The preparation of 8-[4-[4-(2-pyrimidinyl)-1-piperaziny]butyl]-8- azaspiro[4,5] decane-7,9-dione hydrochloride

Article abstract of DOI:10.1007/s11164-011-0311-1

8-[4-[4-(2-Pyrimidinyl)-1-piperaziny]butyl]-8-azaspiro [4,5] decane-7,9-dione hydrochloride (buspirone hydrochloride) was obtained in one pot with a 51.8% overall yield. The key intermediate, 1-(2-pyrimidinyl) piperazine, was synthesized through chlorination and cyclization condensation reaction with diethanolamine as initial material. This modified protocol has the notable advantages of mild reaction condition, convenient operation, and high overall yield.

Full text of DOI:10.1007/s11164-011-0311-1

Res Chem Intermed (2011) 37:1041–1045
DOI 10.1007/s11164-011-0311-1
The preparation of 8-[4-[4-(2-pyrimidinyl)-1-
piperaziny]butyl]-8-azaspiro[4,5] decane-7,9-dione
hydrochloride
•
•
•
•
Hu Luo Wei Xia Chao Qian Xinzhi Chen
Chaohong He
Received: 13 January 2011 / Accepted: 1 April 2011 / Published online: 16 April 2011
Ó Springer Science+Business Media B.V. 2011
Abstract 8-[4-[4-(2-Pyrimidinyl)-1-piperaziny]butyl]-8-azaspiro [4,5] decane-7,9-
dione hydrochloride (buspirone hydrochloride) was obtained in one pot with a 51.8%
overall yield. The key intermediate, 1-(2-pyrimidinyl) piperazine, was synthesized
through chlorination and cyclization condensation reaction with diethanolamine as
initial material. This modified protocol has the notable advantages of mild reaction
condition, convenient operation, and high overall yield.
Keywords Buspirone hydrochloride ꢀ Diethanolamine ꢀ Cyclization ꢀ
One-pot synthesis method
Introduction
Buspirone hydrochloride, 8-[4-[4-(2-pyrimidinyl)-1-piperaziny] butyl]-8-azaspiro
[4,5] decane-7,9-dione hydrochloride (3) is widely used in therapy as an efficient
antianxiety compound [1]. Buspirone hydrochloride’s clinical efficacy is similar to
diazepam, but it does not suffer from the usual side effects of benzodiazepines,
namely sedation and addiction [2–5].
Scheme 1 summarizes the general methods of synthesis employed for buspirone
hydrochloride, all syntheses are based on three fragments [6–8]: 1-(2-pyrimidinyl)
H. Luo ꢀ C. Qian (&) ꢀ X. Chen ꢀ C. He
State Key Laboratory of Chemical Engineering (Zhejiang University),
Department of Chemical and Biological Engineering, Zhejiang University,
Hangzhou 310027, People’s Republic of China
e-mail: supmoney@163.com
W. Xia
Research Institute for Innovation in Sustainable Chemistry, National Institute of Advanced
Industrial Science and Technology (AIST), AIST Tsukuba West, 16-1 Onogawa, Tsukuba,
Ibaraki 305-8569, Japan
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H. Luo et al.
piperazine (i), substituted imide or anhydride (ii), and four-carbon aliphatic chain
(iii). This type of synthesis is mainly done in two steps: coupling of the four carbon
chain iii with one of the fragments i or ii followed by attachment of the second unit
ii or i, respectively. Due to the complex operation, poor industrialized efficiency has
existed in the total synthesis of buspirone hydrochloride. In addition, 2-chloro-
pyrimidine, the raw materials of i, was obtained through diazotization from
2-amine-pyrimidine and excessive zinc chloride with a poor yield less than 60%,
and the excessive zinc chloride caused serious pollution [9]. Thus, the complex
operation and the preparation of i contributed to the poor overall yield and high
production cost of the whole procedure.
In this article, great efforts were made to simplify the synthesis routine of
buspirone hydrochloride as shown in Scheme 2. The key intermediate 1-(2-
pyrimidinyl) piperazine (2) was synthesized from diethanolamine in high yield of
76.9%, and the preparation of compounds 2, 3 were done in one pot with high yield.
This procedure of N-alkylation reaction indicates a great deal of value for the
notable advantages of high overall yield, readily available raw materials and
convenient operation.
Experimental procedure
Melting points were determined on a WSR-I capillary melting point apparatus and
are uncorrected. IR spectras were record on Nicolet EST 560 spectrometer in KBr
1
with absorption in cm-1. H NMR spectras were measured on a Bruker 400 MHz
spectrometer in CDCl3 with TMS as internal standard. All the reagents used in the
experiments were analytical reagents.
1-(2-Pyrimidinyl) piperazine (2)
Diethanolamine (25 g, 0.24 mol) was dissolved in dichloromethane (30 mL,
0.47 mol), and dichloro sulfoxide (70 mL, 0.96 mol) dissolved in dichloromethane
O
O
N
N
N
N
+
Z
.
HCl
N
NH
+
Y
(CH2)4 X
N(CH2)4
O
N
N
i
iii
ii
O
NH
Y=
Z=O
2
Z=NH
Y=X
X=halogen
N
N
N
N
N
NH
NH
NaNO2 HCl ZnCl2
NH2
Cl
N
NH
N
Scheme 1 General methods of synthesis employed for buspirone hydrochloride
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Preparation of buspirone hydrochloride
1043
N
N
i) CH2Cl2 SOCl2
CH2CH2OH
CH2CH2OH
N
HN
NNH
ii)
NH2
N
1
2
O
NH
O
O
N
N
KOH
HCl
K2CO3 C4H9OH
C2H5OH
.
HCl
N(CH2)4
O
N
N
Br(CH2)4Br
N
3
N
NH
N
Scheme 2 Simplified synthesis routine of buspirone hydrochloride
(45 mL, 0.70 mol) was gradually added. The mixture was stirred at 25–30 °C for
1 h and then heated to reflux for 0.5 h. After cooling, the solid was filtered off and
washed with dichloromethane, and 90% of the solvent was recovered. This material
was dried, then dissolved in butanol (92 mL, 1.0 mol) and anhydrous potassium
carbonate (30.53 g, 0.22 mol) was added. Following the gradual addition of
2-amino-pyrimidine (21.1 g, 0.22 mol), the mixture was refluxed for 8 h, after
which time the starting material had been consumed as evidenced by TLC
(developing solvent, EtOAc/petroleum ether = 1:1, V/V) analysis. The resulting
slurry was filtered and concentrated. The thick oily residue was fractionated under
reduced pressure to give the target 2 (32.5 g, 76.9%), BP 115–117 °C (133 Pa), lit
1
[10]. BP 118–120 °C (270 Pa). IR (KBr), m cm-1: 3422, 1629, 1230. H NMR
(CDCl3): d 2.08 (bs, 1H, N–H), 2.82 (m, 4H, 29 CH2), 3.58 (t, 4H, 29 CH2), 6.74
(t, 1H, Ar–H), 8.41 (d, 2H, Ar–H).
8-[4-[4-(2-Pyrimidinyl)-1-piperaziny]butyl]-8-azaspiro[4,5] decane-7,9-dione
hydrochloride (3)
b,b0-tetramethylene glutarimide (30 g, 0.18 mol) was added to ethanol (45 mL,
0.78 mol), and potassium hydroxide (10.2 g, 0.18 mol) dissolved in ethanol
(120 mL) was gradually added. The mixture was stirred at room temperature for
2 h and then the solvent was evaporated. The residue was treated with acetone to
afford potassium compound. This material was gradually added to 1,4-dibromo-
butane (108.0 g, 0.51 mol), and the mixture was stirred at 50 °C for 8 h. The
resulting slurry was cooled, filtered and concentrated. Without purification, the
residue was added to the solution of 2 (30.0 g, 0.17 mol), anhydrous potassium
carbonate (70.5 g, 0.51 mol) and butanol (1100 mL, 12.0 mol). The mixture was
refluxed for 15 h, after which time the starting material had been consumed as
evidenced by TLC (developing solvent, EtOAc/petroleum ether = 1:1, V/V)
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H. Luo et al.
analysis. The solvent was evaporated under reduced pressure and the mixture was
cooled. The solid was filtered off and dissolved in ethanol (56 mL). Then, hydrogen
chloride gas was injected into the solution until crystalline powder was obtained.
After cooling, the solid was filtered off and crystallized with ethanol to give the
target 3 (51.2 g, 67.4%), MP 200–203 °C, lit [7]. MP 201–202 °C. IR (KBr),
1
m cm-1: 2,951, 1,670, 1,635, 1,580, 1,484, 1,383, 953, 793. H NMR (CDCl3): d
1.42 (m, 8H, 49 CH2), 1.55 (m, 4H, 29 CH2), 2.21 (m, 2H, CH2), 2.47 (s, 4H,
29 CH2), 2.72 (m, 4H, 29 CH2), 3.97 (m, 6H, 39 CH2), 6.71 (t, 1H, Ar–H), 8.40
(d, 2H, Ar–H).
Results and discussion
Improving the synthesis of buspirone hydrochloride presented some challenges. The
simple operation and suitable synthetic protocol of 1-(2-pyrimidinyl) piperazine (2)
were key issues. The 1-(2-pyrimidinyl) piperazine (2) was prepared in one pot over
two steps with diethanolamine as raw material. Considering that the dropwise of
dichloro sulfoxide caused a sharp reaction, a mixture of dichloromethane and
dichloro sulfoxide was employed to keep the reaction under control, and 90% of the
solvent was recovered. Without further purification, the intermediate b,b0-dihalo-
genated diethylamine was converted by cyclization condensation with 2-amine-
pyrimidine to 2 in a high yield of 76.9%. Compared with the corresponding product
using 2-chloro-pyrimidine as starting material, this method not only gave a higher
yield, but also with a eco-friendly and convenient operation.
According to the literature method [11], 8-(4-bromobutyl)-8-azaspiro [4,5]
decane-7,9-dione was prepared from b,b0-tetramethylene glutarimide and 1,4-
dibromo-butane at 180–190 °C for 20 h. We chose to firstly treat b,b0-tetrameth-
ylene glutarimide with potassium hydroxide to give the corresponding potassium
salt, which was reacted with 1,4-dibromo-butane at 50 °C for 8 h to afford 8-(4-
bromobutyl)-8-azaspiro [4,5] decane-7,9-dione by Gabriel reaction. Temperature
played a really important role in this reaction, and the alkylation reaction was
accelerated with serious side effects at high temperatures. After the potassium
bromide and excess 1,4-dibromo-butane were separated, the residue was treated
with 1-(2-pyrimidinyl) piperazine to afford buspirone hydrochloride in a yield of
67.4%.
Due to the high yield and convenient operation, the cost of buspirone
hydrochloride decreased greatly by this method and will be suitable for substantive
commercial production, and also provides the foundation for further efforts to
increase access to it.
Conclusion
The synthesis of buspirone hydrochloride was improved by one-pot synthesis
method with a 51.8% overall yield. The key intermediate 1-(2-pyrimidinyl)
piperazine was synthesized in a higher yield from diethanolamine through
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Preparation of buspirone hydrochloride
1045
chlorination with dichloro sulfoxide and cyclization condensation with 2-amine-
pyrimidine. Thus, we have succeeded in developing an improved synthesis route of
buspirone hydrochloride characterized by cheap and readily available materials,
convenient operation and high overall yield.
Acknowledgments We greatly acknowledge the generous financial support by grants from the Natural
Science Foundation of the Zhejiang Province (Y4090045, R4090358) and the Research Foundation of
Education Bureau of Zhejiang Province (Y200908295).
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