87760-53-0

Basic information

• Product Name: TANDOSPIRONE
• Synonyms: TANDOSPIRONE;4,7-Methano-1H-isoindole-1,3(2H)-dione, hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-, (3aa,4b,7b,7aa)-;4,7-Methano-1H-isoindole-1,3(2H)-dione, hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-, (3aR,4S,7R,7aS)-rel- (9CI);(3αα，4β，7β，7αα)-Hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4，7-methano-1H-isoindole-1，3(2H)-dione;Sediel;3a,4,7,7a-Hexahydro-2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-4,7-methano-1H-isoindole-1,3(2H)-dione;Tandospirone [inn:ban];(3aR,4S,7R,7aS)-rel-Hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4,7-methano-1H-isoindole-1,3(2H)-dionehydrochloride
• CAS NO: 87760-53-0
• Molecular Formula: C₂₁H₂₉N₅O₂
• Molecular Weight: 383.49
• Product Categories: Serotonin receptor;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 87760-53-0.mol
• Article Data: 2

Chemical Properties

• Melting Point: 112-113.5°
• Boiling Point: 613.9 °C at 760 mmHg
• Flash Point: 325.1 °C
• Appearance: /
• Density: 1.239g/cm³
• Vapor Pressure: 5.23E-15mmHg at 25°C
• Refractive Index: 1.589
• Storage Temp.: Store at +4°C
• Solubility: DMSO: soluble38mg/mL
• PKA: 7.71±0.10(Predicted)
• CAS DataBase Reference: TANDOSPIRONE(CAS DataBase Reference)
• NIST Chemistry Reference: TANDOSPIRONE(87760-53-0)
• EPA Substance Registry System: TANDOSPIRONE(87760-53-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26
• WGK Germany: 3
• Hazardous Substances Data: 87760-53-0(Hazardous Substances Data)

Usage

Description

Tandospirone is another 5-HT1A receptor agonist under development by Sumitomo Pharmaceutical Co., Ltd., in Japan and Pfizer in the United States. Results of phase II and phase III clinical trials show that tandospirone is effective for the treatment of anxiety neurosis. Significant improvement is also observed in patients with psychosomatic disease, phobia, and depersonalization (Murasaki 1995). The results have shown that initial treatment should be started at 30 mg daily, and the dose should be increased up to 60 mg daily according to symptoms (Murasaki 1995). A double-blind comparative study with diazepam revealed that tandospirone tends to be superior to diazepam in patients with depressive neurosis, whereas diazepam may be more effective than tandospirone in severely ill patients (Murasaki et al. 1992).

Uses

Tandospirone is a 5HT1A receptor partial agonist. Studies indicate that tandospirone significantly reduces haloperidol-induced bradykinesia in a dose dependent manner. The potency of Tandospirone is equal to that of buspirone and approximate one-half that of diazepam. The potency of Tandospirone at dopamine antagonistic action is less than 1/4 that of buspirone.

Preparation

Tandospirone is attained from the exo diels-alder adduct of maleic anhydride and cyclopentadiene in a four step convergent approach.

Brand name

Sediel

Biological Activity

5-HT 1A receptor partial agonist (K i = 27 nM) that displays selectivity over 5-HT 2 , 5-HT 1C , α 1 , α 2 , D 1 and D 2 receptors (K i values ranging from 1300-41000 nM). Inactive at 5-HT uptake sites, 5-HT 1B , β -adrenergic, muscarinic and benzodiazepine receptors. Displays anxiolytic activity.

references

[1] shimizu h1, hirose a, tatsuno t, nakamura m, katsube j. pharmacological properties of sm-3997: a new anxioselective anxiolytic candidate. jpn j pharmacol. 1987 dec; 45(4):493-500.

InChI:InChI=1/C21H29N5O2/c27-19-17-15-4-5-16(14-15)18(17)20(28)26(19)9-2-1-8-24-10-12-25(13-11-24)21-22-6-3-7-23-21/h3,6-7,15-18H,1-2,4-5,8-14H2/t15-,16+,17+,18-

Synthetic route

(1R*,2S*,3R*,4S*)-N-<4-<4-(2-Pyrimidinyl)-1-piperazinyl>-2-butynyl>-2,3-bicyclo<2.2.1>heptanedicarboximide (120596-77-2) → tandospirone (87760-53-0)

Conditions	Yield
With hydrogen; palladium on activated charcoal In tetrahydrofuran for 1.5h; Ambient temperature;	88.6%

N-(2-pyridinyl)piperazine (20980-22-7) + (1R,2S,3R,4S)-N-(4-bromobutyl)-2,3-bicyclo<2.2.1>heptanedicarboximide (99095-09-7) → tandospirone (87760-53-0)

Conditions	Yield
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 90℃; for 1h;	81.3%

exo-bicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (14166-28-0) + 1-(pyrimidin-2-yl)-4-(4-aminobutyl)piperazine (33386-20-8) → tandospirone (87760-53-0)

Conditions	Yield
In pyridine Heating;	59%

1,4-dibromo-butane (110-52-1) + N-(2-pyridinyl)piperazine (20980-22-7) + (3aR,4S,7R,7aS)‑4,7‑methylene‑1H‑isoindole‑1,3(2H)-dione (14805-29-9) → tandospirone (87760-53-0)

Conditions	Yield
With potassium carbonate; benzyltriethylammonium bromide 1.) toluene, reflux, 4 h, 2.) reflux, 5 h; Yield given. Multistep reaction;

8-(2-Pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane Bromide (81461-73-6) + (3aR,4S,7R,7aS)‑4,7‑methylene‑1H‑isoindole‑1,3(2H)-dione (14805-29-9) → tandospirone (87760-53-0)

Conditions	Yield
With potassium carbonate; 18-crown-6 ether In xylene for 6h; Heating;

N-(2-pyridinyl)piperazine (20980-22-7) + methyl halide → tandospirone (87760-53-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 25percent aq. NaOH / acetone / Ambient temperature 2: LiAlH4 / diethyl ether / -10 °C 3: 59 percent / pyridine / Heating View Scheme

N-Propargylbicyclo<2.2.1>heptane-2,3-di-exo-carboximide (105981-36-0) → tandospirone (87760-53-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 99.3 percent / copper sulfate / dioxane; H2O / 1.17 h / 70 - 80 °C 2: 88.6 percent / H2 / 10percent Pd/C / tetrahydrofuran / 1.5 h / Ambient temperature View Scheme

(3aR,4S,7R,7aS)‑4,7‑methylene‑1H‑isoindole‑1,3(2H)-dione (14805-29-9) → tandospirone (87760-53-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90.2 percent / K2CO3 / acetone / 7 h / Heating 2: 81.3 percent / K2CO3, KI / dimethylformamide / 1 h / 90 °C View Scheme
Multi-step reaction with 3 steps 1: 91 percent / K2CO3 / acetone / 1 h / Heating 2: 99.3 percent / copper sulfate / dioxane; H2O / 1.17 h / 70 - 80 °C 3: 88.6 percent / H2 / 10percent Pd/C / tetrahydrofuran / 1.5 h / Ambient temperature View Scheme

(1R,2R,6S,7S)-4-oxa-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (2746-19-2) → tandospirone (87760-53-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95.9 percent / H2 / 10percent Pd-C/ 50percent H2O / tetrahydrofuran / 1.5 h / Ambient temperature 2: 59 percent / pyridine / Heating View Scheme
Multi-step reaction with 4 steps 1: 95.9 percent / H2 / 10percent Pd-C/ 50percent H2O / tetrahydrofuran / 1.5 h / Ambient temperature 2: 80.5 percent / 7percent aq. NH3 / tetrahydrofuran / 2 h / 190 °C 3: 90.2 percent / K2CO3 / acetone / 7 h / Heating 4: 81.3 percent / K2CO3, KI / dimethylformamide / 1 h / 90 °C View Scheme
Multi-step reaction with 5 steps 1: 95.9 percent / H2 / 10percent Pd-C/ 50percent H2O / tetrahydrofuran / 1.5 h / Ambient temperature 2: 80.5 percent / 7percent aq. NH3 / tetrahydrofuran / 2 h / 190 °C 3: 91 percent / K2CO3 / acetone / 1 h / Heating 4: 99.3 percent / copper sulfate / dioxane; H2O / 1.17 h / 70 - 80 °C 5: 88.6 percent / H2 / 10percent Pd/C / tetrahydrofuran / 1.5 h / Ambient temperature View Scheme

exo-bicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (14166-28-0) → tandospirone (87760-53-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80.5 percent / 7percent aq. NH3 / tetrahydrofuran / 2 h / 190 °C 2: 90.2 percent / K2CO3 / acetone / 7 h / Heating 3: 81.3 percent / K2CO3, KI / dimethylformamide / 1 h / 90 °C View Scheme
Multi-step reaction with 4 steps 1: 80.5 percent / 7percent aq. NH3 / tetrahydrofuran / 2 h / 190 °C 2: 91 percent / K2CO3 / acetone / 1 h / Heating 3: 99.3 percent / copper sulfate / dioxane; H2O / 1.17 h / 70 - 80 °C 4: 88.6 percent / H2 / 10percent Pd/C / tetrahydrofuran / 1.5 h / Ambient temperature View Scheme

4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyronitrile (33386-14-0) → tandospirone (87760-53-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: LiAlH4 / diethyl ether / -10 °C 2: 59 percent / pyridine / Heating View Scheme

tandospirone (87760-53-0) + maleic acid (110-16-7) → tandospirone maleic acid

Conditions	Yield
In ethanol; water at 70℃; Temperature; Solvent; Large scale;	99.9%

tandospirone (87760-53-0) → (3aα,4β,7β,7aα)-hexahydro-2-[4[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4,7-methano-1H-isoindole-1,3(2H)-dione sulfate

Conditions	Yield
With sulfuric acid In diethyl ether; acetone at 45℃; Solvent; Temperature;	99.7%

tandospirone (87760-53-0) + citric acid (77-92-9) → tandospirone citrate (112457-95-1)

Conditions	Yield
In diethyl ether; acetone Heating;	99%
In ethyl acetate at 20℃; for 2h; Solvent; Temperature;	95%

tandospirone (87760-53-0) → (1R*,2S*,3R*,4S*)-5-Hydroxy-4-<4-<4-(2-pyrimidinyl)-1-piperazinyl>butyl>-4-azatricyclo<5.2.1.02.6>decan-3-one (138273-97-9)

Conditions	Yield
With sodium hydroxide; sodium tetrahydroborate In water; isopropyl alcohol for 2h; Heating;	72.9%

tandospirone (87760-53-0) → (1R*,2S*,3R*,4S*)-4-<4-<4-(2-Pyrimidinyl)-1-piperazinyl>butyl>-4-azatricyclo<5.2.1.02.6>decane (138273-98-0)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran for 2.5h; Ambient temperature;	68.9%

Upstream product

• 110-52-1 1,4-dibromo-butane 
• 20980-22-7 N-(2-pyridinyl)piperazine 
• 14805-29-9 (3aR,4S,7R,7aS)?4,7?methylene?1H?isoindole?1,3(2H)-dione 
• 99095-09-7 (1R,2S,3R,4S)-N-(4-bromobutyl)-2,3-bicyclo<2.2.1>heptanedicarboximide 
• 33386-14-0 4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyronitrile 
• 14166-28-0 exo-bicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride 
• 2746-19-2 (1R,2R,6S,7S)-4-oxa-tricyclo[5.2.1.0^2,6]dec-8-ene-3,5-dione 
• 105981-36-0 N-Propargylbicyclo<2.2.1>heptane-2,3-di-exo-carboximide 
• 33386-20-8 1-(pyrimidin-2-yl)-4-(4-aminobutyl)piperazine 
• 81461-73-6 8-(2-Pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane Bromide 
• 120596-77-2 (1R*,2S*,3R*,4S*)-N-<4-<4-(2-Pyrimidinyl)-1-piperazinyl>-2-butynyl>-2,3-bicyclo<2.2.1>heptanedicarboximide 

Downstream Products

• 112457-95-1 tandospirone citrate 

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An efficient synthesis of buspirone and its analogues

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