New approach to nonracemic 1-alkylamino-3-aryloxypropan-2-ols belonging to β-blockers via cyclic sulfites

Article abstract of DOI:10.1023/A:1011300921771

Nonracemic β-blockers, viz., (S)-propranolol and (S)-timolol, were prepared from (S)-glycidol in three steps consisting in the reaction with SOCl₂ followed by the reaction of the resulting (4S)-4-chloromethyl-2-oxo-1,3,2-dioxathiolanes with the corresponding phenol and the final cleavage of (4R)-aryloxymethyl sulfites under the action of amines in DMF.

Full text of DOI:10.1023/A:1011300921771

4
36
Russian Chemical Bulletin, International Edition, Vol. 50, No. 3, pp. 436—439, March, 2001
New approach to nonracemic 1-alkylamino-3-aryloxypropan-2-ols
belonging to β-blockers via cyclic sulfites
«
Z. A. Bredikhina, A. V. Pashagin, D. V. Savel´ev, and A. A. Bredikhin
A. E. Arbuzov Institute of Organic and Physical Chemistry Kazan Scientific Center of the Russian Academy of Sciences,
8
ul. Arbuzova, 420088 Kazan, Tatarstan, Russian Federation.
Fax: +7 (843 2) 75 2253. E-mail: baa@iopc.kcn.ru
Nonracemic β-blockers, viz., (S)-propranolol and (S)-timolol, were prepared from
(
S)-glycidol in three steps consisting in the reaction with SOCl followed by the reaction of the
2
resulting (4S)-4-chloromethyl-2-oxo-1,3,2-dioxathiolanes with the corresponding phenol and
the final cleavage of (4R)-aryloxymethyl sulfites under the action of amines in DMF.
Key words: cyclic sulfites, scalemic 1-amino-3-aryloxypropan-2-ols, (S)-propranolol,
(
S)-timolol, β-blockers.
Selective and nonselective β-adrenergic receptor
blockers1 (β-blockers, β-AB) belonging to the class of
Scheme 1
ArOCH2
1
-alkylamino-3-aryloxypropan-2-ols (1), such as pro-
AlkNH2
pranolol (1a), timolol (1b), betaxolol (1c), etc., are
widely used in therapy of vascular pathologies.
rac-1
O
O
S
O
rac-2
, Alk = Pri;
a: Ar =
H
OH
NH
4
oxypropane-1,2-diol and then was treated with isopropyl-
amine resulting in the ring opening.
ArO
*
Alk
O
N
, Alk = But;
b: Ar =
1
a—c
N
N
Scheme 2
S
H
CH Cl
, Alk = Pri
2
c: Ar =
CH2
O
CH CH
OH
SOCl2
2
2
ArOH, NaH
H
O
O
O
S
Of two enantiomers of compounds 1, the (S)-isomers
generally exhibit useful physiological activity. Since only
a few of β-AB are now made commercially in the
enantiomerically pure form (timolol (S)-1b and levo-
betaxolol (S)-1c), interest in the development of new
procedures for the synthesis of scalemic (nonracemic)
β-blocking agents still persists.
O
(S)-4
(4S)-3
H
CH OAr
2
AlkNH2
(
S)-1a,b
Recently, cyclic sulfites have attracted considerable
attention in the preparative chemistry because they
proved to be useful reagents in the synthesis of many
O
O
S
O
2
classes of organic compounds. In the synthesis of race-
(
4R)-2a,b
mic β-AB and structurally related compounds, cyclic
sulfites were used primarily at the stage of introduction
of the amino group (Scheme 1).3
Racemic aryloxymethyl sulfites (2) were prepared from
the corresponding 3-aryloxypropane-1,2-diols either by
transesterificaion of dimethyl sulfite3a or by the reactions
of SOCl2 with glycols.3b In the synthesis of scalemic
propranolol (S)-1a, a mixture of diastereomeric sulfites
O
N
N
Ar =
(a);
(b)
N
S
In the present study, we examined the possibility of
(
4R)-2a was prepared in four steps from (R)-3-benzyl-
the synthesis of scalemic β-AB, viz., (S)-propranolol and
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 417—420, March, 2001.
066-5285/01/5003-436 $25.00 © 2001 Plenum Publishing Corporation
1

New approach to nonracemic β-blockers
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
437
(
S)-timolol, from (S)-glycidol with the use of cyclic
composition also helped in identifying the signals of
individual isomers 2b in the 13C NMR spectra.
sulfites as the key intermediates.
Previously, we have developed a procedure for the
preparation* of a diastereomeric mixture of 4-chloro-
methyl-2-oxo-1,3,2-dioxathiolane (3) by the direct reac-
tion of SOCl2 with glycidol (4).5 In the cited studies,
we have also demonstrated that the chiral center of
glycidol retained its configuration in the final product
and the enantiomeric purities of sulfites 3 were identical
to that of the starting epoxyalcohol.
Prolonged refluxing of sulfites (2RS,4R)-2a with an
i
excess of Pr NH in MeCN under conditions described
2
4
previously did not afford the target product. Treatment
,6
of the reaction mixture involving washing with aqueous
alkali gave rise to (S)-3-(1-naphthyloxy)propane-1,2-
diol (1a) as the major product (m.p. 111—112 °C; cf. lit.
4
20
data: m.p. 110—112 °C; [α]
+7.4 (c 1.0, MeOH); cf.
D
4
20
lit. data: [α]D +7.6 (c 1.0, MeOH)). On the contrary,
treatment of sulfites (4R)-2a,b with Pr NH or Bu NH
2 2
i
t
It was believed that the reactions of rac-3 with aryl
oxide anions proceed anomalously to give achiral sym-
metrical six-membered sulfites.7 We demonstrated that
this conclusion was based on the erroneous interpreta-
tion of the experimental results and that in aprotic
solvents, the chlorine atom is replaced by the phenoxide
anion with retention of the molecular skeleton.8
The reaction of a mixture of (2RS,4S)-3 with the
in DMF at 60—80 °C allowed us to prepare the corre-
sponding (S)-β-blockers (S)-1a and (S)-1b in approxi-
mately 80% yields. Their optical purities are of the same
order of magnitude as that of the initial glycidol.
,2
The procedure for the synthesis of aryloxypropanol-
amines 1 developed in the present study involves an
ingenious stage of the preparation of chloromethyl sulfites
3, whereas the subsequent stages are similar to those
used in the conventional procedure for the commercial
1
-naphthoxide anion, which was generated from 1-naph-
thol and NaH in toluene, proceeded smoothly according
to Scheme 2 to form a mixture of isomers (2R,4R)-2a
and (2S,4R)-2a in a ratio of 59 : 41 in ∼ 80% yield. Both
isomers were isolated and characterized in the individual
form. In the synthesis with the use of 3-hydroxy-4-
morpholino-1,2,5-thiadiazole as the aromatic compo-
nent, the stage of conversion of chloromethyl sulfites
9
preparation of racemic β-AB from epichlorohydrin (6).
Scheme 3
O
–
O
AlkNH2
ArO
Cl
OAr
rac-1
(
2RS,4S)-3 into thiadiazolyloxymethyl sulfites was car-
ried out in DMF because of the low solubility of the
hydroxyl-containing heterocycle in toluene. When the
reaction conditions were changed (DMF, 80—90 °C,
6
7
The reactions of epichlorohydrin with active nucleo-
1
h), an undesirable product of double nucleophilic
substitution, viz., 1,3-bis[(4-morpholino-1,2,5-thiadiazol-
-yl)oxy]propan-2-ol (5), was isolated along with iso-
philes are also accompanied by the formation of undesir-
able bis-adducts analogous to compound 5.10 However,
it should be noted that the behavior of chloromethyl
sulfites 3 as synthetic analogs of 1-chloro-2,3-epoxy-
propane (6) is substantially different.
3
meric (2R,4R)-2b and (2S,4R)-2b formed as the major
products.
It is known11 that the reactions of activated
2
,3-epoxypropanes with nucleophiles involve two direc-
HOCH CH O
N
O
2
tions of the attack, viz., the attack at the C(1) atom and
the attack at the C(3) atom with the opening of the
oxirane ring followed by its regeneration. The final
products formed by different mechanisms contain the
chiral C(2) atom with opposite configurations. Conse-
quently, simultaneous realization of both directions leads
to partial racemization. In the case of the reaction of
epichlorohydrin with the phenoxide anion, the major
2
N
N
S
5
Products 2b and 5 were separated by column chro-
matography, diastereomeric (2R,4R)-2b and (2S,4R)-2b,
which possess similar TLC mobilities, being eluted si-
multaneously. A mixture of sulfites 2b partially crystal-
lized upon storage, the crystalline portion being enriched
with cis-diastereomer (2S,4R)-2b. The assignment of
substituted cyclic sulfites to either cis or trans series was
based on the 1H NMR spectral data and, primarily, on
the fact (see Ref. 6 and references cited therein) that the
methine proton in trans isomers is manifested as an
isolated signal with the chemical shift δ > 5, whereas the
analogous proton in cis isomers gives a signal at higher
field with the chemical shift δ ≤ 5. The changes in the
intensities associated with a change in the diastereomeric
product (7, Ar = Ph; ~90%) was formed as a result of the
attack at the C(3) atom.11a Taking into account that the
mixture contained the minor product (∼ 10%) formed
through the attack at the C(1) atom and in view of the
fact that procedures for blocking nucleophilic substitu-
tion at the C(1) atom are lacking, one should not expect
that the reaction performed according to Scheme 3 even
starting from enantiomerically pure compound 6 will
afford the final products with high enantiomeric purities.
On the contrary, the nucleophilic replacement of the
chlorine atom in chloromethyl sulfites 3 by the aryl
oxide anion occurs predominantly (or even exclusively)
through the attack of the exocyclic carbon atom. This is
*
The scheme of the synthesis has been reported previously.5

4
38
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
Bredikhina et al.
evidenced by the configurations of the final 1-alkylamino-
-aryloxypropan-2-ols 1 as well as by the (S) configura-
morpholino-1,2,5-thiadiazole (1.12 g, 6 mmol), which was
prepared according to a procedure reported previously,15 in
DMF (4 mL) was added with stirring to a suspension of NaH
3
tion and by the high optical purity of the above-men-
tioned 3-(1-naphthyloxy)propane-1,2-diol. Therefore, the
use of sulfite 3 instead of oxirane 6 in Scheme 3 leads to
blocking of at least one of the existing channel for the
racemization of the scalemic final products.
(
0.15 g, 6 mmol) in DMF (2 mL) at 20 °C. The reaction
mixture was heated to 70—80 °C, stirred at this temperature for
0 min, and cooled to ∼ 20 °C. A solution of dioxathiolanes 3
0.94 g, 6 mmol) in DMF (2 mL) was added to the reaction
mixture. To terminate the reaction, the mixture was heated at
0—90 °C for 30 min and then stored for 18 h. The precipitate
3
(
8
that formed was filtered off and washed on a filter with chloro-
form. The combined filtrates were concentrated in vacuo. The
oily residue (1.4 g) was chromatographed on a 150½20-mm
Experimental
The IR spectra of liquid and solid samples were recorded on
a UR-20 spectrometer in thin films and in Nujol mulls, respec-
tively. The NMR spectra were measured on Bruker WM-250
column (silica gel L, 40/100 µm; the heptane—Et O mixture as
2
the eluent). A mixture of isomeric (2RS,4R)-4-[(4-morpholino-
1,2,5-thiadiazol-3-yl)oxymethyl]-2-oxo-1,3,2-dioxathiolanes
(2b) was isolated in a yield of 0.62 g (47%); cis : trans = 3 : 2;
(
250.13 MHz for 1H) and Bruker MSL-400 (400.13 MHz
for 1H; 100.6 MHz for 13C) spectrometers in CDCl3 with
the average Rf value was 0.44 (Et O). Found (%): C, 35.79;
2
Me Si as the internal standard. TLC was carried out on Silufol
H, 4.07; N, 14.18. C H N O S . Calculated (%): C, 35.17;
9 13 3 5 2
4
plates. The optical rotation was measured on a Polamat A
polarimeter. The solvents were purified according to standard
procedures.14
H, 4.26; N, 13.67. 1H NMR (250 MHz, CDCl ), δ: 3.49
3
(distort.t, 4 H, NCH , J = 4.5 Hz); 3.79 (distort.t, 4 H, OCH
2
2
of morpholine, J = 4.5 Hz); 3.55—3.77 and 4.36—4.76 (both m,
The starting (S)-glycidol (S)-4 (ee = 90.1%) and the diaste-
reomers of chloromethylsulfites (2RS,4S)-3 (ee ≈ 90%) were
prepared according to a known procedure.
4 H, OCH ), 4.18—4.31 (m, 0.6 H, CH cis-2b); 5.27—5.39 (m,
2
1
3
0.4 H, CH trans-2b). C NMR (CDCl ), δ: trans isomer
3
6
(2R,4R)-2b, 48.00 (CH N); 66.49 (OCH of morpholine); 68.26
2
2
(
2RS,4R)-4-(1-Naphthyloxy)methyl-2-oxo-1,3,2-dioxa-
thiolanes (2a). A solution of freshly sublimed α-naphthol (1.53 g,
.01 mol) in toluene (8 mL) was added to a suspension of NaH
0.26 g, 10 mmol) in toluene (2 mL). The reaction mixture was
and 69.08 (OCH ); 77.77 (CH); 149.71 (N=C—N); 152.75
2
(N=C—O); cis isomer (2S,4R)-2b, 48.07 (CH N); 66.49 (OCH
2
2
0
(
of morpholine); 46.14 and 71.68 (OCH ); 69.67 (CH); 149.89
2
(N=C—N); 153.54 (N=C—O). IR, ν/cm–1: 960, 1120,
1220, 1240, and 1270 (C—O, S—O, S=O), 1500, 1540
(thiadiazole).
refluxed for 30 min and cooled to ∼ 20 °C. Then a solution of a
mixture of (2S,4S)- and (2R,4S)-2-oxo-4-chloromethyl-1,3,2-
dioxathiolanes (1.66 g, 10 mmol), which were prepared accord-
ing to a known procedure,6 in toluene (5 mL) was added. The
reaction mixture was refluxed for 1 h and then kept for 18 h.
The precipitate that formed was filtered off and the solvent was
removed in vacuo. A raw mixture of dioxathiolanes 2a was
obtained in a yield of 2.38 g (88%). The characteristics of the
resulting mixture are in complete agreement with the published
data.4 Chromatography (silica gel L, 40/100 µm; 200½20 mm
Subsequent elution afforded 1,3-bis[(4-morpholino-1,2,5-
thiadiazol-3-yl)oxy]propan-2-ol (5) in a yield of 0.24 g (24%),
Rf 0.25 (Et O), m.p. 109—110 °C. Found (%): C, 41.72;
2
H, 5.32; N, 19.27; S, 14.47. C15H22N O S . Calculated (%):
6
5 2
1
C, 41.85; H, 5.15; N, 19.52; S, 14.89. H NMR (250 MHz,
CDCl ), δ: 3.40—3.61 (m, 9 H, NCH , OH); 3.68—3.93
3
2
(m,
8
H, OCH2 of morpholine); 4.40—4.70 (m, 5 H,
13
OCH CH(OH)CH O). C NMR (CDCl ), δ: 48.02 (CH N);
2
2
3
2
column; a heptane—CH Cl2 mixture as the eluent) of the
mixture (0.99 g) afforded (2S,4R)-2a in a yield of 0.16 g,
66.48 (OCH2 of morpholine); 68.27 (CH); 71.58 (CH O);
2
2
–
1
149.87 (N=C—N); 153.50 (N=C—O). IR, ν/cm : 1520 and
1540 (thiadiazole); 3300 and 3350 (OH).
(S)-1-Isopropylamino-3-(1-naphthyloxy)propan-2-ol
2
0
R 0.42 (CH Cl ), m.p. 97—99 °C, [α]
–0.5 (c 0.43, CH Cl ).
2 2
f
2
2
D
1
H NMR (400 MHz, CDCl ), δ: 4.46 (dd, 1 H, naph-
3
thyl—OCH , J = 6.4 Hz, J = 10.0 Hz); 4.55 (dd, 1 H,
((S)-propranolol, (S)-1a). A solution of dioxathiolanes 2a (0.4 g,
a
i
naphthyl—OCH , J = 4.8 Hz, J = 10.0 Hz); 4.72 (dd, 1 H,
1.5 mmol) and Pr NH (1.6 g, 27 mmol) in DMF (6 mL) was
b
2
H (5), J = 6.8 Hz, J = 8.6 Hz); 4.82 (dd, 1 H, H (5),
J = 8.1 Hz, J = 8.6 Hz); 5.01 (dddd, 1 H, H(4), J = 6.4 Hz,
J = 4.8 Hz, J = 8.1 Hz, J = 6.8 Hz); 6.83, 7.38, 7.50, 7.82, and
heated at 60—70 °C for ∼ 45 h. After completion of the reaction,
a 1 M aqueous solution of NaOH (20 mL) was added to the
reaction mixture and the mixture was extracted with EtOAc
(3½60 mL). The extract was dried over MgSO4 and the solvent
was removed in vacuo. The residue was dissolved in ether and
dry HCl was passed through the solution until saturation was
achieved. The precipitate that formed was filtered off and the
a
b
8
.26 (all m, 1 H, 1 H, 3 H, 1 H, and 1 H, respectively,
naphthyl). 13C NMR (CDCl ), δ: 67.38 (CH O—naph-
3
2
thyl); 68.83 (C(5)); 80.15 (C(4)); 105.02, 121.23, 121.77,
25.30, 125.56, 125.62, 126.64, 127.45, 134.43, and 153.50
naphthyl).
Subsequent elution afforded (2R,4R)-2a as a viscous oil in a
1
(
hydrochloride was isolated in a yield of 0.35 g (80%). After
i
recrystallization from the Pr OH—Et O mixture, (S)-propra-
2
2
0
yield of 0.32 g, R 0.31 (CH Cl ), [α]
+24.2 (c 0.46,
CH Cl ). H NMR (400 MHz, CDCl ), δ: 4.18 (d, 2 H,
nolol hydrochloride ((S)-1a•HCl) was isolated in a yield of
f
2
2
D
1
20
0.3 g (68%), m.p. 190—192 °C, [α]
D
–22.7 (c 1.1, EtOH) (cf.
2
2
3
1
2
20
naphthyl—OCH , J = 4.7 Hz); 4.56 (dd, 1 H, H (5), J = 4.4 Hz,
lit. data: m.p. 194—196 °C, [α]D –25.1 (c 1.05, EtOH)).
(S)-1-(tert-Butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-
2
a
J = 8.6 Hz); 4.86 (dd, 1 H, H (5), J = 6.6 Hz, J = 8.6 Hz); 5.34
b
(
7
1
(
1
1
tdd, 1 H, H(4), J = 4.7 Hz, J = 4.4 Hz, J = 6.6 Hz); 6.75,
3-yl)oxy]propan-2-ol ((S)-timolol, (S)-1b). A solution of
t
.39, 7.54, 7.84, and 8.22 (all m, 1 H, 1 H, 3 H, 1 H, and
dioxathiolanes 2b (0.2 g, 0.65 mmol) and Bu NH (0.7 g,
2
H, respectively, naphthyl). 13C NMR (CDCl ), δ: 66.65
9.8 mmol) in DMF (1.5 mL) was heated and kept at 70—80 °C
for ∼ 30 h. Then a 1 M aqueous solution of NaOH (10 mL)
was added and the mixture was extracted with EtOAc
(3½30 mL). The extract was dried over MgSO4 and the solvent
was removed in vacuo. Timolol (S)-1b was obtained in a
yield of 0.17 g (83%). The product was characterized as
hemimaleate, m.p. 197—198 °C (EtOH), [α]D20 –6.6 (c 5,
3
CH O—naphthyl); 68.45 (C(5)); 78.11 (C(4)); 104.90, 121.27,
2
21.61, 125.24, 125.53, 125.57, 126.64, 127.49, 134.43, and
53.50 (naphthyl).
Reactions of (2RS,4S)-4-chloromethyl-2-oxo-1,3,2-dioxa-
thiolanes ((2RS,4S)-3) with the sodium salt of 3-hydroxy-4-
morpholino-1,2,5-thiadiazole. solution of 3-hydroxy-4-
A

New approach to nonracemic β-blockers
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
439
1
1
M HCl) (cf. lit. data:13 m.p. 198—199 °C, [α]D20 –7.5 (c 20,
M HCl)).
Nauk, Ser. Khim., 2000, 1586 [Russ. Chem. Bull., Int. Ed.,
2000, 49, 1575].
7
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. D. Ben-Ishay, J. Org. Chem., 1958, 23, 2013.
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Received June 13, 2000;
in revised form October 6, 2000