the nr2b subtype selective nmda antagonists of formula i are readily prepared . the compounds of formula i wherein r 2 and r 5 are taken together forming a chroman - 4 - ol ring and r 1 , r 3 , and r 4 are hydrogen , can be prepared by one or more of the synthetic methods described in u . s . pat . no . 5 , 356 , 905 , referred to above . the compounds of formula i wherein r 2 and r 5 are taken separately and r 1 , r 2 , r 3 and r 4 are hydrogen can be prepared by one or more of the synthetic methods described in u . s . pat . nos . 5 , 185 , 343 , 5 , 272 , 160 , and 5 , 338 , 754 , all of which are referred to above . the compounds of formula i can also be prepared by one or more of the synthetic methods described in u . s . patent application ser . no . 08 / 292 , 651 , abondoned on mar . 14 , 1995 , ser . no . 08 / 189 , 479 , abondoned on dec . 27 , 1999 , and ser . no . 09 / 011 , 426 now u . s pat . no . 6 , 008 , 233 ; pct international application no . pct / ib95 / 00398 , which designates the united states ( filed may 26 , 1995 ) ( corresponding to wo 96 / 37222 ); and pct application no . pct / ib95 / 00380 , which designates the united states ( filed may 18 , 1995 ) ( corresponding to wo 96 / 06081 ), all of which are referred to above . a preferred compound , ( 1s , 2s )- 1 -( 4 - hydroxyphenyl )- 2 -( 4 - hydroxy - 4 - phenylpiperidin - 1 - yl )- 1 - propanol (( 1s , 2s ) free base ), and its tartrate salt , can be prepared as described in u . s . pat . no . 5 , 272 , 160 , referred to above . the resolution of racemic 1 -( 4 - hydroxyphenyl )- 2 -( 4 - hydroxy - 4 - phenylpiperidin - 1 - yl )- 1 - propanol to form the ( 1s , 2s ) free base and the corresponding ( 1r , 2r ) enantiomer can be carried out as described in u . s . patent application ser . no . 09 / 011 , 426 , now u . s pat . no . 6 , 008 , 233 , referred to above , and as exemplified in example 1 below . the anhydrous mesylate of the ( 1s , 2s ) free base can be prepared as described in u . s . pat . no . 5 , 272 , 160 , referred to above . the anhydrous mesylate of the ( 1s , 2s ) free base , when equilibrated in an 81 % relative humidity environment , will convert to the mesylate salt trihydrate of the ( 1s , 2s ) enantiomer . the mesylate salt trihydrate of ( 1s , 2s )- 1 -( 4 - hydroxyphenyl )- 2 -( 4 - hydroxy - 4 - phenylpiperidin - 1 - yl )- 1 - propanol can be prepared from the ( 1s , 2s ) free base as described in united states provisional patent application entitled “( 1s , 2s )- 1 -( 4 - hydroxyphenyl )- 2 -( 4 - hydroxy4 - phenylpiperidin - 1 - yl )- 1 - propanol methanesulfonate trihydrate ”, referred to above . in this method , ( 1 s , 2s ) free base is dissolved in water at 30 ° c . to this solution is added at least 1 equivalent of methane sulfonic acid and the resulting mixture is warmed to 60 - 65 ° c . the warm solution can be filtered to render it particulate free . the solution is concentrated to approximately 40 % of the initial volume , cooled below 10 ° c ., isolated by filtration and dried to a water content ( measured karl fischer titration ) of approximately 11 . 3 %. the resulting crystalline mesylate salt trihydrate can be further purified by recrystallization . another preferred compound , ( 3r , 4s )- 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidin - 1 - yl ]- chroman - 4 , 7 - diol (( 3r , 4s ) chromanol ), can be prepared as described in u . s . pat . no . 5 , 356 , 905 , u . s . patent application ser . no . 08 / 189 , 479 , abandonded on dec . 27 , 1994 , and united states provisional patent application entitled “ process for the resolution of cis - racemic 7 - benzyloxy - 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidin - 1 - yl ]- chroman - 4 - ol dibenzoyl - d - tartrate ”, all three of which are referred to above . the starting materials and reagents required for the synthesis of the ( 3r , 4s ) chromanol are readily available , either commercially , according to synthetic methods disclosed in the literature , or by synthetic methods exemplified in the description provided below . the ( 3r , 4s ) chromanol can be prepared by fractional crystallization of the l - proline ester of racemic cis - 7 - benzyloxy - 3 -[ 4 -( 4 - fluorophenyl ) 4 - hydroxy - piperidin - 1 - yl ]- chroman - 4 - ol , as described in u . s . patent application ser . no . 08 / 189 , 479 abandonded on dec . 27 , 1994 , referred to above . in a preferred method , the resolution method described in united states provisional patent application entitled “ process for the resolution of cis - racemic 7 - benzyloxy - 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidin - 1 - yl ]- chroman - 4 - ol dibenzoyl - d - tartrate ”, referred to above , and as exemplified in example 3 . in this method , the parent chromanol is prepared by dissolving racemic cis - 7 - benzyloxy - 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidin - 1 - yl ]- chroman - 4 - ol with an equal molar amount of dibenzoyl - d - tartaric acid in boiling aqueous ethanol . racemic cis - 7 - benzyloxy - 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidin - 1 - yl ]- chroman - 4 - ol is prepared as described in u . s . patent application ser . no . 08 / 189 , 479 , referred to above . the concentration of aqueous ethanol is not critical and may be varied between 75 % and 95 % ethanol ( etoh ). a concentration of 9 : 1 / etoh : h 2 o has been found to be effective and is preferred . a sufficient amount of the aqueous ethanol solvent to dissolve the racemic compound is required . this amount has been found to be about 17 ml per gram of racemic compound . upon stirring while heating under reflux , the racemic compound dissolves to form a hazy solution which is allowed to cool with stirring whereupon the (+) isomer , ( 3r , 4s )- 7 - benzyloxy - 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidin - yl ]- chroman - 4 - ol dibenzoyl - d - tartrate , precipitates and may be collected by filtration and washed with aqueous ethanol . this is the tartrate salt of the ( 3r , 4s ) chromanol . the lactate and mandelate salts of the ( 3r , 4s ) chromanol are prepared in an analogous manner . this initial product is of about 90 % optical purity . if a higher purity is desired , the product may be heated again with aqueous ethanol , cooled and the product collected and washed . two such treatments were found to yield the (+) isomer of 99 . 4 % optical purity in an overall yield of 74 %. this procedure is preferred over the procedure described in u . s . patent application ser . no . 08 / 189 , 479 , referred to above , in that it avoids a reduction step with lithium aluminum hydride and is therefore more suitable for bulk operations . this procedure also produces a significantly higher yield of the desired product . the above described (+) isomer can be converted to ( 3r , 4s )- 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidin - 1 - yl ]- chroman - 4 , 7 - diol by standard procedures . for example , treatment with dilute base can be used to free the piperidinyl base and subsequent hydrogeneration removes the 7 - benzyl group to yield the ( 3r , 4s ) chromanol . in general , the pharmaceutically acceptable acid addition salts of the compounds of formula i can readily be prepared by reacting the base forms with the appropriate acid . when the salt is of a monobasic acid ( e . g ., the hydrochloride , the hydrobromide , the p - toluenesulfonate , the acetate ), the hydrogen form of a dibasic acid ( e . g ., the dihydrogen phosphate , the citrate ), at least one molar equivalent and usually a molar excess of the acid is employed . however , when such salts as the sulfate , the hemisuccinate , the hydrogen phosphate or the phosphate are desired , the appropriate and exact chemical equivalents of acid will generally be used . the free base and the acid are usually combined in a co - solvent from which the desired salt precipitates , or can be otherwise isolated by concentration and / or addition of a non - solvent . as indicated above , selectivity of compounds for the nr 2 b - subunit containing nmda receptor is defined as an affinity for the racemic [ 3 h ](+)-( 1s , 2s )- 1 -( 4 - hydroxy - phenyl )- 2 -( 4 - hydroxy - 4 - phenylpiperidino )- 1 - propanol binding site in forebrain of rats , as described in chenard and menniti ( antagonists selective for nmda receptors containing the nr 2 b subunit , current pharmaceutical design , 1999 , 5 : 381 - 404 ). this affinity is assessed in a radioligand binding assay as described below . selective compounds are those which displace specific binding of racemic [ 3 h ] cp - 101 , 606 from rat forebrain membranes with an ic 50 ≦ 5 μm . the binding of racemic [ 3 h ] (+)-( 1s , 2s )- 1 -( 4 - hydroxy - phenyl )- 2 -( 4 - hydroxy - 4 - phenylpiperidino )- 1 - propanol to rat forebrain membranes is measured as described by menniti et al . ( cp - 101 , 606 , a potent neuroprotectant selective for forebrain neurons , european journal of pharmacology , 1997 , 331 : 117 - 126 ). forebrains of adult male cd rats are homogenized in 0 . 32m sucrose at 4 ° c . the crude nuclear pellet is removed by centrifugation at 1 , 000 × g for 10 minutes , and the supernatant centrifuged at 17 , 000 × g for 25 minutes . the resulting pellet is resuspended in 5 mm tris acetate ph 7 . 4 at 4 ° c . for 10 minutes to lyse cellular particles and again centrifuged at 17 , 000 × g . the resulting pellet is washed twice in tris acetate , resuspended at 10 mg protein / ml and stored at − 20 ° c . until use . for binding assays , membranes are thawed , homogenized , and diluted to 0 . 5 mg protein / ml with 50 mm tris hcl , ph 7 . 4 . compounds under study are added at various concentrations followed by racemic [ 3 h ] (+)-( 1s , 2s )- 1 -( 4 - hydroxy - phenyl )- 2 -( 4 - hydroxy - 4 - phenylpiperidino )- 1 - propanol ( specific activity 42 . 8 ci / mmol , 5 nm final concentration ). following incubation for 20 min at 30 ° c . in a shaking water bath , samples are filtered onto whatman gfb glass fiber filters using a mb - 48r cell harvester ( brandel research and development laboratories , gaithersburg md .). filters are washed for 10 s with ice cold tris hcl buffer and the radioactivity trapped on the filter quantified by liquid scintillation spectroscopy . nonspecific binding is determined in parallel incubations containing 100 μm racemic (+)-( 1s , 2s )- 1 -( 4 - hydroxy - phenyl )- 2 -( 4 - hydroxy - 4 - phenylpiperidino )- 1 - propanol . specific binding is defined as total binding minus nonspecific binding . compounds of the formula i have selectivity for nr 2 b subunit - containing nmda receptors over α 1 - adrengergic receptors . affinity for the nr 2 b subunit containing nmda receptor is measured as the ic 50 for displacement of specific binding of racemic [ 3 h ] (+)-( 1s , 2s )- 1 -( 4 - hydroxy - phenyl )- 2 -( 4 - hydroxy4 - phenylpiperidino )- 1 - propanol from rat forebrain membranes ( described above ). affinity for the α 1 - adrengergic receptor is defined as the ic 50 for displacement of specific binding of racemic [ 3 h ] prazosin from rat brain membranes , measured as described by greengrass and bremner ( binding characteristics of [ 3 h ] prazosin to rat brain α - adrenergic receptors , european journal of pharmacology , 55 , 323 - 326 , ( 1979 )). a compound with a ratio of ([ 3 h ] prazosin /[ 3 h ] (+)-( 1s , 2s )- 1 -( 4 - hydroxy - phenyl ) 2 -( 4 - hydroxy - 4 - phenylpiperidino )- 1 - propanol ) affinity greater than three is considered selective . forebrains of adult male sprague dawley rats are homogenized in 20 volumes of ice cold 50 mm tris / hcl buffer ( ph 7 . 7 ). the homogenate is centrifuged at 50 , 000 × g for 10 minutes at 4 ° c . the pellet is resuspended and centrifuged under identical conditions and the final pellet is resuspended in 80 volumes of 50 mm tris / hcl ( ph 8 . 0 ) at 4 ° c . for binding assays , compounds under study are added at various concentrations to 500 μg membrane protein in 1 ml of 50 mm tris / hcl buffer , followed by [ 3 h ] prazosin ( amersham , specific activity 33 ci / mmol , 0 . 2 nm final concentration ). following incubation for 30 min at 25 ° c . in a shaking water bath , samples are filtered onto whatman gfb glass fiber filters using a mb - 48r cell harvester ( brandel research and development laboratories , gaithersburg md .). filters are washed three times for 10s with ice cold tris hcl buffer and the radioactivity trapped on the filter quantified by liquid scintillation spectroscopy . nonspecific binding is determined in parallel incubations containing 100 nm prazosin . specific binding is defined as total binding minus nonspecific binding . nr2b selective nmda receptor antagonists useful in the practice of the invention may also be used in the form of a pharmaceutically acceptable salt . the expression “ pharmaceutically - acceptable acid addition salts ” is intended to include but not be limited to such salts as the hydrochloride , hydrobromide , sulfate , hydrogen sulfate , phosphate , hydrogen phosphate , dihydrogenphosphate , acetate , succinate , citrate , tartrate , lactate , mandelate , methanesulfonate ( mesylate ) and p - toluenesulfonate ( tosylate ) salts . the acid addition salts of the compounds of the present invention are readily prepared by reacting the base forms with the appropriate acid . when the salt is of a monobasic acid ( e . g ., the hydrochloride , the hydrobromide , the p - toluenesulfonate , the acetate ), the hydrogen form of a dibasic acid ( e . g ., the hydrogen sulfate , the succinate ) or the dihydrogen form of a tribasic acid ( e . g ., the dihydrogen phosphate , the citrate ), at least one molar equivalent and usually a molar excess of the acid is employed . however when such salts as the sulfate , the hemisuccinate , the hydrogen phosphate or the phosphate are desired , the appropriate and exact chemical equivalents of acid will generally be used . the free base and the acid are usually combined in a co - solvent from which the desired salt precipitates , or can be otherwise isolated by concentration and / or addition of a non - solvent . assays that can be used to determine the neutrophil inhibiting activity of a substance are described in u . s . pat . no . 5 , 919 , 900 , referred to above . nmda receptor antagonists , and , in particular , nr2b selective nmda receptor antagonists , can also be administered in combination with a selective serotonin reuptake inhibitor ( ssri ). examples of selective serotonin reuptake inhibitors that can be administered , either as part of the same pharmaceutical composition or in a separate pharmaceutical composition , with an nr2b selective nmda receptor antagonist , include : fluoxetine , fluvoxamine , paroxetine and sertraline , and pharmaceutically acceptable salts thereof . this invention relates both to methods of treatment in which the nmda antagonist and the other active ingredient in the claimed combinations are administered together , as part of the same pharmaceutical composition , as well as to methods in which the two active agents are administered separately , as part of an appropriate dose regimen designed to obtain the benefits of the combination therapy . the appropriate dose regimen , the amount of each dose administered , and the intervals between doses of the active agents will depend upon the particular nmda antagonist and other active ingredient being used in combination , the type of pharmaceutical formulation being used , the characteristics of the subject being treated and the severity of the disorder being treated . generally , in carrying out the methods of this invention , cox - 2 inhibitors will administered to an average adult human in amounts ranging from about 5 to about 300 mg per day , depending on the cox - 2 inhibitor , severity of the headache and the route of administration . nsaids , in carrying out the methods of this invention , will generally be administered to an average adult human in amounts ranging from about 7 to about 2 , 000 mg per day . nmda receptor antagonists , including glycine site antagonists , in carrying out the methods of this invention , will generally be administered to an average adult human in amounts ranging from about 25 to about 1500 mg per day . nif &# 39 ; s , in carrying out the methods of this invention , will generally be administered to an average adult human in amounts ranging from about 0 . 1 to about 140 mg / kg body weight / per day . calcium channel antagonists , potassium channel openers , sodium channel antagonists , and antioxidants , in carrying out the methods of this invention , will generally be administered to an average adult human in amounts within the ranges used when such agents are administered , respectively , as single active pharmaceutical agents . such dosages are available in the scientific and medical literature , and , for substances that have been approved for human use by the food and drug administration , in the current edition ( presently the 53 rd edition ) of the physician &# 39 ; s desk reference , medical economics company , montvale , n . j . in some instances , dosage levels below the lower limit of the aforesaid range may be more than adequate , while in other cases still larger doses may be employed without causing any harmful side effects , provided that such higher dose levels are first divided into several small doses for administration throughout the day . the pharmaceutically active agents used in the methods and pharmaceutical compositions of this invention can be administered orally , parenterally , or topically , alone or in combination with pharmaceutically acceptable carriers or diluents , and such administration may be carried out in single or multiple doses . more particularly , the therapeutic agents of this invention can be administered in a wide variety of different dosage forms , i . e ., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets , capsules , lozenges , troches , hard candies , powders , sprays , creams , salves , suppositories , jellies , gels , pastes , lotions , ointments , aqueous suspensions , injectable solutions , elixirs , syrups , and the like . such carriers include solid diluents or fillers , sterile aqueous media and various non - toxic organic solvents , etc . moreover , oral pharmaceutical compositions can be suitably sweetened and / or flavored . in general , the therapeutically - effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5 . 0 % to about 70 % by weight . for oral administration , tablets containing various excipients such as microcrystalline cellulose , sodium citrate , calcium carbonate , dicalcium phosphate and glycine may be employed along with various disintegrants such as starch ( and preferably corn , potato or tapioca starch ), alginic acid and certain complex silicates , together with granulation binders like polyvinylpyrrolidone , sucrose , gelatin and acacia . additionally , lubricating agents such as magnesium stearate , sodium lauryl sulfate and talc are often very useful for tabletting purposes . solid compositions of a similar type may also be employed as fillers in gelatin capsules ; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols . when aqueous suspensions and / or elixirs are desired for oral administration , the active ingredient may be combined with various sweetening or flavoring agents , coloring matter or dyes , and , if so desired , emulsifying and / or suspending agents as well , together with such diluents as water , ethanol , propylene glycol , glycerin and various like combinations thereof . for parenteral administration , solutions of a pharmaceutically active agent used in accordance with this invention in either sesame or peanut oil or in aqueous propylene glycol may be employed . the aqueous solutions should be suitably buffered ( preferably ph greater than 8 ) if necessary and the liquid diluent first rendered isotonic . these aqueous solutions are suitable for intravenous injection purposes . the oily solutions are suitable for intra - articular , intramuscular and subcutaneous injection purposes . the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art . additionally , it is also possible to administer the active agents used in accordance with the present invention topically , and this may be done by way of creams , jellies , gels , pastes , patches , ointments and the like , in accordance with standard pharmaceutical practice . certain nmda antagonists of the formula i are illustrated by the following examples . all nonaqueous reactions were run under nitrogen for convenience and generally to maximize yields . all solvents / diluents were dried according to standard published procedures or purchased in a predried form . all reactions were stirred either magnetically or mechanically . nmr spectra are recorded at 300 mhz and are reported in ppm . the nmr solvent was cdcl 3 unless otherwise specified . ir spectra are reported in cm − 1 , generally specifying only strong signals . (+)- tartaric acid ( 300 mg , 2mmol ) was dissolved in 30 ml warm methanol . racemic 1s *, 2s *- 1 -( 4 - hydroxyphenyl )- 2 -( 4 - hydroxy - 4 - phenylpiperidin - 1 - yl )- 1 - propanol ( 655 mg , 2 mmol ) was added all at once . with stirring and gentle warming a colorless homogeneous solution was obtained . upon standing at ambient temperature 24 hours , 319 mg ( 66 %) of a fluffy white precipitate was obtained . this product was recrystallized from methanol to give 263 mg of the (+)- tartrate salt of levorotatory title product as a white solid ; mp 206 . 5 - 207 . 5 ° c . ; [ alpha ] d =− 36 . 2 °. this salt ( 115 mg ) was added to 50 ml of saturated nahco 3 . ethyl acetate ( 5 ml ) was added and the mixture was vigorously stirred 30 minutes . the aqueous phase was repeatedly extracted with ethyl acetate . the organic layers were combined and washed with brine , dried over calcium sulfate , and concentrated . the tan residue was recrystallized from ethyl acetate - hexane to give 32 mg ( 39 %) of white , levorotatory title product ; mp 203 - 204 ° c . ; [ alpha ] d =− 58 . 4 °. anal . calc &# 39 ; d . for c 20 h 25 no 3 : c , 73 . 37 ; h , 7 . 70 ; n , 4 . 28 . found : c , 72 . 61 ; h , 7 . 45 ; n , 4 . 21 . the filtrate from the (+)- tartrate salt preparation above was treated with 100 ml saturated aqueous nahco 3 and extracted well with ethyl acetate . the combined organic extracts were washed with brine , dried over calcium sulfate and concentrated to give 380 mg of recovered starting material ( partially resolved ). this material was treated with (−)- tartaric acid ( 174 mg ) in 30 ml of methanol as above . after standing for 24 hours , filtration gave 320 mg ( 66 %) of product which was further recrystallized from methanol to produce 239 mg of the (−)- tartrate salt of dextrorotatory title product ; mp 206 . 5 - 207 . 5 ° c . [ alpha ] d =+ 33 . 9 °. the latter was converted to dextrorotatory title product in the manner above in 49 % yield ; mp 204 - 205 ° c . ; [ alpha ] d =+ 56 . 9 °. anal . found : c , 72 . 94 ; h , 7 . 64 ; n , 4 . 24 . a 50 gallon glass lined reactor was charged with 17 . 1 gallons of acetone , 8 . 65 kilograms ( kg ) ( 57 . 7 mol ) of 4 ′- hydroxypropiophenone , 9 . 95 kg ( 72 . 0 mol ) of potassium carbonate and 6 . 8 liters ( l ) ( 57 . 7 mol ) of benzylbromide . the mixture was heated to reflux ( 56 ° c .) for 20 hours . analysis of thin layer chromatography ( tlc ) revealed that the reaction was essentially complete . the suspension was atmospherically concentrated to a volume of 10 gallons and 17 . 1 gallons of water were charged . the suspension was granulated at 25 ° c . for 1 hour . the product was filtered on a 30 ″ lapp and washed with 4 . 6 gallons of water followed by a mixture of 6 . 9 gallons of hexane and 2 . 3 gallons of isopropanol . after vacuum drying at 45 ° c ., this yielded 13 . 35 kg ( 96 . 4 %) of the above - depicted product . a second run was carried out with 9 . 8 kg ( 65 . 25 mol ) of 4 ′- hydroxypropiophenone using the procedure described above . after drying 15 . 1 kg ( 96 . 3 %) of the above - depicted product was obtained . under a nitrogen atmosphere , a 100 gallon glass lined reactor was charged with 75 gallons of methylene chloride and 28 . 2 kg ( 117 . 5 mol ) of the product from step 1 . the solution was stirred five minutes and then 18 . 8 kg of bromine was charged . the reaction was stirred for 0 . 5 hours at 22 ° c . analysis of tlc revealed that the reaction was essentially complete . to the solution was charged 37 gallons of water and the mixture was stirred for 15 minutes . the methylene chloride was separated and washed with 18 . 5 gallons of saturated aqueous sodium bicarbonate . the methylene chloride was separated , atmospherically concentrated to a volume of 40 gallons and 60 gallons of isopropanol was charged . the concentration was continued until a pot temperature of 80 ° c . and final volume of 40 gallons were obtained . the suspension was cooled to 20 ° c . and granulated for 18 hours . the product was filtered on a 30 ″ lapp and washed with 10 gallons of isopropanol . after vacuum drying at 45 ° c ., this yielded 29 . 1 kg ( 77 . 6 %) of the above - depicted product . under a nitrogen atmosphere , a 20 gallon glass lined reactor was charged with 4 . 90 kg ( 15 . 3 mol ) of the product from step 2 , 7 . 0 gallons of ethyl acetate , 2 . 70 kg ( 15 . 3 mol ) of 4 - hydroxy - 4 - phenylpiperidine and 1 . 54 kg of triethylamine ( 15 . 3 mol ). the solution was heated to reflux ( 77 ° c .) for 18 hours . the resulting suspension was cooled to 20 ° c . analysis by tlc revealed that the reaction was essentially complete . the byproduct ( triethylamine hydrobromide salt ) was filtered on a 30 ″ lapp and washed with 4 gallons of ethyl acetate . the filtrate was concentrated under vacuum to a volume of 17 liters . the concentrate was charged to 48 liters of hexane and the resulting suspension granulated for 2 hours at 20 ° c . the product was filtered on a 30 ″ lapp and washed with 4 gallons of hexane . after vacuum drying at 50 ° c ., this yielded 4 . 9 kg ( 77 %) of the above - depicted product . a second run was carried out with 3 . 6 kg ( 11 . 3 mol ) of the product from step 2 using the procedure described above . after drying 4 . 1 kg ( 87 %) of the above - depicted product was obtained . under a nitrogen atmosphere , a 100 gallon glass lined reactor was charged with 87 . 0 gallons of 2b ethanol and 1 . 7 kg ( 45 . 2 mol ) of sodium borohydride . the resulting solution was stirred at 25 ° c . and 9 . 4 kg ( 22 . 6 mol ) of the product from step 3 was charged . the suspension was stirred for 18 hours at 25 - 30 ° c . analysis by tlc revealed that the reaction was essentially complete to the desired threo diastereoisomer . to the suspension was charged 7 . 8 liters of water . the suspension was concentrated under vacuum to a volume of 40 gallons . after granulating for 1 hour , the product was filtered on a 30 ″ lapp and washed with 2 gallons of 2b ethanol . the wet product , 9 . 4 gallons of 2b - ethanol and 8 . 7 gallons of water were charged to a 100 gallon glass lined reactor . the suspension was stirred at reflux ( 78 ° c .) for 16 hours . the suspension was cooled to 25 ° c ., filtered on 30 ″ lapp and washed with 7 gallons of water followed by 4 gallons of 2b ethanol . after air drying at 50 ° c ., this yielded 8 . 2 kg ( 86 . 5 %) of the above - depicted product . this material was recrystallized in the following manner . a 100 gallon glass lined reactor was charged with 7 . 9 kg ( 18 . 9 mol ) of the product from step 3 , 20 gallons of 2b ethanol and 4 gallons of acetone . the suspension was heated to 70 ° c . producing a solution . the solution was concentrated atmospherically to a volume of 15 gallons . the suspension was cooled to 25 ° c . and granulated for 1 hour . the product was filtered on a 30 ″ lapp . the wet product and 11 . 7 gallons of 2b ethanol was charged to a 100 gallon glass lined reactor . the suspension was heated to reflux ( 78 ° c .) for 18 hours . the suspension was cooled to 25 ° c ., filtered on a 30 ″ lapp and washed with 2 gallons of 2b ethanol . after air drying at 50 ° c . this yielded 5 . 6 kg ( 70 . 6 %) of the above - depicted product . under a nitrogen atmosphere , a 50 gallon glass lined reactor was charged with 825 g of 10 % palladium on carbon ( 50 % water wet ), 5 . 5 kg ( 13 . 2 mol ) of the product from step 4 and 15 . 5 gallons of tetrahydrofuran ( thf ). the mixture was hydrogenated between 40 - 50 ° c . for 2 hours . at this time , analysis by tlc revealed that the reduction was essentially complete . the reaction was filtered through a 14 ″ sparkler precoated with celite and washed with 8 gallons of thf . the filtrate was transferred to a clean 100 gallon glass lined reactor , vacuum concentrated to a volume of 7 gallons and 21 gallons of ethyl acetate were charged . the suspension was atmospherically concentrated to a volume of 10 gallons and a pot temperature of 72 ° c . the suspension was cooled to 10 ° c ., filtered on a 30 ″ lapp and washed with 2 gallons of ethyl acetate . after air drying at 55 ° c . this yielded a 3 . 9 kg ( 90 %) of the above - depicted product ( i . e ., the free base ). a 100 gallon glass lined reactor was charged with 20 gallons of methanol and 3 . 7 kg ( 11 . 4 mol ) of the product from step 5 ( i . e ., the free base ). the suspension was heated to 60 ° c . and 1 . 7 kg ( 11 . 4 mol ) of d -(−)- tartaric acid were charged . the resulting solution was heated to reflux ( 65 ° c .) for 3 hours after which a suspension formed . the suspension was cooled to 35 ° c ., filtered on a 30 ″ lapp and washed with 1 gallon of methanol . the wet solids were charged to a 100 gallon glass lined reactor with 10 gallons of methanol . the suspension was stirred for 18 hours at 25 ° c . the suspension was filtered on a 30 ″ lapp and washed with 2 gallons of methanol . after air drying at 50 ° c . this yielded 2 . 7 kg ( 101 %) of the above - depicted product ( i . e ., the tartaric acid salt of the free base ( r -(+)- enantiomer )). this material was purified in the following manner : a 100 gallon glass lined reactor was charged with 10 . 6 gallons of methanol and 2 . 67 kg ( 5 . 6 mol ) of the above tartaric acid salt . the suspension was heated to reflux ( 80 ° c .) for 18 hours . the suspension was cooled to 30 ° c ., filtered on a 30 ″ lapp and washed with 4 gallons of methanol . after air drying at 50 ° c ., this yielded 2 . 05 kg ( 76 . 7 %) of the above - depicted product ( i . e ., the tartaric acid salt of the free base ). a 55 liter nalgene tub was charged with 30 liters of water and 1056 g ( 12 . 6 mol ) of sodium bicarbonate at 20 ° c . to the resulting solution was charged 2 . 0 kg ( 4 . 2 mol ) of the product from step 6 ( i . e ., the tartaric acid salt of the free base ). the suspension was stirred for 4 hours during which a great deal foaming occurred . after the foaming ceased , the suspension was filtered on a 32 cm funnel and washed with 1 gallon of water . after air drying at 50 ° c ., this yielded 1 . 28 kg ( 93 . 5 %) of the above - depicted product ( i . e ., the free base ). a 22 liter flask was charged with 1277 g ( 3 . 9 mol ) of product from step 7 and 14 liters of water . the suspension was warmed to 30 ° c . and 375 g ( 3 . 9 mol ) of methane sulfonic acid were charged . the resulting solution was warmed to 60 ° c ., clarified by filtering through diatomaceous earth ( celite ™) and washed with 2 liters of water . the speck - free filtrate was concentrated under vacuum to a volume of 6 liters . the suspension was cooled to 0 - 5 ° c . and granulated for 1 hour . the product was filtered on an 18 ″ filter funnel and washed with 635 ml of speck - free water . after air drying at 25 ° c . for 18 hours , this yielded 1646 g ( 88 %) of the above - depicted product ( i . e ., the mesylate salt trihydrate ). a mixture of 3 - methyl - 4 - triisopropylsilyloxy - α - bromopropiophenone ( 9 . 17 g , 22 . 97 mmol ), 4 -( 4 - fluorophenyl )- 4 - hydroxypiperidine ( 6 . 73 g , 34 . 45 mmol ) and triethylamine ( 8 . 0 ml , 57 . 43 mmol ) in in ethanol ( 180 ml ) was refluxed for 6 hours . the solvent was removed at reduced pressure and the residue was partitioned between ethyl acetate and water . the phases were separated and the organic layer was washed with brine , dried over calcium sulfate and concentrated . the residue was flash chromatographed on silica gel ( 3 × 3 . 5 inches packed in hexane ) with elution proceeding as follows : 10 % ethyl acetate / hexane ( 1000 ml ), nil ; 20 % ethyl acetate / hexane ( 700 ml ), nil ; 20 % ethyl acetate / hexane ( 1300 ml ) and 25 % ethyl acetate / hexane ( 600 ml ), 7 . 66 g ( 65 %) of 1 -( 3 - methyl - 4 - triisopropylsilyloxyphenyl )- 2 -( 4 -( 4 - fluorophenyl )- 4 - hydroxypiperidin - 1 - yl )- propan - 1 - one as a yellow foam which was suitable for use without further purification . a sample recrystallization from ethyl acetate / hexane as white crystals had : m . p . 78 - 82 ° c . a mixture of sodium borohydride ( 0 . 564 g , 14 . 92 mmol ) and ethanol ( 60 ml ) was stirred 10 minutes and then 1 -( 3 - methyl - 4 - triisopropylsilyloxyphenyl )- 2 -( 4 -( 4 - fluorophenyl )- 4 - hydroxypiperidin - 1 - yl )- propan - 1 - one ( 7 . 66 g , 14 . 92 mmol in 10 ml of ethanol ) was added with two 30 ml ethanol rinses . the reaction mixture was stirred at ambient temperature overnight . the white solid that precipitated was collected by filtration and dried to yield 5 . 72 g ( 74 %) of ( 1r *, 2r *)- 1 -( 3 - methyl - 4 - triisopropylsilyloxyphenyl )- 2 -( 4 -( 4 - fluorophenyl )- 4 - hydroxypiperidin - 1 - yl )- propan - 1 - ol , which was suitable for use without further purification and had : m . p . 188 - 189 ° c . the product of the above reaction ( 5 . 72 g , 11 . 1 mmol ) was dissolved in tetrahydrofuran ( 150 ml ) and tetrabutylammonium fluoride ( 12 . 21 ml , 12 . 21 mmol , 1m tetrahydrofuran solution ) was added . the reaction was stirred 1 hour at ambient temperature and then concentrated . the residue was partitioned between ethyl acetate and water and the two phases were separated . the organic layer was slurried with methylene chloride . the white solid that precipitated was collected by filtration and dried to afford 3 . 41 g ( 85 %) of ( 1r *, 2r *)- 1 -( 4 - hydroxy - 3 - methylphenyl )- 2 -( 4 -( 4 - fluorophenyl )- 4 - hydroxypipeidin - 1 - yl )- propan - 1 - ol . a sample ( 0 . 16 g , 0 . 447 mmol ) was converted to the corresponding mesylate salt . the salt was slurried in methanol ( 8 ml ) and methanesulfonic acid ( 0 . 029 ml , 0 . 45 mmol ) was added . the mixture was filtered and concentrated . the mixture was then recrystallized from ethanol to give 0 . 152 g ( 58 %) of the mesylate salt which had : m . p . 215 - 216 ° c . analysis calculated for c 21 h 25 fno 3 . ch 4 so 3 : c , 58 . 01 ; h , 6 . 64 , n , 3 . 07 . found : c , 57 . 99 ; h , 6 . 72 : n , 3 . 17 . a mixture of 2 - bromo - 1 -( 2 , 2 - diphenyl - benzo ( 1 , 3 ) dioxol - 5 - yl )- propan - 1 - one ( 2 . 00 g , 4 . 89 mmol ), 4 - hydroxy - 4 - phenylpiperidine ( 0 . 9 g , 5 . 08 mmol ) and triethylamine ( 1 . 40 ml , 10 . 04 mmol ) in ethanol ( 50 ml ) was refluxed overnight . the solvent was removed at reduced pressure and the residue was partitioned between ether and water . the phases were separated and the organic layer was washed with brine , dried over magnesium sulfate and concentrated . the residue was flash chromatographed on silica gel ( 2 × 5 inches packed with hexane ) with elution proceeding as follows : 20 % ethyl acetate / hexane ( 500 ml ), unweighed forerun ; 50 % ethyl acetate / hexane ( 500 ml ), 1 . 76 g ( 71 %) of 1 -( 2 , 2 )- diphenyl - benzo ( 1 , 3 ) dioxol - 5 - yl )- 2 -( 4 - hydroxy - 4 - phenylpiperidin - 1 - yl )- propan - 1 - one as light tan foam which was suitable for use without further purification and had : nmr δ7 . 81 ( dd , j = 1 . 7 , 8 . 3 hz , 1h ), 7 . 70 ( d , j = 1 . 6 hz , 1h ), 7 . 64 - 7 . 13 ( m , 15h ), 6 . 92 ( d , j = 8 . 2 hz , 1h ), 4 . 07 ( q , j = 7 . 0 hz , 1 h ), 3 . 39 - 3 . 27 ( m , 1h ), 2 . 94 - 2 . 59 ( m , # h ), 2 . 30 - 2 . 04 ( m , 2h ), 1 . 74 ( br t , j = 13 . 2 hz , 2h , 1 . 3 ( d , j = 6 . 8 hz , 3h ). a mixture of sodium borohydride ( 0 . 15 g , 3 . 97 mmol ) and ethanol ( 5 ml ) was stirred 10 minutes and then 1 -( 2 , 2 - diphenyl - benzo ( 1 , 3 ) dioxol - 5 - yl )- 2 -( 4 - hydroxy - 4 - phenylpiperidin - 1 - yl )- propan - 1 - one ( 1 . 70 g , 3 . 36 mmol in 20 ml of ethanol ) was added . the reaction was stirred at ambient temperature over the weekend . the white precipitate was collected , rinsed with ethanol and ether and air dried to afford 1 . 35 g of crude product . the product was recrystallized from ethanol / ethyl acetate / methylene chloride to give 1 . 05 g ( 61 %) of 1r *, 2r *)- 1 -( 2 , 2 - diphenyl - benzo ( 1 , 3 ) dioxol - 5 - yl )- 2 -( 4 - hydroxy - 4 - phenylpiperidin - 1 - yl )- propan - 1 - ol which had : mp 224 - 224 . 5 ° c . analysis calculated for c 33 h 33 no 4 : c , 78 . 08 ; h , 6 . 55 ; n , 2 . 76 . found : c , 78 . 16 ; h , 6 . 46 ; n , 2 . 72 . a mixture of the product of the above reaction ( 1 . 00 g , 1 . 97 mmol ) and 10 % palladium on carbon ( 0 . 175 g ) in methanol ( 50 ml ) and acetic acid ( 1 . 0 ml ) was hydrogenated at 50 psi ( initial pressure ) for 5 hours at ambient temperature . additional catalyst ( 0 . 18 g ) was added and the hydrogenation was continued overnight . the reaction was filtered through diatomaceous earth and the filter pad was rinsed with methanol . the filtrate was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous bicarbonate and stirred vigorously for 1 hour . the phases were separated and the aqueous layer was extracted with ethyl acetate ( 2 ×). the combined organic layer was washed with water and brine , dried over magnesium sulfate and concentrated . the residue was flash chromatographed on silica gel ( 1 × 4 inches ) with elution proceeding as follows : 20 % ethyl acetate / hexane ( 500 ml ), nil ; 10 % methanol / ethyl acetate ( 250 ml ), 20 % methanol / ethyl acetate ( 250 ml ), and 50 % methanol / ethyl acetate , 0 . 51 g ( 75 %) of a light yellow - green solid . the solid was recrystallized from ethanol to afford ( 1r *, 2r *)- 1 -( 3 , 4 - dihydroxyphenyl )- 2 -( 4 - hydroxy - 4 - phenyl - piperidin - 1 - yl )- propan - 1 - ol as a white solid which had : mp 167 - 168 ° c . analysis calculated for c 20 h 25 no 4 . 0 . 5 c 2 h 6 o : c , 68 . 83 ; h , 7 . 70 ; n , 3 . 82 . found : c , 68 . 78 ; h , 8 . 05 ; n , 3 . 70 . the racemic product was dissolved in ethanol and separated into enantiomers by hplc using the following chromatographic conditions : column , chiralcel od ; mobile phase , 25 % ethanol / 75 % hexane ; temperature , ambient ( approximately 22 ° c . ); detection , uv at 215 nm . under these conditions , 1r , 2r 1 -( 4 - hydroxy - 3 - methoxyphenyl )- 2 -( 4 - hydroxy - 4 - phenyl - piperidin - 1 - yl ) propan - 1 - ol eluted with a retention time of approximately 9 . 12 minuntes and 1s , 2s 1 -( 4 - hydroxy - 3 - methoxyphenyl )- 2 -( 4 - hydroxy - 4 - phenyl - piperidin - 1 - yl ) propan - 1 - ol eluted with a retention time of approximately 16 . 26 minutes . a mixture of 7 - benzyloxy - 3 , 3 - dibromochromanone ( 54 . 7 g , 133 mmol ), 4 -( 4 - fluorophenyl )- 4 - hydroxypiperidine ( 52 . 0 g , 266 mmol ), and triethylamine ( 38 ml , 270 mmol ) in acetonitrile ( 2 . 5 l ) was stirred 16 hours at ambient temperature . a yellow precipitate formed and was collected , washed well with water and ether , and air dried . the yield of 7 - benzyloxy - 3 -{ 4 -( 4 - fluorophenyl )- 4 - hydroxy - pipridine - 1 - yl ]- chromenone was 55 . 4 g ( 93 %) which was suitable for use without further purification . a sample recrystallized from ethanol / tetrahydrofuran had mp 220 - 221 ° c . : nmr dmso ∂ σ δ 7 . 99 ( d , j = 9 hz , 2h ), 7 . 56 - 7 . 40 ( m , 8h ), 7 . 18 - 7 . 08 ( m , 4h ), 5 . 25 ( s , 2h ), 5 . 06 ( s , 1h ), 3 . 60 ( br s , 1h ), 3 . 55 - 3 . 35 ( m , 1h , partially obscured by water from the nmr solvent ), 3 . 10 - 2 . 95 ( m , 2h ), 2 . 15 - 2 . 00 ( m , 2h ), 1 . 71 ( br t , j = 13 . 7 hz , 2h ). analysis calculated for c 27 h 24 fno 4 : c , 72 . 80 ; h , 5 . 43 ; n , 3 . 13 . found : c , 72 . 83 ; h , 5 . 82 ; n , 2 . 82 . to a slurry of 7 - benzyloxy - 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidine - 1 - yl ]- chromenone ( 8 . 24 g , 18 . 5 mmol ) in ethanol ( 400 ml ) and tetrahydrofuran ( 600 ml ) was added sodium borohydride ( 7 . 0 g , 185 mmol ). the mixture was stirred overnight . additional sodium borohydride ( 7 . 0 g ) was added and the reaction mixture was stirred for 3 days . water was added and the solvent was removed at reduced pressure at 45 ° c . the solids which formed were collected and washed well with water and then ether . the solid was further dried in vacuo overnight to give 5 . 01 g , 60 % of 3r * 4s * 7 - benzyloxy - 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidin - 1 - yl ]- chroman - 4 - ol which was suitable for use without further purification . a sample recrystallized from ethyl acetate / chloroform had mp . 194 - 195 ° c . ; nmr δ7 . 56 - 7 . 30 ( m , 8h ), 7 . 06 ( long range coupled t , j = 8 . 7 hz , 2h ) 6 . 63 ( dd , j = 2 . 4 , 8 . 5hz , 1 h ), 6 . 47 ( d , j = 2 . 4hz , 1h ), 5 . 04 ( s , 2h ), 4 . 77 ( d , j = 4 . 5 hz , 1h ), 4 . 37 ( dd , j = 3 . 5 , 10 . 4 hz , 1h ), 4 . 13 ( t , j = 10 . 4 hz , 1h ), 3 . 82 ( brs , 1h ), 3 . 11 ( br d , j = 11 . 2 hz , 1h ), 2 . 92 - 2 . 71 ( m , 4h ), 2 . 21 - 2 . 06 ( m , 2h ), 1 . 87 - 1 . 73 ( m , 2h ), 1 . 54 ( s , 1h ). analysis calculated for c 27 h 28 fno 4 : c , 72 . 14 ; h , 6 . 28 ; n , 3 . 12 . found c , 72 . 15 ; h , 6 . 21 ; n , 3 . 12 . a mixture of 3r * 4s * 7 - benzyloxy - 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidin - 1 - yl ]- chroman - 4 - ol ( 0 . 80 g , 1 . 78 mmol ), 10 % palladium on carbon ( 0 . 16 g ), methanol ( 40 ml ), and acetic acid ( 0 . 8 ml ) was hydrogenated for 8 hours with a starting pressure of 48 . 5 psi . the reaction was filtered through celite and the filtrate was concentrated . the residue was stirred vigorously with ether and saturaturated sodium bicarbonate for 1 hour . the solid was washed with water and ether and dried in vacuo . recrystallization from ethanol yielded 0 . 35 g ( 54 %) of 3r * 4s * 3 -[ 4 -( 4 - fluorophenyl )- 4 - hydroxy - piperidin - 1 - yl ]- chroman - 4 , 7 - diol as a white solid which had mp 159 - 160 ° c . ; nmr dmso ∂ σ δ 7 . 55 - 7 . 47 ( m , 2h ), 7 . 11 ( t , j = 9 hz , 2h ), 7 . 02 ( d , j = 8 . 4 hz , 1h ), 6 . 32 ( dd , j = 2 . 3 , 8 . 3 hz , 1h ), 6 . 15 ( d , j = 2 . 3 hz 1h ), 5 . 10 - 4 . 50 ( br m with s at 4 . 63 , 3h ), 4 . 23 ( dd , j = 2 . 8 , 10 . 3 hz , 1h ), 4 . 04 ( t , j = 10 . 5 hz , 1h ), 2 . 99 ( br d , j = 10 . 8 hz , 1h ), 2 . 86 ( br d , j = 10 . 7 hz , 1 h ), 2 . 73 - 2 . 50 ( m , 3h ), 2 . 08 - 1 . 90 ( m , 2h ), 1 . 58 ( br d , j = 13 hz , 2h ). analysis calculated for c 20 h 22 fno 4 . 0 . 25h 2 o ; c , 66 . 01 ; h , 6 . 23 ; n , 3 . 85 . found : c , 66 . 22 ; h , 6 . 58 ; n , 3 . 46 .
this invention relates to methods of treating traumatic brain injury or hypoxic or ischemic stroke , comprising administering to a patient in need of such treatment an nr2b subtype selective n - methyl - d - aspartate receptor antagonist in combination with either : a neutrophil inhibitory factor ; a sodium channel antagonist ; a nitric oxide synthase inhibitor ; a glycine site antagonist ; a potassium channel opener ; an ampa / kainate receptor antagonist ; a calcium channel antagonist ; a gaba - a receptor modulator ; or an antiinflammatory agent .