Synthesis of the metabolites of 4-(2-methyl-1H-imidazol-1-yl)-2,2- diphenylbutanamide (KRP-197/ONO-8025)

Article abstract of DOI:10.1248/cpb.55.1039

We synthesized the six presumed metabolites (2-7) of 4-(2-methyl-1H- imidazol-1-yl)-2,2-diphenylbutanamide [KRP-197/ONO-8025, 1], a urinary incontinence therapeutic agent, in order to confirm the structures of the metabolites. Metabolite (2) was synthesiz

Full text of DOI:10.1248/cpb.55.1039

July 2007
Chem. Pharm. Bull. 55(7) 1039—1043 (2007)
1039
Synthesis of the Metabolites of 4-(2-Methyl-1H-imidazol-1-yl)-2,2-
diphenylbutanamide (KRP-197/ONO-8025)
b
Ichiro ARAYA, ,a Takeshi TSUBUKI,a Tatsuhiro SAITO,a Makoto NUMATA,a and Hiroyuki AKITA
*
a Research Center, Kyorin Pharmaceutical Co., Ltd.; 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329–0114, Japan:
and b School of Parmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan.
Received March 12, 2007; accepted April 28, 2007
We synthesized the six presumed metabolites (2—7) of 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbu-
tanamide [KRP-197/ONO-8025, 1], a urinary incontinence therapeutic agent, in order to confirm the structures
of the metabolites. Metabolite (2) was synthesized via glucuronidaion of compound (1) and methyl 2,3,4-tri-O-
benzoyl-1-methanesulfonyl-a-D-glucopyranuronate. Metabolite (3) was synthesized via 3-(tert-butoxycarbonyl)-2-
methyl-1,3-imidazolidine-4,5-dione. Metabolites (4—7) were synthesized via 4-amino-2-diphenylbutanamide,
respectively. The structures of the metabolites (2—7) in humans were identified by means of synthesis of the
authentic compounds.
Key words KRP-197; ONO-8025; metabolite; glucronide; imidazolidine dion derivative; urinary incontinence
The synthesis and structure–activity relationships of novel thetic route to quaternary N-glucuronide 2 from methyl
4-(imidazoyl-1-yl)butanamide derivatives as antimuscarinic 2,3,4-tri-O-benzoyl-1-methanesulfonyl-a-D-glucopyran-
activity agents were reported by the Kyorin Discovery uronate 9 as a glycosyl donor is shown in Chart 2. 1,2,3,4-
Research group.1—3) Among them, 4-(2-methyl-1H-imidazol- tetra-O-benzoyl-b-D-glucopyranouronate 8, as a starting ma-
1-yl)-2,2-diphenylbutanamide [KRP-197/ONO-8025, 1] is terial, was synthesized from D-(ꢀ)-glucurono-3,6-lacton by
under clinical evaluation as a new type of treatment for uri- applying the reported method.4) 8 was treated with
nary incontinence with highly subtype receptor selective methansulfonic acid in CH2Cl2 to afford a-methansulfonate
antimuscarinic activity. During the course of the metabolite 9 in 49% yield. The glycosidation reaction between 1 and 9
studies of 1, using high performance liquid chromatography was carried out in CHCl3 to provide 10 in 41% yield, and
(HPLC)-mass spectrometry (LC-MS/MS) suggested degra- also stereoselectivity was only obtained for the single b-iso-
dation from the imidazole structure for four of the six mer. Deprotection and hydrolysis of the methyl ester afforded
metabolites of 1, the imidazolidine dione structure and N- ammonium N-glucuronaide 2 as inner salt after HP-20SS
glucuronide (Chart 1). Especially, N-glucuronide was pro- resin treatment.
posed to be the presence of quarter ammonium containing
Synthesis of Imidazolidine Dion 3 The synthesis of the
unique chemical structure 2 as a major metabolite in only hu- metabolite 3 is outlined in Chart 3. N-(1-Aminoethyl)benz-
mans. Thus, our efforts have been focused on the synthesis amide hydrochloride 11, prepared according to Carotti’s
of the above metabolites, which were synthesized in order to method,5) was transformed to 12 on treatment with chloro-
confirm their pharmacological efficacy.
acethyl chloride followed by cyclization and protection by
Synthesis of Ammonium N-Glucronide (2) The syn- the Boc group in 30% yield (3 steps). The ring oxidation re-
Chart 1
Chart 2
∗ To whom correspondence should be addressed. e-mail: ichirou.araya@mb.kyorin-pharm.co.jp
© 2007 Pharmaceutical Society of Japan

1040
Vol. 55, No. 7
Chart 3
Chart 4
action of 12 was achieved by using bromination with N-bro-
mosuccinimide (NBS) followed by pyridinium dichromate
(PDC) treatment to give imidazolidinone 13 in 50% yield.
Debenzoylation of 13 with n-butylamine as a benzoyl group
accepter under high-dilution condition in CH3CN at 0 °C
gave imidazolidinone 14. The obtained 14 was reacted with
4-bromo-2,2-diphenylbutyronitrile in the presence of NaH to
afford the N-alkyl derivative 15, which was subsequently
Chart 5
treated with trifluoroacetic acid in CH2Cl2 and hydration of sis and acetylation gave 6 in overall 47% yield. Amidine de-
the CN group by using N,N-diethylhydroxylamine6) to fur- rivative 7 was synthesized from 16 with S-benzyl thioacetim-
nish the desired 4,5-dioxoimidazolidine compound 3 as a idate hydrobromide8) in 61% yield.
white powder in 41% yield (2 steps).
These synthetic compounds (2—7) were identical with the
1
Synthesis of 4, 5, 6 and 7 The synthesis of the metabo- proposed metabolite structure on the basis of the MS, H-
lite (4—7) from 4-amino-2-diphenylbutanamide 167) as a key NMR and HPLC comparisons. The configuration at the
intermediate is shown in Chart 4. The reaction of 16 and ox- anomeric position of the glucuronic acid moiety of 2 was de-
amic acid in the presence of 1-ethyl-3-[3-(diethylamino)- termined by using H-NMR analysis as shown in Chart 5. A
propyl]carbodiimide hydrochloride (EDC-HCl)/1-hydroxy- doublet at d 5.52 in the H-NMR spectrum was assigned to
1
1
benzotriazole monohydrate (HOBt–H2O) gave 4 in 35% the anomeric proton (C1-H) of the glucuronic acid moiety
yield. The reaction of 16 and ethyl chlorooxoacetate in the and the coupling constant of 8.3 Hz confirmed the b-
presence of Et3N gave oxalamic acid ester congener 17 anomeric assignment (J values for a and b-anomers of glu-
(67%), which was treated with aqueous Na2CO3 afforded 5 curonides are in the range 2 to 4 Hz and 7 to 10 Hz, respec-
(63%). The coupling reaction of 16 and N-(benzyloxycar- tively9)). On the other hand, the conjugated position of the
bonyl)glycine followed by consecutive catalytic hydrogenoly- glucuronic acid moiety on the imidazole ring was confirmed

July 2007
1041
vent was removed under reduced pressure. The residue was dissolved in
water (600 ml), washed three times with CH2Cl2 (300 mlꢅ3). The aqueous
layer was concentrated under reduced pressure. The residue was purified by
synthetic adsorbed beads DIAION HP-20SS column chromatography
(H2O : MeOH (gradient elution, 10 : 0—2 : 1)). The residual crystals were re-
by a heteronuclear multiple bond connectivity (HMBC) spec-
trum, which demonstrated connectivity among C5 of the imi-
dazole ring and the anomeric proton (C1-H), C4 of the imida-
zole ring and 4ꢁ-methyene proton of the butanamide moiety
individually was consistent with the above structure (Chart crystallized two times from 2-propanol/water to give the title compound 2 as
a colorless solid (32.4 g, 85%). 2: mp 210—215 °C (dec). 1H-NMR (D2O) d:
5).
2.50 (3H, s), 2.95—2.98 (2H, m), 3.64—3.80 (3H, m), 4.00 (1H, d,
The antimuscarinic activity of the compounds was evalu-
Jꢃ9.3 Hz), 4.08—4.12 (2H, m), 5.52 (1H, d, Jꢃ8.3 Hz), 7.36—7.48 (11H,
ated in vitro, although all of these compounds were not ac-
tive. Therefore, it is suggested that the metabolites of 1 do
not play a crucial role in the urinary incontinence therapy.
m), 7.67 (1H, d, Jꢃ2.4 Hz). 13C-NMR (D2O) d: 11.9, 40.2, 48.1, 61.5, 73.8,
75.0, 77.9, 81.3, 87.2, 120.9, 124.4, 130.4, 130.9, 131.4., 143.7, 143.9,
147.5, 177.1, 181.2. IR (KBr) cmꢄ1: 3412, 1663, 1625. FAB-MS m/z: 496
(MꢀH)ꢀ. [a]D25 ꢀ9.2° (cꢃ0.52, H2O). Anal. Calcd for C26H29N3O7-1.1H2O
(MW: 515.34): C, 60.60; H, 6.10; N, 8.15. Found: C, 60.43; H, 5.88; N,
8.12.
Experimental
Melting points were determined with a Yanagimoto micromelting point
apparatus and are uncorrected. Elemental analyses are within ꢂ0.3% of the
theoretical values and were determined by a Yanaco CHN coder MT-5. In-
frared spectra were recorded with a JASCO FT/IR-5300 spectrometer. Mass
spectrometry (MS) and high-resolution MS (HR-MS) were performed with
JEOL JMS SX-102A or JEOL JMS-T100LP mass spectrometer. 1H- and
13C-NMR spectra were obtained on a JEOL EX-400 (400 MHz) spectrome-
ter. Spectra were run in either CDCl3 or DMSO-d6 using TMS as internal
standard, or in D2O using TSP as internal standard. Splitting patterns are in-
dicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad peak. Thin-layer chromatography (TLC) plates (Merck: silica gel 60
F254, 0.25 mm, Art 5715) were used for TLC analysis. Columm chromatog-
raphy was performed with silica gel (Merck: silica gel 60 with particle size
0.040—0.063 mm).
1-Benzoyl-3-(tert-butoxycarbonyl)-2-methyl-1,3-imidazolidin-4-one
(12) An ice-cooled suspension of N-(1-aminoethyl)benzamide hydrochlo-
ride 115) (47.2 g, 235 mmol) in anhydrous N,N-dimethylformamide (DMF,
35 ml) was treated with diisopropylethylamine (98.2 ml, 564 mmol) for 1 h,
and then chloroacetylchoride (22.4 ml, 282 mmol) was added dropwise to
the above reaction mixture over a period of 30 min. After the addition, the
reaction mixture was stirred under ice cooling for 2 h and concentrated
under reduced pressure. The residue was dissolved in CH2Cl2 (1500 ml),
washed with water, dried over Na2SO4, and concentrated under reduced
pressure. The residue was triturated with Et2O to give N-{1-[(chloroacetyl)-
amino]ethyl}benzamide (29.8 g) as a crude product. The crude product
(28.9 g, 120 mmol) was dissolved in anhydrous DMF (35 ml). To this solu-
tion was added NaH (60% dispersion in mineral oil, 14.4 g, 360 mmol) at
0 °C, and the reaction mixture was stirred for 4 h at ambient temperature.
The reaction was quenched with AcOH (30 ml). After being stirred for
30 min at room temperature, the mixture was allowed to stand overnight.
The reaction mixture was concentrated under reduced pressure. The residue
was diluted with CH2Cl2 (300 ml) and water (100 ml). The organic layer was
removed and the aqueous layer was extracted four times with CH2Cl2. The
combined organic solution was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue (19.8 g) was dissolved in
anhydrous CH3CN (485 ml). Di(tert-butyl)dicarbonate (Boc2O, 23.3 g,
107 mmol) and 4,4-dimethylaminopyridine (DMAP, 593 mg, 4.85 mmol)
were added to above solution, and the reaction mixture was stirred for 1 h at
room temperature. The reaction mixture was concentrated under reduced
pressure. The residue was purified by silica gel column chromatography
(hexane : AcOEtꢃ2 : 1) and triturated with petroleum ether (50 ml). The pre-
cipitate was collected by filtration, dried under vacuum to give the title com-
Methyl 2,3,4-Tri-O-benzoyl-1-methanesulfonyl-a-D-glucopyranuronate
(9) To a solution of methyl 1,2,3,4-tetra-O-benzoyl-b-D-glucopyrano-
uronate 84) (44.3 g, 72.4 mmol) in anhydrous CH2Cl2 (300 ml), was added
methansulfonic acid (55.8 g, 581 mmol), and the whole mixture was stirred
for 45 min at room temperature. The reaction was quenched with 5% aque-
ous sodium bicarbonate (1400 ml). The organic layer was separated, and the
aqueous layer was extracted two times with CH2Cl2. The combined organic
solution was washed with water, dried over sodium sulfate (Na2SO4), and
concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (CH2Cl2 : hexane : AcOEtꢃ10 : 5 : 1) and recrystal-
lized from CH2Cl2–hexane to give a colorless solid 9 (20.6 g, 49%). 9: mp
1
139—140 °C (dec.). H-NMR (CDCl3) d: 3.11 (3H, s), 3.70 (3H, s), 4.79
(1H, d, Jꢃ9.8 Hz), 5.54 (1H, dd, Jꢃ3.4, 9.8 Hz), 5.75 (1H, t, Jꢃ9.8 Hz),
6.17 (1H, t, Jꢃ9.8 Hz), 6.41 (1H, d, Jꢃ3.4 Hz), 7.31—7.57 (9H, m), 7.88—
7.99 (6H, m). 13C-NMR (CDCl3) d: 39.5, 53.1, 68.7, 69.1, 69.5, 70.8, 95.9,
128.4, 128.4, 128.5, 128.5, 128.5, 128.6, 129.7, 129.8, 129.9, 133.5, 133.6,
133.8, 165.0, 165.2 165.3, 166.7. IR (KBr) cmꢄ1: 1763, 1731, 1272, 707.
FAB-MS m/z: 597 (MꢄH)ꢄ. Anal. Calcd for C29H26O12S (MW: 598.58): C,
58.19; H, 4.38. Found: C, 58.20; H, 4.30.
1
pound 12 as a white powder (20.0 g, 30%). 12: mp 139—141 °C. H-NMR
(CDCl3) d: 1.57—1.66 (12H, m), 4.05—4.28 (2H, m), 6.24 (1H, br), 7.44—
7.52 (5H, m). 13C-NMR (CDCl3) d: 20.1, 28.0, 50.8, 69.0, 84.5, 127.3,
128.7, 131.2, 134.1, 147.7, 166.4, 168.5. IR (KBr) cmꢄ1: 2976, 1802, 1646,
1365, 1153. FAB-MS m/z: 305 (MꢀH)ꢀ. Anal. Calcd for C16H20N2O4 (MW:
304.34): C, 63.14; H, 6.62; N, 9.20. Found: C, 62.97; H, 6.72; N, 9.24.
1-Benzoyl-3-(tert-butoxycarbonyl)-2-methyl-1,3-imidazolidine-4,5-
dione (13) A mixture of 12 (19.2 g, 63.0 mmol), N-bromosuccinimide
(NBS, 12.3 g, 69.3 mmol), benzoyl peroxide (10.0 mg) and tetrachloro-
methane (315 ml) was refluxed for 30 min. After cooling, the reaction mix-
ture was washed with saturated aqueous sodium bicarbonate (200 ml), satu-
rated aqueous sodium aqueous hydrogen sulfite (520 ml) and water (50 ml),
dried over Na2SO4, and concentrated under reduced pressure. The residue
was dissolved in CH2Cl2 (315 ml), and pyridinium dichromate (PDC, 47.4 g,
126 mmol) was added. The reaction mixture was stirred for 20 min at room
temperature. The insoluble part was removed by filtration with the aid of a
celite bed and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane : AcOEtꢃ
2 : 1) and triturated with pentane. The resulting precipitate was collected by
filtration, and dried under vacuum to give the title compound 13 as a white
powder (10.1 g, 50%). 13: mp 139—140 °C. 1H-NMR (CDCl3) d: 1.62 (9H,
s), 1.78 (3H, d, Jꢃ5.9 Hz), 6.07 (1H, q, Jꢃ5.9 Hz), 7.46—7.50 (2H, m),
7.62—7.66 (1H, m), 7.69—7.71 (2H, m). 13C-NMR (CDCl3) d: 20.7, 28.0,
1-(3-Carbamoyl-3,3-diphenylpropy)-3-(2,3,4-tri-O-benzoyl-6-methyl-
b-D-glucopyranuronosyl)-2-methylimidazolium Chloride (10) A solu-
tion of 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide 1 (45.4 g,
142 mmol) and 9 (10.0 g, 16.7 mmol) in anhydrous CHCl3 (500 ml) was re-
fluxed for 13 h under argon. After cooling, the solvent was removed under
reduced pressure. The residue was diluted with CH2Cl2 and 1 M HCl. The or-
ganic layer was removed, and the aqueous layer was extracted with CH2Cl2.
The combined organic solution was washed with 1 M HCl, dried over
Na2SO4, and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (CH2Cl2 : MeOHꢃ20 : 3) and recrys-
tallized from CH2Cl2–hexane to give the title compound 10 as a pale grayish
powder (5.82 g, 41%): 10: mp 164—167 °C (dec.). ESI-MS m/z: 822 (Mꢀ).
1H-NMR (DMSO-d6) d: 2.38—2.45 (1H, m), 2.52 (3H, s), 2.69—2.76 (1H,
m), 3.58 (3H, s), 3.68—3.85 (2H, m), 5.10 (1H, d, Jꢃ9.8 Hz), 5.87 (1H, t,
Jꢃ9.8 Hz), 6.20 (1H, t, Jꢃ8.8 Hz), 6.25 (1H, t, Jꢃ9.3 Hz), 6.68 (1H, d,
Jꢃ8.3 Hz), 6.76 (1H, br s), 7.15—7.85 (27H, m), 8.15 (1H, d, Jꢃ2.4 Hz).
13C-NMR (DMSO-d6) d: 22.8, 38.9, 45.8, 52.7, 58.7, 69.0, 70.7, 72.2, 73.2,
81.5, 119.2, 122.8, 126.9, 127.0, 127.4, 128.1, 128.2, 128.2, 128.5, 128.9,
129.0, 129.0, 129.2, 134.0, 134.1, 134.3, 142.4, 145.1, 164.0, 164.7, 165.0,
166.3, 174.3. IR (KBr) cmꢄ1: 3420, 1734, 1261, 1070, 711. HR-MS (ESI)
m/z: 822.30261 (Calcd for C48H44N3O10: 822.30267).
65.2, 86.2, 128.3, 129.6, 133.7, 147.5, 154.0, 154.2, 167.9. IR (KBr) cmꢄ1
:
1813, 1695, 1388, 1282, 1149. CI-MS m/z: 219, 319 (MꢀH)ꢀ. HR-MS (CI)
m/z: 319.1321 (Calcd for C16H19N2O5: 319.1294).
1-[3-(3-Carbamoyl-3,3-diphenyl)propyl-2-methyl-1-imidazolinio]-1-
deoxy-b-D-glucopyranuronate Hydrate (2) To a solution of 10 (63.0 g,
73.4 mmol) in MeOH (2520 ml) was added 1 M NaOH (50 ml) over 30 min at
ꢄ62 to ꢄ54 °C. After the addition, the cooling bath was removed. The re-
sulting solution was stirred for 30 min at 0 °C and at room temperature for
30 min. The reaction mixture was neutralized with 6 M HCl and then the sol-
3-(tert-Butoxycarbonyl)-2-methyl-1,3-imidazolidine-4,5-dione (14)
A
solution of n-buthylamine (2.27 g, 31.0 mmol) in CH3CN (155 ml) was
added dropwise to an ice-cooled solution of 13 (9.87 g, 31.0 mmol) in
CH3CN (1550 ml) over a period of 2 h. After the addition, the reaction mix-
ture was concentrated under reduced pressure. The residue was triturated

1042
Vol. 55, No. 7
1
with petroleum ether (30 ml). The precipitate was collected by filtration,
pound 17 as a white powder (7.29 g, 67%). 17: mp 203—206 °C. H-NMR
dried over vacuum to give the title compound 14 as a white powder (6.07 g,
(CDCl3) d: 1.36 (3H, t, Jꢃ7.3 Hz), 2.69 (2H, t, Jꢃ6.8 Hz), 3.21 (2H, q,
Jꢃ6.4 Hz), 4.31 (2H, q, Jꢃ7.3 Hz), 5.70 (2H, d, Jꢃ7.8 Hz), 7.26—7.38
1
91%). 14: mp 160—162 °C (dec.). H-NMR (CDCl3) d: 1.59 (9H, s), 1.66
(3H, d, Jꢃ5.9 Hz), 5.38 (1H, q, Jꢃ5.9 Hz,), 9.37 (1H, br s). 13C-NMR
(CDCl3) d: 21.7, 27.9, 63.5, 85.3, 147.7, 157.0, 178.0. IR (KBr) cmꢄ1: 3219,
1794, 1394, 1176. FAB-MS m/z: 213 (MꢄH)ꢄ. Anal. Calcd for C9H14N2O4
(MW: 214.22): C, 50.46; H, 6.69; N, 13.08. Found: C, 50.26; H, 6.56; N,
13.12.
3
(10H, m), 7.96 (1H, br s). C-NMR (CDCl3) d: 13.9, 37.3, 37.8, 59.8, 62.8,
127.4, 128.5, 128.7, 142.7, 156.7 160.6, 176.8. IR (KBr) cmꢄ1: 3443, 1725,
1700, 1660, 1236. FAB-MS m/z: 355 (MꢀH)ꢀ.
N-(3-Carbamoyl-3,3-diphenylpropyl)oxamic Acid (5) A suspension
of 17 (10.6 g, 30.0 mmol) and 10% aqueous sodium carbonate (106 ml) in
EtOH (500 ml) was refluxed for 4 h. After cooling, the reaction mixture was
concentrated under reduced pressure. Water (800 ml) was added to the
residue and the insoluble part was removed by filtration. The filtrate was
washed with CH2Cl2 (400 ml) and AcOEt (400 ml), and neutralized with 2 M
HCl. The precipitate was collected by filtration, and purified by recrystal-
lization from EtOH, dried under vacuum at 100 °C to give the title com-
pound 5 as a white solid (6.16 g, 63%). 5: mp 193—195 °C (dec.). 1H-NMR
(DMSO-d6) d: 2.47—2.51 (2H, m), 2.78—2.83 (2H, m), 6.95 (1H, s),
7.23—7.37 (11H, m), 8.81 (1H, t, Jꢃ5.4 Hz), 13.77 (1H, br s). 13C-NMR
(DMSO-d6) d: 36.3, 36.6, 42.0, 58.8, 126.6, 127.9, 128.8, 143.1, 158.1
161.9, 175.2. IR (KBr) cmꢄ1: 3428, 3319, 3251, 1759, 1654, 1159, 701.
Anal. Calcd for C18H18N2O4 (MW: 326.35): C, 66.25; H, 5.56; N, 8.58.
Found: C, 66.07; H, 5.58; N, 8.64. FAB-MS m/z: 327 (MꢀH)ꢀ.
4-(2-Methyl-4,5-dioxoimidazolidin-1-yl)-2,2-diphenylbutyronitrile
(15) An ice-cooled solution of 14 (6.00 g, 28.0 mmol) in anhydrous DMF
(35 ml) was treated with NaH (60% dispersion in mineral oil, 1.34 g,
33.6 mmol). After stirring for 30 min at the same temperature followed by
stirring for 1 h at room temperature, 4-bromo-2,2-diphenylbutyronitrile
(84.1 g, 280 mmol) was added to the solution, and heated at 80 °C for 2 h.
After cooling, the reaction mixture was concentrated under reduced pres-
sure. The residue was dissolved in AcOEt (500 ml), washed with water,
dried over Na2SO4, and concentrated under reduced pressure. The residue
was dissolved in CH2Cl2 (500 ml). Trifluoroacetic acid (100 ml) was added
to the above ice-cooled solution, and the reaction mixture was stirred for 4 h
at room temperature. The reaction mixture was concentrated under reduced
pressure, and the residue was dissolved in CH2Cl2 (280 ml), washed with
saturated aqueous sodium bicarbonate (200 mlꢅ2) and water (50 ml), dried
over Na2SO4, and concentrated under reduced pressure. The residue was trit-
urated with ether (300 ml). The precipitate was collected by filtration, dried
under vacuum to give the title compound 15 as a white powder (6.53 g,
2-Acetylamino-N-(3-carbamoyl-3,3-diphenylpropyl)acetamide (6) To
a
solution of 16 (509 mg, 2.0 mmol), N-(benzyloxycarbonyl)glycine
(418 mg, 2.00 mmol) and HOBt–H2O (270 mg, 2.00 mmol) in CH2Cl2
(10 ml) were added EDC-HCl (383 mg, 2.0 mmol) and triethylamine (558 ml,
4.00 mmol). After being stirred for 8 h at room temperature, the mixture was
allowed to stand overnight at the same temperature. The reaction mixture
was diluted with AcOEt, washed with 1 M NaOH, 1 M HCl and water, dried
over Na2SO4, and concentrated under reduced pressure to give crude benzyl
[N-(3-carbamoyl-3,3-diphenylpropyl)carbamoylmethyl]carbamic acid as a
colorless solid. The obtained carbamic acid derivative was dissolved in THF
(16 ml), 7.5% Pd–C (162 mg) and acetic anhydride (189 ml, 2.00 mmol) were
added. The reaction mixture was stirred for 6 h at room temperature under
hydrogen atmosphere, and then DMF was added until the resulting precipi-
tate was dissolved. The catalyst was removed by filtration through celite, and
the filtrate was concentrated. The residue was recrystallized from EtOH to
give the title compound 6 as a white solid (320 mg, 47%). 6: mp 214—
1
70%). 15: mp 204—205 °C. H-NMR (CDCl3) d: 1.45 (3H, d, Jꢃ5.9 Hz),
2.66—2.74 (1H, m), 2.82—2.90 (1H, m), 3.38—3.45 (1H, m), 3.70—3.77
(1H, m), 4.90 (1H, q, Jꢃ5.9 Hz), 7.30—7.45 (10H, m), 9.00 (1H, br s). 13C-
NMR (CDCl3) d: 20.3, 36.5, 38.3, 50.0, 63.7, 121.5, 126.6, 128.4, 129.2,
129.2, 138.6, 138.7, 158.5, 160.2. IR (KBr) cmꢄ1: 1777, 1728, 1710, 698.
EI-MS m/z: 333 (Mꢀ), 192, 165. Anal. Calcd for C20H19N3O2 (MW: 333.38):
C, 72.05; H, 5.74; N, 12.60. Found: C, 71.89; H, 5.91; N, 12.58.
4-(2-Methyl-4,5-dioxoimidazolidin-1-yl)-2,2-diphenylbutanamide (3)
A mixture of 15 (6.33 g, 19.0 mmol), N,N-diethylhydroxylamine (100 ml,
950 mmol) and 1,4-dioxane (317 ml) was heated for 96 h at 100 °C. After
cooling, the reaction mixture was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane : AcOEtꢃ
15 : 1) and crystallized from CHCl3, and further purified by recrystallization
(CHCl3/acetone) to give the title compound 3 as a white powder (3.90 g,
58%). 3: mp 203—204 °C. IR (KBr) cmꢄ1: 3236, 1747, 1666. 1H-NMR
(DMSO-d6) d: 1.18 (3H, d, Jꢃ5.9 Hz), 2.38 (1H, ddd, Jꢃ5.4, 12.7, 17.6 Hz),
2.68 (1H, ddd, Jꢃ3.9, 12.7, 16.9 Hz), 2.78—2.85 (1H, m), 3.26 (1H, ddd,
Jꢃ5.4, 13.2, 17.6 Hz), 4.95 (1H, q, Jꢃ5.9 Hz), 6.87 (1H, br s), 7.24—7.36
(11H, m), 9.80 (1H, br s). 13C-NMR (DMSO-d6) d: 19.7, 35.3, 37.5, 58.7,
61.9, 126.7, 126.7, 128.0, 128.6, 128.7, 142.9, 143.0, 158.1, 159.1, 174.7.
EI-MS m/z: 193, 211, 351 (M)ꢀ. Anal. Calcd for C20H21N3O3-0.3H2O (MW:
356.80): C, 67.32; H, 6.10; N, 11.78. Found: C, 67.13; H, 5.99; N, 11.96.
N-(3-Carbamoyl-3,3-diphenylpropyl)oxamide (4) To a solution of
167) (1.58 g, 6.21 mmol), oxamic acid (0.57 g, 6.40 mmol), 1-hydroxybenzo-
triazole monohydrate (HOBt–H2O, 1.70 g, 6.40 mmol) and triethylamine
(0.65 g, 6.42 mmol) in DMF (30 ml) was added 1-(3-dimethylaminopropyl)-
3-ethylcarbodiimide hydrochloride (EDC–HCl, 1.21 g, 6.31 mmol). After
being stirred for 2.5 h at room temperature, the mixture was allowed to stand
overnight at the same temperature. The reaction mixture was poured into
water (150 ml), extracted two times with AcOEt and the combined organic
layer was washed with water, dried over Na2SO4, and concentrated under re-
duced pressure. The residue was purified by silica gel column chromatogra-
phy (AcOEt) and recrystallized from MeOH–H2O to give the title compound
1
215 °C. H-NMR (DMSO-d6) d: 1.84 (3H, s), 2.40—2.44 (2H, m), 2.67—
2.73 (2H, m), 3.58 (2H, d, Jꢃ5.9 Hz), 7.23—7.35 (10H, m). 13C-NMR
(DMSO-d6) d: 22.5, 36.2, 36.8, 42.0, 58.7, 126.4, 127.8, 128.7, 143.2, 169.0
169.5, 175.0. IR (KBr) cmꢄ1: 3432, 1682, 1655, 1632. Anal. Calcd for
C20H23N3O3 (MW: 353.41): C, 67.97; H, 6.56; N, 11.89. Found: C, 67.95; H,
6.65; N, 11.88. FAB-MS m/z: 354 (MꢀH)ꢀ.
4-[(Acetimidoyl)amino]-2,2-diphenylbutanamide (7) S-Benzyl
thioacetimidate hydrobromide8) (4.92 g, 20.0 mmol) was added in small por-
tions to an ice-cooled mixture of 16 (5.09 g, 20.0 mmol) and EtOH (100 ml),
and the solution was stirred for 2 h at the same temperature. The reaction
mixture was concentrated under reduced pressure, and the residue was tritu-
rated with EtOH (50 ml). The resulting precipitates were collected by filtra-
tion, and purified by recrystallization (EtOH) to give the hydrobromide of 7
(3.87 g). The obtained hydrobromide 7 (2.63 g, 7.00 mmol) was suspended
in water (53 ml) and cooled at 5 °C. 1 M NaOH (7.7 ml, 7.70 mmol) was
added to the above mixture, and the mixture was stirred for 2 h at ambient
temperature. The resulting precipitate was collected by filtration, and puri-
fied by recrystallization (CH3CN/IPE) to give the title compound 7 as a
1
white powder (1.26 g, 61%). 7: mp 166—167 °C. H-NMR (DMSO-d6) d:
1.78 (3H, s), 2.52—2.61 (4H, m), 6.21 (2H, br), 7.10 (1H, s), 7.11—7.30
(10H, m), 8.94 (1H, br). 13C-NMR (DMSO-d6) d: 22.8, 36.2, 38.9, 58.4,
126.1, 127.6, 128.6, 144.7, 161.6, 175.1. IR (KBr) cmꢄ1: 3418, 1619, 1384,
695. Anal. Calcd for C18H21N3O (MW: 295.38): C, 73.19; H, 7.17; N, 14.23.
Found: C, 73.04; H, 7.18; N, 14.20. FAB-MS m/z: 296 (MꢀH)ꢀ.
1
4 as a white solid (0.71 g, 35%). 4: mp 178—180 °C. H-NMR (DMSO-d6)
d: 2.47—2.51 (2H, m), 2.78—2.83 (2H, m), 6.99 (1H, s), 7.22—7.32 (6H,
m), 7.73 (1H, s), 8.02 (1H, s), 8.70 (1H, t, Jꢃ5.9 Hz). 13C-NMR (DMSO-d6)
d: 36.3, 36.4, 58.7, 126.4, 127.8, 128.7, 143.2, 160.2, 162.1, 175.1. IR
(KBr) cmꢄ1: 3424, 3360, 3328, 3279, 3191, 1728, 1655, 1620. Anal. Calcd
for C18H19N3O3 (MW: 325.36): C, 66.45; H, 5.89; N, 12.91. Found: C,
66.34; H, 5.87; N, 12.86. FAB-MS m/z: 326 (MꢀH)ꢀ.
References and Notes
1) Miyachi H., Kiyota H., Segawa M., Bioorg. Med. Chem. Lett., 8,
1807—1812 (1998).
Ethyl N-(3-Carbamoyl-3,3-diphenylpropyl)oxamic Acid (17) To a so-
lution of 16 (6.77 g, 26.6 mmol) in CH2Cl2 (200 ml) containing triethylamine
(3.00 g, 29.6 mmol) was added dropwise ethyl chlorooxoacetate (4.00 g,
29.3 mmol) at 0 °C. After the addition, the reaction mixture was stirred at
room temperature for 10 min. The reaction mixture was diluted with CH2Cl2
(200 ml), washed with water (200 ml) and saturated aqueous sodium bicar-
bonate (200 ml), dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was triturated with EtOH (10 ml), and the precipitate
was collected by filtration, and dried under vacuum to give the title com-
2) Miyachi H., Kiyota H., Segawa M., Bioorg. Med. Chem. Lett., 8,
2163—2168 (1998).
3) Miyachi H., Kiyota H., Uchiki H., Segawa M. Bioorg. Med. Chem., 7,
1151—1161 (1999).
4) Scheinmann F., Lumbard K. W., Brown R. T., Mayalarp S. P., Caeter
N. E., WO Patent 9303051 (1993).
5) Carotti A., Cellamare S., Fanizzi F. P., Gavuzzo E., Mazza F., Biopoly-
mers, 60, 322—332 (2001).
6) Miyazawa T., Endo T., Okawara M., Synthesis, 1984, 1034—1036

July 2007
(1984).
1043
the cyano group was hydrated with potassium hydroxide in 2-propanol
to provide an amide compound. The dibenzyl group of the amide com-
pound was hydrogenated with Pearlman’s catalyst to give 4-amino-2,2-
diphenylbutanamide 16 (40%, 3 steps).
7) Synthesis of this compound was carried out starting from diphenylace-
tonitrile based on modification of the procedure by Janssen et al.
[Janssen P. A. J., Demoen P. J. A., Jageneau A. H. M., Loomans J. L.
M., J. Med. Pharm. Chem., 1, 187—194 (1959)] as below: The reac-
tion of diphenylacetonitrile with N-(2-chloroethyl)dibenzylamine in
the presence of NaH in DMF afforded the coupling product, of which
8) Shearew B. G., Oplinger J. A., Lee S., Tetrahedron Lett., 38, 179—182
(1997).
9) Kasperson F. M., Boeckel V., Xenobiotica, 17, 1451—1471 (1987).