32863-32-4

Usage

Uses

Used in Pharmaceutical Industry:
4-Benzofurazancarboxaldehyde is used as a synthetic intermediate for the production of Isradipine, a calcium channel blocker used in the treatment of hypertension and angina pectoris. Its role in the synthesis process is crucial for creating the final drug product, contributing to its therapeutic effects and medical applications.

InChI:InChI=1/C7H4N2O2/c10-4-5-2-1-3-6-7(5)9-11-8-6/h1-4H

Synthetic route

4-hydroxymethylbenzofurazan (175609-19-5) → benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4)

Conditions	Yield
With fluorosulfonyl fluoride; potassium carbonate; dimethyl sulfoxide at 20℃; for 12h; chemoselective reaction;	99%
With manganese(IV) oxide In chloroform for 2h; Ambient temperature;	92%
With pyridinium chlorochromate In dichloromethane at 0 - 30℃; for 2h;
With fluorosulfonyl fluoride; potassium carbonate; dimethyl sulfoxide at 20℃;

4-methyl-benzo[1,2,5]oxadiazole (29091-40-5) → benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4)

Conditions	Yield
With selenium(IV) oxide at 160℃; for 8h;	82%

4-(bromomethyl)benzo[c][1,2,5]oxadiazole (32863-30-2) → benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4)

Conditions	Yield
With sodium hydrogencarbonate In dimethyl sulfoxide at 100 - 150℃; Inert atmosphere;	71.6%
Multi-step reaction with 2 steps 1: 77 percent / calcium carbonate, water / dioxane / 3 h / Heating 2: 92 percent / manganese dioxide / CHCl3 / 2 h / Ambient temperature View Scheme

benzofurazan (273-09-6) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4)

Conditions	Yield
With lithium diisopropyl amide In tetrahydrofuran at -78℃;	59%

4-methylbenzimidazole (4887-83-6) → benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrachloromethane; N-Bromosuccinimide; dibenzoyl peroxide / 80 - 85 °C 2: sodium hydrogencarbonate / dimethyl sulfoxide / 100 - 150 °C / Inert atmosphere View Scheme

2-cyanoethylacetoacetate (65193-87-5) + methyl 3-aminocrotonate (21731-17-9) + benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → C19H18N4O5

Conditions	Yield
In isopropyl alcohol Inert atmosphere; Reflux;	97%

2-chloroethyl acetoacetate (54527-68-3) + benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → 2-[1-Benzo[1,2,5]oxadiazol-4-yl-meth-(E)-ylidene]-3-oxo-butyric acid 2-chloro-ethyl ester (210579-35-4)

Conditions	Yield
With hydrogenchloride In chloroform for 168h; Ambient temperature;	95%

4-amino-6-bromo-1H-indazole (885518-50-3) + benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → N-(benzo[c][1,2,5]oxadiazol-4-ylmethyl)-6-bromo-1H-indazol-4-amine

Conditions	Yield
With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; trifluoroacetic acid In methanol; dichloromethane at 45℃; for 4h;	92%

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → 4-hydroxymethylbenzofurazan (175609-19-5)

Conditions	Yield
With sodium tetrahydroborate In methanol at 0℃;	82%

ethyl acetoacetate (141-97-9) + benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → darodipine (72803-02-2)

Conditions	Yield
With ammonium carbonate at 70℃;	79.5%
With ammonium hydroxide In ethanol at 120℃; for 0.166667h; Hantzsch Dihydropyridine Synthesis; Flow reactor;	76%

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) + methyl 3-aminocrotonate (14205-39-1) → dimethyl 1,4-dihydro-2,6-dimethyl-4-(4-benzofurazanyl)-3,5-pyridinedicarboxylate

Conditions	Yield
With trifluoroacetic acid In ethanol at 0℃; for 1.5h;	70%

4-chloro-aniline (106-47-8) + benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → C13H10ClN3O (1454663-39-8)

Conditions	Yield
With sodium cyanoborohydride; acetic acid In methanol at 0℃;	67%

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → benzofurazan-4-carboxylic acid (32863-21-1)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran at 25℃; for 10h; Reagent/catalyst; Temperature; Solvent;	57%

2-(4-diphenylmethyl-1-piperazinyl)ethyl acetoacetate (89226-49-3) + benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) + methyl 3-aminocrotonate (14205-39-1) → 4-Benzo[1,2,5]oxadiazol-4-yl-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-(4-benzhydryl-piperazin-1-yl)-ethyl] ester 5-methyl ester; hydrochloride (90096-10-9)

Conditions	Yield
In isopropyl alcohol Heating;	45%

1-nitro-2-propanone (10230-68-9) + methyl 3-aminocrotonate (21731-17-9) + benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → 4-benzo[1,2,5]oxadiazol-4-yl-2,6-dimethyl-5-nitro-1,4-dihydro-pyridine-3-carboxylic acid methyl ester (105567-84-8)

Conditions	Yield
In isopropyl alcohol for 5h; Heating;	40%

2-chloro-5-aminoethylpyridine (54127-64-9) + benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → N-(benzo[c][1,2,5]oxadiazol-4-ylmethyl)-2-(6-chloropyridin-3-yl)ethylamine

Conditions	Yield
With sodium tetrahydroborate In methanol for 3h; Cooling with ice; Reflux;	30.21%

1-nitro-2-propanone (10230-68-9) + benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) + (1S,2R)-2-(3,5-dinitrophenylcarbonylamino)-2-methoxycarbonyl-1-methylethyl 3-aminocrotonate (250330-30-4) → (1S,2R)-2-(3,5-dinitrophenylcarbamoyl)-2-(methoxycarbonyl)ethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate (651007-66-8) + (1S,2R)-2-(3,5-dinitrophenylcarbamoyl)-2-(methoxycarbonyl)ethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate (651007-65-7)

Conditions	Yield
In ethanol at 25 - 80℃; for 18h;	A 27% B 20%

6-Amino-1,3-dimethylbarbituric acid (6642-31-5) + 2-(4-diphenylmethyl-1-piperazinyl)ethyl acetoacetate (89226-49-3) + benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → 5-Benzo[1,2,5]oxadiazol-4-yl-1,3,7-trimethyl-2,4-dioxo-1,2,3,4,5,8-hexahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid 2-(4-benzhydryl-piperazin-1-yl)-ethyl ester (97056-86-5)

Conditions	Yield
In isopropyl alcohol Heating;	13.5%

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) + 2-acetonyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (111011-80-4) → (Z)-4-Benzo[1,2,5]oxadiazol-4-yl-3-(5,5-dimethyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-but-3-en-2-one (146139-64-2)

Conditions	Yield
With piperidine; trifluoroacetic acid In toluene for 8h; Heating;	12%

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) + 2-acetonyl-1-oxo-1,3,2-dioxaphosphorinane (115579-08-3) → (E)-4-Benzo[1,2,5]oxadiazol-4-yl-3-(2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yl)-but-3-en-2-one (115578-84-2)

Conditions	Yield
piperdinium acetate In benzene Heating;	8%

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) + diallyl acetonylphosphonate (112057-34-8) → {1-[1-Benzo[1,2,5]oxadiazol-4-yl-meth-(Z)-ylidene]-2-oxo-propyl}-phosphonic acid diallyl ester (112057-49-5, 112057-62-2)

Conditions	Yield
piperdinium acetate In isopropyl alcohol Heating;

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → (-)-(R)-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylic acid (98759-59-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 27 percent / ethanol / 18 h / 25 - 80 °C 2: 50 percent / 1,8-diazabicyclo[5.4.0]undec-7-ene / methanol / 24 h / 25 °C View Scheme

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → (+)-(S)-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylic acid (98759-58-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 20 percent / ethanol / 18 h / 25 - 80 °C 2: 50 percent / 1,8-diazabicyclo[5.4.0]undec-7-ene / methanol / 24 h / 25 °C View Scheme

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → (-)-PN 202-791

Conditions	Yield
Multi-step reaction with 3 steps 1: 27 percent / ethanol / 18 h / 25 - 80 °C 2: 50 percent / 1,8-diazabicyclo[5.4.0]undec-7-ene / methanol / 24 h / 25 °C 3: 89 percent / K2CO3 / dimethylformamide / 24 h / 25 °C View Scheme

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → (+)-PN 202-791

Conditions	Yield
Multi-step reaction with 3 steps 1: 20 percent / ethanol / 18 h / 25 - 80 °C 2: 50 percent / 1,8-diazabicyclo[5.4.0]undec-7-ene / methanol / 24 h / 25 °C 3: 88.8 percent / K2CO3 / dimethylformamide / 24 h / 25 °C View Scheme

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → (-)-(R)-2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate

Conditions	Yield
Multi-step reaction with 3 steps 1: 27 percent / ethanol / 18 h / 25 - 80 °C 2: 50 percent / 1,8-diazabicyclo[5.4.0]undec-7-ene / methanol / 24 h / 25 °C 3: 91 percent / K2CO3 / dimethylformamide / 24 h / 25 °C View Scheme

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → (+)-(S)-2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate

Conditions	Yield
Multi-step reaction with 3 steps 1: 20 percent / ethanol / 18 h / 25 - 80 °C 2: 50 percent / 1,8-diazabicyclo[5.4.0]undec-7-ene / methanol / 24 h / 25 °C 3: 91 percent / K2CO3 / dimethylformamide / 24 h / 25 °C View Scheme

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → (-)-(R,R)-1-methyl-2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate

Conditions	Yield
Multi-step reaction with 3 steps 1: 27 percent / ethanol / 18 h / 25 - 80 °C 2: 50 percent / 1,8-diazabicyclo[5.4.0]undec-7-ene / methanol / 24 h / 25 °C 3: 30 percent / K2CO3 / dimethylformamide / 168 h / 25 °C View Scheme

benzo[c][1,2,5]oxadiazole-4-carbaldehyde (32863-32-4) → (+)-(R,S)-1-methyl-2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate

Conditions	Yield
Multi-step reaction with 3 steps 1: 27 percent / ethanol / 18 h / 25 - 80 °C 2: 50 percent / 1,8-diazabicyclo[5.4.0]undec-7-ene / methanol / 24 h / 25 °C 3: 30 percent / K2CO3 / dimethylformamide / 168 h / 25 °C View Scheme

Upstream product

• 4887-83-6 4-methylbenzimidazole 
• 273-09-6 benzofurazan 
• 68-12-2 N,N-dimethyl-formamide 
• 32863-30-2 4-(bromomethyl)benzo[c][1,2,5]oxadiazole 
• 29091-40-5 4-methyl-benzo[1,2,5]oxadiazole 
• 175609-19-5 4-hydroxymethylbenzofurazan 

Downstream Products

• 104785-90-2 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester 
• 1454663-39-8 C₁₃H₁₀ClN₃O 
• 175609-19-5 4-hydroxymethylbenzofurazan 
• 1454663-40-1 C₁₅H₁₂ClN₃O₂ 
• 1454663-42-3 C₁₅H₁₁ClN₄O₄ 
• 1454663-41-2 C₁₅H₁₁ClN₄O₄ 
• 1454663-37-6 C₁₃H₇ClN₄O₄ 
• 1454663-44-5 C₁₃H₉ClN₄O₃ 
• 1454663-43-4 C₁₃H₉ClN₄O₃ 
• 32863-21-1 benzofurazan-4-carboxylic acid 
• 72803-02-2 darodipine 
• 154026-73-0 methyl 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1-(2-nitrobenzyl)-1,4-dihydropyridine-3,5-dicarboxylate 
• 104246-11-9 4-Benzo[1,2,5]oxadiazol-4-yl-5-(bis-allyloxy-phosphoryl)-2,6-dimethyl-1,4-dihydro-pyridine-3-carboxylic acid 2-(benzyl-methyl-amino)-ethyl ester 
• 651007-66-8 (1S,2R)-2-(3,5-dinitrophenylcarbamoyl)-2-(methoxycarbonyl)ethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate 

Relevant academic research and scientific papers

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A preparation containing [...] method for synthesizing of antihypertensive medicines we surround class

The invention relates to a synthesis method for preparing an antihypertensive medicine having a benzofuroxan ring. In the method, 4-methylbenzofuroxan is used as a raw material, the 2,1,3-benzoxadiazole-4-aldehyde serving as an important intermediate is prepared by bromination and oxidation reactions, and the 2,1,3-benzoxadiazole-4-aldehyde and acetoacetic ester undergo a Hantzsch reaction to form the target compound. Compared with other processes, the method has the characteristics of mild reaction conditions, simple and efficient operation, high yield and the like and has a certain industrial production prospect.

Identification, synthesis and evaluation of substituted benzofurazans as inhibitors of CREB-mediated gene transcription

Cyclic-AMP response-element binding protein (CREB) is a stimulus-activated transcription factor. Its transcription activity requires its binding with CREB-binding protein (CBP) after CREB is phosphorylated at Ser133. The domains involved for CREB-CBP interaction are kinase-inducible domain (KID) from CREB and KID-interacting domain (KIX) from CBP. Recent studies suggest that CREB is an attractive target for novel cancer therapeutics. To identify novel chemotypes as inhibitors of KIX-KID interaction, we screened the NCI-diversity set of compounds using a split renilla luciferase assay and identified 2-[(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio]pyridine 1-oxide (compound 1, NSC228155) as a potent inhibitor of KIX-KID interaction. However, compound 1 was not particularly selective against CREB-mediated gene transcription in living HEK 293T cells. Further structure-activityrelationship studies identified 4-aniline substituted nitrobenzofurazans with improved selectivity.

PROCESS FOR THE MANUFACTURE OF 2,1,3-BENZOXADIAZOLE-4-CARBOXALDEHYDE

The present invention relates to an improved and novel method for the manufacture of 2,1,3-benzoxadiazole-4-carboxaldehyde an intermediate for the preparation of 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester known as Isradipine. More particularly the present invention relates to the process for the manufacture 2,1,3-benzoxadiazole-4-carboxaldehyde from 2,1,3-benzoxadiazole-4-yl-methanol by oxidation using pyridinium chlorochromate (PCC) as oxidant.

Asymmetric N-(3,3-diphenylpropyl)aminoalkyl esters of 4-aryl-2,6- dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acids with antihypertensive activity

A series of asymmetric 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates characterized by the presence of a 3,3-diphenylpropylamino moiety in one of the ester groups were synthesized. They exhibited remarkable antihypertensive activity in spontaneously hypertensive rats as well as affinity for the 1,4- dihydropyridines binding site labelled by 3H-nitrendipine in the calcium channel. Introduction of this bulky and lipophilic amine confers to the whole series an elevated level of antihypertensive activity and a long duration of action, a structure-dependent modulation of the activity being found only in the subset characterized by the presence of a branched propylene bridge between the ester and the amino groups. The presence of the amino group is essential for oral activity. Out of this series, compound 9u (Rec 15/2375- lercanidipine) was selected for clinical development and obtained marketing authorization as an antihypertensive in several countries.

Benzofurazanyl- and benzofuroxanyl-1,4-dihydlropyridines : Synthesis, structure and calcium entry blocker activity

The synthesis, structural characterization and calcium blocking activity of a series of benzofurazanyl-1,4-dihydropyridines (18 and 19) and benzofuroxanyl analogues (20 and 21) are reported. 1H-NMR showed that all the benzofuroxan derivatives exist in solution as tautomeric mixtures. The predominant tautomeric form in solution of the derivative 20 (dimethyl 1,4-dihydro-2,6-dimethyl-4-(4-benzofuroxanyl)-3,5-pyridinedicarboxylate) is also the one preferred in the solid state as shown by X-ray analysis. The conformation in the solid state of the benzofurazanyl analogue is also reported. Calcium entry blocker activity of the dihydropyridine derivatives 18-21 has been evaluated in isolated rabbit basilar artery as relaxation of calcium-induced contractions in high K+-depolarizing solution. All the compounds displayed high potency. The activity of benzofurazan derivatives was not changed by the N-oxidation. The two most active compounds 18 and 20 were as potent as Nifedipine.