Stereoselective Synthesis of Diltiazem via Dynamic Kinetic Resolution

Article abstract of DOI:10.1055/s-2003-42397

An efficient synthesis of diltiazem has been developed using dynamic kinetic resolution (DKR) as a key step. The methyl (2S,3S)-2-chloro-3-hydroxy-3- (4-methoxyphenyl)propionate was synthesized from a racemic mixture of α-chloro-β-keto ester, with high anti diastereoselectivity (92%) and enantioselectivity (95%), based on an asymmetric hydrogenation reaction with a chiral ruthenium(II) catalyst, simply prepared by mixing Ru(cod)(2-methylallyl) ₂ with the atropisomeric ligand (S)-MeO-BIPHEP. By treatment of this α-chloro-β-hydroxy ester with a base, the corresponding trans methyl glycidate, a key intermediate of diltiazem, was easily obtained.

Full text of DOI:10.1055/s-2003-42397

PAPER
2405
Stereoselective Synthesis of Diltiazem via Dynamic Kinetic Resolution
Stereoselective
S
é
l
Diltiaz
i
em via
n
Dynamic
K
i
e
netic Resolution Mordant, Cristina Caño de Andrade,1 Ridha Touati,2 Virginie Ratovelomanana-Vidal,*
Bechir Ben Hassine,2 Jean-Pierre Genêt*
Laboratoire de Synthèse Sélective Organique et Produits Naturels, UMR 7573 C.N.R.S., Ecole Nationale Supérieure de Chimie de Paris,
11, rue P. et M. Curie, 75231 Paris Cedex 05, France
Fax +33(1)44071062; E-mail: genet@ext.jussieu.fr
Received 3 July 2003
OMe
Abstract: An efficient synthesis of diltiazem has been developed
using dynamic kinetic resolution (DKR) as a key step. The methyl
MeO
(2S,3S)-2-chloro-3-hydroxy-3-(4-methoxyphenyl)propionate was
synthesized from a racemic mixture of -chloro- -keto ester, with
high anti diastereoselectivity (92%) and enantioselectivity (95%),
based on an asymmetric hydrogenation reaction with a chiral ruthe-
nium(II) catalyst, simply prepared by mixing Ru(cod)(2-methylal-
lyl)2 with the atropisomeric ligand (S)-MeO-BIPHEP. By treatment
of this -chloro- -hydroxy ester with a base, the corresponding
trans methyl glycidate, a key intermediate of diltiazem, was easily
obtained.
S
N
O
OAc
CO2Me
(2R,3S)
(-)-2
O
Diltiazem (1)
NMe2
Figure 1
Key words: Diltiazem, drugs, kinetic resolution, asymmetric catal-
ysis, hydrogenations, ruthenium
known to give preferentially one of the four possible dia-
stereoisomers via dynamic kinetic resolution (DKR),12
under optimized conditions. The selectivity of this DKR
has already been studied by Noyori and our group and de-
pends on the nature of the group borne at the -position
and on the reaction conditions. Whereas the hydrogena-
tion of -acetamido- -keto esters13 gave the syn adducts,
cyclic -alkyl- -keto esters14,12a,b or -amino- -methyl- -
keto esters derived from (S)-proline15 were reduced to the
corresponding anti -substituted -hydroxy esters. Some
preliminary studies on the asymmetric hydrogenation of
-chloro- -keto esters16a indicated that the anti diastereo-
isomer could also be obtained.16b
Diltiazem (1), a typical calcium channel blocker, is com-
monly used for the treatment of angina pectoris and hy-
pertension.3 Only the (+)-(2S,3S)-isomer among the four
possible stereoisomers presents this potent coronary va-
sodilating activity, therefore diltiazem has been devel-
oped and marketed as a single stereoisomer. For its
synthesis, many pathways had been investigated and the
trans methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (–)-
2 was recognized as a practical and efficient intermediate
(Figure 1). A large number of formal synthesis of (–)-2
have been reported using various strategies including
asymmetric epoxidations,4 aldol5 or Darzens6 reactions,
asymmetric reductions,7 preferential crystallizations8 or
enzymatic approaches.9 At the industrial scale, (–)-2 has
been prepared by enzymatic resolution of the racemic gly-
cidate ( )-2 based on a lipase-catalyzed enantioselective
hydrolysis;9c however the maximum yield cannot exceed
50%. In spite of all these studies, there is still a need for
developing an efficient process for the synthesis of enan-
tiopure (–)-2 in terms of yield, stereoselectivity and
amount of chiral material at stake in the key step.
Therefore, the retrosynthetic plan (Scheme 1) we chose
for diltiazem (1) was designed as follows: diltiazem (1)
would be synthesized from the trans methyl glycidate (–)-
2, which would result from the cyclization of the chloro-
hydroxy ester 3. The anti (2S,3S)- -chloro- -hydroxy es-
ter 3 would be preferentially formed by hydrogenation of
the corresponding racemic -chloro- -keto ester 4 using
Ru(II) catalyst in association with the atropisomeric (S)-
MeO-BIPHEP as a ligand.17
Synthesis of the substrate 4 was achieved in two steps and
81% yield as depicted in Scheme 2. The -keto ester 5
In our continuous work on ruthenium-catalyzed asymmet-
ric hydrogenation,10 and its applications to the synthesis
of biologically and industrially relevant molecules,11 we
report in this paper an asymmetric synthesis of diltiazem
(1) based on the dynamic kinetic resolution of a racemic
-chloro- -keto ester. The asymmetric hydrogenation of
-substituted -keto ester bearing a configurationally la-
bile stereogenic center with chiral Ru(II) catalysts is
MeO
O
Diltiazem (1)
CO2Me
2 (2R,3S)
OH
O
O
O
OMe
OMe
Cl
Cl
MeO
MeO
SYNTHESIS 2003, No. 15, pp 2405–2409
Advanced online publication: 29.09.2003
DOI: 10.1055/s-2003-42397; Art ID: Z09403SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
3
3 (2S,3S)
Scheme 1 Retrosynthetic approach of diltiazem (1)
4

2406
C. Mordant et al.
PAPER
Table 1 Screening of Solvents for the Hydrogenation of 4a
was readily prepared from commercially available 4-
methoxyacetophenone in the presence of sodium hydride
and dimethyl carbonate. After purification, treatment of 5
with sulfuryl chloride afforded 4 in 90% yield.
Solvent
Conv (%)b de (%)c
ee (syn)c
(2R,3S)
ee (anti)c
(2S,3S)
One preliminary example16b to hydrogenate 4, using (S)-
BINAP as a chiral ligand, indicated that this substrate re-
quired rather high pressures of hydrogen (80 bar) and high
temperatures (80 °C) to obtain good conversions in
dichloromethane. Moreover, the in situ generated chiral
catalyst18 developed in our group ‘Ru[(S)-MeO-BI-
PHEP]Br2’ turned out to be inadequate for the hydrogena-
tion of this -chloro- -keto ester since a large amount of
degradation products was isolated, such as the -keto ester
5. We found that by simply mixing Ru(cod)(2-methylal-
lyl)2 and (S)-MeO-BIPHEP, the hydrogenation of 4 pro-
ceeded smoothly.
Toluene
60
73 syn
42 syn
40 syn
88 syn
85 anti
88 anti
98
99
99
9
74
t-Bu-OMe 40
71
EtOAc
MeOH
THFd
45
80
95
80
79
96
98
38
65
CH2Cl2
95
a All reactions were carried out at 80 °C under 80 bar (H2) and for 16
h with 1 mol% of catalyst.
b Conversion (Conv) was determined by 1H NMR.
c De and ee were determined by HPLC analysis.
d Reaction carried out for 60 h.
O
O
O
NaH, (CH3O)2CO
O
ity and enantioselectivity, since the first attempts carried
out in THF gave rather moderate ee.
toluene, reflux
15 min
MeO
MeO
5
Next, we tried to optimize this hydrogenation reaction in
dichloromethane, at the scale of several grams. To prevent
the formation of degradation products and slow down the
reaction rate in order to favor a better discrimination of the
catalyst, we chose to drop the hydrogen pressure to 60 bar.
The diastereoselectivity rose then from moderate levels
(72%) to very good ones (> 90%). It appeared also impor-
tant to conduct the reaction at low concentration (c 0.5
mol/L) to keep a good anti diastereoselectivity. Eventual-
O
O
90% yield
SO2Cl2
O
Cl
MeO
CH2Cl2, reflux
2h
4
90% yield
Scheme 2 Synthesis of the hydrogenation substrate 4
First, we decided to investigate the effect of the solvent on ly, with 0.5 mol% of catalyst (in order to decrease the re-
the reaction. A syn diastereoselectivity was observed for action rate) and a controlled reaction time, we found a
almost all the solvents we considered, except when the hy- compromise between stereoselectivity, conversion and
drogenation was carried out in THF or dichloromethane yield (Table 2). Several grams of anti (2S,3S)- -chloro- -
(Table 1).
hydroxy ester 3 were then prepared by ruthenium-cata-
lyzed hydrogenation of racemic 4 via DKR with excellent
diastereoselectivity (92% which could be raised up to
98% by purification with MPLC, cyclohexane–EtOAc,
9:1) and enantioselectivity (95%).
However the syn diastereoselectivity observed was poor,
except in methanol; but in that case, the enantioselectivity
was surprisingly below 10%. Dichloromethane turned out
to be the most appropriate solvent giving access to the -
chloro- -hydroxy ester 3 with high anti diastereoselectiv-
Table 2 Optimization of the Asymmetric Hydrogenation of 4 in Dichloromethane
S/C
P (H2)
Temp (°C)
Time (h)
Conv (%)b
(Yield, %)
de (%)c
anti
ee (%)c
(2S,3S)
100a
100
200
200
80
60
60
60
80
80
80
80
25
21
21
26
90 (63)
75 (43)
55 (51)
68 (55)e
71
95
92
92
93
94
95
95
a c 0.7 mol/L, otherwise c 0.5 mol/L.
b Conversion was determined by 1H NMR.
c De and ee were determined by HPLC analysis.
d Reactions were all conducted on multigram-scale (1 to 5 grams).
e 32% of the racemic starting material was recovered and reloaded in the Ru-promoted hydrogenation reaction.
Synthesis 2003, No. 15, 2405–2409 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Diltiazem via Dynamic Kinetic Resolution
2407
The trans methyl glycidate (–)-2 was easily obtained by In summary, we have reported a practical total synthesis
treatment of 3 with DBU (1,8-diazabicyclo[5,4,0]undec- of diltiazem in 7 steps with an overall yield of 25% from
7-ene) in 98% yield. The trans–cis ratio of (–)-2 was de- commercially 4-methoxyacetophenone. This convenient
termined by HPLC analysis (Chiralcel OD-H; hexane–2- synthetic procedure involved the ruthenium-promoted hy-
propanol, 98:2, 0.5 mL/min; trans–cis >99.5:0.5, ee 2R,3S drogenation reaction of a -chloro- -keto ester into an
95%) (Scheme 3).
anti -chloro- -hydroxy ester via dynamic kinetic resolu-
tion. High levels of enantio- and diastereoselectivity were
obtained due to the excellent discrimination of the catalyt-
ic ruthenium(II) system, simply formed by mixing
Ru(cod)(2-methylallyl)2 and (S)-MeO-BIPHEP. This re-
action is easy to perform on large scale with high sub-
strate/catalyst ratio and represents thus a highly
convenient synthesis of diltiazem.
Ru(cod)(2-methylallyl)2
O
O
+ (S)-MeO-BIPHEP
OH
O
S/C 200
OMe
OMe
Cl
Cl
MeO
MeO
H2, CH2Cl2
3
4
60b, 80° C, 26h
d.e. anti 92%
e.e. 97.5:2.5
(2S,3S):(2R,3R)
MeO
CH2Cl2 and toluene were distilled from calcium hydride. Other sol-
vents were used without any purification. Chemical shifts ( ) are re-
ported in ppm downfield relative to internal TMS. Coupling
constants (J) are reported in Hz and refer to apparent peak multiplic-
ities (recorded as s, singlet; d, doublet; t, triplet; q, quadruplet; m,
multiplet; and br, broad). All reactions were carried out under an at-
mosphere of argon unless otherwise noted.
DBU
CH2Cl2, 4h
O
CO2Me
trans:cis > 99.5:0.5
e.e. 95% (2R,3S)
2
Scheme 3 Synthesis of trans methyl (2R,3S)-3-(4-methoxyphe-
nyl)glycidate (2) via DKR of racemic 4
Methyl 3-(4-Methoxyphenyl)-3-oxopropionate (5)
In a three-necked flask equipped with an argon inlet and a condens-
er were placed sodium hydride (165 mmol, 2.5 equiv, 6.41 g) (60%
in oil, washed twice with anhyd hexane before use), dimethyl car-
bonate (165 mmol, 2.5 equiv, 13.8 mL) and anhyd toluene (20 mL).
The mixture was stirred at reflux and a solution of 4-methoxyace-
tophenone (66 mmol, 9.9 g) in anhyd toluene (30 mL) was added
dropwise. After 15 min at reflux, the reaction was cooled down and
a solution of HOAc (5 mL) in H2O (20 mL) was added. The organic
layer was separated and the aq layer was extracted with Et2O (2 ×).
The combined organic layers were washed with sat. aq K2CO3,
dried (MgSO4) and concentrated under reduced pressure to give a
The synthesis of diltiazem (1) was achieved in three sub-
sequent steps according to known procedures
(Scheme 4).8b,6a First, ring-opening of 2 with 2-amino-
thiophenol and in situ condensation on the methyl ester af-
forded the benzothiazepinone 6 in 66% yield, whose
characteristics were consistent with literature data {1H
NMR, [ ]D20 +100 (c 0.5 DMF) compared to [ ]D20 +109
(c 0.5 DMF)8b}. Then, alkylation of the amine function
with 2-(dimethylamino)ethyl chloride hydrochloride led
to the N-alkylbenzothiazepinone 7 in 89% isolated yield. yellow oil. The residue was purified by silica gel column chroma-
tography (cyclohexane–EtOAc, 8:2) to give the -keto ester 5 (12.3
g, 90% yield).
Finally, diltiazem (1) was isolated as a white solid after
acetylation of the alcohol function in 90% yield. The spec-
Pale yellow oil; mp <50 °C.
troscopic properties of (1) were similar to those described
earlier.6a
1H NMR (CDCl3, 200 MHz): = 7.93 (d, 2 H, J = 8.9 Hz, Ho), 6.94
(d, 2 H, J = 8.9 Hz, Hm), 3.95 (s, 2 H, CH2), 3.86 (s, 3 H, PhOCH3),
3.74 (s, 3 H, CO2CH3).
13C NMR (CDCl3, 50 MHz):
= 190.7 (CO ketone), 168.1
(CO2CH3), 163.9 (Cp-OMe), 130.8 (Co), 128.9 (CArCO), 113.9 (Cm),
55.4 (PhOCH3), 52.3 (CO2CH3), 45.4 (CH2).
MS (DCI, NH3): m/z = 226 (6%, [M + NH4]+), 209 (100%, [M +
H]+).
HRMS (DCI+): m/z calcd for C11H13O4: 209.0814; found: 209.0816.
Methyl 2-Chloro-3-(4-methoxyphenyl)-3-oxopropionate (4)
A mixture of 5 (59 mmol, 12.3 g), anhyd CH2Cl2 (120 mL) and sul-
furyl chloride (59 mmol, 1 equiv, 4.8 mL) was stirred for 15 min at
r.t. then heated at reflux until the formation of gas stopped. The re-
action was then cooled down and the solvent evaporated. The resi-
dual oil was purified by silica gel column chromatography
(cyclohexane–EtOAc, 8:2) give the -chloro- -keto ester 4.
Yield: 12.9 g (90% yield); white solid; mp < 50 °C.
1H NMR (CDCl3, 200 MHz): = 7.99 (dd, 2 H, J = 2.0, 8.9 Hz, Ho),
6.95 (dd, 2 H, J = 2.0, 8.9 Hz, Hm), 5.60 (s, 1 H, CHCl), 3.89 (s, 3
H, PhOCH3), 3.82 (s, 3 H, CO2CH3).
Scheme 4 Synthesis of diltiazem (1) from pure trans methyl glyci-
date (–)-2
13C NMR (CDCl3, 50 MHz):
= 186.5 (CO ketone), 165.9
(CO2CH3), 164.5 (Cp-OMe), 131.7 (Co), 126.0 (CArCO), 114.1 (Cm),
57.5 (CHCl), 55.5 (PhOCH3), 53.6 (CO2CH3).
Synthesis 2003, No. 15, 2405–2409 © Thieme Stuttgart · New York

2408
C. Mordant et al.
PAPER
MS (DCI, NH3): m/z = 260 (100%, [M + NH4]+), 243 (17%, [M +
13C NMR (CDCl3, 50 MHz): = 168.6 (CO2CH3), 160.1 (Cp-OMe),
127.1 (Co), 126.6 (CAr-CHO), 113.9 (Cm), 57.7 and 56.3 (CHO),
55.1 (PhOCH3), 52.3 (CO2CH3).
H]+).
HRMS (DCI+): m/z calcd for C11H12O4Cl: 243.0424; found:
243.0427.
MS (DCI, NH3): m/z = 226 (100%, [M + NH4]+), 209 (65%, [M +
H]+).
Methyl (2S,3S)-2-Chloro-3-hydroxy-3-(4-methoxyphenyl)pro-
pionate (3)
HRMS (DCI+): m/z calcd for C11H13O4: 209.0814; found: 209.0817.
In a 100-mL flask were placed Ru(cod)[ 3-(CH2)2CHCH3]2 (0.1
mmol, 31.9 mg, 0.5 mol%), (S)-MeO-BIPHEP (0.11 mmol, 64.1
mg, 0.55 mol%) and methyl 2-chloro-3-(4-methoxyphenyl)-3-oxo-
propionate (4) (20 mmol, 4.85 g) and the vessel was purged by one
vacuum-argon cycle. Anhyd CH2Cl2 (40 mL) previously degassed
by three vacuum-argon cycles was added at r.t. The flask was then
placed under argon in a 250-mL stainless steel autoclave. The argon
atmosphere was replaced with hydrogen by three cycles of pressur-
izing and the pressure was adjusted to 60 bar. The autoclave was
heated at 80 °C and stirring was maintained for 26 h. After cooling,
cis-(+)-2,3-Dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-ben-
zothiazepin-4(5H)-one (6)
A solution of trans methyl glycidate 2 (9 mmol, 1.87 g) in chlo-
robenzene (45 mL) was heated at reflux. 2-Aminothiophenol (9.9
mmol, 1.1 equiv, 1.07 mL) and a solution of FeCl3·6 H2O (9.10–4
mmol, 10–4 equiv, 0.24 mg) in MeOH (90 L) were added and the
resulting mixture stirred at reflux for 30 min. Methanesulfonic acid
(0.18 mmol, 0.02 equiv, 11.7 L) was then added and the reflux
maintained for an additional 2 h. After cooling down the reaction,
the solvent was concentrated under reduced pressure to give the
crude benzothiazepinone 6 as a yellow powder. The residue was pu-
rified by silica gel column chromatography (cyclohexane–EtOAc,
8:2) to afford cis-(+)-6.
1
the reaction mixture was concentrated under reduced pressure. H
NMR analysis revealed a conversion of 68%. The residue was puri-
fied by silica gel column chromatography (cyclohexane–EtOAc,
8:2) to afford the -chloro- -hydroxy ester 3.
Yield: 1.79 g (66%); white powder; [ ]D20 +100 (c 0.53, DMF); mp
204–206 °C.
Yield: 2.69 g (55% yield); white solid; 92% de and 95% ee; the di-
astereoisomeric and enantiomeric excess were determined by
HPLC analysis (Chiralcel OJ, hexane–2-propanol, 70:30, 1 mL/
min; detector 254 nm, 30 °C; tR 12.4 and 13.4 min for 2R,3R and
2S,3S, respectively, and tR 16.5 and 20.5 min for 2R,3S and 2S,3R,
respectively); [ ]D20 +36 (c 0.94, CHCl3); mp 83–85 °C.
1H NMR (CDCl3, 400 MHz): = 7.31 (dd, 2 H, J = 2.1, 6.7 Hz, Ho),
6.90 (dd, 2 H, J = 2.1, 6.7 Hz, Hm), 4.99 (dd, 1 H, J = 4.7, 8.0 Hz,
CHOH), 4.36 (d, 1 H, J = 8.0 Hz, CHCl), 3.81 (s, 6 H, PhOCH3,
CO2CH3), 2.87 (d, 1 H, J = 4.7 Hz, OH).
1H NMR (DMSO, 400 MHz): = 10.29 (s, 1 H, NH), 7.59 (dd, 1 H,
J = 1.3, 7.4 Hz, H10), 7.43 (dd, 1 H, J = 1.3, 7.4 Hz, H8), 7.38 (d, 2
H, J = 8.6 Hz, Ho), 7.16 (m, 2 H, H9, H7), 6.88 (d, 2 H, J = 8.6 Hz,
Hm), 5.04 (d, 1 H, J = 6.6 Hz, SCH), 4.74 (m, 1 H, OH), 4.28 (t, 1
H, J = 6.6 Hz, CHOH), 3.74 (s, 3 H, PhOCH3).
13C NMR (DMSO, 50 MHz): = 172.6 (CO), 159.2 (Cp-OMe),
142.1 (C6), 134.0 (C10), 131.1 (Co), 130.1 (C8), 128.6 (C12), 126.4
(C11), 125.7 (C9), 122.8 (C7), 113.5 (Cm), 69.7 (C3), 57.2 (C2),
55.3 (PhOCH3).
13C NMR (CDCl3, 50 MHz): = 169.3 (CO2CH3), 159.8 (Cp-OMe),
130.7 (CAr-CHOH), 128.0 (Co), 113.8 (Cm), 74.8 (CHOH), 59.0
(CHCl), 55.2 (PhOCH3), 52.9 (CO2CH3).
MS (DCI, NH3): m/z = 319 (100%, [M + NH4]+), 302 (23%, [M +
H]+).
HRMS (DCI+) m/z calcd for C16H16O3N: 302.0851; found:
302.0849.
MS (DCI, NH3): m/z 262 (100%, [M + NH4]+), 244 (37%, [M + NH4
– H2O]+), 227 (16%, [M + H – H2O]+).
HRMS (DCI+): m/z calcd for C11H17O4NCl ([M + NH4]+):
262.0846; found: 262.0838.
HRMS (DCI+): m/z calcd for C11H15O3NCl ([M + NH4 – H2O]+):
244.0740; found: 244.0748.
cis-(+)-5-[2-(Dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-
(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (7)
To a solution of benzothiazepinone 6 (5 mmol, 1.5 g) in EtOAc (15
mL) was added 2-(dimethylamino)ethyl chloride hydrochloride
(6.4 mmol, 1.28 equiv, 922 mg). Under vigorous stirring were then
added potassium carbonate (20 mmol, 4 equiv, 2.76 g) and H2O (50
L). The resulting mixture was heated at reflux for 7 h. After cool-
ing, the mixture was filtered to remove salts and the solvent was
concentrated under reduced pressure to give the crude benzothiaze-
pinone 7. The residue was purified by silica gel column chromatog-
raphy (CH2Cl2–MeOH, 98:2) to afford cis-(+)-7.
Methyl trans-(2R,3S)-3-(4-methoxyphenyl)glycidate (2)
DBU (13 mmol, 1.3 equiv, 1.96 mL) was added to a stirred solution
of -chloro- -hydroxy ester 3 (10 mmol, 2.45 g) in anhyd CH2Cl2
(40 mL). After being stirred for 4 hours at r.t., the reaction was
quenched with a buffer solution (pH 7). The organic layer was sep-
arated and the aq layer was extracted with CH2Cl2 (2 ×). The com-
bined organic layers were dried (Na2SO4) and concentrated under
reduced pressure to give the crude glycidate 2. The residue was pu-
rified by silica gel column chromatography (cyclohexane–EtOAc,
6:4) to afford (2R,3S)-2.
Yield: 1.65 g (89%); white powder; [ ]D20 +147 (c 1.0, CHCl3).
1H NMR (CDCl3, 400 MHz): = 7.70 (dd, 1 H, J = 1.4, 7.7 Hz,
H10), 7.39–7.46 (m, 4 H, Ho, H8, H9), 7.26 (m, 1 H, H7), 6.88 (dd,
2 H, J = 1.4, 8.6 Hz, Hm), 4.90 (d, 1 H, J = 7.3 Hz, SCH), 4.48 (m,
1 H, NCH2), 4.30 (br dd, 1 H, J = 7.3, 9.9 Hz, CHOH), 3.82 (s, 3 H,
PhOCH3), 3.71 (m, 1 H, NCH2), 2.85 (d, 1 H, J = 9.9 Hz, OH), 2.70
(m, 1 H, NCH2), 2.48 (m, 1 H, NCH2), 2.28 [s, 6 H, N(CH3)2].
13C NMR (CDCl3, 50 MHz): = 171.0 (CO), 159.5 (Cp-OMe),
144.7 (C6), 135.3 (C10), 131.3 (Co), 130.5 (C8), 129.7 (C12), 127.5
(C9), 126.8 (C11), 124.5 (C7), 113.6 (Cm), 69.2 (C3), 56.7 (C14),
56.5 (C2), 55.2 (PhOCH3), 47.6 (C13), 45.6 [N(CH3)2].
Yield: 1.98 g (95%); colorless amorphous crystals; 95% ee as deter-
mined by HPLC analysis (Chiralcel OD-H, hexane–2-propanol,
98:02, 0.5 mL/min; detector 254 nm, 30 °C, tR 27.3 min and 37.2
min for 2R,3S and 2S,3R, respectively); [ ]D26 –196 (c 1.0, MeOH);
mp 86–88 °C.
1H NMR (CDCl3, 400 MHz): = 7.21 (d, 2 H, J = 8.7 Hz, Ho), 6.89
(d, 2 H, J = 8.7 Hz, Hm), 4.05 (d, 1 H, J = 1.5 Hz, ArCHO), 3.82 (s,
3 H, PhOCH3), 3.81 (s, 3 H, CO2CH3), 3.51 (d, 1 H, J = 1.5 Hz,
CHCO2Me).
MS (DCI, NH3): m/z = 373 (100%, [M + H]+).
HRMS (DCI+): m/z calcd for C20H25O3N2S: 373.1586; found:
373.1584.
Synthesis 2003, No. 15, 2405–2409 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Diltiazem via Dynamic Kinetic Resolution
2409
cis-(+)-3-Acetyloxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-
hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one
(1)
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A mixture of benzothiazepinone 7 (4.45 mmol, 1.65 g), DMAP
(0.22 mmol, 0.05 equiv, 27 mg) and Ac2O (7.6 mmol, 1.7 equiv, 710
L) in CH2Cl2 (25 mL) was heated at reflux for 5 h. After cooling,
the reaction mixture was poured into iced H2O (40 mL) and brine
was added. The organic layer was separated and the aq layer was ex-
tracted with CH2Cl2 (2 ×). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give the crude
diltiazem (1). This latter was purified by silica gel column chroma-
tography (EtOAc–MeOH, 1:1) to afford pure 1.
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Yield: 1.65 g (90%); white powder; [ ]D20 +112 (c 0.56, CHCl3); mp
97–99 °C.
1H NMR (CDCl3, 400 MHz): = 7.71 (dd, 1 H, J = 1.5, 7.7 Hz,
H10), 7.51 (m, 2 H, H8, H9), 7.38 (d, 2 H, J = 8.6 Hz, Ho), 7.31 (m,
1 H, H7), 6.90 (d, 2 H, J = 8.6 Hz, Hm), 5.13 (d, 1 H, J = 7.7 Hz,
SCH), 5.02 (d, 1 H, J = 7.7 Hz, CHOAc), 4.56 (m, 1 H, NCH2), 4.27
(m, 1 H, NCH2), 3.82 (s, 3 H, PhOCH3), 3.32 (m, 1 H, NCH2), 3.15
(m, 1 H, NCH2), 2.32 [s, 6 H, N(CH3)2], 1,90 (s, 3 H, OCOCH3).
13C NMR (CDCl3, 50 MHz): = 175.5 (NCO), 169.9 (OCOMe),
159.7 (Cp-OMe), 145.3 (C6), 135.4 (C10), 131.1 (C8), 130.7 (Co),
128.4 (C12), 127.5 (C9), 126.5 (C11), 124.5 (C7), 113.7 (Cm),
71.1(C3), 55.7 (C14), 55.2 (PhOCH3), 54.4 (C2), 47.1 (C13), 44.7
[N(CH3)2], 20.5 (OCOCH3).
MS (DCI, NH3): m/z = 415 (100%, [M + H]+).
HRMS (DCI+): m/z calcd for C22H24O4N2S: 415.1692; found:
415.1690.
Acknowledgment
We thank Dr. R. Schmid (Hoffman-La-Roche) for samples of (S)-
MeO-BIPHEP = (S)-(–)-6,6 -dimethoxy-2,2 -bis(diphenylphosphi-
no)-1,1 -biphenyl. A fellowship from C.N.R.S./D.G.A. (C.M.) is
gratefully acknowledged.
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Synthesis 2003, No. 15, 2405–2409 © Thieme Stuttgart · New York