Process development and large-scale synthesis of NK1 antagonist

Article abstract of DOI:10.1248/cpb.56.176

A scaleable synthetic route is described to obtain 2-(4-acetylpiperadin-1- yl)-6-[3,5-bis(trifluoromethyl)-phenylmethyl]-4-(2-methylphenyl)-6,7,8, 9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (1, KRP-103) as a neurokinin (NK)₁ antagonist.

Full text of DOI:10.1248/cpb.56.176

176
Chem. Pharm. Bull. 56(2) 176—180 (2008)
Vol. 56, No. 2
Process Development and Large-Scale Synthesis of NK1 Antagonist
b
Ichiro ARAYA, ,a,b Shintaro KANAZAWA,a and Hiroyuki AKITA
*
a Research Center, Kyorin Pharmaceutical Co., Ltd.; 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329–0114, Japan:
and b Faculty of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan.
Received October 25, 2007; accepted November 28, 2007
A scaleable synthetic route is described to obtain 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)-
phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (1, KRP-103) as a
neurokinin (NK)1 antagonist. The key step in the synthesis is the intramolecular cyclization of N-[3,5-bis(trifluo-
romethyl)phenylmethyl]-N-(3-hydroxypropyl)-4-chloro-6-(2-methylphenyl)-2-methylthiopyrimidine-5-carboxam-
ide (15) which was obtained by amide formation between 4-(2-methylphenyl)-2-methylthio-6-oxo-1,6-dihydropy-
rimidine-5-carboxylic acid (8) and 3-[3,5-bis(trifluoromethyl)phenylmethylamino]-1-propanol (3). Treatment
of 15 with 1,8-diazabicyclo[5,4,0]undec-7-ene provided 6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methyl-
phenyl)-2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (6). This intermediate (6) is
transformed into the candidate compound (1) by two steps; oxidation, and substitution reaction of the resultant
sulfone (7) with 1-acetylpiperazine. This synthetic method is free of chromatographic purification and is
amenable to large scale synthesis.
Key words KRP-103; neurokinin (NK)1 antagonist; large-scale production; urinary incontinence; 2-(4-acetylpiperadin-1-yl)-6-
[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one; intramolecular
cyclization
The tachykinin neuropeptides, substance P (SP), neu- b][1,5]oxazocine (5). Suzuki coupling reaction of 5 with o-
rokinin A (NKA), and neurokinin B (NKB), are neurotrans- tolylboronic acid provided the coupled product (6), which
mitters or neuromodulatory agents. Each of these structurally was subjected to oxidation to afford a sulfone (7). Finally,
related neuropeptides has a preferred receptor: the NK1 re- nucleophilic displacement of 7 with 1-acetylpiperazine pro-
ceptor for SP, the NK2 receptor for NKA, and the NK3 recep- vided KRP-103 (1).5—7) However, this method was impracti-
tor for NKB. The NK1 and NK2 receptors are widely distrib- cal for the preparation of large quantities of material for pre-
uted in the central nervous system (CNS) and peripheral tis- clinical development, because it required multiple chromato-
sue; NK3 may be more localized in the CNS.1) Of these pep- graphic purifications and was not cost competitive. The for-
tides, SP2) is known to exhibit a wide variety of biological re- mation of compound (6) by way of Suzuki coupling process
sponses, both centrally and peripherally. Through binding to of 5 with o-tolylboronic acid might be substituted for Kno-
the NK1 receptor, SP has been implicated in the transmission evenagel condensation reaction between o-tolualdehyde and
of pain and stress signals, inflammation, and the contraction malonate followed by construction of 4-aryl-6-oxo-1,6-dihy-
of smooth muscle. Therefore, NK1 antagonists may be effica- dropyrimidine skeleton. Herein, we describe a new practical
cious for the clinical treatment of a wide range of diseases. In process for the synthesis of 1, which requires no chromato-
particular, we were interested in the relationship between graphic purification and is cost-effective to large-scale pro-
tachykinin and the activation of the micturition-related re- duction of KRP-103 (1).
fluxes,3,4) with a view to possible application in the treatment
of pollakiuria and urinary incontinence. Recently, the Kyorin
Discovery Chemistry group reported the design, synthesis,
and evaluation of novel 2-substituted-4-aryl-6,7,8,9-tetra-
hydro-5H-pyrimido[4,5-b][1,5]-oxazocin-5-ones.5—7) Among
these, 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)-
phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-
pyrimido[4,5-b][1,5]oxazocin-5-one (1, KRP-103) was iden-
tified as an effective NK1 antagonist, and was promoted for
development as a drug candidate for the treatment of pollaki-
uria and urinary incontinence.5—7) As a continuation of this
research, a large quantity of 1 was required to support the
preclinical and clinical development work. Furthermore, the
reduced production cost of 1 was a requested requirement in
the early stage. The first synthesis of 1 by the Discovery
Chemistry group is shown in Chart 1.
Condensation of 4,6-dichloro-2-(methylthio)pyrimidine-5-
carboxylic acid (2)8) with 3-[3,5-bis(trifluoromethyl)phenyl-
methylamino]-1-propanol (3),9) via acid chloride produced a
condensation product (4), which was subjected to nucle-
ophilic intramolecular cyclization to afford pyrimido[4,5-
Chart 1
∗ To whom correspondence should be addressed. e-mail: ichirou.araya@mb.kyorin-pharm.co.jp
© 2008 Pharmaceutical Society of Japan

February 2008
177
Results and Discussion
reaction, the water formed must be removed for the reaction
A strategy was devised for the practical synthesis of 1 with to proceed to completion. The coupling step was performed
regard to the process chemistry route shown in Chart 2. The in toluene with piperidine as the base under azeotropic con-
intermediate (6) could be obtained by amide formation of a ditions. The dehydrogenation of 9 was carried out under sev-
4-arylpirimidine derivative (8) with 3, followed by intramole- eral conditions. However, dehydrogenation of 9 using some
cular cyclization. In this process, the use of expensive oxidants, such as MnO2, ceric ammonium nitrate (CAN),
reagents, such as the starting material (2), palladium catalysts Pd–C (ꢀ210 °C), Mn(OAc)3, and CuCl2, did not yield the de-
and phenyl boronic acid compounds, are avoided, which ef- sired compound (13) completely. When 2,3-dichloro-5,6-di-
fectively reduces the target cost. The key intermediate, a 4- cyano-p-benzoquinone (DDQ) was applied to the dehydro-
arylpyrimidine derivative (8) and b-keto ester (9) could be genation of 9 in ethyl acetate (AcOEt), 13 was obtained in
obtained from the starting o-tolualdehyde (11) via the cross- 88% yield after recrystallization of the crude product from
conjugated ester (10). The practical synthesis of 1 from 11 is aqueous ethanol (EtOH). The saponification of 13 in aqueous
shown in Chart 3.
sodium hydroxide under heating afforded a carboxylic acid
A Knoevenagel reaction10,11) of o-tolualdehyde (11) and (8) in 90% yield. In all of the steps, it was not necessary to
ethyl malonate provided the condensation product (10) in use chromatographic purification, and crystallization was ef-
88% yield, which was then treated with 2-methyl-2-thio- fective. Treatment of 8 with phosphorus oxychloride (POCl3)
pseudourea hemisulfate (12) in the presence of potassium bi- at 80 °C provided an acid chloride (14), which was used for
carbonate (KHCO3) in dimethyl sulfoxide (DMSO) to give the next reaction without further purification. The reaction of
the b-keto ester (9) in 85% yield. During the Knoevenagel 14 with 3 in the presence of triethylamine (Et3N) gave an
amide (15). The use of potassium carbonate (K2CO3) in
DMF is effective in the case of intramolecular cyclization of
4,12) while intramolecular cyclization of 15 using this method
did not proceed, and the starting material (15) was recovered.
Therefore, other bases and solvents were examined. The best
result was that where the reaction proceeded in the presence
of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in DMSO to
furnish compound 6 (41% yield from 8) after recrystalliza-
tion of the crude product from 2-propanol (IPA). For the ini-
tial preparation of sulfone 7 from 6 (Chart 1), the use of m-
chloroperbenzoic acid (m-CPBA) is standard protocol. How-
ever, this protocol was not to be applied, because m-CPBA is
Chart 2
potentially explosive and requires purification before use.13)
Chart 3

178
Vol. 56, No. 2
corrected for the detector response. Melting points (mp) were determined
using Yanagimoto micromelting point apparatus and were uncorrected. Ele-
mental analyses are within ꢁ0.3% of the theoretical values and were deter-
mined using a Yanaco CHN coder MT-5. Infrared spectra were recorded
with a Jasco FT/IR-5300 spectrometer. Electron impact-mass spectrometry
Oxidation of the methyl sulfide (6) with 30% aqueous H2O2
in the presence of sodium tungstate (Na2WO4) and acetic
acid (AcOH) as a catalyst,14,15) gave sulfone (7) accompanied
by a small amount of by-product. Contamination by the small
amount of by-product in 7 would affect the purity of KRP- (EI-MS) and fast atom bombardment-mass spectrometry (FAB-MS) was
performed with Jeol JMS SX-102A or Jeol JMS-T100LP mass spectrome-
103 (1). On the other hand, when magnesium bis(monoper-
1
ters. H- and 13C-NMR spectra were obtained on a Jeol EX-400 (400 MHz)
oxyphthalate)hexahydrate (MMPP)16,17) was applied in
spectrometer. Spectra were run in either CDCl3 or DMSO-d6 using tetram-
ethylsilane (TMS) as an internal standard. Splitting patterns are indicated as
CH3CN/EtOH instead of m-CPBA, the reaction proceeded to
give sulfone 7 in 89% yield. Although MMPP is also poten-
tially explosive, it’s stable and low toxic compound than m-
CPBA. Furthermore, this protocol seems to be a simple
work-up, because MMPP and its resulting magnesium phtha-
late are easily soluble in water. Only the resulting precipitate
was collected after water was added to the reaction mixture,
and the resulting crude sulfone was able to be purified by
crystallization to furnish pure 7 (ꢀ99% purity by HPLC).
The final process in the original reaction of 75) with 1-
acetylpiperazine in the presence of diisopropylethylamine
was carried out using 1,4-dioxane as a solvent, and the final
product KRP-103 (1) was obtained in 65% yield. As 1,4-
dioxane is defined as a class 2 solvent in the ICH (Interna-
tional Conference on Harmonization of Technical Require-
ments for Registration of Pharmaceuticals for Human Use)
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad
peak.
Diethyl 2-(2-Methylbenzylidene)malonate (10) A mixture of o-tolu-
aldehyde 11 (150 g, 1.25 mol), diethyl malonate (210 g, 1.25 mol) and piperi-
dine (31.9 g, 375 mmol) in toluene (750 ml) was refluxed for 2.5 h using
Dean–Stark apparatus. During the reflux, piperidine (10.6 g, 125 mmol) was
added to the mixture at 0.5 h and 1 h. After cooling, the reaction mixture was
concentrated under reduced pressure. The crude product was purified by dis-
tillation to give 10 (140 °C/120 Pa) as a pale yellow oil (289 g, 88% yield,
HPLC purity: 95.8 area %). 10: 1H-NMR (CDCl3, 400 MHz) d: 1.17 (3H, t,
Jꢂ7.1 Hz), 1.34 (3H, t, Jꢂ7.1 Hz), 2.38 (3H, s), 4.22 (2H, q, Jꢂ7.1 Hz),
4.32 (2H, q, Jꢂ7.1 Hz), 7.15 (1H, t, Jꢂ7.8 Hz), 7.21 (1H, d, Jꢂ7.6 Hz), 7.27
(1H, dt, Jꢂ1.2, 7.6 Hz), 7.33 (1H, d, Jꢂ7.8 Hz), 7.97 (1H, s). 13C-NMR
(CDCl3, 100 MHz) d: 13.7, 14.0, 19.7, 61.2, 61.4, 125.8, 127.6, 127.8,
129.8, 130.2, 132.6, 137.4, 141.5, 163.9, 166.1. IR (KBr) cmꢃ1: 1729, 1257,
1212, 1067. EI-MS m/z: 217, 262 (Mꢄ). Anal. Calcd for C15H18O4 (MW:
262.30): C, 68.68; H, 6.92. Found: C, 68.84; H, 6.90.
Ethyl 4-(2-Methylphenyl)-2-methylthio-6-oxo-1,4,5,6-tetrahydropy-
guideline,18) residual levels must be controlled. To avoid the rimidine-5-carboxylate (9) Potassium bicarbonate (439 g, 4.38 mol) was
added to a stirred suspension of 10 (287 g, 1.09 mol) and 2-methyl-2-thio-
pseudourea hemisulfate (12: 622 g, 2.19 mol) in DMSO (2.18 l). The reac-
tion mixture was allowed to warm to 50 °C and was stirred for 2.5 h. After
cooling to 20 °C, the reaction mixture was poured into water (1.09 l) and the
use of 1,4-dioxane, another protocol was examined. The best
result was the reaction of 7 with 1-acetylpiperazine in the
presence of Et3N in DMSO at 50—55 °C, which proceeded
smoothly to furnish the final compound 1 with the desired
crystal form in 80% yield after recrystallization of the crude
product from aqueous acetone. The present synthetic route
was composed of a nine-step transformation and did not re-
quire any special handling and chromatographic purification.
The overall yield of KRP-103 (1) from o-tolualdehyde (11)
was found to be 17%. A successive scale-up was conducted
to multi-kilogram scale using a kilo-lab facility, and the over-
all yield of 1 was improved to 26%.
resulting mixture was stirred for 0.5 h at 16—20 °C. The precipitate was col-
lected by filtration and purified by recrystallization from IPA/water (4 : 1) to
give 9 as a white powder (285 g, 85% yield, HPLC purity: 99.4 area %). 9:
mp 135—137 °C. 1H-NMR (CDCl3, 400 MHz) d: 1.15 (3H, t, Jꢂ7.3 Hz),
2.42 (3H, s), 2.44 (3H, s), 3.66 (1H, d, Jꢂ8.3 Hz), 4.15 (2H, q, Jꢂ7.3 Hz),
5.43 (1H, d, Jꢂ8.3 Hz), 7.07—7.10 (1H, m), 7.16—7.21 (3H, m), 8.13 (1H,
br). 13C-NMR (CDCl3, 100 MHz) d: 13.1, 13.8, 19.3, 52.6, 59.1, 61.8,
126.0, 126.2, 127.8, 131.0, 135.8, 137.2, 152.2, 166.1, 167.6. IR (KBr)
cmꢃ1: 3115, 1749, 1715, 1605, 1143, 766. EI-MS m/z: 233, 306 (Mꢄ). Anal.
Calcd for C15H18N2O3S (MW: 306.38): C, 58.80; H, 5.92; N, 9.14. Found: C,
58.36; H, 5.84; N, 9.05.
Ethyl 4-(2-Methylphenyl)-2-methylthio-6-oxo-1,6-dihydropyrimidine-
5-carboxylate (13) DDQ (239 g, 1.02 mol) was added to a stirred suspen-
sion of 9 (284 g, 0.93 mol) in AcOEt (1.42 l), and the reaction mixture was
stirred for 2.5 h at 23—46 °C. After cooling to 25 °C, the insoluble portion
was removed by filtration, and washed with AcOEt (0.28 l). The combined
filtrate was washed with 2.4% aqueous sodium bicarbonate solution (1.42 l),
then water (0.5 lꢅ2), and was concentrated under reduced pressure. The
Conclusions
An efficient and safe process for the preparation of the
drug candidate KRP-103 (1) was developed, which provided
many significant advantages over the original process
achieved by Kyorin Discovery Chemists. The intramolecular
cyclization of 6-aryl-subsutituted-pyrimidine-5-carboxamide residue was crystallized from 50% aqueous EtOH to give 13 as colorless
crystals (249 g, 88% yield, HPLC purity: 99.9 area %). 13: mp 136—139 °C.
15, which is synthesized from commercially available o-tolu-
aldehyde (11) in 6 steps, is the key step in the new synthesis
1H-NMR (CDCl3, 400 MHz) d: 0.84 (3H, t, Jꢂ6.8 Hz), 2.24 (3H, s), 2.58
(3H, s), 4.02 (2H, q, Jꢂ6.8 Hz), 7.14 (1H, d, Jꢂ7.3 Hz), 7.18—7.24 (2H,
of the intermediate 6 possessing 6,7,8,9-tetrahydro-5H-
pyrimido[4,5-b][1,5]oxazocin-5-one skeleton. The current
route avoids the use of undesired chemicals like m-CPBA
and 1,4-dioxane. All starting materials and reagents are
cheap and easily available. Isolation of intermediates and
product is very convenient, and the purity and impurity pro-
files of product and intermediates are all satisfying. The
process for preparing 1 with the preferred crystal form was
successfully scaled up and 1 was reliably obtained in 26%
overall yield from 11 on a multi-kilogram scale in a kilo-lab
facility.
m), 7.28—7.37 (1H, m), 12.40 (1H, br). 13C-NMR (CDCl3, 100 MHz) d:
13.3, 13.5, 19.5, 61.2, 125.3 (2C), 127.6 (2C), 129.0, 130.1, 135.4, 137.9,
164.1, 165.6, 166.3. IR (KBr) cmꢃ1: 2925, 1645, 1537, 1199, 1071, 551. EI-
MS m/z: 231, 304 (Mꢄ). Anal. Calcd for C15H16N2O3S (MW: 304.36): C,
59.19; H, 5.30; N, 9.20. Found: C, 59.41; H, 5.34; N, 9.19.
4-(2-Methylphenyl)-2-methylthio-6-oxo-1,6-dihydropyrimidine-5-car-
boxylic Acid (8) A suspension of 13 (248 g, 814 mmol) in 1 M aqueous
sodium hydroxide (3.26 l) was heated at 80—85 °C for 2.5 h. After cooling
to 10 °C, the reaction mixture was adjusted to pH 2 with 2 M HCl, and the re-
sulting mixture was stirred for 1 h at 10—15 °C. The precipitate was col-
lected by filtration, washed with water (0.99 l), and then air-dried for 0.5 h.
The obtained crude product (273 g) was suspended in IPA (1.73 l), and the
mixture was refluxed for 1 h. After cooling to 10 °C, the mixture was stirred
for 1 h at 7—10 °C. The precipitate was collected by filtration to give 8 as a
white powder (216 g, 90% yield, HPLC purity: 99.9 area %). 8: mp 231—
Experimental
Starting materials were obtained from commercial suppliers and used 233 °C (dec.). 1H-NMR (DMSO-d6, 400 MHz) d: 2.22 (3H, s), 2.49 (3H, s),
without further purification. HPLC analyses were performed on a Hitachi
Series L-6000 liquid chromatograph equipped with a UV detector (GL Sci- 12.9, 19.3, 125.3, 127.7, 128.8, 130.0, 135.1 (3C), 137.0, 162.1, 163.2,
ences Inertsil ODS-3 column, detection at 210 nm). The area percentage was
165.3. IR (KBr) cmꢃ1: 2937, 1720, 1605, 1456, 1005, 775. EI-MS m/z: 231,
7.19—7.36 (4H, m), 13.39 (1H, br). 13C-NMR (DMSO-d6, 100 MHz) d:

February 2008
179
276 (Mꢄ). Anal. Calcd for C13H12N2O3S (MW: 276.31): C, 56.51; H, 4.38;
N, 10.14. Found: C, 56.50; H, 4.34; N, 10.10.
stirred for 3.5 h at 50—55 °C. After cooling to 25 °C, the reaction mixture
was poured into cooling water (2.37 l) at 15—25 °C, and the resulting mix-
ture was then stirred for 0.5 h at 15—20 °C. The precipitate was filtered and
washed with water (0.32 l). The obtained precipitate (280 g) was dissolved in
AcOEt (1.58 l), washed with 10% aqueous sodium chloride (0.40 l), dried
over sodium sulfate and concentrated under reduced pressure. The residue
was purified by crystallization from AcOEt/hexane (1 : 2), and further puri-
fied by recrystallization from acetone/water (1 : 2) to afford 1 as a white
powder (137 g, 80% yield, HPLC analysis: 99.6 area %). 1: mp 186—
187 °C. 1H-NMR (CDCl3, 400 MHz) d: 1.95—2.02 (1H, m), 2.11—2.18
(1H, m), 2.14 (3H, s), 2.25 (3H, s), 3.30 (1H, dd, Jꢂ5.1, 15.4 Hz), 3.50 (2H,
t, Jꢂ5.1 Hz), 3.63—3.67 (2H, m), 3.77—3.93 (6H, m), 4.32—4.41 (2H, m),
5.32 (1H, d, Jꢂ15.1 Hz), 6.95 (1H, d, Jꢂ7.1 Hz), 7.04—7.08 (1H, m),
7.21—7.25 (2H, m), 7.57 (2H, s), 7.81 (1H, s). 13C-NMR (CDCl3, 100 MHz)
d: 19.6, 21.5, 27.3, 41.2, 43.6, 43.7, 43.8, 46.1, 47.1, 63.8, 103.2, 121.8 (t,
Jꢂ4 Hz), 123.1 (q, Jꢂ273 Hz), 125.0, 126.5, 128.5, 128.5, 128.7, 130.3,
132.0 (q, Jꢂ33 Hz), 135.5, 139.1, 139.4, 160.1, 167.8, 168.2, 169.2, 172.5.
IR (KBr) cmꢃ1: 1631, 1565, 1286. FAB-MS (positive) m/z: 622 [MꢄH]ꢄ.
Anal. Calcd for C30H29F6N5O3: C, 57.97; H, 4.70; N, 11.27. Found: C, 58.08;
H, 4.72; N, 11.34.
Large Scale Preparation. Diethyl 2-(2-Methylbenzylidene)malonate
(10) A mixture of o-tolualdehyde 11 (1.12 kg, 10.0 mol), diethyl malonate
(1.60 kg, 10.0 mol) and piperidine (255 g, 3.00 mol) in toluene (6.0 l) was re-
fluxed for 3 h, using Dean–Stark apparatus. During the reflux, piperidine
(85.2 g, 1.00 mol) was added to the mixture at 0.5 h and 1 h. After cooling,
the reaction mixture was concentrated under reduced pressure. The crude
product was purified by distillation to give 10 (160—163 °C/267 Pa) as a
yellow oil (2.35 kg, 90% yield, HPLC purity: 94.8 area %). 10: 1H-NMR
data and MS data of 10 were identical with those of the previous sample
(10).
Ethyl 4-(2-Methylphenyl)-2-methylthio-6-oxo-1,4,5,6-tetrahydropy-
rimidine-5-carboxylate (9) Potassium bicarbonate (3.51 kg, 35.1 mol)
was added to a stirred suspension of 10 (2.30 kg, 8.76 mol) and 12 (4.89 kg,
17.5 mol) in DMSO (17.5 l). The reaction mixture was allowed to warm to
50—55 °C and was stirred for 3 h. After cooling to 25 °C, the reaction mix-
ture was poured into cooling water (87.6 l) at 12—19 °C, and the resulting
mixture was stirred for 1 h at 17—19 °C. The precipitate was collected by
filtration and purified by crystallization from IPA/water (4 : 1) to give 9 as a
white powder (2.15 kg, 80% yield, HPLC purity: 99.3 area %). 9: mp 135—
137 °C. 1H-NMR data and MS data of 9 were identical with those of the pre-
vious sample (9).
Ethyl 4-(2-Methylphenyl)-2-methylthio-6-oxo-1,6-dihydropyrimidine-
5-carboxylate (13) DDQ (1.80 kg, 7.93 mol) was added to a stirred sus-
pension of 9 (2.15 kg, 7.00 mol) in AcOEt (13.0 l), and the reaction mixture
was stirred for 2.5 h at 20—52 °C. After cooling to 23 °C, the insoluble por-
tion was removed by filtration, and washed with AcOEt (2.2 l). The com-
bined filtrate was concentrated under reduced pressure. The obtained residue
was triturated with 8% aqueous sodium bicarbonate (20.0 l), then the result-
ing precipitate was collected by filtration, washed water (3.0 l) to give a
crude material (wet, 2.50 kg). The crude material was crystallized from 50%
aqueous EtOH to give 13 as pale brown crystals (1.93 kg, 90% yield, HPLC
purity: 99.9 area %). 13: mp 136—139 °C. 1H-NMR data and MS data of 13
were identical with those of the previous sample (13).
N-[3,5-Bis(trifluoromethyl)phenylmethyl]-N-(3-hydroxypropyl)-4-
chloro-6-(2-methylphenyl)-2-methylthiopyrimidine-5-carboxamide (15)
A mixture of 8 (215 g, 780 mmol) and phosphorus oxychloride (478 g,
3.11 mmol) was heated at 75—80 °C for 1 h. After cooling to 20 °C, the re-
action mixture was poured into cooling-water (1.51 l) at 0—18 °C, and the
resulting mixture was stirred for 0.5 h at 18—22 °C. The precipitate was col-
lected by filtration, washed with water (0.65 l). The obtained precipitate was
dissolved in AcOEt (2.59 l), and was successively washed with water
(0.86 lꢅ2), 10% aqueous sodium bicarbonate (0.65 l) and 10% aqueous
sodium chloride (0.43 l), to give a solution of 4-chloro-6-(2-methylphenyl)-
2-methylthiopyrimidine-5-carbonyl chloride (14) in AcOEt. The above solu-
tion was added dropwise to a solution of 3 (282 g, 0.94 mol) and Et3N
(158 g, 1.56 mol) in AcOEt (0.43 l) at 4—10 °C, and then the reaction mix-
ture was stirred for 0.5 h at 7—10 °C. The reaction mixture was washed with
water (0.65 l), 0.5 M HCl (0.65 l), 10% aqueous sodium bicarbonate (0.65 l)
and saturated sodium chloride (0.43 l), then dried over sodium sulfate. Con-
centration under reduced pressure yielded a crude material 15 as colorless
crystals (498 g). This compound was used for the next step without further
purification. 15: mp 148—150 °C (50% aqueous IPA); 1H-NMR (CDCl3,
400 MHz) d: 1.44—1.48 (1H, m), 1.60—1.67 (1H, m), 2.29 (3H, s), 2.59
(3H, s), 2.88—3.18 (1H, m), 3.20—3.26 (1H, m), 3.51 (2H, q, Jꢂ5.6 Hz),
4.48 (1H, d, Jꢂ15.1 Hz), 4.78 (1H, d, Jꢂ15.1 Hz), 7.04 (1H, t, Jꢂ7.6 Hz),
7.19—7.31 (3H, m), 7.59 (2H, s), 7.77 (1H, s). 13C-NMR (CDCl3, 100 MHz)
d: 14.2, 19.6, 27.3, 43.8, 47.2, 64.1, 109.2, 109.3, 122.0 (quintet, Jꢂ4 Hz),
123.1 (q, Jꢂ273 Hz), 125.0, 126.6, 128.6, 128.6, 129.1, 130.4, 132.1 (q,
Jꢂ33 Hz), 135.7, 137.8, 138.9, 166.6, 167.3, 171.2, 172.9. IR (KBr) cmꢃ1
:
3474, 1618, 1544, 1277, 1133, 765. FAB-MS (positive) m/z: 578 [MꢄH]ꢄ.
Anal. Calcd for C25H22ClF6N3O2S (MW: 577.97): C, 51.95; H, 3.84; N, 7.27.
Found: C, 51.95; H, 3.82; N, 7.17.
6-[3,5-Bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-2-
methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one
(6) A mixture of crude 15 (498 g) and DBU (142 g, 936 mmol) in DMSO
(1.51 l) was heated at 55—60 °C for 1 h. After cooling to 10 °C, water
(3.02 l) was added at 3—10 °C, and the resulting mixture was stirred for
0.5 h at 8—10 °C. The resulting precipitate was collected by filtration, and
purified by crystallization twice from 75% aqueous IPA to give 6 as color-
less crystals (173 g, 41% yield from 8, HPLC purity: 99.9 area %). 6: mp
144—147 °C. 1H-NMR (CDCl3, 400 MHz) d: 1.97—2.06 (1H, m), 2.16—
2.21 (1H, m), 2.24 (3H, s), 2.56 (3H, s), 3.34 (1H, dd, Jꢂ4.4, 15.6 Hz),
3.72—3.80 (1H, m), 3.87 (1H, d, Jꢂ14.6 Hz), 4.37—4.48 (2H, m), 5.31
(1H, d, Jꢂ15.1 Hz), 6.92 (1H, d, Jꢂ7.3 Hz), 7.04 (1H, t, Jꢂ7.3 Hz), 7.23
(2H, t, Jꢂ7.8 Hz), 7.57 (2H, s), 7.82 (1H, s). 13C-NMR (CDCl3, 100 MHz)
d: 14.2, 19.6, 27.3, 43.8, 47.2, 64.1, 109.2, 109.3, 122.0 (quintet, Jꢂ4 Hz),
123.1 (q, Jꢂ273 Hz), 125.0, 126.6, 128.6, 128.6, 129.1, 130.4, 132.1 (q,
Jꢂ33 Hz), 135.7, 137.8, 138.9, 166.6, 167.3, 171.2, 172.9. IR (KBr) cmꢃ1
:
1634, 1538, 1516, 1281, 1191, 1124, 683. FAB-MS (positive) m/z: 542
[MꢄH]ꢄ. Anal. Calcd for C25H21F6N3O2S (MW: 541.51): C, 55.45; H, 3.91;
N, 7.76. Found: C, 55.34; H, 3.90; N, 7.67.
6-[3,5-Bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-2-
methansulfonyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-
one (7) MMPP (294 g, 475 mmol) was added to a solution of 6 (172 g,
317 mmol) in acetonitrile (0.69 l) and EtOH (0.34 l) at 16—29 °C (exother-
mic reaction), and the reaction mixture was stirred for 4 h at 18—24 °C.
Water (2.06 l) was added to the reaction mixture and was then stirred for 1 h
at 21—24 °C. The precipitate was filtered, washed with water (0.52 l), and
purified by crystallization from a mixed solvent of AcOEt/IPA/water
(1 : 3 : 0.8) to give 7 as a white powder (161 g, 89% yield, HPLC analysis:
99.8 area %). 7: mp 212—213 °C. 1H-NMR (DMSO-d6, 400 MHz) d:
2.05—2.13 (1H, m), 2.23 (3H, s), 2.26—2.31 (1H, m), 3.34 (3H, s), 3.44
(1H, dd, Jꢂ5.4, 15.6 Hz), 3.68—3.76 (1H, m), 3.91 (1H, d, Jꢂ14.6 Hz),
4.48—4.59 (2H, m), 5.30 (1H, d, Jꢂ14.6 Hz), 6.88 (1H, d, Jꢂ7.3 Hz), 7.02
(1H, t, Jꢂ7.3 Hz), 7.24—7.32 (2H, m), 7.58 (2H, s), 7.85 (1H, s). 13C-NMR
(DMSO-d6, 100 MHz) d: 19.2, 27.0, 38.9, 44.0, 46.7, 65.6, 117.2, 121.4
(quintet, Jꢂ4 Hz), 123.2 (q, Jꢂ273 Hz), 124.4, 127.0, 129.0, 129.4, 129.4,
129.8, 130.2 (q, Jꢂ33 Hz), 135.5, 136.8, 139.9, 163.7, 165.3, 167.6, 171.3.
IR (KBr) cmꢃ1: 1642, 1546, 1527, 1279, 1182, 1130, 760. FAB-MS (posi-
tive) m/z: 574 [MꢄH]ꢄ. Anal. Calcd for C25H21F6N3O4S (MW: 573.51): C,
52.36; H, 3.69; N, 7.33. Found: C, 52.34; H, 3.60; N, 7.28.
4-(2-Methylphenyl)-2-methylthio-6-oxo-1,6-dihydropyrimidine-5-car-
boxylic Acid (8) A suspension of 13 (1.93 kg, 6.33 mol) in 1 M aqueous
sodium hydroxide (25.3 l) was heated at 80—83 °C for 1.5 h. After cooling
to 8 °C, the reaction mixture was adjusted to pH 2 with 2 M HCl, and the re-
sulting mixture was stirred for 1 h at 10—13 °C. The precipitate was col-
lected by filtration, washed with water (7.73 l), and then air-dried for 0.5 h.
The obtained crude product (wet, 2.77 kg) was suspended in IPA (13.5 l),
and the mixture was refluxed for 1 h. After cooling to 10 °C, the mixture was
stirred for 1 h at 6—10 °C. The precipitate was collected by filtration to give
8 as a white powder (1.69 kg, 97% yield, HPLC purity: 99.6 area %). 8: mp
232—233 °C (dec.). 1H-NMR data and MS data of 8 were identical with
those of the previous sample (8).
6-[3,5-Bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-2-
methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one
(6) A mixture of 8 (1.34 kg, 4.85 mol) and phosphorus oxychloride
(2.97 kg, 19.4 mol) was heated at 75—82 °C for 1 h. After cooling to 25 °C,
the reaction mixture was poured into ice-cold water (9.38 l) (exothermic re-
action), and the resulting mixture was stirred for 0.5 h at 18—24 °C. The
precipitate was collected by filtration, washed with water (4.02 l). The ob-
tained precipitate (wet, 2.50 kg) was dissolved in AcOEt (16.1 l), and was
successively washed with water (5.36 lꢅ2), 10% aqueous sodium bicarbon-
2-(4-Acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-
4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-
5-one (1, KRP-103) A mixture of 7 (158 g, 276 mmol), 1-acetylpiperazine
(50.0 g, 386 mmol) and Et3N (41.9 g, 414 mmol) in DMSO (0.79 l) was

180
Vol. 56, No. 2
(3.29 kg, 76%, HPLC purity: 99.7 area %). 1: mp 187—188 °C. 1H-NMR
data and MS data of 1 were identical with those of the previous sample (1).
IR(KBr) cmꢃ1: 1631, 1565, 1286. Anal. Calcd for C30H29F6N5O3: C, 57.97;
H, 4.70; N, 11.27. Found: C, 58.01; H, 4.53; N, 11.20.
ate (4.02 l) and 28% aqueous sodium chloride (2.68 l), to give a solution of
14 in AcOEt. The above solution of 14 was added dropwise to a solution of
3 (1.75 kg, 5.82 mol) and Et3N (0.98 kg, 9.70 mol) in AcOEt (2.68 l) at 4—
10 °C, and then the reaction mixture was stirred for 0.5 h at 8—10 °C. The
reaction mixture was washed with water (4.02 l), 0.5 M HCl (4.02 l), 10%
aqueous sodium bicarbonate (4.02 l) and saturated aqueous sodium chloride
(2.68 l), then dried over sodium sulfate. Concentration under reduced pres-
sure yielded a crude amide 15. To a solution of 15 in DMSO (9.38 l), DBU
(886 g, 5.82 mol) was added and the reaction mixture was heated at 55—
60 °C for 1 h. After cooling to 30 °C, the reaction mixture was added to cool-
ing water (18.8 l) at 6—18 °C, and the resulting mixture was stirred for 0.5 h
at 8—10 °C. The resulting precipitate was collected by filtration, washed
with water (6.7 l) to give a crude material (wet, 8.33 kg). The crude material
was crystallized from IPA to give 6 as white crystals (1.79 kg, 68% yield,
HPLC purity: 99.1 area %). 6: mp 146—148 °C. 1H-NMR data and MS data
of 6 were identical with those of the previous sample (6).
6-[3,5-Bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-2-
methansulfonyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-
one (7) MMPP (2.64 kg, 5.33 mol) was added to a solution of 6 (1.54 kg,
2.84 mol) in acetonitrile (6.12 l) and EtOH (3.06 l) at 18 °C, and the reaction
mixture was stirred for 4 h at 18—50 °C (exothermic reaction). Water
(18.4 l) was added to the reaction mixture and was then stirred for 1 h at
20 °C. The precipitate was filtered, washed with water (8.0 l) to give a crude
material (wet, 2.96 kg). The crude material was subjected to crystallization
from a mixed solvent of AcOEt/IPA/water (1 : 3 : 0.8) to give 7 as a white
powder (1.31 kg, 80% yield, HPLC purity: 99.7 area %). 7: mp 210—
212 °C. 1H-NMR data and MS data of 7 were identical with those of the pre-
vious sample (7).
2-(4-Acethylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-
4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-
5-one (1, KRP-103) A mixture of the 7 (4.02 kg, 6.99 mol), 1-acetylpiper-
azine (1.30 kg, 10.2 mol) and Et3N (1.08 kg, 10.7 mol) in DMSO (20.1 l) was
stirred for 3.5 h at 50—56 °C. The reaction mixture was poured into cooling
water (60.2 l) at 10—20 °C, and the resulting mixture was then stirred for
0.5 h at 15—20 °C. The precipitate was filtered and washed with water
(12.0 l). The obtained precipitate (wet, 15.0 kg) was dissolved in AcOEt
(40.1 l), washed with 10% aqueous sodium chloride (10.0 l), dried over
sodium sulfate and concentrated under reduced pressure. The residue was
purified by crystallization from AcOEt/hexane (1 : 2), and further purified by
recrystallization from acetone/water (1 : 2) to afford 1 as white powder
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