CA1172255A - Buspirone process - Google Patents

Buspirone process

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Publication number
CA1172255A
CA1172255A CA000386889A CA386889A CA1172255A CA 1172255 A CA1172255 A CA 1172255A CA 000386889 A CA000386889 A CA 000386889A CA 386889 A CA386889 A CA 386889A CA 1172255 A CA1172255 A CA 1172255A
Authority
CA
Canada
Prior art keywords
formula
azaspiro
dione
decane
labeled
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.)
Expired
Application number
CA000386889A
Other languages
French (fr)
Inventor
Robert R. Covington
Davis L. Temple, Jr.
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Co
Original Assignee
Bristol Myers Co
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Filing date
Publication date
Application filed by Bristol Myers Co filed Critical Bristol Myers Co
Application granted granted Critical
Publication of CA1172255A publication Critical patent/CA1172255A/en
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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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

BUSPIRONE PROCESS

Abstract of the Invention A new process for the preparation of buspirone is described wherein the 2-pyrimidinyl component thereof is introduced in a final alkylation step involving 2-halopyrimidines. Radioactive labeled buspirone can be conveniently and economically obtained according to the process by employing labeled 2-halopyrimidines such as 2-chloro-pyrimidine-14C and 2-chloropyrimidine-15N2.

Description

1~7~5S

BUSPIRONE PROCESS

Description of the Prior Art Yao Hua Wu, et al., U,S. Patent No. 3,717,63'1 disclose synthesis of N-(heteroarcyclic)piperazinvlalkylazaspiroalkanediones 5 of Formula I

~N- A-N N-B

Formula I

by the following methods.
METHOD A
o ~O + H2N-A-N N-B ~ Formula I

Formula II Formula III

1~72~S5 ~IETHOD B
o A-X + B-N~N-B ~ Formula I

Formula IV Formulz V

METHOD C

(~R~ N-N + X-A-N N-B ~ Form~

Formula VI Formula VII

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 instant process differs from methods of Wu, et al., U.S. 3,717,634 in that the 2-pyrimidinyl fragment is introduced as a final step by direct alkylation of preformed 8-[4-(1-piperazinyl)-butyl]-8-azaspiro~4.5]decane-7,9-dione with a 2-halopyrimidine.

" . .

~7Z;~SS
Su~mary of the Inven~ion Broadly described, this invention is concerned with a process for preparation of the pyrimidine compound 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-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 carbon (14C) and stable lSnitrogen (15N) isotopes in specified positions oE the pyrimidinyl eomponent of buspirone. Labeled buspirone is useful in elinical investigation of the absorption and metabolic disposition of this anxiolytic agent.

Detailed Deseription of the Invention The instant invention relates to a proeess for preparation of 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-2zaspiro[4.5]-deeane-7,9-dione eharacterized by Formula I

-(CH2)4-N 3 - (I) whieh eomprises alkylating 8-[4-(1-piperazinyl)butyl]-8-azaspiro[4.5]-deeane-7,9-dione eharaeterized by Formula II

1~72255 ~(CH2)4N NH

(II) with a 2-halopyrimidine characterized by Formula III

X~

(III) wherein X is bromine, iodine or preferably chlorine in a reaction inert solvent at a temperature ranging from 80-170C., preferably in a closed reaction vessel.
The foregoing process is particularly adz.ptable 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 (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 III is 2-chloropyrimidine labeled in the 2 position with 14carbon isotope;
the compou~d of 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 i~7;~55 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 oxyh~lide such as phosphorus oxychloride or phcsphorus oxybromide. By way of illus-tration, the sequence starting with urea-14C for preparation of
2-chloropyrimidine- 1 C (IIIa) is depicted belcw.

~ /NH2 / CH(OCH3)2 HCl ~ N
O=C\ + 2\ ~ \ ~ OH HCl NH2 CH(OCH3)2 EtOH \~=:N
POC13 e ~ Cl (IIIa) The identical sequence starting with urea-15~2 affords 2-chloro-pyrimidine- 5N2 (IIIb) ~ ~ Cl *

(IIIb) 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 80C. to about 170C. is operable, with the preferred temperature being in the range of ~rom 110C. to 120C. Higher and lower tempera-tures may be used, but at a reaction temperature below 80C. the ~7~2~55 reaction is undulv prolonged and adequate condensation does not occur whereas if the reaction temperature exceeds 170C. the reactants tend to undergo decomposition i-o 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-piperazinvl)-butyl~-8-azaspiro[4.53decane-7!9-dione reactant (II). In this regard a tertiary amine such as triethylamine is preferred.
10The process of this invention is further illustrated by the f ollowing examples which are not to be construed as limiting the scope of the present invention.

EYA~PLE 1 Preparation of 8-~4-(1-Piperazinyl)butyl-8-azaspiro[4.5]decane-7,9-dione (II) o ~ ~ 2)4 ~ ~

(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 ~7~2S5 b.p. 165-170C 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-(1-Piperazinyl)butyl-8-azaspiro[~.5]decane-7,9-dione.-A mixture of 8-(4-bromobutyl)-3-azaspiro[4.5]decane-7,9-dione (32.0 g., 0.105 mole), piperazine (50 g., 0.58 mole), and micropu]verized potassium carbonate (80.0 g., 0.58 mole) in 500 ml. 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. ~xcess piperazine, which separates as the hydrochloride, is collected and the filtrate concen-trated under reduced pressure. Distillation of residual oil under reduced pressure affords 13.5 g. (42%) of 8-[4-(1-piperazinyl)butyl-8-azaspiro[4.5]decane-7,9-dione, b.p. 180-200C. at 0.1 mm Hg as the free base.
lS 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.
235-237C.
Anal- Calcd- for C17H19~32 2HCl 1/4H20 C~ 53-06;
20 H, 8.25; N, 10.92. Found: C, 53.06; H, 8.05; N, 10.96.

~72255 E~'~LE 2 Preparation of Labeled 2-Chloropyrimidine 1 C (IIIa) Cl ~,~3 (a) ~-Hydroxypyrimidine C Labeled) hydrochloride.- A
solution of urea (165 mg., 0.002 mole) containing urea-14C (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 ch;lled. The yellow preci-pitated product is collected to afford 274 mg. (77%) of 2-chloro-pyrimidine 1 C used without further purification as follows.
(b) 2-Chloropyrimidine- C labeled).- A mixture of 2-hydroxypyrimidine 14C hydrochloride (274 mg., 0.002 mole) and lO ml. of phosphorus oxychloride is heated at 110C. 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-20 pyrimidine- 14C (190 mg., 83%) used without furth~r purificiation in Example 3.

~7Z255 E~UMPLE 3 8-[4-[4-(2-Pyrimidinyl)-l-piperazinyl]ethyl-8-azaspiro[4.5]decane-7,9-dione- C Labeled (Ia) o ~ -(CH2)4-N ~ ~ ~

A mixture of the 2-chloropyrimidine- l C (190 mg., 0.0016 mole) from Example 2, 8-[~-(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 m].. ethanol is heated at 110-120C. 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 125 mg.
(35~) of free base product radiochemically pure according to thin layer chromatography developed in two separatè solvent systems 20 [CHC13-EtOH (4:1) and CHC13-MeOH-HOAc (10:3:1)] and scanned with a Varian Aerograph-Berthold Radioscanner. Specific activity of the _ g _ 1~L7~2S~
8-[$-~4-(~-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-~,9-dione- l C labeled product is generally about 20 microcurie/mg.
~ nal- Calcd- for C21H31N502: C, 65.43; H, 8.11; N, 18.17.
Found: C, 65.60; H, 8.10; N, 18.24.
EX~LE 4 Preparation of Labeled 2-Chlo_opyrimidine- N2 (IIIb) N
Cl - ~ ~

(a) 2-Hydroxypyrimidine Hydrochloride- 5N2.- A solution of urea-15N2 (3.0 g., 0.049 mole; 90 atom % 15N) and malonaldehyde 10 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-hydro~-pyrimidine- lSN2 hydrochloride, m.p. 210-212C., used without further purification as follows.

(b) ~ s ~ e- I~N2.- A suspension of hydroxy-pyrimidine- 15N2 hydrochloride (5.1 g., 0.038 mole) in 30 ml. phosphorus oxychloride is heated at 110C. 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 Witil 10% sodium bicarbonate until slightly basic and the free base extracted with chloroform. Concentration of the dried chloroform ~7i2ZSS

e~tract provides 3.0 g. (G8,',) of 2-chloropyrimidine- 15N2 used ~ithoue rurther purification in E~ample 5.

EX~PLE 5 8-[4-[4-(2-Pyrimidinyl)-l-piperazinyl]ethyl]-58-azaspiro[4.5]decane-7,9-dione- 15N Labeled (Ib) ~,N-(CN2)4-N

A mixture of 2-chloropyrimidine- ~2 (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 110-120C. in a sealed reaction vessel for a 72 hr. period. After cooling, th~ reaction mixture is concentrated under reduced pressure and r~sidual oil taken up in hot isopropanol.
On cooling, a solid separates which is collected to afford 7;0 g.
(70%) of product, m.p. 101-102C. 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)-l-piperazinyl[ethyl]-8-azaspiro[4.5]decane-7,9-dione- 5N2 hydrochloride, m.p. 185-186C. Mass spectral analysis of the material indicated an 80% l5N lsotopic purity.

Anal. Calcd for C21H31N 0 HCl: C, 59.55; H, 7-61; N, 16-91-20 Found: C, 59.73; H, 7.60; N, 16.54.

Claims (5)

WHAT IS CLAIMED IS:
1. A process for preparation of 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione characterized by Formula I

(I) which comprises alkylating 8-[4-(1-piperazinyl)butyl]-8-azaspiro[4.5]-decane-7,9-dione characterized by Formula II

(II) with a 2-halopyrimidine characterized by Formula III

(III) 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 III 2-halo-pyrimidine is 2-chloropyrimidine.
4. The process of Claim 1 wherein labeled 2-chloropyrimidine-*14C
of Formula IIIa (IIIa) is employed and the product is 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-ethyl-8-azaspiro[4.5]decane-7,9-dione-*14C of Formula Ia (Ia)
5. The process of Claim 1 wherein labeled 2-chloropyrimidine-*15N

of Formula IIIa (IIIa) is employed and the product is 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-ethyl-8-azaspiro[4.5]decane-7,9-dione-*15N2 of Formula Ib (Ib)
CA000386889A 1980-12-11 1981-09-29 Buspirone process Expired CA1172255A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21521480A 1980-12-11 1980-12-11
US215,214 1980-12-11

Publications (1)

Publication Number Publication Date
CA1172255A true CA1172255A (en) 1984-08-07

Family

ID=22802113

Family Applications (1)

Application Number Title Priority Date Filing Date
CA000386889A Expired CA1172255A (en) 1980-12-11 1981-09-29 Buspirone process

Country Status (18)

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JP (1) JPS57122082A (en)
AT (1) AT380686B (en)
AU (1) AU528067B2 (en)
BE (1) BE891446A (en)
CA (1) CA1172255A (en)
CH (1) CH647518A5 (en)
DE (1) DE3149011A1 (en)
DK (1) DK154560C (en)
FI (1) FI73993C (en)
FR (1) FR2496105B1 (en)
GB (1) GB2089341B (en)
GR (1) GR76331B (en)
IE (1) IE51948B1 (en)
IT (1) IT1172073B (en)
LU (1) LU83833A1 (en)
NL (1) NL8105529A (en)
SE (1) SE444438B (en)
YU (1) YU42432B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU212301B (en) * 1989-04-28 1996-05-28 Alkaloida Vegyeszeti Gyar Process for producing buspirone
US5631017A (en) * 1993-03-26 1997-05-20 Beth Israel Deaconess Medical Center, Inc. Topical application of buspirone for treatment of pathological conditions associated with immune responses
US5484788A (en) * 1993-03-26 1996-01-16 Beth Israel Hospital Association Buspirone as a systemic immunosuppressant
KR950014099A (en) * 1993-11-10 1995-06-15 장기하 Method for preparing N- (2-pyrimidyl) piperazinyl butylamide
US5637314A (en) * 1995-06-07 1997-06-10 Beth Israel Deaconess Medical Center, Inc. Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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

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FR2496105A1 (en) 1982-06-18
YU243681A (en) 1984-02-29
FI73993B (en) 1987-08-31
GB2089341B (en) 1984-09-19
GB2089341A (en) 1982-06-23
FR2496105B1 (en) 1985-12-13
DE3149011C2 (en) 1988-08-25
JPH0113476B2 (en) 1989-03-06
SE444438B (en) 1986-04-14
SE8107446L (en) 1982-06-12
GR76331B (en) 1984-08-04
CH647518A5 (en) 1985-01-31
FI813937L (en) 1982-06-12
IE812897L (en) 1982-06-11
DK154560C (en) 1989-04-17
AU528067B2 (en) 1983-04-14
IT1172073B (en) 1987-06-18
NL8105529A (en) 1982-07-01
IT8149718A0 (en) 1981-11-16
DK154560B (en) 1988-11-28
BE891446A (en) 1982-06-11
JPS57122082A (en) 1982-07-29
AT380686B (en) 1986-06-25
FI73993C (en) 1987-12-10
DK548081A (en) 1982-06-12
IE51948B1 (en) 1987-04-29
YU42432B (en) 1988-08-31
LU83833A1 (en) 1982-07-07
AU7604181A (en) 1982-07-15
ATA529581A (en) 1985-11-15
DE3149011A1 (en) 1982-07-15

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