70918-00-2

Basic information

• Product Name: 1-(1,4-Benzodioxane-2-carbonyl)piperazine
• Synonyms: (2,3-DIHYDROBENZO[B][1,4]DIOXIN-3-YL) (PIPERAZIN-1-YL)METHANONE;(2,3-DIHYDRO-BENZO[1,4]DIOXIN-2-YL)-PIPERAZIN-1-YL-METHANONE;2,3-DIHYDRO-1,4-BENZODIOXIN-2-YL(PIPERAZINO)METHANONE;1-[(2,3-DIHYDRO-1,4-BENZODIOXAN-2-YL)CARBONYL]PIPERAZINE;N-[(1,4-BENZODIOXAN-2-YL)CARBONYL]PIPERAZINE;N-[(1,4-BENZODIOXANE-2-YL)CARBONYL]PIPERAZINE;1,4-BENZODIOXAN-2-CARBOXYPIPERAZINE;2,3-Dihydro-1,4-Benzodioxan-2Yl-
• CAS NO: 70918-00-2
• Molecular Formula: C₁₃H₁₆N₂O₃
• Molecular Weight: 248.28
• EINECS: 415-660-9
• Product Categories: Aromatics;Heterocycles
• Mol File: 70918-00-2.mol
• Article Data: 11

Chemical Properties

• Melting Point: 103.0 to 107.0 °C
• Boiling Point: 437.2 °C at 760 mmHg
• Flash Point: 218.2 °C
• Appearance: /
• Density: 1.246 g/cm³
• Vapor Pressure: 7.62E-08mmHg at 25°C
• Solubility: soluble in Methanol
• PKA: 8.32±0.10(Predicted)
• CAS DataBase Reference: 1-(1,4-Benzodioxane-2-carbonyl)piperazine(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(1,4-Benzodioxane-2-carbonyl)piperazine(70918-00-2)
• EPA Substance Registry System: 1-(1,4-Benzodioxane-2-carbonyl)piperazine(70918-00-2)

Safety Data

• Hazard Codes: Xi,N,T
• Statements: 23/24/25-48/22-51/53
• Safety Statements: 53-45-61
• HazardClass: IRRITANT
• Hazardous Substances Data: 70918-00-2(Hazardous Substances Data)

Usage

Chemical Properties

White or light brown powder

InChI:InChI=1/C13H16N2O3/c16-13(15-7-5-14-6-8-15)12-9-17-10-3-1-2-4-11(10)18-12/h1-4,12,14H,5-9H2/p+1/t12-/m1/s1

Synthetic route

piperazine (110-85-0) + 1,4-benzodioxane-2-carboxylic acid (3663-80-7, 34385-93-8, 70918-53-5, 70918-54-6) → (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions	Yield
Stage #1: 1,4-benzodioxane-2-carboxylic acid With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 0 - 5℃; for 0.25h; Stage #2: piperazine With pyridine In dichloromethane at 20℃; for 0.5h;	96%
With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In dichloromethane at 20℃; for 0.166667h;	95%
With 1,1,1,3,3,3-hexamethyl-disilazane at 110℃; for 5h;	91%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	84%
With 1,1,1,3,3,3-hexamethyl-disilazane at 110℃; for 15h;	32%

C18H24N2O5 → (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions	Yield
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 1.25h;	96%

piperazine (110-85-0) + ethyl 2,3-dihydro-1,4-benzodioxin-2-carboxylate (4739-94-0) → (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions	Yield
at 110℃; for 3h;	94%
In methanol; isopropyl alcohol Heating;	73.13%
at 75℃; for 4 - 10h;	30%

piperazine (110-85-0) + ethyl 2,3-dihydro-1,4-benzodioxin-2-carboxylate (4739-94-0) → 1,4-bis-(2,3-dihydro-benzo[1,4]dioxin-2-carbonyl)-piperazine + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions	Yield
at 75 - 80℃; for 10h;	A 11% B 89%
at 70 - 80℃; for 6h;	A 12% B 65%

piperazine (110-85-0) + C12H16O4Si → (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions	Yield
at 110℃; for 5h;

benzene-1,2-diol (120-80-9) → (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 85 percent / potassium hydroxide; polyethylene glycol-400; potassium carbonate / toluene / 3.75 h / Heating 2: 65 percent / 6 h / 70 - 80 °C View Scheme

1,4-benzodioxane-2-carboxylic acid (3663-80-7, 34385-93-8, 70918-53-5, 70918-54-6) → (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2 h / 110 °C 2: 5 h / 110 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate / dichloromethane / -15 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1.25 h / 0 - 20 °C View Scheme

2-hydroxymethyl-2,3-dihydrobenzo[1,4]dioxin (3663-82-9) → (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium hydroxide; potassium permanganate / water / 0 °C 2: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate / dichloromethane / -15 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 1.25 h / 0 - 20 °C View Scheme

2-Iodophenol (533-58-4) → (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions

Yield

Multi-step reaction with 6 steps 1: potassium carbonate / N,N-dimethyl-formamide; water; ethyl acetate / 24 h / 50 °C 2: sodium tetrahydroborate / tetrahydrofuran; methanol / 6 h / 0 °C 3: copper(l) iodide; 1,10-Phenanthroline; caesium carbonate / toluene / 90 °C / Sealed tube; Inert atmosphere 4: potassium hydroxide; potassium permanganate / water / 0 °C 5: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate / dichloromethane / -15 °C / Inert atmosphere 6: trifluoroacetic acid / dichloromethane / 1.25 h / 0 - 20 °C View Scheme

C13H15IO5 → (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions

Yield

Multi-step reaction with 5 steps 1: sodium tetrahydroborate / tetrahydrofuran; methanol / 6 h / 0 °C 2: copper(l) iodide; 1,10-Phenanthroline; caesium carbonate / toluene / 90 °C / Sealed tube; Inert atmosphere 3: potassium hydroxide; potassium permanganate / water / 0 °C 4: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate / dichloromethane / -15 °C / Inert atmosphere 5: trifluoroacetic acid / dichloromethane / 1.25 h / 0 - 20 °C View Scheme

2-(2-iodophenoxy)propane-1,3-diol → (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2)

Conditions

Yield

Multi-step reaction with 4 steps 1: copper(l) iodide; 1,10-Phenanthroline; caesium carbonate / toluene / 90 °C / Sealed tube; Inert atmosphere 2: potassium hydroxide; potassium permanganate / water / 0 °C 3: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate / dichloromethane / -15 °C / Inert atmosphere 4: trifluoroacetic acid / dichloromethane / 1.25 h / 0 - 20 °C View Scheme

2-chloro-4-hydroxyl-6,7-dimethoxyquinazoline (20197-86-8) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → C23H24N4O6

Conditions	Yield
In butan-1-ol for 1h; Temperature; Solvent; Reflux;	95%

7-chloro-1-(2,4-difluorophenyl)-1,4-dihydro-8-methyl-6-nitro-4-oxoquinolone-3-carboxylic acid (1146300-32-4) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → 1-(2,4-difluorophenyl)-1,4-dihydro-7-(4-(2,3-dihydrobenzo[b][1,4]dioxin-2-oyl)piperazin-1-yl)-8-methyl-6-nitro-4-oxoquinoline-3-carboxylic acid (1146300-55-1)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide Microwave irradiation;	93%

1-tert-butyl-7-chloro-1-1,4-dihydro-8-methyl-6-nitro-4-oxoquinolone-3-carboxylic acid (1146300-33-5) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → 1-tert-butyl-1,4-dihydro-8-methyl-7-(4-(2,3-dihydrobenzo[b][1,4]dioxin-2-oyl)piperazin-1-yl)-8-methyl-6-nitro-4-oxoquinoline-3-carboxylic acid (1146300-72-2)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide Microwave irradiation;	91%

7-chloro-1-cyclopropyl-1,4-dihydro-8-methyl-6-nitro-4-oxoquinolone-3-carboxylic acid (1146300-31-3) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → 1-cyclopropyl-1,4-dihydro-7-(4-(2,3-dihydrobenzo[b][1,4]dioxin-2-oyl)piperazin-1-yl)-8-methyl-6-nitro-4-oxoquinoline-3-carboxylic acid (1146300-38-0)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide Microwave irradiation;	90%

4-Chlorophenyl isothiocyanate (2131-55-7) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → N-(4-chlorophenyl)-4-(2,3-dihydrobenzo[b][1,4]-dioxine-2-carbonyl)piperazine-1-carbothioamide

Conditions	Yield
With triethylamine In dichloromethane at 20℃; Cooling;	90%

2-chloro-6,7-dimethoxyquinazolin-4-amine (23680-84-4) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinazoline hydrochloride (70918-01-3)

Conditions	Yield
In butan-1-ol for 3.5h; Heating;	88%
In butan-1-ol for 5h; Heating;
In N-methyl-acetamide; water; butan-1-ol

2-chloro-6,7-dimethoxyquinazolin-4-amine (23680-84-4) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → doxazosin (74191-85-8)

Conditions	Yield
In butan-1-ol Reflux;	88%
In butan-1-ol for 5h; Heating;	83%

2-chloro-6,7-dimethoxyquinazolin-4-amine (23680-84-4) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → UK-36528-27(R)

Conditions	Yield
In butan-1-ol Reflux;	87.9%

1-(4-fluorophenyl)-1,4-dihydro-7-methoxy-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylic acid (960313-86-4) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → C28H22FN5O8

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide microwave irradiation;	85%

(S)-9,10-difluoro-3-methyl-8-nitro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (236743-93-4) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → C26H23FN4O9

Conditions	Yield
In dimethyl sulfoxide microwave irradiation;	83%

1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-nitro-8-methoxy-4-oxoquinoline-3-carboxylic acid (112811-77-5) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → C27H25FN4O9 (1018937-62-6)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide for 0.0333333h; microwave irradiation;	83%

(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) + 7-chloro-1-(4-fluorophenyl)-1,4-dihydro-6-nitro-4-oxoquinoline-3-carboxylic acid (368839-20-7) → 7-(4-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylcarbonyl)piperazin-1-yl)-1-(4-fluorophenyl)-1,4-dihydro-6-nitro-4-oxoquinoline-3-carboxylic acid (1119087-42-1)

Conditions	Yield
In dimethyl sulfoxide Microwave irradiation;	83%

formaldehyd (50-00-0) + propargyl ether mycophenolate + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → mycophenoyl methyl ester-7-(butynyloxy-N-(benzodioxylcarbonylpiperazine))

Conditions	Yield
With copper(l) iodide In 1,4-dioxane at 120℃; for 1h;	81%

1-cyclopropyl-1,4-dihydro-7-methoxy-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylic acid (960313-85-3) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → C25H23N5O8

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide microwave irradiation;	77%

2-chloro-3-fluoro-5,12-dihydro-5-oxobenzothiazolo<3,2-a>quinoline-6-carboxylic acid (102614-43-7) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → C29H22FN3O6S (1028202-94-9)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide microwave irradiation;	77%

2-chloro-3-nitro-5,12-dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid (1028202-77-8) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → C29H22N4O8S (1028202-95-0)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide microwave irradiation;	75%

1-tert-butyl-1,4-dihydro-7-methoxy-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylic acid (960313-87-5) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → C26H27N5O8

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide microwave irradiation;	73%

1-tert-butyl-7-chloro-1,4-dihydro-6-nitro-4-oxoquinoline-3-carboxylic acid (494204-73-8) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → 1-tert-butyl-7-(4-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylcarbonyl)piperazin-1-yl)-1,4-dihydro-6-nitro-4-oxoquinoline-3-carboxylic acid (1119087-94-3)

Conditions	Yield
In dimethyl sulfoxide Microwave irradiation;	71%

levofloxacin Q-acid (100986-89-8) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → C26H24FN3O7

Conditions	Yield
In dimethyl sulfoxide microwave irradiation;	70%

1-cyclopropyl-6-nitro-4-oxo-7-chloro-1,4-dihydroquinoline-3-carboxylic acid (93107-29-0) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → 1-cyclopropyl-7-(4-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylcarbonyl)piperazin-1-yl)-1,4-dihydro-6-nitro-4-oxoquinoline-3-carboxylic acid (1119086-90-6)

Conditions	Yield
In dimethyl sulfoxide Microwave irradiation;	70%

4-chloro-5-(4-chlorophenyl)thieno[2,3-d]pyrimidine-6-carbonitrile (1446090-67-0) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → 5-(4-chlorophenyl)-4-(2,3-dihydrobenzo[b][1,4]dioxin-3-yl)(piperazin-1-yl)methanone-thieno[2,3-d]pyrimidine-6-carbonitrile (1446090-60-3)

Conditions	Yield
In neat (no solvent) at 120 - 130℃; for 6h; Sealed tube;	66%

(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) + 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (112811-72-0) → C27H26FN3O7 (1018937-59-1)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide for 0.0333333h; microwave irradiation;	64%

5-bromo-4,4-dimethyl-6-methylene-5,6-dihydro-1H-pyrrolo-[3,2,1-ij ]quinoline-1,2(4H)-dione + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → 4,4-dimethyl-6-{[4-(2,3-dihydrobenzo[b][1,4]dioxino-2-carbnyl)piperazin-1-yl]methyl}-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile Reflux;	57%

D-tartaric acid (147-71-7) + (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)(piperazin-1-yl)methanone (70918-00-2) → (S)-N-(1,4-benzodioxan-2-carbonyl)piperazine D-tartrate

Conditions	Yield
In water; acetonitrile at 80℃;	50%

Upstream product

• 110-85-0 piperazine 
• 4739-94-0 ethyl 2,3-dihydro-1,4-benzodioxin-2-carboxylate 
• 3663-80-7 1,4-benzodioxane-2-carboxylic acid 
• 533-58-4 2-Iodophenol 
• 3663-82-9 2-hydroxymethyl-2,3-dihydrobenzo[1,4]dioxin 
• 120-80-9 benzene-1,2-diol 

Downstream Products

• 104874-86-4 (R)-doxazosin 
• 1146300-55-1 1-(2,4-difluorophenyl)-1,4-dihydro-7-(4-(2,3-dihydrobenzo[b][1,4]dioxin-2-oyl)piperazin-1-yl)-8-methyl-6-nitro-4-oxoquinoline-3-carboxylic acid 
• 74191-85-8 doxazosin 
• 1446090-60-3 5-(4-chlorophenyl)-4-(2,3-dihydrobenzo[b][1,4]dioxin-3-yl)(piperazin-1-yl)methanone-thieno[2,3-d]pyrimidine-6-carbonitrile 
• 1227170-52-6 2-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)-3-fluorobenzaldehyde 
• 1227170-50-4 2-(4-(2,3-dihydrobenzo[b][1,4]dioxine-2-carbonyl)piperazin-1-yl)-6-fluorobenzaldehyde 
• 1119087-42-1 7-(4-(2,3-dihydrobenzo[b][1,4]dioxin-2-ylcarbonyl)piperazin-1-yl)-1-(4-fluorophenyl)-1,4-dihydro-6-nitro-4-oxoquinoline-3-carboxylic acid 

Relevant articles and documents

An improved one-pot synthesis of N-(2,3-dihydrobenzo[1,4]dioxin-2-carbonyl) piperazine - Useful intermediate for anti-hypertensive drug - Doxazosin

An improved process for the preparation of N-(2,3-dihydrobenzo[1,4]dioxin- 2-carbonyl)piperazine 2 and its hydrochloride from ethyl-2,3-dihydro-1,4- benzodioxin-2-carboxylate 3 and piperazine in a single step has been described. The compound 2 is an important intermediate in the preparation of anti-hypertensive agent, Doxazosin.

Method for synthesizing doxazosin

The invention discloses a method for synthesizing doxazosin and belongs to the technical field of chemical synthesis. According to the method, the doxazosin is synthesized by adopting a synthesis route, represented by formulae shown in the description, different from the conventional technologies, and thus a novel synthesis route is provided for preparing the doxazosin; and the method has the advantages of moderate conditions, simple and convenient steps and high yield, and the doxazosin can be obtained simply and efficiently.

Direct synthesis of N-acylalkylenediamines from carboxylic acids under mild conditions

Monoacylated piperazine derivatives were prepared directly from carboxylic acids and piperazine using triphenylphosphine (TPP) and N-bromosuccinimide (NBS) in dichloromethane. Inexpensive and readily available reagents, excellent yields, short reaction times and mild reaction conditions are important features of this method.