87760-53-0

Usage

Uses

Used in Pharmaceutical Industry:
Tandospirone is used as an anxiolytic agent for the treatment of anxiety neurosis. It has been shown to be effective in phase II and phase III clinical trials, providing significant improvement in patients with psychosomatic disease, phobia, and depersonalization.
Used in Neurological Applications:
Tandospirone is used as a treatment for patients with depressive neurosis. 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.
Used in Neurological Disorders Research:
Tandospirone is used as a 5HT1A receptor partial agonist in studies investigating its potential to reduce haloperidol-induced bradykinesia in a dose-dependent manner. Its potency in dopamine antagonistic action is less than 1/4 that of buspirone, making it a valuable compound for research into neurological disorders and their treatments.

Preparation

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

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 
• 81461-73-6 8-(2-Pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane Bromide 
• 2746-19-2 (1R,2R,6S,7S)-4-oxa-tricyclo[5.2.1.0^2,6]dec-8-ene-3,5-dione 
• 14166-28-0 exo-bicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride 
• 33386-14-0 4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyronitrile 
• 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 
• 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 

Relevant academic research and scientific papers

Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*,2S*3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3-b icyclo[2.2.1]heptanedicarboxime (Tandospirone) and related compounds

A series of cyclic imides bearing a ω-(4-aryl and 4-heteroaryl-1-piperazinyl)alkyl moieties was synthesized and tested in vivo for anxiolytic activity. The in vitro binding affinities of these compounds were also examined for 5-HT(1A) receptor sites. Structure-activity relationships within these series are discussed. One of these compounds, (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3- bicyclo[2.2.1]heptanedicarboximide (1: tandospirone), was found to be equipotent with buspirone in its anxiolytic activity and more anxio-selective than buspirone and diazepam. Tandospirone (1) is currently undergoing clinical evaluation as a selective anxiolytic agent.