WO2002060888A1 - Procedes de preparation d'acides chromanylbenzoiques - Google Patents

Procedes de preparation d'acides chromanylbenzoiques Download PDF

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WO2002060888A1
WO2002060888A1 PCT/IB2002/000041 IB0200041W WO02060888A1 WO 2002060888 A1 WO2002060888 A1 WO 2002060888A1 IB 0200041 W IB0200041 W IB 0200041W WO 02060888 A1 WO02060888 A1 WO 02060888A1
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compound
formula
alkyl
groups
substituted
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PCT/IB2002/000041
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English (en)
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Keith Michael Devries
Geraldine Patricia Taber
Ronald James Post
Stéphane Caron
John Lloyd Tucker
Peter Robert Rose
Brian Kenneth Raymer
Philip Dietrich Hammen
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Pfizer Products Inc.
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Priority to CA002433516A priority Critical patent/CA2433516A1/fr
Priority to JP2002561038A priority patent/JP2004518685A/ja
Priority to MXPA03006876A priority patent/MXPA03006876A/es
Priority to BR0206771-4A priority patent/BR0206771A/pt
Publication of WO2002060888A1 publication Critical patent/WO2002060888A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4

Definitions

  • This invention relates to methods for preparing substituted chromanol derivatives.
  • the substituted chromanol derivatives prepared using the methods of the present invention are disclosed in United States patent application Serial No. 09/511,475, filed Feb. 23, 2000, U.S. Patent Nos. 5,552,435 and 6,096,906, and PCT international application publication nos. WO 96/11925 (published April 25, 1996), WO 96/11920 (published April 25, 1996), and WO 93/15066 (published August 5, 1993).
  • WO 96/11925 published April 25, 1996)
  • WO 96/11920 published April 25, 1996)
  • WO 93/15066 published August 5, 1993.
  • the substituted chromanol derivatives prepared using the methods of the present invention are effective in inhibiting the action of TB , as disclosed in United States Patent No. 5,552,435.
  • the substituted chromanol are therefore useful in the treatment of LTB 4 -induced illnesses such as inflammatory disorders including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, eczema, erythma, pruritis, acne, stroke, graft rejection, autoimmune diseases, and asthma.
  • the present invention provides several enhancements over the prior art methods of preparing substituted chromanol derivatives.
  • 7- halochromanol intermediates to the substituted chromanol derivatives are prepared by initial formation of an acylated chiral auxiliary which then undergoes asymmetric aldol condensation with an aromatic aldehyde, followed by reductive cleavage of the chiral auxiliary and subsequent intramolecular cyclization.
  • the prior method set forth in Serial No. 09/511,475 uses pyrophoric, air sensitive organolithium reagents such as n-butyllithium, which requires the use of cryogenic conditions.
  • the present invention instead uses more convenient and economical reagents such as DMAP and triethylamine. Rather than a reductive cleavage of the chiral auxiliary, the present invention uses a hydrolysis to cleave the chiral auxiliary, providing a significantly higher recovery of the auxiliary and permitting much simpler isolation by crystallization. In addition, the present invention provides higher yields of the pre-cyclization intermediate using reagents that are more readily available on a commercial scale (i.e., sodium borohydride and boron trifluoride diethyl ether complex) than those required by the prior art process (lithium borohydride).
  • reagents that are more readily available on a commercial scale (i.e., sodium borohydride and boron trifluoride diethyl ether complex) than those required by the prior art process (lithium borohydride).
  • the present invention offers significant practical advantages in the formation of the 7-arylcf ⁇ romanol used as a precursor to the substituted chromanol.
  • use of an isopropyl benzoic ester rather than a neopentyl ester to prepare a benzene boronic acid intermediate required for Suzuki cross-coupling with the 7- halochromanol was unexpectedly found to suppress the undesired formation of diisopropylamide and benzophenone (arising from condensation with a molecule of starting ester) side products observed in the method disclosed in Serial No. 09/511,475.
  • the present invention has the added advantage of cleaner formation of the benzene boronic acid intermediate and more facile product isolation by crystallization.
  • the cross- coupling step of the present approach is additionally enhanced over the prior art by use of a more stable palladium phosphine catalyst and a new solvent combination which allows for preparation of substituted chromanols on a significantly larger scale.
  • the present invention further provides improvements in methods disclosed in Serial No.
  • 09/511 ,475 for forming the 7-substituted chromanol penultimate intermediate by coupling a substituted benzene boronic acid and a substituted 7-halochromanol, rather than a substituted halobenzene and a substituted chromanol 7-boronic acid.
  • the isopropyl ester has the added advantage of higher stability for the final ester hydrolysis step, thereby minimizing undesired premature hydrolysis.
  • R 1 is -(CH 2 ) q CHR 5 R 6 wherein q is 0 to 4; each R 2 and R 3 is independently selected from the group consisting of H, fluoro, chloro, Ci-C 6 alkyl, C C 6 alkoxy, phenylsulfinyl, phenylsulfonyl, and -S(0) n (C ⁇ -C 6 alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxy and
  • R 5 is H, C C 6 alkyl, or phenyl optionally substituted by the groups set forth in the definition of R 2 ;
  • R is H, C C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, wherein said aryl and heteroaryl groups are optionally substituted by 1 or 2 substituents independently selected from phenyl, the groups set forth in the definition of R 2 , and phenyl substituted by 1 or 2 groups set forth in the definition of R 2 ; which comprises treating a compound of the formula
  • the compound of formula IX is preferably treated with an aqueous hydroxide base
  • R 1 is preferably benzyl, 4-fluorobenzyl, 4-phenylbenzyl, 4-(4-fluorophenyl)benzyl, or phenethyl
  • R 2 is preferably hydrogen or fluoro
  • R 3 is preferably fluoro, chloro, or methyl optionally substituted by 1 to 3 fluorines.
  • said compound of formula IX is treated with a base comprising aqueous lithium hydroxide, said compound of formula IX is (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4- trifluoromethyl-benzoic acid isopropyl ester, wherein the compound of formula X is (3S,4R)-2- (3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid.
  • said compound of formula IX, or the enantiomer of said compound, wherein R 1 , R 2 , and R 3 are as defined above is prepared by treating a compound of the formula
  • R 3 is as defined above, in the presence of a base or fluoride salt and a palladium catalyst.
  • preferred substituents for R 1 , R 2 , and R 3 are as stated above for said process of making the compound of formula X.
  • X is halo in formula
  • the base or fluoride salt is selected from sodium carbonate, triethylamine, sodium bicarbonate, cesium carbonate, tripotassium phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, barium hydroxide, and tetrabutylammonium fluoride
  • the palladium catalyst is selected from tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenyI- phosphine)palladium(ll), pal-ladium(ll) acetate, allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0), and 10% palladium on carbon.
  • the base or fluoride salt is potassium fluoride
  • the palladium catalyst is 10% palladium on carbon
  • the compound of formula VII is (3S,4R)-(7-bromo-3-benzyl-4-hydroxy-chroman)
  • the compound of formula VIII is isopropyl 4-trifluoromethyl-benzoate 2-boronic acid.
  • the compound of formula VIM is prepared by hydrolyzing a compound of the formula
  • R 3 is as defined above, the dashed line indicates an intramolecular complex between the B and N atoms, n and m are independently 2 to 5, and R 8 is H or C C 6 alkyl.
  • R 8 is preferably H and preferred substituents for R 3 are as stated above for said process of making a compound of formula VIII.
  • said hydrolysis is effected with an aqueous acid, such as hydrochloric acid, and n and m are each 2.
  • said compound of formula XI is 2-[1 ,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid isopropyl ester.
  • C C 8 alkyl encompasses both linear and branched chain alkyl groups, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopentyl, and cyclohexyl.
  • the alkyl group may be unsubstituted or substituted with one or more hydroxyl, halo, cyano, carboxyl, alkylacyl, arylacyl, alkoxycarbonyl, or alkylsulfoxide moieties.
  • CrC 8 alkoxy encompasses ethereal moieties containing any of the C C 8 alkyl groups, both substituted and unsubstituted.
  • aryl encompasses, but not limited to, phenyl, biphenyl, naphthyl, pyridyl, indolyl, pyrazinyl, pyrimidinyl, furanyl, benzofuranyl, benzopyridyl, and thiofuranyl, and may be unsubstituted or substituted with one or more C C 8 alkyl, hydroxyl, halo, cyano, carboxyl, alkylacyl, arylacyl, alkoxycarbonyl, or alkylsulfoxide moieties.
  • aryloxy encompasses ethereal moieties containing any of the aryl groups noted, both unsubstituted and substituted.
  • aryl(C C 8 )alkyl and aryl(C C 8 )alkoxy encompass moieties containing any of the C C 8 alkyl groups, both substituted and unsubstituted and any of the aryl groups noted, both unsubstituted and substituted.
  • aryl(C C 8 )alkyl examples include benzyl, tolylmethyl, xylylmethyl, fluorophenyimethyl, (4-ethylphenyl)methyl, 2-(2-pyridyl)ethyl, 3-(4-hydroxyphenyl)cyclohexyl, and the like.
  • groups termed aryl(C ⁇ -C 8 )alkoxy encompass, but are .not limited to, benzyloxy, (3-tolyl)methyoxy, p-xylylmethoxy, 2-phenylethoxy, 3-phenylbutoxy, pyridylmethoxy, 3-phenyltetrahydrofuranyl, and the like.
  • the compound of formula VII, or the enantiomer of said compound, wherein R 1 and R 2 are as defined above, is prepared by treating the diol having formula VI:
  • the base is potassium tert-butoxide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, cesium carbonate, or sodium hydride.
  • the base is potassium tert-butoxide and the compound of formula VI is (1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane- 1 ,3-diol.
  • the compound of formula VI, or the enantiomer of said compound, wherein R 1 and R 2 are as defined above is prepared by treating a compound of the formula:
  • R 1 , R 2 , and X are as defined above, and R 7 and R 8 are independently hydrogen, C ⁇ -C 6 alkyl, benzyl, phenyl substituted by R 2 , C 3 -C 8 cycloalkyl, or C 6 -C 10 aryl, with a hydride reducing agent.
  • the reducing agent is sodium borohydride in the presence of boron trifluoride diethyl ether complex or boron trifluoride tetrahydrofuran complex, borane tetrahydrofuran complex, or borane dimethyl sulfide complex.
  • the compound of formula V is (2R,3R)-benzylammonium-2- benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionic acid, and the reducing agent is sodium borohydride in the presence of boron trifluoride tetrahydrofuran complex.
  • the compound of formula V, or the enantiomer of said compound, wherein R 1 and R 2 are as defined above is prepared by treating a compound of the formula
  • R 1 , R 2 , and X are as defined above, and R 4 is C C 8 alkyl, aryl or aryl(C 1 -C 8 )alkyl with a base in the presence of a peroxide, then with a reducing agent, and finally with an amine of the formula NHR 7 R 8 , where R 7 and R 8 are independently hydrogen, C C 6 alkyl, benzyl, phenyl substituted by R 2 , C 3 -C 8 cycloalkyl, or C 6 - C 10 aryl,.
  • R 1 , R 2 , and X are as stated above for said process of making the compound of formula VI, and R 4 is benzyl.
  • the base is lithium hydroxide and the peroxide is aqueous hydrogen peroxide, or the base in the presence of a peroxide may be lithium hydroperoxide;
  • the reducing agent is sodium sulfite or sodium thiosulfate, and the amine is benzylamine, dicyclohexylamine or 2- methylbenzylamine.
  • the compound of formula IV is [4R-[3(2R,3R)]]-4-benzyl- 3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one
  • the base is lithium hydroxide
  • the peroxide is aqueous hydrogen peroxide
  • the reducing agent is sodium sulfite
  • the amine is benzylamine.
  • the compound of formula V, or the enantiomer of said compound, wherein R 1 , R 2 and X are as defined above, and at least one of R 7 and R 8 is a chiral moiety is prepared by treating a compound of the formula
  • R 1 , R 2 and X are as defined above, with a chiral amine of the formula NHR 7 R 8 , where R 7 and R 8 are independently hydrogen, CrC 6 alkyl, benzyl, phenyl substituted by R 2 , C 3 -C 8 cycloalkyl, or C 6 -C 10 aryl, and at least one of R 7 and R 8 is a chiral moiety.
  • the compound of formula V is (2R,3R)-[R- ⁇ -methylbenzylammonium]-2-benzyl-3-(4-bror ⁇ o-2-fluoro-phenyl)-3- hydroxy-propionate, and the chiral amine is R- ⁇ -methylbenzylamine.
  • the compound of formula IV, or the enantiomer of said compound, wherein R 1 , R 2 , R 4 and X are as defined above is prepared by treating a compound of the formula
  • R 2 and X are as defined above.
  • R 1 , R 2 , R 4 and X are as stated above for said process of making the compound of formula V.
  • the compounds of formula II and III are treated with a titanium(IV) halide; followed by a tertiary diamine base; then a donor ligand selected from 1-methyl-2-pyrrolidinone, dimethylformamide, 1 ,3-dimethyl- 3,4,5,6-tetrahydro-2(1H)-pyrimidinone, triethylphosphate, and 2,2'-dipyridyl; and finally a protic quench.
  • the compound of formula II is 2-bromo-4- fluorobenzaldehyde
  • the compound of formula III is (R)-4-benzyl-3-[3-phenyl-propionyl]- oxazolidin-2-one
  • the titanium (IV)halide is titanium tetrachloride
  • the tertiary diamine base is ⁇ /,tV, ⁇ /', ⁇ /'-tetramethlethylenediamine
  • the donor ligand is 1-methyl-2-pyrrolidinone
  • the protic quench is aqueous ammonium chloride.
  • the compound of formula III, or the enantiomer of said compound, wherein R 1 and R 4 are as defined above is prepared by treating a compound of the formula
  • R 1 is as defined above, and Y is halo or OH, with a compound of the formula
  • R 4 is as defined above, in the presence of a tertiary amine base and a catalytic additive.
  • the compound of formula I is 3-phenyl-propionyl chloride
  • the compound of formula la is (R)-4-benzyl-oxazolidin-2-one
  • R 1 is benzyl
  • Y Is Cl the tertiary amine base is triethylamine
  • the catalytic additive is dimethylaminopyridine.
  • the compound of formula VIII is prepared by reacting a compound of formula XII having the structure:
  • R 3 is as defined above, with a metal amide in the presence of a trialkylborate.
  • preferred substituents for R 3 is as stated above for said process of preparing a compound of formula XI;
  • the metal amide is selected from lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidine;
  • the trialkylborate is selected from triisopropylborate, triethylborate and trimethylborate.
  • said compound of formula XII is (isopropoxycarbonyl)-3-trifluoromethyl-benzene, the metal amide is lithium diisopropylamide and the trialkylborate is triisopropylborate.
  • the compound of formula XII is prepared by treating a compound of the formula XIII having the structure:
  • R 3 is as defined above and Y is OH or halo, with isopropyl alcohol and a thionyl halide.
  • Substituents for R 3 are as stated above for said process of making a compound of formula XI.
  • said esterification is effected using thionyl chloride or bromide.
  • said compound of formula XIII is 3-trifluoromethyl-benzoyl chloride.
  • chiral auxiliary lla is acylated in the first step of the pathway shown in Scheme 1 with an acylchloride of formula I in the presence of a tertiary amine base.
  • the base may be triethylamine or diethylisopropylamine, and is preferably triethylamine.
  • the reaction is favorably carried out in the presence of an additive such as dimethylaminopyridine or N-methyl imidazole, which is preferably dimethylaminopyridine, in a solvent such as dichloromethane or 1 ,2-dichloroethane, preferably dichloromethane, at a temperature between -20 °C and 40 °C, preferably about room temperature to afford a compound of formula III.
  • an additive such as dimethylaminopyridine or N-methyl imidazole, which is preferably dimethylaminopyridine
  • a solvent such as dichloromethane or 1 ,2-dichloroethane, preferably dichloromethane
  • Acylated chiral auxiliary III is treated with a titanium(IV) halide, preferably titanium tetrachloride, in an aprotic solvent such as dichloromethane, 1 ,2-dichloroethane, or toluene, preferably dichloromethane, at a temperature of about -80 to 0°C, preferably -60 to - 50°C, followed by treatment with a tertiary diamine base, such as N,N,N',N'- tetramethlethylenedia ine, preferably, at a temperature of about -80 to 0°C, preferably -65 to -50°C.
  • a titanium(IV) halide preferably titanium tetrachloride
  • an aprotic solvent such as dichloromethane, 1 ,2-dichloroethane, or toluene, preferably dichloromethane
  • a tertiary diamine base such as N,N,N
  • a donor ligand such as 1-methyl-2-pyrrolidinone, dimethylformamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, triethylphosphate, or 2,2'-dipyridyl, preferably 1-methyl-2-pyrrolidinone, at a temperature of about -80 to 0°C, preferably -65 to -50°C.
  • This mixture is treated with substituted benzaldehyde II at a temperature of about -80 to 0°C, preferably -65 to -50°C, over a period of about 2 hours, and allowed to warm to a temperature of 0 to 30°C, preferably 15°C, over a period of about one to 24 hours, preferably about 4 hours.
  • This mixture is treated with aprotic quench, preferably aqueous ammonium chloride, at a temperature of 0 to 30°C, preferably 15°C, to yield alcohol IV.
  • a protic quench preferably aqueous ammonium chloride
  • the alcohol IV is, in some cases, provided as a crystalline solvate with the donor ligand.
  • Stirring the quenched reaction mixture with a solid support such as CeliteTM for a period of about 12 hours at a temperature of about 20°C improves the filtration of the reaction mixture for removal of titanium byproducts.
  • the third step shown in Scheme 1 is the hydrolysis of the chiral aldol product IV to regenerate the chiral auxiliary lla.
  • Compound IV is treated with lithium hydroxide and aqueous hydrogen peroxide, or lithium hydroperoxide, preferably a mixture of lithium hydroxide and aqueous hydrogen peroxide, in a solvent such as tetrahydrofuran, diisopropyl ether or tert-butyl methyl ether, preferably tetrahydrofuran, at a temperature between 0°C and 40°C, preferably about room temperature, for a period between 5 and 48 hours, preferably about 15 hours.
  • a solvent such as tetrahydrofuran, diisopropyl ether or tert-butyl methyl ether, preferably tetrahydrofuran
  • reaction mixture is treated with a reducing agent such as sodium sulfite or sodium thiosulfate, preferably sodium sulfite, followed by treatment with an amine such as benzylamine, dicyclohexylamine, 2-methylbenzylamine, preferably benzylamine, afford the salt V.
  • a reducing agent such as sodium sulfite or sodium thiosulfate, preferably sodium sulfite
  • an amine such as benzylamine, dicyclohexylamine, 2-methylbenzylamine, preferably benzylamine
  • the recovery of the auxiliary lla is very high and also much simpler because compound XIV (as the free acid) can be crystallized as a salt (V) while auxiliary lla does not form a salt under the conditions used.
  • Compounds V and lla can be separated by a simple crystallization.
  • the formation of the benzylamine salt (V) is high yielding.
  • the use of a chiral amine allows for enantioenrichment of compound XIV.
  • the fourth step in Scheme 1 is the reduction of a carboxylic acid.
  • Compound V is treated with a reducing agent such as sodium borohydride in the presence of boron trifluoride diethyl ether complex or boron trifluoride tetrahydrofuran complex, borane tetrahydrofuran complex, or borane dimethyl sulfide complex, at a temperature between 0°C and reflux, preferably 35-40°C, for a period between 10 and 48 hours, preferably about 29 hours.
  • the reaction is treated with an aqueous acid such as citric acid, to provide an alcohol of formula VI.
  • the fifth step in Scheme 1 is an intramolecular aromatic substitution whereby the primary hydroxyl in diol VI displaces ortho fluorine to generate the chromanol ring system of VII.
  • Diol VI is treated with a base, such as potassium -erf-butoxide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or cesium carbonate, preferably potassium tert-butoxide, in an aprotic solvent such as THF, or 1-methyl-2-pyrrolidinone, preferably THF, at a temperature of between ambient temperature and 130°C, preferably about 70°C, for a period of 30 minutes to 12 hours, typically about one hours, giving chromanol VII.
  • a base such as potassium -erf-butoxide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or cesium carbonate, preferably potassium tert-butoxide
  • an aprotic solvent such as THF, or 1-methyl
  • isopropyl ester XII is treated with a metal amide base such as lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidine preferably lithium diisopropylamide, in the presence of a trialkylborate such as triisopropylborate, triethylborate, or trimethylborate, preferably triisopropylborate, in an ethereal solvent such as tetrahydrofuran, diisopropyl ether, or methyl tert-butyl ether, preferably tetrahydrofuran, over a temperature range of about -40°C to room temperature, preferably at about 0°C. After a period of 10 minutes to 5 hours, typically about 1 hour, the reaction is quenched with aqueous acid giving
  • the third step in Scheme 2 is the formation of the diethanolamine complex XI of the boronic acid (VIII).
  • This complex formation serves to facilitate the handling of boronic acid VIII before proceeding to the second step of Scheme 3, wherein the boronic acid VIII is reacted with diethanolamine in a solvent such as isopropanol, ethanol, methanol, hexanes, toluene, or a combination of the foregoing solvents, preferably isopropanol with hexanes, at a temperature within the range of 0°C to reflux temperature, preferably ambient temperature, for a period of 15 minutes to 10 hours, preferably 10 hours, to provide the diethanolamine complex XI.
  • a solvent such as isopropanol, ethanol, methanol, hexanes, toluene, or a combination of the foregoing solvents, preferably isopropanol with hexanes
  • the first step in Scheme 3 is the hydrolysis of the diethanolamine complex XI to boronic acid VIII according to methods known to those skilled in the art.
  • Such methods include the use of aqueous acid, such as hydrochloric acid in a solvent such as tetrahydrofuran, toluene, tert-butyl methyl ether, diisopropyl ether, or a mixture of the foregoing solvents, preferably a mixture of tetrahydrofuran and toluene, at a temperature between 1°C and 60°C, preferably ambient temperature, for a period of 1 to 12 hours, preferably about 3.5 hours.
  • aqueous acid such as hydrochloric acid
  • a solvent such as tetrahydrofuran, toluene, tert-butyl methyl ether, diisopropyl ether, or a mixture of the foregoing solvents, preferably a mixture of tetrahydrofuran and tolu
  • compound VIII can either be carried on in situ or isolated as a solid prior to the coupling with VII in step 2.
  • Compound X is isolated as a solid by displacing the THF solvent with hexanes or some other non-polar solvent. The use of the isopropyl ester allows for the crystallization of compound IX.
  • the second step 2 in Scheme 3 is a Suzuki coupling between boronic acid VIII and chromanol VII to form the biaryl bound of IX.
  • a mixture is prepared containing boronic acid VIII, chromanol VII, a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(ll), palladium(ll) acetate, optionally in the presence of triphenylphosphine, preferably dichlorobis(triphenylphosphine)palladium(ll), a base, such as sodium carbonate, sodium bicarbonate, cesium carbonate, tripotassium phosphate, or sodium hydroxide, preferably sodium carbonate, and a solvent such as toluene, ethanol, dimethoxyethane, tetrahydrofuran, or a mixture of the foregoing solvents, optionally containing water, preferably a mixture of toluene and tetrahydrofuran containing water, at
  • the third step in Scheme 3 is an ester hydrolysis.
  • Ester IX is treated with aqueous hydroxide base, such as aqueous lithium hydroxide, in a solvent, such as isopropyl alcohol, at a temperature between 40°C and reflux temperature, preferably about 80°C, for a period of about one to about 24 hours, preferably about 6 hours.
  • the reaction mixture is cooled to ambient temperature and partitioned between aqueous base and an organic solvent, such as a mixture of hexane and isopropyl ether.
  • the aqueous solution is acidified, and the final compound X is extracted into an organic solvent such as toluene. This method of extracting compound X with organic solvents removes neutral.
  • lithium hydroxide is used in the hydrolysis of IX to X.
  • the process shown in a preferred embodiment in Scheme 4 is diastereomeric salt formation between carboxylic acid XIV and a chiral amine.
  • a chiral amine such as R- ⁇ - methylbenzylamine, may be added to a solution of XIV in an organic solvent at room temperature. After a solid forms, the diastereomeric salt is isolated by filtration, or by other techniques well known in the art. Other solvent combinations, resolving agents, and temperature ranges would also be apparent to those skilled in the art.
  • the use of chiral amines results in enantioenrichment of one antipode of intermediate Va, e.g., XIV.
  • the compounds prepared by the processes of the invention can be administered to humans for the treatment of LTB 4 induced illnesses, including inflammatory disorders, such as rheumatoid arthritis, osteoarthritis and inflammatory bowel disease, psoriasis, eczema, erythma, pruritis, acne, stroke, graft rejection, autoimmune diseases, and asthma, by various routes including orally, parenteraily and topically, and through the use of suppositories and enemas.
  • dosage levels of about 0.5 to 1000 mg/day, advantageously about 5-500 mg/day may be given in a single dose or up to three divided doses.
  • Intravenous administration dosage levels are about 0.1-500 mg/day, advantageously about 1.0-100 mg/day.
  • Intravenous administration can include a continuous drip. Variations will necessarily occur depending on the age, weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art.
  • the compounds prepared by the processes of the invention may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • They can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous solution which can contain other solutes, for example, enough salt or glucose to make the solution isotonic.
  • the LTB 4 activity of the compounds prepared by the processes of the invention may be determined by comparing the ability of the compounds of the invention to compete with radiolabelled LTB 4 for specific LTB receptor sites on guinea pig spleen membranes.
  • Guinea pig spleen membranes were prepared as described by Chang et al. (J. Pharmacology and Experimental Therapeutics 232: 80, 1985).
  • the 3 H-LTB 4 binding assay was performed in 150 ⁇ l containing 50 mM Tris pH 7.3, 10 mM MgCl.sub.2, 9% Methanol, 0.7 nM 3 H-LTB 4 (NEN, approximately 200 Ci/mmol) and 0.33 mg/ml guinea pig spleen membranes.
  • Unlabeled LTB 4 was added at a concentration 5 ⁇ M to determine non-specific binding.
  • Experimental compounds were added at varying concentrations to evaluate their effects on 3 H-LTB 4 binding. The reactions were incubated at 4° C for 30 minutes. Membrane bound 3 H-LTB 4 was collected by filtration through glass fiber filters and the amount bound was determined by scintillation counting. The IC50 value for an experimental compound is the concentration at which 50% of specific 3 H-LTB binding is inhibited.
  • Residual peroxides were destroyed by addition of 2.62 g sodium sulfite and 70 mL ethyl acetate, followed by 15 mL concentrated hydrochloric acid. The organic (top) layer was separated and partially concentrated by distillation. Ethyl acetate was added and the distillation continued to remove residual water. Benzylamine (5.04 g, 45.9 mmol) was added and the mixture was stirred and then filtered. The solids were dried to give 18.7 g (97% yield) of 6, (2R,3R)-benzylammonium-2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionic acid.
  • a solution of lithium diisopropyl amide was made up by adding hexyl lithium (100 mL of a 2.5M solution in hexanes, 0.25 mol) to a solution of diisopropyl amine (37 mL, 0.26 mol) in 90 mL tetrahydrofuran at 0°C. The solution was then added over 40 minutes to a solution of 4-trifluoromethylbenzoic acid isopropyl ester (9) (40 g, 0.17 mol) and triisopropyl borate (80 g, 0.21 mol) in tetrahydrofuran (200 mL) at 0 °C.
  • (3S.4R)-2-(3-Benzyl-4-hvdroxy-chroman-7-yl)-4-trifluoromethyl-benzoic Acid 13.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrane Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne des procédés de préparation d'un composé de formule X et des énantiomères dudit composé, le groupe acide benzoïque étant attaché en position (6) ou (7) du cycle chromane, et R?1, R2, et R3¿ portant la signification donnée. L'invention concerne également des intermédiaires servant à la préparation dudit composé de formule X.
PCT/IB2002/000041 2001-01-30 2002-01-07 Procedes de preparation d'acides chromanylbenzoiques WO2002060888A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002433516A CA2433516A1 (fr) 2001-01-30 2002-01-07 Procedes de preparation d'acides chromanylbenzoiques
JP2002561038A JP2004518685A (ja) 2001-01-30 2002-01-07 クロマニル安息香酸の調製方法
MXPA03006876A MXPA03006876A (es) 2001-01-30 2002-01-07 Intermedios y procedimientos para preparar derivados de cromanol sustituido.
BR0206771-4A BR0206771A (pt) 2001-01-30 2002-01-07 Processos para a preparação de cidos cromanilbenzóicos

Applications Claiming Priority (2)

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US26513901P 2001-01-30 2001-01-30
US60/265,139 2001-01-30

Publications (1)

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WO2002060888A1 true WO2002060888A1 (fr) 2002-08-08

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JP (1) JP2004518685A (fr)
BR (1) BR0206771A (fr)
CA (1) CA2433516A1 (fr)
MX (1) MXPA03006876A (fr)
WO (1) WO2002060888A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012014114A1 (fr) 2010-07-30 2012-02-02 Ranbaxy Laboratories Limited Inhibiteurs de métalloprotéinase de matrice
CN107586285A (zh) * 2016-07-06 2018-01-16 浙江圣效化学品有限公司 一种2,3‑二氢苯并吡喃‑4‑酮衍生物的制备方法

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WO1993015066A1 (fr) * 1992-01-23 1993-08-05 Pfizer Inc. Benzopyranne et antagonistes du ltb4 apparentes
WO1996011925A1 (fr) * 1994-10-13 1996-04-25 Pfizer Inc. Composes de benzopyranne et composes benzo-fusionnes, leur preparation et leur utilisation comme antagonistes du leucotriene b4' (ltb4)
WO1996011920A1 (fr) * 1994-10-13 1996-04-25 Pfizer Inc. Composes de benzopyranne et composes benzo-fusionnes, leur preparation et leur utilisation comme antagonistes de leucotriene b4 (ltb4)
US5552435A (en) * 1992-01-23 1996-09-03 Pfizer Inc. Benzopyran and related LTB antagonists
US6096906A (en) * 1996-09-16 2000-08-01 Pfizer Inc. Processes for preparing substituted chromanol derivatives

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WO1993015066A1 (fr) * 1992-01-23 1993-08-05 Pfizer Inc. Benzopyranne et antagonistes du ltb4 apparentes
US5552435A (en) * 1992-01-23 1996-09-03 Pfizer Inc. Benzopyran and related LTB antagonists
WO1996011925A1 (fr) * 1994-10-13 1996-04-25 Pfizer Inc. Composes de benzopyranne et composes benzo-fusionnes, leur preparation et leur utilisation comme antagonistes du leucotriene b4' (ltb4)
WO1996011920A1 (fr) * 1994-10-13 1996-04-25 Pfizer Inc. Composes de benzopyranne et composes benzo-fusionnes, leur preparation et leur utilisation comme antagonistes de leucotriene b4 (ltb4)
US6096906A (en) * 1996-09-16 2000-08-01 Pfizer Inc. Processes for preparing substituted chromanol derivatives

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Title
T. HATTORI ET AL.: "Highly Stereospecific Conversion of Planar Chirality of a Cyclophane into Axial Chirality of Binaphthyls", TETRAHEDRON LETTERS, vol. 37, no. 12, 1996, pages 2057 - 2060, XP002197254 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012014114A1 (fr) 2010-07-30 2012-02-02 Ranbaxy Laboratories Limited Inhibiteurs de métalloprotéinase de matrice
CN107586285A (zh) * 2016-07-06 2018-01-16 浙江圣效化学品有限公司 一种2,3‑二氢苯并吡喃‑4‑酮衍生物的制备方法
CN107586285B (zh) * 2016-07-06 2020-09-01 浙江圣效化学品有限公司 一种2,3-二氢苯并吡喃-4-酮衍生物的制备方法

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JP2004518685A (ja) 2004-06-24
MXPA03006876A (es) 2003-11-13
BR0206771A (pt) 2004-02-25
CA2433516A1 (fr) 2002-08-08

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