GB2201417A - 4-(2-Pyrimidinyl)-piperazine derivatives - Google Patents
4-(2-Pyrimidinyl)-piperazine derivatives Download PDFInfo
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- GB2201417A GB2201417A GB08804385A GB8804385A GB2201417A GB 2201417 A GB2201417 A GB 2201417A GB 08804385 A GB08804385 A GB 08804385A GB 8804385 A GB8804385 A GB 8804385A GB 2201417 A GB2201417 A GB 2201417A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
PIPERAZINE DERIVATIVES AND PROCESS FOR THE PREPARATION
THEREOF
This invention relates to a new and improved process for the preparation of pharmaceutical- ly active piperazine derivatives and to new intermediates useful in the preparation thereof and also to a process for the preparation of the said intermediates.
According to an aspect of the present invention there is provided a process for the preparation of the therapeutically active kno-wn 8-{4-[ 4-(2-pyriinidinyl) -1- -piperazinyl]-butyl}-8-aza-1-spiro[4.5]-decane-7,9 -dione of the Formula I.
It is known that the 8-{ 4-f 4-(2-pyrimidinyl) -1-piperazinyl]-butyl}-8-aza-spiro[4.5]decane-7,9-dione of the Formula I possesses valuable anxioselective properties (UK Patent No. 1,332,194). In prior art several methods are disclosed for the preparation of the compound of the Formula I.
According to UK patent No. 1,332,194 the compound of the Formula I is prepared by reacting 8-oxa-spiro[4.5]decane-7,9-dione with 1-(4-aminobutyl) -4-(2'-pyrimidinyl)-piperazine. The reaction is accomplished in pyridine at the boiling point of the reaction mixture. The desired compound of the Formula I is obtained in crude form with medium yield. The crude product is purified in the free base form by crystallization or fractional distillation in vacua. The drawback of the above first purification method is that the losses are significant while fractional distillation in vacuo is carried out at high temperature (240-265 0c) under low pressure (13.3 Pa), which constitutes a severe thermal load and leads to decomposition of the product.
According to an other method disclosed in
UK patent No. 1,332,194 8-(4-chlorobutyl)-8-aza-spiro f4.S7decane-7,9-dione is reacted with N-(2-pyrimidinyl) -piperazine in the presence of sodium carbonate in n -butanol at the boiling point of the reaction mixture for 3 days. The extremely long reaction time makes the process unsuitable for economical industrial scale manufacture. A further disadvantage is that the product can be purified but with the aid of complicated and circumstantial methods. A still further drawback resides in the fact that the l-bromo-4-chloro-butane used as starting material in the preparatipn of 8-(4-chlorobutyl)-8-aza-spiro[4.5]decane-7,9-dione is very difficult te obtain and which can be prepared only by means of complicated methods.
According to a still further process disclosed in UK patent No. 1,332,194 8-oxa-spirof4.57 decane-7,9-dione is first converted into 8-aza-spiro [4.5]decane-7,9-dione. The 1-(4-chlorobutyl)-4-(2 -pyrimidinyl) - piperazine prepared from N-(2-pyrimidinyl) -piperazine and l-bromo-4-chloro-butane is reacted with 8-aza-spiro[4,5]decane-7,9-dione. This process comprises several steps which are very delicate and can be carried out only under serious difficulties. The compound of the Formula I thus obtained is suitable for pharmaceutical purposes only after severalfold purification. A further drawback resides in the poor availability of the 1-bromo- 4- chloro-butane used as starting material.
The l-(4-aminobutyl) -4-(2-pyrimidinyl) -piperazine can be prepared by reacting 1-(2-pyrimidinyl)- -piperazine with 3-chloropropionitrile in n-butanol as medium at the boiling point of the reaction mixture for a longer period of time (the reaction time is 16 hours). The intermediate thus obtained must be subjected to purification by crystallization (yield 70 %). The intermediate nitrile is catalytically hydrogenated under pressure with a yield of about 70 % (UK patent No.
1,332,194).
In Rungarian patent No. 187,999 a further process is set forth. The compound of the Formula I is prepared as follows: from 1-(4-chlorobutyl)-4-(2- -pyrimidinyl) -piperazine first the spiro quaternary ammonium piperazine derivative of the Formula IX
is prepared which is reacted with 8-aza-spiroE 4, - decane-7,9-dione in the presence of a strong base.
This process is accompanied by a number of drawbacks.
Thus the yield is low, the synthesis is a multi step process and the contaminated product obtained can only be purified with difficulty.
According to Swiss patent No. 647,518 8-aza-spiro[4.5]decane-7,9-dione is first reacted with 1,4-dibromo-butane, the 4-bromo-bu-tyl -derivative thus obtained is treated with piperazine, whereupon the product thus obtained is reacted with 2-chloro -pyrimidine. The object of this process is to prepare a compound labelled with 14O isotope and is therefore but of theoretical importance.
According to Spanish patent No. 536,286 the potassium salt of 8-aza-spiro[4.5]decane-7,9- dione is reacted with 4-cnloro-butyraldehyde,where- upon the product thus obtained is reacted with N-(2 -pyrimidinyl) -pfperazine under reductive conditions.
This process is of mere academical significance too and is unsuitable for industrial scale manufacture.
It is the object of the present invention to provide a process which overcomes the drawbacks of the above known methods and enables the favourable preparation of the compound of the Formula I on industrial scale too by using readily available starting materials. It is a further object of the present invention to provide a process which gives the desired compound of the Formula I with good yields and in high purity.
According to the present invention there is provided a process for the preparation of 8-I4-C4-(2- -pyrinidinyl) -l-piperazinyl7-buty1) 8-aza-spirof4.57 decane-7,9-dione of the Formula I and pharmaceutically acceptable acid addition salts thereon which comprises hydrogenating a compound of the general Formula II
(wherein A stands for -C=C- or -CH=CH-) and, if desired, converting the compound of the Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.
According to a form of realization of the process of the present invention the compound of the
Formula IIA is hydrogenated. The reaction may be performed in the presence of a metal catalyst with hydrogen. As catalyst preferably palladium or Raney -nickel can be used One may particularly advantageously proceed by carrying out hydrogenation in the presence of a palladium catalyst applied onto a charcoal carrier.
Hydrogenation of the compound of the Formula IIA
can be accomplished in an inert organic solvent. As reaction medium preferably lower aliphatic alcohols - particularly methanol or ethanol - can be used.
Hydrogenation may be carried out preferably under atmospheric pressure at room temperature.
The compound of Formula I can be isolated from the reaction mixture by known methods. Thus one may proceed by removing the catalyst by filtration and evaporating the filtrate. The catalyst can be re -introduced into tne hydrogenation cycle directly without further treatment.
The compound of the Formula I thus obtained is of high purity and is suitable for pharmaceutical use without any special purification.
According to an other form of realization of the process of the present invention the compound of the Formula IIB
is reduced. The reaction can be performed by catalytic hydrogenation. As metal catalyst preferably palladium can be used. The reaction may be carried out in an inert organic solvent. As reaction medium preferably lower aliphatic alcohols - particularly methanol or ethanol can be used. Hydrogenation of the compound of the
Formula IIB can be accomplished preferably under atmospheric pressure at room temperature.
The compound of the Formula I thus obtained can be converted into an acid addition salt thereof by known methods. Any pharmaceutically suitable inorganic acid (e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid etc.) or organic acid (e.g. maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, succinic acid etc.) can be used.
The starting materials of the general Formula II are new compounds.
According to a further aspect of the present invention there are provided new compounds of the general
Formula II (wherein A stands for -C=C- or -CH=CX-) Thus the following new compounds are provided: 8-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-but-2-inyl}-8 -aza-spiro[4.5]decane-7,9-dione of the Formula IIA, 8-{4-[4-(2-pyrimidinil)-1-piperazinyl]-butene-2-yl}-8 -aza"'spirof4.S7decane-7,9-dione of the Formula lIB.
The compounds of the general Formula II are, on the one hand, useful intermediates suitable for the preparation of the therapeutically active known compound of the Formula I while, on the other hand, possess valuable pharmaceutical properties per se.
According to a further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient a compound of the general Formula II (wherein A is as stated above) or a pharmaceutically acceptable acid addition salt thereof in admixture with suitable inert carriers.
The pharmaceutical compositions of the present invention can be prepared by known methods of pharmaceutical industry and contain conventional pharmaceutical carriers and auxiliary agents.
According to a still further feature of the present invention there is provided a process for the preparation of compounds of the general Formula II (wherein A stands for -C-C- or -CH=CH-) and acid addition salts thereon which comprises
a) for the preparation of the compound of the Formula IIA, subjecting the propine derivative of the Formula III
to Mannich condensation with an amine of the Formula IV;;
or
b) for te preparation of the compound of the Formula IIA, reacting the propine derivative of the Formula III with an alkyl magnesium halide of the general Formula V
R-Mg-Hlg (v) (wherein R stands for C14 alkyl and Hlg is chlorine, iodine or bromine), reacting the compound of the general Formula VI
thus obtained (wherein Hlg is as stated above) with at least one molar equivalent amount of trioxymethylene or formaldehyde, converting the substituted amino alcohol of the Formula VII
into a reactive ester of the general Formula VIII
(wherein X stands for a reactive ester group) and reacting the compound of the general Formula VIII thus obtained with a piperazine derivative of the
Formula IV; or
c) for the preparation of the compound of the FormulaIIB; subjecting the compound of the
Formula IIA to partial hydrogenation; and, if desired, converting a compound of the general
Formula II thus obtained into an acid addition salt thereof or setting free the base from an acid addition salt.
According to method a) the compound of the
Formula IIA is prepared by subjecting the propine derivative of the Formula III t6 Mannich condensation with an amine of the Formula IV. The Manr,ich condensation is carried out by methods known per se Calvin A.
Buehler, Donald E. Pearson: Survey of Organic Syntheses (USA 1970) Vol. 1, page 4657. One may proceed preferably be using formaldehyde in the form of paraformaldehyde.
The reaction may be accomplished preferably under heating, particularly at the boiling point of the reaction mixture.
The reaction may be carried out in an inert organic solvent. As reaction medium preferably an ether (e.g.
diethyl ether, dioxane or tetrahydrofurane) can be used.
From the reaction mixture the compound of the Formula IIA can be isolated in a known manner (e.g. by extraction with a suitable organic solvent).
In the first step of method b) the propine derivative of the Formula III is reacted with an alkyl magnesium halide of the general Formula V. R stands for a straight or branched chain alkyl group having 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, isobutyl etc.).
As compound of the general Formula V preferably methyl magnesium iodide, methyl magnesium bromide, methyl magnesium chloride, ethyl magnesium iodide, ethyl magnesium chloride or ethyl magnesium bromide can be used.
The reaction of the compounds oL the general Formula III and V can be accomplished preferably in anhydrous ethereal medium under heating.
The compound of the general Formula VI thus obtained is reacted - preferably without isolation with at least a molar equivalent amount of trioxymethylene or paraformaldehyde. It is preferred to use gaseous formaldeSyde. The trioxymethylene or form aldehyde is preferably used in an amount of 1 - 1.1 moles - particularly 1.0 - 1.05 moles - related to 1 mole of the compound of the general Formula VI.
The reaction may be carried out preferably under heating. The compound of the general Formula VII can be isolated by evaporating the etheral solution.
The compound of the Formula VII thus obtained is converted into an ester of the general
Formula VIII by methods known per se. X stands preferably for halogen (e.g. chlorine, bromine or iodine), alkyl sulfonyl oxy (e.g. g methanesulfonyloxy) or arl71- sulfonyloxy (e.g. phenylsulfonyloxy, p-bromophenyl- sulfonyloxy, p-toluene-sulfonyloxy etc.). One may preferably proceed by reacting the compound of the
Formula VII with -toluene-sulfonyl chloride. The reaction may be carried out at room temperature or under slight warming.
The compound of the general Formula VIII thus obtained is reacted - without or after isolation, preferably directly without isolation - with a piperazine derivative of the general Formula IV. The reaction may be.accomplished in a manner known per Se.
The reaction may be preferably carried out in an inert organic solvent. As reaction medium e.g.
aromatic hydrocarbons (e.g. benzene, toluene, xylene etc.) can be used. The reaction may be preferably performed under heating, particularly at the boiling point of the reaction mixture.
The compound of the general Formula IIA thus obtained can be isolated in a manner known per se (e.g. by evaporating the reaction mixture).
According to method c) the compound of the Formula IIB is prepared by subjecting the compound of te Formula IIA to partial hydrogenation. Reduction is carried out by catalytic hydrogenation, preferably in the presence of a poisoned metal catalyst. One may preferably proceed by using a palladium catalyst poisoned by quinoline;' calcium carbonate or lead acetate. It is particularly advantageous to use a catalyst poisoned by quinoline rOrg. Synth. Coll.
Vol. 3, 629 (1955) Sartiel hydrogenation may be preferably carried out at room temperature under atmospheric pressure. The reaction may be preferably accomplished in the presence of an inert organic solvent. As reaction medium advantageously a lower aliphatic alcohol (e.g. methanol or ethanol) may be used. The compound of the Formula TIS thus obtained can be isolated by known methods te.g. by filtering the catalyst and evaporating the filtrate).
The compound of the general Formula II can be converted into an acid addition salt thereof by methods known per se-. For salt formation preferably pharmaceutically acceptable inorganic or organic acids can be used (e.g. hydrochloric acid hydrogen bromide, sulfuric acid,' nitric acid, or maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, succinic acid etc.). Salt formation may be advantageously performed by reacting the free base of the general
Formula II with a molar quivalent amount of the corresponding acid in an inert organic solvent.
The compound of the general Formula II can be set free from an acid addition salt thereof in a manner known per se by treating with a suitable base.
The 8-aza-spiro[4.5]decane-7,9-dione-8 -prop-2-ine of the Formula III used as starting material in the above procedures is a known compound.
According to a still further aspect of the present invention there is provided a process for the preparation of 8-aza-spiro[4.5]decane-7,9-dione- -8-prop-2-ine of the Formula III which comprises reacting 8-aza-spiro[4.5]decane-7,9-dione of the
Formula X
with a propargyl halide of the general Formula XI Hal- CH2- C=CH (XI) (wherein Hal stands for bromine, chlorine or iodine) in an inert solvent, in the presence of an acid binding agent.
It is known that the 8-aza-spiro[4.5]- decane-7,9-dione-8-prop-2-ine of the Formula III can be prepared by heating a mixture of 8-oxa-spiro[4.5]- decane-7,9-dione and propargyl amine in pyridine to boiling for 15 hours, evaporating the dilute reaction mixture and purifying the residue by distillation in vacuo fyao-Gua Wu et al: J. Med. Chem. 12, 876-881 (1969) 7. The compound of the Formula III is obtained with a yield of 76 %.
The above process is accompanied by several drawbacks which are particularly serious on industrial scale manufacture. The reaction time is very long (15 hours) and the temperature used is high (above 115 C).
The specific utilization of the volume of the reactor is unfavourable. The treatment,recovery and elimination of the pyridine used as solvent is problematic and comprises serious hazards of environmental pollution.
A further disadvantage resides in the fact that propargyl amine used as starting material is a difficult-to-obtain expensive substance.
It is a further object of the present invention to overcome the above drawbacks of the known procedures and to elaborate an economical process for the peparation of tne compound of the
Formula III which is favourably feasible on industrial scale as well.
The present invention is based on the recognition that on reacting 8-aza-spirof'4.S7decane- -7dione of the Formula X with a propargyl halide of the Formula XI the compound of the Formula III is obtained with good yields and in high purity in a readily feasible simple manner.
As compound of the general Formula XI preferably propargyl bromide may be used.
Tne starting materials of the Formulae X and XI can be used in equimolar amounts but the propargyl halide of the general Formula XI can be applied in a small - 10-20 molar % - excess as well.
The reaction can be carried out in any suitable inert organic solvent. As reaction medium any organic solvent can be used which does not enter into reaction with the components and does not influence the reaction in an adverse manner. It is preferred to use an ether (e.g. tetrahydrofuran , dioxane etc.), ester (e.g. ethyl acetate), nitrile (e,g. acetonitrile) or ketone (e.g. acetone or methyl ethyl ketone) or a mixture thereof as reaction medium.
The reaction is carried out in the presence of an acid binding agent, For this purpose preferably an alkali carbonate (particularly sodium o- potassium carbonate) can be used but other inorganic bases can be applied as well, e.g. an alkaline earth metal carbonate (e.g. calcium carbonate), an alkali hydrogen carbonate (e.g. sodium or potassium hydrogen carbonate), an alkali hydride (e.g. sodium hydride) or alkali amide (e.g. sodium amide etc.). Furthermore, tertiary organic bases can also be used as acid binding agent (e.g. trialkyl amines, such as triethyl amine).
The reaction temperature can vary between wde ranges. Thus one may generally work at 45-110 C, preferably at 55-100 C. The reaction temperature depends on the solvent used.
The reaction takes place very rapidly, the reaction time amounts to a few hours.
The reaction mixture can be worked up in a very simple manner. Thus, one may proceed by cooling the reaction mixture, removing the insoluble substances (alkali carbonate, alkali halide) by filtration or centrifuging arid evaporating the filtrate0 Thus, the compound of the Formula III is obtained in highly pure form which can be used for the further reactions directly without further purification. The sample of analytic purity of the product is obtained by fractional distillation in vacuo.
The advantages of the above process of the present invention can be summarized as follows: - no long reaction time is required; - the reaction can be accomplished at a temperature
not exceeding 100 C; - no pyridine is used and therefore the difficulties
which accompany the recovery and elimination of
this solvent are overcome - the process is more favourable to the environment, - the process is readily feasible on industrial scale,
too; - the specific utilization of the apparatus is favourable, - the yield is very - the desired compound of the Formula III is obtained
in highly pure form and can be used for the further
reaction directly, without further purification.
Further details of the process are to be found in the following Examples without limiting the scope of protection to the said Examples.
Preparation of the compound of formula I
Example 1
8-{4-[4-(2-P vrimidinyl)-1-piperazinyl]
-butyl}-8-aza-spiro[4.5]decane-7,9-dione
To a solution of 38.15 g (0.1 mole) of 8-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-but-2-in-yl} -8-aza-spiro[4.5]decane-7,9-dione in 150 ml of ethanol 1 g of a palladium/charcoal catalyst is added; whereupon the mixture is hydrogenated under atmospheric pressure at room temperature under vigorous stirring until the hydrogen consumption stops (2 equivalents of hydrogen,4 about 5 litres), The catalyst is removed by filtration and can be directly used in the next hydrogenation step. The filtrate is evaporated in vacuo. Thus 36.85 g of the desired compound are obtained, yield 95.6 %. M.P.: 91-99 C (the melting point disclosed in prior art amounts to 90-98 C).
Analysis for the Formula C21H31N5O2 (385.52) calc.: C % = 65.43; H % = 8.11; N % = 18.17; found: C % = 65.01, E % = 8.00; N % = 18.15.
The above base is converted into the hydrochloride by reacting with an equimolar amount of hydrogen chloride in ethanol. The hydrochloride melts at 200-202 C (the melting point disclosed in prior art amounts to 201.5 - 202.5 C).
Analysis for the formula C21H31ClN5O2.HCl (421.98) calc.: C 0A = 59.77; H H = 7.65;' N % = 4.3; Cl %= 8.40; found: C % = 59.51; H % = 7.50; N % = 4.26; Cl %= 8.37.
Preparation of the compound of the
Formula IIA
Example 2
8-{4-[4-(2-Pyrimidinyl)-1-piperazinyl]-but
-2-in-yl}-8-aza-spiro[4.5]decane-7,9-dione
Into a 250 ml round-bottomed flask equipped with a stirrer and reflux condenser 20.5 g (0.1 mole of 8-aza-spiro[4.5]decane-7,9-dione-8-prop-2-ine, 25 ml of dioxane, 17.2 g (0.105 mole) of 1-(2 -pyrimidinyl)-piperazine, 3.6 g of paraformaldehyde and 0.2 g of cupric(II)acetate are introduced. The reaction mixture is heated to boiling for 3 hours, cooled to room temperature, poured into water and extracted three times with 50 ml of benzene each. The united 'benzene solutions are clarified with activated charcoal and evaporated on a hot water-bath. Thus 33.95 g of the desired compound are obtained, yield 89 %, m.p.: 78-80 C (petrolether).
Analysis for the formula C21H27N502 (381.49) calc.: C % = 66.12; H % = 7.13; N % = 18.36; found: C % = 66.02; H % = 7.22; N % = 18.30.
Example 3 8-{4-[4-(2-Pyrimidinyl)-1-pipera@inyl]-but- -2-in-yl}-8-zaz-spiro[4.5]decane-7,9-dione
A Grignard compound is prepared from 15.6 g (0.11 mole) of methyl iodide and 2.68 g (0.11 g-atom) of magnesium in 170 ml of anhydrous ether,whereupon a solution of 20.5 g (0.1 mole) of 8-aza-spirof4.57- decane-7,9-dione-8-prop-2-ine and 50 ml of anhydrous ether is added dropwise under vigorous stirring. The reaction mixture is heated to boiling until the development of methane gas comes to an end, whereupon 3 g (0.1 mole) of trioxymethylene (or 0.1 mole of anhydrous gaseous fromaldehyde) are added.The reaction mixture is heated to boiling for a further period of 4.hours and thereafter poured into a solution of 10 g of ammonium chloride and 35 ml of ice cold water. The etheral solution is spearated, dried over anhydrous magnesium sulfate and evaporated.
The oily residue (22.8 g, 96 % %) is admixed without further purification with a suspension of 3.9 g (0.1 mole) of sodium amide and 70 ml of anhydrous benzene, whereupon,after the termination of the evolution of ammonia gas, at room temperature 19 g (0.1 mole) of y-toluene-sulfonyl chloride are added. The addition having been completed the reaction mixture is stirred at room temperature for some hours and washed successive- ly with 40 ml of water, 40 ml of a saturated sodium bicarbonate solution and 40 ml of water, and dried over anhydrous magnesium sulfate. To the benzene solution g g (0.105 mole) of l-(2-pyrimidinyl)-piperazine are added and the reaction mixture is heated to boiling for some hours.The reaction mixture is washed with an aqueous sodium bicarbonate solution and water, the benzene solution is evaporated in vacuo. The residue is taken up in petrolether and the crystals are filtered.
Thus 23.65 g of the desired compound are obtained in the form of white crystals, yield 62 96, m.p.: 78-79 C.
Analysis for the Formula C21H27N502 (381.49) calc.: C % = 66,12; H % = 7.13; N % = 18.36; found: C % = 65.85; H % = 7.02; N % = 18.10.
Preparation of the compound of the Formula IIB
Example 4
8-{4-[4-(2-Pyrimidinyl)-1-piperazinyl]
-butene-2-yl}-8-aza-spiro[4.5]decane-7,9
-dione
Into a hydrogenating apparatus 38.15 g (0.1 mole) of 8-{4-[4-(2-pyrimidinyl)-1-piperazinyl] -but-2-in-yl}-8-aza-spiro/ 4.5]decane-7,9-dione, 150 ml of ethanol, 1 g of a palladium/charcoal catalyst and 1 ml of "Quinoline S" deactivator are weighed in. The reaction mixture is hydrogenated at room temperature until the theoretical hydrogen amount (1 molar equivalent) is taken up. The catalyst is filtered and the filtrate is evaporated. Thus 37.2 g of the desired compound are obtained, yield 97 .
Analysis for the Formula C21H29N502 (383.5) calc.: C % = 65.77; H % = 7.62; N % = 18.26; found: C % = 65.18; H % = 7.47; N % = 18.15.
Preparation of the compound of the Formula III
Example 5
8-Aza-spiro[4.5]decane-7,9-dione-8-prop-2
-ine Into a round-bottomed flask equipped with a stirrer, dropping funnel and reflux condenser a mixture of 167.2 g (1.0 moles of 8-aza-spirof4.57- decane-7,9-dione, 130.86 g (1.1 moles) of propargyl bromide, 138.2 g (1.0 mole) of potassium carbonate and 250 ml of acetonitrile are added. The reaction mixture is heated to boiling under stirring for some hours, then coole-d to room temperature, filtered and the solvent is removed. Thus 178.6 g of the desired compound are obtained, yield 87 %, b.p.: 150 0C/53.31 Pa.
Colourless viscous oil.
Analysis for the Formula C12H15N02 (205. 26) calc.: C % = 70.22; II = 7.36; N % = 6.82; found: C % = 71.10; H % = 7.42; N % = 6.80.
Example 6
One proceeds according to Example 5 except that potassium carbonate is replaced by 105,9 g (1.0 mole) of sodium carbonate. Thus 162.2 g of the product defined in Example 5 are obtained, yield 79 , b.p.: 150 C/53.31 Pa.
Example 7
One proceeds according to Example 5 except that acetonitrile is replaced by 250 ml of tetrahydrofurane. Thus 149.84 g of the product according to
Example 5 are obtained, yield 73 %,i b.p.: 150 C/53.31 Pa.
Example 8 Ode proceeds according to Example 5 except that acetonitrile is replaced by 240 ml of dioxane.
Thus 170.4 g of the product according to Example 5 are obtained, yield 83%, b.p.: 150 C/53.32 Pa.
Example 9
One proceeds according to Example 5 except that acetonitrile is replaced by 320 ml of ethyl acetate. Thus 145.7 g of the product according to
Example 5 are obtained, yield 71 %, b.p.: 150 0C/53.32 Pa.
Example 10
One proceeds according to Example 5 except that acetonitrile is replaced by 290 ml of acetone.
Thus 153.95 g of the product according to Example 5 are obtained, yield 75 % b.p.: 150 C/53.32 Pa.
Example 11
One proceeds according to Example 5 except that acetonitrile is replaced by 250 ml of methyl ethyl ketone. Thus 178.6g of the product according to
Example 5 are obtained, yield 87 %, b.p.: 150 0C/53.32 Pa.
Claims (41)
- l) Process for the preparation of 8-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}-8-aza spiro[4.5]decane-7,9-dione of the Formula Iand pharmaceutically acceptable acid addition salts thereof, which c o m p r i s e s hydrogenating a compound of he general Formula II(wherein A stands for -C=C- or -CH=CH- and, if desired, converting the compound of the Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.
- 2) Process according to Claim 1, which c o m p r i s e s hydrogenating the compound of the Formula IIA.
- 3) Process according to Claim 1, which c o m p r i s e s hydrogenating the compound of the Formula IIB.
- 4) Process according toClaim 1 or 2,' which c o m p r i s e s hydrogenating the compound of the Formula IIA in the presence of a metal catalyst.
- 5) Process according to Claim 4, which c o m p r i s e s using a palladium or Raney-nickel catalyst.
- 6) Process according to Claim 5, whicn c o m p r i s e s carrying out hydrogenation under atmospheric pressure at room tempeisture.
- 7) Process according to Claim 6, wnicn c o m p r i s e s carrying out hydrogenation in the presence of an inert organic solvent.
- 8) Process according to Claim 7, which c o m p r i s e s using a lower aliphatic alcohol - preferably methanol or ethanol - as inert organic solvent.
- 9) Process according to Claim 1 or 3, which c o m p r i s e s hydrogenating the compound of the general Formula IIB in the presence of a metal catalyst.
- 10) Process according to Claim 9, which c o m p r i s e s using a palladium catalyst.
- 11) Compounds of the general Formula II wherein A stands for -C-=C- or -CH=CHand acid addition salts thereof.
- 12) Compound of the Formula IIA and acid addition salts thereof.
- 13) Compound of the Formula IIB and acid addition salts thereof.
- 14) Process for tne preparation of compounds of tne general Formula II (wherein A stands for -CC- or -CH=CH-) and acid addition salts thereof, which comprises a) for the preparation of the compound of the Formula IIA, sub3ectingthe propine derivative of the Formula IIIto Marmich condensation with an amine of the Formula IV;;or b) for the preparation of the compound of Formula IIA, reacting the propine derivative of the Formula III with an alkyl magnesium halide of ttie general Formula V R-Mg-Elg (V) (wnerein R stands for C1-4 alkyl and Hlg is chlorine, iodine or bromine), reacting the compound of the general Formula VIthus obtained (wherein Hlg is as stated above) with at least one molar equivalent amount of tri oxymethylene or formaldehyde, converting the substituted amino alcohol of the Formula VII thus obtainedinto a reactive ester of the general Formula VIII(wherein X stands for a reactive ester group) and reacting the compound of the general Formula VIII thus obtained with a piperazine derivative of the Formula IV; or c) for the preparation of the compound of the Formula ISIS, subjecting the compound of the Formula IIA to partial hydrogenation; and,' if desired, converting a compound of the general Formula 11 thus obtained into an acid addition salt thereof or setting free the same from an acid addition salt.
- 15) Process according to method a) of Claim 14,' which c o m p r i s e s carrying out Mannich condensation by using paraformaldehyde.
- 16) Process according to Claim 15, which c o m p r i s e s carrying out the reaction under heating preferably at the boiling point of the reaction mixture.
- 17) Process according to any of Claim 14a , and 16, which c o m p r i s e s carrying out the reaction in an inert organic solvent, preferably an ethers particularly dioxane,
- 18) Process according to method b) of Claim i4 which c o m p r i s e s using as alkyl magnesium halide of the general Formula V methyl magnesium iodide,' methyl magnesium bromide, methyl magnesium chloride, ethyl magnesium iodide, ethyl magnesium chloride or ethyl magnesium bromide.
- 19) Process according to Claim 18, which c o m p r i s e s carrying out the reaction of the compounds of the Formulae III and V in ethereal medium under heating.
- 20) Process according to method b) of Claim 14, which c o m p r i s e s reacting the compound of the general Formula VI with trioxymethylene or gaseous formaldehyde under heating.
- 21) Process according to Claim 20, which c o m p r i s e s using tvioxy methylene or form aldehyde in an amount of 1 - 1.1 moles - preferably 1 - 1.05 moles - related to 1 mole of the compound of the general Formula VI.
- 22) Process according to method b) of Claim 14'whicn c o m p r i s e s converting a compound o the Formula VII into an ester of the general Formula VIII, wherein X stands for halogen, alkylsulfonyloxy or arylsulfonyloxy.
- 23) Process according to Claim 22, which c o m p r i s e 5 preparing an ester of the general Formula VIII wherein X stands for chlorine, bromine, iodine, mesyloxy, phenylsulfonyloxy, p-bromo-phenylsulfonyloxy or tosyloxy.
- 24) Process according to Claim 22 or which c o m p r i s e s reacting the compound of the Formula VII with -toluene-sulfonyl chloride.
- 25) Process according to method b) of Claim 14, whicn c o m p r i s e s reacting a compound pf the general Formula VIII with the piperazine derivative of the general Formula IV in an inert organic solvent - preferably an aromatic hydrocarbon, particularly benzene, toluene or xylene under heating.
- 26) Process according to method c) of Claim 14, which c o m p r i s e s hydrogenating the compound of the Formula IIA with hydrogen in the presence of a poisoned catalyst to the compound of the Formula IIB.
- 27) Process according to Claim 26, which c o m p r i s e s using a palladium catalyst poisoned with quinoline, calcium carbonate or lead acetate.
- 28) Process according to Claim 26 or 27, which c o m p r i s e s carrying out partial hydrogenation at room temperature under atmospheric pressure.
- 29) Process according tb any of Claims 26 to 28, which c o m p r i s e s carrying out partial hydrogenation in a lower aliphatic alcohol as medium; preferably in methanol or ethanol.
- 30) Pharmaceutical compositions c o m p r i s i n g as active ingredient a compound of the general Formula II (wherein A stands for -C=C- or -CH=CH-) or a pharmaceutically acceptable acid addition salt thereof in-admixture with suitable inert pharmaceutical carriers.
- 31) Process for the preparation of 8-azaspiro[4.5]decane-7,9-dione-8-prop-2-ine of the Formula III, which c o m p r i s e s reacting 8-aza-spiro[4.5]decane-7.9-dione of the Formula Xwith a propargyl halide of the general Formula XI, Hal-CH2-CmCH - (xI) wherein Hal stands for bromine, chlorine or iodine in an inert solvent, in the presence of an acid binding agent.
- 32) Process according to Claim 31, which c o m p r i s e s using propargyl bromide as compound of the general Formula XI.
- 33) Process according to Claim 31 or 32, which c o m p r i s e s using an ether,' ester, nitrile or ketone as inert solvent.
- 34) Process according to Claim 33, which c o m p r i s e s using tetrahydrofurane, dioxane, ethyl acetate, acetonitrile, acetone or methyl ethyl ketone as inert organic solvent.
- 35) Process according to any of Claims 31 to 34, which c o m p r i s e s using an alkali metal carbonate - preferably sodium or potassium carbonate - as acid binding agent.
- 36) A process a's claimed in claim 1 substantially as hereinbefore described in Example 1.
- 37) A process as claimed in claim 14 substantially as hereinbefore described in any one of Examples 2, 3 or 4.
- 38) A process as claimed in claim 31 substantially as hereinbefore described in any one of Examples 5 to 11.
- 39. A compound of the general formula I prepared by a process as claimed in any one of claims 1 to 10 or 36.
- 40. A compound of the general formula II where A is defined in claim 1 prepared by a process as claimed in any one of claims 14 to 29 or 37.
- 41. A compound of the general formula III prepared by a process as claimed in any one of claims 31 to 34 or 38.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU71887A HU198477B (en) | 1987-02-25 | 1987-02-25 | Process for producing pyrimidinyl piperazine derivatives |
| HU71787A HU198204B (en) | 1987-02-25 | 1987-02-25 | Process for production of derivatives of piperasine |
| HU71687A HU197313B (en) | 1987-02-25 | 1987-02-25 | Process for producing 8-azaspiro <4.5> decane-7,9-dione-8-propine-/2/ |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8804385D0 GB8804385D0 (en) | 1988-03-23 |
| GB2201417A true GB2201417A (en) | 1988-09-01 |
| GB2201417B GB2201417B (en) | 1990-10-31 |
Family
ID=27269942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8804385A Expired - Lifetime GB2201417B (en) | 1987-02-25 | 1988-02-25 | Piperazine derivatives and process for the preparation thereof |
Country Status (20)
| Country | Link |
|---|---|
| KR (1) | KR880009955A (en) |
| CN (1) | CN88100923A (en) |
| AT (1) | AT395851B (en) |
| BE (1) | BE1001464A3 (en) |
| CA (1) | CA1300141C (en) |
| CH (1) | CH677924A5 (en) |
| CS (1) | CS274423B2 (en) |
| DE (1) | DE3806009C2 (en) |
| DK (1) | DK99388A (en) |
| ES (1) | ES2009236A6 (en) |
| FI (1) | FI880895A (en) |
| FR (1) | FR2615853B1 (en) |
| GB (1) | GB2201417B (en) |
| GR (1) | GR1002245B (en) |
| IL (1) | IL85545A (en) |
| IT (1) | IT1217342B (en) |
| NL (1) | NL8800484A (en) |
| PL (1) | PL152958B1 (en) |
| SE (1) | SE8800651L (en) |
| YU (1) | YU46441B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2280185A (en) * | 1993-07-16 | 1995-01-25 | Egyt Gyogyszervegyeszeti Gyar | Spiro[4,5]decane-7,9-dione derivative |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR950014099A (en) * | 1993-11-10 | 1995-06-15 | 장기하 | Method for preparing N- (2-pyrimidyl) piperazinyl butylamide |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE300422B (en) * | 1964-07-03 | 1968-04-29 | Astra Ab | |
| DE1545543B1 (en) * | 1964-07-03 | 1970-01-22 | Astra Apotekarnes Kem Fab | 4-aminobutinylimides, their salts and processes for their preparation |
| US3354178A (en) * | 1965-04-09 | 1967-11-21 | Sterling Drug Inc | Nu-(4-amino-2-butynyl)-nu-alkylcarboxamides |
| BE759371A (en) * | 1969-11-24 | 1971-05-24 | Bristol Myers Co | HETEROCYCLICAL AZASPIRODECANEDIONES AND METHODS FOR THEIR PREPARATION |
| JPS6310760A (en) * | 1986-07-01 | 1988-01-18 | Sumitomo Pharmaceut Co Ltd | Novel production of imide derivative |
| JPS6310786A (en) * | 1986-07-01 | 1988-01-18 | Sumitomo Pharmaceut Co Ltd | Novel imide derivative and production thereof |
-
1988
- 1988-02-23 PL PL1988270815A patent/PL152958B1/en unknown
- 1988-02-23 CH CH675/88A patent/CH677924A5/de not_active IP Right Cessation
- 1988-02-24 CN CN198888100923A patent/CN88100923A/en active Pending
- 1988-02-25 AT AT0047688A patent/AT395851B/en not_active IP Right Cessation
- 1988-02-25 SE SE8800651A patent/SE8800651L/en not_active Application Discontinuation
- 1988-02-25 CA CA000559846A patent/CA1300141C/en not_active Expired - Lifetime
- 1988-02-25 ES ES8800543A patent/ES2009236A6/en not_active Expired
- 1988-02-25 YU YU36288A patent/YU46441B/en unknown
- 1988-02-25 CS CS122288A patent/CS274423B2/en unknown
- 1988-02-25 FI FI880895A patent/FI880895A/en not_active Application Discontinuation
- 1988-02-25 IT IT19545/88A patent/IT1217342B/en active
- 1988-02-25 DE DE3806009A patent/DE3806009C2/en not_active Expired - Fee Related
- 1988-02-25 BE BE8800218A patent/BE1001464A3/en not_active IP Right Cessation
- 1988-02-25 FR FR888802286A patent/FR2615853B1/en not_active Expired - Lifetime
- 1988-02-25 KR KR1019880001939A patent/KR880009955A/en not_active Application Discontinuation
- 1988-02-25 DK DK099388A patent/DK99388A/en not_active Application Discontinuation
- 1988-02-25 GB GB8804385A patent/GB2201417B/en not_active Expired - Lifetime
- 1988-02-25 NL NL8800484A patent/NL8800484A/en not_active Application Discontinuation
- 1988-02-25 GR GR880100108A patent/GR1002245B/en unknown
- 1988-02-25 IL IL85545A patent/IL85545A/en not_active IP Right Cessation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2280185A (en) * | 1993-07-16 | 1995-01-25 | Egyt Gyogyszervegyeszeti Gyar | Spiro[4,5]decane-7,9-dione derivative |
| FR2709128A1 (en) * | 1993-07-16 | 1995-02-24 | Egyt Gyogyszervegyeszeti Gyar | Process for the preparation of high purity Buspiron and its hydrochloride. |
| GB2280185B (en) * | 1993-07-16 | 1997-04-16 | Egyt Gyogyszervegyeszeti Gyar | Process for the preparation of high purity buspiron and the hydrochloride thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| IT8819545A0 (en) | 1988-02-25 |
| GR880100108A (en) | 1988-12-16 |
| ATA47688A (en) | 1992-08-15 |
| CA1300141C (en) | 1992-05-05 |
| KR880009955A (en) | 1988-10-06 |
| SE8800651L (en) | 1988-08-26 |
| PL152958B1 (en) | 1991-02-28 |
| ES2009236A6 (en) | 1989-09-16 |
| FI880895A0 (en) | 1988-02-25 |
| PL270815A1 (en) | 1989-04-03 |
| FR2615853A1 (en) | 1988-12-02 |
| CS274423B2 (en) | 1991-04-11 |
| CS122288A2 (en) | 1990-08-14 |
| FI880895A (en) | 1988-08-26 |
| AT395851B (en) | 1993-03-25 |
| GB2201417B (en) | 1990-10-31 |
| DK99388A (en) | 1988-08-26 |
| GB8804385D0 (en) | 1988-03-23 |
| GR1002245B (en) | 1996-04-22 |
| DE3806009C2 (en) | 1996-09-12 |
| YU36288A (en) | 1989-10-31 |
| IT1217342B (en) | 1990-03-22 |
| DE3806009A1 (en) | 1988-09-08 |
| NL8800484A (en) | 1988-09-16 |
| SE8800651D0 (en) | 1988-02-25 |
| FR2615853B1 (en) | 1991-01-04 |
| DK99388D0 (en) | 1988-02-25 |
| CN88100923A (en) | 1988-09-28 |
| CH677924A5 (en) | 1991-07-15 |
| YU46441B (en) | 1993-10-20 |
| BE1001464A3 (en) | 1989-11-07 |
| IL85545A0 (en) | 1988-08-31 |
| IL85545A (en) | 1992-05-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20050225 |