FI73993C - PROCEDURE FOR THE RADIOACTIVE MAINTENANCE OF MAERKTA 8- / 4- / 4- (2-PYRIMIDINYL) -1-PIPERAZINYL / BUTYL / -8-AZASPIRO / 4.5 / DECAN-7,9-DIONER. - Google Patents

Description

1 73993

Method for radioactive labeling of labeled 8- [N- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [J. The invention relates to a new process for 8- [3- [3- (2-pyrimidinyl) -1-piperazinyl] -butyl] -8-azaspiro [14] T, 5'-decan-7,9-diacan-7 To prepare 9-dione-C of formula Ia

D 2 -O-δ-15 or 8- [3- (N- (2-pyrimidinyl) -1-piperazin-7-butyl] -N-8-azaspiro [4] -disane-7,9-dione-N 2 for the preparation of formula Ib

DcJ-OD "25 8- [3" [3 "(2-pyrimidinyl) -1-piperazinyl tert-butyl] -8-azaspiro [4.57] decane-7,9-dione is known in the United States as" buspirone "(see J. Amer. Med Assoc 225 (1973) 52 £ 7.

Labeled buspirone is useful in the clinical study of the absorption and metabolic distribution of this anxiolytic agent.

Yao Hua Wu, et al., U.S. Patent 3,717,634 describes N- (heteroarcyclic) piperazinylalkylaza-35 spiroalkanediones of formula I

2 73993 and synthesis by the following methods:

Method A:

O

1 ° jj λλΛ / - \ Y O + H „N-A-N N-B -> (I) ^ 1 / \ _ y 2 w 15 (ID (III)

Method B:

O

20 (5 ^ H2) n X N-Ä-X + H-N / N-B -> (I) vYY w, .. (IV) (V)

Method C: 25

(CH) V N-M + X-A-N N-B -> (D

\ L! A_y 30 i (VI) ° VII)

In the above reaction equations, n is an integer of 4 or 5, -A- is a straight or branched divalent C 2-8 alkali chain, B is e.g. one of many heterocyclic radicals, for example 2-pyrimidinyl, X is e.g. chlorine, bromine or iodine and M is an alkali metal salt such as sodium or potassium.

3 73993

The process of the invention differs from the process of U.S. Patent 3,717,634 in that the 2-pyrimidinyl moiety is coupled in the final step by direct alkylation of the previously prepared 8- [N- (1-piperazinyl) butyl] -8-azaspiro / JT. . 57-decan-7,9-dione with 2-halopyrrimidine, whereby the radioactive carbon (C) and residual nitrogen (N) isotopes are attached to specific sites in the pyrimidyl portion of buspirone.

The process according to the invention for the preparation of radiolabelled 8-β- (2-pyrimidinyl) -1-piperazinyl] -7-butyl-7- (8-azaspiro [5] decan-7,9-dione) is characterized by that 8 - [(T- (1-Piperazinyl) butyl] -8-azaspiro [1. 5-decane-7,9-dione of formula II

15 0 Z 'A n- (ch) - / ώ (II) H w 20 is alkylated with radiolabeled 2-halopyrr * * 14 miduni-C,

»-O

Or radiolabeled 2-halopyrimidine-13N2 of formula (III ") * wherein X is bromine, iodine or chlorine, preferably chlorine, in the reaction in an inert solvent at a temperature of 35 to 80-170 ° C.

Preferably a closed reaction vessel is used.

4 73993

The above method for preparing radiolabeled buspirone is both economical and easy. As used herein, the term "labeled" refers to radioactive (C) and persistent (N) isotopes attached to specific positions on buspirone 14. Preferred embodiments of the above process are those for the preparation of labeled buspirone in which the radiolabeled 2-halopyrimidine is 2-chloropyrimidine 14 labeled at the 2-position with the C isotope; or 2-chloro-pyrimidine having 1,3-nitrogen atoms labeled with N-isothiope.

The labeled 2-halopyrimidines of formula III 'or III "are obtained by condensing the appropriately labeled urea with malonaldehyde-bis-dimethylacetal or malonaldehyde-bis-diethylacetal in the presence of an acid to give the corresponding 2-hydroxypyrimidine, then converting the corresponding 2-hydroxypyrimidine to halogen. such as phosphorus oxychloride or phosphorus oxybromide To illustrate this, the reaction equation starting from urea-4C, 2-chloropyrimidine-C (purple) is as follows:

^ NH, CH (OCH,) _ HCl / T ~ N

* 2 32 // V

0 = CtQ + CH2-> \ Λ-— QH-HCl

25 NH2 \ cH (OCH3) 2 EtOH

/ T ~ \ * POC1 _ (/ 7 — Cl 30 -M \ = N / (Ula)

By a similar method starting from urea-15 * 15 N2, 2-chloropyrimidine-N2 (mb) is obtained:

GH

(IHb) 5 73993 In carrying out this process, any solvent which does not adversely affect the reaction, reagents or buspirone product may be used, the preferred solvent being an alkanol such as ethanol, n-propanol, isopropanol and the like.

In general, temperatures of 80 to 170 ° C can be used as the reaction temperature, with the preferred temperature range being 110 to 120 ° C. Higher and lower temperatures can be used, but at temperatures below 80 ° C the reaction is unnecessarily prolonged and there is not enough condensation in the house, whereas when the reaction temperature exceeds 170 ° C the reagents tend to decompose to some extent. When the reaction is carried out at a temperature above the center of the solvent, it is preferable to use a closed reaction vessel.

The hydrogen halide released during the reaction is coupled with an acid scavenger to give basic 8- [4- (1-Piperazinyl) butyl] [7-8-azaspiro [i]. 57decan-7,9-dione (II). For this purpose, it is preferable to use a tertiary amine such as triethylamine.

Example 1 8-ZJ- (1-piperazinyl) butyl] 7-8-azaspiroZ3-. Preparation of 57-decane-7,9-dione (II), 0 25 Λτ / _ ^ (CM2) 4h / ^ ^ nh. 57-decane-7,9-dione 3,3-tetramethylene glutarimide (33.4 g, 0.2 mol), 1,4-dibromobutane (86.4 g, 0.4 mol) and finely divided potassium carbonate (88.6 g, 0.6 mol) is refluxed in toluene (dry, 500 ml) with stirring for 20 h. The reaction mixture is filtered hot and concentrated under reduced pressure, the oily residue 6 73993 is distilled under reduced pressure and the fraction boiling at 165-170 ° C (0.1 mmHg ) is recovered to give 32.0 g (52%) of 8- (4-bromobutyl) -8-azaspiro [4]. 57-decan-7,9-dione as an oil.

5 (b) 8-71- (1-Piperazinyl) butyl-7-8-azaspiro [74-] decan-7,9-dione 8- (4-bromobutyl) -8-azaspiro / 4.57-decane-7,9-dione (32.0 g, 0.105 mol), piperazine (50 g, 0.58 mol) and finely ground potassium carbonate (80.0 g, 0.58 mol) are refluxed in dry toluene (500 ml) with stirring for 18 h. The reaction mixture is filtered hot, concentrated in vacuo and the residue is taken up in ether (100 ml). Excess piperazine, which separates as the hydrochloride, is collected and the mixture is concentrated under reduced pressure. Distillation of oil-15 g under reduced pressure gives 13.5 g (42%) of 8- [T- (1-piperazinyl) butyl] -8-azaspiro [4.57] decane-7,9-dione, b.p. 180-200 ° C (0.1 mmHg), as the free base.

Conversion of this material to its hydrochloride salt and crystallization from ethanol gives analytically pure 8-74- (1-piperazinyl) butyl ± 7-8-azaspiro 74.5 / decane-7,9-dione hydrochloride, m.p. 235-237 ° C.

Analysis:

Calculated for C 17 H 19 N 3 C> 2 * 2HCl * 1 / 4H 2 O: C, 53.06; H 8.25; N 10.92. Found C: 53.06; H 8.05; N 10.96.

25 Example 2 * 14

Preparation of labeled 2-chloropyrimidine-C (IIIa) *} / ^ C1 - \ / 30 * 14 (a) C-labeled hydrochloride of 2-hydroxypyrimidine

A solution of urea (165 mg, 0.002 mol) containing 14 35 urea-Csa (43 mg, 0.0007 mol, 30 mcurie) and malonaldehyde-di-bis-dimethylacetal (443 mg, 0.0027 mol) in ethanol 7 73993 ( 1.0 ml) is treated with concentrated hydrochloric acid (0.5 ml). The acidified solution is heated on a steam bath for 2 h and cooled to ice cold. The yellow precipitated product is collected to give 274 mg (77%) of 2-chloropyro- * 14 5 rimidine-C, which is used without further purification.

* 14 (b) 2-Chloropyrimidine-C (labeled) * 14 A mixture of 2-hydroxypyrimidine-C-hydrochloride (274 mg, 0.002 mol) and phosphorus oxychloride (10 ml) is heated at 110 ° C with stirring for 6 h. the ride is removed under reduced pressure and the oily residue is dissolved in water (15 ml). The aqueous solution is treated with 10% sodium carbonate until it gives a weakly basic reaction to the litmus and extracted with chloroform. Concentration of the dried chloroform extract gives 2-chloropyrimidine-C (190 mg, 83%) which is used crude for Example 3.

Example 3 8-Z3-ZJ- (2-pyrimidinyl) -1-piperazinyl-7-butyl-7-8-aza-spiro-Z.4. £ 7decan-7,9-dione (labeled) (Ia) 20 DCf-OO

* 14 2-Chloropyrimidine-C (190 mg, 0.0016 mol), 8- (JU-30 piperazinyl) butyl37-8-azaspiro / J.57decan-7,9- according to Example 2 mixed with ethanol (15 ml) dione (509 mg, 0.0016 mol) and triethylamine (163 mg, 0.0016 mol) are heated at 110-120 ° C in a sealed reaction vessel for 72 h. After cooling, the reaction mixture is concentrated under reduced pressure and the residue is stirred in isopropanol 35 ( 10 ml). A stoichiometric amount of hydrogen chloride in ethanol is added and the mixture is cooled. White crystals separate which are collected and crystallized from isopropanol to give 281 mg (42%) of the labeled product as the hydrochloride salt.

The salt is dissolved in water and sodium bicarbonate is added under cooling until the solution is basic. A precipitate forms which is collected and crystallized from isopropanol to give 125 mg (35%) of the free base, which is radiochemically pure eluted by thin layer chromatography with two different solvent combinations of CHCl 3 -EtOH (4: 1) and CHCl 3 -MeOH-HOAc (10: 3: 1) and examined with a Varian Aerograph-10 Berthold Radioscanner.

The activity of labeled 8-ZJ- [5- (2-pyrimidinyl) -1-piperazinyl] t-butyl] -8-azaspiro [3,5] decane-7,9-diol-14C is generally about 20 jacurie / mg.

Analysis: Calculated, C 21 H 31 N 5 O 2: C 65-43, H 8.11; N 18.17. Found: C, 65.60; H 8.10; N 18.24.

Example 4 * 15

Preparation of labeled 2-chloropyrimidine-N2 (IIIb) * “= \” a ~ ij * 15 (a) 2-hydroxypyrimidine hydrochloride- Nn 15 ^

Urea-N_ (3.0 g, 15 z 0.049 mol, 90% N-isotope) and malonaldehyde-bis-dimethylacetal (8.2 g, 0.049 mol) dissolved in ethanol (10 ml) are acidified with concentrated hydrochloric acid. . The solution is heated on a steam bath for 2 h and the resulting yellow precipitate is collected to give 5.1 g (80%) of 2-hydroxypyrimidine-N2-hydrochloride, m.p. 210-212 ° C, which is used without further purification as follows: * 15 (b) 2-chloropyrimidine-15

Hydroxypyrimidine N 2 hydrochloride (5.1 g, 0.038 mol) suspended in phosphorus oxide chloride (30 ml) is heated at 110 ° C with stirring for 6 h. The excess phosphorus oxychloride is evaporated off under reduced pressure and the oily residue 9 73993 is dissolved in water (15 ml). The aqueous solution is treated with 10% sodium bicarbonate until slightly basic and the free base is extracted with chloroform. Concentration of the chloroform extract gives 3.0 g (68%) of 2-chloropyridine N2, which is used without purification in Example 5.

Example 5

Labeled e-ZJT-Zjp (2-pyrimidinyl) -1-piperazinyl-7-butyl-N-_-_-15-8-azaspiro [N, N-deca-7,9-dione-N? (Ib) 10 4 - (- 15 * 15 - 2-chloropyrimidine-N 2 (3.0 g, 0.026 mol), β-1α- (1-piperazinyl) butyl) -8-azaspiro [4.5.5] decane-7.9 -dione (8.07 g, 0.026 mol) and triethylamine (2.6 g, 0.026 mol) are stirred in ethanol (25 ml) and heated in an oil bath in a sealed reaction vessel for 72 h. After cooling, the reaction mixture is concentrated under reduced pressure and the residue is dissolved in hot isopropanol. On cooling, a solid separates which is collected to give 7.0 g (70%) of product, 25 mp 101-102 ° C. Conversion of this product to the hydrochloride salt with an equivalent amount of concentrated hydrochloric acid in isopropanol gives the labeled 8- / J-ZJ- (2-pyrimidinyl) -1-piperazinyl-7-butyl-7--azaspiro [2S] decane-7,9-dione- * 15 ° N-hydrocarbon, mp 185-186 C. Based on a mass spectrum, the product has an isotopic purity of 80% n-isotope.

Analysis: Calculated for C 21 H 31 N 5 O 2 · HCl: C, 59.55; H 7.61; N 16.91. Found C 59.73; H 7.60; N 16.54.

Claims (5)

10 73993 A process for the preparation of 8- [4- [N- (2-pyrimidinyl) -1-piperazinyl] -7-butyl] -8-azaspiro [5] decane-7,9-dione - Ia! Amiseksi (^ - / 10. w or 8- [3 "- [C4- (2-pyrimidinyl) -1-piperazinyl] -7-butyl] -8-azaspiro [-4.57] decane-7,9-dione-15N2, which has Formula Ib. DC-OiD "* characterized in that 8 - [? - (1-piperazinyl) butyl] -7-azaspiro [3.7] decan-7,9-dione of formula II / \ 30 O is alkylated with radiolabeled 2-halopyrim- * 14 mididine-C of formula (III ') χ - * / Λ (m-, 11 73993) or with radiolabeled 2-halopyrimidine- * 1, 5N2 is of formula (III ") 5 -f)« m '> wherein X is bromine, iodine or chlorine, preferably chlorine, in a reaction-inert solvent at a temperature of 80 to 170 ° C. Process according to Claim 1, characterized in that it is carried out in a closed reaction vessel. 12 7399 3 A process for the preparation of 8-ZJ-Z3 "- (2-pyrimidinyl) -1-piperazinyl] butyl7-8-azaspiro [2,5-decane-7,9- * 14 5 dione- with the form of I and QC (CK)] 10-or 8 (2-pyrimidinyl) -1-piperazinyl-7-butyl-7--aza-_-15 spiroZ_4,5 / decane-7,9-dione-N, with formyl Ib 15 DQ ^ -O ^ D ”20 Kännetecknat därav, att man alkylerar piperazinyl) buty! 7 “8-azaspiro / J.57decan-7,9-Dione with Formula II ΓλΛ ^ / \ _ / \ 7 · * 14 with radioactive wet 2-halopyrimidine-C with formula III '