Preparation and Anticonvulsant Activity of
`and a-Heteroaromatic Amino Acids
`
`Series of Functionalized a-Aromatic
`
`Med Chem 1990 33 919926
`
`919
`
`Harold Kohnt Kailash
`and
`David Leander1
`
`Sawhney Philippe LeGalIt Judith
`
`Conleyt David
`
`Robertson1
`
`of Chemistry University of Houston Houston
`Texas
`Department
`Company Indianapolis Indiana 46285 Received July 28 1989
`
`77204 -5641 and Lilly Research Laboratories Eli Lilly
`
`2b
`We recently reported the potent anticonvulsant activity of RS-a-acetamido-N-benzyl-a-phenylacetamide
`Selectively substituted derivatives of this compound have now been prepared 23 examples and evaluated in the
`maximal electroshock seizure MES and horizontal
`screen tox tests in mice In several key cases replacement
`heteroaromatic moiety led to
`relatively small electron-rich
`of the a-phenyl substituent
`in 2b by
`8UbStafltial
`The most active compounds were RS-a
`in the anticonvulsant potency of the drug candidate
`improvement
`2i After ip
`2g and RS-a-acetamido-N-benzyl-2-pyrroleacetamide
`acetamido-N-benzyl-2-furanacetamide
`administration the MES ED values for 2g 10.3 mg/kg and 2i 16.1 mg/kg compared well with phenytoin 9.50
`the anticonvulsant activity resided
`mg/kg Evaluation of the two individual enantiomers of 2g demonstrated that
`index 1/ED
`stereoisomer The low ED value 3.3 mg/kg for R-2g contributed to the large protective
`in the
`for this drug candidate which approached
`observed
`
`that of phenytoin
`
`Recently we have reported the excellent anticonvulsant
`activities of functionalized amino acid derivatives L1-5
`
`Selected Physical and Pharmacological Data in Mice for
`Table
`RS.a-Aromatic and a-Heteroaromatic Substituted Functionalized
`Amino Acid Derivatives
`
`CH3CNHHCNH.CH2_Q
`
`R2
`
`2b
`
`C6H
`
`2c
`2d
`
`2e
`
`2f
`
`2g
`
`2h
`
`2i
`
`2j
`
`2k
`
`21
`
`4-C6H4OH
`4CeH4OCH3
`2-OH-5-CH3C6H3
`2-C1OH
`2-furanyl
`
`5.CH2furany1
`
`2-pyrrolyl
`
`5-CH3.2-pyrrolyl
`
`1-CH3.2.pyrrolyl
`
`2-thienyl
`
`2m 3.thjenyl
`
`mp
`202203
`
`232235
`196198
`183185
`210-211
`178179
`
`148150
`
`174175
`
`167168
`
`179181
`167169
`
`198199
`
`tox
`
`TD
`40
`
`300
`40
`
`75.4
`
`30 100
`
`30 100
`
`100
`
`MES
`ED
`
`32.1
`27.540.2
`300
`300
`300
`300
`10.3
`9.1-11.6
`19.2
`
`16.4-23.8
`16.1
`
`13.2-199
`36.5
`30.6-57.1
`-300
`
`44.8
`38951.4
`87.8
`69.9150
`100 300
`300
`100 300
`
`9.5
`
`A2
`
`II
`
`CH3NH.C.CNHCH2
`
`Z.aR2-CH3
`A2
`Ph
`
`data suggested that these compounds
`The pharmacological
`new and important class of anticonvulsant
`comprised
`The structureactivity profile for
`indicated that
`agents.6
`stringent steric and electronic requirements existed for
`Excellent protection
`optimal anticonvulsant activity
`seizures MES in mice was
`against maximal electroshock
`observed
`for functionalized amino acid racemates C0fl
`taming an N-benzylamide moiety an acetylated amino
`group and either methyl 2a or
`phenyl 2b substit-
`uent on the a-carbon The median effective doses ED
`for 2a and 2b in mice ip were 76.5 and 20.3 mg/kg re-
`These values compared favorably with the
`spectively.3
`corresponding ED value obtained for the proven an-
`tiepileptic phenobarbital 21.8 mg/kg.7
`Significantly
`evaluation of the individual enantiomers of 2a and 2b
`showed that the anticonvulsant activity resided primarily
`isomer was
`stereoisomers.45 In both cases the
`in the
`over 10 times more effective in the MES test than the
`enantiomer This difference in activity
`corresponding
`represented the greatest eudismic ratio8 reported to date
`for MES-selective anticonvulsants
`The pronounced activity observed for 2b prompted our
`investigation of the anticonvulsant properties of
`select
`series of functionalized amino acids in which the a-sub-
`stituent is either an aromatic or
`heteroaromatic group
`In this paper the synthesis physical properties and an-
`ticonvulsant activities of these compounds are described
`Evidence is presented that placement of
`relatively small
`electron-rich heteroaromatic moiety at the a-site leads to
`substantial enhancement
`in the anticonvulsant activity
`the high eudismic ratio
`of the drug candidate and that
`observed for 2a and 2b is preserved for the most active
`member of this series of compounds
`
`Selection of Compounds
`RS-a-Acetamido-N-benzyl-a-phenylacetamide8
`
`2b
`
`to whom correspondence
`Author
`the University of Houston
`tUniversity of Houston
`Lilly Research Laboratories
`
`should be addressed
`
`to at
`
`2n benzo 195196
`2p benzo 226227
`
`2o
`
`indol-3-yl
`
`213214
`
`100 300
`300
`100 300
`65.5
`52.572.1
`8.110.4
`69.0
`21.8
`62.872.9
`15.022.5
`426
`272
`247338
`369450
`intraperitoneally ED and
`The compounds were administered
`TD values are in mg/kg Numbers in parentheses are 95% confidence
`are uncorrected MES
`intervals
`Melting points
`electroshock seizure test Tox
`neurologic toxicity determined from
`tNot determined
`horizontal screen Reference
`5Reference
`
`phenytoint
`
`phenobarbital
`
`valproatet
`
`maximal
`
`served as the parent compound in this study Table
`In
`the first series of functionalized amino acid derivatives
`
`Chem Br 1988 24 231
`Kohn
`Conley
`Kohn
`Liao Z.-K Watson
`Cortes
`1985 28 601
`Conley
`Kohn
`371
`Conley
`
`Kohn
`Conley
`
`Med Chem 1987 30 567
`Brain Res 1988 457
`Leander
`
`Kohn
`
`unpublished results
`
`Med Chem
`
`Breckenridge Exhibit 1018
`Breckenridge v. Research Corporation Technologies, Inc.
`
`0022-2623/90/1833-0919$02.50/0
`
`1990 American Chemical Society
`
`

`
`920
`
`Journal of Medicinal Chemistry 1990 Vol 33 No
`
`Kohn et al
`
`Table II Selected Physical and Pharmacological
`for Fluoro-Substituted
`RS-a-Acetamido-N-substituted-benzyl-2-furanacetamides
`
`Data in Mice
`
`Selected Physical and Pharmacological Data in Mice
`Table Ill
`for Functionalized Amino Acid Stereoisomers
`
`CR3CNHHCNHCH2_Q
`
`CH3CNHCHCNHCH
`
`II
`
`__________________________________________________________
`MESC
`toxd
`ED
`
`no
`
`Ar
`
`mpb
`
`TD
`40
`
`10.3
`9.111.6
`40.0
`
`2g
`
`C6H5
`
`178179
`
`3a
`3b
`
`3c
`
`3d
`
`2-FC6H4
`3-FC6H4
`
`4-FC6H4
`
`25-FC6H
`
`3e
`
`26-F2C6H3
`
`193195
`163165
`
`188190
`
`177178
`
`136
`115162
`144
`123171
`
`13.3
`11.515.3
`12.7
`10.415.1
`23.8
`20.228.4
`25 100
`237239
`compounds were administered intraperitoneally ED and
`TD values are in mg/kg Numbers in parentheses are 95% con-
`MES
`toxicity de-
`
`fidence intervals Melting points
`maximal electroshock
`seizure test
`termined from horizontal screen
`
`and uncorrected
`dTox
`neurologic
`Not determined
`
`selected for synthesis the a-substituent was systematically
`varied Both aromatic 2cf and heteroaromatic 2gp
`moieties were incorporated into the amino acid backbone
`In all cases the functionalized amino acid racemates were
`prepared and tested
`The pharmacological properties observed for 2g war-
`ranted further investigation of this compound Accord
`ingly two different
`types of structural modifications of the
`N-terminal benzyl moiety were made First
`series of
`racemic fluorine-substituted benzylamides 3ae were
`synthesized Table II
`Impetus for this study was pro-
`vided by an earlier observation that modest
`improvement
`of the overall activity of 2a in mice ip was obtained upon
`fluorine atom at
`the meta position of
`incorporation of
`the aromatic ring.3 The second structural modification
`the N-
`examined for 2g involved the replacement of
`benzylamide group by the corresponding N-a-methyl-
`Use of R-a-methylbenzylamine and
`benzylamides
`S-a-methylbenzylamine in the synthesis permitted the
`preparation and pharmacological
`evaluation of each of the
`four individual diastereomers of
`
`CH3CNHHCNH-C
`
`II
`
`II
`
`The final group of drug candidates
`individual R- and S- stereoisomers of 2g Table III
`The marked selectivity previously noted45 for the mdi-
`vidual enantiomers of 2a and 2b prompted this investi-
`gation
`
`synthesized were the
`
`the related aa-di
`For the pharmacological
`properties of
`alkyl-a-phthalimidoacetamides and ao-dialkyl-a-benzamido-
`Org Chem
`see Upham
`Dermer
`acetamides
`1957 22 799
`Porter
`Kupferberg
`1984 51 293
`Eudismic ratio
`See Lehmann
`
`Cereghino
`
`Scoville
`
`Gladding
`White
`
`Hessie
`Cleveland Clin
`
`the two enantiomers
`ratio of activities of
`103
`Trends Pharmacol Sci 1982
`
`no
`RS-2g
`
`R-2g
`
`mpg
`
`2-furanyl
`
`178179
`
`2-furanyl
`
`196197
`
`S-2g
`RS2aC
`
`2-furanyl
`CH3
`
`R2ae
`
`S-2a8
`
`CH3
`
`CH
`
`RS-2W C6H5
`
`R-2b
`
`C6H5
`
`C6H5
`
`196197
`139141
`
`139141
`
`139142
`
`202203
`
`219221
`
`MESC
`EDo
`
`10.3
`9.111.6
`3.3
`2.83.9
`25
`
`toxd
`
`TD50
`
`23.8
`
`200
`454
`417501
`214
`148262
`841
`691954
`40
`
`80
`
`76.5
`66.689.0
`54.8
`50.359.7
`548
`463741
`32.1
`27.540.2
`26.4
`21.132.0
`100 300
`300
`S-2b1
`221222
`The compounds were administered intraperitoneally ED and
`TD values are in mg/kg Numbers in parentheses are 95% con
`MES
`are uncorrected
`fidence intervals Melting points
`neurologic toxicity de
`Tox
`maximal electroshock
`seizure test
`termined from horizontal screen
`the Epi
`Values determined at
`lepsy Branch NINCD NIH see ref
`The median toxic dose
`
`TD was determined by using the rotorod test see Durham
`Am Pharm Assoc 1957 46 208 PReference
`
`Miya
`
`Scheme
`Preparation of Compound
`Anhydride Method
`
`via the Mixed Carbonic
`
`Ra
`
`OH
`
`CICOR
`
`tertiary
`amme
`
`1NH.CJ.O.tOR
`
`R3NH2
`
`R2
`
`RNH-C-tNHR
`
`Chemistry
`The strategies employed in the synthesis of the func
`tionalized amino acid derivatives were patterned after
`The preparation of
`previously employed
`procedures
`compounds 2ceg--iklnp have been reported.9
`In
`troduction of the aromatic or heteroaromatic group at
`in compounds 2c-eglnp was accomplished by
`carbon
`using 2-acetamido-N-
`an amidoalkylation reaction
`BF and the appropriate
`benzyl-2-ethoxyacetamide
`aromatic substrate The reactions proceeded in moderate
`yields 2867% with excellent regioselectivity
`ccc
`
`CH3CNH-C-CNHCH2
`
`The remaining compounds
`in this study were prepared
`by the mixed carbonic anhydride method Scheme J.b0
`In
`
`Sawhney
`Conley
`LeGall
`Pept Protein Res 1988 32 279
`
`Kohn
`
`lot
`
`

`
`a-Aromatic and a-Heteroaromatic Amino Acids
`
`Journal of Medicinal Chemistry 1990 Vol 33 No
`
`921
`
`Scheme II
`Improved Procedure for the Preparation of
`Acid 10
`RS-a-Acetamido-2-furanacetic
`
`CH3
`
`NHC-COCH2CH3
`
`Br2
`
`cc4
`hv
`
`OBrO
`
`II occ
`
`CH3CN
`
`ZnCI2
`
`THF
`
`co ____ 1/O
`
`KOH/90%EtOH
`
`H3O
`
`CH3CNHOHCOCF42CH3
`
`II
`
`IF
`
`cH3cNHcHcc4-1
`
`IF
`
`II
`
`was treated
`this procedure the N-acylated amino acid
`with an alkyl chloroformate in the presence of
`tertiary
`amine to generate the mixed N-acyl amino acid carbonic
`This intermediate was not isolated but
`ester anhydride
`in situ with the appropriate amine R3NH2 to
`reacted
`amide
`produce the N-acyl amino acid N-substituted
`The starting N-acylated amino acid selected for the syn-
`thesis of 2f was N-t-Boc-RS-2-naphthylglycine
`
`CH3-O.gNH.CC-OH
`
`CR3
`
`II
`
`HO
`
`CR3 NH
`
`COH
`HO
`
`ii
`
`removal CF3CO2H of the N-protecting group
`Subsequent
`after the mixed carbonic anhydride coupling step followed
`by acetylation with acetyl chloride and triethylamine
`In the synthesis of RS-2g R-2g S-2g 2m
`yielded 2f
`and
`the appropriate N-acetyl amino acid was directly
`employed thereby simplifying the experimental procedure
`Synthesis of RS-a-acetamido-3-thiopheneacetic
`acid
`was readily accomplished beginning with RS-a-amino-
`acid and acetic anhydride An improved
`3-thiopheneacetic
`procedure Scheme II was developed for the s3mthesis of
`RS-a-acetamido.2-furanacetic acid 10 This func
`tionalized amino acid served as the starting material for
`The method adopted took ad-
`compounds 2g
`and
`report on the employment of pro-
`vantage of the recent
`tected a-bromo amino acid derivatives as electrophilic
`glycine templates in amino acid synthesis.2 Accordingly
`ethyl acetamido-2-bromoacetate3 12 was prepared from
`ethyl acetamidoacetate 11 and then treated with furan
`and ZnC12 to give 13 Hydrolysis of the ethyl ester yielded
`10 the necessary precursor for the mixed carbonic anhy-
`The overall yield
`dride coupling procedure Scheme
`for 10 in this three-step sequence was 65%
`and tertiary
`Several different alkyl chioroformates
`amines were examined for the mixed carbonic anhydride
`reaction beginning with 10 Higher conversion rates were
`generally obtained with isobutyl chloroformate and 4-
`methylmorpholine The yields for the final coupling step
`
`10 For an excellent discussion and review of this method see
`Am
`Zimmerman
`Anderson
`Callahan
`Chem Soc 1967 89 5012
`11 Kukoija
`Draheim
`Holmes
`Graves
`Webber
`Kinneck
`Med Chem 1985 28 1886
`12 Williams
`Sinclair
`Chem Soc 1988 110 1547
`13 Kuber
`Liebigs Ann Chem 1983 599
`Steglich
`
`Zhai
`
`Chen
`
`Am
`
`Pfeil
`Neel
`Vasileff
`
`Cooper
`Huffman
`Foster
`
`oam view of compound R-2g with atom labeling
`Figure
`scheme The thermal ellipsoids are 20% equiprobability enve
`lopes with hydrogens
`as spheres of arbitrary diameter Only one
`ring is shown
`orientation of the disordered phenyl
`
`for the preparation of the fluorine-substituted aryl amides
`ranged from 50 to 88% comparable syn
`Table II
`thetic protocol was adopted for methylbenzyl amides
`The configuration at C-2 in each of the four individual
`diastereomers of was not determined
`Synthesis of the two enantiomeric forms of 2g R-2g
`and S-2g Table III was achieved by resolution of ra
`cemic 10 via fractional
`recrystallization of the diastereo
`meric salts formed with R- and S-a-methylbenzylamine
`respectively and then coupling the individual stereoiso
`mers with benzylamine Use of isobutyl chioroformate and
`in the mixed carbonic
`4-methylmorpholine
`anhydride
`coupling procedure did not lead to significant amounts of
`racemization of 2g An X-ray crystallographic structural
`determination of R-2g was conducted
`to provide basic
`the solid-state structure of this
`information concerning
`compound and the ORTEP view is presented in Figure
`Thermal disorder limited the amount of data obtainable
`in this determination but some useful observations con
`cerning the structure of the molecular backbone of R-2g
`be made Significant double
`in the solid state can still
`in the CN peptide linkages were indicated
`bond character
`by unusually short N1C2 1.338
`and N2C4 1.323
`bond lengths and unusually long C1C2 1.509
`and C3C4 1.534
`Csp2C-
`bond lengths
`sp3 Comparable observations have been previously
`noted in related compounds.4 The torsion angles about
`N1C2 and N2C4 are essentially
`as would be expected
`in this highly conjugated system and the sum of the angles
`about both nitrogens is 359 indicating virtual planarity
`and substantial delocalization of the lone electron pairs
`The absolute configurations of the enantiomers of 10
`were determined by converting an enriched sample of
`R-10 to the corresponding methyl ester R-14 with
`diazomethane The optical rotation observed for this ad
`95
`MeOH was comparable to
`duct
`sample obtained after treatment of racemic 14 with papain
`
`cR3cNHHcoc4
`
`in aqueous DMF This enzymatic system has been re
`
`14
`
`Tanabe
`Acta Crystallogr 1983
`Inoue
`Ishida
`Tanaka
`C39 110
`Ibid 1982
`Ashida
`Kojima
`Hansen
`B38 221
`Hagen
`Loennechen
`Acta Chem Scand 1982 B36 327
`Aubry
`Aasen
`Marraud mt
`Pept Protein
`Boussard
`Vitoux
`Res 1981 18 195 and references therein
`
`

`
`922
`
`Journal of Medicinal Chemistry 1990 Vol 33 No
`
`Kohn et al
`
`ported to selectively hydrolyze racemic N-protected fu-
`ryiglycine methyl esters to the free S-acids and unreacted
`R-esters in high enantiomeric excess.15
`Several attempts were conducted
`to directly employ
`chiral R-13 or R-14 obtained by papain-mediated hy-
`the corresponding racemic esters for
`the
`drolysis of
`preparation of R-2g Unfortunately treatment of either
`ester with benzylamine in the absence or presence of
`NaCN gave racemic 2g.16
`Pharmacological Evaluation
`The N-acetyl amino acid N-substituted amides 24 were
`tested for anticonvulsant activity by using the procedures
`described by Krall et al.7 All compounds were admin-
`istered intraperitoneally ip in mice Tables IIll
`the
`list
`median effective dose ED0 values required to prevent
`seizures in the MES test by racemic
`and the
`racemic
`individual enantiomers of 2g respectively
`Included in
`these tables are the median toxic dose TD0 values de-
`termined for select compounds by using the horizontal
`screen test.8
`Table
`lists the pharmacological data for those com-
`pounds in which only the a-carbon moiety has been
`modified Evaluation of this subset of results revealed
`several
`important observations First addition of elec-
`tron-releasing hydroxy i.e 2c and 2e or methoxy i.e
`2d groups to the a-substituted
`phenyl group in 2b or
`expansion of the aromatic ring from the phenyl group in
`2b to the naphthyl
`precipitous drop
`residue in 21 led to
`in anticonvulsant potency Second replacement of the
`a-phenyl ring in 2b with an electron-rich five-membered
`improvement
`heteroaromatic ring resulted in substantial
`in the potency of the compound in the MES test Notable
`protection against seizures were observed for the racemates
`of 2gj and 21 The ED0 values for these compounds
`compared favorably with the reported data for phenytoin.7
`Third placement of methyl substituent on the five-
`membered heteroaromatic ring was accompanied
`by
`decrease in the potency of the drug candidate versus the
`i.e 2h versus 2g 2j 2k versus
`unsubstituted compounds
`2i Fourth replacement of the a-heteroaromatic sub-
`stituent by the corresponding benzoheteroaromatic group
`reduction in biological activity i.e 2np This
`led to
`observation paralleled the results obtained for 2b versus
`2f
`The second and third series of compounds tested for
`anticonvulsant activity were adducts in which the terminal
`N-benzylamicle moiety in 2g was altered Table II
`lists the
`comparative data obtained for five fluorine-substituted
`derivatives
`All
`the compounds exhibited pronounced
`activity in the MES test The meta 3b and para 3c
`fluoro adducts displayed activities comparable to that of
`2g while
`small reduction in activity versus 2g was noted
`for ortho derivative 3a and the two difluoro analogues 3d
`and 3e These data contrasted with the pharmacological
`results secured from the ci-methylbenzylamides 4ad
`Increasing the size of the benzylamide moiety by incor-
`poration of an a-methyl group resulted in
`significant
`decrease in the anticonvulsant potency of the drug can-
`relationship be-
`didate regardless of the stereochemical
`tween the two asymmetric centers The MES ED0 values
`
`____________________________________________________
`15 Drueckhanmer
`Wong C-H
`Barbas
`Nozaki
`Org Chem 1988 53 1607
`Wood
`Ciufolini
`16 Hogberg
`Org Chem
`Strom Ebner
`Ramsby
`1987 52 2033
`17 Krall
`White
`Penry
`Epilepsia 1978 19 409
`Swinyard
`18 Coughenour
`McLean
`Parker
`Biochem Behav 1977
`351
`
`Kupferberg
`
`Pharmacol
`
`for these compounds were all greater than 100 mg/kg
`similar trend was previously noted in the 2-acetamido-N-
`benzylpropionamide 2a series
`Table III
`the two
`lists the pharmacological data for
`isomers of 2g along with the racemic mixture
`individual
`as well as the corresponding data for 2a and 2b.4
`In all
`three series of compounds
`pronounced
`improvement
`in
`anticonvulsant potency was noted for the
`enantiomer
`isomer or the racemate Moreover
`versus either the
`each case little activity in the MES test was observed for
`The ED0 value of R-2g was 3.3
`enantiomer
`the
`mg/kg which was considerably lower than that reported
`for phenytoin7 ED0
`9.5 mg/kg The enhanced potency
`of R-2g contributed to the observed high protective index
`TDIJ/ED0
`7.2 for this compound which compared
`favorably with the value observed for phenytoin TD0/
`ED0
`6.9
`
`in
`
`Conclusions
`
`The pharmacological
`data obtained in this investigation
`significantly extended the structureactivity profile pre
`functionalized amino acid deriva
`viously reported for
`tives The observed data supported our hypothesis that
`stringent steric and electronic requirements exist
`maximal anticonvulsant activity in this novel
`class of
`compounds
`The outstanding potencies noted for 2g and
`in the MES test suggested that the placement of rela
`2i
`tively small electron-rich groups at the a-position in was
`beneficial for anticonvulsant activity Furthermore our
`the primary activity of 2g resided in the
`finding that
`enantiomer provided additional evidence for the marked
`stereospecificity exhibited in this new class of anticon
`vulsants Additional studies are in progress investigating
`the generality of this class of compounds
`as well as their
`mode of action
`
`for
`
`Experimental Section
`Chemistry General Methods Melting points were deter-
`Thomas-Hoover melting point apparatus and are
`mined with
`Infrared spectra IR were run on Perkin-Eliner 1330
`uncorrected
`the 1601 cm band
`and 283 spectrometers
`and calibrated against
`of polystyrene Absorption values are expressed in wavenumbers
`cm1 Proton 1H NMR and carbon 53C NMR nuclear mag
`netic resonance spectra were taken on Nicolet NT-300 and General
`Electric QE-300 NMR instruments Chemical shifts
`are in
`parts per million ppm relative to Me4Si and coupling constants
`values are in hertz Low-resolution mass spectra MS were
`Varian MAT CH-5
`recorded at an ionizing voltage of 70 eV with
`spectrometer at the Lilly Research Laboratories Microanalyses
`were provided by the Physical Chemistry Department of the Lilly
`Research Laboratories
`Thin- and thick-layer chromatography
`were run on precoated silica gel GHLF microscope
`slides 2.5
`10 cm Analtech No 21521 or silica gel GHLF 20
`20 cm
`Analtech 11187
`Preparation of RS-2-Acetamido-N-benzyl-2-5-
`methylpyrrolylacetamide 2j 2-Acetaxnido-N-benzyl-2-eth-
`mmol was suspended in anhydrous
`oxyacetamide9
`EtO 175 mL and then BF3.Et20 1.38
`9.7 mmol was added
`and the resulting solution was stirred 15 mm 2-Methylpyrrole9
`10 mmol was then added and the reaction mixture was
`0.85
`days during which time the color of the
`stirred under
`reaction mixture turned reddish brown and
`dark-brown deposit
`formed at the bottom of the flask The clear solution was decanted
`and treated with an aqueous saturated NaHCO3 solution con
`taining ice 100 mL for 30 mm The aqueous reaction mixture
`30 mL The combined extracts
`was extracted with EtOAc
`were dried NaS04 and the solvent was removed in vacuo The
`brown oily residue was purified by flash column chromatography
`using 2% MeOH/CHCI as the eluent to yield 0.20 9% of the
`
`2.00
`
`19 Castro
`
`Hugo
`Deck
`Org Chem 1963 28 857
`
`Marsh
`
`Pfiffer
`
`

`
`a-Aromatic and a-Heteroaromatic Amino Acids
`
`Journal of Medicinal Chemistry 1990 Vol 33 No
`
`923
`
`desired product Compound 2j was recrystallized from ethyl
`light yellow amorphous solid R1 0.44
`acetate/hexane to give
`955 CHC1/MeOH mp 167168 eC IR KBr 3250 1630 1520
`NMR
`1420 1360 1300 1260 1230 1160 1110 1020 cnf
`DMSO-d6
`4.27 br
`7.4 Hz
`7.197.30
`
`1.87
`
`2.13
`
`5.33
`
`5.77
`
`5.60
`5.5 Hz
`7.4 Hz
`NMR DMSO-d6 12.74 22.49 42.11 51.21 105.09 106.07
`126.16 126.64 126.85 127.09
`139.33 168.88
`
`8.22
`
`8.45
`
`10.38
`
`128.17
`
`7.53
`
`3.50
`
`127.5 127.9 128.3
`
`128.6 133.0 133.2 135.9 137.7 155.3
`
`in vacuo and the residue
`
`leaving
`
`4.33
`
`5.18
`
`12
`
`8.78
`
`9.06
`
`1.94
`
`4.30
`
`12
`
`169.79 ppm Anal C6H9NO
`Preparation of
`-2-Acetamldo-N-benzyl-2-2-
`naphthylacetamide 2f N-t-Boc-RS-2-naphthylglycine
`N-Benzylainide N-t-Boc-RS-2-naphthylglycine
`25 mmol was combined with CHCN 100 rnL and the mixture
`Et5N 2.53
`was placed into an ice/salt water bath
`mL 25 rnmol was added dropwise followed by ethyl chioro-
`2.40 rnL 25 mmol All additions were done slowly
`formate 2.71
`so that the temperature of the mixture did not rise above
`20 mm Benzylamine
`The mixture was then stirred at
`3.0 mL 27.5 mmol
`in CHCN 10 mL was added dropwise
`2.95
`and then room tern-
`and the mixture was stirred at
`perature 18
`The brown mixture was concentrated in vacuo
`and the residue was combined with hot THF and cooled in the
`resulting in the formation of white precipitate
`freezer
`The mixture was filtered and the precipitate was collected dried
`in vacuo and identified as EtNHCL The filtrate was concentrated
`in vacuo and the resulting solid was recrystallized from chloro-
`yield 4.18 43% mp 127129
`IR KBr 3240
`form/hexane
`NMR DMSO-d6
`1635 1520 1505 1460 1370 720 705 crn1
`7.147.79 ni 12
`1.31
`4.32
`5.42
`NMR DMSO-d6 28.2
`the N-H protons were not detected
`3C 43.3 58.3 80.0 124.6 126.1 126.2 126.3 127.1 127.2
`170.3 ppm Anal C4HNO
`-2-Naphthylglycine N-Benzylamide Methane-
`sulfonate The Boc-protected amino acid N-benzylaniide 391
`10 mmol was dissolved in trifluoroacetic acid 25 rnL and was
`stirred at room temperature 30 mm during which time gas
`evolved The solution was concentrated
`was redissolved in MeOH 50 mL Methanesulfonic acid 0.96
`0.65 mL 10 mmol was added dropwise and stirred mm
`After concentrating the solution in vacuo the residue was re-
`peatedly dissolved in MeOH and the solvent was removed
`50 mL The residue was then dried under vacuum 18
`yellow oil Trituration with CHCl gave white solid yield
`2.48 83% mp 180182
`IR KBr 3245 1655 1460 1385
`730 700 cm NMR DMSO-d6
`2.35 83
`5.5 Hz
`7.158.09
`NMR DMSO-d6 39.5 42.3 55.7 124.8
`5.5 Hz
`126.6 126.7 127.0 127.5 127.8 128.0
`128.3 131.4 132.4
`132.8 138.3 167.1 ppm The resonances
`for the remaining aro-
`matic carbons were not detected Anal C0HN04S
`-2-Acetamido-N-benzyl-2-2-naphthylacetamide
`2f RS-2-Naphthylgiycine N-benzylamide methanesulfonate
`4.1 mmol was suspended in CHCN 25 mL and was then
`1.59
`1.20 mL 8.2 mmol was added
`cooled in an ice bath EtN 0.83
`0.30 mL 4.1 mmol
`dropwise followed by acetyl chloride 0.32
`The ice bath was removed and stirring was continued at room
`temperature 18
`The solution was concentrated
`in vacuo and
`the residue was recrystallized from 11 95% EtOH/HO yield
`1.31 95% mp 210211
`IR KBr 3230 1710 1625 1535
`1465 760 710 cm NMR DMSO-d6
`5.2 Hz
`7.9 Hz
`7.157.91
`5.86
`NMR
`7.9 Hz
`5.2 Hz
`8.63
`8.33
`DMSO-d6 22.5 42.2 56.6 125.5 126.0 126.1 126.3 126.8 127.1
`127.5 127.7 127.9 128.2
`132.4 132.8 136.5 139.1
`169.2 170.0 ppm Anal CH0NO
`of RS-a-Acetaniido-N-benzyl-3-
`Preparation
`2m
`thiopheneacetamide
`-a-Acetamido-3-
`thiopheneacetic Acid
`RS-a-Aznino-3-thiopheneacetic
`acid
`25 minol was combined with H20 55 mL and was cooled
`3.92
`in an ice water bath Solid NaOH 1.00
`25 mmol was added
`in one portion and the reaction mixture was stirred until ho-
`4.70 mL 50 mmol was added dropwise
`mogeneous AcO 5.10
`followed by aqueous NaOH
`15 niL The solution was
`15 mm Acidification of
`temperature below 25
`stirred at
`
`the reaction solution with concentrated HC1 pH 15 mL led
`The mixture was filtered and
`to the formation of
`precipitate
`from 11 95%
`the collected white solid was recrystallized
`EtOH/HO producing light yellow crystals yield 3.55 75%
`NMR DMSO-d6
`mp 190192
`1.90
`7.6 Hz
`5.0 Hz
`7.507.55
`NMR DMSO-d6 22.3
`7.6 Hz
`52.2 123.3 126.5 127.2 137.3 169.3 171.8 ppm Anal C8H9-
`NOS
`RS-a-Acetamido-N-benzyl-3-thiopheneacetamide 2m
`With the procedure previously described for the preparation of
`N-t-Boc-RS-2-naphthylglycine N-benzylamide compound
`2.10 mL 15 minol
`15 mmol was treated with EtN 1.51
`2.99
`1.43 rnL 15 rnmol and benz-
`and ethyl chloroforrnate 1.63
`16.5 mrnol The filtrate upon workup was
`ylarnine 1.77
`concentrated in vacuo and the resulting yellow solid was re
`crystallized from 11 95% EtOH/HO yield 1.91 44% mp
`IR KBr 3460 1675 1570 1400 720 695 cmi
`198199
`NMR DMSO-d6 61.91
`5.2 Hz
`4.29
`7.9 Hz
`7.9 Hz
`7.147.50 rn
`NMR DMSO-d6 22.342.052.5
`
`7.13
`
`12.89
`
`5.42
`
`8.69
`
`8.55
`
`5.61
`
`8.74
`
`128.2
`
`139.0 139.2 169.0
`
`4.00
`
`1.90
`
`4.31
`
`5.58
`
`lit.9
`
`6.276.33
`7.607.64
`6.0 Hz
`RS-a-Acetamido-N-2-fluorobenzyl-2-furanacetamide
`3a Using 2-fluorobenzylamine 1.13
`9.0 mmol and racemic
`
`8.57
`
`5.2 Hz
`122.4 126.1 126.7 127.0
`169.8 ppm Anal CH16N02S
`Synthesis of RS-Ethyl a-Acetamido-2-furanacetate 13
`28.00 mL 0.028 mol was added
`An ethereal solution of ZnC1
`stirred solution of 12 4.40
`0.019 mol and furan 11.23
`to
`0.165 mol in dry THF 100 rnL and allowed to stir at room
`The mixture was then treated with HO 50
`temperature
`mL the organic phase was separated and the aqueous layer was
`100 mL The organic layers were
`extracted with CHCl
`combined and dried NaS04 and the volatile materials were
`removed by distillation
`in vacuo to give approximately
`97% of light-brown semisolid material TLC analysis showed
`major spot at R1 0.30 1% MeOH/CHC1
`The desired corn
`pound was purified by flash column chromatography on silica gel
`as the eluent to give 3.60 87% of
`using 1% MeOH/CHC1
`beige solid mp 6870
`lit.9 rnp 6970
`Preparation of RS-a-Acetamido-2-furanacetic Acid 10
`19 mmol was dissolved in 9010 EtOH/HO
`Compound 13 4.00
`150 mL and then KOH 2.00
`35 mmol was added and the
`resulting solution was stirred at room temperature 48
`The
`reaction was concentrated in vacuo and the residue was diluted
`50 mL The aqueous
`with HO and then washed with EtO
`layer was then made acidic with 8.5% HP04 and extracted with
`150 rnL The organic layers were combined dried
`EtOAc
`NaS04 and evaporated
`to dryness in vacuo to give 10 yield
`2.65 76% mp 172174C lit mp 171172
`R10.37 811
`2-propanol/NH4OH/HO
`Synthesis of RS-a-Acetamido-N-benzyl-substituted
`2-furanacetamides 24 General Procedure
`4-Methyl-
`equiv was added to
`equiv in
`morpholine
`solution of 10
`dry THF 75 mL/10 mmol at 10 to 15
`under
`After
`stirring mm isobutyl chloroformate
`equiv was added
`leading to the precipitation of white solid The reaction was
`allowed to proceed for two additional minutes and then
`solution
`equiv in THF 10 mL/10 mmol
`of the substituted benzylamine
`at 10 to 15
`The reaction mixture
`mm
`was added over
`was allowed to stir at room temperature for
`mm
`and then the
`4-methylmorpholine hydrochloride salt was filtered The organic
`layer was concentrated
`in vacuo the residue was triturated with
`EtOAc and the remaining white solid was filtered Concentration
`of the EtOAc layer led to additional amounts of the white solid
`The desired product was purified by recrystallization
`or flash
`chromatography of the combined solid material
`Using this procedure the following compounds were prepared
`RS-a-Acetamido-N-benzyl-2-furanacetamide 2g
`2.56 mrnol and racemic 10 0.47
`Using benzylamine 0.27
`65% of 2g The product was recrys
`2.56 rnmol gave 0.46
`tallized from EtOAc to give white solid mp 177178
`NMR
`R1 0.30 2% MeOH/CHCI
`mp 178179
`6.0 Hz
`DMSO-d6
`8.1 Hz
`6.406.44
`8.1 Hz
`
`7.207.36
`
`8.73
`
`

`
`924
`
`Journal of Medicinal Chemistry 1990 Vol 33 No
`
`Kohn et al
`
`5.58
`
`6.28
`
`8.61
`
`4.33
`
`6.29
`
`5.5
`
`8.76
`
`9.0
`jc 244.4
`
`8.2 mmol gave 1.20 50% of 3a mp 193195
`acid 10 1.50
`0C recrystallized from EtOAc R0.36 4% MeOH/CHC13
`JR
`KBr 3270 1630 1520 1440 1360 1220 1180 1140 1100 1000
`740 cm NMR DMSO-d6 tä 1.89
`Hz
`8.0 Hz
`8.0 Hz
`7.137.35
`7.62
`NMR DMSO-d6 22.35 36.12
`55 Hz
`JCF
`6.6 Hz 50.88 107.64 110.43 115.04
`21.4 Hz 124.29
`CF
`4.2 Hz 125.64
`15.0 Hz 128.94
`CF
`CF
`Hz 129.27
`5.5 Hz 142.66 151.07 159.99
`Hz 168.17 169.24 ppm Anal C5H5NOF
`RS-a-Acetamido-N-3-fluorobenzyl-2-furanacetamide
`3b Making use of 3-fluorobenzylamine 1.13
`9.0 mmol and
`8.2 mmol gave 1.90 80% of 3b mp 163165
`racemic 10 1.50
`recrystallized from EtOAc R1 0.30 4% MeOH/CHCI3 JR
`KBr 3230 1630 1540 1440 1360 1220 1140 1000 730 cm
`NMR DMSO-d6
`5.5 Hz
`7.8 Hz
`6.987.37
`
`5.55
`
`Hz
`113.50
`CF
`
`1.89
`
`4.31
`
`6.31
`
`6.42
`
`7.62
`
`8.61
`
`8.70
`
`5.5
`
`7.8 Hz
`NMR DMSO-d6 22.35 41.71 51.01 107.73 110.59
`21.6 Hz 113.60
`22.3 Hz 122.95 130.18
`cF
`jCF
`8.6 Hz 142.21
`7.5 Hz 142.66 151.03 162.28
`JCF
`243.3 Hz 168.23 169.31 ppm Anal CHN03F
`
`1.88
`
`6.27
`
`7.61
`
`4.27
`
`6.41
`
`8.58
`
`8.75
`
`RS-a-Acetainido-N-4-fluorobenzyl-2-furanacetamide
`3c Using racemic acid 10 1.50
`8.2 mmol and 4-fluoro-
`88% of 3c mp
`9.0 mmol gave 2.10
`benzylamine 1.13
`recrystallized from EtOAc R1 0.30 4% MeOH/
`188190
`CHCI JR KBr 3230 1620 1500 1360 1320 1260 1210 1140
`NMR DMSO-d6
`1000 820 780 730 cm1
`5.5 Hz
`8.0 Hz
`5.55
`7.097.15
`7.217.27
`3C NMR DMSO-d6
`8.0 Hz
`5.5 Hz
`21.1 Hz 129.48
`CF
`22.28 41.51 50.87 107.52 110.46 114.90
`8.3 Hz 135.23
`3.2 Hz 142.53 151.08 161.12
`169.13 ppm Anal CHNOF
`242.2 Hz 167.95
`RS -a-Acetamido-N-25-difluorobenzyl-2-furanacet-
`amide 3d Using 25-difluorobenzylamine
`9.0 mmol
`1.30
`8.2 mmol gave 1.60 64% of 3d
`and racemic acid 10 1.50
`recrystallized from EtOAc R1 0.38 4%
`mp 177178
`JR KBr 3230 1620 1520 1480 1360 1260 1230
`MeOH/CHCI
`1180 1140 1000 860 810 730 710 cm NMR DMSO-d6
`5.5 Hz
`7.7 Hz
`5.55
`7.227.25 in
`NMR
`7.7 Hz
`5.5 Hz
`8.62
`5.8 Hz 51.02 107.81 110.58
`CF
`DMSO.d6 22.30 35.98
`19.5 25.6 Hz 115.16 dd 1ca
`15.6 24.7 Hz
`115.06 dd
`10.1 23.9 Hz 127.98 dd JCF
`9.2 17.7 Hz
`116.52 dd CF
`239.0 Hz 158.18
`CF
`142.69 150.78 155.89
`jCF
`Hz 168.38 169.35 ppm Anal C15H4NOF
`RS-a-Acetaniido-N-26-difluorobenzyl-2-furanacet-
`amide 3e Making use of 26-difiuorobenzylainine
`1.30
`9.0
`8.2 mmol gave 1.90 73%
`mmol and racemic acid 10 1.50
`recrystallized from EtOH JR KBr 3230
`of 3e mp 237239
`1620 1530 1460 1360 1320 1260 1220 1160 1140 1030 1000
`820 780 750 740 710 cm NMR DMSO-d5 61.86
`4.5 Hz
`8.3 Hz
`7.057.10
`7.367.41
`NMR
`8.3 Hz
`4.5 Hz
`4.4 Hz 50.48 107.24 110.40
`DMSOda 22.33 30.74
`Jcr
`8.0 25.1 Hz 113.67
`111.61 dd Jc
`19.5 Hz 129.98
`JCF
`10.5 Hz 14250 151.23 160.93
`Jc 248.1 Hz 161.10
`CF
`248.1 Hz 167.59 169.00 ppm Anal CH4NOF
`CF
`-a-Acetamido-N-R -a-niethylbenzyl-2-furanacet-
`-a-Acetamido-N-R -a-methylbenzyl-2-
`amide and
`furanacetamide 4a and 4b Using R-a-methylbenzylamine
`8.2 mmol gave
`9.0 mmol and racemic
`1.10
`10 1.50
`crude
`mixture 2.00
`which was purified by flash column chroma-
`tography on SiO gel using 2% MeOH/CHC1
`as the eluent
`to
`give 4a and 4b
`Compound 4a yield 0.70 30% mp 224226
`MeOH
`127.4
`tallized from EtOAc
`2% MeOl/CHC1 JR CBr 3250 1620 1520 1440 1360 1300
`1270 1220 1140 1000 800 740 690 cm NMR DMSO-d6
`
`1.89
`
`6.32
`
`4.31
`
`6.43
`
`8.78
`
`7.62
`
`4.33
`
`6.38
`
`8.52
`
`5.53
`
`8.66
`
`6.17
`
`7.60
`
`238.8
`
`recrys-
`0.32
`
`1.31
`
`6.9 Hz
`8.2 Hz
`
`6.27
`
`1.86
`
`6.42
`
`5.61
`
`0.10
`
`recrys
`0.27
`
`1.90
`
`4.855.00
`
`1.36
`
`5.64
`
`4.854.98
`7.227.32
`8.2 Hz
`7.9 Hz
`7.62
`8.51
`8.70
`add