NO821086L - PROCEDURE FOR PREPARING 8- (4- (4- (2-PYRIMIDINYL) -1-PIPERAZINYL) -BUTYL) -8-AZASPIRO (4,5) DECAN-7,9-DION - Google Patents

PROCEDURE FOR PREPARING 8- (4- (4- (2-PYRIMIDINYL) -1-PIPERAZINYL) -BUTYL) -8-AZASPIRO (4,5) DECAN-7,9-DION

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Publication number
NO821086L
NO821086L NO821086A NO821086A NO821086L NO 821086 L NO821086 L NO 821086L NO 821086 A NO821086 A NO 821086A NO 821086 A NO821086 A NO 821086A NO 821086 L NO821086 L NO 821086L
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Norway
Prior art keywords
compound
formula
azaspiro
butyl
pyrimidinyl
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NO821086A
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Norwegian (no)
Inventor
Pekka Juhani Kairisalo
Erkki Juhani Honkanen
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Orion Yhtymae Oy
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Application filed by Orion Yhtymae Oy filed Critical Orion Yhtymae Oy
Publication of NO821086L publication Critical patent/NO821086L/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic 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 three or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/12Heterocyclic 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Description

Denne oppfinnelse angår en ny fremgangsmåte for fremstilling av 8-(4-(4-(2-pyrimidinyi)-1-piperazinyl) -butyl) -8-azaspiro(4,5)dekan-7,9-dion (I). This invention relates to a new process for the preparation of 8-(4-(4-(2-pyrimidinyl)-1-piperazinyl)-butyl)-8-azaspiro(4,5)decane-7,9-dione (I).

Fremgangsmåten karakteriseres ved at forbindelsen med formel II hvor M er et alkalimetall såsom natrium, omsettes med en forbindelse med formel III hvor X, er et halogenatom såsom klor, og R er en alkyl- eller arylgruppe, såsom metyl eller p-tolyl, til en forbindelse med formel IV som på i og for seg kjent måte omsettes med en forbindelse med formel V. The method is characterized in that the compound of formula II where M is an alkali metal such as sodium is reacted with a compound of formula III where X is a halogen atom such as chlorine, and R is an alkyl or aryl group, such as methyl or p-tolyl, to a compound of formula IV which is reacted in a manner known per se with a compound of formula V.

Forbindelsen med formel I, som også kjennes under navnet buspiron, er et kjent legemiddel. Fra U.S. patent 3 717 634 kjennes en fremgangsmåte for fremstilling derav, hvor 8-oksa-spiro(4,5)-dekan-7,9-dion omsettes med 4-amino-l-butanol til 8-(4-hydroksybutyl) -8-azaspiro (4 , 5) dekan-7 ,'9-dion, som om-vandles til 8-(4-klorbutyl)-8-azaspiro(4,5)dekan-7,9-dion (IV), som til slutt omsettes med 1-(2-pyrimidinyl)-piperazin (V). The compound of formula I, which is also known under the name buspirone, is a known drug. From the U.S. patent 3 717 634 discloses a method for its preparation, where 8-oxa-spiro(4,5)-decane-7,9-dione is reacted with 4-amino-1-butanol to 8-(4-hydroxybutyl)-8- azaspiro (4,5)decane-7,'9-dione, which is converted to 8-(4-chlorobutyl)-8-azaspiro(4,5)decane-7,9-dione (IV), which finally is reacted with 1-(2-pyrimidinyl)-piperazine (V).

Fremgangsmåten for fremstilling av mellomproduktet IV, som hører til denne kjente fremgangsmåte, er imidlertid ikke tilfredsstillende med tanke på industriell produksjon, ettersom utbyttet er ganske lavt (ca. 40%), og etter de to faser av fremgangsmåten bør produktene renses ved destillasjon i høyvakuum. Dessuten er 4-amino-l-butanol, som anvendes som det ene utgangsstoff, særskilt vanskelig å fremstille og er dyr. However, the method for producing the intermediate IV, which belongs to this known method, is not satisfactory from the point of view of industrial production, as the yield is quite low (approx. 40%), and after the two phases of the method the products should be purified by distillation in a high vacuum . Furthermore, 4-amino-1-butanol, which is used as the starting material, is particularly difficult to produce and is expensive.

I U.S. patent 3 717 6 34 ér også beskrevet en fremgangsmåte hvor en forbindelse med formel II omsettes•med 1-(4-klor-butyl) -4- (2-pyrimidinyl) piperazin. Dette kommer imidlertid ikke på tale i praksis, ettersom 1-(4-klorbutyl)-4-(2-pyrimi-dinyl) piperazin ikke er en stabil forbindelse, men ringslut-ter seg spontant til en kvartær arttmoniumf orbindelse. In the U.S. patent 3 717 6 34 also describes a method in which a compound of formula II is reacted with 1-(4-chloro-butyl)-4-(2-pyrimidinyl)piperazine. However, this is out of the question in practice, as 1-(4-chlorobutyl)-4-(2-pyrimidinyl)piperazine is not a stable compound, but ring-closes spontaneously to a quaternary ammonium compound.

Det er nå funnet at forbindelsen med formel IV kan fremstilles merkbart enklere og med særdeles godt utbytte når 8-alkalimetall-8-azaspiro(4,5)dekan-7,9-dion (II) omsettes med 4-halogen-l-butylalkyl(eller aryl)-sulfonat (III). Som alkali-. metall anvendes fordelaktig natrium og som halogen klor* Av. sulfonatene kommer særlig på tale metansulfonatet og p-toiylsulfonatet. Omsetningen utføres fordelaktig i et polart,- aprotisk oppløsningsmiddel såsom N,N-dimetylformamid eller N,N-dimetylacetamid, ved,50-15D°C, mest fordelaktig ved ca. 8 0°C. It has now been found that the compound of formula IV can be prepared noticeably more easily and with particularly good yield when 8-alkali metal-8-azaspiro(4,5)decane-7,9-dione (II) is reacted with 4-halo-1-butylalkyl (or aryl)-sulfonate (III). As alkali-. metal is advantageously used sodium and as a halogen chlorine* Av. the sulphonates include methane sulphonate and p-toyl sulphonate in particular. The reaction is advantageously carried out in a polar, aprotic solvent such as N,N-dimethylformamide or N,N-dimethylacetamide, at 50-15°C, most advantageously at approx. 80°C.

Det er kjent å fremstille forbindelser med formel III fra R-sulfonsyreklorid og 4-halogen-l-butanol. ved å utføre omsetningen i pyridin (Can. J. Chem. 3jL (1956) 757) . Det er imidlertid mer fordelaktig å anvende et inert organisk oppløs-ningsmiddel og minst en ekvimolar mengde tertiært amin. Særlig kommer métylenklorid og trietylamin på tale. It is known to prepare compounds of formula III from R-sulfonic acid chloride and 4-halo-1-butanol. by carrying out the reaction in pyridine (Can. J. Chem. 3jL (1956) 757). However, it is more advantageous to use an inert organic solvent and at least an equimolar amount of tertiary amine. In particular, methylene chloride and triethylamine are mentioned.

Forbindelsen med formel II kan fremstilles for eksempel ved å bringe 3,3-tetrametylenglutarsyre til å reagere med urinstoff til det tilsvarende imid og. dette videre med alkali-metallalkoksyd til forbindelsen med formel II, The compound of formula II can be prepared, for example, by reacting 3,3-tetramethyleneglutaric acid with urea to the corresponding imide and. this further with alkali metal alkoxide to the compound of formula II,

Følgende eksempel illustrerer oppfinnelsen.The following example illustrates the invention.

Eksempel 1. 8-(4-klorbutyl)-8-azaspiro(4,5)dekan-7,9-dion En blanding som inneholder 12u g (0,63 mol.) 8-natrium-8-azaspiro(4,5)dekan-7,9-dibn og 165 g (0,63 mol) 4-klorbutyl-p-toluensulfonat (eller 118 g 4-klorbutylmetansulfonat) i ■ 700 ml N,N-dimetylformamid (eller N,N-dimetylacetamid), opp-varmes under omrøring i 2 timer ved 80°C Blandingen nedkjø-les til 20°C og filtreres. Oppløsningsmidlet fjernes under nedsatt trykk. Til den flytende resten settes 1000 ml mety-lenklorid, og den oppnådde oppløsning.vaskes 2 ganger med 500 ml. 0,5 N NaOH-oppløsning og 2 ganger med 500 ml vann.-Oppløsningsmidlet fjernes under nedsatt trykk hvorved 140^- ' Example 1. 8-(4-Chlorobutyl)-8-azaspiro(4,5)decane-7,9-dione A mixture containing 12 µg (0.63 mol.) of 8-sodium-8-azaspiro(4,5 )decane-7,9-dibn and 165 g (0.63 mol) 4-chlorobutyl-p-toluenesulfonate (or 118 g 4-chlorobutylmethanesulfonate) in ■ 700 ml N,N-dimethylformamide (or N,N-dimethylacetamide), heated with stirring for 2 hours at 80°C. The mixture is cooled to 20°C and filtered. The solvent is removed under reduced pressure. 1000 ml of methylene chloride is added to the liquid residue, and the resulting solution is washed twice with 500 ml. 0.5 N NaOH solution and 2 times with 500 ml of water.-The solvent is removed under reduced pressure whereby 140^- '

148 g (85-90%) ønsket produkt oppnås som en oljelignende væske. 1H-NMR . (CDC13) : 6 1,6 (12H,m) 2,5 (4H,s) , .3,5 (2H,t), 148 g (85-90%) of the desired product is obtained as an oil-like liquid. 1H-NMR. (CDCl 3 ) : 6 1.6 (12H,m) 2.5 (4H,s) , .3.5 (2H,t),

3,75 (2H,t).. 3.75 (2H,t)..

Eksempel 2.. 8- (4-(4-( 2-pyrimidihyl) -1-piperazinyl) -butyl) - 8-azaspiro(4,5)dekan-7,9-dion (buspiron) Example 2.. 8-(4-(4-(2-pyrimidyl)-1-piperazinyl)-butyl)-8-azaspiro(4,5)decane-7,9-dione (buspirone)

En blanding som .inneholder 50,0 g (0,19 mol) 8-(4-klor-butyl)-8-azaspiro(4,5)dekan-7,9-dion, 31,8 g (0,19 mol)" 1- (2-pyrimidinyl)piperazin og 4l g natriumkarbonat i 300 ml N,N-dimetylformamid tilbakeløpsbehåndles i 18 timer. Opp-løsningen filtreres, og oppløsningsmidlet fjernes under nedsatt trykk. Den oljelignende resten krystalliseres fra 2- propanol, hvorved man får 5 8,3 g 85% ønsket produkt som farveløse krystaller (sm.p. 109-110°G). ^H-NMR (CDC13): 6 1,5 (12H,m), 2,45 (6h,t), 2,55 (4H,s), 3,75 (6H,m), 6,4 (1H,t) , '8,25 (2H,d) . A mixture containing 50.0 g (0.19 mol) 8-(4-chloro-butyl)-8-azaspiro(4,5)decane-7,9-dione, 31.8 g (0.19 mol )" 1-(2-pyrimidinyl)piperazine and 4l g of sodium carbonate in 300 ml of N,N-dimethylformamide are refluxed for 18 hours. The solution is filtered, and the solvent is removed under reduced pressure. The oil-like residue is crystallized from 2-propanol, whereby gives 5 8.3 g 85% of the desired product as colorless crystals (m.p. 109-110°G). ), 2.55 (4H,s), 3.75 (6H,m), 6.4 (1H,t) , '8.25 (2H,d) .

Claims (2)

1. Fremgangsmåte for fremstilling av 8-(4-(4-(2-pyrimidi- nyl) -1-piperazinyl)butyl)-8-azaspiro(4,5)dekan-7,9-dion I 1. Process for the preparation of 8-(4-(4-(2-pyrimidi- nyl)-1-piperazinyl)butyl)-8-azaspiro(4,5)decane-7,9-dione I karakterisert ved at en forbindelse med formel II characterized in that a compound of formula II hvor M er et alkalimetall som natrium, omsettes med en forbindelse med formel III, where M is an alkali metal such as sodium, is reacted with a compound of formula III, hvor X er et halogenatom såsom klor, og R er en alkyl- eller en arylgruppe såsom metyl eller p-tolyl, for å danne en forbindelse med formel IV > where X is a halogen atom such as chlorine, and R is an alkyl or an aryl group such as methyl or p-tolyl, to form a compound of formula IV> som på i og for seg kjent måte omsettes med en forbindelse med formel V. which is reacted in a manner known per se with a compound of formula V. 2. Fremgangsmåte ifølge krav 1, karakterisert ved at omsetningen mellom forbindelsen med formel II og forbindelsen med formel III utføres i et polart, aprotisk oppløsningsmiddel, såsom N ,N-dimetylformamid eller N,N-di-^ metylacetamid, ved 50-150°C, fordelaktig ved ca. 80°C. 2. Process according to claim 1, characterized in that the reaction between the compound of formula II and the compound of formula III is carried out in a polar, aprotic solvent, such as N,N-dimethylformamide or N,N-dimethylacetamide, at 50-150° C, advantageous at approx. 80°C.
NO821086A 1981-04-09 1982-03-31 PROCEDURE FOR PREPARING 8- (4- (4- (2-PYRIMIDINYL) -1-PIPERAZINYL) -BUTYL) -8-AZASPIRO (4,5) DECAN-7,9-DION NO821086L (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FI811108 1981-04-09

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NO821086L true NO821086L (en) 1982-10-11

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NO821086A NO821086L (en) 1981-04-09 1982-03-31 PROCEDURE FOR PREPARING 8- (4- (4- (2-PYRIMIDINYL) -1-PIPERAZINYL) -BUTYL) -8-AZASPIRO (4,5) DECAN-7,9-DION

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DK (1) DK152730C (en)
NO (1) NO821086L (en)
SE (1) SE449224B (en)

Also Published As

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SE8202132L (en) 1982-10-10
SE449224B (en) 1987-04-13
DK152730B (en) 1988-05-02
DK152730C (en) 1988-10-03
DK160082A (en) 1982-10-10

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