Development and Kilogram-Scale Synthesis of a D2/5-HT2A Receptor Dual Antagonist (±)-SIPI 6360

Article abstract of DOI:10.1021/acs.oprd.6b00220

The kilogram-scale synthesis of a D₂/5-HT_2A receptor dual antagonist (±)-SIPI 6360 was developed as an alternative treatment for schizophrenia. Specifically, three conditions were modified and optimized, including the Vilsmeier condi

Full text of DOI:10.1021/acs.oprd.6b00220

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Full Paper
Development and Kilogram-Scale Synthesis of a
D2/5-HT2A Receptor Dual Antagonist (±)-SIPI 6360
Xiaowen Chen, Yu Liu, Xunqi Jin, Yuanyuan Sun, Shunlin Gu, Lei Fu, and Jianqi Li
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00220 • Publication Date (Web): 24 Aug 2016
Downloaded from http://pubs.acs.org on August 25, 2016
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Development and Kilogram-Scale Synthesis of a D2/5-HT2A Receptor Dual
5
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Antagonist (±)-SIPI 6360
XiaoꢀWen Chen,†,‡ Yu Liu,‡ XunꢀQi Jin,‡ YuanꢀYuan Sun,‡ ShunꢀLin Gu,§ Lei Fu,*,†
JianꢀQi Li*,‡
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†School of Pharmacy, Shanghai JiaoTong University, 800 Dongchuan Rd, Shanghai
200240, PR China
‡Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of
Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini
Rd, Shanghai 201203, PR China
§School of Pharmaceutical Engineering and Life Science, Changzhou University, 1 Gehu
Rd, Changzhou, Jiangsu Province 213164, PR China
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ABSTRACT: The kilogramꢀscale synthesis of a D2/5ꢀHT2A receptor dual antagonist
(±)ꢀSIPI 6360 was developed as an alternative treatment for schizophrenia. Specifically,
three conditions were modified and optimized, including the Vilsmeier conditions, to
prepare quinoline 3. In addition, the palladiumꢀcatalyzed hydrogenation was modified to
synthesize dihydroquinolinꢀ2(1H)ꢀone 5, and the reduction of βꢀchloroamide was altered
to form 3ꢀchloropropanamine 8. Ultimately these improvements led to the preparation of
1.5 kilogram of (±)ꢀSIPI 6360 batch in eight steps with an overall yield of 34% and purity
of 99.8%.
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Keywords: schizophrenia, D2/5ꢀHT2A receptor antagonist, Vilsmeier condition,
palladiumꢀcatalyzed hydrogenation
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INTRODUCTION
Schizophrenia is one of the most serious mental illnesses, causing suicides and a broad
societal burden.1,2 As potent dopamine D2 receptor antagonists, the “typical”
antipsychotic agents (e.g., Haloperidol) are effective in the treatment of positive
symptoms of schizophrenia, but largely ineffective in the management of negative
symptoms and cognitive impairment. Typical antipsychotics can also induce severe side
effects, such as extrapyramidal symptoms (EPS).3 These extrapyramidal
symptoms include acute dyskinesia and dystonic reactions, tardive dyskinesia,
Parkinsonism, akinesia, akathisia, and neuroleptic malignant syndrome. Characterized by
a multiple target effect, the “atypical” antipsychotic agents, such as the D2/5ꢀHT2A
receptor dual antagonist Risperidone, offer therapeutic advantages over typical
antipsychotics accompanied by a lower incidence of EPS .4
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Our research team has been devoted to the discovery of potential atypical
antipsychotics for several years,5 and we have discovered a series of novel and potent
aralkyl substituted piperidine or piperazine D2/5ꢀHT2A receptor dual antagonist
candidates, such as (±)ꢀSIPI 6360 (Scheme 1).6 To support preclinical development and
safety studies, it was necessary to produce a scalable and practical synthesis of (±)ꢀSIPI
6360 suitable for kilogramꢀscale preparation..
According to the initial synthetic route for (±)ꢀSIPI 6360, its increase in scale
appears to be a great challenge due to the following specific disadvantages: (a) the low
yield in preparation of quinoline 3; (b) the chromatographic step and low yield in
preparation of both 3,4ꢀdihydroꢀ2(1H)ꢀquinolinone 5 and 3ꢀchloropropanamine 8; (c) the
1% overall yield. Herein, we report a kilogramꢀscale chromatographyꢀfree synthesis of
(±)ꢀSIPI 6360 in which critical conditions were modified and optimized to yield an
overall high yield of excellent purity.
Scheme 1. Initial Synthesis of (±)-SIPI 6360
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Figure 1. Chemical structures of byproducts 9, 10 and 11.
RESULTS AND DISCUSSION
Our efforts were made to optimize the existing process to improve the yield of
quinoline 3. This yield of 3 was obtained under Vilsmeier conditions7 accompanied by
formation of a regioisomer 98 (Figure 1), which was removed via recrystallization, and
resulting in a massive loss of 3 (31% isolated yield, Table 1, entry 1). Previously,
Vázquez and colleagues found that regioselectivity is governed by temperature and the
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addition of the POCl3 reagent for their aldehyde products under Vilsmeier conditions.9
Our tentative experiments showed that a lower temperature favored the formation of the
desired regioisomer 3 (entry 2). Further investigation into the amount of reagent revealed
that the formation of the undesired regioisomer 9 was reduced with the decreasing usage
of DMF (entry 3). Thus, an optimal feed ratio of DMF was further studied to facilitate the
regioselectivity. As shown in Table 1, a 1.5 equivalent of DMF was deemed the optimal
amount with < 0.1% content of 9, which was removed by slurry in petroleum ether with a
good yield (86%) of 3 (entry 4). Moreover, decreasing the POCl3 reagent amount from 7
to 5.5 equivalent barely influenced the regioselectivity (entry 5). The reaction mixture
was semiꢀsolidified and difficult to stir after decreasing the POCl3 reagent amount to 5.0
equivalent. Thus, 5.5 equivalent of POCl3 was regarded as the optimal amount for the
reaction. This improvement facilitated the isolation of regioisomer 9 and work up of 3 in
good yield (84%) and high purity (> 99.9%, HPLC).
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Table 1. The optimization of Vilsmeier conditions for 3
DMF
POCl3
Moles
temp
(°C)
yield
(%)b
entry
3 (area %)a 9 (area %)a
Moles
90.9c
98.6d
95.3c
98.9d
97.0c
99.1d
98.1c
99.6d
7.4c
1.2d
3.1c
0.7d
1.4c
0.5d
0.3c
0.1d
1
2
3
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5.5
5.5
4
7
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7
95
80
80
80
31
48
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71
3
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98.6c
0.04c
0e
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1.5
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86
84
> 99.9e
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0.06c
0e
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> 99.9e
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a
b
c
d
Determined by HPLC analysis. Isolated yield. Crude product. Recrystallization.
eSlurry.
The quinoline 3 was subsequently hydrolyzed in the presence of acetic acid to give
the quinolone 4 at kilogramꢀscale.
Further synthetic modifications were carried out for the yield improvement of 5. The
low yield (30% isolated yield) was attributed to the insufficient conversion of 4 and the
chromatography work up. Furthermore, the unconverted 4 took part in the following steps
forming a byproduct 1010, which was detrimental to purity control of the API (active
pharmaceutical ingredient). To address this issue, palladiumꢀcatalyzed hydrogenation11
was employed instead of a magnesium system. As shown in Table 2, ethanol was found
to be the optimal solvent to drive the reaction process after the screening of several other
solvents (entry 1ꢀ3). Temperature was another influencing factor and an almost 80%
conversion of 4 was detected at reflux (entry 5). When the pressure was increased to 2.5
MPa, 4 was completely consumed in 24 hours (entry 6ꢀ7). In order to reduce cost, the
catalytic performance of 5% PdꢀC was investigated under the same amount of PdꢀC
compared with 10% PdꢀC. 5% PdꢀC showed poor catalytic performance (entry 8).
Eventually, the conditions of 10% PdꢀC/EtOH at 2.5 MPa and 90°C were applied for the
scaling of 5. These synthetic modifications resulted in a kilogramꢀscale (> 2 kg) batch of
5 in excellent yield (92%) without chromatography. These kilogram quantities of 5 were
subsequently converted to 6 by demethylation in 40% aqueous hydrobromic acid.
Table 2. Hydrogenation of 4 under different conditions
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pressure
4
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entry
catalyst
solvent temp (°C)
time (h)
(MPa)
0.1
(area %)a (area %)a
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10% Pd/C AcOH
10% Pd/C THF
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80.1
96.3
71.6
48.5
23.7
14.2
0
19.9
3.7
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0.1
10% Pd/C EtOH
10% Pd/C EtOH
10% Pd/C EtOH
10% Pd/C EtOH
10% Pd/C EtOH
0.1
28.4
51.5
76.3
85.8
100
0.1
0.1
1.5
2.5
5% Pd/C
EtOH
2.5
47.9
52.1
aDetermined by HPLC analysis.
Finally we utilized a more practical approach for the work up of 8. Initially, the
coupling of 6ꢀfluoroꢀ3ꢀ(piperidinꢀ4ꢀyl)benzo[d]isoxazole hydrochloride (7) and
1ꢀbromoꢀ3ꢀchloropropane resulted in low yield (20% isolated yield) when compared to a
literature yield12 due to the formation of a bilateral substituent byproduct (11)13 (Figure 1),
which could only be removed by chromatography. Investigation of alternative bases
(NaHCO3, diisopropylethylamine and triethylamine), solvents (acetonitrile, ethanol,
DMF, etc.) and a reagent (12, free base of 7) failed to improve the yield and inhibited the
formation of 11 (Table 3). In an attempt to develop a more practical process to synthesize
8, we envisioned three possible methods to prepare 8 by avoiding or decreasing the
formation of 11 (Scheme 2).
Table 3. Condensation conditions for preparing 8
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entry
reagent
solvent
Acetone
Acetone
CH3CN
EtOH
base
K2CO3
NaHCO3
K2CO3
K2CO3
K2CO3
DIPEA
DIPEA
Et3N
temp (°C) yield (%)a
1
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90
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3
7
4
7
5
DMF
7
6
DMF
7
7
NMP
7
8
NMP
7
9
DMSO
DIPEA
7
aIsolated yield.
Scheme 2. New process for the synthesis of 8
In method 1, the coupling of 12 and 3ꢀchloropropanꢀ1ꢀol resulted in low yield
(5~10%) due to substantial unreacted 12 after investigation into the reaction conditions,
such as solvent, base and temperature, which inhibited this approach.
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The major drawback of method 2 was the low yield (10%) of the coupling between
active ester 15 and 12. Considerable unconverted 12 was detected by HPLC analysis
despite the consumption of 15. This large amount was attributed to the selfꢀelimination of
15 in an alkaline condition. Based on these results, it is unsuitable to produce 8 on a large
scale via method 1 or method 2.
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In method 3, compound 16 was obtained in high yield (91%) via acylation. The
subsequent reduction of the amide group was implemented in the presence of BH3 at
reflux, resulting 8 in only 14% isolated yield (Table 4, entry 1) due to multiple
byproducts and chromatographic purification. Lowering the temperature was found to
favor the yield (38%, entry 2) until above the 0°C point. In addition, different reductants
were screened and we found that Vitride (entry 4) and sodium borohydride systems
(entry 5ꢀ6)14ꢀ17 were ineffective, whereas lithium aluminum hydride was effective (71%
isolated yield, entry 7), in situations where an allylic product 1718 (10.5%, HPLC) (Figure
2) and a deꢀchlorination product 1819 (2.4%, HPLC, Figure 2) were detected. Early
studies indicated that acidic hydrides retard reduction of the halogen whereas more basic
reagents, such as lithium aluminum hydride, facilitate the reduction.20 Those results
illustrated that 18 had formed in the presence of lithium aluminum hydride.
It is known that 17 can be formed through a selfꢀelimination process under alkaline
conditions, and so the lithium aluminum hydrideꢀaluminum chloride reagent as acidic
hydride was therefore employed to prepare 8. Under this acidic condition only small
quantities 17 and 18 (2.6% and 0.5%, respectively) were observed in crude 8 by HPLC
analysis, and these were easily removed by recrystallization (petroleum ether/ethyl
acetate, 1:1) with 85% isolated yield and 99.3% HPLC purity of 8. Similar conditions
were successfully applied for the scale up of 8, resulting in a chromatographyꢀfree
production of 8 in good yield (77%) via two steps from 7 at >1ꢀkg scale.
Table 4. Screening of reductants
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entry
reductant
BH3
temp (°C)
time (h)
yield (%)a
1
2
70
25
5
16
8
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0
BH3
3
BH3
0
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Vitride
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0
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NaBH4/I2
25
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NaBH4/(Me)3SiClc
NaBH4/(Me)3SiCld
25
0
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70
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NaBH4/AlCl3
70
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9
LiAlH4
0~10
0~10
71
85
10
LiAlH4/AlCl3
3
aIsolated yield. bSee ref 14. cSee ref 15. dSee ref 16. eSee ref 17.
Figure 2. Chemical structures of byproducts 17 and 18.
The synthesis of (±)ꢀSIPI 6360 was then completed by the SN2 coupling of 6 and 8
under mild basic conditions followed by slurry of the crude API from ethanol to give the
product at kilogramꢀscale in 34% overall yield and high purity (99.8%, HPLC).
Through these improvements, the final process route (Scheme 3) was established for
the kilogramꢀscale preparation of (±)ꢀSIPI 6360.
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Scheme 3. Final process route for the synthesis of (±)-SIPI 6360
6
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CONCLUSION
In summary, we have developed a manageable and kilogramꢀscale eightꢀstep process for
the preparation of (±)ꢀSIPI 6360 and improved the overall yield from 1% to 34%. We
achieved this by controlling the formation of undesired regioisomer 9 to obtain 3, careful
screening of reduction conditions in the preparation of 5, and rational route design and
careful reductant screening in the preparation of 8. Finally, we have successfully
optimized protocols for the preparation of 3, 5 and 8 which resulted in
chromatographyꢀfree production of 1.5 kilogram of (±)ꢀSIPI 6360 in 99.8% purity.
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EXPERIMENTAL SECTION
5
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Reaction progress and compound purity was determined by high performance liquid
chromatography (HPLC). HPLC method A: Welch Ultimate® XBꢀC18 column, C18 (5
ꢁm, 250 mm × 4.6 mm); mobile phase A (0.05% trifluoroacetic acid in water) and B
(CH3CN), from 75:25 A/B to 5:95 A/B over 25 min; detection at 237 nm; flow rate = 1.0
mL/min; temp 42 °C. HPLC method B: Welch Ultimate® XBꢀC18 column, C18 (5 ꢁm,
250 mm ×4.6 mm); mobile phase A (CH3CN) and B (20 mM NaH2PO4 (pH = 5.5)), 20:80
v/v; detection at 254 nm; flow rate = 1.0 mL/min; temp 30 °C.
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N-(3-methoxyphenyl)propionamide (2). To a stirred solution of 3ꢀmethoxyaniline
(1) (3.0 kg, 24.4 mol) and 10% aqueous sodium hydroxide (13.4 L) in dichloromethane
(12 L) was added propionyl chloride (2.5 kg, 26.8 mol) in dichloromethane (2.5 L) at
0ꢀ5 °C and stirred at room temperature for 3 h. The organic layer was washed with water
(5 L), brine (5 L), dried over anhydrous sodium sulfate, and evaporated in vacuo to give
compound 2 (4.1 kg, 93%) as a white solid with 99.7% purity (HPLC method A, tR = 9.6
min). Mp 74ꢀ75 °C; 1H NMR (400 Hz, CDCl3) δ 7.67 (br, 1H), 7.33 (s, 1H), 7.20ꢀ7.16 (m,
1H), 6.98 (d, J = 8.0 Hz, 1H), 6.64 (dd, J = 8.0, 0.8 Hz, 1H), 3.77 (s, 3H), 2.38 (q, J = 7.6
Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.44, 160.11, 139.44,
129.61, 111.96, 110.03, 105.53, 55.26, 30.73, 9.68; MS m/z 180.4 [M + H]+.
2-Chloro-7-methoxy-3-methylquinoline (3). To
a
stirred solution of
N,Nꢀdimethylformamide (2.5 L) was added phosphorus oxychloride (18.8 kg, 122.6 mol)
at 0°C. The resulting mixture was stirred at room temperature for 20 min, followed by
addition of 2 (4.0 kg, 22.3 mol) in batches at 0°C over 1 h. The mixture was stirred at
room temperature for 20 min and heated at 80 °C for 9 h. The reaction mixture was
cooled to room temperature, poured into iceꢀwater and stirred for 2 h. The precipitate was
collected by filtration, washed with water, and dried to give crude 3, which was further
purified by slurry in petroleum ether and dried to give compound 3 (3.7 kg, 84%) as a
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160.75, 152.17, 148.11, 137.62, 127.75, 127.50, 122.72, 119.96, 106.44, 55.52, 19.81;
MS m/z 208.0 [M + H]+; HRMS (ESI) m/z calcd for C11H11ClNO [M + H]+ 208.0524,
found 208.0523.
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7-Methoxy-3-methylquinolin-2(1H)-one (4). A mixture of 3 (3.5 kg, 16.9 mol) and
acetic acid (17.5 L) was stirred at 125 °C for 15 h. The resulting mixture was cooled to
60ꢀ70 °C and evaporated in vacuo to give a light yellow solid, which was slurried in
water (3 L) at room temperature to give compound 4 (2.7 kg, 85%) as a white solid with
98.9% purity (HPLC method A, tR = 9.0 min). Mp 174ꢀ176 °C; 1H NMR (400 Hz, CDCl3)
δ 12.08 (br, 1H), 7.58 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.78 (dd,
J = 8.8, 2.4 Hz, 1H), 3.90 (s, 3H), 2.26 (d, J = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 165.07, 160.80, 139.21, 137.43, 128.11, 126.53, 114.58, 111.85, 98.16, 55.55, 16.57;
MS m/z 190.1 [M + H]+.
7-Methoxy-3-methyl-3,4-dihydroquinolin-2(1H)-one (5). To a stirred solution of 4
(2.5 kg, 13.2 mol) and ethanol (12.5 L) was added 10% PdꢀC (125 g, dry catalyst, 4: 10%
PdꢀC = 20: 1 (w/w)) in ethanol (500 mL) at room temperature. The resulting solution was
hydrogenated of H2 (2.5 Mpa) at 90 °C for 24 h. After cooling to room temperature, the
reaction mixture was filtered through a Celite pad and washed with EtOH (1 L × 2).
Concentration in vacuo provided compound 5 (2.3 kg, 92%) as a whitish solid with 99.3%
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purity (HPLC method A, tR = 10.5 min). Mp 113ꢀ115 °C; H NMR (400 Hz, CDCl3) δ
8.70 (br, 1H), 7.27 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.52 (dd, J = 8.4, 2.4 Hz, 1H), 6.38
(d, J = 2.4 Hz, 1H), 3.78 (s, 3H), 2.92ꢀ2.89 (m, 1H), 2.67ꢀ2.61 (m, 2H), 1.29ꢀ1.24 (m,
13
3H); C NMR (100 MHz, CDCl3) δ 174.84, 159.16, 138.14, 128.73, 115.74, 107.96,
101.38, 55.41, 35.22, 32.66, 15.33; MS m/z 192.2 [M + H]+.
7-Hydroxy-3-methyl-3,4-dihydroquinolin-2(1H)-one (6). A mixture of 5 (2.0 kg,
10.5 mol) and 40% HBr (20 L) was stirred at 135 °C for 16 h. The resulting mixture was
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cooled to room temperature and filtered to obtain a whitish solid, which was dissolved in
methanol (1 L), stirred for 0.5 h, and filtered. The filtrate was evaporated in vacuo to give
a whitish solid, which was slurried in 95% ethanol (3 L) at room temperature to give
compound 6 (1.6 kg, 88%) as a white solid with 99.9% purity (HPLC method A, tR = 6.3
min). Mp 233ꢀ235 °C; 1H NMR (400 Hz, DMSOꢀd6) δ 9.91 (br, 1H), 9.24 (s, 1H), 6.90 (d,
J = 8.0 Hz, 1H), 6.33ꢀ6.29 (m, 2H), 2.81ꢀ2.74 (m, 1H), 2.50ꢀ2.36 (m, 2H), 1.23ꢀ1.06 (m,
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3H); C NMR (100 MHz, DMSOꢀd6) δ 172.91, 156.43, 138.86, 128.32, 113.60, 109.06,
102.00, 34.52, 32.08, 15.47; MS m/z 178.1 [M + H]+; HRMS (ESI) m/z calcd for
C10H12NO2 [M + H]+ 178.0863, found 178.0863.
3-Chloro-1-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propan-1-one (16).
To a stirred solution of 6ꢀfluoroꢀ3ꢀ(piperidinꢀ4ꢀyl)benzo[d]isoxazole hydrochloride (1.5
kg, 5.9 mol) and 20% aqueous sodium hydroxide (2.4 L) in dichloromethane (7.5 L) was
added 3ꢀchloropropanoyl chloride (0.9 kg, 7.1 mol) in dichloromethane (1 L) at 0ꢀ5 °C
and stirred at room temperature for 5 h. The organic layer was washed with water (2 L),
brine (2 L), dried over anhydrous sodium sulfate, evaporated in vacuo, and slurried in 95%
ethanol (1.5 L) at room temperature to give compound 16 (1.6 kg, 91%) as a light yellow
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solid with 99.7% purity (HPLC method A, tR = 15.0 min). Mp 88ꢀ90 °C; H NMR (400
Hz, CDCl3) δ 7.64ꢀ7.62 (m, 1H), 7.27ꢀ7.26 (m, 1H), 7.13ꢀ7.07 (m, 1H), 4.67ꢀ4.65 (m,
1H), 4.03ꢀ4.01 (m, 1H), 3.87 (t, J = 4.8 Hz, 2H), 3.38ꢀ3.29 (m, 2H), 2.98ꢀ2.83 (m, 3H),
2.18ꢀ2.14 (m, 2H), 2.06ꢀ2.00 (m, 1H), 1.95ꢀ1.89 (m, 1H); 13C NMR (100 MHz,
DMSOꢀd6) δ 168.04, 164.98, 163.55ꢀ163.34 (m), 161.37, 124.26 (d, J = 7.0 Hz), 117.59,
113.04 (d, J = 17.0 Hz), 97.84 (d, J = 18.0 Hz), 45.12, 41.24, 35.69, 33.66, 30.72; MS
m/z 311.1 [M + H]+.
3-(1-(3-Chloropropyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole (8). To a stirred
solution of THF (12 L) was added lithium aluminum hydride (0.40 kg, 11.1 mol) at
0ꢀ10 °C and stirred for 1 h. The resulting mixture was added aluminum chloride (0.70 kg,
5.1 mol) in batches and stirred for 3 h at 0ꢀ10 °C, followed by addition of 16 (1.5 kg, 4.8
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mol) at 0ꢀ5 °C. The solution was kept at 0ꢀ5 °C and stirred for 2 h. Water (2 L) was added
dropwise to the solution at 0ꢀ5 °C and stirred for 2 h. The resulting mixture was stirred
for another 1 h at room temperature, followed by addition of magnesium sulfate (400 g),
stirring for 1 h, and filtration. The filter cake was slurried in THF (2 L) at room
temperature and filtrated. The combined filtrate was evaporated in vacuo followed by
recrystallization in petroleum ether/ethyl acetate (1:1) to give compound 8 (1.3 kg, 85%)
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as a white solid with 99.3% purity (HPLC method A, tR = 7.8 min). Mp 71ꢀ72 °C; H
NMR (400 Hz, CDCl3) δ 7.62 (dd, J = 5.6, 3.2 Hz, 1H), 7.19ꢀ7.16 (m, 1H), 6.99ꢀ6.97 (m,
1H), 3.56 (t, J = 4.4 Hz, 2H), 3.03ꢀ2.96 (m, 3H), 2.48 (t, J = 4.8 Hz, 2H), 2.20ꢀ2.10 (m,
13
2H), 2.08ꢀ1.90 (m, 6H); C NMR (100 MHz, CDCl3) δ 163.91, 162.87 (d, J = 9.0 Hz),
160.06, 121.54 (d, J = 8.0 Hz), 116.29, 111.30 (d, J = 17.0 Hz), 96.43 (d, J = 18.0 Hz),
54.65, 52.60, 42.27, 33.57, 29.56, 29.04; MS m/z 296.6 [M + H]+; HRMS (ESI) m/z calcd
for C15H19ClFN2O [M + H]+ 297.1170, found 297.1171.
7-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methyl-3,4-di
hydroquinolin-2(1H)-one ((±)-SIPI 6360). A mixture of 6 (0.80 kg, 4.2 mol), 8 (1.2 kg,
4.0 mol), potassium carbonate (1.7 kg, 12.1 mol), and N,Nꢀdimethylformamide (12 L)
was stirred at 60°C for 12 h. The resulting mixture was cooled to room temperature and
evaporated in vacuo to remove most of the solvent. The resulting residue was poured into
water (16 L), stirred for 1 h, and filtrated. The filter cake was slurried in ethanol (2 L) at
60 °C and filtrated to afford 1.5 kg of (±)ꢀSIPI 6360 in 99.8% purity (HPLC method B, tR
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= 12.6 min) as a white solid (81% yield). Mp 154ꢀ155 °C; H NMR (400 Hz, CDCl3) δ
8.41 (br, 1H), 7.70 (dd, J = 8.8, 5.2 Hz, 1H), 7.27ꢀ7.23 (m, 1H), 7.08ꢀ7.03 (m, 2H), 6.53
(dd, J = 8.0, 2.4 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 4.02 (t, J = 6.0 Hz, 2H), 3.11ꢀ3.08 (m,
3H), 2.94ꢀ2.92 (m, 1H), 2.67ꢀ2.56 (m, 4H), 2.18ꢀ2.00 (m, 8H), 1.28 (d, J = 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 174.61, 164.10 (d, J = 249.0 Hz), 163.86 (d, J = 14.0 Hz),
161.11, 158.59, 138.06, 128.74, 122.59 (d, J = 11.0 Hz), 117.30, 115.71, 112.31 (d, J =
25.0 Hz), 108.45, 101.96, 97.44 (d, J = 27.0 Hz), 66.43, 55.38, 53.62, 35.25, 34.61, 32.68,
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30.55, 26.88, 15.34; MS m/z 437.6 [M + H]+; HRMS (ESI) m/z calcd for C25H29FN3O3
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[M + H]+ 438.2193, found 438.2210.
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AUTHOR INFORMATION
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Corresponding Author
Jianqi Li.
*Telephone: +86 21 20572000. Eꢀmail: lijianqb@126.com.
Lei Fu.
*Telephone: +86 21 34204791. Eꢀmail: leifu@sjtu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is supported by National Natural Science Foundation of China (Grant No.
81302630), Key Technologies R&D Program of Shanghai Municipal Science and
Technology Commission (Grant No. 13431900201), Natural Science Foundation of
Shanghai (Grant No. 14ZR1440300), and the National Science and Technology Major
Project (Grant No. 2012ZX09102101ꢀ014).
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REFERENCES
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(1) Carlborg, A.; Winnerback, K.; Jonsson, E. G.; Jokinen, J.; Nordstrom, P. Expert Rev.
Neurother. 2010, 10, 1153.
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(2) Millier, A.; Schmidt, U.; Angermeyer, M. C.; Chauhan, D.; Murthy, V.; Toumi, M.;
CadiꢀSoussi, N. J. Psychiatr. Res. 2014, 54, 85.
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(3) Miyamoto, S.; Miyake, N.; Jarskog, L. F.; Fleischhacker, W. W.; Lieberman, J. A. Mol.
Psychiatry 2012, 17, 1206.
(4) Moller, H. J. Risperidone: a review. Expert Opin. Pharmacother. 2005, 6, 803.
(5) Peng, S. P.; Yu, L. P.; Li, J. Q. Acta pharm. Sinica 2009, 44, 994.
(6) Li, J. Q.; Peng, S. P.; Cai, W. P.; Gao, K. Aralkyl substituted piperidine or piperazine
derivatives and their use for treating schizophrenia. U.S. Patent 2011/0160199, Jun 30,
2011; Chem. Abstr. 2010, 152, 215325.
(7) (a) MethꢀCohn, O.; Narine, B. Tetrahedron Lett. 1978, 19, 2045. (b) MethꢀCohn, O.;
Rhouati, S.; Tarnowski, B.; Robinson, A. J. Chem. Soc. Perkin Trans. 1, 1981, 1537. (c)
MethꢀCohn, O. Heterocycles 1993, 35, 539. (d) MethꢀCohn, O.; Narine, B.; Tarnowski, B.
Tetrahedron Lett. 1979, 33, 3111. (e) MethꢀCohn, O.; Rhouati, S.;Tarnowski, B.
Tetrahedron Lett. 1979, 50, 4885. (f) MethꢀCohn, O.; Taylor, D. L. Tetrahedron 1995, 51,
12869.
(8) The byproduct 9 was isolated by preparative separation method (Instrument:
Shimadzu LCꢀ20AP Prep HPLC (PrepLꢀGB); Column: Luna C18, 10µm, 250 × 50 mm
I.D.; Mobile phase: A for H2O and B for Acetonitrile; Gradient: B 50ꢀ80% in 30 min
linearly; Flow rate: 80 mL/min; Column temperature: R.T.; Wavelength: 254 nm; Sample
preparation: Compound dissolved in ~30 mL Acetonitrile; Injection: 8 mL per injection.)
1
and confirmed by 1H NMR, MS and HRMS. Mp 105ꢀ107 °C; H NMR (400 Hz, CDCl3)
δ 8.39 (s, 1H), 7.59ꢀ7.56 (m, 2H), 6.47 (dd, J = 5.2, 2.8 Hz, 1H), 4.00 (s, 3H), 2.54 (s,
3H); MS m/z 208.0 [M + H]+; HRMS (ESI) m/z calcd for C11H11ClNO [M + H]+
208.0524, found 208.0523.
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(9) Vázquez, M. T.; Romero, M.; Pujol, M. D. Bioorg. Med. Chem. 2004, 12, 949.
(10) The byproduct 10 was isolated by column chromatography (CH2Cl2/MeOH,
100:1ꢀ40:1) and recrystallization ( ethyl acetate/MeOH, 2:1), and confirmed by 1H NMR
9
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and MS. Mp 130ꢀ132 °C; H NMR (400 Hz, CDCl3) δ 11.95 (br, 1H), 7.70 (dd, J = 5.6,
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3.2 Hz, 1H), 7.57 (s, 1H), 7.38 (d, J = 5.6 Hz, 1H), 7.24 (dd, J = 5.6, 1.2 Hz, 1H), 7.05
(dd, J = 6.0, 1.2 Hz, 1H), 6.80 (s, 1H), 6.79 (d, J = 1.2 Hz, 1H), 4.14 (t, J = 4.0 Hz, 2H),
3.12ꢀ3.06 (m, 3H), 2.61 (t, J = 4.8 Hz, 2H), 2.27 (s, 3H), 2.22ꢀ2.17 (m, 2H), 2.13ꢀ1.95 (m,
6H); MS m/z 436.3 [M + H]+.
(11) Teramoto, S.; Tanaka, M.; Shimizu, H.; Fujioka, T.; Tabusa, F.; Imaizumi, T.;
Yoshida, K.; Fujiki, H.; Mori, T.; Sumida, T.; Tominaga, M. J. Med. Chem. 2003, 46,
3033.
(12) (a) Vertessy M. Process for the preparation of iloperidone. U.S. Patent 20100076196,
Mar 25, 2010; Chem. Abstr. 2010, 152, 405725. (b) Xie, Y. S.; Zhao, L. Y. Process for
preparation of iloperidone. China Patent 102212063, Oct 12, 2011; Chem. Abstr.
2011,155, 536133.
(13) The byproduct 11 was isolated by column chromatography (CH2Cl2/MeOH,
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100:1ꢀ50:1) and confirmed by H NMR and MS. Mp 127ꢀ129 °C; H NMR (400 Hz,
CDCl3) δ 7.72ꢀ7.69 (m, 2H), 7.26ꢀ7.23 (m, 2H), 7.08ꢀ7.03 (m, 2H), 3.11ꢀ3.08 (m, 6H),
2.48ꢀ2.33 (m, 4H), 2.20ꢀ2.08 (m, 12H), 1.83ꢀ1.75 (m, 2H); MS m/z 481.2 [M + H]+.
(14) (a) Prasad, A. S. B.; Kanth, J. V. B.; Periasamy, M. Tetrahedron 1992, 48, 4623. (b)
Liu, X.; Liu, Y.; He, H.; Cai, Z.; Yang, Y. Synth. Commun. 2014, 44, 451.
(15) Jiang, B.; Feng, Y.; Zheng, J. Tetrahedron Lett. 2000, 41, 10281.
(16) Giannis, A.; Sandhoff, K. Angew. Chem. Int. Ed. Engl. 1989, 28, 218.
(17) Brown, H. C.; Rao, B. C. S. J. Am Chem. Soc. 1956, 78, 2582.
(18) The byproduct 17 was isolated by column chromatography (CH2Cl2/MeOH,
100:1ꢀ20:1) and confirmed by 1H NMR and MS. Mp 78ꢀ79 °C; 1H NMR (400 Hz, CDCl3)
δ 7.11 (dd, J = 6.0, 4.4 Hz, 1H), 7.25ꢀ7.23 (m, 1H), 7.10ꢀ7.03 (m, 1H), 5.95ꢀ5.88 (m, 1H),
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5.24ꢀ5.17 (m, 2H), 3.09ꢀ3.06 (m, 5H), 2.17ꢀ2.07 (m, 6H); MS m/z 261.3 [M + H]+.
(19) The byproduct 18 was isolated by column chromatography (CH2Cl2/MeOH,
100:1ꢀ20:1) and confirmed by 1H NMR and MS. Mp 58ꢀ59 °C; 1H NMR (400 Hz, CDCl3)
δ 7.14 (dd, J = 8.8, 5.2 Hz, 1H), 7.25ꢀ7.23 (m, 1H), 7.07ꢀ7.02 (m, 1H), 3.10ꢀ3.05 (m, 3H),
2.38ꢀ2.34 (m, 2H), 2.16ꢀ2.05 (m, 6H), 1.61ꢀ1.51 (m, 2H), 0.93 (t, J = 7.6 Hz, 3H); MS
m/z 262.8 [M + H]+.
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(20) Nystrom, R. F. J. Am Chem. Soc. 1959, 81, 610.
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