Synthetic study of 4-substituted piperidine ring in elarofiban, RWJ-50042, tirofiban and paroxetine

Article abstract of DOI:10.1002/jccs.200200156

A new strategy for synthesizing a 4-substituted piperidine ring uses the formal [3+3] cycloaddition reaction as the key protocol. This method provides a convenient formal synthesis of elarofiban, RWJ-50042, tirofiban and paroxetine.

Full text of DOI:10.1002/jccs.200200156

Journal of the Chinese Chemical Society, 2002, 49, 1079-1088
1079
Synthetic Study of 4-Substituted Piperidine Ring in Elarofiban,
RWJ-50042, Tirofiban and Paroxetine
Meng-Yang Changa (
Shui-Tein Chen*a (
), John, Yi-Chung Lina (
) and Nein-Chen Changb (
),
)
aInstitute of Bio l o g i c a l Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, R.O.C.
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, R.O.C.
A new strategy for synthesizing a 4-substituted piperidine ring uses the formal [3+3] cycloaddition rea c -
tion as the key protocol. This method provides a convenient formal synthesis of elarofiban, RWJ-50042,
tirofiban and paroxetine.
INTRODUCTION
Piperidine-based compounds are important skeletal
important piperidine class of compounds. We will report a
facile route towards the substituted piperidines 4, 5 and 6 in
each skeleton of elarofiban (1a), RWJ-50042 (1b), tirofiban
(2) and paroxetine (3a).
templates and are frequently recognized in the structures of
numerous naturally occurring alkaloids and synthetic com-
pounds with biological and pharmacological activities.1,2
Some of their therapeutic applications are as antithrombotic
agents,3-5 anti-depressant and anti-Parkinson agents,6 kappa-
opioid analgesics,7 and antiinflammatory agents.8 As a con-
sequence, the development of general methods for the syn-
thesis of piperidine derivatives has been the focus of cons i d -
erable synthetic efforts. Recently, many syntheses of 4-sub-
stituted or 3,4-substituted piperidine have been published.9-10
Compounds with a 4-substituted piperidine ring like elaro-
fiban (RWJ-53308),10b,g RWJ-50042,5c,10a and tirofiban
(MK-383, L-700,462),5a-b,10c and with a 3,4-substituted piper-
idine ring like paroxetine11 and femoxetine11q are und e r clini -
cal trials or are already marketed as drugs and belong to this
[1-[3-(4-Piperidyl)propionyl]nipecotamido]-3-pyridine-
propionic acid, also known as elarofiban (1a), and one of its
derivatives RWJ-50042 (1b), based on the KQAGD (Lys-
Gln-Ala-Gly-Asp, 406-410) sequence, have been designed
and synthesized for therapeutic use as a potent glycoprotein
IIb/IIIa (GPIIb/IIIa) blocker.5c N-(Butanesulfonyl)-O-(4-(4-
piperidinyl)butyl)-(S)-tyrosine, also known as tirofiban (2),
is also a potent GPIIb/IIIa blocker and is marketed under the
trade name Aggrastat.10c It is an anti-platelet aggregation
agent used in various vascular pathologies. The inhibitor 2
(IC50 = 9 nM) is low molecular weight and appears to derive
significate potency enhancement from interaction with GP
IIb/IIIa.
Compounds 1a, 1b and 2 were all designed based on the
H
N
H
H
N
N
OAr
O
CO2H
R
O
O
CO2H
HN
O
N
N
H
S
O
R'
tirofiban (2)
(L-700,462)
O
O
R =
elarofiban (1a)
(RWJ-53308)
RWJ-50042 (1b)
Ar =
, R' = F
N
R = H
paroxetine (3a)
Ar =
H3CO
femoxetine (3b)
, R' = H
Fig. 1. Structure of elarofiban (1a), RWJ-50042 (1b), tirofiban (2), paroxetine (3a) and femoxetine (3b).

1080 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
Chang et al.
integrin tripeptide recognition motif, Arg-Gly-Asp (RGD).
According to recent studies,10d these compounds must have a
carboxylate and an ammonium functionality within a dis-
tance of 11-15 Å to be effective inhibitors. Moreover, it has
been shown that the basic group may be also represented by
amine functional groups such as guanidine, piperidine or a
benzamidine moiety. Compounds 1a, 1b and 2 are also small
organic molecular inhibitors of platelet fibrinogen receptor
GPIIb/IIIa blockers4 and have been evaluated for their ability
to prevent platelet aggregation. They are currently und e r clin-
ical development as injectable antithrombotic agents for the
treatment and prevention of acute coronary syndromes.
Paroxetine (3a), marketed as Paxil/Saroxat, is a selec-
tive serotonin (5-hydroxytryptamine) reuptake inhibitor used
as an anti-depressant and anti-Parkinson agent.12 And its high
sales in excess of $1.5 billion/year have induced many at-
tempts to synthesize compound 3a.11 Several procedures
have been used for the preparation of paroxetine (3a). Physi -
cal reso l u t i o n and enzymatically assisted kinetic reso l u t i o n
of an advanced racemic intermediate are the most common
methods employed.
Scheme I Retrosynthetic analysis of piperidine ring
of elarofiban (1a), RWJ-50042 (1b), tiro-
fiban (2) and paroxetine (3a)
X
N
X
N
O
O
elarofiban (1a)
RWJ-50042 (1b)
tirofiban (2)
Z
TolO2S
paroxetine (3a)
Y
Y
7 X = Bn, Y = (CH2)3OBn
8 X = Bn, Y = (CH2)4OBn
9 X = PMB, Y = 4-F-C6H4
4 X = Bn, Y = (CH2)2CO2Et, Z = H
5 X = Bn, Y = (CH2)4Br, Z = H
6 X =
, Y = 4-F-C6H4, Z = CH2OH
Ph
X
EtO
O
NH
O
[3+3]
+
TolO2S
Y
11a Y = (CH2)3OBn
11b Y = (CH2)4OBn
11c Y = 4-F-C6H4
10a X = Bn
10b X = PMB
10c X =
Ph
decreases the nucleophilicity of the amide 10c, thereby re-
tarding the intramolecular cyclization. The cyclized products
7, 8 and 9 were produced in moderate yields. The regio-
selectivity of 7, 8 and 9 between 4-substituted and -sulfonyl
group were proven by 1H-NMR spectra (ca. 4.0, br s, 1H).
RESULTS AND DISCUSSION
Retrosynthetic analy s i s of piperidine ring on elarofiban
(1a), RWJ-50042 (1b), tirofiban (2) and paroxetine (3a)
The retrosynthetic analysis for the formal synthesis of
elarofiban (1a), RWJ-50042 (1b), tirofiban (2) and parox-
etine (3a) are shown in Scheme I. The piperidines 4, 5 and 6
were synthesized from glutarimides 7, 8 and 9, which in turn
were derived from the formal [3+3] cycloaddition reaction of
a-sulfonyl acetamides 10a, 10b with , -unsaturated ethyl
esters 11a, 11b and 11c.
Synthesis of piperidine ring on elarofiban (1a) and
RWJ-50042 (1b)
In Scheme II, glutarimide 7 was prepared from acet-
amide 10a and ethyl ester 11a und e r basic conditions (NaH/
THF). Debenzylation of compound 7 by catalytic hydrog -
enolysis (10% Pd/C) produced primary alcohol 12. Desul-
fonation of compound 12 with dissolved sodium in liqu i d am-
monia produced symmetric glutarimide. Reduction of the
symmetric glutarimide by lithi u m alum i n u m hydride pro-
Reaction of -sulfonyl acetamides 10a, 10b and 10c with
, -unsaturated ethyl esters 11a, 11b and 11c
Scheme II Synthesis of piperidine ring of elarofiban
(1a) and RWJ-50042 (1b)
-Sulfonyl acetamides 10a, 10b and 10c were pro-
duced in 85-90% yield from the two-step reaction of three
amines with chloroacetyl chloride (acylation and substitu-
tion).13 Acetamides 10a and 10b reacted with , -unsatu-
Bn
N
Bn
N
EtO
O
O
O
O
O
NaH, THF
(54%)
H2, Pd/C, EA
(94%)
10a
+
rated ethyl esters 11a, 11b and 11c to give 4-substituted
-
TolO2S
TolO2S
sulfonyl glutarimides 7, 8 and 9 under the formal [3+3] cyclo-
addition conditions. In contrast, reaction of acetamide 10c
with , -unsaturated ethyl esters 11a, 11b and 11c gave start-
ing material 10c without the desired products. Therefore, the
-methylbenzyl group on the acetamide 10c might exert
steric factors unfavorable to the course of the cycloaddition
reaction. This steric shielding of the -methylbenzyl group
OBn
Bn
OBn
OH
11a
7
12
Bn
N
N
1) Jone's Ox.
2) EtOH, TFA
1) Na, NH3(l)
2) LAH, THF
O
(two steps 68%)
(two steps 62%)
OEt
OH
13
4

Synthetic Study of 4-Substituted Piperidine Ring in Elarofiban
J. Chin. Chem. Soc., Vol. 49, No. 6, 2002 1081
duced hydroxy-amine 13. Oxidation of alcohol 13 by Jones
reagent yielded an acid. In order to separate the acid easily,
the acid was converted to ethyl ester 4 und e r acidic cond i -
tions (TFA/EtOH). By this route, the compound 4 was pro-
duced in 21% overall yield. Ester 4 is the intermediate for the
synthesis of elarofiban (1a)10b and RWJ-50042 (1b).5c,10a
Scheme IV Synthesis of piperidine ring of paroxetine
(3a)
PMB
N
PMB
N
NaHMDS, PhNTf2
EtO
O
O
NaH, THF
(68%)
O
O
10b
+
then H2, Pd/C
(44%)
TolO2S
TolO2S
4-F-C6H4
4-F-C6H4
4-F-C6H4
16
11c
9
Synthesis of piperidine ring on tirofiban (2)
Ph
Ph
In previous reports,5b,10d the preparation of 4-sub-
stituted piperidinyl bromide required about seven steps, used
expensive reagents, was based on 4-substituted pyridine (4-
pyridinylpropanol or 4-pyridinacetic acid) as the starti n g ma-
terial and produced products in mode s t yields. Chung et al.
demonstrated an efficient synthesis of 4-substituted pyridinyl
chloride10e in kilogram scale using the 4-picoline as the start-
ing material. In Scheme III, we provide another five-step syn-
thetic strategy for bromide 5. Glutarimide 8 was prepared
from acetamide 10a and ethyl ester 11b under bas i c cond i -
tions. Debenzylation of compound 8 by catalytic hydroge-
nolysis (10% Pd/C) produced primary alcohol 14. Desul-
fonation of compound 14 with dissolved sodium in liqu i d am-
monia produced symmetric glutarimide. Reduction of the
symmetric glutarimide with lithium aluminum hydride pro-
duced hydroxy-amine 15. Alcohol 15 treated with triphenyl-
phosphine and carbon tetrabromide gave a bromide. The
compound 5 was produced in 22% overall yield. Bromide 5 is
the intermediate for the synthesis of tirofiban (2).5a-b,10d-e
1) Na(Hg), MeOH (78%)
2) CAN, MeCN/H2O
1) NaH, ClCO2Me
O
N
N
Cl
2) LAH, THF
(two steps 72%)
3) NaH,
OH
Ph
(two steps 55%)
4-F-C6H4
4-F-C6H4
17
6
fonation and hydrogenation. O-Enolate ion of compound 9
was generated in situ by treating with sodium hexamethyl-
disilazane and trapped with N-phenyltrifluoromethanesul-
fonimide to give vinyl triflate. In the next step, the vinyl tri-
flate was hydrogenated to yield piperidione 16. Without fur-
ther purification, crude compound 16 was desulfonated with
sodium amalgam to produce N-PMB piperidione. This is a
new methodology to prepare piperidione from glutarimide.
In another method, compound 16 was desulfonated with dis-
solved sodium in ammonia, but the p-fluoro group was also
reduced in the process.
For formation of piperidine 6, a key intermediate to-
ward paroxetine (3),11r we changed the N-protected group
from p-methoxybenzyl to -methylbenzyl group. N-PMB
piperidione was treated with ceric ammonium nitrate (CAN)
to produce deN-PMB piperidione. Acylation at -carbon of
piperidione 17 was affected by treatment with sodium hy-
Scheme III Synthesis of piperidine ring of tirofiban (2)
Bn
N
Bn
N
1
dride and methyl chloroformate. The H NMR spectra of
O
O
O
O
EtO
O
H2, Pd/C, EA
(95%)
NaH, THF
(59%)
trans-3,4-disubstituted piperidione showed excellent diaster-
eoselectivity. Reduction of 3,4-disubstituted piperidione
with lithium aluminum hydride provided piperidine 6 in 90%
yield. Piperidine 6 is transformed into paroxetine in three
steps based on the literature.11r
+
10a
OH
OBn
TolO2S
TolO2S
OBn
Bn
N
Bn
8
14
11b
N
1) Na, NH3(l)
CBr4, PPh3
(68%)
Br
OH
2) LAH, THF
(two steps 58%)
15
5
CONCLUSION
Synthesis of piperidine ring on paroxetine (3)
In summary, we developed a new strategy to synthesize
a 4-substituted piperidine ring using the formal [3+3]
cycloaddition reaction as the key protocol. This method pro-
vides a convenient formal synthesis of elarofiban, RWJ-
50042, tirofiban and paroxetine. We are currently studying
the scope of this process as well as additional applications of
the methodology to the synthesis of other unusual imido-
amino acids.
We chose compound 6 as the targ e t structure towards
the synthesis of paroxetine (3a).12r Because acetamide 10c
did not react with , -unsaturated ethyl esters 11c, we chose
the alternative acetamide 10b. Coupling of 10b with ethyl es-
ter 11a gave the glutarimide 9 (Scheme IV). The transforma-
tion from glutarimide 9 to piperidione 16 is described be-
low.14 The transformation included prot o n abstraction, O-sul-

1082 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
Chang et al.
EXPERIMENT SECTION
For , -unsaturated ethyl esters 11c
A solution of 4-fluorobenzaldehyde (3.0 mmol) in
methylene chloride (10 mL) was added to a rapidly stirred so-
lution of Ph3P=CHCO2Et (3.1 mmol) in methylene chloride
(20 mL), then stirred at room temperature for 2 h. The result-
ing mixture was concentrated und e r reduced pressure. Water
(20 mL) was added to the residue and extracted with ethyl ac-
etate (3 50 mL). The combined organic layers were washed
with brine (2 20 mL), dried over anhydrous magnesium sul-
fate, filtered and evaporated. Evaporation of the solvent fol-
lowed by purification of the crude product by colu m n chro-
matography on silica gel with hexane/ethyl acetate (20/1~
15/1) produced , -unsaturated ethyl esters 11c in 81%
yield.
General
Tetrahydrofuran was distilled prior to use from a deep-
blue solution of sodium-benzophenone ketyl. All other re-
agents and solvents were obtained from commercial sources
and used without further purification. Reactions were rou-
tinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Organic layers were dried with anhydrous
magnesium sulfate before concentration in vacuo. Crude
products were purified by colu m n chromatography on silica
gel. All reported temperatures are uncorrected.
Preparation of , -unsaturated ethyl esters 11a~11c
For , -unsaturated ethyl esters 11a and 11b
N-Benzyl-2-p-toluenesulfonylacetamide (10a)
A solution of 1,3-propandiol or 1,4-butandiol (50.0
mmol) in tetrahydrofuran (100 mL) was added to a rapidly
stirred suspension of sodium hydride (60%, 40.0 mmol) in
tetrahydrofuran (500 mL). After the reaction mixture was
stirred at room temperature for 1 h, a solution of benzyl bro-
mide (40.0 mmol) in tetrahydrofuran (200 mL) was added for
2 h. The resulting mixture was stirred at room temperature for
20 h, quenched with saturated ammonium chloride solution
(10 mL), and concentrated under reduced pressure. The crude
product was extracted with ethyl acetate (3 200 mL), and
the combined organic laye r s were washed with brine (2 100
mL), dried over anhydrous magnesium sulfate, filtered and
evaporated. The crude products in methylene chloride (100
mL) were added to a mixture of pyridinium chlorochromate
(40.0 mmol) and Celite (30 g) in methylene chloride (150
mL). After being stirred at room temperature for 4 h, the mix-
ture was filtered through a short silica gel column. The fil-
trate was dried with magnesium sulfate, filtered and added to
a rapidly stirred solution of Ph3P=CHCO2Et (40 mmol) in
methylene chloride (200 mL). After the reaction mixture was
stirred at room temperature for 2 h, the resulting mixture was
concentrated und e r reduced pressure. Water (100 mL) was
added to the residue and extracted with ethyl acetate (3 150
mL). The combined organic layers were washed with brine (2
100 mL), dried over anhydrous magnesium sulfate, filtered
and evaporated. Evaporation of the solvent followed purifi-
cation of the crude product by column chromatography on
silica gel with hexane/ethyl acetate (20/1~15/1) afforded var-
ious , -unsaturated ethyl esters 11a or 11b. Diol was con-
verted to , -unsaturated ethyl esters 11a or 11b in three
steps of monobenzylation, oxidation and olefination. The to-
tal yield was 44% from 1,3-propandiol and 50% from 1,4-
butandiol.
Chloroacetyl chloride (5.99 g, 53.0 mmol) in tetrah y -
drofuran (40 mL) was added to a solution of benzylamine
(5.35 g, 50.0 mmol) and triethylamine (5.57 g, 55.0 mmol) in
tetrahydrofuran (100 mL) in an ice bath for 1 h, then stirred at
room temperature for 4 h. The mixture was concentrated un-
der reduced pressure. Water (30 mL) was added to the crude
product and extracted with ethyl acetate (3 100 mL). The
combined organic layers were washed with brine (2 50
mL), dried over anhydrous magnesium sulfate, filtered and
evaporated. Without purification, the crude product with
p-toluenesulfinic acid sodium salt (TolSO2Na-2H2O, 16.05 g,
75.0 mmol) was refluxed in dioxane (150 mL) and water (150
mL) for 10 h. The mixture was concentrated under reduced
pressure and the residue was extracted with ethyl acetate (3
150 mL). The combined organic layers were washed with
brine (2 50 mL), dried over anhydrous magnesium sulfate,
filtered and evaporated. Recrystallization on hexane (150
mL) and ethyl acetate (100 mL) yielded 12.88 g (85%, two
steps) of 10a as a solid: mp 157-159 C; IR (CHCl3) 2361,
1664, 1528, 1290, 1147 cm-1; ESI-MS: C16H18NO3S m/z (%)
= 91 (100), 154 (65), 304 (M++1, 85); HRMS (ESI, M++1)
1
calcd for C16H18NO3S 304.1008, found 304.1009; H NMR
(400 MHz, CDCl3) 7.65 (d, J = 8.2 Hz, 2H), 7.33-7.24 (m,
7H), 7.06 (br s, 1H), 4.42 (d, J = 5.9 Hz, 2H), 3.99 (s, 2H),
2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): 160.64, 145.58,
137.35, 135.12, 130.04, 128.74, 128.16 (4 ), 127.97 (2 ),
127.70, 62.01, 44.02, 21.70; Anal. Calcd for C16H17NO3S C,
63.34; H, 5.65. Found C, 63.14; H, 5.44.
N-p-Methoxybenzyl-2-p-toluenesulfonylacetamide (10b)
Chloroacetyl chloride (1.2 g, 10.6 mmol) in tetrahydro-
furan (20 mL) was added to a solution of p-methoxybenzyl-

Synthetic Study of 4-Substituted Piperidine Ring in Elarofiban
J. Chin. Chem. Soc., Vol. 49, No. 6, 2002 1083
amine (1.37 g, 10.0 mmol) and triethylamine (1.06 g, 10.5
mmol) in tetrahydrofuran (30 mL) in an ice bath for 30 min,
then stirred at room temperature for 4 h. The mixture was
concentrated under reduced pressure. Water (30 mL) was
added to the crude product and extracted with ethyl acetate (3
50 mL). The combined organic laye r s were washed with
brine (2 20 mL), dried over anhydrous magnesium sulfate,
filtered and evaporated. Without purification, the crude prod-
uct with p-toluenesulfinic acid sodium salt (3.2 g, 16.5
mmol) was refluxed in dioxane (70 mL) and water (70 mL)
for 5 h. The mixture was concentrated under reduced pres-
sure, and the residue was extracted with ethyl acetate (3 100
mL). The combined organic layers were washed with brine
(2 20 mL), dried over anhydrous magnesium sulfate, fil-
tered and evaporated. Recrystallization on hexane (60 mL)
and ethyl acetate (30 mL) yielded 3.0 g (90%, two steps) of
10b: IR (CHCl3) 1668, 1533, 1230, 1080 cm-1; ESI-MS:
C17H20NO4S m/z (%) = 334 (M++1, 100); HRMS (ESI, M++1)
2H), 7.37-7.23 (m, 7H), 6.95 (br s, 1H), 5.08-5.00 (m, 1H),
3.96 (dd, J = 14.2, 14.2 Hz, 2H), 2.40 (s, 3H), 1.50 (d, J = 6.9
Hz, 3H); 13C NMR (100 MHz, CDCl3): 159.78, 145.51,
142.41, 135.00, 129.96 (2 ), 128.73, 128.17 (4 ), 127.58,
126.29, 67.07, 62.13, 49.56, 21.67; Anal. Calcd for C17H19NO3S
C, 64.33; H, 6.03. Found C, 64.61; H, 5.97.
1-Benzyl-4-(3-benzyloxypropyl)-3-p-toluenesulfonyl-
piperidine-2,6-dione (7)
A solution of acetamide 10a (3.03 g, 10.0 mmol) in
tetrahydrofuran (30 mL) was added to a rapidly stirred sus-
pension of sodium hydride (880 mg, 22.0 mmol, 60%) in
tetrahydrofuran (30 mL). After the reaction mixture was
stirred at room temperature for 15 min, a solution of ethyl es-
ter 11a (2.48 g, 10.0 mmol) in tetrahydrofuran (30 mL) was
added. The resulting mixture was refluxed for 30 min,
quenched with saturated ammonium chloride solution (2 mL)
in an ice bath and the mixture was concentrated under re-
duced pressure. Water (20 mL) was added to the crude prod-
uct and extracted with ethyl acetate (3 50 mL). The com-
bined organic laye r s were washed with brine (2 20 mL),
dried over anhydrous magnesium sulfate, filtered and evapo -
rated. Purification on silica gel (hexane/ethyl acetate = 2/1)
yielded 2.73 g (54%) of 7 as a solid: mp 79-82 C; IR (CHCl3)
2938, 2860, 1727, 1680, 1382, 1148, 737 cm-1; ESI-MS:
C29H32NO5S m/z (%) = 91 (100), 181 (19), 398 (4), 506
(M++1, 18); HRMS (ESI, M++1) calcd for C29H32NO5S
1
calcd for C17H20NO4S 334.1114, found 334.1110; H NMR
(400 MHz, CDCl3) 7.65 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3
Hz, 2H), 7.21-7.18 (m, 2H), 6.93 (br s, 1H), 6.88-6.85 (m,
2H), 4.36 (d, J = 5.8 Hz, 2H), 3.98 (s, 2H), 3.81 (s, 3H), 2.43
(s, 3H); Anal. Calcd for C17H19NO4S C, 61.24; H, 5.74.
Found C, 61.40; H, 5.88.
N- -Methylbenzyl-2-p-toluenesulfonylacetamide (10c)
Chloroacetyl chloride (1.2 g, 10.6 mmol) in tetrahydro-
furan (20 mL) was added to a solution of -methylbenzyl-
amine (1.21 g, 10.0 mmol) and triethylamine (1.06 g, 10.5
mmol) in tetrahydrofuran (30 mL) in an ice bath for 30 min,
then stirred at room temperature for 4 h. The mixture was
concentrated under reduced pressure. Water (30 mL) was
added to the crude product and extracted with ethyl acetate (3
50 mL). The combined organic laye r s were washed with
brine (2 20 mL), dried over anhydrous magnesium sulfate,
filtered and evaporated. Without purification, the crude prod-
uct with p-toluenesulfinic acid sodium salt (3.2 g, 16.5 mmol)
was refluxed in dioxane (70 mL) and water (70 mL) for 8 h.
Then the mixture was concentrated under reduced pressure
and the residue was extracted with ethyl acetate (3 100 mL).
The combined organic layers were washed with brine (2 20
mL), dried over anhydrous magnesium sulfate, filtered and
evaporated. Recrystallization on hexane (40 mL) and ethyl
acetate (20 mL) yielded 2.76 g (87%, two steps) of 10c as a
solid: mp 89-93 C; IR (CHCl3) 1655, 1540, 1318, 1156,
1084 cm-1; ESI-MS: C17H20NO3S m/z (%) = 105 (47), 136
(65), 154 (100), 214 (20), 307 (25), 318 (M++1, 32); HRMS
(ESI, M++1) calcd for C17H20NO3S 318.1165, found
318.1165; 1H NMR (400 MHz, CDCl3) 7.60 (d, J = 8.1 Hz,
1
506.2002, found 506.2001; H NMR (400 MHz, CDCl3)
7.43 (d, J = 8.3 Hz, 2H), 7.35-7.23 (m, 12H), 5.06 (d, J = 14.0
Hz, 1H), 4.85 (d, J = 14.0 Hz, 1H), 4.43 (s, 2H), 3.94 (br s,
1H), 3.48 (dd, J = 6.0, 18.1 Hz, 1H), 3.46-3.37 (m, 2H),
3.02-2.98 (m, 1H), 2.70 (d, J = 18.1 Hz, 1H), 2.42 (s, 3H),
1.55-1.35 (m, 4H); 13C NMR (100 MHz, CDCl3): 170.39,
164.32, 145.68, 138.13, 136.42, 134.59, 129.81 (3 ), 128.94
(4 ), 128.63 (2 ), 128.44 (2 ), 128.35, 127.71, 127.48,
73.09, 70.75, 69.12, 43.36, 34.33, 30.99, 28.75, 26.94, 21.76;
Anal. Calcd for C29H31NO5S C, 68.89; H, 6.18. Found C,
69.16; H, 6.03.
1-Benzyl-4-(3-hydroxypropyl)-3-p-toluenesulfonyl-
piperidine-2,6-dione (12)
O-Benzyl glutarimide 7 (2.08 g, 5.0 mmol) was dis-
solved in ethyl acetate (60 mL) and 10% palladium on act i -
vated carbon as catalyst (200 mg) was added. Hydrogen was
bubbled into the mixture for 10 min, and stirred at room tem-
perature for 3 h. Filtration through a short plug of Celite and
washing with ethyl acetate (3 20 mL) resulted in the desired
crude compound 12. Purification on silica gel (hexane/ethyl
acetate = 1/2) yielded hydroxy-glutarimide 12 (1.95 g, 94%)

1084 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
Chang et al.
as a solid: mp 97-100 C; IR (CHCl3) 3390, 2941, 2868,
1727, 1679, 1383, 1148, 744 cm-1; ESI-MS: C22H26NO5S m/z
(%) = 91 (100), 137 (19), 154 (18), 260 (10), 416 (M++1, 50);
HRMS (ESI, M++1) calcd for C22H26NO5S 416.1533, found
416.1536; 1H NMR (400 MHz, CDCl3): 7.45 (d, J = 8.3 Hz,
2H), 7.37-7.15 (m, 7H), 5.06 (d, J = 14.0 Hz, 1H), 4.85 (d, J =
14.0 Hz, 1H), 3.94 (br s, 1H), 3.67 (t, J = 5.7 Hz, 2H), 3.49
(dd, J = 6.1, 18.1 Hz, 1H), 3.03-2.98 (m, 1H), 2.70 (d, J = 18.1
Hz, 1H), 2.42 (s, 3H), 1.75-1.43 (m, 5H); Anal. Calcd for
C22H25NO5S C, 63.59; H, 6.06. Found C, 63.16; H, 6.21.
and extracted with diethyl ether (4 10 mL). The combined
organic layers were dried by magnesium sulfate, filtered and
evaporated. Without further purification, the anhydrous etha -
nol (20 mL) was added to crude acid (200 mg) and trifluoro-
acetic acid (1 mL) at room temperature for 5 h. The reaction
mixture was evaporated and purified on silica gel (hexane/
ethyl acetate = 1/1) yielded 184 mg (68%, two steps) of 4 as a
viscous oil: IR (CHCl3) 2918, 2799, 2759, 1734, 1449, 1369,
1263, 1179 cm-1; ESI-MS: C17H26NO2 m/z (%) = 91 (100),
276 (M++1, 91); HRMS (ESI, M++1) calcd for C17H26NO2
1
276.1965, found 276.1969; H NMR (400 MHz, CDCl3)
3-(1-Benzyl-4-piperidinyl)propanol (13)
7.34-7.20 (m, 5H), 4.09 (q, J = 7.2 Hz, 2H), 3.48 (s, 2H), 2.86
(br d, J = 11.3 Hz, 2H), 2.28 (t, J = 7.7 Hz, 2H), 1.92 (br t, J =
10.7 Hz, 2H), 1.64-1.53 (m, 4H), 1.31-1.21 (m, 6H); 13C
NMR (100 MHz, CDCl3) 173.86, 138.15, 129.27 (2 ),
128.14 (2 ), 126.98, 63.36, 60.22, 53.67 (2 ), 35.25, 31.88
(2 ), 31.81, 31.46, 14.23; Anal. Calcd for C17H25NO2 C,
74.14; H, 9.15. Found C, 74.29; H, 9.22.
Sodium (200 mg, 8.7 mmol) in small pieces was added
to a solution of compound 12 (1.25 g, 3.0 mmol) in liquid am-
monia (30 mL) at -78 C. The reaction mixture was stirred at
-78 C for 1 h and it was warmed to -30 C for 1 h. A mixture
of water (20 mL) and diethyl ether (30 mL) was poured onto
the reaction mixture and extracted with diethyl ether (3 30
mL). The combined organic layers were washed with brine (2
20 mL), dried over anhydrous magnesium sulfate, filtered
and evaporated. Without purification, a solution of symmet-
ric glutarimide (520 mg, 2.0 mmol) in tetrahydrofuran (10
mL) via syringe was added to a solution of lithium aluminum
hydride (190 mg, 5.0 mmol) in tetrahydrofuran (20 mL) in an
ice bath for 30 min. Then the mixture was refluxed for 2 h,
quenched with saturated aqueous ammonium chloride sol u -
tion (5 mL) und e r cooling, and concentrated. Water (15 mL)
was added to the residue and extracted with ethyl acetate (3
30 mL). The combined organic layers were washed with
brine (2 20 mL), dried over anhydrous magnesium sulfate,
filtered and evaporated. Purification on silica gel (hexane/
ethyl acetate = 1/2) yielded 433 mg (62%, two steps) of 13 as
a viscous oil: IR (CHCl3) 3354, 2923, 2859, 1452, 1365, 1068
cm-1; ESI-MS: C15H24NO m/z (%) = 91 (100), 234 (M++1,
40); HRMS (ESI, M++1) calcd for C15H24NO 234.1859,
found 234.1866; 1H NMR (400 MHz, CDCl3) 7.29-7.18 (m,
5H), 3.59 (t, J = 6.6 Hz, 2H), 3.48 (s, 2H), 2.87 (br d, J = 11.4
Hz, 2H), 2.31-2.26 (m, 2H), 2.01-1.90 (m, 2H), 1.65-1.50 (m,
4H), 1.29-1.21 (m, 4H); 13C NMR (100 MHz, CDCl3)
137.94, 129.39, 128.14 (3 ), 127.00, 63.39, 63.07, 53.79
(2 ), 35.51, 32.54, 31.86 (2 ), 30.00; Anal. Calcd for
C15H23NO C, 77.21; H, 9.93. Found C, 77.48; H, 9.86.
1-Benzyl-4-(3-benzyloxybutyl)-3-p-toluenesulfonyl-
piperidine-2,6-dione (8)
A solution of acetamide 10a (3.03 g, 10.0 mmol) in
tetrahydrofuran (30 mL) was added to a rapidly stirred sus-
pension of sodium hydride (880 mg, 22.0 mmol, 60%) in
tetrahydrofuran (30 mL). After the reaction mixture was
stirred at room temperature for 15 min, a solution of ethyl es-
ter 11b (2.62 g, 10.0 mmol) in tetrahydrofuran (30 mL) was
added. The resulting mixture was refluxed for 30 min,
quenched with saturated ammonium chloride solution (5 mL)
in an ice bath and the mixture was concentrated under re-
duced pressure. Water (20 mL) was added to the crude prod-
uct and extracted with ethyl acetate (3 50 mL). The com-
bined organic laye r s were washed with brine (2 20 mL),
dried over anhydrous magnesium sulfate, filtered and evapo -
rated. Purification on silica gel (hexane/ethyl acetate = 2/1)
yielded 3.06 g (59%) of 8 as a solid: mp 67-70 C; IR (CHCl3)
2938, 2860, 1728, 1682, 1383, 750 cm-1; ESI-MS: C30H34NO5S
m/z (%) = 91 (100), 181 (11), 520 (M++1, 5); HRMS (ESI,
M++1) calcd for C30H34NO5S 520.2159, found 520.2158; 1H
NMR (400 MHz, CDCl3): 7.45 (d, J = 8.3 Hz, 2H), 7.34-
7.23 (m, 12H), 5.06 (d, J = 14.0 Hz, 1H), 4.85 (d, J = 14.0 Hz,
1H), 4.44 (s, 2H), 3.90 (br s, 1H), 3.47 (dd, J = 6.1, 18.1 Hz,
1H), 3.39 (t, J = 5.9 Hz, 2H), 2.97-2.95 (m, 1H), 2.69 (d, J =
18.1 Hz, 1H), 2.42 (s, 3H), 1.55-1.35 (m, 6H); 13C NMR (100
MHz, CDCl3): 170.41, 164.32, 145.68, 138.39, 136.44,
134.58, 129.81 (3 ), 128.94, 128.66 (3 ), 128.40 (2 ),
128.35, 127.67 (2 ), 127.61, 127.50, 72.95, 70.73, 69.54,
43.32, 34.31, 33.80, 29.16, 28.80, 23.47, 21.74; Anal. Calcd
for C30H33NO5S C, 69.34; H, 6.40. Found C, 69.39; H, 6.38.
Ethyl 3-(1-benzyl-4-piperidinyl)propanoate (4)
Excess Jones reagent was added to a solution of alcohol
13 (230 mg, 1.0 mmol) in acetone (10 mL) in an ice bath. The
mixture was stirred for 10 min and treated with 2-propanol
(0.5 mL) to destroy the unreacted oxidation reagent. After the
solvent was removed, water (10 mL) was added to the residue

Synthetic Study of 4-Substituted Piperidine Ring in Elarofiban
J. Chin. Chem. Soc., Vol. 49, No. 6, 2002 1085
1-Benzyl-4-(4-hydroxybutyl)-3-p-toluenesulfonyl-
ture was refluxed for 2 h, quenched with saturated aqueous
ammonium chloride solution (5 mL) und e r cooling, and con-
centrated. Water (15 mL) was added to the residue and ex-
tracted with ethyl acetate (3 30 mL). The combined organic
layers were washed with brine (2 20 mL), dried over anh y -
drous magnesium sulfate, filtered and evaporated. Purifica-
tion on silica gel (hexane/ethyl acetate = 1/2) yielded 430 mg
(58%, two steps) of 15 as a viscous oil: IR (CHCl3) 3354,
2928, 2855, 1450, 1069 cm-1; ESI-MS: C16H26NO m/z (%) =
91 (100), 248 (M++1, 60); HRMS (ESI, M++1) calcd for
piperidine-2,6-dione (14)
O-Benzyl glutarimide 8 (2.60 g, 5.0 mmol) was dis-
solved in ethyl acetate (60 mL) and 10% palladium on act i -
vated carbon as catalyst (200 mg) was added. Then hydrogen
was bubbled into the mixture for 10 min, and stirring oc-
curred at room temperature for 3 h. Filtration through a short
plug of Celite and washing with ethyl acetate (3 20 mL) re-
sulted in the desired crude compound 14. Purification on silica
gel (hexane/ethyl acetate = 1/2) yielded hydroxy-glutarimide
2.04 g (95%) of 14 as a solid: mp 80-83 C; IR (CHCl3) 3390,
2938, 2863, 1727, 1681, 1386, 753 cm-1; ESI-MS: C23H28NO5S
m/z (%) = 91 (100), 430 (M++1, 22); HRMS (ESI, M++1)
1
C16H26NO 248.2016, found 248.2018; H NMR (400 MHz,
CDCl3): 7.30-7.19 (m, 5H), 3.60 (t, J = 6.4 Hz, 2H), 3.46 (s,
2H), 2.84 (br d, J = 11.3 Hz, 2H), 1.92-1.87 (m, 3H), 1.63-
1.48 (m, 4H), 1.37-1.21 (m, 7H); 13C NMR (100 MHz,
CDCl3): 138.48, 129.28 (2 ), 128.10 (2 ), 126.86, 63.55,
62.84, 53.95 (2 ), 36.39, 35.73, 33.00, 32.34 (2 ), 23.00;
Anal. Calcd for C16H25NO C, 77.68; H, 10.19. Found C,
77.92; H, 10.27.
1
calcd for C23H28NO5S 430.1689, found 430.1690; H NMR
(400 MHz, CDCl3): 7.45 (d, J = 8.1 Hz, 2H), 7.35-7.23 (m,
7H), 5.05 (d, J = 14.0 Hz, 1H), 4.85 (d, J = 14.0 Hz, 1H), 3.92
(br s, 1H), 3.54 (t, J = 5.3 Hz, 2H), 3.47 (dd, J = 6.0, 18.1 Hz,
1H), 3.00-2.95 (m, 1H), 2.69 (d, J = 18.1 Hz, 1H), 2.41 (s,
3H), 1.75-1.23 (m, 7H); 13C NMR (100 MHz, CDCl3):
170.47, 164.33, 145.74, 136.40, 134.50, 129.83 (2 ), 128.94
(2 ), 128.69 (2 ), 128.34 (2 ), 127.53, 70.70, 62.13, 43.34,
34.31, 33.80, 31.92, 28.80, 22.95, 21.74; Anal. Calcd for
C23H27NO5S C, 64.31; H, 6.34. Found C, 64.21; H, 6.40.
3-(1-Benzyl-4-piperidinyl)butyl bromide (5)
A solution of alcohol 15 (247 mg, 1.0 mmol) in methy l -
ene chloride (5 mL) was added to a solution of triphenyl-
phosphine (393 mg, 1.5 mmol) and carbon tetrabromide (430
mg, 1.3 mmol) in methylene chloride (60 mL). The reaction
mixture was stirred at room temperature for 4 h, quenched
with saturated aqueous ammonium chloride solution (5 mL)
and concentrated. Water (15 mL) was added to the residue
and extracted with ethyl acetate (3 30 mL). The combined
organic layers were washed with brine (2 20 mL), dried
over anhydrous magnesium sulfate, filtered and evaporated.
Purification on silica gel (hexane/ethyl acetate = 1/2) yielded
210 mg (68%) of 5 as a viscous oil: ESI-MS: C16H24BrN m/z
(%) = 91 (100), 310 (M++1, 20); 1H NMR (400 MHz, CDCl3):
7.29-7.20 (m, 5H), 3.48 (s, 2H), 3.38 (t, J = 6.7 Hz, 2H),
2.86 (br d, J = 11.2 Hz, 2H), 1.94-1.81 (m, 3H), 1.81-1.78 (m,
4H), 1.66-1.20 (m, 6H); 13C NMR (100 MHz, CDCl3):
138.38, 129.30 (2 ), 128.12 (2 ), 126.94, 63.39, 53.80 (2 ),
35.62, 35.52, 33.92, 32.95, 32.20 (2 ), 25.39.
4-(1-Benzyl-4-piperidinyl)butanol (15)
Sodium (200 mg, 8.7 mmol) in small pieces was added
to a solution of compound 14 (1.29 g, 3.0 mmol) in liquid am-
monia (30 mL) at -78 C. The reaction mixture was stirred at
-78 C for 1 h then it was warmed to -30 C for 1 h. A mixture
of water (10 mL) and diethyl ether (30 mL) was poured into
the reaction mixture and extracted with diethyl ether (3 30
mL). The combined organic layers were washed with brine (2
20 mL), dried over anhydrous magnesium sulfate, filtered
and evaporated. Purification on silica gel (hexane/ethyl ace -
tate = 1/1) yielded symmetric hydroxy-glutarimide as a vis-
cous oil (550 mg, 67%): IR (CHCl3) 3440, 2926, 2862, 1725,
1671, 1346, 1215, 1140 cm-1; ESI-MS: C16H22NO3 m/z (%) =
91 (75), 137 (67), 154 (96), 276 (M++1, 100); HRMS (ESI,
M++1) calcd for C16H22NO3 276.1600, found 276.1603; 1H
NMR (500 MHz, CDCl3): 7.34-7.20 (m, 5H), 4.92 (s, 2H),
3.59 (t, J = 6.5 Hz, 2H), 2.78 (dd, J = 4.0, 17.0 Hz, 2H), 2.30
(dd, J = 11.0, 17.5 Hz, 2H), 2.15 (br s, 1H), 2.07-2.00 (m,
1H), 1.55-1.49 (m, 2H), 1.41-1.32 (m, 4H); 13C NMR (125
MHz, CDCl3): 172.08 (2 ), 137.02, 128.51 (2 ), 128.22
(2 ), 127.27, 62.10, 42.58, 38.77 (2 ), 34.37, 32.19, 29.03,
22.46. A solution of symmetric glutarimide (550 mg, 2.0
mmol) in tetrahydrofuran (10 mL) via syringe was added to a
solution of lithium aluminum hydride (190 mg, 5.0 mmol) in
tetrahydrofuran (20 mL) in an ice bath for 30 min. The mix-
1-p-Methoxybenzyl-4-p-fluorophenyl-3-p-toluenesulfonyl-
piperidine-2,6-dione (9)
A solution of acetamide 10b (333 mg, 1.0 mmol) in
tetrahydrofuran (10 mL) was added to a rapidly stirred sus-
pension of sodium hydride (88 mg, 2.2 mmol, 60%) in
tetrahydrofuran (10 mL). After the reaction mixture was
stirred at room temperature for 15 min, a solution of ethyl es-
ter 11c (194 mg, 1.0 mmol) in tetrahydrofuran (10 mL) was
added. The resulting mixture was refluxed for 30 min,
quenched with saturated ammonium chloride solution (2 mL)

1086 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
Chang et al.
in an ice bath and the mixture was concentrated under re-
duced pressure. Water (20 mL) was added to the crude prod-
uct and extracted with ethyl acetate (3 30 mL). The com-
bined organic laye r s were washed with brine (2 10 mL),
dried over anhydrous magnesium sulfate, filtered and evapo -
rated. Purification on silica gel (hexane/ethyl acetate = 2/1)
yielded 327 mg (68%) of 9 as a solid: mp 159-162 C; IR
(CHCl3) 2950, 1722, 1674, 1512, 1322, 1147, 1084 cm-1;
ESI-MS: C26H25FNO5S m/z (%) = 121 (100), 149 (15), 326 (9),
482 (M++1, 5); HRMS (ESI, M++1) calcd for C26H25FNO5S
(M++Na+, 10); HRMS (ESI, M++1) calcd for C26H27FNO4S
1
468.1646, found 468.1649; H NMR (400 MHz, CDCl3)
7.50-6.79 (m, 12H), 4.81 (d, J = 14.2 Hz, 1/5H), 4.62 (d, J =
14.3 Hz, 4/5H), 4.52 (d, J = 14.3 Hz, 4/5H), 4.22 (d, J = 14.2
Hz, 1/5H), 3.80 (s, 3H), 3.67-3.42 (m, 4H), 2.96-2.88 (m,
1H), 2.58 (dd, J = 6.9, 17.2 Hz, 1H), 2.59 (s, 3/5H), 2.57 (s,
12/5H).
1- -Methylbenzyl-4-p-fluorophenylpiperidine-2-one (17)
6% Sodium amalgam (Na/Hg, 300 mg) was added to a
solution of compound 16 (94 mg, 0.2 mmol) and sodium
phosphate (71 mg, 0.5 mmol) in HPLC-grade methanol (5
mL). The mixture was vigorously stirred for 1 h at room tem-
perature. The residue was filtered and washed with methanol
(2 10 mL). The combined organic laye r s were concentrated
to get the crude desulfonate compound (50 mg, 78%). The
crude compound (50 mg) was dissolved in acetonitrile (3 mL)
and water (1 mL). Excess ceric ammonium nitrate reagent (6
eq, 1.5 mmol) was added in six equal aliquots into the sol u -
tion over the reaction time of 5 h. The reaction was monitored
after each addition using TLC plate at room temperature to
ensure progress of the reaction. After concentration of the so-
lution, methylene chloride (10 mL) was added to the residue.
The mixture was placed in a short colu m n (3 cm), and the
crude eluent was collected and concentrated. -Methyl-
phenyl chloride (43 mg, 0.3 mmol) in tetrahydrofuran (2 mL)
was added to a stirred suspension solution of crude lactam
(29 mg, 0.15 mmol) and sodium hydride (40 mg, 1.0 mmol,
60%) in tetrahydrofuran (5 mL) at room temperature then
stirred at room temperature for 4 h. The mixture was concen-
trated und e r reduced pressure. Water (5 mL) was added to the
crude product and extracted with ethyl acetate (3 10 mL),
and the combined organic laye r s were washed with brine (2
20 mL), dried over anhydrous magnesium sulfate, filtered
and evaporated. Purification on silica gel (hexane/ethyl ace -
tate = 2/1) yielded 26 mg (55%) of 17 as a solid: mp 160-164
C; IR (CHCl3) 2942, 1631, 1508, 1449, 1314 cm-1; ESI-MS:
C19H21FNO m/z (%) = 105 (53), 136 (40), 154 (57), 194 (22),
298 (M++1, 100); HRMS (ESI, M++1) calcd for C19H21FNO
1
482.1439, found 482.1435; H NMR (400 MHz, CDCl3)
7.55 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.23-7.22
(m, 2H), 6.90-6.79 (m, 6H), 5.01 (d, J = 13.7 Hz, 1H), 4.86 (d,
J = 13.7 Hz, 1H), 4.29 (d, J = 6.8 Hz, 1H), 4.15 (t, J = 1.7 Hz,
1H), 3.79 (s, 3H), 3.71 (dd, J = 6.9, 18.2 Hz, 1H), 2.99 (dd, J =
1.7, 18.2 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3):
170.10, 164.00, 163.33, 160.87, 159.15, 146.00, 135.33,
134.30, 130.64 (2 ), 129.96, 129.93, 129.08 (3 ), 128.39,
128.30, 116.37, 116.15, 113.62, 71.67, 55.29, 42.89, 35.11,
33.09, 21.79; Anal. Calcd for C26H24FNO5S C, 64.85; H,
5.02. Found C, 64.71; H, 4.64.
1-p-Methoxybenzyl-4-p-fluorophenyl-5-p-toluenesulfonyl-
piperidine-2-one (16)
A solution of sodium hexamethyldisilazane (NaHMDS,
1 M, 0.6 mL, 0.6 mmol) in tetrahydrofuran was added to a so-
lution of glutarimide 9 (241 mg, 0.5 mmol) in anhydrous
tetrahydrofuran (20 mL) over 5 min at -78 oC, and the mixture
was stirred for 1 h. Distilled hexamethylphosphoric triamide
(HMPA, 0.17 mL, 1.0 mmol) was added; the solution was
stirred for an additional 10 min. A solution of N-phenyltri-
fluoromethanesulfonimide (215 mg, 0.6 mmol) in anhydrous
tetrahydrofuran (5 mL) was added to the solution and the
mixture was allowed to warm to room temperature and left to
react for 10 h. Water (20 mL) was added to the reaction, and
the organic products were extracted with diethyl ether (3 30
mL), and washed with 1% aqueous sodium hydroxide (10
mL). The combined organic layers were washed with brine (2
10 mL), dried over anhydrous magnesium sulfate, filtered
and evaporated. Without purification, the crude product (200
mg) was dissolved in ethyl acetate (20 mL), and 10% pall a -
dium on activated carbon as catalyst (20 mg) was added. Hy-
drogen was bubbled into the mixture for 10 min, and stirred at
room temperature for 3 h. Filtration through a short plug of
Celite and washing with ethyl acetate (3 20 mL) resulted in
the desired crude compound 16 as a viscous oil: IR (CHCl3)
3005, 2926, 2839, 1651, 1508, 1302, 1246, 1144 cm-1; ESI-
MS: C26H27FNO4S m/z (%) = 121 (100), 468 (M++1, 12), 490
1
298.1608, found 298.1609; H NMR (400 MHz, CDCl3)
7.34-7.24 (m, 5H), 7.14-6.96 (m, 2H), 6.19-6.14 (m, 2H),
6.17 (q, J = 7.1 Hz, 1H), 3.11 (dt, J = 4.8, 13.0 Hz, 1H),
3.03-2.96 (m, 1H), 2.82-2.71 (m, 2H), 2.54 (dd, J = 10.2, 17.5
Hz, 1H), 2.02-1.95 (m, 1H), 1.86-1.77 (m, 1H), 1.49 (d, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) 168.81, 162.85,
160.41, 140.00, 128.50 (2 ), 128.00 (2 ), 127.93, 127.59,
127.41, 115.61, 115.40, 49.96, 40.36, 39.57, 37.48, 30.41,
15.14; Anal. Calcd for C19H20FNO C, 76.74; H, 6.78. Found

Synthetic Study of 4-Substituted Piperidine Ring in Elarofiban
C, 76.79; H, 6.77.
J. Chin. Chem. Soc., Vol. 49, No. 6, 2002 1087
11.0 Hz, 1H), 2.93-2.90 (m, 1H), 2.24 (td, J = 4.4, 11.3 Hz,
1H), 2.13-2.04 (m, 1H), 1.96-1.90 (m, 2H), 1.88-1.62 (m,
3H), 1.45 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
144.52, 140.32, 128.61 (2 ), 128.20 (2 ), 127.86 (2 ),
127.51 (2 ), 126.99, 126.46, 65.10, 64.35, 54.67, 50.91,
45.35, 44.33, 34.42, 19.50; Anal. Calcd for C20H24FNO C,
76.65; H, 7.72. Found C, 76.48; H, 7.66.
1- -Methylbenzyl-3-hydroxymethyl-4-p-fluorophenyl-
piperidine (6)
A solution of lactam 17 (24 mg, 0.08 mmol) in tetra-
hydrofuran (3 mL) was added to a rapidly stirred suspension
of sodium hydride (10 mg, 0.24 mmol, 60%) in tetrahydro-
furan (4 mL). After the reaction mixture was stirred at room
temperature for 15 min, a solution of methyl chloroformate
(15 mg, 0.16 mmol) in tetrahydrofuran (3 mL) was added.
The resulting mixture was refluxed for 4 h, quenched with
saturated ammonium chloride solution (2 mL) in an ice bath,
and the mixture was concentrated und e r reduced pressure.
Water (5 mL) was added to the crude product and extracted
with ethyl acetate (3 10 mL). The combined organic laye r s
were washed with brine (2 5 mL), dried over anhydrous
magnesium sulfate, filtered and evaporated. Purification on
silica gel (hexane/ethyl acetate = 1/1) yielded 26 mg (90%) of
3-methoxycarbonyl piperidinone as a solid: mp 77-80 C; IR
(CHCl3) 2973, 2950, 1738, 1635, 1512, 1432, 1330, 1222,
1159 cm-1; ESI-MS: C21H23FNO3 m/z (%) = 105 (100), 220
(12), 252 (20), 356 (M++1, 83); HRMS (ESI, M++1) calcd for
C21H23FNO3 356.1663, found 356.1667; 1H NMR (400 MHz,
CDCl3) 7.37-7.24 (m, 5H), 7.14-7.09 (m, 2H), 7.00-6.95
(m, 2H), 6.11 (q, J = 7.0 Hz, 1H), 3.65 (s, 3H), 3.59 (d, J =
10.2 Hz, 1H), 3.33 (td, J = 3.6, 10.8 Hz, 1H), 3.11 (dt, J = 4.7,
12.6 Hz, 1H), 2.85-2.79 (m, 1H), 2.02-1.83 (m, 2H), 1.51 (d,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) 170.67,
165.40, 160.69, 139.43, 137.42, 128.65 (2 ), 128.60 (2 ),
128.32, 128.24, 127.74, 115.82, 115.61, 56.60, 52.37, 50.43,
41.37, 40.52, 29.44, 15.09; Anal. Calcd for C21H22FNO3 C,
70.97; H, 6.24. Found C, 76.96; H, 6.19. A solution of lactam
(26 mg, 0.07 mmol) in tetrahydrofuran (5 mL) via syringe
was added to a stirred solution of lithium aluminum hydride
(76 mg, 2.0 mmol) in tetrahydrofuran (5 mL) in an ice bath.
The mixture was refluxed for 6 h, quenched with saturated
aqueous ammonium chloride solution (2 mL) und e r cooling,
and concentrated. The residue was diluted with water (4 mL)
and extracted with ethyl acetate (3 10 mL). The combined
organic laye r s were washed with brine (2 5 mL), dried over
anhydrous magnesium sulfate, filtered and evaporated. Pur i -
fication on silica gel (hexane/ethyl acetate = 1/2) yielded 17.5
mg (80%) of 6 as a solid: mp 130-132 C; IR (CHCl3) 3362,
2926, 2799, 1492, 1448, 1068, 1012 cm-1; ESI-MS: C20H22FN
m/z (%) = 105 (100), 218 (12), 280 (45), 296 (M++1-H2O,
50); HRMS (ESI, M++1-H2O) calcd for C20H22FN 296.1816,
ACKNOWLEDGMENT
The authors would like to thank the National Science
Council of the Republic of China for financial support.
Received May 8, 2002.
Key Words
Piperidine; Glutarimide; Elarofiban; RWJ-50042;
Tirofiban; Paroxetine; Femoxetine.
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