GB2089341A - Busipirone Process - Google Patents
Busipirone Process Download PDFInfo
- Publication number
- GB2089341A GB2089341A GB8132370A GB8132370A GB2089341A GB 2089341 A GB2089341 A GB 2089341A GB 8132370 A GB8132370 A GB 8132370A GB 8132370 A GB8132370 A GB 8132370A GB 2089341 A GB2089341 A GB 2089341A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- dione
- decane
- azaspiro
- chloropyrimidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 26
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000005695 2-halopyrimidines Chemical class 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 11
- WTVNFKVGGUWHQC-UHFFFAOYSA-N decane-2,4-dione Chemical compound CCCCCCC(=O)CC(C)=O WTVNFKVGGUWHQC-UHFFFAOYSA-N 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 239000000460 chlorine Chemical group 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
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 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 10
- 229960002495 buspirone Drugs 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
- 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
- 239000000463 material Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 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
- 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
- XHTYQFMRBQUCPX-UHFFFAOYSA-N 1,1,3,3-tetramethoxypropane Chemical compound COC(OC)CC(OC)OC XHTYQFMRBQUCPX-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
- -1 alkali metal salt Chemical class 0.000 description 3
- 239000012458 free base Substances 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
- 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
- 239000002026 chloroform extract Substances 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 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
- UNCQVRBWJWWJBF-DOMIDYPGSA-N 2-chloro(214C)pyrimidine Chemical compound Cl[14C]1=NC=CC=N1 UNCQVRBWJWWJBF-DOMIDYPGSA-N 0.000 description 1
- 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 1
- 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 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
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)
Abstract
Busipirone of the formula <IMAGE> 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
SPECIFICATION
Buspirone process
This invention relates to a new process for the preparation of buspirone.
Description of the Prior Art
Yao Hua Wu, et al., U.S. Patent No. 3,717,634 disclose synthesis of N-(heteroarcyclic)piperazinylalkylazaspiroalkanediones of formula I
Formula I by the following methods.
MFrHOD A
Formula II Formula III
METHOD B
Formula IV Formula V
METHOD C
Formula VI Formula VII
In the above reaction schemes, the symbol "n" is the integer 4 or 5, the symbol -Arepresents 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 instant process differs from methods of Wu, et al., U.S. 3,717,634 in that the 2pyrimidinyl fragment is introduced as a final step by direct alkylation of preformed 8- (4-(1- piperazinyl)-butyl]-8-azaspiro[4.5]decane-7, 9 dione with a 2-halopyrimidine.
Summary of the Invention
Broadly described, this invention is concerned with a process for preparation of the pyrimidine compound 8-[4-4-(2-pyrimidinyl)- 1 -piperazinylyl]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 instant process provides a new and novel route for preparation of buspirone and more particularly to a method for incorporating radioactive '4carbon (14C) and stable '5nitrogen ('5N) isotapes 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.
Detailed Description of the Invention
The instant invention relates to a process for preparation of 8-[4--(pyrimidinyl)-1 -piperazin- yl]butyl]-8-azaspiro(4. 5]-decane-7, 9-dione characterized by Formula I
which comprises alkylating 8-(4-( I -piperazinyl)butylj-8-azaspirn(4. 5]-decane-7, 9-dione characterized by Formula II
with a 2-halopyrimidine characterized by Formula Ill
wherein X is bromine, iodine or preferably chlorine in a reaction inert solvent at a temperature ranging from 80-1 70'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 (14C) and stable (15N) 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 Ill is 2-chloropyrirnidine labeled in the 2 position with 14carbon isotape;
the compound of Formula Ill is 2-chloropyrimidine in which the 1,3-nitrogen atoms are labeled with 15nitrogen isotape.
The labeled Formula Ill 2-halopyrimidines are obtained by condensation of appropriately labeled urea with malonaldehyde 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 phosphorus oxyhalide sych as phosphorus oxychloride or phosphorus oxybromide. By way of illustration, the sequence starting with urea-l4C for preparation of 2-chloropyrimidine-14C (ill) is depicted below.
The identical sequence starting with urea-l5N2 affords 2-chloropyrimidine-'l5N2 (Illb)
In carrying out the instant 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 ethanol, n-propanol, isopropanol and the like.
Generally a reaction temperature in the range of from about 80"C. to about 1 70 C is operable, with the preferred temperature being in the range of from 11 0'C. to 1 20 C. Higher and lower temperatures may be used, but at a reaction temperature below 80"C. the reaction is unduly prolonged and adequate condensation does not occur whereas if the reaction temperature exceeds 1 70 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-( 1 -piperazinyl)-butyl]-8-azaspiro[4. 5]decane-7, 9-dione reactant (II). In this regard a tertiary amine such as triethylamine is preferred.
The process of this invention is further illustrated by the following examples which are not to be construed as limiting the scope of the present invention.
EXAMPLE 1
Preparation of 8-f4-Piperazin yI)r4. 5]decane-8-azaspiro[4. 5]decane- 7, 9-dion e (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 500 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. (52%) of 8-(4-bromobutyl)-8 azaspiro[4. 5]decane-7,9-dione as an oil.
(b) 8-[4-(l-Piperrazinyl)butyl-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 ml. of dry toluene is stirred at reflux temperature for 1 8 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 1 3.5 g. (42%) of 8-[4-(1-piperazinyl) butyl-8-azaspirn[4.5]decane-7,9dione, 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-(1 -piperazinyl)butyl-8-azaspiro[4. 5]decane-7, 9-dione hydrochloride, m. p.
235-237"C.
Anal. Calcd. for Cl7HlgN302 C, 53.06; H, 8.25; N, 10.92. Found: C, 53.06; H, 8.05; N, 10.96.
EXAMPLE 2
Preparation of Labeled 2-Chloropyrimidine *14C (Illa)
(a) 2-Hydroxypyrimidine*14C Labeled) hydrochlorida-A solution of urea (165 mg., 0.002 mole) containing urea-l4C (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-chloropyrimidine*l4C used without further purification as follows.
(b) 2-chloropyrimidine-*'4C labeled).-A mixture of 2-hydroxypyrimidine*1 4C hydrochloride (274 mg., 0.002 mole) and 10 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-pyrimidine-*14C (190 mg ., 83%) used without further purification in Example 3.
EXAMPLE 3 8-F4-r4-(2-Pyrimidinyl)- 1 piperazinyljethyl-S-azaspiro [4. 5] decane-7,9-dione- *14C Labeled (la)
A mixture of the 2-chloropyrimidine-*14C (190 mg., 0.0016 mole) from Example 2, 8-[4(1- piperazinyl)butyl]-8-azaspiro(4.5]decane 7,9-dione (509 mg., 0.0016 mole) and triethylamine (162 mg., 0.0016 mole) in 1 5 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 10 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 to 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 1 25 mg.(35%) of free base product radiochemically pure according to thin layer chromatography developed in two separate solvent systems [CHCI3-EtOH (4:1) and CHCI3-MeOH-HOAc (10:3:1)] and scanned with a Varian Aerograph-Berthold Radioscanner. Specific activity of the 8-[4-(2-pyrimidi nyl)- 1 -piperazinyl]butyl]-8-azaspirn(4. 5]decane-7 , 9-dione-*14C labeled product is generally about 20 microcurie/mg.
Anal. Calcd. for C21H31N502: C, 65.43; H, 8.11; N, 18.17.
Found: C, 65.60; H, 8.10; N, 18.24.
EXAMPLE 4
Preparation of Labeled 2-Chloropyrimidine-*'5N2 (Illb)
(a) 2-Hydroxypyrimidine Hydrochloride-*'5N2. A solution of urea-15N2 (3.0 g., 0.049 mole; 90 atom % 15N) and malonaldehyde bis(dimethylacetal) (8.2 g., 0.049 mole) in 10 ml. ethanol is acidified with 10 ml. concentrated 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-hydroxy-pyrimidine-*15N2 hydrochloride, m.p. 210-212"C ., used without further purification as follows.
(b) 2-Chloropyrimidine-*15N2.-A suspension of hydroxy-pyrimidine-*15N2 hydrochloride (5.1 g., 0.038 mole) in 30 ml. phosphorus oxychloride is heated at 110"C . with stirring for a 6hr.
period. Excess phosphorus oxychloride is removed under reduced pressure and residual oil dissolved in 1 5 ml. water. The aqueous solution is treated with 10% sodium bicarbonate until slightly basic and the free base extracted with chloroform. Concentration of the dried chloroform extract provides 3.0 g. (68%) of 2-chloropyrimidine-*15N2 used without further purification in
Example 5.
EXAMPLE 5 8-C4-f4-(2-Pyrim idin yl)- 1-piperazinyl]ethyl]- 8-azaspiro[4. 5]decane- 7, 9-dione-*'5N2 Labeled (Ib)
A mixture of 2-chloropyrimidine-*15N2 (3.0 g., 0.026 mole), 8-[4-(1-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 110-120"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 produce, 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-[-(2-pyrimidinyl)-1-piperazinyl[ethyl]-8-azaspiro[4.5]decane- 7, 9-dione-*15N2 hydrochloride, m.p. 185-186 C . Mass spectral analysis of the material -indicated an 80% 15N isotopic purity.
Anal. Calcd for C2aH31N502.HCI: C, 59.55; H, 7.61; N, 16.91.
Found: C, 59.73; H, 7.60; N, 16.54
Claims (7)
1. A process for preparation of 8-4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]de- cane-7,9-dione characterized by Formula I
which comprises alkylating 8-(4-( I -piperazinyl)buIj-8-azaspirn4. 5]- decane-7, 9-dione characterized by Formula II
with a 2-halopyrimidine characterized by Formula Ill
wherein X is bromine, iodine or chlorine in a reaction inert solvent at a temperature ranging from 80-170"C.
2. The process of Claim 1 carried out in a closed reaction vessel.
3. The process of Claim 1 wherein the Formula Ill 2-halo-pyrimidine is 2-chloropyrimidine.
4. The process of Claim 1 wherein labeled 2-chloropyrimidine-*14C of formula Illa
is employed and the product is 8-4-[4-(2-pyrimidinyl)-1 -piperazinyl]-ethyl-8-azaspiro[4.5] de cane-7,9-dione-*14C of Formula la
5. The process of Claim 1 wherein labeled 2-chloropyrimidine-*15N of Formula Illa
is employed and the product is 8-E4(4(2-pyrimidinyl)-1 -piperazinylj-ethyl-8-azaspiro(4.5j decane-7,9-dione-*15N2 of Formula Ib
6. A process for making a compound as defined in claim 1 substantially as hereinbefore specifically described in the examples.
7. A compound 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 |
|---|---|
| GB2089341A true GB2089341A (en) | 1982-06-23 |
| GB2089341B GB2089341B (en) | 1984-09-19 |
Family
ID=22802113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8132370A Expired GB2089341B (en) | 1980-12-11 | 1981-10-27 | 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) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0395192A3 (en) * | 1989-04-28 | 1991-05-02 | Alkaloida Vegyeszeti Gyar | Process for the preparation of 8-(4-(4-pyrimidin-2-yl-piperazinyl)-butyl)-8-aza-spiro(4.5)decane-7,9-dione (buspiron) |
| EP0655449A1 (en) * | 1993-11-10 | 1995-05-31 | Jin Ro Limited | A process for preparing N-( 2-pyrimidyl) piperazinyl butyl imides |
| 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 |
| 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 NL NL8105529A patent/NL8105529A/en active Search and Examination
- 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
- 1981-12-09 JP JP56197037A patent/JPS57122082A/en active Granted
- 1981-12-10 AT AT0529581A patent/AT380686B/en not_active IP Right Cessation
- 1981-12-10 IE IE2897/81A patent/IE51948B1/en not_active IP Right Cessation
- 1981-12-10 DK DK548081A patent/DK154560C/en not_active IP Right Cessation
- 1981-12-10 DE DE19813149011 patent/DE3149011A1/en active Granted
- 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
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0395192A3 (en) * | 1989-04-28 | 1991-05-02 | Alkaloida Vegyeszeti Gyar | Process for the preparation of 8-(4-(4-pyrimidin-2-yl-piperazinyl)-butyl)-8-aza-spiro(4.5)decane-7,9-dione (buspiron) |
| 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 |
| EP0655449A1 (en) * | 1993-11-10 | 1995-05-31 | Jin Ro Limited | A process for preparing N-( 2-pyrimidyl) piperazinyl butyl imides |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| FI73993B (en) | 1987-08-31 |
| DK154560B (en) | 1988-11-28 |
| YU243681A (en) | 1984-02-29 |
| JPH0113476B2 (en) | 1989-03-06 |
| AU528067B2 (en) | 1983-04-14 |
| YU42432B (en) | 1988-08-31 |
| BE891446A (en) | 1982-06-11 |
| FR2496105B1 (en) | 1985-12-13 |
| IT8149718A0 (en) | 1981-11-16 |
| CA1172255A (en) | 1984-08-07 |
| FI73993C (en) | 1987-12-10 |
| DE3149011A1 (en) | 1982-07-15 |
| GR76331B (en) | 1984-08-04 |
| LU83833A1 (en) | 1982-07-07 |
| SE8107446L (en) | 1982-06-12 |
| NL8105529A (en) | 1982-07-01 |
| FR2496105A1 (en) | 1982-06-18 |
| IE51948B1 (en) | 1987-04-29 |
| ATA529581A (en) | 1985-11-15 |
| FI813937L (en) | 1982-06-12 |
| IT1172073B (en) | 1987-06-18 |
| CH647518A5 (en) | 1985-01-31 |
| IE812897L (en) | 1982-06-11 |
| DE3149011C2 (en) | 1988-08-25 |
| DK154560C (en) | 1989-04-17 |
| AU7604181A (en) | 1982-07-15 |
| AT380686B (en) | 1986-06-25 |
| SE444438B (en) | 1986-04-14 |
| GB2089341B (en) | 1984-09-19 |
| DK548081A (en) | 1982-06-12 |
| JPS57122082A (en) | 1982-07-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PE20 | Patent expired after termination of 20 years |
Effective date: 20011026 |