211
`
`212
`
`6,066,650
`
`TABLl_i G-continued
`
`TABLIL G-continued
`
`Y
`\
`/VK_/ Z
`
`N
`
`.
`.
`1' Ind‘-"“Yl' 1 W‘:
`C01T1]J0U11d5
`
`O
`
`N
`
`or
`
`X :
`
`Y
`\
`/fi[\/ Z
`
`5'
`
`X
`
`0
`
`N
`
`or
`
`X:
`
`6| Indcn yl-'l'},-"pt:
`Compounds
`
`X
`
`_
`3
`
`10
`
`15
`
`0
`
`N
`
`0
`
`O
`
`O O
`
`or
`
`x
`II
`
`01.
`
`II
`N
`
`20
`
`—\
`
`0
`
`H
`
`or
`
`0
`
`N
`
`0
`
`_
`
`0
`
`or R
`
`‘~\X‘
`
`1
`O
`
`or R
`
`0
`H
`S
`VII
`0
`
`25 Y- R
`_
`
`"-.
`
`H
`
`0
`
`O
`
`or R
`
`0
`
`o
`
`Y = R
`
`‘N
`II
`
`or R
`
`R = prnia}-‘l or [TI-"CH2
`
`>9
`
`(‘I-I;
`
`CH3
`
`R = propyl or ('TFjC[I_.
`
`\/ Q
`
`C1";
`
`l-'
`
`[1,c
`
`OEIH3
`
`F
`
`F
`
`5 g %
`
`*3"
`
`\ /
`
`10
`
`40
`
`45
`
`5“
`
`55
`
`G0
`
`65
`
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`
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`
`

`
`213
`
`'1‘/\BLl_i G-continued
`
`Y
`W3
`
`X
`
`X
`
`in Indcn yl-'l')"p::
`Compounds
`
`X:
`
`N
`
`or
`
`O 0
`
`N
`
`O
`
`O
`
`or
`
`\-
`H
`
`or
`
`()
`
`O
`
`Y : R...‘
`
`E
`
`or R
`
`R = propyl or CFACIIZ
`
`NII
`
`()
`H
`or R‘\ZS
`F,
`
`6,066,650
`
`214
`
`O
`RT STN
`
`
`
`X is H or F
`
`Example of R
`
`F
`
`Q.
`
`CF3
`
`()
`
`E
`
`H
`
`AC
`
`-‘RC3
`
`g
`
`\
`
`\04
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55 65
`
`109 of 162
`
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`216
`EXAMPI .13 340
`
`2—[ 1—[f4—[9_(Buty lsulfonyl)—9H—flu oren—9—y1]butyl]—4—
`p1peridinyl]-2,3-dihydro-1II-isomdol-1-one
`
`A.
`
`10
`
`009
`
`[I
`
`BuS
`
`
`
`6
`
`0
`
`A solution of 9-hydroxy-(91I)-llourene (1.58 g, 10.0
`15 mmol) and butanethiol (0.72 g, 8.00 mmol) in 10 mL of
`dichloromethane at -20° C. was treated with horontriIluo-
`
`ride cthcrale (1.28 g, 9.00 mmol). The reaction was stirred
`for 1 h at —20° C. and warmed to room temperature. After
`stirring for 18 h the contents of the flask were purified by
`20 column chromatography on silica gel (10() g) with hexanes
`
`followed by 1:9 dichloromethanei’hexanes to give 1.54 g
`
`(75%) of title compound as a colorless oil.
`TLC Silica gel (129 dichloromethanefhexanes) RJ,=0.5.
`
`1
`
`30
`
`BuS
`
`C1
`
`In the foregoing Tables which set out compounds of the
`Asolution of PartAcompound (1.0 g, 3.93 mmol) in 10
`invention of formulae I and II,
`that is compounds which
`include the 4—substituted piperidinc isomers, it willbc under— _ mL of THF at —78° C. was treated with n—butyllithium in
`stood that the formulae I and II compounds may he subsli- 3'-1 HCXHFICS (1.75 lT|lz, 4-40 ITIITIO1) 10110W€£1 by 1-Ch10f0-4-
`tuted with compounds of the invention of formulae li and lli,
`111'01110‘11U131111 (031 8» 4'70 1111111111- T110 10511311011 W115 511111511
`that is compounds which mcludc the 3_SubSmme(| pipcl-i_
`for 0.5 h and warmed to room temperature for 18 h. The
`dine i50mm.5_
`contents of the flask were diluted with 30 ml. of aqueous
`NlI,1(Il solution and 30 ml. of ethyl acetate. The organic
`40 fraction was dried (Na:SO,,) and concentrated. The remain-
`der was purilied by column chromatography on silica gel (50
`g) with 2:98 acetonefdichloromethane (5()() ml.) followed by
`15:85 dichloromethanefhexanes to give 100 (73%) of title
`compound as a colorless oil.
`TLC Silica gel (228 dichloromethanefhexanes) RJ,=0.4.
`M353 S1130 (ES: '1' 10115) 11113 255 (M—SC.:Hg)-
`C.
`
`¢_~;_e,_9_[4-[4-(2,3_])ihydm_111_iS(,ind01-g_y])_]-
`piperidinyl]butyl]-N-propyl-9ll-Iluorene-9-
`carboxamide, N-oxide
`
`45
`
`EXAMPLE 339
`
`©
`
`=
`
`||\/\/
`0
`
`C1
`
`A slurry of 3-chloroperoxyhenzoic acid (approx. 50%) 511
`
`(341 mg, 0.99 mmol) in CH2Cl2 (1 mL) was added dropwise
`to a solution of Example 310 compound (524 mg, 0.99
`mmol) in CHZCIZ (1 mL) at 0° C. under argon. The reaction
`was stirred at 0° c. for 20 min, diluted with CH3CL3 (15 mL),
`washed with saturated Naiico, (5 mi.) and brine (5 ml.), 55
`then dried over M gSO,,. Evaporation gave 612 mg of a white
`foam, which was purified by flash chromatography on silica
`Q‘-11 (75 8) 011111118 ‘V1111 3- 51°F 81511115111 of 4% 10 5% 10 7% 10
`10% M°01'11C1'1::C1':. 10 8111011115 13111131111-"1111“»1 (308 1113: 58%)
`315 31 Whilfi 1Ua1'1'1-
`
`MS(ES)1 538 [M+H]
`
`Anal. Calcd. for C34H3_.,N303.1.5 H30: C, 72.29; H, 7.50;
`N, 7.44 Found: C, 72.32; II, 7.28; N, 7.41.
`
`To a solution of Part B compound (0.3() g, 0.86 mmol) in
`dichloromethane (5 ml.) at 0° C. was added
`60 3-chloroperoxybenmic acid (m-Cl-‘I3/\) (0.37 g, 80% by
`weight -30.1.72 mmol) in one portion. The mixture was
`stirred for 1 h when it was diluted with 0.1 M KZCO3 (20
`ml.) and ether (30 m[.). The organic fraction was dried
`(Na2SO,,) and concentrated. The remainder was purified by
`65 column chromatography on silica gel (50 g) with 15:85 ethyl
`aoetatethexanes to give 0.24 g (75%) of title compound as a
`colorless Oil.
`
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`218
`n-butyllithium (%.5 ml., 2.5 M in hexanes, 66.3 mmol] was
`added over 15 min. The resulting slurry was stirred for 1 h
`and cooled to -78° C. Neat dibromobutane (6.() ml., 50.0
`mmol) was added in one portion and the reaction was
`allowed to warm to room temperature over the course of 6
`h. After an additional 14 h, the reaction mixture was poured
`into "I M hydrochloric acid (70 ml.) and extracted twice with
`ethyl acetate. The combined organic extracts were dried
`(Na2SO,,) and evaporated. The semi—solid residue was tritu—
`rated with hexanes and filtered to give 11.32 g of an
`olT-white solid.
`
`To a slurry of the above solid (11.0 g) in 25 ml. of
`dichloromethane at
`room temperature under argon was
`added a solution of oxalyl chloride (25 mL, 2.0 M in
`dichloromethane, 50 mmol) followed by 0.5 ml. (6.0 mmol)
`of DMF. After 1 h, the reaction was evaporated at less than
`25° C. and the residue redissolved in 30 ml. of THF. This
`solution was added over 20 min to a solution of 2,2,2-
`trifluoroethyl amine (6.10 g, 61.5 mmol) in 25 mL of THF
`at —10° (I. under argon. After 2 h, the reaction was quenched
`with 10% citric acid solution and extracted twice with ethyl
`acetate. The organic extract was dried (Na2S0_,) and evapo-
`rated. Purfication by flash chromatography (12><20 cm
`column, 7:3 dichloromethanefhexanes as elutant) on silica
`gel provided title compound as a white solid, 9.03 g, 60%
`yield from Example 312 Part 13 compound, mp l47—148° C.
`
`B. 9-[4-[[4-[(1,1-[)imethylethoxy)carbonyl]amino]-
`1-piperidinyl]butyl]-2,7-difluoro-N-(2,2,2-
`triiluoroethyl)-91I-iluorene-9-carboxamide
`
`To a stirred solution of Part A compound (5.48 g, 11.9
`mmol) in 20 mL of DMF at room temperature under argon
`was added Example 1 Part B compound (2.85 g, 14.2 mmol).
`The reaction was heated to 50° C. After 14 h, the reaction
`was quenched with 10% NaHSO3 solution and extracted
`with ethyl acetate. The organic extract was dried (MgS04),
`evaporated and re—evaporatcd twice from toluene. Purifica-
`tion hy [lash chromatography on silica gel (2.5x15 cm
`column, ethyl acetate elutant) gave title compound, as a
`white solid, 6.23 g, 90%, mp 152—154° C.
`EXAMP1 .E 342
`
`9-[4-[4-[(2-Phenoxybenzoyl)amino]-'1 -piperidinyl]
`butyl]—N—(2,2,2—trifluoroethyl)—9H—fluorene—9—
`carboxamide, monohydrochloride
`
`Following the procedure in Example 321 Part B,
`2-phenoxybenzoic acid (2.0 g, 9.34 mmol) was transformed
`into the acid chloride then reacted with Example 346 Part 1)
`compound (4.84 g, 9.34 mmol) to give a white solid (5.0 g).
`The product was dissolved in MeOH (5 mL), then 0.77M
`HCl in ethyl ether (15 mL) was added. The solution was
`evaporated and heated in a vacuum oven (55° C.) overnight
`to give title compound (51 g, 82%) as a white solid.
`mp. 'l23—127° C.
`MS (ES, + ion): 656 (M+II).
`Anal. Calc. for C3,51I3.,Cll-‘3N3(J2.0.7 1130: C, 66.07; 11,
`5.90; N, 6.08; 1-‘, 8.25 Found: C, 66.05; 11, 5.97; N, 5.96; 1-‘,
`8.21.
`
`EXAMPLE 343
`
`9—[4—[[4—(Benzoy1amino)—l —piperidiny1]butyl]—2,7—
`di[luoro-N-(2,2,2-triiluoroethyl)-91I-iluorene-9-
`carb oxa mide
`
`A solution of Example 341 compound (2.07 g, 3.56
`mmol) in 10 mL of 4 N hydrogen chloride in dioxanc was
`
`U:
`
`10
`
`20
`
`30
`
`40
`
`50
`
`55
`
`217
`
`Tl.C Silica gel (2:8 dichloromethanefhexanes) RJ,=0.07'.
`I}.
`
`To a solution of Part C compound (0.24 g, 0.64 mmol) in
`2-butanone (10 ml.) at RT was added Nal (1.00 g, 6.66
`mmol] in one portion. The mixture was refluxed for 30 h
`when it was diluted with water (20 ml.) and ether (30 ml.).
`The organic fraction was dried (Na2S(),,) and concentrated.
`The remainder was purified by column chromatography on
`silica gel (5() g) with 15:85 ethyl acelatefhexanes to give
`0.24 g (81%) of title compound as a colorless oil.
`
`E. 2—[1—[4—[9—(Buty1sulfonyl)—9H—fluoren—9—yl]
`bulyl]-4-piperidinyl]-2,3-dihydro-1II-isoindol-1-one
`
`To a stirred solution of 0.70 g (1.49 mmol) of Part I)
`compound in 6 ml. of DMF at RT was added 0.38 g (1.80
`mmol] of Example 2 Part Acompound. The reaction mixture
`was warmed to 55° C. and allowed to stir for 24 h. The
`mixture was diluted with NaIIC()3 solution (50 ml and
`ethyl acetate (50 ml.). The layers were separated, the organ-
`ics dried (Na2SO4) and concentrated. The remainder was
`purified by flash column chromatography on silica gel (100
`g) eluting with 5:95 methanolfdichloromethanc (700 mL)
`followed by 5:95:0.5 melhanolfdichloromelhanefNlI3 (1 1.).
`Pure fractions were pooled and concentrated to give 0.70 g
`(85%) of title compound as a thick oil which solidilied after
`standing.
`mp: 130-132” C.
`Tl.C Silica gel (5:95:1 meIhanolfdichloromethane,r'NII3)
`Rf=0.35.
`Anal. Calcd. for C34H40N;._SO3+0.5 H30: C, 72.79; H,
`7.30; N, 4.95;
`5.68 Found: (3, 72.25; 11, 7.15; N, 5.00; 5,
`5.69.
`
`EXAMPLE 341
`
`9-[4-[[4-[(1,1-[)irnethylethoxy)carbony1]amino]-1-
`piperidinyl]buty1]—2,7"—difluoro—N—(2,2,2—
`trifluoroethy1)—9H—fluorene—9—carboxamide
`
`Br
`
`
`
`c()xHcH2c.‘H3
`
`A Solution of Example 312 Part B compound (8.00 g,
`32.5 mmol) in 100 ml. of THF at room temperature was
`carefully evacuated and then purged with argon four times.
`The stirred solution was cooled to —25° (7. and a solution of
`
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`
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`
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`
`219
`stirred, protected by a calcium chloride drying tube, for 3 h.
`The solution was evaporated at 30° C. and the resulting solid
`was re-dissolved in 20 ml. of Tlll-'. To this stirred solution,
`cooled to -10° C. under argon, was added triethylamine
`(1.24 ml., 8.9 mmol) and then bCI17K)yl chloride (0.46 mmol,
`4.0 mmol) over 10 min. After 1 h, the reaction was quenched
`with saturated sodium bicarbonate solution and extracted
`
`twice with ethyl acetate. The organic extract was dried
`(Na2SO,,) and evaporated. Purfication by flash chromatog-
`raphy on silica gel
`(5x2() cm column, 1:19 methanol}
`ethylacetate as elutant) provided, after recrystallization from
`ethyl acetatefhexancs, title compound as a white solid, 1.83
`g, 87% yield, mp 177—179° C.
`Anal. Ca1c’d for C32II321"SN302<U<25 H30: C, 65.13; 11,
`5.55; 1-‘, 15.10; N, 7.12 Found: (3, 65.10; 11, 5.49; 1-‘, 15.85;
`N, 7.12.
`
`MA (electrospray, + ions) mic 586 (M+H).
`
`EXAMPLE 344
`
`9—[4—[[4-(1,3-Dihydro—1,3-dioxo—2H—isoindol—2—yl)—
`1—piperidinyl]butyl]—2,7—difluoro—N—(2,2,2—
`trilluoroethyl)-91l-Iluorene-9-carboxaniide
`
`A solution of l_-Example 341 compound (2.02 g, 3.47
`mmol) in 10 mL of 4 N hydrogen chloride in dioxane was
`stirred, protected by a calcium chloride drying tube, for 3 h.
`The solution was evaporated at 3()° C. and partitioned
`between saturated sodium bicarbonate solution and dichlo-
`
`romethane. The organic layer was separated, dried (Na2S(),,)
`and evaporated to give a white solid. To this residue was
`added 550 mg (3.71 mmol) of phthalic anhydride under an
`argon atmosphere. The solids were melted together at 150°
`C. for 6 h. On cooling, the resulting solid was recrystallized
`from ethyl acetatefhexanes to give title compound as a white
`solid, 1.71 g, 80% yield, mp l86—188° C.
`Anal. Calc’d for c:_,,,11,,.,1-‘_,N_.,()_,.n.13 11,0; (3, 64.56; 11,
`4.94; N 6.87 Found: (1, 64.56; 11, 5.03; N 6.81.
`MS (electrospray, + ions) mfe 612.2 (M+ll).
`
`EXAMPLE 345
`
`2,7—Diflu oro —9—[4—[ [4—[ (2—p heno xybe nzoyl)amino]— 1-
`peridinyl]butyl]-N-(2,2,2-trit1uoroethyl)-9H-
`i‘luorene—9—carboxamide
`
`To a solution of 565 mg (2.64 mmol) of
`2-pherroxybenzoic acid (Aldrich)
`in 10 ml. of dichlo-
`romethane under argon, was added 2 ml. of oxalyl chloride
`(2.0 M in dichloromethane, 4.0 mmol) and then 0.1 mL of
`DMF. After 1 h, the reaction was evaporated and the residue,
`2—phenoxybenzoyl chloride, was redissolved in 10 mL of
`THF.
`
`10
`
`20
`
`30
`
`40
`
`50
`
`220
`Anal. Calc’d for (I3,,ll3fili5N3[)3: C, 67.35; II, 5.35; 1’,
`14.02; N 6.20 Found: C, 67.20; H, 5.35; F, 14.33; N 6.08.
`MS (electrospray, — ions) mfe 676.3 (M—ll).
`
`I_".XAMl-’l .l_". 346
`
`9—[4—[4—(Be n7.oylamino)—1 —pipe ridinyl]b1.1tyl]—N—( 2,2,
`2-trilluoroethyl)-91l-Iluorene-9-carboxamide,
`monohydrochloride
`
`9; "
`
`Br
`
`To a solution of 9-lluorenecarboxylic acid (50 g, 240
`mmol) in 'I'lII" (1200 ml.) at 0° C. was added dropwise a
`solution of n—|)utyllithium (2.5M, 211 m1., 530 mmol) in
`'I'lI|". The yellow reaction was stirred at 0° C. for 1 h, then
`1,4dibromobutane (31.3 mL, 260 mmol) was added drop-
`wise over 30 min. The reaction was stirred at 0° C. for 30
`min, then the reaction was warmed to RT for 30 h. The
`reaction was extracted with water (3x750 ml.). The com-
`bined aqueous layers were extracted with ethyl ether (800
`mL). The aqueous layer was made acidic with HCl solution
`(IN, 500 ml.), then extracted with dichloromethane (32<750
`mL). The combined organic layers were dried over MgS0,,.
`Evaporation gave title compound (71 g, 85%) as a white
`solid.
`
`I20
`
`(TF3
`
`Iir
`
`To a solution of Part A acid (60 g, 173 mmol) and DMF
`A solution of l_-Example 341 compound (1.00 g, 1.76
`mmol) in 10 mL of 4 N hydrogen chloride in dioxane was
`(100 ;tL) in CH3Cl2 (600 mL) under argon at 0° C. was
`stirred, protected by a calcium chloride drying tube, for 3 h. 55 added oxalyl chloride (104 ml., 2.0M in CH: C12 , 208 mmol)
`The solution was evaporated at 30° C. and the resulting solid
`dropwise. The reaction was stirred at 0° C. for 10 min, then
`was re—dissolved in 10 mL of THF. To this stirred solution,
`warmed to RT and stirred for 1.5 h. The reaction was
`cooled to —1()° C. under argon was added triethylamine (0.95
`concentrated in vacuo to give the crude acid chloride as a
`mL, 6.5 mmol) and then the 2—phenoxybenzoyl chloride
`yellow oil. To a suspension of 2,2,2—trifluoroethylamine
`solution prepared above over 10 min. After 1 h, the reaction 60 hydrochloride (25.9 g, 191 mmol) in CH2Cl2 (500 ml.) at 0°
`was quenched with saturated sodium bicarbonate solution
`C. under argon was added triethylamine (73 mL, 521 mmol)
`and extracted twice with ethyl acetate. The organic extract
`followed by dropwise addition of a solution of the crude acid
`was dried (Na2SO,,) and evaporated. Purfication by flash
`chloride in CH2Cl2 (15 mL). The reaction was stirred at 0°
`chromatography on silica gel
`(5><20 cm column, 1:19
`C. for 1 h, diluted with CH,_Cl,_ (500 mL), and washed with
`methanolfethylacetate as elutant) provided, after reerystal- 65 water (2><?-00 mL), 1N HCl (2x300 mL), saturated NaHCO_.,
`lization from ethyl acetatefhcxanes, title compound as a
`(2><300 mL), and brine (2><300 mL), then dried over MgS04.
`white solid, 1.01 g, 85% yield, mp 168—69° C.
`Evaporation gave 80 g of a oil which was purified by flash
`
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`221
`chromatography on silica gel (2.5 kg). The crude product
`was loaded in a mixture of Cl-l:,_Cl,_ and hexane, and eluted
`with a step gradient of 10% l:'.l()Ac1’hexane (4 I.) to 15%
`I:'.t()Ac,u"hexane (2 I.) to 2()% l_-"l0/\c,r’hexane (4 L). Pure
`fractions were combined and evaporated to give title com-
`pound (52.5 g, 71%) as a while solid (mp 88-92” (7.).
`
`
`
`NI IBOC
`
`A mixture of Part B compound (29.5 g, 69.2 mmol),
`Example 1 Part B compound (14.5 g, 72.7 mmol), and
`anhydrous potassium carbonate (11.5 g, 83.0 mmol) in DMF
`(100 ml.) was stirred at 50° C. for 48 h, concentrated to
`dryness, and taken up in Cll:Cl: (50(l ml The solution was
`washed with saturated NallCO3 (32<80 ml.) and brine (2x80
`ml .), then dried over MgSO,,. l:'.vaporation gave a yellow oil
`which was purified by flash chromatography on silica gel
`(600 g), loaded in Cll:,_Cl:,_, and eluted with a step gradient
`of 2% Mco11,rc11,(:1, (3 1.) l0 3% Mco11;(:11,(71, (4 1.).
`Pure fractions were combined and evaporated to give title
`compound (30 g, 86%) as a white foamy gum.
`
`(TF3
`
`°2lIC|
`
`N1-12
`
`To a solution of Part C compound (30.5 g, 60.4 mmol) in
`dioxane (120 mL) was added 4N HCl in dioxane (121 ml...
`483 mmol). The reaction was stirred at RT for 4 h, then
`concentrated in vacuo to provide title compound (30 g) as a
`white foamy solid, containing a residual amount of dioxane.
`
`E. 9—[4—[4—(Benzoylamino)—1—piperidinyl]butyl]—N—
`(2,2,2-tri lluoroethyl)-91 I-lluorene -9-carb ox amide,
`monohydroehloride
`
`To a solution of Part D compound (1.6 g, 3.08 mmol) and
`triethylamine (1.5 ml., 10.8 mmol) in dichloromethane (10
`mL) at 0° C. was added dropwise benzoyl chloride (0.4 ml...
`3.40 mmol). The reaction was stirred at 0° C. for 30 min.
`Diehloromethane (200 mL) was added and the solution was
`washed with water (2:-<50 mL), brine (2><S0 mL) and dried
`
`222
`over MgS(),,. Purillcation was performed by flash chroma-
`tography on silica gel (100 g), loaded and eluted with 25%
`methanol in dichloromethane. Pure fractions were combined
`
`5
`
`10
`
`and evaporated to give a white solid. The product was
`dissolved in methanol (5 mL) and a solution of HCl in ethyl
`ether (0.Tr'N, 5.19 ml.) was added. The reaction was stirred
`at RT for 10 min, then evaporated to dryness. After drying
`in a vacuum oven (65° C., 72 h),
`title compound was
`obtained (1.3 g, 72%) as a white solid.
`
`m.p. 132—137° C.
`
`MS (C1, + ion): 550 (M+ll).
`
`Anal. (Ialc. for (13211,,c:11-‘,N,o,.11.2 11,0: (3, 65.18; 11,
`6.05; N, 7.13; (:1, 6.01; 1-‘,9.661-‘mind: C, 65.45; 11, 6.06; N,
`6.83; CI, 5.16; F, 9.30.
`
`EXAMPI .l:'. 347
`
`2,3-Dihydro-2-[1-[4-[9-(1-oxopentyl)-9ll-lluoren-9-
`yl]hutyl]—4—piperidinyl]—'l H—isoindol—'1 —one,
`monohydrochloride
`
`A.
`
`1
`
`A/V()'l‘l3S
`
`20
`
`30
`
`11(1).
`
`HO
`
`{)'I‘13s
`
`(TBS is Si(Cll_a)gt-Bu)
`
`40
`
`To a solution of 49 mL (055 mol) of 1,4—butanediol in 25
`ml. of DMIV, under argon at 0° C, was added 10.5 g (0.15
`mol) of imidazole followed by 20.7 g (0.14 mol) of
`t-butyldimethylsilyl chloride. The reaction was slowly
`wanrled to RT and stirred for 18 h at which time the reaction
`
`was diluted with ether and washed with NH_,Cl, water,
`Na2C()3, brine and dried (MgS()_,). The resulting title com-
`pound in the form of a colorless liquid, 50 g, contained
`approximately 15% of the disilylated compound.
`
`50
`
`55
`
`65
`
`11(2).
`
`I
`
`WOTES
`
`To a solution of 8.5 g (42 mmol) of Part /\(1) compound
`in 50 ml. ofTl-IF, under argon at 0° C, was added 7.3 g (108
`mmol) olimidazole and 16.7 g (64 mmol) of triphenylphos-
`phine. This mixture was stirred for 45 min (solution became
`homogeneoLLs) at which time 16.2 g (64 mmol) of iodine in
`50 ml. of Tllli was added dropwise over 20 min. The
`reaction was stirred for 1 h, diluted with hexane.-3 and washed
`with 1M sodium bisullite, Na2C()3, brine and dried
`(Na2S04). The resulting residue was triturated with ether
`(3><),
`filtered (to remove triphenylphosphine oxide) and
`evaporated to provided 10 g (61%) of title compound as a
`pale yellow oil.
`
`TLC Silica gel (421 hexanesfethyl acetate) Rj=0.60.
`
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`223
`
`224
`
`6,066,650
`
`'3'
`
`D.
`
`O
`
`otrlss
`
`O
`
`_OFBS
`
`it)
`
`15
`
`_
`To a solution of 5 g (23.78 mmol) of 9-Iluoreneearboxylic
`A To a solution of 340 mg (0.96 mmol)-:31‘ Part C compouind
`acid (Aldrich) in 20 mi, of '1‘}11.‘, iihdcr argon ai 0° (:1, was
`In 3 ml. uf'I‘|II*, under argon at 9° _C—. was addtjd dmpwlse
`added 20.5 mi, (52.32 mmol) of n-hutyllithium (2.5 M in
`hexaries) dropwise. The orar1ge—red ariiori was stirred for 0.5 20 463 "111 (l_-15 "1_"""l) Ur "'_b111Yl111h111m (3-5 M _111 hfixaflfi-"91
`h, at which iii-nc 75 g (2378 iiiiiici) of
`The resulting anion was stirred for 0.5 h, at which time 140
`ml. (1.16 mmol) of freshly distilled valeryl chloride
`(Aldrich) was added dropwise. The reaction was stirred for
`2 h, at which time it was diluted with ether and quenched
`25 with NaIIC()3. The organics were washed with water, brine,
`dried (NaSO4) and evaporated. Flash chromatography was
`
`/\\//\//()'I‘I3s
`
`I
`
`performed on 100 g of silica gel eluting with 95:5 hexariesi’
`(prepared as described in part A) was added dmpwisc The
`dlchlowmclhanc [0 providu 290 mg (69%) of ml‘: com"
`reaction gradually warmed to RT and was stirred for 36 h, at
`which time it was diluted with a l:l mixture of ethyl 30 pound as 3 palc ycllow 011'
`acetateflli._O (250 ml.). The organic; were washed with
`Na[I(:()3! brine» dricd (N31250:) Em‘-l c"’aP0r3l‘3d‘ Fla-‘ih Chm‘
`niatography was performed on 250 g of silica gel eluting
`
`'l'I .(I: Silica gel (95:5 hexanesfethyl acetate) RJ,=0.36.
`
`with 9:1 dichloromethanefisopropanol
`(52%) of title compound as a yellow oil.
`
`_
`_
`‘
`to provide 4.9 g T
`'3 M5 ((‘I—N”-3’ + Ions) mic 397 (M+H)'
`
`(921 diehloromethanelisopropanol)
`
`TLC: Silica gel
`Ri.=0.5U.
`
`9-
`
`v
`
`OTBS
`
`40
`
`45
`
`50
`
`55
`
`Anal. Calcd. for C,,iH32O3Si+0.15 mol H20: C, 72.20; H,
`8.15 Found: C, 72.20; [1, 7.88.
`
`I-:_
`
`.
`
`Me
`
`OH
`
`To 200 mg (0.46 mmol) of Part 1) compound was added
`1 .mL of 5:95 aqueous I._I.HaCcI0nm-110' Hie rcilcnoil “fa?
`To 550 mg (1.38 mmol) of Part B compound was added
`stirred under argon at RI, for 3 h, at which time it was
`.
`.
`.
`.
`.
`.
`,
`5 mL ot DMSO. The reaction was stirred for 18 h, under
`argon at H1‘ at which time it was diluted with ether and 60 dllulcd W111] elhflr and Wasl-ma wuh Nancoa’ water (ax),
`washed witli water Bx)
`l-‘lash chromatography was per-
`brmc’ dried (MgSO‘l) and cvaporamd Flash chromatogra-
`'
`”
`.'.
`.
`.
`”
`phy was performed on 50 g of silica gel eluting with 7:3
`formed on 100 g of silica gel eluting with 95:5 hexaiiesfethyl
`.
`.
`,
`.
`.
`i __
`hexanesfethyl acetate to provide 120 mg (81%) ot
`title
`_
`_
`_
`.
`.
`_
`_
`acetate to provide 340 mg (70%) of title compound as a pale
`_l
`d
`I
`H
`yflllow 01.1’
`65 eompoun as a pa e ye ow oi .
`
`TLC: Silica gel (95:5 hexanesfethylacetate) RJ,=0.3l.
`
`'l‘I.(I: Silica gel (8:2 hexanesi‘ethyl acetate) R!=0.l5.
`
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`
`DR 0
`
`Me
`
`6,066,650
`
`226
`the reaction and the resulting solution was washed with I120
`(40 mL), saturated sodium bicarbonate solution (40 ml.),
`brine (40 ml.) and dried over MgS(),,. I.-Evaporation gave a
`crude gum. Purification was perfonried by flash chromatog-
`raphy on silica gel (100 g), loaded and eluted with 2.5%
`methanol in dichloromethane. Pure fractions were combined
`
`and evaporated to give title compound (610 m g, 72%) as a
`olT-white solid.
`
`10
`
`rn.p. t66—]69° c:.
`MS (FAB, + ion): 425 (M+H)
`Anal. Calc. for c,,,H,,,N,0,.1,1 H30: C, 75.68; H, 6.85;
`N, 6.30 Found: C, 75.50; H, 0.45; N, 524,
`
`H
`'
`
`To a solution of 120 rn
`0.37 mmol of Part E com ound
`in 1.5 mL of THF, underga(rgon at 0°
`was added £5 mg
`(0.81 mmol) of imidazole followed by 126 mg (0.48 mmol)
`of triphenylphosphine. The mixture was stirred for 0.5 h, at
`which time 122 mg (0.48 mmol) of iodine in 1 ml. ofTIlF 20
`was added dropwise. The reaction was stirred for 1 h at 0°
`C., 1 h at RT, then diluted with hexanes and washed with
`fresh sodium bisullite solution, NaIICO3, water, brine, dried
`(MgS(J4) and evaporated. l-‘lash chromatography was per-
`formed on 25 g of silica gel eluting with 9:1 hexanesiethyl as
`acetate to provide 130 mg (81%) of title compound as a “
`colorless oil.
`
`TLC: Silica gel (9:1 hexanesfethyl acetate) RJ,=0.40.
`
`G. 2,3-Dihydro-2-[1-[4-[9-(1-oxopentyl)-9lI-
`lluoren-9-yl]butyl]-4-pipei‘idinyl]-1II-isoindol-l-
`one, monohydrochloride
`
`30
`
`EXAMPLE 349
`.
`[1'[4'[9'[(?m[lylamlm)Carblmyl]igII'fiu0rm'9'yl]
`hmy]]'3'p1pcndmyl]Carbam1C acid? phenylmclhyl
`ester’ mmmhydmchlondc
`
`
`
`(702191
`
`I5.
`
`A 1111X1“1"‘* Of EXa_mP1° 314 P1111 A C0Y1'1P°1-111d(3-3318» 530
`To a solution of 130 mg (0.30 mmol) of Part F compound
`mmol) and clhyl ml3°‘301al° (13 ml-s 8-28 mmol) in DMF
`in 1.5 ml, of DMI-', under argon at RT, was added 20 mg
`(0.15 mmol) of K,c0, and 84 rr1g(0.39 mmol) of Example 35 (3.5 mL) under argon was heated at 60° C- for 23 h. then
`2 part A compmmd The reaction was Stirred for 13 h, at
`cooled to RT. The solvent was removed under reduced
`which time it was poured into water. The precipitate was
`P1'°55U1'°v T110 1"35“111118 0131180 1'0-51d‘-1°
`‘Va-5 d155°1V°‘1 111
`collected, dissolved into ether, dried (Na2SO,,) and evapo—
`CH2C12 (50 mL)- Washfid ‘V1111 5311-11'a1°d NEIHCO3 (2><15
`rated to provide a pale yellow solid. The solid was dissolved
`mL) and b1'111° (20 IUL)» 111°“ d1'1°d 0"“ Nazso-p E"'<1P01'a'
`in ether and treated with 305 mL (0.30 mmol) of HCl (1 M 40 ticgneavd 3-6 2; of an orange gum, which was dissolved in a
`in ether).The ether was decanted oIT,the solids collected and
`11115151511 3-muum of Cllzclz and P‘-‘fined by fla5h Chroma‘
`dried for 13 l'1(50° C. under vacuum) id provide 115 mg
`tography on 511164 gel (175 g) cluting with 2_% Mc0_H»’
`(74%)0fm1c compound as a pale yellow Solid
`CIIZCI? to provide 2.65 g of product contaminated with
`mp 96400.; 0
`approximately 20 mol % DM_1-7. The product was dissolved
`Tl Cl’ §ilica
`el (995 dichloromethanefiso ro ai1ol+1% 45 1” EIOAC (00 mL).’ washed with water (3x20
`and brine
`N“ (‘)i‘i)‘R_0§6
`‘ "
`‘ P P
`(20 mL), then dned over Na2S(J4. Evaporation gave title
`"
`f" ‘
`'
`compound (2.38 g, 75%) as an amber oil.
`Ms (i.-‘S, Nii,,()11, + ions) me 521 (M+Il).
`(I,
`Anal. Calcd.
`for C_.,5II,mN2(]2 IICl+0.5 mo] H20:
`74.25; H, 7.48; N, 4.95 Found: C, 74.24; H, 7.45; N, 4.98. 59
`
`EXAMPLE 348
`2,3—Dihydro—2—[1—(1—oxo—3,3—diphenylpropyl)—4—
`
`55
`
`piperidinyl]—1H—isoindol—1—one
`To a solution of 3,3-diphenylpropionic acid (500 mg, 2.21
`mmol) and l)Ml-' (1 drop) in dichloromethane (5 ml.) at RT
`was added dropwise a solution of oxalyl chloride in dichlo-
`romethane (2.()M, 1.66 ml., 3.32 mmol). Bubbling of escap-
`ing gasses continued for 10 min after addition. The reaction 60
`was stirred at RT for 60 min, then concentrated in vacuo to
`give a crude oil. To a solution of crude acid chloride and
`triethylamine (1.4 ml,, 10.0 mmol) in dichloromethane (10
`Palladium on carbon (10%) (273 mg, 0.258 mmol) was
`ml,) at 0° C. under argon was added dropwise a solution of
`Example 2 Part A compound (434 mg, 2.00 mmol)
`in 65 added to a solution of Part Acompound (2.37 g, 5.15 mmol)
`dichloromelhane (2 ml.). The reaction was stirred at 0° (3.
`in a mixture of EIOAC (10 mL) and EIOH (15 mL). The
`for 10 min. [)ich1oromethane (10() ml.) was added to dilute
`mixture was hydrogenated (balloon) at RT for 1.5 h, filtered
`
`0 0
`‘ N/\/
`
`H
`
`N
`
`COGEI
`'
`
`115 of 162
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`
`6,066,650
`
`227
`through Celite, and washed with l:'.t()Ac (3x20 ml.). The
`filtrate was concentrated in vacuo to give title compound
`(2.42 g, 100%) as a pale yellow oil.
`
`{I
`
`228
`EXAMPLE‘ 350
`
`9—[4—[4—(2,3—Dihydro—1—oxo—1H—isoindo1—2—yl)—l—
`piperidin yl]butyl]-N -(2,2,2-trilluoroeth yl) -91 l-
`fluorene-9-carboxamide, hydrochloride salt
`
`A.
`
`t E/\\/
`
`in ®.
`
`0
`
`\
`
`N
`
`C02“
`
`15
`
`11
`
`\
`
`(TF3
`
`C‘
`
`' H“
`
`To a sti1Ted solution of 10.0 g (33.5 mmol) of compound
`prepared in Ijxample 314 Part A llrst paragraph in 10() ml.
`20 of dichloromethane at RT was added 20.0 ml . (40 mmol] of
`2M oxalyl chloride in dichloromethane followed by 30 ml.
`of DMF. The reaction was allowed to stir at RT for 2 h when
`AQUEOUS KOH (5.6 ml, IN. 5.6 IIIIIIOI) Was a(lCl0Cl 10 a
`the solvent was evaporated and the semisolid residue
`solution of Part B compound (2.17 g, 4.70 mmol) in Tl-IF (10
`P11111P‘1"d
`(“*1 111111
`13113511511113)
`[01 0-5 hv
`11113
`1351110115 W115
`ml.) under argon. The biphasic mixture was stirred at RT for
`4 h, then heated at 5()° C. for 48 h. The reaction was cooled 25 °'°°?lV°d b_y‘°°:°m1g 300
`(iii-,{;"'5h°r °n6d7°°°l°dlt° 01.
`32°
`1° RT and °°i°ifi°° to PH 15 with TN Hm‘ Th° cloudy
`i1iii]lluLcl)i":)elli1d§lairii:iEile°andvivarmed tdg rtgorn llr1:$0e.)ra(t)ure°’Tli<;
`Rfaclgilln was dihlwd “Th Walt” (30 ml’) “Ed °x1‘ra°1°d “Th
`mixture wall. diluted with 150 ml. of ethyl acgtate and 100
`(-1 [(-13 (3X1[)0 ml’): 1111311 1111911 OVCT N11250:‘ 1-‘-V'3l1““71””"
`ml. of 0.5 M Il(fI.. The lavers were separated, the organics
`511]-1111117‘-1 111113 CU1'1'1P0111'1d (2-2 g) 100% Crude) 35 51
`r113"1Y
`dried (Na2S(),,) and concehtrated. 'lhe remainder was puri-
`white solid.
`lied by flash column chromatography on silica gel (250 g)
`eluting with 1:9 ethyl acetatefhexanes [800 ml.) followed by
`1:5 ethyl acetatefhexanes (1 l.). Pure fractions were pooled
`andlponceilitaated to give 925 g (73%) of title compound as
`H '1 ‘:1 '_°8';:§0,, C
`"
`P’
`'
`"
`Is.
`
`3"
`
`D_ [1_[4_[9_Hpropylamim)carbony1]_911_flu0mn_9_
`yl]—butyl]—3—piperidinyl]carbamie acid,
`phenylmethyl ester, monohydrochloride
`
`(7 compound (336 mg,
`To a cloudy suspension of Part
`0.714 mmol) and triethylarnine (238 ,uL, 1.71 mmol) in 40
`
`E
`
`\
`
`gas
`
`N
`
`O
`
`\_
`'
`
`dioxane under argon was added diphenylphosphoryl azide .
`(184,ul., 0.857 mmol). The mixture was heated at 80° C. for
`2 h (N: evolution observed soon after heating commenced).
`O
`llenzyl alcohol (367 fl.l., 3.57 mmol] was added, and the
`reaction was heated at 80° C. ovemight. The reaction was 45
`cooled to RT and the solvent was distilled oll under reduced
`pressure. The resulting residue was partitioned between
`Cl [2Cl: (20 ml
`and saturated NallCO_., (5 ml The organic
`‘D
`layer was washed with brine (5 mL) and dried over Na2S0,,.
`Evaporation gave 760 mg of a yellow oil, which was purified "
`by flash chromatography on silica gel (50 g) eluting with 3%
`M°OH‘iCH3Cl3 to give 215 mg of a Colorlcss Oil‘
`
`__
`The free amine was dissolved in l_".t2O (3 ml.) and treated Sq
`W1111 0-77“ “C1 111 131:0 (3 "11=l- T116 W111“? P1”11C1P11111¢‘v W113
`filtered, washed with Et2O (2><3 ml.), then dried under high
`vacuum at 50° C. overnight to give title comound (173 mg,
`42%) as a white foamy Solid‘
`
`MS (ES) 540 [M+H]
`
`65
`
`To a sti1Ted solution of 6.54 g (17.22 mmol) of Part A
`compound in 6 mL of DMF at RT was added 4.00 g (18.51
`l
`fE
`l2PrtA
`d
`d2.41
`17.50
`[Egg]; Sf
`fihc riactiofiorggfill1: ‘:3: warmcfi E0 400
`and allowed to stir for 20 h. The mixture was diluted with
`200 mL of water and 2 mL of 1M NaOH Solution (pH=11).
`The white Solids were collected by filtration and dried to
`60 give 10.0-g (100%) of title compound.
`TLC Silica gel (5:95:1 methanolfdiehloi'omethanei’NH3)
`R,=0.35.
`C. 9—[4—[4—(2,3—Dihydro—1—oxo—1H—isoindol—2—yl)—1—
`piperidinyl]butyl]—N—(2,2,2—trifluoroethyl)—9H—
`lluorene-9-carboxamide
`
`(:,
`T01’
`Anal.
`7-33; N. 733- 1"01-lfldi (7. 70111; 11, 7124; N. 7-09.
`
`II,
`
`rnrnol) of Part B cofnpound
`g
`Asuspcnsion of
`in 80 mLofethanol was treated with 0.5 g of 10% Prlfcarbon
`
`116 01 162
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`6,066,650
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`229
`and placed under an atmosphere of llz (balloon pressure).
`The reaction mixture was stirred for 25 h when it was filtered
`
`through a pad of Celite and concentrated. The remainder was
`triturated with warm water to give 9.0 g (93%) of title
`compound as a while solid.
`mp: 143-146” C.
`TLC Silica gel (5:95:1 rnethanolfdiehloromethanc7’NH3)
`R,=0.35.
`
`D. 9-[4-[4-(2,3-l)ihydro-1-oxo-l l I-isoindol-2-yl)-l -
`piperidinyl]butyl]—N—(2,2,2—tritluoroethyl)—9H—
`fluorcne-9-earhoxamide, hydrochloride salt
`
`A suspension of 9.()[] g (-=-l6 mmol) of Part B compound
`in 200 mL of ethyl ether was treated with 8 mL (32 mmol)
`of 4M llCl in dioxane and the reaction mixture stin'ed for l
`
`h under an atmosphere of NE. The reaction mixture was
`filtered and the white solid collected. The solid was dried at
`40° C. under vaccuum to give 9.0 g (93%) of title compound
`as a white solid.
`
`mp: 139—141‘’ C.
`Tl.C Silica gel (5:95:l methanol7'dichloromethane,t'NlI3)
`R,=0.35.
`MS (ES, + ions) rnfz 562 (M+H).
`Anal. Caled. for C33H35N-O;._F3Cl: C, 66.27; H, 5.90; N,
`7.03; 1-", 9.53 Found: C, 66.53; H, 5.82; N, 6.78, F, 8.99.
`EXAM Pl.l_-' 351
`
`9—[4—[4—(2,3—Dihydro-1—oxo—1H—isoindol—2—yl)—1—
`piperidinyl]butyl]—N—(2,2,2—tritluoroethyl)—9H—
`fluorene—9—carboxarnide, hydrochloride salt
`
`To a stirred solution of 4.00 g (9.38 mmol) of Example
`346 Part B compound in 6 mLo[ DM1’ at R'l'was added 2.44
`g (18.51 mmol) of Example 2 Part Aeornpound and 1.59 g
`(11.30 mmol) of K2C03. The reaction mixture was warmed
`to 50° C. and allowed to stir for 18 h. The mixture was
`diluted with 200 mL of water and 2 mL of 1M NaOH
`
`solution (pl lull). The white solids were collected by filtra-
`tion and dried to give 4.50 g of title compound.
`
`B. 9-[4-[4-(2,3-Dihydro-1-oxo-1ll-isoindol-2-yl)-'l-
`piperidinyl]butyl]-N-(2,2,2-trilluoroethyl)-91l-
`fluorene—9—carboxarnide, hydrochloride salt
`
`Asuspension of 4.00 g (===9.00 mmol) of Part Aeompound
`in 200 ml. of ethyl ether was treated with 8 ml. (32 mmol)
`of 4M HCl in dioxane and the reaction mixture stirred for 1
`
`h under an atmosphere of N2. The reaction mixture was
`filtered and the cream colored solid collected. The solid was
`dried at 40° C. under vacuum to give 3.8 g (73%) of title
`compound.
`
`230
`
`mp: 139-] 41° C.
`MS
`+ ions) m/z. 562 (M+ll).
`Anal. Calcd. for C33H35N3O2F_.,Cl: C, 66.27; H, 5.90; N,
`7.031-‘ound; C, 65.87; 11, 6.14; N, 6.71.
`
`l_".XAMl-‘l .138 352-360
`
`Following the procedures set out herein, the following
`compounds were prepared.
`
`EXAMPLE 352
`