A Practical synthesis of novel Rho-kinase inhibitor, (S)-4-fluoro-5-(2- methyl-1,4-diazepan-1-ylsulfonyl)-isoquinoline

Article abstract of DOI:10.3987/COM-11-12230

A practical synthesis of novel Rho-kinase inhibitor, (S)-4-fluoro-5- (2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline hydrochloride dihydrate (1) was achieved in a pilot-scale production. We have demonstrated the regioselective chlorosulfonylation of 4-fluoroisoquinoline in an one-pot reaction to afford 4-fluoroisoquinoline-5-sulfonyl chloride and the asymmetric construction of the (S)-2-methyl-1,4-diazepane moiety as key steps. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-11-12230

HETEROCYCLES, Vol. 83, No. 8, 2011
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HETEROCYCLES, Vol. 83, No. 8, 2011, pp. 1771 - 1781. © The Japan Institute of Heterocyclic Chemistry
Received, 8th April, 2011, Accepted, 13th May, 2011, Published online, 24th May, 2011
DOI: 10.3987/COM-11-12230
A PRACTICAL SYNTHESIS OF NOVEL RHO-KINASE INHIBITOR,
(S)-4-FLUORO-5-(2-METHYL-1,4-DIAZEPAN-1-YLSULFONYL)-
ISOQUINOLINE
Noriaki Gomi,a Tadaaki Ohgiya,a Kimiyuki Shibuya,a* Jyunji Katsuyama,b
Masayuki Masumoto,b and Hitoshi Sakaib
a
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa
Company, Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan;
E-mail: k-sibuya@kowa.co.jp
b
Fuji Chemical Industry Company, Ltd., 1, Gohkakizawa, Kamiichi-machi,
Nakaniikawa-gun, Toyama 930-0397, Japan
Abstract – A practical synthesis of novel Rho-kinase inhibitor, (S)-4-fluoro-5-
(2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline hydrochloride dihydrate (1) was
achieved in a pilot-scale production. We have demonstrated the regioselective
chlorosulfonylation of 4-fluoroisoquinoline in an one-pot reaction to afford
4-fluoroisoquinoline-5-sulfonyl chloride and the asymmetric construction of the
(S)-2-methyl-1,4-diazepane moiety as key steps.
INTRODUCTION
A highly potent and selective Rho-kinase inhibitor, (S)-4-fluoro-5-(2-methyl-1,4-diazepan-1-ylsulfonyl)-
isoquinoline hydrochloride dihydrate (1)1 has been developed from Fasudil (2).2,3 Both compounds have
the same core structure of 5-(1,4-diazepan-1-ylsulfonyl)isoquinoline as shown in Figure 1. Fasudil has been
recognized as a potent Rho-kinase inhibitor and clinically used for the treatment of cerebral vasospasm.2
Furthermore the recent studies revealed that 2 could enhance memory and improve the prognosis of
Alzheimer’s patients,3a angina3b and pulmonary arterial hypertension.3c After exploring the chemical
derivatives of 2, the incorporation of fluorine atom at C4 position of isoquinoline moiety and the chiral
attachment of the methyl group at C2’ position of 1,4-diazepane moiety dramatically improved the
pharmacological action. As can be seen, 1 showed much more potent and selective Rho-kinase inhibitory
activity than Fasudil1a and would be potentially expected to cure the Cerebral Vascular Disorder.1b
Especially, it is noteworthy that 1 can be effective on the ocular hypertension with intraocular pressure
(IOP)-lowering activity and neuroprotection of retinal ganglion cells injured in glaucoma.1a

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HETEROCYCLES, Vol. 83, No. 8, 2011
HN
HN
N
N
2'
SO2
F
SO2
4
HCl•2H2O
N
N
1
2: Fasudil
IC50 = 0.03 M
IC50 = 0.50 M
Figure 1. Structure and Activity of Rho-kinase inhibitors
As part of our drug research and development plans, we required the practical synthesis of 1 in
multi-kilogram scale and be easily scalable to commercial scale. However, there are two major issues.
First, we needed to develop a regioselective chlorosulfonylation reaction at C5 position of
4-fluoroisoquinoline. Second, we had to guarantee the stereochemical purity in (S)-2-methyl-1,4-
diazepane moiety. Herein we disclose the synthesis of 1 starting from 4-fluoroisoquinoline at pilot-scale.
RESULTS AND DISCUSSION
In our retrosynthetic analysis (Scheme 1), we set out to synthesize the intermediate 3 and verify that the
absolute stereochemistry at the C2’ position would be retained to form the enantiomerically pure
(S)-2-methyl-1,4-diazepane moiety. Intramolecular cyclization of the sulfonamide alcohol (3) would afford
1 by a Mitsunobu reaction. The precursor of 3 could be identified the combination of 4 and readily available
(S)-2-aminopropanol by the disconnection bond between C3’ position and N4’ position. The sulfonamide
7'
6'
disconection
SO2
OH
disconection
SO2
disconection
SO2
H
N
1'
H
N
1'
HN
3'
2'
4'
2'
N
5'
3'
HO
F
N
H
F
F
N
N
N
HCl•2H2O
1
3
4
disconection
SO2
Cl
F
F
N
N
HCl
5
6
Scheme 1
. Retrosynthetic analysis of
1

HETEROCYCLES, Vol. 83, No. 8, 2011
1773
alcohol (4) can be easily prepared from 4-fluoroisoquinoline-5-sulfonyl chloride (5). An efficient
chlorosulfonylation of 4-fluoroisoquinoline (6)4 is the most important issue to provide 5.
Although several methods for synthesis of 5 were previously reported, these syntheses were not amenable
due to many steps, low yields, troublesome purifications and tedious reaction conditions (e.g., diazonium
salt intermediates).5 Accordingly, we needed to establish the reproducible synthesis of 5 from 6 that is
applicable for a large-scale production. In order to prepare 5, we investigated a variety of reaction condition
on the regioselective sulfonylation of 6 and its efficient purification.
Some methods for the synthesis of arylsulfonychlorides from the corresponding aromatics have been
achieved by stepwise sulfonylation and subsequent chlorination with phosphorus pentachloride,
phosphorus oxychloride, thionyl chloride,6 or directly with chlorosulfuric acid,6a,7 or treatment with a
combination of sulfinic acid and NCS.8 These methodologies have been already applied to some
isoquinolines.6b,6c,7b
We attempted to transform 6 into 7 with a combination of concd H2SO4 and SO3 to produce fuming sulfuric
acid in situ (Table 1). The initial conditions by applying 2.2 eq of concd H2SO4 and 8.6 eq of SO3 took 18 h
at 30 °C to complete (Table 1, Entries 1, 2). While the quantity of concd H2SO4 accelerated the reaction
(Entries 1 - 3), the low concentration of SO3 decreased the reaction rate and the regioselectivity between the
C5 position and the C8 position (Entries 4, 5). The presence of ca. 2 eq of concd H2SO4 seemed to be
favorable in the sulfonylation reaction conditions. Using a vast excess of SO3, the sulfonylation yield was
improved for the desired 7 at 0 °C to 15 °C for 4 h (Entries 6 - 8). However, these conditions were
unsuitable for a large-scale production, since the bulk amounts of concd H2SO4 make it difficult and
expensive to neutralize for waste disposal compared to Entry 2. In addition, it was too difficult to stir the
viscous reaction mixtures under these conditions. On the other hand, heating the reaction to 50 °C
facilitated the stirring, but eroded the regioselectivity (Entry 9). We also investigated the influences of
added Lewis Acids on the sulfonylation reaction in combination with concd H2SO4 and SO3 system.
Unfortunately, the separate addition of 1 eq of MgCl2, AlCl3, ZnCl2, or H3BO3 decreased the yield of 7
(Entries 10 - 13). Half of equivalent of FeCl3 or AgNO3 had no impact on the yield of 7 (Entries 14, 15), but
FeCl3 did afford the highest regioselectivity in the reaction. In the procedure on a large-scale production,
the handling of 6 was found to be troublesome because of its low melting point.4
–
Then we investigated the HSO4 salt of 6 for easy handling in the sulfonylation reaction. Remarkably, we
–
found that the HSO4 salt of 6 was very effective in the reaction providing high yield as shown in Entry 16
with decreased H2SO4 equivalents and good regioselectivity. As the result, we selected the best conditions
as Entry 16 and Entry 2 as a second choice for the sulfonylation of 6.

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HETEROCYCLES, Vol. 83, No. 8, 2011
Table 1. Results of the Sulfonylation Reaction of Isoquinoline (6)
concd H2SO4 SO3
Additive
(eq)
Temp. Time
6a
7+8a
Entry
7/8a
(eq)
(eq)
（°C)
(h)
(%)
(%)
1
2
2.2
2.2
-
8.6
8.6
9.0
8.4
8.4
12
-
30
30
30
30
30
0
3
18
22
22
22
4
49
1
51
98
48
30
14
96
99
92
91
26
33
58
35
80
65
94
1.8
1.5
1.5
1.4
1.1
2.1
1.8
1.9
1.3
1.7
1.8
1.9
1.9
2.4
2.1
1.8
-
3
-
43
54
75
4
4
4.3
8.8
2.2
2.1
6.6
2.2
2.2
2.2
2.2
2.2
2.2
2.2
-
-
5
-
6
-
7
17
-
30
15
50
30
30
30
30
30
30
30
4
0
8
17
-
4
8
9
7.1
8.6
8.6
8.6
8.6
8.6
-
48
3
9
10
11
12
13
14
15
16 b
MgCl2 (1)
AlCl3 (1)
ZnCl2 (1)
H3BO3 (1)
FeCl3 (0.5)
71
67
41
63
20
10
0
3
3
3
3
8.6 AgNO3 (0.5)
8.6
3
-
16
a Determined by HPLC. b No additional H2SO4 added but HSO4 salt (6a) was used.
–
Next, we developed a concise one-pot reaction for production of the sulfonyl chloride (5) via the
corresponding sulfonic acid (7) prepared in a combination of concd H2SO4 and SO3 from 6 and which was
subsequently exposed upon SOCl2 (Table 2). Our first attempt for a simple procedure was as follows. The
4-fluoroisoquinoline (6) in SOCl2 was treated with a mixture of concd H2SO4 and SO3. This reaction was
failed and gave only a trace amount of 5 and 9 with the recovered 6 (63%) (Table 2, Entry 1). Accordingly,
we conducted stepwise the sulfonylation of 6 with concd H2SO4 and SO3 and subsequently the chlorination
of the prepared 7 and 8 with SOCl2 in one-pot reaction (Entry 2). The similar result was obtained by
–
application of HSO4 salt of 6 (Entry 3). The ratio of 7 and 8 was not changed in the chlorination process.
Satisfactory results were obtained to afford extra pure 5 in 41% and 39% yield after crystallization as the

HETEROCYCLES, Vol. 83, No. 8, 2011
1775
HCl salt respectively. Fortunately, the 8-sulfonyl chloride (9) as by-product can be easily removed by
filtration in the mother liquid during the crystallization procedure.
Table 2. One-Pot Sulfonylation and Chlorination Reaction from 6
concd H2SO4 SO3
Time
(h)
6a
SOCl2
(eq)
5+9b
Entry
7/8a
5:9c
(eq)
(eq)
(%)
(%)
1d
2e
3e,f
2.2
2.2
-
8.6
8.6
8.6
18
18
16
63
0
-
14
5.4
4
-
-
1.6
1.8
41
39
98 : 0.3
>99 : 0.4
0
a Determined by HPLC.
b Isolated yields as the HCl salt.
c After isolation by crystallization, the ratio of each compound was determined by HPLC.
d To a solution of 6 in SOCl2 was added the solution of concd H2SO4 and SO3.
e Sulfonylation and subsequently chlorination in one-pot stepwise reaction.
–
f HSO4 salt (6a) was used.
Thus obtained sulfonyl chloride 5 in one-pot reaction9 was further utilized in the synthesis of our
Rho-kinase inhibitor (1) as depicted in Scheme 2. Sulfonylamidation of 5 with (S)-2-aminopropanol gave
the corresponding sulfonylamide (4) in 84% yield. Mesylation of 4 led to a mixture of the mesylate (10) and
the aziridine intermediate (11).10 N-Alkylation was carried out in situ, the mixture of 10 and 11 was directly
treated with 3-aminopropanol to afford the desired 3 in a high yield. Two reaction pathways can be
postulated for the nucleophilic attack on Site A or Site B of the aziridine. The ratio of the isomer 3b to 3a
was greatly influenced by the reaction temperature. The desired addition (attacked from site A) was
controlled by carrying out the reaction at low temperature.11 However, we had to remove 3b to the
minimum at this stage. In order to avoid using the column chromatography separation especially in a
large-scale production, we attempted to purify 3a by way of a crystalline oxalate salt. As expected, the
oxalate salt of 3a was obtained as colorless crystals in 73% yield from 4. Thus we succeeded in minimizing
the amount of the contaminating isomer 3b (attack from site B) to 0.3%.

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HETEROCYCLES, Vol. 83, No. 8, 2011
H
H
N
N
HO
SO2
F
MsO
SO2
F
a
b
5
N
N
84%
4
10
OH
OH
site A
site B
2'
1'
H
N
H
N
N
SO2
F
N
H
F
N
H
SO2
SO2
F
c
N
N
N
(CO2H)2
3a (73% overall yield from 4)
(CO2H)2
3b
11
Scheme 2. Reagent and conditions; (a) (S)-2-aminopropanol, Et3N, CH2Cl2, 20 °C.
(b) MsCl, Et3N, THF, 0 °C, then 3-aminopropanol was added, 25 °C. (c) (CO2H)2,
aq. IPA, 75 °C, and cooled to 25 °C.
After basifying of the oxalate salt of 3a to afford the free amine (3) (Scheme 3), the intramolecular
cyclization was conducted by treating 3 under Mitsunobu conditions.12 The reaction proceeded smoothly to
provide the desired product (12) in 90% yield (95% purity by HPLC). Finally, the purification of 1 was
accomplished by the crystallization as the HCl salt in 73% yield over two steps (>99.9% ee). The crystalline
1 was sufficiently pure for GMP production and clinical use.
In conclusion, we have achieved the practical synthesis of novel Rho-kinase inhibitor,
(S)-4-fluoro-5-(2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline hydrochloride dihydrate (1) starting from
4-fluoroisoquinoline in a pilot-scale production. We developed and reported the concise one-pot
chlorosulfonylation of 4-fluoroisoquinoline and the regioselective construction of the chiral 1,4-diazepane

HETEROCYCLES, Vol. 83, No. 8, 2011
1777
by a Mitsunobu reaction intramolecular cyclization as the key steps. Application of 1 for the treatment of
ocular hypertension is currently under study.
EXPERIMENTAL
General. All reactions were carried out under a N2 atmosphere unless otherwise noted. Optical rotations
were measured on a JASCO P-2200 polarimeter with sodium (D line) lamp. IR spectra were recorded on a
Thermo Nicolet 370 FT-IR spectrometer. 1H-NMR spectra and 13C-NMR spectra were obtained on a JEOL
JNM-AL 400 MHz spectrometer using CDCl3 or DMSO-d6 solvents with tetramethylsilane as internal
standard unless otherwise noted. Mass spectra were obtained on a JEOL MS-BU20 mass spectrometer.
Elemental analyses (C, H, N) were performed by Yanaco MT-5. Elemental analyses (Cl) were performed
by Kyoto Electronics Manufacturing AT-510. Elemental analyses (S, F) were performed by Nippon Dionex
ICS-1500. Melting points were determined in open glass capillaries on a Buchi B-545 melting point
apparatus. The HPLC analyses were performed using Hitachi D-7000 equipment. The optical purity was
determined by HPLC analysis (CHIRALPAK AD, Daicel Chemical Industries Limited).
4-Fluoroisoquinoline sulfate (6a)
To a solution of 4-fluoroisoquinoline (6)4 (9.40 kg, 63.9 mol) in acetone (28 kg) was carefully and
gradually added concd H2SO4 (6.58 kg, 67.1 mol) at 0 – 10 °C, and the mixture was stirred at the same
temperature for 2 h. The precipitated crystals were filtered, washed with acetone (22 kg), and dried under
reduced pressure to yield 6a (15.5 kg, 99%) as a colorless crystalline solid.: mp 166-167 °C; IR (KBr) 1659,
1617, 1601, 1558, 1506, 1407 cm-1; 1H-NMR (DMSO-d6) δ: 8.09 (1H, t, J = 7.9 Hz), 8.25 (1H, t, J = 7.9
Hz), 8.31 (1H, d, J = 7.9 Hz), 8.60 (1H, d, J = 7.9 Hz), 8.87 (1H, d, J = 3.7 Hz), 9.74 (1H, s), 12.18 (2H, s);
13C-NMR (DMSO-d6) δ: 119.7 (J = 3.3 Hz), 122.2 (J = 32.3 Hz), 127.8 (J = 14.9 Hz), 128.8 (J = 5.0 Hz),
129.8, 131.0, 135.6, 146.5 (J = 4.1 Hz), 155.8 (J = 256.6 Hz); FABMS m/z 148 (M+H–H2SO4)+; Anal.
Calcd for C9H8FNO4S: C, 44.08; H, 3.29; F, 7.75; N, 5.71. Found: C, 43.90; H, 3.31; F, 7.81; N, 5.73.
4-Fluoroisoquinoline-5-sulfonyl chloride hydrochloride (5)
To liquid sulfur trioxide (47.7 kg, 596 mol) was gradually added 6a (15.8 kg, 64.4 mol) at 30 °C for 3 h and
the resulting mixture was stirred at the same temperature for 16 h. To this reaction mixture was gradually
added SOCl2 (42.2 kg, 355 mol) at the same temperature for 3 h. The mixture was heated with stirring to
70 °C for 4h and allowed to cool to 20 °C. The reaction mixture was slowly added to a mixture of water
(208 kg), NaCl (48 kg), ice (200 kg) and CH2Cl2 (320 kg) at a temperature of less than 5 °C. The organic
layer was partitioned. The aqueous layer was extracted with CH2Cl2 (3 x 126 kg). The combined organic
layers were washed with saturated brine (85 kg), NaHCO3 (9 kg) in water (117 kg) and saturated brine (93
kg) and dried over anhydrous Na2SO4 (24 kg). Na2SO4 was filtered, washed with additional CH2Cl2 (210
kg) and combined. To this solution was slowly added 4 M HCl/EtOAc (18 kg) at 35 °C and the resulting

1778
HETEROCYCLES, Vol. 83, No. 8, 2011
mixture was stirred at 35 °C for 1 h. The precipitated crystals were filtered, washed with CH2Cl2 (63 kg)
and dried under reduced pressure to yield 5 (7.04 kg, 39%) as a colorless crystalline solid. The crystalline
solids contained a trace amount of the C8-isomer (9) which was determined by HPLC (Ratio of 5 and 9 was
99.64:0.36).: mp 200-201 °C (decomp); IR (KCl) 2993, 2303, 2086, 1654, 1495, 1375, 1184 cm-1; 1H-NMR
(DMSO-d6) δ: 7.94 (1H, t, J = 7.8 Hz), 8.45-8.49 (1H, m), 8.67 (1H, dd, J = 7.8, 1.2 Hz), 8.77 (1H, d, J = 5.4
Hz), 9.62 (1H, s), 14.80 (1H, br s); 13C-NMR (DMSO-d6) δ: 124.2 (J = 13.4 Hz), 127.3 (J = 32.4 Hz), 129.2,
130.8, 130.9 (J = 3.8 Hz), 133.8, 142.4 (J = 5.7 Hz), 147.5 (J = 4.8 Hz), 155.0 (J = 268.0 Hz); 1H-NMR
(CDCl3, as free base) δ: 7.84 (1H, t, J = 7.8 Hz), 8.40-8.44 (1H, m), 8.71 (1H, d, J = 4.4 Hz), 8.72 (1H, dd,
J = 7.8, 1.5 Hz), 9.25 (1H, s); 13C-NMR (CDCl3, as free base) δ: 121.1 (J = 13.2 Hz), 126.6 (J = 1.7 Hz),
130.6, 134.5 (J = 28.1 Hz), 134.9, 135.7 (J = 1.7 Hz), 138.0 (J = 4.1 Hz), 149.2 (J = 5.8 Hz), 152.0 (J =
265.7 Hz); FABMS m/z 246 (M(as 35Cl)+H–HCl)+; Anal. Calcd for C9H6Cl2FNO2S: C, 38.32; H, 2.14; Cl,
25.13; F, 6.73; N, 4.96; S, 11.37. Found: C, 38.26; H, 2.09; Cl, 25.14; F, 6.58; N, 4.95; S, 11.34. Data for the
intermediate (7): 1H-NMR (DMSO-d6) δ: 6.93 (1H, br s), 7.76 (1H, t, J = 7.8 Hz), 8.23-8.29 (1H, m), 8.49
1
(1H, dd, J = 7.8, 1.0 Hz), 8.52 (1H, d, J = 5.2 Hz), 9.28 (1H, s). Data for the intermediate (8): H-NMR
(DMSO-d6) δ: 7.20 (1H, br s), 8.10 (1H, t, J = 7.8 Hz), 8.26 (2H, d, J = 7.8 Hz), 8.82 (1H, d, J = 3.4 Hz),
10.08 (1H, s).
(S)-4-Fluoro-N-(1-hydroxypropan-2-yl)isoquinoline-5-sulfonamide (4)
To a solution of (S)-2-aminopropanol (2.08 kg, 27.7 mol) in CH2Cl2 (92 kg) was added Et3N (6.30 kg, 62.3
mol) and the solution was cooled below –10 °C. To this mixture was gradually added 5 (7.04 kg, 25.0 mol)
at –10 °C over 1 h. The resulting mixture was stirred at the same temperature for 30 min and allowed to stir
at 20 °C for 18 h. After completion of the reaction, the mixture was diluted with additional CH2Cl2 (99 kg).
The organic layer was washed with water (3 x 12 kg) and concentrated under reduced pressure. The residue
was dissolved in IPA (36 kg) at 74 °C. The solution was allowed to cool to 25 °C and crystals were formed.
The mixture was further cooled with stirring at 5 °C for 1 h. The precipitated crystals were filtered, washed
with IPA (11 kg) and dried under reduced pressure at 40 °C to yield 4 (5.92 kg, 84%) as an off-white
crystalline solid.: mp 149-151 °C; []19D –18.36 (c 0.54, CHCl3); IR (KBr) 3397, 3329, 3092, 1492, 1329,
1159, 1054 cm-1; 1H-NMR (CDCl3) δ: 1.06 (3H, d, J = 6.3 Hz), 1.78 (1H, t, J = 5.1 Hz), 3.43-3.59 (3H, m),
5.34 (1H, t, J = 7.1 Hz), 7.77 (1H, t, J = 7.8 Hz), 8.23-8.28 (1H, m), 8.60 (1H, d, J = 5.4 Hz), 8.68 (1H, dd,
J = 7.8, 1.2 Hz), 9.19 (1H, s); 13C-NMR (CDCl3) δ: 18.0, 51.8, 66.0, 121.8 (J = 12.4 Hz), 127.1, 130.8 (J =
2.5 Hz), 132.9, 133.0 (J = 29.8 Hz), 134.1 (J = 4.1 Hz), 134.9, 149.6 (J = 4.1 Hz), 152.8 (J = 259.9 Hz);
FABMS m/z 285 (M+H)+; Anal. Calcd for C12H13FN2O3S: C, 50.69; H, 4.61; F, 6.68; N, 9.85; S, 11.28.
Found: C, 50.75; H, 4.49; F, 6.38; N, 9.93; S, 11.30.
(S)-4-Fluoro-N-[1-(3-hydroxypropylamino)propan-2-yl]isoquinoline-5-sulfonamide oxalate (3a)

HETEROCYCLES, Vol. 83, No. 8, 2011
1779
To a solution of 4 (5.92 kg, 20.8 mol) in THF (65.1 kg) was added Et3N (3.16 kg, 31.2 mmol) at 20 °C. To
the mixture was gradually added MsCl (2.50 kg, 21.8 mol) at –10 °C for 35 min. The reaction mixture was
stirred at 0 °C for 30 min and then 3-aminopropanol (6.26 kg, 83.3 mol) was added. The reaction mixture
was allowed to warm to 25 °C and stirred for 20 h. After completion of the reaction, the reaction mixture
was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (170 kg) and NaHCO3
(1.00 kg) in water (12.0 kg). The organic layer was partitioned and concentrated under reduced pressure.
The residue was dissolved in IPA (107 kg) and water (7.10 kg). To this solution was gradually added oxalic
acid dihydrate (2.62 kg, 20.8 mol) in the solution of IPA (26.4 kg) and water (1.80 kg) at 70 °C for 35 min.
The reaction mixture was allowed to cool to 25 °C and crystals were formed. The precipitated crystals were
filtered, washed with IPA (23.3 kg) and dried under reduced pressure at 40 °C to yield 3a (6.55 kg, 73%) as
a colorless crystalline solid. The crystalline solids contained a trace amount of 3b which was determined by
HPLC (0.3%).: mp 176-177 °C; []19D –42.29 (c 0.54, DMSO); IR (KBr) 3287, 3080, 1717, 1589, 1332,
1164 cm-1; 1H-NMR (DMSO-d6) δ: 0.89 (3H, d, J = 6.6 Hz), 1.66-1.77 (2H, m), 2.89-3.01 (4H, m), 3.46
(2H, t, J = 6.0 Hz), 3.59-3.69 (1H, m), 7.94 (1H, t, J = 7.8 Hz), 8.57 (2H, d, J = 7.8 Hz), 8.74 (1H, d, J = 4.9
Hz), 9.39 (1H, s); 13C-NMR (DMSO-d6) δ: 18.3, 28.5, 45.3, 46.7, 51.5, 58.2, 120.8 (J = 13.2 Hz), 127.6,
130.6 (J = 1.7 Hz), 132.5 (J = 28.1 Hz), 133.3, 134.1 (2C), 149.9 (J = 5.0 Hz), 152.1 (J = 263.2 Hz), 164.5
(2C); FABMS m/z 342 (M+H–(CO2H)2)+; Anal. Calcd for C17H22FN3O7S: C, 47.33; H, 5.14; F, 4.40; N,
9.74; S, 7.43. Found: C, 47.37; H, 4.99; F, 4.26; N, 9.84; S, 7.37.
(S)-4-Fluoro-5-(2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline hydrochloride dihydrate (1)
To a solution of 3a (6.55 kg, 15.2 mol) in CH2Cl2 (85.2 kg) was added a solution of K2CO3 (5.00 kg, 36.2
mol) in water (11.1 kg) at 20 °C. The reaction mixture was stirred at the same temperature for 1 h. The
organic layer was partitioned and the aqueous layer was extracted with CH2Cl2 (2 x 43.9 kg). The combined
organic layers were concentrated under reduced pressure. The residue was dissolved in toluene (5.24 kg)
and THF (5.90 kg). The solution was azeotropically evaporated to remove water under reduced pressure.
The residue was dissolved in THF (93.7 kg). To this solution was added Ph3P (5.12 kg, 19.5 mol) and a
solution of DIAD (95%, 4.10 kg, 19.3 mol) in toluene (5.90 kg) at 20 °C. The resulting mixture was stirred
at 25 °C for 30 min and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2
(41.9 kg). To this mixture was added 1.05 M HCl solution (34.7 kg) at 10 °C. The aqueous layer was
partitioned, washed with CH2Cl2 (46.5 kg) and stirred with activated carbon (0.33 kg) at 25 °C for 1 h. The
mixture was filtered to remove the activated carbon. The activated carbon was washed with water (10.0 kg).
The combined aqueous layers were cooled to 10 °C and neutralized with 8.3 M sodium hydroxide solution
(7.86 kg) until pH>8 and then extracted with CH2Cl2 (3 x 21.0 kg). The combined organic layers were
washed with water (13.0 kg) and concentrated under reduced pressure. The residue was dissolved in
acetone (31.2 kg). To this solution was gradually added concd HCl (1.52 kg, 15.0 mol) at 10 °C. The

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HETEROCYCLES, Vol. 83, No. 8, 2011
reaction mixture was stirred at 15 °C for 20 h and then cooled to 5 °C and stirred at the same temperature for
2h. The precipitated crystals were filtered, washed with acetone (8.80 kg) and dried under reduced pressure
to yield 1 (4.41 kg, 73%, >99.9% ee) as a white crystalline solid.: mp 258-259 °C (decomp); []20D –8.82 (c
1.00, H2O); IR (KCl) 3406, 2983, 2763, 1588, 1324, 1146, 1129 cm-1; 1H-NMR (DMSO-d6) δ: 1.20 (3H, d,
J = 6.6 Hz), 1.98-2.07 (2H, m), 3.06-3.16 (1H, m), 3.22-3.31 (2H, m), 3.35 (4H, s), 3.44 (1H, dd, J = 14.1,
4.4 Hz), 3.59-3.74 (2H, m), 4.37-4.47 (1H, m), 7.93 (1H, t, J = 7.8 Hz), 8.32 (1H, d, J = 7.8 Hz), 8.54-8.60
(1H, m), 8.72 (1H, d, J = 4.9 Hz), 9.39 (1H, s), 9.51 (2H, br s); 13C-NMR (DMSO-d6) δ: 16.6, 26.8, 42.9,
45.5, 50.3, 50.9, 120.9 (J = 12.4 Hz), 127.5, 130.7 (J = 1.7 Hz), 132.2, 132.5 (J = 27.3 Hz), 133.2 (J = 5.0
Hz), 133.3, 149.8 (J = 5.0 Hz), 152.0 (J = 264.0 Hz); FABMS m/z 324 (M+H–HCl–2H2O)+, Anal. Calcd for
C15H23ClFN3O4S: C, 45.51; H, 5.86; Cl, 8.96; F, 4.80; N, 10.61. Found: C, 45.44; H, 5.65; Cl, 8.87; F, 4.68;
N, 10.78.
ACKNOWLEDGEMENTS
We are grateful to Dr. H. Hidaka, CSO, of D. Western Therapeutics Institute for promotion study. We thank
Dr. S. Tanabe, Director, for his encouragement and support and also Dr. K. Mizuno, Manager, for
pharmacology suggestions at Tokyo New Drug Research Laboratories, Kowa Co., Ltd. We also wish to
thank Dr. Kevin Swiss, Director, Kowa Research Institute, for his help in preparing the manuscript.
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