WO 00/17203
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`PCT/US99/21560
`
`gas
`acetate (3.0 equiv, 54.7 g, 558 mmol) and PdCL,(dppf) (0.03 equiv, 4.65 g, 5.58
`
`mmol) in degassed DMF (1 1) was heated at 80°C undernitrogen for 16 h. The DMF
`
`was removed under reduced pressure and the resulting dark solid residue was
`
`dissolved in CH,C1, (500 mL). The inorganic residues were removedbyfiltration
`
`through a silica gel pad andthefiltrate was purified by column chromatography
`
`using a 10% to 15% EtOAc: heptane gradient to afford the product as a yellow
`
`viscousoil which crystallized on standing to give tert-butyl N-[2-fluoro-4-(4,4, 5,5-
`tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (56.5 g, 92 %), 'H NMR
`
`(400 MHz, CDCL) 1.33 (12 H, s), 1.53 (9 H, s), 6.82 (1H, brs), 7.46 (1H, d, J 11
`
`10
`
`Hz), 7.55 (1 H,br @), and 8.12 (1 H, ort), m/z 337.2, and RP-HPLC(5 to 100 %
`
`CH,CN in 0.1 N aqueous ammonium acetate over 15 min at 1 mL/min using a
`Hypersil HyPurity Elite C18, 5m, 200 A, 250 x 4.6 mm column) t= 10.16 min, 90%.
`
`c) tert-Butyl N-4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl-7H-pyrrolo[2,3-
`
`15
`
`d]pyrimidin-5-y1]-2-fluorophenylcarbamate
`
`A suspension of the 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-
`
`pyrrolo[2,3-d]pyrimidine (31.18 g, 74.41 mmol),tert-butyl N-[2-fluoro-4-(4,4,5,5-
`
`tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl|carbamate (1.5 equiv, 37.6 g, 111.6
`
`mmol}, sodium carbonate (2.5 equiv, 19.72 g, 186 mmol) and Pd(PPh,), (4 mol%,
`
`20
`
`3.44 g, 2.98 mmol)in DME (1.2 1) and degassed H,O (230 mL) was heated at 80°C
`
`under nitrogen for 17h. Additional Pd catalyst (1 mol%, .86 g, 0.74 mmol) was
`
`added and the reaction was continued heating at 80°C for a further 24 h. at which
`
`point the reaction had proceeded to completion (t.L.c. analysis using 3:7
`EtOAc:heptaneas the eluent, Rf=0.7). The solvent was removed under reduced
`
`25
`
`pressure and the residue dissolved in EtOAc (500 mL) andthe inorganics were
`
`removed byfiltration through a celite pad. The filtrate was washed with 10% aq.
`
`Na,CO, (200 mL) and brine (200 mL), dried (MgSO,) and concentrated in vacuo.
`
`Column chromatography purification oversilica gel using 1:2 EtOAc:heptane
`
`afforded tert-buty] N-4-[4-chloro-7-(1,4-dioxaspiro[4.5 ]dec-8-y!)-7H-pyrrolo[2,3-
`d]pyrimidin-5-yl]-2-fluorophenylcarbamate as an off-white solid (21.0 g, 56%), 'H
`
`30
`
`NMR (400 MHz, CDC1,) 1.55 (9 H,s), 1.89 (4 H, m), 2.07 (4 H, m),4.01 (45,s),
`
`SANDOZINC.
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`IPR2023-00478
`
`Ex. 1023, p. 295 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 295 of 891
`
`

`

`WO 00/17203
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`PCT/US99/21560
`
`AA’
`
`4.89 (1 H, m), 6.75 (1 H, brs), 7.23 (1 H, brs), 7.25 (1 H, brs), 7.34 (1 H, brs),
`8.14 (1 H,br t), and 8.64 (1 H, s) and RP-HPLC (5 to 100 % CH,CN in 0.1 N
`aqueous ammonium acetate over 15 min at 1 mL/min using a Hypersil HyPurity
`Elite C18, 5m, 200A, 250 x 4.6 mm column) t= 10.48 min., 100%.
`
`d) 5-(4-Amino-3-fluoropheny])-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-
`d|pyrimidin-4-amine
`
`A cloudy mixture oftert-butyl N-4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-
`yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylcarbamate ( 10.5 g, 20.92
`mmol), aq. ammonium hydroxide (28 - 30 %, 100 mL) and dioxane (100 mL) was
`placedin a sealed vessel at ambient temperature then heated to 120°C withstirring
`for 24 h.(t.l.c. analysis using 9:1 EtOAc:heptaneas the eluent). The reaction was
`concentrated in vacuo, diluted with EtOAc (300 mL), washed with brine (2x 150
`mL), dried (Na,SO,) and concentrated under reduced pressure and scrupulously
`dried to afford 5-(4-Amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-
`Pyrrolo[2,3-d]pyrimidin-4-amine as a yellow solid (7.93 g, 99 %), 'H NMR (400
`MHz, d,-DMSO)1.74 (4 H, m), 1.90 (2 H, m), 2.06 (2 H, m), 3.90 (4 H, m), 4.64 (1
`H, m), 5.18 (2 H, br s), 6.02 (2 H,brs), 6.84 (1H, 4, 6.97 (1 H, d), 7.08 (1 H, d),
`7.26 (1 H, s) and 8.10 (1 H, s) and m/z 384.2 (MH").
`
`e) 4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-
`cyclohexanone
`
`5M HCl (300 mL) was added slowly to a solution of 5-(4-amino-3-
`fluoropheny!)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
`(18.49 g, 48.28 mmol)in acetone (800 mL) at 0°C theresulting dark orange-brown
`solution was heated at 60°C for 4h. (t.l.c. analysis using 10% MeOH in CH,Cl,).
`The acetone was removed under reduced pressure and the acidic layer was basified
`to approx. pH 8 using sat. aq. Na,CO,. The resulting precipitate was collect by
`filtration and scrupulouslydried to afford 4-[4-amino-5-(4-amino-3-fluorophenyl)-
`7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone as a light brown solid (12.67 g,
`77%). A second crop was also obtained from the mother liquor on standing (2.01 g,
`12%), 'H NMR (400 MHz, d,-DMSO) 2.27 (2 H, m), 2.30 (4 H,brd), 2.73 (2 H, m),
`
`10
`
`15
`
`20
`
`25
`
`30
`
`SANDOZINC.
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`IPR2023-00478
`
`Ex. 1023, p. 296 of 891
`
`SANDOZ INC.
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`IPR2023-00478
`
`Ex. 1023, p. 296 of 891
`
`

`

`WO 00/17203
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`.
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`PCT/US99/21560
`
`a2
`5.14 (1 H, m), 5.20 (2 H,brs), 6.05 (2 H, drs), 6.85 (1 H,A, 6.97 (1 H,da), 7.06 (1
`H,dd), 7.35 (1 H, s) and 8.12 (1 H, s) and m/z 340.1 (MA").
`
`cis- and trans- 5-(4-Amino-3-fluorophenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-
`
`7H-pyrrolo[2,3-d]pyrimidin-4-
`
`Example 304: cis-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexylI]-7H-
`
`pyrrolo[2,3-d]pyrimidin-5-y!}-2-fluoropheny!)-4-fluoro-1-benzenesulfonamide tri-
`
`maleate
`
`10
`
`15
`
`To a solution of 4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-
`
`d]pyrimidin-7-yl]-1-cyclohexanone(1.0 g, 2.95 mmol), N-methylpiperazine (3
`
`equiv, 0.885 g, 8.85 mmol, 0.98 mL) andglacial acetic acid (3 equiv., 0.51 mL, 8.85
`
`mmol) in dichloroethane (50 mL) under nitrogen was added sodium
`
`triacetoxyborohydride (1.3 equiv., 0.81 g, 3.84 mmol). The solution was stirred for
`
`18 hr then additional sodium triacetoxyborohydride (0.40 g, 1.9 mmol) was added
`and the reaction continued for a further 48 hr. The reaction was concentrated in
`
`vacuo, partitioned between dichlorornethane (100 mL) and sat. aq. NaHCO, (100
`
`mL). The aqueous layer was further extracted with dichloromethane (4 x 100 mL)
`
`and the combined organic layers were dried over magnesium sulfate and evaporated
`
`20
`
`to dryness to give a yellow foam (0.95 g). Purification by column chromatography
`
`oversilica gel using a dichloromethane:methanol (9:1 to 5:1) gradient afforded cis-
`
`5-(4-amino-3-fluocrophenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-
`
`d]pyrimidin-4-amine, the higher running component, as a cream solid (400 mg, 32
`%) ‘H NMR (d, DMSO,400 MHz) 1.56 (3H,br t), 1.68 (2H,br d), 1.99 (SH, m),
`2.20 (3H,s), 2.43 (7H, br m), 4.65 (1H, m), 5.20 (2H, s), 6.01 (2H,br s}, 6.85 (1H,t,
`J= 9.6 Hz), 6.98 (1H, dd, J= 8.0 and 1.6 Hz), 7.10 (1H, dd, J=12.4 and 1.6 Hz), 7.12
`(1H,s), and 8.10 (1H, s) and RP-HPLC (10 to 90 % CH,CNin 0.1 N aqueous
`
`ammonium acetate over 12 min at 2 mL/min using a Waters Symmetry C18, 250 x
`
`4.6 mm column) tr= 8.619 min., 96%
`
`30
`
`A mixed fraction was obtained which contained both cis- and trans-isomers (440
`
`mg, 50:50 mixture), and in addition the lower running fraction contained trans-5-(4-
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 297 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 297 of 891
`
`

`

`WO00/17203
`
`PCT/US99/21560
`
`Jae
`amino-3-fluorophenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo{2,3-
`d]pyrimidin-4-amine, as a yellow solid (110 mg, 9%), 'H NMR (d, DMSO,400
`
`MHz) 1.94 (6H, m), 2.17 (3H,s), 2.33 (7H, br m), 2.51 (3H, m), 3.28 (1H, m), 4.51
`(1H, m), 5.18 (2H, s), 6.01 (2H,br s), 6.84 (1H,t), 6.96 (1H,dd), 7.04 (1H,dd), 7.30
`(1H,s), and 8.08 (1H, s) and RP-HPLC(10 to 40 % CH,CN in 0.1 N aqueous
`ammonium acetate over 12 min at 2 mL/min using a Waters Symmetry C18, 250 x
`4.6 mm column) t= 7.595 min, 97%
`
`10
`
`15
`
`20
`
`25
`
`30
`
`trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-
`Example 305:
`pyrrolo[2,3-d]pyrimidin-5-yl} -2-fluorophenyl)-4-fluoro-1-benzenesulfonamidetri-
`
`maleate
`
`4-Fluorobenzenesulfonyl! chloride (45.9 mg, 0.236 mmol) was added to a
`solution of trans-5-(4-amino-3-fluorophenyl)-7-[4-(4-
`
`methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.236
`mmol) in pyridine (2 mL) at 400C. After 27 hr at 40°C the reaction had reached
`
`completion and was concentrated in vacuo. Purification by column chromatography
`oversilica gel using 10% to 50% MeOHin dichloromethaneas the gradient afforded
`as a colurless oil (0.78 mmol). The product was dissolved in ethanol] and maleic
`
`acid (3 equiv., 27 mg, 0.233 mmol) added. The mixture was heated until
`homogeneous and trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-
`pyrrolo{2,3-d]pyrimidin-5-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide
`trimaleate crystallised on cooling as a fawn solid (37 mg, 17 %), RP-HPLC(10 to
`40 % CH,CN in 0.1 N aqueous ammonium acetate over 12 min at 2 mL/min using a
`Waters Symmetry C18, 250 x 4.6 mm column) t= 14.528 min., 96% and m/z 582.0
`(MH).
`
`Example 306: cis-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-
`pyrrolo[2,3-d]pyrimidin-5-yl} -2-fluorophenyl)-4-fluoro-1-benzenesulfonamide
`
`cis-N1-(4{-4-amino-7-[4-(4-methylpiperazino) evelohexyl]-7H-pyrrolof2,3-
`a/pyrimidin-5-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide was prepared
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 298 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 298 of 891
`
`

`

`WO 00/17203
`
`PCT/US99/21560
`
`I2d
`using the same procedure as detailedfor thefree base oftrans-N1-(4{-4-amino-7-[4-
`
`(4-methylpiperazino)cyclohexyl]-7H-pyrrolof[2, 3-d[pyrimidin-5-yl}-2-fluorophenyl)-
`
`4-fluoro-1-benzenesulfonamide except on a 3.36 mmolscale.
`
`(400 mg, 32%), RP-HPLC (10 to 40 % CH,CN in 0.1 N aqueous ammonium acetate
`
`over 12 min at 2 mL/min using a Waters Symmetry C18, 250 x 4.6 mm column) t=
`
`15.232, 94% min. and m/z = 582.1 (MH").
`
`Example 307: 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4-piperidyl)-7H-pyrrolo{72, 3-
`
`10
`
`d/pyrimidin-4-amine
`
`a) 7-(1-benzyl-4-piperidyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
`
`Diethyl diazodicarboxylate (2.0 equiv., 18.19 g, 41.2 mL, 104.8 mmol) was
`
`added dropwise over approx. 1 h to a solution of 4-chloro-3-iodopyrrolo[2,3-
`
`15
`
`d]pyrimidine (14.55 g, 52.4 mmol), 1-benzyl-4-hydroxypiperidine (3.0 equiv., 30.06
`
`g, 157.16 mmol) and triphenylphosphine (2.0 equiv., 27.51 g, 104.8 mmol) in THF
`
`(730 mL) at room temperature under nitrogen. The reaction reached completion
`
`after 72 h (t.l.c. analysis using 1:1 EtOAc:heptane as the eluent, Rf= 0.2). The
`
`reaction was concentrated in vacuo and 1:4 ethyl acetate : heptane was added until a
`
`20
`
`precipitate in a clear solution was observed. The precipitate was collected by
`
`filtration (Ph3PO) andthe filtrate was concentrated, dissolved in ethyl acetate (500
`
`mL) and extracted with aq. HCI (1M, 3 x 200 mL). The combined acidic layers
`
`werebasified with aq NaOH (4 N) to pH 12 then extracted into ethyl acetate(3 x 300
`mL), dried (MgS04) and concentrated in vacuo. Purification by column
`chromatography using 5:4 light petroleum (30-60 °C):ethyl acetate oversilica gel
`
`gave 2 main fractions of which thefirst fraction contained the product as a pale
`
`yellow crystalline solid which was recrystallised from ethyl! acetate to give 7-(1-
`
`benzyl-4-piperidy])-4-chloro-5-iodo-7A-pyrrolo[2,3-d]pyrimidine as a cream
`
`crystalline solid (5.7 g, 24 %); ‘H NMR (400 MHz, CDC1,) 2.02 (4H, m), 2.24 (2H,
`
`m), 3.06 (2H,br d), 3.58 (2H,s), 4.76 (1H, m), 7.27 (2H, m), 7.32 (3H, m), 7.49
`
`25
`
`30
`
`(1H,s) and 8.60 (1H, s) and m/z = 452.8 (MH’).
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 299 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 299 of 891
`
`

`

`WO 00/17203
`
`PCT/US99/21560
`
`222
`
`b) tert-butyl N-4-[7-(1-benzy!-4-piperidyl)-4-chloro-7H-pyrrolo[2,3-d}pyrimidin-5-
`
`yl]-2-fluorophenylcarbamate
`A suspension of 7-(1-benzyl-4-piperidy!)-4-chloro-5-iodo-7H-pyrrolo[2,3-
`d|pyrimidine (5.7 g, 12.6 mmol), tert-butyl N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-
`dioxaborolan-2-yl)phenyl]carbamate (1.5 equiv, 18.9 g, 6.38 mmol), sodium
`carbonate (2.5 equiv, 3.34 g, 31.5 mmol) and Pd(PPh,), (4 mol%, 0.58 g, 0.5 mmol)
`in DME (210 mL) and degassed water (37 mL) washeated at 80°C under nitrogen
`for 17h(t.L.c. analysis using 1:1 EtOAc:heptaneas the eluent). The reaction mixture
`was concentrated in vacuo, dissolved in ethyl acetate (400 mL) and washed with 10
`10
`% aq. Na,CO, (3 x 200 mL). The organic layer was dried (MgSO,), concentrated
`and purified by column chromatography using 1:1 ethyl acetate:heptane as the eluent
`to afford tert-butyl N-4-[7-(1-benzyl-4-piperidy])-4-chloro-7#-pyrrolo[2,3-
`d\pyrimidin-5-yl]-2-fluorophenylcarbamate as a white crystalline solid (5.2 g, 9.7
`mmol, 77%), 'H NMR (400 MHz, CDCL) 1.55 (9 H, s), 2.05 (4H, m), 2.24 (2H, m),
`3.06 (2H,br d), 3.60 (2H, s), 4.83 (1H, m), 7.25 (2H, m), 7.29 (1H, m), 7.33 (6H, m),
`
`15
`
`8.12 (1H,br 2) and 8.64 (1H,s).
`
`20
`
`25
`
`30
`
`c) 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4-piperidyl)-7H-pyrrolo[2,3-
`
`djpyrimidin-4-amine
`A mixture of the sert-butyl N-4-[7-(1-benzy!-4-piperidyl)-4-chloro-7H-
`
`pyrrolo[2,3-d]pyrimidin-5-y1]-2-fluorophenylcarbamate (5.2 g, 9.7 mmol),aq.
`ammonium hydroxide (28 - 30 %, 100 mL) and 1,4-dioxane (100 mL) wasplaced in
`a sealed vessel at ambient temperature then heated to 120 °C with stirring for 16h.
`(t.Lc. analysis using EtOAcas the eluent). The reaction was concentrated im vacuo,
`diluted with EtOAc (300 mL), washed with brine (2x 200 mL), dried (Na,SO,) and
`concentrated under reduced pressure to afford a brown solid which wastriurated
`with ether (approx. 50 mL) to give 5-(4-amino-3-fluorophenyl)-7-(.1-benzyl-4-
`piperidyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-amine as a cream solid (3.0 g, 74 %), 'H
`NMR (400 MHz, CDC1,) 2.06 (4 H, m), 2.27 (2 H, m), 3.06 (2 H, m), 3.59 (2H, br
`s), 3.70 (2 H, brs), 4.73 (1H, m), 5.12 (2 H, s), 6.85 (1 H, 4), 7.011 H, s), 7.06 (1 H,
`dd), 7.10 (1 H, dd), 7.28 (2 H, m), 7.34 (3H, m) and 8.31 (1 H, s) and m.p. 141-142
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 300 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 300 of 891
`
`

`

`WO 00/17203
`
`°C.
`
`PCT/US99/21560
`
`Example 308: N1-4-[4-amino-7-(1-benzy!-4-piperidyl)-7H-pyrrolo[2,3-
`
`d]pyrimidin-5-y1]-2-fluoropheny!-4-fluoro-1-benzenesulfonamide
`' N1-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-
`
`2-fluorophenyl-4-fluoro-1-benzenesulfonamide (470981) was prepared using the
`
`same procedure as detailed for trans-N1-(4- {4-amino-7-[4-(4-
`
`methylpiperazino)cyclohexy!]-7H-pyrrolo[2,3-d]pyrimidin-5-y]} -2-fluoropheny!)-4-
`fluoro-1-benzenesulfonamide tri-maleate except on a 6.96 mmolscale. N1-4-[4-
`
`10
`
`amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl-4-
`
`fluoro-1-benzenesulfonamide was obtained as a cream solid (3.2 g, 80%), m/z 575
`
`(MH*) and m.p. 265-6 °C.
`
`Example 309: N1-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo[2,3-
`
`15
`
`d]pyrimidin-5-y1]-2-fluorophenyl-2,3-dichloro-1-benzenesulfonamide
`
`N1-4-[4-amino-7-(1-benzyl-4-piperidy!)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-
`
`2-fluorophenyl-2,3-dichloro-1-benzenesulfonamide was prepared in the same
`
`manner as detailed above on a 5.04 mmol scale. The resulting N/-4-[4-amino-7-(1-
`
`benzyl-4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl-4-fluoro-1-
`benzenesulfonamide was obtained as a brown solid (1.0 g, 32%), m/z 625 (MH") and
`
`20
`
`RP-HPLC(5 to 85 % CH,CN in 0.1 N aqueous ammonium acetate over 20 min at 1
`mL/min using a Waters Delta pack 5m C18, 300A, 150 x 3.9 mm column) t=
`
`14.963 min., 95%.
`
`25
`
`Example 310: N1-4-[4-amino-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-y1]}-2-
`
`fluoropheny!-4-fluoro-1-benzenesulfonamide
`
`A mixture containing N1-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H- .
`
`pyrrolo[2,3-d]pyrimidin-5-yl}-2-fluoropheny]-4-fluoro-1-benzenesulfonamide (2.40
`
`g, 4.18 mmol), ammonium formate (10 equiv., 41.8 mmol, 2.62 g), palladium on
`
`30
`
`carbon (10%, 1.2g) and ethanol (100 mL) was heated at reflux with vigorous stirring
`
`for 6h., filtered and concentrated in vacuo. The solid was partitioned between
`
`dichloromethane (50 mL) and water (50 mL). The brown solid which formedat the
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 301 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 301 of 891
`
`

`

`wo
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`00/17203
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`PCT/US99/21560
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`J 3a-
`
`phase boundary was collected and analysed for N/-4-[4-amino-7-(4-piperidyl)-7H-
`
`pyrrolo{2, 3-d]pyrimidin-5-yl]-2-fluorophenyl-4-fluoro-1-benzenesulfonamide (0.33
`
`g), m/z 485 (MH") and m.p. 238-9 °C (dec.).
`
`Example 311: N1-4-[4-amino-7-(1-formyl-4-piperidyl)-7H-pyrrolo[2,3-
`
`d|pyrimidin-5-y1]-2-fluorophenyl-4-fluoro-1-benzenesulfonamide
`
`The procedure detailed for the preparation of N1-4-[4-amino-7-(4-piperidyl)-
`
`7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenyl-4-fluoro-1-benzenesulfonamide
`was performed on a smaller scale (0.35 mmol) where the combined organic layers
`from the work up wereisolated, dried (Na,SO,) and the solvent removed under
`
`reduced pressure to afford a white oil which was purified by preparative HPLC
`
`(100% pH 4.5 50mM ammonium acetate to 100% CH,CN in 8.5 minutes with a 1.5
`
`minute hold at 25 mL/min using a Hypersil 5m BDS C18, 100x 21.2mm column) to
`
`yield N1-4-[4-amino-7-(1-formyl-4-piperidyl)-7H-pyrrolof[2,3-d]pyrimidin-5-yl]-2-
`
`fluorophenyl-4-fluoro-1-benzenesulfonamide as a white solid (50 mg, 27 %), m/z =
`512.9 (MH") and RP-HPLC(5 to 85 % CH,CN in 0.1 N aqueous ammonium acetate
`over 20 min at 1 mL/min using a Waters Delta pack 5m C18, 300A, 150 x 3.9 mm
`
`column) t= 13.091 min., 95%.
`
`Example 312: N1-[4-(4-amino-7-1~-[(1-methyl-1H-4-imidazolyl)sulfony1]-4-
`piperidyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-1-
`benzenesulfonamide dimaleate
`
`1-Methylimidazoi-4-yl sulphony] chloride (1.1 equiv., 0.068 mmol, 12.3 mg)
`
`was added to a suspension of 5-(4-amino-3-fluorophenyl)-7-(1 -benzyl-4-piperidyl)-
`
`7H-pyrrolo[2,3-d]pyrimidin-4-amine (30 mg, 0.062 mmol) and triethylamine (3
`
`equiv., 0.186 mmol, 26 1) in dichloromethane (1 mL) and stirred at ambient
`
`temperature for 24 h. The reaction was concentrated in vacuo, partitioned between
`dichloromethane (100 mL) and water (50 ml) and the aqueous layer was further
`
`extracted with dichloromethane (3 x 100 mL). The combined organic layers were
`
`dried over magnesium sulfate and concentrated in vacuo. Purification by column
`
`chromatographyoversilica gel using 10 % methanol in dichloromethaneyielded a
`
`waxy white solid (10 mg). Maleic acid (2 equiv., 4 mg) was addedto the product in
`
`10
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`20
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`25
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`30
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 302 of 891
`
`SANDOZ INC.
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`IPR2023-00478
`
`Ex. 1023, p. 302 of 891
`
`

`

`WO 00/17203
`
`PCT/US99/21560
`
`a 7s
`
`hot ethanol and N/-{4-(4-amino-7-1-[(1-methyl-1H-4-imidazolyl)sulfonyl]-4-
`
`piperidyl-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)-2-fluerophenyl]-4-fluoro-1-
`
`benzenesulfonamide dimaleatesalt crystallized on cooling (10 mg), RP-HPLC(5 to
`
`85 % CH,CNin 0.1 N aqueous ammonium acetate over 20 min at 1 mL/min using a
`Waters Delta pack 5m C18, 300A, 150 x 3.9 mm column) t= 14.186, 100% min.
`and m/z = 629 (MH).
`
`Example 313: N1-[4-(4-amino-7-1-[(1,2-dimethyl-1H-4-imidazolyl)sulfonyl]-4-
`piperidyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-1-
`benzenesulfonamide
`
`Usingthe procedure detailed for the synthesis of the free base of N1-[4-(4-
`amino-7-1-[(1-methyl-1H-4-imidazolyl)sulfony1]-4-piperidyl-7H-pyrrolo[2,3-
`d]pyrimidin-5-y1)-2-fluoropheny]]-4-fluoro-1-benzenesulfonamide dimaleate, N/-/4-
`(4-amino-7-1-[(1,2-dimethyl-1H-4-imidazolyl)sulfonyl]-4-piperidyl-7H-pyrrolo[2, 3-
`d]pyrimidin-5-yl)-2-fluorophenyl]-4fluoro-1-benzenesulfonamide was prepared as a
`cream solid (9 mg), m.p. 217-8 °C and m/z = 643.2 (MH).
`
`Example 314: N1-[4-(4-amino-7-1-[(1,3-dimethyl-1H-5-pyrazolyl)carbonyl1]-4-
`piperidyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-1-
`benzenesulfonamide
`
`1,3-Dimethylpyrazole-5-carbonyl chloride (1.5 equiv., 14.8 mg, 0.093 mmol)
`was addedto a stirred suspension of 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4-
`piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (30 mg, 0.062 mmol) and potassium
`carbonate (2 equiv., 17.1 mg, 0.124 mmol) in N-methylpyrrolidinone (2 mL) and the
`resulting mixture wasstirred at ambient temperature undernitrogen for 16 h. The
`solvent was removed in vacuo and the mixture purified by column chromatography
`oversilica gel using 5 % methanolin dichloromethaneas the eluent to give NI -[4-
`(4-amino-7-1-[(1,3-dimethyl-1H-5-pyrazolyl)carbonyl]-4-piperidyl-7H-pyrrolo[2, 3-
`d]pyrimidin-5-yl)-2-fluorophenyl]-4-fluoro-1-benzenesulfonamide as a colourless
`glass (10 mg), RP-HPLC HPLC (100% pH 4.5 50mM ammonium acetate to 100%
`CH;CN in 4.5 minutes with a 0.5 minute hold at 3.5 mL/min using a Perkin Elmer
`
`10
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`15
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`20
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`25
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`30
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 303 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 303 of 891
`
`

`

`WO 00/17203
`
`PCT/US99/21560
`
`224
`Pecosphere 3m C18 (33 x 4.6mm) column) t= 2.98 min., 96% and m/z = 629
`
`(MH’).
`
`Example 315: N1-(4-{4-amino-7-[1-(2-pyridylcarbonyl)-4-piperidyl]-7H-
`
`pyrrolo[2,3-d]pyrimidin-5-y]} -2-fluorophenyl)-4-fluoro-1-benzenesulfonamide
`
`N1-(4- {4-amino-7-[1-(2-pyridylcarbonyl)-4-piperidyl]-7H-pyrrolo[2,3-
`d]pyrimidin-5-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide was prepared
`using the same procedure as detailed for N1-[4-(4-amino-7-1-[(1,3-dimethyl-1H-5-
`pyrazolyl)carbony1]-4-piperidyl-7H-pyrrolo[2,3-d]pyrimidin-5-y!)-2-fluorophenyl]-
`
`4-fluoro-1-benzenesulfonamide, (12 mg), RP-HPLC HPLC (100% pH 4.5 50mM
`ammonium acetate to 100% CH,CNin 4.5 minutes with a 0.5 minute hold at 3.5
`
`mL/min using a Perkin Elmer Pecosphere 3m C18 (33 x 4.6mm) column)t= 2.73
`min., 98% and m/z = 590.2 (MH").
`
`Example 316: Ni-4-(4-amino-7-{4-[1-(1-methylpiperid-4-yl)piperidy1]-7H-
`pyrrolo[2,3-d]pyrimidin-5-yl} )-2-fluoropheny!-4-fluoro-1-benzenesulfonamidetri-
`maleate
`
`Sodium triacetoxyborohydride (28.1 mg, 0.134 mmol) was added to a
`
`solution of N1-4-[4-amino-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-
`fluoropheny!-4-fluoro-1-benzenesulfonamide (50 mg, 0.103 mmol) and 1-
`methylpiperid-4-one (0.92 ml, 0.155 mmol) in glacial acetic acid (0.025 mL) and
`NMP (3 mL). The reaction wasstirred for 20 h at room temperature then additional
`sodium triacetoxyborohydride (1.3 equiv.)
`
`was added. After a further 24 h the reaction had proceeded to completion and was
`
`concentrated iz vacuo, partitioned between dichloromethane (100 mL)andsat.aq.
`
`NaHCO, (100 mL). The aqueous layer was further extracted with dichloromethane
`
`(4 x 100 mL) and the combined organic layers were dried over magnesium sulfate
`and evaporated to dryness. Purification by column chromatographyoversilica gel
`using dichloromethane:methanol:ammonium hydroxide (78:19:3) as the eluent to
`
`10
`
`15
`
`20
`
`25
`
`30
`
`afford a brown solid. The tri maleate salt was then formed by standard methodsto
`
`give N/-4-(4-amino-7-{4-[1-(]-methylpiperid-4-yl)piperidyl]-7H-pyrrolo{2,3-
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 304 of 891
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1023, p. 304 of 891
`
`

`

`WO 00/17203
`
`PCT/US99/21560
`
`D357
`
`d]pyrimidin-5-yl})-2-fluorophenyl-4-fluoro-1-benzenesulfonamidetri-maleaie as a
`brownsolid (45 mg, 75%), m/z 582 (MH~) and RP-HPLC (5 to 85 % CH;CN in 0.1
`N aqueous ammonium acetate over 20 min at 1 mL/min using a Waters Delta pack
`5m C18, 300A, 150 x 3.9 mm column) t= 10.658 min., 95%.
`
`Example 317: N1-4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-
`yl]-2-methoxyphenylbenzamide
`
`a) To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 0.09 mol),
`
`1,4-dioxaspiro[4.5]decan-8-ol (35.8 g, 0.0267 mol) and triphenylphosphine (46.7 g,
`
`10
`
`0.178 mol) in THF (1.2 L) was added diethylazodicarboxylate (30.9 g, 0.178 mol)
`
`under nitrogen. The solution wasstirred for 20 hr and the majority of solvent was
`
`then evaporated (250 mL remaining). EtOAc (450 mL) was then added and the
`
`resulting solid was filtered, washed with EtOAc (2x 50 mL) and dried in vacuo to
`
`give 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
`(22.5 g, 60%) as a cream solid. 'H NMR (d; DMSO, 400 MHz) 8.64 (1H,s), 8.10
`
`15
`
`(1H,s), 4.74 (1H, m), 3.90 (4H, m), 2.12 (2H, m), 1.91 (2H, m), 1,71-1.83 (4H, m).
`
`R,in 1:4 EtOAc : heptane = 0.12.
`
`20
`
`25
`
`b) A solution of tert-butyl N-[2-methoxy-4-(4,4,5 ,5-tetramethyl-1,3,2-
`
`dioxaborolan-2-yl)phenyl]carbamate (8.2 g, 23.5 mmol), 4-chloro-7-(1,4-
`dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (6.57 g, 15.7 mmol),
`tetrakistriphenylphosphinepalladium (1.1 g, 0.93 mmol), sodium carbonate (4.16 g,
`
`39.2 mmol) in-dimethoxyethane (200 mL) and water (100 mL) was heated at 80°C
`
`for 20 hr under nitrogen. The resulting solution was cooled to room temperature and
`
`partitioned between EtOAc (300 mL) and water (100 mL). The aqueous layer was
`
`extracted with EtOAc (3 x 150 mL) and the combined organics were washed with
`water (1 x 150 mL). The organics were dried (sodium sulphate), filtered and.
`evaporated to leave a solid. On attempting to dissolve in EtOAc/heptane (1:4), a
`
`cream solid (2.5 g) crashed out. Thefiltrate was adsorbed onto silica and purified by
`
`30
`
`flash silica gel column chromatography using 10:1 heptane:EtOAc, 4:1 heptane :
`
`EtOAc , 1:1 heptane:EtOAc and 4:1 EtOAc:heptane. The appropriate fractions were
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 305 of 891
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1023, p. 305 of 891
`
`

`

`WO 00/17203
`
`PCT/US99/21560
`
`QS &
`combinedto give a white solid which was triturated with heptane/EtOAc (5:1) to
`give tert-butyl N-4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolof2,3-
`d\pyrimidin-5-yl]-2-methoxyphenylcarbamate
`as a solid (3.2 g), combined yield is 71%.
`'H NMR (d, DMSO, 400 MHz): 8.66 (1H,s), 7.93 (2H, m), 7.74 (1H, m), 7.19 (1H,
`s), 7.07 (1H,d), 4.81 (1H, m), 3.93 (4H, m), 3.91 (3H,s), 2.18 (2H, m), 1.99 (2H,
`m), 1.79 (4H,m), 1. 48 (9H, s). HPLC (conditions: 5 to 95% CH,;CN in0.1N
`aqueous ammonium acetate over 20 min.) t, = 21.24 min, 100%.
`
`10
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`15
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`20
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`25
`
`30
`
`tert-Butyl N-4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7A-pyrrolo[2,3-
`c)
`d|pyrimidin-5-y1]-2-methoxyphenylcarbamate (5.7 g, 0.011 mol), conc. ammonia
`solution (100 mL) and dioxan (100 mL) were heated in a pressure vessel for 20 hr at
`120°C. The solvent was evaporated and the residue reconstituted in EtOAc/water
`(250 mL/100 mL). The organic layer was separated , dried (sodium sulphate),
`filtered and evaporated to give a solid which by HPLC (conditions: 5 to 95%
`CH,CN in 0.1 N aqueous ammonium acetate over 20 min.) was observed to be a 2:1
`mixture of tert-butyl N-4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7A-pyrrolo[2,3-
`d\pyrimidin-5-yl]-2-methoxyphenylcarbamate and 5-(4-amino-3-methoxyphenyl)-7-
`(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. The mixture was
`dissolved in acetone (200 mL) and HCI (5N, 100 mL) was added dropwise over 0.5
`br. The resulting solution was stirred at room temperature overnight and the solvent
`was then evaporated. The acidic solution was basified with 2N NaOH (ice-cooling)
`and extracted with EtOAc (3 x 150 mL). The combined organics were washed with
`water (2 x 100 mL). During the extraction process a solid precipitated. This solid
`was filtered and triturated in hot Et1OAc/MeOH.Theinsolubles werefiltered, the
`filtrate evaporated and then resulting solid triturated with diethylether/ethyl acetate
`to give a yellow solid. The organic layers from the original extraction were dried
`(sodium sulphate), filtered and evaporated. The resulting solid was triturated with
`diethyl ether/ethyl acetate (5:1) andfiltered to give 4-[4-amino-5-(4-amino-3-
`methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanoneas a yellow
`solid. (2.3 g, combined yield = 78%). 'H NMR (d, DMSO, 400 MHz): 8.17 CH,s),
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 306 of 891
`
`SANDOZ INC.
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`IPR2023-00478
`
`Ex. 1023, p. 306 of 891
`
`

`

`WO 00/17203
`
`PCT/US99/21560
`
`(3°
`
`Example 148: Ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-
`
`7-yl]propionate
`
`Sodium hydride (120 mg, of a 60% dispersion in mineral oil) was added to a
`
`mixture of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (906 mg) in
`
`dry dimethyformamide (30 ml) and the mixture was stirred under nitrogen for 30
`
`minutes at ambient temperature. A solution of ethyl 2-bromopropionate (543 mg) in
`
`dry DMF (10 ml) was added dropwise via a syringe over 10 minutes. The mixture
`
`was stirred at ambient temperature for 2 hours and then left for 18 hours. The
`
`10
`
`mixture was evaporated under vacuum and the residue was washed with waterto
`
`give a solid which was triturated with ether and filtered to give ethyl 2-[4-amino-5-
`
`(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yljpropionate, m.p. 139-140°C.
`
`15
`
`20
`
`Example 149; N-(2-dimethylaminoethyl)-2-[4-amino-5-(4-phenoxypheny1)-7H-
`
`pyrrolo[2,3-d]pyrimidin-7-yl)propionamide
`A mixture of ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-
`_ d]pyrimidin-7-yl]propionate (425 mg), N,N-dimethylethylenediamine (2 ml) and
`methanol (20 ml) was boiled under reflux for 18 hours with the exclusion of carbon
`
`dioxide. The mixture was cooled andfiltered, the filtrate was diluted with water
`
`(50 ml) and stirred with ether. The mixture wasleft standing for 18 hours and the
`solid which precipitated was collected byfiltration, washed with water and then
`ether and dried to give N-(2-dimethylaminoethy])-2-[4-amino-5-(4-phenoxyphenyl)-
`
`7H-pytrolo[2,3-d]pyrimidin-7-ylpropionamide, m.p. 163-164°C.
`
`25
`
`Example 150: Ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-
`
`7-yljacetate
`
`A mixture of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine
`
`(906 mg), sodium hydride (120 mg, of a 60% dispersion in mineral oil) and dry
`
`dimethylformamide (30 ml) was stirred at ambient temperature under nitrogen for 30
`
`30
`
`minutes. Ethyl bromoacetate (0.5 g) in dimethylformamide (10 ml) was added over
`
`5 minutes at 0-5°C with stirring. The mixture. wasstirred for 30 minutes at ambient
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 307 of 891
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1023, p. 307 of 891
`
`

`

`WO00/17203
`
`PCT/US99/21560
`
`138
`temperature and then allowed to stand for 18 hours. The mixture was evaporated
`
`under vacuum and the residue was triturated with water and ether. Thesolid
`
`obtained. was collected by filtration, washed with water and then with ether to give
`
`ethyl 2-[4-amino-5-(4-phenoxypheny])-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetate,
`
`m.p. 161-161.3°C.
`
`Examples 151-156
`
`General Method
`
`Ethyl 2-[4-amino-5-(4-phenoxypheny])-7H-pyrrolo[2,3-d]pyrimidin-7-
`
`10
`
`yllacetate (194 mg) was heated at 62°C andstirred with 10 molar equivalents of the
`
`appropriate amineas listed below in methanol (12 m1) for 18 hoursto give after
`
`work up the following compounds:
`
`15
`
`20
`
`25
`
`Example 151
`
`N-[2-hydroxyethyl-1, 1-di¢hydroxymethyl])]-2-[4-amino-5-(4-
`
`phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetamide, m.p, 222-223°C with
`
`decomposition, from 2-hydroxyethyl-1,1-di(hydroxymethyl)ethylamine.
`
`Example 152
`
`N-[2-(piperazin-1-yl)ethy1]-2-[4-amino-5-[4-phenoxyphenyl)-7H-
`
`pyrrolo[2,3-d]-pyrimidin-7-yl]acetamide, m.p.138-140°C, from 2-(piperazin-1-
`
`ylethylamine.
`
`Example 153
`
`N-(2-morpholinoethyl)-2-[4-amino-5-(4-phenoxypheny])-7H-pyrrolo[2,3-
`
`d]pyrimidin-7-yl]acetamide, m.p. 164-165°C, from 2-morpholinoethylamine.
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1023, p. 308 of 891
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1023, p. 308 of 891
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`

`

`WO 00/17203
`
`PCT/US99/21560
`
`ASG
`
`4.74 (1H, m), 3.82 (3H,s), 3.23 (5H, m), 2.78 (3H, s), 2.51 (3H, m), 2.41 (1H,s),
`
`2.09 (4H, m), 1.70 (4H, m). HPLC: ( 5 to 95% CH,CN in 0.1 N aqueous ammonium
`
`acetate over 20 min.) t, = 13.30 min , 94%.
`
`F28-45 gave a glassy foam (186 mg) which was dissolvedin in ethyl acetate (10
`
`mL) and treated with maleic acid (114 mg) in ethyl acetate (3 mL). Theresulting
`
`solid was filtered under nitrogen and dried in vacuo for 4 hr to give trans- benzyl N-
`
`(4- {4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-
`
`yl} -2-methoxyphenyl)carbamatetri-maleate salt (250 mg) as a cream solid. M.pt
`146-148°C. HPLC: (5 to 95% CH;CN in 0.1 N aqueous ammonium acetate over 20
`
`10
`
`min.) t,= 13.54 min , 94.6%. 'H NMR (d, DMSO, 400 MHz): 8.72 (1H,s), 8.25
`
`(1H,s), 7.77 (1H, d), 7.51 (1H,s), 7.35 (5H, m), 7.10 (1H,s), 7.04 (1H, d), 6.16
`
`(6H, s), 5.17 (2H, s), 4.59 (1H, m), 3.86 (3H,s), 2.70-3.10 (11H, m), 2.50 (3H,s),
`
`1.97 (6H, m), 1.56 (2H, m).
`
`15
`
`20
`
`25
`
`30
`
`Exxample 320: Trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-
`
`pyrrolo[2,3-d]pyrimidin-5-yl} -2-methoxyphenyl)benzamide
`
`To a solution of N1-4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolof2,3-
`
`d)pyrimidin-5-yl]-2-methoxyphenylbenzamide (1.2 g, 2.66 mmol), N-
`
`methylpiperazine (0.80 g, 7.98 mmol) and glacial acetic acid (0.48 g, 7.98 mmol) in
`dichloroethane (150 mL) undernitrogen was added sodium triacetoxyborohydride
`(0.85 g, 3.99 mmol) portionwise. The solution was stirred at room temperature
`
`overnight and then