Apr. 8, 2004  36  US 2004/0067216 Al  pyl)-3-ethylcarbodiimide.HCl (EDC.HCl) (1940 g) was  added portionwise over 15-30 min. The reaction temperature  was kept below 35°  C. When the reaction appeared complete  (approx. two hours, <5% pyrazine 2-carboxylic acid by LC  assay), the reaction mixture (yellow/white slurry) was  diluted with 10% ~CO$_{3 }$ in water (24 L, 20 mL/g acid) and  the reaction slurry was kept below 35°  C. The slurry was  cooled to 10°  C., aged for two hours and filtered (mother  liquor assay=3-4 mg/mL). The wet cake was washed with  deionized water (12 L, 10 mL/g acid) and dried under  vacuum (22" Hg) at 40°  C. with a nitrogen purge. Theoreti› cal yield of 1816 g . Actual yield 1533 g (84%).  [0399]  $^{1}$H NMR: (CD$_{3}$ CN, 400 MHz): o9.29(d,  1=1.5  Hz,  lH), 8.82 (d,  1=2.5  Hz, lH), 8.63 (dd, 1=2.6,1.4 Hz, lH),  8.40 (bs, lH), 4.14 (dq,  1=9.4,  6.8 Hz, 2H).  [0400]  HPLC Assay conditions: Waters Xterra RPS col› umn, elution with acetonitrile and 5 mM K phosphate  adjusted to pH=8, detection at 220 nm.  [0401]  Step Two:  [0402]  Preparation of the piperazine amide  [0403]  Pyrazine amide (60.2 g 0.268 mol, not corrected  for water content) was suspended in absolute ethanol (550  mL) in a 1.0 L autoclave hydrogenation vessel and cooled to  15°  C. Wet 20% Pd(OH)iC 11.0 g (20 wt %, S0wt % wet)  was added and reaction was purged with N$_{2 }$ three times.  H$_{2 }$ (5 psig) was introduced with stirring and the temperature  maintained at 15°  C. for 60 minutes. The temperature was  then increased to 60°  C. and the hydrogen pressure increased  to 40 psig and the reaction mixture stirred for 18 additional  hours. The reaction was considered complete when conver› sion is >99% by LC assay. The reaction mixture was filtered  through Solka-Floc and the catalyst solids were washed with  ethanol 2x110 mL. Assay of the combined filtrate and  washes gave 53.5 g of racemic piperazine amide (Yield=  86%)  [0404]  $^{1}$H NMR (CD$_{3}$ CN, 400 MHz): 07.58 (bs, lH), 3.90  (dq,  1=9.5,6.7  Hz, 2H), 3.24(dd,  1=7.9,  5.5 Hz, lH), 2.96  (dd, 1=12.1, 3.6 Hz, lH), 2.84-2.78 (m, lH), 2.77-2.67 (m,  3H), 2.66-2.56 (m, lH), 1.90 (s, 2 H).  [0405]  HPLC Assay conditions: YMC Basic column, elu› tion with acetonitrile and 0.1 % aqueous H$_{3}$PO$_{4}$, detection at  210 nm.  [0406]  Step Three:  [0407]  Resolution of the piperazine amide  [0408]  The pip amide ethanol filtrate (116.37 g containing  10.3 g of racemic pip amide by LC assay) was concentrated  in vacuo to a final volume of 40.2 mL (3.9 mL per gram of  pip amide) and the slurry is diluted with 82.4 mL (8 mL per  gram pip amide) of acetonitrile  (ACN)  and stirred until  homogenous. Separately (S)-camphorsulfonic acid  ((S)› CSA)  (19.26 g, MW=232.30, 1.7 eq) was dissolved in 185  mL of ACN (18 mL per gram of pip amide). The water  content of the two solutions was then determined by Karl  Fisher titration. The CSA solution was added to the pip  amide solution giving a small exotherm to approx. 31-32°  C.  Water (11.02 mL, 1.118 mL per gram of pip amide minus the  total water content of the two solutions) was then added,  such that the acetonitrile:ethanol:water ratio was 26:2.9:1.1  (v/v/v). Solids began to form after 15-30 min. The solution/  slurry was heated to 72°  C. to completely dissolve all solids.  The yellow solution was recooled to 62°  C. and seeded with  a slurry of 10.3 mg of pip amide salt in 1 mL of acetonitrile.  After a two hour age at 62°  C. the slurry was allowed to cool  to room temperature overnight ( crystallization was complete  when loss to mother liquors was <21 mg pip amide/mL by  LC assay. The slurry was filtered then washed with 2x30 mL  of ACN:EtOH:H$_{2}$O [(26:2.9:1.1), (v:v:v)] solution. The wet  cake (-13 g, white solid) was dried at 40°  C. in a vacuum  oven (24 in Hg, nitrogen sweep) to give 11.16 g of product  (yield=33%). Assay method (Pip Amide) as above. Chiral  assay gives an enantiomeric excess (ee) of 98.0%.  [0409]  $^{1}$H NMR (CD$_{3}$OD, 400 MHz): d4.84(bs, SH), 4.64  (dd, 1=12.0, 3.6 Hz, lH), 4.13-3.9 (m, 3H), 3.77 (m, 2H),  3.66 (m, lH), 3.54-3.43 (m, 2H), 3.28(d, 1=14.7 Hz, 2H),  2.82 (d, 14.7 Hz, 2H), 2.55 (m, 2H), 2.36 (m, 2H), 2.12- 1.998 (m, 4H), 1.92 (d, 1=18.4 Hz, 2H), 1.72 (m, 2H), 1.45  (m, 2H), 1.09 (s, 6H), 0.87 (s, 6H).  [0410]  Enantiomeric excess determined by chiral HPLC  of the mono BOC piperazine amide. HPLC assay condi› tions: Chiral AGP column, elution with acetonitrile and 10  mM Kphospate, pH=6.5, detection at 210 nm.  Pd(OH)vC, H2  EtOH  (S)-CSA  ACN:EtOH:H20  26:2.9:1.1 