NL8105529A - METHOD FOR PREPARING THE BUS PIRONE. - Google Patents
METHOD FOR PREPARING THE BUS PIRONE. Download PDFInfo
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- NL8105529A NL8105529A NL8105529A NL8105529A NL8105529A NL 8105529 A NL8105529 A NL 8105529A NL 8105529 A NL8105529 A NL 8105529A NL 8105529 A NL8105529 A NL 8105529A NL 8105529 A NL8105529 A NL 8105529A
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- Prior art keywords
- formula
- azaspiro
- dione
- decane
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- 238000000034 method Methods 0.000 title claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 17
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 7
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 claims description 5
- 150000005695 2-halopyrimidines Chemical class 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- ZOVNKFCHBFUAIS-UHFFFAOYSA-N 8-(4-piperazin-1-ylbutyl)-8-azaspiro[4.5]decane-7,9-dione Chemical compound C1C(=O)N(CCCCN2CCNCC2)C(=O)CC21CCCC2 ZOVNKFCHBFUAIS-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 229960002495 buspirone Drugs 0.000 description 9
- -1 alkali metal salt Chemical class 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- IAJINJSFYTZPEJ-UHFFFAOYSA-N 1h-pyrimidin-3-ium-2-one;chloride Chemical compound Cl.O=C1N=CC=CN1 IAJINJSFYTZPEJ-UHFFFAOYSA-N 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- WTVNFKVGGUWHQC-UHFFFAOYSA-N decane-2,4-dione Chemical compound CCCCCCC(=O)CC(C)=O WTVNFKVGGUWHQC-UHFFFAOYSA-N 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XHTYQFMRBQUCPX-UHFFFAOYSA-N 1,1,3,3-tetramethoxypropane Chemical compound COC(OC)CC(OC)OC XHTYQFMRBQUCPX-UHFFFAOYSA-N 0.000 description 2
- QQCVFKSWYYHXMA-UHFFFAOYSA-N 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione Chemical compound C1C(=O)N(CCCCBr)C(=O)CC11CCCC1 QQCVFKSWYYHXMA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- KVJHGPAAOUGYJX-UHFFFAOYSA-N 1,1,3,3-tetraethoxypropane Chemical compound CCOC(OCC)CC(OCC)OCC KVJHGPAAOUGYJX-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- WSHYXQVPEVIBPK-UHFFFAOYSA-N 4-(4-piperazin-1-ylbutyl)-8-azaspiro[4.5]decane-7,9-dione Chemical compound N1(CCNCC1)CCCCC1CCCC11CC(NC(C1)=O)=O WSHYXQVPEVIBPK-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- VXDSLUMUNWTSDB-UHFFFAOYSA-N acetic acid;chloroform;methanol Chemical compound OC.CC(O)=O.ClC(Cl)Cl VXDSLUMUNWTSDB-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- YRTHJMQKDCXPAY-UHFFFAOYSA-N azaspirodecanedione Chemical compound C1C(=O)NC(=O)CC11CCCC1 YRTHJMQKDCXPAY-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
<« - * 4 VO 2440<«- * 4 VO 2440
Titel: Werkwijze voor het bereiden van buspirone.Title: Method for preparing buspirone.
In het Amerikaanse octrooischrift 3.717.634 wordt door Yao Hua Wu et al. de synthese beschreven van N-(heteroarcyclische) piperazinylaJcylazaspiroalkasndionen met formule 1 volgens de op het formuleblad weergegeven methoden A-C.In U.S. Pat. No. 3,717,634, Yao Hua Wu et al. Discloses the synthesis of N- (heteroarcyclic) piperazinylacylazaspiroalkionndions of formula 1 by the methods A-C shown on the formula sheet.
5 In deze reactie schema's stelt het symbool n het gehele5 In these reaction schemes, the symbol n represents the whole
getal 4 of 5 voor, stelt het symbool -A- een.rechte of vertakte tweewaardige alkaleen keten met 2 tot_6 koolstofatomen voor, stelt het symbool E onder andere verschillende heterocyclische · radicalen voor, waaronder 2-pyrimidinyl, stelt het symbool Xrepresents number 4 or 5, the symbol -A- represents a straight or branched divalent alkalene chain of 2 to 6 carbon atoms, the symbol E represents various heterocyclic radicals, including 2-pyrimidinyl, the symbol X
10 onder andere chloor, broom, jodium voor en stelt het symbool M een alkalimetaalzout, zoals natrium of kalium voor.10 represents, inter alia, chlorine, bromine, iodine and the symbol M represents an alkali metal salt, such as sodium or potassium.
De onderhavige werkwijze verschilt van de methoden uit het Amerikaanse octrooischrift 3.717.634 doordat het 2-pyrimidinyl fragmentgeïntroduceerd wordt als laatste trap door directe- , 15 alkylering van vooraf gevormd 8-[4-(l-piperazinyl)-butyl]-8-azaspiro [4.5]debaan-7,9-dion met een 2-halogeenpyrimidine.The present process differs from the methods of U.S. Pat. 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] deban-7,9-dione with a 2-halopyrimidine.
Ruim omschreven heeft de uitvinding betrekking op een werkwijze voor het bereiden van de pyrimidine verbinding 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl]-8-azaspiro[4.5]decaan-7,9-dion, 20 die hier ook wel aangeduid wordt met de United States Adopted Name "buspirone", zie J. Amer.Med.Assoc., 225, 520 (1973). De‘onderhavige werkwijze verschaft een nieuwe route voor het bereiden van buspirone en heeft meer in het bijzonder betrekking op een werkwijze 14 14 15 voor het opnemen van radioactieve koolstof ( C) en stabiele 25 stikstof (1¾) isotopen in bepaalde posities van de pyrimidinyl component van buspirone. Gelabeld buspirone is nuttig in clinisch onderzoek van de absorptie en metabolische aard van dit anxiolytisch middel.Broadly described, the invention relates to a process for preparing the pyrimidine compound 8- [4- [4- (2-pyrimidinyl) piperazinyl-1-yl] butyl] -8-azaspiro [4.5] decane-7,9-dione, 20 which is also referred to herein by the United States Adopted Name "buspirone", see J. Amer.Med.Assoc., 225, 520 (1973). The present method provides a new route for the preparation of buspirone and more particularly relates to a method of incorporating radioactive carbon (C) and stable nitrogen (1 stikstof) isotopes in certain positions of the pyrimidinyl component from buspirone. Labeled buspirone is useful in clinical studies of the absorption and metabolic nature of this anxiolytic agent.
De onderhavige uitvinding heeft betrekking op een werkwijze 30 voor het bereiden van 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]- 8-azaspiro[4.5]decaan-7,9-dion met formule 8, waarbij 8-[4-(1-piperazinyl)butyl]-8-azaspiro[4.5]-decaan-7,9-dion met formule 9 wordt gealkyleerd met een 2-halogeenpyrimidine met formule 10 8 1 0 5 5 2 9.............. “ ' * / -2- waarin X broom, jodium of bij voorkeur chloor voorstelt, in een voor deThe present invention relates to a process for preparing 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione of formula 8 wherein 8- [4- (1-piperazinyl) butyl] -8-azaspiro [4.5] -decano-7,9-dione of formula 9 is alkylated with a 2-halopyrimidine of formula 10 8 1 0 5 5 2 9. ............. '' * / -2- in which X represents bromine, iodine or preferably chlorine, in one for the
OO
reactie inert oplosmiddel bij een temperatuur van 80-170 C, bij voorkeur in een gesloten reactievat.reaction inert solvent at a temperature of 80-170 ° C, preferably in a closed reaction vessel.
De bovenstaande werkwijze is bijzonder toepasbaar op de bereiding 5 van radioactief gelabeld buspirone en is in dat opzicht zowel economisch als gemakkelijk. De term gelabeld duidt hier op de opname op specifieke 14 15 posities van buspirone van radioactieve ( C) en stabiele ( N) isotopen. Voorkeursuitvoeringsvormen van de bovenstaande werkwijze zijn die voor de bereiding van gelabeld buspirone, waarin de verbinding met formule 10 14 10 2-chloropyrimidine is, op de 2-positie gelabeld met koolstofisotoop, de verbinding met formule 10 2-chloropyrimidine is, waarin de 1,3-stik-stofatomen gelabeld zijn met ^stikstof isotoop.The above method is particularly applicable to the preparation of radiolabeled buspirone and is both economical and convenient in that regard. The term labeled here refers to the uptake at specific positions of buspirone from radioactive (C) and stable (N) isotopes. Preferred embodiments of the above method are those for the preparation of labeled buspirone, wherein the compound of formula 10 14 is 10 2-chloropyrimidine, labeled 2 in the carbon isotope, the compound of formula 10 is 2-chloropyrimidine, wherein the 1, 3 nitrogen atoms are labeled with nitrogen isotope.
De gelabelde 2-halogeenpyrimidine met formule 10 worden verkregen door condensatie. van geschikt gelabeld ureum met malonaldehyde ,bis,(di- f t 15 methylacetaal) of malonaldehyde bis(diethylacetaal) in tegenwoordigheid van zuur om het overeenkomstige 2-hydroxypyrimidine te verkrijgen, dat vervolgens wordt omgezet in de halogeenverbinding met behulp van fosfor- oxyhalogenide zoals fosforoxychloride of forforoxybromide. Bij wijze van : 14 ' · toelichting wordt de volgorde, uitgaande van ureum- c voor de bereiding £14 * 20 van 2-chloro-pyrimidine- C (10a) op het middenblad met schema D afge- L .The labeled 2-halopyrimidine of formula 10 is obtained by condensation. of suitably labeled urea with malonaldehyde, bis, (di-15 methyl acetal) or malonaldehyde bis (diethyl acetal) in the presence of acid to obtain the corresponding 2-hydroxypyrimidine, which is then converted to the halogen compound using phosphorus oxyhalide such as phosphorus oxychloride or forforoxy bromide. By way of: 14 'explanation, the sequence, starting from urea-c for the preparation £ 14 * 20, of 2-chloro-pyrimidine-C (10a) is shown on the middle sheet with scheme D.
beeld. - 15statue. - 15
Een identieke volgorde uitgaande van ureum- N_ levert 2-chloro- il5 λ pyrimidine- (10b).An identical sequence starting from urea-N_ yields 2-chlorol5 λ pyrimidine- (10b).
Bij het uitvoeren van de onderhavige werkwijze kan elk oplosmiddel 25 dat de reactie en de reactiecomponenten en het buspironeprodukt niet nadelig beïnvloedt worden gebruikt, waarbij het geprefereerde oplosmiddel een alkanol is, bijvoorbeel ethanol, n-propanol, isopropanol en dergelijke. !In the practice of the present process, any solvent that does not adversely affect the reaction and the reactants and the buspirone product can be used, wherein the preferred solvent is an alkanol, for example ethanol, n-propanol, isopropanol and the like. !
In het algemeen is de: reactietemperatuur in het gebied van ongeveer - 30 80°C tot 170°C bruikbaar, waarbij de temperatuur bij voorkeur ligt in O o het gebied van 110 C tot 120 C. Hogere en lagere temperaturen kunnen worden gebruikt, maar bij een reactietemperatuur beneden 80°C duurt de reactie onnodig lang en vindt geen adequate condensatie plaats, terwijl wanneer de reactietemperatuur boven 170°C komt de reactiecomponenten in 35 enige mate tot ontleding neigen. Wanneer de werkwijze wordt uitgevoerd bij temperaturen boven het kookpunt van het reactieoplosmiddel, wordt bij ' eTö'ssT'e * -3- -* ·* voorkeur een. gesloten reactievat gebruikt.Generally, the reaction temperature in the range of about 80 ° C to 170 ° C is useful, the temperature preferably being in the range of 110 ° C to 120 ° C. Higher and lower temperatures can be used, but at a reaction temperature below 80 ° C, the reaction takes an unnecessarily long time and no adequate condensation takes place, while when the reaction temperature exceeds 170 ° C, the reaction components tend to decompose to some extent. When the process is carried out at temperatures above the boiling point of the reaction solvent, 'eTos'sT'e * -3- - * · * is preferred. closed reaction vessel used.
Het in de loop van de reactie ontwikkelde waterstofhalogenide wordt opgenomen door een zuuracceptor om de basische reactiecomponent 8-[4-1-piperazinyl)-butyl]-8-azaspiro[4.5]decaan-7,9-dion met formule 9 5 te behouden. In dit opzicht wordt een tertiair amine zoals triethylamine geprefereerd.The hydrogen halide developed in the course of the reaction is taken up by an acid acceptor to retain the basic reactant 8- [4-1-piperazinyl) -butyl] -8-azaspiro [4.5] decane-7,9-dione of formula 95 . In this regard, a tertiary amine such as triethylamine is preferred.
De werkwijze volgens de uitvinding wordt verder aan de hand van de volgende voorbeelden nader toegelicht, welke voorbeelden niet zodanig , moeten worden uitgelegd, dat ze de omvang van de onderhavige uitvinding 10 beperken.The method according to the invention is further elucidated by means of the following examples, which examples should not be construed to limit the scope of the present invention.
Voorbeeld IExample I
Bereiding van 8-[4-(piperazinyl)butyl-8-azaspiro[4.5]decaan-7,9-diori (formule 9).Preparation of 8- [4- (piperazinyl) butyl-8-azaspiro [4.5] decane-7,9-diori (Formula 9).
(a) 8-(4-bromobutyl)-8-azaspiro[4.5]decaan-7,9-dion.(a) 8- (4-Bromobutyl) -8-azaspiro [4.5] decane-7,9-dione.
15 Een mengsel van(33,4 g, 0,2 mol), 3,3-tetramethyleen glutarimide * « 86.4 g, 0,4 mol 1,4-dibromobutaan en 88,6 g, 0,6 mol kaliumcarbonaat dat tot microscopisch kleine afmetingen was verpoederd, in 500 ml droge tolueen werd gedurende een periode van 2o uur bij refluxtempera-tuur geroerd. Het reactiemengsel werd nog heet gefiltreerd en onder ver-20 minderde druk geconcentreerd. Resterende olie werd onder verminderde druk gedestilleerd en de fractie met een kookpunt van 165-170°C bij 0,1 Hg werd verzameld, waarbij 32,0 g (52%) 8-(4-bromobutyl)-8-azaspiro [4.5]decaan-7,9 dion als olie werd verkregen- (b) 8-[4-(l-piperazinyl)butyl-8-azaspiro[4.5]decaan-7,.9-dion.A mixture of (33.4 g, 0.2 mole), 3,3-tetramethylene glutarimide * 86.4 g, 0.4 mole 1,4-dibromobutane and 88.6 g, 0.6 mole potassium carbonate which is microscopic small dimensions had been pulverized, stirred in 500 ml of dry toluene for a period of 20 hours at reflux temperature. The reaction mixture was filtered while hot and concentrated under reduced pressure. Residual oil was distilled under reduced pressure and the fraction boiling at 165-170 ° C at 0.1 Hg was collected, giving 32.0 g (52%) of 8- (4-bromobutyl) -8-azaspiro [4.5] decane-7.9 dione as an oil was obtained- (b) 8- [4- (1-piperazinyl) butyl-8-azaspiro [4.5] decane-7, 9-dione.
25 Een mengsel van 32,0 g, 0,105 mol 8-(4-bromobutyl)-8-azaspiro]4.53 decaan-7,9-dion, 50 g, 0,58 mol piperazine en 80,0 g, 0,58 mol kaliumcarbonaat dat tot microscopisch kleine afmetingen was verpoederd in 500 ml droge tolueen werde gedurende 18 uur bij refluxtemperatuur geroerd. Het reactiemengsel werd nog heet gefiltreerd, onder verminderde 30 druk geconcentreerd en resterend materiaal werd met 100 ml ether geroerd. Overmaat piperazine, dat zich als het hydrochloride afscheidde, werd verzameld en het filtraat werd onder verminderde druk geconcentreerd. Destillatie van de resterende olie onder verminderde druk leidde tot 13.5 g (42%) 8-[4-(l-piperazine)butyl-8-azaspiror4.5]decaan-7,9 dion 35 met een kookpunt van 180-200°C bij 0,1 mm Hg als vrije base. ? 6105529 -4-A mixture of 32.0 g, 0.105 mole of 8- (4-bromobutyl) -8-azaspiro] 4.53 decane-7,9-dione, 50 g, 0.58 mole of piperazine and 80.0 g, 0.58 mole potassium carbonate powdered to microscopic size in 500 ml dry toluene was stirred at reflux temperature for 18 hours. The reaction mixture was filtered while hot, concentrated under reduced pressure and residual material was stirred with 100 ml of ether. Excess piperazine, which separated as the hydrochloride, was collected and the filtrate concentrated under reduced pressure. Distillation of the residual oil under reduced pressure gave 13.5 g (42%) 8- [4- (1-piperazine) butyl-8-azaspiror4.5] decane-7.9 dione 35, bp 180-200 ° C at 0.1 mm Hg as a free base. ? 6105529 -4-
Omzetting van dit materiaal in het hydrochloride zout en kristallisatie uit ethanol leverde analytisch zuiver 8-(4-(l-piperazinyl)-butyl- o 8-azaspiro[4.5]decaan-7,9-dion hydrochloride, smeltpunt 235-237 C.Conversion of this material to the hydrochloride salt and crystallization from ethanol gave analytically pure 8- (4- (1-piperazinyl) butyl-8-azaspiro [4.5] decane-7,9-dione hydrochloride, mp 235-237 ° C.
Analyse: berekend voor .2HC1.1/4^0: C:53,06; H:8,25; 5 N:10/92. Gevonden: C:53,06; H8,05; N:10,96.Analysis: Calculated for .2HC1.1 / 4 ^ O: C: 53.06; H: 8.25; 5 N: 10/92. Found: C: 53.06; H8.05; N: 10.96.
Voorbeeld IIExample II
*14* 14
Bereiding van gelabeld 2-chloropyrimidine „ .G (formule 10a) *14 (a) _:C gelabeld 2-hydrocypyrimidine hydrochloride.Preparation of Labeled 2-Chloropyrimidine-G (Formula 10a) * 14 (a): C-Labeled 2-Hydrocypyrimidine Hydrochloride.
Een oplossing van 165 mg, 0,002 mol ureum dat 43 mg, 0,0007 mol, 14 10 30 millicurie ureum- C bevatte en 443 mg, 0,0027 mol malonaldehyde 'bis (dimethylacetaal) in 1,0 ml'ethanol werd behandeld met 0,5 ml geconcentreerd zoutzuur. De aangezuurde oplossing werd op een stoombad gedurende een periode van. 2 uur verwarmd, en afgekoeld. Het gele neergeslagen *14A solution of 165 mg, 0.002 mole of urea containing 43 mg, 0.0007 mole, 14 milligrams of urea-C and 443 mg, 0.0027 mole of malonaldehyde bis (dimethyl acetal) in 1.0 ml of ethanol was treated with 0.5 ml concentrated hydrochloric acid. The acidified solution was left on a steam bath for a period of. Heated for 2 hours and cooled. The yellow one knocked down * 14
produkt werd verzameld, waarbij 274 mg (77%) 2-chloropyrimidine - Cproduct was collected, yielding 274 mg (77%) of 2-chloropyrimidine-C
15 werd verkregen dat zonder verdere zuivering als volgt werd gebruikt-*14 (b) '.-.C gelabeld 2-chloropyrimldine.15 was obtained which was used as follows without further purification - 14 (b) - C-labeled 2-chloropyrimldine.
*14* 14
Een mengsel van 274 mg, 0,02 mol 2-hydroxypyrimidine £. hydro- . .A mixture of 274 mg, 0.02 mole of 2-hydroxypyrimidine. hydro-. .
• · i chloride en 10 ml fosforoxychloride gedurende een periode van 6 uur onder i·-. roeren op 110°C verwarmd. Overmaat fosforoxychloride werd onder verminder! 20 de druk verwijderd en het resterende olieachtige residu werd in 15 ml water opgelost. De waterige oplossing werd met 10% natriumbicarbonaat be-ί handeld totdat hij licht basisch was op lakmoes en werd geextraheerd met• i chloride and 10 ml of phosphorus oxychloride over a period of 6 hours under i - -. stirring heated to 110 ° C. Excess phosphorus oxychloride was reduced under The pressure was removed and the residual oily residue was dissolved in 15 ml of water. The aqueous solution was treated with 10% sodium bicarbonate until it was slightly basic on litmus and extracted with
chloroform. Concentratie van het gedroogde chloroformextract gaf 190 mg, Ichloroform. Concentration of the dried chloroform extract gave 190 mg, I.
*14* 14
83% 2-chloropyrimidine- C dat zonder verdere zuivering in voorbeeld III83% 2-chloropyrimidine-C obtained without further purification in Example III
25 . werd gebruikt. >25. was used. >
Voorbeeld III _ *14 C gelabeld 8-&-I4-(2-pyrimidinyl) -l-piperazinyH'ethyl-r8-azastpiro [4 ,-53.,.. - 1 8 1 0 5 5 2 9 ~ ' xlecaan-7«Stadion .(formule 8a). “· ; — -Example III * 14 C labeled 8 - & - 14- (2-pyrimidinyl) -1-piperazinyHethyl-r8-azastpiro [4, -53., - 1 8 1 0 5 5 2 9 -xlecane- 7 «Stadium. (Formula 8a). "·; - -
Een mengsel van 190 mg, o,0016 mol van het 2-chloropyrimidine- C ί 30 van voorbeeld II, 509 mg, 0,0016 mol 8-[4-(1-piperazinyl)butyl]-8-aza-spirof4.5]decaan-7,9-dion en 162 mg, 0,0016 mol triethylamine in 15 ml ethanol werd gedurende een periode van 72 uur in een gesloten reactievat · op 110-120°C verwarmd. Na afkoelen werd het reactiemengsel onder verminderde druk geconcentreerd en werd overblijvend materiaal in 10 ml iso-35 propanol opgenomen. Een stoechiometrische hoeveelheid waterstofchloride in ethanol werd aan de isopropanoloplossing toegevoegd en het mengsel f werd gekoeld. Witte kristallen scheidden zich af die verzameld werden c ^ -5- en uit isopropanol werd gekristalliseerd, waarbij 281 mg.(42%) gelabeld produkt als hydrochloridezout werd verkregen.A mixture of 190 mg, 0.0016 mol of the 2-chloropyrimidine-C 30 of Example II, 509 mg, 0.0016 mol of 8- [4- (1-piperazinyl) butyl] -8-aza-spirof4.5 ] decane-7,9-dione and 162 mg, 0.0016 mol of triethylamine in 15 ml of ethanol were heated to 110-120 ° C in a closed reaction vessel over a period of 72 hours. After cooling, the reaction mixture was concentrated under reduced pressure and residual material was taken up in 10 ml of iso-35 propanol. A stoichiometric amount of hydrogen chloride in ethanol was added to the isopropanol solution and the mixture was cooled. White crystals separated which were collected c 5-5 and crystallized from isopropanol to give 281 mg (42%) of the labeled product as the hydrochloride salt.
Het zout werd in water opgelost en natriumbicarbonaat werd toegevoegd onder afkoeling totdat het mengsel basisch was. Er vormde zich een 5 neerslag, dat verzameld en uit isopropanol gekristalliseerd werd, waardoor 125 mg (35%) vrije base produkt werd verkregen dat radiochemisch zuiver was volgens de laag chromatografie, ontwikkeld in twee afzonderlijke oplosmiddelsystemen [CHCl3-EtOH (4:1) en CHCl3-MeOH-HOAc (10:3,:1)] en afgetast met een Varian Aerograph-Berthold Bradioscanner. De speci- 10 fieke activiteit van het 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl-8- ±14 azaspiro[4.5]decaan-7,9-dion- C gelabeld produkt was in het algemeen ongeveer 20 microcurie/mg.The salt was dissolved in water and sodium bicarbonate was added with cooling until the mixture was basic. A precipitate formed which was collected and crystallized from isopropanol to yield 125 mg (35%) of free base product which was radiochemically pure according to the layer chromatography developed in two separate solvent systems [CHCl3-EtOH (4: 1) and CHCl3-MeOH-HOAc (10: 3,: 1)] and scanned with a Varian Aerograph-Berthold Bradioscanner. The specific activity of the 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl-8- ± 14 azaspiro [4.5] decane-7,9-dione-C labeled product was in the generally about 20 microcurie / mg.
Analyse: berekend voor C2iS3iN502: C: 65,43; H: 8,11; N: 18,17. gevonden: C: 65,60; H 8,10; N: 18,24.Analysis: Calculated for C 21 SiN 502: C: 65.43; H: 8.11; N: 18.17. found: C: 65.60; H 8.10; N: 18.24.
15 Voorbeeld IV '15 Example IV '
Bereiding van gelabeld 2-chloropyrimidine-1^(formule 10b) (a) 2-Hydroxypyrimidine hydrochloride-** .Preparation of labeled 2-chloropyrimidine-1 ^ (formula 10b) (a) 2-Hydroxypyrimidine hydrochloride - **.
2 15 15 -2 15 15 -
Een oplossing van 3,0 g, 0,049 mol; 90 atoom% N ureum- N2 en 8,2 g, 0,049 mol malonaldehyde bis(dimethylacetaal) in 10 ml ethanol 20 werd met 10 ml geconcentreerd zoutzuur aangezuurd. De oplossing werd gedurende een periode van 2 uur op een stoombad verwarmd, en het zich vormende gele neerslag-werd verzameld, waardoor 5,1 g (80%) 2-hydroxy-pyri-±15 midine- hydrochloride werd verkregen met een smeltpunt van '· ' 210-212°c, dat zonder verdere zuivering als volgt werd gebruikt.A solution of 3.0 g, 0.049 mol; 90 atomic% N urea-N2 and 8.2 g, 0.049 mol of malonaldehyde bis (dimethylacetal) in 10 ml of ethanol were acidified with 10 ml of concentrated hydrochloric acid. The solution was heated on a steam bath for 2 hours, and the yellow precipitate that formed was collected to obtain 5.1 g (80%) of 2-hydroxy-pyrimidine hydrochloride, m.p. 210-212 ° C, which was used as follows without further purification.
±15 25 (b) 2-Chloropyrimidine- N0.± 15 (b) 2-Chloropyrimidine-N0.
2 ±152 ± 15
Een suspensie van 5,1 g, 0,038 mol hydroxypyrimidine- ^hydrochloride in 30 ml fosforoxychloride werd onder roeren gedurende een . periode van 6 uur op 110°C verwarmd. Overmaat forforoxychloride werd ver-- wijderd onder verminderde druk en resterende olie werd in 15 ml water 30 opgelost. De waterige oplossing werd met 10% natriumbicarbonaat behandeld ' totdat hij licht basisch was en de vrije base werd met chloroform geëxtraheerd. Concentratie van het gedroogde chloroformextract gaf 3,0 g 5 (68%) 2-chloropyrimidine- .. ^/dat zonder verdere zuivering in voorbeeld V werd gebruikt.A suspension of 5.1 g, 0.038 mol of hydroxypyrimidine hydrochloride in 30 ml of phosphorus oxychloride was stirred for one. heated at 110 ° C for 6 hours. Excess forforoxy chloride was removed under reduced pressure and residual oil was dissolved in 15 ml of water. The aqueous solution was treated with 10% sodium bicarbonate until slightly basic and the free base extracted with chloroform. Concentration of the dried chloroform extract gave 3.0 g of 5 (68%) 2-chloropyrimidine-2 which was used in Example V without further purification.
8105529 ___ ________________1 -6-8105529 ___ ________________1 -6-
c i' Vc i 'V
Voorfaeeld VForefront V
8- [4- [4-(2-pyrimidinyl) -l-piperazinyl] ethyl] -8-azaspiro [4.5] decaan-7,9- - *15 dion- . N„ gelabeld (formule 8b).8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] ethyl] -8-azaspiro [4.5] decane-7.9- * 15 dione-. N „labeled (formula 8b).
^ *15^ * 15
Een mengsel van 3,0 g, 0,026 mol 2-chloropyrimidine- , 8,7 g, 5 0,026 mol 8[4-(l-piperazinyl)butyl]-8-azaspiro[4.5]decaan-7,9-dion en 2,6 g, 0,026 mol triethylaffiine in 25 ml ethanol werd in een oliebad opgelost op. 110-120°C verwarmd in een gesloten reactievat gedurende een periode van 72 uur..Na afkoeling werd het reactiemengsel geconcentreerd onder verminderde druk en werd resterende olie opgenomen in hete isopropa-10 nol. Bij afkoeling scheidde zich een vaste stof af, die verzameld werd, waardoor 7,0 g (70%) produkt met een smeltpunt van 101-102°C werd verkregen. Omzetting van dit materiaal in het hydrochloridezout met een equivalent geconcentreerd zoutzuur in isopropanol gaf witte kristallen van het gelabelde 8-[4-[-(-2-pyrimidinyl)-l-piperazinyl[ethyl]-8-azaspiro 15 [4.5]decaan-7,9-d£on-*^^N0 hydrochloride, smeltpunt 185-186°C. Massaspec- ' λ 15 trum analyse van het materiaal liet een 80% N isotope . zuiverheid zien.A mixture of 3.0 g, 0.026 mole of 2-chloropyrimidine, 8.7 g, 5 0.026 mole of 8 [4- (1-piperazinyl) butyl] -8-azaspiro [4.5] decane-7,9-dione and 2 .6 g, 0.026 mol of triethylaffiin in 25 ml of ethanol were dissolved in an oil bath. Heated to 110-120 ° C in a closed reaction vessel for a period of 72 hours. After cooling, the reaction mixture was concentrated under reduced pressure and residual oil was taken up in hot isopropanol. Upon cooling, a solid separated and collected, yielding 7.0 g (70%) of product, mp 101-102 ° C. Conversion of this material to the hydrochloride salt with an equivalent concentrated hydrochloric acid in isopropanol gave white crystals of the labeled 8- [4 - [- (- 2-pyrimidinyl) -1-piperazinyl [ethyl] -8-azaspiro 15 [4.5] decane- 7.9-d-p on - * ^ ^ N0 hydrochloride, mp 185-186 ° C. Mass spectrum analysis of the material showed an 80% N isotope. see purity.
Analyse: berekend voor C_.H_.N_0_.HC1: C: 59,55; H: 7,61; N: 16,91 [ 21 21 O 2 . .. - .. gevonden: C:59,73; H: 7,60; N: 16,54. - · · - T ] - . ' ' . \ · f ' _ 5 - ? ** · - ... ; it /· ' .Analysis: Calculated for C_.H_.N_0_.HC1: C: 59.55; H: 7.61; N: 16.91 [21 21 O 2. .. - .. found: C: 59.73; H: 7.60; N: 16.54. - · - - T] -. ''. \ 'F' _ 5 -? ** · - ...; it / · '.
ΐ ' ; ...4 - - / | ; ' . " i .ΐ '; ... 4 - - / | ; ". "i.
NN
; / ' i ~Tï 0 5521 '; / 'i ~ Ti 0 5521'
Claims (5)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21521480A | 1980-12-11 | 1980-12-11 | |
| US21521480 | 1980-12-11 |
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| JP (1) | JPS57122082A (en) |
| AT (1) | AT380686B (en) |
| AU (1) | AU528067B2 (en) |
| BE (1) | BE891446A (en) |
| CA (1) | CA1172255A (en) |
| CH (1) | CH647518A5 (en) |
| DE (1) | DE3149011A1 (en) |
| DK (1) | DK154560C (en) |
| FI (1) | FI73993C (en) |
| FR (1) | FR2496105B1 (en) |
| GB (1) | GB2089341B (en) |
| GR (1) | GR76331B (en) |
| IE (1) | IE51948B1 (en) |
| IT (1) | IT1172073B (en) |
| LU (1) | LU83833A1 (en) |
| NL (1) | NL8105529A (en) |
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| HU212301B (en) * | 1989-04-28 | 1996-05-28 | Alkaloida Vegyeszeti Gyar | Process for producing buspirone |
| US5631017A (en) * | 1993-03-26 | 1997-05-20 | Beth Israel Deaconess Medical Center, Inc. | Topical application of buspirone for treatment of pathological conditions associated with immune responses |
| US5484788A (en) * | 1993-03-26 | 1996-01-16 | Beth Israel Hospital Association | Buspirone as a systemic immunosuppressant |
| KR950014099A (en) * | 1993-11-10 | 1995-06-15 | 장기하 | Method for preparing N- (2-pyrimidyl) piperazinyl butylamide |
| US5637314A (en) * | 1995-06-07 | 1997-06-10 | Beth Israel Deaconess Medical Center, Inc. | Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis |
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| BE759371A (en) * | 1969-11-24 | 1971-05-24 | Bristol Myers Co | HETEROCYCLICAL AZASPIRODECANEDIONES AND METHODS FOR THEIR PREPARATION |
| DE2341925A1 (en) * | 1973-08-20 | 1975-03-06 | Thomae Gmbh Dr K | 2,4, (opt.5-), 6-substd. pyriminidines as antithrombic agents - e.g. 6-methyl-5-nitro-2-piperazino-4-thiomorpolino-pyrimidine |
-
1981
- 1981-09-29 CA CA000386889A patent/CA1172255A/en not_active Expired
- 1981-10-05 AU AU76041/81A patent/AU528067B2/en not_active Expired
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| AU7604181A (en) | 1982-07-15 |
| CA1172255A (en) | 1984-08-07 |
| SE8107446L (en) | 1982-06-12 |
| FR2496105B1 (en) | 1985-12-13 |
| LU83833A1 (en) | 1982-07-07 |
| IT8149718A0 (en) | 1981-11-16 |
| IE51948B1 (en) | 1987-04-29 |
| JPH0113476B2 (en) | 1989-03-06 |
| DE3149011C2 (en) | 1988-08-25 |
| IT1172073B (en) | 1987-06-18 |
| AT380686B (en) | 1986-06-25 |
| ATA529581A (en) | 1985-11-15 |
| IE812897L (en) | 1982-06-11 |
| FR2496105A1 (en) | 1982-06-18 |
| FI73993B (en) | 1987-08-31 |
| FI73993C (en) | 1987-12-10 |
| DK154560B (en) | 1988-11-28 |
| CH647518A5 (en) | 1985-01-31 |
| YU243681A (en) | 1984-02-29 |
| YU42432B (en) | 1988-08-31 |
| DK154560C (en) | 1989-04-17 |
| DK548081A (en) | 1982-06-12 |
| BE891446A (en) | 1982-06-11 |
| GB2089341B (en) | 1984-09-19 |
| DE3149011A1 (en) | 1982-07-15 |
| FI813937L (en) | 1982-06-12 |
| AU528067B2 (en) | 1983-04-14 |
| SE444438B (en) | 1986-04-14 |
| GB2089341A (en) | 1982-06-23 |
| JPS57122082A (en) | 1982-07-29 |
| GR76331B (en) | 1984-08-04 |
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