DK154560B - PROCEDURE FOR PREPARING RADIOACTIVALLY MARKED 8-OE4-OE4- (2-PYRIMIDINYL) -1-PIPERAZINYLAABUTYLAA-8-AZASPIRO-OE4.5AADEKAN-7,9-DION - Google Patents

Description

in

DK 154560 B

The present invention relates to a particular process for the preparation of radiolabeled 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione.

U.S. Patent No. 3,717,634 discloses the preparation of N-5 (heteroacyclic) piperazinylalkyllazaspiroalkandions of formula I

o ^ λ / Λ λ ~ \ (CIVn X N-A-N 71-2 io vii / vv \ _y

1U II

ISLAND

Formula I

using the following methods.

15

Process A

island

20 (^ Vn + h2n-a-n ^ _ ^ n-b -v Formula I

ISLAND

Method B

island

£ 7V 'M — A — X + H- / -. Formula I

vVW \ _ / 30 fj o ·

Formula IV Formula V

Method C 35 0

n-m + x-a-n ^ N-B Formula I

νιννγ \ _y n

DK 154560 B

2 In the above reaction schemes, "n" is the whole number 4 or 5, -A- represents a straight or branched divalent alkaline chain having a total of 2-6 carbon atoms. various heterocyclic radicals including "2-pyrimidinyl"; chlorine, bromine or iodine, and 5 "M" is an alkali metal salt such as sodium or potassium.

The present process differs from the methods of U.S. Patent No. 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-halo-pyrimidine.

Broadly, the invention relates to a process for the preparation of radiolabelled labeled 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione to which the term "buspiron" adopted in the United States is hereinafter referred to, see J. Amer. With.

Assoc., 225, 520 (1973). The present process provides a particular and novel method for producing radiolabelled buspirone and more particularly a method for incorporating radioactive carbon (C) and stable nitrogen (N) isotopes at certain positions on the pyrimidinyl component of buspirone. The labeled buspirone is valuable for clinical investigation of the absorption and metabolic disposition of this anxiolytic agent.

Thus, the present invention relates to a process for the preparation of radiolabeled 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione which is characterized by Formula Ia or Ib

, DC ^ OO

ί la), ° 35 γλ / λ f- \ / k ~ \ - * N — 7

ISLAND

(Ib)

DK 154560 B

3

which process is characterized in that 8- [4- (1-piperazinyl) -butyl] -8-azaspiro [4.5] decane-7,9-dione of formula II

LyVY 24v / o (II) is alkylated with radiolabeled 2-halogenpyrimidine of formula IIla or Illb 15 x7 ~ \ \ = / (Illa) (Illb) 20 wherein X is bromine, iodine or chlorine in a reaction-inert solvent at a temperature in the range of 80-170 ° C. In the process of the invention, radiolabeled 2-chloropyrimidine is preferably used and the reaction is preferably carried out in a closed reaction vessel.

By the method of the invention, it is possible to prepare radiolabelled buspirone which is of importance for clinical studies of the absorption and metabolic reaction of buspirone. The process according to the invention in this connection has both technical and economic advantages. Thus, it is of great importance to be able to incorporate the costly radioactive pyrimidinyl moiety into buspirone during the last 30 steps of synthesis rather than into an intermediate product.

The compound of formula IIa is 2-halogenpyrimidine labeled in the 2-position of carbon isotope and the compound of formula IIIb is 2-halogenpyrimidine wherein the 1.3 to 15 nitrogen atoms are labeled with nitrogen isotope.

The labeled 2-halo pyrimidines of formula IIa are obtained by condensing appropriately labeled urea with malonaldehyde bis (dimethyl acetal) or malonaldehyde bis (diethyl acetal) in the presence of acid to give the corresponding 2-hydroxypyrimidine which is then converted

DK 154560 B

4 to the halogen compound by phosphorus oxyhalide such as a phosphorus oxychloride or phosphorus oxybromide. By way of illustration, the sequence beginning with urea-14C to produce 2-chloro-pyrimi- * 14 din-C (IIa) is depicted below.

5 ym2 cH «ch3) 2 hci 0 = C ^ + CH2 \ ^ -> - (y- OH-HCl NH2 CH (OCH3) 2 EtOH V = -N.

10 Ρ0 ^ 3 ^ 01 (Illa) 15 15

The identical sequence beginning with urea- N «provides- * 1R ^ produces 2-chloropyrimidine- Ng (Hib) / -N * 20 / -V-oi

\ -N

A.

(IIIb)

In carrying out the present process, any solvent which does not adversely affect the reaction or the reactants and the buspirone product can be used, the preferred solvent being an alkanol such as ethanol, n-propanol, isopropanol and the like.

Generally, a reaction temperature in the range of from

80 ° C to approx. 170 ° C, the preferred temperature being in the range of 110 ° C to 120 ° C. Higher and lower temperatures may be used, but at a reaction temperature below 80 ° C, the reaction is unnecessarily prolonged and appropriate condensation does not occur, while reactants tend to decompose to some extent if the reaction temperature exceeds 170 ° C. When the process is carried out at temperatures above the boiling point of the reaction solvent, a closed reaction vessel is preferably used.

The hydrogen halide developed during the reaction is collected with an acid acceptor to preserve the basic 8- [4 - (- 1-piperazinyl] butyl] -

DK 154560 B

8-Azaspiro [4.5] decane-7,9-dione reactant (II). In this regard, a tertiary amine such as triethylamine is preferred.

The process according to the invention is further elucidated in the following Examples 3 and 5.

5

Example 1

Preparation of 8- [4 - (- 1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione (II) 10

ISLAND

(A) 8- (4-Bromobutyl) -8-azaspiro [4.5] decane-7,9-dione - A mixture of 3,3-tetramethylene glutarimide (33.4 g, 0-2 mol), 1.4- dibromobutane (86.4 g, 0.4 mole) and carbulsified potassium carbonate (88.6 g, 0.6 mole) in 500 ml of dry toluene are stirred at reflux temperature for a period of 20 to 20 hours. The reaction mixture is filtered while warm and concentrated under reduced pressure. Residual oil is distilled under reduced pressure and the fraction having a boiling point of 165-170 ° C at 0.1 mm Hg is collected to give 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 [4.5] decane-7,9-dione - A mixture of 8- (4-bromobutyl) -8-azaspiro [4.5] decane 7,9-dione (32.0 g, 0.105 mole), piperazine (50 g, 0.58 mole) and carb carbonized potassium carbonate (80.0 g, 0.58 mole) in 500 ml of dry toluene are stirred at reflux 18 hours. The reaction mixture is filtered while hot, concentrated under reduced pressure and the remaining material is stirred with 100 ml of ether. Excess piperazine, which separates as hydrochloride, is collected and the filtrate is concentrated under reduced pressure. Distillation of residual oil under reduced pressure gives 13.5 g (42%) of 8- [4- (1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione, boiling point 180-200 ° C 35 at 0.1 mm Hg as the free base.

Conversion of this material to the hydrochloride salt and recrystallization with ethanol give analytically pure 8- [4- (1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione hydrochloride, mp 235-237 ° C.

DK 154560 B

6

Analysis: Calculated for C17 H20 N3 O2.2HCl.1 / 4H2 O: C, 53.06; H, 8.25; N, 10.92 Found: C, 53.06; H, 8.05; N, 10.96

Example 2 * 14

Preparation of labeled 2-chloropyrimidine C (IIa) 10 d - / - "N - = / * 14 (a) 2-hydroxypyrimidine C-labeled hydrochloride - A solution of 14 urea (165 mg, 0.002 mol) containing urea-C (43 mg, 0.0007 mol, 30 ml 11 in curie) and malonaldehyde bi s (dimethyl acetal) (443 mg, 0.0027 mol) in 1.0 ml ethanol are treated with 0.5 ml concentrated hydrochloric acid. Heat over a steam bath for a period of 2 hours and cool.The yellow precipitated product is collected to give 274 mg * 14 20 (77%) of 2-chloropyrimidine C used without further purification as follows.

* 14 (b) 2-Chloropyrimidine C-Labeled - A mixture of 2-hydroxypyritinic * 14 din C hydrochloride (274 mg, 0.002 mol) and 10 ml phosphorus oxychloride is heated to 110 ° C with stirring for a period of 6 hours. Excess 25 phosphorus oxychloride is removed under reduced pressure and residual oil is dissolved in 15 ml of water. The aqueous solution is treated with 10% sodium bicarbonate until slightly alkaline on paper and extracted with chloroform. Concentration of the dried chloroform extract gives 2-chloropyrimidine-1 ° C (190 mg, 83%) used without further purification in Example 3.

Example 3 8- [4- [4- (2-Pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9- * 14 dione C-labeled (Ia)

35 O

o * 14

DK 154560 B

7

A mixture of 2-chloropyrimidine-C (190 mg, 0.0016 mol) from Example 2, 8- [4- (1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7, -9- dione (509 mg, 0.0016 mol) and triethylamine (162 mg, 0.0016 mol) in 15 ml ethanol are heated to 110-120 ° C in a closed reaction vessel for a period of 5 72 hours. After cooling, the reaction mixture is concentrated under reduced pressure. pressure and the remaining material are taken up in 10 mlisopropanol A stoichiometric amount of hydrogen chloride in ethanol is added to the isopropanol solution and the mixture is cooled. labeled product as the hydrochloride salt.

The salt is dissolved in water and sodium bicarbonate is added while cooling until the mixture is basic. A precipitate is formed which is collected and recrystallized with isopropanol to give 125 mg (35%) of free base product which is radiochemically pure by thin layer chromatography, produced in two separate solvent systems [CHCl3 -EtOH (4: 1) and CHClg-MeOH-HOAc (10: 3: 1)] and scanned using a "Varian Aerograph-Berthold Radio Scanner". Specific activity of 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione 14C-labeled product is generally about 20 microcurie / mg.

20

Analysis: Calculated for C £ 1H₂ 31O 5₂: C, 65.43; H, 8.11; N, 18.17 Found: C, 65.60; H, 8.10; N, 18.24

Example 4 * 15

Preparation labeled 2-chloropyrimidine N2 (Hib)

-ISLAND

N '

* 1 P

(a) 2-hydroxypyrimidine hydrochloride N2 - A solution of urea-15N2 (3.0 g, 0.049 mole, 90 atom% 15N) and malonaldehyde bis (dimethyl acetal) (8.2 g, 0.049 mole) in 10 ml ethanol is acidified with 10 ml of concentrated hydrochloric acid. The solution is heated over a steam bath for a period of 2 hours and the yellow precipitate formed is collected to give 5.1 g

DK 154560 B

8 (80%) 2-hydroxypyrimidine ** ® N 2 hydrochloride, m.p. 210-212 ° C used

Without further cleaning as follows.

* 15 (b) 2-Chloropyrimidine-N 2 - - A suspension of hydroxypyrimidine * 15 3 N 2 hydrochloride (5.1 g, 0.038 mol) and 30 ml of phosphorus oxychloride is heated to 110 ° C with stirring for a period of 6 hours. hours. Excess phosphorus oxychloride is removed under reduced pressure and residual oil is dissolved in 15 ml of water. The aqueous solution is treated with 10% sodium bicarbonate until slightly basic and the free base is extracted with chloroform. Concentration of the dried chloroform extract gives 3.0 g (68%) of 2- * 15 chloropyrimidine N 2 used without further purification in Example 5.

Example 5 8- [4- [4- (2-Pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7.9-15 dione * 1®l-labeled (Ib) 20 * 15

A mixture of 2-chloropyrimidine-N 2 (3.0 g, 0.026 mmol), 8- [4- (1-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 of ethanol are heated in an oil bath to 110-120 ° C in a closed reaction vessel for a period of 72 hours.

After cooling, the reaction mixture is concentrated under reduced pressure and the residual oil is taken up in hot isopropanol. On cooling, a solid collected to give 7.0 g (70%) of product, m.p. 101-102 ° C. Conversion of this material to the hydrochloride salt with one equivalent of concentrated hydrochloric acid in isopropanol affords white crystals of the labeled 8- [4- (2-pyrimidinyl) -1-piperazinyl] ethyl] -8-azaspiro [4.5] decane-15 o 7, 9-dione-N9 hydrochloride, m.p. 185-186 C. Mass spectral analysis of the c 15 material shows an 80% N in sotopic purity.

Analysis: Calculated for C 21 H 31 N 5 ° 2 * HCl: 35 C, 59.55; H, 7.61; N, 16.91

Found: C, 59.73; H, 7.60; N, 16.54

Claims (4)

2. A method according to claim 1, characterized in that it is carried out in a closed reaction vessel. 3. A process according to claim 1, characterized in that alkylation * 14 is labeled with 2-chloropyrimidine-C of formula IIa 5 * - (Λ (IIa) 10) to prepare 8- [4- [4- (2-pyrimidinyl)] -1-piperazinyl] -butyl] -8- * 14 azaspiro [4,5] decane-7,9-dione-C of formula Ia 4. A process according to claim 1, characterized in that alkylation * 15 is labeled with 2-chloropyrimidine-N of formula IIla 20 * Cl-V Ulla) to prepare 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-aza-spiro [4.5] decane-7,9-dione-N 2 of Formula Ib DCi 35 ° (35 Ib)