A practical procedure for preparation of N-(endo-8-(3-hydroxy)propyl-8-azabicyclo [3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinoline-carboxamide (TS-951)

Article abstract of DOI:10.3987/COM-00-9026

Effective and convergent process for the preparation of a potent and selective 5-HT₄ receptor agonist, the title compound, by reaction of 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid (6) with endo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octane dihydrochloride (20) has been described. Furthermore, this process was developed to pilot plant scale. 1-Isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid (6) was prepared from 2-aminobenzyl alcohol (12) in 65.6% overall yield and endo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octane dihydrochloride (20) was prepared from 2,5-dimethoxyfuran (16) in 43.4% overall yield.

Full text of DOI:10.3987/COM-00-9026

HETEROCYCLES, Vol. 53, No11, 2000, pp. 2471 - 2485, Received, 1st August, 2000
A PRACTICAL PROCEDURE FOR PREPARATION OF N-(endo-8-
(3-HYDROXY)PROPYL-8-AZABICYCLO[3.2.1]OCT-3-YL)-1-
ISOPROPYL-2-OXO-1,2-DIHYDRO-3-QUINOLINE-
CARBOXAMIDE (TS-951)
Masaji Suzuki, * Toshie Kaneko, Hiroaki Kamiyama, Yutaka Ohuchi and
Sadakazu Yokomori
Research Center Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-Cho,
Ohmiya, Saitama, 330-8530, Japan
Abstract － Effective and convergent process for the preparation of a
potent and selective 5-HT4 receptor agonist, the title compound, by
reaction of 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid
(6) with endo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octane
dihydrochloride (20) has been described. Furthermore, this process
was developed to pilot plant scale.
1-Isopropyl-2-oxo-1,2-dihydro-3-
quinolinecarboxylic acid (6) was prepared from 2-aminobenzyl alcohol
(12) in 65.6% overall yield and endo-3-amino-8-(3-hydroxypropyl)-8-
azabicyclo[3.2.1]octane dihydrochloride (20) was prepared from 2,5-
dimethoxyfuran (16) in 43.4% overall yield.
Introduction
Serotonin (5-HT) is a neurotransmitter which is widely distributed in humans and has a
remarkable variety of physiological effects.1 Among them, the existence of 5-HT4 receptor
was reported by Dumuis.2 In the gut,3 it participates in the induction and maintenance of
gastrointestinal motility, and its stimulants activate gastrointestinal motor function. We
recently reported
a
potent and selective 5-HT4 receptor agonist, (N-endo-8-(3-
hydroxy)propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinoline-
carboxamide (TS-951).4 In the present paper, we describe an effective and convergent
process for preparation of TS-951 and development to its pilot plant scale.
Our initial approach to TS-951 is outlined in Scheme 1. 2-Nitrobenzaldehyde (1) was
condensed with diethyl malonate in acetic anhydride in the presence of NaHCO3 at 100 ℃
to give diethyl benzylidenemalonate (2),5 which was transformed into the quinoline-
carboxylate (3) by reduction of nitro group and spontaneous cyclization. Alkylation of 3
with isopropyl iodide in the presence of sodium hydride in DMF led to a separable mixture

Scheme 1
CHO
COOEt
COOEt
COOEt
O
COOEt
O
b
c
a
N
NO2
N
NO2
H
3
1
2
4
NMe
NMe
O
NH2
COCl
O
COOH
d,e
8
g
N
f
H
N
N
O
O
N
6
7
9
NH
N
OH
O
O
O
j
N
h,i
N
H
H
O
N
N
10
TS-951
Reagents: (a) diethyl malonate, NaHCO3, Ac2O; (b) Fe, AcOH; (c) i-PrI, NaH, DMF; (d)
NaOH, EtOH, H2O; (e) HCl; (f) SOCl2, toluene; (g) NaOH, H2O, toluene; (h)
ClCOOCH(Cl)Me, ClCH2CH2Cl; (i) MeOH; (j) BrCH2CH2CH2OH, K2CO3, EtOH
of N-isopropylquinolinecarboxylate (4) and O-isopropyl isomer (5). In the case of pyridine
derivatives,6 the ratio of N-isopropyl isomer vs O-isopropyl isomer was 1:1 to 1:2, while in
this case, O-isopropylation proceeded predominantly to yield 4 in only 7%, although the
reason is uncertain. Quinolinecarboxylate (4) was transformed into acid chloride (7) in a
7
usual manner, which was condensed with 3α-aminotropane (8) to give carboxamide (9).
Furthermore, carboxamide (9) was demethylated by treatment with 1-chloroethyl
8
chloroformate followed by methanolysis to give demethylated product (10), from which
TS-951 was prepared by alkylation with 3-bromo-1-propanol under basic conditions.
Although a sequence of the process mentioned above was sufficient for the supplies of
modified derivatives of TS-951, it was undesirable to prepare their large amounts for the
following problems; 1. The yield in the process from 3 to 4 is very low and it needs
separation by column chromatography; 2. 8-Methyl group of 3α-aminotropane (8) has to be
demethylated in two-step demethylation processes.
In order to solve the above problems, the following plans were made. 1. Increase the yield
of 4. 2. Develop newly direct syntheses of compound (11) as intermediate.

Results and discussion
Preparation of 6
In order to improve the yield in alkylation of 3, we changed a sequence of alkylation and
cyclization for preparation of 4. The synthetic pathway to 6 was depicted in Scheme 2.
Scheme 2
CHO
NH
COOEt
d,e
O
COOH
O
OH
NH
OH
NH2
c
b
a
N
N
12
13
14
4
6
Reagents: (a) acetone, NaBH4, AcONa, AcOH, EtOH, H2O; (b) PCC/Al2O3, benzene; (c)
diethyl malonate, NaHCO3, Ac2O; (d) NaOH, EtOH, H2O; (e) HCl
2-Aminobenzyl alcohol (12) reacted with acetone and NaBH4 to give 2-
isopropylaminobenzyl alcohol (13)9in 70.7% yield. In this reaction, 1,2-dihydro-2,2-
dimethyl-4H-3,1-benzoxazine (15) was formed as a sideproduct and precipitated as a
crystalline solid from the reaction mixture. Fortunately, we found that 15 led to 13 by
10
NaBH4 reduction in EtOH
or catalytic reduction with platinum carbon in MeOH.
Therefore, N-alkylation route through benzoxazine (15) was tried (Scheme 3).
Scheme 3
c
a
d
O
b
12
13
14
6
N
H
15
Reagents: (a) acetone, AcOH, H2O; (b) H2/5%Pt-C, MeOH; (c) MnO2, toluene; (d) Meldrum's
acid, ethylenediamine, AcOH, MeOH
Namely, amino alcohol (12) reacted with acetone containing AcOH to give 15 as a solid,
catalytic hydrogenation of which produced to 2-isopropylaminobenzyl alcohol (13).
Although in this catalytic hydrogenation unchanged amino alcohol (12) was found to be
removed by washing with water, at the same time some of 13 was transferred into aqueous
layer by this washing process, and it caused somewhat decrease of yield of 13. Oxidation of
13 to benzaldehyde (14) was carried out by using manganese dioxide (MnO2).11,12
Unexpectedly, commercially available MnO2 did not give satisfactory results except for two
13
companies. Finally, we could find preferable MnO2 (CMD-100®)
for this oxidation.
Furthermore, the oxidation in toluene, acetonitrile and hexane gave good results, while that
in acetone and ether did not proceed. As a result, the oxidation was performed with CMD-

100® in toluene to give 14 in 62% yield. Reaction of 14 with diethyl malonate under basic
conditions took place simultaneously to give quinolinecarboxylate (4), which was turned into
carboxylic acid (6) by hydrolysis. However, the reaction of 14 with diethyl malonate
requires long reaction time and high reaction temperature. Since unchanged 14 were still
remained despite of long reaction time, it caused somewhat decrease of yield of 4.
Therefore, employment of more reactive malonate seemed to be required. Thus, the
reaction of compound (14) with Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione)
instead of diethyl malonate was investigated. First, solvent and catalyst were examined.
After several attempts, the reaction was found to proceed smoothly in the presence of
ethylenediamine diacetate in MeOH. Next, we investigated combination of ethylenediamine
diacetate / MeOH system (Table 1). As shown in Table 1, the condition of Run 16 resulted
in the highest yield (92%). Based on these investigations, the pilot plant scale conditions
Table 1. The reaction of 14 with Meldrum's acid a)
Run MeOH Ethylendiamine AcOH Meldrum's acid (6) b)
(vol.)
10
5
10
10
10
10
10
10
(eq)
1.0
1.0
0.1
0.5
2.0
1.0
1.0
1.0
(eq)
2.0
2.0
0.2
1.0
4.0
2.0
2.0
2.0
(eq)
1.8
1.8
1.8
1.8
1.8
1.2
1.5
3.0
(%)
84
87
63
86
61
52
71
90
1
2
3
4
5
6
7
8
9 c)
10
10
10
10
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
1.8
1.8
1.8
1.8
85
85
84
83
10 d)
11 e)
12 f)
13 g)
14
15
16
17
18 g)
10
5
5
5
5
1.0
0.5
0.5
0.5
0.5
2.0
1.0
1.0
1.0
1.0
1.8
1.8
1.5
2.0
2.2
85
90
86
92
92
5
0.5
1.0
1.8
89
a) The reaction was carried out at 0 ℃ for 2 h and then at rt overnight,
unless otherwise noted.
b) Purity of 6 is >99% by HPLC analysis.
c) at rt overnight.
d) at 40 ℃ for 2 h and at rt overnight.
e) at reflux for 2 h and then at rt overnight.
f) at 0 ℃ for 2 h and then at rt for 2 d.
g) at 0 ℃ for 0.5 h and reflux for 1 h.

were determined. This reaction has 3 advantages. 1) This reaction undergoes at room
temperature to give carboxylic acid (6) directly. 2) Carboxylic acid (6) is crystallized from
reaction mixture because of its insolubility in the used solvent. So that work-up is
performed only by filtration. 3) The product is obtained in high yield (92%) and high purity
(>99% by HPLC). Therefore, no purification step is required. Thus, we could develop
synthetic route of 6 fitting for scale-up as depicted in Scheme 3.
Synthesis of compound 11
In the original route, 8-methyl group in 8 had to be removed for preparation of 11.
Consequently, direct synthesis of 8-(3-hydroxy)propyl-3α-aminotoropane (11) was required
(Scheme 4). A solution of 17 in water, 3-amino-1-propanol and acetonedicarboxylic acid was
Scheme 4
O
N
OH
MeO
OMe
c,d
N
OHC
CHO
a
b
O
16
17
18
OH
2HCl
e
f
N
OH
N
OH
HO
N
HCl
NH2
NH2
19
11
20
Reagents: (a) HCl; (b) 3-amino-1-propanol, acetonedicarboxylic acid, pH 5;
(c) H2NOH, EtOH; (d) HCl; (e) H2-PtO2, AcOH; (f) HCl
reacted at pH4-5 to give tropinone (18).14 Also dimethyl acetonedicarboxylate could be
used instead of acetonedicarboxylic acid. Tropinone (18) reacted with hydroxylamine in
EtOH followed by treatment in a usual manner to lead to HCl salt (19) of tropinone oxime.
3
The reduction of 19 to amine (11) was accomplished by the catalytic reduction using Adams
catalyst. This reduction was sensitive to the reaction temperature. The reaction did not
start under 35 ℃ and hydrolysis of oxime function occurred over 50 ℃. Consequently,
the yield was less than 60% because of hydrolysis of 19 to tropinone (18). Since amine (11)
from oxime (19) was not obtained in high purity, purification step was required. For this
aim, conversion of 11 to the oxalate appeared to be preferable because of its facile
recrystallization. However, in the reaction of oxalate of 11 with acid chloride (7),
neutralization process was needed to remove oxalic acid, because oxalic acid reacts with 7.
From the above reasons, we gave up a route through oxime (19) as a procedure for scale-up.
A route by reductive amination of 18 was examined (Scheme 5). Tropinone (18) reacted
with benzylamine under reductive conditions to give amino product, which was converted
into HCl salt (21). Debenzylation reaction of 21 produced. Aminotropane (20) which
hydroxypropyl chain was introduced in advance was synthesized, so that demethylation and

Scheme 5
N
OH
2HCl
b
a
18
20
NH
21
Reagents: (a) benzylamine, H2-5%Pt/C, MeOH; (b) H2-5%Pd/C, MeOH
alkylation steps could be taken off. Therefore, a manufacturing process to TS-951 in 2 steps
shorter than the original route was accomplished.
Preparation of TS-951
Condensation reaction of 20 with acid chloride (7) was performed in a two-phase system
using toluene and aqueous NaOH solution. The reaction produced TS-951 accompanied with
a little amount of diacylated product (22), which increased at elevated reaction temperature.
O
O
N
Scheme 6
N
O
O
O
b,c
a
N
H
6
7
+
20
TS-951
N
22
Reagents: (a) SOCl2, toluene; (b) NaOH, H2O, toluene; (c) NaOH, EtOH, H2O
Fortunately, 22 was removed effectively by hydrolysis of the reaction mixture with 10%
aqueous NaOH solution in EtOH. After the hydrolysis, the product was precipitated by
addition of water to the reaction mixture and collected by filtration. Thus, TS-951 was
obtained as crystals from the reaction mixture without any separation process.
Pilot Plant Result
Carboxylic acid (6) was synthesized according to synthetic route developed as depicted in
Scheme 3. Both cyclization of 12 to 15 and catalytic hydrogenation of 15 to 13 were
performed similar to laboratory examination. Oxidation of 13 to 14 was performed in
higher yield than that in laboratory examination. In laboratory, some of 14 were lost in
filtration and purification processes. Also condensation step to 6 performed higher yield.
We used centrifugal separator in pilot plant, which required very little amount of solvent for
washing crystals and free from loss of product. It was confirmed from the HPLC analysis
that some of product was transferred to mother liquid in laboratory examination. According
to developed synthetic route, carboxylic acid (6) was synthesized from 12 in 4 steps (65.6%
overall yield). Compound (20) was synthesized according to synthetic route developed as

depicted in Scheme 5. Reductive amination of 18 to 21 and reductive debenzylation of 21
to 20 were performed under higher hydrogen pressure (4.0-5.0 Mpa) than that (0.5 Mpa) in
laboratory procedure, which did not result in unpreferable difference in reaction. Thus,
compound (20) was synthesized in 3 steps and 43.4% yield. Carboxylic acid (6) was turned
into acid chloride (7) with SOCl2 in toluene. The reaction mixture was vigorously bubbled
even if SOCl2 was added slowly. The reaction proceeded very clearly and 7 was obtained in
>99% purity by HPLC analysis. The acid chloride solution was added to a solution of
NaOH and 20 in water over 1 h to prevent rising of reaction temperature. After work-up,
TS-951 was prepared in 92.6% yield as crystals. It was result similar to that obtained in
laboratory examination.
Conclusions
Effective and convergent process for the preparation of TS-951 has been examined.
Synthesis of 1-isopropyl-2-oxo-3-quinolinecarboxylic acid (6) by a sequence containing
reductive cleavage of oxazine ring, oxidation using MnO2, and condensation with Meldrum’s
acid was accomplished. Also HCl salt (20) of 8-(3-hydroxypropyl)-3α-aminotropane was
synthesized effectively through reductive amination. Compounds (6) and (20) were
condensed under phase-transfer conditions to produce TS-951 in good yield. This process
could be developed to a pilot plant scale.
EXPERIMENTAL
Melting points were determined by a Buchi 535 melting point apparatus and are uncorrected.
IR spectra (KBr) were taken on a Perkin-Elmer 1760 spectrometer. 1H-NMR spectra were
recorded on a Varian VXL-200 spectrometer in CDCl3, unless otherwise noted. Chemical
shifts are reported in ppm (δ) values, based on tetramethylsilane as an internal standard.
MS were taken on a JEOL JMS-SX102 spectrometer. Elemental analyses were taken on a
Perkin-Elmer 2400. TLC was performed on silicagel pre-coated plates (Merck, Kieselgel
60F-254). Column chromatography was carried out over silicagel (Asahi glass, M. S. GEL.
SIL.)
5
Diethyl (2-nitrobenzylidene)malonate (2)
To a solution of 2-nitrobenzaldehyde (1) (70.0 g, 0.46 mol) in acetic anhydride (175 mL)
were added diethyl malonate (70.3 mL, 0.46 mol) and NaHCO3 (58.4 g, 0.70 mol). The
reaction mixture was heated at 100 ℃ for 6 h. After being cooled, the reaction mixture
was partitioned between AcOEt and water. The organic layer was washed successively with
water, 5% Na2CO3 and brine, and dried over Na2SO4. The solvent was removed in vacuo to
give a residue, which was triturated with EtOH to give 77.1 g (56.7%) of 2 as a pale yellow
1
solid: mp 49-51 ℃ (recrystallized from EtOH). H-NMR δ: 1.02 (3H, t, J = 7.2 Hz), 1.36
(3H, t, J = 7.2 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.35 (2H, q, J = 7.2 Hz), 7.39-7.48 (1H, m),
7.50-7.70 (2H, m), 8.20 (1H, s), 8.16-8.26 (1H, s). MS m/z: 293 (M+).
Ethyl 2-oxo-1,2-dihydro-3-quinolinecarboxylate (3)

To a pre-heated (80 ℃) solution of 2 (46 g, 0.15 mol) in acetic acid (500 mL) was added iron
powder (53 g, 0.95 mol). The reaction mixture was heated at 80 ℃ for 6.5 h and then
cooled and filtered through a Celite pad. The filtrate was evaporated in vacuo to leave a
residue, which was purified by column chromatography using CHCl3/MeOH 10:1, to give
21.3 g (62.5%) of 3 as a yellow solid: mp 175-179 ℃ (recrystallized from AcOEt-hexane).
1H-NMR δ: 1.45 (3H, t, J = 7.2 Hz), 4.46 (2H, q, J = 7.2 Hz), 7.20-7.30 (1H, m), 7.50 (1H,
d, J = 7.8 Hz), 7.61 (1H, ddd, J = 1.4, 7.0, 8.4 Hz), 7.65 (1H, d, J = 8.0 Hz), 8.56 (1H, s),
12.51 (1H, s). IR cm-1: 3009, 2901, 1732, 1641, 1211. MS m/z: 217 (M+). Anal. Calcd
for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.11; H, 5.24; N, 6.20.
Ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate (4)
To a suspension of sodium hydride (60% mineral oil suspension, 8.9 g, 0.38 mol) in DMF
(200 mL) was added ethyl 2-oxo-1,2-dihydro-3-quinolinecarboxylate (3) (40 g, 0.18 mol)
and isopropyl iodide (62.6 g, 0.36 mol). The reaction mixture was heated at 70 ℃ for 8 h.
It was then diluted with water and extracted with AcOEt. The organic layer was washed
with brine, dried over Na2SO4 and evaporated in vacuo to afford a residue, which was
purified by column chromatography using AcOEt/hexane 1:4, to give 3.1 g (6.5%) of 4 as a
yellow solid: mp 54-57 ℃ (recrystallized from AcOEt-hexane). 1H-NMR δ: 1.42 (3H, t,
J = 7.2 Hz), 1.66 (6H, d, J = 7.2 Hz), 4.41 (2H, q, J = 7.2 Hz), 5.15-5.80 (1H, br), 7.17-7.27
(1H, m), 7.54-7.69 (3H, m), 8.30 (1H, s). IR cm-1: 3454, 1732, 1646. MS m/z: 259 (M+).
Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.28; H, 6.72; N, 5.18.
1-Isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid (6)
To a mixture of ethylenediamine (0.41 mL, 6.1 mmol), acetic acid (0.70 mL, 12.2 mmol), 14
(1.00 g, 6.1 mmol) and MeOH (10 mL) was added meldrum’s acid (1.59 g, 11.0 mmol) at
0 ℃ and the mixture was stirred for 2 h at same temperature. The reaction mixture was
stirred at rt overnight. The resulting precipitates was filtered and washed with MeOH to
give 1.17 g (84%) of 6 as a yellow solid: mp 167-169 ℃ (recrystallized from acetone-H2O).
1H-NMR δ: 1.71 (6H, d, J = 7.2 Hz), 5.25-5.75 (1H, br), 7.36-7.45 (1H, m), 7.69-7.85 (3H,
m), 8.88 (1H, s), 14.76 (1H, s). IR cm-1: 2535, 1734, 1631. MS m/z: 231 (M+). Anal.
Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.42; H, 5.54; N, 6.07.
1-Isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid chloride (7)
3-Quinolinecarboxylic acid (6) (10.0 g, 43.2 mmol) was dissolved in thionyl chloride (20mL,
274 mmol) and the mixture was heated at reflux for 4 h. It was evaporated in vacuo to leave
a residue, which was dissolved in toluene (30 mL). It was evaporated in vacuo again to give
10.6 g of crude 7 as a pale yellow solid.
N-(endo-8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-
quinolinecarboxamide (9)
To a solution of crude 7 (540 mg) obtained above in toluene (2 mL), 3α-aminotropane (8)
(404 mg, 2.8 mmol) in toluene (3 mL) was added and the whole was stirred at rt for 1 h.
The reaction mixture was then poured into 5%NaHCO3 and extracted with CHCl3. The

organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum. The
residue was purified by column chromatography using CHCl3 to give a solid, which was
recrystallized from AcOEt to give 391 mg (51%) of 9 as a colorless solid: mp 173-177 ℃.
1H-NMR δ: 1.68 (6H, d, J = 7.2 Hz), 1.76-1.83 (2H, m), 2.00-2.40 (6H, m), 2.34 (3H, s),
3.10-3.28 (2H, m), 4.30 (1H, q, J = 7.0 Hz), 5.40-5.90 (1H, br), 7.22-7.33 (1H, m), 7.55-7.70
(2H, m), 7.75 (1H, d, J = 7.8 Hz), 8.83 (1H, s), 10.48 (1H, d, J = 7.2 Hz). IR cm-1: 3263,
2961, 1673, 1616, 1585, 1568, 1528. MS m/z: 353 (M+). Anal. Calcd for C21H27N3O2: C,
71.36; H, 7.70; N, 11.88. Found: C, 71.21; H, 7.67; N, 11.84.
N-(endo-8-Azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinoline-
carboxamide (10)
To a solution of 9 (1.0 g, 2.8 mmol) in 1,2-dichloroethane (10 mL) was added 1-chloroethyl
chloroformate (0.41 g, 2.8 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h and
refluxed for 1 h. It was evaporated in vacuo and the residue was dissolved in MeOH (10
mL). The solution was stirred at reflux for 1 h and was then evaporated in vacuo. The
residue was purified by column chromatography using CHCl3/MeOH (saturated with NH3)
20:1 to leave a solid, which was recrystallized from AcOEt to give 530 mg (55%) of 10 as a
colorless solid: mp 202-203 ℃. 1H-NMR δ: 1.69 (6H, d, J = 7.2Hz), 1.78-2.40 (9H, m),
3.55-3.68 (2H, m), 4.38 (1H, q, J = 7.0 Hz), 5.40-5.82 (1H, br), 7.23-7.35 (1H, m), 7.56-7.70
(2H, m), 7.75 (1H, d, J = 7.8 Hz), 8.83 (1H, s), 10.54 (1H, d, J = 7.2 Hz). IR cm-1: 3257,
2971, 1674, 1622, 1569, 1531. MS m/z: 339 (M+). Anal. Calcd for C20H25N3O2: C, 70.77;
H, 7.42; N, 12.38. Found: C, 70.57; H, 7.49; N, 12.44.
1,2-Dihydro-2,2-dimethyl-4H-3,1-benzoxadine(15)
To a mixture of 2-aminobenzyl alcohol (12) (500 g, 4.63 mol), acetic acid (8.3 g, 0.14 mol)
and water (4000 mL) was added acetone (509 mL, 6.94 mol). The reaction mixture was
stirred at rt for 1 h and was then stirred at 0 ℃ for 1 h. Resulting precipitates were filtered,
washed with water and dried to give 700 g (93%) of 15 as a yellow solid: mp 119-121 ℃
(recrystallized from acetone-H2O). 1H-NMR δ: 1.48 (6H, s), 3.97 (1H, s), 4.83 (2H, s),
6.64 (1H, d, J = 7.0 Hz), 6.79 (1H, t, J = 7.0 Hz), 6.95 (1H, d, J = 7.0 Hz), 7.08 (1H, t, J =
7.0 Hz). IR cm-1: 3310, 1612, 1592. MS m/z: 163 (M+). Anal. Calcd for C10H13NO: C,
73.59; H, 8.03; N, 8.58. Found: C, 73.40; H, 7.97; N, 8.64.
2-Isopropylaminobenzyl alcohol (13)
From 12: To a mixture of 12 (150 g, 1.22 mol), acetic acid (850 mL), sodium acetate hydrate
(300 g), acetone (500 mL), EtOH (275 mL) and water (950 mL) was added a solution of
sodium borohydride (140 g, 3.68 mol) in 5% NaOH aqueous solution (500 mL) at 0-5 ℃
over a period of 2 h. The reaction mixture was stirred for 1 h and basified with K2CO3.
The mixture was extracted with hexane. The organic layer was washed with water, and brine.
The solvent was evaporated in vacuo and the resulting oily residue was distilled under
reduced pressure to give 142 g (70.7%) (bp 114 ℃ / 4 mmHg) of 13 as a yellow oil:1H-

NMR δ: 1.24 (6H, d, J = 7.2 Hz), 3.78 (1H, sept, J = 7.2 Hz), 4.62 (2H, s), 6.57-6.72 (2H,
m), 7.02-7.05 (1H, m), 7.15-7.27 (1H, m). IR cm-1: 3391, 1608, 1587. MS m/z: 165 (M+).
Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.30; H, 9.33; N, 8.88.
From 15: A mixture of 15 (7.0 g, 43 mmol), 5%Pt-C (0.14 g) and MeOH (70 mL) was heated
at 40 ℃ for 15 h under hydrogen pressure of 0.5 MPa. The reaction mixture was filtered
and filtrate was concentrated in vacuo. The residue was dissolved in toluene and washed
with water repeatedly. The solvent was evaporated in vacuo to give 5.6 g of crude 13 as a
yellow oil.
2-Isopropylaminobenzaldehyde (14)
To a solution of crude 13 (33.62 g) in toluene (300 mL) was added MnO2(CMD-100®) (44.12
g, 0.51 mol) and the mixture was stirred at reflux for 2 h. The reaction mixture was filtered
and filtrate was evaporated in vacuo. The residue was purified by column chromatography
using hexane/AcOEt = 10:1 to give 20.59 g of 14 as a yellow oil: 1H-NMRδ: 1.28 (6H, d, J=
6.4 Hz), 3.75 (1H, sept, J = 6.4 Hz), 6.61-6.72 (2H, m), 7.33-7.47 (2H, m), 8.28 (1H, br),
9.80 (1H, s). IR cm-1: 3317, 1652, 1610, 1579. MS m/z: 163 (M+). Anal. Calcd for
C10H13NO･0.25H2O: C, 71.61; H, 8.11; N, 8.35. Found: C, 71.64; H, 7.92; N, 8.65.
To a solution of 14 (1.00 g, 6.13 mmol) in AcOEt (5 mL) was added 4 mol/L HCl in AcOEt
(1.5 mL) and the mixture was stirred at 0 ℃ for 2 h. The resulting precipitates was filtered
and washed with AcOEt to give 1.02 g of 2-isopropylaminobenzaldehyde hydrochloride as a
1
orange prism: mp 133-136 ℃ (recrystallized from IPA-AcOEt). H-NMRδ: 1.45 (6H, d, J
= 7.0 Hz), 3.74 (1H, sept, J = 7.0 Hz), 7.48 (1H, dt, J = 1.5, 7.0 Hz), 7.60-7.95 (5H, m),
10.00 (1H, s). IR cm-1: 3372, 2980, 2630, 1692, 1610, 1588. MS m/z: 163 (M+). Anal.
Calcd for C10H13NO･HCl･0.1H2O: C, 59.61; H, 7.10; N, 6.95. Found: C, 59.65; H, 6.91; N,
6.91.
8-(3-Hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one (18)
To a stirred mixture of 2,5-dimethoxytetrahydrofuran 16 (120 mL, 0.93 mol) and water (300
mL) was added concentrated HCl (45 mL) at rt. After 20 min, the reaction mixture became
homogeneous. Thereafter, water (450 mL), a solution of 3-amino-1-propanol (105 mL,1.37
mol) and concentrated HCl (138 mL) in water (600 mL), a solution of 1,3-
acetonedicarboxylic acid (150 g, 1.03 mol) in water (700 mL), and a solution ofNa2HPO4 (66
g) in water (300 mL) were successively added to the homogeneous reaction mixture.
Furthermore, pH of the resulting solution was then adjusted to the range of 4 to 5 with 40%
aqueous NaOH solution (215 mL). After bubbling of carbon dioxide (CO2) was confirmed,
the mixture was stirred at rt overnight. Then concentrated HCl was added to adjust pH of
the reaction mixture to 3. The reaction mixture was heated to 80 ℃ and stirring was
continued until bubbling of CO2 was not observed. After completion of the reaction, the
reaction mixture was cooled and 20% aqueous NaOH solution was added thereto to render
alkaline. Thereafter sodium chloride was added, and the mixture was extracted with CHCl3.
The organic layer was washed with water and dried over Na2SO4. The organic layer was

evaporated in vacuo to give 18 (178.1 g) as a crude product: mp 42-43 ℃. (recrystallized
1
from acetone-hexane) H-NMR δ: 1.57-1.68 (2H, m), 1.73-1.83 (2H, m), 2.00-2.17 (4H,m),
2.20-2.29 (2H, m), 2.66 (2H, dd, J = 4.4, 16.1 Hz), 2.84 (2H, t, J = 5.7 Hz), 3.62-3.66 (2H,
m), 3.90 (2H, t, J = 5.7 Hz), 5.12 (1H, brs). IR cm-1: 1714. MS m/z: 183 (M+). Anal.
Calcd for C10H17NO2 0.1H2O: C, 64.91; H, 9.37; N, 7.57. Found: C, 64.53; H, 9.40; N,7.57.
8-(3-Hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one oxime hydrochloride (19)
A crude product of 18 (178.1g) obtained above was dissolved in EtOH (1200 mL) and 50%
aqueous hydroxylamine solution (72.9 g, 1.10 mol) was added to the solution at rt. The
reaction mixture was stirred at rt overnight. The reaction mixture was evaporated in vacuo
and toluene was added to the residue. The solvent was again evaporated in vacuo and the
residue was dissolved in EtOH. To a solution was added concentrated HCl and the
crystalline precipitates were filtered to give 161 g (73.9% from 16) of 19 as a colorless solid:
mp 239-242 ℃ (decomp, recrystallized from MeOH-EtOH). 1H-NMR(MeOH-d4) δ:
1.75-2.08 (4H, m), 2.21-2.56 (4H, m), 2.83-2.93 (1H, m), 3.19-3.45 (3H, m), 3.73 (2H, t, J =
5.7 Hz), 4.14-4.20 (2H, m). IR cm-1: 1658. MS m/z: 198 (M+). Anal. Calcd for
C10H19N2O2Cl: C, 51.17; H, 8.16; N, 11.93. Found: C, 51.17; H, 8.15; N, 11.93.
endo-3-Amino-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octane (11)
To a solution of 19 (100 g, 0.43 mol) in AcOH (500 mL) was added platinum oxide (5.0 g)
and the whole was stirred at 45 ℃ for 18 h under hydrogen pressure of 0.5 MPa. To the
reaction mixture was added water and the mixture was filtered. The filtrate was evaporated
in vacuo. The residue was dissolved in water (50 mL) and MeOH (100 mL). To asolution
was added a solution of oxalic acid (38.4 g) in MeOH (200 mL) and further MeOH (200 mL)
was added. The mixture was stirred at rt overnight. The precipitated crystals were filtered
to give 71.3 g (53.9%) of endo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octane
hydrochloride oxalate as a colorless solid: mp 230-233 ℃ (decomp, recrystallized from
MeOH). 1H-NMR(DMSO-d6)δ 1.66-1.94 (6H, m), 1.94-2.25 (6H, m), 2.38-2.63 (2H, m),
2.71-3.10 (3H, m), 3.35-3.61 (3H, m), 3.63-4.00 (3H, m). IR cm-1: 3414, 2115, 1634. MS
m/z: 184 (M+). Anal. Calcd for C12H23N2O4Cl: C, 48.89; H, 7.86; N, 9.50. Found: C,
48.59; H, 8.10; N, 9.77.
To a solution of oxalate obtained above (30.0 g, 0.097 mol) in water (300 mL) was added
KHCO3 (48.3 g) and stirring was continued at rt for 4 h. Then, EtOH (300 mL) was added.
After stirring for 1 h, the precipitated matters were filtered off and the filtrate was
concentrated. Again EtOH (300m L) was added to the residue. The precipitated matters
were filtered off and the filtrate was concentrated. The residue was dissolved in CHCl3
(300 mL). After drying over Na2SO4, the solvent was evaporated in vacuo to give 18.5 g of
crude 11 as a colorless oil: 1H-NMR δ: 1.43-1.50 (2H, m), 1.54-1.71 (2H, m), 1.85-2.14
(6H, m), 2.60 (2H, t, J = 5.6 Hz), 3.19-3.37 (3H, m), 3.85 (2H, t, J = 5.2 Hz).
endo-3-Amino-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octane dihydrochloride (20)
To a solution of oxime hydrochloride (19) (100 g, 0.43 mol) in AcOH (500 mL) was added

platinum oxide (5.0 g) and the reaction mixture was stirred at 45 ℃ for 18 h under hydrogen
pressure of 0.5 MPa. Water was added to the reaction mixture and the mixture was filtered.
Concentrated HCl was added to the filtrate and the mixture was evaporated in vacuo. The
residue was recrystallized from MeOH-EtOH to give 66.4 g (50.2%) of 20 as a colorless
solid: mp >270℃. 1H-NMR (D2O) δ: 1.95-2.03 (2H, m), 2.03-2.35 (4H, m), 2.35-2.58
(2H, m), 2.58-2.75 (2H, m), 3.10-3.25 (2H, m), 3.70 (2H, t, J = 6.0 Hz), 3.80 (1H, t, J = 5.4
Hz), 4.05-4.25 (2H, m). IR cm-1: 3408, 2989, 2849, 1597, 1505. MS m/z: 185 (M+). Anal.
Calcd for C10H22N2OCl2: C, 46.70; H, 8.62; N, 10.89. Found: C, 46.70; H, 8.77; N, 10.85.
N-(endo-8-(3-Hydroxy)propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-
dihydro-3-quinolinecarboxamide (TS-951)
From 10: To a solution of 10 (2.00 g, 5.9 mmol) in EtOH (50 mL) were added3-bromo-1-
propanol (0.53 mL, 5.9 mmol) and K2CO3 (0.81 g, 5.9 mmol). The reaction mixture was
stirred at reflux for 10 h and was then evaporated in vacuo. To the residue was added water
and the mixture was extracted with CHCl3. The organic layer was dried over Na2SO4 and
evaporated in vacuo.
The residue was purified by column chromatography using
CHCl3/MeOH (saturated with NH3) 40:1, to afford a solid, which was recrystallized from
AcOEt to give 510 mg (21.8%) of TS-951 as a colorless solid.
From 6 and 20: To a solution of 6 (0.99 g, 4.3 mmol) in toluene (10 mL) was added thionyl
chloride (0.77 g, 6.5 mmol) and the whole was stirred at 80 ℃ for 1 h. The reaction
mixture was used in next step without purification.
To a solution of NaOH (0.93 g, 23.3 mmol) and 20 (1.00 g, 3.89 mmol) in water (10 mL) was
added a solution of acid chloride at 5-15 ℃. After being stirred for 0.5 h, the reaction
mixture was concentrated in vacuo. To the resulting residue were added EtOH (10 mL) and
10% aqueous NaOH solution (10 mL), and the whole was stirred at rt for 0.5 h. Additional
water (20 mL) was added to the reaction mixture. The resulting precipitates was filtered to
give 1.44 g (93%) of TS-951 as a colorless solid: mp 171-172 ℃ (recrystallized from
EtOH-H2O). 1H-NMR δ: 1.68 (6H, d, J = 7.2 Hz), 1.62-1.78 (2H, m), 1.80-196 (2H, m),
2.00-2.38 (6H, m), 2.72 (2H, t, J = 7.0 Hz), 3.32-3.52 (2H, m), 3.88 (2H, t, J = 7.0 Hz), 4.30
(1H, q, J = 7.0 Hz), 5.45-5.80 (1H, br), 7.23-7.33 (1H, m), 7.56-7.70 (2H, m), 7.75 (1H, d, J
= 7.8 Hz), 8.83 (1H, s), 10.51 (1H, d, J = 7.2 Hz). IR cm-1: 3431, 3240, 1669. MS m/z:
397 (M+). Anal. Calcd for C23H31N3O3: C, 69.49; H, 7.86; N, 10.57. Found: C, 69.22; H,
7.90; N, 10.43.
A procedure for pilot plant scale
1,2-Dihydro-2,2-dimethyl-4H-3,1-benzoxadine (15)
To a mixture of 2-aminobenzyl alcohol (12) (49.5 kg, 402 mol), acetic acid (0.73 kg, 12.1
mol) and water (360 kg) was added acetone (35.0 kg, 603 mol). The reaction mixture was
stirred at rt for 1 h and the whole was stirred at 5 ℃ for overnight. Resulting precipitates
was filtered, washed with water and dried, to give 62.2 kg (purity 98.9%, yield 94.8%) of 15
as a brown solid.

2-Isopropylaminobenzyl alcohol (13)
A mixture of 15 (31.1 kg, 191 mol), 5%Pt-C (wet) (1.2 kg as dry weight) and MeOH (160kg)
was stirred at 35 ℃ for 5 h under hydrogen pressure of 3.0 MPa. The reaction mixture was
filtered. This reaction was repeated twice and combined filtrate was concentrated in vacuo.
The residue was dissolved in toluene (250 kg) and washed three times with water (130 kg).
This toluene solution was estimated including 49.3 kg of 13 by GC, which was advanced
directly to next oxidation step.
2-Isopropylaminobenzaldehyde (14)
To a solution of 13 (estimated 49.3 kg by GC) in toluene (250 kg) was added MnO2 (CMD-
100®) (66 kg, 759 mol) and the mixture was stirred at reflux for 5 h. Additional MnO2
(CMD-100®) (14 kg, 161 mol) and toluene (50 kg) were added to the reaction mixture and the
reaction mixture was then heated at reflux for 2 h. The reaction mixture was filtered and
filtrate was evaporated in vacuo to give 45.9 kg of crude 14.
1-Isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid (6)
To a solution of crude 14 (45.9 kg) in MeOH (184 kg) were added ethylenediamine (8.5 kg,
141 mol), acetic acid (16.9 kg, 281 mol) and meldrum’s acid (73.0 kg, 507 mol) at 0-10 ℃.
After the reaction mixture was stirred at room temperature overnight, it was cooled to 5 ℃.
The resulting precipitates was filtered, washed with MeOH (10 kg) and dried, to give 61.0 kg
(purity: 99.7%, yield: 65.6% from 12) of 6 as a yellow solid.
8-(3-Hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one (18)
To a cooled solution of 3-amino-1-propanol (56.3 kg, 750 mol) in water (330 kg) was added
36% HCl (91.2 kg, 900 mol). To a stirred mixture of 2,5-dimethoxytetrahydrofuran (16)
(66.1 kg) in water (230 kg) was added 36% HCl (30.4 kg) at rt. After 20 min, 3-amino-1-
propanol hydrochloride solution obtained above, water (180 kg), dimethyl
acetonedicarboxylate (100 kg, 574 mol) in water (390 kg), Na2HPO4 12H2O (90 kg) solution
in water (100 kg) were added to the reaction mixture. After addition was completed, pH of
the resulting solution was then adjusted to the range of 4 to 5 with 25 kg of 48% aqueous
NaOH solution. After the mixture was stirred for overnight, 188 kg of 48% aqueous NaOH
solution was added and heated at 80 ℃ for 2 h. The mixture was cooled and 36% HCl (235
kg) was added. The mixture was stirred at 80 ℃ for 1 h, then cooled to rt. 110 kg of 48%
aqueous NaOH solution was added thereto to render alkaline. Thereafter NaCl (325 kg) was
added, and the mixture was extracted with CH2Cl2. The organic layer was washed with 25%
aqueous NaCl solution and dried over Na2SO4 (30 kg). The organic layer was evaporated in
vacuo, and the resulting residue was dissolved in MeOH (480 kg). The solution was
evaporated in vacuo again, and the residue was dissolved in MeOH (640 kg). The solution
was estimated including 63.2 kg of 18 by GC.
endo-3-Benzylamino-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octane dihydrochloride
(21)
To a solution of 18 (estimated 63.2 kg by GC) in MeOH (640 kg), benzylamine (56.7 kg, 524

mol), 5%Pt-C (wet) (9.2 kg as dry weight) and MeOH (120 kg) were added. The reaction
mixture was stirred for 18 h at 45 ℃ under hydrogen pressure of 4.0 MPa. The reaction
mixture was filtered and the filtrate was evaporated in vacuo. To the residue was added
8.4% HCl in MeOH (567 kg), and then diisopropyl ether (329 kg) was added. The mixture
was cooled to 0 ℃ and stirred for overnight. Resulting precipitates were filtered to give
83.3 kg of wet 21: mp 246-249 ℃ (recrystallized from MeOH-diisopropyl ether).1H-NMR
(DMSO-d6) δ: 1.64-2.00 (2H, m), 2.05-2.46 (6H, m), 2.67-2.90 (2H, m), 2.90-3.12
(2H, m), 3.23-3.60 (3H, m), 3.80-4.05 (2H, m), 4.25 (2H, s), 7.37-7.52 (3H, m), 7.60-7.78
(2H, m), 9.43-9.80 (2H, br), 10.50-10.80 (1H, br). IR cm-1: 3302, 1590. MS m/z:274 (M+).
Anal. Calcd for C17H28N2OCl2: C, 58.79; H, 8.13; N, 8.07. Found: C, 58.50; H, 8.21; N,
8.02.
endo-3-Amino-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octane dihydrochloride (20)
The mixture of wet 21 (83.3 kg), 5%Pd-C (wet) (9.3 kg as dry weight), 36% HCl (11.4 kg),
MeOH (640 kg) and water (200 kg) was stirred for 3.5 h under hydrogen pressure of 5.0 Mpa
at 60 ℃. The reaction mixture was filtered and the filtrate was evaporated in vacuo. To
the residue were added water (6.3 kg) and EtOH (160 kg). The mixture was refluxed to
dissolve a solid and then additional EtOH (200 kg) was added. It was cooled to 0 ℃ and
stirred for overnight. Resulting precipitates were filtered and dried in vacuo to give 55.9kg
(purity 100%, yield 43.4% from 16) of 20 as a colorless solid. mp >270℃.
N-(endo-8-(3-Hydroxy)propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-
dihydro-3-quinolinecarboxamide (TS-951)
To a mixture of 6 (13.0 kg, 56.2 mol) and toluene (56.2 kg) were added thionyl chloride (10.0
kg, 84.3 mol) and the mixture was stirred at 80 ℃ for 3 h. The reaction mixture bubbled
vigorously in early stage of reaction. After the reaction was completed by HPLC analysis,
it was cooled to rt. The acid chloride solution was used in following condensation step
without work-up. To a solution of NaOH (12.3 kg, 307 mol) and 20 (13.2 kg, 51.1 mol) in
water (132 kg), above obtained acid chloride solution was added under 15 ℃. The reaction
mixture was stirred at rt overnight. The reaction mixture was heated to 70 ℃ and the
organic layer was separated from aqueous layer. The organic layer was concentrated in
vacuo. To the resulting residue were added EtOH (72.2 kg), 45.1 kg of 14% aqueous NaOH
solution, and water (20.0 kg). The mixture was stirred at 38 ℃ for 1 h. After hydrolysis
was completed by HPLC analysis, additional water (237 kg) was added. The resulting
precipitates was filtered and dried to give 18.8 kg (purity 99.8%, yield 92.6%) of TS-951 as a
pale yellow solid.
ACKNOWLEDGEMENTS
The authors wish to thank Mr. Kyoichi Hasegawa and Mr. Masato Ito for their technical
assistance.

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15
11. Compound (13) was oxidized to benzaldehyde (14) with PCC or DDQ
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but both of
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