wo 2010/132601
`
`ExampleCN
`
`Cbz N ) - -0 - -
`~
`~
`1 Br
`'
`11
`\\
`II
`
`:
`
`CNv-~~t
`
`H
`
`+
`
`HO
`' __/\____
`,B~NHBoc
`HO
`
`Pd(PPh3)4,
`K2C03
`
`DMEIH20
`85 ·c
`
`PCT /US201 0/034600
`
`CbzN~
`NJJ" -~NHBoc
`CH
`
`2-[5-(4'-tert-Butoxycarbonylamino(cid:173)
`biphenyl-4-yl)-1 H-lmldazol-2-yl}(cid:173)
`pyrrolidine-1-carboxytic acid benzyl ester
`
`2-[5-(4-Bromo-phenyt)-1 H(cid:173)
`imidazol-2-yl]-pyrrolidine-1-
`carboxylic acid benzyl ester
`
`(4-tert(cid:173)
`Butoxycarbonylamino
`phenyt)-boronic acid
`
`+
`
`HATU, DIPEA
`DMF
`
`2-Methoxycarbonylamino-3-
`methyl-butyric acid
`
`1. HCI, MeOH
`H
`0
`2. Boc-Pro-OH,
`EIOCOCI, Et3N, N~ )l_~,
`THF
`
`~__)!..N~HN u
`3. H2. Pd/C, EIOH c H
`
`-P
`
`yrrolidine-2-carboxylic acid [4'-(2-pyrrolidln-
`2 -yi-3H-imidazol-4-yl)-biphenyt-4-yl]-a mide
`
`4. HCI, MeOH
`
`0
`H
`II
`'o--"N'
`
`'~"6tto-O-lD~o
`
`0
`
`H 0-
`'N-{
`
`(1-{2-[5-(4'-{11-(2-Methoxycarbonylamino-3-methyl-butyryl)(cid:173)
`pyrrotid ine-2-ca rbonyl}-amino}-biphenyl-4-yl)-1 H-imidazol-2-yl}(cid:173)
`pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester
`
`2-[5-( 4' -tert-Butoxycarbonylamino-biphenyl-4-yl)-lH -imidazol-2-yl]-pyrrolidine-1-
`
`carboxylic acid benzyl ester: 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-l(cid:173)
`
`carboxylic acid benzyl ester (2.31 g, 5.42 mmol), ( 4-tert-Butoxycarbonylaminophenyl)-boronic
`
`acid (1.28 g, 5.42 mmol), Pd(PPh3)4 (313 mg, 0.271 mmol) and K2C03 (6 mL of2 M aqueous
`solution, 11.92 mmol) were combined with I ,2-dimethoxyethane (20 mL). The suspension was
`
`stirred while N2 was bubbled through the solution for 14 min. A reflux condenser was attached
`and the suspension was heated to 85"C for 15 hours. It was then cooled, diluted with ethyl
`
`acetate (150 mL), washed with water and brine, dried over sodium sulfate and concentrated.
`
`The crude product was purified by silica column chromatography (25% to 50% EtOAclhexanes)
`
`to provide 2-[5-( 4'-tert-Butoxycarbonylamino-biphenyl-4-yl)-1 H-imidazol-2-yl]-pyrrolidine-1-
`
`carboxylic acid benzyl ester (1.20 g, 41 %).
`
`Pyrrolidine-2-carboxylic acid [4'-(2-pyrrolidin-2-yi-3H-imidazol-4-yl)-biphenyl-4-yl)(cid:173)
`
`amide: 2-[5-(4'-tert-Butoxycarbonylamino-biphenyl-4-yl)-1 H-imidazol-2-yl]-pyrrolidine-1-
`
`carboxylic acid benzyl ester (1.75 g, 3.25 mmol) was dissolved in methanol (40 mL) and
`concentrated HCl (2 mL) was added. The solution was stirred at so·c for 19 hours before being
`concentrated to a volume of 10 mL, poured into saturated NaHC03 (60 mL). The organic phase
`was extracted 3 times with 30 mL dichloromethane. The combined organic phases were dried
`
`with sodium sulfate and concentrated. A portion of the resulting residue (963 mg, 2.20 mmol)
`
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`
`was dissolved in THF ( 4 mL). In a separate flask, ethylchlorofonnate (0.231 mL, 2.24 mmol)
`was added dropwise to a stirred o·c solution ofBoc-Pro-OH (568 mg, 2.64 mmol) and
`triethylamine (0.368 mL, 2.69 mmol) in THF (6 mL). After 10 minutes, the solution of biphenyl
`
`compound was added by cannula followed by a 2 mL rinse with THF. Following addition, the
`
`mixture was warmed toRT. After 70 min, the mixture was diluted with ethyl acetate (60 mL)
`
`and washed with water and brine. The organic phase was dried over sodium sulfate and
`
`concentrated. The residue was purified by silica column chromatogmphy (25% to 50%
`
`EtOAclhexanes) to provide the Boc-Pro compound (470 mg, 63%). This material was dissolved
`
`in ethanol (40 mL) and 10% Pd/C (300 mg) was added before the flask was sealed and a bladder
`
`containing hydrogen gas was attached. A venting needle was placed in the septum for 30 s to
`
`allow hydrogen to bubble through the solution. After 14 h, the mixture was filtered over
`
`CELITE and concentrated. A portion of this residue (169 mg, 0.337 mmol) was dissolved in
`
`methanol (20 mL) and concentrated HCl (2 mL) was added. The mixture was stirred at 60"C
`
`before being concentrated to provide Pyrrolidine-2-carboxylic acid [4'-(2-pyrrolidin-2-yl-3H(cid:173)
`
`imidazol-4-yl)-biphenyl-4-yl]-amide (135 mg, 100%).
`
`(1-{2-[ 5-( 4'-{[ 1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl](cid:173)
`
`amino }-biphenyl-4-yl)-1 H-imidazol-2-yl] -pyrrolidine-1-carbony J}-2-met by 1-propyJ)(cid:173)
`
`carbamic acid methyl ester: Pyrrolidine-2-carboxylic acid [4'-(2-pyrrolidin-2-yl-3H-imidazol-
`
`4-yl)-biphenyl-4-yl]-amide (135 mg, 0.337 mmol), 2-Methoxycarbonylamino-3-methyl-butyric
`
`acid (118 mg, 0.674 mmol) and HATU (282 mg, 0.741 mmol) were suspended in DMF (6 mL)
`and cooled to o·c before DIPEA (0.470 mL, 2.70 mmol) was added. After 60 min, the mixture
`was warmed to RTthen filtered and purified by reverse phase preparative HPLC, giving (1-{2-
`
`[ 5-( 4'-{ [ 1-(2-Methoxycarbonylamino-3-methyl -butyryl)-pyrrolidine-2-carbonyl]-amino}(cid:173)
`
`biphenyl-4-yl)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl} -2-methyl-propyl)-carbamic acid
`methylester(l36mg,56%). 1HNMR(DMSO-d6,400MHz) 10.16(s, 1H),8.07(s, 1H), 7.80
`(d, J= 4.5 Hz, 4H), 7.70 (d, J= 4.5 Hz, 4H), 7.30 (m, 1H), 5.09 (m, 1H), 4.44 (m, I H), 4.08 (m,
`
`1H), 4.02 (m, 1H), 3.85-3.77 (m, 3H), 3.61 (m, lH), 3.54 (s, 3H), 3.53 (s, 3H), 2.37 (m, 1H),
`2.16-1.84 (m, lOH), 0.92 (d, J= 6.7 Hz, 3H), 0.86 (d, 6.5 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H), 0.75
`(d, J= 6.6 Hz, 3H); MS (ESI) mlz 716 [M + Ht.
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`Example CO
`
`~ vy
`
`CQOTf
`Tf20,
`~
`
`-&
`
`+
`
`OH
`
`OTI
`Trifluoro-methanesulfcnic edd
`5-trifluoromethanesulfonyloxy(cid:173)
`naphthalen-1 "fl ester
`
`PCT /US201 0/034600
`
`Boc N}-Q-- of
`
`a:
`0
`
`1 ~~ ~ 9
`CNy-~
`
`H
`'
`2-{5;4-{4,4,5,5-Tetramethy~
`(1,3,2)dioxaborolar>-2-yt)-phenyt]-1 H-imidazol-2-
`yl}-pymllidin&-1-<:arboxylic acid let! -butyl ester
`
`Pd(PPh3)4.
`~
`PhMe
`100'C
`
`Boc
`Pd(PPh,)4 ,
`I ~~Br~
`CNy-~
`DME/HzO
`85'C
`
`H
`
`'
`
`2-{5;4-{5-Trifluoromelhanesu~onyloxy­
`naphthalen-1-yl)ilhenyl]-1 H-imidazol-2-yl](cid:173)
`pyrrolidine-1-<:artoxylic acid lett-butyl ester
`
`2-{5;4-{5;4,4,5,5-T etramethyl-(1,3,2]diaxaborolan-2- 2-{5-Bromo-1H-imidazol-2-yiH>yrrolidin&-
`1-<:arboxylic acid lett-butyl ester
`yt)-naphthaler>-1-yl]-phenyf)-1 H-imidazol-2-yl)-
`pyrroidine-1-<:arboxylic acid lett-butyl ester
`
`+
`
`1.HCI,Me0H
`2.HATU, DIPEA
`DMF
`
`2-(5-{4-{5; 1 H-imidazo~2-yl)-pyrrolidine-1-<:arboxylic acid
`lett-butyt ester)-naphthalen-1-yl)i>henyl)-1 H-imidazo~2-
`yt)-pyrrolidine-1-<:arboXylic acid lett-butyl ester
`
`2-Methoxycarbonylamino-3-
`methyl-butyric acid
`
`(1-{2-{5;4-(5-{2-(1-{2-Methoxycarbonylamino-3-<nelhyl-butyryl)(cid:173)
`pyrrolldin-2-yi]-3H-imidazo~-yl)-naphthalen-1-yt)-phenyi]-1H-imidazo~2-
`yt)-pyrrolidine-1-<:arbonyl)-2-methyl-propyt}-cart>amic edd methyl ester
`
`Trifluoro-methanesulfonic acid 5-trifluoromethanesulfonyloxy-naphthalen-1-yl ester:
`
`Naphthalene-1,5-diol (1 g, 6.25 mmol) was dissolved in dichloromethane (25 mL) and
`
`triethylamine (2.6 mL, 18.73 mmol) and trifluoromethanesulfonic anhydride (1.58 mL, 9.86
`
`mmol) were added. After stirring for 16 h, the mixture was diluted with ethyl acetate (250 mL)
`
`and washed with water, saturated aqueous sodium bicarbonate and brine. The organic phase was
`
`dried over sodium sulfate, concentrated and purified by silica column chromatography (0% to
`
`10% EtOAc/hexanes) to provide Trifluoro-methanesulfonic acid 5-trifluoromethanesulfonyloxy(cid:173)
`
`naphthalen-1-yl ester (957 mg, 48%).
`
`2-{5-[ 4-(5-Trifluoromethanesulfonyloxy-naphthalen-1-yl)-phenyl]-1 H-imidazol-2-yl}(cid:173)
`
`pyrrolidine-1-carboxylic acid tert-butyl ester: 2-{ 5-[ 4-( 4,4,5,5-Tetramethyl-
`
`[ 1 ,3,2]dioxaborolan-2-yl)-phenyl]-l H-imidazol-2-yl} -pyrrolidine-1-carboxylic acid tert-butyl
`
`ester (1.30 g, 2.96 mmol), Trifluoro-methanesulfonic acid 5-trifluoromethanesulfonyloxy(cid:173)
`
`naphthalen-l-yl ester (982 mg, 231 mmol), Pd(PPh3)4 ( 134 mg, 0.116 mmol) and potassium
`
`carbonate (639 mg, 4.62 mmol) were suspended in toluene. After degassing with nitrogen for
`28 min, the stirred suspension was heated to 1 oo·c for 18 hours. The reaction mixture was then
`
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`cooled toRT, diluted with ethyl acetate (250 mL), washed with water, brine, dried over
`
`magnesium sulfate and concentrated. The resulting residue was purified by silica column
`
`chromatography (0% to 60% EtOAc/hexanes) to provide 2-{5-[4-(5-
`
`Trifluoromethanesulfonyloxy-naphthalen-1-yl)-phenyl]-1 H-imidazol-2-yl }-pyrrolidine-1-
`
`carboxylic acid tert-butyl ester (1.09g, 80%).
`
`2-(S-{4-[ S-( 4,4,5,5-Tetramethyl-[1 ,3,2] dioxaborolan-2-yl)-naphthalen-1-yl]-phenyl}-1 H(cid:173)
`
`imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: 2-{ 5-[ 4-(5-
`
`Trifluoromethanesulfonyloxy-naphthalen-1-yl)-phenyl]-1 H-imidazol-2-yl }-pyrrolidine-1-
`
`carboxylic acid tert-butyl ester ( 468 mg, 0. 796 mmol), bis(pinaco1ato )diboron (202 mg, 0. 796
`
`mmol), Pd(dppt)2Ch (29 mg, 0.0398 mmol) and potassiwn acetate (234 mg, 2.39 mmol) were
`
`suspended in dioxane (4 mL) and heated to 100"C for 90 min. After cooling toRT, the reaction
`
`mixture was diluted with ethyl acetate (100 mL) and washed with water and brine. The organic
`
`phase was dried over magnesium sulfate and concentrated. The resulting residue was purified
`
`by silica column chromatography (40% to 60% EtOAc/hexanes) to provide 2-(5-{4-[5-(4,4,5,5-
`
`Tetramethyl-[ I ,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-phenyl} -1 H-imidazol-2-yl)-pyrrolidine-
`
`1-carboxylic acid tert-butyl ester (450 mg, 100%).
`
`2-(S-{4-[ S-(1 H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester)-naphthalen-1-
`
`yl]-phenyl}-lH-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: 2-(5-{ 4-[5-
`
`( 4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-phenyl} -1 H-imidazol-2-yl)(cid:173)
`
`pyrrolidine-1-carboxylic acid tert-butyl ester (159 mg, 0.281 mmol), 2-(5-Bromo-IH-imidazol-
`
`2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (178 mg (0.562 mmol), Pd(PPh3) 4 (65 mg,
`0.0562 mmol) and K2C03 (0.281 mL of a 2 M aqueous solution, 0.562 mmol) were combined in
`
`1,2-dimethoxyethane (3 mL) and degassed with bubbling N2 for 12 min. The mixture was then
`heated to 8s·c for 22 hours then cooled toRT, diluted with ethyl acetate (50 mL) and washed
`
`with water and brine. The organic phase was dried over magnesium sulfate and concentrated.
`
`The crude residue was purified by silica colwnn chromatography (80% to 100%
`
`EtOAc/hexanes) to afford 2-(5-{ 4-[5-(1 H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert(cid:173)
`
`butyl ester)-naphthalen-1-yl]-phenyl} -1 H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert(cid:173)
`
`butyl ester (42 mg, 22%).
`
`[1-(2-{S-(4-(S-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H(cid:173)
`
`imidazol-4-yl}-naphthalen-1-yl)-phenyl]-l H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-
`
`methyl-propyl]-carbamic acid methyl ester: 2-(5-{4-[5-(lH-imidazol-2-yl)-pyrrolidine-1-
`
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`carboxylic acid lert-butyl ester)-naphthalen-1-yl]-phenyl} -1 H-imidazol-2-yl)-pyrrolidine-1-
`
`carboxylic acid tert-butyl ester (41 mg, 0.0607 mg) was dissolved in methanol (5 mL) and
`
`concentrated HCl (1 mL) was added. The mixture was stirred at 60"C for 2 hours then cooled
`
`and concentrated. To the residue was added 2-Methoxycarbonylamino-3-methyl-butyric acid
`
`(32 mg, 0.182 mmol), HA TU (51 mg, 0.133 mmol) and DMF (2 mL). The mixture was cooled
`to o·c and DIPEA (0.063 mL, 0.364 mmol) was added. After 30 min, water (1 mL) was added
`and the mixture was filtered and purified by reverse phase preparative HPLC, giving (1-(2-{5-
`
`[ 4-( 5-{2-[ 1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl ]-3 H -imidazol-4-y I}(cid:173)
`
`naphthalen-1-yl)-phenyl]-l H-imidazol-2-yl }-pyrrolidine-1-carbonyl)-2-methyl-propyl](cid:173)
`carbamic acid methyl ester (17.6 mg, 38%). 1H NMR (MeOH-d4, 400 MHz) 8.03 (d, J= 8.6
`Hz, lH), 7.98 (d,J= 8.6 Hz, lH), 7.89 (m, 2H), 7.72-7.57 (m, 6H), 7.16 (m, lH), 5.28 (m, 2H),
`
`4.25 (m, 2H), 4.11 (m, 3H), 3.86 (m, 3H), 3.67 (s, 3H), 3.65 (s, 3H), 2.59 (m, 2H), 2.30-2.04 (m,
`8H), 0.95-0.89 (m, l2H)~ MS (ESI) mlz 789 [M + Ht.
`
`ExampleCP
`
`2-(5-{+{5-(4.4,5,5-Tetramethyl-!1 ,3,2]dloxaborolart-2-
`yl}-naphthalen-1-yl)-phenyl}-1 H-imidazol-2-yl)-
`pyrrolidine-1-carboxytic acid tert-bu1yl ester
`
`2-(5-(4-Bromo-phenyl}-1 H-
`imidazol-2-yl)-pyrrotidine-1-
`carboxylic acid tert-bu1yl ester
`
`2·Me1hoxycarbonylamino-3-
`methyl-bu1yric acid
`
`+
`
`0 .....
`
`1. Pd(PPh,)..
`
`as·c
`
`2.HCI,MeOH
`3. HATU, OIPEA
`OMF
`
`H.NA,
`~~;o -..0Jt .H ~ o...~......O
`~ N 1 T
`-
`N
`'-., ... ·l~oN
`~ A t'l~N
`_
`I TJ~ ' /.
`H
`N
`"
`C' ~
`
`~ ~
`
`~ ~
`-
`
`11
`
`= H
`{ 1-[2-(5-(+{5-(4-{2-( 1-(2-Methoxycarbonylamino-3-methyl-bu1yryl}-pyrrolidin-
`2-yi]-3H-imidazol-4-yl}-phenyl}-naphlhalen-1-yl)-phenyl)-1 H-imidazol-2-yl)(cid:173)
`pyrrolidine-1-carbonyl)-2-methyl-propyl}-c:arbamic acid methyl ester
`
`{ 1-(2-( 5-{ 4-[ 5-( 4-{2-( 1-(2-Methoxycarbony lamino-3-metbyl-butyryl)-pyrrolidin-2-y I] -3H(cid:173)
`
`imidazol-4-yl}-phenyl)-naphthalen-1-yl]-pbenyl}-1 H-imidazol-2-yl)-pyrrolidine-1-
`
`carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: 2-(5-{ 4-[5-( 4,4,5,5-Tetramethyl-
`
`[ I ,3,2]dioxaborolan-2-yl)-naphthalen-l-yl]-phenyl }-1 H-imidazol-2-yl)-pyrrolidine-l-carboxylic
`
`acid tert-butyl ester (98 mg, 0.173 mmol), 2-[5-( 4-Bromo-phenyl)-1 H-imidazol-2-yl](cid:173)
`
`pyrrolidine-l-carboxylic acid tert-butyl ester (102 mg, 0.260 mmol), Pd(PPh3)4 (40 mg, 0.035
`mmol) and potassium carbonate (0.173 mL of a 2 M aqueous solution, 0.346 mmol) were
`
`suspended in 1,2-dimethoxyethane. The mixture was degassed for 10 min then heated to 85"C
`
`for 4 hours. The contents were then cooled toRT, diluted with ethyl acetate (50 mL), washed
`
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`with water and brine, dried over magnesium sulfate and concentrated. The crude residue was
`
`purified by silica column chromatography (80% to I 00% EtOAc/hexanes) to provide { 1-[2-(5-
`
`{ 4-[ 5-( 4-{2-[ 1-(2-Methoxycarbonylamioo-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H -imidazol-4-
`
`yl }-phenyl)-naphthalen-1-yl]-phenyl} -1 H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert butyl
`
`ester (28 mg, 22%). The Suzuki product was dissolved in methanol (5 mL) and treated with
`
`concentrated HCl (1 mL). The mixture was heated to 60"C for 100 min then cooled and
`
`concentrated. To the residue was added 2-Methoxycarbonylamino-3-methyl-butyric acid (20
`
`mg, 0.112 mmol), HATU (31 mg, 0.0821 mmol) and DMF (2 mL). The stirred mixture was
`cooled to o·c then DIPEA (0.033 mL, 0.187 mmol) was added. After 50 min, the reaction
`mixture was diluted with 1 mL of water and purified by reverse phase preparative HPLC to
`
`provide { 1-[2-(5-{ 4-[5-( 4-{2-[ I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-
`
`3H-imidazol-4-yl} -phenyl)-naphthalen-1-yl]-phenyl} -I H-imidazol-2-yl)-pyrrolidine-l(cid:173)
`carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (12 mg, 38%). 1H NMR (Me0H-d4,
`
`400 MHz) 7.89-7.87 (m, 4H), 7.80-7.78 (m, 4H), 7.49-7.41 (m, 8H), 5.22 (m, 2H), 4.26 (m, 2H),
`4.02 (m, 2H), 3.91 (m, 2H), 3.66 (s, 6H), 2.40-2.19 (m, 6H), 2.11-2.03 (m, 4H), 0.96 (d, J = 6.6
`Hz, 6H), 0.92 (d, J = 6.6 Hz, 6H); MS (ESI) mlz 865 [M + Ht.
`
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`Example CQ
`
`PCT /US201 0/034600
`
`BocN~
`11 ~Br
`I
`
`CNY~
`
`H
`
`NaH, SEMCI
`
`OMF
`
`BocN~
`11 ~Br
`I
`
`N'v""'N C .\
`
`n-Buli, DMF
`THF
`
`BocN~
`11 ~CHO
`I
`
`N'v""'N C .\
`
`:
`SEM
`:
`SEM
`:
`2-[5-Bromo-1-(2-trimethylsilanyl-
`. .
`. .
`2-[5-Formyl-1-(2-trimethylsilanyi-
`2-(5-Bromo-1 H-tmid.azol-2-yl)-pyrrohdme- ethoxymethyl)-1 H-imidazol-2-yl]-pyrrolidine- ethoxymethyQ-1 H-imidazol-2-yl)-pyrrolid ine-
`1-carboxyllc acid lett-bu1yl ester
`1-carboxylic acid tert-butyl ester
`1-carboxylic acid tart-butyl aster
`
`dimethyl-1 ~iazo-2-
`oxopropylphosphonate,
`K2C03
`
`MeOHfTHF
`
`rcN"' -~~~ +
`Ny-~ c
`
`SEM
`2-{5-Ethynyl-1-(2-trimethylsilanyl-
`elhoxymethyt)-1 H-imidazol-2-yl]-pyrrolidine-
`1-carboxylic acid tert-butyl ester
`
`2-Methoxycarbonylamino-3-
`methyl-butyric acid
`
`1. HCI, dioxane
`2. HATU, DIPEA
`DMF
`3. TFA. DCM
`
`Pd(PPh3)4,
`Cui, Et3N
`DMF
`
`{1-[2-(5-Ethynyi-1H-imidazol-2-yl)·
`pyrrolidine-1-carbonyl]-2 -methyl(cid:173)
`propyl}-carbamic acid methyl ester
`
`( 1-{2-{ 5-( 4-Bromo-phenyl)-1 H-imidazol-2-
`yl]-pyrrolidine-1-carbonyl}-2-methyl(cid:173)
`propyf)-carbamic acid methyl ester
`
`0
`'o.Jl.N.H
`
`)···~o~~ -~~f)~N (
`CN'v""'N~N
`
`;
`
`H
`
`···'
`H'NI(O'
`0
`(1-{2-{5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-bu1yryl)(cid:173)
`pyrrolidin-2-yi]-3H-imidazol-4-yl}-phenylethynyl)-1 H-imidazol-2-yl](cid:173)
`pyrrolidine-1-carbonyl}-2-methyl-propyt)-carbamic acid methyl ester
`
`0
`
`2-[ 5-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]-pyrrolidine-1-
`
`carboxylic acid tert-butyl ester: 2-(5-Bromo-1 H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid
`tert-butyi ester (4 g, 12.65 mmol) was dissolved in DMF and cooled to o·c. NaH (658 mg of
`60% mineral oil dispersion, 16.45 mmol) was added and the reaction mixture was aged for 13
`
`min before addition of SEMCI (2. 7 mL, 15.18 mmol) and wanning to RT. After 16 h, the
`
`reaction was quenched by water, diluted with ethyl acetate (300 mL) and washed with water and
`
`brine. The organic phase was dried over magnesium sulfate and concentrated. The crude
`
`residue was purified by silica column chromatography (1 0% to 30% EtOAc/hexanes) to afford
`
`2-[5-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]-pyrrolidine-1-carboxylic
`
`acid tert-butyl ester (4.67 g, 83%).
`
`2-[ 5-Formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]-pyrrolidine-1-
`carboxylic acid tert-butyl ester: 2-[5-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-
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`imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (3 .804 g, 8.52 mmol) was dissolved
`in THF (42 mL) and cooled to -78·c. n-BuLi (3.4 mL of a 2.5 M hexane solution, 8.52 mmol)
`
`was added dropwise over 3 min. After 65 min, DMF (4 mL) was added and the reaction mixture
`
`was warmed to RT. After stirring at RT for 75 min, a saturated aqueous solution of ammonium
`
`chloride (50 mL) was added and the entire content of the flask was poured into saturated
`
`aqueous sodium bicarbonate. The aqueous phase was extracted 3 times with diethyl ether. The
`
`combined organic layers were dried over magnesium sulfate, concentrated and purified by silica
`
`column chromatography (30% to 70% EtOAclhexanes) to provide 2-[5-Forrnyl-1-(2-
`
`trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyi ester
`
`(1.50 g, 45%).
`
`2-( 5-Ethynyl-1-(2-trimethy lsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]-pyrrolidine-1-
`
`carboxylic acid tert-butyl ester: 2-[5-Formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1 H(cid:173)
`
`imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.625 g, 4.11 mmol) and dimethyl-
`
`1-diazo-2-oxopropylphosphonate (1.056 g, 5.50 mmol) were dissolved in 1:1 MeOWfHF (10
`
`mL) and potassium carbonate (1.14 g, 8.25 mmol) was added. After stirring for 200 min, more
`
`potassium carbonate ( 1.14 g, 8.25 mmol) was added. 45 min later, the reaction mixture was
`
`poured into 100 mL 1:1 water/saturated aqueous sodium bicarbonate. The aqueous phase was
`
`extracted 3 times with diethyl ether. The combined organic phases were dried with magnesium
`
`sulfate and concentrated. The crude residue was purified by silica column chromatography
`
`(20% to 45% EtOAc/hexanes) to afford 2-[5-Ethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1 H(cid:173)
`
`imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.234 g, 77%).
`
`{1-(2-(5-Ethynyi-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic
`
`acid methyl ester: 2-[5-Ethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl](cid:173)
`
`pyrrolidine-1-carboxylic acid tert-butyl ester (1.002 g, 2.56 mmol) was dissolved in dioxane (5
`
`mL) and 4 M HCl in dioxane (5 mL) was added. The reaction mixture was stirred for 3 hours
`
`and concentrated. To the residue was added 2-Methoxycarbonylamino-3-methyl-butyric acid
`
`(561 mg, 3.20 mmol), HATU (1.22 g, 3.20 mmol) and DMF (15 mL). The stirred reaction
`
`mixture was cooled to o·c and DIPEA (2.23 mL, 12.8 mmol) was added). After stirring for 3 h,
`
`the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution
`
`of sodium bicarbonate and brine. The combined organic layers were dried over magnesium
`
`sulfate and concentrated. The crude residue was purified by silica column chromatography
`
`(40% to 75% EtOAclhexanes) to provide the coupled compound (741 mg, 65% over 2 steps).
`
`This material was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was
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`added. The stirred reaction mixture was heated to reflux for 4 h, then cooled toRT, and poured
`
`into a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted 3
`
`times with dichloromethane. The combined organic layers were dried over magnesium sulfate
`
`and concentrated. The crude residue was purified by silica column chromatography (0% to 1 0%
`
`MeOH/DMC) to provide { 1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl(cid:173)
`
`propyl}-carbamic acid methyl ester (525 mg, 100%).
`
`(l-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yi]-3H(cid:173)
`
`imidazol-4-yl} -pheny lethyny 1)-1 H -imidazol-2-y 1]-py rrolidine-1-carbony I}-2-methy 1-
`
`propyl)-carbamic acid methyl ester: { 1-[2-(5-Ethynyl-1 H-imidazol-2-yl)-pyrrolidine-1-
`
`carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (46 mg, 0.144 mmol), (1-{2-[5-(4-
`
`Bromo-phenyl}-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl }-2-methyl-propyl)-carbamic acid
`
`methyl ester (78 mg, 0.173 mmol), Pd(PPh3)4 (17 mg, 0.0144 mmol), Cui (5 mg, 0.0288 mmol)
`
`and triethylamine (0.200 mL, 1.44 mmol) were suspended in DMF (1.5 mL). The reaction
`mixture was stirred at so·c for 2 hours then 1 mL of water was added and the mixture was
`purified by reverse phase preparative HPLC, giving (1-{2-[5-(4-{2-[1-(2-
`
`Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-
`
`1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl }-2-methyl-propyl)-carbamic acid methyl ester (24
`mg, 24%). 1H NMR (Me0H-d4, 400 MHz) 7.65 (d, J= 8.2 hz, 2H), 7.45 (d, J= 8.2 hz, 2H),
`7.38(s, 1H}, 7.22(s, IH),6.98(m, 1H},5.17(m, 1H),5.11 (m, 1H),4.25-4.20(m,2H),4.01-
`3.79 (m, 4H}, 3.66 (s, 6H), 2.37-2.00 (m, 10H}, 0.99-0.89 (m, 12H); MS (ESI) m/z 687 [M +
`Ht.
`
`ExampleCR
`
`{ 1-12-(S-Ethynyl-1 H-lmldazol-2-yl)(cid:173)
`pyrrolidine-1-carbonyl}-2-meth~
`propyl)-carbamic acid methyl ester
`
`Phi(0Ac)2, PdC~.
`PPh3, Cui, Et3N
`THF
`
`H'N'J(O'
`0
`(1 -i2-fS-(4-i2-[1 -i2-Methoxycarbonylamino-3-methy~butyTyl)­
`pyrrolldin-2-yi}-3H-Imidazo~-yl}-buta-1,3-dlynyi)-1H-Imldazo~2-yl}­
`pyrrolidine-1-eart>onyl}-2-melhy~propyl)-carbamic acid methyl ester
`
`'oJlN,H
`, .... l_o
`
`~ C)
`
`l!~'(~ .. .(
`
`(1-{2-[ 5-( 4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yi]-3H(cid:173)
`
`imidazol-4-yl}-buta-1 ,3-diynyi)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl(cid:173)
`
`propyl)-carbamic acid methyl ester: Triethylamine (0.270 mL, 1.92 mmol) was added to a
`
`mixture of { 1-[2-(5-Ethynyl-1 H-imidazol-2-yl)-pyrrolidine-1 -carbonyl]-2-methyl-propyl}(cid:173)
`
`carbamic acid methyl ester (61 mg, 0.192 mmol), Phi(0Ac)2 (247 mg, 0.766 mmol), PdCh
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`(7mg, 0.0389 mmol), PPh3 (30 mg, 0.115 mmol) and Cui (7 mg, 0.0389 mmol) in THF (2 mL).
`
`After 50 min, the reaction mixture was filtered, concentrated and purified by reverse phase
`
`preparative HPLC, giving ( 1-{2-[5-( 4-{2-[l-(2-Methoxycarbonylamino-3-methyl-butyryl)(cid:173)
`
`pyrrolidin-2-yl]-3H-imidazol-4-yl}-buta-1 ,3-diynyl)-1 H-imidazol-2-yl]-pyrrolidine-1-
`carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (3 mg, 5%). 1H NMR (MeOH-d4, 400
`MHz) 7.33 (s, 2H), 6.95 (d, J= 8.3 Hz, 2H), 5.07 (m, 2H), 4.18 (m, 2H), 3.95 (m, 2H), 3.82 (m,
`2H), 3.64 (s, 6H), 2.31-1.98 (m, 10H), 1.02-0.87 (m, 12H); MS (ESI) m/z 635 [M + Ht.
`
`Example CS
`0
`'o)l,_wH
`'y·yoN~
`lfN - +
`
`{ 1-(2-{~thyny~ 1 H-lmldaz<*2·yl)-
`pyrr01idin&-1-carbonyl}-2-me1h~
`propyl)-cart>amic acid methyl ester
`
`( 1-{2-[6-(4-Bromo-phenyl)-1 H-
`benzolmidazo~2-yl}-pyrrolldin&-1-carllonyl}-
`2ofllethy~propyl)-catbamic acid methyl ester
`
`Pd(PPh:Jl ••
`Cui, Et,N
`
`DMF
`
`( 1-{2-[ 6-( 4-{2-[ 1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl J-3H-
`
`im idazol-4-ylethyny I} -pheny 1)-1 H -benzoimidazol-2-y 1]-pyrrolidine-1-carbony I}-2-methy 1-
`
`propyl)-carbamic acid methyl ester: { 1-[2-(5-Ethynyl-1 H-imidazol-2-yl)-pyrrolidine-1-
`
`carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (62 mg, 0.195 mmol), (1-{2-[6-(4-
`
`Bromo-phenyl)-1 H -benzoimidazol-2-yl]-pyrrolidine-1-carbonyl} -2-methyl-propyl)-carbamic
`
`acid methyl ester (73 mg, 0.146 mmol), Pd(PPh3)4 (11 mg, 0.00975 mmol), Cui (4 mg, 0.0195
`
`mmol) and triethylamine (0.271 mL, 1.95 mmol) were suspended in DMF (2 mL). The reaction
`
`mixture was stirred at 80"C for 3 hours then 1 mL of water was added and the mixture was
`
`purified by reverse phase preparative HPLC, giving (1-{2-[6-(4-{2-[I-(2-
`
`Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenyl)-
`
`1 H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl} -2-methyl-propyl)-carbamic acid methyl ester
`( 12 mg, 11 %). 1H NMR (Me0H-d4, 400 MHz) 7.66-7.64 (m, 2H), 7.59-7.50 {m, 4H), 7.24 (s,
`I H), 6.98 (m, 1H), 5.28 {m, 1H), 5.12 (m, 1H), 4.28-4.19 (m, 2H), 4.04-3.82 (m, 4H), 3.66 (s,
`3H), 3.65 (s, 3H), 2.43-2.01 (m, IOH), 0.99-0.87 (m, 12H); MS (ESI) mlz 737 [M + Ht.
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`ExampleCT
`
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`
`+ ¢
`
`Br
`
`Pd(PPh3)4,
`Cui, Et3N
`
`DMF
`
`{1-{2-(5-Ethynyl-1 H-imidazol-2-yl)-
`pyrrolidine-1-<:arbonyl}-2-methyl-
`propyl}-carbamic acid methyl ester
`
`1,4-Dibromo-benzene
`
`+
`
`Pd(PP~)4,
`Cui, Et3N,
`
`DMF
`
`( 1-{2-[5-( 4-Bromo-phenylethynyl)-1 H(cid:173)
`lmldazol-2 -yl}-pyrrolidine-1-<:arbonyl)-2-
`methyl-propyl)-<:arbamic acid methyl ester
`
`(1-{2 -(5-Ethynyl-1 H-imidazol-2-yl)(cid:173)
`pyrrolidine-1-carbonyl}-2-methyl(cid:173)
`propyl}-carbamic acid methyl ester
`
`0
`"o)!._N~H
`
`H
`
`'r·1)_~~?~
`C
`
`o--·'('"-
`wNyo,
`0
`(1-{2 -[5-( 4-{2-( 1-{2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrotidin-
`2-yi)-3H-Imidazol-4-ylethynyl}-phenylethynyl)-1H-imidazot-2-yl}(cid:173)
`pyrrolidine-1-<:arbonyl}-2-methyl-propyl)-<:arbamlc acid methyl ester
`
`(1-{2-[ 5-( 4-Bromo-phenylethynyi)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl(cid:173)
`
`propyl)-carbamic acid methyl ester: { 1-[2-(5-Ethynyl-1 H-imidazol-2-yl)-pyrrolidine-1-
`
`carbonyl]-2-methyl-propyl }-carbamic acid methyl ester (57 mg, 0.179 mrnol), I ,4-
`
`dibromobenzene (211 mg, 0.895 mrnol), Pd(PPh3) 4 (10 mg, 0.00895 mmol), Cui (3 mg, 0.0179
`mmol) and triethylamine (0.249 mL, 1.79 mmol) were suspended in DMF (2 mL) and the
`mixture was degassed for I 0 min with nitrogen. The reaction mixture was stirred at so·c for 70
`min then diluted with 20 mL ethyl acetate and washed with saturated aqueous sodium
`
`bicarbonate and brine. The organic phase was dried with magnesium sulfate and concentrated.
`
`The crude residue was purified by silica column chromatography (0% to 5% MeOHIDCM) to
`
`afford ( 1-{2-[ 5-( 4-Bromo-phenylethynyl)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl} -2-methyl(cid:173)
`
`propyl)-carbamic acid methyl ester (43 mg, 51%).
`
`( 1-{2-[ 5-( 4-{2-[ 1-(2Methoxycarbonylamino-3-metbyl-butyryl)-pyrrolidin-2-yiJ-3H(cid:173)
`
`imidazol-4-yletbyny I }-pbenylethyny 1)-1 H-im id azo 1-2-y IJ-py rro lid in e-1-carbonyl }-2-metbyl(cid:173)
`
`propyl)-carbamic acid methyl ester: { 1-[2-(5-Ethynyl-1 H-imidazol-2-yl)-pyrrolidine-1-
`
`carbonyl]-2-methyl-propyl}-carbamic acid methyl ester ( 49 mg, 0.154 mrnol), (1-{2-[5-(4-
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`bromo-phenylethynyl)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl} -2-methyl-propyl)-carbamic
`
`acid methyl ester (43 mg, 0.0908 mmol), Pd(PPh3)4 (10 mg, 0.00908 mmol), Cui (2 mg, 0.00908
`
`mrnol) and triethylamine (0.127 mL, 0.908 mmol) were suspended in DMF (2 mL) and the
`
`mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 8o·c for 4
`
`hours then cooled toRT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture
`
`was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4-{2-[1-(2-
`
`Methoxycarbonylamino-3-me thy I-butyry I)-pyrro I idin-2-yl]-3 H-imidazo 1-4-yl ethyn yl}(cid:173)
`
`phenylethynyl)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl} -2-methyl-propyl)-carbamic acid
`methyl ester (11 mg, 17%). 1H NMR (MeOH-d4, 400 MHz) 7.46 (d, J= 3.9 Hz, 4H), 7.25 (s,
`2H), 6.96 (d, J= 8.4 Hz, 2H), 5.10 (m, 2H), 4.20 (m, 2H), 3.97 (m, 2H), 3.83 (m, 2H), 3.64 (s,
`6H), 2.32-2.00 (m, 10H), 0.98-0.88 (m, 12H); MS (ESI) m/z 711 [M + Ht.
`
`Example CU
`0
`'o.J!._wH
`)···~oN~
`c:_!-~ -
`
`{1-(2-(5-Ethynyl-1 H-imidazol-2-yl)(cid:173)
`pyrrolidine-1-carbonyl)-2-methyl(cid:173)
`propyl}-carbamic acid methyl ester
`
`+ 69
`
`on
`Trifluoro-methanesulfonic acid
`5-trifluoromethanesulfonyloxy(cid:173)
`naphthalen-1-yl ester
`
`Pd(PPh3)4,
`Cui, Et3N,
`DMF
`
`'o.JN.H
`
`')'••'1)~~ ~ h
`
`i:-)
`'i
`C: H
`N-./"N
`~ h ==
`~ ~ o~··'(
`N
`H • y 0 '
`0
`
`:
`( 1-{2i5-{5-{2i 1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-
`yi)-3H-imidazol-4-ylethynyl}-naphthalen-1-ylethynyl)-1 H-imidazol-2-yl)-
`pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester
`
`(l-{2-[ 5-(5-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yi]-3H(cid:173)
`
`imidazol-4-ylethynyl}-naphthalen-l-ylethynyi)-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl}-
`
`2-methyl-propyl)-carbamic acid methyl ester: { 1-[2-(5-Ethynyl-1 H-imidazol-2-yl)(cid:173)
`
`pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98 mg, 0.207 mmol),
`
`trifluoro-methanesulfonic acid 5-trifluoromethanesulfonyloxy-naphthalen-1-yl ester (29 mg,
`
`0.0683 mmol), Pd(PPh3) 4 (12 mg, 0.0104 mmol), Cui (2 mg, 0.0104 mmol) and triethylamine
`(0.144 mL, 1.04 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10
`
`min with nitrogen. The reaction mixture was stirred at 8o·c for 90 min then cooled toRT.
`
`Formic acid (0.1 mL) and water (I mL) were added and the mixture was purified by reverse
`
`phase preparative HPLC, giving (1-{2-[5-(5-{2-[1-(2-Methoxycarbonylamino-3-methyl-
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`butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl }-naphthalen-1-ylethynyl)-1 H-imidazol-2-yl](cid:173)
`pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (30 mg, 58%). 1H NMR
`(MeOH-d4,400MHz)8.38(d,J=8.2Hz,2H}, 7.71 (d,J=7.2Hz,2H), 7.57-7.51 (m,2H},
`7.35 (s, 2H), 6.96 (d, J := 8.4 Hz, 2H), 5.13 (m, 2H), 4.20 (m, 2H), 3.95 (m, 2H), 3.83 (m, 2H),
`3.63 (s, 6H), 2.33-1.98 (m, 10H), 0.97-0.87 (m, 12H); MS (ESI) mlz 761 [M + Ht.
`
`Example CV
`0
`'o)lwH
`)···~oN~
`c:_~-~ - +
`
`Pd(PPh3)4,
`Cui, Et3N
`DMF
`
`( 1·(2-(5-Ethynyl-1 H-imidazoi·2·YIJ·
`pyrrolidine-1-carbonyl)·2·methyl(cid:173)
`propyl)-carbamic acid methyl ester
`
`{1-(2·(5-(4'-Bromo-biphenyl-4-yi)-1H(cid:173)
`imldazol-2-yl)-pyrrolldine-1-carbonyl}-2-
`methyl-propyl)-carbamic acid methyl ester
`
`0
`'o.JlwH
`
`/'•''1)~i?/
`c H
`
`0"')·'''-
`. . H'N'Y"o,
`hy
`.
`(1-(2-(5-(4'-(2-(1-(2-Methoxycarbonylammo-3-met 1-butyryl)-pyrrohdtn-
`11
`o
`2-yi)-3H-imidazol-4-ylethyny 1)-biphenyl-4-yl)-1 H-imidazol-2-yl)-
`pyrrolidine-t-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester
`
`(1-{2-(5-(4'-{2-(1-(2-Metboxycarbonylamino-3-metbyl-butyryl}-pyrrolidin-2-yi)-3H(cid:173)
`
`imidazol-4-ylethyny I }-bipheny 1-4-yl)-1 H -imidazol-2-yl] -pyrrolidine-1-carbony I}-2-methyl(cid:173)
`
`propyl)-carbamic acid methyl ester: { 1-[2-(5-Ethyny1-1 H-imidazo1-2-yl)-pyrrolidine-1-
`
`carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (44 mg, 0.138 mmol), (1-{2-[5-(4'(cid:173)
`
`Bromo-biphenyl-4-yl)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl} -2-methyl-propyl)-carbamic
`
`acid methyl ester (67 mg, 0.128 mmol), Pd(PPh3)4 (15 mg, 0.0128 mmol), Cui (2 mg, 0.0128
`mmol) and triethylamine (0.180 mL, 1.28 mmol) were suspended in DMF (2 mL) and the
`
`mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 8o·c for 15
`
`hours then cooled toRT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture
`
`was purified by