IE51948B1 - Buspirone process - Google Patents
Buspirone processInfo
- Publication number
- IE51948B1 IE51948B1 IE2897/81A IE289781A IE51948B1 IE 51948 B1 IE51948 B1 IE 51948B1 IE 2897/81 A IE2897/81 A IE 2897/81A IE 289781 A IE289781 A IE 289781A IE 51948 B1 IE51948 B1 IE 51948B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- dione
- azaspiro
- decane
- labeled
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 title description 10
- 229960002495 buspirone Drugs 0.000 title description 9
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000005695 2-halopyrimidines Chemical class 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000000460 chlorine Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 229910052801 chlorine Chemical group 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- WTVNFKVGGUWHQC-UHFFFAOYSA-N decane-2,4-dione Chemical compound CCCCCCC(=O)CC(C)=O WTVNFKVGGUWHQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 230000002285 radioactive effect Effects 0.000 abstract description 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 abstract description 3
- 230000029936 alkylation Effects 0.000 abstract description 2
- 238000005804 alkylation reaction Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 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 11
- 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
- 239000000203 mixture Substances 0.000 description 7
- 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
- 239000000243 solution Substances 0.000 description 5
- 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
- 239000011541 reaction mixture 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
- -1 alkali metal salt Chemical class 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 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
- 239000012458 free base Substances 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
- IDXKTTNFXPPXJY-UHFFFAOYSA-N pyrimidin-1-ium;chloride Chemical compound Cl.C1=CN=CN=C1 IDXKTTNFXPPXJY-UHFFFAOYSA-N 0.000 description 2
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 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
- 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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 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
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- YRTHJMQKDCXPAY-UHFFFAOYSA-N azaspirodecanedione Chemical compound C1C(=O)NC(=O)CC11CCCC1 YRTHJMQKDCXPAY-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 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
- 239000002026 chloroform extract Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 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
- 230000000155 isotopic effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 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
- 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
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 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
Abstract
Busipirone of the formula is prepared in a new process wherein the 2-pyrimidinyl component thereof is introduced in a final alkylation step involving 2-halopyrimidines. Radioactive labelled busipirone can be obtained according to the process by employing 2-chloro- pyrimidine-<14>C 2-chloropyrimidine- <15> N2.
Description
In the above reaction schemes, the symbol n Is the integer 4 or 5, the symbol -A- represents a straight or branched divalent alkalene chain of two to six carbon atoms inclusive, the symbol B represents inter alia various heterocyclic radicals including 2-pyrimidinyl, the symbol X inter alia is chlorine, bromine, iodine, and the symbol M an alkali metal salt such as sodium or potassium.
The present process differs from methods of Wu, fit dl·,
U.S. 3,717,636 in that the 2-pyrimidinyl fragment is introduced as a final step by direct alkylation of preformed 8-[4-(l-piperazinyl)butylj-8-azasplro[4.5]decane-7,9-dione with a 2-halopyrimidine.
Broadly described, this invention is concerned with a process for preparation of the pyrimidine compound 8-[4-[4-(2pyrimidinyl)-l-piperazinyl]butylJ-8-azaspiro[4.5]decane-7,9-dione also referred to herein by the United States Adopted Name buspirone see J. Amer. Med. Assoc., 225, 520 (1973). The present process provides a new and novel route for preparation of buspirone and more 14 14 particularly to a method for incorporating radioactive carbon ( C) and stable ^^nitrogen (^N) isotopes in specified positions of the pyrimidinyl component of buspirone. Labeled buspirone is useful in clinical investigation of the absorption and metabolic disposition of this anxiolytic agent.
The present invention relates to a process for preparation of 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione characterized by Formula I
which comprises alkylating 8-[4-(l-piperazinyl)butyl]-8-azaspiro[4.5] decane-7,9-dione characterized by Formula II
51848
with a 2-halopyrimidine characterized by Formula III
(III) wherein X is bromine, iodine or preferably chlorine in a reaction inert solvent at a temperature ranging from 80-170’C., preferably in a closed reaction vessel.
The foregoing process is particularly adaptable to the preparation of radioactive labeled buspirone and in that respect is both economical and convenient. As used herein, the term labeled
refers to radioactive ( C) and stable ( N) Isotopes incorporated at specific positions of buspirone. Preferred embodiments of the foregoing process are those for the preparation of labeled buspirone wherein:
the compound of Formula III is 2-chloropyrimidine labeled 14 in the 2 position with carbon isotope;
the compound oi Formula III is 2-chloropyrimidine in which the 1,3-nitrogen atoms are labeled with 15nitrogen isotope. The labeled Formula III 2-halopyrimidines are obtained by condensation of appropriately labeled urea with malonaldehyde
519 4 8 bis(dimethylacetal) or malonaldehyde bis(diethylacetal) in the presence of acid to afford the corresponding 2-hydroxypyrimidine subsequently converted to the halo compound by means of phcsphorus oxyhalide such as phosphorus oxychloride or phosphorus oxybromide. By way of illus14 tration, the sequence starting with urea- C for preparation of *14
2-chloropyrimidine- C (Ilia) is depicted below.
The identical sequence starting with ureac pyrimidine- t»2 (Illb)
,, affords 2-chloro* (Illb)
In carrying out the present process, any solvent which does not adversely affect the reaction as well as the reactants and the buspirone product may be used with the preferred solvent being an alkanol such as, for exanple, ethanol, n-propanol or isopropanol.
Generally a reaction temperature in the range of from about 80’C. to about 170°C. is operable, with the preferred temperature being in the range of from 110°C. to 120°C. Higher and lower temperatures may be used, but at a reaction temperature below 8Q°C, the
81848 reaction is unduly prolonged and adequate condensation does not occur whereas if the reaction temperature exceeds 170°C. the reactants tend to undergo decomposition to some extent. When the process is carried out at temperatures above the boiling point of the reaction solvent, a closed reaction vessel is preferably employed.
The hydrohalide evolved in the course of the reaction is taken up with an acid acceptor to conserve the basic 8-[4-(l-piperazinyl)butyl]-8-azaspiro[4.5]decane-7,9-dione reactant (XI). Xn this regard a tertiary amine such as triethylamine is preferred.
The process of this invention is further illustrated hy the following examples which are not to be construed as limiting the scope of the present invention.
EXAMPLE 1
Preparation of
8-[4-(l-Piperazinyl)butyl-8-azaspiro[4.5]decane-7,9-dlone (II)
(a) 8-(4-Bromobutyl)-8-azaspiro[4,5]decane-7,9-dione.- A mixture of 3,3-tetramethylene glutarimide (33.4 g., 0-2 mole), 1,4-dibromobutane (86.4 g., 0.4 mole) and micropulverized potassium carbonate (88.6 g., 0.6 mole) in 50° ml. dry toluene is stirred at reflux temperature for a 20 hr period. The reaction mixture is filtered while hot and concentrated under reduced pressure. Residual oil is distilled under reduced pressure and the fraction having a
b.p. 165-170°C at 0.1 mm Hg. collected to afford 32.0 g. (5ZZ) of
8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione as an oil.
(b) 8-(4-(1-Piperaziny1)bu ty1-8-azaspiro[4.5]decane-7,9-dione.
A mixture of 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione (32.0 g.,
0.105 mole), piperazine (50 g., 0.58 mole), and micropulverized potassium carbonate (80.0 g., 0.58 mole) in 500 mi. of dry toluene is stirred at reflux temperature for 18 hrs. The reaction mixture is filtered while hot, concentrated under reduced pressure and residual material stirred with 100 ml. ether. Excess piperazine, which separates as the hydrochloride, is collected and the filtrate concentrated under reduced pressure. Distillation of residual oil under reduced pressure affords 13.5 g. (42Z) of 8-[4-(l-piperazinyl)butyl8-azaspiro[4.5]decane-7,9-dione, b.p. 180-200°C. at 0.1 mm Hg as the free base.
Conversion of this material to the hydrochloride salt and crystallization from ethanol affords analytically pure 8-(4-(1piperaziny1)buty1-8-azaspiro[4.5]decane-7,9-dione hydrochloride, m.p. 235-237°C.
Anal. Calcd. for CpH.^N.jtyMCl'iMH^: C, 53.06;
E, 8.25; N, 10.92. Found: C, 53.06; H, 8.05; S, 10.96.
EXAMPLE 2
Preparation of Labeled *14
2-Chloropyrimidine C (Ilia)
Cl (a) 2-Hydroxypyrimidine Labeled) hydrochloride.- A solution of urea (165 mg., 0.002 mole) containing urea- C (43 mg., 0.0007 mole, 30 millicurie) and malonaldehyde bis(dimethylacetal) (443 mg., 0.0027 mole) in 1.0 ml. ethanol is treated with 0.5 ml. concentrated hydrochloric acid. The acidified solution is warmed on a steam bath for a period of 2 hrs., and chilled. The yellow precipitated product is collected to afford 274 mg. (77%) of 2-chloro*14 pyrimidine C used without further purification as follows.
(b) 2-Chloropyrimidine- labeled).- A mixture of 2-hydroxypyrimidine hydrochloride (274 mg., 0.002 mole) and ml. of phosphorus oxychloride is heated at 110’C. with stirring for a 6 hr. period. Excess phosphorus oxychloride is removed under reduced pressure and remaining oily residue dissolved in 15 ml. water. The aqueous solution is treated with 10% sodium bicarbonate until slightly basic to litmus and extracted with chloroform.
Concentration of the dried chloroform extract provides 2-chloro*14 pyrimidine- C (190 mg., 83%) used without further purificiation in Example 3.
EXAMPLE 3
8-[4-[4-(2-Pyrimidinyl)-l-piperazinyl]ethy1-8*14 azaspiro[4.5]decane-7,9-dione- C Labeled (Ia)
*14
A mixture of the 2-chloropyrimidine- C (190 mg., 0.0016 mole) from Example 2, 8-[4-(l-piperazinyl)butyl]-8-azaspiro[4.5]decane 7,9-dione (509 mg., 0.0016 mole) and triethylamine (162 mg., 0.0016 mole) in 15 ml. ethanol is heated at 110-120°C. in a sealed reaction vessel for a 72 hr. period. After cooling, the reaction mixture is concentrated under reduced pressure and residual material taken up in
ml. of isopropanol. A stoichiometric amount of hydrogen chloride in ethanol is added to the isopropanol solution and the mixture cooled. White crystals separate which are collected and crystallized from isopropanol co give 281 mg. (42%) of labeled product as the hydrochloride salt.
The salt is dissolved in water and sodium bicarbonate added with cooling until the mixture Is basic. A precipitate forms which is collected and crystallized from isopropanol thus providing 125 mg. (35%) of free base product radiochemically pure according to thin layer chromatography developed in too separate solvent systems [CHClj-EtOH (4:1) and CHCl3-MeOH-HOAc (10:3:1)] and scanned with a Varian Aerograph-Berthold Radioscanner (Varian is a Trade Mark). Specific activity of the
51848
8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro(4.5Jdecane7,9-dione-*1^C labeled product is generally about 20 microcurie/mg.
Anal. Calcd. for C^H^N^: C, 65.43; H, 8.11; N, 18.17. Found: C, 65.6'); H, 8.10; N, 18.24.
EXAMPLE 4
Preparation of Labeled 2-Chloropyrlmidine- (Illb) *
(a) 2-Hydroxypyrlmldine Hydrochloride-*15^.- A solution
of urea- N2 (3.0 g,, 0.049 mole; 90 atom X N) and malonaldehyde bis(dimethylacetal) (8.2 g., 0.049 mole) in 10 al. ethanol is acidified with 10 ml. concentrate! hydrochloric acid. The solution is warmed on a steam bath for a period of 2 hrs., and the yellow precipitate which forms collected thus affording 5.1 g. (80%) of 2-hydroxyΛ1 5 pyrimidine- hydrochloride, m.p. 210-212°C., used without further purification as follows.
*15 (b) 2-Chloropyrimidlne- Kn.- A suspension of hydroxy*15 pyrimidine- hydrochloride (5.1 g., 0.038 mole) in 30 ml. phosphorus oxychloride is heated at 110°C. with stirring for a 6 hr. period.
Excess phosphorus oxychloride is removed under reduced pressure and residual oil dissolved in 15 ml. water. The aqueous solution is treated with 10% sodium bicarbonate until slightly basic and the free oase extracted with chloroform. Concentration of the. dried chloroform *15 extract provides 3.0 g. (68%) of 2-chloropyrimidine- Nj used without further purification in Example 5.
EXAMPLE 5
8-[4-[4-(2-Pyrimidinyl)-l-piperazinyl]ethyl)-
A mixture of 2-chloropyrimidine- (3.0 g., 0.026 mole),
8-[4-(l-piperazinyl)butyl)-8-azaspiro[4.5]decane-7,9-dione (8.07 g.,
0.026 mole) and triethylamine (2.6 g., 0.026 mole) in 25 ml. ethanol and heated in an oil bath at 110-l?0°C. in a sealed reaction vessel for a 72 hr. period. After cooling, the reaction mixture is concentrated under reduced pressure and residual oil taken up in hot isopropanol.
On cooling, a solid separates which is collected to afford 7.0 g.
(70%) of product, m.p. 101-102’C. Conversion of this material to the hydrochloride salt with one equivalent of concentrated hydrochloric acid in ispropanol affords white crystals of the labeled 8-(4-(-(2pyrimidinyl)-l-piperazinyl[ethyl)-8-azaspiro[4.5]decane-7,9-dionehydrochloride, m.p. 185-186°C. Mass spectral analysis of the material 15 indicated an 80% N isotopic purity.
Anal. Caled for C^H^NjO^HCl: C, 59.55; H, 7.61; N, 16.91.
Found: C, 59.73; H, 7.60; N, 16.54.
S1S48
Claims (7)
1. CLAIMS ϊ1. A process for the preparation of 8-£4-(4-(2-pyrimldinyl)-1piperazinyi]butyl]-8-3zaspiro[4.5]decane-7,9-dione characterized by Formula J which comprises alkylating 8-(4-(l-piperazinyl)butyl]-8-azaspiro[4.5]decane-7,9-dione characterized by Formula II with a 2-halopyrimidine characterized by Formula III -Μ wherein X is bromine, iodine or chlorine in a reaction inert solvent at a temperature ranging from 80-170°C. (III)
2. The process of Claim 1 carried out in a closed reaction vessel.
3. The process of Claim 1 wherein the Formula III Z-halopyrimidine is 2-chloropyrimidine. *14
4. The process of Claim 1 wherein labeled 2-chloropyrimidine- C of Formula IIIa (IIIa) is employed and the product is 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]*14 echyl-8-azaspiro[4.5Jdecane-7,9-dione- C of Formula Ia (Ia)
5. The process of Claim 1 wherein labeled 2-chloropyrimidineof Formula IIIa *15 * (IIIa) 81848 is employed and the product is 8- [4-[4-(2-pyrimidinyl)-1piperazinyl]-ethyl-8-azaspiro [4.5]decane-7,9-dione * 15 N 2 of Formula Ib 5
6. A process according to Claim 1, for making a compound as defined in Claim 1 substantially as hereinbefore specifically described in the Examples 3 and 5.
7. A compound as defined in Claim 1 when produced by a process as claimed in any one of claims 1 to 6.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21521480A | 1980-12-11 | 1980-12-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE812897L IE812897L (en) | 1982-06-11 |
| IE51948B1 true IE51948B1 (en) | 1987-04-29 |
Family
ID=22802113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2897/81A IE51948B1 (en) | 1980-12-11 | 1981-12-10 | Buspirone process |
Country Status (18)
| Country | Link |
|---|---|
| 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) |
| SE (1) | SE444438B (en) |
| YU (1) | YU42432B (en) |
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 (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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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
- 1981-10-09 YU YU2436/81A patent/YU42432B/en unknown
- 1981-10-27 GB GB8132370A patent/GB2089341B/en not_active Expired
- 1981-11-16 IT IT49718/81A patent/IT1172073B/en active
- 1981-11-27 GR GR66636A patent/GR76331B/el unknown
- 1981-12-08 FI FI813937A patent/FI73993C/en not_active IP Right Cessation
- 1981-12-08 CH CH7842/81A patent/CH647518A5/en not_active IP Right Cessation
- 1981-12-08 FR FR8122916A patent/FR2496105B1/en not_active Expired
- 1981-12-08 NL NL8105529A patent/NL8105529A/en active Search and Examination
- 1981-12-09 JP JP56197037A patent/JPS57122082A/en active Granted
- 1981-12-10 IE IE2897/81A patent/IE51948B1/en not_active IP Right Cessation
- 1981-12-10 DE DE19813149011 patent/DE3149011A1/en active Granted
- 1981-12-10 AT AT0529581A patent/AT380686B/en not_active IP Right Cessation
- 1981-12-10 DK DK548081A patent/DK154560C/en not_active IP Right Cessation
- 1981-12-11 SE SE8107446A patent/SE444438B/en not_active IP Right Cessation
- 1981-12-11 LU LU83833A patent/LU83833A1/en unknown
- 1981-12-11 BE BE0/206810A patent/BE891446A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57122082A (en) | 1982-07-29 |
| FI813937L (en) | 1982-06-12 |
| CH647518A5 (en) | 1985-01-31 |
| GB2089341B (en) | 1984-09-19 |
| BE891446A (en) | 1982-06-11 |
| NL8105529A (en) | 1982-07-01 |
| FI73993C (en) | 1987-12-10 |
| DE3149011C2 (en) | 1988-08-25 |
| YU42432B (en) | 1988-08-31 |
| AT380686B (en) | 1986-06-25 |
| FR2496105B1 (en) | 1985-12-13 |
| ATA529581A (en) | 1985-11-15 |
| GB2089341A (en) | 1982-06-23 |
| IT1172073B (en) | 1987-06-18 |
| IT8149718A0 (en) | 1981-11-16 |
| CA1172255A (en) | 1984-08-07 |
| FI73993B (en) | 1987-08-31 |
| GR76331B (en) | 1984-08-04 |
| FR2496105A1 (en) | 1982-06-18 |
| DE3149011A1 (en) | 1982-07-15 |
| SE444438B (en) | 1986-04-14 |
| SE8107446L (en) | 1982-06-12 |
| JPH0113476B2 (en) | 1989-03-06 |
| LU83833A1 (en) | 1982-07-07 |
| DK548081A (en) | 1982-06-12 |
| AU528067B2 (en) | 1983-04-14 |
| YU243681A (en) | 1984-02-29 |
| DK154560C (en) | 1989-04-17 |
| IE812897L (en) | 1982-06-11 |
| DK154560B (en) | 1988-11-28 |
| AU7604181A (en) | 1982-07-15 |
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| MK9A | Patent expired |