33386-08-2

Basic information

• Product Name: Buspirone hydrochloride
• Synonyms: 8-[4-[4-(2-PYRIMIDINYL)-1-PIPERAZINYL]BUTYL]-8-AZASPIRO[4,5]DECANE-7,9-DIONE HYDROCHLORIDE;BUSPIRONE HCL;BUSPIRONE HYDROCHLORIDE;N-[4-(4-[2-PYRIMIDINYL]-1-PIPERAZINYL)BUTYL]-8-AZASPIRO[4,5]DECANE-7,9-DIONE HYDROCHLORIDE;1-cyclopentanediacetimide,n-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-h;8-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-8-azaspiro(4.5)decane-9-dione;axoren;bespar
• CAS NO: 33386-08-2
• Molecular Formula: C₂₁H₃₁N₅O₂*ClH
• Molecular Weight: 421.96
• EINECS: 251-489-4
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Serotonin receptor;Inhibitors
• Mol File: 33386-08-2.mol

Chemical Properties

• Melting Point: 201.5-202.50C
• Boiling Point: 613.9 °C at 760 mmHg
• Flash Point: 9℃
• Appearance: white solid
• Density: 1.24g/cm3
• Vapor Pressure: 5.24E-15mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: Freely soluble in water and in methanol, practically insoluble in acetone.
• Water Solubility: Soluble in methanol (50 mg/ml), water (partly), DMSO (100 mM).
• CAS DataBase Reference: Buspirone hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Buspirone hydrochloride(33386-08-2)
• EPA Substance Registry System: Buspirone hydrochloride(33386-08-2)

Safety Data

• Hazard Codes: T,Xn,F
• Statements: 25-36/37/38-20/21/22-39/23/24/25-23/24/25-11
• Safety Statements: 45-36-26-36/37-16
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• RTECS: CL9915000
• HazardClass: 6.1
• Hazardous Substances Data: 33386-08-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Buspirone hydrochloride is used as a pharmaceutical secondary standard for quality control in pharmaceutical laboratories and manufacturing. It provides a convenient and cost-effective alternative to the preparation of in-house working standards.
Used in Medical Treatment:
Buspirone hydrochloride is used as an anxiolytic agent for the treatment of anxiety disorders. It acts as a serotonin receptor agonist, specifically targeting the 5-HT1 receptors, which helps in managing anxiety without the sedative and muscle relaxant side effects associated with benzodiazepines.
Used in Research and Development:
Buspirone hydrochloride is used as a research compound for studying the effects of 5-HT1 receptor agonists on anxiety and related disorders. This helps in the development of new treatments and a better understanding of the underlying mechanisms of anxiety and depression.

Originator

Mead Johnson (USA)

Manufacturing Process

There is the 3 methods for preparing of 8-azaspiro(4.5)decane-7,9-dione, 8- (4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl) monohydrochloride (U.S. Patent 3,717,634). One of them is follows: a mixture of 0.1 mole of the substituted glutaric anhydride, 0.1 mole of l-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (U.S. Pat. 3,398151), and 300 ml of pyridine was refluxed until imide formation was completed. The degree of reaction was readily followed by taking an aliquot portion of the reaction mixture, removing the solvent, and obtaining the infrared absorption spectrum of the residue. When reaction is complete, the spectrum exhibited typical infrared imide bands at 1701 and 1710 cm-1 whereas if incomplete, the infrared spectrum contains amide and carboxyl absorption bands at 1680, 1760 and 3300 cm-1. 1-(3-Cyanopropyl)-4-(2-pyrimidinyl)-piperazine. A mixture of 1-(2- pyrimidinyl)piperazine (6.0 g, 0.04 mole), 4.6 g (0.044 mole) of 3- chloropropionitrile and sodium carbonate (4.24 g, 0.04 mole) in 50 ml of nbutanol was gently refluxed for 16 hours. The reaction mixture was concentrated in vacuo and the residual oil dissolved in about 100 ml of cyclohexane. On standing a white crystalline material separated which was crystallized from cyclohexane to provide 6.5 g (yield 70%) of the cyano intermediate, m.p. 56.6-58°C. A solution of 11.5 g (0.05 mole) of 1-(3- cyanopropyl)-4-(2-pyrimidinyl)piperazine in 150 ml of absolute ethanol was saturated with ammonia. W-6 Raney nickel catalyst was added and the mixture hydrogenated under 1200 p.s.i. When the hydrogenation was completed the mixture was filtered and the residual oil distilled under reduced pressure to provide 8.2 g (70% ) of 1-(4-aminobutyl)-4-(2- pyrimidinyl)piperazine, b.p. 143-146°C at 0.1 mm. (nD 26 = 1.5582). The azospiroalkenedione 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8- azaspiro[4.5]decane-7,9-dione was purified as free base by stripping off the pyridine solvent and crystallizing the residue from a suitable solvent or by vacuum distillation thereof hydrochloric salt of it was prepared by treating of an ethanol solution of free base with equimolar amount of HCl.

Therapeutic Function

Anxiolytic

Biological Activity

Classic 5-HT 1A partial agonist with relatively high affinity (K i = 9.3 - 29.5 nM). A clinically effective anxiolytic.

Biochem/physiol Actions

5-HT1A serotonin receptor agonist; anxiolytic.

Clinical Use

Anxiolytic

Veterinary Drugs and Treatments

Buspirone may be effective in treating certain behavior disorders in dogs and cats, principally those that are fear/phobia related and especially those associated with social interactions. Buspirone may also be useful for urine spraying or treatment of motion sickness in cats.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration increased by erythromycin - reduce dose; concentration reduced by rifampicin. Antidepressants: avoid with tranylcypromine; risk of severe hypertension with MAOIs - avoid. Antifungals: concentration increased by itraconazole - reduce dose. Antipsychotics: enhanced sedative effects; haloperidol concentration increased. Antivirals: concentration increased by ritonavir, increased risk of toxicity. Calcium-channel blockers: concentration increased by diltiazem and verapamil - reduce dose. Grapefruit juice: concentration increased by grapefruit juice - reduce dose. Methylthioninium: possible risk of CNS toxicity - avoid if possible.

Metabolism

Systemic bioavailability of buspirone is low because of extensive first-pass metabolism. Metabolism in the liver is extensive via the cytochrome P450 isoenzyme CYP3A4; hydroxylation yields several inactive metabolites and oxidative dealkylation produces 1-(2-pyrimidinyl)- piperazine, which is reported to be about 25% as potent as the parent drug in one model of anxiolytic activity. Buspirone is excreted mainly as metabolites in the urine, and also the faeces.

InChI:InChI=1/C21H31N5O2/c27-18-16-21(6-1-2-7-21)17-19(28)26(18)11-4-3-10-24-12-14-25(15-13-24)20-22-8-5-9-23-20/h5,8-9H,1-4,6-7,10-17H2/p+1

Upstream product

• 94021-22-4 1-(2-pyrimidyl)piperazine dihydrochloride 
• 1359159-58-2 8-(4,4-dimethoxybutyl)-8-azaspiro[4.5]decane-7,9-dione 
• 1075-89-4 tetramethylene glutarimide 
• 110-52-1 1,4-dibromo-butane 
• 20980-22-7 N-(2-pyridinyl)piperazine 

Relevant articles and documents

An efficient synthesis of aripiprazole, buspirone and NAN-190 by the reductive alkylation of amines procedure

The reductive alkylation of amines procedure was applied for the synthesis of aripiprazole 1a, buspirone 1b, and NAN-190 1c. The reductive alkylation of amines procedure was applied for the synthesis of aripiprazole 1a, buspirone 1b, and NAN-190 1c. Copyright

The preparation of 8-[4-[4-(2-pyrimidinyl)-1-piperaziny]butyl]-8- azaspiro[4,5] decane-7,9-dione hydrochloride

8-[4-[4-(2-Pyrimidinyl)-1-piperaziny]butyl]-8-azaspiro [4,5] decane-7,9-dione hydrochloride (buspirone hydrochloride) was obtained in one pot with a 51.8% overall yield. The key intermediate, 1-(2-pyrimidinyl) piperazine, was synthesized through chlorination and cyclization condensation reaction with diethanolamine as initial material. This modified protocol has the notable advantages of mild reaction condition, convenient operation, and high overall yield.

Process for the preparation of high purity buspiron and the hydrochloride thereof

Process for the preparation of 8 -[4 -[4-(pyrimidine-2-yl)-piperazine-1-yl]-butyl]-8-aza-spiro[4.5]decane-7,9-dione (buspiron) of the Formula I STR1 and the hydrochlorides thereof having high purity by continuously adding a solution of 8-[4-[4-(pyrimidine-2-yl)-piperazine-1-yl]-but-2 -inyl]-8-aza-spiro[4.5]decane-7,9-dione of the formula II STR2 formed with an inert organic solvent having a concentration of at least 40% by weight to a suspension of a hydrogenation catalyst in an inert organic solvent and optionally converting the 8-[4-[4-(pyrimidine-2-yl)-piperazine-1-yl]-butyl]-8-aza-spiro[4.5]decane-7,9-dione thus obtained into the hydrochloride thereof.

Pharmaceutically useful polymorphic modification of buspirone

Buspirone hydrochloride can exist in two polymorphic forms and the newly discoverd lower melting form, which is thermodynamically favored at pharmaceutically relevant temperatures, offers advantage in manufacture of buspirone pharmaceutical compositions .

Process for buspirone hydrochloride polymorphic crystalline form conversion

A process for conversion of one polymorphic crystalline form of buspirone into its other polymorphic crystalline form.

Spiro-quaternary ammonium halides and N-(2-pyrimidinyl)piperazinylalkylazaspiroalkanedione process

Novel spiro-quaternary ammonium halides are disclosed. The new compounds are particularly valuable as intermediates in preparation of N-(2-pyrimidinyl)piperazinylalkyl derivatives of azaspiroalkanediones such as the psychopharmacologic agent 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione.