176 Chem. Pharm. Bull, 56(2) 176—180 (2008) Vol. 56, No. 2
`
`Process Development and Large-Scale Synthesis of NK; Antagonist
`
`Ichiro ArAva,*%® Shintaro Kanazawa,? and Hiroyuki Axrra®
`
`“ Research Center, Kyorin Pharmaceutical Co., Ltd.; 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-011 4, Japan:
`and ® Faculty of Pharmaceutical Sciences, Toho University; 2-2—1 Miyama, Funabashi, Chiba 274-8510, Japan.
`Received QOctober 25, 2007; accepted November 28, 2007
`
`A scaleable synthetic route is described to obtain 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(triffuoromethyl)-
`phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5 H-pyrimido{4,5-b][1,5]oxazocin-5-one (1, KRP-103) as a
`neurekinin (NK), antagonist. The key step in the synthesis is the intramolecular cyclization of N-[3,5-bis(trifluo-
`romethyl)phenylmethyl]-N-(3-hydroxypropyl)-4-chlore-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-5S-carboxylic acid (8) and 3-[3,5-bis(trifftuoromethyl}phenylmethylamino]-1-propanol (3). Treatment
`of 15 with 1,8-diazabicyclo[5,4,0Jundec-7-ene provided 6-[3,5-bis(triffuoromethyl)phenylmethyl]-4-(2-methyl-
`phenyl)-2-methylthio-6,7,8,9-tetrahydro-5SH-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), 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-5 H-pyrimido[4,5-b][ 1,5 ]oxazocin-5-one; intramolecular
`
`cyclization
`
`The tachykinin neuropeptides, substance P (SP), neu-
`rokinin A (NKA), and neurokinin B (NKB), are neurotrans-
`mitters or neuromodulatory agents. Each of these structurally
`related neuropeptides has a preferred receptor: the NK, re-
`ceptor for SP, the NK, receptor for NKA, and the NK, recep-
`tor for NKB. The NK; and NK, receptors are widely distrib-
`uted in the central nervous system (CNS) and peripheral tis-
`sue; NK, may be more localized in the CNS." Of these pep-
`tides, SP? is known to exhibit a wide variety of biological re-
`sponses, both centrally and peripherally. Through binding to
`the NK, receptor, SP has been implicated in the transmission
`of pain and stress signals, inflammation, and the contraction
`of smooth muscle. Therefore, NK, antagonists may be effica-
`cious for the clinical treatment of a wide range of diseases. In
`particular, we were interested in the relationship between
`tachykinin and the activation of the micturition-related re-
`fluxes,>® 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.”~” 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 NK; antagonist, and was promoted for
`development as a drug candidate for the treatment of pollaki-
`uria and urinary incontinence.”™” 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)® with 3-[3,5-bis(trifluoromethyl)phenyl-
`methylamino}-1-propanol (3),” via acid chloride produced a
`condensation product (4), which was subjected to nucle-
`ophilic intramolecular cyclization to afford pyrimidof4,5-
`
`* To whom correspondence should be addressed.
`
`e-mail: ichirou.araya@mb.kyorin-pharm.co.jp
`
`bi{1,5]oxazocine (5). Suzuki coupling reaction of 5 with o-
`tolylboronic acid provided the coupled product (6), which
`was subjected to oxidation to afford a sulfone (7). Finally,
`nucleophilic displacement of 7 with 1-acetylpiperazine pro-
`vided KRP-103 (1).>~” However, this method was impracti-
`cal for the preparation of large quantities of material for pre-
`clinical development, because it required multiple chromato-
`graphic purifications and was not cost competitive. The for-
`mation of compound (6) by way of Suzuki coupling process
`of § with o-tolylboronic acid might be substituted for Kno-
`evenagel condensation reaction between o-tolualdehyde and
`malonate followed by construction of 4-aryl-6-oxo-1,6-dihy-
`dropyrimidine skeleton. Herein, we describe a new practical
`process for the synthesis of 1, which requires no chromato-
`graphic purification and is cost-effective to large-scale pro-
`duction of KRP-103 (1).
`
`5
`o c o
`1)SOCH, K,C0y
`N COH j‘]\ X N
`| 2 CF 7 CF, F
`McS)\N/ ; ) 3 " Mes” "N i 3 DMF
`e No~OH OH
`
`2 4
`/BN 3
`
`CFs
`Ct 0, /—Q B(Oll)l m-CPBA
`N,
`NZ ] CFy PA(PPhy), THF
`q)*N o 2q.Ng,CO;
`5
`
`loluene/ dioxane
`
`CFy
`
`HN NAc
`
`PrNE N )
`dioxane 0>~ )E\)
`
`MeOfi
`KRP-103 (1)
`
`Chart 1
`
`© 2008 Pharmaceutical Society of Japan
`
`HELSINN EXHIBIT 2064
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`
`Page 1 of 5 IPR2025-00945
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`
`
`February 2008
`
`Results and Discussion
`
`A strategy was devised for the practical synthesis of 1 with
`regard to the process chemistry route shown in Chart 2. The
`intermediate (6) could be obtained by amide formation of a
`4-arylpirimidine derivative (8) with 3, followed by intramole-
`cular cyclization. In this process, the use of expensive
`reagents, such as the starting material (2), palladium catalysts
`and phenyl boronic acid compounds, are avoided, which ef-
`fectively reduces the target cost. The key intermediate, a 4-
`arylpyrimidine derivative (8) and f-keto ester (9) could be
`obtained from the starting o-tolualdehyde (11) via the cross-
`conjugated ester (10). The practical synthesis of 1 from 11 is
`shown in Chart 3.
`
`A Knoevenagel reaction'™V of o-tolualdehyde (11) and
`ethyl malonate provided the condensation product (10) in
`88% vyield, which was then treated with 2-methyl-2-thio-
`pseudourea hemisulfate (12) in the presence of potassium bi-
`carbonate (KHCO,) in dimethyl sulfoxide (DMSO) to give
`the fS-keto ester (9) in 85% yield. During the Knoevenagel
`
`Me Me
`KRP-103 (1) c=—=> § ) N N COH N CO,Et
`i l[ § l
`Me A MeS'*N 0
`H
`5
`
`177
`
`reaction, the water formed must be removed for the reaction
`to proceed to completion. The coupling step was performed
`in toluene with piperidine as the base under azeotropic con-
`ditions. The dehydrogenation of 9 was carried out under sev-
`eral conditions. However, dehydrogenation of 9 using some
`oxidants, such as MnO,, ceric ammonium nitrate (CAN),
`Pd—C (>210°C), Mn{(OAc), and CuCl,, did not yield the de-
`sired compound (13) completely. When 2,3-dichloro-5,6-di-
`cyano-p-benzoquinone (DDQ) was applied to the dehydro-
`genation of 9 in ethyl acetate (AcOEt), 13 was obtained in
`88% vyield after recrystallization of the crude product from
`aqueous ethanol (EtOH). The saponification of 13 in aqueous
`sodium hydroxide under heating afforded a carboxylic acid
`(8) in 90% yield. In all of the steps, it was not necessary to
`use chromatographic purification, and crystallization was ef-
`fective. Treatment of 8 with phosphorus oxychloride (POCl;)
`at 80 °C provided an acid chloride (14), which was used for
`the next reaction without further purification. The reaction of
`14 with 3 in the presence of triethylamine (Et;N) gave an
`amide (15). The use of potassium carbonate (K,CO,) in
`DMF is effective in the case of intramolecular cyclization of
`4,'2 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
`
`8" N O . .
`H g result was that where the reaction proceeded in the presence
`+ of 1,8-diazabicyclo[5,4,0]lundec-7-ene (DBU) in DMSO to
`furnish compound 6 (41% yield from 8) after recrystalliza-
`Me Me tion of the crude product from 2-propanol (IPA). For the ini-
`s O = tial preparation of sulfone 7 from 6 (Chart 1), the use of m-
`CHO i . .
`€Oyt chloroperbenzoic acid (m-CPBA) is standard protocol. How-
`w0 i ever, this protocol was not to be applied, because m-CPBA is
`Chart 2 potentially explosive and requires purification before use.'>
`SMe
`o Me ( A )stm
`Me 'COLEL H;N”™ TNH €
`Crr, o Qo 20 L
`i = N 2
`CHO piperidine o,k KHCO, /1|\
`toluene DMSO MeS E 0
`11 88% 10 85% 9
`DDQ Me aq. NaOH Me POC
`NN O NN Ol
`AcOE! )I\ 90% );\
`8% MeS” N O MeS” N° O
`H H
`13 8
`CF
`Me 3/EyN Me « 0 /_Q DBU
`coct | T N N ————— 6
`N7 AcOEt M CF, DMSO
`Mo Mes” N7l 41%
`MeS” 'N° Cl
`OH (3 steps from 8)
`14 is
`VY
`MMPP HNuNAc
`B KRP-103 (1)
`EtOH/ CHyCN BN
`89% DMSO
`80%
`falslog
`MMPP ; IC[co,H ] e
`Chart 3
`
`Page 2 of 5
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`
`
`178
`
`Oxidation of the methyl sulfide (6) with 30% aqueous H,0,
`in the presence of sodium tungstate (Na,WO,) and acetic
`acid (AcOH) as a catalyst,'*'® 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-
`103 (1). On the other hand, when magnesium bis(monoper-
`oxyphthalate)hexahydrate (MMPP)'%!” was applied in
`CH,CN/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 7% with I-
`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)
`guideline,'® residual levels must be controlled. To avoid the
`use of 1,4-dioxane, another protocol was examined. The best
`result was the reaction of 7 with l-acetylpiperazine in the
`presence of Et,;N 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%.
`
`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
`15, which is synthesized from commercially available o-tolu-
`aldehyde (11) in 6 steps, is the key step in the new synthesis
`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.
`
`Experimental
`
`Starting materials were obtained from commercial suppliers and used
`without further purification. HPLC analyses were performed on a Hitachi
`Series L-6000 liquid chromatograph equipped with a UV detector (GL Sci-
`ences Inertsil ODS-3 column, detection at 210 nm). The area percentage was
`
`Page 3 of 5
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`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
`(EI-MS) and fast atom bombardment-mass spectrometry (FAB-MS) was
`performed with Jeol JMS SX-102A or Jeol JMS-T100LP mass spectrome-
`ters, 'H- and *C-NMR spectra were obtained on a Jeol EX-400 (400 MHz)
`spectrometer. Spectra were run in either CDCl; or DMSO-d,; using tetram-
`ethylsilane (TMS) as an internal standard. Splitting patterns are indicated as
`follows: s, singlet; d, doublet; t, triplet; g, 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 (31.9g, 375mmol) in toluene (750ml) was refiuxed for 2.5h using
`Dean-Stark apparatus. During the reflux, piperidine (10.6 g, 125 mmol) was
`added to the mixture at 0.5h 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/120Pa) as a pale yellow oil (289 g, 88% yield,
`HPLC purity: 95.8 area %). 16: 'H-NMR (CDCl,, 400 MHz) &: 1.17 (3H, 1,
`J=7.1Hz), 1.34 (34, t, J=7.1 Hz), 2.38 (3H, s), 422 (2H, q, J=7.1Hz),
`4.32 (2H, q, /=7.1Hz), 7.15 (1H, t, J=7.8 Hz), 7.21 (1H, d, /=7.6 Hz), 7.27
`(1H, dt, J=1.2, 7.6Hz), 7.33 (1H, d, J=7.8Hz), 7.97 (1H, s). *C-NMR
`(CDCl;, 100MHz) 8: 13.7, 14.0, 19.7, 61.2, 614, 125.8, 127.6, 127.8,
`129.8, 130.2, 132.6, 137.4, 141.5, 163.9, 166.1. IR (KBr) cm*: 1729, 1257,
`1212, 1067. EI-MS mfz: 217, 262 (M™). Anal. Caicd for C;;H,;0, (MW:
`262.30): C, 68.68; H, 6.92. Found: C, 68.84; H, 6.90.
`
`Ethyl 4-(2-Methylphenyl)-2-methylthio-6-0xo-1,4,5,6-tetrahydropy-
`rimidine-5-carboxylate (9) Potassium bicarbonate (439 g, 4.38 mol) was
`added to a stirred suspension of 10 (287 g, 1.09mol) and 2-methyl-2-thio-
`pseudourea hemisulfate (12: 622 g, 2.19mol) in DMSO (2.181). The reac-
`tion mixture was allowed to warm to 50°C and was stirred for 2.5h. After
`cooling to 20 °C, the reaction mixture was poured into water {1.091) and the
`resulting mixture was stirred for 0.5h 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. 'H-NMR (CDCl,, 400MHz) &: 1.15 (3H, t, J=7.3Hz),
`2.42 (3H, s), 2.44 (3H, s), 3.66 (1H, d, J=8.3Hz), 4.15 (2H, q, J=7.3Hz),
`5.43 (1H, d, J=8.3 Hz), 7.07—7.10 (1H, m), 7.16—7.21 (3H, m), 8.13 (1H,
`br). PC-NMR (CDCl,, 100MHz) & 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)
`em™: 3115, 1749, 1715, 1605, 1143, 766. EI-MS m/z: 233, 306 (M*). Anal.
`Calcd for C,H,gN,0,S (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-oxe-1,6-dihydropyrimidine-
`5-carboxylate (13) DDQ (239 g, 1.02mol) was added to a stirred suspen-
`sion of 9 (284 g, 0.93 mol) in AcOEt (1.421), and the reaction mixture was
`stirred for 2.5h at 23--46 °C. After cooling to 25 °C, the insoluble portion
`was removed by filtration, and washed with AcOEt (0.281). The combined
`filtrate was washed with 2.4% agueous sodium bicarbonate solution (1.421),
`then water (0.51X2), and was concentrated under reduced pressure. The
`residue was crystallized from 50% aqueous EtOH fo give 13 as colorless
`crystals (249 g, 88% yield, HPLC purity: 99.9 area %). 13: mp 136--139°C.
`'H-NMR (CDCl,, 400MHz) &: 0.84 (3H, t, /=6.8 Hz), 2.24 (3H, s), 2.58
`(3H, s), 4.02 (2H, q, J/=6.8Hz), 7.14 (1H, 4, J=7.3Hz), 7.18—7.24 (2H,
`m), 7.28—7.37 (1H, m), 12.40 (IH, br). *C-NMR (CDCl,, 100MHz) &:
`13.3, 13,5, 19.5, 61.2, 1253 (2C), 127.6 (2C), 129.0, 130.1, 135.4, 137.9,
`164.1, 165.6, 166.3. IR (KBr) ecm™: 2925, 1645, 1537, 1199, 1071, 551. ElL-
`MS miz: 231, 304 (M*). 4nal. Caled for C,sH,N,0,S (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-6-0xo-1,6-dihydropyrimidine-5-car-
`boxylic Acid (8) A suspension of 13 (248 g, 814 mmol) in 1M agueous
`sodium hydroxide (3.261) was heated at 80—85°C for 2.5h. After cooling
`to 10 °C, the reaction mixture was adjusted to pH 2 with 2 m HC, and the re-
`suiting mixture was stirred for 1h at 10—15°C. The precipitate was col-
`lected by filtration, washed with water (0.991), and then air-dried for 0.5h.
`The obtained crude product (273 g} was suspended in IPA (1.731), and the
`mixture was refluxed for 1 h. After cooling to 10 °C, the mixture was stirred
`for 1h 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—
`233 °C (dec.). "H-NMR (DMSO-d;, 400 MHz) &: 2.22 (3H, s), 2.49 (3H, s),
`7.19—7.36 (4H, m), 13.39 (1H, br). PC-NMR (DMSO-d,, 100MHz) &:
`12.9, 19.3, 1253, 127.7, 128.8, 130.0, 135.1 (3C), 137.0, 162.1, 163.2,
`165.3. IR (KBr) cm™*: 2937, 1720, 1605, 1456, 1005, 775, EI-MS m/z: 231,
`
`
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`
`February 2008
`
`276 (M*). Anal. Caled for C,3H,,)N,0,8 (MW: 276.31): C, 56.51; H, 4.38;
`N, 10.14. Found: C, 56.50; H, 4.34; N, 10.10.
`N-[3,5-Bis(triflueromethyl)phenylmethyl]-~N-(3-hydroxypropyi)-4-
`chloro-6-(2-methylphenyl)-2-methylthiopyrimidine-5-carboxamide (15)
`A mixture of 8 (21Sg, 780mmol} and phosphorus oxychloride (478 g,
`3.11 mmol} was heated at 75—80°C for 1h. After cooling to 20°C, the re-
`
`action mixture was poured into cooling-water (1.511) at 0—18°C, and the
`
`resulting mixture was stirred for 0.5h at 18—22 °C. The precipitate was col-
`lected by filtration, washed with water (0.651). The obtained precipitate was
`dissolved in AcOEt (2.591), and was successively washed with water
`(0.861X2), 10% aqueous sodium bicarbonate (0.651) and 10% aqueous
`sodium chloride (0.43 1), to give a solution of 4-chloro-6-(2-methylphenyl)-
`2-methylthiopyrimidine-5-carbony! chloride (14) in AcOEt. The above solu-
`tion was added dropwise to a solution of 3 (282g, 0.94mol) and Et,N
`(158 g, 1.56 mol} in AcOEt (0.431) 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 (0.651), 0.5Mm HC (0.651), 10% aqueous sedium bicarbonate (0.651)
`and saturated sodium chloride (0.43 1}, then dried over sodium sutfate. 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); 'H-NMR (CDCl,,
`400 MHz) §: 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, g, J=5.6Hz),
`448 (14, ¢, J=15.1Hz), 4.78 (1H, 4, /=15.1Hz), 7.04 (1H, t, J=7.6 Hz),
`7.19—7.31 (3H, m), 7.59 (2H, 5), 7.77 (1H, s). >*C-NMR (CDCl;, 100 MHz)
`5. 14.2, 19.6, 27.3, 43.8, 47.2, 64.1, 109.2, 109.3, 122.0 (quintet, J=4 Hz),
`123.1 (q, J=273Hz), 125.0, 126.6, 128.6, 128.6, 129.1, 130.4, 132.1 (q,
`J=33Hz), 135.7, 137.8, 138.9, 166.6, 167.3, 171.2, 172.9. IR (KBr) em™:
`3474, 1618, 1544, 1277, 1133, 765. FAB-MS (positive) m/z: 578 [M~+H]*.
`Anal. Caled for C,H,,CIFN;O,8 (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-SH-pyrimido[4,5-b][1,5]oxazocin-5-one
`(6) A mixture of crude 15 (498 g) and DBU (142 g, 936 mumol) in DMSO
`(1.511) was heated at 55—60°C for 1h. After cooling to 10°C, water
`(3.021) was added at 3-——10°C, and the resulting mixture was stirred for
`0.5h 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, 'H-NMR (CDCl,, 400 MHz) &: 1.97—2.06 (1H, m), 2.16—
`2.21 (14, m), 2.24 (3H, s), 2.56 (3H, s), 3.34 (1H, dd, J=4.4, 15.6Hz),
`3.72—-3.80 (1H, m), 3.87 (1H, d, J=14.6Hz), 4.37—4.48 (2H, m), 5.31
`(1H, d, J/=15.1Hz), 6.92 (1H, d, /=73 Hz), 7.04 (1H, ¢, J=7.3Hz), 7.23
`(2H, t, J=7.8Hz), 7.57 (2H, 5), 7.82 (1H, s). BC-NMR (CDCl,, 100 MHz)
`&: 14.2, 19.6, 27.3, 43.8, 47.2, 64.1, 109.2, 109.3, 122.0 {quintet, /=4 Hz),
`123.1 (g, J=273Hz), 125.0, 126.6, 128.6, 128.6, 129.1, 130.4, 132.1 (q,
`J=33Hz), 135.7, 137.8, 138.9, 166.6, 167.3, 171.2, 172.9. IR (KBr) cm™":
`1634, 1538, 1516, 1281, 1191, 1124, 683. FAB-MS (positive) m/z; 542
`IM+H]". Anal. Calcd for C,sH, FN;0,S (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(triflueromethyl}phenylmethyl)-4-(2-methylphenyl)-2-
`methansulfonyl-6,7,8,9-tetrahydro-5H-pyrimide[4,5-b][1,5] oxazocin-5-
`one (7) MMPP (294 g, 475 mmol) was added to a solution of 6 (172g,
`317 mmol) in acetonitrile (0.69 1) and EtOH (0.341) at 16—29 °C (exother-
`mic reaction), and the reaction mixture was stirred for 4h at 18—24°C.
`‘Water (2.06 ) was added to the reaction mixtare and was then stirred for 1 h
`at 2124 °C, The precipitate was filtered, washed with water (0.521), and
`purified by crystailization 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. 'H-NMR (DMSO-d,, 400MHz) &:
`2.05—2.13 (1H, m), 2.23 (34, s), 2.26—2.31 (1H, m), 3.34 (3H, s), 3.44
`(1H, dd, J=54, 15.6Hz), 3.68—3.76 (1H, m), 391 (IH, 4, J=14.6Hz),
`4.48—4.59 (2H, m), 5.30 (1H, d, J=14.6 Hz), 6.88 (1H, d, J=7.3Hz}, 7.02
`(1H, t, J=7.3 Hz), 7.24—7.32 (2H, m), 7.58 (2H, s), 7.85 (1H, s). P*C-NMR
`(DMSO-d,, 100MHz) &: 19.2, 27.0, 38.9, 44.0, 46.7, 65.6, 117.2, 121.4
`(quintet, J=4Hz), 123.2 (g, /=273 Hz), 1244, 127.0, 129.0, 129.4, 129.4,
`129.8, 130.2 (q, J=33 Hz), 135.5, 136.8, 139.9, 163.7, 165.3, 167.6, 171.3.
`IR (KBr) cm™'; 1642, 1546, 1527, 1279, 1182, 1130, 760. FAB-MS (posi-
`tive) m/z: 574 [M+H]*. Anal. Caled for C,5H, FN,0,8 (MW: 573.51): C,
`52.36; H, 3.69; N, 7.33. Found: C, 52.34; H, 3.60; N, 7.28.
`2-(4-Acetylpiperadin-1-yl)-6-[3,5-bis(triflnoromethyl)phenylmethyl}~
`4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimidof4,5-b}{1,5}oxazocin-
`5-one (1, KRP-103) A mixture of 7 (158 g, 276 mmol), {-acetylpiperazine
`(50.0g, 386 mmol) and Et,N (41.9g, 414mmol} in DMSO (0.791} was
`
`Page 4 of 5
`
`179
`
`stirred for 3.5h at 50—55°C. After cooling to 25°C, the reaction mixture
`was poured into cooling water (2.371) at 15—25°C, and the resulting mix-
`ture was then stirred for 0.5h at 15—20°C. The precipitate was filtered and
`washed with water (0.32 1). The obtained precipitate (280 g} was dissolved in
`AcOEt (1.581), washed with 10% aqueous sodium chloride (0.401), 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 (137g, 80% yield, HPLC analysis: 99.6 area %). 1: mp 186—
`187°C. '"H-NMR (CDCl,, 400 MHz) &: 1.95—2.02 (1H, m), 2.11—2.18
`(1H, m), 2.14 (3H, s), 2.25 (3H, s), 3.30 (1H, dd, /=5.1, 15.4 Hz), 3.50 (2H,
`t, J=5.1Hz), 3.63—3.67 (2H, m), 3.77—3.93 (6H, m), 4.32—4.41 (2H, m),
`532 (1H, 4 J=15.1Hz), 6.95 (1H, d, /=7.1Hz), 7.04—7.08 (1H, m),
`7.21—7.25 (2H, m), 7.57 (2H, 5), 7.81 (1H, 5). *C-NMR (CDCl,, 100 MHz)}
`8: 19.6, 21.5, 27.3, 41.2, 43.6, 43.7, 43.8, 46.1, 47.1, 63.8, 103.2, 121.8 (4,
`J=4Hz), 123.1 (q, J=273Hz), 125.0, 126.5, 128.5, 128.5, 128.7, 130.3,
`132.0 {q, J=33 Hz), 135.5, 139.1, 139.4, 160.1, 167.8, 168.2, 169.2, 172.5.
`IR (KBr) cm™': 1631, 1565, 1286. FAB-MS (positive) m/z: 622 [M+H]*.
`Anal, Caled for CyH,0FN:O,: 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, 10.0mol), diethy! malonate
`(1.60kg, 10.0mol} and piperidine (255 g, 3.00 mol) in toluene (6.0 1) was re-
`fluxed for 3h, using Dean—Stark apparatus. During the reflux, piperidine
`(85.2 g, 1.00 mol) was added to the mixture at 0.5h and 1 h. After cooling,
`the reaction mixture was concenirated under reduced pressure. The crude
`product was purified by distillation to give 10 (160—163 °C/267Pa) as a
`yellow oil (2.35kg, 90% yield, HPLC purity: 94.8 area %). 10: 'H-NMR
`data and MS data of 10 were identical with those of the previous sample
`(10).
`
`Ethyl 4-(2-Methylphenyl)-2-methylthio-6-0x0-1,4,5,6-tetrahydropy-
`rimidine-5-carboxylate (9) Potassium bicarbonate (3.51kg, 35.1mol)
`was added to a stirred suspension of 10 (2.30kg, 8.76 mol) and 12 (4.89kg,
`17.5mol) in DMSO (17.51). 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 (87.61) at 12—19°C, and the resulting
`mixture was stirred for 1h 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 (2.15kg, 80% yield, HPLC purity: 99.3 area %). 9: mp 135
`137°C. 'H-NMR data and MS data of 9 were identical with those of the pre-
`vious sample (9).
`
`Ethyl 4-(2-Methylphenyl)-2-methylthio-6-ox0-1,6-dikydropyrimidine-
`5-carboxylate (13) DDQ (1.80kg, 7.93 mol) was added to a stirred sus-
`pension of 9 (2.15kg, 7.00mol) in AcOEt (13.01), and the reaction mixture
`was stirred for 2.5h at 20—52 °C, After cooling to 23 °C, the insoluble por-
`tion was removed by filtration, and washed with AcOEt (2.21). The com-
`bined filtrate was concentrated under reduced pressure. The obtained residue
`was triturated with 8% aqueous sodium bicarbonate (20.01), then the result-
`ing precipitate was coilected by filtration, washed water (3.01) to give a
`crude material (wet, 2.50kg). The crude material was crystaliized from 50%
`aqueous EtOH to give 13 as pale brown crystals (1.93kg, 90% yield, HPLC
`purity: 99.9 area %). 13: mp 136—139°C. 'H-NMR data and MS data of 13
`were identical with those of the previous sample (13).
`
`4-(2-Methylphenyl}-2-methylthio-6-oxe-1,6-dihydropyrimidine-5-car-
`boxylic Acid (8) A suspension of 13 (1.93kg, 6.33mol) in 1M aqueous
`sodium hydroxide (25.3 1) was heated at 80—83 °C for 1.5h. After cooling
`to 8 °C, the reaction mixtare was adjusted to pH 2 with 2m HCI, and the re-
`sulting mixture was stirred for 1h at 10—13 °C. The precipitate was col-
`lected by filtration, washed with water (7.731), and then air-dried for 0.5h.
`The obtained crude product (wet, 2.77kg) was suspended in IPA (13.51),
`and the mixture was refluxed for 1h. After cooling to 10 °C, the mixture was
`stirred for 1h 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.). '"H-NMR data and MS data of 8 were identical with
`those of the previous sample (8).
`
`6-{3,5-Bis(trifftuoromethyl)phenylmethyi]-4-(2-methylphenyl)-2-
`methylthio-6,7,8,9-tetrahydro-SH-pyrimide[4,5-b}{1,5]exazocin-5-one
`(6) A mixture of 8 (1.34kg, 4.85mol)} and phosphorus oxychioride
`(2.97kg, 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 (9.381) (exothermic re-
`action), and the resulting mixture was stirred for 0.5h at 18—24°C. The
`precipitate was coliected by filration, washed with water (4.021). The ob-
`tained precipitate (wet, 2.50kg) was dissolved in AcOEt (16.11), and was
`successively washed with water (5.361X2), 10% aqueous sodium bicarbon-
`
`
`
`
`
`
`
`
`180
`
`ate (4.021) and 28% aqueous sodium chloride (2.681), to give a solution of
`14 in AcOEt. The above solution of 14 was added dropwise to a solution of
`3 (1.75kg, .82 mol) and Et;N (0.98kg, 9.70mol) in AcOEt (2.681) at 4—
`10°C, and then the reaction mixture was stirred for 0.5h at 8—10°C. The
`reaction mixture was washed with water (4.021), 0.5M HCI (4.021), 10%
`aqueous sodium bicarbonate (4.021) and saturated aqueous sodium chloride
`(2.681), then dried over sodium sulfate. Concentration under reduced pres-
`sure yielded a crude amide 15. To a solution of 15 in DMSO (9.381), DBU
`(886 g, 5.82mol) 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 (18.81) at 6—18 °C, and the resulting mixture was stirred for 0.5h
`at 8—10°C. The resulting precipitate was collected by filtration, washed
`with water {(6.71) to give a crude material (wet, 8.33kg). The crude materiaj
`was crystallized from [PA to give 6 as white crystals (1.79kg, 68% yield,
`HPLC purity: 99.1 area %). 6: mp 146—148°C. 'H-NMR data and MS data
`of 6 were identical with those of the previous sample (6).
`6-[3,5-Bis(trifiuoromethyl)phenylmethyl]-4-(2-methylphenyl)-2-
`methansnlfonyl-6,7,8,9-tetrahydro-5H-pyrimidof4,5-b][1,5]oxazecin-5-
`one (7) MMPP (2.64kg, 5.33 mol) was added to a solution of 6 (1.54kg,
`2.84 mol) in acetonitrile (6.121) and EtOH (3.06 ) at 18 °C, and the reaction
`mixture was stirred for 4h at 18—50°C (exothermic reaction). Water
`(18.41) was added to the reaction mixture and was then stirred for 1h at
`20°C. The precipitate was filtered, washed with water (8.01) to give a crude
`material (wet, 2.96 kg). The crude material was subjected to crystallization
`from a mixed sclvent of AcOEt/IPA/water (1:3:0.8) to give 7 as a white
`powder (1.31kg, 80% yield, HPLC purity: 99.7 area %). 7: mp 210—
`212°C. 'H-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-SH-pyrimide[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 (1.30kg, 10.2 mol) and E;N (1.08 kg, 10.7 mol) in DMSO (20.11) was
`stirred for 3.5h at 5056 °C. The reaction mixture was poured into cooling
`water (60.21) at 10-—20°C, and the resulting mixture was then stirred for
`0.5h at 15—20°C. The precipitate was filtered and washed with water
`(12.01). The obtained precipitate (wet, 15.0kg) was dissolved in AcOEt
`(40.11), washed with 10% aqueous sodium chloride (10.01), 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
`
`Page 5 of 5
`
`Vol. 56, No, 2
`
`(3.29kg, 76%, HPLC purity: 99.7 area %). 1: mp 187—188°C. 'H-NMR
`data and MS data of 1 were identical with those of the previous sample (1).
`IR(KBr) cm™': 1631, 1565, 1286. Anal. Caled for CyH,,FNsOy: C, 57.97;
`H, 4.70; N, 11.27. Found: C, 58.01; H, 4.53; N, 11.20.
`
`References and Notes
`
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`
`2) VonEuler U, S,, Gaddum J. H., J. Physiol., 72, 74—87 (1931).
`
`3) Maggi C. A., Gen. Pharmacol., 22, 1—22 (1991).
`
`4) Lecci A., Giuliani S., Garret C., Maggi C. A., Neuroscience, 54, 827—
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`
`5) Seto S., Tanioka A., Ikeda M., Izawa S., Bioorg. Med. Chem., 13,
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`
`6) Seto S., Tanioka A., Ikeda M., zawa S., Bioorg. Med. Chem. Leit., 15,
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`
`7) Seto S., Tanicka A., Ikeda M., Izawa S., Bioorg. Med. Chem. Lett., 15,
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`
`8) Yamada K., Omori K., Kikukawa K., WO 2001083460 (2001) [Chem.
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`
`9) Natsugari B., Ikeura Y., Kamo L, Ishimaru T., Ishichi Y., Fujishima A.,
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`3993 (1999).
`
`10) Jones G., Org. React., 15, 204—599 (1967).
`
`11) Tietze L., Beifuss J., “Comprehensive Organic Synthesis,” Vol. 2, ed.
`by Trost B. M., Pergamon, Elmsford, New York, 1991, p. 341—388.
`
`12) Seto S., Tetrahedron Lett., 45, 8475—8478 (2004).
`
`13) Rao A. S, Mohan H. R., “Encyclopedia of Reagents for Organic Syn-
`thesis,” ed. by Paquette L. A., Wiley & Sones, Chichester, UK., 1995,
`p. 1192—1198,
`
`14) Hirao K., Tsutiya R., Yano Y., Tsue H., Heterocycles, 42, 415—422
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`15) Briet N., Brookes M., Davenport R. I, Galvin E C. A., Gilbert . J,,
`Mack S. R., Sabin V., Tetrahedron, 58, 5761—5766 (2002).
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`16) Brougham P, Cooper M. S., Cummerson D. A., Heaney H., Thompson
`N., Synthesis, 1987, 1015—1017 (1987).
`
`17) Taubert K., Siegemund A., Eilfeld A., Baumann S, Sieler J,, Schuize
`B., Synthesis, 2003,