Synthesis of Am80 (tamibarotene) prodrug candidates, congeners and metabolites

Article abstract of DOI:10.1248/cpb.c13-00356

Compound 1 (IT-M-07000) was previously reported as a candidate prodrug of Am80 (Tamibarotene; used to treat acute promyelocytic leukemia), and shown to be efficiently metabolized to Am80 via β-oxidation. Here, we describe in detail the synthesis of 1, together with another tetradeuterated candidate prodrug, IT-YA-00616 (2), as well as two congeners, and several metabolic intermediates of 1 previously detected in mouse plasma.

Full text of DOI:10.1248/cpb.c13-00356

846
Regular Article
Chem. Pharm. Bull. 61(8) 846–852 (2013)
Vol. 61, No. 8
Synthesis of Am80 (Tamibarotene) Prodrug Candidates, Congeners and
Metabolites
,a
,a
Hideaki Muratake,* Yohei Amano,a Takahiro Toda,a,† Kiyoshi Sugiyama,b and Koichi Shudo*
a Research Foundation Itsuu Laboratory; 2–28–10 Tamagawa, Setagaya-ku, Tokyo 158–0094, Japan: and
b Department of Clinical Pharmacokinetics, Hoshi University; 2–4–41 Ebara, Shinagawa-ku, Tokyo 142–8501, Japan.
Received May 9, 2013; accepted June 4, 2013
Compound 1 (IT-M-07000) was previously reported as a candidate prodrug of Am80 (Tamibaro-
tene; used to treat acute promyelocytic leukemia), and shown to be efficiently metabolized to Am80 via
β-oxidation. Here, we describe in detail the synthesis of 1, together with another tetradeuterated candidate
prodrug, IT-YA-00616 (2), as well as two congeners, and several metabolic intermediates of 1 previously de-
tected in mouse plasma.
Key words Am80; prodrug; β-oxidation; deuteration; isotope effect
Am80 (Tamibarotene) is a synthetic retinoic acid receptor dence time (MRT) of Am80 derived from 1, compared with
(RAR)-α,β-selective agonist that does not bind to the proin- those after administration of Am80 itself. These results con-
flammatory RAR-γ subtype or to retinoid X receptors (RXRs). firmed that 1 is a promising candidate for an Am80 prodrug
Because of this activity profile, Am80 does not induce un- with reduced side effects and longer duration of drug efficacy.
favorable side-effects caused by RAR pan-agonists, such as
In the present paper, we describe in detail the synthesis
all-trans retinoic acid (ATRA)1) (Fig. 1). It is also character- of 1 and its metabolic intermediates. We also synthesized
ized by high stability to light, heat, and oxidation in air, un- IT-YA-00616 (2) (Fig. 1), the 2,2,3,3-tetradeuterated derivative
like retinoic acid. Am80 was approved in Japan in 2005 as a of 1, as another candidate prodrug of Am80, aiming at further
therapeutic agent for recurrent refractory acute promyelocytic improvement of the pharmacokinetic parameters, as well two
leukemia (APL).2,3) Furthermore, it has recently been suggest- congeners, the 2,2- and 3,3-dideuterated compounds, for ex-
ed that stimulation of the RARα and RARβ signaling path- amination of the isotope effect.
way with agonists enhances clearance of amyloid β, so that
retinoids, including Am80, may be promising candidates for
Results and Discussion
Synthesis of IT-M-07000 (1) Our first Am80 prodrug
treatment of Alzheimer’s disease.4,5) However, in the required
case of long-term administration of retinoids such as Am80, candidate 1 was readily prepared via two routes, A and B
the patients are consistently threatened by the side-effects (Chart 1).
endemic to retinoids (retinoic acid syndrome): dyspnea, fever,
Route A: Methyl 3-(4-carboxy)phenylpropionate (3)11,12) was
treated with thionyl chloride, then condensed with 1,1,4,4-tet-
weight gain, hypotension, and pulmonary infiltrates.6)
With these facts in mind, we previously designed a candi- ramethyl-1,2,3,4-tetrahydro-6-aminonaphthalene (4)13) in the
date prodrug of Am80, aiming at sustained-release character presence of triethylamine to provide 5, which was easily
and consequential reduction of the above described retinoic hydrolyzed to 1. But, although this route is straightforward,
acid syndrome. We envisaged that IT-M-07000 (1) (Fig. 1), compound 3 is not readily available.
a two-carbon-elongated propionic acid derivative of Am80,
would be readily metabolized to Am80 via the carboxylic
acid β-oxidation pathway, which involves i) dehydrogenation
by flavin adenine dinucleotide (FAD) to form α,β-unsaturated
acyl-CoA, ii) hydration on the β-carbon to afford 3-hydroxy-
acyl-CoA, iii) oxidation by oxidized form of nicotinamide
adenine dinucleotide (NAD+) to yield 3-ketoacyl-CoA, iv)
thiolysis of 3-ketoacyl CoA by another molecule of coen-
zyme A.7,8) Sodium phenylbutyrate (Buphenyl®) is a typical
example of a prodrug that utilizes this β-oxidation process to
release sodium phenylacetate, which is clinically used for the
treatment of urea cycle disorders.9) In our earlier work, we
synthesized 1, and examined its disposition in mice, reporting
its efficient metabolism to Am80, and identifying the meta-
bolic intermediates of the β-oxidation pathway.10) We further
showed that administration of 1 to mice resulted in larger area
under the curve (AUC), lower Cmax, and longer t1/2, mean resi-
Route B: Am80, which is readily available at this labora-
The authors declare no conflict of interest.
† Present address: Yokohama College of Pharmacy; 601 Matanocho, To-
tsuka-ku, Yokohama 245–0066, Japan.
Fig. 1. Structure of Am80, 1 and 2
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: hmuratake@itsuu.or.jp; kshudo@itsuu.or.jp

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(a) SOCl2, benzene, reflux; (b) 6-amino-1,2,3,4-tetrahydro-1,2,3,4-tetramethylnaphthalene (4), Et3N, CH2Cl2, rt, 97% from 4; (c) LiOH, MeOH–DME–H2O (3:2:1),
reflux, 93% from 5, 98% from 9; (d) ClCOOMe, Et3N, THF, −20°C, then NaBH4, H2O, 0°C–rt, 94%; (e) MnO2, CH2Cl2, reflux, 96%; (f) triethylphosphonoacetate, K2CO3,
EtOH, 62–64°C, 97%; (g) H2, Pd/C, EtOH, rt, 99%.
Chart 1. Two Preparation Methods of Am80 Prodrug 1
(a) LiCH2COOt-Bu, THF, −78°C, 16 59%, 17 35%; (b) TFA, CH2Cl2, 0°C–rt, 13′ 84%, 12′ 91%; (c) NaBH4, EtOH, 0°C, 97%.
Chart 2. Metabolic Pathway from 1 to Am80 and Preparation of Metabolic Intermediates 12′ and 13′
tory, was converted to α,β-unsaturated ester 8 by way of al- in mouse.
cohol 6 and aldehyde 7 in three steps in a high overall yield.
Hydrogenation of 8 followed by hydrolysis of the resulting 9 ated Congener 30 Based on the previous finding that 1 is a
conveniently afforded 1. promising candidate as a prodrug of Am80, we considered a
Synthesis of IT-YA-00616 (2) and Its 3,3-Dideuter-
Preparation of Metabolic Intermediates of 1 We next further modification in order to improve the pharmacokinetics.
planned to synthesize putative intermediates for confirmation We hypothesized that deuteration of the ethylene moiety of 1,
of the metabolic disposition of 1. Chart 2 shows the expected affording 2, would be effective, because the rate of a reaction
metabolic pathway of 1 to Am80 via β-oxidation. Compounds involving a carbon–deuterium (C–D) bond is typically 2 to 10
11′, 12′, and 13′, corresponding to hydrolyzed products of the times slower than that of the corresponding carbon–hydrogen
CoA intermediates 11–13, respectively, were selected for syn- (C–H) bond.14) Accordingly, introduction of deuterium was
thesis. The α,β-unsaturated carboxylic acid 11′ was prepared expected to improve the sustained-release characteristics, due
by simple hydrolysis of compound 8. The anion of tert-butyl to the kinetic isotope effect.
acetate was allowed to react with Am80 methyl ester 15 to
Initially, we developed a bulk preparation method of
yield β-ketoester 16 and by-product 17 (Chart 2). Treatment 3-(4-carboxy)phenylpropionic acid (21) (Chart 3) as the sub-
of 16 with trifluoroacetic acid (TFA) readily provided 13′. strate for ethylene deuteration, because although 21 is com-
The remaining compound 12′ was acquired by reduction of mercially available, it is very expensive. Terephthalaldehydic
16 with sodium borohydride followed by TFA treatment of the acid 19 (0.8 m scale) was condensed with malonic acid in the
resulting tert-butyl 3-hydroxypropionate 18.
presence of a catalytic amount of piperidine in hot pyridine to
Among the three putative metabolic intermediates, 11′ and afford p-carboxycinnamic acid 20 in 98% yield.15) The desired
12′ were confirmed to be identical with metabolites in plasma 21 was readily obtained in 95% yield by hydrogenation (H2
of mice treated with 1 by comparison of their retention times 0.3MPa) of 20 over a palladium-carbon catalyst in the pres-
in HPLC and their MS spectra.10) Two other peaks were iden- ence of sodium carbonate (1.15eq) in water.
tified as 1 itself and Am80. However, 13′ was not detected
Our next task was deuteration of 21 employing the Pd/C–
in plasma, whole blood, or liver. After intravenous admin- H2–D2O system reported by Sajiki and colleagues.16) (Chart
istration of 13′, only Am80, but not 13′ itself, was detected. 3). After optimization of temperature, reaction time, amount
These results suggest that 13′ is rapidly converted to Am80 of palladium catalyst, initial hydrogen pressure, and reac-

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Vol. 61, No. 8
(a) Malonic acid, piperidine, pyridine, 80°C, 98%; (b) H2 (0.3MPa), Pd/C, Na2CO3, H2O, 95%; (c) H2, D2O, Pd/C, Na2CO3, 130°C, 97%; (d) H2, D2O, Pd/C, Na2CO3,
100°C, 97%; (e) MeOH, cat. SOCl2 (1–2mol%), rt, 24 88%, 25 4%, recovery 1% from 22 (0.10mol) and 26 86%, 27 6%, recovery 1% from 23 (14.5mmol); (f) SOCl2, cat.
DMF, benzene, reflux, then 3, Et3N, CH2Cl2, rt, 28 96% from 24, 29 97% from 26; (g) LiOH, MeOH–DME–H2O (3:2:1), reflux, 2 98%, 30 98%.
Chart 3. Bulk Preparation of Deuterated 3-(4-Carboxpheny)propionic Acids 22 and 23, and Their Conversion to 2 and 30
tion vessel, we eventually obtained the desired 22 in high
yield (29.8g, 97% yield, D ratio of X=97–98%, Y=98%) from
21 (30.0g, 0.155mol) in a globular shape reaction vessel at
130°C (see Experimental). It is noteworthy that only partial
deuteration occurred to provide the 3,3-d2 product 23 (D ratio
of X=0, Y>98%) when the reaction was carried out in a Parr
reaction vessel (circular cylinder) at 100°C. We found that the
shape of the reaction vessel strongly influenced the deutera-
tion ratio even under the other conditions such as temperature,
(a) Meldrum’s acid, Hantzsch ester, l-proline, CH3CN, rt, 85%; (b) D2O, pyri-
dine, reflux, 80%.
reaction time were identical.
With the requisite deuterated compound 22 in hand, the
prodrug candidate 2 and the corresponding 3,3-dideuterated
Chart 4. Preparation of 2,2-Dideuterated Derivatives 32
30 were synthesized (Chart 3). Monoesterification of the di-
carboxylic acids 22 and 23 was carried out with a catalytic rected. MS and high-resolution MS (HR-MS) were recorded
amount of thionyl chloride in methanol.12) By-product diester on a Hitachi M-80B spectrometer in a direct inlet (DI) mode
(25, 27, respectively) and a mixture of acidic compounds (24 at an ionizing voltage of 70eV, and figures in parentheses
and recovered 22, 26 and recovered 23, respectively) were indicate the relative intensities. IR spectra were measured
1
extractively separated and the starting material 22 or 23 was on a Shimadzu IR-460 spectrophotometer. H-NMR spectra
conveniently recovered from the mixture by simple filtration were obtained on a Varian Mercury 300 (300MHz) and cou-
of a slightly slurried dichloromethane solution. The desired 24 pling constants (J values) are rounded to the nearest 0.5Hz.
and 26 were easily isolated in excellent yields by evaporation 13C-NMR spectra were measured on a Varian Mercury 300
of the respective filtrates and recrystallization of the residues (75MHz) under proton-decoupled conditions. Column chro-
from dichloromethane–hexane. These monocarboxylic acids matography was conducted on silica gel (SiO2, Fuji Davison
were readily led to 2 and 30 by way of esters 28 and 29, re- BW 200), and preparative TLC (PTLC) was carried out on
spectively, according to the method already shown in Chart 1. glass plates (20×20cm) coated with Merck Silica gel 60PF254
Preparation of 2,2-Dideuterated Congener 32 The un- (0.8mm thick) unless otherwise specified, and the developing
expectedly acquired compound 30 was expected to be useful solvent is indicated in parentheses. Usual work-up refers to
for pharmacokinetic profiling of 2. Therefore, we also synthe- washing of the organic layers with water or brine, drying over
sized the other 2,2-dideuterated congener 32, by reductively anhydrous Na2SO4, and evaporating off the solvents under
condensing aldehyde 7 with Meldrum’s acid according to reduced pressure. Tetrahydrofuran (THF) was distilled from
Ramachary’s method17) to give 31, which was readily trans- sodium/benzophenone ketyl prior to use.
formed to 32 in refluxing dry pyridine in the presence of
Synthesis of 1 Methyl 3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-
tetramethyl-2-naphthyl)carbamoyl]phenyl]propionate (5):
D2O18) (Chart 4).
SOCl2 (0.65mL, 8.91mmol) was added to a slurry of 3
(460mg, 2.21mmol) in benzene (6mL), and the mixture was
Conclusion
We present full details of the synthesis of two Am80 pro- refluxed with stirring for 1.5h. The volatile materials were
drug candidates, IT-M-07000 (1) and IT-YA-00616 (2). Com- evaporated off, then benzene (4mL) was added to the result-
pound 1 was previously characterized as a promising Am80 ing residue and evaporated again to dryness. The residue was
prodrug. The new candidate 2, corresponding to tetradeuter- dissolved in CH2Cl2 (2mL) and the solution was cooled in an
ated 1, is expected to show a superior pharmacokinetic profile ice bath. A solution of 4 (359mg, 1.77mmol), Et3N (0.98mL,
to 1 as an Am80 prodrug, owing to the deuterium isotope 7.04mmol) in CH2Cl2 (4mL) was added to this and the mix-
effect. We also synthesized two other congeners (30, 32), and ture was stirred at an ambient temperature for 18h. Saturated
several metabolic intermediates of 1 previously detected in NaHCO3–H2O was added and the whole was extracted with
mouse plasma. Mechanistic and kinetic studies of 2 are in EtOAc. Usual work-up and purification by column chroma-
progress.
tography (CHCl3) gave 5 (674mg, 97% from 4) as colorless
prisms, mp 135–136°C (CH2Cl2–hexane). HR-MS Calcd for
C25H31NO3: 393.2302. Found: 393.2315. MS (m/z): 393 (M+,
Experimental
General Melting points were determined on a Yanagimo- 35), 378 (100), 362 (5), 191 (76), 131 (35), 103 (18), 91 (10), 59
1
to micro-melting point apparatus (hot plate), and are not cor- (7), 43 (10). IR (KBr) cm−1: 1707, 1659. H-NMR (CDCl3) δ:

August 2013
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1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.67 (2H, t, J=7.5Hz), 7.79 (1H, brs, NH), 7.99 (2H, A2B2, J=8.5Hz), 8.03 (2H,
3.02 (2H, t, J=7.5Hz), 3.68 (3H, s), 7.30 (1H, d, J=8.5Hz), A2B2, J=8.5Hz), 10.10 (1H, s).
7.32 (2H, A2B2, J=8Hz), 7.41 (1H, dd, J=8.5, 2.5Hz), 7.53
(1H, d, J=2.5Hz), 7.69 (1H, brs, CONH), 7.80 (2H, A2B2, naphthyl)carbamoyl]phenyl]propenoate (8): K2CO3 (910mg,
J=8 Hz). 6.59mmol) was added to a solution of 7 (1.765g, 5.27mmol)
Ethyl (2E)-3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-
3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)- and triethyl phosphonoacetate (1.523g, 6.80mmol) in EtOH
carbamoyl]phenyl]propionic Acid (IT-M-07000, 1): The com- (40mL), and the mixture was heated at 62–64°C for 3h. After
pound 5 (525mg, 1.34mmol) was dissolved in MeOH–1,2-di- cooling, satd. NH4Cl–H2O was added and the whole was ex-
methoxyethane (DME)–H2O (3:2:1, 9mL) and LiOH·H2O tracted with EtOAc. Usual work-up and column chromatogra-
(85mg, 2.02mmol) was added and the mixture was stirred phy [hexane–EtOAc (39:1 to 14:1)] afforded 8 (2.076g, 97%)
under reflux for 2.5h. The reaction was quenched by addi- as colorless needles, 166–166.5°C (CH2Cl2–hexane). HR-MS
tion of HCl–H2O (1n, 2.10mL, 2.10mmol) and the whole was Calcd for C26H31NO3: 405.2302. Found: 405.2292. MS (m/z):
extracted with EtOAc. Usual work-up followed by recrystal- 405 (M+, 31), 390 (100), 203 (60), 175 (22), 102 (29), 91 (20).
1
lization afforded 1 (470mg, 93%) as colorless fine needles, mp IR (KBr) cm−1: 1697, 1663, 1644. H-NMR (CDCl3) δ: 1.28
230–231°C (EtOAc). Anal. Calcd for C24H29NO3: C, 75.96; H, (6H, s), 1.30 (6H, s), 1.35 (3H, t, J=7Hz), 1.70 (4H, s), 4.29
7.70; N, 3.69. Found: C, 76.17; H, 7.63; N, 3.76. HR-MS Calcd (2H, q, J=7Hz), 6.52 (1H, d, J=16Hz), 7.31 (1H, d, J=8.5Hz),
for C24H29NO3: 379.2146. Found: 379.2131. MS (m/z): 379 (M+, 7.43 (1H, dd, J=8.5, 2.5Hz), 7.53 (1H, d, J=2.5Hz), 7.63 (2H,
33), 364 (100), 177 (92), 131 (14), 107 (22), 103 (20), 77 (16). A2B2, J=8Hz), 7.71 (1H, d, J=16Hz), 7.74 (1H, brs, NH), 7.89
1
IR (KBr) cm−1: 1711, 1616. H-NMR (CDCl3) δ: 1.28 (6H, s), (2H, A2B2, J=8 Hz).
1.30 (6H, s), 1.69 (4H, s), 2.72 (2H, t, J=7.5Hz), 3.04 (2H, t,
Ethyl 3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naph-
J=7.5Hz), 7.30 (1H, d, J=8.5Hz), 7.33 (2H, A2B2, J=8.5Hz), thyl)carbamoyl]phenyl]propionate (9): A slurry of 8 (1.010 g,
7.41 (1H, dd, J=8.5, 2Hz), 7.53 (1H, d, J=2Hz), 7.73 (1H, brs, 2.49mmol) and Pd/C (10%, 25mg, 23.5mgatom) in EtOH
CONH), 7.80 (2H, A2B2, J=8.5Hz). 13C-NMR (DMSO-d6) (25mL) was hydrogenated under H2 atmosphere (1atm) at an
δ: 30.2, 31.6, 31.7, 33.5, 34.0, 34.59, 34.63, 34.9, 118.0, 118.2, ambient temperature for 2h. Filtration through Celite bed,
126.4, 127.6, 128.2, 132.8, 136.7, 139.7, 144.5, 144.6, 165.1, washing with CHCl3, and evaporation of the solvents left a
173.6.
crystalline residue which was recrystallized to provide 9
4-Hydroxymethyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- (1.007g, 99%) as colorless fine needles, mp 132–132.5°C
2-naphthyl)benzamide (6): To a cooled (−20°C) solution of (CH2Cl2–hexane). HR-MS Calcd for C26H33NO3: 407.2459.
Am80 (320mg, 0.91mmol) in THF (5mL), Et3N (152µL, Found: 407.2445. MS (m/z): 407 (M+, 36), 329 (100), 362 (5),
1.09mmol) was added a solution of ClCOOMe (82µL, 205 (61), 177 (12), 131 (37), 103 (18), 77 (10). IR (KBr) cm−1:
1
1.06mmol) in THF (2mL) and the mixture was stirred at that 1724, 1642. H-NMR (CDCl3) δ: 1.24 (3H, t, J=7Hz), 1.28
temperature for 1h. The mixture was filtered through a Celite (6H, s), 1.30 (6H, s), 1.62 (4H, brs), 2.65 (2H, t, J=7.5Hz),
bed and the Celite was rinsed with THF (3mL). The filtrate 3.02 (2H, t, J=7.5Hz), 4.13 (2H, q, J=7Hz), 7.30 (1H, d,
and the THF wash were combined and the whole was cooled J=8.5Hz), 7.32 (2H, A2B2, J=8Hz), 7.41 (1H, dd, J=8.5,
in an ice bath. After addition of NaBH4 (208mg, 5.47mmol), 2.5Hz), 7.53 (1H, d, J=2.5Hz), 7.72 (1H, brs, NH), 7.79 (2H,
H2O (4mL) was gradually added dropwise during 15min with A2B2, J=8 Hz).
vigorous stirring, and the resulting mixture was further stirred
Preparation of 1 from 9: In the completely same manner as
at 0°C to an ambient temperature for 18h. The reaction was for the preparation of 1 from 5, 9 (556mg, 1.37mmol) was hy-
quenched by addition of satd. NH4Cl–H2O and the whole was drolyzed to give 1 (496mg, 96%) as colorless needles.
extracted with EtOAc. Usual work-up followed by column
Preparation of Metabolites (2E)-3-[4-[(5,6,7,8-Tetra-
chromatography [hexane–EtOAc (2:1)] provided 6 (290mg, hydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]phenyl]prope-
94%) as colorless prisms, mp 161–162.5°C (CH2Cl2–hexane). noic Acid (11′): In the same manner as for the preparation
HR-MS Calcd for C22H27NO2: 337.2040. Found: 337.2045. MS of 1 from 5, 8 (109mg, 0.269mmol) was hydrolyzed with
(m/z): 337 (M+, 27), 322 (87), 135 (100), 107 (18), 89 (34), 77 LiOH·H2O (15mg, 0.357mmol) to leave a residue which was
1
(28). IR (KBr) cm−1: 1634. H-NMR (CDCl3) δ: 1.28 (6H, s), recrystallized to afford 11′ (96mg, 95%) as colorless prisms,
1.30 (6H, s), 1.69 (4H, s), 1.93 (1H, t, J=4.5Hz, OH), 4.78 mp 226–227°C (CH2Cl2). HR-MS Calcd for C24H27NO3:
(2H, d, J=4.5Hz), 7.30 (1H, d, J=8.5Hz), 7.43 (1H, dd, J=8.5, 377.1989. Found: 377.1988. MS (m/z): 377 (M+, 29), 362 (100),
2.5Hz), 7.47 (2H, A2B2, J=8Hz), 7.54 (1H, d, J=2.5Hz), 7.76 175 (96), 147 (18), 102 (17), 91 (41), 44 (32). IR (KBr) cm−1:
1
(1H, brs, NH), 7.85 (2H, A2B2, J=8 Hz).
1682, 1646, 1625. H-NMR (CDCl3) δ: 1.29 (6H, s), 1.31 (6H,
4-Formyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- s), 1.70 (4H, s), 6.54 (1H, d, J=16Hz), 7.32 (1H, d, J=8.5Hz),
naphthyl)benzamide (7): A slurry of 6 (1.891g, 5.61mmol) and 7.43 (1H, dd, J=8.5, 2.5Hz), 7.53 (1H, d, J=2.5Hz), 7.66 (2H,
MnO2 (3.905g, 44.9mmol) in CH2Cl2 (35mL) was refluxed A2B2, J=8Hz), 7.74 (1H, brs, NH), 7.81 (1H, d, J=16Hz), 7.91
with stirring for 2h. The mixture was filtered through a Celite (2H, A2B2, J=8 Hz).
bed and the Celite was washed with CHCl3. After evaporation
tert-Butyl
3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-
of the solvent, resulting crystalline mixture was recrystallized naphthyl)carbamoyl]phenyl]-3-oxopropionate (16) and Di-
to give 7 (1.802g, 96%) as colorless prisms, mp 185.5–186.5°C tert-butyl 3-Hydroxy-3-[4-[(5,6,7,8-tetrahydro-5,5,8,8-tetra-
(CH2Cl2–hexane). HR-MS Calcd for C22H25NO2: 335.1884. methyl-2-naphthyl)carbamoyl]phenyl]glutarate (17): n-BuLi
Found: 335.1913. MS (m/z): 335 (M+, 32), 320 (100), 133 (68), (1.64 m/hexane, 2.00mL, 3.28mmol) was added to a cooled
1
105 (28), 77 (24), 51 (9). IR (KBr) cm−1: 1690, 1662. H-NMR (−20°C) solution of i-Pr2NH (0.46mL, 3.29mmol) in THF
(CDCl3) δ: 1.29 (6H, s), 1.30 (6H, s), 1.70 (4H, s), 7.33 (1H, d, (10mL) and the mixture was stirred for 15min. It was
J=8.5Hz), 7.44 (1H, dd, J=8.5, 2Hz), 7.53 (1H, d, J=2Hz), then cooled to −78°C and to this was added dropwise

850
Vol. 61, No. 8
CH3COOtert-Bu (0.44mL, 3.28mmol) and stirred at the same carbamoyl]phenyl]-3-hydroxypropionic Acid (12′): In the
temperature for 30min. A solution of 15 (240mg, 0.657mmol) same manner as for the preparation of 13′ from 16, 18 (30mg,
in THF (5mL) was added to this and the whole was stirred 66.5µmol) was treated with CF3COOH to afford 12′ (24mg,
at −78°C to an ambient temperature for 4h. Quenching with 91%) as colorless prisms, mp 185–187°C (CH2Cl2–hexane).
satd. NH4Cl–H2O, extraction with EtOAc, usual work-up and HR-MS Calcd for C24H29NO4: 395.2095. Found: 395.2071.
purification by PTLC [hexane–EtOAc (10:1)] afforded 16 MS (m/z): 395 (M+, 5), 380 (100), 362 (11), 320 (11), 193 (66),
(175mg, 59%) and 17 (129mg, 35%) in order of increasing 133 (33), 105 (43), 77 (31), 43 (23). IR (KBr) cm−1: 1700, 1621,
1
polarity. 16: Colorless foam. HR-MS Calcd for C28H35NO4: 1608. H-NMR (DMSO-d6) δ: 1.22 (6H, s), 1.23 (6H, s), 1.63
449.2564. Found: 449.2568. MS (m/z): 449 (M+, 27), 434 (36), (4H, s), 2.53 (1H, dd, J=15, 8Hz), 2.59 (1H, dd, J=15, 5.5Hz),
360 (38), 334 (48), 173 (24), 147 (59), 104 (25), 59 (100), 57 5.01 (1H, dd, J=8, 5.5Hz), 5.58 (1H, brs, OH), 7.26 (1H, d,
1
(71), 43 (27), 41 (49). IR (CHCl3) cm−1: 1725, 1676. H-NMR J=8.5Hz), 7.49 (2H, A2B2, J=8Hz), 7.56 (1H, dd, J=8.5,
of keto- and enol-form (ca. 2.7:1, CDCl3) δ: 1.20 (6H, s), 1.21 2Hz), 7.67 (1H, d, J=2Hz), 7.90 (2H, A2B2, J=8Hz), 10.03
(6H, s), 1.35 and 1.47 (9H, s each), 1.61 (4H, brs), 3.85 (2H (1H, s), 12.16 (1H, brs, COOH).
of keto form, s, D2O exchangeable), 5.57 (1H of enol form,
Synthesis of 2 and 30 (E)-3-(4-Carboxyphenyl)propenoic
s), 7.22 and 7.21 (1H, d each, J=8.5Hz), 7.34–7.41 (1H, m), Acid (20): A slurry of 19 (120.0g, 0.80mol), malonic acid
7.45–7.51 (1H, m), 7.86 and 7.74 (2H, A2B2 each, J=8.5Hz), (124.8g, 1.20mol), and piperidine (8.0mL, 81mmol) in pyri-
7.91 and 7.81 (2H, A2B2 each, J=8.5Hz), 8.02 and ca. 7.94 dine (350mL) was heated with stirring at 80°C for 1.5h. Then
(1H, brs each, NH), 12.71 (1H of enol form s, D2O exchange- pyridine (50mL) was added to this and the whole was further
able). 17: Colorless foam. HR-MS Calcd for C34H47NO6: heated at 100°C for 2h, and at reflux for 3h. After hav-
565.3401. Found: 565.3423. MS (m/z): 565 (M+, 27), 550 ing been cooled, the mixture was poured into an ice cooled
(17), 436 (11), 334 (10), 251 (15), 147 (20), 57 (100), 41 (27). HCl–H2O (6n, 1.6L), and precipitated crystals were collected
1
IR (CHCl3) cm−1: 1711, 1667. H-NMR (CDCl3) δ: 1.27 (6H, by filtration under reduced pressure, washed with H2O, and
s), 1.29 (6H, s), 1.30 (18H, s), 1.68 (4H, brs), 2.85 (2H, d, thoroughly dried over P2O5 in vacuo to yield 20 (150.5g, 98%)
J=15Hz), 2.91 (2H, d, J=15Hz), 4.87 (1H, s, OH), 7.28 (1H, as slightly yellowish powder, mp >300°C (lit. mp 362–363°C,
1
d, J=8.5Hz), 7.43 (1H, dd, J=8.5, 2.5Hz), 7.55 (2H, A2B2, decomp15)). H-NMR (DMSO-d6) δ: 6.62 (1H, d, J=16Hz),
J=8Hz), 7.59 (1H, d, J=2.5Hz), 7.86 (2H, A2B2, J=8Hz), 7.98 7.61 (1H, d, J=16Hz), 7.78 (A2B2, J=8.5Hz), 7.94 (A2B2,
(1H, brs, NH).
J=8.5 Hz).
3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
3-(4-Carboxyphenyl)propionic Acid (21): The acid 20
carbamoyl]phenyl]-3-oxopropionic Acid (13′): CF3COOH (50.0g, 0.26mol) was added in small portions to a solution
(0.30mL, 3.89mmol) was added to a cooled (0°C) solution of Na2CO3 (31.8g, 0.30mol) in H2O (250mL) in a Parr vessel
of 16 (42mg, 93.5µmol) in CH2Cl2 (2.7mL) and the mixture (500mL) with stirring. Pd/C (10%, 750mg) was added to this
was stirred at 0°C for 15min and at an ambient temperature and the resulting slurry was hydrogenated under H2 atmo-
for 1.5h. Volatile materials were evaporated off and the result- sphere (0.3MPa) for 70h. The mixture was filtered through
ing crystalline residue was recrystallized to yield 13′ (31mg, a Celite bed and the Celite was rinsed with H2O. The filtrate
84%) as colorless prisms, mp 183–184°C (CH2Cl2–hexane). and wash water were combined and conc. HCl–H2O was
MS (m/z): 349 (M+−CO2, 31), 334 (100), 292 (6), 147 (70), 119 added dropwise to adjust pH to ca. 2. Precipitated crystals
(18), 104 (15), 91 (28), 76 (13), 43 (30). IR (KBr) cm−1: 1729, were collected as above to give 21 (47.9g, 95%) as a color-
1
1665, 1648. H-NMR of keto- and two enol-forms (ca. 12:5:3, less powder, mp 286–290°C [lit. mp 286–289°C (HOAc)19)].
1
DMSO-d6) δ: 1.23 (6H, s), 1.24 (6H, s), 1.64 (4H, s), 4.12 (2H IR (KBr) cm−1: 1693, 1681. H-NMR (DMSO-d6) δ: 2.55 (2H,
of keto-form, s, D2O exchangeable), 5.74 and 5.96 (two OHs t, J=7.5Hz), 2.87 (2H, t, J=7.5Hz), 7.33 (A2B2, J=8Hz), 7.83
of enol-form, s each), 7.28 (1H, d, J=8Hz), 7.57 (1H, dd, J=8, (A2B2, J=8 Hz).
2Hz), 7.67 (1H, d, J=2Hz), 7.92–8.11 (4H, m), 10.20 (NH, of
an enol-form, brs), 10.26 (NH of keto- and the other enol- dium-carbon (10%, 1.50g) was added to a slightly slurried
form, brs), 12.74, 12.99, and 13.43 (1H, brs each, COOH). solution of 21 (30.0g, 0.155mol), Na2CO3 (16.4g, 0.155mol) in
tert-Butyl 3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2- D2O (99%D, 300mL) in a vessel (500mL, Ace Glass, globu-
3-(4-Carboxyphenyl)propionic Acid-2,2,3,3-d4 (22): Palla-
naphthyl)carbamoyl]phenyl]-3-hydroxypropionate (18): NaBH4 lar shape), and it was purged with hydrogen gas (1atm) and
(9mg, 0.237mmol) was added to a cooled (0°C) solution of sealed, and then heated in an oil bath (130°C) for 64h. After
16 (36mg, 80.2µmol) in EtOH (3mL), and the mixture was termination of the reaction (checked by NMR of the aliquot
stirred at that temperature for 40min. Quenching with satd. in D2O), the mixture was filtered through a Celite bed under
NH4Cl–H2O, extraction with EtOAc, usual work-up, and reduced pressure, and the filtrate was distilled to recover D2O
PTLC [hexane–EtOAc (5:2)] provided 18 (35mg, 97%) as (247mL, 82% at 57–58°C/120mmHg). The resulting residue
a colorless foam. HR-MS Calcd for C28H37NO4: 451.2721. and wash water of the Celite bed were combined, and the
Found: 451.2709. MS (m/z): 451 (M+, 53), 436 (72), 380 (39), solution was made acidic (pH ca. 2) with conc. HCl–H2O.
193 (63), 133 (34), 105 (34), 57 (100), 41 (39). IR (CHCl3) Precipitated crystals were collected by filtration under reduced
1
cm−1: 1701, 1665, 1607. H-NMR (CDCl3) δ: 1.27 (6H, s), 1.29 pressure, washed with water, and then thoroughly dried over
(6H, s), 1.45 (9H, s), 1.68 (4H, s), 2.64 (2H, d, J=6.5Hz), 3.77 P2O5 in vacuo to provide desired 22 (29.8g, 97%, D ratio of
(1H, d, J=3Hz, OH), 5.11 (1H, dt, J=3, 6.5Hz), 7.29 (1H, X=97–98%, Y=98%) as a colorless powder, mp 271–273°C.
d, J=8.5Hz), 7.43 (2H, A2B2, J=8Hz), 7.45 (1H, dd, J=8.5, HR-MS: Calcd for C10H6D4O4: 198.0830. Found: 198.0825.
2Hz), 7.55 (1H, d, J=2Hz), 7.82 (2H, A2B2, J=8Hz), 7.96 (1H, MS (m/z): 198 (M+, 67), 181 (11), 152 (50), 137 (61), 109 (100),
1
brs, NH).
93 (19), 79 (25), 45 (28). IR (KBr) cm−1: 1683. H-NMR (1%
3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)- Na2CO3–D2O) δ: 2.35 (0.04–0.06H, brs), 2.79 (0.04H, brs),

August 2013
851
7.22 (A2B2, J=8Hz), 7.68 (A2B2, J=8 Hz).
2.95–3.02 (0.03H, m), 3.67 (3H, s), 3.90 (3H, s), 7.27 (A2B2,
3-(4-Carboxyphenyl)propionic Acid-3,3-d2 (23): Palladium- J=8.5Hz), 7.96 (A2B2, J=8.5 Hz).
carbon (10%, 250mg) was added to a slightly slurried solution
Methyl 3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naph-
of 21 (5.00g, 25.8mmol), Na2CO3 (3.28g, 30.9mmol) in D2O thyl)carbamoyl]phenyl]propionate-2,2,3,3-d4 (28): Different
(99%D, 100mL) in a Parr vessel (500mL, circular cylinder), from the case of the preparation of 5, the yield of 28 was
and it was purged with hydrogen gas (1atm) and sealed, and calculated not from 4, but from the time-consuming com-
then heated at 100°C for 48h. After termination of the reac- pound 24. SOCl2 (10.3mL, 141mmol) and N,N-dimethyl-
tion (NMR check as above), the mixture was treated in the formamide (DMF) (0.15mL, 1.94mmol) were added to a
same manner as above to yield 23 (4.90g, 97%, D ratio of slurry of 24 (10.00g, 47.2mmol) in benzene (75mL), and the
X=0%, Y>98%) along with recovered D2O (84mL, 84%). mixture was refluxed with stirring for 6h. The volatile materi-
23: Colorless powder, mp 273–276°C. HR-MS: Calcd for als were evaporated off, then benzene (40mL) was added to
C10H8D2O4: 196.0704. Found: 196.0698. MS (m/z): 196 (M+, the resulting residue and evaporated again to dryness. The
70), 179 (8), 150 (49), 137 (64), 109 (100), 106 (31), 93 (23), residue was dissolved in CH2Cl2 (80mL) and the solution was
1
78 (33), 45 (30). IR (KBr) cm−1: 1697, 1683. H-NMR (1% cooled in an ice bath. A solution of 4 (10.06g, 49.6mmol)
Na2CO3–D2O) δ: 2.38 (2H, s), ca. 2.77–2.83 (<0.04H, m), 7.23 and Et3N (19.7mL, 142mmol) in CH2Cl2 (20mL) was added
(A2B2, J=8Hz), 7.69 (A2B2, J=8 Hz).
to this and the mixture was stirred at that temperature for
Methyl 3-(4-Carboxyphenyl)propionate-2,2,3,3-d4 (24) and 30min, and at an ambient temperature for 15h. Saturated
Diester 25: SOCl2 (14 µL, 0.192mmol) was added to a cooled NaHCO3–H2O was added and the whole was extracted with
(0°C) slurry of 22 (1.93g, 9.75mmol) in MeOH (30mL) and CHCl3. Usual work-up followed by purification by recrystal-
the mixture was stirred at an ambient temperature for 16h. lization and column chromatography [hexane–EtOAc (4:1)]
The resulting clear solution was made slightly acidic (pH 6) gave 28 (18.06g, 96%) as colorless prisms, mp 136.5–137.5°C
by addition of satd. NaHCO3–H2O (0.8mL) and the solvent (CH2Cl2–hexane). The H2O layer was made acidic to pH ca. 2
was evaporated off. Et2O was added to the residue and the with 10% HCl–H2O and extracted with EtOAc. Usual work-up
mixture was extracted with Na2CO3–H2O (10% w/v). The and recrystallization recovered 24 (85mg, 1%). HR-MS: Calcd
Et2O layer was washed with satd. NH4Cl–H2O and then for C25H27D4NO3: 397.2553. Found: 397.2569. MS (m/z): 397
treated as usual. Purification by PTLC [hexane–EtOAc (5:1)] (M+, 36), 382 (100), 366 (4), 195 (65), 137 (12), 134 (16), 108
1
gave 25 (118mg, 5%). On the other hand, conc. HCl–H2O (8), 107 (8). IR (KBr) cm−1: 1708, 1659. H-NMR (CDCl3) δ:
was added dropwise to the cooled (0°C) basic water layer 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.64 (0.03–0.04H, brs),
to adjust pH to ca. 2, and a precipitated mixture of 24 and 2.99 (0.02–0.03H, brs), 3.68 (3H, s), 7.30 (1H, d, J=8.5Hz),
recovered 22 was collected and dried as above. The mixture 7.31 (A2B2, J=8Hz), 7.41 (1H, dd, J=8.5, 2Hz), 7.53 (1H, d,
was dissolved in CH2Cl2 to make a slight slurry, which was J=2Hz), 7.71 (1H, brs, NH), 7.80 (A2B2, J=8 Hz).
filtered through a filter paper to recover 22 (54mg, 3%). The
Methyl 3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naph-
filtrate was recrystallized to yield 24 (1.80g, 87%) as color- thyl)carbamoyl]phenyl]propionate-3,3-d4 (29): In the same
less scales, mp 149–150.5°C (CH2Cl2–hexane). HR-MS: Calcd manner as for the preparation of 28, 26 (2.402g, 11.4mmol)
for C11H8D4O4: 212.0986. Found: 212.1001. MS (m/z): 212 was condensed with 3 (2.438g, 12.0mmol) to form 29 (4.364g,
(M+, 34), 195 (4), 181 (12), 152 (100), 137 (40), 134 (18), 123 97%) as colorless prisms, mp 135–136°C (CH2Cl2–hexane).
1
(15), 109 (76), 79 (16). IR (KBr) cm−1: 1719, 1681. H-NMR From the H2O layer, 26 (33mg, 1%) was recovered as above.
(CDCl3) δ: 2.65 (0.02–0.03H, brs), 3.01 (0.02H, brs), 3.67 (3H, HR-MS: Calcd for C25H29D2NO3: 395.2428. Found: 395.2430.
s), 7.32 (A2B2, J=8.5Hz), 8.04 (A2B2, J=8.5Hz). 13C-NMR MS (m/z): 395 (M+, 37), 380 (100), 193 (68), 132 (19), 105 (14),
1
(CDCl3) δ: 30.2 (quint, JCD=20Hz), 34.4 (quint, JCD=20.5Hz), 43 (8). IR (KBr) cm−1: 1709, 1660, 1608. H-NMR (CDCl3) δ:
51.7, 127.5, 128.5, 130.5, 146.8, 172.0, 173.0. 25: colorless oil. 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.65 (2H, s), 2.97–3.04
HR-MS: Calcd for C12H10D4O4: 226.1142. Found: 226.1146. MS (ca. 0.03H, m), 3.68 (3H, s), 7.30 (1H, d, J=8.5Hz), 7.32 (A2B2,
(m/z): 226 (M+, 47), 195 (69), 166 (100), 151 (50), 134 (46), 123 J=8Hz), 7.41 (1H, dd, J=8.5, 2.5Hz), 7.52 (1H, d, J=2.5Hz),
1
(47), 59 (26). IR (neat) cm−1: 1727, 1714. H-NMR (CDCl3) δ: 7.39 (1H, brs, NH), 7.80 (A2B2, J=8 Hz).
2.60–2.64 (0.02–0.03H, m), ca. 2.98 (0.02H, brs), 3.67 (3H, s),
3.90 (3H, s), 7.27 (A2B2, J=8.5Hz), 7.96 (A2B2, J=8.5 Hz).
3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
carbamoyl]phenyl]propionic Acid-2,2,3,3-d4 (IT-YA-00616, 2):
Methyl 3-(4-Carboxyphenyl)propionate-3,3-d2 (26) and In the same manner as for the preparation of 1 from 5, 28
Diester 27: In the same manner as for the preparation of 24 (10.25g, 25.8mmol) was hydrolyzed with LiOH·H2O (1.30g,
and 25, 23 (2.84g, 14.5mmol) was treated with SOCl2 (21 µL, 31.0mmol) to afford 2 (9.70g, 98%) as colorless fine needles,
0.29mmol) in MeOH (40mL) to provide 26 (2.61g, 86%), 27 mp 230.5–231.5°C (EtOAc). Anal. Calcd for C24H25D4NO3:
(0.21g, 6%) along with recovered 23 (23mg, 1%). 26: Color- C, 75.16; H(+D), 7.62; N, 3.65. Found: C, 75.00; H(+D), 7.57;
less scales, mp 149–150°C (CH2Cl2–hexane). HR-MS: Calcd N, 3.64. HR-MS: Calcd for C24H25D4NO3: 383.2397. Found:
for C11H10D2O4: 210.0860. Found: 210.0844. MS (m/z): 210 383.2395. MS (m/z): 383 (M+, 37), 368 (100), 326 (2), 189
(M+, 36), 179 (13), 150 (100), 137 (42), 132 (15), 123 (14), 109 (6), 181 (73), 109 (19), 107 (8), 43 (6). IR (KBr) cm−1: 1707,
1
1
(21), 107 (18), 78 (19). IR (KBr) cm−1: 1720, 1681. H-NMR 1615. H-NMR (CDCl3) δ: 1.27 (6H, s), 1.30 (6H, s), 1.69 (4H,
(CDCl3) δ: 2.66 (2H, s), ca. 2.98–3.04 (ca. 0.03H, m), 3.68 s), 2.69 (ca. 0.04H, brs), 3.01 (ca. 0.03H, brs), 7.30 (1H, d,
(3H, s), 7.31 (A2B2, J=8.5Hz), 8.03 (A2B2, J=8.5Hz). 27: J=8.5Hz), 7.33 (A2B2, J=8Hz), 7.42 (1H, dd, J=8.5, 2Hz),
Colorless oil. HR-MS: Calcd for C12H12D2O4: 224.1017. Found: 7.53 (1H, d, J=2Hz), 7.76 (1H, brs, NH), 7.80 (A2B2, J=8Hz).
224.1004. MS (m/z): 224 (M+, 49), 193 (66), 164 (100), 151 13C-NMR (DMSO-d6) δ: 31.62, 31.64, 33.5, 34.0, 34.58, 34.63,
(39), 132 (39), 123 (43), 105 (20), 92 (20), 59 (24). IR (neat) 118.0, 118.2, 126.3, 127.6, 128.2, 132.8, 136.7, 139.7, 144.46,
1
cm−1: 1730 (sh), 1715. H-NMR (CDCl3) δ: 2.64 (2H, s), ca. 144.54, 165.1, 173.6. The 13C-NMR spectrum was measured in

852
Vol. 61, No. 8
DMSO-d6 in order to obtain a sufficiently high concentration of the residue provided 32 (96mg, 80%) as colorless scales,
of 2, but the signals ascribed to two CD2 carbons were ob- mp 226.5–227.5°C (EtOAc–hexane). HR-MS Calcd for
served only as broadened weak peaks at somewhat higher field C24H27D2NO3: 381.2271. Found: 381.2256. MS (m/z): 381 (M+,
(ca. 29.4 and 34.2ppm) than those of 1 (30.2 and 34.9ppm).
38), 366 (100), 179 (78), 107 (17), 105 (11). IR (KBr) cm−1:
1
3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)- 1712, 1619. H-NMR (CDCl3) δ: 1.28 (6H, s), 1.30 (6H, s), 1.69
carbamoyl]phenyl]propionic Acid-3,3-d2 (30): In the same (4H, s), 3.03 (2H, brs), 7.30 (1H, d, J=8.5Hz), 7.33 (A2B2,
manner as for the preparation of 1 from 5, 29 (4.05g, J=8.5Hz), 7.42 (1H, dd, J=8.5, 2Hz), 7.53 (1H, d, J=2Hz),
10.3mmol) was hydrolyzed with LiOH·H2O (0.52g, 7.73 (1H, brs, NH), 7.81 (A2B2, J=8.5 Hz).
12.4mmol) to afford 30 (3.84g, 98%) as colorless fine needles,
mp 229.5–230°C (EtOAc). HR-MS: Calcd for C24H27D2NO3:
381.2271. Found: 381.2253. MS (m/z): 381 (M+, 33), 366 (100),
149 (90), 109 (27), 105 (19), 79 (11). IR (KBr) cm−1: 1707,
References
1) Kagechika H., Shudo K., J. Med. Chem., 48, 5875–5883 (2005).
2) Miwako I., Kagechika H., Drugs Today (Barc.), 43, 563–568 (2007).
3) Tobita T., Takeshita A., Kitamura K., Ohnishi K., Yanagi M., Hi-
raoka A., Karasuno T., Takeuchi M., Miyawaki S., Ueda R., Naoe
T., Ohno R., Blood, 90, 967–973 (1997).
1
1616. H-NMR (CDCl3) δ: 1.28 (6H, s), 1.30 (6H, s), 1.69
(4H, s), 2.71 (2H, s), ca. 2.99–3.04 (ca. 0.03H, m), 7.30 (1H,
d, J=8.5Hz), 7.33 (A2B2, J=8.5Hz), 7.41 (1H, dd, J=8.5,
2Hz), 7.53 (1H, d, J=2Hz), 7.74 (1H, brs, NH), 7.80 (A2B2,
J=8.5 Hz).
Preparation of the Congener 32 5-[4-[(5,6,7,8-
Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]ben-
4) Goncalves M. B., Clarke E., Hobbs C., Malmqvist T., Deacon R.,
Jack J., Corcoran J. P. T., Eur. J. Neurosci., 2013, 1–11 (2013).
5) Fukasawa H., Nakagomi M., Yamagata N., Katsuki H., Kawahara
K., Kitaoka K., Miki T., Shudo K., Biol. Pharm. Bull., 35, 1206–
1212 (2012).
zyl]-2,2-dimethyl-1,3-dioxane-4,6-dione
(31):
Meldrum’s
6) Tallman M. S., Leukemia, 16, 160–161 (2002), and references cited
therein.
acid (59mg, 0.409mmol), diethyl 1,4-dihydro-2,6-dimethyl-
3,5-pyridinedicarboxylate (Hantzsch ester, 99mg, 0.392mmol)
and l-proline (9mg, 78.2µmol) were added in this order to
a slurry of 1 (125mg, 0.373mmol) in CH3CN (3mL) and
the mixture was stirred at an ambient temperature for
22h. At this point, the mixture became nearly clear. The
solvent was evaporated off and the resulting residue was
subjected to column chromatography [hexane–EtOAc (2:1)]
to yield 31 (146mg, 85%) as colorless fine needles, mp
145–146°C (decomp. CH2Cl2–hexane). MS (m/z): 379 (M+−
7) Lynen F., Ochoa S., Biochim. Biophys. Acta, 12, 299–314 (1953).
8) Drysdale G. R., Lardy H. A., J. Biol. Chem., 202, 119–136 (1953).
9) Piscitelli S. C., Thibault A., Figg W. D., Tompkins A., Headlee
D., Lieberman R., Samid D., Myers C. E., J. Clin. Pharmacol., 35,
368–373 (1995).
10) Sugitani M., Abe R., Ikarashi N., Ito K., Muratake H., Shudo K.,
Sugiyama K., Biol. Pharm. Bull., 32, 1997–2001 (2009).
11) Oates L. J., Jackson R. F. W., Block M. H., Org. Biomol. Chem., 1,
140–144 (2003).
12) SmithKline Beecham Corp. Patent WO2005/12220 A2 (2005).
C4H4O2, 31, converted to 1 in the MS chamber), 364 (100), 13) Kagechika H., Kawachi E., Hashimoto Y., Himi T., Shudo K., J.
177 (67), 107 (18), 57 (25), 43 (25). IR (KBr) cm−1: 1780, 1740,
Med. Chem., 31, 2182–2192 (1988).
14) Simmons E. M., Hartwig J. F., Angew. Chem. Int. Ed., 51, 3066–
3072 (2012), and references cited therein.
15) Kluger R., Shen L., Xiao H., Jones R. T., J. Am. Chem. Soc., 118,
8782–8486 (1996).
16) Esaki H., Aoki F., Umemura M., Kato M., Maegawa T., Monguchi
Y., Sajiki H., Chemistry, 13, 4052–4063 (2007).
17) Ramachary D. B., Kishor M., Ramakumar K., Tetrahedron Lett., 47,
1
1641. H-NMR (CDCl3) δ: 1.27 (6H, s), 1.30 (6H, s), 1.61 (3H,
s), 1.69 (4H, s), 1.77 (3H, s), 3.54 (2H, d, J=5Hz), 3.80 (1H, t,
J=5Hz), 7.30 (1H, d, J=8.5Hz), 7.41 (1H, dd, J=8.5, 2.5Hz),
7.44 (A2B2, J=8.5Hz), 7.53 (1H, d, J=2.5Hz), 7.76 (1H, brs,
NH), 7.79 (A2B2, J=8.5 Hz).
3-[4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
carbamoyl]phenyl]propionic Acid-2,2-d2 (32): D2O (0.5mL)
was added to a solution of 31 (145mg, 0.313mmol) in pyri-
dine (5mL) and the mixture was stirred under reflux for 16h.
After cooling, HCl–H2O (2n) was added and the whole was
extracted with CHCl3. Usual work-up and recrystallization
651–656 (2006).
18) Kadam A. J., Desai U. V., Mane R. B., J. Labelled Comp. Radio-
pharm., 42, 835–842 (1999).
19) Everson W. S., Heimsch R. A., J. Am. Chem. Soc., 72, 5152–5154
(1950).