCI, HOBT, NMM, and O-benzylhydroxylamine hydrochloride, warmed to room temperature, and stirred for 30 minutes to provide compounds of formula (11).
  • Compounds of formula (11) can be converted to compounds of formula (12) by treatment with a diazo compound and a triaryl- or trialkylphosphine.
  • Representative diazo compounds include DIAD and DEAD, while representative phosphines include triphenylphosphine and tributylphosphine.
  • Examples of solvents used in these reactions are THF, MTBE, diethyl ether, and DME.
  • the reaction temperature is about 20 °C to 70 °C and depends on the process chosen.
  • the reaction time is typically 0.5 to 3 hours.
  • compounds of formula (11) in THF at 40 °C are treated with DEAD and triphenylphosphine and stirred for 2 hours to provide compounds of formula (12).
  • Conversion of compounds of formula (12) to compounds of formula (13) can be accomplished by treatment with an aqueous hydroxide base.
  • Representative bases include sodium hydroxide, lithium hydroxide, and potassium hydroxide.
  • solvents used in these reactions include toluene, hexanes, benzene, THF, water, and mixtures thereof.
  • the reaction temperature is about 30 °C to 80 °C and depends on the process chosen. Reaction times are typically 1 to 24 hours.
  • compounds of formula (12) in toluene are treated with aqueous lithium hydroxide, heated to 60 °C for 3 hours, cooled to room temperature, and stirred for 16 hours to provide compounds of formula (13).
  • Compounds of formula (13) can be converted to compounds of formula (14) by treatment with diphenylphosphoryl azide and base.
  • Representative bases include diisopropylethyl amine, triethylamine, and pyridine.
  • solvents used in these reactions include THF, diethyl ether, MTBE, and dioxane.
  • the reaction temperature is about 25 °C to 100 °C and depends on the process chosen. Reaction times are typically 1 to 24 hours.
  • compounds of formula (13) in THF are treated with diphenylphosphoryl azide and diisopropylethyl amine, heated to reflux, and stirred for 3 hours to provide compounds of formula (14), which cyclize under the reaction conditions to provide compounds of formula (5-c).
  • compounds of formula (5) can be converted to compounds of formula (15) by treatment with base.
  • Representative bases include potassium hydroxide, sodium hydroxide, and lithium hydroxide.
  • solvents used in these reactions include water, THF, acetonitrile, and mixtures thereof.
  • the reaction temperature is about 30 °C to 120 °C and depends on the process chosen. Reaction times are typically 1 to 24 hours.
  • compounds of formula (5) in water are treated with potassium hydroxide, heated to reflux, and stirred for 9 hours to provide compounds of formula (15).
  • compounds of formula (15-a) can be converted to compounds of formula (16) by treatment with an appropriately substituted aldehyde (R CHO).
  • R CHO aldehyde
  • solvents used in this reaction include toluene, hexanes, heptane, and benzene.
  • the reaction temperature is about 30 °C to 120 °C and depends on the process chosen. Reaction times are about 1 to 36 hours.
  • compounds of formula (15-a) in toluene are treated with an aldehyde (R CHO) and heated to 80 °C for 2 hours to provide compounds of formula (16).
  • Conversion of compounds of formula (16) to compounds of formula (18) can be accomplished by treatment with compounds of formula (17) and a diazo compound and a triaryl- or trialkylphosphine.
  • Representative diazo compounds include DIAD and DEAD, while representative phosphines include triphenylphosphine and tributylphosphine.
  • reaction temperature is about -10 °C to 35 °C and depends on the process chosen. Reaction times are typically 0.5 to 12 hours.
  • compounds of formula (16) in THF at 1 °C are treated with compounds of formula (17), DIAD, and triphenylphosphine over 1.25 hours to provide compounds of formula (18).
  • Compounds of formula (18) can be converted to compounds of formula (19) by treatment with an oxidizing agent.
  • oxidizing agents include m-CPB A, trifluoroperacetic acid, and 2,5-dinitroperoxybenzoic acid.
  • solvents used in these reactions include MTBE, THF, and diethyl ether. The reaction temperature is about -78
  • reaction times are typically 0.5 to 4 hours.
  • Conversion of compounds of formula (19) to compounds of formula (20) can be accomplished by treatment with N-hydroxylamine followed by treatment with aqueous base.
  • Representative bases include sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • solvents used in this reaction include water, THF, dioxane, and mixtures thereof.
  • the reaction temperature is about -10 °C to 35 °C and depends on the process chosen.
  • Reaction times are typically 0.5 to 48 hours.
  • compounds of formula (19) in THF at 1 °C are treated with N-hydroxylamine hydrochloride in water over 1 hour, warmed to room temperature, and stirred for 18 hours to provide compounds of formula
  • compounds of formula (15-b) can be converted to compounds of formula (22) by treatment with compounds of formula (21).
  • solvents used in this reaction include THF, diethyl ether, MTBE, and dioxane.
  • the reaction temperature is about 20 °C to 40 °C and depends on the process chosen. Reaction times are typically 0.5 to 12 hours.
  • compounds of formula (15-b) in THF at room temperature are treated with compounds of formula (21) and stirred for 0.5 hours to provide compounds of formula (22) .
  • Coversion of compounds of formula (22) to compounds of formula (20-c) can be accomplished by treatment with acid.
  • Representative acids include hydrochloric acid, sulfuric acid, and nitric acid.
  • solvents used in these reactions include water, THF, dioxane, and mixtures thereof. Reaction times are about 1 to 24 hours.
  • compounds of formula (22) in THF are treated with 6M HCl, heated to reflux, and stirred for 6 hours to provide compounds of formula (20-c).
  • compounds of formula (20) can be converted to compounds of formula (23) by treatment with a formylating agent.
  • Representative formylating agents include acetic anhydride/formic acid and 2,2,2-trifluoroethyl formate.
  • solvents used in these reactions include formic acid, THF, MTBE, and mixtures thereof.
  • the reaction temperature is about 25 °C to 65 °C and depends on the process chosen. Reaction times are typically 15 minutes to 6 hours.
  • Example 1A methyl (4S)-2-oxo-l ,3-oxazolidine-4-carboxylate
  • a solution of L-serine methyl ester hydrochloride (3.063 kg) in dichloromethane (24.1 L) at 0 °C was treated with triethylamine (5.908 kg), stirred for 30 minutes, treated with triphosgene (1.949 kg) in dichloromethane (5.356 kg) over 6.5 hours, stirred for 45 minutes, treated with hexanes (12.23 kg), stirred for 55 minutes, and filtered with ethyl acetate (16.013 kg).
  • Example IB (4R)-4-(hydroxymethyl)- 1 ,3-oxazolidin-2-one
  • the solution of Example 1 A was concentrated to remove the bulk of the ethyl acetate, treated with ethanol (6.79 kg), concentrated to approximately one half of its original volume, treated again with ethanol (53.36 kg), cooled to 0° C, treated with sodium borohydride (855 g) over 3 hours and 42 minutes, stirred for 60 minutes, treated with phosphoric acid (2.20 kg) over 51 minutes, and warmed to room temperature over 18 hours to provide a reaction mixture with a pH of 5.55. The reaction mixture was filtered with ethanol (27.4 kg).
  • Example IB ((4S)-2-oxo- 1 ,3 -oxazolidin-4-yl)methyl 4-methylbenzenesulfonate
  • pyridine (12.82 kg) at 5 °C
  • para-toluenesulfonyl chloride 6.02 kg
  • water 55.0 kg
  • warmed to room temperature stirred for 17 hours
  • filtered with water 28.2 kg.
  • the filtrate was suction dried then vacuum dried (100 rnmHg) at 50 °C with a nitrogen bleed to provide 6.895 kg (84.6%, >99% ee) of the desired product.
  • Example IC (4.154 kg), potassium carbonate (2.522 kg), and 4-bromophenol (3.183 kg) in acetonitrile (30.3 kg) was stirred at 70 °C for 23.5 hours, cooled to 55 °C, treated with 2% (w/w) K 2 CO 3 (41.52 kg) over 20 minutes, cooled to room temperature, and separated into an aqueous fraction and an organic fraction.
  • the organic fraction was concentrated to approximately one third of its original volume, treated with the aqueous fraction to provide a precipitate, concentrated to remove the remainder of the acetonitrile, treated with the 2% (w/w) K 2 CO 3 solution (41.52 kg), stirred at room temperature for 18 hours, and filtered.
  • the filter cake was rinsed with 2% K 2 CO 3 (16.62 L) air-dried, slurried in ethyl acetate (9.44 kg), and heated at 55 °C. This solution was treated with hexanes (23.615 kg) and cooled to room temperature to provide a solid.
  • Example IE 4-(trifluoromethoxy)phenylboronic acid
  • a solution of l-bromo-4-(trifluoromethoxy)benzene (1.69 kg) and triisopropyl borate (1.46 kg) in THF (6.75 L) at -70 °C was treated with 2.25 M butyllithium in hexanes (3.27 L) over 2.3 hours, stirred for 10 minutes, treated with 6M HCl (1.52 L) over 50 minutes, stirred for 18 hours at room temperature, and poured into a mixture of heptane (8.43 L) and 20 % (w/w) sodium chloride (8.44 kg). This mixture was stirred for 10 minutes and separated into an aqueous fraction and an organic fraction. The organic fraction was concentrated to provide a white paste. The paste was dried under vacuum (100 rnmHg) at ambient temperature with a nitrogen bleed for 2 days then at
  • a room temperature solution of potassium phosphate (9.22 kg, 43.4 mol) in water (25 L) was treated sequentially with Example ID (3.94 kg), a solution of Example IE (3.15 kg) in THF (19.6 L), and THF (5.1 L), sparged with nitrogen for 20 minutes, treated with
  • the mixture was filtered through a pad of silica gel 60 (10.3 kg slurried with THF) and the pad was thoroughly rinsed with THF.
  • the combined filtrates were concentrated to a volume of approximately 11 L, treated with heptanes (59.7 L), stirred for 1 hour and filtered.
  • the solid was washed with heptanes (2 x 14.6 L) and dried at 45 °C under vacuum for 18 hours to provide 4.93 kg (97 %, >99% ee) of the desired product.
  • Example 1G (2S)-2-amino-3 -((4'-(trifluoromethoxy)( 1 , 1 '-biphenyl)-4-yl)oxy)- 1 -propanol
  • KOH 2.502 kg
  • Example IF stirred at 80 °C for 7 hours, treated with water (37.059 kg) over 25 minutes, and cooled to room temperature over 18 hours to provide a solid.
  • Example 1G A solution of Example 1G (3.236 kg) and para-anisaldehyde (1.484 kg) in toluene (6.631 kg) was heated at 80 °C for 2 hours, treated with heptane (33.147 kg) over 50 minutes, cooled to room temperature over 20 hours, and filtered. The filter cake was rinsed with heptane (6.994 kg), air dried, then vacuum dried (100 rnmHg) at 50 °C to provide 4.297 kg (97.6%) of the desired product.
  • Example 1J 3 ((2S)-2-(3 -(4-methoxy ⁇ henyl)- 1 ,2-oxaziridin-2-yl)-3 -((4'-(trifluoromethoxy)(l , 1 '- biphenyl)-4-yl)oxy)propyl)-5,5-dimethyl-2,4-imidazolidinedione
  • the solution of Step II was cooled to -67 °C, treated with a solution of 3-chloroperoxybenzoic acid (3.15 kg) in THF (6.30 kg) over 30 minutes, and warmed to 0-2 °C over 100 minutes to provide a solution of the desired product.
  • Example IK 3-((2S)-2-(hydroxyamino)-3-((4'-(trifluoromethoxy)(l,r-biphenyl)-4-yl)oxy)propyl)-5,5- dimethyl-2,4-imidazolidinedione, para toluene sulfononic acid salt
  • the solution of Example 1 J was diluted with toluene (27.34 kg) and washed sequentially with 10% (w/w) sodium thiosulfate (31 kg), 5% (w/w) sodium bicarbonate (31 kg), and 10% (w/w) sodium chloride (30 kg).
  • the mixture was treated with para- , toluenesulfonic acid hydrate (1.79 kg), stirred at ambient temperature several hours, treated with a solution of N-hydroxylamine hydrochloride (0.88 kg) in water (2.8 kg), and stirred at ambient temperature several hours.
  • the reaction mixture was washed with 10% (w/w) sodium carbonate (31 kg) and 5% (w/w) sodium bicarbonate (30 kg), diluted with ethyl acetate (9.47 kg), washed with 10% (w/w) sodium chloride (30 kg), concentrated, and diluted to a concentration of 30 mg/mL in toluene.
  • the solution was treated with para- toluenesulfonic acid hydrate (19.5 g), stirred for 2 hours, filtered through a pad of diatomaceous earth (Celite 521), treated with para-toluenesulfonic acid hydrate (1.05 kg), and warmed to 50 °C to provide a white suspension which thickened after 30 minutes. After six hours the heating was discontinued, the suspension was cooled to ambient temperature, stirred for 18 hours, and filtered. The filter cake was rinsed with toluene (29 kg), suction dried, then vacuum dried (100 mm Hg) at 40-45 °C with a nitrogen bleed to provide 3.422 kg (83% potency adjusted yield) of the desired product.
  • Example IL 2,2,2-trifluoroethyl formate A solution of 2,2,2-trifluoroethanol (18.212 kg) and formic acid (36.324 kg) was stirred at 80 °C for 6 hours, cooled to room temperature, and sirred for 18 hours to provide a mixture of product and unreacted starting materials. The mixture was distilled (head temperature 60-80 °C) over 23 hours to provide a distillate (14.79 kg) comprising 10.64 kg (71.9% (w/w) solution, 45.5%) of the desired product in addition to unreacted starting materials.
  • Example 1M 4-yl)oxy)methyl)ethyl(hydroxy)formamide
  • the filter cake was rinsed with 1:2 (v/v) ethyl acatate/heptane (5.63 kg), suction dried, then vacuum dried (100 mmHg) at 100 °C with a nitrogen bleed to provide 2.685 kg (91.8%, ⁇ 99% ee) of the desired product.
  • Example 2A (2S)-2-amino-3-(4-bromophenoxy)- 1 -propanol
  • the desired product (160 g) was prepared by substituting Example ID (177 g) for Example IF in Example 1G. !
  • Example 2C 3-((2S)-3-(4-bromophenoxy)-2-(((E)-(4-methoxyphenyl)methylidene)amino)propyl)-5,5- dimethyl-2,4-imidazolidinedione
  • the desired product was prepared without isolation by substituting Example 2B (208 g) for Example IH in Example II.
  • Example 2D 3-((2S)-3-(4-bromophenoxy)-2-(3-(4-methoxyphenyl)-l,2-oxaziridin-2-yl)propyl)-5,5- dimethy 1-2 ,4-imidazolidinedione
  • Example 2C The desired product was prepared without isolation by substituting the in situ derived Example 2C for Example II in Example 1 J.
  • Example 2E 3-((2S)-3-(4-bromophenoxy)-2-(hydroxyamino)propyl)-5,5-dimethyl-2,4-imidazolidinedione
  • the desired product (113 g) was prepared by substituting in situ prepared Example 2D for Example 1 J in Example IK.
  • 1H NMR 300 MHz, DMSO-d 6 ) ⁇ 8.22 (br s, IH), 7.35 (m, 2H), 7.22 (br s, IH), 6.80 (m, 2H), 5.74 (br s, IH), 3.85 (m, 2H), 3.47 (m, 2H), 3.25 (m, IH), 1.19 (s, 3H), 1.17 (s, 3H).
  • Example 1M 3 ((2S)-2-(hydroxyamino)-3 -((4'-(trifluoromethoxy)( 1 , 1 '-biphenyl)-4-yl)oxy)propyl)-5 ,5- dimethy 1-2 ,4-imidazolidinedione
  • the desired product (94 g) was prepared by substituting Example 2E (108 g) for Example ID in Example IF.
  • Example 3A ethyl 4-(4-bromophenoxy)-3-oxobutanoate A solution of 50% (w/w) NaOH in water (188 mL) in DMSO (800 mL) was stirred at room temperature until a precipitate formed, treated dropwise with a solution of 4-bromophenol (101.2 g) in DMSO (200 mL) over 25 minutes, stirred for 25 minutes, treated with ethyl 4-chloro-3-oxobutanoate (102.2 g) over 40 minutes, adjusted to pH 3 with 6M HCl, treated with water (200 mL) over 12 minutes, stirred for 5 hours, treated with water (150 mL) over 20 minutes, and filtered.
  • 4-bromophenol 101.2 g
  • DMSO 200 mL
  • ethyl 4-chloro-3-oxobutanoate 102.2 g
  • Example 3B ethyl 4-(4-bromophenoxy)-3-hydroxybutanoate
  • a solution of Example 3A (99.5 g) in ethanol (480 mL) was deoxygenated with nitrogen, treated with ( u 2 Cl 5 (R)-B ⁇ NAP 2 ) " Et 2 NH 2 + (825 mg) and 2M HCl (0.5 mL), flushed with nitrogen, heated to 100 °C with shaking under 50 psi of hydrogen for 8 hours, cooled, treated with hexanes (30 mL), and filtered to provide a solution of the desired product.
  • Example 3C (3 S)-4-(4-bromophenoxy)-3 -hydroxybutanoic acid
  • the solution of Example 3B (154.2 g) was cooled to 5 °C treated with 44% (w/w) KOH over 10 minutes, warmed to room temperature, treated with water (150 mL), concentrated, treated with isopropyl acetate (500 mL) and water (200 mL), cooled to 5 °C, adjusted to pH 2 with 6M HCl, and treated with additional isopropyl acetate (500 mL). The aqueous phase was extracted with isopropyl acetate (100 mL).
  • the extract was washed with brine, dried (Na 2 SO ), filtered, concentrated to a volume of 310 mL, and treated with isopropyl acetate (70 mL) and heptane (1.2 L) dropwise over 4 hours to provide a precipitate.
  • the precipitate was collected by filtration, washed with 20% isopropyl acetate in heptane (700 mL), and dried under vacuum (100 mm Hg) at 50 °C with a nitrogen bleed to provide 121.3 g of the desired product.
  • Example 3E (3R)-3-((benzyloxy)amino)-4-(4-bromophenoxy)butanoic acid lithium salt
  • a solution of triphenylphosphine (121 g) in THF (1.9 L) was treated with DEAD (80. Ig) over 30 minutes, treated with a solution of Example 3D in DMF (600 mL) at 40 °C by cannula over 90 minutes and a solution of triphenylphosphine (6.2 g) and DEAD (3.8 mL) in THF (20 mL), concentrated, treated with toluene (350 mL), and concentrated.
  • This solution was treated with a solution of LiOH (27.3 g) in water (240 mL), heated to 60 °C for 3 hours, cooled to room temperature, stirred for 16 hours, treated with a solution of lithium hydroxide (12.3 g) in water (120 mL), heated to 65 °C for 16 hours, cooled to room temperature, stirred for 2 hours, and filtered.
  • the precipitate was washed with toluene (200 mL), and the filtrate was concentrated to half the original volume, treated with a small amount of the collected solid, and stirred at room temperature for 16 hours.
  • the resulting precipitate was collected by filtration, and the combined solids were treated with toluene (920 mL), heated to 95 °C, cooled to room temperature, and stirred for 16 hours. The resulting precipitate was collected by filtration, then dried under vacuum (100 mm Hg) at 50 °C with a nitrogen bleed to provide 87.1 g of the desired product.
  • Example 3E A suspension of Example 3E in THF (2.1 L) was treated with DPPA (90.5 g) and diisopropylethyl amine (56 mL), heated to reflux, stirred for 3 hours, cooled to 30 °C, poured into ice cold 10% HCl, and stirred vigorously. The organic phase was treated with 10% HCl (500 mL) and NaCl (75 g). The aqueous phase was separated and washed with ethyl acetate. The extract was washed sequentially with water, saturated NaHCO 3 , and brine and concentrated.
  • DPPA diisopropylethyl amine
  • the concentrate was treated with toluene (550 mL), warmed to reflux, cooled to 35 °C, treated with heptane (800 mL) over 2 hours, and filtered.
  • the solid was dissolved in 1 :1 THF/toluene (700 mL), and the resulting solution was washed with saturated NaHCO 3 and brine, and concentrated.
  • the solid was dried under vacuum (100 mm Hg) at 50 °C with a nitrogen bleed to provide 54.6 g of the desired product.
  • Example 3G (19.7 g) in THF (100 mL) at room temperature was treated with the solution of the methyl 2-isocyanato-2-methylpropanoate in THF, stirred for 25 minutes, and concentrated to a volume of 170 mL.
  • the concentrate was treated with THF (80 mL) and 6M HCl (95 mL), heated to reflux, stirred for 6 hours, cooled to room temperature, concentrated, and extracted with isopropyl acetate.
  • Example 31 benzyloxy((lR)-2-(4-bromophenoxy)-l-((4,4-dimethyl-2,5-dioxo-l- imidazolidinyl)methyl)ethyl)formamide
  • a solution of Example 3H (57.7 g) in formic acid (200 mL) was treated with a mixture of acetic anhydride (35 mL) in formic acid (35 mL) over 10 minutes, stirred for 10 minutes, and concentrated.
  • the concentrate was dissolved in ethyl acetate (500 mL), washed sequentially with 1 :1 /water. -brine, saturated NaHCO , and brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate was dissolved in warm (60 °C) toluene, cooled, and filtered.
  • the solid was washed with l:l/toluene:heptane then dried under vacuum (100 mm Hg) at 50 °C with a nitrogen bleed to provide 51.7 g of the desired product.
  • Example 3J 4-(((2R)-2-((benzyloxy)(formyl)amino)-3-(4,4-dimethyl-2,5-dioxo-l- imidazolidinyl)propyl)oxy)-4'-(frifluoromethoxy)- 1 , 1 '-biphenyl
  • THF 100 mL
  • l-bromo-4-(trifluoromethoxy)benzene 30.8 g
  • heated to reflux stirred for 16 hours
  • treated with triisopropyl borate (34 mL) over 10 minutes stirred for 1 hour, cooled to 0 °C, treated with 6M HCl (50 mL), stirred for 45 minutes, and extracted with isopropyl acetate.
  • Example 3J 4-yl)oxy)methyl)ethyl(hydroxy)formamide
  • ethyl acetate 450 mL
  • 10% Pd/C 10 g
  • filtered a 0.45 ⁇ m nylon millipore filter
  • the filtrate was cooled to room temperature, treated with heptane (100 mL) over 45 minutes, stirred for 72 hours, and filtered.
  • the solid was washed with heptane and dried under vacuum (100 mm Hg) at 50 °C with a nitrogen bleed to provide 39.7 g of the desired product.

Abstract

La présente invention porte sur un procédé de synthèse d'inhibiteurs de métalloprotéinases matricielles.
PCT/US2001/010276 2000-03-31 2001-03-30 Procede de preparation d'inhibiteurs de metalloproteinases matricielles WO2001074792A2 (fr)

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FR2545488A1 (fr) * 1983-05-02 1984-11-09 Delalande Sa Nouveaux carbamates cycliques a chaine laterale du type arylmethyle ou aryloxymethyle, leurs procedes de preparation et leur application en therapeutique
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2847473A1 (fr) * 2002-11-25 2004-05-28 Expanscience Lab Composition comprenant au moins une oxazolidinone, son utilisation cosmetique et comme medicament

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