Note: Descriptions are shown in the official language in which they were submitted.
1~7~5S
BUSPIRONE PROCESS
Description of the Prior Art
Yao Hua Wu, et al., U,S. Patent No. 3,717,63'1 disclose
synthesis of N-(heteroarcyclic)piperazinvlalkylazaspiroalkanediones
5 of Formula I
~N- A-N N-B
Formula I
by the following methods.
METHOD A
o
~O + H2N-A-N N-B ~ Formula I
Formula II Formula III
1~72~S5
~IETHOD B
o
A-X + B-N~N-B ~ Formula I
Formula IV Formulz V
METHOD C
(~R~ N-N + X-A-N N-B ~ Form~
Formula VI Formula VII
In the above reaction schemes, the symbol "n" is the
integer 4 or 5, the symbol -A- represents a straight or branched
divalent alkalene chain of two to six carbon atoms inclusive, the
symbol "B" represents inter alia various heterocyclic radicals
including "2-pyrimidinyl", the symbol "X" inter alia is chlorine~
bromine, iodine, and the symbol "M" an alkali metal salt such as
sodium or potassium.
The instant process differs from methods of Wu, et al.,
U.S. 3,717,634 in that the 2-pyrimidinyl fragment is introduced as a
final step by direct alkylation of preformed 8-[4-(1-piperazinyl)-
butyl]-8-azaspiro~4.5]decane-7,9-dione with a 2-halopyrimidine.
" . .
~7Z;~SS
Su~mary of the Inven~ion
Broadly described, this invention is concerned with a
process for preparation of the pyrimidine compound 8-[4-[4-(2-
pyrimidinyl)-l-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione
also referred to herein by the United States Adopted Name "buspirone";
see J. Amer. Med. Assoc., 225, 520 (1973). The instant process
provides a new and novel route for preparation of buspirone and more
particularly to a method for incorporating radioactive carbon (14C)
and stable lSnitrogen (15N) isotopes in specified positions oE the
pyrimidinyl eomponent of buspirone. Labeled buspirone is useful in
elinical investigation of the absorption and metabolic disposition of
this anxiolytic agent.
Detailed Deseription of the Invention
The instant invention relates to a proeess for preparation
of 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-2zaspiro[4.5]-
deeane-7,9-dione eharacterized by Formula I
-(CH2)4-N 3
- (I)
whieh eomprises alkylating 8-[4-(1-piperazinyl)butyl]-8-azaspiro[4.5]-
deeane-7,9-dione eharaeterized by Formula II
1~72255
~(CH2)4N NH
(II)
with a 2-halopyrimidine characterized by Formula III
X~
(III)
wherein X is bromine, iodine or preferably chlorine in a reaction
inert solvent at a temperature ranging from 80-170C., preferably in a
closed reaction vessel.
The foregoing process is particularly adz.ptable to the
preparation of radioactive labeled buspirone and in that respect is
both economical and convenient. As used herein, the term "labeled"
refers to radioactive ( C) and stable (15N~ isotopes incorporated at
specific positions of buspirone. Preferred embodiments of the
foregoing process are those for the preparation of labeled buspirone
wherein:
the compound of Formula III is 2-chloropyrimidine labeled
in the 2 position with 14carbon isotope;
the compou~d of Formula III is 2-chloropyrimidine in which
the 1,3-nitrogen atoms are labeled with 15nitrogen isotope.
The labeled Formula III 2-halopyrimidines are obtained by
condensation of appropriately labeled urea with malonaldehyde
i~7;~55
bis(dimethylacetal) or malonaldehyde bis(diethylacetal) in the presence
of acid tO afford the corresponding 2-hydroxypyrimidine subsequently
converted to the halo compound by means of phcsphorus oxyh~lide such
as phosphorus oxychloride or phcsphorus oxybromide. By way of illus-
tration, the sequence starting with urea-14C for preparation of
2-chloropyrimidine- 1 C (IIIa) is depicted belcw.
~ /NH2 / CH(OCH3)2 HCl ~ N
O=C\ + 2\ ~ \ ~ OH HCl
NH2 CH(OCH3)2 EtOH \~=:N
POC13 e ~ Cl
(IIIa)
The identical sequence starting with urea-15~2 affords 2-chloro-
pyrimidine- 5N2 (IIIb)
~ ~ Cl
*
(IIIb)
In carrying out the instant process, any solvent which does
not adversely affect the reaction as well as the reactants and the
buspirone product may be used with the preferred solvent being an
alkanol such as ethanol, n-propanol, isopropanol and the like.
Generally a reaction temperature in the range of from about
80C. to about 170C. is operable, with the preferred temperature
being in the range of ~rom 110C. to 120C. Higher and lower tempera-
tures may be used, but at a reaction temperature below 80C. the
~7~2~55
reaction is undulv prolonged and adequate condensation does not occur
whereas if the reaction temperature exceeds 170C. the reactants tend
to undergo decomposition i-o some extent. When the process is carried
out at temperatures above the boiling point of the reaction solvent,
a closed reaction vessel is preferably employed.
The hydrohalide evolved in the course of the reaction is
taken up with an acid acceptor to conserve the basic 8-[4-(1-piperazinvl)-
butyl~-8-azaspiro[4.53decane-7!9-dione reactant (II). In this regard
a tertiary amine such as triethylamine is preferred.
10The process of this invention is further illustrated by the
f ollowing examples which are not to be construed as limiting the
scope of the present invention.
EYA~PLE 1
Preparation of
8-~4-(1-Piperazinyl)butyl-8-azaspiro[4.5]decane-7,9-dione (II)
o
~ ~ 2)4 ~ ~
(a) 8-(4-Bromobutyl)-8-azaspiro~4.5~decane-7,9-dione.- A
mixture of 3,3-tetramethylene glutarimide (33.4 g., 0-2 mole),
1,4-dibromobutane (86.4 g., 0.4 mole) and micropulverized potassium
carbonate (88.6 g., 0.6 mole) in 500 ml. dry toluene is stirred at
reflux temperature for a 20 hr. period. The reaction mixture is
filtered while hot and concentrated under reduced pressure. Residual
oil is distilled under reduced pressure and the fraction having a
~7~2S5
b.p. 165-170C at 0.1 mm Hg. collected to afford 32.0 g. (52~) of
8-(4-bromobutyl)-8-azaspiro~4.5]decane-7,9-dione as an oil.
(b) 8-~4-(1-Piperazinyl)butyl-8-azaspiro[~.5]decane-7,9-dione.-
A mixture of 8-(4-bromobutyl)-3-azaspiro[4.5]decane-7,9-dione (32.0 g.,
0.105 mole), piperazine (50 g., 0.58 mole), and micropu]verized
potassium carbonate (80.0 g., 0.58 mole) in 500 ml. of dry toluene is
stirred at reflux temperature for 18 hrs. The reaction mixture is
filtered while hot, concentrated under reduced pressure and residual
material stirred with 100 ml. ether. ~xcess piperazine, which
separates as the hydrochloride, is collected and the filtrate concen-
trated under reduced pressure. Distillation of residual oil under
reduced pressure affords 13.5 g. (42%) of 8-[4-(1-piperazinyl)butyl-
8-azaspiro[4.5]decane-7,9-dione, b.p. 180-200C. at 0.1 mm Hg as the
free base.
lS Conversion of this material to the hydrochloride salt and
crystallization from ethanol affords analytically pure 8-[4-(1-
piperazinyl)butyl-8-azaspiro[4.5]decane-7,9-dione hydrochloride, m.p.
235-237C.
Anal- Calcd- for C17H19~32 2HCl 1/4H20 C~ 53-06;
20 H, 8.25; N, 10.92. Found: C, 53.06; H, 8.05; N, 10.96.
-- 7 --
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E~'~LE 2
Preparation of Labeled
2-Chloropyrimidine 1 C (IIIa)
Cl ~,~3
(a) ~-Hydroxypyrimidine C Labeled) hydrochloride.- A
solution of urea (165 mg., 0.002 mole) containing urea-14C (43 mg.,
0.0007 mole, 30 millicurie) and malonaldehyde bis(dimethylacetal)
(443 mg., 0.0027 mole) in 1.0 ml. ethanol is treated with 0.5 ml.
concentrated hydrochloric acid. The acidified solution is warmed on
a steam bath for a period of 2 hrs., and ch;lled. The yellow preci-
pitated product is collected to afford 274 mg. (77%) of 2-chloro-
pyrimidine 1 C used without further purification as follows.
(b) 2-Chloropyrimidine- C labeled).- A mixture of
2-hydroxypyrimidine 14C hydrochloride (274 mg., 0.002 mole) and
lO ml. of phosphorus oxychloride is heated at 110C. with stirring
for a 6 hr. period. Excess phosphorus oxychloride is removed under
reduced pressure and remaining oily residue dissolved in 15 ml.
water. The aqueous solution is treated with 10% sodium bicarbonate
until slightly basic to litmus and extracted with chloroform.
Concentration of the dried chloroform extract provides 2-chloro-
20 pyrimidine- 14C (190 mg., 83%) used without furth~r purificiation in
Example 3.
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E~UMPLE 3
8-[4-[4-(2-Pyrimidinyl)-l-piperazinyl]ethyl-8-
azaspiro[4.5]decane-7,9-dione- C Labeled (Ia)
o
~ -(CH2)4-N ~ ~ ~
A mixture of the 2-chloropyrimidine- l C (190 mg., 0.0016
mole) from Example 2, 8-[~-(l-piperazinyl)butyl]-8-azaspiro[4.5]decane-
7,9-dione (509 mg,, 0.0016 mole) and triethylamine (162 mg., 0.0016
mole) in 15 m].. ethanol is heated at 110-120C. in a sealed reaction
vessel for a 72 hr. period. After cooling, the reaction mixture is
concentrated under reduced pressure and residual material taken up in
10 ml. of isopropanol. A stoichiometric amount of hydrogen chloride
in ethanol is added to the isopropanol solution and the mixture
cooled. White crystals separate which are collected and crystallized
from isopropanol to give 281 mg. (42~) of labeled product as the
hydrochloride salt.
The salt is dissolved in water and sodium bicarbonate added
with cooling until the mixture is basic. A precipitate forms which
is collected and crystallized from isopropanol thus providing 125 mg.
(35~) of free base product radiochemically pure according to thin
layer chromatography developed in two separatè solvent systems
20 [CHC13-EtOH (4:1) and CHC13-MeOH-HOAc (10:3:1)] and scanned with a
Varian Aerograph-Berthold Radioscanner. Specific activity of the
_ g _
1~L7~2S~
8-[$-~4-(~-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-
~,9-dione- l C labeled product is generally about 20 microcurie/mg.
~ nal- Calcd- for C21H31N502: C, 65.43; H, 8.11; N, 18.17.
Found: C, 65.60; H, 8.10; N, 18.24.
EX~LE 4
Preparation of Labeled
2-Chlo_opyrimidine- N2 (IIIb)
N
Cl - ~ ~
(a) 2-Hydroxypyrimidine Hydrochloride- 5N2.- A solution
of urea-15N2 (3.0 g., 0.049 mole; 90 atom % 15N) and malonaldehyde
10 bis(dimethylacetal) (8.2 g., 0.049 mole) in 10 ml. ethanol is acidified
with 10 ml. concentrated hydrochloric acid. The solution is warmed
on a steam bath for a period of 2 hrs.,-and the yellow precipitate
which forms collected thus affording 5.1 g. (80%) of 2-hydro~-
pyrimidine- lSN2 hydrochloride, m.p. 210-212C., used without further
purification as follows.
(b) ~ s ~ e- I~N2.- A suspension of hydroxy-
pyrimidine- 15N2 hydrochloride (5.1 g., 0.038 mole) in 30 ml. phosphorus
oxychloride is heated at 110C. with stirring for a 6 hr. period.
Excess phosphorus oxychloride is removed under reduced pressure and
residual oil dissolved in 15 ml. water. The aqueous solution is
treated Witil 10% sodium bicarbonate until slightly basic and the free
base extracted with chloroform. Concentration of the dried chloroform
- 10
~7i2ZSS
e~tract provides 3.0 g. (G8,',) of 2-chloropyrimidine- 15N2 used
~ithoue rurther purification in E~ample 5.
EX~PLE 5
8-[4-[4-(2-Pyrimidinyl)-l-piperazinyl]ethyl]-
58-azaspiro[4.5]decane-7,9-dione- 15N Labeled (Ib)
~,N-(CN2)4-N
A mixture of 2-chloropyrimidine- ~2 (3-0 g., 0.026 mole),
8-[4-(l-piperazinyl)butyl]-8-azaspiro[4.5]decane-7,9-dione (8.07 g.,
0.026 mole) and triethylamine (2.6 g., 0.026 mole) in 25 ml. ethanol
and heated in an oil bath at 110-120C. in a sealed reaction vessel
for a 72 hr. period. After cooling, th~ reaction mixture is concentrated
under reduced pressure and r~sidual oil taken up in hot isopropanol.
On cooling, a solid separates which is collected to afford 7;0 g.
(70%) of product, m.p. 101-102C. Conversion of this material to
the hydrochloride salt with one equivalent of concentrated hydrochloric
acid in ispropanol affords white crystals of the labeled 8-[4-[-(2-
pyrimidinyl)-l-piperazinyl[ethyl]-8-azaspiro[4.5]decane-7,9-dione- 5N2
hydrochloride, m.p. 185-186C. Mass spectral analysis of the material
indicated an 80% l5N lsotopic purity.
Anal. Calcd for C21H31N 0 HCl: C, 59.55; H, 7-61; N, 16-91-
5 2
20 Found: C, 59.73; H, 7.60; N, 16.54.
