DK154560B - Fremgangsmaade til fremstilling af radioaktivt maerket 8-oe4-oe4-(2-pyrimidinyl)-1-piperazinylaabutylaa-8-azaspiro-oe4.5aadekan-7,9-dion - Google Patents
Fremgangsmaade til fremstilling af radioaktivt maerket 8-oe4-oe4-(2-pyrimidinyl)-1-piperazinylaabutylaa-8-azaspiro-oe4.5aadekan-7,9-dion Download PDFInfo
- Publication number
- DK154560B DK154560B DK548081A DK548081A DK154560B DK 154560 B DK154560 B DK 154560B DK 548081 A DK548081 A DK 548081A DK 548081 A DK548081 A DK 548081A DK 154560 B DK154560 B DK 154560B
- Authority
- DK
- Denmark
- Prior art keywords
- azaspiro
- pyrimidinyl
- decane
- dione
- piperazinyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 22
- 229920004518 DION® Polymers 0.000 title 1
- AFNJMVYFZNHDRX-UHFFFAOYSA-N [C]1=NC=CC=N1 Chemical class [C]1=NC=CC=N1 AFNJMVYFZNHDRX-UHFFFAOYSA-N 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 7
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229960002495 buspirone Drugs 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 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
- 239000000047 product Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 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
- 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 3
- 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 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000376 reactant Substances 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
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- 150000005695 2-halopyrimidines Chemical class 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 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
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- YRTHJMQKDCXPAY-UHFFFAOYSA-N azaspirodecanedione Chemical compound C1C(=O)NC(=O)CC11CCCC1 YRTHJMQKDCXPAY-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring 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
- IAJINJSFYTZPEJ-UHFFFAOYSA-N 1h-pyrimidin-3-ium-2-one;chloride Chemical compound Cl.O=C1N=CC=CN1 IAJINJSFYTZPEJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 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
- XSQUKJJJFZCRTK-NJFSPNSNSA-N UREA C 14 Chemical compound N[14C](N)=O XSQUKJJJFZCRTK-NJFSPNSNSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- -1 alkali metal salt Chemical class 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- XSQUKJJJFZCRTK-SUEIGJEOSA-N bis(azanyl)methanone Chemical compound [15NH2]C([15NH2])=O XSQUKJJJFZCRTK-SUEIGJEOSA-N 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
- 238000004140 cleaning Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 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
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 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
- 238000010183 spectrum analysis 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
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229950000184 urea c 14 Drugs 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
Description
i
DK 154560 B
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af radioaktivt mærket 8-[4-[4-(2-pyrimidinyl)-l-pipera-zinyl]butyl]-8-azaspiro[4.5]decan-7,9-dion.
I US-patentskrift nr. 3.717.634 beskrives fremstilling af N-5 (heteroacyklisk)piperazinylalkylazaspiroalkandioner med formel I
o ^λ/Λ λ~\ (CIVn X N-A-N 71-2 io vii/vv \_y
1U II
O
Formel I
ved hjælp af de efterfølgende fremgangsmåder.
15
Fremgangsmåde A
o
20 (^Vn + h2n-a-n^_^n-b -v Formel I
O
25 Fremgangsmåde B
o
£7V 'M—A—X + H-/ - . Formel I
vVW \_/ 30 fj o ·
Formel IV Formel V
Fremgangsmåde C 35 0
n-m + x-a-n^ N-B Formel I
νιννγ \_y n
DK 154560 B
2 I de ovenstående reaktionsskemaer er "n" det hele tal 4 eller 5, -A- betegner en ligekædet eller forgrenet divalent alkalenkæde med ialt 2-6 carbonatomer, "B" betegner bl.a. forskellige heterocykliske radikaler, herunder "2-pyrimidinyl", "X" er bl.a. chlor, brom eller iod, og 5 "M" er et alkalimetalsalt såsom natrium eller kalium.
Den foreliggende fremgangsmåde afviger fra fremgangsmå-derne ifølge US-patentskrift nr. 3,717,634 ved at 2-pyrimidinyl-fragmentet indføres som et afsluttende trin ved direkt alkylering af forud dannet 8-[4-(l-piperazinyl)butyl]-8-azaspiro[4.5]decan-7,9-dion med en 2-halogenpyr-10 imidin.
I store træk angår opfindelsen en fremgangsmåde til fremstilling af radi oakti vt mærket 8-[4-[4-(2-pyrimidinyl)-1-pi perazi nyl]butyl]-8-azaspiro[4.5]decan-7,9-dion, hvortil der i det efterfølgende også henvises med den i USA vedtagne betegnelse "buspiron", se J. Amer. Med.
15 Assoc., 225, 520 (1973). Den foreliggende fremgangsmåde tilvejebringer en særlig og hidtil ukendt metode til fremstilling af radioaktivt mærket buspiron og mere specielt en fremgangsmåde til inkorporering af radio- 14 14 15 15 aktive carbon (C) og stabile nitrogen ( N) isotoper i bestemte positioner på pyrimidinylkomponenten af buspiron. Mærket buspiron er 20 værdifuld til klinisk undersø-gelse af absorptionen og den metaboliske disposition af dette anxiolytiske middel.
Den foreliggende opfindelse angår således en fremgangsmåde til fremstilling af radioaktivt mærket 8-[4-[4-(2-pyrimidinyl)-l-pipera-zinyl]butyl]-8-azaspiro[4.5]decan-7,9-dion, der er karakteriseret ved 25 formel la eller Ib
, DC^OO
ί la) ,° 35 γλ/λ f-\ /k~\ - *N—7
O
(Ib)
DK 154560 B
3
hvilken fremgangsmåde er ejendommelig ved, at 8-[4-(l-piperazinyl)-butyl]-8-azaspiro[4.5]decan-7,9-dion med formel II
LyVY 24v_/ o (II) 10 alkyleres med radioaktivt mærket 2-halogenpyrimidin med formel Illa eller Illb 15 x7~\ \=/ (Illa) (Illb) 20 hvori X er brom, iod eller chlor, i et reaktions-inert opløsningsmiddel ved en temperatur i området fra 80-170°C. Ved fremgangsmåden ifølge opfindelsen anvendes fortrinsvis radio-aktivt mærket 2-chlorpyrimidin, og omsætningen udføres fortrins vist i en lukket reaktionsbeholder.
Ved fremgangsmåden ifølge opfindelsen er det muligt at fremstille 25 radioaktivt mærket buspiron, der er af betydning for kliniske undersøgelser af absorption og metabolisk omsætning af buspiron. Fremgangsmåden ifølge opfindelsen indebærer i denne forbindelse både tekniske og økonomiske fordele. Det er således af stor betydning at kunne inkorporere den kostbare radioaktive pyrimidinyldel i buspiron under sidste 30 syntesetrin frem for i et mellemprodukt.
Forbindelsen med formel IIla er 2-halogenpyrimidin mærket i 2-stil-14 lingen med carbon isotop, og forbindelsen med formel Illb er 2-halogenpyrimidin, hvori 1,3- 15 nitrogenatomerne er mærket med nitrogen isotop.
35 De mærkede 2-halogenpyrimidiner med formel Illa opnås ved kondensering af passende mærket urinstof med malonaldehyd bis-(dimethyl-acetal) eller malonaldehyd bi s(diethyl acetal) i nærværelse af syre til opnåelse af den tilsvarende 2-hydroxypyrimidin, der derefter omdannes
DK 154560 B
4 til halogenforbindelsen ved hjælp af phosphoroxyhalogenid såsom en phosphoroxychlorid eller phosphoroxybromid. Til illustrering er sekvensen, der begynder med urinstof-14C til fremstilling af 2-chlor-pyrimi- *14 din- C (Illa), afbildet nedenfor.
5 ym2 cH«ch3)2 hci 0=C^ + CH2\^ ->- ( y- OH-HCl NH2 CH(OCH3)2 EtOH V=-N .
10 Ρ0^3 ^ 01 (Illa) 15 15
Den identiske sekvens, der begynder med urinstof- N«, tilveje- *1R ^ bringer 2-chlorpyrimidin- Ng (Hib) /—N* 20 / -V-oi
\-N
A.
(Illb)
Ved udførelse af den foreliggende fremgangsmåde kan der anvendes 25 ethvert opløsningsmiddel, som hverken indvirker ugunstigt på omsætningen eller på reaktanterne og buspironproduktet, idet det foretrukne opløsningsmiddel er en alkanol såsom ethanol, n-propanol, isopropanol o.l.
Generelt kan der anvendes en reaktionstemperatur i området fra ca.
80°C til ca. 170°C, idet den foretrukne temperatur ligger i området fra 30 110°C til 120°C. Højere og lavere temperaturer kan anvendes, men ved en reaktionstemperatur under 80°C forlænges reaktionen unødvendigt og passende kondensering indtræffer ikke, mens reaktanterner har en tendens til at dekomponere i et vist omfang, hvis reaktionstemperaturen overstiger 170°C. Når fremgangsmåden udføres ved temperaturer over koge-35 punktet af reaktionsopløsningsmidlet, anvendes fortrinsvis en lukket reaktionsbeholder.
Det under reaktionen udviklede hydrogenhalogenid opsamles med en syreacceptor for at konservere den basiske 8-[4-(-l-piperazinyl]butyl]-
DK 154560 B
5 8-azaspiro[4.5]decan-7,9-dion-reaktant (II). I denne henseende foretrækkes en tertiær amin såsom triethylamin.
Fremgangsmåden ifølge opfindelsen belyses nærmere i de efterfølgende eksempler 3 og 5.
5
Eksempel 1
Fremstilling af 8-[4-(-l-piperazinyl]butyl]-8-azaspiro[4.5]decan-7,9-dion (II) 10 _/ —j ^ v—7
O
15 (a) 8-(4-brombutyl)-8-azaspiro[4.5]decan-7,9-dion - En blanding af 3,3-tetramethylenglutarimid (33,4 g, 0-2 mol), 1,4-dibrombutan (86,4 g, 0,4 mol) og mi kropul veri seret kaliumcarbonat (88,6 g, 0,6 mol) i 500 ml tør toluen omrøres ved tilbagesvalingstemperatur i et tidsrum på 20 20 timer. Reaktionsblandingen filtreres, mens den er varm, og koncentreres under reduceret tryk. Resterende olie destilleres under reduceret tryk og fraktionen, der har et kogepunkt på 165-170°C ved 0,1 mm Hg, opsamles til opnåelse af 32,0 g (52%) 8-(4-brombutyl)-8-azaspiro[4.5]decan-7,9-dion som en olie.
25 (b) 8-[4-(l-piperazinyl)butyl]-8-azaspiro[4.5]decan-7,9-dion - En blanding af 8-(4-brombutyl)-8-azaspiro[4.5]decan-7,9-dion (32,0 g, 0,105 mol), piperazin (50 g, 0,58 mol) og mi kropul veriseret kaliumcarbonat (80,0 g, 0,58 mol) i 500 ml tør toluen omrøres ved tilbagesvalingstemperatur i 18 timer. Reaktionblandingen filtreres, mens den er varm, 30 koncentreres under reduceret tryk og resterende materiale omrøres med 100 ml ether. Overskydende piperazin, der fraseparerer som hydrochlo-ridet, opsamles og filtratet koncentreres under reduceret tryk. Destillation af resterende olie under reduceret tryk giver 13,5 g (42%) 8-[4-(1-piperazinyl]butyl]-8-azaspiro[4.5]decan-7,9-dion, kogepunkt 180-200°C 35 ved 0,1 mm Hg som den fri base.
Omdannelse af dette materiale til hydrochloridsaltet og omkrystallisering med ethanol giver analytisk rent 8-[4-(1-piperazinyl]butyl]-8-azaspiro[4.5]decan-7,9-dion-hydrochlorid, smp. 235-237°C.
DK 154560 B
6
Analyse: Beregnet for C17HjgN302.2HCl.1/4H20: C, 53,06; H, 8,25; N, 10,92 Fundet: C, 53,06; H, 8,05; N, 10,96 5
Eksempel 2 *14
Fremstilling af mærket 2-chlorpyrimidin C (Illa) 10 d -/"Λ N-=/ *14 (a) 2-hydroxypyrimidin C-mærket hydrochlorid - En opløsning af 14 15 urinstof (165 mg, 0,002 mol) indeholdende urinstof- C (43 mg, 0,0007 mol, 30 mi 11 i curie) og malonaldehyd bi s(dimethyl acetal) (443 mg, 0,0027 mol) i 1,0 ml ethanol behandles med 0,5 ml koncentreret saltsyre. Den surgjorte opløsning opvarmes over et dampbad i et tidsrum på 2 timer og afkøles. Det gule, bundfældede produkt opsamles til opnåelse af 274 mg *14 20 (77%) 2-chlorpyrimidin C, der anvendes uden yderligere rensning som følger.
*14 (b) 2-chlorpyrimidin- C-mærket - En blanding af 2-hydroxypyritni-*14 din C hydrochlorid (274 mg, 0,002 mol) og 10 ml phosphoroxychlorid opvarmes til 110°C under omrøring i et tidsrum på 6 timer. Overskydende 25 phosphoroxychlorid fjernes under reduceret tryk og resterende olie opløses i 15 ml vand. Den vandige opløsning behandles med 10% natriumbicar-bonat indtil den er let basisk på lakmuspapir og ekstraheres med chloroform. Koncentrering af den tørrede chloroformekstrakt giver 2-chlorpyr-imidin- 1^C (190 mg, 83%), der anvendes uden yderligere rensning i 30 eksempel 3.
Eksempel 3 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-azaspiro[4.5]decan-7,9- *14 dion C-mærket (la)
35 O
o *14
DK 154560 B
7
En blanding af 2-chlorpyrimidin- C (190 mg, 0,0016 mol) fra eksempel 2, 8- [4- (1 -pi perazi nyl ] butyl ] -8-azaspi ro[4.5]decan-7,-9-dion (509 mg, 0,0016 mol) og triethylamin (162 mg, 0,0016 mol) i 15 ml ethanol opvarmes til 110-120°C i en lukket reaktionsbeholder i et tidsrum på 5 72 timer. Efter afkøling koncentreres reaktionsblandingen under reduceret tryk og det resterende materiale optages i 10 mlisopropanol. En støkiometrisk mængde hydrogenchlorid i ethanol sættes til isopropanol-opløsningen og blandingen køles. Der fraseparerer hvide krystaller, som opsamles og omkrystalliseres med isopropanol, til opnå-el se af 281 mg 10 (42%) mærket produkt som hydrochloridsaltet.
Saltet opløses i vand og natriumbicarbonat tilsættes under køling indtil blandingen er basisk. Der dannes et bundfald, som opsamles og omkrystalli seres med isopropanol og således giver 125 mg (35%) fri baseprodukt, der er radiokemisk rent ifølge tyndtlagskromatografi, frem-15 kaldt i to adskilte opløsningsmiddel systemer [CHCl^-EtOH (4:1) og CHClg-Me0H-H0Ac (10:3:1)] og scannet ved hjælp af en "Varian Aerograph-Berthold Radioscanner”. Specific aktivitet af8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-azaspiro[4.5]decan-7,9-dion 14C-mærket produkt er generelt ca. 20 microcurie/mg.
20
Analyse: Beregnet for C£1^31^5®2: C, 65,43; H, 8,11; N, 18,17 Fundet: C, 65,60; H, 8,10; N, 18,24 25
Eksempel 4 *15
Fremstilling afmærket 2-chlorpyrimidin N2 (Hib)
-O
N-'
*1 P
(a) 2-hydroxypyrimidinhydrochlorid N2 - En opløsning af urinstof-35 15N2 (3,0 g, 0,049 mol, 90 atom-% 15N) og malonaldehyd bis(dimethyla-cetal) (8,2 g, 0,049 mol) i 10 ml ethanol surgøres med 10 ml koncentreret saltsyre. Opløsningen opvarmes over et dampbad i et tidsrum på 2 timer og det gule bundfald, der dannes, opsamles og giver således 5,1 g
DK 154560 B
8 (80%) 2-hydroxypyrimidin**®N2-hydrochlorid, smp. 210-212°C, der anvendes
Uden yderligere rensning som følger.
*15 (b) 2-chlorpyrimidin- N„- - En suspension af hydroxypyrimidin *15 ^ N2 hydrochlorid (5,1 g, 0,038 mol) og 30 ml phosphoroxychlorid opvar-5 mes til 110°C under omrøring i et tidsrum på 6 timer. Overskydende phosphoroxychlorid fjernes under reduceret tryk og resterende olie opløses i 15 ml vand. Den vandige opløsning behandles med 10% natriumbicarbonat indtil den er let basisk, og den fri base ekstraheres med chloroform. Koncentrering af den tørrede chloroformekstrakt giver 3,0 g (68%) 2- *15 10 chlorpyrimidin- N2 , der anvendes uden yderligere rensning i eksempel 5.
Eksempel 5 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-azaspiro[4.5]decan-7,9-15 dion*1®!^-mærket (Ib)) 20 0 *15
En blanding af 2-chlorpyrimidin- N2 (3,0 g, 0,026.mol), 8-[4-(1-piperazinyljbutyl]-8-azaspiro[4.5]decan-7,9-dion (8,07 g, 0,026 mol) og triethylamin (2,6 g, 0,026 mol) i 25 ml ethanol opvarmes i et oliebad til 110-120°C i en lukket reaktionsbeholder i ett tidsrum på 72 timer.
25 Efter afkøling koncentreres reaktionsblandingen under reduceret tryk og den resterende olie optages i varm isopropanol. Ved afkøling fraseparerer et fast stof, der opsamles til opnåelse af 7,0 g (70%) produkt, smp. 101-102°C. Omdannelse af dette materiale til hydrochloridsaltet med ét ækvivalent koncentreret saltsyre i isopropanol giver hvide krystaller af 30 mærket 8-[4-(2-pyrimidinyl)-l-piperazinyl]ethyl]-8-azaspiro[4.5]decan-*15 o 7,9-dion- N9 hydrochlorid, smp. 185-186 C. Hassespektralanalyse af c 15 materialet viser en 80% N i sotopisk renhed.
Analyse: Beregnet for C21H31N5°2*HC1: 35 C, 59,55; H, 7,61; N, 16,91
Fundet: C, 59,73; H, 7,60; N, 16,54
Claims (4)
- 2. Fremgangsmåde ifølge krav 1, KENDETEGNET ved, at den udføres i en lukket reaktionsbeholder.
- 3. Fremgangsmåde ifølge krav 1, KENDETEGNET ved, at der alkyleres *14 med mærket 2-chlorpyrimidin- C med formel Illa 5 *-(Λ (Illa) 10 til fremstilling af 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]-butyl]-8- *14 azaspiro[4,5]decan-7,9-dion- C med formel la o „ DC^-CKD o (la)
- 4. Fremgangsmåde ifølge krav 1, KENDETEGNET ved, at der alkyleres *15 med mærket 2-chlorpyrimidin- N med formel Illa 20 * Cl- V
- 25 Ulla) til fremstilling af 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-aza- *15 spiro[4.5]decan-7,9-dion- N2 med formel Ib DCi'^O-O o * 35 (Ib)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21521480A | 1980-12-11 | 1980-12-11 | |
| US21521480 | 1980-12-11 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK548081A DK548081A (da) | 1982-06-12 |
| DK154560B true DK154560B (da) | 1988-11-28 |
| DK154560C DK154560C (da) | 1989-04-17 |
Family
ID=22802113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK548081A DK154560C (da) | 1980-12-11 | 1981-12-10 | Fremgangsmaade til fremstilling af radioaktivt maerket 8-oe4-oe4-(2-pyrimidinyl)-1-piperazinylaabutylaa-8-azaspiro-oe4.5aadekan-7,9-dion |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS57122082A (da) |
| AT (1) | AT380686B (da) |
| AU (1) | AU528067B2 (da) |
| BE (1) | BE891446A (da) |
| CA (1) | CA1172255A (da) |
| CH (1) | CH647518A5 (da) |
| DE (1) | DE3149011A1 (da) |
| DK (1) | DK154560C (da) |
| FI (1) | FI73993C (da) |
| FR (1) | FR2496105B1 (da) |
| GB (1) | GB2089341B (da) |
| GR (1) | GR76331B (da) |
| IE (1) | IE51948B1 (da) |
| IT (1) | IT1172073B (da) |
| LU (1) | LU83833A1 (da) |
| NL (1) | NL8105529A (da) |
| SE (1) | SE444438B (da) |
| YU (1) | YU42432B (da) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU212301B (en) * | 1989-04-28 | 1996-05-28 | Alkaloida Vegyeszeti Gyar | Process for producing buspirone |
| US5484788A (en) * | 1993-03-26 | 1996-01-16 | Beth Israel Hospital Association | Buspirone as a systemic immunosuppressant |
| 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 |
| KR950014099A (ko) * | 1993-11-10 | 1995-06-15 | 장기하 | N-(2-피리미딜)피페라지닐 부틸아미드의 제조방법 |
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE759371A (fr) * | 1969-11-24 | 1971-05-24 | Bristol Myers Co | Azaspirodecanediones heterocycliques et procedes pour leur preparation |
| DE2341925A1 (de) * | 1973-08-20 | 1975-03-06 | Thomae Gmbh Dr K | Neue pyrimidinderivate und verfahren zu ihrer herstellung |
-
1981
- 1981-09-29 CA CA000386889A patent/CA1172255A/en not_active Expired
- 1981-10-05 AU AU76041/81A patent/AU528067B2/en not_active Expired
- 1981-10-09 YU YU2436/81A patent/YU42432B/xx unknown
- 1981-10-27 GB GB8132370A patent/GB2089341B/en not_active Expired
- 1981-11-16 IT IT49718/81A patent/IT1172073B/it active
- 1981-11-27 GR GR66636A patent/GR76331B/el unknown
- 1981-12-08 FI FI813937A patent/FI73993C/fi not_active IP Right Cessation
- 1981-12-08 CH CH7842/81A patent/CH647518A5/de not_active IP Right Cessation
- 1981-12-08 FR FR8122916A patent/FR2496105B1/fr not_active Expired
- 1981-12-08 NL NL8105529A patent/NL8105529A/nl active Search and Examination
- 1981-12-09 JP JP56197037A patent/JPS57122082A/ja active Granted
- 1981-12-10 DK DK548081A patent/DK154560C/da not_active IP Right Cessation
- 1981-12-10 DE DE19813149011 patent/DE3149011A1/de active Granted
- 1981-12-10 AT AT0529581A patent/AT380686B/de not_active IP Right Cessation
- 1981-12-10 IE IE2897/81A patent/IE51948B1/en not_active IP Right Cessation
- 1981-12-11 SE SE8107446A patent/SE444438B/sv not_active IP Right Cessation
- 1981-12-11 BE BE0/206810A patent/BE891446A/fr not_active IP Right Cessation
- 1981-12-11 LU LU83833A patent/LU83833A1/fr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK548081A (da) | 1982-06-12 |
| IE51948B1 (en) | 1987-04-29 |
| AT380686B (de) | 1986-06-25 |
| JPH0113476B2 (da) | 1989-03-06 |
| FR2496105B1 (fr) | 1985-12-13 |
| FR2496105A1 (fr) | 1982-06-18 |
| SE444438B (sv) | 1986-04-14 |
| DE3149011C2 (da) | 1988-08-25 |
| DE3149011A1 (de) | 1982-07-15 |
| LU83833A1 (fr) | 1982-07-07 |
| DK154560C (da) | 1989-04-17 |
| GB2089341A (en) | 1982-06-23 |
| NL8105529A (nl) | 1982-07-01 |
| ATA529581A (de) | 1985-11-15 |
| SE8107446L (sv) | 1982-06-12 |
| YU243681A (en) | 1984-02-29 |
| FI813937L (fi) | 1982-06-12 |
| IE812897L (en) | 1982-06-11 |
| IT1172073B (it) | 1987-06-18 |
| CA1172255A (en) | 1984-08-07 |
| CH647518A5 (de) | 1985-01-31 |
| IT8149718A0 (it) | 1981-11-16 |
| GR76331B (da) | 1984-08-04 |
| JPS57122082A (en) | 1982-07-29 |
| GB2089341B (en) | 1984-09-19 |
| FI73993C (fi) | 1987-12-10 |
| AU528067B2 (en) | 1983-04-14 |
| YU42432B (en) | 1988-08-31 |
| FI73993B (fi) | 1987-08-31 |
| AU7604181A (en) | 1982-07-15 |
| BE891446A (fr) | 1982-06-11 |
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