CH647518A5 - METHOD FOR PRODUCING BUSPIRON. - Google Patents

Description

The invention relates to a new process for the production of buspirone and in particular also of buspirone, which has radioactive 14-carbon (I4C) and stable 15-nitrogen (15N) -45 isotopes in certain positions of the pyrimidinyl component. Buspirone is a USAN for 8- {4- [4- (2-pyrimidinyl) -1 -piperazinyl] butyl} -8-azaspiro [4,5] decan-7,9-dione (see also J. Amer Med. Assoc., 225,520; 1973).

Labeled buspirone is useful for clinical studies of the absorption and metabolic distribution of this anxiolytic agent.

Yao Hua Wu, et al., U.S. PS 3,717,634 describes the synthesis of N- (heteroacyclic) piperazinylalkylazasiroal candions of the formula 1:

(Ia)

characterized in that * 14C-labeled 2-chloro-S 'pyrimidine of the formula purple: 60'

(purple)

used.

using one of the following methods:

3rd

647518

Method A

/ \

0 + H-N-A-N N_B

V_ /

Method B

N-A-X + H-N

/ A

î

\

N-B

1

Method C

(CHJ 2 n

A ~ \

N-M + X-A-N N-B

v_ /

In the above reaction scheme, n stands for the integer 4 or 5,

A for a straight-chain or branched, divalent alkylene radical having 2 to 6 carbon atoms, including,

B inter alia for various heterocyclic radicals including the 2-pyrimidinyl radical,

X among others for a chlorine, bromine or iodine atom and M for an alkali metal such as sodium or potassium.

The inventive method differs from that of Wu et al. described methods in that the last step was the 2-pyrimidinyl residue by direct alkylation of the 8- [4- (l-piperazinyI) butylJ-8-azaspiro [4,5] decane-7,9-dione with a second -Halogen pyrimidine is introduced.

The present invention accordingly relates to a process for the preparation of 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl} butyl] -8-azaspiro [4,5] decane-7,9-dione of the formula I:

azinyl) butyl] -8-azaspiro [4,5] decan-7,9-dione of the formula II:

(CH) N 2 4

/

!

V

\

NH

y cid with a 2-halopyrimidine of the formula III:

50

you)

55

N- (CH) 4-N

(I)

which is characterized in that 8- [4- (l-piper-

wherein X is a bromine, iodine or chlorine atom, alkylated in a solvent which is inert under the reaction conditions at a temperature of 80 to 170 ° C.

This process also allows economical and convenient production of radio-labeled buspirone. The term “marked” refers to radioactive, 4C and stable I5N isotopes that are introduced at certain points in the bus piron. The process 6s for producing labeled buspirone is preferably characterized in that a 2-chloropyrimidine which is labeled in the 2-position, 4C-isotope is used.

In one embodiment of the inventive

647518

4th

driving is used to produce labeled buspirone 2-chloropyrimidine, the 1,3-nitrogen atoms of which are labeled with I5N isotopes.

The labeled 2-halopyrimidines of the formula III are obtained, for example, by condensation of appropriately labeled urea with malonaldehyde-bis-dimethylacetal or malonaldehyde-bis-diethyl acetal in the presence of a

Acid. The 2-hydroxypyrimidines obtained in this way are then converted into the corresponding halogen compound using a phosphorus oxyhalide, such as phosphorus oxychloride or phosphorus oxybromide. The following formula scheme explains, for example, the preparation of 14C-2-chloropyrimidine of the formula purple, starting from 14C-urea:

*. o = c

• NHa

• NH2

+ CHi

, CH (OCH3) 2

XH (OCH3) 2

HCl

EtOH

oh-hci

POCh

The same reaction, starting from 15n2-urea leads to is 15n2-2-chloropyrimidine of the formula (Illb):

rN

Va vende oil is distilled under reduced pressure, the fraction having a boiling point of 165-170 ° C at 0.13 m bar 32.0 g (52%) 8- (4-bromobutyl) -8-azaspiro [4.5 ] decan-7,9-dione as an oil.

(Illb) 20 b) 8- [4- (l-piperazinyl) butyl] -8-azaspiro [4,5] decane-7,9-

Any solvent which does not adversely affect the reaction and does not change both the reactants and the buspirone can be used to carry out the process according to the invention. Preferred solvents are alkanols such as ethanol, n-propanol, isopropanol and the like.

The reaction temperature is in the range from 80 to 30

170 ° C, the preferred temperature range being 110 to 120 ° C. At reaction temperatures below 80 ° C, the reaction time increases excessively and the condensation does not take place accordingly. At temperatures above 170 ° C, however, the reactants partially decompose. A closed reaction vessel is preferably used to carry out the process at temperatures which are above the boiling point of the solvent.

The hydrogen halide liberated in the course of the reaction is expediently bound with an acid acceptor 40 in order to prevent the basic 8- [4- (l-piperazinyl) butyl] -8-azaspiro- [4,5] decane-7,9 -dione of formula II is withdrawn from the reaction. For this purpose, a tertiary amine such as triethylamine is preferably used.

The process according to the invention is illustrated by the following 45 examples.

example 1

Preparation of 8- [4- (l-piperazinyl) butyl] -8-azaspiro [4,5] decan-7,9-dione (II) so 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 mol) and micropulverized Potassium carbonate (88.6 g; 0.6 mol) in 500 ml dry toluene is refluxed with stirring for 20 hours. The reaction mixture is filtered hot and concentrated under reduced pressure. The lag

dion

A mixture of 8- (4-bromobutyl) -8-azasiro [4,5] decane-7,9-dione (32.0 g; 0.105 mol), piperazine (50 g; 0.58 mol) and micropulverized potassium carbonate ( 80.0 g; 0.58 mol) in 500 ml of dry toluene is heated under reflux with stirring for 18 hours. The reaction mixture is filtered hot and concentrated under reduced pressure. The residue is stirred with 100 ml of ether. Excess piperazine, which settles out as the hydrochloride, is filtered off, and the filtrate is concentrated under reduced pressure. Distillation of the oily residue under reduced pressure gives 13.5 g (42%) of 8- [4- (l-piperazinyl) butyl] -8-aza-spiro [4,5] decan-7,9-dione, from the boiling point 180 to 200 ° C at 0.13 m bar in the form of the free base.

Conversion of this material into the hydrochloride and its recrystallization from ethanol gives pure 8- [4- (1-piperazinyl) butyl] -8-azaspiro [4,5] decan-7,9-dione hydrochloride with melting point 235 to 237 ° C.

Analysis Ci7Hi9N302 * 2HCI * V4H2O:

Calculated: C 53.06; H 8.25; N 10.92%

Found: C 53.06; H 8.05; N 10.96%

Example 2

Preparation of labeled * 14C-2-chloropyrimidine (purple)

N - =>

ss a) * 14C-labeled 2-hydroxypyrimidine hydrochloride 165 mg urea (0.002 mol) containing 43 mg CI4-urea (0.0007 mol; 30 millicuries) and malonaldehyde bis (dimethylacetal) (443 mg; 0 , 0027 mol) are dissolved in 1.0 ml of ethanol and treated with 0.5 ml of concentrated hydrochloric acid 60. The acidified solution is heated on a steam bath for 2 hours and then cooled. Isolation of the yellow precipitate provides 274 mg (77%) * I4C-2-hydroxypyrimidine hydrochloride, which is reacted further without further purification.

65

b) * 14C-labeled 2-chloropyrimidine A mixture of CI4 * -2-hydroxypyrimidine hydrochloride (274 mg; 0.002 mol) and 10 ml phosphorus oxychloride

647 518

is heated to 110 ° C. for 6 hours with stirring. Excess phosphorus oxychloride is removed under reduced pressure, the remaining oily residue is dissolved in 15 ml of water. The aqueous solution is treated with 10% sodium bicarbonate until it reacts slightly basic to litmus and extracted with chloroform. Concentration of the dried chloroform extract provides * 14C-2-chloro-pyrimidine (190 mg; 83%), which is used in Example 3 without further purification.

Example 3

* 14C-labeled 8- {4- [4- (2-pyrimidinyl) -l-piperazinyl] butyl} -8-azaspiro [4,5] decane-7,9-dione (Ia)

- (ch2) 4-n

A mixture of * 14C-2-chloropyrimidine (190 mg; 0.0016 mol) obtained according to Example 2.8- [4- (l-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 of ethanol are heated in a closed reaction vessel at 110 to 120 ° C. for 72 hours. After cooling, the reaction mixture is concentrated under reduced pressure, the residue is taken up in 10 ml of isopropanol. A stoichiometric amount of a solution of hydrogen chloride in ethanol is added to the isopropanol solution and the mixture is cooled. Colorless crystals are deposited which, when isolated and recrystallized from isopropanol, give 281 mg (42%) of the labeled product in the form of the hydrochloride.

The salt is dissolved in water and sodium bicarbonate is added with cooling until the mixture is basic. A precipitate is formed which, isolated and recrystallized from isopropanol, provides 125 mg (35%) of the free base. The product turns out to be radiochemically pure based on the thin layer chromatogram, which was developed in two different solvent systems [CHCh-EtOH (4; 1) and CHCh-MeOH-HO Ac (10: 3: 1)]. It was measured radiochemically in a Varian Aerograph Berthold radio scanner. The specific activity of the * 14C-labeled 8- {4- [4- (2-pyrimidinyl) -l-piperazinyl] -butyl} -8-azaspiro [4,5] decane-7,9-dione is generally included about 20 microcurie / mg.

Analysis C21H31N5O2:

Calculated: C 65.43; H 8.11; N 18.17%

Found: C 65.60; H 8.10; N 18.24%.

Example 4

Preparation of * 15N2-labeled 2-chloropyrimidine (Illb)

*

, N "= ^

\ /

30th

35

40

45

a) * '5 n2-2-hydroxy pyrimidine hydrochloride A solution of N15-urea (3.0 g; 0.049 mol; 90 atom% N15) and malonaldehyde bis (dimethyl acetal) (8.2 g; 0.049 mol ) in 10 ml of ethanol is acidified with 10 ml of concentrated hydrochloric acid. The solution is heated on a steam bath for 2 hours and the yellow precipitate is isolated. 5.1 g (80%) of N, s * -2-hydroxypyrimidine hydrochloride with a melting point of 210 to 212 ° C. are obtained, which can be used without further purification, b) * 15n2-2-chloropyrimidine A suspension of * 15n2-hydroxypyrimidine hydro -chloride (5.1 g; 0.038 mol) in 30 ml of phosphorus oxychloride is heated to 110 ° C. with stirring for 6 hours. Excess phosphorus oxychloride is removed under reduced pressure and the oily residue is dissolved in 15 ml of water. The aqueous solution is treated with 10% sodium bicarbonate until the reaction is slightly basic and the free base is extracted with chloroform. Concentration of the dried chloroform phase gives 3.0 g (68%) * 15n2-2-chloropyrimidine, which is used according to Example 5 without further purification.

Example 5

* 15N2-labeled 8- [4- [4- (2-pyrimidinyl) -l-piper-azinyl] butyl] -8-azaspiro [4,5] decane-7,9-dione (Ib)

n- (ch2 ^

A mixture of * 15N2-2-chloropyrimidine (3.0 g; 0.026 mol), 8- [4- (l-piperazinyl) butyl] -8-azaspiro [4,5] decan-7,9-dione (8 , 07 g; 0.026 mol) and triethylamine (2.6 g; 0.026 mol) in 25 ml of ethanol are heated in a closed reaction vessel in an oil bath at 110 to 120 ° C. for 72 hours. After cooling, the reaction mixture is concentrated under reduced pressure and the oily residue is taken up in hot isopropanol. Upon cooling, 7.0 g (70%) of the desired product from the melting point 101-102 ° C. This material is treated with 1 equivalent of concentrated hydrochloric acid in isopropanol to give * I5N2-labeled 8- {4- [4- (2-pyrimidinyl) -l-piper-azinyl] butyl} -8-azaspiro [4,5] decan-7,9-dione hydrochloride in the form of white crystals with a melting point of 185 to 186 ° C. According to the mass spectrometric analysis, the material had an I5N isotope purity of 80%.

Analysis C2iH3iNs02 * HCl:

es calc .: C 59.55; Found: C 59.73;

H 7.61; H 7.60;

N 16.91% N 16.54%.

B

Claims (4)

647 518 2 4. The method of claim 1 for the production of * 15N2- 1. Process for the preparation of 8- {4- [4- (2-pyrimidinyl) -1 - labeled 8- {4- [4- (2-pyrimidinyl) -1 -piperazinyl] -butyl} -8- piperazinyl] butyl} -8-azaspiro [4,5] decane-7,9-dione of the formula aza-spiro [4,5] decane-7,9-dione of the formula Ib: I: 0 0 // ^ ^ T "N" \\ R- (CH2) A-N (I) characterized in that 8- [4- (l-piperazinyl) butyl] -8-azaspiro [4,5] decan-7,9-dione of the formula II If) characterized in that * 15N2-labeled 2-chloro-pyrimidine of the formula Illb: 20th jry (cr2> W o with a 2-halopyrimidine of the formula III (ii) 25th N "W \ (im used. 5. The method according to any one of claims 1 to 4, characterized in that one uses a closed reaction vessel. (iii) wherein X represents a bromine, iodine or chlorine atom, alkylated in a solvent inert under the reaction conditions at a temperature of 80 to 170 ° C. 2. The method according to claim 1, characterized in that 2-chloropyrimidine is used as the 2-halopyrimidine. 3. The method according to claim 1 for the preparation of * I4C-labeled 8- {4-t4- (2-pyrimidinyl) -1 -piperazinyl] -butyl} -8-azaspiro [4,5] decane-7,9-dione- * I4C of formula Ia: , N- (ch2) a-N 40 Process for the production of buspirone