98224-03-4

Basic information

• Product Name: 1-(2,3-DIHYDRO-1,4-BENZODIOXIN-5-YL)-PIPERAZINE HYDROCHLORIDE
• Synonyms: 1-(2,3-DIHYDRO-1,4-BENZODIOXIN-5-YL)-PIPERAZINE HYDROCHLORIDE;ELTOPRAZINE HYDROCHLORIDE;EltoprazineHCl;1-[(2,3-Dihydro-1,4-benzodioxin)-5-yl]piperazine;5-(Piperazin-1-yl)-2,3-dihydro-1,4-benzodioxin;5-Piperazino-2,3-dihydro-1,4-benzodioxin;DU-28853;1-(2,3-DIHYDROBENZO[B][1,4]DIOXIN-5-YL)PIPERAZINE HYDROCHLORIDE
• CAS NO: 98224-03-4
• Molecular Formula: C₁₂H₁₆N₂O₂
• Molecular Weight: 256.73
• Product Categories: Pyrans, Piperidines &Piperazines;Pyrans, Piperidines & Piperazines
• Mol File: 98224-03-4.mol
• Article Data: 11

Chemical Properties

• Boiling Point: 384.3°Cat760mmHg
• Flash Point: 186.2°C
• Appearance: /
• Density: 1.18g/cm³
• Vapor Pressure: 4.13E-06mmHg at 25°C
• Storage Temp.: Store at RT
• CAS DataBase Reference: 1-(2,3-DIHYDRO-1,4-BENZODIOXIN-5-YL)-PIPERAZINE HYDROCHLORIDE(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(2,3-DIHYDRO-1,4-BENZODIOXIN-5-YL)-PIPERAZINE HYDROCHLORIDE(98224-03-4)
• EPA Substance Registry System: 1-(2,3-DIHYDRO-1,4-BENZODIOXIN-5-YL)-PIPERAZINE HYDROCHLORIDE(98224-03-4)

Safety Data

• Hazardous Substances Data: 98224-03-4(Hazardous Substances Data)

Usage

Uses

Eltoprazine is a partial agonist at SR-1 and SR-2C. Also, it is a 5-HT1A/1B receptor agonist.

Biological Activity

5-HT 1 and 5-HT 2C receptor partial agonist (K i values are 40, 52 and 81 nM for 5-HT 1A , 5-HT 1B and 5-HT 2C receptors respectively). Reduces 5-HIAA levels in the striatum and exhibits antiaggressive behavior in vivo .

InChI:InChI=1/C12H16N2O2.ClH/c1-2-10(14-6-4-13-5-7-14)12-11(3-1)15-8-9-16-12;/h1-3,13H,4-9H2;1H

Synthetic route

piperazine (110-85-0) + 5-bromo-2,3-dihydrobenzo[1,4]dioxin (58328-39-5) → eltoprazine (98224-03-4)

Conditions	Yield
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 100℃; for 4h; Sealed tube;	59%

bis-(2-chloroethyl)amine hydrochloride (821-48-7) + 1,4-benzodioxan-5-amine (16081-45-1) → eltoprazine (98224-03-4)

Conditions	Yield
In chlorobenzene Reflux;	51%
With potassium carbonate In chlorobenzene for 24h; Heating;
With sodium hydroxide In chlorobenzene
In sodium hydroxide; chlorobenzene
In sodium hydroxide; chlorobenzene

4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester → eltoprazine (98224-03-4)

Conditions	Yield
With trifluoroacetic acid In dichloromethane Ambient temperature; Yield given;

5-bromo-2,3-dihydrobenzo[1,4]dioxin (58328-39-5) → eltoprazine (98224-03-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: tri(o-tolyl)phosphine, bis(dibenzylideneacetone)palladium(O), sodium tert-butoxide / toluene / 100 °C 2: trifluoroacetic acid / CH2Cl2 / Ambient temperature View Scheme

2,3-dihydro-1,4-benzodioxine-5-carboxylic acid (4442-53-9) → eltoprazine (98224-03-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / water; acetone / 0 °C 2.1: sodium azide / water; acetone 2.2: Heating 3.1: hydrogenchloride / water / Reflux 4.1: chlorobenzene / Reflux View Scheme

C12H12O6 → eltoprazine (98224-03-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium azide / water; acetone 1.2: Heating 2.1: hydrogenchloride / water / Reflux 3.1: chlorobenzene / Reflux View Scheme

C9H7NO3 (1155139-88-0) → eltoprazine (98224-03-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / water / Reflux 2: chlorobenzene / Reflux View Scheme

2-bromoindanone (1775-27-5) + eltoprazine (98224-03-4) → 2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]-1-indanone

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h;	100%

3-(2-bromoethyl)-1H-indole (3389-21-7) + eltoprazine (98224-03-4) → 3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; potassium iodide In acetonitrile Heating;	99%

formaldehyd (50-00-0) + eltoprazine (98224-03-4) + 6,7,8,8a-tetrahydro-5H-imidazo[1,5-a]pyridine-1,3(2H,5H)-dione (4705-52-6) → 2-[[4-(2,3-dihydro-1,4-benzodioxan-5-yl)piperazin-1-yl]methyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine

Conditions	Yield
In methanol; water Mannich reaction; Heating;	88%

eltoprazine (98224-03-4) + 7-bromo-3-(4-chlorobutyl)-4-fluorobenzo[b]thiophene (522648-64-2) → 1-[4-(7-bromo-4-fluorobenzo[b]thiophen-3-yl)butyl]-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)piperazine (522649-03-2)

Conditions	Yield
With potassium carbonate; sodium iodide In acetonitrile at 80℃; for 18h;	86%

eltoprazine (98224-03-4) + 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (129722-34-5) → 7-(4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (1354030-74-2)

Conditions	Yield
Stage #1: 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone With sodium iodide In acetonitrile for 0.5h; Reflux; Stage #2: eltoprazine With potassium carbonate In acetonitrile for 4h; Reflux;	83%

4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yloxy)butyl methanesulfonate (1354030-18-4) + eltoprazine (98224-03-4) → 7-(4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazin-1-yl)butoxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

Conditions	Yield
Stage #1: 4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yloxy)butyl methanesulfonate With sodium iodide In acetonitrile for 0.5h; Reflux; Stage #2: eltoprazine With potassium carbonate In acetonitrile for 4h; Reflux;	83%

n-decanoyl chloride (112-13-0) + eltoprazine (98224-03-4) → 1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-(1-oxodecyl)piperazine (151143-81-6)

Conditions	Yield
With triethylamine In acetonitrile at 20℃; for 2h;	80%

chloroacetonitrile (107-14-2) + eltoprazine (98224-03-4) → 1-(cyanomethyl)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (161312-72-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; sodium iodide In N,N-dimethyl-formamide for 2h; Heating;	78%
With triethylamine In 1-methyl-pyrrolidin-2-one

eltoprazine (98224-03-4) + 2-chloro-ethanol (107-07-3) → 4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazineethanol

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; sodium iodide In acetonitrile for 16h; Heating;	78%

tert-butyl (2R)-2-(2-oxoethyl)pyrrolidine-1-carboxylate (916263-26-8) + eltoprazine (98224-03-4) → (R)-tert-butyl 2-{2-[4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazin-1-yl]ethyl}pyrrolidine-1-carboxylate

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran at 20℃; for 4h;	78%

n-octanoic acid chloride (111-64-8) + eltoprazine (98224-03-4) → 1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-(1-oxooctyl)piperazine

Conditions	Yield
With triethylamine In acetonitrile at 20℃; for 2h;	77%

(S)-4,5-dihydro-5-methyl-3-(2-pyridyl)-3H-[1,2,3]-oxathiazole-2,2-dioxide (174854-87-6) + eltoprazine (98224-03-4) → {(R)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propyl}pyridin-2-ylamine (187795-96-6)

Conditions	Yield
Stage #1: (S)-4,5-dihydro-5-methyl-3-(2-pyridyl)-3H-[1,2,3]-oxathiazole-2,2-dioxide; eltoprazine With potassium carbonate In acetonitrile at 55 - 60℃; for 72h; Stage #2: With hydrogenchloride at 50℃; for 6h;	77%

3-(1H-indol-3-yl)propyl methanesulfonate (116578-61-1) + eltoprazine (98224-03-4) → 3-{3-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-1H-indole

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; potassium iodide In acetonitrile for 18h; Heating;	77%
With N-ethyl-N,N-diisopropylamine; potassium iodide In acetonitrile for 18h; Heating / reflux;	77%

eltoprazine (98224-03-4) → 2-[4-(2,3-Dihydro[1,4]benzodioxin-5-yl)piperazin-1-yl]-6-methoxy-indan-1-one (222991-98-2)

Conditions	Yield
With potassium carbonate In N-methyl-acetamide; 2-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one; water	74%

eltoprazine (98224-03-4) + 3-chloro-1-(5-nitro-benzo[b]thiophen-3-yl)-propan-1-one (219907-04-7) → 1-(5-nitrobenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propan-1-one (433303-53-8)

Conditions	Yield
With potassium carbonate In tetrahydrofuran at 20℃; for 72h;	72%

eltoprazine (98224-03-4) + tert-butyl (2S)-2-(2-oxoethyl)pyrrolidine-1-carboxylate (198493-30-0) → (S)-tert-butyl 2-{2-[4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazin-1-yl]ethyl}pyrrolidine-1-carboxylate

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran at 20℃; for 4h;	72%

(R)-4,5-dihydro-5-methyl-3-(2-pyridyl)-3H-[1,2,3]-oxathiazole-2,2-dioxide + eltoprazine (98224-03-4) → {(S)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propyl}pyridin-2-ylamine (603992-48-9)

Conditions	Yield
Stage #1: (R)-4,5-dihydro-5-methyl-3-(2-pyridyl)-3H-[1,2,3]-oxathiazole-2,2-dioxide; eltoprazine With potassium carbonate In acetonitrile at 55 - 60℃; for 72h; Stage #2: With hydrogenchloride at 50℃; for 6h;	70%

eltoprazine (98224-03-4) + 3-chloro-1-(5-methylbenzo[b]thiophen-3-yl)-1-propanone (391669-08-2) → 1-(5-methylbenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propan-1-one

Conditions	Yield
With potassium carbonate In tetrahydrofuran at 20℃; for 72h;	62%

5-(4-bromobutoxy)-2-methylbenzo[d]thiazole + eltoprazine (98224-03-4) → 5-(4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazin-1-yl)-butoxy)-2-methylbenzo[d]thiazole

Conditions	Yield
Stage #1: 5-(4-bromobutoxy)-2-methylbenzo[d]thiazole With sodium iodide In acetonitrile for 0.5h; Reflux; Stage #2: eltoprazine In acetonitrile for 6h; Reflux;	61%

benzoyl chloride (98-88-4) + eltoprazine (98224-03-4) → 1-benzoyl-4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine

Conditions	Yield
With triethylamine In acetonitrile at 20℃; for 0.5h;	59%

n-valeryl chloride (638-29-9) + eltoprazine (98224-03-4) → 1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-(1-oxopentenyl)piperazine

Conditions	Yield
With triethylamine In acetonitrile at 20℃; for 2h;	57%

2-(chloromethyl)benzimidazole-4-carboxylic acid hydrochloride salt + eltoprazine (98224-03-4) → 2-[[4-(2,3-dihydro-1,4-benzodioxan-5-yl)piperazin-1-yl]methyl]benzimidazole-4-carboxylic acid (620950-02-9)

Conditions	Yield
With triethylamine In acetonitrile at 60℃; for 20h;	57%

eltoprazine (98224-03-4) + cyclohexanylcarbonyl chloride (2719-27-9) → 1-(1-cyclohexylcarbonyl)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine

Conditions	Yield
With triethylamine In acetonitrile at 20℃; for 2h;	54%

cyclohexylacetic acid chloride (23860-35-7) + eltoprazine (98224-03-4) → 1-(cyclohexylacetyl)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine

Conditions	Yield
With triethylamine In acetonitrile at 20℃; for 2h;	53%

eltoprazine (98224-03-4) + 4-(5-Fluoro-1H-3-indolyl)-cyclohexanone (185383-64-6) → 3-{(1,4-cis)-4-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-5-fluoro-1H-indole + 3-{(1,4-trans)-4-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-5-fluoro-1H-indole

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 12h;	A 53% B 27%
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane

4-(4-fluoro-1H-indol-3-yl)-cyclohexanone (282547-09-5) + eltoprazine (98224-03-4) → 3-{(1,4-cis)-4-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-4-fluoro-1H-indole + 3-{(1,4-trans)-4-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-4-fluoro-1H-indole

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 12h;	A 53% B 14%

1,2-epoxy-6-nitroindane (124369-38-6) + eltoprazine (98224-03-4) → trans-1-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperid-1-yl] 6-nitroindan-2-ol

Conditions	Yield
In acetonitrile for 4h; Heating;	52%

Upstream product

• 110-85-0 piperazine 
• 58328-39-5 5-bromo-2,3-dihydrobenzo[1,4]dioxin 
• 821-48-7 bis-(2-chloroethyl)amine hydrochloride 
• 16081-45-1 1,4-benzodioxan-5-amine 
• 1155139-88-0 5-isocyanato-2,3-dihydrobenzo[b][1,4]dioxine 
• 4442-53-9 2,3-dihydro-1,4-benzodioxine-5-carboxylic acid 

Downstream Products

• 890043-23-9 C₂₆H₃₁F₃N₂O₃ 
• 890043-25-1 C₂₅H₂₉F₃N₂O₃ 
• 349549-41-3 1-[3-(2-Chloro-phenoxy)-propyl]-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine, Oxalate 
• 349550-78-3 1-[1,4-benzodioxan-5-yl]-4-[3,4-dichlorophenylthiomethylcarbonyl]piperazine 
• 187794-52-1 3-amino-4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-2-methyl-1-phenyl-3-pyrazolin-5-one 
• 187794-64-5 5-amino-4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-3-cyclopropyl-1-phenylpyrazole 
• 187794-65-6 3,5-diamino-4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-1-phenylpyrazole 
• 187794-96-3 4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-4-methyl-2-phenyl-2-imidazolin-5-one 
• 890043-18-2 C₂₄H₂₇F₃N₂O₃ 
• 349549-69-5 1-[3-(2-Bromo-4-fluoro-phenoxy)-propyl]-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine 
• 153607-45-5 S 15931 

Relevant articles and documents

Characterization of potent and selective antagonists at postsynaptic 5- HT(1A) receptors in a series of N4-substituted arylpiperazines

Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT(1A) receptors. From the numerous arylpiperazines described in the literature, 1- (2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT(1A) receptors versus α1- , α2-, and β-adrenergic receptors, as well as dopamine D1 and D2 receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin- 6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. All compounds showed high affinity at 5-HT(1A) sites (8.10 ≤ pK(i)s ≤ 9.35), and the majority behaved as antagonists in viva in blocking the hypothermia induced by the 5-HT(1A) agonist 8-OH-DPAT in the absence of a marked effect alone at equivalent doses. An in vivo evaluation of dopamine D2 receptor antagonist properties revealed that the majority of compounds was devoid of activity at this site, in marked contrast to BMY 7378 which displayed virtually no selectivity far 5-HT(1A) versus dopamine D2 receptors. Moreover, six compounds of the present series, 8, 10, 11, 14, 25, and, 37, showed > 10-fold selectivity in vitro for 5-HT(1A) versus α1- adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pK(i) = 8.75), marked antagonist activity, and selectivity toward α1-adrenergic (81-fold) and dopamine D2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT(1A) antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT(1A) receptors.

COMPOUNDS

The present invention relates to compounds of Formula I as defined herein, and salts and solvates thereof. (I) The present invention also relates to pharmaceutical compositions comprising compounds of Formula(I), and to compounds of Formula(I) for use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which inhibition of a RAS-effector protein-protein interaction is implicated.

FUNCTIONALLY SELECTIVE LIGANDS OF DOPAMINE D2 RECEPTORS

The present invention relates to novel functionally selective ligands of dopamine D2 receptors, including agonists, antagonists, and inverse agonists. The invention further relates to the use of these compounds for treating central nervous system disorders related to D2 receptors.